Infectious Diseases

The 2012 US Food and Drug Administration (FDA) approval of daily emtricitabine plus tenofovir disoproxil fumarate as HIV pre-exposure prophylaxis (PrEP) re-energized the field of human immunodeficiency virus (HIV) prevention. In subsequent years, PrEP uptake has increased, particularly in people at high risk of HIV infection.

However, since 2012, progress in controlling the HIV epidemic has been uneven across communities and populations. For instance, in 2014, the southern United States accounted for an estimated 50% of infections, but PrEP uptake has remained low there, with only 1% of the estimated number of eligible people taking PrEP.^1,2 Among African American men who have sex with men (MSM), it is predicted that 1 of every 2 will become infected in his lifetime; among Latino MSM, the prediction is 1 of every 5.³ The expanding opioid epidemic is further jeopardizing the progress made in reducing HIV infection among people who inject drugs.

A “test and treat” strategy is insufficient. Mathematical modeling suggests that “test and treat” without a higher level of coverage is insufficient to control the HIV epidemic.⁴ In the absence of an HIV vaccine, these models find that widespread uptake of PrEP among people at risk of HIV acquisition is needed—in combination with HIV treatment as prevention, condom promotion, and needle exchange—to realize the potential to end the HIV epidemic.⁴

A recent proposal by the US Department of Health and Human Services would establish an initiative to address the continuing HIV public health crisis, with a goal of reducing the numbers of incident HIV infections in the United States by 75% in 5 years and then by 90% in 10 years. That strategic initiative includes 4 “pillars” for preventing HIV acquisition—one of which is the use of PrEP by at-risk people.⁵

Although PrEP is often prescribed by HIV specialists and in sexually transmitted infection (STI) clinics, many patients seek PrEP from family physicians (and other primary care clinicians), who are now also being called on to identify patients in their practice at risk of HIV infection⁶ and to offer them PrEP. In this article, we provide an overview of PrEP and discuss how best to integrate PrEP into a family medicine practice.

Understanding PrEP and how it is used

PrEP is one of 2 related biomedical interventions to prevent HIV acquisition. Many clinicians are familiar with postexposure prophylaxis, a regimen of 3 anti-HIV medications given for 1 month to patients who are within 72 hours of a possible exposure. In contrast, PrEP is a once-daily, fixed-dose combination of 2 medications commonly used in the treatment of HIV infection: emtricitabine, 200 mg, and tenofovir disoproxil fumarate, 300 mg. This combination is the only FDA-approved regimen for daily use as PrEP in the United States.

At-risk patients should take PrEP daily—regardless of how often they engage in risky behaviors.

PrEP is indicated for people whose ongoing sexual or drug injection behaviors put them at substantial risk of HIV infection, and should be taken daily regardless of the frequency of risk-taking behavior. Since 2010, several randomized placebo-controlled trials (RCTs) have reported that, when medication adherence is high (measured by drug levels in blood), PrEP can reduce new HIV infections by more than 90% in high-risk populations.⁷ In clinical practice, HIV infection is uncommon because of the effectiveness of daily PrEP; when infections have occurred, almost all have been in patients not taking the medications as prescribed.⁸

Continue to: Infection with HIV...

Infection with HIV in which viral mutations are associated with emtricitabine or tenofovir resistance is rare among the few people infected with HIV after starting PrEP.⁹ In RCTs, most drug resistance occurred among people who started PrEP when they were already HIV-positive (because they were screened with antibody-only HIV tests that did not detect recent infection).¹⁰

Other medications, routes of administration, and dosing schedules are being studied for safety and efficacy as PrEP for HIV infection.^11,12

For whom should PrEP be prescribed? There are 2 ways to identify candidates for PrEP:

• Passive prescribing relies on patients self-identifying as being at risk of HIV infection and asking about PrEP. Many at-risk patients do not recognize their need for PrEP, however.¹³
• Active screening requires that physicians, or their staff, take a sexual history from all patients. However, reviewing detailed sexual histories with every patient in a busy practice can be overwhelming. One way to begin identifying patients for whom PrEP is appropriate is to commit to talking to subsets of potentially high-risk patients, such as MSM or transgender patients.⁶ Sexual orientation and gender identity are not direct risk factors; a nuanced sexual history is often needed to understand potential exposures. A diagnosis of syphilis or other bacterial STI is a marker of high risk of HIV acquisition.¹⁴

To help identify which of your patients might benefit from PrEP, the PrEP guidelines from the Centers for Disease Control and Prevention (CDC)¹⁵ and tools developed by other sources^16,17 recommend several key screening questions about sexual behavior and substance abuse (TABLE 1^15-17).

Familiarity with PrEP and comfort taking a sexual history to screen for risk of HIV acquisition are essential first steps in prescribing PrEP under CDC guidelines.^6,18 In primary care, female patients are routinely questioned to assess their need for contraception; similarly, screening questions to assess PrEP eligibility can be easily incorporated into practice.

Continue to: What are the indications for PrEP?

Patients in whom PrEP is indicated include sexually active adults and adolescents (> 35 kg)¹⁹ whose use of a condom is inconsistent or who have had multiple recent sex partners; those with a recent bacterial STI; and men or women with a sexual or injection partner known to be HIV-infected (TABLE 2).¹⁵

What steps should be taken before and after initiating PrEP?

Providing PrEP is a harm-reduction strategy similar to prescribing other common preventive medications, such as statins to reduce hyperlipidemia and prevent myocardial infarction; oral contraceptives to prevent unwanted pregnancy; and metformin to prevent complications of diabetes. There are a few screening criteria prior to initiating PrEP (TABLE 3)¹⁰:

• A patient starting PrEP should be (1) HIV-negative, ideally screened by a laboratory-based antigen–antibody (ie, fourth-generation) HIV test or HIV RNA test, and (2) without symptoms of acute HIV infection.²⁰ (Note: Do not hold off PrEP and HIV testing until the patient has achieved a period of sexual abstinence.)
• A patient starting PrEP should have normal renal function and should not be taking contraindicated medications, such as long-term high-dose nonsteroidal anti-inflammatory agents.
• Hepatitis B virus (HBV) surface antigen, surface antibody, and core antibody should be tested because both emtricitabine and tenofovir are active against HBV. For a patient who has active HBV infection, particularly with cirrhosis, there is a theoretical concern that starting and stopping PrEP can lead to flares of HBV infection. Patients who are not HBV-immune should be vaccinated.
• Baseline hepatitis C virus testing is recommended for patients who inject drugs, MSM, or those who were born between 1945 and 1965; annual hepatitis C virus testing is recommended for patients who inject drugs.¹⁵

When it has been determined that a patient is eligible for PrEP, a prescription is written for no longer than 90 days to ensure regular monitoring for HIV infection, STIs, and renal function.

Adherence counseling is a key component of PrEP delivery—as it is with oral contraception, antihypertensive medical therapy, and other medications. As noted, HIV acquisition in PrEP users is most often reported in patients with poor adherence,⁸ especially among adolescents.²¹ PrEP is part of comprehensive sexual health care, and safer sex behaviors, such as condom use, should be encouraged to reduce the risk of acquiring other STIs. Condom use should not, however, be a requirement for continuing to receive PrEP.

Is PrEP safe?

Although PrEP might be new to many family physicians and their patients, trials and observational studies have repeatedly shown that for people without HIV infection, taking daily emtricitabine and tenofovir for prevention of HIV infection is safe. No clinically significant renal, bone, or other toxicity has been reported, although there is concern about potential toxicity after decades of use.^22,23 A recent narrative review from the David Geffen School of Medicine at the University of California Los Angeles compared safety findings from 5 major studies on PrEP with 2 major studies on aspirin safety and found that PrEP is as safe as aspirin, although the authors cautioned that more study on long-term use is needed.²⁴

Continue to: What to tell patients

What to tell patients. Tell patients that within the first weeks of starting PrEP, they might experience a start-up syndrome that typically manifests as gastrointestinal symptoms, headache, and fatigue. These symptoms usually resolve without the need to discontinue the medications.²⁵

Any other concerns about PrEP?

When PrEP was first approved by the FDA, many physicians raised concern about the possibility that PrEP use would lead to increased community-level HIV drug resistance and that behavioral disinhibition might diminish the benefit of PrEP and lead to rampant STIs.²⁶ To date, these fears have not been borne out.

When medication adherence is high, PrEP can reduce new HIV infections by more than 90% in high-risk populations.

Acquired drug resistance, which happens after a person becomes HIV-positive, is a real concern, particularly among people who are screened with antibody-only HIV tests that cannot detect HIV in the so-called window period and who then start PrEP during acute HIV infection. If a person is truly HIV-negative when he (she) starts PrEP, the risk of either acquired or transmitted HIV drug resistance is low and is far outweighed by the preventive benefit of PrEP.²⁷

Similarly, there is a suggestion that syphilis infection is increasing among HIV-negative MSM due to decreased HIV-related stigma and increased mixing between HIV-negative and HIV-positive people. The evidence that PrEP has led to an increase in STI rates²⁸ is mixed, however, and is confounded by temporal increases in STI rates and increased detection of asymptomatic STIs among people on PrEP as a result of regular screening.²⁹

Who pays for PrEP?

The cost of PrEP medications and associated clinical care is covered by nearly all private, employer, and public health insurance. Prior authorization might be required to ensure that testing has excluded HIV infection before prescribing and then refilling prescriptions.

Continue to: For patients who have health insurance...

For patients who have health insurance, assistance with copays or coinsurance is available through the producer of PrEP (Gilead Sciences, Inc.) and other national foundations. Many people who seek PrEP might be eligible for Medicaid if they are otherwise uninsured. Other low-income and uninsured people, including those who are not legal residents or US citizens, usually qualify for the PrEP medication assistance program; the application for this benefit must be completed by the physician.

One way to identify patients for whom PrEP might be appropriate is to talk to subsets of potentially high-risk patients, such as men who have sex with men and transgender patients.

A billing guide on PrEP for physicians is available to assist with International Classification of Disease (ICD)-10 coding.^30,31 If a patient has difficulty with laboratory copays, free HIV and STI testing might be available at local STI clinics and acquired immunodeficiency syndrome (AIDS) service organizations.

Providing PrEP within a primary care setting

The unmet need for PrEP highlights how important it is for family medicine and other primary care practices to incorporate HIV prevention into their suite of services.³²

Patients are most likely to experience adverse effects during the first month of taking PrEP—the same period in which they are establishing their pattern of adherence. It might be helpful to check in with patients at the end of the first month to assess their symptoms and adherence. After this phase, quarterly follow-up is simple, with routine lab monitoring and check-in about continued risk of HIV and adherence challenges (TABLE 3¹⁰).

At our local Ryan White HIV/AIDS Program-funded HIV clinic, which also provides PrEP, computer-ordering checklists (so-called smartsets) for the PrEP initial visit and follow-up visits are programmed into the records system (TABLE 4¹⁵). Other clinics also have developed templates for PrEP visit notes. Adherence monitoring, behavioral counseling, and other preventive services can be integrated into the regular paper- or computer-based intake survey, so that conversations are focused on areas of need.⁶ Family physicians in large practices can develop in-office protocols, based on CDC PrEP guidelines, to assign roles (eg, paperwork assistant, behavioral counselor, prescriber) to staff members.

Continue to: Partnering with HIV specialists, organizations, and pharmacists

Family physicians who are unsure about initiating PrEP might consider referring complex patients, such as those with unclear eligibility or active HBV infection, to an infectious disease or HIV specialist or clinic for the initial evaluation. Once a patient has been started on PrEP, quarterly monitoring is simple and can be easily completed in a family medicine practice.

Depending on location and available services, pharmacists and local HIV and AIDS organizations might provide behavioral and adherence counseling and repeat testing during follow-up appointments. In our experience, working with a primary pharmacy that is familiar with patient assistance programs and prior authorization requirements facilitates smoother prescribing. The result? Lower cost to patients because of knowledge of copays and other assistance programs and willingness to use these secondary payers.

Bringing PrEP into the practice is workable

Providing PrEP is well within your scope of practice as a family physician. To assist you in making PrEP an effective component of your practice, we provide a list of sources of PrEP support in TABLE 5.

Because some physicians might still be reluctant to prescribe PrEP for patients who maintain their risk of HIV acquisition, we recommend that you think of PrEP as you do about statins. Discussing diet and exercise as a means of reducing cardiovascular events for every patient with hyperlipidemia is often insufficient; most physicians therefore also prescribe medication for patients who cannot change behaviors sufficiently to modify their cardiovascular risk factors. Similarly, you now have a preventive for HIV—a costly, lifelong infection—that is as cost-effective as statins are.^26,33

CORRESPONDENCE
Joanne D. Stekler, MD, MPH, Box 359931, Harborview Medical Center, 325 9th Avenue, Seattle, WA 98104; [email protected].

The 2012 US Food and Drug Administration (FDA) approval of daily emtricitabine plus tenofovir disoproxil fumarate as HIV pre-exposure prophylaxis (PrEP) re-energized the field of human immunodeficiency virus (HIV) prevention. In subsequent years, PrEP uptake has increased, particularly in people at high risk of HIV infection.

However, since 2012, progress in controlling the HIV epidemic has been uneven across communities and populations. For instance, in 2014, the southern United States accounted for an estimated 50% of infections, but PrEP uptake has remained low there, with only 1% of the estimated number of eligible people taking PrEP.^1,2 Among African American men who have sex with men (MSM), it is predicted that 1 of every 2 will become infected in his lifetime; among Latino MSM, the prediction is 1 of every 5.³ The expanding opioid epidemic is further jeopardizing the progress made in reducing HIV infection among people who inject drugs.

A “test and treat” strategy is insufficient. Mathematical modeling suggests that “test and treat” without a higher level of coverage is insufficient to control the HIV epidemic.⁴ In the absence of an HIV vaccine, these models find that widespread uptake of PrEP among people at risk of HIV acquisition is needed—in combination with HIV treatment as prevention, condom promotion, and needle exchange—to realize the potential to end the HIV epidemic.⁴

A recent proposal by the US Department of Health and Human Services would establish an initiative to address the continuing HIV public health crisis, with a goal of reducing the numbers of incident HIV infections in the United States by 75% in 5 years and then by 90% in 10 years. That strategic initiative includes 4 “pillars” for preventing HIV acquisition—one of which is the use of PrEP by at-risk people.⁵

Although PrEP is often prescribed by HIV specialists and in sexually transmitted infection (STI) clinics, many patients seek PrEP from family physicians (and other primary care clinicians), who are now also being called on to identify patients in their practice at risk of HIV infection⁶ and to offer them PrEP. In this article, we provide an overview of PrEP and discuss how best to integrate PrEP into a family medicine practice.

Understanding PrEP and how it is used

PrEP is one of 2 related biomedical interventions to prevent HIV acquisition. Many clinicians are familiar with postexposure prophylaxis, a regimen of 3 anti-HIV medications given for 1 month to patients who are within 72 hours of a possible exposure. In contrast, PrEP is a once-daily, fixed-dose combination of 2 medications commonly used in the treatment of HIV infection: emtricitabine, 200 mg, and tenofovir disoproxil fumarate, 300 mg. This combination is the only FDA-approved regimen for daily use as PrEP in the United States.

At-risk patients should take PrEP daily—regardless of how often they engage in risky behaviors.

PrEP is indicated for people whose ongoing sexual or drug injection behaviors put them at substantial risk of HIV infection, and should be taken daily regardless of the frequency of risk-taking behavior. Since 2010, several randomized placebo-controlled trials (RCTs) have reported that, when medication adherence is high (measured by drug levels in blood), PrEP can reduce new HIV infections by more than 90% in high-risk populations.⁷ In clinical practice, HIV infection is uncommon because of the effectiveness of daily PrEP; when infections have occurred, almost all have been in patients not taking the medications as prescribed.⁸

Continue to: Infection with HIV...

Infection with HIV in which viral mutations are associated with emtricitabine or tenofovir resistance is rare among the few people infected with HIV after starting PrEP.⁹ In RCTs, most drug resistance occurred among people who started PrEP when they were already HIV-positive (because they were screened with antibody-only HIV tests that did not detect recent infection).¹⁰

Other medications, routes of administration, and dosing schedules are being studied for safety and efficacy as PrEP for HIV infection.^11,12

For whom should PrEP be prescribed? There are 2 ways to identify candidates for PrEP:

• Passive prescribing relies on patients self-identifying as being at risk of HIV infection and asking about PrEP. Many at-risk patients do not recognize their need for PrEP, however.¹³
• Active screening requires that physicians, or their staff, take a sexual history from all patients. However, reviewing detailed sexual histories with every patient in a busy practice can be overwhelming. One way to begin identifying patients for whom PrEP is appropriate is to commit to talking to subsets of potentially high-risk patients, such as MSM or transgender patients.⁶ Sexual orientation and gender identity are not direct risk factors; a nuanced sexual history is often needed to understand potential exposures. A diagnosis of syphilis or other bacterial STI is a marker of high risk of HIV acquisition.¹⁴

To help identify which of your patients might benefit from PrEP, the PrEP guidelines from the Centers for Disease Control and Prevention (CDC)¹⁵ and tools developed by other sources^16,17 recommend several key screening questions about sexual behavior and substance abuse (TABLE 1^15-17).

Familiarity with PrEP and comfort taking a sexual history to screen for risk of HIV acquisition are essential first steps in prescribing PrEP under CDC guidelines.^6,18 In primary care, female patients are routinely questioned to assess their need for contraception; similarly, screening questions to assess PrEP eligibility can be easily incorporated into practice.

Continue to: What are the indications for PrEP?

Patients in whom PrEP is indicated include sexually active adults and adolescents (> 35 kg)¹⁹ whose use of a condom is inconsistent or who have had multiple recent sex partners; those with a recent bacterial STI; and men or women with a sexual or injection partner known to be HIV-infected (TABLE 2).¹⁵

What steps should be taken before and after initiating PrEP?

Providing PrEP is a harm-reduction strategy similar to prescribing other common preventive medications, such as statins to reduce hyperlipidemia and prevent myocardial infarction; oral contraceptives to prevent unwanted pregnancy; and metformin to prevent complications of diabetes. There are a few screening criteria prior to initiating PrEP (TABLE 3)¹⁰:

• A patient starting PrEP should be (1) HIV-negative, ideally screened by a laboratory-based antigen–antibody (ie, fourth-generation) HIV test or HIV RNA test, and (2) without symptoms of acute HIV infection.²⁰ (Note: Do not hold off PrEP and HIV testing until the patient has achieved a period of sexual abstinence.)
• A patient starting PrEP should have normal renal function and should not be taking contraindicated medications, such as long-term high-dose nonsteroidal anti-inflammatory agents.
• Hepatitis B virus (HBV) surface antigen, surface antibody, and core antibody should be tested because both emtricitabine and tenofovir are active against HBV. For a patient who has active HBV infection, particularly with cirrhosis, there is a theoretical concern that starting and stopping PrEP can lead to flares of HBV infection. Patients who are not HBV-immune should be vaccinated.
• Baseline hepatitis C virus testing is recommended for patients who inject drugs, MSM, or those who were born between 1945 and 1965; annual hepatitis C virus testing is recommended for patients who inject drugs.¹⁵

When it has been determined that a patient is eligible for PrEP, a prescription is written for no longer than 90 days to ensure regular monitoring for HIV infection, STIs, and renal function.

Adherence counseling is a key component of PrEP delivery—as it is with oral contraception, antihypertensive medical therapy, and other medications. As noted, HIV acquisition in PrEP users is most often reported in patients with poor adherence,⁸ especially among adolescents.²¹ PrEP is part of comprehensive sexual health care, and safer sex behaviors, such as condom use, should be encouraged to reduce the risk of acquiring other STIs. Condom use should not, however, be a requirement for continuing to receive PrEP.

Is PrEP safe?

Although PrEP might be new to many family physicians and their patients, trials and observational studies have repeatedly shown that for people without HIV infection, taking daily emtricitabine and tenofovir for prevention of HIV infection is safe. No clinically significant renal, bone, or other toxicity has been reported, although there is concern about potential toxicity after decades of use.^22,23 A recent narrative review from the David Geffen School of Medicine at the University of California Los Angeles compared safety findings from 5 major studies on PrEP with 2 major studies on aspirin safety and found that PrEP is as safe as aspirin, although the authors cautioned that more study on long-term use is needed.²⁴

Continue to: What to tell patients

What to tell patients. Tell patients that within the first weeks of starting PrEP, they might experience a start-up syndrome that typically manifests as gastrointestinal symptoms, headache, and fatigue. These symptoms usually resolve without the need to discontinue the medications.²⁵

Any other concerns about PrEP?

When PrEP was first approved by the FDA, many physicians raised concern about the possibility that PrEP use would lead to increased community-level HIV drug resistance and that behavioral disinhibition might diminish the benefit of PrEP and lead to rampant STIs.²⁶ To date, these fears have not been borne out.

When medication adherence is high, PrEP can reduce new HIV infections by more than 90% in high-risk populations.

Acquired drug resistance, which happens after a person becomes HIV-positive, is a real concern, particularly among people who are screened with antibody-only HIV tests that cannot detect HIV in the so-called window period and who then start PrEP during acute HIV infection. If a person is truly HIV-negative when he (she) starts PrEP, the risk of either acquired or transmitted HIV drug resistance is low and is far outweighed by the preventive benefit of PrEP.²⁷

Similarly, there is a suggestion that syphilis infection is increasing among HIV-negative MSM due to decreased HIV-related stigma and increased mixing between HIV-negative and HIV-positive people. The evidence that PrEP has led to an increase in STI rates²⁸ is mixed, however, and is confounded by temporal increases in STI rates and increased detection of asymptomatic STIs among people on PrEP as a result of regular screening.²⁹

Who pays for PrEP?

The cost of PrEP medications and associated clinical care is covered by nearly all private, employer, and public health insurance. Prior authorization might be required to ensure that testing has excluded HIV infection before prescribing and then refilling prescriptions.

Continue to: For patients who have health insurance...

For patients who have health insurance, assistance with copays or coinsurance is available through the producer of PrEP (Gilead Sciences, Inc.) and other national foundations. Many people who seek PrEP might be eligible for Medicaid if they are otherwise uninsured. Other low-income and uninsured people, including those who are not legal residents or US citizens, usually qualify for the PrEP medication assistance program; the application for this benefit must be completed by the physician.

One way to identify patients for whom PrEP might be appropriate is to talk to subsets of potentially high-risk patients, such as men who have sex with men and transgender patients.

A billing guide on PrEP for physicians is available to assist with International Classification of Disease (ICD)-10 coding.^30,31 If a patient has difficulty with laboratory copays, free HIV and STI testing might be available at local STI clinics and acquired immunodeficiency syndrome (AIDS) service organizations.

Providing PrEP within a primary care setting

The unmet need for PrEP highlights how important it is for family medicine and other primary care practices to incorporate HIV prevention into their suite of services.³²

Patients are most likely to experience adverse effects during the first month of taking PrEP—the same period in which they are establishing their pattern of adherence. It might be helpful to check in with patients at the end of the first month to assess their symptoms and adherence. After this phase, quarterly follow-up is simple, with routine lab monitoring and check-in about continued risk of HIV and adherence challenges (TABLE 3¹⁰).

At our local Ryan White HIV/AIDS Program-funded HIV clinic, which also provides PrEP, computer-ordering checklists (so-called smartsets) for the PrEP initial visit and follow-up visits are programmed into the records system (TABLE 4¹⁵). Other clinics also have developed templates for PrEP visit notes. Adherence monitoring, behavioral counseling, and other preventive services can be integrated into the regular paper- or computer-based intake survey, so that conversations are focused on areas of need.⁶ Family physicians in large practices can develop in-office protocols, based on CDC PrEP guidelines, to assign roles (eg, paperwork assistant, behavioral counselor, prescriber) to staff members.

Continue to: Partnering with HIV specialists, organizations, and pharmacists

Family physicians who are unsure about initiating PrEP might consider referring complex patients, such as those with unclear eligibility or active HBV infection, to an infectious disease or HIV specialist or clinic for the initial evaluation. Once a patient has been started on PrEP, quarterly monitoring is simple and can be easily completed in a family medicine practice.

Depending on location and available services, pharmacists and local HIV and AIDS organizations might provide behavioral and adherence counseling and repeat testing during follow-up appointments. In our experience, working with a primary pharmacy that is familiar with patient assistance programs and prior authorization requirements facilitates smoother prescribing. The result? Lower cost to patients because of knowledge of copays and other assistance programs and willingness to use these secondary payers.

Bringing PrEP into the practice is workable

Providing PrEP is well within your scope of practice as a family physician. To assist you in making PrEP an effective component of your practice, we provide a list of sources of PrEP support in TABLE 5.

Because some physicians might still be reluctant to prescribe PrEP for patients who maintain their risk of HIV acquisition, we recommend that you think of PrEP as you do about statins. Discussing diet and exercise as a means of reducing cardiovascular events for every patient with hyperlipidemia is often insufficient; most physicians therefore also prescribe medication for patients who cannot change behaviors sufficiently to modify their cardiovascular risk factors. Similarly, you now have a preventive for HIV—a costly, lifelong infection—that is as cost-effective as statins are.^26,33

CORRESPONDENCE
Joanne D. Stekler, MD, MPH, Box 359931, Harborview Medical Center, 325 9th Avenue, Seattle, WA 98104; [email protected].

The 2012 US Food and Drug Administration (FDA) approval of daily emtricitabine plus tenofovir disoproxil fumarate as HIV pre-exposure prophylaxis (PrEP) re-energized the field of human immunodeficiency virus (HIV) prevention. In subsequent years, PrEP uptake has increased, particularly in people at high risk of HIV infection.

However, since 2012, progress in controlling the HIV epidemic has been uneven across communities and populations. For instance, in 2014, the southern United States accounted for an estimated 50% of infections, but PrEP uptake has remained low there, with only 1% of the estimated number of eligible people taking PrEP.^1,2 Among African American men who have sex with men (MSM), it is predicted that 1 of every 2 will become infected in his lifetime; among Latino MSM, the prediction is 1 of every 5.³ The expanding opioid epidemic is further jeopardizing the progress made in reducing HIV infection among people who inject drugs.

A “test and treat” strategy is insufficient. Mathematical modeling suggests that “test and treat” without a higher level of coverage is insufficient to control the HIV epidemic.⁴ In the absence of an HIV vaccine, these models find that widespread uptake of PrEP among people at risk of HIV acquisition is needed—in combination with HIV treatment as prevention, condom promotion, and needle exchange—to realize the potential to end the HIV epidemic.⁴

A recent proposal by the US Department of Health and Human Services would establish an initiative to address the continuing HIV public health crisis, with a goal of reducing the numbers of incident HIV infections in the United States by 75% in 5 years and then by 90% in 10 years. That strategic initiative includes 4 “pillars” for preventing HIV acquisition—one of which is the use of PrEP by at-risk people.⁵

Although PrEP is often prescribed by HIV specialists and in sexually transmitted infection (STI) clinics, many patients seek PrEP from family physicians (and other primary care clinicians), who are now also being called on to identify patients in their practice at risk of HIV infection⁶ and to offer them PrEP. In this article, we provide an overview of PrEP and discuss how best to integrate PrEP into a family medicine practice.

Understanding PrEP and how it is used

PrEP is one of 2 related biomedical interventions to prevent HIV acquisition. Many clinicians are familiar with postexposure prophylaxis, a regimen of 3 anti-HIV medications given for 1 month to patients who are within 72 hours of a possible exposure. In contrast, PrEP is a once-daily, fixed-dose combination of 2 medications commonly used in the treatment of HIV infection: emtricitabine, 200 mg, and tenofovir disoproxil fumarate, 300 mg. This combination is the only FDA-approved regimen for daily use as PrEP in the United States.

At-risk patients should take PrEP daily—regardless of how often they engage in risky behaviors.

PrEP is indicated for people whose ongoing sexual or drug injection behaviors put them at substantial risk of HIV infection, and should be taken daily regardless of the frequency of risk-taking behavior. Since 2010, several randomized placebo-controlled trials (RCTs) have reported that, when medication adherence is high (measured by drug levels in blood), PrEP can reduce new HIV infections by more than 90% in high-risk populations.⁷ In clinical practice, HIV infection is uncommon because of the effectiveness of daily PrEP; when infections have occurred, almost all have been in patients not taking the medications as prescribed.⁸

Continue to: Infection with HIV...

Infection with HIV in which viral mutations are associated with emtricitabine or tenofovir resistance is rare among the few people infected with HIV after starting PrEP.⁹ In RCTs, most drug resistance occurred among people who started PrEP when they were already HIV-positive (because they were screened with antibody-only HIV tests that did not detect recent infection).¹⁰

Other medications, routes of administration, and dosing schedules are being studied for safety and efficacy as PrEP for HIV infection.^11,12

For whom should PrEP be prescribed? There are 2 ways to identify candidates for PrEP:

• Passive prescribing relies on patients self-identifying as being at risk of HIV infection and asking about PrEP. Many at-risk patients do not recognize their need for PrEP, however.¹³
• Active screening requires that physicians, or their staff, take a sexual history from all patients. However, reviewing detailed sexual histories with every patient in a busy practice can be overwhelming. One way to begin identifying patients for whom PrEP is appropriate is to commit to talking to subsets of potentially high-risk patients, such as MSM or transgender patients.⁶ Sexual orientation and gender identity are not direct risk factors; a nuanced sexual history is often needed to understand potential exposures. A diagnosis of syphilis or other bacterial STI is a marker of high risk of HIV acquisition.¹⁴

To help identify which of your patients might benefit from PrEP, the PrEP guidelines from the Centers for Disease Control and Prevention (CDC)¹⁵ and tools developed by other sources^16,17 recommend several key screening questions about sexual behavior and substance abuse (TABLE 1^15-17).

Familiarity with PrEP and comfort taking a sexual history to screen for risk of HIV acquisition are essential first steps in prescribing PrEP under CDC guidelines.^6,18 In primary care, female patients are routinely questioned to assess their need for contraception; similarly, screening questions to assess PrEP eligibility can be easily incorporated into practice.

Continue to: What are the indications for PrEP?

Patients in whom PrEP is indicated include sexually active adults and adolescents (> 35 kg)¹⁹ whose use of a condom is inconsistent or who have had multiple recent sex partners; those with a recent bacterial STI; and men or women with a sexual or injection partner known to be HIV-infected (TABLE 2).¹⁵

What steps should be taken before and after initiating PrEP?

Providing PrEP is a harm-reduction strategy similar to prescribing other common preventive medications, such as statins to reduce hyperlipidemia and prevent myocardial infarction; oral contraceptives to prevent unwanted pregnancy; and metformin to prevent complications of diabetes. There are a few screening criteria prior to initiating PrEP (TABLE 3)¹⁰:

• A patient starting PrEP should be (1) HIV-negative, ideally screened by a laboratory-based antigen–antibody (ie, fourth-generation) HIV test or HIV RNA test, and (2) without symptoms of acute HIV infection.²⁰ (Note: Do not hold off PrEP and HIV testing until the patient has achieved a period of sexual abstinence.)
• A patient starting PrEP should have normal renal function and should not be taking contraindicated medications, such as long-term high-dose nonsteroidal anti-inflammatory agents.
• Hepatitis B virus (HBV) surface antigen, surface antibody, and core antibody should be tested because both emtricitabine and tenofovir are active against HBV. For a patient who has active HBV infection, particularly with cirrhosis, there is a theoretical concern that starting and stopping PrEP can lead to flares of HBV infection. Patients who are not HBV-immune should be vaccinated.
• Baseline hepatitis C virus testing is recommended for patients who inject drugs, MSM, or those who were born between 1945 and 1965; annual hepatitis C virus testing is recommended for patients who inject drugs.¹⁵

When it has been determined that a patient is eligible for PrEP, a prescription is written for no longer than 90 days to ensure regular monitoring for HIV infection, STIs, and renal function.

Adherence counseling is a key component of PrEP delivery—as it is with oral contraception, antihypertensive medical therapy, and other medications. As noted, HIV acquisition in PrEP users is most often reported in patients with poor adherence,⁸ especially among adolescents.²¹ PrEP is part of comprehensive sexual health care, and safer sex behaviors, such as condom use, should be encouraged to reduce the risk of acquiring other STIs. Condom use should not, however, be a requirement for continuing to receive PrEP.

Is PrEP safe?

Although PrEP might be new to many family physicians and their patients, trials and observational studies have repeatedly shown that for people without HIV infection, taking daily emtricitabine and tenofovir for prevention of HIV infection is safe. No clinically significant renal, bone, or other toxicity has been reported, although there is concern about potential toxicity after decades of use.^22,23 A recent narrative review from the David Geffen School of Medicine at the University of California Los Angeles compared safety findings from 5 major studies on PrEP with 2 major studies on aspirin safety and found that PrEP is as safe as aspirin, although the authors cautioned that more study on long-term use is needed.²⁴

Continue to: What to tell patients

What to tell patients. Tell patients that within the first weeks of starting PrEP, they might experience a start-up syndrome that typically manifests as gastrointestinal symptoms, headache, and fatigue. These symptoms usually resolve without the need to discontinue the medications.²⁵

Any other concerns about PrEP?

When PrEP was first approved by the FDA, many physicians raised concern about the possibility that PrEP use would lead to increased community-level HIV drug resistance and that behavioral disinhibition might diminish the benefit of PrEP and lead to rampant STIs.²⁶ To date, these fears have not been borne out.

When medication adherence is high, PrEP can reduce new HIV infections by more than 90% in high-risk populations.

Acquired drug resistance, which happens after a person becomes HIV-positive, is a real concern, particularly among people who are screened with antibody-only HIV tests that cannot detect HIV in the so-called window period and who then start PrEP during acute HIV infection. If a person is truly HIV-negative when he (she) starts PrEP, the risk of either acquired or transmitted HIV drug resistance is low and is far outweighed by the preventive benefit of PrEP.²⁷

Similarly, there is a suggestion that syphilis infection is increasing among HIV-negative MSM due to decreased HIV-related stigma and increased mixing between HIV-negative and HIV-positive people. The evidence that PrEP has led to an increase in STI rates²⁸ is mixed, however, and is confounded by temporal increases in STI rates and increased detection of asymptomatic STIs among people on PrEP as a result of regular screening.²⁹

Who pays for PrEP?

The cost of PrEP medications and associated clinical care is covered by nearly all private, employer, and public health insurance. Prior authorization might be required to ensure that testing has excluded HIV infection before prescribing and then refilling prescriptions.

Continue to: For patients who have health insurance...

For patients who have health insurance, assistance with copays or coinsurance is available through the producer of PrEP (Gilead Sciences, Inc.) and other national foundations. Many people who seek PrEP might be eligible for Medicaid if they are otherwise uninsured. Other low-income and uninsured people, including those who are not legal residents or US citizens, usually qualify for the PrEP medication assistance program; the application for this benefit must be completed by the physician.

One way to identify patients for whom PrEP might be appropriate is to talk to subsets of potentially high-risk patients, such as men who have sex with men and transgender patients.

A billing guide on PrEP for physicians is available to assist with International Classification of Disease (ICD)-10 coding.^30,31 If a patient has difficulty with laboratory copays, free HIV and STI testing might be available at local STI clinics and acquired immunodeficiency syndrome (AIDS) service organizations.

Providing PrEP within a primary care setting

The unmet need for PrEP highlights how important it is for family medicine and other primary care practices to incorporate HIV prevention into their suite of services.³²

Patients are most likely to experience adverse effects during the first month of taking PrEP—the same period in which they are establishing their pattern of adherence. It might be helpful to check in with patients at the end of the first month to assess their symptoms and adherence. After this phase, quarterly follow-up is simple, with routine lab monitoring and check-in about continued risk of HIV and adherence challenges (TABLE 3¹⁰).

At our local Ryan White HIV/AIDS Program-funded HIV clinic, which also provides PrEP, computer-ordering checklists (so-called smartsets) for the PrEP initial visit and follow-up visits are programmed into the records system (TABLE 4¹⁵). Other clinics also have developed templates for PrEP visit notes. Adherence monitoring, behavioral counseling, and other preventive services can be integrated into the regular paper- or computer-based intake survey, so that conversations are focused on areas of need.⁶ Family physicians in large practices can develop in-office protocols, based on CDC PrEP guidelines, to assign roles (eg, paperwork assistant, behavioral counselor, prescriber) to staff members.

Continue to: Partnering with HIV specialists, organizations, and pharmacists

Family physicians who are unsure about initiating PrEP might consider referring complex patients, such as those with unclear eligibility or active HBV infection, to an infectious disease or HIV specialist or clinic for the initial evaluation. Once a patient has been started on PrEP, quarterly monitoring is simple and can be easily completed in a family medicine practice.

Depending on location and available services, pharmacists and local HIV and AIDS organizations might provide behavioral and adherence counseling and repeat testing during follow-up appointments. In our experience, working with a primary pharmacy that is familiar with patient assistance programs and prior authorization requirements facilitates smoother prescribing. The result? Lower cost to patients because of knowledge of copays and other assistance programs and willingness to use these secondary payers.

Bringing PrEP into the practice is workable

Providing PrEP is well within your scope of practice as a family physician. To assist you in making PrEP an effective component of your practice, we provide a list of sources of PrEP support in TABLE 5.

Because some physicians might still be reluctant to prescribe PrEP for patients who maintain their risk of HIV acquisition, we recommend that you think of PrEP as you do about statins. Discussing diet and exercise as a means of reducing cardiovascular events for every patient with hyperlipidemia is often insufficient; most physicians therefore also prescribe medication for patients who cannot change behaviors sufficiently to modify their cardiovascular risk factors. Similarly, you now have a preventive for HIV—a costly, lifelong infection—that is as cost-effective as statins are.^26,33

CORRESPONDENCE
Joanne D. Stekler, MD, MPH, Box 359931, Harborview Medical Center, 325 9th Avenue, Seattle, WA 98104; [email protected].

Pediatric herpes zoster declined by 72% in the years following introduction of routine varicella vaccination, with the rates in vaccinated children 78% lower than those in unvaccinated children.

KatarzynaBialasiewicz/Thinkstock

The benefit became largely apparent after children received the second vaccination in the recommended series, and persisted throughout childhood, Sheila Weinmann, PhD, of Kaiser Permanente Northern California, Oakland, and colleagues said.*

The analysis included 6.37 million children in the Kaiser Permanente database, 50% of whom were vaccinated for all or some of the study period stretching from 2003 to 2014. Overall, the crude lab-confirmed herpes zoster (HZ) incidence rate was 74/100,000 person-years. When stratified by vaccine status, the crude rate of HZ among vaccinated children was 78% lower than among unvaccinated children (38 vs. 170 cases per 100,000 person years).

Herpes zoster was more common among girls than boys and up to six times more common in immunosuppressed children than in nonimmunosuppressed children.

The authors also found that unvaccinated children benefited from the high rate of vaccination around them. Although the HZ rate was always lower among vaccinated children, the rate among unvaccinated children fell sharply after 2007.

“The trend of decreasing HZ incidence among children who were unvaccinated is likely due to a lack of primary VZV [varicella-zoster virus] infection resulting from herd immunity in a highly vaccinated population,” Dr. Weinmann and her associates said.

There was some variability among age groups, especially among the youngest who were not fully vaccinated.

“In the group aged 1-2 years, the confirmation-adjusted HZ rate among children who were vaccinated was 70% higher than among those who were unvaccinated,” the authors said. In the “older groups, HZ rates were significantly higher in children who were unvaccinated than in those who were vaccinated,” the researchers noted.

The highest incidence was among vaccinated 1-year-olds, who had a 140% higher risk of HZ than did unvaccinated 1-year-olds. But this risk elevation disappeared by age 2 years. For everyone else, aged 2-17 years, the rate of HZ remained significantly lower in vaccinated children.

“Among the small number of children vaccinated at 11 months of age (for whom the vaccine is not recommended), the HZ incidence rate was significantly higher than in children vaccinated at 1 year of age and older. Similarly, children who contract wild-type varicella infection at younger than 1 year of age also have a higher risk of HZ (relative risk, 13.5). The immature adaptive T-cell response in children less than 1 year of age appears less able to contain VZV as a latent infection, compared with older children.

“Our findings for 11-month-olds who were vaccinated should be interpreted with caution because this population included only three cases of HZ and could have included children participating in a prelicensure study with a vaccine formulation different from Varivax,” Dr. Weinmann and her associates said.

Dr. Weinmann and her associates reported no relevant financial disclosures. The study was supported by the Centers for Disease Control and Prevention.

[email protected]

SOURCE: Weinmann S et al. Pediatrics. 2019 Jun 10. doi: 10.1542/peds.2018-2917.

* This article was updated 6/14/2019

Pediatric herpes zoster declined by 72% in the years following introduction of routine varicella vaccination, with the rates in vaccinated children 78% lower than those in unvaccinated children.

KatarzynaBialasiewicz/Thinkstock

The benefit became largely apparent after children received the second vaccination in the recommended series, and persisted throughout childhood, Sheila Weinmann, PhD, of Kaiser Permanente Northern California, Oakland, and colleagues said.*

The analysis included 6.37 million children in the Kaiser Permanente database, 50% of whom were vaccinated for all or some of the study period stretching from 2003 to 2014. Overall, the crude lab-confirmed herpes zoster (HZ) incidence rate was 74/100,000 person-years. When stratified by vaccine status, the crude rate of HZ among vaccinated children was 78% lower than among unvaccinated children (38 vs. 170 cases per 100,000 person years).

Herpes zoster was more common among girls than boys and up to six times more common in immunosuppressed children than in nonimmunosuppressed children.

The authors also found that unvaccinated children benefited from the high rate of vaccination around them. Although the HZ rate was always lower among vaccinated children, the rate among unvaccinated children fell sharply after 2007.

“The trend of decreasing HZ incidence among children who were unvaccinated is likely due to a lack of primary VZV [varicella-zoster virus] infection resulting from herd immunity in a highly vaccinated population,” Dr. Weinmann and her associates said.

There was some variability among age groups, especially among the youngest who were not fully vaccinated.

“In the group aged 1-2 years, the confirmation-adjusted HZ rate among children who were vaccinated was 70% higher than among those who were unvaccinated,” the authors said. In the “older groups, HZ rates were significantly higher in children who were unvaccinated than in those who were vaccinated,” the researchers noted.

The highest incidence was among vaccinated 1-year-olds, who had a 140% higher risk of HZ than did unvaccinated 1-year-olds. But this risk elevation disappeared by age 2 years. For everyone else, aged 2-17 years, the rate of HZ remained significantly lower in vaccinated children.

“Among the small number of children vaccinated at 11 months of age (for whom the vaccine is not recommended), the HZ incidence rate was significantly higher than in children vaccinated at 1 year of age and older. Similarly, children who contract wild-type varicella infection at younger than 1 year of age also have a higher risk of HZ (relative risk, 13.5). The immature adaptive T-cell response in children less than 1 year of age appears less able to contain VZV as a latent infection, compared with older children.

“Our findings for 11-month-olds who were vaccinated should be interpreted with caution because this population included only three cases of HZ and could have included children participating in a prelicensure study with a vaccine formulation different from Varivax,” Dr. Weinmann and her associates said.

Dr. Weinmann and her associates reported no relevant financial disclosures. The study was supported by the Centers for Disease Control and Prevention.

[email protected]

SOURCE: Weinmann S et al. Pediatrics. 2019 Jun 10. doi: 10.1542/peds.2018-2917.

* This article was updated 6/14/2019

Pediatric herpes zoster declined by 72% in the years following introduction of routine varicella vaccination, with the rates in vaccinated children 78% lower than those in unvaccinated children.

KatarzynaBialasiewicz/Thinkstock

The benefit became largely apparent after children received the second vaccination in the recommended series, and persisted throughout childhood, Sheila Weinmann, PhD, of Kaiser Permanente Northern California, Oakland, and colleagues said.*

The analysis included 6.37 million children in the Kaiser Permanente database, 50% of whom were vaccinated for all or some of the study period stretching from 2003 to 2014. Overall, the crude lab-confirmed herpes zoster (HZ) incidence rate was 74/100,000 person-years. When stratified by vaccine status, the crude rate of HZ among vaccinated children was 78% lower than among unvaccinated children (38 vs. 170 cases per 100,000 person years).

Herpes zoster was more common among girls than boys and up to six times more common in immunosuppressed children than in nonimmunosuppressed children.

The authors also found that unvaccinated children benefited from the high rate of vaccination around them. Although the HZ rate was always lower among vaccinated children, the rate among unvaccinated children fell sharply after 2007.

“The trend of decreasing HZ incidence among children who were unvaccinated is likely due to a lack of primary VZV [varicella-zoster virus] infection resulting from herd immunity in a highly vaccinated population,” Dr. Weinmann and her associates said.

There was some variability among age groups, especially among the youngest who were not fully vaccinated.

“In the group aged 1-2 years, the confirmation-adjusted HZ rate among children who were vaccinated was 70% higher than among those who were unvaccinated,” the authors said. In the “older groups, HZ rates were significantly higher in children who were unvaccinated than in those who were vaccinated,” the researchers noted.

The highest incidence was among vaccinated 1-year-olds, who had a 140% higher risk of HZ than did unvaccinated 1-year-olds. But this risk elevation disappeared by age 2 years. For everyone else, aged 2-17 years, the rate of HZ remained significantly lower in vaccinated children.

“Among the small number of children vaccinated at 11 months of age (for whom the vaccine is not recommended), the HZ incidence rate was significantly higher than in children vaccinated at 1 year of age and older. Similarly, children who contract wild-type varicella infection at younger than 1 year of age also have a higher risk of HZ (relative risk, 13.5). The immature adaptive T-cell response in children less than 1 year of age appears less able to contain VZV as a latent infection, compared with older children.

“Our findings for 11-month-olds who were vaccinated should be interpreted with caution because this population included only three cases of HZ and could have included children participating in a prelicensure study with a vaccine formulation different from Varivax,” Dr. Weinmann and her associates said.

Dr. Weinmann and her associates reported no relevant financial disclosures. The study was supported by the Centers for Disease Control and Prevention.

[email protected]

SOURCE: Weinmann S et al. Pediatrics. 2019 Jun 10. doi: 10.1542/peds.2018-2917.

* This article was updated 6/14/2019

The Diagnosis: Plasmablastic Lymphoma 

Histopathologic examination revealed a diffuse dense proliferation of large, atypical, and pleomorphic mononuclear cells with prominent nucleoli and many mitotic figures representing plasmacytoid cells in the dermis (Figure). Immunostaining was positive for MUM-1 (marker of late-stage plasma cells and activated T cells) and BCL-2 (antiapoptotic marker). Fluorescent polymerase chain reaction was positive for clonal IgH gene arrangement, and fluorescence in situ hybridization was positive for C-MYC rearrangement in 94% of cells. Epstein-Barr encoding region in situ hybridization also was positive. Rare cells stained positive for T-cell markers. CD20, BCL-6, and CD30 immunostains were negative, suggesting that these cells were not B or T cells, though terminally differentiated B cells also can lack these markers. Bone marrow biopsy showed a similar staining pattern to the skin with 10% atypical plasmacytoid cells. Computed tomography of the left leg showed an enlargement of the semimembranosus muscle with internal areas of high density and heterogeneous enhancement. The patient underwent decompression of the left peroneal nerve. Biopsy showed a staining pattern similar to the right skin nodule and bone marrow, consistent with lymphoma.  

He was diagnosed with stage IV human immunodeficiency virus (HIV)-associated plasmablastic lymphoma (PBL) and received 6 cycles of R-EPOCH (rituximab, etoposide phosphate, prednisone, vincristine sulfate, cyclophosphamide, doxorubicin hydrochloride) without vincristine with intrathecal methotrexate, followed by 3 cycles of DHAP (dexamethasone, high dose Ara C, cisplatin) with bortezomib and daratumumab after relapse. Ultimately, he underwent autologous stem cell transplantation and was alive 13 months after diagnosis.  

Plasmablastic lymphoma is a rare subtype of non-Hodgkin lymphoma that most commonly arises in the oral cavity of individuals with HIV.¹ In addition to HIV infection, PBL also is seen in patients with other causes of immunodeficiency such as iatrogenic immunosuppression following solid organ transplantation.¹ The typical disease presentation is an expanding mass in the oral cavity; however, 34% (52/151) of reported cases arose at extraoral primary sites, with a minority of cases confined to cutaneous sites with no systemic involvement.² Cutaneous PBL presentations may include flesh-colored or purple, grouped or solitary nodules; an erythematous infiltrated plaque; or purple-red ulcerated nodules. The lesions usually are asymptomatic and located on the arms and legs.³  

On histologic examination, PBL is characterized by a diffuse monomorphic lymphoid infiltrate that sometimes invades the surrounding soft tissue.^4-6 The neoplastic cells have eccentric round nucleoli. Plasmablastic lymphoma characteristically displays a high proliferation index with many mitotic figures and signs of apoptosis.^4-6 Definitive diagnosis requires immunohistochemical staining. Typical B-cell antigens (CD20) as well as CD45 are negative, while plasma cell markers such as CD38 are positive. Other B- and T-cell markers usually are negative.^5,7 The pathogenesis of PBL is thought to be related to Epstein-Barr virus or human herpesvirus 8 infection. In a series of PBL cases, Epstein-Barr virus and human herpesvirus 8 was positive in 75% (97/129) and 17% (13/75) of tested cases, respectively.¹ 

The prognosis for PBL is poor, with a median overall survival of 15 months and a 3-year survival rate of 25% in HIV-infected individuals.⁸ However, cutaneous PBL without systemic involvement has a considerably better prognosis, with only 1 of 12 cases resulting in death.^2,3,9 Treatment of PBL depends on the extent of the disease. Cutaneous PBL can be treated with surgery and adjuvant radiation.³ Chemotherapy is required for patients with multiple lesions or systemic involvement. Current treatment regimens are similar to those used for other aggressive lymphomas such as CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone).¹ Transplant recipients should have their immunosuppression reduced, and HIV-infected patients should have their highly active antiretroviral therapy regimens optimized. Patients presenting with PBL without HIV should be tested for HIV, as PBL has previously been reported to be the presenting manifestation of HIV infection.¹⁰ 

The differential diagnosis for a rapidly expanding, vascular-appearing, red mass on the legs in an immunosuppressed individual includes abscess, malignancy, Kaposi sarcoma, Sweet syndrome, and tertiary syphilis.  

Acknowledgment
We thank Sameera Husain, MD (New York, New York), for her assistance with histopathologic photographs and interpretation.  

The Diagnosis: Plasmablastic Lymphoma 

Histopathologic examination revealed a diffuse dense proliferation of large, atypical, and pleomorphic mononuclear cells with prominent nucleoli and many mitotic figures representing plasmacytoid cells in the dermis (Figure). Immunostaining was positive for MUM-1 (marker of late-stage plasma cells and activated T cells) and BCL-2 (antiapoptotic marker). Fluorescent polymerase chain reaction was positive for clonal IgH gene arrangement, and fluorescence in situ hybridization was positive for C-MYC rearrangement in 94% of cells. Epstein-Barr encoding region in situ hybridization also was positive. Rare cells stained positive for T-cell markers. CD20, BCL-6, and CD30 immunostains were negative, suggesting that these cells were not B or T cells, though terminally differentiated B cells also can lack these markers. Bone marrow biopsy showed a similar staining pattern to the skin with 10% atypical plasmacytoid cells. Computed tomography of the left leg showed an enlargement of the semimembranosus muscle with internal areas of high density and heterogeneous enhancement. The patient underwent decompression of the left peroneal nerve. Biopsy showed a staining pattern similar to the right skin nodule and bone marrow, consistent with lymphoma.  

He was diagnosed with stage IV human immunodeficiency virus (HIV)-associated plasmablastic lymphoma (PBL) and received 6 cycles of R-EPOCH (rituximab, etoposide phosphate, prednisone, vincristine sulfate, cyclophosphamide, doxorubicin hydrochloride) without vincristine with intrathecal methotrexate, followed by 3 cycles of DHAP (dexamethasone, high dose Ara C, cisplatin) with bortezomib and daratumumab after relapse. Ultimately, he underwent autologous stem cell transplantation and was alive 13 months after diagnosis.  

Plasmablastic lymphoma is a rare subtype of non-Hodgkin lymphoma that most commonly arises in the oral cavity of individuals with HIV.¹ In addition to HIV infection, PBL also is seen in patients with other causes of immunodeficiency such as iatrogenic immunosuppression following solid organ transplantation.¹ The typical disease presentation is an expanding mass in the oral cavity; however, 34% (52/151) of reported cases arose at extraoral primary sites, with a minority of cases confined to cutaneous sites with no systemic involvement.² Cutaneous PBL presentations may include flesh-colored or purple, grouped or solitary nodules; an erythematous infiltrated plaque; or purple-red ulcerated nodules. The lesions usually are asymptomatic and located on the arms and legs.³  

On histologic examination, PBL is characterized by a diffuse monomorphic lymphoid infiltrate that sometimes invades the surrounding soft tissue.^4-6 The neoplastic cells have eccentric round nucleoli. Plasmablastic lymphoma characteristically displays a high proliferation index with many mitotic figures and signs of apoptosis.^4-6 Definitive diagnosis requires immunohistochemical staining. Typical B-cell antigens (CD20) as well as CD45 are negative, while plasma cell markers such as CD38 are positive. Other B- and T-cell markers usually are negative.^5,7 The pathogenesis of PBL is thought to be related to Epstein-Barr virus or human herpesvirus 8 infection. In a series of PBL cases, Epstein-Barr virus and human herpesvirus 8 was positive in 75% (97/129) and 17% (13/75) of tested cases, respectively.¹ 

The prognosis for PBL is poor, with a median overall survival of 15 months and a 3-year survival rate of 25% in HIV-infected individuals.⁸ However, cutaneous PBL without systemic involvement has a considerably better prognosis, with only 1 of 12 cases resulting in death.^2,3,9 Treatment of PBL depends on the extent of the disease. Cutaneous PBL can be treated with surgery and adjuvant radiation.³ Chemotherapy is required for patients with multiple lesions or systemic involvement. Current treatment regimens are similar to those used for other aggressive lymphomas such as CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone).¹ Transplant recipients should have their immunosuppression reduced, and HIV-infected patients should have their highly active antiretroviral therapy regimens optimized. Patients presenting with PBL without HIV should be tested for HIV, as PBL has previously been reported to be the presenting manifestation of HIV infection.¹⁰ 

The differential diagnosis for a rapidly expanding, vascular-appearing, red mass on the legs in an immunosuppressed individual includes abscess, malignancy, Kaposi sarcoma, Sweet syndrome, and tertiary syphilis.  

Acknowledgment
We thank Sameera Husain, MD (New York, New York), for her assistance with histopathologic photographs and interpretation.  

The Diagnosis: Plasmablastic Lymphoma 

Histopathologic examination revealed a diffuse dense proliferation of large, atypical, and pleomorphic mononuclear cells with prominent nucleoli and many mitotic figures representing plasmacytoid cells in the dermis (Figure). Immunostaining was positive for MUM-1 (marker of late-stage plasma cells and activated T cells) and BCL-2 (antiapoptotic marker). Fluorescent polymerase chain reaction was positive for clonal IgH gene arrangement, and fluorescence in situ hybridization was positive for C-MYC rearrangement in 94% of cells. Epstein-Barr encoding region in situ hybridization also was positive. Rare cells stained positive for T-cell markers. CD20, BCL-6, and CD30 immunostains were negative, suggesting that these cells were not B or T cells, though terminally differentiated B cells also can lack these markers. Bone marrow biopsy showed a similar staining pattern to the skin with 10% atypical plasmacytoid cells. Computed tomography of the left leg showed an enlargement of the semimembranosus muscle with internal areas of high density and heterogeneous enhancement. The patient underwent decompression of the left peroneal nerve. Biopsy showed a staining pattern similar to the right skin nodule and bone marrow, consistent with lymphoma.  

He was diagnosed with stage IV human immunodeficiency virus (HIV)-associated plasmablastic lymphoma (PBL) and received 6 cycles of R-EPOCH (rituximab, etoposide phosphate, prednisone, vincristine sulfate, cyclophosphamide, doxorubicin hydrochloride) without vincristine with intrathecal methotrexate, followed by 3 cycles of DHAP (dexamethasone, high dose Ara C, cisplatin) with bortezomib and daratumumab after relapse. Ultimately, he underwent autologous stem cell transplantation and was alive 13 months after diagnosis.  

Plasmablastic lymphoma is a rare subtype of non-Hodgkin lymphoma that most commonly arises in the oral cavity of individuals with HIV.¹ In addition to HIV infection, PBL also is seen in patients with other causes of immunodeficiency such as iatrogenic immunosuppression following solid organ transplantation.¹ The typical disease presentation is an expanding mass in the oral cavity; however, 34% (52/151) of reported cases arose at extraoral primary sites, with a minority of cases confined to cutaneous sites with no systemic involvement.² Cutaneous PBL presentations may include flesh-colored or purple, grouped or solitary nodules; an erythematous infiltrated plaque; or purple-red ulcerated nodules. The lesions usually are asymptomatic and located on the arms and legs.³  

On histologic examination, PBL is characterized by a diffuse monomorphic lymphoid infiltrate that sometimes invades the surrounding soft tissue.^4-6 The neoplastic cells have eccentric round nucleoli. Plasmablastic lymphoma characteristically displays a high proliferation index with many mitotic figures and signs of apoptosis.^4-6 Definitive diagnosis requires immunohistochemical staining. Typical B-cell antigens (CD20) as well as CD45 are negative, while plasma cell markers such as CD38 are positive. Other B- and T-cell markers usually are negative.^5,7 The pathogenesis of PBL is thought to be related to Epstein-Barr virus or human herpesvirus 8 infection. In a series of PBL cases, Epstein-Barr virus and human herpesvirus 8 was positive in 75% (97/129) and 17% (13/75) of tested cases, respectively.¹ 

The prognosis for PBL is poor, with a median overall survival of 15 months and a 3-year survival rate of 25% in HIV-infected individuals.⁸ However, cutaneous PBL without systemic involvement has a considerably better prognosis, with only 1 of 12 cases resulting in death.^2,3,9 Treatment of PBL depends on the extent of the disease. Cutaneous PBL can be treated with surgery and adjuvant radiation.³ Chemotherapy is required for patients with multiple lesions or systemic involvement. Current treatment regimens are similar to those used for other aggressive lymphomas such as CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone).¹ Transplant recipients should have their immunosuppression reduced, and HIV-infected patients should have their highly active antiretroviral therapy regimens optimized. Patients presenting with PBL without HIV should be tested for HIV, as PBL has previously been reported to be the presenting manifestation of HIV infection.¹⁰ 

The differential diagnosis for a rapidly expanding, vascular-appearing, red mass on the legs in an immunosuppressed individual includes abscess, malignancy, Kaposi sarcoma, Sweet syndrome, and tertiary syphilis.  

Acknowledgment
We thank Sameera Husain, MD (New York, New York), for her assistance with histopathologic photographs and interpretation.  

Case Report

A 65-year-old woman presented with stage IVA2 mycosis fungoides (MF)(T4N3M0B2)/Sézary syndrome (SS). A peripheral blood count contained 6000 Sézary cells with cerebriform nuclei, a CD2^+/−CD3⁺CD4⁺CD5^+/−CD7⁺CD8⁻CD26⁻immunophenotype, and a highly abnormal CD4 to CD8 ratio (70:1). Positron emission tomography and computed tomography demonstrated hypermetabolic subcutaneous nodules in the base of the neck and generalized lymphadenopathy. Lymph node biopsy showed involvement by T-cell lymphoma and dominant T-cell receptor γ clonality by polymerase chain reaction.

On initial presentation to the Cutaneous Lymphoma Clinic at the University of Wisconsin-Madison, the patient was erythrodermic. She also was noted to have undulating wavy bands and concentric annular, ringlike, thin, erythematous plaques with trailing scale, giving a wood grain, zebra hide–like appearance involving the buttocks, abdomen, and lower extremities (Figure 1). Lesions were markedly pruritic and were advancing rapidly. A diagnosis of erythema gyratum repens (EGR)–like eruption was made.

Interferon alfa-2b and methotrexate therapy was initiated. Additionally, oral terbinafine (250 mg/d) was initiated for 14 days, resulting in complete resolution of the EGR-like eruption; nevertheless, diffuse erythema remained. Subsequently, within 3 months of treatment, the cutaneous T-cell lymphoma (CTCL) improved with continued interferon alfa-2b and methotrexate. Erythroderma became minimal; the circulating Sézary cell count decreased by 50%. The patient ultimately had multiple relapses in erythroderma and progression of SS. Erythema gyratum repens–like lesions recurred on multiple occasions, with a temporary response to repeat courses of oral terbinafine.

Comment

Defining True EGR vs EGR-like Eruption
Sézary syndrome represents the leukemic stage of CTCL, which is defined by the triad of erythroderma; generalized lymphadenopathy; and neoplastic T cells in the skin, lymph nodes, and peripheral blood. It is well known that CTCL can mimic multiple benign and malignant dermatoses. One rare presentation of CTCL is an EGR-like eruption.

Erythema gyratum repens presents as rapidly advancing, erythematous, concentric bands that can be figurate, gyrate, or annular, with a fine trailing edge of scale (wood grain pattern). The diagnosis is based on the characteristic clinical pattern of EGR and by ruling out other mimicking conditions with biopsy.¹ Patients with the characteristic clinical pattern but with an alternate underlying dermatosis are described as having an EGR-like eruption rather than true EGR.

True EGR is most often but not always associated with underlying malignancy. Biopsy of true EGR eruptions show nonspecific histopathologic features, with perivascular superficial mononuclear dermatitis, occasional mild spongiosis, and focal parakeratosis; specific features of an alternate dermatosis are lacking.² In addition to CTCL, EGR-like eruptions have been described in a number of diseases, including systemic lupus erythematosus, erythema annulare centrifugum, bullous dermatosis, erythrokeratodermia variabilis, urticarial vasculitis, leukocytoclastic vasculitis, and neutrophilic dermatoses.

Prior Reports of EGR-like Eruption in Association With MF
According to a PubMed search of articles indexed for MEDLINE using the terms erythema gyratum repens in mycosis fungoides, mycosis fungoides with tinea, and concentric wood grain erythema, there have been 6 other cases of an EGR-like eruption in association with MF (Table). Poonawalla et al³ first described an EGR-like eruption (utilizing the term tinea pseudoimbricata) in a 55-year-old man with stage IB MF (T2N0M0B0). The patient had a preceding history of tinea pedis and tinea corporis that preceded the diagnosis of MF. At the time of MF diagnosis, the patient presented with extensive concentric, gyrate, wood grain, annular lesions. His MF was resistant to topical mechlorethamine, psoralen plus UVA, and oral bexarotene. The body surface area involvement decreased from 60% to less than 1% after institution of oral and topical antifungal therapy. It was postulated that the widespread dermatophytosis that preceded the development of MF may have been the persistent antigen leading to his disease. Preceding the diagnosis of MF, skin scrapings were floridly positive for dermatophyte hyphae. Fungal cultures from the affected areas of skin grew T rubrum.³

Moore et al⁴ described an EGR-like eruption on the trunk of a 73-year-old man with stage IA MF (T1N0M0B0). Biopsy was consistent with MF, but no fungal organisms were seen. Potassium hydroxide preparation and fungal cultures of the lesions also were negative for organisms. The patient was successfully treated with topical betamethasone.⁴Jouary et al⁵ described an EGR-like eruption in a 77-year-old man with stage III erythrodermic MF (T4N1M0B0). Biopsy showed mycelia on PAS stain. Subsequent culture isolated T rubrum. Terbinafine (250 mg/d) and ketoconazole cream 2% daily were initiated and the patient’s EGR-like rash quickly cleared, while MF progressed to SS.⁵

Cerri et al⁶ later described a case of EGR-like eruption in a 61-year-old man with stage I MF and an EGR-like eruption. Microscopic examination of potassium hydroxide (KOH) preparations and fungal culture of the lesions failed to demonstrate mycotic infection. There was no mention of PAS stain of skin biopsy specimens. In this case, the authors mentioned that EGR-like lesions preceded exacerbation of MF and questioned the prognostic significance of the EGR-like eruption in relation to MF.⁶

Holcomb et al⁷ reported the next case of a 75-year-old man with stage IIB MF (T3N0M0B0) with CD25⁺ and CD30⁺ large cell transformation who presented with an EGR-like eruption. In this case, PAS stain and KOH preparations were repeatedly negative for mycotic infection. Disease progression was not mentioned following the appearance of the EGR-like eruption.⁷

Nagase et al⁸ most recently described a case of a 73-year-old Japanese man with stage IB (T2N0M0B0) CD4⁻CD8⁻ MF and lung cancer who developed a cutaneous eruption mimicking EGR. Microscopy and culture excluded the presence of a mycotic infection. The patient achieved partial remission with photochemotherapy (psoralen plus UVA) combined with topical corticosteroids. No major changes in the patient’s skin lesions were noted following surgical resection of the lung cancer.⁸

Dermatophyte Infection
It is known that conventional tinea corporis can occur in the setting of CTCL. However, EGR-like eruptions in CTCL can be distinguished from standard tinea corporis by the classic morphology of EGR and clinical history of rapid migration of these characteristic lesions.

Tinea imbricata is known to have a clinical appearance that is similar to EGR, but the infection is caused by Tinea concentricum, which is limited to southwest Polynesia, Melanesia, Southeast Asia, India, and Central America. Although T rubrum was the dermatophyte isolated by Poonawalla et al,³ Jouary et al,⁵ and in our case, whether T rubrum infection in the setting of CTCL has any impact on prognosis needs further study.

Our case of an EGR-like eruption presented in a patient with SS and tinea corporis. Biopsy specimens showed CTCL and concomitant dermatophytic infection that was confirmed with PAS stain and identified as T rubrum. Interestingly, our patient’s EGR-like eruption cleared with oral terbinafine therapy, consistent with findings described by Poonawalla et al³ and Jouary et al⁵ in which treatment of the dermatophytic infection led to resolution of the EGR-like eruption, suggesting a causative role.

However, testing for dermatophytes was negative in the other reported cases of EGR-like eruptions in patients with MF, despite screening for the presence of fungal microorganisms using KOH preparation, PAS staining, or fungal culture, or a combination of these methods,^3-8 which raises the question: Do the cases reported without dermatophytic infection represent false-negative test results, or can the distinct clinical appearance of EGR indeed be seen in patients with CTCL who lack superimposed dermatophytosis? In 3 prior reported cases of EGR-like eruptions in MF, the eruption was preceded by immunosuppressive therapy.^5-7

Further investigation is needed to correlate the role of dermatophytic infection in EGR-like eruptions. Our case and the Jouary et al⁵ case reported dermatophyte-positive EGR-like eruptions in MF and SS detected with histopathologic analysis and PAS stain. This low-cost screening method should be considered in future cases. If the test result is dermatophyte positive, a 14-day course of oral terbinafine (250 mg/d) might induce resolution of the EGR-like eruption.

Conclusion

The role of dermatophyte-induced EGR or EGR-like eruptions in other settings also warrants further investigation to shed light on this poorly understood yet striking dermatologic condition. Our patient showed both MF and dermatophytes in skin biopsy results, regardless of whether those sites showed erythroderma or EGR-like features clinically. On 3 occasions, antifungal treatment cleared the EGR-like lesions and associated pruritus but not erythroderma. Therefore, it appears that the mere presence of dermatophytes was necessary but not sufficient to produce the EGR-like lesions observed in our case.

Case Report

A 65-year-old woman presented with stage IVA2 mycosis fungoides (MF)(T4N3M0B2)/Sézary syndrome (SS). A peripheral blood count contained 6000 Sézary cells with cerebriform nuclei, a CD2^+/−CD3⁺CD4⁺CD5^+/−CD7⁺CD8⁻CD26⁻immunophenotype, and a highly abnormal CD4 to CD8 ratio (70:1). Positron emission tomography and computed tomography demonstrated hypermetabolic subcutaneous nodules in the base of the neck and generalized lymphadenopathy. Lymph node biopsy showed involvement by T-cell lymphoma and dominant T-cell receptor γ clonality by polymerase chain reaction.

On initial presentation to the Cutaneous Lymphoma Clinic at the University of Wisconsin-Madison, the patient was erythrodermic. She also was noted to have undulating wavy bands and concentric annular, ringlike, thin, erythematous plaques with trailing scale, giving a wood grain, zebra hide–like appearance involving the buttocks, abdomen, and lower extremities (Figure 1). Lesions were markedly pruritic and were advancing rapidly. A diagnosis of erythema gyratum repens (EGR)–like eruption was made.

Interferon alfa-2b and methotrexate therapy was initiated. Additionally, oral terbinafine (250 mg/d) was initiated for 14 days, resulting in complete resolution of the EGR-like eruption; nevertheless, diffuse erythema remained. Subsequently, within 3 months of treatment, the cutaneous T-cell lymphoma (CTCL) improved with continued interferon alfa-2b and methotrexate. Erythroderma became minimal; the circulating Sézary cell count decreased by 50%. The patient ultimately had multiple relapses in erythroderma and progression of SS. Erythema gyratum repens–like lesions recurred on multiple occasions, with a temporary response to repeat courses of oral terbinafine.

Comment

Defining True EGR vs EGR-like Eruption
Sézary syndrome represents the leukemic stage of CTCL, which is defined by the triad of erythroderma; generalized lymphadenopathy; and neoplastic T cells in the skin, lymph nodes, and peripheral blood. It is well known that CTCL can mimic multiple benign and malignant dermatoses. One rare presentation of CTCL is an EGR-like eruption.

Erythema gyratum repens presents as rapidly advancing, erythematous, concentric bands that can be figurate, gyrate, or annular, with a fine trailing edge of scale (wood grain pattern). The diagnosis is based on the characteristic clinical pattern of EGR and by ruling out other mimicking conditions with biopsy.¹ Patients with the characteristic clinical pattern but with an alternate underlying dermatosis are described as having an EGR-like eruption rather than true EGR.

True EGR is most often but not always associated with underlying malignancy. Biopsy of true EGR eruptions show nonspecific histopathologic features, with perivascular superficial mononuclear dermatitis, occasional mild spongiosis, and focal parakeratosis; specific features of an alternate dermatosis are lacking.² In addition to CTCL, EGR-like eruptions have been described in a number of diseases, including systemic lupus erythematosus, erythema annulare centrifugum, bullous dermatosis, erythrokeratodermia variabilis, urticarial vasculitis, leukocytoclastic vasculitis, and neutrophilic dermatoses.

Prior Reports of EGR-like Eruption in Association With MF
According to a PubMed search of articles indexed for MEDLINE using the terms erythema gyratum repens in mycosis fungoides, mycosis fungoides with tinea, and concentric wood grain erythema, there have been 6 other cases of an EGR-like eruption in association with MF (Table). Poonawalla et al³ first described an EGR-like eruption (utilizing the term tinea pseudoimbricata) in a 55-year-old man with stage IB MF (T2N0M0B0). The patient had a preceding history of tinea pedis and tinea corporis that preceded the diagnosis of MF. At the time of MF diagnosis, the patient presented with extensive concentric, gyrate, wood grain, annular lesions. His MF was resistant to topical mechlorethamine, psoralen plus UVA, and oral bexarotene. The body surface area involvement decreased from 60% to less than 1% after institution of oral and topical antifungal therapy. It was postulated that the widespread dermatophytosis that preceded the development of MF may have been the persistent antigen leading to his disease. Preceding the diagnosis of MF, skin scrapings were floridly positive for dermatophyte hyphae. Fungal cultures from the affected areas of skin grew T rubrum.³

Moore et al⁴ described an EGR-like eruption on the trunk of a 73-year-old man with stage IA MF (T1N0M0B0). Biopsy was consistent with MF, but no fungal organisms were seen. Potassium hydroxide preparation and fungal cultures of the lesions also were negative for organisms. The patient was successfully treated with topical betamethasone.⁴Jouary et al⁵ described an EGR-like eruption in a 77-year-old man with stage III erythrodermic MF (T4N1M0B0). Biopsy showed mycelia on PAS stain. Subsequent culture isolated T rubrum. Terbinafine (250 mg/d) and ketoconazole cream 2% daily were initiated and the patient’s EGR-like rash quickly cleared, while MF progressed to SS.⁵

Cerri et al⁶ later described a case of EGR-like eruption in a 61-year-old man with stage I MF and an EGR-like eruption. Microscopic examination of potassium hydroxide (KOH) preparations and fungal culture of the lesions failed to demonstrate mycotic infection. There was no mention of PAS stain of skin biopsy specimens. In this case, the authors mentioned that EGR-like lesions preceded exacerbation of MF and questioned the prognostic significance of the EGR-like eruption in relation to MF.⁶

Holcomb et al⁷ reported the next case of a 75-year-old man with stage IIB MF (T3N0M0B0) with CD25⁺ and CD30⁺ large cell transformation who presented with an EGR-like eruption. In this case, PAS stain and KOH preparations were repeatedly negative for mycotic infection. Disease progression was not mentioned following the appearance of the EGR-like eruption.⁷

Nagase et al⁸ most recently described a case of a 73-year-old Japanese man with stage IB (T2N0M0B0) CD4⁻CD8⁻ MF and lung cancer who developed a cutaneous eruption mimicking EGR. Microscopy and culture excluded the presence of a mycotic infection. The patient achieved partial remission with photochemotherapy (psoralen plus UVA) combined with topical corticosteroids. No major changes in the patient’s skin lesions were noted following surgical resection of the lung cancer.⁸

Dermatophyte Infection
It is known that conventional tinea corporis can occur in the setting of CTCL. However, EGR-like eruptions in CTCL can be distinguished from standard tinea corporis by the classic morphology of EGR and clinical history of rapid migration of these characteristic lesions.

Tinea imbricata is known to have a clinical appearance that is similar to EGR, but the infection is caused by Tinea concentricum, which is limited to southwest Polynesia, Melanesia, Southeast Asia, India, and Central America. Although T rubrum was the dermatophyte isolated by Poonawalla et al,³ Jouary et al,⁵ and in our case, whether T rubrum infection in the setting of CTCL has any impact on prognosis needs further study.

Our case of an EGR-like eruption presented in a patient with SS and tinea corporis. Biopsy specimens showed CTCL and concomitant dermatophytic infection that was confirmed with PAS stain and identified as T rubrum. Interestingly, our patient’s EGR-like eruption cleared with oral terbinafine therapy, consistent with findings described by Poonawalla et al³ and Jouary et al⁵ in which treatment of the dermatophytic infection led to resolution of the EGR-like eruption, suggesting a causative role.

However, testing for dermatophytes was negative in the other reported cases of EGR-like eruptions in patients with MF, despite screening for the presence of fungal microorganisms using KOH preparation, PAS staining, or fungal culture, or a combination of these methods,^3-8 which raises the question: Do the cases reported without dermatophytic infection represent false-negative test results, or can the distinct clinical appearance of EGR indeed be seen in patients with CTCL who lack superimposed dermatophytosis? In 3 prior reported cases of EGR-like eruptions in MF, the eruption was preceded by immunosuppressive therapy.^5-7

Further investigation is needed to correlate the role of dermatophytic infection in EGR-like eruptions. Our case and the Jouary et al⁵ case reported dermatophyte-positive EGR-like eruptions in MF and SS detected with histopathologic analysis and PAS stain. This low-cost screening method should be considered in future cases. If the test result is dermatophyte positive, a 14-day course of oral terbinafine (250 mg/d) might induce resolution of the EGR-like eruption.

Conclusion

The role of dermatophyte-induced EGR or EGR-like eruptions in other settings also warrants further investigation to shed light on this poorly understood yet striking dermatologic condition. Our patient showed both MF and dermatophytes in skin biopsy results, regardless of whether those sites showed erythroderma or EGR-like features clinically. On 3 occasions, antifungal treatment cleared the EGR-like lesions and associated pruritus but not erythroderma. Therefore, it appears that the mere presence of dermatophytes was necessary but not sufficient to produce the EGR-like lesions observed in our case.

Case Report

A 65-year-old woman presented with stage IVA2 mycosis fungoides (MF)(T4N3M0B2)/Sézary syndrome (SS). A peripheral blood count contained 6000 Sézary cells with cerebriform nuclei, a CD2^+/−CD3⁺CD4⁺CD5^+/−CD7⁺CD8⁻CD26⁻immunophenotype, and a highly abnormal CD4 to CD8 ratio (70:1). Positron emission tomography and computed tomography demonstrated hypermetabolic subcutaneous nodules in the base of the neck and generalized lymphadenopathy. Lymph node biopsy showed involvement by T-cell lymphoma and dominant T-cell receptor γ clonality by polymerase chain reaction.

On initial presentation to the Cutaneous Lymphoma Clinic at the University of Wisconsin-Madison, the patient was erythrodermic. She also was noted to have undulating wavy bands and concentric annular, ringlike, thin, erythematous plaques with trailing scale, giving a wood grain, zebra hide–like appearance involving the buttocks, abdomen, and lower extremities (Figure 1). Lesions were markedly pruritic and were advancing rapidly. A diagnosis of erythema gyratum repens (EGR)–like eruption was made.

Interferon alfa-2b and methotrexate therapy was initiated. Additionally, oral terbinafine (250 mg/d) was initiated for 14 days, resulting in complete resolution of the EGR-like eruption; nevertheless, diffuse erythema remained. Subsequently, within 3 months of treatment, the cutaneous T-cell lymphoma (CTCL) improved with continued interferon alfa-2b and methotrexate. Erythroderma became minimal; the circulating Sézary cell count decreased by 50%. The patient ultimately had multiple relapses in erythroderma and progression of SS. Erythema gyratum repens–like lesions recurred on multiple occasions, with a temporary response to repeat courses of oral terbinafine.

Comment

Defining True EGR vs EGR-like Eruption
Sézary syndrome represents the leukemic stage of CTCL, which is defined by the triad of erythroderma; generalized lymphadenopathy; and neoplastic T cells in the skin, lymph nodes, and peripheral blood. It is well known that CTCL can mimic multiple benign and malignant dermatoses. One rare presentation of CTCL is an EGR-like eruption.

Erythema gyratum repens presents as rapidly advancing, erythematous, concentric bands that can be figurate, gyrate, or annular, with a fine trailing edge of scale (wood grain pattern). The diagnosis is based on the characteristic clinical pattern of EGR and by ruling out other mimicking conditions with biopsy.¹ Patients with the characteristic clinical pattern but with an alternate underlying dermatosis are described as having an EGR-like eruption rather than true EGR.

True EGR is most often but not always associated with underlying malignancy. Biopsy of true EGR eruptions show nonspecific histopathologic features, with perivascular superficial mononuclear dermatitis, occasional mild spongiosis, and focal parakeratosis; specific features of an alternate dermatosis are lacking.² In addition to CTCL, EGR-like eruptions have been described in a number of diseases, including systemic lupus erythematosus, erythema annulare centrifugum, bullous dermatosis, erythrokeratodermia variabilis, urticarial vasculitis, leukocytoclastic vasculitis, and neutrophilic dermatoses.

Prior Reports of EGR-like Eruption in Association With MF
According to a PubMed search of articles indexed for MEDLINE using the terms erythema gyratum repens in mycosis fungoides, mycosis fungoides with tinea, and concentric wood grain erythema, there have been 6 other cases of an EGR-like eruption in association with MF (Table). Poonawalla et al³ first described an EGR-like eruption (utilizing the term tinea pseudoimbricata) in a 55-year-old man with stage IB MF (T2N0M0B0). The patient had a preceding history of tinea pedis and tinea corporis that preceded the diagnosis of MF. At the time of MF diagnosis, the patient presented with extensive concentric, gyrate, wood grain, annular lesions. His MF was resistant to topical mechlorethamine, psoralen plus UVA, and oral bexarotene. The body surface area involvement decreased from 60% to less than 1% after institution of oral and topical antifungal therapy. It was postulated that the widespread dermatophytosis that preceded the development of MF may have been the persistent antigen leading to his disease. Preceding the diagnosis of MF, skin scrapings were floridly positive for dermatophyte hyphae. Fungal cultures from the affected areas of skin grew T rubrum.³

Moore et al⁴ described an EGR-like eruption on the trunk of a 73-year-old man with stage IA MF (T1N0M0B0). Biopsy was consistent with MF, but no fungal organisms were seen. Potassium hydroxide preparation and fungal cultures of the lesions also were negative for organisms. The patient was successfully treated with topical betamethasone.⁴Jouary et al⁵ described an EGR-like eruption in a 77-year-old man with stage III erythrodermic MF (T4N1M0B0). Biopsy showed mycelia on PAS stain. Subsequent culture isolated T rubrum. Terbinafine (250 mg/d) and ketoconazole cream 2% daily were initiated and the patient’s EGR-like rash quickly cleared, while MF progressed to SS.⁵

Cerri et al⁶ later described a case of EGR-like eruption in a 61-year-old man with stage I MF and an EGR-like eruption. Microscopic examination of potassium hydroxide (KOH) preparations and fungal culture of the lesions failed to demonstrate mycotic infection. There was no mention of PAS stain of skin biopsy specimens. In this case, the authors mentioned that EGR-like lesions preceded exacerbation of MF and questioned the prognostic significance of the EGR-like eruption in relation to MF.⁶

Holcomb et al⁷ reported the next case of a 75-year-old man with stage IIB MF (T3N0M0B0) with CD25⁺ and CD30⁺ large cell transformation who presented with an EGR-like eruption. In this case, PAS stain and KOH preparations were repeatedly negative for mycotic infection. Disease progression was not mentioned following the appearance of the EGR-like eruption.⁷

Nagase et al⁸ most recently described a case of a 73-year-old Japanese man with stage IB (T2N0M0B0) CD4⁻CD8⁻ MF and lung cancer who developed a cutaneous eruption mimicking EGR. Microscopy and culture excluded the presence of a mycotic infection. The patient achieved partial remission with photochemotherapy (psoralen plus UVA) combined with topical corticosteroids. No major changes in the patient’s skin lesions were noted following surgical resection of the lung cancer.⁸

Dermatophyte Infection
It is known that conventional tinea corporis can occur in the setting of CTCL. However, EGR-like eruptions in CTCL can be distinguished from standard tinea corporis by the classic morphology of EGR and clinical history of rapid migration of these characteristic lesions.

Tinea imbricata is known to have a clinical appearance that is similar to EGR, but the infection is caused by Tinea concentricum, which is limited to southwest Polynesia, Melanesia, Southeast Asia, India, and Central America. Although T rubrum was the dermatophyte isolated by Poonawalla et al,³ Jouary et al,⁵ and in our case, whether T rubrum infection in the setting of CTCL has any impact on prognosis needs further study.

Our case of an EGR-like eruption presented in a patient with SS and tinea corporis. Biopsy specimens showed CTCL and concomitant dermatophytic infection that was confirmed with PAS stain and identified as T rubrum. Interestingly, our patient’s EGR-like eruption cleared with oral terbinafine therapy, consistent with findings described by Poonawalla et al³ and Jouary et al⁵ in which treatment of the dermatophytic infection led to resolution of the EGR-like eruption, suggesting a causative role.

However, testing for dermatophytes was negative in the other reported cases of EGR-like eruptions in patients with MF, despite screening for the presence of fungal microorganisms using KOH preparation, PAS staining, or fungal culture, or a combination of these methods,^3-8 which raises the question: Do the cases reported without dermatophytic infection represent false-negative test results, or can the distinct clinical appearance of EGR indeed be seen in patients with CTCL who lack superimposed dermatophytosis? In 3 prior reported cases of EGR-like eruptions in MF, the eruption was preceded by immunosuppressive therapy.^5-7

Further investigation is needed to correlate the role of dermatophytic infection in EGR-like eruptions. Our case and the Jouary et al⁵ case reported dermatophyte-positive EGR-like eruptions in MF and SS detected with histopathologic analysis and PAS stain. This low-cost screening method should be considered in future cases. If the test result is dermatophyte positive, a 14-day course of oral terbinafine (250 mg/d) might induce resolution of the EGR-like eruption.

Conclusion

The role of dermatophyte-induced EGR or EGR-like eruptions in other settings also warrants further investigation to shed light on this poorly understood yet striking dermatologic condition. Our patient showed both MF and dermatophytes in skin biopsy results, regardless of whether those sites showed erythroderma or EGR-like features clinically. On 3 occasions, antifungal treatment cleared the EGR-like lesions and associated pruritus but not erythroderma. Therefore, it appears that the mere presence of dermatophytes was necessary but not sufficient to produce the EGR-like lesions observed in our case.

Pennsylvania had more reported cases of tick-borne disease from 2004 to 2016 than any other state, but these diseases are becoming a national threat, according to the Centers for Disease Control and Prevention.

There were 73,000 cases reported in Pennsylvania over that period, and tick-borne diseases, including Lyme disease, anaplasmosis/ehrlichiosis, spotted fever rickettsiosis, babesiosis, tularemia, and Powassan virus, among others, affected almost 492,000 people nationwide, with Lyme disease representing the majority of cases, the CDC said in a Vital Signs report.

Although it’s no surprise that Pennsylvania, New York, and Connecticut were tick-borne disease hot spots, non-Northeastern states like Virginia, Wisconsin, and Minnesota also were among the top 10 in cases. States even further away from the Northeast can be found in the next 10: Arkansas had more than 7,000 cases in 13 years, and Oklahoma had over 4,600 cases, data from the National Notifiable Diseases Surveillance System show.


Nationally, the number of cases more than doubled from 23,000 in 2004 to 49,000 in 2016, and tick-borne disease hit every state except Hawaii. Over that same time, seven new tick-borne pathogens were discovered or introduced into the United States, the CDC reported.

“Local and state health departments and vector control organizations face increasing demands to respond to these threats,” the CDC said, but “more than 80% of vector control organizations report needing improvement in one or more of five core competencies, such as testing for pesticide resistance [and using] data to drive local decisions about vector control.”

[email protected]

Pennsylvania had more reported cases of tick-borne disease from 2004 to 2016 than any other state, but these diseases are becoming a national threat, according to the Centers for Disease Control and Prevention.

There were 73,000 cases reported in Pennsylvania over that period, and tick-borne diseases, including Lyme disease, anaplasmosis/ehrlichiosis, spotted fever rickettsiosis, babesiosis, tularemia, and Powassan virus, among others, affected almost 492,000 people nationwide, with Lyme disease representing the majority of cases, the CDC said in a Vital Signs report.

Although it’s no surprise that Pennsylvania, New York, and Connecticut were tick-borne disease hot spots, non-Northeastern states like Virginia, Wisconsin, and Minnesota also were among the top 10 in cases. States even further away from the Northeast can be found in the next 10: Arkansas had more than 7,000 cases in 13 years, and Oklahoma had over 4,600 cases, data from the National Notifiable Diseases Surveillance System show.


Nationally, the number of cases more than doubled from 23,000 in 2004 to 49,000 in 2016, and tick-borne disease hit every state except Hawaii. Over that same time, seven new tick-borne pathogens were discovered or introduced into the United States, the CDC reported.

“Local and state health departments and vector control organizations face increasing demands to respond to these threats,” the CDC said, but “more than 80% of vector control organizations report needing improvement in one or more of five core competencies, such as testing for pesticide resistance [and using] data to drive local decisions about vector control.”

[email protected]

Pennsylvania had more reported cases of tick-borne disease from 2004 to 2016 than any other state, but these diseases are becoming a national threat, according to the Centers for Disease Control and Prevention.

There were 73,000 cases reported in Pennsylvania over that period, and tick-borne diseases, including Lyme disease, anaplasmosis/ehrlichiosis, spotted fever rickettsiosis, babesiosis, tularemia, and Powassan virus, among others, affected almost 492,000 people nationwide, with Lyme disease representing the majority of cases, the CDC said in a Vital Signs report.

Although it’s no surprise that Pennsylvania, New York, and Connecticut were tick-borne disease hot spots, non-Northeastern states like Virginia, Wisconsin, and Minnesota also were among the top 10 in cases. States even further away from the Northeast can be found in the next 10: Arkansas had more than 7,000 cases in 13 years, and Oklahoma had over 4,600 cases, data from the National Notifiable Diseases Surveillance System show.


Nationally, the number of cases more than doubled from 23,000 in 2004 to 49,000 in 2016, and tick-borne disease hit every state except Hawaii. Over that same time, seven new tick-borne pathogens were discovered or introduced into the United States, the CDC reported.

“Local and state health departments and vector control organizations face increasing demands to respond to these threats,” the CDC said, but “more than 80% of vector control organizations report needing improvement in one or more of five core competencies, such as testing for pesticide resistance [and using] data to drive local decisions about vector control.”

[email protected]

“There is a house in New Orleans. They call the Rising Sun. And it’s been the ruin of many a poor boy. And, God, I know I’m one.”

The 1960s rock band the Animals will tell you a tale to convince you to get vaccinated. Don’t believe me? Follow along.

The first hints of the song “House of the Rising Sun” rolled out of the hills of Appalachia.

Somewhere in the Golden Triangle, far away from New Orleans, where Virginia, Kentucky, and Tennessee rise in quiet desolation, a warning song about a tailor and a drunk emerged. Sometime around the Civil War, a hint of a tune began. Over the next century, it evolved, until it became cemented in rock culture 50 years ago by The Animals, existing as the version played most commonly today.

In the mid-19th century, medicine shows rambled through the South, stopping in places like Noetown or Daisy. The small towns would empty out for the day to see the entertainers, singers, and jugglers perform. Hundreds gathered in the hot summer day, the entertainment solely a pretext for the traveling doctors to sell their wares, the snake oil, and cure-alls, as well as various patent medicines.

These were isolated towns, with no deliveries, few visitors, and the railroad yet to arrive. Frequently, the only news from outside came from these caravans of entertainers and con men who swept into town. They were like Professor Marvel from The Wizard of Oz, or a current-day Dr. Oz, luring the crowd with false advertising, selling colored water, and then disappearing before you realized you were duped. Today, traveling doctors of the same ilk convince parents to not vaccinate their children, tell them to visit stem cell centers that claim false cures, and offer them a shiny object with one hand while taking their cash with the other.

Yet, there was a positive development in the wake of these patent medicine shows: the entertainment lingered. New songs traveled the same journeys as these medicine shows – new earworms that would then be warbled in the local bars, while doing chores around the barn, or simply during walks on the Appalachian trails.

In 1937, Alan Lomax arrived in Noetown, Ky., with a microphone and an acetate record and recorded the voice of 16-year-old Georgia Turner singing “House of the Rising Sun.” She didn’t know where she heard that song, but most likely picked it up at the medicine show.

One of those singers was Clarence Ashley, who would croon about the Rising Sun Blues. He sang with Doc Cloud and Doc Hauer, who offered tonics for whatever ailed you. Perhaps Georgia Turner heard the song in the early 1900s as well. Her 1937 version contains the lyrics most closely related to the Animals’ tune.

Lomax spent the 1940s gathering songs around the Appalachian South. He put these songs into a songbook and spread them throughout the country. He would also return to New York City and gather in a room with legendary folk singers. They would hear these new lyrics, new sounds, and make them their own.

In that room would be Lead Belly, Pete Seeger, Woody Guthrie, and Josh White, the fathers of folk music. The music Lomax pulled out of the mountains in small towns would become new again in the guitars and harmonicas of the Greenwich Village singers and musicians. Pete Seeger performed with the Weavers, named because they would weave songs from the past into new versions.

“House of the Rising Sun” was woven into the folk music landscape, evolving and growing. Josh White is credited with changing the song from a major key into the minor key we know today. Bob Dylan sang a version. And then in 1964, Eric Burdon and The Animals released their version, which became the standard. An arpeggio guitar opening, the rhythm sped up, a louder sound, and that minor key provides an emotional wallop for this warning song.

Numerous covers followed, including a beautiful version of “Amazing Grace”, sung to the tune of “House of the Rising Sun” by the Blind Boys of Alabama.

The song endures for its melody as well as for its lyrics. This was a warning song, a universal song, “not to do what I have done.” The small towns in Kentucky may have heard of the sinful ways of New Orleans and would spread the message with these songs to avoid the brothels, the drink, and the broken marriages that would reverberate with visits to the Crescent City.

“House of the Rising Sun” is one of the most covered songs, traveling wide and far, no longer with the need for a medicine show. It was a pivotal moment in rock ‘n roll, turning folk music into rock music. The Animals became huge because of this song, and their version became the standard on which all subsequent covers based their version. It made Bob Dylan’s older version seem quaint.

The song has been in my head for a while now. My wife is hoping writing about it will keep it from being played in our household any more. There are various reasons it has been resonating with me, including the following:

• It traces the origins of folk music and the importance of people like Lomax and Guthrie to collect and save Americana.
• The magic of musical evolution – a reminder of how art is built on the work of those who came before, each version with its unique personality.
• The release of “House of the Rising Sun” was a seminal, transformative moment when folk became rock music.
• The lasting power of warning songs.
• The hucksters that enabled this song to be kept alive.

That last one has really stuck with me. The medicine shows are an important part of American history. For instance, Coca-Cola started as one of those patent medicines; it was one of the many concoctions of the Atlanta pharmacist John Stith Pemberton, sold to treat all that ails us. Dr. Pepper, too, was a medicine in a sugary bottle – another that often contained alcohol or cocaine. Society wants a cure-all, and the marketing and selling done during these medicine shows offered placebos.

The hucksters exist in various forms today, selling detoxifications, magic diet cures, psychic powers of healing, or convincing parents that their kids don’t need vaccines. We need a warning song that goes viral to keep our children safe. We are blessed to be in a world without smallpox, almost rid of polio, and we have the knowledge and opportunity to rid the world of other preventable illnesses. Measles was declared eliminated in the United States in 2000; now, outbreaks emerge in every news cycle.

The CDC admits they have not been targeting misinformation well. How can we spread the science, the truth, the message faster than the lies? Better marketing? The answer may be through stories and narratives and song, with the backing of good science. “House of the Rising Sun” is a warning song. Maybe we need more. We need that deep history, that long trail to remind us of the world before vaccines, when everyone knew someone, either in their own household or next door, who succumbed to one of the childhood illnesses.

Let the “House of the Rising Sun” play on. Create a new version, and let that message reverberate, too.

Tell your children; they need to be vaccinated.
 

Dr. Messler is a hospitalist at Morton Plant Hospitalist group in Clearwater, Fla. He previously chaired SHM’s Quality and Patient Safety Committee and has been active in several SHM mentoring programs, most recently with Project BOOST and Glycemic Control. This article appeared originally in SHM's official blog The Hospital Leader. Read more recent posts here.

“There is a house in New Orleans. They call the Rising Sun. And it’s been the ruin of many a poor boy. And, God, I know I’m one.”

The 1960s rock band the Animals will tell you a tale to convince you to get vaccinated. Don’t believe me? Follow along.

The first hints of the song “House of the Rising Sun” rolled out of the hills of Appalachia.

Somewhere in the Golden Triangle, far away from New Orleans, where Virginia, Kentucky, and Tennessee rise in quiet desolation, a warning song about a tailor and a drunk emerged. Sometime around the Civil War, a hint of a tune began. Over the next century, it evolved, until it became cemented in rock culture 50 years ago by The Animals, existing as the version played most commonly today.

In the mid-19th century, medicine shows rambled through the South, stopping in places like Noetown or Daisy. The small towns would empty out for the day to see the entertainers, singers, and jugglers perform. Hundreds gathered in the hot summer day, the entertainment solely a pretext for the traveling doctors to sell their wares, the snake oil, and cure-alls, as well as various patent medicines.

These were isolated towns, with no deliveries, few visitors, and the railroad yet to arrive. Frequently, the only news from outside came from these caravans of entertainers and con men who swept into town. They were like Professor Marvel from The Wizard of Oz, or a current-day Dr. Oz, luring the crowd with false advertising, selling colored water, and then disappearing before you realized you were duped. Today, traveling doctors of the same ilk convince parents to not vaccinate their children, tell them to visit stem cell centers that claim false cures, and offer them a shiny object with one hand while taking their cash with the other.

Yet, there was a positive development in the wake of these patent medicine shows: the entertainment lingered. New songs traveled the same journeys as these medicine shows – new earworms that would then be warbled in the local bars, while doing chores around the barn, or simply during walks on the Appalachian trails.

In 1937, Alan Lomax arrived in Noetown, Ky., with a microphone and an acetate record and recorded the voice of 16-year-old Georgia Turner singing “House of the Rising Sun.” She didn’t know where she heard that song, but most likely picked it up at the medicine show.

One of those singers was Clarence Ashley, who would croon about the Rising Sun Blues. He sang with Doc Cloud and Doc Hauer, who offered tonics for whatever ailed you. Perhaps Georgia Turner heard the song in the early 1900s as well. Her 1937 version contains the lyrics most closely related to the Animals’ tune.

Lomax spent the 1940s gathering songs around the Appalachian South. He put these songs into a songbook and spread them throughout the country. He would also return to New York City and gather in a room with legendary folk singers. They would hear these new lyrics, new sounds, and make them their own.

In that room would be Lead Belly, Pete Seeger, Woody Guthrie, and Josh White, the fathers of folk music. The music Lomax pulled out of the mountains in small towns would become new again in the guitars and harmonicas of the Greenwich Village singers and musicians. Pete Seeger performed with the Weavers, named because they would weave songs from the past into new versions.

“House of the Rising Sun” was woven into the folk music landscape, evolving and growing. Josh White is credited with changing the song from a major key into the minor key we know today. Bob Dylan sang a version. And then in 1964, Eric Burdon and The Animals released their version, which became the standard. An arpeggio guitar opening, the rhythm sped up, a louder sound, and that minor key provides an emotional wallop for this warning song.

Numerous covers followed, including a beautiful version of “Amazing Grace”, sung to the tune of “House of the Rising Sun” by the Blind Boys of Alabama.

The song endures for its melody as well as for its lyrics. This was a warning song, a universal song, “not to do what I have done.” The small towns in Kentucky may have heard of the sinful ways of New Orleans and would spread the message with these songs to avoid the brothels, the drink, and the broken marriages that would reverberate with visits to the Crescent City.

“House of the Rising Sun” is one of the most covered songs, traveling wide and far, no longer with the need for a medicine show. It was a pivotal moment in rock ‘n roll, turning folk music into rock music. The Animals became huge because of this song, and their version became the standard on which all subsequent covers based their version. It made Bob Dylan’s older version seem quaint.

The song has been in my head for a while now. My wife is hoping writing about it will keep it from being played in our household any more. There are various reasons it has been resonating with me, including the following:

• It traces the origins of folk music and the importance of people like Lomax and Guthrie to collect and save Americana.
• The magic of musical evolution – a reminder of how art is built on the work of those who came before, each version with its unique personality.
• The release of “House of the Rising Sun” was a seminal, transformative moment when folk became rock music.
• The lasting power of warning songs.
• The hucksters that enabled this song to be kept alive.

That last one has really stuck with me. The medicine shows are an important part of American history. For instance, Coca-Cola started as one of those patent medicines; it was one of the many concoctions of the Atlanta pharmacist John Stith Pemberton, sold to treat all that ails us. Dr. Pepper, too, was a medicine in a sugary bottle – another that often contained alcohol or cocaine. Society wants a cure-all, and the marketing and selling done during these medicine shows offered placebos.

The hucksters exist in various forms today, selling detoxifications, magic diet cures, psychic powers of healing, or convincing parents that their kids don’t need vaccines. We need a warning song that goes viral to keep our children safe. We are blessed to be in a world without smallpox, almost rid of polio, and we have the knowledge and opportunity to rid the world of other preventable illnesses. Measles was declared eliminated in the United States in 2000; now, outbreaks emerge in every news cycle.

The CDC admits they have not been targeting misinformation well. How can we spread the science, the truth, the message faster than the lies? Better marketing? The answer may be through stories and narratives and song, with the backing of good science. “House of the Rising Sun” is a warning song. Maybe we need more. We need that deep history, that long trail to remind us of the world before vaccines, when everyone knew someone, either in their own household or next door, who succumbed to one of the childhood illnesses.

Let the “House of the Rising Sun” play on. Create a new version, and let that message reverberate, too.

Tell your children; they need to be vaccinated.
 

Dr. Messler is a hospitalist at Morton Plant Hospitalist group in Clearwater, Fla. He previously chaired SHM’s Quality and Patient Safety Committee and has been active in several SHM mentoring programs, most recently with Project BOOST and Glycemic Control. This article appeared originally in SHM's official blog The Hospital Leader. Read more recent posts here.

“There is a house in New Orleans. They call the Rising Sun. And it’s been the ruin of many a poor boy. And, God, I know I’m one.”

The 1960s rock band the Animals will tell you a tale to convince you to get vaccinated. Don’t believe me? Follow along.

The first hints of the song “House of the Rising Sun” rolled out of the hills of Appalachia.

Somewhere in the Golden Triangle, far away from New Orleans, where Virginia, Kentucky, and Tennessee rise in quiet desolation, a warning song about a tailor and a drunk emerged. Sometime around the Civil War, a hint of a tune began. Over the next century, it evolved, until it became cemented in rock culture 50 years ago by The Animals, existing as the version played most commonly today.

In the mid-19th century, medicine shows rambled through the South, stopping in places like Noetown or Daisy. The small towns would empty out for the day to see the entertainers, singers, and jugglers perform. Hundreds gathered in the hot summer day, the entertainment solely a pretext for the traveling doctors to sell their wares, the snake oil, and cure-alls, as well as various patent medicines.

These were isolated towns, with no deliveries, few visitors, and the railroad yet to arrive. Frequently, the only news from outside came from these caravans of entertainers and con men who swept into town. They were like Professor Marvel from The Wizard of Oz, or a current-day Dr. Oz, luring the crowd with false advertising, selling colored water, and then disappearing before you realized you were duped. Today, traveling doctors of the same ilk convince parents to not vaccinate their children, tell them to visit stem cell centers that claim false cures, and offer them a shiny object with one hand while taking their cash with the other.

Yet, there was a positive development in the wake of these patent medicine shows: the entertainment lingered. New songs traveled the same journeys as these medicine shows – new earworms that would then be warbled in the local bars, while doing chores around the barn, or simply during walks on the Appalachian trails.

In 1937, Alan Lomax arrived in Noetown, Ky., with a microphone and an acetate record and recorded the voice of 16-year-old Georgia Turner singing “House of the Rising Sun.” She didn’t know where she heard that song, but most likely picked it up at the medicine show.

One of those singers was Clarence Ashley, who would croon about the Rising Sun Blues. He sang with Doc Cloud and Doc Hauer, who offered tonics for whatever ailed you. Perhaps Georgia Turner heard the song in the early 1900s as well. Her 1937 version contains the lyrics most closely related to the Animals’ tune.

Lomax spent the 1940s gathering songs around the Appalachian South. He put these songs into a songbook and spread them throughout the country. He would also return to New York City and gather in a room with legendary folk singers. They would hear these new lyrics, new sounds, and make them their own.

In that room would be Lead Belly, Pete Seeger, Woody Guthrie, and Josh White, the fathers of folk music. The music Lomax pulled out of the mountains in small towns would become new again in the guitars and harmonicas of the Greenwich Village singers and musicians. Pete Seeger performed with the Weavers, named because they would weave songs from the past into new versions.

“House of the Rising Sun” was woven into the folk music landscape, evolving and growing. Josh White is credited with changing the song from a major key into the minor key we know today. Bob Dylan sang a version. And then in 1964, Eric Burdon and The Animals released their version, which became the standard. An arpeggio guitar opening, the rhythm sped up, a louder sound, and that minor key provides an emotional wallop for this warning song.

Numerous covers followed, including a beautiful version of “Amazing Grace”, sung to the tune of “House of the Rising Sun” by the Blind Boys of Alabama.

The song endures for its melody as well as for its lyrics. This was a warning song, a universal song, “not to do what I have done.” The small towns in Kentucky may have heard of the sinful ways of New Orleans and would spread the message with these songs to avoid the brothels, the drink, and the broken marriages that would reverberate with visits to the Crescent City.

“House of the Rising Sun” is one of the most covered songs, traveling wide and far, no longer with the need for a medicine show. It was a pivotal moment in rock ‘n roll, turning folk music into rock music. The Animals became huge because of this song, and their version became the standard on which all subsequent covers based their version. It made Bob Dylan’s older version seem quaint.

The song has been in my head for a while now. My wife is hoping writing about it will keep it from being played in our household any more. There are various reasons it has been resonating with me, including the following:

• It traces the origins of folk music and the importance of people like Lomax and Guthrie to collect and save Americana.
• The magic of musical evolution – a reminder of how art is built on the work of those who came before, each version with its unique personality.
• The release of “House of the Rising Sun” was a seminal, transformative moment when folk became rock music.
• The lasting power of warning songs.
• The hucksters that enabled this song to be kept alive.

That last one has really stuck with me. The medicine shows are an important part of American history. For instance, Coca-Cola started as one of those patent medicines; it was one of the many concoctions of the Atlanta pharmacist John Stith Pemberton, sold to treat all that ails us. Dr. Pepper, too, was a medicine in a sugary bottle – another that often contained alcohol or cocaine. Society wants a cure-all, and the marketing and selling done during these medicine shows offered placebos.

The hucksters exist in various forms today, selling detoxifications, magic diet cures, psychic powers of healing, or convincing parents that their kids don’t need vaccines. We need a warning song that goes viral to keep our children safe. We are blessed to be in a world without smallpox, almost rid of polio, and we have the knowledge and opportunity to rid the world of other preventable illnesses. Measles was declared eliminated in the United States in 2000; now, outbreaks emerge in every news cycle.

The CDC admits they have not been targeting misinformation well. How can we spread the science, the truth, the message faster than the lies? Better marketing? The answer may be through stories and narratives and song, with the backing of good science. “House of the Rising Sun” is a warning song. Maybe we need more. We need that deep history, that long trail to remind us of the world before vaccines, when everyone knew someone, either in their own household or next door, who succumbed to one of the childhood illnesses.

Let the “House of the Rising Sun” play on. Create a new version, and let that message reverberate, too.

Tell your children; they need to be vaccinated.
 

Dr. Messler is a hospitalist at Morton Plant Hospitalist group in Clearwater, Fla. He previously chaired SHM’s Quality and Patient Safety Committee and has been active in several SHM mentoring programs, most recently with Project BOOST and Glycemic Control. This article appeared originally in SHM's official blog The Hospital Leader. Read more recent posts here.

LJUBLJANA, SLOVENIA – A “surprisingly low” prevalence of protective antibodies against measles is present in adolescents and adults living with HIV infection despite their prior vaccination against the resurgent disease, Raquel M. Simakawa, MD, reported at the annual meeting of the European Society for Paediatric Infectious Diseases.

Bruce Jancin/MDedge News

“With the present concern about the global reemergence of measles, we should consider measuring measles antibodies in people living with HIV, especially those who acquired the infection vertically, and then revaccinating those with low titers,” said Dr. Simakawa of the Federal University of São Paolo.

She presented interim findings of an ongoing study of the measles immunologic status of persons living with HIV, which for this analysis included 57 patients who acquired HIV from their mother via vertical transmission and 24 with horizontally acquired HIV. The vertical-transmission group was significantly younger, with a median age of 20 years, compared with 31 years in the horizontal group, who were diagnosed with HIV infection at an average age of 24 years. The vast majority of subjects were on combination antiretroviral therapy. No detectable HIV viral load had been present for a median of 70 months in the vertical group and 25 months in the horizontal group.

Only a mere 7% of the vertical transmission group had protective levels of measles IgG antibodies as measured by enzyme-linked immunosorbent assay, as did 29% of the horizontal group. The likely explanation for the higher rate of protection in the horizontal group, she said, is that they received their routine measles vaccination before they acquired HIV infection, and some of them didn’t lose their protective antibodies during their immune system’s fight against HIV infection.

Session chair Nico G. Hartwig, MD, of Franciscus Hospital in Rotterdam, the Netherlands, posed a question: Given the sky-high rate of measles seronegativity status among the vertically transmitted HIV-positive group – the patient population pediatricians focus on – why bother to measure their measles antibody level? Why not just give them all a measles booster?

Dr. Simakawa replied that that’s worth considering in routine clinical practice now that her study has shown that this group is more vulnerable to measles because of their poor response to immunization. But the study is ongoing, with larger numbers of patients to be enrolled. Also, in the second phase of the study, which will include a control group, measles IgG antibodies will be remeasured 1 month after administration of a new dose of measles vaccine.

She reported having no financial conflicts regarding this study, conducted free of commercial support.

[email protected]

LJUBLJANA, SLOVENIA – A “surprisingly low” prevalence of protective antibodies against measles is present in adolescents and adults living with HIV infection despite their prior vaccination against the resurgent disease, Raquel M. Simakawa, MD, reported at the annual meeting of the European Society for Paediatric Infectious Diseases.

Bruce Jancin/MDedge News

“With the present concern about the global reemergence of measles, we should consider measuring measles antibodies in people living with HIV, especially those who acquired the infection vertically, and then revaccinating those with low titers,” said Dr. Simakawa of the Federal University of São Paolo.

She presented interim findings of an ongoing study of the measles immunologic status of persons living with HIV, which for this analysis included 57 patients who acquired HIV from their mother via vertical transmission and 24 with horizontally acquired HIV. The vertical-transmission group was significantly younger, with a median age of 20 years, compared with 31 years in the horizontal group, who were diagnosed with HIV infection at an average age of 24 years. The vast majority of subjects were on combination antiretroviral therapy. No detectable HIV viral load had been present for a median of 70 months in the vertical group and 25 months in the horizontal group.

Only a mere 7% of the vertical transmission group had protective levels of measles IgG antibodies as measured by enzyme-linked immunosorbent assay, as did 29% of the horizontal group. The likely explanation for the higher rate of protection in the horizontal group, she said, is that they received their routine measles vaccination before they acquired HIV infection, and some of them didn’t lose their protective antibodies during their immune system’s fight against HIV infection.

Session chair Nico G. Hartwig, MD, of Franciscus Hospital in Rotterdam, the Netherlands, posed a question: Given the sky-high rate of measles seronegativity status among the vertically transmitted HIV-positive group – the patient population pediatricians focus on – why bother to measure their measles antibody level? Why not just give them all a measles booster?

Dr. Simakawa replied that that’s worth considering in routine clinical practice now that her study has shown that this group is more vulnerable to measles because of their poor response to immunization. But the study is ongoing, with larger numbers of patients to be enrolled. Also, in the second phase of the study, which will include a control group, measles IgG antibodies will be remeasured 1 month after administration of a new dose of measles vaccine.

She reported having no financial conflicts regarding this study, conducted free of commercial support.

[email protected]

LJUBLJANA, SLOVENIA – A “surprisingly low” prevalence of protective antibodies against measles is present in adolescents and adults living with HIV infection despite their prior vaccination against the resurgent disease, Raquel M. Simakawa, MD, reported at the annual meeting of the European Society for Paediatric Infectious Diseases.

Bruce Jancin/MDedge News

“With the present concern about the global reemergence of measles, we should consider measuring measles antibodies in people living with HIV, especially those who acquired the infection vertically, and then revaccinating those with low titers,” said Dr. Simakawa of the Federal University of São Paolo.

She presented interim findings of an ongoing study of the measles immunologic status of persons living with HIV, which for this analysis included 57 patients who acquired HIV from their mother via vertical transmission and 24 with horizontally acquired HIV. The vertical-transmission group was significantly younger, with a median age of 20 years, compared with 31 years in the horizontal group, who were diagnosed with HIV infection at an average age of 24 years. The vast majority of subjects were on combination antiretroviral therapy. No detectable HIV viral load had been present for a median of 70 months in the vertical group and 25 months in the horizontal group.

Only a mere 7% of the vertical transmission group had protective levels of measles IgG antibodies as measured by enzyme-linked immunosorbent assay, as did 29% of the horizontal group. The likely explanation for the higher rate of protection in the horizontal group, she said, is that they received their routine measles vaccination before they acquired HIV infection, and some of them didn’t lose their protective antibodies during their immune system’s fight against HIV infection.

Session chair Nico G. Hartwig, MD, of Franciscus Hospital in Rotterdam, the Netherlands, posed a question: Given the sky-high rate of measles seronegativity status among the vertically transmitted HIV-positive group – the patient population pediatricians focus on – why bother to measure their measles antibody level? Why not just give them all a measles booster?

Dr. Simakawa replied that that’s worth considering in routine clinical practice now that her study has shown that this group is more vulnerable to measles because of their poor response to immunization. But the study is ongoing, with larger numbers of patients to be enrolled. Also, in the second phase of the study, which will include a control group, measles IgG antibodies will be remeasured 1 month after administration of a new dose of measles vaccine.

She reported having no financial conflicts regarding this study, conducted free of commercial support.

[email protected]

Study Overview

Objective. To evaluate the efficacy and safety of a once-daily 2-drug antiretroviral (ARV) regimen, dolutegravir plus lamivudine, for the treatment of HIV-1 infection in adults naive to antiretroviral therapy (ART).

Design. GEMINI-1 and GEMINI-2 were 2 identically designed multicenter, double-blind, randomized, noninferiority, phase 3 clinical trials conducted between July 18, 2016 and March 31, 2017. Participants were stratified to receive 1 of 2 once-daily HIV regimens: the study regimen, consisting of once-daily dolutegravir 50 mg plus lamivudine 300 mg, or the standard-of-care regimen, consisting of once-daily dolutegravir 50 mg plus tenofovir disoproxil fumarate (TDF) 300 mg plus emtricitabine 200 mg. While this article presents results at week 48, both trials are scheduled to evaluate participants up to week 148 in an attempt to evaluate long-term efficacy and safety.

Setting and participants. Eligible participants had to be aged 18 years or older with treatment-naive HIV-1 infection. Women were eligible if they were not (1) pregnant, (2) lactating, or (3) of reproductive potential, defined by various means, including tubal ligation, hysterectomy, postmenopausal, and the use of highly effective contraception. Initially, eligibility screening restricted participation to those with viral loads between 1000 and 100,000 copies/mL. However, the upper limit was later increased to 500,000 copies/mL based on an independent review of results from other clinical trials^1,2 evaluating dual therapy with dolutegravir and lamivudine, which indicated efficacy in patients with viral loads up to 500,000.^3-5

Notable exclusion criteria included: (1) major mutations to nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, and protease inhibitors; (2) evidence of hepatitis B infection; (3) hepatitis C infection with anticipation of initiating treatment within 48 weeks of study enrollment; and (4) stage 3 HIV disease, per Centers for Disease Control and Prevention criteria, with the exception of cutaneous Kaposi sarcoma and CD4 cell counts < 200 cells/mL.

Main outcome measures. The primary endpoint was demonstration of noninferiority of the 2-drug ARV regimen through assessment of the proportion of participants who achieved virologic suppression at week 48 in the intent-to-treat-exposed population. For the purposes of this study, virologic suppression was defined as having fewer than 50 copies of HIV-1 RNA per mL at week 48. For evaluation of safety and toxicity concerns, renal and bone biomarkers were assessed at study entry and at weeks 24 and 48. In addition, participants who met virological withdrawal criteria were evaluated for integrase strand transfer inhibitor mutations. Virological withdrawal was defined as the presence of 1 of the following: (1) HIV RNA > 200 copies/mL at week 24, (2) HIV RNA > 200 copies/mL after previous HIV RNA < 200 copies/mL (confirmed rebound), and (3) a < 1 log₁₀ copies/mL decrease from baseline (unless already < 200 copies/mL).

Main results. GEMINI-1 and GEMINI-2 randomized a combined total of 1441 participants to receive either the once-daily 2-drug ARV regimen (dolutegravir and lamivudine, n = 719) or the once-daily 3-drug ARV regimen (dolutegravir, TDF, and emtricitabine, n = 722). Of the 533 participants who did not meet inclusion criteria, the predominant reasons for exclusion were either having preexisting major viral resistance mutations (n = 246) or viral loads outside the range of 1000 to 500,000 copies/mL (n = 133).

Baseline demographic and clinical characteristics were similar between both groups. The median age was 33 years (10% were over 50 years of age), and participants were mostly male (85%) and white (68%). Baseline HIV RNA counts of > 100,000 copies/mL were found in 293 participants (20%), and 188 (8%) participants had CD4 counts of ≤ 200 cells/mL.

Noninferiority of the once-daily 2-drug versus the once-daily 3-drug ARV regimen was demonstrated in both the GEMINI-1 and GEMINI-2 trials for the intent-to-treat-exposed population. In GEMINI-1, 90% (n = 320) in the 2-drug ARV group achieved virologic suppression at week 48 compared to 93% (n = 332) in the 3-drug ARV group (no statistically significant difference). In GEMINI-2, 93% (n =335 ) in the 2-drug ARV group achieved virologic suppression at week 48 compared to 94% (n = 337) in the 3-drug ARV group (no statistically significant difference).

A subgroup analysis found no significant impact of baseline HIV RNA (> 100,000 compared to ≤ 100,000 copies/mL) on achieving virologic suppression at week 48. However, a subgroup analysis did find that participants with CD4 counts < 200 copies/mL had a reduced response in the once-daily 2-drug versus 3-drug ARV regimen for achieving virologic response at week 48 (79% versus 93%, respectively).

Overall, 10 participants met virological withdrawal criteria during the study period, and 4 of these were on the 2-drug ARV regimen. For these 10 participants, genotypic testing did not find emergence of resistance to either nucleoside reverse transcriptase or integrase strand transfer inhibitors.

Regarding renal biomarkers, increases of both serum creatinine and urinary excretion of protein creatinine were significantly greater in the 3-drug ARV group. Also, biomarkers indicating increased bone turnover were elevated in both groups, but the degree of elevation was significantly lower in the 2-drug ARV regimen cohort. It is unclear whether these findings reflect an increased or decreased risk of developing osteopenia or osteoporosis in the 2 study groups.

Conclusion. The once-daily 2-drug ARV regimen dolutegravir and lamivudine is noninferior to the guideline-recommended once-daily 3-drug ARV regimen dolutegravir, TDF, and emtricitabine at achieving viral suppression in ART-naive HIV-1 infected individuals with HIV RNA counts < 500,000 copies/mL. However, the efficacy of this ARV regimen may be compromised in individuals with CD4 counts < 200 cells/mL.

Currently, the mainstay of HIV pharmacotherapy is a 3-drug regimen consisting of 2 nucleoside reverse transcriptase inhibitors in combination with 1 drug from another class, with an integrase strand transfer inhibitor being the preferred third drug.⁶ Despite the improved tolerability of contemporary ARVs, there remains concern among HIV practitioners regarding potential toxicities associated with cumulative drug exposure, specifically related to nucleoside reverse transcriptase inhibitors. As a result, there has been much interest in evaluating 2-drug ARV regimens for HIV treatment in order to reduce overall drug exposure.^7-10

The 48-week results of the GEMINI-1 and GEMINI-2 trials, published in early 2019, further expand our understanding regarding the efficacy and safety of 2-drug regimens in HIV treatment. These identically designed studies evaluated once-daily dolutegravir and lamivudine for HIV in a treatment-naive population. This goes a step further than the SWORD-1 and SWORD-2 trials, which evaluated once-daily dolutegravir and rilpivirine as a step-down therapy for virologically suppressed individuals and led to the U.S. Food and Drug Administration (FDA) approval of the single-tablet combination regimen dolutegravir/rilpivirine (Juluca).¹⁰ Therefore, whereas the SWORD trials evaluated a 2-drug regimen for maintenance of virologic suppression, the GEMINI trials assessed whether a 2-drug regimen can both achieve and maintain virologic suppression.

The results of the GEMINI trials are promising for a future direction in HIV care. The rates of virologic suppression achieved in these trials are comparable to those seen in the SWORD trials.¹⁰ Furthermore, the virologic response seen in the GEMINI trials is comparable to that seen in similar trials that evaluated a 3-drug ARV regimen consisting of an integrase strand transfer inhibitor–based backbone in ART-naive individuals.^11,12

A major confounder to the design of this trial was that it included TDF as one of the components in the comparator arm, an agent that has already been demonstrated to have detrimental effects on both renal and bone health.^13,14 Additionally, the bone biomarker results were inconclusive, and the agents’ effects on bone would have been better demonstrated through bone mineral density testing, as had been done in prior trials.

Applications for Clinical Practice

Given the recent FDA approval of the single-tablet combination regimen dolutegravir and lamivudine (Dovato), this once-daily 2-drug ARV regimen will begin making its way into clinical practice for certain patients. Prior to starting this regimen, hepatitis B infection first must be ruled out due to poor efficacy of lamivudine monotherapy for management of chronic hepatitis B infection.¹⁵ Additionally, baseline genotype testing should be performed prior to starting this ART given that approximately 10% of newly diagnosed HIV patients have baseline resistance mutations.¹⁶ Obtaining rapid genotype testing may be difficult to accomplish in low-resource settings where such testing is not readily available. Finally, this approach may not be applicable to those presenting with acute HIV infection, in whom viral loads are often in the millions of copies per mL. It is likely that dolutegravir/lamivudine could assume a role similar to that of dolutegravir/rilpivirine, in which patients who present with acute HIV step down to a 2-drug regimen once their viral loads have either dropped below 500,000 copies/mL or have already been suppressed.

—Evan K. Mallory, PharmD, Banner-University Medical Center Tucson, and Norman L. Beatty, MD, University of Arizona College of Medicine, Tucson, AZ

Study Overview

Objective. To evaluate the efficacy and safety of a once-daily 2-drug antiretroviral (ARV) regimen, dolutegravir plus lamivudine, for the treatment of HIV-1 infection in adults naive to antiretroviral therapy (ART).

Design. GEMINI-1 and GEMINI-2 were 2 identically designed multicenter, double-blind, randomized, noninferiority, phase 3 clinical trials conducted between July 18, 2016 and March 31, 2017. Participants were stratified to receive 1 of 2 once-daily HIV regimens: the study regimen, consisting of once-daily dolutegravir 50 mg plus lamivudine 300 mg, or the standard-of-care regimen, consisting of once-daily dolutegravir 50 mg plus tenofovir disoproxil fumarate (TDF) 300 mg plus emtricitabine 200 mg. While this article presents results at week 48, both trials are scheduled to evaluate participants up to week 148 in an attempt to evaluate long-term efficacy and safety.

Setting and participants. Eligible participants had to be aged 18 years or older with treatment-naive HIV-1 infection. Women were eligible if they were not (1) pregnant, (2) lactating, or (3) of reproductive potential, defined by various means, including tubal ligation, hysterectomy, postmenopausal, and the use of highly effective contraception. Initially, eligibility screening restricted participation to those with viral loads between 1000 and 100,000 copies/mL. However, the upper limit was later increased to 500,000 copies/mL based on an independent review of results from other clinical trials^1,2 evaluating dual therapy with dolutegravir and lamivudine, which indicated efficacy in patients with viral loads up to 500,000.^3-5

Notable exclusion criteria included: (1) major mutations to nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, and protease inhibitors; (2) evidence of hepatitis B infection; (3) hepatitis C infection with anticipation of initiating treatment within 48 weeks of study enrollment; and (4) stage 3 HIV disease, per Centers for Disease Control and Prevention criteria, with the exception of cutaneous Kaposi sarcoma and CD4 cell counts < 200 cells/mL.

Main outcome measures. The primary endpoint was demonstration of noninferiority of the 2-drug ARV regimen through assessment of the proportion of participants who achieved virologic suppression at week 48 in the intent-to-treat-exposed population. For the purposes of this study, virologic suppression was defined as having fewer than 50 copies of HIV-1 RNA per mL at week 48. For evaluation of safety and toxicity concerns, renal and bone biomarkers were assessed at study entry and at weeks 24 and 48. In addition, participants who met virological withdrawal criteria were evaluated for integrase strand transfer inhibitor mutations. Virological withdrawal was defined as the presence of 1 of the following: (1) HIV RNA > 200 copies/mL at week 24, (2) HIV RNA > 200 copies/mL after previous HIV RNA < 200 copies/mL (confirmed rebound), and (3) a < 1 log₁₀ copies/mL decrease from baseline (unless already < 200 copies/mL).

Main results. GEMINI-1 and GEMINI-2 randomized a combined total of 1441 participants to receive either the once-daily 2-drug ARV regimen (dolutegravir and lamivudine, n = 719) or the once-daily 3-drug ARV regimen (dolutegravir, TDF, and emtricitabine, n = 722). Of the 533 participants who did not meet inclusion criteria, the predominant reasons for exclusion were either having preexisting major viral resistance mutations (n = 246) or viral loads outside the range of 1000 to 500,000 copies/mL (n = 133).

Baseline demographic and clinical characteristics were similar between both groups. The median age was 33 years (10% were over 50 years of age), and participants were mostly male (85%) and white (68%). Baseline HIV RNA counts of > 100,000 copies/mL were found in 293 participants (20%), and 188 (8%) participants had CD4 counts of ≤ 200 cells/mL.

Noninferiority of the once-daily 2-drug versus the once-daily 3-drug ARV regimen was demonstrated in both the GEMINI-1 and GEMINI-2 trials for the intent-to-treat-exposed population. In GEMINI-1, 90% (n = 320) in the 2-drug ARV group achieved virologic suppression at week 48 compared to 93% (n = 332) in the 3-drug ARV group (no statistically significant difference). In GEMINI-2, 93% (n =335 ) in the 2-drug ARV group achieved virologic suppression at week 48 compared to 94% (n = 337) in the 3-drug ARV group (no statistically significant difference).

A subgroup analysis found no significant impact of baseline HIV RNA (> 100,000 compared to ≤ 100,000 copies/mL) on achieving virologic suppression at week 48. However, a subgroup analysis did find that participants with CD4 counts < 200 copies/mL had a reduced response in the once-daily 2-drug versus 3-drug ARV regimen for achieving virologic response at week 48 (79% versus 93%, respectively).

Overall, 10 participants met virological withdrawal criteria during the study period, and 4 of these were on the 2-drug ARV regimen. For these 10 participants, genotypic testing did not find emergence of resistance to either nucleoside reverse transcriptase or integrase strand transfer inhibitors.

Regarding renal biomarkers, increases of both serum creatinine and urinary excretion of protein creatinine were significantly greater in the 3-drug ARV group. Also, biomarkers indicating increased bone turnover were elevated in both groups, but the degree of elevation was significantly lower in the 2-drug ARV regimen cohort. It is unclear whether these findings reflect an increased or decreased risk of developing osteopenia or osteoporosis in the 2 study groups.

Conclusion. The once-daily 2-drug ARV regimen dolutegravir and lamivudine is noninferior to the guideline-recommended once-daily 3-drug ARV regimen dolutegravir, TDF, and emtricitabine at achieving viral suppression in ART-naive HIV-1 infected individuals with HIV RNA counts < 500,000 copies/mL. However, the efficacy of this ARV regimen may be compromised in individuals with CD4 counts < 200 cells/mL.

Currently, the mainstay of HIV pharmacotherapy is a 3-drug regimen consisting of 2 nucleoside reverse transcriptase inhibitors in combination with 1 drug from another class, with an integrase strand transfer inhibitor being the preferred third drug.⁶ Despite the improved tolerability of contemporary ARVs, there remains concern among HIV practitioners regarding potential toxicities associated with cumulative drug exposure, specifically related to nucleoside reverse transcriptase inhibitors. As a result, there has been much interest in evaluating 2-drug ARV regimens for HIV treatment in order to reduce overall drug exposure.^7-10

The 48-week results of the GEMINI-1 and GEMINI-2 trials, published in early 2019, further expand our understanding regarding the efficacy and safety of 2-drug regimens in HIV treatment. These identically designed studies evaluated once-daily dolutegravir and lamivudine for HIV in a treatment-naive population. This goes a step further than the SWORD-1 and SWORD-2 trials, which evaluated once-daily dolutegravir and rilpivirine as a step-down therapy for virologically suppressed individuals and led to the U.S. Food and Drug Administration (FDA) approval of the single-tablet combination regimen dolutegravir/rilpivirine (Juluca).¹⁰ Therefore, whereas the SWORD trials evaluated a 2-drug regimen for maintenance of virologic suppression, the GEMINI trials assessed whether a 2-drug regimen can both achieve and maintain virologic suppression.

The results of the GEMINI trials are promising for a future direction in HIV care. The rates of virologic suppression achieved in these trials are comparable to those seen in the SWORD trials.¹⁰ Furthermore, the virologic response seen in the GEMINI trials is comparable to that seen in similar trials that evaluated a 3-drug ARV regimen consisting of an integrase strand transfer inhibitor–based backbone in ART-naive individuals.^11,12

A major confounder to the design of this trial was that it included TDF as one of the components in the comparator arm, an agent that has already been demonstrated to have detrimental effects on both renal and bone health.^13,14 Additionally, the bone biomarker results were inconclusive, and the agents’ effects on bone would have been better demonstrated through bone mineral density testing, as had been done in prior trials.

Applications for Clinical Practice

Given the recent FDA approval of the single-tablet combination regimen dolutegravir and lamivudine (Dovato), this once-daily 2-drug ARV regimen will begin making its way into clinical practice for certain patients. Prior to starting this regimen, hepatitis B infection first must be ruled out due to poor efficacy of lamivudine monotherapy for management of chronic hepatitis B infection.¹⁵ Additionally, baseline genotype testing should be performed prior to starting this ART given that approximately 10% of newly diagnosed HIV patients have baseline resistance mutations.¹⁶ Obtaining rapid genotype testing may be difficult to accomplish in low-resource settings where such testing is not readily available. Finally, this approach may not be applicable to those presenting with acute HIV infection, in whom viral loads are often in the millions of copies per mL. It is likely that dolutegravir/lamivudine could assume a role similar to that of dolutegravir/rilpivirine, in which patients who present with acute HIV step down to a 2-drug regimen once their viral loads have either dropped below 500,000 copies/mL or have already been suppressed.

—Evan K. Mallory, PharmD, Banner-University Medical Center Tucson, and Norman L. Beatty, MD, University of Arizona College of Medicine, Tucson, AZ

Study Overview

Objective. To evaluate the efficacy and safety of a once-daily 2-drug antiretroviral (ARV) regimen, dolutegravir plus lamivudine, for the treatment of HIV-1 infection in adults naive to antiretroviral therapy (ART).

Design. GEMINI-1 and GEMINI-2 were 2 identically designed multicenter, double-blind, randomized, noninferiority, phase 3 clinical trials conducted between July 18, 2016 and March 31, 2017. Participants were stratified to receive 1 of 2 once-daily HIV regimens: the study regimen, consisting of once-daily dolutegravir 50 mg plus lamivudine 300 mg, or the standard-of-care regimen, consisting of once-daily dolutegravir 50 mg plus tenofovir disoproxil fumarate (TDF) 300 mg plus emtricitabine 200 mg. While this article presents results at week 48, both trials are scheduled to evaluate participants up to week 148 in an attempt to evaluate long-term efficacy and safety.

Setting and participants. Eligible participants had to be aged 18 years or older with treatment-naive HIV-1 infection. Women were eligible if they were not (1) pregnant, (2) lactating, or (3) of reproductive potential, defined by various means, including tubal ligation, hysterectomy, postmenopausal, and the use of highly effective contraception. Initially, eligibility screening restricted participation to those with viral loads between 1000 and 100,000 copies/mL. However, the upper limit was later increased to 500,000 copies/mL based on an independent review of results from other clinical trials^1,2 evaluating dual therapy with dolutegravir and lamivudine, which indicated efficacy in patients with viral loads up to 500,000.^3-5

Notable exclusion criteria included: (1) major mutations to nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, and protease inhibitors; (2) evidence of hepatitis B infection; (3) hepatitis C infection with anticipation of initiating treatment within 48 weeks of study enrollment; and (4) stage 3 HIV disease, per Centers for Disease Control and Prevention criteria, with the exception of cutaneous Kaposi sarcoma and CD4 cell counts < 200 cells/mL.

Main outcome measures. The primary endpoint was demonstration of noninferiority of the 2-drug ARV regimen through assessment of the proportion of participants who achieved virologic suppression at week 48 in the intent-to-treat-exposed population. For the purposes of this study, virologic suppression was defined as having fewer than 50 copies of HIV-1 RNA per mL at week 48. For evaluation of safety and toxicity concerns, renal and bone biomarkers were assessed at study entry and at weeks 24 and 48. In addition, participants who met virological withdrawal criteria were evaluated for integrase strand transfer inhibitor mutations. Virological withdrawal was defined as the presence of 1 of the following: (1) HIV RNA > 200 copies/mL at week 24, (2) HIV RNA > 200 copies/mL after previous HIV RNA < 200 copies/mL (confirmed rebound), and (3) a < 1 log₁₀ copies/mL decrease from baseline (unless already < 200 copies/mL).

Main results. GEMINI-1 and GEMINI-2 randomized a combined total of 1441 participants to receive either the once-daily 2-drug ARV regimen (dolutegravir and lamivudine, n = 719) or the once-daily 3-drug ARV regimen (dolutegravir, TDF, and emtricitabine, n = 722). Of the 533 participants who did not meet inclusion criteria, the predominant reasons for exclusion were either having preexisting major viral resistance mutations (n = 246) or viral loads outside the range of 1000 to 500,000 copies/mL (n = 133).

Baseline demographic and clinical characteristics were similar between both groups. The median age was 33 years (10% were over 50 years of age), and participants were mostly male (85%) and white (68%). Baseline HIV RNA counts of > 100,000 copies/mL were found in 293 participants (20%), and 188 (8%) participants had CD4 counts of ≤ 200 cells/mL.

Noninferiority of the once-daily 2-drug versus the once-daily 3-drug ARV regimen was demonstrated in both the GEMINI-1 and GEMINI-2 trials for the intent-to-treat-exposed population. In GEMINI-1, 90% (n = 320) in the 2-drug ARV group achieved virologic suppression at week 48 compared to 93% (n = 332) in the 3-drug ARV group (no statistically significant difference). In GEMINI-2, 93% (n =335 ) in the 2-drug ARV group achieved virologic suppression at week 48 compared to 94% (n = 337) in the 3-drug ARV group (no statistically significant difference).

A subgroup analysis found no significant impact of baseline HIV RNA (> 100,000 compared to ≤ 100,000 copies/mL) on achieving virologic suppression at week 48. However, a subgroup analysis did find that participants with CD4 counts < 200 copies/mL had a reduced response in the once-daily 2-drug versus 3-drug ARV regimen for achieving virologic response at week 48 (79% versus 93%, respectively).

Overall, 10 participants met virological withdrawal criteria during the study period, and 4 of these were on the 2-drug ARV regimen. For these 10 participants, genotypic testing did not find emergence of resistance to either nucleoside reverse transcriptase or integrase strand transfer inhibitors.

Regarding renal biomarkers, increases of both serum creatinine and urinary excretion of protein creatinine were significantly greater in the 3-drug ARV group. Also, biomarkers indicating increased bone turnover were elevated in both groups, but the degree of elevation was significantly lower in the 2-drug ARV regimen cohort. It is unclear whether these findings reflect an increased or decreased risk of developing osteopenia or osteoporosis in the 2 study groups.

Conclusion. The once-daily 2-drug ARV regimen dolutegravir and lamivudine is noninferior to the guideline-recommended once-daily 3-drug ARV regimen dolutegravir, TDF, and emtricitabine at achieving viral suppression in ART-naive HIV-1 infected individuals with HIV RNA counts < 500,000 copies/mL. However, the efficacy of this ARV regimen may be compromised in individuals with CD4 counts < 200 cells/mL.

Currently, the mainstay of HIV pharmacotherapy is a 3-drug regimen consisting of 2 nucleoside reverse transcriptase inhibitors in combination with 1 drug from another class, with an integrase strand transfer inhibitor being the preferred third drug.⁶ Despite the improved tolerability of contemporary ARVs, there remains concern among HIV practitioners regarding potential toxicities associated with cumulative drug exposure, specifically related to nucleoside reverse transcriptase inhibitors. As a result, there has been much interest in evaluating 2-drug ARV regimens for HIV treatment in order to reduce overall drug exposure.^7-10

The 48-week results of the GEMINI-1 and GEMINI-2 trials, published in early 2019, further expand our understanding regarding the efficacy and safety of 2-drug regimens in HIV treatment. These identically designed studies evaluated once-daily dolutegravir and lamivudine for HIV in a treatment-naive population. This goes a step further than the SWORD-1 and SWORD-2 trials, which evaluated once-daily dolutegravir and rilpivirine as a step-down therapy for virologically suppressed individuals and led to the U.S. Food and Drug Administration (FDA) approval of the single-tablet combination regimen dolutegravir/rilpivirine (Juluca).¹⁰ Therefore, whereas the SWORD trials evaluated a 2-drug regimen for maintenance of virologic suppression, the GEMINI trials assessed whether a 2-drug regimen can both achieve and maintain virologic suppression.

The results of the GEMINI trials are promising for a future direction in HIV care. The rates of virologic suppression achieved in these trials are comparable to those seen in the SWORD trials.¹⁰ Furthermore, the virologic response seen in the GEMINI trials is comparable to that seen in similar trials that evaluated a 3-drug ARV regimen consisting of an integrase strand transfer inhibitor–based backbone in ART-naive individuals.^11,12

A major confounder to the design of this trial was that it included TDF as one of the components in the comparator arm, an agent that has already been demonstrated to have detrimental effects on both renal and bone health.^13,14 Additionally, the bone biomarker results were inconclusive, and the agents’ effects on bone would have been better demonstrated through bone mineral density testing, as had been done in prior trials.

Applications for Clinical Practice

Given the recent FDA approval of the single-tablet combination regimen dolutegravir and lamivudine (Dovato), this once-daily 2-drug ARV regimen will begin making its way into clinical practice for certain patients. Prior to starting this regimen, hepatitis B infection first must be ruled out due to poor efficacy of lamivudine monotherapy for management of chronic hepatitis B infection.¹⁵ Additionally, baseline genotype testing should be performed prior to starting this ART given that approximately 10% of newly diagnosed HIV patients have baseline resistance mutations.¹⁶ Obtaining rapid genotype testing may be difficult to accomplish in low-resource settings where such testing is not readily available. Finally, this approach may not be applicable to those presenting with acute HIV infection, in whom viral loads are often in the millions of copies per mL. It is likely that dolutegravir/lamivudine could assume a role similar to that of dolutegravir/rilpivirine, in which patients who present with acute HIV step down to a 2-drug regimen once their viral loads have either dropped below 500,000 copies/mL or have already been suppressed.

—Evan K. Mallory, PharmD, Banner-University Medical Center Tucson, and Norman L. Beatty, MD, University of Arizona College of Medicine, Tucson, AZ

LJUBLJANA, SLOVENIA – An expanded indication for the meningococcal group B vaccine known as Trumenba in patients aged 1-9 years is being considered by the Food and Drug Administration under the agency’s Breakthrough Therapy designation.

Breakthrough Therapy status is reserved for accelerated review of therapies considered to show substantial preliminary promise of effectively targeting a major unmet medical need.

The unmet need here is that there is no meningococcal group B vaccine approved for use in children under age 10 years. Yet infants and children under 5 years of age are at greatest risk of invasive meningococcal B disease, with reported case fatality rates of 8%-9%, Jason D. Maguire, MD, noted at the annual meeting of the European Society for Paediatric Infectious Diseases.

Trumenba has been approved in the United States for patients aged 10-25 years and in the European Union for individuals aged 10 years or older.

Dr. Maguire, of Pfizer’s vaccine clinical research and development program, presented the results of the two phase 2 randomized safety and immunogenicity trials conducted in patients aged 1- 9 years that the company has submitted to the FDA in support of the expanded indication. One study was carried out in 352 1-year-old toddlers, the other in 400 children aged 2-9 years, whose mean age was 4 years. The studies were carried out in Australia, Finland, Poland, and the Czech Republic.

In a pooled analysis of the vaccine’s immunogenicity when administered in a three-dose schedule of 120 mcg at 0, 2, and 6 months to 193 toddlers and 274 of the children aged 2-9 years, robust bactericidal antibody responses were seen against the four major Neisseria meningitidis group B strains that cause invasive disease. In fact, at least a fourfold rise in titers from baseline to 1 month after dose three was documented in the same high proportion of 1- to 9-year-olds as previously seen in the phase 3 trials that led to vaccine licensure in adolescents and young adults.

“These results support that the use of Trumenba, when given to children ages 1 to less than 10 years at the same dose and schedule that is currently approved in adolescents and young adults, can afford a high degree of protective antibody responses that correlate with immunity in this population,” Dr. Maguire said.

The safety and tolerability analysis included all 752 children in the two phase 2 studies, including the 110 toddlers randomized to three 60-mcg doses of the vaccine, although it has subsequently become clear that 120 mcg is the dose that provides the best immunogenicity with an acceptable safety profile, according to the physician.

Across the age groups, local reactions, including redness and swelling, were more common in Trumenba recipients than in controls who received hepatitis A vaccine and saline injections. So were systemic adverse events. Fever – a systemic event of particular interest to parents and clinicians – occurred in 37% of toddlers after vaccination, compared with 25% of 2- to 9-year-olds and 10%-12% of controls. Of note, prophylactic antipyretics weren’t allowed in the study.

“There’s somewhat of an inverse relationship between age and temperature. So as we go down in age, the rate of fever rises. But after each subsequent dose, regardless of age, there’s a reduction in the incidence of fever,” Dr. Maguire observed.

Most fevers were less than 39.0° C. Only 3 of 752 (less than 1%) patients experienced fever in excess of 40.0° C.

Two children withdrew from the study after developing hip synovitis, which was transient. Another withdrew because of prolonged irritability, fatigue, and decreased appetite.

“Although Trumenba had an acceptable safety and tolerability profile in 1- to 9-year-olds, this analysis wasn’t powered enough to detect uncommon adverse events, so we’ll continue to monitor safety for things like synovitis,” he said.

In 10- to 25-year-olds, the meningococcal vaccine can be given concomitantly with other vaccines without interference. There are plans to study concurrent vaccination with MMR and pneumococcal vaccines in 1- to 9-year-olds as well, according to Dr. Maguire.

Pfizer also now is planning clinical trials of the vaccine in infants, another important group currently unprotected against meningococcal group B disease, he added.

Dr. Maguire is an employee of Pfizer, who funded the studies.

[email protected]

LJUBLJANA, SLOVENIA – An expanded indication for the meningococcal group B vaccine known as Trumenba in patients aged 1-9 years is being considered by the Food and Drug Administration under the agency’s Breakthrough Therapy designation.

Breakthrough Therapy status is reserved for accelerated review of therapies considered to show substantial preliminary promise of effectively targeting a major unmet medical need.

The unmet need here is that there is no meningococcal group B vaccine approved for use in children under age 10 years. Yet infants and children under 5 years of age are at greatest risk of invasive meningococcal B disease, with reported case fatality rates of 8%-9%, Jason D. Maguire, MD, noted at the annual meeting of the European Society for Paediatric Infectious Diseases.

Trumenba has been approved in the United States for patients aged 10-25 years and in the European Union for individuals aged 10 years or older.

Dr. Maguire, of Pfizer’s vaccine clinical research and development program, presented the results of the two phase 2 randomized safety and immunogenicity trials conducted in patients aged 1- 9 years that the company has submitted to the FDA in support of the expanded indication. One study was carried out in 352 1-year-old toddlers, the other in 400 children aged 2-9 years, whose mean age was 4 years. The studies were carried out in Australia, Finland, Poland, and the Czech Republic.

In a pooled analysis of the vaccine’s immunogenicity when administered in a three-dose schedule of 120 mcg at 0, 2, and 6 months to 193 toddlers and 274 of the children aged 2-9 years, robust bactericidal antibody responses were seen against the four major Neisseria meningitidis group B strains that cause invasive disease. In fact, at least a fourfold rise in titers from baseline to 1 month after dose three was documented in the same high proportion of 1- to 9-year-olds as previously seen in the phase 3 trials that led to vaccine licensure in adolescents and young adults.

“These results support that the use of Trumenba, when given to children ages 1 to less than 10 years at the same dose and schedule that is currently approved in adolescents and young adults, can afford a high degree of protective antibody responses that correlate with immunity in this population,” Dr. Maguire said.

The safety and tolerability analysis included all 752 children in the two phase 2 studies, including the 110 toddlers randomized to three 60-mcg doses of the vaccine, although it has subsequently become clear that 120 mcg is the dose that provides the best immunogenicity with an acceptable safety profile, according to the physician.

Across the age groups, local reactions, including redness and swelling, were more common in Trumenba recipients than in controls who received hepatitis A vaccine and saline injections. So were systemic adverse events. Fever – a systemic event of particular interest to parents and clinicians – occurred in 37% of toddlers after vaccination, compared with 25% of 2- to 9-year-olds and 10%-12% of controls. Of note, prophylactic antipyretics weren’t allowed in the study.

“There’s somewhat of an inverse relationship between age and temperature. So as we go down in age, the rate of fever rises. But after each subsequent dose, regardless of age, there’s a reduction in the incidence of fever,” Dr. Maguire observed.

Most fevers were less than 39.0° C. Only 3 of 752 (less than 1%) patients experienced fever in excess of 40.0° C.

Two children withdrew from the study after developing hip synovitis, which was transient. Another withdrew because of prolonged irritability, fatigue, and decreased appetite.

“Although Trumenba had an acceptable safety and tolerability profile in 1- to 9-year-olds, this analysis wasn’t powered enough to detect uncommon adverse events, so we’ll continue to monitor safety for things like synovitis,” he said.

In 10- to 25-year-olds, the meningococcal vaccine can be given concomitantly with other vaccines without interference. There are plans to study concurrent vaccination with MMR and pneumococcal vaccines in 1- to 9-year-olds as well, according to Dr. Maguire.

Pfizer also now is planning clinical trials of the vaccine in infants, another important group currently unprotected against meningococcal group B disease, he added.

Dr. Maguire is an employee of Pfizer, who funded the studies.

[email protected]

LJUBLJANA, SLOVENIA – An expanded indication for the meningococcal group B vaccine known as Trumenba in patients aged 1-9 years is being considered by the Food and Drug Administration under the agency’s Breakthrough Therapy designation.

Breakthrough Therapy status is reserved for accelerated review of therapies considered to show substantial preliminary promise of effectively targeting a major unmet medical need.

The unmet need here is that there is no meningococcal group B vaccine approved for use in children under age 10 years. Yet infants and children under 5 years of age are at greatest risk of invasive meningococcal B disease, with reported case fatality rates of 8%-9%, Jason D. Maguire, MD, noted at the annual meeting of the European Society for Paediatric Infectious Diseases.

Trumenba has been approved in the United States for patients aged 10-25 years and in the European Union for individuals aged 10 years or older.

Dr. Maguire, of Pfizer’s vaccine clinical research and development program, presented the results of the two phase 2 randomized safety and immunogenicity trials conducted in patients aged 1- 9 years that the company has submitted to the FDA in support of the expanded indication. One study was carried out in 352 1-year-old toddlers, the other in 400 children aged 2-9 years, whose mean age was 4 years. The studies were carried out in Australia, Finland, Poland, and the Czech Republic.

In a pooled analysis of the vaccine’s immunogenicity when administered in a three-dose schedule of 120 mcg at 0, 2, and 6 months to 193 toddlers and 274 of the children aged 2-9 years, robust bactericidal antibody responses were seen against the four major Neisseria meningitidis group B strains that cause invasive disease. In fact, at least a fourfold rise in titers from baseline to 1 month after dose three was documented in the same high proportion of 1- to 9-year-olds as previously seen in the phase 3 trials that led to vaccine licensure in adolescents and young adults.

“These results support that the use of Trumenba, when given to children ages 1 to less than 10 years at the same dose and schedule that is currently approved in adolescents and young adults, can afford a high degree of protective antibody responses that correlate with immunity in this population,” Dr. Maguire said.

The safety and tolerability analysis included all 752 children in the two phase 2 studies, including the 110 toddlers randomized to three 60-mcg doses of the vaccine, although it has subsequently become clear that 120 mcg is the dose that provides the best immunogenicity with an acceptable safety profile, according to the physician.

Across the age groups, local reactions, including redness and swelling, were more common in Trumenba recipients than in controls who received hepatitis A vaccine and saline injections. So were systemic adverse events. Fever – a systemic event of particular interest to parents and clinicians – occurred in 37% of toddlers after vaccination, compared with 25% of 2- to 9-year-olds and 10%-12% of controls. Of note, prophylactic antipyretics weren’t allowed in the study.

“There’s somewhat of an inverse relationship between age and temperature. So as we go down in age, the rate of fever rises. But after each subsequent dose, regardless of age, there’s a reduction in the incidence of fever,” Dr. Maguire observed.

Most fevers were less than 39.0° C. Only 3 of 752 (less than 1%) patients experienced fever in excess of 40.0° C.

Two children withdrew from the study after developing hip synovitis, which was transient. Another withdrew because of prolonged irritability, fatigue, and decreased appetite.

“Although Trumenba had an acceptable safety and tolerability profile in 1- to 9-year-olds, this analysis wasn’t powered enough to detect uncommon adverse events, so we’ll continue to monitor safety for things like synovitis,” he said.

In 10- to 25-year-olds, the meningococcal vaccine can be given concomitantly with other vaccines without interference. There are plans to study concurrent vaccination with MMR and pneumococcal vaccines in 1- to 9-year-olds as well, according to Dr. Maguire.

Pfizer also now is planning clinical trials of the vaccine in infants, another important group currently unprotected against meningococcal group B disease, he added.

Dr. Maguire is an employee of Pfizer, who funded the studies.

[email protected]

Measles, an ancient, highly contagious disease with a history of successful control by vaccination, is now threatening to have an epidemic resurgence. Until recently, measles vaccination largely controlled outbreaks in the United States. The Global Vaccine Action Plan under the World Health Organization aimed to eliminate measles worldwide. Nonetheless, the vaccine refusal movement and slow rollout of vaccine programs globally have interfered with control of the virus. A record number of measles cases have emerged in recent months: more than 700 since January 2019.¹ Approximately 70% of recent cases were in unvaccinated patients, and almost all were in US residents.

This update reviews the history, presentation and diagnosis, complications, management, contagion control, and emerging threat of a measles epidemic. It concludes with recommendations for clinical practice in the context of the current measles outbreaks.

FROM UBIQUITOUS TO ERADICATED—AND BACK

Before the measles vaccine was developed and became available in the 1960s, outbreaks of measles occurred predictably every year in the United States and other temperate regions. During yearly outbreaks, measles was so contagious that household contacts had attack rates above 95%. Most cases occurred in very young children, and because infection with the virus causes lifelong immunity, it could be safely assumed that by adulthood, everyone was immune. In an outbreak in the Faroe Islands in 1846, no one who had been alive in the last major outbreak 65 years earlier became ill, but everyone under age 65 was at high risk with “high attack rates,” estimated as 99% from other outbreaks (reviewed by Krugman et al²).

In isolated regions previously free of measles, adults did not have immunity, and when exposed, they often developed severe disease. When European settlers brought measles and smallpox to the Americas beginning in the late 15th century, these diseases decimated whole populations of native peoples who had never been exposed to them.

From the US Centers for Disease Control and Prevention.

That was premature. A number of outbreaks have occurred since then; the largest in the United States (before 2019) was in 2000. Over half of the 667 cases reported during that outbreak were in an underimmunized Amish community in Ohio.³

Now it emerges again.

PRESENTATION CAN VARY

From the US Centers for Disease Control and Prevention.

From the US Centers for Disease Control and Prevention.

The presentation varies somewhat among certain groups.

Nonimmune pregnant women have an especially severe course, likely related to the relative immune suppression of pregnancy.

In immune-suppressed states, measles is not only more severe, it is also difficult to diagnose because the rash can be absent.

In partially vaccinated children and adults, the disease may present atypically, without cough, conjunctivitis, and coryza, and it may be milder, lacking some of the extreme malaise typical of measles and with a shortened course. Measles infection in people who received the inactivated measles vaccine that was briefly available from 1963 to 1967 is also associated with atypical measles syndrome, a severe hypersensitivity reaction to the measles virus. Atypical measles can be prevented by revaccination with a live-virus vaccine.

The diagnosis of measles is straightforward when all of the signs and symptoms are present. In partially vaccinated populations, however, the diagnosis may need to be confirmed by serologic or polymerase chain reaction (PCR) testing.

Differential diagnosis

The differential diagnosis of the fever and a rash typical of measles in children, especially when accompanied by severe malaise, includes the following:

Kawasaki disease. However, the red eyes of Kawasaki are an injection of the bulbar conjunctivae with sparing of the limbus. No eye exudate is present, and respiratory illness is not part of the disease.

Drug eruptions can present with a morbilliform rash and sometimes fever, but not the other signs of measles in either adults or children.

Scarlet fever has a different rash, the sandpaper rash typical of toxin-mediated disease.

Rubella tends to cause mild respiratory symptoms and illness rather than the severe disease of measles and other rash-causing viral infections in children and infants.

Confirmation in confusing cases

To confirm a diagnosis of measles, samples from throat, nasal, and posterior nasopharyngeal swabs should be collected with a blood specimen for serology and sent to the state public health laboratory.⁴ The US Centers for Disease Control and Prevention gives instructions on who should be tested and with which tests.⁴

Most testing now uses PCR for viral RNA, as viral culture is more costly and takes longer. For accurate diagnosis, samples for PCR must be obtained during the acute illness.

The serologic gold standard for diagnosis is a 4-fold rise or fall in immunoglobulin G (IgG) titer of paired serum samples sent 10 days to 2 weeks apart around the illness. The IgM test may be negative initially, and a negative test cannot be used to rule out the diagnosis. Confirmed cases should be reported to public health authorities.

COMPLICATIONS: EARLY AND LATE

Frequent complications of measles infection include those related to the primary viral infection of respiratory tract mucosal surfaces, as well as bacterial superinfections. Complications are most likely in children under age 5, nonimmune adults, pregnant women, and immunocompromised people. Typical complications include otitis media, laryngotracheobronchitis (presenting as a croupy cough), pneumonia, and diarrhea.

Late sequelae of measles infection are related in part to serious mucosal damage and generalized immune suppression caused by the virus. Even after recovery from acute infection, children can have persistent diarrhea and failure to thrive, with increased mortality risk in the months after infection. Tuberculosis can reactivate in patients already infected, and new tuberculosis infection can be especially severe. Further, tuberculosis skin tests become less reliable immediately after measles infection. Severe disease and fatalities are increased in populations that have baseline vitamin A deficiency and malnutrition.

Death from measles is most often caused by viral pneumonia, secondary bacterial pneumonia, and postviral encephalitis. Before the vaccine era, measles encephalitis occurred in the United States in about 1 in 1,000 measles cases.

Subacute sclerosing panencephalitis is a rare, late, and often fatal complication of measles that presents 7 to 10 years after acute measles infection, usually in adolescence. Beginning with myoclonic jerks, stiffening, and slow mental deterioration, it progresses over 1 to 3 years, with a relentless degenerative course leading to death. Since the introduction of the measles vaccine in 1957, this disease has essentially disappeared in the United States.

SUPPORTIVE CARE, INFECTION CONTROL

Management of measles and its complications is primarily supportive.

Preventing contagion

Measles infection has an incubation period of 8 to 12 days. Individuals are contagious 4 days before to 4 days after rash onset in the normal host but longer in those lacking immune function. Cases can occur up to 21 days after exposure during the contagious period.

The disease is highly contagious, so hospitalized patients should be cared for with airborne precautions. It is crucial that caretakers be vaccinated properly, so that they can care for patients safely. Recommendations for preventing secondary cases by prompt vaccination and giving immune globulin are detailed below, including specific recommendations for individuals with immune system suppression.

The current US public health policy regarding measles vaccine booster doses began in response to the widespread measles outbreak in the United States from 1989 to 1991. Cases occurred more commonly in unvaccinated individuals and in young adults who had received only 1 dose of vaccine.

Today, the policy in areas where measles has been controlled is to vaccinate between 12 and 15 months of age and to boost with a second dose before starting kindergarten. In outbreak situations, the first dose should be given at 6 months of age, with a repeat dose at 12 to 15 months of age and the usual booster before starting kindergarten.

Those born before 1957 can be presumed to have had natural measles, which confers lifelong immunity (Table 3).⁷

In 2000, measles was considered controlled in the United States, thanks to the national vaccination policy. But despite overall control, small numbers of cases continued to occur each year, related to exposure to cases imported from areas of the world endemic with measles.

Within the last year, however, major outbreaks have emerged. Incompletely vaccinated populations and unvaccinated individuals are the reason for the progression of current outbreaks.⁸

Until there is broader acceptance of the vaccine and better adherence to vaccine policies nationally and globally, measles cannot be completely eradicated. But with high vaccination rates, it is predicted that this infection can be controlled and ultimately eradicated.

RECOMMENDATIONS

In the midst of an outbreak and with rising public awareness of the threat of measles, it is important to recognize that MMR vaccination is the most effective way to prevent spread of the virus and maintain measles elimination in the United States. With this in mind, there are several key facts and recommendations regarding vaccination:

Recommendations on vaccination

• In measles-controlled populations, all children should be vaccinated between 12 and 15 months of age and again before kindergarten.
• In outbreak settings, children should receive a first vaccine dose at 6 months of age, a second at 12 to 15 months of age, and a third before kindergarten.
• Children who have received 2 measles vaccine doses can be assumed to be fully vaccinated and thus protected as long as the first dose was after 12 months of age. If the first dose was before 12 months of age, a child needs 3 doses.
• Adults born before 1957 can be assumed to have had measles infection and to be immune.
• Adults who were immunized with the inactivated measles vaccine available between 1963 and 1967 should receive 1 dose of live virus vaccine.
• Boosters are recommended for young adults who did not receive a second dose of vaccine and for adults with an uncertain history of immunization. There is no need to check titers before giving a booster, but if a positive titer is available in an adult, a booster is not needed.
• Heathcare providers should vaccinate unvaccinated or undervaccinated US residents traveling internationally (as long as they do not have contraindications) or traveling within the country to areas with outbreaks of measles.

Recommendations on vaccination after exposure to measles

• Vaccine is recommended for a nonimmune contact, including anyone with a history of only a single dose of vaccine.
• If a child got a first dose of vaccine before 12 months of age, give the second dose as soon as he or she turns 1 year old, or at least 28 days after the first dose.
• Vaccine must be given within 72 hours of exposure to confer protection (or at least decrease disease severity).
• The second dose of vaccine should be given at least 28 days after the first dose.

Recommendations on immune globulin after exposure to measles

• Immune globulin is recommended for anyone with exposure and no history of vaccination or immunity.
• Immune globulin can be given up to 6 days after exposure to prevent or decrease the severity of measles in immunocompromised hosts who have not been previously vaccinated. It is best to give it as early as possible.
• Immune globulin is given intramuscularly at 0.5 mL/kg, up to a to maximum dose of 15 mL.
• Pregnant women and immunocompromised hosts without immunity should receive immunoglobulin intravenously. Children and adults who have had a recent bone marrow transplant and likely do not yet have a reconstituted immune system should be treated with immune globulin to prevent infection, as vaccine cannot be given immediately after transplant. This is also true for other immunocompromised individuals who have not been vaccinated and who are not candidates for vaccine because of the severity of their immune suppression.
• Children with human immunodeficiency virus infection are routinely vaccinated. As long as they have evidence of serologic immunity, they do not need additional treatment.

Measles, an ancient, highly contagious disease with a history of successful control by vaccination, is now threatening to have an epidemic resurgence. Until recently, measles vaccination largely controlled outbreaks in the United States. The Global Vaccine Action Plan under the World Health Organization aimed to eliminate measles worldwide. Nonetheless, the vaccine refusal movement and slow rollout of vaccine programs globally have interfered with control of the virus. A record number of measles cases have emerged in recent months: more than 700 since January 2019.¹ Approximately 70% of recent cases were in unvaccinated patients, and almost all were in US residents.

This update reviews the history, presentation and diagnosis, complications, management, contagion control, and emerging threat of a measles epidemic. It concludes with recommendations for clinical practice in the context of the current measles outbreaks.

FROM UBIQUITOUS TO ERADICATED—AND BACK

Before the measles vaccine was developed and became available in the 1960s, outbreaks of measles occurred predictably every year in the United States and other temperate regions. During yearly outbreaks, measles was so contagious that household contacts had attack rates above 95%. Most cases occurred in very young children, and because infection with the virus causes lifelong immunity, it could be safely assumed that by adulthood, everyone was immune. In an outbreak in the Faroe Islands in 1846, no one who had been alive in the last major outbreak 65 years earlier became ill, but everyone under age 65 was at high risk with “high attack rates,” estimated as 99% from other outbreaks (reviewed by Krugman et al²).

In isolated regions previously free of measles, adults did not have immunity, and when exposed, they often developed severe disease. When European settlers brought measles and smallpox to the Americas beginning in the late 15th century, these diseases decimated whole populations of native peoples who had never been exposed to them.

From the US Centers for Disease Control and Prevention.

That was premature. A number of outbreaks have occurred since then; the largest in the United States (before 2019) was in 2000. Over half of the 667 cases reported during that outbreak were in an underimmunized Amish community in Ohio.³

Now it emerges again.

PRESENTATION CAN VARY

From the US Centers for Disease Control and Prevention.

From the US Centers for Disease Control and Prevention.

The presentation varies somewhat among certain groups.

Nonimmune pregnant women have an especially severe course, likely related to the relative immune suppression of pregnancy.

In immune-suppressed states, measles is not only more severe, it is also difficult to diagnose because the rash can be absent.

In partially vaccinated children and adults, the disease may present atypically, without cough, conjunctivitis, and coryza, and it may be milder, lacking some of the extreme malaise typical of measles and with a shortened course. Measles infection in people who received the inactivated measles vaccine that was briefly available from 1963 to 1967 is also associated with atypical measles syndrome, a severe hypersensitivity reaction to the measles virus. Atypical measles can be prevented by revaccination with a live-virus vaccine.

The diagnosis of measles is straightforward when all of the signs and symptoms are present. In partially vaccinated populations, however, the diagnosis may need to be confirmed by serologic or polymerase chain reaction (PCR) testing.

Differential diagnosis

The differential diagnosis of the fever and a rash typical of measles in children, especially when accompanied by severe malaise, includes the following:

Kawasaki disease. However, the red eyes of Kawasaki are an injection of the bulbar conjunctivae with sparing of the limbus. No eye exudate is present, and respiratory illness is not part of the disease.

Drug eruptions can present with a morbilliform rash and sometimes fever, but not the other signs of measles in either adults or children.

Scarlet fever has a different rash, the sandpaper rash typical of toxin-mediated disease.

Rubella tends to cause mild respiratory symptoms and illness rather than the severe disease of measles and other rash-causing viral infections in children and infants.

Confirmation in confusing cases

To confirm a diagnosis of measles, samples from throat, nasal, and posterior nasopharyngeal swabs should be collected with a blood specimen for serology and sent to the state public health laboratory.⁴ The US Centers for Disease Control and Prevention gives instructions on who should be tested and with which tests.⁴

Most testing now uses PCR for viral RNA, as viral culture is more costly and takes longer. For accurate diagnosis, samples for PCR must be obtained during the acute illness.

The serologic gold standard for diagnosis is a 4-fold rise or fall in immunoglobulin G (IgG) titer of paired serum samples sent 10 days to 2 weeks apart around the illness. The IgM test may be negative initially, and a negative test cannot be used to rule out the diagnosis. Confirmed cases should be reported to public health authorities.

COMPLICATIONS: EARLY AND LATE

Frequent complications of measles infection include those related to the primary viral infection of respiratory tract mucosal surfaces, as well as bacterial superinfections. Complications are most likely in children under age 5, nonimmune adults, pregnant women, and immunocompromised people. Typical complications include otitis media, laryngotracheobronchitis (presenting as a croupy cough), pneumonia, and diarrhea.

Late sequelae of measles infection are related in part to serious mucosal damage and generalized immune suppression caused by the virus. Even after recovery from acute infection, children can have persistent diarrhea and failure to thrive, with increased mortality risk in the months after infection. Tuberculosis can reactivate in patients already infected, and new tuberculosis infection can be especially severe. Further, tuberculosis skin tests become less reliable immediately after measles infection. Severe disease and fatalities are increased in populations that have baseline vitamin A deficiency and malnutrition.

Death from measles is most often caused by viral pneumonia, secondary bacterial pneumonia, and postviral encephalitis. Before the vaccine era, measles encephalitis occurred in the United States in about 1 in 1,000 measles cases.

Subacute sclerosing panencephalitis is a rare, late, and often fatal complication of measles that presents 7 to 10 years after acute measles infection, usually in adolescence. Beginning with myoclonic jerks, stiffening, and slow mental deterioration, it progresses over 1 to 3 years, with a relentless degenerative course leading to death. Since the introduction of the measles vaccine in 1957, this disease has essentially disappeared in the United States.

SUPPORTIVE CARE, INFECTION CONTROL

Management of measles and its complications is primarily supportive.

Preventing contagion

Measles infection has an incubation period of 8 to 12 days. Individuals are contagious 4 days before to 4 days after rash onset in the normal host but longer in those lacking immune function. Cases can occur up to 21 days after exposure during the contagious period.

The disease is highly contagious, so hospitalized patients should be cared for with airborne precautions. It is crucial that caretakers be vaccinated properly, so that they can care for patients safely. Recommendations for preventing secondary cases by prompt vaccination and giving immune globulin are detailed below, including specific recommendations for individuals with immune system suppression.

The current US public health policy regarding measles vaccine booster doses began in response to the widespread measles outbreak in the United States from 1989 to 1991. Cases occurred more commonly in unvaccinated individuals and in young adults who had received only 1 dose of vaccine.

Today, the policy in areas where measles has been controlled is to vaccinate between 12 and 15 months of age and to boost with a second dose before starting kindergarten. In outbreak situations, the first dose should be given at 6 months of age, with a repeat dose at 12 to 15 months of age and the usual booster before starting kindergarten.

Those born before 1957 can be presumed to have had natural measles, which confers lifelong immunity (Table 3).⁷

In 2000, measles was considered controlled in the United States, thanks to the national vaccination policy. But despite overall control, small numbers of cases continued to occur each year, related to exposure to cases imported from areas of the world endemic with measles.

Within the last year, however, major outbreaks have emerged. Incompletely vaccinated populations and unvaccinated individuals are the reason for the progression of current outbreaks.⁸

Until there is broader acceptance of the vaccine and better adherence to vaccine policies nationally and globally, measles cannot be completely eradicated. But with high vaccination rates, it is predicted that this infection can be controlled and ultimately eradicated.

RECOMMENDATIONS

In the midst of an outbreak and with rising public awareness of the threat of measles, it is important to recognize that MMR vaccination is the most effective way to prevent spread of the virus and maintain measles elimination in the United States. With this in mind, there are several key facts and recommendations regarding vaccination:

Recommendations on vaccination

• In measles-controlled populations, all children should be vaccinated between 12 and 15 months of age and again before kindergarten.
• In outbreak settings, children should receive a first vaccine dose at 6 months of age, a second at 12 to 15 months of age, and a third before kindergarten.
• Children who have received 2 measles vaccine doses can be assumed to be fully vaccinated and thus protected as long as the first dose was after 12 months of age. If the first dose was before 12 months of age, a child needs 3 doses.
• Adults born before 1957 can be assumed to have had measles infection and to be immune.
• Adults who were immunized with the inactivated measles vaccine available between 1963 and 1967 should receive 1 dose of live virus vaccine.
• Boosters are recommended for young adults who did not receive a second dose of vaccine and for adults with an uncertain history of immunization. There is no need to check titers before giving a booster, but if a positive titer is available in an adult, a booster is not needed.
• Heathcare providers should vaccinate unvaccinated or undervaccinated US residents traveling internationally (as long as they do not have contraindications) or traveling within the country to areas with outbreaks of measles.

Recommendations on vaccination after exposure to measles

• Vaccine is recommended for a nonimmune contact, including anyone with a history of only a single dose of vaccine.
• If a child got a first dose of vaccine before 12 months of age, give the second dose as soon as he or she turns 1 year old, or at least 28 days after the first dose.
• Vaccine must be given within 72 hours of exposure to confer protection (or at least decrease disease severity).
• The second dose of vaccine should be given at least 28 days after the first dose.

Recommendations on immune globulin after exposure to measles

• Immune globulin is recommended for anyone with exposure and no history of vaccination or immunity.
• Immune globulin can be given up to 6 days after exposure to prevent or decrease the severity of measles in immunocompromised hosts who have not been previously vaccinated. It is best to give it as early as possible.
• Immune globulin is given intramuscularly at 0.5 mL/kg, up to a to maximum dose of 15 mL.
• Pregnant women and immunocompromised hosts without immunity should receive immunoglobulin intravenously. Children and adults who have had a recent bone marrow transplant and likely do not yet have a reconstituted immune system should be treated with immune globulin to prevent infection, as vaccine cannot be given immediately after transplant. This is also true for other immunocompromised individuals who have not been vaccinated and who are not candidates for vaccine because of the severity of their immune suppression.
• Children with human immunodeficiency virus infection are routinely vaccinated. As long as they have evidence of serologic immunity, they do not need additional treatment.

Measles, an ancient, highly contagious disease with a history of successful control by vaccination, is now threatening to have an epidemic resurgence. Until recently, measles vaccination largely controlled outbreaks in the United States. The Global Vaccine Action Plan under the World Health Organization aimed to eliminate measles worldwide. Nonetheless, the vaccine refusal movement and slow rollout of vaccine programs globally have interfered with control of the virus. A record number of measles cases have emerged in recent months: more than 700 since January 2019.¹ Approximately 70% of recent cases were in unvaccinated patients, and almost all were in US residents.

This update reviews the history, presentation and diagnosis, complications, management, contagion control, and emerging threat of a measles epidemic. It concludes with recommendations for clinical practice in the context of the current measles outbreaks.

FROM UBIQUITOUS TO ERADICATED—AND BACK

Before the measles vaccine was developed and became available in the 1960s, outbreaks of measles occurred predictably every year in the United States and other temperate regions. During yearly outbreaks, measles was so contagious that household contacts had attack rates above 95%. Most cases occurred in very young children, and because infection with the virus causes lifelong immunity, it could be safely assumed that by adulthood, everyone was immune. In an outbreak in the Faroe Islands in 1846, no one who had been alive in the last major outbreak 65 years earlier became ill, but everyone under age 65 was at high risk with “high attack rates,” estimated as 99% from other outbreaks (reviewed by Krugman et al²).

In isolated regions previously free of measles, adults did not have immunity, and when exposed, they often developed severe disease. When European settlers brought measles and smallpox to the Americas beginning in the late 15th century, these diseases decimated whole populations of native peoples who had never been exposed to them.

From the US Centers for Disease Control and Prevention.

That was premature. A number of outbreaks have occurred since then; the largest in the United States (before 2019) was in 2000. Over half of the 667 cases reported during that outbreak were in an underimmunized Amish community in Ohio.³

Now it emerges again.

PRESENTATION CAN VARY

From the US Centers for Disease Control and Prevention.

From the US Centers for Disease Control and Prevention.

The presentation varies somewhat among certain groups.

Nonimmune pregnant women have an especially severe course, likely related to the relative immune suppression of pregnancy.

In immune-suppressed states, measles is not only more severe, it is also difficult to diagnose because the rash can be absent.

In partially vaccinated children and adults, the disease may present atypically, without cough, conjunctivitis, and coryza, and it may be milder, lacking some of the extreme malaise typical of measles and with a shortened course. Measles infection in people who received the inactivated measles vaccine that was briefly available from 1963 to 1967 is also associated with atypical measles syndrome, a severe hypersensitivity reaction to the measles virus. Atypical measles can be prevented by revaccination with a live-virus vaccine.

The diagnosis of measles is straightforward when all of the signs and symptoms are present. In partially vaccinated populations, however, the diagnosis may need to be confirmed by serologic or polymerase chain reaction (PCR) testing.

Differential diagnosis

The differential diagnosis of the fever and a rash typical of measles in children, especially when accompanied by severe malaise, includes the following:

Kawasaki disease. However, the red eyes of Kawasaki are an injection of the bulbar conjunctivae with sparing of the limbus. No eye exudate is present, and respiratory illness is not part of the disease.

Drug eruptions can present with a morbilliform rash and sometimes fever, but not the other signs of measles in either adults or children.

Scarlet fever has a different rash, the sandpaper rash typical of toxin-mediated disease.

Rubella tends to cause mild respiratory symptoms and illness rather than the severe disease of measles and other rash-causing viral infections in children and infants.

Confirmation in confusing cases

To confirm a diagnosis of measles, samples from throat, nasal, and posterior nasopharyngeal swabs should be collected with a blood specimen for serology and sent to the state public health laboratory.⁴ The US Centers for Disease Control and Prevention gives instructions on who should be tested and with which tests.⁴

Most testing now uses PCR for viral RNA, as viral culture is more costly and takes longer. For accurate diagnosis, samples for PCR must be obtained during the acute illness.

The serologic gold standard for diagnosis is a 4-fold rise or fall in immunoglobulin G (IgG) titer of paired serum samples sent 10 days to 2 weeks apart around the illness. The IgM test may be negative initially, and a negative test cannot be used to rule out the diagnosis. Confirmed cases should be reported to public health authorities.

COMPLICATIONS: EARLY AND LATE

Frequent complications of measles infection include those related to the primary viral infection of respiratory tract mucosal surfaces, as well as bacterial superinfections. Complications are most likely in children under age 5, nonimmune adults, pregnant women, and immunocompromised people. Typical complications include otitis media, laryngotracheobronchitis (presenting as a croupy cough), pneumonia, and diarrhea.

Late sequelae of measles infection are related in part to serious mucosal damage and generalized immune suppression caused by the virus. Even after recovery from acute infection, children can have persistent diarrhea and failure to thrive, with increased mortality risk in the months after infection. Tuberculosis can reactivate in patients already infected, and new tuberculosis infection can be especially severe. Further, tuberculosis skin tests become less reliable immediately after measles infection. Severe disease and fatalities are increased in populations that have baseline vitamin A deficiency and malnutrition.

Death from measles is most often caused by viral pneumonia, secondary bacterial pneumonia, and postviral encephalitis. Before the vaccine era, measles encephalitis occurred in the United States in about 1 in 1,000 measles cases.

Subacute sclerosing panencephalitis is a rare, late, and often fatal complication of measles that presents 7 to 10 years after acute measles infection, usually in adolescence. Beginning with myoclonic jerks, stiffening, and slow mental deterioration, it progresses over 1 to 3 years, with a relentless degenerative course leading to death. Since the introduction of the measles vaccine in 1957, this disease has essentially disappeared in the United States.

SUPPORTIVE CARE, INFECTION CONTROL

Management of measles and its complications is primarily supportive.

Preventing contagion

Measles infection has an incubation period of 8 to 12 days. Individuals are contagious 4 days before to 4 days after rash onset in the normal host but longer in those lacking immune function. Cases can occur up to 21 days after exposure during the contagious period.

The disease is highly contagious, so hospitalized patients should be cared for with airborne precautions. It is crucial that caretakers be vaccinated properly, so that they can care for patients safely. Recommendations for preventing secondary cases by prompt vaccination and giving immune globulin are detailed below, including specific recommendations for individuals with immune system suppression.

The current US public health policy regarding measles vaccine booster doses began in response to the widespread measles outbreak in the United States from 1989 to 1991. Cases occurred more commonly in unvaccinated individuals and in young adults who had received only 1 dose of vaccine.

Today, the policy in areas where measles has been controlled is to vaccinate between 12 and 15 months of age and to boost with a second dose before starting kindergarten. In outbreak situations, the first dose should be given at 6 months of age, with a repeat dose at 12 to 15 months of age and the usual booster before starting kindergarten.

Those born before 1957 can be presumed to have had natural measles, which confers lifelong immunity (Table 3).⁷

In 2000, measles was considered controlled in the United States, thanks to the national vaccination policy. But despite overall control, small numbers of cases continued to occur each year, related to exposure to cases imported from areas of the world endemic with measles.

Within the last year, however, major outbreaks have emerged. Incompletely vaccinated populations and unvaccinated individuals are the reason for the progression of current outbreaks.⁸

Until there is broader acceptance of the vaccine and better adherence to vaccine policies nationally and globally, measles cannot be completely eradicated. But with high vaccination rates, it is predicted that this infection can be controlled and ultimately eradicated.

RECOMMENDATIONS

In the midst of an outbreak and with rising public awareness of the threat of measles, it is important to recognize that MMR vaccination is the most effective way to prevent spread of the virus and maintain measles elimination in the United States. With this in mind, there are several key facts and recommendations regarding vaccination:

Recommendations on vaccination

• In measles-controlled populations, all children should be vaccinated between 12 and 15 months of age and again before kindergarten.
• In outbreak settings, children should receive a first vaccine dose at 6 months of age, a second at 12 to 15 months of age, and a third before kindergarten.
• Children who have received 2 measles vaccine doses can be assumed to be fully vaccinated and thus protected as long as the first dose was after 12 months of age. If the first dose was before 12 months of age, a child needs 3 doses.
• Adults born before 1957 can be assumed to have had measles infection and to be immune.
• Adults who were immunized with the inactivated measles vaccine available between 1963 and 1967 should receive 1 dose of live virus vaccine.
• Boosters are recommended for young adults who did not receive a second dose of vaccine and for adults with an uncertain history of immunization. There is no need to check titers before giving a booster, but if a positive titer is available in an adult, a booster is not needed.
• Heathcare providers should vaccinate unvaccinated or undervaccinated US residents traveling internationally (as long as they do not have contraindications) or traveling within the country to areas with outbreaks of measles.

Recommendations on vaccination after exposure to measles

• Vaccine is recommended for a nonimmune contact, including anyone with a history of only a single dose of vaccine.
• If a child got a first dose of vaccine before 12 months of age, give the second dose as soon as he or she turns 1 year old, or at least 28 days after the first dose.
• Vaccine must be given within 72 hours of exposure to confer protection (or at least decrease disease severity).
• The second dose of vaccine should be given at least 28 days after the first dose.

Recommendations on immune globulin after exposure to measles

• Immune globulin is recommended for anyone with exposure and no history of vaccination or immunity.
• Immune globulin can be given up to 6 days after exposure to prevent or decrease the severity of measles in immunocompromised hosts who have not been previously vaccinated. It is best to give it as early as possible.
• Immune globulin is given intramuscularly at 0.5 mL/kg, up to a to maximum dose of 15 mL.
• Pregnant women and immunocompromised hosts without immunity should receive immunoglobulin intravenously. Children and adults who have had a recent bone marrow transplant and likely do not yet have a reconstituted immune system should be treated with immune globulin to prevent infection, as vaccine cannot be given immediately after transplant. This is also true for other immunocompromised individuals who have not been vaccinated and who are not candidates for vaccine because of the severity of their immune suppression.
• Children with human immunodeficiency virus infection are routinely vaccinated. As long as they have evidence of serologic immunity, they do not need additional treatment.