Drug Therapy

To the Editor: We found the article by Drs. Lansang and Kramer¹ on glucocorticoid-induced diabetes and adrenal suppression in the November 2011 issue to be a useful and clinically oriented review. However, we strongly believe there is an issue that should be addressed.

It is well accepted that the short cosyntropin (Cortrosyn) stimulation test is the best screening maneuver for assessing adrenocortical insufficiency. The authors state, however, that 250 μg is preferable to lower doses (10 μg or 1 μg), since these are not yet widely accepted, and refer to an article by Axelrod from 1976.²

Based on studies showing that 250 μg of cosyntropin is a pharmacologic rather than a physiologic stimulus that may overstimulate partially atrophied or mildly dysfunctional adrenal glands, multiple studies in the last 20 years have shown that the low-dose test has an equal or better result than the classic 250-μg dose test.³ Dorin et al,⁴ in a meta-analysis of the diagnosis of adrenocortical insufficiency that included more than 30 studies, found similar sensitivity and specificity in primary and secondary adrenal insufficiency comparing the 250-μg dose vs the low dose. In cases of mild primary adrenal failure, the low-dose test has better performance. A previous investigation in our research center contrasting 250 μg vs 10 μg proved that 10 μg had a better sensitivity than the standard dose, with excellent reproducibility and interchangeability.⁵ Similar findings have been shown by other authors contrasting 1 μg vs 250 μg of cosyntropin.⁶

We believe that the limited use of the low-dose cosyntropin test is not a matter of acceptance or performance but a consequence of the lack of vials containing lower doses of cosyntropin (1 to 10 μg), which makes this test technically challenging.^2,4 The steps needed for one-dose testing and the preservation time of the preparation are strong limitations to its wide use in clinical practice and endocrine laboratories.

To the Editor: We found the article by Drs. Lansang and Kramer¹ on glucocorticoid-induced diabetes and adrenal suppression in the November 2011 issue to be a useful and clinically oriented review. However, we strongly believe there is an issue that should be addressed.

It is well accepted that the short cosyntropin (Cortrosyn) stimulation test is the best screening maneuver for assessing adrenocortical insufficiency. The authors state, however, that 250 μg is preferable to lower doses (10 μg or 1 μg), since these are not yet widely accepted, and refer to an article by Axelrod from 1976.²

Based on studies showing that 250 μg of cosyntropin is a pharmacologic rather than a physiologic stimulus that may overstimulate partially atrophied or mildly dysfunctional adrenal glands, multiple studies in the last 20 years have shown that the low-dose test has an equal or better result than the classic 250-μg dose test.³ Dorin et al,⁴ in a meta-analysis of the diagnosis of adrenocortical insufficiency that included more than 30 studies, found similar sensitivity and specificity in primary and secondary adrenal insufficiency comparing the 250-μg dose vs the low dose. In cases of mild primary adrenal failure, the low-dose test has better performance. A previous investigation in our research center contrasting 250 μg vs 10 μg proved that 10 μg had a better sensitivity than the standard dose, with excellent reproducibility and interchangeability.⁵ Similar findings have been shown by other authors contrasting 1 μg vs 250 μg of cosyntropin.⁶

We believe that the limited use of the low-dose cosyntropin test is not a matter of acceptance or performance but a consequence of the lack of vials containing lower doses of cosyntropin (1 to 10 μg), which makes this test technically challenging.^2,4 The steps needed for one-dose testing and the preservation time of the preparation are strong limitations to its wide use in clinical practice and endocrine laboratories.

To the Editor: We found the article by Drs. Lansang and Kramer¹ on glucocorticoid-induced diabetes and adrenal suppression in the November 2011 issue to be a useful and clinically oriented review. However, we strongly believe there is an issue that should be addressed.

It is well accepted that the short cosyntropin (Cortrosyn) stimulation test is the best screening maneuver for assessing adrenocortical insufficiency. The authors state, however, that 250 μg is preferable to lower doses (10 μg or 1 μg), since these are not yet widely accepted, and refer to an article by Axelrod from 1976.²

Based on studies showing that 250 μg of cosyntropin is a pharmacologic rather than a physiologic stimulus that may overstimulate partially atrophied or mildly dysfunctional adrenal glands, multiple studies in the last 20 years have shown that the low-dose test has an equal or better result than the classic 250-μg dose test.³ Dorin et al,⁴ in a meta-analysis of the diagnosis of adrenocortical insufficiency that included more than 30 studies, found similar sensitivity and specificity in primary and secondary adrenal insufficiency comparing the 250-μg dose vs the low dose. In cases of mild primary adrenal failure, the low-dose test has better performance. A previous investigation in our research center contrasting 250 μg vs 10 μg proved that 10 μg had a better sensitivity than the standard dose, with excellent reproducibility and interchangeability.⁵ Similar findings have been shown by other authors contrasting 1 μg vs 250 μg of cosyntropin.⁶

We believe that the limited use of the low-dose cosyntropin test is not a matter of acceptance or performance but a consequence of the lack of vials containing lower doses of cosyntropin (1 to 10 μg), which makes this test technically challenging.^2,4 The steps needed for one-dose testing and the preservation time of the preparation are strong limitations to its wide use in clinical practice and endocrine laboratories.

The treatment of hepatitis c virus (HCV) infection is on the brink of major changes with the recent approval of the first direct-acting antiviral agents, the protease inhibitors boceprevir (Victrelis) and telaprevir (Incivek).

Both drugs were approved by the US Food and Drug Administration (FDA) Advisory Panel for Chronic Hepatitis C in May 2011 and are believed to significantly improve treatment outcomes for patients with HCV genotype 1 infection.

A MAJOR PUBLIC HEALTH PROBLEM

HCV infection is a major public health problem. Nearly 4 million people in the United States are infected.^6,7 Most patients with acute HCV infection become chronically infected, and up to 25% eventually develop cirrhosis and its complications, making HCV infection the leading indication for liver transplantation.^8–10

Chronic HCV infection has a large global impact, with 180 million people affected across all economic and social groups.¹¹ The highest prevalence of HCV has been reported in Egypt (14%), in part due to the use of inadequately sterilized needles in mass programs to treat endemic schistosomiasis. In developed countries, hepatocellular carcinoma associated with HCV has the fastest growing cancer-related death rate.¹²

CURRENTLY, FEWER THAN 50% OF PATIENTS ARE CURED

The goal of HCV treatment is to eradicate the virus. However, most infected patients (especially in the United States and Europe) are infected with HCV genotype 1, which is the most difficult genotype to treat.

Successful treatment of HCV is defined as achieving a sustained virologic response—ie, the absence of detectable HCV RNA in the serum 24 weeks after completion of therapy. Once a sustained virologic response is achieved, lifetime “cure” of HCV infection is expected in more than 99% of patients.¹³

The current standard therapy for HCV, pegylated interferon plus ribavirin for 48 weeks, is effective in only 40% to 50% of patients with genotype 1 infection.¹⁴ Therefore, assessing predictors of response before starting treatment can help select patients who are most likely to benefit from therapy.

Viral factors associated with a sustained virologic response include HCV genotypes other than genotype 1 and a low baseline viral load.

Beneficial patient-related factors include younger age, nonblack ethnicity, low body weight (≤ 75 kg), low body mass index, absence of insulin resistance, and absence of advanced fibrosis or cirrhosis.

More recently, a single-nucleotide polymorphism near the interleukin 28B (IL28B) gene, coding for interferon lambda 3, was found to be associated with a twofold difference in the rates of sustained virologic response: patients with the favorable genotype CC were two times more likely to achieve a sustained virologic response than patients with the CT or TT genotypes.^15–17

PROTEASE INHIBITORS: MECHANISM OF ACTION

NS3/4A protease inhibitors rely on the principle of end-product inhibition, in which the cleavage product of the protease (a peptide) acts to inhibit the enzyme activity; this is why they are called peptidomimetics. The active site of the NS3/4A protease is a shallow groove composed of three highly conserved amino acid residues, which may explain why protease inhibitors display high antiviral efficacy but pose a low barrier to the development of resistance.²⁰

Protease inhibitors are prone to resistance

The development of viral resistance to protease inhibitors has been a major drawback to their use in patients with chronic HCV infection.²¹

HCV is a highly variable virus with many genetically distinct but closely related quasispecies circulating in the blood at any given time. Drug-resistant, mutated variants preexist within the patient’s quasispecies, but only in small quantities because of their lesser replication fitness compared with the wild-type virus.²² When direct-acting antiviral therapy is started, the quantity of the wild-type virus decreases and the mutated virus gains replication fitness. Using protease inhibitors as monotherapy selects resistant viral populations rapidly within a few days or weeks.

HCV subtypes 1a and 1b may have different resistance profiles. With genotype 1a, some resistance-associated amino acid substitutions require only one nucleotide change, but with genotype 1b, two nucleotide changes are needed, making resistance less frequent in patients with HCV genotype 1b.²³

BOCEPREVIR

Boceprevir is a specific inhibitor of the HCV viral protease NS3/4A.

In phase 3 clinical trials, boceprevir 800 mg three times a day was used with pegylated interferon alfa-2b (PegIntron) 1.5 μg/kg/week and ribavirin (Rebetol) 600 to 1,400 mg daily according to body weight.

Before patients started taking boceprevir, they went through a 4-week lead-in phase, during which they received pegylated interferon and ribavirin. This schedule appeared to reduce the incidence of viral breakthrough in phase 2 trials, and it produced higher rates of sustained virologic response and lower relapse rates compared with triple therapy without a lead-in phase.

Rapid virologic response was defined as undetectable HCV RNA at week 4 of boceprevir therapy (week 8 of the whole regimen).

Boceprevir in previously untreated patients with HCV genotype 1: The SPRINT-2 trial

The Serine Protease Inhibitor Therapy 2 (SPRINT-2) trial¹ included more than 1,000 previously untreated adults with HCV genotype 1 infection (938 nonblack patients and 159 black patients; two other nonblack patients did not receive any study drug and were not included in the analysis). In this double-blind trial, patients were randomized into three groups:

• The control group received the standard of care with pegylated interferon and ribavirin for 48 weeks
• The response-guided therapy group received boceprevir plus pegylated interferon and ribavirin for 24 weeks after the 4-week lead-in phase; if HCV RNA was undetectable from week 8 to week 24, treatment was considered complete, but if HCV RNA was detectable at any point from week 8 to week 24, pegylated interferon and ribavirin were continued for a total of 48 weeks.
• The fixed-duration therapy group received boceprevir, pegylated interferon, and ribavirin for 44 weeks after the lead-in period.

The rate of relapse was 8% and 9% in the boceprevir groups vs 23% in the control group. Patients in the boceprevir groups who had a decrease in HCV RNA of less than 1 log₁₀ during the lead-in phase were found to have a significantly higher rate of boceprevirresistant variants than those who achieved a decrease of HCV RNA of 1 log₁₀ or more.

Boceprevir in previously treated patients with HCV genotype 1: The RESPOND-2 trial

The Retreatment With HCV Serine Protease Inhibitor Boceprevir and PegIntron/Rebetol 2) (RESPOND-2) trial² was designed to assess the efficacy of combined boceprevir, pegylated interferon, and ribavirin for repeat treatment of patients with HCV genotype 1. These patients had previously undergone standard treatment and had a reduction of 2 log₁₀ or more in HCV RNA after 12 weeks of therapy but with detectable HCV RNA during the therapy period or had had a relapse (defined as undetectable HCV RNA at the end of a previous course of therapy with HCV RNA positivity thereafter). Importantly, null-responders (those who had a reduction of less than 2 log₁₀ in HCV RNA after 12 weeks of therapy) were excluded from this trial.

After a lead-in period of interferon-ribavirin treatment for 4 weeks, 403 patients were assigned to one of three treatment groups:

• Pegylated interferon and ribavirin for 44 weeks (the control group)
• Boceprevir, pegylated interferon, and ribavirin in a response-guided regimen
• Boceprevir, pegylated interferon, and ribavirin for 44 weeks (the fixed-duration group).

Sustained virologic response was achieved in only 21% of patients in the control group. Adding boceprevir increased the rate to 59% in the response-guided therapy group and to 67% in the fixed-duration group. Previous relapsers had better rates than partial responders (69%–75% vs 40%–52%).

Importantly, patients who had a poor response to pegylated interferon and ribavirin during the lead-in phase (defined as having less than a 1-log decrease in the virus before starting boceprevir) had significantly lower rates of sustained virologic response and higher rates of resistance-associated virus variants.

Side effects of boceprevir

Overall, boceprevir is well tolerated. The most common side effects of triple therapy are those usually seen with pegylated interferon and ribavirin, such as flulike symptoms and fatigue (Table 2). However, anemia was more frequent in the boceprevir groups in both SPRINT-2 and RESPOND-2 (45%–50% compared with 20%–29% in the control groups). Erythropoietin was allowed in these studies and was used in about 40% of patients.

The other common side effect associated with boceprevir was dysgeusia (alteration of taste). Dysgeusia was reported by approximately 40% of patients; however, most dysgeusia events were mild to moderate in intensity and did not lead to treatment cessation.

In the SPRINT-2 trial,¹ the study drugs had to be discontinued in 12% to 16% of patients in the boceprevir groups because of adverse events, which was similar to the rate (16%) in the control group. Erythropoietin was allowed in this trial, and it was used in 43% of patients in the boceprevir groups compared with 24% in the control group, with discontinuation owing to anemia occurring in 2% and 1% of cases, respectively.

TELAPREVIR

Telaprevir, the other protease NS3/4A inhibitor, has also shown efficacy over current standard therapy in phase 3 clinical trials. It was used in a dose of 750 mg three times a day with pegylated interferon alfa-2a (Pegasys) 180 μg per week and ribavirin (Copegus) 1,000 to 1,200 mg daily according to body weight. A lead-in phase with pegylated interferon and ribavirin was not applied with telaprevir, as it was in the boceprevir trials. Extended rapid virologic response was defined as an undetectable HCV RNA at weeks 4 and 12 of therapy.

Telaprevir in previously untreated patients with HCV genotype 1

The ADVANCE study³ was a double-blind randomized trial assessing the efficacy and safety of telaprevir in combination with pegylated interferon and ribavirin in more than 1,000 previously untreated patients. The three treatment groups received:

• Telaprevir, pegylated interferon, and ribavirin for 8 weeks, followed by pegylated interferon and ribavirin alone for 16 weeks in patients who achieved an extended rapid virologic response (total duration of 24 weeks) or 40 weeks in patients who did not (total duration of 48 weeks)
• Telaprevir, pegylated interferon, and ribavirin for 12 weeks, followed by pegylated interferon-ribavirin alone for 12 (total of 24 weeks) or 36 weeks (total of 48 weeks) according to extended rapid virologic response
• Standard care with pegylated interferon and ribavirin for 48 weeks.

The rate of sustained virologic response was 69% in the group that received telaprevir for 8 weeks and 75% in the group that received it for 12 weeks compared with 44% in the control group (P < .0001 for both) (Table 2). Patients infected with HCV genotype 1b had a higher sustained virologic response rate (79%) than those infected with HCV genotype 1a (71%).

Sustained virologic response rates were lower in black patients and patients with bridging fibrosis or cirrhosis, but were still significantly higher in the telaprevir groups than in the control group. The results of this subset analysis were limited by small numbers of patients in each category.

In total, 57% of those who received telaprevir for 8 weeks and 58% of those who received it for 12 weeks achieved an extended rapid virologic response and were able to cut the duration of their therapy in half (from 48 weeks to 24 weeks).

The relapse rates were 9% in the telaprevir groups and 28% in the control group.

The rate of virologic failure was lower in patients who received triple therapy than in those who received interferon-ribavirin alone (8% in the group that got telaprevir for 12 weeks and 13% in the group that got it for 8 weeks, vs 32% in the control group). The failure rate was also lower in patients with HCV genotype 1b infection than in those with genotype 1a.

The ILLUMINATE study⁴ (Illustrating the Effects of Combination Therapy With Telaprevir) investigated whether longer duration of treatment than that given in the ADVANCE trial increased the rate of sustained virologic response. Previously untreated patients received telaprevir, interferon, and ribavirin for 12 weeks, and those who achieved an extended rapid virologic response were randomized at week 20 to continue interferonribavirin treatment for 24 or 48 weeks of total treatment.

The sustained virologic response rates in patients who achieved an extended rapid virologic response were 92% in the group that received pegylated interferon and ribavirin for 12 weeks, and 88% in those who received it for 48 weeks. Thus, the results of this study support the use of response-guided therapy for telaprevir-based regimens.

In this phase 3 placebo-controlled trial,⁵ 622 patients with prior relapse, partial response, or null response were randomly allocated into one of three groups:

• Telaprevir for 12 weeks plus pegylated interferon and ribavirin for 48 weeks
• Lead-in for 4 weeks followed by 12 weeks of triple therapy and another 32 weeks of pegylated interferon and ribavirin
• Pegylated interferon and ribavirin for 48 weeks (the control group).

The overall sustained virologic response rates were 66% and 64%, respectively, in the telaprevir groups vs 17% in the control group (P < .0001). The sustained virologic response rates in the telaprevir groups were 83% to 88% in prior relapsers, 54% to 59% in partial responders, and 29% to 33% in null-responders. Of note, patients did not benefit from the lead-in phase.

This was the only trial to investigate the response to triple therapy in null-responders, a group in which treatment has been considered hopeless. A response rate of approximately 31% was encouraging, especially if we compare it with the 5% response rate achieved with the current standard of care with pegylated interferon and ribavirin.

Telaprevir side effects

As with boceprevir-based triple therapy, the most common adverse events were related to pegylated interferon (Table 2).

Nearly 50% of patients who receive telaprevir develop a skin rash that is primarily eczematous, can be managed with topical steroids, and usually resolves when telaprevir is discontinued. Severe rashes occurred in 3% to 6% of patients in the ADVANCE trial,³ and three suspected cases of Stevens-Johnson syndrome have been reported to the FDA.

Other side effects that were more frequent with telaprevir included pruritus, nausea, diarrhea, and anemia. On average, the hemoglobin level decreased by an additional 1 g/dL in the telaprevir treatment groups compared with the groups that received only pegylated interferon-ribavirin. Erythropoietin use was not allowed in the phase 3 telaprevir studies, and anemia was managed by ribavirin dose reduction.

In the ADVANCE trial,³ study drugs were discontinued owing to adverse events in 7% to 8% of the patients in the telaprevir groups compared with 4% in the control group. In the ILLUMINATE trial,⁴ 17% of patients had to permanently discontinue all study drugs due to adverse events.

FDA-APPROVED TREATMENT REGIMENS FOR BOCEPREVIR AND TELAPREVIR

For treatment algorithms, see the eFigures that accompany this article online.

Boceprevir in previously untreated patients

• Week 0—Start pegylated interferon and ribavirin
• Week 4—Add boceprevir
• Week 8—Measure HCV RNA
• Week 12—Measure HCV RNA; stop treatment if it is more than 100 IU/mL
• Week 24—Measure HCV RNA; stop treatment if it is detectable
• Week 28—Stop all treatment if HCV RNA was undetectable at weeks 8 and 24
• Week 36—Measure HCV RNA; stop boceprevir
• Week 48—Stop all treatment (eFigure 1).

Boceprevir in previously treated patients

• Week 0—Start pegylated interferon and ribavirin
• Week 4—Add boceprevir
• Week 8—Measure HCV RNA
• Week 12—Measure HCV RNA; stop treatment if it is more than 100 IU/mL
• Week 24—Measure HCV RNA; stop treatment if it is detectable
• Week 36—if HCV RNA was not detectable at week 8, stop all treatment now; if HCV RNA was detectable at week 8, stop boceprevir now but continue pegylated interferon and ribavirin
• Week 48—Stop all treatment (eFigure 2).

Telaprevir in previously untreated patients and prior relapsers

• Week 0—start telaprevir, pegylated interferon, and ribavirin
• Week 4—measure HCV RNA; stop all treatment if it is more than 1,000 IU/mL
• Week 12—Stop telaprevir; measure HCV RNA; stop all treatment if HCV RNA is more than 1,000 IU/mL
• Week 24—Stop pegylated interferon and ribavirin if HCV RNA was undetectable at week 12; measure HCV RNA and stop treatment if it is detectable; otherwise, continue pegylated interferon and ribavirin
• Week 48—Stop all treatment (eFigure 3).

Telaprevir in patients who previously achieved a partial or null response

• Week 0—Start telaprevir, pegylated interferon, and ribavirin
• Week 4—Measure HCV RNA; stop treatment if it is more than 1,000 IU/mL
• Week 12—Measure HCV RNA; stop all treatment if it is more than 1,000 IU/mL; if less than 1,000 IU/mL then stop telaprevir but continue pegylated interferon and ribavirin
• Week 24—Measure HCV RNA; stop treatment if HCV RNA is detectable
• Week 48—Stop all treatment (eFigure 4).

Drug interactions with boceprevir and telaprevir

Both boceprevir and telaprevir inhibit cytochrome P450 3A (CYP3A) and thus are contraindicated in combination with drugs highly dependent on CYP3A for clearance and with drugs for which elevated plasma concentrations are associated with serious adverse events, such as atorvastatin (Lipitor), simvastatin (Zocor), sildenafil (Viagra), midazolam (Versed), and St. John’s wort. Giving potent inducers of CYP3A with boceprevir or telaprevir may lead to lower exposure and loss of efficacy of both protease inhibitors.

EMERGING THERAPIES FOR HCV

Thanks to a better understanding of the biology of HCV infection, the effort to develop new therapeutic agents started to focus on targeting specific steps of the viral life cycle, including attachment, entry into cells, replication, and release.²⁴

Currently, more than 50 clinical trials are evaluating new direct-acting antivirals to treat HCV infection.²⁵ Monoclonal and polyclonal antibodies that target the molecular process involved in HCV attachment and entry are being developed.²⁶ The nonstructural protein NS5B (RNA polymerase) is intimately involved in viral replication and represents a promising target.²⁷ Several nucleosides and nonnucleoside protease inhibitors have already entered clinical trials.

The low fidelity of the HCV replication machinery leads to a very high mutation rate, thus enabling the virus to quickly develop mutations that resist agents targeting viral enzymes.²⁸ Therefore, a novel approach is to target host cofactors that are essential for HCV replication. An intriguing study by Lanford et al²⁹ demonstrated that antagonizing microRNA-122 (the most abundant microRNA in the liver and an essential cofactor for viral RNA replication) by the oligonucleotide SPC3649 caused marked and prolonged reduction of HCV viremia in chronically infected chimpanzees.²⁹

Although we are still in the early stages of drug development, the future holds great promise for newer drugs to improve the sustained virologic response, shorten the duration of treatment, improve tolerability with interferon-sparing regimens, and decrease viral resistance.

FUTURE PERSPECTIVES

With the introduction of the first direct-acting antiviral medications for HCV (boceprevir and telaprevir), 2011 will be marked as the year that changed hepatitis C treatment for the better. Triple therapy with pegylated interferon, ribavirin, and either boceprevir or telaprevir has the potential for increasing the rate of sustained virologic response to around 70% in previously untreated patients and 65% in previously treated patients who are infected with HCV genotype 1. The IL28B polymorphisms appear to play a role in the rate of sustained virologic response achieved with triple therapy, with preliminary data showing a better response rate in patients who have the CC genotype.¹⁷

These drugs will add up to $50,000 to the cost of treating hepatitis C virus infection, depending on the drug used and the length of treatment. However, they may be well worth it if they prevent liver failure and the need for transplantation.

Many questions remain, such as how to use these new regimens to treat special patient populations—for example, those with a recurrence of HCV infection after liver transplantation, those co-infected with HCV and human immunodeficiency virus, and those infected with HCV genotypes other than genotype 1.

Other direct-acting antiviral agents that specifically target the replication cycle of HCV are currently in clinical development. In fact, the future has already started with the release of the Interferon-Free Regimen for the Management of HCV (INFORM-1) study results.³⁰ This was the first trial to evaluate an interferon-free regimen for patients with chronic HCV infection using two direct-acting antiviral drugs (the protease inhibitor danoprevir and the polymerase inhibitor RG7128), with promising results.

The treatment of hepatitis c virus (HCV) infection is on the brink of major changes with the recent approval of the first direct-acting antiviral agents, the protease inhibitors boceprevir (Victrelis) and telaprevir (Incivek).

Both drugs were approved by the US Food and Drug Administration (FDA) Advisory Panel for Chronic Hepatitis C in May 2011 and are believed to significantly improve treatment outcomes for patients with HCV genotype 1 infection.

A MAJOR PUBLIC HEALTH PROBLEM

HCV infection is a major public health problem. Nearly 4 million people in the United States are infected.^6,7 Most patients with acute HCV infection become chronically infected, and up to 25% eventually develop cirrhosis and its complications, making HCV infection the leading indication for liver transplantation.^8–10

Chronic HCV infection has a large global impact, with 180 million people affected across all economic and social groups.¹¹ The highest prevalence of HCV has been reported in Egypt (14%), in part due to the use of inadequately sterilized needles in mass programs to treat endemic schistosomiasis. In developed countries, hepatocellular carcinoma associated with HCV has the fastest growing cancer-related death rate.¹²

CURRENTLY, FEWER THAN 50% OF PATIENTS ARE CURED

The goal of HCV treatment is to eradicate the virus. However, most infected patients (especially in the United States and Europe) are infected with HCV genotype 1, which is the most difficult genotype to treat.

Successful treatment of HCV is defined as achieving a sustained virologic response—ie, the absence of detectable HCV RNA in the serum 24 weeks after completion of therapy. Once a sustained virologic response is achieved, lifetime “cure” of HCV infection is expected in more than 99% of patients.¹³

The current standard therapy for HCV, pegylated interferon plus ribavirin for 48 weeks, is effective in only 40% to 50% of patients with genotype 1 infection.¹⁴ Therefore, assessing predictors of response before starting treatment can help select patients who are most likely to benefit from therapy.

Viral factors associated with a sustained virologic response include HCV genotypes other than genotype 1 and a low baseline viral load.

Beneficial patient-related factors include younger age, nonblack ethnicity, low body weight (≤ 75 kg), low body mass index, absence of insulin resistance, and absence of advanced fibrosis or cirrhosis.

More recently, a single-nucleotide polymorphism near the interleukin 28B (IL28B) gene, coding for interferon lambda 3, was found to be associated with a twofold difference in the rates of sustained virologic response: patients with the favorable genotype CC were two times more likely to achieve a sustained virologic response than patients with the CT or TT genotypes.^15–17

PROTEASE INHIBITORS: MECHANISM OF ACTION

NS3/4A protease inhibitors rely on the principle of end-product inhibition, in which the cleavage product of the protease (a peptide) acts to inhibit the enzyme activity; this is why they are called peptidomimetics. The active site of the NS3/4A protease is a shallow groove composed of three highly conserved amino acid residues, which may explain why protease inhibitors display high antiviral efficacy but pose a low barrier to the development of resistance.²⁰

Protease inhibitors are prone to resistance

The development of viral resistance to protease inhibitors has been a major drawback to their use in patients with chronic HCV infection.²¹

HCV is a highly variable virus with many genetically distinct but closely related quasispecies circulating in the blood at any given time. Drug-resistant, mutated variants preexist within the patient’s quasispecies, but only in small quantities because of their lesser replication fitness compared with the wild-type virus.²² When direct-acting antiviral therapy is started, the quantity of the wild-type virus decreases and the mutated virus gains replication fitness. Using protease inhibitors as monotherapy selects resistant viral populations rapidly within a few days or weeks.

HCV subtypes 1a and 1b may have different resistance profiles. With genotype 1a, some resistance-associated amino acid substitutions require only one nucleotide change, but with genotype 1b, two nucleotide changes are needed, making resistance less frequent in patients with HCV genotype 1b.²³

BOCEPREVIR

Boceprevir is a specific inhibitor of the HCV viral protease NS3/4A.

In phase 3 clinical trials, boceprevir 800 mg three times a day was used with pegylated interferon alfa-2b (PegIntron) 1.5 μg/kg/week and ribavirin (Rebetol) 600 to 1,400 mg daily according to body weight.

Before patients started taking boceprevir, they went through a 4-week lead-in phase, during which they received pegylated interferon and ribavirin. This schedule appeared to reduce the incidence of viral breakthrough in phase 2 trials, and it produced higher rates of sustained virologic response and lower relapse rates compared with triple therapy without a lead-in phase.

Rapid virologic response was defined as undetectable HCV RNA at week 4 of boceprevir therapy (week 8 of the whole regimen).

Boceprevir in previously untreated patients with HCV genotype 1: The SPRINT-2 trial

The Serine Protease Inhibitor Therapy 2 (SPRINT-2) trial¹ included more than 1,000 previously untreated adults with HCV genotype 1 infection (938 nonblack patients and 159 black patients; two other nonblack patients did not receive any study drug and were not included in the analysis). In this double-blind trial, patients were randomized into three groups:

• The control group received the standard of care with pegylated interferon and ribavirin for 48 weeks
• The response-guided therapy group received boceprevir plus pegylated interferon and ribavirin for 24 weeks after the 4-week lead-in phase; if HCV RNA was undetectable from week 8 to week 24, treatment was considered complete, but if HCV RNA was detectable at any point from week 8 to week 24, pegylated interferon and ribavirin were continued for a total of 48 weeks.
• The fixed-duration therapy group received boceprevir, pegylated interferon, and ribavirin for 44 weeks after the lead-in period.

The rate of relapse was 8% and 9% in the boceprevir groups vs 23% in the control group. Patients in the boceprevir groups who had a decrease in HCV RNA of less than 1 log₁₀ during the lead-in phase were found to have a significantly higher rate of boceprevirresistant variants than those who achieved a decrease of HCV RNA of 1 log₁₀ or more.

Boceprevir in previously treated patients with HCV genotype 1: The RESPOND-2 trial

The Retreatment With HCV Serine Protease Inhibitor Boceprevir and PegIntron/Rebetol 2) (RESPOND-2) trial² was designed to assess the efficacy of combined boceprevir, pegylated interferon, and ribavirin for repeat treatment of patients with HCV genotype 1. These patients had previously undergone standard treatment and had a reduction of 2 log₁₀ or more in HCV RNA after 12 weeks of therapy but with detectable HCV RNA during the therapy period or had had a relapse (defined as undetectable HCV RNA at the end of a previous course of therapy with HCV RNA positivity thereafter). Importantly, null-responders (those who had a reduction of less than 2 log₁₀ in HCV RNA after 12 weeks of therapy) were excluded from this trial.

After a lead-in period of interferon-ribavirin treatment for 4 weeks, 403 patients were assigned to one of three treatment groups:

• Pegylated interferon and ribavirin for 44 weeks (the control group)
• Boceprevir, pegylated interferon, and ribavirin in a response-guided regimen
• Boceprevir, pegylated interferon, and ribavirin for 44 weeks (the fixed-duration group).

Sustained virologic response was achieved in only 21% of patients in the control group. Adding boceprevir increased the rate to 59% in the response-guided therapy group and to 67% in the fixed-duration group. Previous relapsers had better rates than partial responders (69%–75% vs 40%–52%).

Importantly, patients who had a poor response to pegylated interferon and ribavirin during the lead-in phase (defined as having less than a 1-log decrease in the virus before starting boceprevir) had significantly lower rates of sustained virologic response and higher rates of resistance-associated virus variants.

Side effects of boceprevir

Overall, boceprevir is well tolerated. The most common side effects of triple therapy are those usually seen with pegylated interferon and ribavirin, such as flulike symptoms and fatigue (Table 2). However, anemia was more frequent in the boceprevir groups in both SPRINT-2 and RESPOND-2 (45%–50% compared with 20%–29% in the control groups). Erythropoietin was allowed in these studies and was used in about 40% of patients.

The other common side effect associated with boceprevir was dysgeusia (alteration of taste). Dysgeusia was reported by approximately 40% of patients; however, most dysgeusia events were mild to moderate in intensity and did not lead to treatment cessation.

In the SPRINT-2 trial,¹ the study drugs had to be discontinued in 12% to 16% of patients in the boceprevir groups because of adverse events, which was similar to the rate (16%) in the control group. Erythropoietin was allowed in this trial, and it was used in 43% of patients in the boceprevir groups compared with 24% in the control group, with discontinuation owing to anemia occurring in 2% and 1% of cases, respectively.

TELAPREVIR

Telaprevir, the other protease NS3/4A inhibitor, has also shown efficacy over current standard therapy in phase 3 clinical trials. It was used in a dose of 750 mg three times a day with pegylated interferon alfa-2a (Pegasys) 180 μg per week and ribavirin (Copegus) 1,000 to 1,200 mg daily according to body weight. A lead-in phase with pegylated interferon and ribavirin was not applied with telaprevir, as it was in the boceprevir trials. Extended rapid virologic response was defined as an undetectable HCV RNA at weeks 4 and 12 of therapy.

Telaprevir in previously untreated patients with HCV genotype 1

The ADVANCE study³ was a double-blind randomized trial assessing the efficacy and safety of telaprevir in combination with pegylated interferon and ribavirin in more than 1,000 previously untreated patients. The three treatment groups received:

• Telaprevir, pegylated interferon, and ribavirin for 8 weeks, followed by pegylated interferon and ribavirin alone for 16 weeks in patients who achieved an extended rapid virologic response (total duration of 24 weeks) or 40 weeks in patients who did not (total duration of 48 weeks)
• Telaprevir, pegylated interferon, and ribavirin for 12 weeks, followed by pegylated interferon-ribavirin alone for 12 (total of 24 weeks) or 36 weeks (total of 48 weeks) according to extended rapid virologic response
• Standard care with pegylated interferon and ribavirin for 48 weeks.

The rate of sustained virologic response was 69% in the group that received telaprevir for 8 weeks and 75% in the group that received it for 12 weeks compared with 44% in the control group (P < .0001 for both) (Table 2). Patients infected with HCV genotype 1b had a higher sustained virologic response rate (79%) than those infected with HCV genotype 1a (71%).

Sustained virologic response rates were lower in black patients and patients with bridging fibrosis or cirrhosis, but were still significantly higher in the telaprevir groups than in the control group. The results of this subset analysis were limited by small numbers of patients in each category.

In total, 57% of those who received telaprevir for 8 weeks and 58% of those who received it for 12 weeks achieved an extended rapid virologic response and were able to cut the duration of their therapy in half (from 48 weeks to 24 weeks).

The relapse rates were 9% in the telaprevir groups and 28% in the control group.

The rate of virologic failure was lower in patients who received triple therapy than in those who received interferon-ribavirin alone (8% in the group that got telaprevir for 12 weeks and 13% in the group that got it for 8 weeks, vs 32% in the control group). The failure rate was also lower in patients with HCV genotype 1b infection than in those with genotype 1a.

The ILLUMINATE study⁴ (Illustrating the Effects of Combination Therapy With Telaprevir) investigated whether longer duration of treatment than that given in the ADVANCE trial increased the rate of sustained virologic response. Previously untreated patients received telaprevir, interferon, and ribavirin for 12 weeks, and those who achieved an extended rapid virologic response were randomized at week 20 to continue interferonribavirin treatment for 24 or 48 weeks of total treatment.

The sustained virologic response rates in patients who achieved an extended rapid virologic response were 92% in the group that received pegylated interferon and ribavirin for 12 weeks, and 88% in those who received it for 48 weeks. Thus, the results of this study support the use of response-guided therapy for telaprevir-based regimens.

In this phase 3 placebo-controlled trial,⁵ 622 patients with prior relapse, partial response, or null response were randomly allocated into one of three groups:

• Telaprevir for 12 weeks plus pegylated interferon and ribavirin for 48 weeks
• Lead-in for 4 weeks followed by 12 weeks of triple therapy and another 32 weeks of pegylated interferon and ribavirin
• Pegylated interferon and ribavirin for 48 weeks (the control group).

The overall sustained virologic response rates were 66% and 64%, respectively, in the telaprevir groups vs 17% in the control group (P < .0001). The sustained virologic response rates in the telaprevir groups were 83% to 88% in prior relapsers, 54% to 59% in partial responders, and 29% to 33% in null-responders. Of note, patients did not benefit from the lead-in phase.

This was the only trial to investigate the response to triple therapy in null-responders, a group in which treatment has been considered hopeless. A response rate of approximately 31% was encouraging, especially if we compare it with the 5% response rate achieved with the current standard of care with pegylated interferon and ribavirin.

Telaprevir side effects

As with boceprevir-based triple therapy, the most common adverse events were related to pegylated interferon (Table 2).

Nearly 50% of patients who receive telaprevir develop a skin rash that is primarily eczematous, can be managed with topical steroids, and usually resolves when telaprevir is discontinued. Severe rashes occurred in 3% to 6% of patients in the ADVANCE trial,³ and three suspected cases of Stevens-Johnson syndrome have been reported to the FDA.

Other side effects that were more frequent with telaprevir included pruritus, nausea, diarrhea, and anemia. On average, the hemoglobin level decreased by an additional 1 g/dL in the telaprevir treatment groups compared with the groups that received only pegylated interferon-ribavirin. Erythropoietin use was not allowed in the phase 3 telaprevir studies, and anemia was managed by ribavirin dose reduction.

In the ADVANCE trial,³ study drugs were discontinued owing to adverse events in 7% to 8% of the patients in the telaprevir groups compared with 4% in the control group. In the ILLUMINATE trial,⁴ 17% of patients had to permanently discontinue all study drugs due to adverse events.

FDA-APPROVED TREATMENT REGIMENS FOR BOCEPREVIR AND TELAPREVIR

For treatment algorithms, see the eFigures that accompany this article online.

Boceprevir in previously untreated patients

• Week 0—Start pegylated interferon and ribavirin
• Week 4—Add boceprevir
• Week 8—Measure HCV RNA
• Week 12—Measure HCV RNA; stop treatment if it is more than 100 IU/mL
• Week 24—Measure HCV RNA; stop treatment if it is detectable
• Week 28—Stop all treatment if HCV RNA was undetectable at weeks 8 and 24
• Week 36—Measure HCV RNA; stop boceprevir
• Week 48—Stop all treatment (eFigure 1).

Boceprevir in previously treated patients

• Week 0—Start pegylated interferon and ribavirin
• Week 4—Add boceprevir
• Week 8—Measure HCV RNA
• Week 12—Measure HCV RNA; stop treatment if it is more than 100 IU/mL
• Week 24—Measure HCV RNA; stop treatment if it is detectable
• Week 36—if HCV RNA was not detectable at week 8, stop all treatment now; if HCV RNA was detectable at week 8, stop boceprevir now but continue pegylated interferon and ribavirin
• Week 48—Stop all treatment (eFigure 2).

Telaprevir in previously untreated patients and prior relapsers

• Week 0—start telaprevir, pegylated interferon, and ribavirin
• Week 4—measure HCV RNA; stop all treatment if it is more than 1,000 IU/mL
• Week 12—Stop telaprevir; measure HCV RNA; stop all treatment if HCV RNA is more than 1,000 IU/mL
• Week 24—Stop pegylated interferon and ribavirin if HCV RNA was undetectable at week 12; measure HCV RNA and stop treatment if it is detectable; otherwise, continue pegylated interferon and ribavirin
• Week 48—Stop all treatment (eFigure 3).

Telaprevir in patients who previously achieved a partial or null response

• Week 0—Start telaprevir, pegylated interferon, and ribavirin
• Week 4—Measure HCV RNA; stop treatment if it is more than 1,000 IU/mL
• Week 12—Measure HCV RNA; stop all treatment if it is more than 1,000 IU/mL; if less than 1,000 IU/mL then stop telaprevir but continue pegylated interferon and ribavirin
• Week 24—Measure HCV RNA; stop treatment if HCV RNA is detectable
• Week 48—Stop all treatment (eFigure 4).

Drug interactions with boceprevir and telaprevir

Both boceprevir and telaprevir inhibit cytochrome P450 3A (CYP3A) and thus are contraindicated in combination with drugs highly dependent on CYP3A for clearance and with drugs for which elevated plasma concentrations are associated with serious adverse events, such as atorvastatin (Lipitor), simvastatin (Zocor), sildenafil (Viagra), midazolam (Versed), and St. John’s wort. Giving potent inducers of CYP3A with boceprevir or telaprevir may lead to lower exposure and loss of efficacy of both protease inhibitors.

EMERGING THERAPIES FOR HCV

Thanks to a better understanding of the biology of HCV infection, the effort to develop new therapeutic agents started to focus on targeting specific steps of the viral life cycle, including attachment, entry into cells, replication, and release.²⁴

Currently, more than 50 clinical trials are evaluating new direct-acting antivirals to treat HCV infection.²⁵ Monoclonal and polyclonal antibodies that target the molecular process involved in HCV attachment and entry are being developed.²⁶ The nonstructural protein NS5B (RNA polymerase) is intimately involved in viral replication and represents a promising target.²⁷ Several nucleosides and nonnucleoside protease inhibitors have already entered clinical trials.

The low fidelity of the HCV replication machinery leads to a very high mutation rate, thus enabling the virus to quickly develop mutations that resist agents targeting viral enzymes.²⁸ Therefore, a novel approach is to target host cofactors that are essential for HCV replication. An intriguing study by Lanford et al²⁹ demonstrated that antagonizing microRNA-122 (the most abundant microRNA in the liver and an essential cofactor for viral RNA replication) by the oligonucleotide SPC3649 caused marked and prolonged reduction of HCV viremia in chronically infected chimpanzees.²⁹

Although we are still in the early stages of drug development, the future holds great promise for newer drugs to improve the sustained virologic response, shorten the duration of treatment, improve tolerability with interferon-sparing regimens, and decrease viral resistance.

FUTURE PERSPECTIVES

With the introduction of the first direct-acting antiviral medications for HCV (boceprevir and telaprevir), 2011 will be marked as the year that changed hepatitis C treatment for the better. Triple therapy with pegylated interferon, ribavirin, and either boceprevir or telaprevir has the potential for increasing the rate of sustained virologic response to around 70% in previously untreated patients and 65% in previously treated patients who are infected with HCV genotype 1. The IL28B polymorphisms appear to play a role in the rate of sustained virologic response achieved with triple therapy, with preliminary data showing a better response rate in patients who have the CC genotype.¹⁷

These drugs will add up to $50,000 to the cost of treating hepatitis C virus infection, depending on the drug used and the length of treatment. However, they may be well worth it if they prevent liver failure and the need for transplantation.

Many questions remain, such as how to use these new regimens to treat special patient populations—for example, those with a recurrence of HCV infection after liver transplantation, those co-infected with HCV and human immunodeficiency virus, and those infected with HCV genotypes other than genotype 1.

Other direct-acting antiviral agents that specifically target the replication cycle of HCV are currently in clinical development. In fact, the future has already started with the release of the Interferon-Free Regimen for the Management of HCV (INFORM-1) study results.³⁰ This was the first trial to evaluate an interferon-free regimen for patients with chronic HCV infection using two direct-acting antiviral drugs (the protease inhibitor danoprevir and the polymerase inhibitor RG7128), with promising results.

The treatment of hepatitis c virus (HCV) infection is on the brink of major changes with the recent approval of the first direct-acting antiviral agents, the protease inhibitors boceprevir (Victrelis) and telaprevir (Incivek).

Both drugs were approved by the US Food and Drug Administration (FDA) Advisory Panel for Chronic Hepatitis C in May 2011 and are believed to significantly improve treatment outcomes for patients with HCV genotype 1 infection.

A MAJOR PUBLIC HEALTH PROBLEM

HCV infection is a major public health problem. Nearly 4 million people in the United States are infected.^6,7 Most patients with acute HCV infection become chronically infected, and up to 25% eventually develop cirrhosis and its complications, making HCV infection the leading indication for liver transplantation.^8–10

Chronic HCV infection has a large global impact, with 180 million people affected across all economic and social groups.¹¹ The highest prevalence of HCV has been reported in Egypt (14%), in part due to the use of inadequately sterilized needles in mass programs to treat endemic schistosomiasis. In developed countries, hepatocellular carcinoma associated with HCV has the fastest growing cancer-related death rate.¹²

CURRENTLY, FEWER THAN 50% OF PATIENTS ARE CURED

The goal of HCV treatment is to eradicate the virus. However, most infected patients (especially in the United States and Europe) are infected with HCV genotype 1, which is the most difficult genotype to treat.

Successful treatment of HCV is defined as achieving a sustained virologic response—ie, the absence of detectable HCV RNA in the serum 24 weeks after completion of therapy. Once a sustained virologic response is achieved, lifetime “cure” of HCV infection is expected in more than 99% of patients.¹³

The current standard therapy for HCV, pegylated interferon plus ribavirin for 48 weeks, is effective in only 40% to 50% of patients with genotype 1 infection.¹⁴ Therefore, assessing predictors of response before starting treatment can help select patients who are most likely to benefit from therapy.

Viral factors associated with a sustained virologic response include HCV genotypes other than genotype 1 and a low baseline viral load.

Beneficial patient-related factors include younger age, nonblack ethnicity, low body weight (≤ 75 kg), low body mass index, absence of insulin resistance, and absence of advanced fibrosis or cirrhosis.

More recently, a single-nucleotide polymorphism near the interleukin 28B (IL28B) gene, coding for interferon lambda 3, was found to be associated with a twofold difference in the rates of sustained virologic response: patients with the favorable genotype CC were two times more likely to achieve a sustained virologic response than patients with the CT or TT genotypes.^15–17

PROTEASE INHIBITORS: MECHANISM OF ACTION

NS3/4A protease inhibitors rely on the principle of end-product inhibition, in which the cleavage product of the protease (a peptide) acts to inhibit the enzyme activity; this is why they are called peptidomimetics. The active site of the NS3/4A protease is a shallow groove composed of three highly conserved amino acid residues, which may explain why protease inhibitors display high antiviral efficacy but pose a low barrier to the development of resistance.²⁰

Protease inhibitors are prone to resistance

The development of viral resistance to protease inhibitors has been a major drawback to their use in patients with chronic HCV infection.²¹

HCV is a highly variable virus with many genetically distinct but closely related quasispecies circulating in the blood at any given time. Drug-resistant, mutated variants preexist within the patient’s quasispecies, but only in small quantities because of their lesser replication fitness compared with the wild-type virus.²² When direct-acting antiviral therapy is started, the quantity of the wild-type virus decreases and the mutated virus gains replication fitness. Using protease inhibitors as monotherapy selects resistant viral populations rapidly within a few days or weeks.

HCV subtypes 1a and 1b may have different resistance profiles. With genotype 1a, some resistance-associated amino acid substitutions require only one nucleotide change, but with genotype 1b, two nucleotide changes are needed, making resistance less frequent in patients with HCV genotype 1b.²³

BOCEPREVIR

Boceprevir is a specific inhibitor of the HCV viral protease NS3/4A.

In phase 3 clinical trials, boceprevir 800 mg three times a day was used with pegylated interferon alfa-2b (PegIntron) 1.5 μg/kg/week and ribavirin (Rebetol) 600 to 1,400 mg daily according to body weight.

Before patients started taking boceprevir, they went through a 4-week lead-in phase, during which they received pegylated interferon and ribavirin. This schedule appeared to reduce the incidence of viral breakthrough in phase 2 trials, and it produced higher rates of sustained virologic response and lower relapse rates compared with triple therapy without a lead-in phase.

Rapid virologic response was defined as undetectable HCV RNA at week 4 of boceprevir therapy (week 8 of the whole regimen).

Boceprevir in previously untreated patients with HCV genotype 1: The SPRINT-2 trial

The Serine Protease Inhibitor Therapy 2 (SPRINT-2) trial¹ included more than 1,000 previously untreated adults with HCV genotype 1 infection (938 nonblack patients and 159 black patients; two other nonblack patients did not receive any study drug and were not included in the analysis). In this double-blind trial, patients were randomized into three groups:

• The control group received the standard of care with pegylated interferon and ribavirin for 48 weeks
• The response-guided therapy group received boceprevir plus pegylated interferon and ribavirin for 24 weeks after the 4-week lead-in phase; if HCV RNA was undetectable from week 8 to week 24, treatment was considered complete, but if HCV RNA was detectable at any point from week 8 to week 24, pegylated interferon and ribavirin were continued for a total of 48 weeks.
• The fixed-duration therapy group received boceprevir, pegylated interferon, and ribavirin for 44 weeks after the lead-in period.

The rate of relapse was 8% and 9% in the boceprevir groups vs 23% in the control group. Patients in the boceprevir groups who had a decrease in HCV RNA of less than 1 log₁₀ during the lead-in phase were found to have a significantly higher rate of boceprevirresistant variants than those who achieved a decrease of HCV RNA of 1 log₁₀ or more.

Boceprevir in previously treated patients with HCV genotype 1: The RESPOND-2 trial

The Retreatment With HCV Serine Protease Inhibitor Boceprevir and PegIntron/Rebetol 2) (RESPOND-2) trial² was designed to assess the efficacy of combined boceprevir, pegylated interferon, and ribavirin for repeat treatment of patients with HCV genotype 1. These patients had previously undergone standard treatment and had a reduction of 2 log₁₀ or more in HCV RNA after 12 weeks of therapy but with detectable HCV RNA during the therapy period or had had a relapse (defined as undetectable HCV RNA at the end of a previous course of therapy with HCV RNA positivity thereafter). Importantly, null-responders (those who had a reduction of less than 2 log₁₀ in HCV RNA after 12 weeks of therapy) were excluded from this trial.

After a lead-in period of interferon-ribavirin treatment for 4 weeks, 403 patients were assigned to one of three treatment groups:

• Pegylated interferon and ribavirin for 44 weeks (the control group)
• Boceprevir, pegylated interferon, and ribavirin in a response-guided regimen
• Boceprevir, pegylated interferon, and ribavirin for 44 weeks (the fixed-duration group).

Sustained virologic response was achieved in only 21% of patients in the control group. Adding boceprevir increased the rate to 59% in the response-guided therapy group and to 67% in the fixed-duration group. Previous relapsers had better rates than partial responders (69%–75% vs 40%–52%).

Importantly, patients who had a poor response to pegylated interferon and ribavirin during the lead-in phase (defined as having less than a 1-log decrease in the virus before starting boceprevir) had significantly lower rates of sustained virologic response and higher rates of resistance-associated virus variants.

Side effects of boceprevir

Overall, boceprevir is well tolerated. The most common side effects of triple therapy are those usually seen with pegylated interferon and ribavirin, such as flulike symptoms and fatigue (Table 2). However, anemia was more frequent in the boceprevir groups in both SPRINT-2 and RESPOND-2 (45%–50% compared with 20%–29% in the control groups). Erythropoietin was allowed in these studies and was used in about 40% of patients.

The other common side effect associated with boceprevir was dysgeusia (alteration of taste). Dysgeusia was reported by approximately 40% of patients; however, most dysgeusia events were mild to moderate in intensity and did not lead to treatment cessation.

In the SPRINT-2 trial,¹ the study drugs had to be discontinued in 12% to 16% of patients in the boceprevir groups because of adverse events, which was similar to the rate (16%) in the control group. Erythropoietin was allowed in this trial, and it was used in 43% of patients in the boceprevir groups compared with 24% in the control group, with discontinuation owing to anemia occurring in 2% and 1% of cases, respectively.

TELAPREVIR

Telaprevir, the other protease NS3/4A inhibitor, has also shown efficacy over current standard therapy in phase 3 clinical trials. It was used in a dose of 750 mg three times a day with pegylated interferon alfa-2a (Pegasys) 180 μg per week and ribavirin (Copegus) 1,000 to 1,200 mg daily according to body weight. A lead-in phase with pegylated interferon and ribavirin was not applied with telaprevir, as it was in the boceprevir trials. Extended rapid virologic response was defined as an undetectable HCV RNA at weeks 4 and 12 of therapy.

Telaprevir in previously untreated patients with HCV genotype 1

The ADVANCE study³ was a double-blind randomized trial assessing the efficacy and safety of telaprevir in combination with pegylated interferon and ribavirin in more than 1,000 previously untreated patients. The three treatment groups received:

• Telaprevir, pegylated interferon, and ribavirin for 8 weeks, followed by pegylated interferon and ribavirin alone for 16 weeks in patients who achieved an extended rapid virologic response (total duration of 24 weeks) or 40 weeks in patients who did not (total duration of 48 weeks)
• Telaprevir, pegylated interferon, and ribavirin for 12 weeks, followed by pegylated interferon-ribavirin alone for 12 (total of 24 weeks) or 36 weeks (total of 48 weeks) according to extended rapid virologic response
• Standard care with pegylated interferon and ribavirin for 48 weeks.

The rate of sustained virologic response was 69% in the group that received telaprevir for 8 weeks and 75% in the group that received it for 12 weeks compared with 44% in the control group (P < .0001 for both) (Table 2). Patients infected with HCV genotype 1b had a higher sustained virologic response rate (79%) than those infected with HCV genotype 1a (71%).

Sustained virologic response rates were lower in black patients and patients with bridging fibrosis or cirrhosis, but were still significantly higher in the telaprevir groups than in the control group. The results of this subset analysis were limited by small numbers of patients in each category.

In total, 57% of those who received telaprevir for 8 weeks and 58% of those who received it for 12 weeks achieved an extended rapid virologic response and were able to cut the duration of their therapy in half (from 48 weeks to 24 weeks).

The relapse rates were 9% in the telaprevir groups and 28% in the control group.

The rate of virologic failure was lower in patients who received triple therapy than in those who received interferon-ribavirin alone (8% in the group that got telaprevir for 12 weeks and 13% in the group that got it for 8 weeks, vs 32% in the control group). The failure rate was also lower in patients with HCV genotype 1b infection than in those with genotype 1a.

The ILLUMINATE study⁴ (Illustrating the Effects of Combination Therapy With Telaprevir) investigated whether longer duration of treatment than that given in the ADVANCE trial increased the rate of sustained virologic response. Previously untreated patients received telaprevir, interferon, and ribavirin for 12 weeks, and those who achieved an extended rapid virologic response were randomized at week 20 to continue interferonribavirin treatment for 24 or 48 weeks of total treatment.

The sustained virologic response rates in patients who achieved an extended rapid virologic response were 92% in the group that received pegylated interferon and ribavirin for 12 weeks, and 88% in those who received it for 48 weeks. Thus, the results of this study support the use of response-guided therapy for telaprevir-based regimens.

In this phase 3 placebo-controlled trial,⁵ 622 patients with prior relapse, partial response, or null response were randomly allocated into one of three groups:

• Telaprevir for 12 weeks plus pegylated interferon and ribavirin for 48 weeks
• Lead-in for 4 weeks followed by 12 weeks of triple therapy and another 32 weeks of pegylated interferon and ribavirin
• Pegylated interferon and ribavirin for 48 weeks (the control group).

The overall sustained virologic response rates were 66% and 64%, respectively, in the telaprevir groups vs 17% in the control group (P < .0001). The sustained virologic response rates in the telaprevir groups were 83% to 88% in prior relapsers, 54% to 59% in partial responders, and 29% to 33% in null-responders. Of note, patients did not benefit from the lead-in phase.

This was the only trial to investigate the response to triple therapy in null-responders, a group in which treatment has been considered hopeless. A response rate of approximately 31% was encouraging, especially if we compare it with the 5% response rate achieved with the current standard of care with pegylated interferon and ribavirin.

Telaprevir side effects

As with boceprevir-based triple therapy, the most common adverse events were related to pegylated interferon (Table 2).

Nearly 50% of patients who receive telaprevir develop a skin rash that is primarily eczematous, can be managed with topical steroids, and usually resolves when telaprevir is discontinued. Severe rashes occurred in 3% to 6% of patients in the ADVANCE trial,³ and three suspected cases of Stevens-Johnson syndrome have been reported to the FDA.

Other side effects that were more frequent with telaprevir included pruritus, nausea, diarrhea, and anemia. On average, the hemoglobin level decreased by an additional 1 g/dL in the telaprevir treatment groups compared with the groups that received only pegylated interferon-ribavirin. Erythropoietin use was not allowed in the phase 3 telaprevir studies, and anemia was managed by ribavirin dose reduction.

In the ADVANCE trial,³ study drugs were discontinued owing to adverse events in 7% to 8% of the patients in the telaprevir groups compared with 4% in the control group. In the ILLUMINATE trial,⁴ 17% of patients had to permanently discontinue all study drugs due to adverse events.

FDA-APPROVED TREATMENT REGIMENS FOR BOCEPREVIR AND TELAPREVIR

For treatment algorithms, see the eFigures that accompany this article online.

Boceprevir in previously untreated patients

• Week 0—Start pegylated interferon and ribavirin
• Week 4—Add boceprevir
• Week 8—Measure HCV RNA
• Week 12—Measure HCV RNA; stop treatment if it is more than 100 IU/mL
• Week 24—Measure HCV RNA; stop treatment if it is detectable
• Week 28—Stop all treatment if HCV RNA was undetectable at weeks 8 and 24
• Week 36—Measure HCV RNA; stop boceprevir
• Week 48—Stop all treatment (eFigure 1).

Boceprevir in previously treated patients

• Week 0—Start pegylated interferon and ribavirin
• Week 4—Add boceprevir
• Week 8—Measure HCV RNA
• Week 12—Measure HCV RNA; stop treatment if it is more than 100 IU/mL
• Week 24—Measure HCV RNA; stop treatment if it is detectable
• Week 36—if HCV RNA was not detectable at week 8, stop all treatment now; if HCV RNA was detectable at week 8, stop boceprevir now but continue pegylated interferon and ribavirin
• Week 48—Stop all treatment (eFigure 2).

Telaprevir in previously untreated patients and prior relapsers

• Week 0—start telaprevir, pegylated interferon, and ribavirin
• Week 4—measure HCV RNA; stop all treatment if it is more than 1,000 IU/mL
• Week 12—Stop telaprevir; measure HCV RNA; stop all treatment if HCV RNA is more than 1,000 IU/mL
• Week 24—Stop pegylated interferon and ribavirin if HCV RNA was undetectable at week 12; measure HCV RNA and stop treatment if it is detectable; otherwise, continue pegylated interferon and ribavirin
• Week 48—Stop all treatment (eFigure 3).

Telaprevir in patients who previously achieved a partial or null response

• Week 0—Start telaprevir, pegylated interferon, and ribavirin
• Week 4—Measure HCV RNA; stop treatment if it is more than 1,000 IU/mL
• Week 12—Measure HCV RNA; stop all treatment if it is more than 1,000 IU/mL; if less than 1,000 IU/mL then stop telaprevir but continue pegylated interferon and ribavirin
• Week 24—Measure HCV RNA; stop treatment if HCV RNA is detectable
• Week 48—Stop all treatment (eFigure 4).

Drug interactions with boceprevir and telaprevir

Both boceprevir and telaprevir inhibit cytochrome P450 3A (CYP3A) and thus are contraindicated in combination with drugs highly dependent on CYP3A for clearance and with drugs for which elevated plasma concentrations are associated with serious adverse events, such as atorvastatin (Lipitor), simvastatin (Zocor), sildenafil (Viagra), midazolam (Versed), and St. John’s wort. Giving potent inducers of CYP3A with boceprevir or telaprevir may lead to lower exposure and loss of efficacy of both protease inhibitors.

EMERGING THERAPIES FOR HCV

Thanks to a better understanding of the biology of HCV infection, the effort to develop new therapeutic agents started to focus on targeting specific steps of the viral life cycle, including attachment, entry into cells, replication, and release.²⁴

Currently, more than 50 clinical trials are evaluating new direct-acting antivirals to treat HCV infection.²⁵ Monoclonal and polyclonal antibodies that target the molecular process involved in HCV attachment and entry are being developed.²⁶ The nonstructural protein NS5B (RNA polymerase) is intimately involved in viral replication and represents a promising target.²⁷ Several nucleosides and nonnucleoside protease inhibitors have already entered clinical trials.

The low fidelity of the HCV replication machinery leads to a very high mutation rate, thus enabling the virus to quickly develop mutations that resist agents targeting viral enzymes.²⁸ Therefore, a novel approach is to target host cofactors that are essential for HCV replication. An intriguing study by Lanford et al²⁹ demonstrated that antagonizing microRNA-122 (the most abundant microRNA in the liver and an essential cofactor for viral RNA replication) by the oligonucleotide SPC3649 caused marked and prolonged reduction of HCV viremia in chronically infected chimpanzees.²⁹

Although we are still in the early stages of drug development, the future holds great promise for newer drugs to improve the sustained virologic response, shorten the duration of treatment, improve tolerability with interferon-sparing regimens, and decrease viral resistance.

FUTURE PERSPECTIVES

With the introduction of the first direct-acting antiviral medications for HCV (boceprevir and telaprevir), 2011 will be marked as the year that changed hepatitis C treatment for the better. Triple therapy with pegylated interferon, ribavirin, and either boceprevir or telaprevir has the potential for increasing the rate of sustained virologic response to around 70% in previously untreated patients and 65% in previously treated patients who are infected with HCV genotype 1. The IL28B polymorphisms appear to play a role in the rate of sustained virologic response achieved with triple therapy, with preliminary data showing a better response rate in patients who have the CC genotype.¹⁷

These drugs will add up to $50,000 to the cost of treating hepatitis C virus infection, depending on the drug used and the length of treatment. However, they may be well worth it if they prevent liver failure and the need for transplantation.

Many questions remain, such as how to use these new regimens to treat special patient populations—for example, those with a recurrence of HCV infection after liver transplantation, those co-infected with HCV and human immunodeficiency virus, and those infected with HCV genotypes other than genotype 1.

Other direct-acting antiviral agents that specifically target the replication cycle of HCV are currently in clinical development. In fact, the future has already started with the release of the Interferon-Free Regimen for the Management of HCV (INFORM-1) study results.³⁰ This was the first trial to evaluate an interferon-free regimen for patients with chronic HCV infection using two direct-acting antiviral drugs (the protease inhibitor danoprevir and the polymerase inhibitor RG7128), with promising results.

Contraceptive counseling is both an art and a science. The role of the health care provider is to determine the patient’s medical eligibility and match her preferences and lifestyle to an appropriate method for both contraceptive and potentially noncontraceptive benefits, while minimizing the risk of unintended pregnancy.

Women throughout the range of reproductive years need appropriate counseling and education on hormones, the menstrual cycle, and the efficacy of contraception as part of their routine gynecologic evaluation. Issues of access to birth control, cost, possible side effects, and actual effectiveness of methods are important to discuss.

In this paper we will discuss common clinical practice case scenarios to illustrate contraceptive counseling and management, including:

• Perimenopausal women
• Women with thrombophilia
• Women who contemplate becoming pregnant in the future
• Women with psychiatric illness
• Women with hypertension.

HALF OF ALL PREGNANCIES ARE UNPLANNED

Although many contraceptive options are available, 48% of all pregnancies in the United States are unintended.¹ In 2009, the national teen birth rate was 39.1 births per 1,000 girls and women age 15 to 19 years, which was 37% lower than in 1991.² Still, African American and Hispanic teenagers living in southern states have disproportionately higher rates.

The rate of unintended pregnancy is a little lower at the older end of the reproductive age range, but still high: 35% of all pregnancies in women over 40 years old are also unintended.²

To find out why these numbers are so high, in 2007 the US Centers for Disease Control and Prevention (CDC) conducted a survey³ that included 8,000 women reporting unintended pregnancy who had not used contraception. Of these, 39% were married. Surprisingly, more than one-third of women said they did not know they could get pregnant when they did.³

WHAT’S NEW IN CONTRACEPTION?

The “pill” was approved by the US Food and Drug Administration (FDA) more than 50 years ago, and it is still the most commonly used contraceptive method (followed by surgical sterilization). Enovid, the pill formulated by Dr. John Rock and Dr. Gregory Pincus in the 1950s, contained 150 μg of mestranol (equivalent to 90 μg of ethinyl estradiol) and 9.85 mg of norethynodrel, a very potent progestin. Our current oral contraceptive pills contain much lower hormone doses and have fewer androgenic side effects.⁴

In May 2010, the CDC and the World Health Organization (WHO) updated their safety guidelines for all hormonal contraceptives and the use of these agents in patients with various medical and family histories. They ranked contraceptive methods from those with no restriction to those with unacceptable risk to their use. This document can be accessed at www.cdc.gov/mmwr/preview/mmwrhtml/rr5904a13.htm.⁵

New developments in oral contraceptives are notably in the 19-nortestosterone derivatives, the family that includes the second-generation progestogens already available such as norgestimate (contained in Ortho-Cyclen) and norethindrone (contained in Loestrin). A newer progestin, dienogest, is available in a preparation that also contains estradiol valerate (Natazia). Drospirenone, which is similar to spironolactone, is contained in Yaz, Yasmin, and newer products that also contain levomefolate calcium (Beyaz, Safyral).

LoLoestrin Fe, which contains active pills containing 10 μg of ethinyl estradiol and 1 mg of norethindrone and placebo pills with 75 mg of ferrous fumarate, was recently approved by the FDA and offers an ultra-low dose of estrogen.

Depot medroxyprogesterone acetate now comes in a 104-mg suspension for subcutaneous injection every 3 months; it is called depo-subQ provera 104. Standard medroxyprogesterone acetate 150 mg for intramuscular injection every 3 months (Depo-Provera) is still available and has gone generic. The newer product offers the advantages of lower dose and less weight-gain. Also, it allows capable and willing patients to self-administer their contraceptives. However, it is more expensive—$ 104 per injection for a patient without insurance at Cleveland Clinic, compared with $46 for Depo-Provera and $10 for the generic intramuscular preparation for a patient with insurance.

A new option for emergency contraception, ulipristal (ella) is a progesterone antagonist-agonist available only by prescription. Taken in a single oral dose of 30 μg, it is effective for up to 120 hours after unprotected intercourse. It joins Plan B (levonorgestrel 1.5 mg in a single dose) and Next Choice (two doses of levonorgestrel 0.75 mg each), which are available over-the-counter for women age 17 years or older, and by prescription for those 16 years and younger, for use up to 72 hours after unprotected intercourse.

CASE 1: CONTRACEPTION IN PERIMENOPAUSE

A 48-year-old attorney who has had two children complains of irregular menstrual cycles and of occasional hot flashes at night that wake her from sleep. She keeps a menstrual calendar; it shows her last menstrual period was 3 months ago. She took oral contraceptives for 15 years before she had her first child. She is using condoms intermittently for contraception. Her body mass index is normal at 24 kg/m², and she does not smoke. How do you counsel her?

A variety of hormonal options

This healthy perimenopausal woman has a variety of hormonal contraception options that would have the added benefit of regulating her menstrual cycle or suppressing it altogether. These include the levonorgestrel intrauterine system (Mirena IUS), various injectable products (such as Depo-Provera or the newer depo-subQ provera 104), contraceptive pills, the Ortho Evra contraceptive patch, and the vaginal contraceptive ring (NuvaRing). Of these, low-dose birth control pills may be the best option, as they would help with cycle control, offer contraception, and better regulate hormonal fluctuations to reduce her hot flashes.

Hormonal contraception can safely be used in women in their 30s and 40s, and often until menopause if the benefit outweighs the risk.

An estradiol valerate-dienogest oral contraceptive with a quadriphasic dosing schedule (Natazia) has been studied in women up to age 50. Although it was approved in 2010 in the United States, this pill has been used in Europe since the 1990s. The 26 active pills contain tapering doses of the active drugs, with the aim of mimicking the natural menstrual cycle, similar to triphasic pills. Estradiol valerate is a bioidentical estrogen, as it is rapidly metabolized to estradiol (E2), which is identical to 17-beta estradiol and estrone (E3) produced by the ovary. A dose of 2 mg of estradiol valerate is equivalent to 10 μg of ethinyl estradiol, which is the estrogen component in most other oral contraceptives. Low-dose pills by definition contain less than 50 μg of ethinyl estradiol. Dienogest, the progesterone component, has a 17-cyanomethyl group that accounts for its strongly progestogenic and weakly antiandrogenic properties.

All oral hormonal contraceptives can increase triglycerides by inducing the CYP450 system in the liver. However, in clinical trials, estradiol valerate-dienogest also caused other changes in lipid metabolism, such as a nonsignificant increase in high-density lipoprotein cholesterol and a slight reduction in low-density lipoprotein cholesterol and lipoprotein(a) compared with ethinyl estradiol-levonorgestrel preparations.⁶

It is important to advise patients that, compared with users of other oral contraceptives, estradiol valerate-dienogest users may experience fewer days of menstrual bleeding and more cycles without withdrawal bleeding. This product can therefore be an effective alternative for women with menorrhagia.

All classes of hormonal contraception carry a similar risk of side effects, such as headache, breast tenderness, nausea, irregular bleeding, and mood changes. Some women have no side effects.

CASE 2: THROMBOPHILIA

A 39-year-old woman with a body mass index of 31 kg/m² (obese) has a history of protein S deficiency with active lower-extremity deep vein thrombosis, for which she is taking warfarin (Coumadin). She experiences menorrhagia and dysmenorrhea due to intramural fibroids and possible adenomyosis seen on transvaginal ultrasonography and confirmed by magnetic resonance imaging. Hysteroscopy reveals no polyps or submucosal fibroids. An endometrial biopsy is negative for malignancy.

She desires contraception. How do you counsel her?

Estrogens are contraindicated—except, perhaps, in select cases

This patient has many reasons for heavy bleeding. She is on warfarin, which effectively inhibits synthesis of vitamin K-dependent coagulation factor. She also has fibroids and adenomyosis. The latter is a difficult condition to control, as the location of the intramuscular glands makes treatments such as ablation, dilation and curettage, and oral agents ineffective.

All estrogen-containing formulations (pills, ring, patch) are contraindicated in women with acute venous thromboembolism (VTE) and known thrombophilia. A newer agent approved for treating menorrhagia (not for contraception), tranexamic acid (Lysteda), also carries a contraindication for patients with thrombophilia or history of VTE; however, the evidence for the latter is controversial.⁷

The updated CDC guidelines for the use of hormonal contraceptives state that patients who receive anticoagulation for at least 3 months and who have no history of VTE or a low risk of recurrent VTE (no evidence of active cancer, no known thrombophilia) may use estrogen-containing contraceptives in select cases (category 3—theoretical risk outweighs benefits, but not an absolute contraindication).⁵ Although this is not common clinical practice, select patients may benefit from menstrual cycle control while receiving anticoagulation. However, other contraceptive alternatives are preferred if possible.

Progestin-only treatments such as the Mirena IUS (if the fibroids do not distort the uterine cavity) and the etonogestrel implant (Implanon) are nonsurgical options that may reduce menorrhagia and are safer alternatives for patients with thrombophilia.

The Paragard (copper) intrauterine device would provide nonhormonal contraception without diminishing menorrhagia. Obviously, barrier methods (which are less effective than hormonal contraception) can be suggested for contraception alone. A viable option for women finished with childbearing is hysterectomy, which provides contraceptive benefit and definitive treatment of menorrhagia due to adenomyosis.

Laboratory screening for VTE is not required before starting estrogen-containing contraceptives. However, one should take a detailed history and inquire about VTE events or a family history of recurrent VTE.

VTE rates among reproductive-age women are 4 to 5 per 10,000 women per year.⁸ The rate of VTE in oral contraceptive users is estimated as 9 to 10 per 10,000 women per year.⁹ However, rates of VTE associated with pregnancy and postpartum states are exponentially greater. Although recent studies have shown some discrepancy in rates of VTE across different classes of progestins,^10,11 the absolute risk of VTE with hormonal contraceptives is very low.

In December 2011, an FDA panel voted 15 to 11 that the benefits of drospirenone-containing contraceptives (eg, Yaz, Yasmin, Beyaz, Safyral), such as preventing pregnancy, outweigh the potential risk. However, product labeling may change in the future to more accurately reflect the risk-benefit ratio. Stay tuned for better-designed trials to further assess VTE risk across progestins.

Health care providers should engage patients in an informed discussion about all risks and benefits of hormonal contraceptives and note this risk of VTE is higher in gravid women.

CASE 3: FUTURE FERTILITY

A 30-year-old surgical resident who has never been pregnant comes for her annual examination. She currently desires birth control but would like to be pregnant 1 to 2 years from now. She has no history of significant medical illness. Her body mass index is 23 kg/m², and she takes no medications. How do you counsel her?

Many options; also consider folic acid

Effective counseling leads to patient-centered decision-making for all treatments and procedures. Contraceptive counseling should elicit the patient’s perspective about hormonal methods and educate her on efficacy, proper use, and common adverse effects.

Contraception should fit the patient’s lifestyle. Questions as simple as “Are you a good pill-taker?” or “Are you comfortable with injections?” will help you and the patient assess what will work effectively and will maintain good adherence.

Deciding on a contraceptive option that is cost-effective is crucial, particularly for many young women or adolescents. Many oral contraceptives are widely available as generic formulations for less than $10 per month. Although generic drugs are not required to be 100% bioequivalent to their brand-name counterparts, they can provide a more economical option. For a complete guide to different hormonal contraceptive formulations, we suggest Choosing a birth control method, available on the Web site of the Association of Reproductive Health Professionals at www.arhp.org/upload-Docs/choosingqrg.pdf.¹²

As discussed earlier, half of all pregnancies are unplanned, and so women of childbearing age should be ingesting 400 μg of folic acid daily. Debate exists as to whether Americans who eat a balanced diet need a multivitamin.¹³ However, there is no debate about folic acid, which is proven to prevent neural tube defects. Newer formulations of ethinyl estradiol-drospirenone (Beyaz, Safyral) now contain an active form of folic acid (levomefolate calcium 451 mg in each pill). For the above patient who needs contraception and is willing to take birth control, the addition of folic acid provides an essential element in preconception counseling.

Regardless of the current contraceptive choice, patients who actively desire pregnancy should take a prenatal vitamin that contains folic acid and iron.

In addition to combined oral contraceptives, other options for this patient include medroxyprogesterone acetate (intramuscular or subcutaneous), NuvaRing, or intrauterine devices. The Ortho Evra patch is also an option for this patient. However, since 2008 the patch has carried an FDA warning that the risk of VTE is twice as high with this product than with oral contraceptives that contain 30 μg of ethinyl estradiol plus levonorgestrel.¹⁴ Postmarketing data did not show any higher risk of VTE in patch users compared with oral contraceptive users less than 40 years of age, however.¹⁵

CASE 4: PSYCHIATRIC ILLNESS

A 21-year-old woman who has bipolar II disorder comes to your office for her annual gynecologic evaluation. She has one sexual partner and desires oral contraceptive pills. Lithium treatment has failed for her, but her condition is stable on carbamazepine (Tegretol). She asks if it is true that women can still get pregnant while on the birth control pill. How do you counsel her?

Possible interactions with psychiatric drugs

Like the woman in case 3, this patient has many options, including estrogen-containing pills, the vaginal ring, the patch, injectable contraceptives, and intrauterine devices.

Certain antiepileptic, antipsychotic, or headache medications such as carbamezapine, phenytoin (Dilantin), oxcarbazepine (Trileptal), and topiramate (Topamax) decrease levels of hormonal contraceptives by induction of the CYP450 enzymes. Conversely, it is suggested that lamotrigine (Lamictal) levels decrease by up to 49% while patients concomitantly take oral contraceptive pills, which can induce seizure activity.¹⁶ Also, antibiotics such as rifampin (Rifadin) and even herbs such as St. John’s Wort can decrease the effectiveness of hormonal contraceptives by increasing their metabolism.

On the positive side, depot medroxyprogesterone acetate raises the seizure threshold by a mechanism attributed to high levels of progestins and is a better option for epileptic patients. A bulletin of the American College of Gynecologists addresses the paucity of data on hormonal treatments in depressed patients. However, some evidence points to slight improvement of depressive symptoms after 1 year in patients who took Depo-Provera compared with those who discontinued the drug.¹⁷

The Pearl index, a measure of contraceptive efficacy

We refer to the Pearl index when answering our patients’ questions about contraceptive efficacy. The Pearl index is defined as the number of unintended pregnancies per 100 women per year. The typical (or actual) effectiveness for each contraceptive method is quoted rather than the theoretical (perfect-use) efficacy.

We suggest simplifying this discussion with patients. For example, for every 100 women using male condoms for contraception, 15 women have unintended pregnancies per year. With hormonal contraceptives (pill, patch, or ring), for every 100 women there are 8 per year with unintended pregnancy, 3 of 100 with Depo-Provera, and less than 1 in 100 using intrauterine devices or female or male sterilization.¹⁸

Efficacy decreases (and the failure rate increases) with frequency of intercourse, irregular menstrual cycles, missed pills, improper dosing, and drug-drug interactions as described above.

CASE 5: HYPERTENSION

A 33-year-old woman who has been pregnant twice experienced preeclampsia in her last pregnancy, and now her blood pressure is consistently approximately 140/90 mm Hg on multiple office visits and ambulatory monitoring. She desires contraception. How do you counsel her?

Avoid estrogen-containing products

According to the WHO and CDC guidelines,⁵ women with controlled or uncontrolled hypertension should not be offered combined oral contraceptives, the patch, or the ring (category 3—theoretical or proven risks outweigh the benefits, and category 4 for systolic blood pressure greater than 160 mm Hg or diastolic blood pressure greater than 100 mm Hg).

The progesterone-only pill (“mini pill”), medroxyprogesterone acetate (intramuscular or subcutaneous), Mirena IUS, the copper intrauterine device, and the etonogestrel implant are all safer options.

A small subset of patients develop elevated blood pressure after starting hormonal contraceptives. Estrogen-containing hormones can increase the liver’s output of angiotensinogen, which is a renin substrate that activates the renin-angiotensin-aldosterone system. If this becomes clinically apparent, these patients should refrain from estrogen-containing products and use progestin-only formulations as a safer alternative.

Patients with isolated elevated hypertriglyceridemia should avoid oral contraceptives. However, the patch, the ring, and progestin-only methods may be acceptable.

Diabetic patients with microvascular complications of retinopathy or nephropathy and any patient with macrovascular disease (stroke, cardiovascular disease) should not be offered estrogen-containing contraception.

Contraceptive counseling is both an art and a science. The role of the health care provider is to determine the patient’s medical eligibility and match her preferences and lifestyle to an appropriate method for both contraceptive and potentially noncontraceptive benefits, while minimizing the risk of unintended pregnancy.

Women throughout the range of reproductive years need appropriate counseling and education on hormones, the menstrual cycle, and the efficacy of contraception as part of their routine gynecologic evaluation. Issues of access to birth control, cost, possible side effects, and actual effectiveness of methods are important to discuss.

In this paper we will discuss common clinical practice case scenarios to illustrate contraceptive counseling and management, including:

• Perimenopausal women
• Women with thrombophilia
• Women who contemplate becoming pregnant in the future
• Women with psychiatric illness
• Women with hypertension.

HALF OF ALL PREGNANCIES ARE UNPLANNED

Although many contraceptive options are available, 48% of all pregnancies in the United States are unintended.¹ In 2009, the national teen birth rate was 39.1 births per 1,000 girls and women age 15 to 19 years, which was 37% lower than in 1991.² Still, African American and Hispanic teenagers living in southern states have disproportionately higher rates.

The rate of unintended pregnancy is a little lower at the older end of the reproductive age range, but still high: 35% of all pregnancies in women over 40 years old are also unintended.²

To find out why these numbers are so high, in 2007 the US Centers for Disease Control and Prevention (CDC) conducted a survey³ that included 8,000 women reporting unintended pregnancy who had not used contraception. Of these, 39% were married. Surprisingly, more than one-third of women said they did not know they could get pregnant when they did.³

WHAT’S NEW IN CONTRACEPTION?

The “pill” was approved by the US Food and Drug Administration (FDA) more than 50 years ago, and it is still the most commonly used contraceptive method (followed by surgical sterilization). Enovid, the pill formulated by Dr. John Rock and Dr. Gregory Pincus in the 1950s, contained 150 μg of mestranol (equivalent to 90 μg of ethinyl estradiol) and 9.85 mg of norethynodrel, a very potent progestin. Our current oral contraceptive pills contain much lower hormone doses and have fewer androgenic side effects.⁴

In May 2010, the CDC and the World Health Organization (WHO) updated their safety guidelines for all hormonal contraceptives and the use of these agents in patients with various medical and family histories. They ranked contraceptive methods from those with no restriction to those with unacceptable risk to their use. This document can be accessed at www.cdc.gov/mmwr/preview/mmwrhtml/rr5904a13.htm.⁵

New developments in oral contraceptives are notably in the 19-nortestosterone derivatives, the family that includes the second-generation progestogens already available such as norgestimate (contained in Ortho-Cyclen) and norethindrone (contained in Loestrin). A newer progestin, dienogest, is available in a preparation that also contains estradiol valerate (Natazia). Drospirenone, which is similar to spironolactone, is contained in Yaz, Yasmin, and newer products that also contain levomefolate calcium (Beyaz, Safyral).

LoLoestrin Fe, which contains active pills containing 10 μg of ethinyl estradiol and 1 mg of norethindrone and placebo pills with 75 mg of ferrous fumarate, was recently approved by the FDA and offers an ultra-low dose of estrogen.

Depot medroxyprogesterone acetate now comes in a 104-mg suspension for subcutaneous injection every 3 months; it is called depo-subQ provera 104. Standard medroxyprogesterone acetate 150 mg for intramuscular injection every 3 months (Depo-Provera) is still available and has gone generic. The newer product offers the advantages of lower dose and less weight-gain. Also, it allows capable and willing patients to self-administer their contraceptives. However, it is more expensive—$ 104 per injection for a patient without insurance at Cleveland Clinic, compared with $46 for Depo-Provera and $10 for the generic intramuscular preparation for a patient with insurance.

A new option for emergency contraception, ulipristal (ella) is a progesterone antagonist-agonist available only by prescription. Taken in a single oral dose of 30 μg, it is effective for up to 120 hours after unprotected intercourse. It joins Plan B (levonorgestrel 1.5 mg in a single dose) and Next Choice (two doses of levonorgestrel 0.75 mg each), which are available over-the-counter for women age 17 years or older, and by prescription for those 16 years and younger, for use up to 72 hours after unprotected intercourse.

CASE 1: CONTRACEPTION IN PERIMENOPAUSE

A 48-year-old attorney who has had two children complains of irregular menstrual cycles and of occasional hot flashes at night that wake her from sleep. She keeps a menstrual calendar; it shows her last menstrual period was 3 months ago. She took oral contraceptives for 15 years before she had her first child. She is using condoms intermittently for contraception. Her body mass index is normal at 24 kg/m², and she does not smoke. How do you counsel her?

A variety of hormonal options

This healthy perimenopausal woman has a variety of hormonal contraception options that would have the added benefit of regulating her menstrual cycle or suppressing it altogether. These include the levonorgestrel intrauterine system (Mirena IUS), various injectable products (such as Depo-Provera or the newer depo-subQ provera 104), contraceptive pills, the Ortho Evra contraceptive patch, and the vaginal contraceptive ring (NuvaRing). Of these, low-dose birth control pills may be the best option, as they would help with cycle control, offer contraception, and better regulate hormonal fluctuations to reduce her hot flashes.

Hormonal contraception can safely be used in women in their 30s and 40s, and often until menopause if the benefit outweighs the risk.

An estradiol valerate-dienogest oral contraceptive with a quadriphasic dosing schedule (Natazia) has been studied in women up to age 50. Although it was approved in 2010 in the United States, this pill has been used in Europe since the 1990s. The 26 active pills contain tapering doses of the active drugs, with the aim of mimicking the natural menstrual cycle, similar to triphasic pills. Estradiol valerate is a bioidentical estrogen, as it is rapidly metabolized to estradiol (E2), which is identical to 17-beta estradiol and estrone (E3) produced by the ovary. A dose of 2 mg of estradiol valerate is equivalent to 10 μg of ethinyl estradiol, which is the estrogen component in most other oral contraceptives. Low-dose pills by definition contain less than 50 μg of ethinyl estradiol. Dienogest, the progesterone component, has a 17-cyanomethyl group that accounts for its strongly progestogenic and weakly antiandrogenic properties.

All oral hormonal contraceptives can increase triglycerides by inducing the CYP450 system in the liver. However, in clinical trials, estradiol valerate-dienogest also caused other changes in lipid metabolism, such as a nonsignificant increase in high-density lipoprotein cholesterol and a slight reduction in low-density lipoprotein cholesterol and lipoprotein(a) compared with ethinyl estradiol-levonorgestrel preparations.⁶

It is important to advise patients that, compared with users of other oral contraceptives, estradiol valerate-dienogest users may experience fewer days of menstrual bleeding and more cycles without withdrawal bleeding. This product can therefore be an effective alternative for women with menorrhagia.

All classes of hormonal contraception carry a similar risk of side effects, such as headache, breast tenderness, nausea, irregular bleeding, and mood changes. Some women have no side effects.

CASE 2: THROMBOPHILIA

A 39-year-old woman with a body mass index of 31 kg/m² (obese) has a history of protein S deficiency with active lower-extremity deep vein thrombosis, for which she is taking warfarin (Coumadin). She experiences menorrhagia and dysmenorrhea due to intramural fibroids and possible adenomyosis seen on transvaginal ultrasonography and confirmed by magnetic resonance imaging. Hysteroscopy reveals no polyps or submucosal fibroids. An endometrial biopsy is negative for malignancy.

She desires contraception. How do you counsel her?

Estrogens are contraindicated—except, perhaps, in select cases

This patient has many reasons for heavy bleeding. She is on warfarin, which effectively inhibits synthesis of vitamin K-dependent coagulation factor. She also has fibroids and adenomyosis. The latter is a difficult condition to control, as the location of the intramuscular glands makes treatments such as ablation, dilation and curettage, and oral agents ineffective.

All estrogen-containing formulations (pills, ring, patch) are contraindicated in women with acute venous thromboembolism (VTE) and known thrombophilia. A newer agent approved for treating menorrhagia (not for contraception), tranexamic acid (Lysteda), also carries a contraindication for patients with thrombophilia or history of VTE; however, the evidence for the latter is controversial.⁷

The updated CDC guidelines for the use of hormonal contraceptives state that patients who receive anticoagulation for at least 3 months and who have no history of VTE or a low risk of recurrent VTE (no evidence of active cancer, no known thrombophilia) may use estrogen-containing contraceptives in select cases (category 3—theoretical risk outweighs benefits, but not an absolute contraindication).⁵ Although this is not common clinical practice, select patients may benefit from menstrual cycle control while receiving anticoagulation. However, other contraceptive alternatives are preferred if possible.

Progestin-only treatments such as the Mirena IUS (if the fibroids do not distort the uterine cavity) and the etonogestrel implant (Implanon) are nonsurgical options that may reduce menorrhagia and are safer alternatives for patients with thrombophilia.

The Paragard (copper) intrauterine device would provide nonhormonal contraception without diminishing menorrhagia. Obviously, barrier methods (which are less effective than hormonal contraception) can be suggested for contraception alone. A viable option for women finished with childbearing is hysterectomy, which provides contraceptive benefit and definitive treatment of menorrhagia due to adenomyosis.

Laboratory screening for VTE is not required before starting estrogen-containing contraceptives. However, one should take a detailed history and inquire about VTE events or a family history of recurrent VTE.

VTE rates among reproductive-age women are 4 to 5 per 10,000 women per year.⁸ The rate of VTE in oral contraceptive users is estimated as 9 to 10 per 10,000 women per year.⁹ However, rates of VTE associated with pregnancy and postpartum states are exponentially greater. Although recent studies have shown some discrepancy in rates of VTE across different classes of progestins,^10,11 the absolute risk of VTE with hormonal contraceptives is very low.

In December 2011, an FDA panel voted 15 to 11 that the benefits of drospirenone-containing contraceptives (eg, Yaz, Yasmin, Beyaz, Safyral), such as preventing pregnancy, outweigh the potential risk. However, product labeling may change in the future to more accurately reflect the risk-benefit ratio. Stay tuned for better-designed trials to further assess VTE risk across progestins.

Health care providers should engage patients in an informed discussion about all risks and benefits of hormonal contraceptives and note this risk of VTE is higher in gravid women.

CASE 3: FUTURE FERTILITY

A 30-year-old surgical resident who has never been pregnant comes for her annual examination. She currently desires birth control but would like to be pregnant 1 to 2 years from now. She has no history of significant medical illness. Her body mass index is 23 kg/m², and she takes no medications. How do you counsel her?

Many options; also consider folic acid

Effective counseling leads to patient-centered decision-making for all treatments and procedures. Contraceptive counseling should elicit the patient’s perspective about hormonal methods and educate her on efficacy, proper use, and common adverse effects.

Contraception should fit the patient’s lifestyle. Questions as simple as “Are you a good pill-taker?” or “Are you comfortable with injections?” will help you and the patient assess what will work effectively and will maintain good adherence.

Deciding on a contraceptive option that is cost-effective is crucial, particularly for many young women or adolescents. Many oral contraceptives are widely available as generic formulations for less than $10 per month. Although generic drugs are not required to be 100% bioequivalent to their brand-name counterparts, they can provide a more economical option. For a complete guide to different hormonal contraceptive formulations, we suggest Choosing a birth control method, available on the Web site of the Association of Reproductive Health Professionals at www.arhp.org/upload-Docs/choosingqrg.pdf.¹²

As discussed earlier, half of all pregnancies are unplanned, and so women of childbearing age should be ingesting 400 μg of folic acid daily. Debate exists as to whether Americans who eat a balanced diet need a multivitamin.¹³ However, there is no debate about folic acid, which is proven to prevent neural tube defects. Newer formulations of ethinyl estradiol-drospirenone (Beyaz, Safyral) now contain an active form of folic acid (levomefolate calcium 451 mg in each pill). For the above patient who needs contraception and is willing to take birth control, the addition of folic acid provides an essential element in preconception counseling.

Regardless of the current contraceptive choice, patients who actively desire pregnancy should take a prenatal vitamin that contains folic acid and iron.

In addition to combined oral contraceptives, other options for this patient include medroxyprogesterone acetate (intramuscular or subcutaneous), NuvaRing, or intrauterine devices. The Ortho Evra patch is also an option for this patient. However, since 2008 the patch has carried an FDA warning that the risk of VTE is twice as high with this product than with oral contraceptives that contain 30 μg of ethinyl estradiol plus levonorgestrel.¹⁴ Postmarketing data did not show any higher risk of VTE in patch users compared with oral contraceptive users less than 40 years of age, however.¹⁵

CASE 4: PSYCHIATRIC ILLNESS

A 21-year-old woman who has bipolar II disorder comes to your office for her annual gynecologic evaluation. She has one sexual partner and desires oral contraceptive pills. Lithium treatment has failed for her, but her condition is stable on carbamazepine (Tegretol). She asks if it is true that women can still get pregnant while on the birth control pill. How do you counsel her?

Possible interactions with psychiatric drugs

Like the woman in case 3, this patient has many options, including estrogen-containing pills, the vaginal ring, the patch, injectable contraceptives, and intrauterine devices.

Certain antiepileptic, antipsychotic, or headache medications such as carbamezapine, phenytoin (Dilantin), oxcarbazepine (Trileptal), and topiramate (Topamax) decrease levels of hormonal contraceptives by induction of the CYP450 enzymes. Conversely, it is suggested that lamotrigine (Lamictal) levels decrease by up to 49% while patients concomitantly take oral contraceptive pills, which can induce seizure activity.¹⁶ Also, antibiotics such as rifampin (Rifadin) and even herbs such as St. John’s Wort can decrease the effectiveness of hormonal contraceptives by increasing their metabolism.

On the positive side, depot medroxyprogesterone acetate raises the seizure threshold by a mechanism attributed to high levels of progestins and is a better option for epileptic patients. A bulletin of the American College of Gynecologists addresses the paucity of data on hormonal treatments in depressed patients. However, some evidence points to slight improvement of depressive symptoms after 1 year in patients who took Depo-Provera compared with those who discontinued the drug.¹⁷

The Pearl index, a measure of contraceptive efficacy

We refer to the Pearl index when answering our patients’ questions about contraceptive efficacy. The Pearl index is defined as the number of unintended pregnancies per 100 women per year. The typical (or actual) effectiveness for each contraceptive method is quoted rather than the theoretical (perfect-use) efficacy.

We suggest simplifying this discussion with patients. For example, for every 100 women using male condoms for contraception, 15 women have unintended pregnancies per year. With hormonal contraceptives (pill, patch, or ring), for every 100 women there are 8 per year with unintended pregnancy, 3 of 100 with Depo-Provera, and less than 1 in 100 using intrauterine devices or female or male sterilization.¹⁸

Efficacy decreases (and the failure rate increases) with frequency of intercourse, irregular menstrual cycles, missed pills, improper dosing, and drug-drug interactions as described above.

CASE 5: HYPERTENSION

A 33-year-old woman who has been pregnant twice experienced preeclampsia in her last pregnancy, and now her blood pressure is consistently approximately 140/90 mm Hg on multiple office visits and ambulatory monitoring. She desires contraception. How do you counsel her?

Avoid estrogen-containing products

According to the WHO and CDC guidelines,⁵ women with controlled or uncontrolled hypertension should not be offered combined oral contraceptives, the patch, or the ring (category 3—theoretical or proven risks outweigh the benefits, and category 4 for systolic blood pressure greater than 160 mm Hg or diastolic blood pressure greater than 100 mm Hg).

The progesterone-only pill (“mini pill”), medroxyprogesterone acetate (intramuscular or subcutaneous), Mirena IUS, the copper intrauterine device, and the etonogestrel implant are all safer options.

A small subset of patients develop elevated blood pressure after starting hormonal contraceptives. Estrogen-containing hormones can increase the liver’s output of angiotensinogen, which is a renin substrate that activates the renin-angiotensin-aldosterone system. If this becomes clinically apparent, these patients should refrain from estrogen-containing products and use progestin-only formulations as a safer alternative.

Patients with isolated elevated hypertriglyceridemia should avoid oral contraceptives. However, the patch, the ring, and progestin-only methods may be acceptable.

Diabetic patients with microvascular complications of retinopathy or nephropathy and any patient with macrovascular disease (stroke, cardiovascular disease) should not be offered estrogen-containing contraception.

Contraceptive counseling is both an art and a science. The role of the health care provider is to determine the patient’s medical eligibility and match her preferences and lifestyle to an appropriate method for both contraceptive and potentially noncontraceptive benefits, while minimizing the risk of unintended pregnancy.

Women throughout the range of reproductive years need appropriate counseling and education on hormones, the menstrual cycle, and the efficacy of contraception as part of their routine gynecologic evaluation. Issues of access to birth control, cost, possible side effects, and actual effectiveness of methods are important to discuss.

In this paper we will discuss common clinical practice case scenarios to illustrate contraceptive counseling and management, including:

• Perimenopausal women
• Women with thrombophilia
• Women who contemplate becoming pregnant in the future
• Women with psychiatric illness
• Women with hypertension.

HALF OF ALL PREGNANCIES ARE UNPLANNED

Although many contraceptive options are available, 48% of all pregnancies in the United States are unintended.¹ In 2009, the national teen birth rate was 39.1 births per 1,000 girls and women age 15 to 19 years, which was 37% lower than in 1991.² Still, African American and Hispanic teenagers living in southern states have disproportionately higher rates.

The rate of unintended pregnancy is a little lower at the older end of the reproductive age range, but still high: 35% of all pregnancies in women over 40 years old are also unintended.²

To find out why these numbers are so high, in 2007 the US Centers for Disease Control and Prevention (CDC) conducted a survey³ that included 8,000 women reporting unintended pregnancy who had not used contraception. Of these, 39% were married. Surprisingly, more than one-third of women said they did not know they could get pregnant when they did.³

WHAT’S NEW IN CONTRACEPTION?

The “pill” was approved by the US Food and Drug Administration (FDA) more than 50 years ago, and it is still the most commonly used contraceptive method (followed by surgical sterilization). Enovid, the pill formulated by Dr. John Rock and Dr. Gregory Pincus in the 1950s, contained 150 μg of mestranol (equivalent to 90 μg of ethinyl estradiol) and 9.85 mg of norethynodrel, a very potent progestin. Our current oral contraceptive pills contain much lower hormone doses and have fewer androgenic side effects.⁴

In May 2010, the CDC and the World Health Organization (WHO) updated their safety guidelines for all hormonal contraceptives and the use of these agents in patients with various medical and family histories. They ranked contraceptive methods from those with no restriction to those with unacceptable risk to their use. This document can be accessed at www.cdc.gov/mmwr/preview/mmwrhtml/rr5904a13.htm.⁵

New developments in oral contraceptives are notably in the 19-nortestosterone derivatives, the family that includes the second-generation progestogens already available such as norgestimate (contained in Ortho-Cyclen) and norethindrone (contained in Loestrin). A newer progestin, dienogest, is available in a preparation that also contains estradiol valerate (Natazia). Drospirenone, which is similar to spironolactone, is contained in Yaz, Yasmin, and newer products that also contain levomefolate calcium (Beyaz, Safyral).

LoLoestrin Fe, which contains active pills containing 10 μg of ethinyl estradiol and 1 mg of norethindrone and placebo pills with 75 mg of ferrous fumarate, was recently approved by the FDA and offers an ultra-low dose of estrogen.

Depot medroxyprogesterone acetate now comes in a 104-mg suspension for subcutaneous injection every 3 months; it is called depo-subQ provera 104. Standard medroxyprogesterone acetate 150 mg for intramuscular injection every 3 months (Depo-Provera) is still available and has gone generic. The newer product offers the advantages of lower dose and less weight-gain. Also, it allows capable and willing patients to self-administer their contraceptives. However, it is more expensive—$ 104 per injection for a patient without insurance at Cleveland Clinic, compared with $46 for Depo-Provera and $10 for the generic intramuscular preparation for a patient with insurance.

A new option for emergency contraception, ulipristal (ella) is a progesterone antagonist-agonist available only by prescription. Taken in a single oral dose of 30 μg, it is effective for up to 120 hours after unprotected intercourse. It joins Plan B (levonorgestrel 1.5 mg in a single dose) and Next Choice (two doses of levonorgestrel 0.75 mg each), which are available over-the-counter for women age 17 years or older, and by prescription for those 16 years and younger, for use up to 72 hours after unprotected intercourse.

CASE 1: CONTRACEPTION IN PERIMENOPAUSE

A 48-year-old attorney who has had two children complains of irregular menstrual cycles and of occasional hot flashes at night that wake her from sleep. She keeps a menstrual calendar; it shows her last menstrual period was 3 months ago. She took oral contraceptives for 15 years before she had her first child. She is using condoms intermittently for contraception. Her body mass index is normal at 24 kg/m², and she does not smoke. How do you counsel her?

A variety of hormonal options

This healthy perimenopausal woman has a variety of hormonal contraception options that would have the added benefit of regulating her menstrual cycle or suppressing it altogether. These include the levonorgestrel intrauterine system (Mirena IUS), various injectable products (such as Depo-Provera or the newer depo-subQ provera 104), contraceptive pills, the Ortho Evra contraceptive patch, and the vaginal contraceptive ring (NuvaRing). Of these, low-dose birth control pills may be the best option, as they would help with cycle control, offer contraception, and better regulate hormonal fluctuations to reduce her hot flashes.

Hormonal contraception can safely be used in women in their 30s and 40s, and often until menopause if the benefit outweighs the risk.

An estradiol valerate-dienogest oral contraceptive with a quadriphasic dosing schedule (Natazia) has been studied in women up to age 50. Although it was approved in 2010 in the United States, this pill has been used in Europe since the 1990s. The 26 active pills contain tapering doses of the active drugs, with the aim of mimicking the natural menstrual cycle, similar to triphasic pills. Estradiol valerate is a bioidentical estrogen, as it is rapidly metabolized to estradiol (E2), which is identical to 17-beta estradiol and estrone (E3) produced by the ovary. A dose of 2 mg of estradiol valerate is equivalent to 10 μg of ethinyl estradiol, which is the estrogen component in most other oral contraceptives. Low-dose pills by definition contain less than 50 μg of ethinyl estradiol. Dienogest, the progesterone component, has a 17-cyanomethyl group that accounts for its strongly progestogenic and weakly antiandrogenic properties.

All oral hormonal contraceptives can increase triglycerides by inducing the CYP450 system in the liver. However, in clinical trials, estradiol valerate-dienogest also caused other changes in lipid metabolism, such as a nonsignificant increase in high-density lipoprotein cholesterol and a slight reduction in low-density lipoprotein cholesterol and lipoprotein(a) compared with ethinyl estradiol-levonorgestrel preparations.⁶

It is important to advise patients that, compared with users of other oral contraceptives, estradiol valerate-dienogest users may experience fewer days of menstrual bleeding and more cycles without withdrawal bleeding. This product can therefore be an effective alternative for women with menorrhagia.

All classes of hormonal contraception carry a similar risk of side effects, such as headache, breast tenderness, nausea, irregular bleeding, and mood changes. Some women have no side effects.

CASE 2: THROMBOPHILIA

A 39-year-old woman with a body mass index of 31 kg/m² (obese) has a history of protein S deficiency with active lower-extremity deep vein thrombosis, for which she is taking warfarin (Coumadin). She experiences menorrhagia and dysmenorrhea due to intramural fibroids and possible adenomyosis seen on transvaginal ultrasonography and confirmed by magnetic resonance imaging. Hysteroscopy reveals no polyps or submucosal fibroids. An endometrial biopsy is negative for malignancy.

She desires contraception. How do you counsel her?

Estrogens are contraindicated—except, perhaps, in select cases

This patient has many reasons for heavy bleeding. She is on warfarin, which effectively inhibits synthesis of vitamin K-dependent coagulation factor. She also has fibroids and adenomyosis. The latter is a difficult condition to control, as the location of the intramuscular glands makes treatments such as ablation, dilation and curettage, and oral agents ineffective.

All estrogen-containing formulations (pills, ring, patch) are contraindicated in women with acute venous thromboembolism (VTE) and known thrombophilia. A newer agent approved for treating menorrhagia (not for contraception), tranexamic acid (Lysteda), also carries a contraindication for patients with thrombophilia or history of VTE; however, the evidence for the latter is controversial.⁷

The updated CDC guidelines for the use of hormonal contraceptives state that patients who receive anticoagulation for at least 3 months and who have no history of VTE or a low risk of recurrent VTE (no evidence of active cancer, no known thrombophilia) may use estrogen-containing contraceptives in select cases (category 3—theoretical risk outweighs benefits, but not an absolute contraindication).⁵ Although this is not common clinical practice, select patients may benefit from menstrual cycle control while receiving anticoagulation. However, other contraceptive alternatives are preferred if possible.

Progestin-only treatments such as the Mirena IUS (if the fibroids do not distort the uterine cavity) and the etonogestrel implant (Implanon) are nonsurgical options that may reduce menorrhagia and are safer alternatives for patients with thrombophilia.

The Paragard (copper) intrauterine device would provide nonhormonal contraception without diminishing menorrhagia. Obviously, barrier methods (which are less effective than hormonal contraception) can be suggested for contraception alone. A viable option for women finished with childbearing is hysterectomy, which provides contraceptive benefit and definitive treatment of menorrhagia due to adenomyosis.

Laboratory screening for VTE is not required before starting estrogen-containing contraceptives. However, one should take a detailed history and inquire about VTE events or a family history of recurrent VTE.

VTE rates among reproductive-age women are 4 to 5 per 10,000 women per year.⁸ The rate of VTE in oral contraceptive users is estimated as 9 to 10 per 10,000 women per year.⁹ However, rates of VTE associated with pregnancy and postpartum states are exponentially greater. Although recent studies have shown some discrepancy in rates of VTE across different classes of progestins,^10,11 the absolute risk of VTE with hormonal contraceptives is very low.

In December 2011, an FDA panel voted 15 to 11 that the benefits of drospirenone-containing contraceptives (eg, Yaz, Yasmin, Beyaz, Safyral), such as preventing pregnancy, outweigh the potential risk. However, product labeling may change in the future to more accurately reflect the risk-benefit ratio. Stay tuned for better-designed trials to further assess VTE risk across progestins.

Health care providers should engage patients in an informed discussion about all risks and benefits of hormonal contraceptives and note this risk of VTE is higher in gravid women.

CASE 3: FUTURE FERTILITY

A 30-year-old surgical resident who has never been pregnant comes for her annual examination. She currently desires birth control but would like to be pregnant 1 to 2 years from now. She has no history of significant medical illness. Her body mass index is 23 kg/m², and she takes no medications. How do you counsel her?

Many options; also consider folic acid

Effective counseling leads to patient-centered decision-making for all treatments and procedures. Contraceptive counseling should elicit the patient’s perspective about hormonal methods and educate her on efficacy, proper use, and common adverse effects.

Contraception should fit the patient’s lifestyle. Questions as simple as “Are you a good pill-taker?” or “Are you comfortable with injections?” will help you and the patient assess what will work effectively and will maintain good adherence.

Deciding on a contraceptive option that is cost-effective is crucial, particularly for many young women or adolescents. Many oral contraceptives are widely available as generic formulations for less than $10 per month. Although generic drugs are not required to be 100% bioequivalent to their brand-name counterparts, they can provide a more economical option. For a complete guide to different hormonal contraceptive formulations, we suggest Choosing a birth control method, available on the Web site of the Association of Reproductive Health Professionals at www.arhp.org/upload-Docs/choosingqrg.pdf.¹²

As discussed earlier, half of all pregnancies are unplanned, and so women of childbearing age should be ingesting 400 μg of folic acid daily. Debate exists as to whether Americans who eat a balanced diet need a multivitamin.¹³ However, there is no debate about folic acid, which is proven to prevent neural tube defects. Newer formulations of ethinyl estradiol-drospirenone (Beyaz, Safyral) now contain an active form of folic acid (levomefolate calcium 451 mg in each pill). For the above patient who needs contraception and is willing to take birth control, the addition of folic acid provides an essential element in preconception counseling.

Regardless of the current contraceptive choice, patients who actively desire pregnancy should take a prenatal vitamin that contains folic acid and iron.

In addition to combined oral contraceptives, other options for this patient include medroxyprogesterone acetate (intramuscular or subcutaneous), NuvaRing, or intrauterine devices. The Ortho Evra patch is also an option for this patient. However, since 2008 the patch has carried an FDA warning that the risk of VTE is twice as high with this product than with oral contraceptives that contain 30 μg of ethinyl estradiol plus levonorgestrel.¹⁴ Postmarketing data did not show any higher risk of VTE in patch users compared with oral contraceptive users less than 40 years of age, however.¹⁵

CASE 4: PSYCHIATRIC ILLNESS

A 21-year-old woman who has bipolar II disorder comes to your office for her annual gynecologic evaluation. She has one sexual partner and desires oral contraceptive pills. Lithium treatment has failed for her, but her condition is stable on carbamazepine (Tegretol). She asks if it is true that women can still get pregnant while on the birth control pill. How do you counsel her?

Possible interactions with psychiatric drugs

Like the woman in case 3, this patient has many options, including estrogen-containing pills, the vaginal ring, the patch, injectable contraceptives, and intrauterine devices.

Certain antiepileptic, antipsychotic, or headache medications such as carbamezapine, phenytoin (Dilantin), oxcarbazepine (Trileptal), and topiramate (Topamax) decrease levels of hormonal contraceptives by induction of the CYP450 enzymes. Conversely, it is suggested that lamotrigine (Lamictal) levels decrease by up to 49% while patients concomitantly take oral contraceptive pills, which can induce seizure activity.¹⁶ Also, antibiotics such as rifampin (Rifadin) and even herbs such as St. John’s Wort can decrease the effectiveness of hormonal contraceptives by increasing their metabolism.

On the positive side, depot medroxyprogesterone acetate raises the seizure threshold by a mechanism attributed to high levels of progestins and is a better option for epileptic patients. A bulletin of the American College of Gynecologists addresses the paucity of data on hormonal treatments in depressed patients. However, some evidence points to slight improvement of depressive symptoms after 1 year in patients who took Depo-Provera compared with those who discontinued the drug.¹⁷

The Pearl index, a measure of contraceptive efficacy

We refer to the Pearl index when answering our patients’ questions about contraceptive efficacy. The Pearl index is defined as the number of unintended pregnancies per 100 women per year. The typical (or actual) effectiveness for each contraceptive method is quoted rather than the theoretical (perfect-use) efficacy.

We suggest simplifying this discussion with patients. For example, for every 100 women using male condoms for contraception, 15 women have unintended pregnancies per year. With hormonal contraceptives (pill, patch, or ring), for every 100 women there are 8 per year with unintended pregnancy, 3 of 100 with Depo-Provera, and less than 1 in 100 using intrauterine devices or female or male sterilization.¹⁸

Efficacy decreases (and the failure rate increases) with frequency of intercourse, irregular menstrual cycles, missed pills, improper dosing, and drug-drug interactions as described above.

CASE 5: HYPERTENSION

A 33-year-old woman who has been pregnant twice experienced preeclampsia in her last pregnancy, and now her blood pressure is consistently approximately 140/90 mm Hg on multiple office visits and ambulatory monitoring. She desires contraception. How do you counsel her?

Avoid estrogen-containing products

According to the WHO and CDC guidelines,⁵ women with controlled or uncontrolled hypertension should not be offered combined oral contraceptives, the patch, or the ring (category 3—theoretical or proven risks outweigh the benefits, and category 4 for systolic blood pressure greater than 160 mm Hg or diastolic blood pressure greater than 100 mm Hg).

The progesterone-only pill (“mini pill”), medroxyprogesterone acetate (intramuscular or subcutaneous), Mirena IUS, the copper intrauterine device, and the etonogestrel implant are all safer options.

A small subset of patients develop elevated blood pressure after starting hormonal contraceptives. Estrogen-containing hormones can increase the liver’s output of angiotensinogen, which is a renin substrate that activates the renin-angiotensin-aldosterone system. If this becomes clinically apparent, these patients should refrain from estrogen-containing products and use progestin-only formulations as a safer alternative.

Patients with isolated elevated hypertriglyceridemia should avoid oral contraceptives. However, the patch, the ring, and progestin-only methods may be acceptable.

Diabetic patients with microvascular complications of retinopathy or nephropathy and any patient with macrovascular disease (stroke, cardiovascular disease) should not be offered estrogen-containing contraception.

A 37-year-old man presented to the emergency department with an 8-week history of a mildly productive cough and shortness of breath accompanied by high fevers, chills, and night sweats. He also had some nausea but no vomiting.

Four days earlier, he had been evaluated by his primary care physician, who prescribed a 14-day course of one double-strength trimethoprim-sulfamethoxazole tablet (Bactrim DS) every 12 hours for presumed acute bronchitis, but his symptoms did not improve.

He was unemployed, living in Arizona, married with children. He denied any use of tobacco, alcohol, or injection drugs. On further questioning, he disclosed that he had unintentionally lost 30 pounds over the past 2 to 3 months and had been feeling tired.

When asked about his medical history, he revealed that he had been diagnosed with human immunodeficiency virus (HIV) infection in 2008 and that recently he had not been taking his antiretroviral medication, a once-daily combination pill containing efavirenz, emtricitabine, and tenofovir (Atripla). He had no other significant medical history, and the only medication he was currently taking was the trimethoprim-sulfamethoxazole.

On examination, his temperature was 38.7°C (101.7°F), blood pressure 109/68 mm Hg, heart rate 60 beats per minute, respiratory rate 18 breaths per minute, and oxygen saturation 100% while breathing supplemental oxygen via nasal cannula at 2 L/min. He did not appear seriously ill.

Initial blood tests (Table 1) showed a normal white blood cell count, normal results on a complete metabolic panel, and a lactate dehydrogenase level of 539 IU/L (reference range 313–618). His serum lactate level was within normal limits.

HIV-specific tests performed on the second day of hospitalization showed extreme immunosuppression, with a CD4 count of 5 cells/μL (normal 326–1,404 cells/μL).

WHICH ORGANISM IS CAUSING HIS LUNG INFECTION?

1. Which of the following organisms is the least likely to be associated with this patient’s condition?

• Mycobacterium tuberculosis
• Pneumocystis jirovecii
• Coccidioides immitis
• Candida albicans
• Streptococcus pneumoniae
• Cytomegalovirus

Bacterial, fungal, and viral lung infections are common in HIV-infected patients, especially if they are not on antiretroviral therapy and their CD4 lymphocyte counts are low. Clues to the cause can be derived from the history, physical examination, and general laboratory studies. For instance, knowing where the patient lives and where he has travelled recently provides insight into exposure to endemic infectious agents.

The complete blood cell count with differential white blood cell count can help narrow the differential diagnosis but rarely helps exclude a possibility. Neutrophilia is common in bacterial infections. Lymphocytosis can be seen in tuberculosis, in fungal and viral infections, and, rarely, in hematologic malignancies. Eosinophilia can be seen in acute retroviral syndrome, fungal and helminthic infections, adrenal insufficiency, autoimmune disease, and lymphoma.

A caveat to these clues is that in severely immunocompromised hosts, like this man, diagnoses should not be excluded without firm evidence. This patient has severe, active immunosuppression, and only one of the six answer choices above is not a possible causative agent: C albicans rarely causes lung infection, even in immunocompromised people.

Mycobacterium tuberculosis

Tuberculosis can be the first manifestation of HIV infection. It can occur at any CD4 count, but as the count decreases, the risk of dissemination increases.¹ Classic symptoms are fever, night sweats, hemoptysis, and weight loss.

The CD4 count also affects the radiographic presentation. If the count is higher than 350 cells/μL, then infiltration of the upper lobe is likely; if it is lower than 200 cells/μL, then middle, lower, miliary, and extrapulmonary manifestations are likely.^1,2 Cavitation is less common in HIV-infected patients, but mediastinal adenopathy is more common.¹

Definitive diagnosis is via sputum examination, blood culture, nucleic acid amplification, or microscopic study of biopsy specimens of affected tissues to look for acid-fast bacilli.¹

Interferon-gamma-release assays such as the QuantiFERON test (Cellestis, Valencia, CA) or a tuberculin skin test can be used to check for latent tuberculosis infection. These tests can also provide evidence of active infection in the appropriate clinical context.³

Interferon-gamma-release assays have several advantages over skin testing: they are more sensitive (76% to 80%) and specific (97%); they do not give false-positive results in people who previously received bacille Calmette-Guérin vaccine; they react only minimally to previous exposure to nontuberculous mycobacteria; and interpretation is not subject to interreader variability.^4,5 However, concordance between skin testing and interferon-gamma-release assays is low. Therefore, either or both tests can be used if tuberculosis is strongly suspected, and a positive result on either test should prompt further workup.^6,7

Of note, both tests may be affected by immunosuppression, making both susceptible to false-negative results as the CD4 count declines.³

In any case, a positive acid-fast bacillus smear, radiographic evidence of latent infection, or pulmonary symptoms should be presumed to represent active tuberculosis. In such a situation, directly observed treatment with the typical four-drug regimen—rifampin (Rifadin), isoniazid, pyrazinamide, and ethambutol (Myambutol)—is recommended while awaiting definitive results from culture or polymerase chain reaction (PCR) testing.¹

P jirovecii was previously known as P carinii, and P jirovecii pneumonia is an AIDS-defining illness. Most cases occur when the CD4 count falls below 200 cells/μL.¹ Symptoms, including a nonproductive cough, develop insidiously over days to weeks.

Physical examination may reveal inspiratory crackles; however, half of the time the physical examination is nondiagnostic. Oral candidiasis is a common coinfection. The lactate dehydrogenase level may be elevated.^1,8 Radiographs show bilateral interstitial infiltrates, and in 10% to 20% of patients lung cysts develop—hence the name of the organism.¹ Pneumothorax in a patient with HIV should prompt a workup for P jirovecii pneumonia.^9,10

No consensus exists for the diagnosis. However, if sputum examination is unrevealing but suspicion is high, then bronchoalveolar lavage can help.^11–13

Trimethoprim-sulfamethoxazole for 21 days is the first-line treatment, with glucocorticoids added if the Pao₂ is less than 70 mm Hg or if the alveolar-arterial oxygen gradient is greater than 35 mm Hg.¹

Coccidioides species

Coccidioides infection is typically due to either C immitis or C posadasii.¹⁴ People living in or travelling to areas where it is endemic, such as the southwestern United States, Mexico, and Central and South America, are at higher risk.¹⁴

Typical signs and symptoms of this fungal infection include an influenza-like illness with fever, cough, adenopathy, and wasting, and when combined with erythema nodosum, erythema multiforme, arthralgia, or ocular involvement, this constellation is colloquially termed “valley fever.”¹⁵ Most HIV-infected patients who have CD4 counts higher than 250 cells/μL present with focal pneumonia, while lower counts predispose to disseminated disease.^1,2,16

Findings on examination are nonspecific and depend on the various pulmonary manifestations, which include acute, chronic progressive, or diffuse pneumonia, nodules, or cavities.¹⁴ Eosinophilia may accompany the infection.¹⁵

The diagnosis can be made by finding the organisms on direct microscopic examination of involved tissues or secretions or on culture of clinical specimens.^1,2,14 Serologic tests, antigen detection tests, or culture can be helpful if positive, but negative results do not rule out the diagnosis.^1,2,14

A caveat about testing: if the pretest probability of infection is low, positive tests for immunoglobulin M (IgM) do not necessarily equal infection, and the IgM test should be followed up with confirmatory testing. Along the same lines, a high pretest probability should not be ignored if initial tests are negative, and patients in this situation should also undergo further evaluation.¹⁷

Therapy with an azole drug such as fluconazole (Diflucan) or one of the amphotericin B preparations should be started, depending on the severity of the disease.^1,2,14,18

Candida albicans

C albicans is a rare cause of lung infection.^19,20 It is, however, a common inhabitant of the upper airway tract, and pulmonary infection is usually the result of aspiration or hematogenous spread from either the gastrointestinal tract or an infected central venous catheter.²⁰

The presentation is relatively nonspecific. Fever despite broad-spectrum antibacterial therapy is a major clue. Radiographic abnormalities usually are due to other causes, such as superimposed infections or pulmonary hemorrhage.²¹ Sputum culture is unreliable because of colonization. The definitive diagnosis is based on lung biopsy demonstrating organisms within the tissue.^19,20,22

Therapy with a systemic antifungal agent is recommended.

Streptococcus pneumoniae

S pneumoniae is one of the most common bacterial causes of community-acquired pneumonia in people with or without HIV.^23–25 Moreover, two or more episodes of bacterial pneumonia in 12 months can be an AIDS-defining condition in patients with a positive serologic test for HIV.¹⁶ Therefore, in patients with fever, cough, and pulmonary infiltrates on chest radiography, S pneumoniae must always be considered.

Urinary antigen testing has a relatively high positive predictive value (> 89%) and specificity (96%) for diagnosing S pneumoniae pneumonia.²⁶ Blood and sputum cultures should be done not only to confirm the diagnosis, but also because the rates of bacteremia and drug resistance are higher with S pneumoniae infection in the HIV-infected.¹

A combination of a beta-lactam and a macrolide or respiratory fluoroquinolone is the treatment of choice.¹

Cytomegalovirus

Although influenza is the most common cause of viral pneumonia in HIV-infected people, cytomegalovirus is an opportunistic cause.² This is usually a reactivation of latent infection rather than new infection.²⁷ Typically, infections occur at CD4 counts lower than 50 cells/μL, with cough, dyspnea, and fever that last for 2 to 4 weeks.²

Crackles may be heard on lung examination. The lactate dehydrogenase level can be elevated, as in P jirovecii pneumonia.² Radiography can show a wide range of nonspecific findings, from reticular and ground-glass opacities to alveolar or interstitial infiltrates to nodules.

The diagnosis of cytomegalovirus pneumonia is not always clear. Since HIV-infected patients typically shed the virus in their airways, bronchoalveolar lavage is not adequate because a positive finding does not necessarily mean the patient has active viral pneumonitis.²⁷ For this reason, infection should be confirmed by biopsy demonstrating characteristic cytomegalovirus inclusions in lung tissue.²

Importantly, once cytomegalovirus pneumonia is confirmed, the patient should be screened for cytomegalovirus retinitis even if he or she has no visual symptoms, as cytomegalovirus pneumonitis is typically a part of a disseminated infection.¹

Treatment with intravenous ganciclovir (Cytovene) is required.¹

CASE CONTINUED: POSITIVE TESTS FOR COCCIDIOIDES

Our patient began empiric treatment for community-acquired pneumonia with intravenous ceftriaxone (Rocephin) and azithromycin (Zithromax).

On the basis of these findings, the patient was immediately placed in negative pressure respiratory isolation and underwent induced sputum examinations for tuberculosis. Further tests for S pneumoniae, S aureus, Mycoplasma, Legionella, influenza, Pneumocystis, Cryptococcus, Histoplasma, and Coccidioides species were performed.

QuantiFERON testing was negative, and blood cultures were sterile. The first induced sputum examination was negative for acid-fast bacilli. PCR testing for mycobacterial DNA in the sputum was also negative.

Both silver and direct fluorescent antibody staining of the sputum were negative for Pneumocystis. On the basis of these findings and the patient’s lack of clinical improvement with trimethoprim-sulfamethoxazole, Pneumocystis infection was excluded.

THE PATIENT BEGINS TREATMENT

2. Which treatment is most appropriate for this patient?

• Posaconazole (Noxafil)
• Caspofungin (Cancidas) and surgery
• Fluconazole
• Voriconazole (Vfend) and surgery
• Amphotericin B

Solitary pulmonary cavities tend to be asymptomatic and do not require treatment, even if coccidioidal infection is microbiologically confirmed.

However, if there is pain, hemoptysis, or bacterial superinfection, antifungal therapy may result in improvement but not closure of the cavity.¹⁸ Therefore, in all cases of symptomatic coccidioidal pulmonary cavities, surgical resection is the only definitive treatment.

Coccidioidal cavities may rupture and cause pyopneumothorax, but this is an infrequent complication, and antifungal therapy combined with surgical decortication is the treatment of choice.¹⁸

Commonly prescribed antifungals include fluconazole and amphotericin B, the latter usually reserved for patients with significant hypoxia or rapid clinical deterioration.¹⁸ At this time, there are not enough clinical data to show that voriconazole or posaconazole is effective, and thus neither is approved for the treatment of coccidioidomycosis. Likewise, there have been no human trials of the efficacy of caspofungin against Coccidioides infection, although it has been shown to be active in mouse models.¹⁸

Our patient was started on oral fluconazole and observed for clinical improvement or, conversely, for signs of dissemination. After 2 days, he had markedly improved, and within 1 week he was almost back to his baseline level of health. Testing for all other infectious etiologies was unrevealing, and he was removed from negative pressure isolation.

However, as we mentioned above, his CD4 count was 5 cells/μL. We discussed the issue with the patient, and he said he was willing to comply with his treatment for both his Coccidioides and his HIV infection. After much deliberation, he said he was also willing to start and comply with prophylactic treatment for opportunistic infections.

PREVENTING OPPORTUNISTIC INFECTIONS IN HIV PATIENTS

3. Which of the following prophylactic regimens is most appropriate for this patient?

• Trimethoprim-sulfamethoxazole, atovaquone (Mepron), and azithromycin
• Trimethoprim-sulfamethoxazole and azithromycin
• Pentamidine (Nebupent), dapsone, and clarithromycin (Biaxin)
• Dapsone and clarithromycin
• Trimethoprim-sulfamethoxazole by itself

According to guidelines for the prevention of opportunistic diseases in patients with HIV, he needs primary prophylaxis against the following organisms: P jirovecii, Toxoplasma gondii, and Mycobacterium avium complex.¹

The CD4 count dictates the appropriate time to start therapy. If the count is lower than 200 cells/μL or if the patient has oropharyngeal candidiasis regardless of the CD4 count, trimethoprim-sulfamethoxazole is indicated to prevent P jirovecii pneumonia. In those who cannot tolerate trimethoprim-sulfamethoxazole or who are allergic to it, dapsone, pentamidine, or atovaquone can be substituted.¹

In patients seropositive for T gondii, a CD4 count lower than 100/μL indicates the need for prophylaxis.¹ Prophylactic measures are similar to those for Pneumocystis. However, if the patient cannot tolerate trimethoprim-sulfamethoxazole, the recommended alternative is dapsone-pyrimethamine with leucovorin, which is also effective against Pneumocystis.¹

Finally, if the CD4 count is lower than 50 cells/μL, prophylaxis against M avium complex is mandatory, with either azithromycin weekly or clarithromycin daily.¹

Given our patient’s degree of immunosuppression, trimethoprim-sulfamethoxazole plus azithromycin is his most appropriate option.

Trimethoprim-sulfamethoxazole and azithromycin were added to his antimicrobial regimen before he was discharged. Two weeks later, he noted no side effects from any of the medications, he had no new symptoms, he was feeling well, and his cough had improved greatly. He did not have any signs of dissemination of his coccidioidal infection, and we concluded that the primary and only infection was located in the lungs.

DISSEMINATED COCCIDIOIDOMYCOSIS

4. Which of the following extrapulmonary sites is Coccidioides least likely to infect?

• Brain
• Skin
• Meninges
• Lymph nodes
• Bones
• Joints

Extrapulmonary coccidioidomycosis can involve almost any site. However, the most common sites of dissemination are the skin, lymph nodes, bones, and joints.¹⁴ The least likely site is the brain.

Central nervous system involvement

In the central nervous system, involvement is typically with the meninges, rather than frank involvement of the brain parenchyma.^18,28,29 Although patients with HIV or those who are otherwise severely immunocompromised are at higher risk for coccidioidal meningitis, it is rare even in this population.^30,31 Meningitis most commonly presents as headache, vomiting, meningismus, confusion, or diplopia.^32,33

If neurologic findings are absent, experts do not generally recommend lumbar puncture because the incidence of meningeal involvement is low. When cerebrospinal fluid is obtained in an active case of coccidioidal meningitis, fluid analysis typically finds elevated protein, low glucose, and lymphocytic pleocytosis.^1,32

Meningeal enhancement on CT or magnetic resonance imaging is common.³⁴ The diagnosis is established by culture or serologic testing of cerebrospinal fluid (IgM titer, IgG titer, immunodiffusion, or complement fixation).¹⁴

Of note, cerebral infarction and hydrocephalus are feared complications and pose a serious risk of death in any patient.^32,35 In these cases, treatment with antifungals is lifelong, regardless of immune system status.¹⁸

Skin involvement

Skin involvement is variable, consisting of nodules, verrucae, abscesses, or ulcerations.^15,16 Hemorrhage from the skin is relatively common.³⁶ From the skin, the infection can spread to the lymph nodes, leading to regional lymphadenopathy.^14,15 Nodes can ulcerate, drain, or even become necrotic.

Bone and joint involvement

Once integrity of the blood vessels is disrupted, Coccidioides can spread via the blood to the bones or joints,^14,15 causing osteomyelitis, septic arthritis, or synovitis. Subcutaneous abscesses or sinus tracts may subsequently develop.^14,15

HOW LONG MUST HE BE TREATED?

On follow-up, the patient asked how long he needed to continue his antifungal regimen and if any other testing for his coccidioidal infection was necessary, since he was feeling better.

5. Which is the most appropriate response to the patient’s question?

• He can discontinue his antifungal drugs; no further testing is necessary
• He needs 14 more days of antifungal therapy and periodic serologic tests
• He needs 2.5 more months of antifungal therapy and monthly blood cultures
• He needs lifelong antifungal therapy and periodic urinary antigen levels
• He needs 5.5 more months of antifungal therapy; bronchoscopy with bronchoalveolar lavage at 1 year

How long to treat and how to monitor for coccidioidomycosis vary by patient.

Duration of therapy depends on symptoms and immune status

The severity of infection (Table 2) and the immune status are important factors that must be considered when tailoring a therapeutic regimen.

Immunocompetent patients without symptoms or with mild symptoms usually do not need therapy and are followed periodically for signs of improvement.^14,18,29

Immunocompetent patients with severe symptoms typically receive 3 to 6 months of antifungal therapy.¹⁸

Immunocompromised patients (especially HIV-infected patients with CD4 counts < 250 cells/μL) need antifungal treatment, regardless of the severity of infection.^14,18,29 In many cases, the type of infection will dictate the duration of therapy.

Diffuse pneumonia or extrapulmonary dissemination typically requires treatment for at least 1 year regardless of immune status.^14,18 For those with HIV and diffuse pneumonia, dissemination, or meningitis, guidelines dictate that secondary prophylaxis be started after at least 1 year of therapy and improvement in clinical status; it should be continued indefinitely to prevent reactivation of latent infection.¹⁸

The guidelines say that in patients with higher CD4 counts (presumably > 250 cells/μL) and nonmeningeal coccidioidomycosis, providers may consider discontinuing secondary prophylaxis, as long as there is clinical evidence of improvement and control of the primary infection.¹⁸ However, many experts advocate continuing secondary prophylaxis regardless of the CD4 count, as the rates of relapse and dissemination are high.^1,16,37

Monitoring

Regardless of the therapy chosen, disease monitoring every 2 to 4 months with clinical history and examination, radiography, and coccidioidal-specific testing is recommended for at least 1 year, and perhaps longer, to ensure complete resolution and to monitor for signs of dissemination.^14,18

Which test to use is not clear. Serologic testing identifies antibodies (IgM or IgG) to coccidioidal antigens. IgM appears during the acute infection, and tests include immunodiffusion, latex agglutination, and enzymelinked immunoassays. The last two are highly sensitive but have a significant false-positive rate, and should be confirmed with the former if found to be positive.^17,18 IgG appears weeks after the acute infection and can be evaluated with immunodiffusion or enzyme-linked immunoassay as well.

Keep in mind that these tests provide only qualitative results on the presence of these antibodies, not quantitative information. Furthermore, enzyme-linked immunoassay is not as accurate as immunodiffusion, which has a sensitivity in immunocompromised patients of only approximately 50%.^38,39

For that reason, complement fixation titers are extremely helpful because they reflect the severity of infection, can be used to monitor the response to treatment, and can even provide insight into the prognosis.¹⁸ The sensitivity of this test in immunocompromised hosts is 60% to 70%.³⁸ Titers can be checked to confirm the diagnosis and can be periodically monitored throughout the treatment course to ensure efficacy of therapy and to watch for reactivation of the infection.¹ In fact, an initial complement fixation titer of 1:2 or 1:4 is associated with favorable outcomes, while a titer greater than 1:16 portends dissemination.¹⁸

The caveat to any serologic test (immunodiffusion, enzyme-linked immunoassay, and complement fixation) is that severely immunocompromised patients (as in our case) may not mount an immune response and may have falsely low titers even in the face of a severe infection, and therefore these tests may not be reliable.³⁸ In these situations, urinary coccidioidal antigen detection assay (sensitivity 71%) or nucleic acid amplification of coccidioidal DNA (sensitivity 75%) may be of more help.^40,41

Therefore, in the setting of HIV infection, an asymptomatic pulmonary cavity, and diffuse pulmonary involvement secondary to coccidioidal infection, lifelong antibiotics (treatment plus secondary prophylaxis) with periodic testing of urinary coccidioidal antigen levels is the best response to the patient’s question, given that his complement fixation titers were initially negative and antigen levels were positive.

CASE CONCLUDED

The patient continues to be followed for his HIV infection. He is undergoing serologic and urinary antigen testing for Coccidioides infection every 3 months in addition to his maintenance HIV testing. He is on chronic suppressive therapy with fluconazole. He has not had a recurrence of his Coccidioides infection, nor have there been any signs of dissemination.

CAVITARY LUNG LESIONS IN HIV PATIENTS

In patients with HIV, cavitary lung lesions on chest radiography can be due to a wide variety of etiologies that range from infection to malignancy. Historical clues, including environmental exposure, occupation, geographic residence, sick contacts, travel, or animal contact can be helpful in ordering subsequent confirmatory testing, especially in the case of infection.

Tuberculosis should be suspected, and appropriate isolation precautions should be taken until it is ruled out.

Laboratory testing, including the complete blood cell count with differential and CD4 count, provide ancillary data to narrow the differential diagnosis. For example, if the CD4 count is greater than 200 cells/μL, mycobacterial infection should be strongly suspected; however, lower CD4 counts should also prompt a search for opportunistic infections. In the appropriate clinical scenario, malignancies including Kaposi sarcoma, non-Hodgkin lymphoma, and bronchogenic carcinoma can be seen and should also be considered.

Nevertheless, the evaluation hinges on the sputum examination and CT scan of the chest to further characterize the cavity, surrounding lung parenchyma, lymph nodes, and potential fluid collections. Usually, further serologic tests and even bronchoscopy with bronchoalveolar lavage and transbronchial biopsy are required. Treatment should begin once the most likely diagnosis is established.

Coccidioidal pneumonia should be considered in all patients with immunodeficiency, including HIV patients, transplant recipients, those undergoing chemotherapy, and those with intrinsic immune system defects, especially if they have a history of exposure or if they are from an endemic region. Antifungal therapy should be initiated early, and dissemination must be ruled out. Suppressive therapy is mandatory for those with a severely compromised immune system, and serologic testing to ensure remission of the infection is needed. Patients who were previously exposed to Coccidioides or who vacationed or live in the southwestern United States (where it is prevalent) are at risk and may present with any number of symptoms.

A 37-year-old man presented to the emergency department with an 8-week history of a mildly productive cough and shortness of breath accompanied by high fevers, chills, and night sweats. He also had some nausea but no vomiting.

Four days earlier, he had been evaluated by his primary care physician, who prescribed a 14-day course of one double-strength trimethoprim-sulfamethoxazole tablet (Bactrim DS) every 12 hours for presumed acute bronchitis, but his symptoms did not improve.

He was unemployed, living in Arizona, married with children. He denied any use of tobacco, alcohol, or injection drugs. On further questioning, he disclosed that he had unintentionally lost 30 pounds over the past 2 to 3 months and had been feeling tired.

When asked about his medical history, he revealed that he had been diagnosed with human immunodeficiency virus (HIV) infection in 2008 and that recently he had not been taking his antiretroviral medication, a once-daily combination pill containing efavirenz, emtricitabine, and tenofovir (Atripla). He had no other significant medical history, and the only medication he was currently taking was the trimethoprim-sulfamethoxazole.

On examination, his temperature was 38.7°C (101.7°F), blood pressure 109/68 mm Hg, heart rate 60 beats per minute, respiratory rate 18 breaths per minute, and oxygen saturation 100% while breathing supplemental oxygen via nasal cannula at 2 L/min. He did not appear seriously ill.

Initial blood tests (Table 1) showed a normal white blood cell count, normal results on a complete metabolic panel, and a lactate dehydrogenase level of 539 IU/L (reference range 313–618). His serum lactate level was within normal limits.

HIV-specific tests performed on the second day of hospitalization showed extreme immunosuppression, with a CD4 count of 5 cells/μL (normal 326–1,404 cells/μL).

WHICH ORGANISM IS CAUSING HIS LUNG INFECTION?

1. Which of the following organisms is the least likely to be associated with this patient’s condition?

• Mycobacterium tuberculosis
• Pneumocystis jirovecii
• Coccidioides immitis
• Candida albicans
• Streptococcus pneumoniae
• Cytomegalovirus

Bacterial, fungal, and viral lung infections are common in HIV-infected patients, especially if they are not on antiretroviral therapy and their CD4 lymphocyte counts are low. Clues to the cause can be derived from the history, physical examination, and general laboratory studies. For instance, knowing where the patient lives and where he has travelled recently provides insight into exposure to endemic infectious agents.

The complete blood cell count with differential white blood cell count can help narrow the differential diagnosis but rarely helps exclude a possibility. Neutrophilia is common in bacterial infections. Lymphocytosis can be seen in tuberculosis, in fungal and viral infections, and, rarely, in hematologic malignancies. Eosinophilia can be seen in acute retroviral syndrome, fungal and helminthic infections, adrenal insufficiency, autoimmune disease, and lymphoma.

A caveat to these clues is that in severely immunocompromised hosts, like this man, diagnoses should not be excluded without firm evidence. This patient has severe, active immunosuppression, and only one of the six answer choices above is not a possible causative agent: C albicans rarely causes lung infection, even in immunocompromised people.

Mycobacterium tuberculosis

Tuberculosis can be the first manifestation of HIV infection. It can occur at any CD4 count, but as the count decreases, the risk of dissemination increases.¹ Classic symptoms are fever, night sweats, hemoptysis, and weight loss.

The CD4 count also affects the radiographic presentation. If the count is higher than 350 cells/μL, then infiltration of the upper lobe is likely; if it is lower than 200 cells/μL, then middle, lower, miliary, and extrapulmonary manifestations are likely.^1,2 Cavitation is less common in HIV-infected patients, but mediastinal adenopathy is more common.¹

Definitive diagnosis is via sputum examination, blood culture, nucleic acid amplification, or microscopic study of biopsy specimens of affected tissues to look for acid-fast bacilli.¹

Interferon-gamma-release assays such as the QuantiFERON test (Cellestis, Valencia, CA) or a tuberculin skin test can be used to check for latent tuberculosis infection. These tests can also provide evidence of active infection in the appropriate clinical context.³

Interferon-gamma-release assays have several advantages over skin testing: they are more sensitive (76% to 80%) and specific (97%); they do not give false-positive results in people who previously received bacille Calmette-Guérin vaccine; they react only minimally to previous exposure to nontuberculous mycobacteria; and interpretation is not subject to interreader variability.^4,5 However, concordance between skin testing and interferon-gamma-release assays is low. Therefore, either or both tests can be used if tuberculosis is strongly suspected, and a positive result on either test should prompt further workup.^6,7

Of note, both tests may be affected by immunosuppression, making both susceptible to false-negative results as the CD4 count declines.³

In any case, a positive acid-fast bacillus smear, radiographic evidence of latent infection, or pulmonary symptoms should be presumed to represent active tuberculosis. In such a situation, directly observed treatment with the typical four-drug regimen—rifampin (Rifadin), isoniazid, pyrazinamide, and ethambutol (Myambutol)—is recommended while awaiting definitive results from culture or polymerase chain reaction (PCR) testing.¹

P jirovecii was previously known as P carinii, and P jirovecii pneumonia is an AIDS-defining illness. Most cases occur when the CD4 count falls below 200 cells/μL.¹ Symptoms, including a nonproductive cough, develop insidiously over days to weeks.

Physical examination may reveal inspiratory crackles; however, half of the time the physical examination is nondiagnostic. Oral candidiasis is a common coinfection. The lactate dehydrogenase level may be elevated.^1,8 Radiographs show bilateral interstitial infiltrates, and in 10% to 20% of patients lung cysts develop—hence the name of the organism.¹ Pneumothorax in a patient with HIV should prompt a workup for P jirovecii pneumonia.^9,10

No consensus exists for the diagnosis. However, if sputum examination is unrevealing but suspicion is high, then bronchoalveolar lavage can help.^11–13

Trimethoprim-sulfamethoxazole for 21 days is the first-line treatment, with glucocorticoids added if the Pao₂ is less than 70 mm Hg or if the alveolar-arterial oxygen gradient is greater than 35 mm Hg.¹

Coccidioides species

Coccidioides infection is typically due to either C immitis or C posadasii.¹⁴ People living in or travelling to areas where it is endemic, such as the southwestern United States, Mexico, and Central and South America, are at higher risk.¹⁴

Typical signs and symptoms of this fungal infection include an influenza-like illness with fever, cough, adenopathy, and wasting, and when combined with erythema nodosum, erythema multiforme, arthralgia, or ocular involvement, this constellation is colloquially termed “valley fever.”¹⁵ Most HIV-infected patients who have CD4 counts higher than 250 cells/μL present with focal pneumonia, while lower counts predispose to disseminated disease.^1,2,16

Findings on examination are nonspecific and depend on the various pulmonary manifestations, which include acute, chronic progressive, or diffuse pneumonia, nodules, or cavities.¹⁴ Eosinophilia may accompany the infection.¹⁵

The diagnosis can be made by finding the organisms on direct microscopic examination of involved tissues or secretions or on culture of clinical specimens.^1,2,14 Serologic tests, antigen detection tests, or culture can be helpful if positive, but negative results do not rule out the diagnosis.^1,2,14

A caveat about testing: if the pretest probability of infection is low, positive tests for immunoglobulin M (IgM) do not necessarily equal infection, and the IgM test should be followed up with confirmatory testing. Along the same lines, a high pretest probability should not be ignored if initial tests are negative, and patients in this situation should also undergo further evaluation.¹⁷

Therapy with an azole drug such as fluconazole (Diflucan) or one of the amphotericin B preparations should be started, depending on the severity of the disease.^1,2,14,18

Candida albicans

C albicans is a rare cause of lung infection.^19,20 It is, however, a common inhabitant of the upper airway tract, and pulmonary infection is usually the result of aspiration or hematogenous spread from either the gastrointestinal tract or an infected central venous catheter.²⁰

The presentation is relatively nonspecific. Fever despite broad-spectrum antibacterial therapy is a major clue. Radiographic abnormalities usually are due to other causes, such as superimposed infections or pulmonary hemorrhage.²¹ Sputum culture is unreliable because of colonization. The definitive diagnosis is based on lung biopsy demonstrating organisms within the tissue.^19,20,22

Therapy with a systemic antifungal agent is recommended.

Streptococcus pneumoniae

S pneumoniae is one of the most common bacterial causes of community-acquired pneumonia in people with or without HIV.^23–25 Moreover, two or more episodes of bacterial pneumonia in 12 months can be an AIDS-defining condition in patients with a positive serologic test for HIV.¹⁶ Therefore, in patients with fever, cough, and pulmonary infiltrates on chest radiography, S pneumoniae must always be considered.

Urinary antigen testing has a relatively high positive predictive value (> 89%) and specificity (96%) for diagnosing S pneumoniae pneumonia.²⁶ Blood and sputum cultures should be done not only to confirm the diagnosis, but also because the rates of bacteremia and drug resistance are higher with S pneumoniae infection in the HIV-infected.¹

A combination of a beta-lactam and a macrolide or respiratory fluoroquinolone is the treatment of choice.¹

Cytomegalovirus

Although influenza is the most common cause of viral pneumonia in HIV-infected people, cytomegalovirus is an opportunistic cause.² This is usually a reactivation of latent infection rather than new infection.²⁷ Typically, infections occur at CD4 counts lower than 50 cells/μL, with cough, dyspnea, and fever that last for 2 to 4 weeks.²

Crackles may be heard on lung examination. The lactate dehydrogenase level can be elevated, as in P jirovecii pneumonia.² Radiography can show a wide range of nonspecific findings, from reticular and ground-glass opacities to alveolar or interstitial infiltrates to nodules.

The diagnosis of cytomegalovirus pneumonia is not always clear. Since HIV-infected patients typically shed the virus in their airways, bronchoalveolar lavage is not adequate because a positive finding does not necessarily mean the patient has active viral pneumonitis.²⁷ For this reason, infection should be confirmed by biopsy demonstrating characteristic cytomegalovirus inclusions in lung tissue.²

Importantly, once cytomegalovirus pneumonia is confirmed, the patient should be screened for cytomegalovirus retinitis even if he or she has no visual symptoms, as cytomegalovirus pneumonitis is typically a part of a disseminated infection.¹

Treatment with intravenous ganciclovir (Cytovene) is required.¹

CASE CONTINUED: POSITIVE TESTS FOR COCCIDIOIDES

Our patient began empiric treatment for community-acquired pneumonia with intravenous ceftriaxone (Rocephin) and azithromycin (Zithromax).

On the basis of these findings, the patient was immediately placed in negative pressure respiratory isolation and underwent induced sputum examinations for tuberculosis. Further tests for S pneumoniae, S aureus, Mycoplasma, Legionella, influenza, Pneumocystis, Cryptococcus, Histoplasma, and Coccidioides species were performed.

QuantiFERON testing was negative, and blood cultures were sterile. The first induced sputum examination was negative for acid-fast bacilli. PCR testing for mycobacterial DNA in the sputum was also negative.

Both silver and direct fluorescent antibody staining of the sputum were negative for Pneumocystis. On the basis of these findings and the patient’s lack of clinical improvement with trimethoprim-sulfamethoxazole, Pneumocystis infection was excluded.

THE PATIENT BEGINS TREATMENT

2. Which treatment is most appropriate for this patient?

• Posaconazole (Noxafil)
• Caspofungin (Cancidas) and surgery
• Fluconazole
• Voriconazole (Vfend) and surgery
• Amphotericin B

Solitary pulmonary cavities tend to be asymptomatic and do not require treatment, even if coccidioidal infection is microbiologically confirmed.

However, if there is pain, hemoptysis, or bacterial superinfection, antifungal therapy may result in improvement but not closure of the cavity.¹⁸ Therefore, in all cases of symptomatic coccidioidal pulmonary cavities, surgical resection is the only definitive treatment.

Coccidioidal cavities may rupture and cause pyopneumothorax, but this is an infrequent complication, and antifungal therapy combined with surgical decortication is the treatment of choice.¹⁸

Commonly prescribed antifungals include fluconazole and amphotericin B, the latter usually reserved for patients with significant hypoxia or rapid clinical deterioration.¹⁸ At this time, there are not enough clinical data to show that voriconazole or posaconazole is effective, and thus neither is approved for the treatment of coccidioidomycosis. Likewise, there have been no human trials of the efficacy of caspofungin against Coccidioides infection, although it has been shown to be active in mouse models.¹⁸

Our patient was started on oral fluconazole and observed for clinical improvement or, conversely, for signs of dissemination. After 2 days, he had markedly improved, and within 1 week he was almost back to his baseline level of health. Testing for all other infectious etiologies was unrevealing, and he was removed from negative pressure isolation.

However, as we mentioned above, his CD4 count was 5 cells/μL. We discussed the issue with the patient, and he said he was willing to comply with his treatment for both his Coccidioides and his HIV infection. After much deliberation, he said he was also willing to start and comply with prophylactic treatment for opportunistic infections.

PREVENTING OPPORTUNISTIC INFECTIONS IN HIV PATIENTS

3. Which of the following prophylactic regimens is most appropriate for this patient?

• Trimethoprim-sulfamethoxazole, atovaquone (Mepron), and azithromycin
• Trimethoprim-sulfamethoxazole and azithromycin
• Pentamidine (Nebupent), dapsone, and clarithromycin (Biaxin)
• Dapsone and clarithromycin
• Trimethoprim-sulfamethoxazole by itself

According to guidelines for the prevention of opportunistic diseases in patients with HIV, he needs primary prophylaxis against the following organisms: P jirovecii, Toxoplasma gondii, and Mycobacterium avium complex.¹

The CD4 count dictates the appropriate time to start therapy. If the count is lower than 200 cells/μL or if the patient has oropharyngeal candidiasis regardless of the CD4 count, trimethoprim-sulfamethoxazole is indicated to prevent P jirovecii pneumonia. In those who cannot tolerate trimethoprim-sulfamethoxazole or who are allergic to it, dapsone, pentamidine, or atovaquone can be substituted.¹

In patients seropositive for T gondii, a CD4 count lower than 100/μL indicates the need for prophylaxis.¹ Prophylactic measures are similar to those for Pneumocystis. However, if the patient cannot tolerate trimethoprim-sulfamethoxazole, the recommended alternative is dapsone-pyrimethamine with leucovorin, which is also effective against Pneumocystis.¹

Finally, if the CD4 count is lower than 50 cells/μL, prophylaxis against M avium complex is mandatory, with either azithromycin weekly or clarithromycin daily.¹

Given our patient’s degree of immunosuppression, trimethoprim-sulfamethoxazole plus azithromycin is his most appropriate option.

Trimethoprim-sulfamethoxazole and azithromycin were added to his antimicrobial regimen before he was discharged. Two weeks later, he noted no side effects from any of the medications, he had no new symptoms, he was feeling well, and his cough had improved greatly. He did not have any signs of dissemination of his coccidioidal infection, and we concluded that the primary and only infection was located in the lungs.

DISSEMINATED COCCIDIOIDOMYCOSIS

4. Which of the following extrapulmonary sites is Coccidioides least likely to infect?

• Brain
• Skin
• Meninges
• Lymph nodes
• Bones
• Joints

Extrapulmonary coccidioidomycosis can involve almost any site. However, the most common sites of dissemination are the skin, lymph nodes, bones, and joints.¹⁴ The least likely site is the brain.

Central nervous system involvement

In the central nervous system, involvement is typically with the meninges, rather than frank involvement of the brain parenchyma.^18,28,29 Although patients with HIV or those who are otherwise severely immunocompromised are at higher risk for coccidioidal meningitis, it is rare even in this population.^30,31 Meningitis most commonly presents as headache, vomiting, meningismus, confusion, or diplopia.^32,33

If neurologic findings are absent, experts do not generally recommend lumbar puncture because the incidence of meningeal involvement is low. When cerebrospinal fluid is obtained in an active case of coccidioidal meningitis, fluid analysis typically finds elevated protein, low glucose, and lymphocytic pleocytosis.^1,32

Meningeal enhancement on CT or magnetic resonance imaging is common.³⁴ The diagnosis is established by culture or serologic testing of cerebrospinal fluid (IgM titer, IgG titer, immunodiffusion, or complement fixation).¹⁴

Of note, cerebral infarction and hydrocephalus are feared complications and pose a serious risk of death in any patient.^32,35 In these cases, treatment with antifungals is lifelong, regardless of immune system status.¹⁸

Skin involvement

Skin involvement is variable, consisting of nodules, verrucae, abscesses, or ulcerations.^15,16 Hemorrhage from the skin is relatively common.³⁶ From the skin, the infection can spread to the lymph nodes, leading to regional lymphadenopathy.^14,15 Nodes can ulcerate, drain, or even become necrotic.

Bone and joint involvement

Once integrity of the blood vessels is disrupted, Coccidioides can spread via the blood to the bones or joints,^14,15 causing osteomyelitis, septic arthritis, or synovitis. Subcutaneous abscesses or sinus tracts may subsequently develop.^14,15

HOW LONG MUST HE BE TREATED?

On follow-up, the patient asked how long he needed to continue his antifungal regimen and if any other testing for his coccidioidal infection was necessary, since he was feeling better.

5. Which is the most appropriate response to the patient’s question?

• He can discontinue his antifungal drugs; no further testing is necessary
• He needs 14 more days of antifungal therapy and periodic serologic tests
• He needs 2.5 more months of antifungal therapy and monthly blood cultures
• He needs lifelong antifungal therapy and periodic urinary antigen levels
• He needs 5.5 more months of antifungal therapy; bronchoscopy with bronchoalveolar lavage at 1 year

How long to treat and how to monitor for coccidioidomycosis vary by patient.

Duration of therapy depends on symptoms and immune status

The severity of infection (Table 2) and the immune status are important factors that must be considered when tailoring a therapeutic regimen.

Immunocompetent patients without symptoms or with mild symptoms usually do not need therapy and are followed periodically for signs of improvement.^14,18,29

Immunocompetent patients with severe symptoms typically receive 3 to 6 months of antifungal therapy.¹⁸

Immunocompromised patients (especially HIV-infected patients with CD4 counts < 250 cells/μL) need antifungal treatment, regardless of the severity of infection.^14,18,29 In many cases, the type of infection will dictate the duration of therapy.

Diffuse pneumonia or extrapulmonary dissemination typically requires treatment for at least 1 year regardless of immune status.^14,18 For those with HIV and diffuse pneumonia, dissemination, or meningitis, guidelines dictate that secondary prophylaxis be started after at least 1 year of therapy and improvement in clinical status; it should be continued indefinitely to prevent reactivation of latent infection.¹⁸

The guidelines say that in patients with higher CD4 counts (presumably > 250 cells/μL) and nonmeningeal coccidioidomycosis, providers may consider discontinuing secondary prophylaxis, as long as there is clinical evidence of improvement and control of the primary infection.¹⁸ However, many experts advocate continuing secondary prophylaxis regardless of the CD4 count, as the rates of relapse and dissemination are high.^1,16,37

Monitoring

Regardless of the therapy chosen, disease monitoring every 2 to 4 months with clinical history and examination, radiography, and coccidioidal-specific testing is recommended for at least 1 year, and perhaps longer, to ensure complete resolution and to monitor for signs of dissemination.^14,18

Which test to use is not clear. Serologic testing identifies antibodies (IgM or IgG) to coccidioidal antigens. IgM appears during the acute infection, and tests include immunodiffusion, latex agglutination, and enzymelinked immunoassays. The last two are highly sensitive but have a significant false-positive rate, and should be confirmed with the former if found to be positive.^17,18 IgG appears weeks after the acute infection and can be evaluated with immunodiffusion or enzyme-linked immunoassay as well.

Keep in mind that these tests provide only qualitative results on the presence of these antibodies, not quantitative information. Furthermore, enzyme-linked immunoassay is not as accurate as immunodiffusion, which has a sensitivity in immunocompromised patients of only approximately 50%.^38,39

For that reason, complement fixation titers are extremely helpful because they reflect the severity of infection, can be used to monitor the response to treatment, and can even provide insight into the prognosis.¹⁸ The sensitivity of this test in immunocompromised hosts is 60% to 70%.³⁸ Titers can be checked to confirm the diagnosis and can be periodically monitored throughout the treatment course to ensure efficacy of therapy and to watch for reactivation of the infection.¹ In fact, an initial complement fixation titer of 1:2 or 1:4 is associated with favorable outcomes, while a titer greater than 1:16 portends dissemination.¹⁸

The caveat to any serologic test (immunodiffusion, enzyme-linked immunoassay, and complement fixation) is that severely immunocompromised patients (as in our case) may not mount an immune response and may have falsely low titers even in the face of a severe infection, and therefore these tests may not be reliable.³⁸ In these situations, urinary coccidioidal antigen detection assay (sensitivity 71%) or nucleic acid amplification of coccidioidal DNA (sensitivity 75%) may be of more help.^40,41

Therefore, in the setting of HIV infection, an asymptomatic pulmonary cavity, and diffuse pulmonary involvement secondary to coccidioidal infection, lifelong antibiotics (treatment plus secondary prophylaxis) with periodic testing of urinary coccidioidal antigen levels is the best response to the patient’s question, given that his complement fixation titers were initially negative and antigen levels were positive.

CASE CONCLUDED

The patient continues to be followed for his HIV infection. He is undergoing serologic and urinary antigen testing for Coccidioides infection every 3 months in addition to his maintenance HIV testing. He is on chronic suppressive therapy with fluconazole. He has not had a recurrence of his Coccidioides infection, nor have there been any signs of dissemination.

CAVITARY LUNG LESIONS IN HIV PATIENTS

In patients with HIV, cavitary lung lesions on chest radiography can be due to a wide variety of etiologies that range from infection to malignancy. Historical clues, including environmental exposure, occupation, geographic residence, sick contacts, travel, or animal contact can be helpful in ordering subsequent confirmatory testing, especially in the case of infection.

Tuberculosis should be suspected, and appropriate isolation precautions should be taken until it is ruled out.

Laboratory testing, including the complete blood cell count with differential and CD4 count, provide ancillary data to narrow the differential diagnosis. For example, if the CD4 count is greater than 200 cells/μL, mycobacterial infection should be strongly suspected; however, lower CD4 counts should also prompt a search for opportunistic infections. In the appropriate clinical scenario, malignancies including Kaposi sarcoma, non-Hodgkin lymphoma, and bronchogenic carcinoma can be seen and should also be considered.

Nevertheless, the evaluation hinges on the sputum examination and CT scan of the chest to further characterize the cavity, surrounding lung parenchyma, lymph nodes, and potential fluid collections. Usually, further serologic tests and even bronchoscopy with bronchoalveolar lavage and transbronchial biopsy are required. Treatment should begin once the most likely diagnosis is established.

Coccidioidal pneumonia should be considered in all patients with immunodeficiency, including HIV patients, transplant recipients, those undergoing chemotherapy, and those with intrinsic immune system defects, especially if they have a history of exposure or if they are from an endemic region. Antifungal therapy should be initiated early, and dissemination must be ruled out. Suppressive therapy is mandatory for those with a severely compromised immune system, and serologic testing to ensure remission of the infection is needed. Patients who were previously exposed to Coccidioides or who vacationed or live in the southwestern United States (where it is prevalent) are at risk and may present with any number of symptoms.

A 37-year-old man presented to the emergency department with an 8-week history of a mildly productive cough and shortness of breath accompanied by high fevers, chills, and night sweats. He also had some nausea but no vomiting.

Four days earlier, he had been evaluated by his primary care physician, who prescribed a 14-day course of one double-strength trimethoprim-sulfamethoxazole tablet (Bactrim DS) every 12 hours for presumed acute bronchitis, but his symptoms did not improve.

He was unemployed, living in Arizona, married with children. He denied any use of tobacco, alcohol, or injection drugs. On further questioning, he disclosed that he had unintentionally lost 30 pounds over the past 2 to 3 months and had been feeling tired.

When asked about his medical history, he revealed that he had been diagnosed with human immunodeficiency virus (HIV) infection in 2008 and that recently he had not been taking his antiretroviral medication, a once-daily combination pill containing efavirenz, emtricitabine, and tenofovir (Atripla). He had no other significant medical history, and the only medication he was currently taking was the trimethoprim-sulfamethoxazole.

On examination, his temperature was 38.7°C (101.7°F), blood pressure 109/68 mm Hg, heart rate 60 beats per minute, respiratory rate 18 breaths per minute, and oxygen saturation 100% while breathing supplemental oxygen via nasal cannula at 2 L/min. He did not appear seriously ill.

Initial blood tests (Table 1) showed a normal white blood cell count, normal results on a complete metabolic panel, and a lactate dehydrogenase level of 539 IU/L (reference range 313–618). His serum lactate level was within normal limits.

HIV-specific tests performed on the second day of hospitalization showed extreme immunosuppression, with a CD4 count of 5 cells/μL (normal 326–1,404 cells/μL).

WHICH ORGANISM IS CAUSING HIS LUNG INFECTION?

1. Which of the following organisms is the least likely to be associated with this patient’s condition?

• Mycobacterium tuberculosis
• Pneumocystis jirovecii
• Coccidioides immitis
• Candida albicans
• Streptococcus pneumoniae
• Cytomegalovirus

Bacterial, fungal, and viral lung infections are common in HIV-infected patients, especially if they are not on antiretroviral therapy and their CD4 lymphocyte counts are low. Clues to the cause can be derived from the history, physical examination, and general laboratory studies. For instance, knowing where the patient lives and where he has travelled recently provides insight into exposure to endemic infectious agents.

The complete blood cell count with differential white blood cell count can help narrow the differential diagnosis but rarely helps exclude a possibility. Neutrophilia is common in bacterial infections. Lymphocytosis can be seen in tuberculosis, in fungal and viral infections, and, rarely, in hematologic malignancies. Eosinophilia can be seen in acute retroviral syndrome, fungal and helminthic infections, adrenal insufficiency, autoimmune disease, and lymphoma.

A caveat to these clues is that in severely immunocompromised hosts, like this man, diagnoses should not be excluded without firm evidence. This patient has severe, active immunosuppression, and only one of the six answer choices above is not a possible causative agent: C albicans rarely causes lung infection, even in immunocompromised people.

Mycobacterium tuberculosis

Tuberculosis can be the first manifestation of HIV infection. It can occur at any CD4 count, but as the count decreases, the risk of dissemination increases.¹ Classic symptoms are fever, night sweats, hemoptysis, and weight loss.

The CD4 count also affects the radiographic presentation. If the count is higher than 350 cells/μL, then infiltration of the upper lobe is likely; if it is lower than 200 cells/μL, then middle, lower, miliary, and extrapulmonary manifestations are likely.^1,2 Cavitation is less common in HIV-infected patients, but mediastinal adenopathy is more common.¹

Definitive diagnosis is via sputum examination, blood culture, nucleic acid amplification, or microscopic study of biopsy specimens of affected tissues to look for acid-fast bacilli.¹

Interferon-gamma-release assays such as the QuantiFERON test (Cellestis, Valencia, CA) or a tuberculin skin test can be used to check for latent tuberculosis infection. These tests can also provide evidence of active infection in the appropriate clinical context.³

Interferon-gamma-release assays have several advantages over skin testing: they are more sensitive (76% to 80%) and specific (97%); they do not give false-positive results in people who previously received bacille Calmette-Guérin vaccine; they react only minimally to previous exposure to nontuberculous mycobacteria; and interpretation is not subject to interreader variability.^4,5 However, concordance between skin testing and interferon-gamma-release assays is low. Therefore, either or both tests can be used if tuberculosis is strongly suspected, and a positive result on either test should prompt further workup.^6,7

Of note, both tests may be affected by immunosuppression, making both susceptible to false-negative results as the CD4 count declines.³

In any case, a positive acid-fast bacillus smear, radiographic evidence of latent infection, or pulmonary symptoms should be presumed to represent active tuberculosis. In such a situation, directly observed treatment with the typical four-drug regimen—rifampin (Rifadin), isoniazid, pyrazinamide, and ethambutol (Myambutol)—is recommended while awaiting definitive results from culture or polymerase chain reaction (PCR) testing.¹

P jirovecii was previously known as P carinii, and P jirovecii pneumonia is an AIDS-defining illness. Most cases occur when the CD4 count falls below 200 cells/μL.¹ Symptoms, including a nonproductive cough, develop insidiously over days to weeks.

Physical examination may reveal inspiratory crackles; however, half of the time the physical examination is nondiagnostic. Oral candidiasis is a common coinfection. The lactate dehydrogenase level may be elevated.^1,8 Radiographs show bilateral interstitial infiltrates, and in 10% to 20% of patients lung cysts develop—hence the name of the organism.¹ Pneumothorax in a patient with HIV should prompt a workup for P jirovecii pneumonia.^9,10

No consensus exists for the diagnosis. However, if sputum examination is unrevealing but suspicion is high, then bronchoalveolar lavage can help.^11–13

Trimethoprim-sulfamethoxazole for 21 days is the first-line treatment, with glucocorticoids added if the Pao₂ is less than 70 mm Hg or if the alveolar-arterial oxygen gradient is greater than 35 mm Hg.¹

Coccidioides species

Coccidioides infection is typically due to either C immitis or C posadasii.¹⁴ People living in or travelling to areas where it is endemic, such as the southwestern United States, Mexico, and Central and South America, are at higher risk.¹⁴

Typical signs and symptoms of this fungal infection include an influenza-like illness with fever, cough, adenopathy, and wasting, and when combined with erythema nodosum, erythema multiforme, arthralgia, or ocular involvement, this constellation is colloquially termed “valley fever.”¹⁵ Most HIV-infected patients who have CD4 counts higher than 250 cells/μL present with focal pneumonia, while lower counts predispose to disseminated disease.^1,2,16

Findings on examination are nonspecific and depend on the various pulmonary manifestations, which include acute, chronic progressive, or diffuse pneumonia, nodules, or cavities.¹⁴ Eosinophilia may accompany the infection.¹⁵

The diagnosis can be made by finding the organisms on direct microscopic examination of involved tissues or secretions or on culture of clinical specimens.^1,2,14 Serologic tests, antigen detection tests, or culture can be helpful if positive, but negative results do not rule out the diagnosis.^1,2,14

A caveat about testing: if the pretest probability of infection is low, positive tests for immunoglobulin M (IgM) do not necessarily equal infection, and the IgM test should be followed up with confirmatory testing. Along the same lines, a high pretest probability should not be ignored if initial tests are negative, and patients in this situation should also undergo further evaluation.¹⁷

Therapy with an azole drug such as fluconazole (Diflucan) or one of the amphotericin B preparations should be started, depending on the severity of the disease.^1,2,14,18

Candida albicans

C albicans is a rare cause of lung infection.^19,20 It is, however, a common inhabitant of the upper airway tract, and pulmonary infection is usually the result of aspiration or hematogenous spread from either the gastrointestinal tract or an infected central venous catheter.²⁰

The presentation is relatively nonspecific. Fever despite broad-spectrum antibacterial therapy is a major clue. Radiographic abnormalities usually are due to other causes, such as superimposed infections or pulmonary hemorrhage.²¹ Sputum culture is unreliable because of colonization. The definitive diagnosis is based on lung biopsy demonstrating organisms within the tissue.^19,20,22

Therapy with a systemic antifungal agent is recommended.

Streptococcus pneumoniae

S pneumoniae is one of the most common bacterial causes of community-acquired pneumonia in people with or without HIV.^23–25 Moreover, two or more episodes of bacterial pneumonia in 12 months can be an AIDS-defining condition in patients with a positive serologic test for HIV.¹⁶ Therefore, in patients with fever, cough, and pulmonary infiltrates on chest radiography, S pneumoniae must always be considered.

Urinary antigen testing has a relatively high positive predictive value (> 89%) and specificity (96%) for diagnosing S pneumoniae pneumonia.²⁶ Blood and sputum cultures should be done not only to confirm the diagnosis, but also because the rates of bacteremia and drug resistance are higher with S pneumoniae infection in the HIV-infected.¹

A combination of a beta-lactam and a macrolide or respiratory fluoroquinolone is the treatment of choice.¹

Cytomegalovirus

Although influenza is the most common cause of viral pneumonia in HIV-infected people, cytomegalovirus is an opportunistic cause.² This is usually a reactivation of latent infection rather than new infection.²⁷ Typically, infections occur at CD4 counts lower than 50 cells/μL, with cough, dyspnea, and fever that last for 2 to 4 weeks.²

Crackles may be heard on lung examination. The lactate dehydrogenase level can be elevated, as in P jirovecii pneumonia.² Radiography can show a wide range of nonspecific findings, from reticular and ground-glass opacities to alveolar or interstitial infiltrates to nodules.

The diagnosis of cytomegalovirus pneumonia is not always clear. Since HIV-infected patients typically shed the virus in their airways, bronchoalveolar lavage is not adequate because a positive finding does not necessarily mean the patient has active viral pneumonitis.²⁷ For this reason, infection should be confirmed by biopsy demonstrating characteristic cytomegalovirus inclusions in lung tissue.²

Importantly, once cytomegalovirus pneumonia is confirmed, the patient should be screened for cytomegalovirus retinitis even if he or she has no visual symptoms, as cytomegalovirus pneumonitis is typically a part of a disseminated infection.¹

Treatment with intravenous ganciclovir (Cytovene) is required.¹

CASE CONTINUED: POSITIVE TESTS FOR COCCIDIOIDES

Our patient began empiric treatment for community-acquired pneumonia with intravenous ceftriaxone (Rocephin) and azithromycin (Zithromax).

On the basis of these findings, the patient was immediately placed in negative pressure respiratory isolation and underwent induced sputum examinations for tuberculosis. Further tests for S pneumoniae, S aureus, Mycoplasma, Legionella, influenza, Pneumocystis, Cryptococcus, Histoplasma, and Coccidioides species were performed.

QuantiFERON testing was negative, and blood cultures were sterile. The first induced sputum examination was negative for acid-fast bacilli. PCR testing for mycobacterial DNA in the sputum was also negative.

Both silver and direct fluorescent antibody staining of the sputum were negative for Pneumocystis. On the basis of these findings and the patient’s lack of clinical improvement with trimethoprim-sulfamethoxazole, Pneumocystis infection was excluded.

THE PATIENT BEGINS TREATMENT

2. Which treatment is most appropriate for this patient?

• Posaconazole (Noxafil)
• Caspofungin (Cancidas) and surgery
• Fluconazole
• Voriconazole (Vfend) and surgery
• Amphotericin B

Solitary pulmonary cavities tend to be asymptomatic and do not require treatment, even if coccidioidal infection is microbiologically confirmed.

However, if there is pain, hemoptysis, or bacterial superinfection, antifungal therapy may result in improvement but not closure of the cavity.¹⁸ Therefore, in all cases of symptomatic coccidioidal pulmonary cavities, surgical resection is the only definitive treatment.

Coccidioidal cavities may rupture and cause pyopneumothorax, but this is an infrequent complication, and antifungal therapy combined with surgical decortication is the treatment of choice.¹⁸

Commonly prescribed antifungals include fluconazole and amphotericin B, the latter usually reserved for patients with significant hypoxia or rapid clinical deterioration.¹⁸ At this time, there are not enough clinical data to show that voriconazole or posaconazole is effective, and thus neither is approved for the treatment of coccidioidomycosis. Likewise, there have been no human trials of the efficacy of caspofungin against Coccidioides infection, although it has been shown to be active in mouse models.¹⁸

Our patient was started on oral fluconazole and observed for clinical improvement or, conversely, for signs of dissemination. After 2 days, he had markedly improved, and within 1 week he was almost back to his baseline level of health. Testing for all other infectious etiologies was unrevealing, and he was removed from negative pressure isolation.

However, as we mentioned above, his CD4 count was 5 cells/μL. We discussed the issue with the patient, and he said he was willing to comply with his treatment for both his Coccidioides and his HIV infection. After much deliberation, he said he was also willing to start and comply with prophylactic treatment for opportunistic infections.

PREVENTING OPPORTUNISTIC INFECTIONS IN HIV PATIENTS

3. Which of the following prophylactic regimens is most appropriate for this patient?

• Trimethoprim-sulfamethoxazole, atovaquone (Mepron), and azithromycin
• Trimethoprim-sulfamethoxazole and azithromycin
• Pentamidine (Nebupent), dapsone, and clarithromycin (Biaxin)
• Dapsone and clarithromycin
• Trimethoprim-sulfamethoxazole by itself

According to guidelines for the prevention of opportunistic diseases in patients with HIV, he needs primary prophylaxis against the following organisms: P jirovecii, Toxoplasma gondii, and Mycobacterium avium complex.¹

The CD4 count dictates the appropriate time to start therapy. If the count is lower than 200 cells/μL or if the patient has oropharyngeal candidiasis regardless of the CD4 count, trimethoprim-sulfamethoxazole is indicated to prevent P jirovecii pneumonia. In those who cannot tolerate trimethoprim-sulfamethoxazole or who are allergic to it, dapsone, pentamidine, or atovaquone can be substituted.¹

In patients seropositive for T gondii, a CD4 count lower than 100/μL indicates the need for prophylaxis.¹ Prophylactic measures are similar to those for Pneumocystis. However, if the patient cannot tolerate trimethoprim-sulfamethoxazole, the recommended alternative is dapsone-pyrimethamine with leucovorin, which is also effective against Pneumocystis.¹

Finally, if the CD4 count is lower than 50 cells/μL, prophylaxis against M avium complex is mandatory, with either azithromycin weekly or clarithromycin daily.¹

Given our patient’s degree of immunosuppression, trimethoprim-sulfamethoxazole plus azithromycin is his most appropriate option.

Trimethoprim-sulfamethoxazole and azithromycin were added to his antimicrobial regimen before he was discharged. Two weeks later, he noted no side effects from any of the medications, he had no new symptoms, he was feeling well, and his cough had improved greatly. He did not have any signs of dissemination of his coccidioidal infection, and we concluded that the primary and only infection was located in the lungs.

DISSEMINATED COCCIDIOIDOMYCOSIS

4. Which of the following extrapulmonary sites is Coccidioides least likely to infect?

• Brain
• Skin
• Meninges
• Lymph nodes
• Bones
• Joints

Extrapulmonary coccidioidomycosis can involve almost any site. However, the most common sites of dissemination are the skin, lymph nodes, bones, and joints.¹⁴ The least likely site is the brain.

Central nervous system involvement

In the central nervous system, involvement is typically with the meninges, rather than frank involvement of the brain parenchyma.^18,28,29 Although patients with HIV or those who are otherwise severely immunocompromised are at higher risk for coccidioidal meningitis, it is rare even in this population.^30,31 Meningitis most commonly presents as headache, vomiting, meningismus, confusion, or diplopia.^32,33

If neurologic findings are absent, experts do not generally recommend lumbar puncture because the incidence of meningeal involvement is low. When cerebrospinal fluid is obtained in an active case of coccidioidal meningitis, fluid analysis typically finds elevated protein, low glucose, and lymphocytic pleocytosis.^1,32

Meningeal enhancement on CT or magnetic resonance imaging is common.³⁴ The diagnosis is established by culture or serologic testing of cerebrospinal fluid (IgM titer, IgG titer, immunodiffusion, or complement fixation).¹⁴

Of note, cerebral infarction and hydrocephalus are feared complications and pose a serious risk of death in any patient.^32,35 In these cases, treatment with antifungals is lifelong, regardless of immune system status.¹⁸

Skin involvement

Skin involvement is variable, consisting of nodules, verrucae, abscesses, or ulcerations.^15,16 Hemorrhage from the skin is relatively common.³⁶ From the skin, the infection can spread to the lymph nodes, leading to regional lymphadenopathy.^14,15 Nodes can ulcerate, drain, or even become necrotic.

Bone and joint involvement

Once integrity of the blood vessels is disrupted, Coccidioides can spread via the blood to the bones or joints,^14,15 causing osteomyelitis, septic arthritis, or synovitis. Subcutaneous abscesses or sinus tracts may subsequently develop.^14,15

HOW LONG MUST HE BE TREATED?

On follow-up, the patient asked how long he needed to continue his antifungal regimen and if any other testing for his coccidioidal infection was necessary, since he was feeling better.

5. Which is the most appropriate response to the patient’s question?

• He can discontinue his antifungal drugs; no further testing is necessary
• He needs 14 more days of antifungal therapy and periodic serologic tests
• He needs 2.5 more months of antifungal therapy and monthly blood cultures
• He needs lifelong antifungal therapy and periodic urinary antigen levels
• He needs 5.5 more months of antifungal therapy; bronchoscopy with bronchoalveolar lavage at 1 year

How long to treat and how to monitor for coccidioidomycosis vary by patient.

Duration of therapy depends on symptoms and immune status

The severity of infection (Table 2) and the immune status are important factors that must be considered when tailoring a therapeutic regimen.

Immunocompetent patients without symptoms or with mild symptoms usually do not need therapy and are followed periodically for signs of improvement.^14,18,29

Immunocompetent patients with severe symptoms typically receive 3 to 6 months of antifungal therapy.¹⁸

Immunocompromised patients (especially HIV-infected patients with CD4 counts < 250 cells/μL) need antifungal treatment, regardless of the severity of infection.^14,18,29 In many cases, the type of infection will dictate the duration of therapy.

Diffuse pneumonia or extrapulmonary dissemination typically requires treatment for at least 1 year regardless of immune status.^14,18 For those with HIV and diffuse pneumonia, dissemination, or meningitis, guidelines dictate that secondary prophylaxis be started after at least 1 year of therapy and improvement in clinical status; it should be continued indefinitely to prevent reactivation of latent infection.¹⁸

The guidelines say that in patients with higher CD4 counts (presumably > 250 cells/μL) and nonmeningeal coccidioidomycosis, providers may consider discontinuing secondary prophylaxis, as long as there is clinical evidence of improvement and control of the primary infection.¹⁸ However, many experts advocate continuing secondary prophylaxis regardless of the CD4 count, as the rates of relapse and dissemination are high.^1,16,37

Monitoring

Regardless of the therapy chosen, disease monitoring every 2 to 4 months with clinical history and examination, radiography, and coccidioidal-specific testing is recommended for at least 1 year, and perhaps longer, to ensure complete resolution and to monitor for signs of dissemination.^14,18

Which test to use is not clear. Serologic testing identifies antibodies (IgM or IgG) to coccidioidal antigens. IgM appears during the acute infection, and tests include immunodiffusion, latex agglutination, and enzymelinked immunoassays. The last two are highly sensitive but have a significant false-positive rate, and should be confirmed with the former if found to be positive.^17,18 IgG appears weeks after the acute infection and can be evaluated with immunodiffusion or enzyme-linked immunoassay as well.

Keep in mind that these tests provide only qualitative results on the presence of these antibodies, not quantitative information. Furthermore, enzyme-linked immunoassay is not as accurate as immunodiffusion, which has a sensitivity in immunocompromised patients of only approximately 50%.^38,39

For that reason, complement fixation titers are extremely helpful because they reflect the severity of infection, can be used to monitor the response to treatment, and can even provide insight into the prognosis.¹⁸ The sensitivity of this test in immunocompromised hosts is 60% to 70%.³⁸ Titers can be checked to confirm the diagnosis and can be periodically monitored throughout the treatment course to ensure efficacy of therapy and to watch for reactivation of the infection.¹ In fact, an initial complement fixation titer of 1:2 or 1:4 is associated with favorable outcomes, while a titer greater than 1:16 portends dissemination.¹⁸

The caveat to any serologic test (immunodiffusion, enzyme-linked immunoassay, and complement fixation) is that severely immunocompromised patients (as in our case) may not mount an immune response and may have falsely low titers even in the face of a severe infection, and therefore these tests may not be reliable.³⁸ In these situations, urinary coccidioidal antigen detection assay (sensitivity 71%) or nucleic acid amplification of coccidioidal DNA (sensitivity 75%) may be of more help.^40,41

Therefore, in the setting of HIV infection, an asymptomatic pulmonary cavity, and diffuse pulmonary involvement secondary to coccidioidal infection, lifelong antibiotics (treatment plus secondary prophylaxis) with periodic testing of urinary coccidioidal antigen levels is the best response to the patient’s question, given that his complement fixation titers were initially negative and antigen levels were positive.

CASE CONCLUDED

The patient continues to be followed for his HIV infection. He is undergoing serologic and urinary antigen testing for Coccidioides infection every 3 months in addition to his maintenance HIV testing. He is on chronic suppressive therapy with fluconazole. He has not had a recurrence of his Coccidioides infection, nor have there been any signs of dissemination.

CAVITARY LUNG LESIONS IN HIV PATIENTS

In patients with HIV, cavitary lung lesions on chest radiography can be due to a wide variety of etiologies that range from infection to malignancy. Historical clues, including environmental exposure, occupation, geographic residence, sick contacts, travel, or animal contact can be helpful in ordering subsequent confirmatory testing, especially in the case of infection.

Tuberculosis should be suspected, and appropriate isolation precautions should be taken until it is ruled out.

Laboratory testing, including the complete blood cell count with differential and CD4 count, provide ancillary data to narrow the differential diagnosis. For example, if the CD4 count is greater than 200 cells/μL, mycobacterial infection should be strongly suspected; however, lower CD4 counts should also prompt a search for opportunistic infections. In the appropriate clinical scenario, malignancies including Kaposi sarcoma, non-Hodgkin lymphoma, and bronchogenic carcinoma can be seen and should also be considered.

Nevertheless, the evaluation hinges on the sputum examination and CT scan of the chest to further characterize the cavity, surrounding lung parenchyma, lymph nodes, and potential fluid collections. Usually, further serologic tests and even bronchoscopy with bronchoalveolar lavage and transbronchial biopsy are required. Treatment should begin once the most likely diagnosis is established.

Coccidioidal pneumonia should be considered in all patients with immunodeficiency, including HIV patients, transplant recipients, those undergoing chemotherapy, and those with intrinsic immune system defects, especially if they have a history of exposure or if they are from an endemic region. Antifungal therapy should be initiated early, and dissemination must be ruled out. Suppressive therapy is mandatory for those with a severely compromised immune system, and serologic testing to ensure remission of the infection is needed. Patients who were previously exposed to Coccidioides or who vacationed or live in the southwestern United States (where it is prevalent) are at risk and may present with any number of symptoms.

Treatment for lupus nephritis has changed dramatically in recent years. Only 10 years ago, rheumatologists and nephrologists, whether specializing in adult or pediatric medicine, treated lupus nephritis with a similar regimen of monthly intravenous cyclophosphamide (Cytoxan) and glucocorticoids. Although the regimen is effective, side effects such as infection, hair loss, and infertility were extremely common.

Effective but very toxic therapy is common in autoimmune diseases. In the last decade, clinical trials have shown that less toxic drugs are as effective for treating lupus nephritis. This article will review new developments in therapy for lupus nephritis, which can be viewed as a prototype for other fields of medicine.

DEMOGRAPHICS ARE IMPORTANT

Although numerous factors have prognostic value in lupus nephritis (eg, serum creatinine, proteinuria, renal biopsy findings), the most important to consider when designing and interpreting studies are race and socioeconomic variables.

A retrospective study in Miami, FL,¹ evaluated 213 patients with lupus nephritis, of whom 47% were Hispanic, 44% African American, and 20% white. At baseline, African Americans had higher blood pressure, higher serum creatinine levels, and lower household income. After 6 years, African Americans fared the worst in terms of doubling of serum creatinine, developing end-stage renal disease, and death; whites had the best outcomes, and Hispanics were in between. Low income was found to be a significant risk factor, independent of racial background.

In a similar retrospective study in New York City in 128 patients (43% white, 40% Hispanic, and 17% African American) with proliferative lupus nephritis,² disease was much more likely to progress to renal failure over 10 years in patients living in a poor neighborhood, even after adjustment for race.

We need to keep in mind that racial and socioeconomic factors correlate with disease severity when we design and interpret studies of lupus nephritis. Study groups must be carefully balanced with patients of similar racial and socioeconomic profiles. Study findings must be interpreted with caution; for example, whether results from a study from China are applicable to an African American with lupus nephritis in New York City is unclear.

OLDER STANDARD THERAPY: EFFECTIVE BUT TOXIC

The last large National Institutes of Health study that involved only cyclophosphamide and a glucocorticoid was published in 2001,³ with 21 patients receiving cyclophosphamide alone and 20 patients receiving cyclophosphamide plus methylprednisolone. Although lupus nephritis improved, serious side effects occurred in one-third to one-half of patients in each group and included hypertension, hyperlipidemia, valvular heart disease, avascular necrosis, premature menopause, and major infections, including herpes zoster.

Less cyclophosphamide works just as well

The multicenter, prospective Euro-Lupus Nephritis Trial⁴ randomized 90 patients with proliferative lupus nephritis to receive either standard high-dose intravenous (IV) cyclophosphamide therapy (six monthly pulses and two quarterly pulses, with doses increasing according to the white blood cell count) or low-dose IV cyclophosphamide therapy (six pulses every 2 weeks at a fixed dose of 500 mg). Both regimens were followed by azathioprine (Imuran).

At 4 years, the two treatment groups were not significantly different in terms of treatment failure, remission rates, serum creatinine levels, 24-hour proteinuria, and freedom from renal flares. However, the rates of side effects were significantly different, with more patients in the low-dosage group free of severe infection.

One problem with this study is whether it is applicable to an American lupus nephritis population, since 84% of the patients were white. Since this study, others indicate that this regimen is probably also safe and effective for different racial groups in the United States.

At 10-year follow-up,⁵ both treatment groups still had identical excellent rates of freedom from end-stage renal disease. Serum creatinine and 24-hour proteinuria were also at excellent levels and identical in both groups. Nearly three quarters of patients still needed glucocorticoid therapy and more than half still needed immunosuppressive therapy, but the rates were not statistically significantly different between the treatment groups.

The cumulative dose of cyclophosphamide was 9.5 g in the standard-treatment group and 5.5 g in the low-dose group. This difference in exposure could make a tremendous difference to patients, not only for immediate side effects such as early menopause and infections, but for the risk of cancer in later decades.

This study showed clearly that low-dose cyclophosphamide is an option for induction therapy. Drawbacks of the study were that the population was mostly white and that patients had only moderately severe disease.

Low-dose cyclophosphamide has largely replaced the older National Institutes of Health regimen, although during the last decade drug therapy has undergone more changes.

MYCOPHENOLATE AND AZATHIOPRINE: ALTERNATIVES TO CYCLOPHOSPHAMIDE

In a Chinese study, mycophenolate was better than cyclophosphamide for induction

In a study in Hong Kong, Chan et al⁶ randomized 42 patients with severe lupus nephritis to receive either mycophenolate mofetil (available in the United States as CellCept; 2 g/day for 6 months, then 1 g/day for 6 months) or oral cyclophosphamide (2.5 mg/kg per day for 6 months) followed by azathioprine (1.5–2.0 mg/kg per day) for 6 months. Both groups also received prednisolone during the year.

At the end of the first year, the two groups were not significantly different in their rates of complete remission, partial remission, and relapse. The rate of infection, although not significantly different, was higher in the cyclophosphamide group (33% vs 19%). Two patients (10%) died in the cyclophosphamide group, but the difference in mortality rates was not statistically significant.

Nearly 5 years later,⁷ rates of chronic renal failure and relapse were still statistically the same in the two groups. Infections were fewer in the mycophenolate group (13% vs 40%, P = .013). The rate of amenorrhea was 36% in the cyclophosphamide group and only 4% in the mycophenolate group (P = .004). Four patients in the cyclophosphamide group and none in the mycophenolate group reached the composite end point of end-stage renal failure or death (P = .062).

This study appeared to offer a new option with equal efficacy and fewer side effects than standard therapy. However, its applicability to non-Chinese populations remained to be shown.

In a study in Miami,⁸ 59 patients with lupus nephritis were given standard induction therapy with IV cyclophosphamide plus glucocorticoids for 6 months, then randomly assigned to one of three maintenance therapies for 1 to 3 years: IV injections of cyclophosphamide every 3 months (standard therapy), oral azathioprine, or oral mycophenolate. The population was 93% female, their average age was 33 years, and nearly half were African American, with many of the others being Hispanic. Patients tended to have severe disease, with nearly two-thirds having nephrotic syndrome.

After 6 years, there had been more deaths in the cyclophosphamide group than in the azathioprine group (P = .02) and in the mycophenolate group, although the latter difference was not statistically significant (P = .11). The combined rate of death and chronic renal failure was significantly higher with cyclophosphamide than with either of the oral agents. The cyclophosphamide group also had the highest relapse rate during the maintenance phase.

The differences in side effects were even more dramatic. Amenorrhea affected 32% of patients in the cyclophosphamide group, and only 7% and 6% in the azathioprine and mycophenolate groups, respectively. Rates of infections were 68% in the cyclophosphamide group and 28% and 21% in the azathioprine and mycophenolate groups, respectively. Patients given cyclophosphamide had 13 hospital days per patient per year, while the other groups each had only 1.

This study showed that maintenance therapy with oral azathioprine or mycophenolate was more effective and had fewer adverse effects than standard IV cyclophosphamide therapy. As a result of this study, oral agents for maintenance therapy became the new standard, but the question remained whether oral agents could safely be used for induction.

In a US study, mycophenolate was better than cyclophosphamide for induction

In a noninferiority study, Ginzler et al⁹ randomized 140 patients with severe lupus nephritis to receive either monthly IV cyclophosphamide or oral mycophenolate as induction therapy for 6 months. Adjunctive care with glucocorticoids was given in both groups. The study population was from 18 US academic centers and was predominantly female, and more than half were African American.

After 24 weeks, 22.5% of the mycophenolate patients were in complete remission by very strict criteria vs only 4% of those given cyclophosphamide (P = .005). The trend for partial remissions was also in favor of mycophenolate, although the difference was not statistically significant. The rate of complete and partial remissions, a prespecified end point, was significantly higher in the mycophenolate group. Although the study was trying to evaluate equivalency, it actually showed superiority for mycophenolate induction therapy.

Serum creatinine levels declined in both groups, but more in the mycophenolate group by 24 weeks. Urinary protein levels fell the same amount in both groups. At 3 years, the groups were statistically equivalent in terms of renal flares, renal failures, and deaths. However, the study groups were small, and the mycophenolate group did have a better trend for both renal failure (N = 4 vs 7) and deaths (N = 4 vs 8).

Mycophenolate also had fewer side effects, including infection, although again the numbers were too small to show statistical significance. The exception was diarrhea (N = 15 in the mycophenolate group vs 2 in the cyclophosphamide group).

A drawback of the study is that it was designed as a crossover study: a patient for whom therapy was failing after 3 months could switch to the other group, introducing potential confounding. Other problems involved the small population size and the question of whether results from patients in the United States were applicable to others worldwide.

In a worldwide study, mycophenolate was at least equivalent to cyclophosphamide for induction

The Aspreva Lupus Management Study (ALMS)¹⁰ used a similar design with 370 patients worldwide (United States, China, South America, and Europe) in one of the largest trials ever conducted in lupus nephritis. Patients were randomized to 6 months of induction therapy with either IV cyclophosphamide or oral mycophenolate but could not cross over.

At 6 months, response rates were identical between the two groups, with response defined as a combination of specific improvement in proteinuria, serum creatinine, and hematuria (50%–55%). In terms of individual renal and nonrenal variables, both groups appeared identical.

However, the side effect profiles differed between the two groups. As expected for mycophenolate, diarrhea was the most common side effect (occurring in 28% vs 12% in the cyclophosphamide group). Nausea and vomiting were more common with cyclophosphamide (45% and 37% respectively vs 14% and 13% in the mycophenolate group). Cyclophosphamide also caused hair loss in 35%, vs 10% in the mycophenolate group.

There were 14 deaths overall, which is a very low number considering the patients’ severity of illness, and it indicates the better results now achieved with therapy. The mortality rate was higher in the mycophenolate group (5% vs 3%), but the difference was not statistically significant. Six of the nine deaths with mycophenolate were from the same center in China, and none were from Europe or the United States. In summary, the study did not show that mycophenolate was superior to IV cyclophosphamide for induction therapy, but that they were equivalent in efficacy with different side effect profiles.

Membranous nephropathy: Mycophenolate vs cyclophosphamide

Less evidence is available about treatment for membranous disease, which is characterized by heavy proteinuria and the nephrotic syndrome but usually does not progress to renal failure. Radhakrishnan et al¹¹ combined data from the trial by Ginzler et al⁹ and the ALMS trial¹⁰ and found 84 patients with pure membranous lupus, who were equally divided between the treatment groups receiving IV cyclophosphamide and mycophenolate. Consistent with the larger group’s data, mycophenolate and cyclophosphamide performed similarly in terms of efficacy, but there was a slightly higher rate of side effects with cyclophosphamide.

Maintenance therapy: Mycophenolate superior to azathioprine

The ALMS Maintenance Trial¹² evaluated maintenance therapy in the same worldwide population that was studied for induction therapy. Of the 370 patients involved in the induction phase that compared IV cyclophosphamide and oral mycophenolate, 227 responded sufficiently to be rerandomized in a controlled, double-blinded trial of 36 months of maintenance therapy with corticosteroids and either mycophenolate (1 g twice daily) or azathioprine (2 mg/kg per day).

In intention-to-treat analysis, the time to treatment failure (ie, doubling of the serum creatinine level, progressing to renal failure, or death) was significantly shorter in the azathioprine group (P = .003). Every individual end point—end-stage renal disease, renal flares, doubling of serum creatinine, rescue immunosuppression required—was in favor of mycophenolate maintenance. At 3 years, the completion rate was 63% with mycophenolate and 49% with azathioprine. Serious adverse events and withdrawals because of adverse events were more common in the azathioprine group.

In summary, mycophenolate was superior to azathioprine in maintaining renal response and in preventing relapse in patients with active lupus nephritis who responded to induction therapy with either mycophenolate or IV cyclophosphamide. Mycophenolate was found to be superior regardless of initial induction treatment, race, or region and was confirmed by all key secondary end points.

Only one of the 227 patients died during the 3 years—from an auto accident. Again, this indicates the dramatically improved survival today compared with a decade ago.

RITUXIMAB: PROMISING BUT UNPROVEN

Rituximab (Rituxan) was originally approved to treat tumors, then rheumatoid arthritis, and most recently vasculitis. Evidence thus far is mixed regarding its use as a treatment for lupus nephritis. Although randomized clinical trials have not found it to be superior to standard regimens, there are many signs that it may be effective.

Rituximab in uncontrolled studies

Terrier et al¹³ analyzed prospective data from 136 patients with systemic lupus erythematosus, most of whom had renal disease, from the French Autoimmunity and Rituximab registry. Response occurred in 71% of patients using rituximab, with no difference found between patients receiving rituximab monotherapy and those concomitantly receiving immunosuppressive agents.

Melander et al¹⁴ retrospectively studied 19 women and 1 man who had been treated with rituximab for severe lupus nephritis and followed for at least 1 year. Three patients had concurrent therapy with cyclophosphamide, and 10 patients continued rituximab as maintenance therapy; 12 patients had lupus nephritis that had been refractory to standard treatment, and 6 had relapsing disease.

At a median follow-up of 22 months, 12 patients (60%) had achieved complete or partial renal remission.

Condon et al¹⁵ treated 21 patients who had severe lupus nephritis with two doses of rituximab and IV methylprednisolone 2 weeks apart, then maintenance therapy with mycophenolate without any oral steroids. At a mean follow-up of 35 months ( ± 14 months), 16 (76%) were in complete remission, with a mean time to remission of 12 months. Two (9.5%) achieved partial remission. The rate of toxicity was low.

Thus, rituximab appears promising in uncontrolled studies.

Placebo-controlled trials fail to prove rituximab effective

LUNAR trial. On the other hand, the largest placebo-controlled trial to evaluate rituximab in patients with proliferative lupus nephritis, the Lupus Nephritis Assessment With Rituximab (LUNAR) trial¹⁶ found differences in favor of rituximab, but none reached statistical significance. The trial randomized 140 patients to receive either mycophenolate plus periodic rituximab infusions or mycophenolate plus placebo infusions for 1 year. All patients received the same dosage of glucocorticoids, which was tapered over the year.

At the end of 1 year, the groups were not statistically different in terms of complete renal response and partial renal response. Rituximab appeared less likely to produce no response, but the difference was not statistically significant.

African Americans appeared to have a higher response rate to rituximab (70% in the rituximab group achieved a response vs 45% in the control group), but again, the difference did not reach statistical significance, and the total study population of African Americans was only 40.

Rituximab did have a statistically significant positive effect on two serologic markers at 1 year: levels of anti-dsDNA fell faster and complement rose faster. In addition, rates of adverse and serious adverse events were similar between the two groups, with no new or unexpected “safety signals.”

This study can be interpreted in a number of ways. The number of patients may have been too small to show significance and the follow-up may have been too short. On the other hand, it may simply not be effective to add rituximab to a full dose of mycophenolate and steroids, an already good treatment.

EXPLORER trial. Similarly, for patients with lupus without nephritis, the Exploratory Phase II/III SLE Evaluation of Rituximab (EXPLORER) trial¹⁷ also tested rituximab against a background of an effective therapeutic regimen and found no additional benefit. This study had design problems similar to those of the LUNAR trial.

Rituximab as rescue therapy

The evidence so far indicates that rituximab may have a role as rescue therapy for refractory or relapsing disease. Rituximab must be used with other therapies, but maintenance corticosteroid therapy is not necessary. Its role as a first-line agent in induction therapy for lupus nephritis remains unclear, although it may have an important role for nonwhites. In general, it has been well tolerated. Until a large randomized trial indicates otherwise, it should not be used as a first-line therapy.

The US Food and Drug Administration (FDA) sent out a warning about the danger of progressive multifocal leukoencephalopathy as an adverse effect of rituximab and of mycophenolate, but this does not appear to be a major concern for most patients and is only likely to occur in those who have been over-immunosuppressed for many years.

MULTITARGET THERAPY

The concept of using multiple drugs simultaneously—such as mycophenolate, steroids, and rituximab—is increasingly being tried. Multi-target therapy appears to offer the advantages of combining different modes of action with better results, and it offers fewer side effects because dosages of each individual drug can be lower when combined with other immunosuppressives.

Bao et al¹⁸ in China randomly assigned 40 patients with diffuse proliferative and membranous nephritis to 6 to 9 months of induction treatment with either multitarget therapy (mycophenolate, tacrolimus [Prograf], and glucocorticoids) or IV cyclophosphamide. More complete remissions occurred in the multitarget therapy group, both at 6 months (50% vs 5%) and at 9 months (65% vs 15%). Most adverse events were less frequent in the multitarget therapy group, although three patients (15%) in the multitarget therapy group developed new-onset hypertension vs none in the cyclophosphamide group.

NEW MEDICATIONS

Entirely new classes of drugs are being developed with immunomodulatory effects, including tolerance molecules, cytokine blockers, inhibitors of human B lymphocyte stimulator, and costimulatory blockers.

Belimumab offers small improvement for lupus

Belimumab (Benlysta) is a human monoclonal antibody that inhibits the biologic activity of human B lymphocyte stimulator; it has recently been approved by the FDA for lupus nephritis. In a worldwide study,¹⁹ 867 patients with systemic lupus erythematosus were randomized to receive either belimumab (1 mg/kg or 10 mg/kg) or placebo.

The primary end point was the reduction of disease activity by a scoring system (SELENA-SLEDAI) that incorporated multiple features of lupus, including arthritis, vasculitis, proteinuria, rash, and others. Patients in the belimumab group had better outcomes, but the results were not dramatic. Because the drug is so expensive (about $25,000 per year) and the improvement offered is only incremental, this drug will not likely change the treatment of lupus very much.

Moreover, patients with lupus nephritis were not included in the study, but a new study is being planned to do so. Improvement is harder to demonstrate in lupus nephritis than in rheumatoid arthritis and systemic lupus erythematosus: significant changes in creatinine levels and 24-hour urinary protein must be achieved, rather than more qualitative signs and symptoms of joint pain, rash, and feeling better. Although belimumab is still unproven for lupus nephritis, it might be worth trying for patients failing other therapy.

Laquinimod: A promising experimental drug

Laquinimod is an oral immunomodulatory drug with a number of effects, including down-regulating major histocompatability complex II, chemokines, and adhesion-related molecules related to inflammation. It has been studied in more than 2,500 patients with multiple sclerosis. Pilot studies are now being done for its use for lupus nephritis. If it shows promise, a large randomized, controlled trial will be conducted.

Abatacept is in clinical trials

Abatacept (Orencia), a costimulation blocker, is undergoing clinical trials in lupus nephritis. Results should be available shortly.

INDIVIDUALIZE THERAPY

This past decade has seen such an increase in options to treat lupus nephritis that therapy can now be individualized.

Choosing IV cyclophosphamide vs mycophenolate

As a result of recent trials, doctors in the United States are increasingly using mycophenolate as the first-line drug for lupus nephritis. In Europe, however, many are choosing the shorter regimen of IV cyclophosphamide because of the results of the Euro-Lupus study.

Nowadays, I tend to use IV cyclophosphamide as the first-line drug only for patients with severe crescenteric glomerulonephritis or a very high serum creatinine level. In such cases, there is more experience with cyclophosphamide, and such severe disease does not lend itself to the luxury of trying out different therapies sequentially. If such a severely ill patient insists that a future pregnancy is very important, an alternative therapy of mycophenolate plus rituximab should be considered. I prefer mycophenolate for induction and maintenance therapy in most patients.

Dosing and formulation considerations for mycophenolate

Large dosages of mycophenolate are much better tolerated when broken up throughout the day. A patient who cannot tolerate 1 g twice daily may be able to tolerate 500 mg four times a day. The formulation can also make a difference. Some patients tolerate sustained-release mycophenolate (Myfortic) better than CellCept, and vice versa.

For patients who cannot tolerate mycophenolate, azathioprine is an acceptable alternative. In addition, for a patient who is already doing well on azathioprine, there is no need to change to mycophenolate.

Long maintenance therapy now acceptable

The ALMS Maintenance Trial¹² found 3 years of maintenance therapy to be safe and effective. Such a long maintenance period is increasingly viewed as important, especially for patients in their teens and 20s, as it allows them to live a normal life, ie, to finish their education, get married, and become settled socially. Whether 5 years of maintenance therapy or even 10 years is advisable is still unknown.

Treatment during pregnancy

Neither mycophenolate nor azathioprine is recommended during pregnancy, although their effects are unknown. Because we have much more renal transplant experience with azathioprine during pregnancy, I recommend either switching from mycophenolate to azathioprine or trying to stop medication altogether if the patient has been well controlled.

Treatment for lupus nephritis has changed dramatically in recent years. Only 10 years ago, rheumatologists and nephrologists, whether specializing in adult or pediatric medicine, treated lupus nephritis with a similar regimen of monthly intravenous cyclophosphamide (Cytoxan) and glucocorticoids. Although the regimen is effective, side effects such as infection, hair loss, and infertility were extremely common.

Effective but very toxic therapy is common in autoimmune diseases. In the last decade, clinical trials have shown that less toxic drugs are as effective for treating lupus nephritis. This article will review new developments in therapy for lupus nephritis, which can be viewed as a prototype for other fields of medicine.

DEMOGRAPHICS ARE IMPORTANT

Although numerous factors have prognostic value in lupus nephritis (eg, serum creatinine, proteinuria, renal biopsy findings), the most important to consider when designing and interpreting studies are race and socioeconomic variables.

A retrospective study in Miami, FL,¹ evaluated 213 patients with lupus nephritis, of whom 47% were Hispanic, 44% African American, and 20% white. At baseline, African Americans had higher blood pressure, higher serum creatinine levels, and lower household income. After 6 years, African Americans fared the worst in terms of doubling of serum creatinine, developing end-stage renal disease, and death; whites had the best outcomes, and Hispanics were in between. Low income was found to be a significant risk factor, independent of racial background.

In a similar retrospective study in New York City in 128 patients (43% white, 40% Hispanic, and 17% African American) with proliferative lupus nephritis,² disease was much more likely to progress to renal failure over 10 years in patients living in a poor neighborhood, even after adjustment for race.

We need to keep in mind that racial and socioeconomic factors correlate with disease severity when we design and interpret studies of lupus nephritis. Study groups must be carefully balanced with patients of similar racial and socioeconomic profiles. Study findings must be interpreted with caution; for example, whether results from a study from China are applicable to an African American with lupus nephritis in New York City is unclear.

OLDER STANDARD THERAPY: EFFECTIVE BUT TOXIC

The last large National Institutes of Health study that involved only cyclophosphamide and a glucocorticoid was published in 2001,³ with 21 patients receiving cyclophosphamide alone and 20 patients receiving cyclophosphamide plus methylprednisolone. Although lupus nephritis improved, serious side effects occurred in one-third to one-half of patients in each group and included hypertension, hyperlipidemia, valvular heart disease, avascular necrosis, premature menopause, and major infections, including herpes zoster.

Less cyclophosphamide works just as well

The multicenter, prospective Euro-Lupus Nephritis Trial⁴ randomized 90 patients with proliferative lupus nephritis to receive either standard high-dose intravenous (IV) cyclophosphamide therapy (six monthly pulses and two quarterly pulses, with doses increasing according to the white blood cell count) or low-dose IV cyclophosphamide therapy (six pulses every 2 weeks at a fixed dose of 500 mg). Both regimens were followed by azathioprine (Imuran).

At 4 years, the two treatment groups were not significantly different in terms of treatment failure, remission rates, serum creatinine levels, 24-hour proteinuria, and freedom from renal flares. However, the rates of side effects were significantly different, with more patients in the low-dosage group free of severe infection.

One problem with this study is whether it is applicable to an American lupus nephritis population, since 84% of the patients were white. Since this study, others indicate that this regimen is probably also safe and effective for different racial groups in the United States.

At 10-year follow-up,⁵ both treatment groups still had identical excellent rates of freedom from end-stage renal disease. Serum creatinine and 24-hour proteinuria were also at excellent levels and identical in both groups. Nearly three quarters of patients still needed glucocorticoid therapy and more than half still needed immunosuppressive therapy, but the rates were not statistically significantly different between the treatment groups.

The cumulative dose of cyclophosphamide was 9.5 g in the standard-treatment group and 5.5 g in the low-dose group. This difference in exposure could make a tremendous difference to patients, not only for immediate side effects such as early menopause and infections, but for the risk of cancer in later decades.

This study showed clearly that low-dose cyclophosphamide is an option for induction therapy. Drawbacks of the study were that the population was mostly white and that patients had only moderately severe disease.

Low-dose cyclophosphamide has largely replaced the older National Institutes of Health regimen, although during the last decade drug therapy has undergone more changes.

MYCOPHENOLATE AND AZATHIOPRINE: ALTERNATIVES TO CYCLOPHOSPHAMIDE

In a Chinese study, mycophenolate was better than cyclophosphamide for induction

In a study in Hong Kong, Chan et al⁶ randomized 42 patients with severe lupus nephritis to receive either mycophenolate mofetil (available in the United States as CellCept; 2 g/day for 6 months, then 1 g/day for 6 months) or oral cyclophosphamide (2.5 mg/kg per day for 6 months) followed by azathioprine (1.5–2.0 mg/kg per day) for 6 months. Both groups also received prednisolone during the year.

At the end of the first year, the two groups were not significantly different in their rates of complete remission, partial remission, and relapse. The rate of infection, although not significantly different, was higher in the cyclophosphamide group (33% vs 19%). Two patients (10%) died in the cyclophosphamide group, but the difference in mortality rates was not statistically significant.

Nearly 5 years later,⁷ rates of chronic renal failure and relapse were still statistically the same in the two groups. Infections were fewer in the mycophenolate group (13% vs 40%, P = .013). The rate of amenorrhea was 36% in the cyclophosphamide group and only 4% in the mycophenolate group (P = .004). Four patients in the cyclophosphamide group and none in the mycophenolate group reached the composite end point of end-stage renal failure or death (P = .062).

This study appeared to offer a new option with equal efficacy and fewer side effects than standard therapy. However, its applicability to non-Chinese populations remained to be shown.

In a study in Miami,⁸ 59 patients with lupus nephritis were given standard induction therapy with IV cyclophosphamide plus glucocorticoids for 6 months, then randomly assigned to one of three maintenance therapies for 1 to 3 years: IV injections of cyclophosphamide every 3 months (standard therapy), oral azathioprine, or oral mycophenolate. The population was 93% female, their average age was 33 years, and nearly half were African American, with many of the others being Hispanic. Patients tended to have severe disease, with nearly two-thirds having nephrotic syndrome.

After 6 years, there had been more deaths in the cyclophosphamide group than in the azathioprine group (P = .02) and in the mycophenolate group, although the latter difference was not statistically significant (P = .11). The combined rate of death and chronic renal failure was significantly higher with cyclophosphamide than with either of the oral agents. The cyclophosphamide group also had the highest relapse rate during the maintenance phase.

The differences in side effects were even more dramatic. Amenorrhea affected 32% of patients in the cyclophosphamide group, and only 7% and 6% in the azathioprine and mycophenolate groups, respectively. Rates of infections were 68% in the cyclophosphamide group and 28% and 21% in the azathioprine and mycophenolate groups, respectively. Patients given cyclophosphamide had 13 hospital days per patient per year, while the other groups each had only 1.

This study showed that maintenance therapy with oral azathioprine or mycophenolate was more effective and had fewer adverse effects than standard IV cyclophosphamide therapy. As a result of this study, oral agents for maintenance therapy became the new standard, but the question remained whether oral agents could safely be used for induction.

In a US study, mycophenolate was better than cyclophosphamide for induction

In a noninferiority study, Ginzler et al⁹ randomized 140 patients with severe lupus nephritis to receive either monthly IV cyclophosphamide or oral mycophenolate as induction therapy for 6 months. Adjunctive care with glucocorticoids was given in both groups. The study population was from 18 US academic centers and was predominantly female, and more than half were African American.

After 24 weeks, 22.5% of the mycophenolate patients were in complete remission by very strict criteria vs only 4% of those given cyclophosphamide (P = .005). The trend for partial remissions was also in favor of mycophenolate, although the difference was not statistically significant. The rate of complete and partial remissions, a prespecified end point, was significantly higher in the mycophenolate group. Although the study was trying to evaluate equivalency, it actually showed superiority for mycophenolate induction therapy.

Serum creatinine levels declined in both groups, but more in the mycophenolate group by 24 weeks. Urinary protein levels fell the same amount in both groups. At 3 years, the groups were statistically equivalent in terms of renal flares, renal failures, and deaths. However, the study groups were small, and the mycophenolate group did have a better trend for both renal failure (N = 4 vs 7) and deaths (N = 4 vs 8).

Mycophenolate also had fewer side effects, including infection, although again the numbers were too small to show statistical significance. The exception was diarrhea (N = 15 in the mycophenolate group vs 2 in the cyclophosphamide group).

A drawback of the study is that it was designed as a crossover study: a patient for whom therapy was failing after 3 months could switch to the other group, introducing potential confounding. Other problems involved the small population size and the question of whether results from patients in the United States were applicable to others worldwide.

In a worldwide study, mycophenolate was at least equivalent to cyclophosphamide for induction

The Aspreva Lupus Management Study (ALMS)¹⁰ used a similar design with 370 patients worldwide (United States, China, South America, and Europe) in one of the largest trials ever conducted in lupus nephritis. Patients were randomized to 6 months of induction therapy with either IV cyclophosphamide or oral mycophenolate but could not cross over.

At 6 months, response rates were identical between the two groups, with response defined as a combination of specific improvement in proteinuria, serum creatinine, and hematuria (50%–55%). In terms of individual renal and nonrenal variables, both groups appeared identical.

However, the side effect profiles differed between the two groups. As expected for mycophenolate, diarrhea was the most common side effect (occurring in 28% vs 12% in the cyclophosphamide group). Nausea and vomiting were more common with cyclophosphamide (45% and 37% respectively vs 14% and 13% in the mycophenolate group). Cyclophosphamide also caused hair loss in 35%, vs 10% in the mycophenolate group.

There were 14 deaths overall, which is a very low number considering the patients’ severity of illness, and it indicates the better results now achieved with therapy. The mortality rate was higher in the mycophenolate group (5% vs 3%), but the difference was not statistically significant. Six of the nine deaths with mycophenolate were from the same center in China, and none were from Europe or the United States. In summary, the study did not show that mycophenolate was superior to IV cyclophosphamide for induction therapy, but that they were equivalent in efficacy with different side effect profiles.

Membranous nephropathy: Mycophenolate vs cyclophosphamide

Less evidence is available about treatment for membranous disease, which is characterized by heavy proteinuria and the nephrotic syndrome but usually does not progress to renal failure. Radhakrishnan et al¹¹ combined data from the trial by Ginzler et al⁹ and the ALMS trial¹⁰ and found 84 patients with pure membranous lupus, who were equally divided between the treatment groups receiving IV cyclophosphamide and mycophenolate. Consistent with the larger group’s data, mycophenolate and cyclophosphamide performed similarly in terms of efficacy, but there was a slightly higher rate of side effects with cyclophosphamide.

Maintenance therapy: Mycophenolate superior to azathioprine

The ALMS Maintenance Trial¹² evaluated maintenance therapy in the same worldwide population that was studied for induction therapy. Of the 370 patients involved in the induction phase that compared IV cyclophosphamide and oral mycophenolate, 227 responded sufficiently to be rerandomized in a controlled, double-blinded trial of 36 months of maintenance therapy with corticosteroids and either mycophenolate (1 g twice daily) or azathioprine (2 mg/kg per day).

In intention-to-treat analysis, the time to treatment failure (ie, doubling of the serum creatinine level, progressing to renal failure, or death) was significantly shorter in the azathioprine group (P = .003). Every individual end point—end-stage renal disease, renal flares, doubling of serum creatinine, rescue immunosuppression required—was in favor of mycophenolate maintenance. At 3 years, the completion rate was 63% with mycophenolate and 49% with azathioprine. Serious adverse events and withdrawals because of adverse events were more common in the azathioprine group.

In summary, mycophenolate was superior to azathioprine in maintaining renal response and in preventing relapse in patients with active lupus nephritis who responded to induction therapy with either mycophenolate or IV cyclophosphamide. Mycophenolate was found to be superior regardless of initial induction treatment, race, or region and was confirmed by all key secondary end points.

Only one of the 227 patients died during the 3 years—from an auto accident. Again, this indicates the dramatically improved survival today compared with a decade ago.

RITUXIMAB: PROMISING BUT UNPROVEN

Rituximab (Rituxan) was originally approved to treat tumors, then rheumatoid arthritis, and most recently vasculitis. Evidence thus far is mixed regarding its use as a treatment for lupus nephritis. Although randomized clinical trials have not found it to be superior to standard regimens, there are many signs that it may be effective.

Rituximab in uncontrolled studies

Terrier et al¹³ analyzed prospective data from 136 patients with systemic lupus erythematosus, most of whom had renal disease, from the French Autoimmunity and Rituximab registry. Response occurred in 71% of patients using rituximab, with no difference found between patients receiving rituximab monotherapy and those concomitantly receiving immunosuppressive agents.

Melander et al¹⁴ retrospectively studied 19 women and 1 man who had been treated with rituximab for severe lupus nephritis and followed for at least 1 year. Three patients had concurrent therapy with cyclophosphamide, and 10 patients continued rituximab as maintenance therapy; 12 patients had lupus nephritis that had been refractory to standard treatment, and 6 had relapsing disease.

At a median follow-up of 22 months, 12 patients (60%) had achieved complete or partial renal remission.

Condon et al¹⁵ treated 21 patients who had severe lupus nephritis with two doses of rituximab and IV methylprednisolone 2 weeks apart, then maintenance therapy with mycophenolate without any oral steroids. At a mean follow-up of 35 months ( ± 14 months), 16 (76%) were in complete remission, with a mean time to remission of 12 months. Two (9.5%) achieved partial remission. The rate of toxicity was low.

Thus, rituximab appears promising in uncontrolled studies.

Placebo-controlled trials fail to prove rituximab effective

LUNAR trial. On the other hand, the largest placebo-controlled trial to evaluate rituximab in patients with proliferative lupus nephritis, the Lupus Nephritis Assessment With Rituximab (LUNAR) trial¹⁶ found differences in favor of rituximab, but none reached statistical significance. The trial randomized 140 patients to receive either mycophenolate plus periodic rituximab infusions or mycophenolate plus placebo infusions for 1 year. All patients received the same dosage of glucocorticoids, which was tapered over the year.

At the end of 1 year, the groups were not statistically different in terms of complete renal response and partial renal response. Rituximab appeared less likely to produce no response, but the difference was not statistically significant.

African Americans appeared to have a higher response rate to rituximab (70% in the rituximab group achieved a response vs 45% in the control group), but again, the difference did not reach statistical significance, and the total study population of African Americans was only 40.

Rituximab did have a statistically significant positive effect on two serologic markers at 1 year: levels of anti-dsDNA fell faster and complement rose faster. In addition, rates of adverse and serious adverse events were similar between the two groups, with no new or unexpected “safety signals.”

This study can be interpreted in a number of ways. The number of patients may have been too small to show significance and the follow-up may have been too short. On the other hand, it may simply not be effective to add rituximab to a full dose of mycophenolate and steroids, an already good treatment.

EXPLORER trial. Similarly, for patients with lupus without nephritis, the Exploratory Phase II/III SLE Evaluation of Rituximab (EXPLORER) trial¹⁷ also tested rituximab against a background of an effective therapeutic regimen and found no additional benefit. This study had design problems similar to those of the LUNAR trial.

Rituximab as rescue therapy

The evidence so far indicates that rituximab may have a role as rescue therapy for refractory or relapsing disease. Rituximab must be used with other therapies, but maintenance corticosteroid therapy is not necessary. Its role as a first-line agent in induction therapy for lupus nephritis remains unclear, although it may have an important role for nonwhites. In general, it has been well tolerated. Until a large randomized trial indicates otherwise, it should not be used as a first-line therapy.

The US Food and Drug Administration (FDA) sent out a warning about the danger of progressive multifocal leukoencephalopathy as an adverse effect of rituximab and of mycophenolate, but this does not appear to be a major concern for most patients and is only likely to occur in those who have been over-immunosuppressed for many years.

MULTITARGET THERAPY

The concept of using multiple drugs simultaneously—such as mycophenolate, steroids, and rituximab—is increasingly being tried. Multi-target therapy appears to offer the advantages of combining different modes of action with better results, and it offers fewer side effects because dosages of each individual drug can be lower when combined with other immunosuppressives.

Bao et al¹⁸ in China randomly assigned 40 patients with diffuse proliferative and membranous nephritis to 6 to 9 months of induction treatment with either multitarget therapy (mycophenolate, tacrolimus [Prograf], and glucocorticoids) or IV cyclophosphamide. More complete remissions occurred in the multitarget therapy group, both at 6 months (50% vs 5%) and at 9 months (65% vs 15%). Most adverse events were less frequent in the multitarget therapy group, although three patients (15%) in the multitarget therapy group developed new-onset hypertension vs none in the cyclophosphamide group.

NEW MEDICATIONS

Entirely new classes of drugs are being developed with immunomodulatory effects, including tolerance molecules, cytokine blockers, inhibitors of human B lymphocyte stimulator, and costimulatory blockers.

Belimumab offers small improvement for lupus

Belimumab (Benlysta) is a human monoclonal antibody that inhibits the biologic activity of human B lymphocyte stimulator; it has recently been approved by the FDA for lupus nephritis. In a worldwide study,¹⁹ 867 patients with systemic lupus erythematosus were randomized to receive either belimumab (1 mg/kg or 10 mg/kg) or placebo.

The primary end point was the reduction of disease activity by a scoring system (SELENA-SLEDAI) that incorporated multiple features of lupus, including arthritis, vasculitis, proteinuria, rash, and others. Patients in the belimumab group had better outcomes, but the results were not dramatic. Because the drug is so expensive (about $25,000 per year) and the improvement offered is only incremental, this drug will not likely change the treatment of lupus very much.

Moreover, patients with lupus nephritis were not included in the study, but a new study is being planned to do so. Improvement is harder to demonstrate in lupus nephritis than in rheumatoid arthritis and systemic lupus erythematosus: significant changes in creatinine levels and 24-hour urinary protein must be achieved, rather than more qualitative signs and symptoms of joint pain, rash, and feeling better. Although belimumab is still unproven for lupus nephritis, it might be worth trying for patients failing other therapy.

Laquinimod: A promising experimental drug

Laquinimod is an oral immunomodulatory drug with a number of effects, including down-regulating major histocompatability complex II, chemokines, and adhesion-related molecules related to inflammation. It has been studied in more than 2,500 patients with multiple sclerosis. Pilot studies are now being done for its use for lupus nephritis. If it shows promise, a large randomized, controlled trial will be conducted.

Abatacept is in clinical trials

Abatacept (Orencia), a costimulation blocker, is undergoing clinical trials in lupus nephritis. Results should be available shortly.

INDIVIDUALIZE THERAPY

This past decade has seen such an increase in options to treat lupus nephritis that therapy can now be individualized.

Choosing IV cyclophosphamide vs mycophenolate

As a result of recent trials, doctors in the United States are increasingly using mycophenolate as the first-line drug for lupus nephritis. In Europe, however, many are choosing the shorter regimen of IV cyclophosphamide because of the results of the Euro-Lupus study.

Nowadays, I tend to use IV cyclophosphamide as the first-line drug only for patients with severe crescenteric glomerulonephritis or a very high serum creatinine level. In such cases, there is more experience with cyclophosphamide, and such severe disease does not lend itself to the luxury of trying out different therapies sequentially. If such a severely ill patient insists that a future pregnancy is very important, an alternative therapy of mycophenolate plus rituximab should be considered. I prefer mycophenolate for induction and maintenance therapy in most patients.

Dosing and formulation considerations for mycophenolate

Large dosages of mycophenolate are much better tolerated when broken up throughout the day. A patient who cannot tolerate 1 g twice daily may be able to tolerate 500 mg four times a day. The formulation can also make a difference. Some patients tolerate sustained-release mycophenolate (Myfortic) better than CellCept, and vice versa.

For patients who cannot tolerate mycophenolate, azathioprine is an acceptable alternative. In addition, for a patient who is already doing well on azathioprine, there is no need to change to mycophenolate.

Long maintenance therapy now acceptable

The ALMS Maintenance Trial¹² found 3 years of maintenance therapy to be safe and effective. Such a long maintenance period is increasingly viewed as important, especially for patients in their teens and 20s, as it allows them to live a normal life, ie, to finish their education, get married, and become settled socially. Whether 5 years of maintenance therapy or even 10 years is advisable is still unknown.

Treatment during pregnancy

Neither mycophenolate nor azathioprine is recommended during pregnancy, although their effects are unknown. Because we have much more renal transplant experience with azathioprine during pregnancy, I recommend either switching from mycophenolate to azathioprine or trying to stop medication altogether if the patient has been well controlled.

Treatment for lupus nephritis has changed dramatically in recent years. Only 10 years ago, rheumatologists and nephrologists, whether specializing in adult or pediatric medicine, treated lupus nephritis with a similar regimen of monthly intravenous cyclophosphamide (Cytoxan) and glucocorticoids. Although the regimen is effective, side effects such as infection, hair loss, and infertility were extremely common.

Effective but very toxic therapy is common in autoimmune diseases. In the last decade, clinical trials have shown that less toxic drugs are as effective for treating lupus nephritis. This article will review new developments in therapy for lupus nephritis, which can be viewed as a prototype for other fields of medicine.

DEMOGRAPHICS ARE IMPORTANT

Although numerous factors have prognostic value in lupus nephritis (eg, serum creatinine, proteinuria, renal biopsy findings), the most important to consider when designing and interpreting studies are race and socioeconomic variables.

A retrospective study in Miami, FL,¹ evaluated 213 patients with lupus nephritis, of whom 47% were Hispanic, 44% African American, and 20% white. At baseline, African Americans had higher blood pressure, higher serum creatinine levels, and lower household income. After 6 years, African Americans fared the worst in terms of doubling of serum creatinine, developing end-stage renal disease, and death; whites had the best outcomes, and Hispanics were in between. Low income was found to be a significant risk factor, independent of racial background.

In a similar retrospective study in New York City in 128 patients (43% white, 40% Hispanic, and 17% African American) with proliferative lupus nephritis,² disease was much more likely to progress to renal failure over 10 years in patients living in a poor neighborhood, even after adjustment for race.

We need to keep in mind that racial and socioeconomic factors correlate with disease severity when we design and interpret studies of lupus nephritis. Study groups must be carefully balanced with patients of similar racial and socioeconomic profiles. Study findings must be interpreted with caution; for example, whether results from a study from China are applicable to an African American with lupus nephritis in New York City is unclear.

OLDER STANDARD THERAPY: EFFECTIVE BUT TOXIC

The last large National Institutes of Health study that involved only cyclophosphamide and a glucocorticoid was published in 2001,³ with 21 patients receiving cyclophosphamide alone and 20 patients receiving cyclophosphamide plus methylprednisolone. Although lupus nephritis improved, serious side effects occurred in one-third to one-half of patients in each group and included hypertension, hyperlipidemia, valvular heart disease, avascular necrosis, premature menopause, and major infections, including herpes zoster.

Less cyclophosphamide works just as well

The multicenter, prospective Euro-Lupus Nephritis Trial⁴ randomized 90 patients with proliferative lupus nephritis to receive either standard high-dose intravenous (IV) cyclophosphamide therapy (six monthly pulses and two quarterly pulses, with doses increasing according to the white blood cell count) or low-dose IV cyclophosphamide therapy (six pulses every 2 weeks at a fixed dose of 500 mg). Both regimens were followed by azathioprine (Imuran).

At 4 years, the two treatment groups were not significantly different in terms of treatment failure, remission rates, serum creatinine levels, 24-hour proteinuria, and freedom from renal flares. However, the rates of side effects were significantly different, with more patients in the low-dosage group free of severe infection.

One problem with this study is whether it is applicable to an American lupus nephritis population, since 84% of the patients were white. Since this study, others indicate that this regimen is probably also safe and effective for different racial groups in the United States.

At 10-year follow-up,⁵ both treatment groups still had identical excellent rates of freedom from end-stage renal disease. Serum creatinine and 24-hour proteinuria were also at excellent levels and identical in both groups. Nearly three quarters of patients still needed glucocorticoid therapy and more than half still needed immunosuppressive therapy, but the rates were not statistically significantly different between the treatment groups.

The cumulative dose of cyclophosphamide was 9.5 g in the standard-treatment group and 5.5 g in the low-dose group. This difference in exposure could make a tremendous difference to patients, not only for immediate side effects such as early menopause and infections, but for the risk of cancer in later decades.

This study showed clearly that low-dose cyclophosphamide is an option for induction therapy. Drawbacks of the study were that the population was mostly white and that patients had only moderately severe disease.

Low-dose cyclophosphamide has largely replaced the older National Institutes of Health regimen, although during the last decade drug therapy has undergone more changes.

MYCOPHENOLATE AND AZATHIOPRINE: ALTERNATIVES TO CYCLOPHOSPHAMIDE

In a Chinese study, mycophenolate was better than cyclophosphamide for induction

In a study in Hong Kong, Chan et al⁶ randomized 42 patients with severe lupus nephritis to receive either mycophenolate mofetil (available in the United States as CellCept; 2 g/day for 6 months, then 1 g/day for 6 months) or oral cyclophosphamide (2.5 mg/kg per day for 6 months) followed by azathioprine (1.5–2.0 mg/kg per day) for 6 months. Both groups also received prednisolone during the year.

At the end of the first year, the two groups were not significantly different in their rates of complete remission, partial remission, and relapse. The rate of infection, although not significantly different, was higher in the cyclophosphamide group (33% vs 19%). Two patients (10%) died in the cyclophosphamide group, but the difference in mortality rates was not statistically significant.

Nearly 5 years later,⁷ rates of chronic renal failure and relapse were still statistically the same in the two groups. Infections were fewer in the mycophenolate group (13% vs 40%, P = .013). The rate of amenorrhea was 36% in the cyclophosphamide group and only 4% in the mycophenolate group (P = .004). Four patients in the cyclophosphamide group and none in the mycophenolate group reached the composite end point of end-stage renal failure or death (P = .062).

This study appeared to offer a new option with equal efficacy and fewer side effects than standard therapy. However, its applicability to non-Chinese populations remained to be shown.

In a study in Miami,⁸ 59 patients with lupus nephritis were given standard induction therapy with IV cyclophosphamide plus glucocorticoids for 6 months, then randomly assigned to one of three maintenance therapies for 1 to 3 years: IV injections of cyclophosphamide every 3 months (standard therapy), oral azathioprine, or oral mycophenolate. The population was 93% female, their average age was 33 years, and nearly half were African American, with many of the others being Hispanic. Patients tended to have severe disease, with nearly two-thirds having nephrotic syndrome.

After 6 years, there had been more deaths in the cyclophosphamide group than in the azathioprine group (P = .02) and in the mycophenolate group, although the latter difference was not statistically significant (P = .11). The combined rate of death and chronic renal failure was significantly higher with cyclophosphamide than with either of the oral agents. The cyclophosphamide group also had the highest relapse rate during the maintenance phase.

The differences in side effects were even more dramatic. Amenorrhea affected 32% of patients in the cyclophosphamide group, and only 7% and 6% in the azathioprine and mycophenolate groups, respectively. Rates of infections were 68% in the cyclophosphamide group and 28% and 21% in the azathioprine and mycophenolate groups, respectively. Patients given cyclophosphamide had 13 hospital days per patient per year, while the other groups each had only 1.

This study showed that maintenance therapy with oral azathioprine or mycophenolate was more effective and had fewer adverse effects than standard IV cyclophosphamide therapy. As a result of this study, oral agents for maintenance therapy became the new standard, but the question remained whether oral agents could safely be used for induction.

In a US study, mycophenolate was better than cyclophosphamide for induction

In a noninferiority study, Ginzler et al⁹ randomized 140 patients with severe lupus nephritis to receive either monthly IV cyclophosphamide or oral mycophenolate as induction therapy for 6 months. Adjunctive care with glucocorticoids was given in both groups. The study population was from 18 US academic centers and was predominantly female, and more than half were African American.

After 24 weeks, 22.5% of the mycophenolate patients were in complete remission by very strict criteria vs only 4% of those given cyclophosphamide (P = .005). The trend for partial remissions was also in favor of mycophenolate, although the difference was not statistically significant. The rate of complete and partial remissions, a prespecified end point, was significantly higher in the mycophenolate group. Although the study was trying to evaluate equivalency, it actually showed superiority for mycophenolate induction therapy.

Serum creatinine levels declined in both groups, but more in the mycophenolate group by 24 weeks. Urinary protein levels fell the same amount in both groups. At 3 years, the groups were statistically equivalent in terms of renal flares, renal failures, and deaths. However, the study groups were small, and the mycophenolate group did have a better trend for both renal failure (N = 4 vs 7) and deaths (N = 4 vs 8).

Mycophenolate also had fewer side effects, including infection, although again the numbers were too small to show statistical significance. The exception was diarrhea (N = 15 in the mycophenolate group vs 2 in the cyclophosphamide group).

A drawback of the study is that it was designed as a crossover study: a patient for whom therapy was failing after 3 months could switch to the other group, introducing potential confounding. Other problems involved the small population size and the question of whether results from patients in the United States were applicable to others worldwide.

In a worldwide study, mycophenolate was at least equivalent to cyclophosphamide for induction

The Aspreva Lupus Management Study (ALMS)¹⁰ used a similar design with 370 patients worldwide (United States, China, South America, and Europe) in one of the largest trials ever conducted in lupus nephritis. Patients were randomized to 6 months of induction therapy with either IV cyclophosphamide or oral mycophenolate but could not cross over.

At 6 months, response rates were identical between the two groups, with response defined as a combination of specific improvement in proteinuria, serum creatinine, and hematuria (50%–55%). In terms of individual renal and nonrenal variables, both groups appeared identical.

However, the side effect profiles differed between the two groups. As expected for mycophenolate, diarrhea was the most common side effect (occurring in 28% vs 12% in the cyclophosphamide group). Nausea and vomiting were more common with cyclophosphamide (45% and 37% respectively vs 14% and 13% in the mycophenolate group). Cyclophosphamide also caused hair loss in 35%, vs 10% in the mycophenolate group.

There were 14 deaths overall, which is a very low number considering the patients’ severity of illness, and it indicates the better results now achieved with therapy. The mortality rate was higher in the mycophenolate group (5% vs 3%), but the difference was not statistically significant. Six of the nine deaths with mycophenolate were from the same center in China, and none were from Europe or the United States. In summary, the study did not show that mycophenolate was superior to IV cyclophosphamide for induction therapy, but that they were equivalent in efficacy with different side effect profiles.

Membranous nephropathy: Mycophenolate vs cyclophosphamide

Less evidence is available about treatment for membranous disease, which is characterized by heavy proteinuria and the nephrotic syndrome but usually does not progress to renal failure. Radhakrishnan et al¹¹ combined data from the trial by Ginzler et al⁹ and the ALMS trial¹⁰ and found 84 patients with pure membranous lupus, who were equally divided between the treatment groups receiving IV cyclophosphamide and mycophenolate. Consistent with the larger group’s data, mycophenolate and cyclophosphamide performed similarly in terms of efficacy, but there was a slightly higher rate of side effects with cyclophosphamide.

Maintenance therapy: Mycophenolate superior to azathioprine

The ALMS Maintenance Trial¹² evaluated maintenance therapy in the same worldwide population that was studied for induction therapy. Of the 370 patients involved in the induction phase that compared IV cyclophosphamide and oral mycophenolate, 227 responded sufficiently to be rerandomized in a controlled, double-blinded trial of 36 months of maintenance therapy with corticosteroids and either mycophenolate (1 g twice daily) or azathioprine (2 mg/kg per day).

In intention-to-treat analysis, the time to treatment failure (ie, doubling of the serum creatinine level, progressing to renal failure, or death) was significantly shorter in the azathioprine group (P = .003). Every individual end point—end-stage renal disease, renal flares, doubling of serum creatinine, rescue immunosuppression required—was in favor of mycophenolate maintenance. At 3 years, the completion rate was 63% with mycophenolate and 49% with azathioprine. Serious adverse events and withdrawals because of adverse events were more common in the azathioprine group.

In summary, mycophenolate was superior to azathioprine in maintaining renal response and in preventing relapse in patients with active lupus nephritis who responded to induction therapy with either mycophenolate or IV cyclophosphamide. Mycophenolate was found to be superior regardless of initial induction treatment, race, or region and was confirmed by all key secondary end points.

Only one of the 227 patients died during the 3 years—from an auto accident. Again, this indicates the dramatically improved survival today compared with a decade ago.

RITUXIMAB: PROMISING BUT UNPROVEN

Rituximab (Rituxan) was originally approved to treat tumors, then rheumatoid arthritis, and most recently vasculitis. Evidence thus far is mixed regarding its use as a treatment for lupus nephritis. Although randomized clinical trials have not found it to be superior to standard regimens, there are many signs that it may be effective.

Rituximab in uncontrolled studies

Terrier et al¹³ analyzed prospective data from 136 patients with systemic lupus erythematosus, most of whom had renal disease, from the French Autoimmunity and Rituximab registry. Response occurred in 71% of patients using rituximab, with no difference found between patients receiving rituximab monotherapy and those concomitantly receiving immunosuppressive agents.

Melander et al¹⁴ retrospectively studied 19 women and 1 man who had been treated with rituximab for severe lupus nephritis and followed for at least 1 year. Three patients had concurrent therapy with cyclophosphamide, and 10 patients continued rituximab as maintenance therapy; 12 patients had lupus nephritis that had been refractory to standard treatment, and 6 had relapsing disease.

At a median follow-up of 22 months, 12 patients (60%) had achieved complete or partial renal remission.

Condon et al¹⁵ treated 21 patients who had severe lupus nephritis with two doses of rituximab and IV methylprednisolone 2 weeks apart, then maintenance therapy with mycophenolate without any oral steroids. At a mean follow-up of 35 months ( ± 14 months), 16 (76%) were in complete remission, with a mean time to remission of 12 months. Two (9.5%) achieved partial remission. The rate of toxicity was low.

Thus, rituximab appears promising in uncontrolled studies.

Placebo-controlled trials fail to prove rituximab effective

LUNAR trial. On the other hand, the largest placebo-controlled trial to evaluate rituximab in patients with proliferative lupus nephritis, the Lupus Nephritis Assessment With Rituximab (LUNAR) trial¹⁶ found differences in favor of rituximab, but none reached statistical significance. The trial randomized 140 patients to receive either mycophenolate plus periodic rituximab infusions or mycophenolate plus placebo infusions for 1 year. All patients received the same dosage of glucocorticoids, which was tapered over the year.

At the end of 1 year, the groups were not statistically different in terms of complete renal response and partial renal response. Rituximab appeared less likely to produce no response, but the difference was not statistically significant.

African Americans appeared to have a higher response rate to rituximab (70% in the rituximab group achieved a response vs 45% in the control group), but again, the difference did not reach statistical significance, and the total study population of African Americans was only 40.

Rituximab did have a statistically significant positive effect on two serologic markers at 1 year: levels of anti-dsDNA fell faster and complement rose faster. In addition, rates of adverse and serious adverse events were similar between the two groups, with no new or unexpected “safety signals.”

This study can be interpreted in a number of ways. The number of patients may have been too small to show significance and the follow-up may have been too short. On the other hand, it may simply not be effective to add rituximab to a full dose of mycophenolate and steroids, an already good treatment.

EXPLORER trial. Similarly, for patients with lupus without nephritis, the Exploratory Phase II/III SLE Evaluation of Rituximab (EXPLORER) trial¹⁷ also tested rituximab against a background of an effective therapeutic regimen and found no additional benefit. This study had design problems similar to those of the LUNAR trial.

Rituximab as rescue therapy

The evidence so far indicates that rituximab may have a role as rescue therapy for refractory or relapsing disease. Rituximab must be used with other therapies, but maintenance corticosteroid therapy is not necessary. Its role as a first-line agent in induction therapy for lupus nephritis remains unclear, although it may have an important role for nonwhites. In general, it has been well tolerated. Until a large randomized trial indicates otherwise, it should not be used as a first-line therapy.

The US Food and Drug Administration (FDA) sent out a warning about the danger of progressive multifocal leukoencephalopathy as an adverse effect of rituximab and of mycophenolate, but this does not appear to be a major concern for most patients and is only likely to occur in those who have been over-immunosuppressed for many years.

MULTITARGET THERAPY

The concept of using multiple drugs simultaneously—such as mycophenolate, steroids, and rituximab—is increasingly being tried. Multi-target therapy appears to offer the advantages of combining different modes of action with better results, and it offers fewer side effects because dosages of each individual drug can be lower when combined with other immunosuppressives.

Bao et al¹⁸ in China randomly assigned 40 patients with diffuse proliferative and membranous nephritis to 6 to 9 months of induction treatment with either multitarget therapy (mycophenolate, tacrolimus [Prograf], and glucocorticoids) or IV cyclophosphamide. More complete remissions occurred in the multitarget therapy group, both at 6 months (50% vs 5%) and at 9 months (65% vs 15%). Most adverse events were less frequent in the multitarget therapy group, although three patients (15%) in the multitarget therapy group developed new-onset hypertension vs none in the cyclophosphamide group.

NEW MEDICATIONS

Entirely new classes of drugs are being developed with immunomodulatory effects, including tolerance molecules, cytokine blockers, inhibitors of human B lymphocyte stimulator, and costimulatory blockers.

Belimumab offers small improvement for lupus

Belimumab (Benlysta) is a human monoclonal antibody that inhibits the biologic activity of human B lymphocyte stimulator; it has recently been approved by the FDA for lupus nephritis. In a worldwide study,¹⁹ 867 patients with systemic lupus erythematosus were randomized to receive either belimumab (1 mg/kg or 10 mg/kg) or placebo.

The primary end point was the reduction of disease activity by a scoring system (SELENA-SLEDAI) that incorporated multiple features of lupus, including arthritis, vasculitis, proteinuria, rash, and others. Patients in the belimumab group had better outcomes, but the results were not dramatic. Because the drug is so expensive (about $25,000 per year) and the improvement offered is only incremental, this drug will not likely change the treatment of lupus very much.

Moreover, patients with lupus nephritis were not included in the study, but a new study is being planned to do so. Improvement is harder to demonstrate in lupus nephritis than in rheumatoid arthritis and systemic lupus erythematosus: significant changes in creatinine levels and 24-hour urinary protein must be achieved, rather than more qualitative signs and symptoms of joint pain, rash, and feeling better. Although belimumab is still unproven for lupus nephritis, it might be worth trying for patients failing other therapy.

Laquinimod: A promising experimental drug

Laquinimod is an oral immunomodulatory drug with a number of effects, including down-regulating major histocompatability complex II, chemokines, and adhesion-related molecules related to inflammation. It has been studied in more than 2,500 patients with multiple sclerosis. Pilot studies are now being done for its use for lupus nephritis. If it shows promise, a large randomized, controlled trial will be conducted.

Abatacept is in clinical trials

Abatacept (Orencia), a costimulation blocker, is undergoing clinical trials in lupus nephritis. Results should be available shortly.

INDIVIDUALIZE THERAPY

This past decade has seen such an increase in options to treat lupus nephritis that therapy can now be individualized.

Choosing IV cyclophosphamide vs mycophenolate

As a result of recent trials, doctors in the United States are increasingly using mycophenolate as the first-line drug for lupus nephritis. In Europe, however, many are choosing the shorter regimen of IV cyclophosphamide because of the results of the Euro-Lupus study.

Nowadays, I tend to use IV cyclophosphamide as the first-line drug only for patients with severe crescenteric glomerulonephritis or a very high serum creatinine level. In such cases, there is more experience with cyclophosphamide, and such severe disease does not lend itself to the luxury of trying out different therapies sequentially. If such a severely ill patient insists that a future pregnancy is very important, an alternative therapy of mycophenolate plus rituximab should be considered. I prefer mycophenolate for induction and maintenance therapy in most patients.

Dosing and formulation considerations for mycophenolate

Large dosages of mycophenolate are much better tolerated when broken up throughout the day. A patient who cannot tolerate 1 g twice daily may be able to tolerate 500 mg four times a day. The formulation can also make a difference. Some patients tolerate sustained-release mycophenolate (Myfortic) better than CellCept, and vice versa.

For patients who cannot tolerate mycophenolate, azathioprine is an acceptable alternative. In addition, for a patient who is already doing well on azathioprine, there is no need to change to mycophenolate.

Long maintenance therapy now acceptable

The ALMS Maintenance Trial¹² found 3 years of maintenance therapy to be safe and effective. Such a long maintenance period is increasingly viewed as important, especially for patients in their teens and 20s, as it allows them to live a normal life, ie, to finish their education, get married, and become settled socially. Whether 5 years of maintenance therapy or even 10 years is advisable is still unknown.

Treatment during pregnancy

Neither mycophenolate nor azathioprine is recommended during pregnancy, although their effects are unknown. Because we have much more renal transplant experience with azathioprine during pregnancy, I recommend either switching from mycophenolate to azathioprine or trying to stop medication altogether if the patient has been well controlled.

General internists need to be able to recognize community-acquired pneumonia (CAP) so that diagnostic and therapeutic interventions can be initiated promptly. It is also important to understand the most likely and possible causes of CAP so that appropriate initial antimicrobial therapy can be chosen. Especially during flu season, influenza can present as CAP and should be included in the differential diagnosis.

When managing a patient with CAP, the internist must decide which level of care, diagnostic tests, antimicrobial agents, and follow-up plans are needed. These topics will be reviewed in this article.

TWO TERMS TO REMEMBER

• CAP refers to pneumonia acquired outside a health care facility. It can be either bacterial or viral.
• CABP (community-acquired bacterial pneumonia) refers only to those cases caused by bacterial pathogens.

NUMBERS AND TRENDS

In the United States, CAP is the number-one cause of death from infection and the sixth leading cause of death overall.¹ Each year, it is responsible for about 4.2 million outpatient visits, more than 60,000 deaths, and more than $17 billion in health care expenses.²

Community-acquired bacterial pneumonia: Common, serious

In a population-based US study in 1991, the incidence of CABP requiring hospitalization was 266.8 per 100,000 people.³

Estimates of overall mortality in CABP vary depending on the severity of illness and comorbid conditions. A meta-analysis published in 1996 found the overall mortality rate to be 13.7%, with a range of 5.1% to 36.5% depending on severity.⁴

In hospitalized patients, mortality rates and length of hospital stay appear to be declining over time. Between 1993 and 2005, the age-adjusted mortality rate decreased from 8.9% to 4.1%, and the average length of stay decreased from 7.5 to 5.7 days, with an overall reduction in hospital cost.⁵

CABP is more prevalent in older people than in the general population, and it increases with age from 18.2 cases per 1,000 patient-years in patients 60 to 69 years to 52.3 cases per 1,000 patient-years in those older than 85 years.⁶ Risk factors for pneumonia in the elderly include heart disease, chronic lung disease, immunosuppressive drugs, alcoholism, and increasing age.⁷ Similar to the trend in the general population, the mortality rate in elderly CABP patients appears to be decreasing over time, possibly thanks to rising rates of pneumococcal and influenza vaccination.⁸

Among the general population, risk factors for developing CABP also include smoking, occupational dust exposure, history of childhood pneumonia, unemployment, and single marital status.⁹ The incidence of CABP does not appear to be higher among pregnant women, although it is the most frequent cause of nonobstetric death in this population.¹⁰

The use of proton pump inhibitors may be an emerging risk factor for CABP.¹¹ Also, use of nonsteroidal anti-inflammatory drugs among patients with CABP is associated with a blunted inflammatory response as well as a higher risk of pleuropulmonary complications and a delay in presentation.¹²

Influenza is also common, potentially severe

Influenza is also very common and potentially severe. It can cause a spectrum of disease, from mild upper respiratory tract symptoms to severe viral pneumonia that can be life-threatening and complicated by respiratory failure and the acute respiratory distress syndrome (ARDS).

Influenza infection can also be complicated by subsequent bacterial pneumonia. However, the epidemiology of influenza infection differs from that of CABP in that influenza occurs seasonally.

In the United States, seasonal influenza causes 36,000 deaths and 200,000 hospitalizations annually.^13,14 As with CABP, the risk of death from influenza increases with age: it is 16 times greater in people age 85 and older than in those ages 65 to 69.¹³

During yearly seasonal epidemics, those at the highest risk of hospitalization and death are at the extremes of age. Risk factors for complicated influenza include heart disease, lung disease, diabetes, renal failure, rheumatologic conditions, dementia, and neurologic disease.^15,16 During the 2009 H1N1 influenza pandemic, unexpected severity was seen in previously healthy young adults as well as those with obesity, neurodegenerative disease, pregnancy, and asthma.¹⁷

PATHOGENS: TYPICAL, ATYPICAL, VIRAL

Identifying the etiologic organism in CAP is confounded by limitations in the available diagnostic tests and also by poor-quality specimens that often are contaminated with bacteria that colonize the upper airways. Given these caveats, the primary pathogens responsible for CAP broadly include typical bacterial pathogens, atypical bacterial pathogens, and viruses.

Typical bacterial pathogens include Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus, Moraxella catarrhalis, and, less commonly, a variety of aerobic and anaerobic gram-negative rods including Pseudomonas aeruginosa, Acinetobacter species, and Klebsiella pneumoniae.

Atypical bacterial pathogens include Mycoplasma pneumoniae, Chlamydia pneumoniae, and Legionella species.¹⁸

Viruses implicated in adult CAP include influenza A and B, parainfluenza viruses, respiratory syncytial virus, and adenovirus.¹⁹ More recently, human metapneumovirus has been described as a cause of adult CAP.²⁰

Clues to uncommon microbes

Specific historic features or coexisting conditions that may suggest an uncommon microbiologic diagnosis include²¹:

• Recent travel to the southwestern United States or Southeast Asia
• Ill contacts
• Exposure to birds, bats, rabbits, or farm animals
• Alcoholism
• Chronic obstructive pulmonary disease
• Human immunodeficiency virus infection
• Structural lung disease
• Prolonged cough with whoop or posttussive vomiting
• Aspiration
• Bioterrorism.

In cases in which one or more of these conditions exist, CAP may also be caused by other agents not listed above, including Mycobacterium tuberculosis, oral anaerobes, atypical mycobacteria, Histoplasma capsulatum, Chlamydophila psittaci, Francisella tularensis, Coxiella burnettii, Pneumocystis jiroveci, Cryptococcus, Aspergillus, Coccidioides, Hantavirus, avian influenza, Burkholderia pseudomallei, severe acute respiratory syndrome virus, Bordetella pertussis, Bacillus anthracis, and Yersinia pestis.

HOW BACTERIA INVADE THE LUNGS

The pathophysiology of CABP involves both host defense and microbial virulence factors.

The airways are most commonly exposed to microbes by microaspiration of upper airway flora, although hematogenous seeding of the lungs in a bacteremic patient or contiguous spread of infection from an adjacent site can also occur.

Mucociliary clearance and the cough reflex are important initial defenses against infection and can be inhibited by neurologic diseases and conditions that impair the mucociliary mechanism. Mucosal immune cells, including macrophages and neutrophils, recognize invading pathogens and generate an antibody response.

Regulation of the host inflammatory response to infection depends on a complex interaction between immune cells, inflammatory cytokines (eg, tumor necrosis factor alpha, interleukin 1-beta, and interleukin 6), and anti-inflammatory cytokines such as interleukin 1 receptor antagonist and soluble tumor necrosis factor receptor type I.²²

The interaction and timing of the inflammatory and anti-inflammatory response are essential in manifesting an appropriate host response to infection. An inadequate inflammatory response can lead to sepsis and death, but an excessive, late anti-inflammatory response can lead to a systemic inflammatory response such as ARDS. Polymorphisms within the genes coding for these factors may explain the variation in severity of illness among patients with CABP.²³

HOW INFLUENZA DOES ITS DAMAGE

There are three types of influenza virus: A, B, and C. Type A causes most human infections. The influenza A virus envelope comprises a lipid bilayer that contains the projecting glycoproteins hemagglutinin and neuraminidase. Influenza viruses are named on the basis of these proteins and are designated with an H and an N, respectively, each followed by a number referring to the subtype.

Influenza infection begins when the virus makes contact with the epithelium. Hemagglutinin binds to the host cell and allows viral entry, where it begins replication. Neuraminidase prevents viral aggregation and facilitates the release of virus from infected cells.²⁴

Mature virions are released and spread to neighboring host cells; this process is associated with desquamation and inflammation of the airways, causing cough, rhinorrhea, and sore throat. Systemic symptoms are associated with the induction of interferon, which causes fever and myalgia.²⁵

Recovery and immunity to influenza infection occurs through both humoral and cell-mediated immunity, with antibodies directed against the specific hemagglutinin and neuraminidase antigens of the infecting virus. Immunity wanes over time and with antigenic drift of circulating viruses, making the host susceptible to recurrent influenza infection.²⁴

Influenza is often complicated by bacterial superinfection

The influenza virus acts synergistically with certain bacteria to increase infectivity, and this may explain why influenza is often complicated by bacterial superinfection.

Mechanisms leading to bacterial superinfection include increased binding and invasion of bacteria, increased viral replication, and modification of the host inflammatory response. Some S aureus strains produce a protease that directly activates influenza virus hemagglutinin; other bacteria can activate plasminogen to promote influenza replication. The resulting increase in proteases in host tissues promotes activation of influenza through cleavage of hemagglutinin.²⁶

The influenza virus also causes damage to the airway epithelial layer, leading to increased exposure of the binding sites necessary for adherence of S pneumoniae.²⁷

CLINICAL PRESENTATION OF COMMUNITY-ACQUIRED PNEUMONIA

Although CAP is common, agreement on its essential clinical signs and symptoms is surprisingly limited, due in part to heterogeneous patient presentations and in part to interobserver variability. The reader is referred to two excellent reviews on this topic.^28,29

The diagnosis of CAP is made on clinical grounds, based on a combination of signs and symptoms. Symptoms of pneumonia can include cough, fever, chills, sputum production, dyspnea, and pleuritic pain. Physical findings can include tachypnea, tachycardia, hypoxemia, and consolidation or rales on auscultation. Laboratory data may show leukocytosis or elevated C-reactive protein, and radiographic studies may show evidence of a new infiltrate.^21,30,31

Clinical presentation of influenza

Seasonal influenza as a cause of CAP is difficult to distinguish from bacterial causes. The clinical presentation of seasonal influenza most commonly includes fever or subjective feverishness, cough, myalgia, and weakness.³² In a recent multivariate analysis, five clinical features were shown to be predictive of pandemic H1N1 influenza pneumonia rather than CABP: age younger than 65 years, absence of confusion, white blood cell count less than 12 × 10⁹/L, temperature higher than 38°C (100.4°F), and bilateral opacities on radiography.^32,33

Complicated influenza infection can be either primary viral pneumonia or bacterial superinfection.

During the 1918 influenza pandemic, which predated the ability to isolate viruses, two clinical syndromes emerged: an ARDS associated with the rapid onset of cyanosis, delirium, and frothy blood-tinged sputum; and an acute bronchopneumonia characterized by necrosis, hemorrhage, edema, and vasculitis.^34,35 The first syndrome has subsequently been shown to be associated with primary viral pneumonia, while the second is caused by bacterial superinfection. Modern reexamination of 1918 data has shown that bacterial superinfection was likely the reason for the distinctly fulminant presentation of that pandemic.^36,37

The 2009 H1N1 influenza pandemic caused relatively mild disease in most patients. However, those with severe pneumonia more commonly developed ARDS from primary influenza pneumonia than from bacterial superinfection.¹⁷

A third influenza-associated infection is secondary bacterial pneumonia, which follows influenza infection and mimics the presentation of CABP. A typical patient presents with a recent history of influenza-like illness, followed 4 to 14 days later by a recurrence of fever, dyspnea, productive cough, and consolidation on chest radiographs.³⁸ Leukocytosis with an increased number of immature neutrophil forms, prolonged duration of fever, and elevated erythrocyte sedimentation rate are more likely in patients with secondary bacterial pneumonia.³⁹ Isolates from sputum samples commonly include S pneumoniae, S aureus, H influenzae, and other gram-negative rods.⁴⁰

In recent flu seasons, methicillin-resistant S aureus (MRSA) has emerged as a cause of severe secondary pneumonia. Most of these isolates carry genes for the toxin Panton-Valentine leukocidin; the associated mortality rate is as high as 33%.^41,42 Although community-acquired MRSA pneumonia has only been reported in case series, distinct clinical features that have been described include severe pneumonia with high fever, hypotension, shock, respiratory failure, leukopenia, and multilobar and cavitary infiltrates.⁴³

WHEN TO SUSPECT INFLUENZA

The triad of fever, cough, and abrupt onset are the best predictors of influenza, but no single combination of signs and symptoms predict influenza infection with 100% certainty. Therefore, an understanding of local epidemiologic data regarding circulating influenza is essential to maintain a high index of suspicion.⁴⁴

It is appropriate to suspect influenza in:

• Anyone who is epidemiologically linked to a known outbreak of influenza
• Children, adults, and health care workers who have fever and abrupt onset of respiratory symptoms
• Patients with fever plus exacerbation of underlying pulmonary disease
• Severely ill patients with fever or hypothermia, especially during influenza season.⁴⁵

DIAGNOSTIC TESTING

Once the diagnosis of pulmonary infection is suggested by clinical features, the initial evaluation should include measurement of vital signs, physical examination, and radiographic imaging of the chest. Additional diagnostic measures to consider include viral testing, blood culture, sputum culture, urinary antigen testing for Legionella and for S pneumoniae, fungal culture, and mycobacterial smear and culture.

Chest radiography (with posterior-anterior and lateral films) is the study that usually demonstrates the presence of a pulmonary infiltrate. If initial chest radiographs do not show an infiltrate, imaging can be repeated after treatment is started if the patient’s clinical presentation still suggests pneumonia. Chest radiographs are of limited value in predicting the pathogen, but they help to determine the extent of pneumonia and to detect parapneumonic effusion.⁴⁶

A caveat: anterior-posterior, posterior-anterior, and lateral views can miss more than 10% of effusions large enough to warrant thoracentesis, especially when there is lower-lobe consolidation.⁴⁷

Blood cultures are recommended for patients admitted to the intensive care unit and for those with cavitary infiltrates, leukopenia, alcohol abuse, severe liver disease, asplenia, positive pneumococcal urinary antigen testing, or a pleural effusion.²¹ However, blood cultures are positive in only 3% to 14% of hospitalized patients with CABP, and the impact of a positive blood culture on management decisions in CABP appears to be quite small.^48–50

For the highest yield, blood culture results should be obtained before antibiotics are given. Not only is this good practice, but obtaining blood culture results before starting antibiotics is one of the quality measures evaluated by the Center for Medicare and Medicaid Services.⁵¹

Sputum culture is considered optional for outpatients and patients with less-severe pneumonia.²¹ While it can provide a rapid diagnosis in certain cases, a good-quality sputum sample is obtained in only 39% to 54% of patients with CABP, yields a predominant morphotype in only 45% of cases, and provides a useful microbiologic diagnosis in only 14.4%.^52,53 Fungal and mycobacterial cultures are only indicated in certain situations such as cavitary infiltrates or immunosuppression.

Urinary antigen testing for Legionella and S pneumoniae should be done in patients with more severe illness and in those for whom outpatient therapy has failed.²¹S pneumoniae testing has been shown to allow early diagnosis of pneumococcal pneumonia in 26% more patients than with Gram staining, but it fails to identify 22% of the rapid diagnoses initially identified by Gram staining.⁵⁴ Thus, a sequential approach is reasonable, with urinary antigen testing for patients at high risk without useful results from sputum Gram staining. Also, recent data suggest that the pneumococcal urinary antigen test may allow optimization of antimicrobial therapy with good clinical outcomes.⁵⁵

Endotracheal tests. If the patient is intubated, collection of endotracheal aspirates, bronchoscopy, or nonbronchoscopic bronchial lavage (sometimes called “mini-BAL”) should be performed.

Thoracentesis and pleural fluid cultures should be done if a pleural effusion is found. Empyema, large or loculated effusions, and parapneumonic effusions with a pH lower than 7.20, glucose levels less than 3.4 mmol/L (60 mg/dL), or positive results on microbial staining or culture should be drained by chest tube or surgically.⁵⁶

Testing for influenza should be done if it will change the clinical management, such as the choice of antibiotic or infection control practices. Specimens should be obtained with either a nasopharyngeal swab or aspirate and tested with reverse transcriptase polymerase chain reaction, immunofluorescent staining, or rapid antigen detection, depending on local availability.⁴⁵

Inflammatory biomarkers such as C-reactive protein and procalcitonin have been receiving interest as ways to predict the etiology and prognosis of CAP and to guide therapy. Several studies have shown that C-reactive protein can help distinguish between CAP and bronchitis, with higher values suggesting more severe pneumonia and pneumonia caused by S pneumoniae or L pneumophila.⁵⁷ Procalcitonin may help discriminate between severe lower respiratory tract infections of bacterial and 2009 H1N1 origin, although less effectively than C-reactive protein. Low procalcitonin values, particularly when combined with low C-reactive protein levels, suggest that bacterial infection is unlikely.⁵⁸

RISK STRATIFICATION AND SITE-OF-CARE DECISIONS

Following a presumptive diagnosis of CAP, it is important to decide not only what treatment the patient will receive but whether he or she should be hospitalized. If the patient is to be admitted to the hospital, the clinician must also decide if his or her condition warrants intensive care.

Severity-of-illness scores

A recent meta-analysis compared the performance characteristics of the PSI and CURB-65 scores for predicting mortality in CAP and found no significant differences in overall test performance.⁶¹

Another meta-analysis found that the PSI was more sensitive than the CURB-65 and had a low false-negative rate, and so was better at showing which patients do not need to be hospitalized. Conversely, the CURB-65 was more specific and had a higher positive predictive value, and thus was more likely to correctly classify high-risk patients.⁶²

Other scoring systems that aid in deciding about hospital admission and level of care include the CRB-65⁶³ (which can be used instead of the CURB-65 if laboratory values are not available), SMART-COP,⁶⁴ and SCAP.^,65

Guidelines on when to admit to the intensive care unit

Guidelines from the Infectious Diseases Society of America (IDSA) and the American Thoracic Society (ATS) also provide guidance on when intensive care admission is advised,²¹ and their criteria were recently validated.⁶⁶ The guidelines advocate direct admission to the intensive care unit for patients requiring vasopressors or mechanical ventilation, and intensive care unit or high-level monitoring for patients with three of the following criteria for severe CAP²¹:

• Respiratory rate ≥ 30
• Pao₂/Fio₂ ratio ≤ 250
• Multilobar infiltrates
• Confusion or disorientation
• Uremia (blood urea nitrogen ≥ 20 mg/dL)
• Leukopenia (white blood cell count < 4.0 × 10⁹/L)
• Thrombocytopenia (platelet count < 100 × 10⁹/L)
• Hypothermia (core temperature < 36.0°C [96.8°F])
• Hypotension requiring aggressive fluid resuscitation.

None of these scoring systems or criteria is meant to replace clinical judgment. A recent study has suggested that an oxygen saturation of less than 92% is an appropriate threshold for hospital admission, in view of higher rates of adverse events in outpatients with saturations below this value.⁶⁷

TREATMENT

Multiple studies have shown that treatment of CAP in accordance with guidelines has led to improved clinical outcomes.^21,68–70

How fast must antibiotics be started?

Based on studies that showed a lower mortality rate when antibiotics were started sooner, Medicare and Medicaid adopted a quality measure calling for starting antibiotics within 4 hours in patients being admitted to the hospital.^50,71 However, several subsequent studies showed that the diagnosis of pneumonia is often incorrect and that rapid administration of antibiotics could lead to misdiagnosis, overuse of antibiotics, and a higher risk of Clostridium difficile infection.^72,73

The current IDSA/ATS guidelines²¹ recommend that the first antibiotic dose be given while the patient is still in the emergency department, but do not give a specific time within which it should be given. Medicare and Medicaid later updated their quality measure to antibiotic administration within 6 hours.

Which antibiotics should be used?

The selection of antimicrobial agent depends upon the patient’s severity of illness and comorbid conditions.

Although most studies of combination antibiotic therapy have been retrospective and observational, they suggest that a macrolide (ie, one of the “mycins”) added to a beta-lactam antibiotic is beneficial, possibly by covering atypical organisms or via anti-inflammatory action.^74–76 The choice of one antibiotic over another appears to be less important, and a recent Cochrane review concluded that there was no significant difference in efficacy among five antibiotic pairs studied.⁷⁷

Empiric outpatient treatment of a previously healthy patient with CAP and no risk factors for drug-resistant S pneumoniae should include either a macrolide (azithromycin [Zithromax], clarithromycin [Biaxin], or erythromycin) or doxycycline. If the patient has a chronic comorbid condition such as heart, lung, liver, or renal disease, diabetes mellitus, alcoholism, malignancy, asplenia, or immunosuppression or has received antimicrobials within the preceding 3 months, then treatment should include either a respiratory fluoroquinolone (moxifloxacin [Avelox] or levofloxacin [Levaquin]) or a beta-lactam plus a macrolide.²¹

Overall, published data suggest that the survival rate is about the same with fluoroquinolone monotherapy as with beta-lactam plus macrolide combination therapy, and better than with beta-lactam monotherapy.⁷⁸

Selection of antibiotics for inpatient treatment of CAP is influenced by severity of illness. Inpatients who do not require intensive care should be treated with either a respiratory fluoroquinolone or combination therapy with a beta-lactam (cefotaxime [Claforan], ceftriaxone [Rocephin], ampicillin, or ertapenem [Invanz]) plus a macrolide or doxycycline.^21,76,79

If a specific microbiologic diagnosis is made, then treatment can be narrowed. However in certain cases, such as invasive pneumococcal infection, combination therapy may still be superior.^80,81 For patients who need intensive care, treatment should always include a beta-lactam plus either azithromycin or a respiratory fluoroquinolone.²¹ In certain situations, additional antibiotics may be added as well, such as agents to treat Pseudomonas, community-acquired MRSA, or both.

Switching to oral therapy; short-course therapy

In the interest of avoiding unnecessary antibiotics, numerous studies have addressed the issue of an “early switch” to oral antibiotics and “short-course” therapy for CAP. In general, once clinically stable, patients with CAP, including bacteremic S pneumoniae pneumonia, can be safely switched to oral antibiotics.⁸²

The issue of short-course therapy is more complicated, and the appropriate length of therapy for CAP is not well established. However, 5 days of levofloxacin 750 mg was shown to be as successful as 7 to 10 days of levofloxacin 500 mg.⁸³ In another study, in patients who improved after 3 days of intravenous therapy for CAP, there was no difference in clinical outcome between those who were changed to oral therapy for 5 more days and those who received an oral placebo.⁸⁴

Most patients who achieve clinical stability in the first week do not need prolonged antibiotic therapy. However, certain conditions, such as S aureus bacteremic pneumonia, complicated pneumonia, and pneumonia due to unusual organisms, may require prolonged treatment.

Other therapies

Additional therapies studied in patients with pneumonia include early mobilization, adjunctive corticosteroids, and statin drugs.

Early mobilization was shown in one study to decrease hospital length of stay without increasing adverse effects.⁸⁵

Corticosteroids are not supported as a standard of care for patients with severe CAP according to current available studies.^86,87 Furthermore, a randomized, controlled trial showed that prednisolone daily for a week did not improve outcomes in hospitalized patients with CAP, and it was associated with increased late failure.⁸⁸

Statin trials under way. Several observational studies have suggested that statins might be beneficial in managing sepsis through their effects on endothelial cell function, antioxidant effects, anti-inflammatory effects, and immunomodulatory effects.⁸⁹ However, a recent large prospective multicenter cohort study of hospitalized patients with CAP did not find evidence of a protective effect of statins on clinically meaningful outcomes in CAP or significant differences in circulating biomarkers.⁹⁰ Several randomized trials of statin therapy in patients with both ventilator-associated pneumonia and CAP are under way.

INFLUENZA TREATMENT: MOST EFFECTIVE WITHIN 48 HOURS

Treatment with antiviral drugs is most effective if started within 48 hours after symptom onset, although some patients with confirmed influenza who are either not improving or who are critically ill may still benefit from treatment started later.

Treatment should be considered in patients with laboratory-confirmed or suspected influenza who are at risk of developing complicated influenza and in otherwise healthy patients who wish to reduce the duration of illness or who have close contact with patients who are at high risk of complications.

Antiviral medications are oseltamivir (Tamiflu), zanamivir (Relenza), and the adamantines amantadine (Symmetrel) and rimantadine (Flumadine).

Due to evolving viral resistance patterns, the choice of antiviral drug depends on the strain. Seasonal H1N1 is best treated with zanamivir or an adamantine, while pandemic 2009 H1N1 and H3N2 are best treated with zanamivir or oseltamivir. When strain typing is not available, empiric therapy should be with either zanamivir monotherapy or a combination of oseltamivir plus rimantadine. Influenza B viruses are resistant to adamantines and should be treated only with either zanamivir or oseltamivir.⁴⁵

FOLLOW-UP AND PREVENTION

Patients with CAP can generally be expected to improve within 3 to 7 days.⁹¹ However, it may be several weeks before they return to baseline.⁹²

Follow-up plans may be guided by the time to clinical stability. For patients who do not achieve clinical stability until more than 72 hours after admission, more aggressive follow-up on discharge is indicated, since they are more likely to experience early readmission and death.⁹³

Pneumococcal vaccination. Because S pneumoniae remains the most common cause of CAP, efforts should be made to vaccinate patients appropriately. The Advisory Committee on Immunization Practices (ACIP) and the US Centers for Disease Control and Prevention recommend that the pneumococcal polysaccharide vaccine (Pneumovax 23; PPSV23) be given to those over age 65. Those who were vaccinated before age 65 should receive another dose at age 65 or later if at least 5 years have passed since their previous dose. Those who receive it at or after age 65 should receive only a single dose. A second dose is recommended 5 years after the first dose for people age 19 to 64 years with functional or anatomic asplenia and for those who are immunocompromised.

Influenza vaccination for all. Of note, the ACIP updated its guidelines on influenza vaccination beginning with the 2010–2011 influenza season. It no longer advocates a risk-stratified approach. Instead, it recommends universal influenza vaccination for everybody more than 6 months old.⁹⁴

Smoking cessation should be addressed. Smoking cessation is a Medicare and Medicaid quality measure and should be encouraged after an episode of CAP because quitting smoking reduces the risk of pneumococcal disease by approximately 14% each year thereafter.⁹⁵