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To the Editor: I read with interest the review of dabigatran (Pradaxa) by Drs. Wartak and Bartholomew, which provides an excellent overview of this new oral anticoagulant.¹

This article does not mention clearly two key points about the guidelines for using dabigatran, which are different in the United States than in the other 75 countries where it has been approved.¹ First, the RE-LY trial^2,3 excluded patients with a creatinine clearance rate less than 30 mL/min/1.73 m², a common situation in the elderly. Second, in contrast to other countries, the US Food and Drug Administration (FDA) approved dabigatran for patients with a creatinine clearance rate of 15 to 30 mL/min/1.73 m², although at a lower dose.³ No dose adjustment is suggested in patients with less severe (mild or moderate) renal impairment.³ This may lead to potential misuse and problems. In fact, lethal side effects have been reported in France by Legrand et al.⁴ Furthermore, a report is in press on dabigatran-associated acute renal failure,⁵ and recently the German publication Die Zeit reported 50 deaths from bleeding in patients with atrial fibrillation treated with dabigatran.⁶

Therefore, despite suggestions that dabigatran does not require monitoring of its effects during treatment,^1,3 renal, hematologic, and hepatic variables should be monitored before and after initiation of dabigatran⁵ until more experience is gained with this new drug, and especially in the elderly and those with chronic kidney disease that is stage 4 (estimated glomerular filtration rate 15–29 mL/min/1.73 m²) or stage 5 (< 15 mL/min/1.73 m²).

To the Editor: I read with interest the review of dabigatran (Pradaxa) by Drs. Wartak and Bartholomew, which provides an excellent overview of this new oral anticoagulant.¹

This article does not mention clearly two key points about the guidelines for using dabigatran, which are different in the United States than in the other 75 countries where it has been approved.¹ First, the RE-LY trial^2,3 excluded patients with a creatinine clearance rate less than 30 mL/min/1.73 m², a common situation in the elderly. Second, in contrast to other countries, the US Food and Drug Administration (FDA) approved dabigatran for patients with a creatinine clearance rate of 15 to 30 mL/min/1.73 m², although at a lower dose.³ No dose adjustment is suggested in patients with less severe (mild or moderate) renal impairment.³ This may lead to potential misuse and problems. In fact, lethal side effects have been reported in France by Legrand et al.⁴ Furthermore, a report is in press on dabigatran-associated acute renal failure,⁵ and recently the German publication Die Zeit reported 50 deaths from bleeding in patients with atrial fibrillation treated with dabigatran.⁶

Therefore, despite suggestions that dabigatran does not require monitoring of its effects during treatment,^1,3 renal, hematologic, and hepatic variables should be monitored before and after initiation of dabigatran⁵ until more experience is gained with this new drug, and especially in the elderly and those with chronic kidney disease that is stage 4 (estimated glomerular filtration rate 15–29 mL/min/1.73 m²) or stage 5 (< 15 mL/min/1.73 m²).

To the Editor: I read with interest the review of dabigatran (Pradaxa) by Drs. Wartak and Bartholomew, which provides an excellent overview of this new oral anticoagulant.¹

This article does not mention clearly two key points about the guidelines for using dabigatran, which are different in the United States than in the other 75 countries where it has been approved.¹ First, the RE-LY trial^2,3 excluded patients with a creatinine clearance rate less than 30 mL/min/1.73 m², a common situation in the elderly. Second, in contrast to other countries, the US Food and Drug Administration (FDA) approved dabigatran for patients with a creatinine clearance rate of 15 to 30 mL/min/1.73 m², although at a lower dose.³ No dose adjustment is suggested in patients with less severe (mild or moderate) renal impairment.³ This may lead to potential misuse and problems. In fact, lethal side effects have been reported in France by Legrand et al.⁴ Furthermore, a report is in press on dabigatran-associated acute renal failure,⁵ and recently the German publication Die Zeit reported 50 deaths from bleeding in patients with atrial fibrillation treated with dabigatran.⁶

Therefore, despite suggestions that dabigatran does not require monitoring of its effects during treatment,^1,3 renal, hematologic, and hepatic variables should be monitored before and after initiation of dabigatran⁵ until more experience is gained with this new drug, and especially in the elderly and those with chronic kidney disease that is stage 4 (estimated glomerular filtration rate 15–29 mL/min/1.73 m²) or stage 5 (< 15 mL/min/1.73 m²).

In Reply: Dabigatran has gained significant popularity in the United States. From its approval in October 2010 and through August 2011, approximately 1.1 million prescriptions for it were dispensed, and 371,000 patients received it from US outpatient retail pharmacies.¹ We appreciate the letters from Drs. Pazmiño and Hirsch and believe there are reasons to be vigilant when using dabigatran.

In response to the letter from Dr. Pazmiño, we agree with his concerns and have covered them in our review. We would like to emphasize that our review was intended to help US clinicians understand this new drug and was not restricted to the RE-LY trial. The limitations of the trials of dabigatran to date (including the lack of patients with renal impairment in the RE-LY trial) have been mentioned in many articles, including ours. Please see the section TOPICS OF FUTURE INTEREST.²

The FDA did not recommend any dose adjustment for patients with moderate renal impairment (creatinine clearance 30–50 mL/min), as it was convinced that the 150-mg dose had a superior risk-benefit profile, even for patients with a higher risk of bleeding, compared with the 110-mg dose.³ It is hard for us to comment on the specific reasoning behind the FDA’s approval for using 75 mg of dabigatran in patients with creatinine clearance between 15 and 30 mL/min. However, we know this was based on pharmacokinetic and pharmacodynamic modeling and not on efficacy and safety data.³ With respect to dosing and monitoring, we did stress this point in our article, stating that the use of dabigatran obviates the need for routine laboratory monitoring. However, one may measure the drug’s activity in certain situations (suspected overdose, bleeding, need for emergency surgery, impaired renal function, pregnancy, and obesity, and in children). Please see the section DOES DABIGATRAN NEED MONITORING? CAN IT EVEN BE MONITORED? in our review.²

Dr. Pazmiño suggests renal, hematologic and hepatic variables should be monitored before and after starting dabigatran. We agree that renal function should be monitored and have covered this point. Please see the section WHO SHOULD NOT RECEIVE DABIGATRAN.² Hematologic and hepatic variables can be monitored if a clinician decides to do so, but this is not limited specifically to dabigatran. Also, to clarify, dabigatran is not approved for those with stage 5 chronic kidney disease. And we share his concern about the lack of experience with this new drug, and we included a word of caution in the section ADVANTAGES AND DISADVANTAGES OF DABIGATRAN.²

We agree with Dr. Hirsch’s concerns about recombinant factor VIIa. We are not recommending its use as a routine practice but as an available option. Our article was a global review on dabigatran, and our aim was to cover the best available evidence and treatment options in a comprehensive way. However, in response to Dr. Hirsch’s comments, the systematic review by Yank et al⁴ drew its data from 16 randomized controlled trials but excluded patients on anticoagulants (except for those in a few observational studies), and factor VIIa was compared with placebo.⁴ So these findings are not applicable to patients with dabigatran-related bleeding, and to draw any definite conclusion would not be correct. If recombinant factor VIIa has failed to show a benefit in terms of a lower mortality rate, we could also point out that there was no mortality benefit seen in reversing warfarin anticoagulation in patients with acute intracranial hemorrhage with the use of vitamin K, fresh-frozen plasma, or prothrombin complex concentrate.⁵ This should not lead one to stop using these treatments.

Clinicians are well accustomed to managing warfarin- or heparin-related bleeding using specific antidotes. It is very important to understand the mechanism of action of dabigatran, and to realize that there is no antidote. Recombinant factor VIIa is a potent hemostatic agent, and there are many published case reports and case series highlighting its efficacy in preventing bleeding.^6–12 It is used when all other options are exhausted. It is never a routine practice: it is always a last resort a clinician takes to prevent catastrophic bleeding. We believe economic concerns are very important, but it will be difficult to extrapolate a specific benchmark while treating for an individual case. At present, it seems unlikely that a randomized trial of recombinant factor VIIa will be conducted, and guidance is to be based on available animal studies and clinical anecdotes. A recent review on reversing anticoagulation therapy¹³ proposes treating major bleeding complications of direct thrombin inhibitors with activated prothrombin complex and recombinant factor VIIa.¹³

We acknowledge that serious, even fatal bleeding events have been reported with dabigatran. The FDA is evaluating postmarketing reports and is also using an active surveillance system to compare new users of dabigatran and warfarin with respect to the likelihood of their being hospitalized for bleeding.¹ With time and experience, we will learn more.

Finally, as with any new drug, the absence of data on long-term safety and efficacy is an important issue and should be considered when prescribing this new medication.

In Reply: Dabigatran has gained significant popularity in the United States. From its approval in October 2010 and through August 2011, approximately 1.1 million prescriptions for it were dispensed, and 371,000 patients received it from US outpatient retail pharmacies.¹ We appreciate the letters from Drs. Pazmiño and Hirsch and believe there are reasons to be vigilant when using dabigatran.

In response to the letter from Dr. Pazmiño, we agree with his concerns and have covered them in our review. We would like to emphasize that our review was intended to help US clinicians understand this new drug and was not restricted to the RE-LY trial. The limitations of the trials of dabigatran to date (including the lack of patients with renal impairment in the RE-LY trial) have been mentioned in many articles, including ours. Please see the section TOPICS OF FUTURE INTEREST.²

The FDA did not recommend any dose adjustment for patients with moderate renal impairment (creatinine clearance 30–50 mL/min), as it was convinced that the 150-mg dose had a superior risk-benefit profile, even for patients with a higher risk of bleeding, compared with the 110-mg dose.³ It is hard for us to comment on the specific reasoning behind the FDA’s approval for using 75 mg of dabigatran in patients with creatinine clearance between 15 and 30 mL/min. However, we know this was based on pharmacokinetic and pharmacodynamic modeling and not on efficacy and safety data.³ With respect to dosing and monitoring, we did stress this point in our article, stating that the use of dabigatran obviates the need for routine laboratory monitoring. However, one may measure the drug’s activity in certain situations (suspected overdose, bleeding, need for emergency surgery, impaired renal function, pregnancy, and obesity, and in children). Please see the section DOES DABIGATRAN NEED MONITORING? CAN IT EVEN BE MONITORED? in our review.²

Dr. Pazmiño suggests renal, hematologic and hepatic variables should be monitored before and after starting dabigatran. We agree that renal function should be monitored and have covered this point. Please see the section WHO SHOULD NOT RECEIVE DABIGATRAN.² Hematologic and hepatic variables can be monitored if a clinician decides to do so, but this is not limited specifically to dabigatran. Also, to clarify, dabigatran is not approved for those with stage 5 chronic kidney disease. And we share his concern about the lack of experience with this new drug, and we included a word of caution in the section ADVANTAGES AND DISADVANTAGES OF DABIGATRAN.²

We agree with Dr. Hirsch’s concerns about recombinant factor VIIa. We are not recommending its use as a routine practice but as an available option. Our article was a global review on dabigatran, and our aim was to cover the best available evidence and treatment options in a comprehensive way. However, in response to Dr. Hirsch’s comments, the systematic review by Yank et al⁴ drew its data from 16 randomized controlled trials but excluded patients on anticoagulants (except for those in a few observational studies), and factor VIIa was compared with placebo.⁴ So these findings are not applicable to patients with dabigatran-related bleeding, and to draw any definite conclusion would not be correct. If recombinant factor VIIa has failed to show a benefit in terms of a lower mortality rate, we could also point out that there was no mortality benefit seen in reversing warfarin anticoagulation in patients with acute intracranial hemorrhage with the use of vitamin K, fresh-frozen plasma, or prothrombin complex concentrate.⁵ This should not lead one to stop using these treatments.

Clinicians are well accustomed to managing warfarin- or heparin-related bleeding using specific antidotes. It is very important to understand the mechanism of action of dabigatran, and to realize that there is no antidote. Recombinant factor VIIa is a potent hemostatic agent, and there are many published case reports and case series highlighting its efficacy in preventing bleeding.^6–12 It is used when all other options are exhausted. It is never a routine practice: it is always a last resort a clinician takes to prevent catastrophic bleeding. We believe economic concerns are very important, but it will be difficult to extrapolate a specific benchmark while treating for an individual case. At present, it seems unlikely that a randomized trial of recombinant factor VIIa will be conducted, and guidance is to be based on available animal studies and clinical anecdotes. A recent review on reversing anticoagulation therapy¹³ proposes treating major bleeding complications of direct thrombin inhibitors with activated prothrombin complex and recombinant factor VIIa.¹³

We acknowledge that serious, even fatal bleeding events have been reported with dabigatran. The FDA is evaluating postmarketing reports and is also using an active surveillance system to compare new users of dabigatran and warfarin with respect to the likelihood of their being hospitalized for bleeding.¹ With time and experience, we will learn more.

Finally, as with any new drug, the absence of data on long-term safety and efficacy is an important issue and should be considered when prescribing this new medication.

In Reply: Dabigatran has gained significant popularity in the United States. From its approval in October 2010 and through August 2011, approximately 1.1 million prescriptions for it were dispensed, and 371,000 patients received it from US outpatient retail pharmacies.¹ We appreciate the letters from Drs. Pazmiño and Hirsch and believe there are reasons to be vigilant when using dabigatran.

In response to the letter from Dr. Pazmiño, we agree with his concerns and have covered them in our review. We would like to emphasize that our review was intended to help US clinicians understand this new drug and was not restricted to the RE-LY trial. The limitations of the trials of dabigatran to date (including the lack of patients with renal impairment in the RE-LY trial) have been mentioned in many articles, including ours. Please see the section TOPICS OF FUTURE INTEREST.²

The FDA did not recommend any dose adjustment for patients with moderate renal impairment (creatinine clearance 30–50 mL/min), as it was convinced that the 150-mg dose had a superior risk-benefit profile, even for patients with a higher risk of bleeding, compared with the 110-mg dose.³ It is hard for us to comment on the specific reasoning behind the FDA’s approval for using 75 mg of dabigatran in patients with creatinine clearance between 15 and 30 mL/min. However, we know this was based on pharmacokinetic and pharmacodynamic modeling and not on efficacy and safety data.³ With respect to dosing and monitoring, we did stress this point in our article, stating that the use of dabigatran obviates the need for routine laboratory monitoring. However, one may measure the drug’s activity in certain situations (suspected overdose, bleeding, need for emergency surgery, impaired renal function, pregnancy, and obesity, and in children). Please see the section DOES DABIGATRAN NEED MONITORING? CAN IT EVEN BE MONITORED? in our review.²

Dr. Pazmiño suggests renal, hematologic and hepatic variables should be monitored before and after starting dabigatran. We agree that renal function should be monitored and have covered this point. Please see the section WHO SHOULD NOT RECEIVE DABIGATRAN.² Hematologic and hepatic variables can be monitored if a clinician decides to do so, but this is not limited specifically to dabigatran. Also, to clarify, dabigatran is not approved for those with stage 5 chronic kidney disease. And we share his concern about the lack of experience with this new drug, and we included a word of caution in the section ADVANTAGES AND DISADVANTAGES OF DABIGATRAN.²

We agree with Dr. Hirsch’s concerns about recombinant factor VIIa. We are not recommending its use as a routine practice but as an available option. Our article was a global review on dabigatran, and our aim was to cover the best available evidence and treatment options in a comprehensive way. However, in response to Dr. Hirsch’s comments, the systematic review by Yank et al⁴ drew its data from 16 randomized controlled trials but excluded patients on anticoagulants (except for those in a few observational studies), and factor VIIa was compared with placebo.⁴ So these findings are not applicable to patients with dabigatran-related bleeding, and to draw any definite conclusion would not be correct. If recombinant factor VIIa has failed to show a benefit in terms of a lower mortality rate, we could also point out that there was no mortality benefit seen in reversing warfarin anticoagulation in patients with acute intracranial hemorrhage with the use of vitamin K, fresh-frozen plasma, or prothrombin complex concentrate.⁵ This should not lead one to stop using these treatments.

Clinicians are well accustomed to managing warfarin- or heparin-related bleeding using specific antidotes. It is very important to understand the mechanism of action of dabigatran, and to realize that there is no antidote. Recombinant factor VIIa is a potent hemostatic agent, and there are many published case reports and case series highlighting its efficacy in preventing bleeding.^6–12 It is used when all other options are exhausted. It is never a routine practice: it is always a last resort a clinician takes to prevent catastrophic bleeding. We believe economic concerns are very important, but it will be difficult to extrapolate a specific benchmark while treating for an individual case. At present, it seems unlikely that a randomized trial of recombinant factor VIIa will be conducted, and guidance is to be based on available animal studies and clinical anecdotes. A recent review on reversing anticoagulation therapy¹³ proposes treating major bleeding complications of direct thrombin inhibitors with activated prothrombin complex and recombinant factor VIIa.¹³

We acknowledge that serious, even fatal bleeding events have been reported with dabigatran. The FDA is evaluating postmarketing reports and is also using an active surveillance system to compare new users of dabigatran and warfarin with respect to the likelihood of their being hospitalized for bleeding.¹ With time and experience, we will learn more.

Finally, as with any new drug, the absence of data on long-term safety and efficacy is an important issue and should be considered when prescribing this new medication.

Myelofibrosis

Ruxolitinib can ease the symptoms of myelofibrosis and improve patient survival, according to results of the COMFORT-I study.

Detailed data from this phase 3 trial, which led to the US approval of ruxolitinib in November, appear in the March 1 edition of The New England Journal of Medicine. Some of these data were also presented at the recent ASH meeting.

“The phase 1/2 clinical trial showed that ruxolitinib improves quality of life for many patients with myelofibrosis, and now this phase 3 study indicates that the drug extends survival in a patient population that has lacked effective treatments,” said principal investigator Srdan Verstovsek, MD, PhD, of The University of Texas MD Anderson Cancer Center.

The trial, which was funded by the maker of ruxolitinib, enrolled 309 patients from 89 US centers. The researchers randomized patients to receive ruxolitinib (n=155) or placebo (n=154) orally twice daily.

Patients recorded their symptoms over the course of the 24-week study using an electronic diary. And the investigators monitored patients’ spleen volumes via MRI. The primary endpoint of the study was a 35% reduction in spleen volume.

Most patients on placebo experienced progressive splenomegaly and a worsening of myelofibrosis-related symptoms. For this reason, 38 patients in the placebo arm withdrew from the study, and 111 patients crossed over to the ruxolitinib arm.

The median time to cross over was 41 weeks. Only 2 patients remained on placebo at the time of analysis.

Reduction in splenomegaly

“It quickly became apparent who was getting the placebo and who was getting the drug,” said study author Jason Gotlib, MD, of Stanford University Medical Center.

Dr Gotlib noted that the spleen volume in patients receiving the drug began to decrease within 1 to 2 weeks. In fact, 41.9% of treated patients experienced at least 35% shrinkage in their spleen volume. And the spleen remained smaller in 67% of those responders for 48 weeks or longer.

In comparison, 0.7% of patients in the placebo group experienced spleen reduction by 35%. At week 24, the ruxolitinib group had an average reduction in spleen volume of 31.6%, while the placebo group experienced an average increase in spleen volume of 8.1%.

Symptom improvement

Every night, patients completed the Myelofibrosis Symptom Assessment Form, an electronic diary. They evaluated the intensity of night sweats, itching, abdominal discomfort, pain under the ribs on the left side, a feeling of fullness, muscle and bone pain, and inactivity.

In the treated group, 45.9% of patients reported a reduction of 50% or more in their total symptom score over 24 weeks, compared to 5.3% in the placebo group. In addition, treated patients gained weight, while patients in the placebo group lost weight.

Improvements usually occurred within the first 4 weeks of treatment and were not limited to patients who also experienced reduction in spleen size, Dr Verstovsek said.

Adverse events and other drawbacks

Nonhematologic adverse events occurred at similar rates in both treatment arms. And roughly 11% of patients in each arm withdrew from the study due to adverse events.

However, anemia and thrombocytopenia were more common among patients who received ruxolitinib. One patient discontinued the drug due to anemia and one due to thrombocytopenia.

Other shortcomings of the drug are that it failed to reverse bone marrow damage and did not have a lasting effect on splenomegaly. Although many patients maintained a smaller spleen volume for at least 48 weeks while on ruxolitinib, their spleens began to enlarge again if they stopped taking the drug.

“Ruxolitinib doesn’t cure the disease,” Dr Gotlib said. “But the degree of benefit is clinically meaningful and substantial and allows many patients to re-engage in their daily activities.”

Mysteries of survival and mechanism

At a median follow-up of 51 weeks, there had been 13 deaths (8.4%) in the ruxolitinib group, compared with 24 (15.7%) in the placebo group. This represents a nearly 50% reduction in mortality, but Dr Gotlib indicated that the long-term implications of these data are not clear.

Another puzzler is how, exactly, ruxolitinib works. The drug is an inhibitor of JAK1 and JAK2, but patients responded to the drug whether or not they had the JAK2^V617F mutation.

“Ruxolitinib is inhibiting overactive JAK/STAT intracellular signaling pathway no matter what,” Dr Verstovsek said.

Myelofibrosis

Ruxolitinib can ease the symptoms of myelofibrosis and improve patient survival, according to results of the COMFORT-I study.

Detailed data from this phase 3 trial, which led to the US approval of ruxolitinib in November, appear in the March 1 edition of The New England Journal of Medicine. Some of these data were also presented at the recent ASH meeting.

“The phase 1/2 clinical trial showed that ruxolitinib improves quality of life for many patients with myelofibrosis, and now this phase 3 study indicates that the drug extends survival in a patient population that has lacked effective treatments,” said principal investigator Srdan Verstovsek, MD, PhD, of The University of Texas MD Anderson Cancer Center.

The trial, which was funded by the maker of ruxolitinib, enrolled 309 patients from 89 US centers. The researchers randomized patients to receive ruxolitinib (n=155) or placebo (n=154) orally twice daily.

Patients recorded their symptoms over the course of the 24-week study using an electronic diary. And the investigators monitored patients’ spleen volumes via MRI. The primary endpoint of the study was a 35% reduction in spleen volume.

Most patients on placebo experienced progressive splenomegaly and a worsening of myelofibrosis-related symptoms. For this reason, 38 patients in the placebo arm withdrew from the study, and 111 patients crossed over to the ruxolitinib arm.

The median time to cross over was 41 weeks. Only 2 patients remained on placebo at the time of analysis.

Reduction in splenomegaly

“It quickly became apparent who was getting the placebo and who was getting the drug,” said study author Jason Gotlib, MD, of Stanford University Medical Center.

Dr Gotlib noted that the spleen volume in patients receiving the drug began to decrease within 1 to 2 weeks. In fact, 41.9% of treated patients experienced at least 35% shrinkage in their spleen volume. And the spleen remained smaller in 67% of those responders for 48 weeks or longer.

In comparison, 0.7% of patients in the placebo group experienced spleen reduction by 35%. At week 24, the ruxolitinib group had an average reduction in spleen volume of 31.6%, while the placebo group experienced an average increase in spleen volume of 8.1%.

Symptom improvement

Every night, patients completed the Myelofibrosis Symptom Assessment Form, an electronic diary. They evaluated the intensity of night sweats, itching, abdominal discomfort, pain under the ribs on the left side, a feeling of fullness, muscle and bone pain, and inactivity.

In the treated group, 45.9% of patients reported a reduction of 50% or more in their total symptom score over 24 weeks, compared to 5.3% in the placebo group. In addition, treated patients gained weight, while patients in the placebo group lost weight.

Improvements usually occurred within the first 4 weeks of treatment and were not limited to patients who also experienced reduction in spleen size, Dr Verstovsek said.

Adverse events and other drawbacks

Nonhematologic adverse events occurred at similar rates in both treatment arms. And roughly 11% of patients in each arm withdrew from the study due to adverse events.

However, anemia and thrombocytopenia were more common among patients who received ruxolitinib. One patient discontinued the drug due to anemia and one due to thrombocytopenia.

Other shortcomings of the drug are that it failed to reverse bone marrow damage and did not have a lasting effect on splenomegaly. Although many patients maintained a smaller spleen volume for at least 48 weeks while on ruxolitinib, their spleens began to enlarge again if they stopped taking the drug.

“Ruxolitinib doesn’t cure the disease,” Dr Gotlib said. “But the degree of benefit is clinically meaningful and substantial and allows many patients to re-engage in their daily activities.”

Mysteries of survival and mechanism

At a median follow-up of 51 weeks, there had been 13 deaths (8.4%) in the ruxolitinib group, compared with 24 (15.7%) in the placebo group. This represents a nearly 50% reduction in mortality, but Dr Gotlib indicated that the long-term implications of these data are not clear.

Another puzzler is how, exactly, ruxolitinib works. The drug is an inhibitor of JAK1 and JAK2, but patients responded to the drug whether or not they had the JAK2^V617F mutation.

“Ruxolitinib is inhibiting overactive JAK/STAT intracellular signaling pathway no matter what,” Dr Verstovsek said.

Myelofibrosis

Ruxolitinib can ease the symptoms of myelofibrosis and improve patient survival, according to results of the COMFORT-I study.

Detailed data from this phase 3 trial, which led to the US approval of ruxolitinib in November, appear in the March 1 edition of The New England Journal of Medicine. Some of these data were also presented at the recent ASH meeting.

“The phase 1/2 clinical trial showed that ruxolitinib improves quality of life for many patients with myelofibrosis, and now this phase 3 study indicates that the drug extends survival in a patient population that has lacked effective treatments,” said principal investigator Srdan Verstovsek, MD, PhD, of The University of Texas MD Anderson Cancer Center.

The trial, which was funded by the maker of ruxolitinib, enrolled 309 patients from 89 US centers. The researchers randomized patients to receive ruxolitinib (n=155) or placebo (n=154) orally twice daily.

Patients recorded their symptoms over the course of the 24-week study using an electronic diary. And the investigators monitored patients’ spleen volumes via MRI. The primary endpoint of the study was a 35% reduction in spleen volume.

Most patients on placebo experienced progressive splenomegaly and a worsening of myelofibrosis-related symptoms. For this reason, 38 patients in the placebo arm withdrew from the study, and 111 patients crossed over to the ruxolitinib arm.

The median time to cross over was 41 weeks. Only 2 patients remained on placebo at the time of analysis.

Reduction in splenomegaly

“It quickly became apparent who was getting the placebo and who was getting the drug,” said study author Jason Gotlib, MD, of Stanford University Medical Center.

Dr Gotlib noted that the spleen volume in patients receiving the drug began to decrease within 1 to 2 weeks. In fact, 41.9% of treated patients experienced at least 35% shrinkage in their spleen volume. And the spleen remained smaller in 67% of those responders for 48 weeks or longer.

In comparison, 0.7% of patients in the placebo group experienced spleen reduction by 35%. At week 24, the ruxolitinib group had an average reduction in spleen volume of 31.6%, while the placebo group experienced an average increase in spleen volume of 8.1%.

Symptom improvement

Every night, patients completed the Myelofibrosis Symptom Assessment Form, an electronic diary. They evaluated the intensity of night sweats, itching, abdominal discomfort, pain under the ribs on the left side, a feeling of fullness, muscle and bone pain, and inactivity.

In the treated group, 45.9% of patients reported a reduction of 50% or more in their total symptom score over 24 weeks, compared to 5.3% in the placebo group. In addition, treated patients gained weight, while patients in the placebo group lost weight.

Improvements usually occurred within the first 4 weeks of treatment and were not limited to patients who also experienced reduction in spleen size, Dr Verstovsek said.

Adverse events and other drawbacks

Nonhematologic adverse events occurred at similar rates in both treatment arms. And roughly 11% of patients in each arm withdrew from the study due to adverse events.

However, anemia and thrombocytopenia were more common among patients who received ruxolitinib. One patient discontinued the drug due to anemia and one due to thrombocytopenia.

Other shortcomings of the drug are that it failed to reverse bone marrow damage and did not have a lasting effect on splenomegaly. Although many patients maintained a smaller spleen volume for at least 48 weeks while on ruxolitinib, their spleens began to enlarge again if they stopped taking the drug.

“Ruxolitinib doesn’t cure the disease,” Dr Gotlib said. “But the degree of benefit is clinically meaningful and substantial and allows many patients to re-engage in their daily activities.”

Mysteries of survival and mechanism

At a median follow-up of 51 weeks, there had been 13 deaths (8.4%) in the ruxolitinib group, compared with 24 (15.7%) in the placebo group. This represents a nearly 50% reduction in mortality, but Dr Gotlib indicated that the long-term implications of these data are not clear.

Another puzzler is how, exactly, ruxolitinib works. The drug is an inhibitor of JAK1 and JAK2, but patients responded to the drug whether or not they had the JAK2^V617F mutation.

“Ruxolitinib is inhibiting overactive JAK/STAT intracellular signaling pathway no matter what,” Dr Verstovsek said.

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

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

A MAJOR PUBLIC HEALTH PROBLEM

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

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

CURRENTLY, FEWER THAN 50% OF PATIENTS ARE CURED

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

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

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

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

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

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

PROTEASE INHIBITORS: MECHANISM OF ACTION

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

Protease inhibitors are prone to resistance

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

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

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

BOCEPREVIR

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Side effects of boceprevir

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

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

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

TELAPREVIR

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

Telaprevir in previously untreated patients with HCV genotype 1

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

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

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

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

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

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

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

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

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

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

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

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

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

Telaprevir side effects

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

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

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

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

FDA-APPROVED TREATMENT REGIMENS FOR BOCEPREVIR AND TELAPREVIR

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

Boceprevir in previously untreated patients

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

Boceprevir in previously treated patients

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

Telaprevir in previously untreated patients and prior relapsers

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

Telaprevir in patients who previously achieved a partial or null response

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

Drug interactions with boceprevir and telaprevir

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

EMERGING THERAPIES FOR HCV

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

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

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

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

FUTURE PERSPECTIVES

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

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

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

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

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

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

A MAJOR PUBLIC HEALTH PROBLEM

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

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

CURRENTLY, FEWER THAN 50% OF PATIENTS ARE CURED

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

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

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

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

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

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

PROTEASE INHIBITORS: MECHANISM OF ACTION

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

Protease inhibitors are prone to resistance

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

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

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

BOCEPREVIR

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Side effects of boceprevir

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

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

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

TELAPREVIR

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

Telaprevir in previously untreated patients with HCV genotype 1

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

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

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

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

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

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

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

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

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

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

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

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

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

Telaprevir side effects

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

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

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

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

FDA-APPROVED TREATMENT REGIMENS FOR BOCEPREVIR AND TELAPREVIR

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

Boceprevir in previously untreated patients

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

Boceprevir in previously treated patients

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

Telaprevir in previously untreated patients and prior relapsers

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

Telaprevir in patients who previously achieved a partial or null response

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

Drug interactions with boceprevir and telaprevir

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

EMERGING THERAPIES FOR HCV

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

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

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

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

FUTURE PERSPECTIVES

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

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

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

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

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

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

A MAJOR PUBLIC HEALTH PROBLEM

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

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

CURRENTLY, FEWER THAN 50% OF PATIENTS ARE CURED

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

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

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

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

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

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

PROTEASE INHIBITORS: MECHANISM OF ACTION

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

Protease inhibitors are prone to resistance

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

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

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

BOCEPREVIR

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Side effects of boceprevir

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

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

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

TELAPREVIR

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

Telaprevir in previously untreated patients with HCV genotype 1

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

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

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

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

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

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

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

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

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

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

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

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

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

Telaprevir side effects

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

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

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

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

FDA-APPROVED TREATMENT REGIMENS FOR BOCEPREVIR AND TELAPREVIR

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

Boceprevir in previously untreated patients

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

Boceprevir in previously treated patients

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

Telaprevir in previously untreated patients and prior relapsers

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

Telaprevir in patients who previously achieved a partial or null response

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

Drug interactions with boceprevir and telaprevir

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

EMERGING THERAPIES FOR HCV

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

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

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

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

FUTURE PERSPECTIVES

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

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

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

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

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

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

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

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

HALF OF ALL PREGNANCIES ARE UNPLANNED

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

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

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

WHAT’S NEW IN CONTRACEPTION?

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

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

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

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

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

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

CASE 1: CONTRACEPTION IN PERIMENOPAUSE

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

A variety of hormonal options

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

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

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

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

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

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

CASE 2: THROMBOPHILIA

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

She desires contraception. How do you counsel her?

Estrogens are contraindicated—except, perhaps, in select cases

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

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

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

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

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

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

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

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

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

CASE 3: FUTURE FERTILITY

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

Many options; also consider folic acid

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

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

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

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

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

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

CASE 4: PSYCHIATRIC ILLNESS

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

Possible interactions with psychiatric drugs

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

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

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

The Pearl index, a measure of contraceptive efficacy

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

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

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

CASE 5: HYPERTENSION

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

Avoid estrogen-containing products

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

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

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

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

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

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

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

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

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

HALF OF ALL PREGNANCIES ARE UNPLANNED

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

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

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

WHAT’S NEW IN CONTRACEPTION?

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

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

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

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

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

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

CASE 1: CONTRACEPTION IN PERIMENOPAUSE

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

A variety of hormonal options

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

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

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

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

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

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

CASE 2: THROMBOPHILIA

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

She desires contraception. How do you counsel her?

Estrogens are contraindicated—except, perhaps, in select cases

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

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

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

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

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

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

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

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

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

CASE 3: FUTURE FERTILITY

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

Many options; also consider folic acid

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

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

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

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

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

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

CASE 4: PSYCHIATRIC ILLNESS

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

Possible interactions with psychiatric drugs

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

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

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

The Pearl index, a measure of contraceptive efficacy

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

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

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

CASE 5: HYPERTENSION

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

Avoid estrogen-containing products

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

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

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

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

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

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

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

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

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

HALF OF ALL PREGNANCIES ARE UNPLANNED

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

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

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

WHAT’S NEW IN CONTRACEPTION?

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

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

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

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

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

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

CASE 1: CONTRACEPTION IN PERIMENOPAUSE

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

A variety of hormonal options

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

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

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

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

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

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

CASE 2: THROMBOPHILIA

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

She desires contraception. How do you counsel her?

Estrogens are contraindicated—except, perhaps, in select cases

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

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

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

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

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

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

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

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

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

CASE 3: FUTURE FERTILITY

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

Many options; also consider folic acid

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

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

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

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

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

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

CASE 4: PSYCHIATRIC ILLNESS

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

Possible interactions with psychiatric drugs

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

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

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

The Pearl index, a measure of contraceptive efficacy

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

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

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

CASE 5: HYPERTENSION

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

Avoid estrogen-containing products

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

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

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

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

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

Endoscopic ultrasonography (EUS) is a minimally invasive test that provides high-resolution imaging of the pancreas.^1,2 As such, it is proving useful.

Accurate diagnosis and timely intervention are essential in managing acute and chronic pancreatitis, which are often encountered in the clinic and the hospital. However, the cause of acute pancreatitis is not always easy to determine. Furthermore, recurrent bouts can progress to chronic pancreatitis if the cause is not identified and eliminated. EUS has been studied extensively in the evaluation of both acute and chronic pancreatitis, as it can identify obstructive and biliary causes of acute pancreatitis and early structural features of chronic pancreatitis.

This article will review the indications and evidence for EUS in the evaluation of acute and chronic pancreatitis.

SPECIALIZED TRAINING REQUIRED

EUS involves passage of a specialized endoscope through the esophagus and stomach and into the duodenum. The scope has a very small ultrasound probe at the tip, allowing detailed imaging of the upper gastrointestinal tract and surrounding organs.

There are two types of EUS endoscope: radial and linear. A radial scope provides a 360° range of view perpendicular to the long axis of the scope. A linear scope provides a 150° view parallel to the long axis of the scope. Many endosonographers favor linear EUS for imaging the pancreas because it permits fine-needle aspiration biopsy of masses, cysts, and lymph nodes.

Specialized training beyond the gastroenterology fellowship is usually required to become proficient in performing EUS, in recognizing the anatomy it reveals, and in performing fine-needle aspiration biopsy.

ENDOSCOPIC ULTRASONOGRAPHY IN ACUTE PANCREATITIS

Finding the cause of acute pancreatitis can be challenging in patients who do not have typical risk factors, eg, those who do not drink substantial amounts of alcohol and in whom transabdominal ultrasonography fails to reveal gallstones.

Several studies have evaluated the role of EUS in recurrent “idiopathic” pancreatitis.^3–5 Causes of acute pancreatitis detectable with EUS included gallbladder and bile duct microlithiasis (stones smaller than 3 mm), cysts, intraductal papillary mucinous neoplasms, ampullary neoplasms, pancreas divisum, and pancreatic masses.

Stones, sludge. Transabdominal ultrasonography is often performed in the workup of acute pancreatitis to rule out gallbladder stones and biliary dilation. Unfortunately, it does a poor job of imaging the distal common bile duct, where culprit stones may reside.

EUS provides a high-quality view of the bile duct from the ampulla of Vater to the region of the hepatic hilum and is safer than endoscopic retrograde cholangiopancreatography (ERCP). The available evidence supports the use of EUS as a diagnostic test for bile duct stones.^3–7 In fact, using ERCP as the reference standard, EUS has been found to be more sensitive than transabdominal ultrasonography for bile duct stones.⁴

The yield of EUS for finding biliary sludge and stones may be high in patients with unexplained pancreatitis. EUS detected sludge, microlithiasis, or both in 33 of 35 patients with idiopathic acute pancreatitis who underwent transabdominal ultrasonography with negative results.⁸ Furthermore, most were symptom-free at an average of 10 months after cholecystectomy, suggesting that microlithiasis was the cause of the “idiopathic” pancreatitis.

EUS can also decrease the number of unnecessary ERCP procedures in patients with suspected biliary pancreatitis. In these patients, EUS can be performed as an initial diagnostic test to exclude retained biliary stones. If a stone is present, the endoscopist can proceed to ERCP for sphincterotomy and stone removal during the same endoscopic session. If EUS is negative, the endoscopy can be concluded without cannulating the bile duct and putting the patient at risk of acute pancreatitis. In one report, this approach eliminated the need for ERCP in five of six patients with suspected biliary pancreatitis.⁶

Tumors and other causes of bile duct obstruction can also cause recurrent acute pancreatitis and may be difficult to detect with cross-sectional imaging. EUS, on the other hand, can detect small pancreatic masses (< 2 cm), which may be missed by conventional computed tomography. Also, a linear EUS scope, with its forward oblique view, can image the duodenum and ampulla, where obstructing inflammation, tumors, and polyps may be found. One should strongly suspect occult malignancy in elderly patients with unexplained acute pancreatitis. In those patients, repeat imaging with high-resolution dual-phase computed tomography or with EUS should be considered after a few weeks once the acute inflammation resolves.

Pancreas divisum is a relatively common congenital abnormality in which the dorsal and ventral pancreatic ducts do not properly fuse during embryonic development. To rule out pancreas divisum, the endosonographer must carefully trace the pancreatic duct from the dorsal pancreas into the ventral pancreas, where it connects with the bile duct at the duodenal wall.

In summary, EUS appears to be safe and accurate for diagnosing bile duct stones and other structural causes of idiopathic acute pancreatitis.

ENDOSCOPIC ULTRASONOGRAPHY IN CHRONIC PANCREATITIS

Chronic pancreatitis, a relatively common and sometimes debilitating cause of chronic upper abdominal pain, may be difficult to diagnose using noninvasive imaging tests. Minimal-change chronic pancreatitis is defined as a syndrome of pancreatic abdominal pain with no or slight structural changes detected on imaging but with histologic inflammation and fibrosis diagnostic of chronic pancreatitis.⁹

A clinical rationale for trying to detect chronic pancreatitis early in its course is that interventions can be started earlier. These include abstinence from alcohol, giving exogenous pancreatic enzymes, and advanced interventions such as celiac plexus blocks for pain control. Some patients may even benefit from resection of the pancreas if pain is severe and resistant to conservative measures.

EUS can detect both parenchymal and ductal changes that correlate with histologic fibrosis.¹⁰ Parenchymal changes include hyperechoic foci, hyperechoic strands, lobularity, cysts, and shadowing calcifications. Ductal changes include dilation of the main pancreatic duct, irregularity, hyperechoic duct margins, and visible side branches.

Several studies have evaluated the ability of EUS to diagnose early chronic pancreatitis.^9,11–15 Reference standards used to determine the accuracy of EUS have included histology,^10,16–18 pancreatic function testing,^19–22 and ERCP.^11,15,23,24

The best diagnostic test may be pancreatic histology. However, biopsy of the pancreas is impractical and exposes patients to high risk. In addition, the patchy and focal distribution of histologic changes may decrease its reliability. Fortunately, the histologic findings of fibrosis have been shown to correlate with EUS criteria in patients undergoing EUS before surgical resection in three recent studies.^16–18 A threshold of four or more criteria out of a possible nine was found to provide the optimal sensitivity and specificity for histologic pancreatic fibrosis.^16,17 The criteria used were four parenchymal features (hyperechoic foci, strands, hypoechoic lobules, cysts) and five ductal features (irregularity of the main pancreatic duct, dilation, hyperechoic duct walls, visible side branches, and calcifications or stones).

EUS is sensitive for chronic pancreatitis, but ‘true’ accuracy is impossible to know

Unfortunately, greater sensitivity may come at the expense of worse specificity. Certain demographic variables may alter the EUS appearance of the pancreas. A multivariate analysis²⁵ found several variables that predicted abnormalities on EUS even in the absence of clinically evident pancreatitis; the strongest were heavy ethanol use (odds ratio [OR] 5.1, 95% confidence interval [CI] 3.1–8.5), male sex (OR 1.8, 95% CI 1.3–2.55), clinical suspicion of pancreatic disease (OR 1.7, 95% CI 1.2–2.3), and heavy smoking (OR 1.7, 95% CI 1.2–2.4). More prospective studies are needed to further differentiate true disease from false-positive findings of chronic pancreatitis.

Also, traditional EUS scoring symptoms have counted features in an unweighted fashion and assigned an arbitrary cut point (eg, four or more features) for diagnosis. This approach fails to account for the greater importance of some features (eg, calcifications) compared with others.

Interobserver variability is another important limitation of EUS in diagnosing chronic pancreatitis.^26,27 In one multicenter study of EUS interpretation, the overall kappa (agreement beyond chance) was only 0.45 for overall chronic pancreatitis diagnosis and worse for many individual criteria for chronic pancreatitis. The endosonographers disagreed most about hyperechoic strands and foci, main pancreatic duct irregularity, and visible side branches (kappa < 0.4).

The Rosemont classification

These limitations led a group of experts to meet in Chicago, IL, to develop a consensus-based and weighted EUS scoring system for the diagnosis of chronic pancreatitis, termed the Rosemont classification.

In this system, the previous parenchymal and ductal features are assigned stricter definitions and reclassified as major and minor criteria. Based on the presence of major and minor features, EUS results are stratified as “normal,” “indeterminate for chronic pancreatitis,” “suggestive of chronic pancreatitis,” or “most consistent with chronic pancreatitis.”^15,28

Further validation of this scoring system is needed before it can be used widely.

ENDOSCOPIC ULTRASONOGRAPHY PLUS PANCREATIC FUNCTION TESTING

The best way to diagnose minimal-change chronic pancreatitis may be a combination of sensitive structural and functional testing. Although clinically apparent steatorrhea typically occurs late in the course of chronic pancreatitis, mild exocrine insufficiency may occur early and is detectable with hormone-stimulated pancreatic function testing. Therefore, pancreatic function tests are considered sensitive for diagnosing chronic pancreatitis.^20,21,29

Endoscopic pancreatic function testing involves injecting secretin intravenously and then collecting duodenal aspirates through the endoscope. The duodenal fluid is analyzed for bicarbonate concentration as a measure of exocrine function.²⁹

We have studied combined EUS and endoscopic pancreatic function testing in the diagnosis of chronic pancreatitis.¹⁶ The combination gives a simultaneous structural and functional assessment of the pancreas and may optimize sensitivity for detecting minimal-change chronic pancreatitis. In a small study, we found the combination had 100% sensitivity for noncalcific chronic pancreatitis compared with a histologic reference standard.¹⁶

Endoscopic ultrasonography (EUS) is a minimally invasive test that provides high-resolution imaging of the pancreas.^1,2 As such, it is proving useful.

Accurate diagnosis and timely intervention are essential in managing acute and chronic pancreatitis, which are often encountered in the clinic and the hospital. However, the cause of acute pancreatitis is not always easy to determine. Furthermore, recurrent bouts can progress to chronic pancreatitis if the cause is not identified and eliminated. EUS has been studied extensively in the evaluation of both acute and chronic pancreatitis, as it can identify obstructive and biliary causes of acute pancreatitis and early structural features of chronic pancreatitis.

This article will review the indications and evidence for EUS in the evaluation of acute and chronic pancreatitis.

SPECIALIZED TRAINING REQUIRED

EUS involves passage of a specialized endoscope through the esophagus and stomach and into the duodenum. The scope has a very small ultrasound probe at the tip, allowing detailed imaging of the upper gastrointestinal tract and surrounding organs.

There are two types of EUS endoscope: radial and linear. A radial scope provides a 360° range of view perpendicular to the long axis of the scope. A linear scope provides a 150° view parallel to the long axis of the scope. Many endosonographers favor linear EUS for imaging the pancreas because it permits fine-needle aspiration biopsy of masses, cysts, and lymph nodes.

Specialized training beyond the gastroenterology fellowship is usually required to become proficient in performing EUS, in recognizing the anatomy it reveals, and in performing fine-needle aspiration biopsy.

ENDOSCOPIC ULTRASONOGRAPHY IN ACUTE PANCREATITIS

Finding the cause of acute pancreatitis can be challenging in patients who do not have typical risk factors, eg, those who do not drink substantial amounts of alcohol and in whom transabdominal ultrasonography fails to reveal gallstones.

Several studies have evaluated the role of EUS in recurrent “idiopathic” pancreatitis.^3–5 Causes of acute pancreatitis detectable with EUS included gallbladder and bile duct microlithiasis (stones smaller than 3 mm), cysts, intraductal papillary mucinous neoplasms, ampullary neoplasms, pancreas divisum, and pancreatic masses.

Stones, sludge. Transabdominal ultrasonography is often performed in the workup of acute pancreatitis to rule out gallbladder stones and biliary dilation. Unfortunately, it does a poor job of imaging the distal common bile duct, where culprit stones may reside.

EUS provides a high-quality view of the bile duct from the ampulla of Vater to the region of the hepatic hilum and is safer than endoscopic retrograde cholangiopancreatography (ERCP). The available evidence supports the use of EUS as a diagnostic test for bile duct stones.^3–7 In fact, using ERCP as the reference standard, EUS has been found to be more sensitive than transabdominal ultrasonography for bile duct stones.⁴

The yield of EUS for finding biliary sludge and stones may be high in patients with unexplained pancreatitis. EUS detected sludge, microlithiasis, or both in 33 of 35 patients with idiopathic acute pancreatitis who underwent transabdominal ultrasonography with negative results.⁸ Furthermore, most were symptom-free at an average of 10 months after cholecystectomy, suggesting that microlithiasis was the cause of the “idiopathic” pancreatitis.

EUS can also decrease the number of unnecessary ERCP procedures in patients with suspected biliary pancreatitis. In these patients, EUS can be performed as an initial diagnostic test to exclude retained biliary stones. If a stone is present, the endoscopist can proceed to ERCP for sphincterotomy and stone removal during the same endoscopic session. If EUS is negative, the endoscopy can be concluded without cannulating the bile duct and putting the patient at risk of acute pancreatitis. In one report, this approach eliminated the need for ERCP in five of six patients with suspected biliary pancreatitis.⁶

Tumors and other causes of bile duct obstruction can also cause recurrent acute pancreatitis and may be difficult to detect with cross-sectional imaging. EUS, on the other hand, can detect small pancreatic masses (< 2 cm), which may be missed by conventional computed tomography. Also, a linear EUS scope, with its forward oblique view, can image the duodenum and ampulla, where obstructing inflammation, tumors, and polyps may be found. One should strongly suspect occult malignancy in elderly patients with unexplained acute pancreatitis. In those patients, repeat imaging with high-resolution dual-phase computed tomography or with EUS should be considered after a few weeks once the acute inflammation resolves.

Pancreas divisum is a relatively common congenital abnormality in which the dorsal and ventral pancreatic ducts do not properly fuse during embryonic development. To rule out pancreas divisum, the endosonographer must carefully trace the pancreatic duct from the dorsal pancreas into the ventral pancreas, where it connects with the bile duct at the duodenal wall.

In summary, EUS appears to be safe and accurate for diagnosing bile duct stones and other structural causes of idiopathic acute pancreatitis.

ENDOSCOPIC ULTRASONOGRAPHY IN CHRONIC PANCREATITIS

Chronic pancreatitis, a relatively common and sometimes debilitating cause of chronic upper abdominal pain, may be difficult to diagnose using noninvasive imaging tests. Minimal-change chronic pancreatitis is defined as a syndrome of pancreatic abdominal pain with no or slight structural changes detected on imaging but with histologic inflammation and fibrosis diagnostic of chronic pancreatitis.⁹

A clinical rationale for trying to detect chronic pancreatitis early in its course is that interventions can be started earlier. These include abstinence from alcohol, giving exogenous pancreatic enzymes, and advanced interventions such as celiac plexus blocks for pain control. Some patients may even benefit from resection of the pancreas if pain is severe and resistant to conservative measures.

EUS can detect both parenchymal and ductal changes that correlate with histologic fibrosis.¹⁰ Parenchymal changes include hyperechoic foci, hyperechoic strands, lobularity, cysts, and shadowing calcifications. Ductal changes include dilation of the main pancreatic duct, irregularity, hyperechoic duct margins, and visible side branches.

Several studies have evaluated the ability of EUS to diagnose early chronic pancreatitis.^9,11–15 Reference standards used to determine the accuracy of EUS have included histology,^10,16–18 pancreatic function testing,^19–22 and ERCP.^11,15,23,24

The best diagnostic test may be pancreatic histology. However, biopsy of the pancreas is impractical and exposes patients to high risk. In addition, the patchy and focal distribution of histologic changes may decrease its reliability. Fortunately, the histologic findings of fibrosis have been shown to correlate with EUS criteria in patients undergoing EUS before surgical resection in three recent studies.^16–18 A threshold of four or more criteria out of a possible nine was found to provide the optimal sensitivity and specificity for histologic pancreatic fibrosis.^16,17 The criteria used were four parenchymal features (hyperechoic foci, strands, hypoechoic lobules, cysts) and five ductal features (irregularity of the main pancreatic duct, dilation, hyperechoic duct walls, visible side branches, and calcifications or stones).

EUS is sensitive for chronic pancreatitis, but ‘true’ accuracy is impossible to know

Unfortunately, greater sensitivity may come at the expense of worse specificity. Certain demographic variables may alter the EUS appearance of the pancreas. A multivariate analysis²⁵ found several variables that predicted abnormalities on EUS even in the absence of clinically evident pancreatitis; the strongest were heavy ethanol use (odds ratio [OR] 5.1, 95% confidence interval [CI] 3.1–8.5), male sex (OR 1.8, 95% CI 1.3–2.55), clinical suspicion of pancreatic disease (OR 1.7, 95% CI 1.2–2.3), and heavy smoking (OR 1.7, 95% CI 1.2–2.4). More prospective studies are needed to further differentiate true disease from false-positive findings of chronic pancreatitis.

Also, traditional EUS scoring symptoms have counted features in an unweighted fashion and assigned an arbitrary cut point (eg, four or more features) for diagnosis. This approach fails to account for the greater importance of some features (eg, calcifications) compared with others.

Interobserver variability is another important limitation of EUS in diagnosing chronic pancreatitis.^26,27 In one multicenter study of EUS interpretation, the overall kappa (agreement beyond chance) was only 0.45 for overall chronic pancreatitis diagnosis and worse for many individual criteria for chronic pancreatitis. The endosonographers disagreed most about hyperechoic strands and foci, main pancreatic duct irregularity, and visible side branches (kappa < 0.4).

The Rosemont classification

These limitations led a group of experts to meet in Chicago, IL, to develop a consensus-based and weighted EUS scoring system for the diagnosis of chronic pancreatitis, termed the Rosemont classification.

In this system, the previous parenchymal and ductal features are assigned stricter definitions and reclassified as major and minor criteria. Based on the presence of major and minor features, EUS results are stratified as “normal,” “indeterminate for chronic pancreatitis,” “suggestive of chronic pancreatitis,” or “most consistent with chronic pancreatitis.”^15,28

Further validation of this scoring system is needed before it can be used widely.

ENDOSCOPIC ULTRASONOGRAPHY PLUS PANCREATIC FUNCTION TESTING

The best way to diagnose minimal-change chronic pancreatitis may be a combination of sensitive structural and functional testing. Although clinically apparent steatorrhea typically occurs late in the course of chronic pancreatitis, mild exocrine insufficiency may occur early and is detectable with hormone-stimulated pancreatic function testing. Therefore, pancreatic function tests are considered sensitive for diagnosing chronic pancreatitis.^20,21,29

Endoscopic pancreatic function testing involves injecting secretin intravenously and then collecting duodenal aspirates through the endoscope. The duodenal fluid is analyzed for bicarbonate concentration as a measure of exocrine function.²⁹

We have studied combined EUS and endoscopic pancreatic function testing in the diagnosis of chronic pancreatitis.¹⁶ The combination gives a simultaneous structural and functional assessment of the pancreas and may optimize sensitivity for detecting minimal-change chronic pancreatitis. In a small study, we found the combination had 100% sensitivity for noncalcific chronic pancreatitis compared with a histologic reference standard.¹⁶

Endoscopic ultrasonography (EUS) is a minimally invasive test that provides high-resolution imaging of the pancreas.^1,2 As such, it is proving useful.

Accurate diagnosis and timely intervention are essential in managing acute and chronic pancreatitis, which are often encountered in the clinic and the hospital. However, the cause of acute pancreatitis is not always easy to determine. Furthermore, recurrent bouts can progress to chronic pancreatitis if the cause is not identified and eliminated. EUS has been studied extensively in the evaluation of both acute and chronic pancreatitis, as it can identify obstructive and biliary causes of acute pancreatitis and early structural features of chronic pancreatitis.

This article will review the indications and evidence for EUS in the evaluation of acute and chronic pancreatitis.

SPECIALIZED TRAINING REQUIRED

EUS involves passage of a specialized endoscope through the esophagus and stomach and into the duodenum. The scope has a very small ultrasound probe at the tip, allowing detailed imaging of the upper gastrointestinal tract and surrounding organs.

There are two types of EUS endoscope: radial and linear. A radial scope provides a 360° range of view perpendicular to the long axis of the scope. A linear scope provides a 150° view parallel to the long axis of the scope. Many endosonographers favor linear EUS for imaging the pancreas because it permits fine-needle aspiration biopsy of masses, cysts, and lymph nodes.

Specialized training beyond the gastroenterology fellowship is usually required to become proficient in performing EUS, in recognizing the anatomy it reveals, and in performing fine-needle aspiration biopsy.

ENDOSCOPIC ULTRASONOGRAPHY IN ACUTE PANCREATITIS

Finding the cause of acute pancreatitis can be challenging in patients who do not have typical risk factors, eg, those who do not drink substantial amounts of alcohol and in whom transabdominal ultrasonography fails to reveal gallstones.

Several studies have evaluated the role of EUS in recurrent “idiopathic” pancreatitis.^3–5 Causes of acute pancreatitis detectable with EUS included gallbladder and bile duct microlithiasis (stones smaller than 3 mm), cysts, intraductal papillary mucinous neoplasms, ampullary neoplasms, pancreas divisum, and pancreatic masses.

Stones, sludge. Transabdominal ultrasonography is often performed in the workup of acute pancreatitis to rule out gallbladder stones and biliary dilation. Unfortunately, it does a poor job of imaging the distal common bile duct, where culprit stones may reside.

EUS provides a high-quality view of the bile duct from the ampulla of Vater to the region of the hepatic hilum and is safer than endoscopic retrograde cholangiopancreatography (ERCP). The available evidence supports the use of EUS as a diagnostic test for bile duct stones.^3–7 In fact, using ERCP as the reference standard, EUS has been found to be more sensitive than transabdominal ultrasonography for bile duct stones.⁴

The yield of EUS for finding biliary sludge and stones may be high in patients with unexplained pancreatitis. EUS detected sludge, microlithiasis, or both in 33 of 35 patients with idiopathic acute pancreatitis who underwent transabdominal ultrasonography with negative results.⁸ Furthermore, most were symptom-free at an average of 10 months after cholecystectomy, suggesting that microlithiasis was the cause of the “idiopathic” pancreatitis.

EUS can also decrease the number of unnecessary ERCP procedures in patients with suspected biliary pancreatitis. In these patients, EUS can be performed as an initial diagnostic test to exclude retained biliary stones. If a stone is present, the endoscopist can proceed to ERCP for sphincterotomy and stone removal during the same endoscopic session. If EUS is negative, the endoscopy can be concluded without cannulating the bile duct and putting the patient at risk of acute pancreatitis. In one report, this approach eliminated the need for ERCP in five of six patients with suspected biliary pancreatitis.⁶

Tumors and other causes of bile duct obstruction can also cause recurrent acute pancreatitis and may be difficult to detect with cross-sectional imaging. EUS, on the other hand, can detect small pancreatic masses (< 2 cm), which may be missed by conventional computed tomography. Also, a linear EUS scope, with its forward oblique view, can image the duodenum and ampulla, where obstructing inflammation, tumors, and polyps may be found. One should strongly suspect occult malignancy in elderly patients with unexplained acute pancreatitis. In those patients, repeat imaging with high-resolution dual-phase computed tomography or with EUS should be considered after a few weeks once the acute inflammation resolves.

Pancreas divisum is a relatively common congenital abnormality in which the dorsal and ventral pancreatic ducts do not properly fuse during embryonic development. To rule out pancreas divisum, the endosonographer must carefully trace the pancreatic duct from the dorsal pancreas into the ventral pancreas, where it connects with the bile duct at the duodenal wall.

In summary, EUS appears to be safe and accurate for diagnosing bile duct stones and other structural causes of idiopathic acute pancreatitis.

ENDOSCOPIC ULTRASONOGRAPHY IN CHRONIC PANCREATITIS

Chronic pancreatitis, a relatively common and sometimes debilitating cause of chronic upper abdominal pain, may be difficult to diagnose using noninvasive imaging tests. Minimal-change chronic pancreatitis is defined as a syndrome of pancreatic abdominal pain with no or slight structural changes detected on imaging but with histologic inflammation and fibrosis diagnostic of chronic pancreatitis.⁹

A clinical rationale for trying to detect chronic pancreatitis early in its course is that interventions can be started earlier. These include abstinence from alcohol, giving exogenous pancreatic enzymes, and advanced interventions such as celiac plexus blocks for pain control. Some patients may even benefit from resection of the pancreas if pain is severe and resistant to conservative measures.

EUS can detect both parenchymal and ductal changes that correlate with histologic fibrosis.¹⁰ Parenchymal changes include hyperechoic foci, hyperechoic strands, lobularity, cysts, and shadowing calcifications. Ductal changes include dilation of the main pancreatic duct, irregularity, hyperechoic duct margins, and visible side branches.

Several studies have evaluated the ability of EUS to diagnose early chronic pancreatitis.^9,11–15 Reference standards used to determine the accuracy of EUS have included histology,^10,16–18 pancreatic function testing,^19–22 and ERCP.^11,15,23,24

The best diagnostic test may be pancreatic histology. However, biopsy of the pancreas is impractical and exposes patients to high risk. In addition, the patchy and focal distribution of histologic changes may decrease its reliability. Fortunately, the histologic findings of fibrosis have been shown to correlate with EUS criteria in patients undergoing EUS before surgical resection in three recent studies.^16–18 A threshold of four or more criteria out of a possible nine was found to provide the optimal sensitivity and specificity for histologic pancreatic fibrosis.^16,17 The criteria used were four parenchymal features (hyperechoic foci, strands, hypoechoic lobules, cysts) and five ductal features (irregularity of the main pancreatic duct, dilation, hyperechoic duct walls, visible side branches, and calcifications or stones).

EUS is sensitive for chronic pancreatitis, but ‘true’ accuracy is impossible to know

Unfortunately, greater sensitivity may come at the expense of worse specificity. Certain demographic variables may alter the EUS appearance of the pancreas. A multivariate analysis²⁵ found several variables that predicted abnormalities on EUS even in the absence of clinically evident pancreatitis; the strongest were heavy ethanol use (odds ratio [OR] 5.1, 95% confidence interval [CI] 3.1–8.5), male sex (OR 1.8, 95% CI 1.3–2.55), clinical suspicion of pancreatic disease (OR 1.7, 95% CI 1.2–2.3), and heavy smoking (OR 1.7, 95% CI 1.2–2.4). More prospective studies are needed to further differentiate true disease from false-positive findings of chronic pancreatitis.

Also, traditional EUS scoring symptoms have counted features in an unweighted fashion and assigned an arbitrary cut point (eg, four or more features) for diagnosis. This approach fails to account for the greater importance of some features (eg, calcifications) compared with others.

Interobserver variability is another important limitation of EUS in diagnosing chronic pancreatitis.^26,27 In one multicenter study of EUS interpretation, the overall kappa (agreement beyond chance) was only 0.45 for overall chronic pancreatitis diagnosis and worse for many individual criteria for chronic pancreatitis. The endosonographers disagreed most about hyperechoic strands and foci, main pancreatic duct irregularity, and visible side branches (kappa < 0.4).

The Rosemont classification

These limitations led a group of experts to meet in Chicago, IL, to develop a consensus-based and weighted EUS scoring system for the diagnosis of chronic pancreatitis, termed the Rosemont classification.

In this system, the previous parenchymal and ductal features are assigned stricter definitions and reclassified as major and minor criteria. Based on the presence of major and minor features, EUS results are stratified as “normal,” “indeterminate for chronic pancreatitis,” “suggestive of chronic pancreatitis,” or “most consistent with chronic pancreatitis.”^15,28

Further validation of this scoring system is needed before it can be used widely.

ENDOSCOPIC ULTRASONOGRAPHY PLUS PANCREATIC FUNCTION TESTING

The best way to diagnose minimal-change chronic pancreatitis may be a combination of sensitive structural and functional testing. Although clinically apparent steatorrhea typically occurs late in the course of chronic pancreatitis, mild exocrine insufficiency may occur early and is detectable with hormone-stimulated pancreatic function testing. Therefore, pancreatic function tests are considered sensitive for diagnosing chronic pancreatitis.^20,21,29

Endoscopic pancreatic function testing involves injecting secretin intravenously and then collecting duodenal aspirates through the endoscope. The duodenal fluid is analyzed for bicarbonate concentration as a measure of exocrine function.²⁹

We have studied combined EUS and endoscopic pancreatic function testing in the diagnosis of chronic pancreatitis.¹⁶ The combination gives a simultaneous structural and functional assessment of the pancreas and may optimize sensitivity for detecting minimal-change chronic pancreatitis. In a small study, we found the combination had 100% sensitivity for noncalcific chronic pancreatitis compared with a histologic reference standard.¹⁶

The last several decades have seen a dramatic surge in the prevalence of asthma. In 2009, there were an estimated 17.5 million adults and almost 7.1 million children with asthma in the United States,¹ up from 9.5 million adults and slightly more than 5 million children in 1995.²

Multiple factors contribute to these disparities, including genetics, socioeconomic factors, cultural factors, health maintenance behaviors, provider-patient communication, air quality, and obesity.

GENETICS: 70% OF DESTINY?

The trend towards personalized medicine has spurred extensive research into the genetics of asthma. Studies in twins and familial aggregation studies suggest genetics plays a significant role, with estimates of the heritability of asthma as high as 70%.^4,5 More than 100 candidate genes have been shown to be associated with asthma and atopy, 30 of them in five or more independent studies.⁶

Researchers face many challenges when investigating the genetics involved in asthma for a particular race. Race is both a biologic and a social construct and, as such, is a poor substitute for genetics. Race constitutes not only genetic differences in individuals, but also the behaviors, beliefs, and experiences that vary among races.

The clinical disease—the phenotype—is the product of the interaction of genes and these differing behaviors and exposures. Genetics can affect how environmental factors found in association with socioeconomic factors relate to asthma morbidity and mortality.

For example, as we will discuss below, African Americans are more likely than whites to be sensitized to cockroach allergen, even after controlling for socioeconomic variables that may be associated with greater exposure.⁷ High-level exposure to cockroach allergen in sensitized children has been associated with poor asthma outcomes.⁸ This suggests that a genetic difference may exist between African Americans and whites with respect to the potential to develop cockroach sensitization, and this difference may be of particular importance for those African Americans living in areas with higher levels of cockroach exposure.

Two polymorphisms

Two polymorphisms have garnered attention for their influence on African Americans with asthma:

TheADRB2gene. This gene codes for the beta-2 adrenergic receptor and resides at chromosome 5q13.⁹ The receptor is found on several types of cells in the lung, including airway smooth muscle and epithelial cells, and is responsible for the salutary effects of inhaled beta-2 agonists such as albuterol (eg, Proventil).

Allelic polymorphisms of this gene are clinically relevant. The substitution of arginine (Arg) for glycine (Gly) at codon 16 of this gene is responsible for differences in response to short-acting beta-2 agonists. The allelic frequency of Arg16 is lower in white Americans (39.3%) than in African Americans (49.2%), and thus African Americans are more likely to be homozygous for Arg16 (ie, to have the Arg/Arg genotype).¹⁰

People who are homozygous for Arg16 who use albuterol on a regular basis are at higher risk of untoward asthma outcomes.¹¹ This is important, for several reasons. In general, adherence to inhaled corticosteroids is poor (not only in African Americans),¹² and patients who do not take their inhaled corticosteroids as they should may rely on short-acting beta-2 agonists more frequently. Furthermore, African Americans may have a poorer response to the repeated doses of albuterol that are typically given in the emergency department and in the hospital for severe asthma exacerbations.¹³ Additionally, data suggest that Arg/Arg individuals have more frequent exacerbations independent of beta-agonist use,¹⁴ although curiously, patients who are homozygous for Arg16 have a greater benefit from single doses of short-acting beta-2 agonists than those who are Gly16 homozygous.¹⁵

TheCD14gene. An interesting relationship between innate immunity and asthma has recently been described. Polymorphisms of CD14, which codes for a receptor for endotoxin, have been uncovered. The single-nucleotide polymorphism variant thymine (T) at position −260 has been found in greater frequency in whites than in African Americans, who are more likely to have the cytosine (C) allele.¹⁶ An association between the CC genotype and atopy has been reported,¹⁶ although this has not been consistent.¹⁷

A possible explanation for these inconsistencies may lie in complex gene-environment interactions. The amount of endotoxin exposure may play a role in phenotypic expression. Individuals with the CC genotype were at lower risk of developing atopy when exposed to high levels of endotoxin; however, when exposed to lower levels of endotoxin, the CC genotype was associated with a higher risk of atopy.¹⁸ Nonfarm homes in westernized countries tend to have lower levels of endotoxin than farm homes, even in low-income urban areas.¹⁹ This implies that individuals with the CC allele, who are more likely to be African American, would be at greater risk for atopy in the United States. Greater knowledge of these types of gene-environment interactions may lead to improved understanding of the observations that have generated controversy concerning the “hygiene hypothesis.”

The details of how microbial exposure can influence the human immune response to antigen exposure are still being elucidated.²⁰

These examples highlight not only the importance of genetics in the development of asthma, but also the role genes play in variation of treatment response and subsequent risk of morbidity and death. An understanding of these genetic differences among patients is clearly important for moving towards personalized treatment strategies for asthma.

A developing strategy to assess the differences in asthma prevalence, severity, and response to treatment between racial groups is the use of ancestry-informative markers (AIMs).

AIMs are single-nucleotide polymorphisms that occur in varying allelic frequencies between ancestral groups, eg, continental Africans or European whites.²¹ AIMs provide an estimate of an individual’s proportion of ancestry—ie, of how “African” an African American is genetically.

African ancestry, determined using AIMs, was found to be associated with asthma in people living on the Caribbean coast of Colombia.²² However, one study found that AIMs could not predict an individual’s response to inhaled corticosteroids.²³

Further research is necessary to find a technique to determine how groups of individuals can be characterized more precisely and managed more appropriately.

SOCIOECONOMIC FACTORS

African Americans living in low-income urban areas have an even greater prevalence of asthma and a greater risk of asthma-related morbidity and death than African Americans overall.^3,24,25 Urban areas typically have a high proportion of residents living at or below the poverty level, and minorities often constitute a substantial proportion of the population in these areas. Evidence suggests that both African American race and lower socioeconomic status are independent risk factors for asthma prevalence, morbidity, and death.^3,25

To provide better care for African Americans living in low-income urban areas, it is important to understand the factors that may be contributing to the higher morbidity and mortality rates in low-income urban areas.

Inadequate follow-up

Proper and routine follow-up for evaluation of asthma symptoms is essential for appropriate management. The Expert Panel Report 3 (EPR-3) of the National Education and Prevention Program Guidelines for the Diagnosis and Management of Asthma,²⁶ published in 2007, recommends that patients be seen at least every 6 months if they have been experiencing good control. While gaining control, patients should be seen every 2 to 6 weeks.²⁶

Despite these recommendations, numerous studies have suggested that African Americans do not receive adequate follow-up. Children who are poor, are nonwhite or Hispanic, or are underinsured are more likely to lack routine health care²⁷ and, more specifically, routine asthma care.²⁸ Low-income patients are also more likely to receive care in a large hospital-run clinic or neighborhood clinic,^27,28 where continuity of care may be less than ideal.²⁹ Even among patients enrolled in Medicaid or Medicare, African American children with a primary care provider have fewer asthma visits compared with white Medicaid-insured children.³⁰

Insufficient follow-up care contributes to greater asthma morbidity, resulting in, for example, more emergency department visits for asthma in African Americans.^27,31,32

Suboptimal care

Data also suggest that the quality of care that residents of low-income urban areas receive is often suboptimal. Many people living in low-income urban areas are not provided with the knowledge and tools to treat asthma exacerbations at home.³³ African Americans are also less likely to be seen by an asthma specialist^31,34 as recommended for those with moderate or severe asthma.²⁶

The EPR-3 guidelines also stress the importance of inhaled corticosteroids as the preferred therapy for all patients with persistent asthma. Even after controlling for the number of primary care visits, insurance status, and disease severity, African Americans are less likely to receive a prescription for inhaled corticosteroids, or they receive the same dosage of inhaled corticosteroids in the face of more severe disease.^31,33,35,36

The reasons for these differences in treatment are not fully understood but are likely multiple. Lack of access to an asthma specialist and financial or formulary constraints are some of the potential barriers to optimal asthma care outcomes.

Misdiagnosis in the acute setting may also be a source of less-than-ideal care, as patients seen in emergency departments may be misdiagnosed with viral infection or bronchitis.

African Americans may report different symptoms than whites

Intriguing studies suggest that African Americans report different symptoms while describing asthma exacerbations.

In one study, compared with whites, African Americans were less likely to report nocturnal symptoms, dyspnea, or chest pain during exacerbations.³⁷ In another study, when given a methacholine challenge that induced a significant drop in forced expiratory volume in 1 second (FEV₁), African Americans with asthma were more likely to complain of upper airway symptoms as opposed to lower airway symptoms, compared with white patients.³⁸

The symptoms that African Americans describe, such as having a tight throat or voice, are not typically regarded as related to asthma; for this reason, such descriptions may be an obstacle to correct diagnosis, management, and follow-up.

Asthma care providers should be aware of these observations to ensure that their patients are managed appropriately.

Lack of social support

Living in a low-income urban area presents many challenges that can interfere with proper asthma control.

Asthma diagnosis, management, and morbidity are affected by family support.³⁹ Patients with asthma who lack sufficient financial support for treatment, who lack adequate psychological support, and who have more major life stressors are at higher risk of untoward outcomes. Disruption and dysfunction of the family and the supports available have been associated with greater asthma morbidity.^40–42 Unfortunately, these types of stressors are all too common in families living in low-income urban areas.^43–45

Multiple stressors that can occur more often in low-income urban areas, including exposure to violent crime, have also been linked to greater asthma morbidity.^45–47

POOR PHYSICIAN-PATIENT COMMUNICATION

A consistent theme in focus groups of African Americans living in inner-city areas is the perception that health care providers are not effectively communicating and taking the time to listen to their concerns.^48,49 Respondents believed they had better insight into their illness than their providers, and for this reason were better able to manage their disease.

The importance of an optimal provider-patient relationship was highlighted by a prospective cohort study in which Medicaid children receiving care at physician’s offices with the highest cultural competency scores were more adherent with their asthma controller medications.⁵⁰

MEDICATION ADHERENCE RATES ARE DISTURBINGLY LOW

Rates of medication adherence for chronic diseases is disturbingly low, and may be even worse for pulmonary diseases.⁵¹ Reported rates of adherence to asthma medications among all patients range from 50% to 60%.^52,53 Several studies showed that African Americans have a lower rate of adherence than do whites,^53–55 even after adjusting for multiple socioeconomic variables.⁵⁶

Many explanations have been proposed for this discrepancy, and all likely play a role in particular environments. For example, the incidence of crime in the surrounding area was inversely related to medication adherence after adjusting for socioeconomic factors.⁵⁷ African Americans may have more concern about side effects associated with inhaled corticosteroid use and may be less likely to understand how these drugs work.^52,53 A poor provider-patient relationship has also been cited as a barrier to adherence.^55,57 Finally, physicians are more likely to underestimate asthma severity in an African American patient than in a white patient.⁵⁸

Taking the time to ensure that patients truly understand all aspects of their disease and establishing a health care environment that is culturally appropriate may have a significant impact in patients with asthma.

ENVIRONMENTAL EXPOSURES

Air quality contributes to the greater asthma morbidity observed in urban residents, including African Americans. While poor outdoor air quality has not been clearly linked to a higher incidence of asthma, it has been associated with greater asthma morbidity. Poor air quality may affect individuals of all races, but with respect to ambient pollutants such as particulate matter and diesel exhaust, outdoor air quality is worse in urban environments where greater proportions of people of low socioeconomic status reside.^59,60

The most extensively studied components of air pollution are ozone, sulfur dioxide, and particulate matter. These pollutants have been associated with a higher rate of emergency department visits,^61,62 worse asthma symptoms,^63,64 and higher exhaled nitric oxide levels.⁶⁵

Tobacco smoke

Despite the substantial success of smoking cessation efforts nationwide, exposure to tobacco smoke continues to be common and is a significant risk factor for poor asthma control. Recent data suggest that African Americans and whites have a similar prevalence of smoking,⁶⁶ but a study found a very high prevalence in low-income African Americans.⁶⁷

Active smoking has been associated with worse asthma control and a higher risk of death.⁶⁸ People with asthma who smoke are less likely to improve in their lung function and symptom scores when treated with short courses of oral glucocorticoids compared with both nonsmokers and former smokers.⁶⁹

Secondhand smoke hurts too. Many children living in low-income urban areas are exposed to secondhand smoke or environmental tobacco smoke.^70,71 Passive exposure in children has been associated with worse asthma outcomes, and data suggest such exposure may be a cause of asthma.^68,72–74

Environmental tobacco smoke has also been implicated in gene-environment interactions. Patients who are either homozygous or heterozygous for the Arg allele at codon 16 of the ADRB2 gene (discussed above) had significantly lower FEV₁ and forced vital capacity (FVC) values when exposed to passive tobacco smoke. This difference was not seen in people who were not exposed.⁷⁵

Cockroach allergen

The type and condition of a person’s housing also plays a role in asthma-related morbidity and death. Across several socioeconomic levels, it has been suggested that African Americans have poorer-quality housing compared with whites.⁷⁶ Some of the conditions found in low-quality houses, such as interruptions in heat, plumbing leaks, and the presence of rodents, have been associated with a higher prevalence of asthma in the household.⁷⁷

Cockroach allergen exposure and sensitization is a major contributor to asthma morbidity in African Americans, particularly those living in poorer urban areas where cockroach allergen may be the most common indoor allergen.⁸ Living in older housing in urban areas is associated with higher exposure to cockroach allergen, and with subsequent sensitization.^78,79 Exposure to high levels of the major cockroach allergen, Bla g 1, in sensitized individuals has been linked to a greater risk of hospitalization and unscheduled medical visits for asthma. This was not found to be the case for other common indoor allergens, such as dust mite and cat dander.⁸

However, it is not only exposure to high cockroach allergen levels that puts African Americans at risk. African Americans living in low-income urban areas may also be more likely than whites living in low-income urban areas to become sensitized to cockroach allergen.^7,80 This suggests a gene-environment interaction that may be unique to African Americans. Moreover, cockroach sensitization may occur early in life.^81,82

While successful cockroach avoidance measures and environmental control may be challenging, such measures have been shown to decrease rates of asthma morbidity.⁸³

OBESITY

Obesity has been linked to an ever-growing list of diseases, one of which is asthma. Obesity is not a unique challenge for African Americans, but recent data from the US Centers for Disease Control and Prevention show that African Americans have a 51% higher prevalence of obesity compared with whites.⁸⁴

Obesity is a risk factor for greater asthma morbidity and is a significant challenge in the African American community. The rise in obesity rates has paralleled the rise in asthma in recent decades. The higher one’s body mass index, the higher one’s risk of asthma.⁸⁵ This association appears to be stronger in people without concurrent atopic disease.⁸⁶ Obesity has also been associated with a poorer response to inhaled corticosteroids and a higher risk of asthma exacerbations.⁸⁷ Interestingly, significant weight loss has been associated with improvements in both asthma control and lung function.^88,89

The underlying pathogenic mechanisms have not been completely elucidated, and they are likely multiple.

Adipokines (cytokines secreted by adipocytes) have been implicated. Two of the most extensively studied adipokines are leptin and adiponectin. Leptin production is increased in obesity, and it has inflammatory effects on both the innate and adaptive immune systems.⁹⁰ The opposite is true for adiponectin, which may have anti-inflammatory properties and which decreases as the body mass index increases.⁹⁰ The precise role these molecules may have in lung disease is undergoing further investigation.

Mechanical alterations in lung function may also contribute. Obese people have a lower functional residual capacity and expiratory reserve volume. Breathing with a lower-volume functional residual capacity results in decreased airway diameter and contributes to increased airway resistance.⁹⁰ The decreased airway diameter may alter the contractile properties of airway smooth muscle and lead to increased airway responsiveness.⁹⁰ These differences are in addition to the lower mean values of common spirometry indices such as the FEV₁ and FVC, found in nonasthmatic African Americans compared with whites.⁹¹

Data suggest these differences are primarily due to anthropometric factors, with nutritional and environmental factors playing a less significant role.⁹² On this basis, the American Thoracic Society recommends applying race-specific reference standards for use with spirometry in order to accurately gauge lung function in African Americans.

APPROPRIATE CARE AND EDUCATION

The cause of greater asthma prevalence and severity among African Americans is multifactorial. It is likely that a number of factors work together, rather than separately, in influencing the development of asthma and its course.

Some risk factors are avoidable, and it is important to identify and ameliorate them. Others are not preventable, but knowledge of them may provide more specific management strategies and may lead to new therapies in the future.

While more work is needed to further unravel the complex risk factors associated with asthma, ensuring that higher-risk patients are provided the appropriate care and the knowledge to help control their disease is a necessary step in improving the disparities in asthma care outcomes.

The last several decades have seen a dramatic surge in the prevalence of asthma. In 2009, there were an estimated 17.5 million adults and almost 7.1 million children with asthma in the United States,¹ up from 9.5 million adults and slightly more than 5 million children in 1995.²

Multiple factors contribute to these disparities, including genetics, socioeconomic factors, cultural factors, health maintenance behaviors, provider-patient communication, air quality, and obesity.

GENETICS: 70% OF DESTINY?

The trend towards personalized medicine has spurred extensive research into the genetics of asthma. Studies in twins and familial aggregation studies suggest genetics plays a significant role, with estimates of the heritability of asthma as high as 70%.^4,5 More than 100 candidate genes have been shown to be associated with asthma and atopy, 30 of them in five or more independent studies.⁶

Researchers face many challenges when investigating the genetics involved in asthma for a particular race. Race is both a biologic and a social construct and, as such, is a poor substitute for genetics. Race constitutes not only genetic differences in individuals, but also the behaviors, beliefs, and experiences that vary among races.

The clinical disease—the phenotype—is the product of the interaction of genes and these differing behaviors and exposures. Genetics can affect how environmental factors found in association with socioeconomic factors relate to asthma morbidity and mortality.

For example, as we will discuss below, African Americans are more likely than whites to be sensitized to cockroach allergen, even after controlling for socioeconomic variables that may be associated with greater exposure.⁷ High-level exposure to cockroach allergen in sensitized children has been associated with poor asthma outcomes.⁸ This suggests that a genetic difference may exist between African Americans and whites with respect to the potential to develop cockroach sensitization, and this difference may be of particular importance for those African Americans living in areas with higher levels of cockroach exposure.

Two polymorphisms

Two polymorphisms have garnered attention for their influence on African Americans with asthma:

TheADRB2gene. This gene codes for the beta-2 adrenergic receptor and resides at chromosome 5q13.⁹ The receptor is found on several types of cells in the lung, including airway smooth muscle and epithelial cells, and is responsible for the salutary effects of inhaled beta-2 agonists such as albuterol (eg, Proventil).

Allelic polymorphisms of this gene are clinically relevant. The substitution of arginine (Arg) for glycine (Gly) at codon 16 of this gene is responsible for differences in response to short-acting beta-2 agonists. The allelic frequency of Arg16 is lower in white Americans (39.3%) than in African Americans (49.2%), and thus African Americans are more likely to be homozygous for Arg16 (ie, to have the Arg/Arg genotype).¹⁰

People who are homozygous for Arg16 who use albuterol on a regular basis are at higher risk of untoward asthma outcomes.¹¹ This is important, for several reasons. In general, adherence to inhaled corticosteroids is poor (not only in African Americans),¹² and patients who do not take their inhaled corticosteroids as they should may rely on short-acting beta-2 agonists more frequently. Furthermore, African Americans may have a poorer response to the repeated doses of albuterol that are typically given in the emergency department and in the hospital for severe asthma exacerbations.¹³ Additionally, data suggest that Arg/Arg individuals have more frequent exacerbations independent of beta-agonist use,¹⁴ although curiously, patients who are homozygous for Arg16 have a greater benefit from single doses of short-acting beta-2 agonists than those who are Gly16 homozygous.¹⁵

TheCD14gene. An interesting relationship between innate immunity and asthma has recently been described. Polymorphisms of CD14, which codes for a receptor for endotoxin, have been uncovered. The single-nucleotide polymorphism variant thymine (T) at position −260 has been found in greater frequency in whites than in African Americans, who are more likely to have the cytosine (C) allele.¹⁶ An association between the CC genotype and atopy has been reported,¹⁶ although this has not been consistent.¹⁷

A possible explanation for these inconsistencies may lie in complex gene-environment interactions. The amount of endotoxin exposure may play a role in phenotypic expression. Individuals with the CC genotype were at lower risk of developing atopy when exposed to high levels of endotoxin; however, when exposed to lower levels of endotoxin, the CC genotype was associated with a higher risk of atopy.¹⁸ Nonfarm homes in westernized countries tend to have lower levels of endotoxin than farm homes, even in low-income urban areas.¹⁹ This implies that individuals with the CC allele, who are more likely to be African American, would be at greater risk for atopy in the United States. Greater knowledge of these types of gene-environment interactions may lead to improved understanding of the observations that have generated controversy concerning the “hygiene hypothesis.”

The details of how microbial exposure can influence the human immune response to antigen exposure are still being elucidated.²⁰

These examples highlight not only the importance of genetics in the development of asthma, but also the role genes play in variation of treatment response and subsequent risk of morbidity and death. An understanding of these genetic differences among patients is clearly important for moving towards personalized treatment strategies for asthma.

A developing strategy to assess the differences in asthma prevalence, severity, and response to treatment between racial groups is the use of ancestry-informative markers (AIMs).

AIMs are single-nucleotide polymorphisms that occur in varying allelic frequencies between ancestral groups, eg, continental Africans or European whites.²¹ AIMs provide an estimate of an individual’s proportion of ancestry—ie, of how “African” an African American is genetically.

African ancestry, determined using AIMs, was found to be associated with asthma in people living on the Caribbean coast of Colombia.²² However, one study found that AIMs could not predict an individual’s response to inhaled corticosteroids.²³

Further research is necessary to find a technique to determine how groups of individuals can be characterized more precisely and managed more appropriately.

SOCIOECONOMIC FACTORS

African Americans living in low-income urban areas have an even greater prevalence of asthma and a greater risk of asthma-related morbidity and death than African Americans overall.^3,24,25 Urban areas typically have a high proportion of residents living at or below the poverty level, and minorities often constitute a substantial proportion of the population in these areas. Evidence suggests that both African American race and lower socioeconomic status are independent risk factors for asthma prevalence, morbidity, and death.^3,25

To provide better care for African Americans living in low-income urban areas, it is important to understand the factors that may be contributing to the higher morbidity and mortality rates in low-income urban areas.

Inadequate follow-up

Proper and routine follow-up for evaluation of asthma symptoms is essential for appropriate management. The Expert Panel Report 3 (EPR-3) of the National Education and Prevention Program Guidelines for the Diagnosis and Management of Asthma,²⁶ published in 2007, recommends that patients be seen at least every 6 months if they have been experiencing good control. While gaining control, patients should be seen every 2 to 6 weeks.²⁶

Despite these recommendations, numerous studies have suggested that African Americans do not receive adequate follow-up. Children who are poor, are nonwhite or Hispanic, or are underinsured are more likely to lack routine health care²⁷ and, more specifically, routine asthma care.²⁸ Low-income patients are also more likely to receive care in a large hospital-run clinic or neighborhood clinic,^27,28 where continuity of care may be less than ideal.²⁹ Even among patients enrolled in Medicaid or Medicare, African American children with a primary care provider have fewer asthma visits compared with white Medicaid-insured children.³⁰

Insufficient follow-up care contributes to greater asthma morbidity, resulting in, for example, more emergency department visits for asthma in African Americans.^27,31,32

Suboptimal care

Data also suggest that the quality of care that residents of low-income urban areas receive is often suboptimal. Many people living in low-income urban areas are not provided with the knowledge and tools to treat asthma exacerbations at home.³³ African Americans are also less likely to be seen by an asthma specialist^31,34 as recommended for those with moderate or severe asthma.²⁶

The EPR-3 guidelines also stress the importance of inhaled corticosteroids as the preferred therapy for all patients with persistent asthma. Even after controlling for the number of primary care visits, insurance status, and disease severity, African Americans are less likely to receive a prescription for inhaled corticosteroids, or they receive the same dosage of inhaled corticosteroids in the face of more severe disease.^31,33,35,36

The reasons for these differences in treatment are not fully understood but are likely multiple. Lack of access to an asthma specialist and financial or formulary constraints are some of the potential barriers to optimal asthma care outcomes.

Misdiagnosis in the acute setting may also be a source of less-than-ideal care, as patients seen in emergency departments may be misdiagnosed with viral infection or bronchitis.

African Americans may report different symptoms than whites

Intriguing studies suggest that African Americans report different symptoms while describing asthma exacerbations.

In one study, compared with whites, African Americans were less likely to report nocturnal symptoms, dyspnea, or chest pain during exacerbations.³⁷ In another study, when given a methacholine challenge that induced a significant drop in forced expiratory volume in 1 second (FEV₁), African Americans with asthma were more likely to complain of upper airway symptoms as opposed to lower airway symptoms, compared with white patients.³⁸

The symptoms that African Americans describe, such as having a tight throat or voice, are not typically regarded as related to asthma; for this reason, such descriptions may be an obstacle to correct diagnosis, management, and follow-up.

Asthma care providers should be aware of these observations to ensure that their patients are managed appropriately.

Lack of social support

Living in a low-income urban area presents many challenges that can interfere with proper asthma control.

Asthma diagnosis, management, and morbidity are affected by family support.³⁹ Patients with asthma who lack sufficient financial support for treatment, who lack adequate psychological support, and who have more major life stressors are at higher risk of untoward outcomes. Disruption and dysfunction of the family and the supports available have been associated with greater asthma morbidity.^40–42 Unfortunately, these types of stressors are all too common in families living in low-income urban areas.^43–45

Multiple stressors that can occur more often in low-income urban areas, including exposure to violent crime, have also been linked to greater asthma morbidity.^45–47

POOR PHYSICIAN-PATIENT COMMUNICATION

A consistent theme in focus groups of African Americans living in inner-city areas is the perception that health care providers are not effectively communicating and taking the time to listen to their concerns.^48,49 Respondents believed they had better insight into their illness than their providers, and for this reason were better able to manage their disease.

The importance of an optimal provider-patient relationship was highlighted by a prospective cohort study in which Medicaid children receiving care at physician’s offices with the highest cultural competency scores were more adherent with their asthma controller medications.⁵⁰

MEDICATION ADHERENCE RATES ARE DISTURBINGLY LOW

Rates of medication adherence for chronic diseases is disturbingly low, and may be even worse for pulmonary diseases.⁵¹ Reported rates of adherence to asthma medications among all patients range from 50% to 60%.^52,53 Several studies showed that African Americans have a lower rate of adherence than do whites,^53–55 even after adjusting for multiple socioeconomic variables.⁵⁶

Many explanations have been proposed for this discrepancy, and all likely play a role in particular environments. For example, the incidence of crime in the surrounding area was inversely related to medication adherence after adjusting for socioeconomic factors.⁵⁷ African Americans may have more concern about side effects associated with inhaled corticosteroid use and may be less likely to understand how these drugs work.^52,53 A poor provider-patient relationship has also been cited as a barrier to adherence.^55,57 Finally, physicians are more likely to underestimate asthma severity in an African American patient than in a white patient.⁵⁸

Taking the time to ensure that patients truly understand all aspects of their disease and establishing a health care environment that is culturally appropriate may have a significant impact in patients with asthma.

ENVIRONMENTAL EXPOSURES

Air quality contributes to the greater asthma morbidity observed in urban residents, including African Americans. While poor outdoor air quality has not been clearly linked to a higher incidence of asthma, it has been associated with greater asthma morbidity. Poor air quality may affect individuals of all races, but with respect to ambient pollutants such as particulate matter and diesel exhaust, outdoor air quality is worse in urban environments where greater proportions of people of low socioeconomic status reside.^59,60

The most extensively studied components of air pollution are ozone, sulfur dioxide, and particulate matter. These pollutants have been associated with a higher rate of emergency department visits,^61,62 worse asthma symptoms,^63,64 and higher exhaled nitric oxide levels.⁶⁵

Tobacco smoke

Despite the substantial success of smoking cessation efforts nationwide, exposure to tobacco smoke continues to be common and is a significant risk factor for poor asthma control. Recent data suggest that African Americans and whites have a similar prevalence of smoking,⁶⁶ but a study found a very high prevalence in low-income African Americans.⁶⁷

Active smoking has been associated with worse asthma control and a higher risk of death.⁶⁸ People with asthma who smoke are less likely to improve in their lung function and symptom scores when treated with short courses of oral glucocorticoids compared with both nonsmokers and former smokers.⁶⁹

Secondhand smoke hurts too. Many children living in low-income urban areas are exposed to secondhand smoke or environmental tobacco smoke.^70,71 Passive exposure in children has been associated with worse asthma outcomes, and data suggest such exposure may be a cause of asthma.^68,72–74

Environmental tobacco smoke has also been implicated in gene-environment interactions. Patients who are either homozygous or heterozygous for the Arg allele at codon 16 of the ADRB2 gene (discussed above) had significantly lower FEV₁ and forced vital capacity (FVC) values when exposed to passive tobacco smoke. This difference was not seen in people who were not exposed.⁷⁵

Cockroach allergen

The type and condition of a person’s housing also plays a role in asthma-related morbidity and death. Across several socioeconomic levels, it has been suggested that African Americans have poorer-quality housing compared with whites.⁷⁶ Some of the conditions found in low-quality houses, such as interruptions in heat, plumbing leaks, and the presence of rodents, have been associated with a higher prevalence of asthma in the household.⁷⁷

Cockroach allergen exposure and sensitization is a major contributor to asthma morbidity in African Americans, particularly those living in poorer urban areas where cockroach allergen may be the most common indoor allergen.⁸ Living in older housing in urban areas is associated with higher exposure to cockroach allergen, and with subsequent sensitization.^78,79 Exposure to high levels of the major cockroach allergen, Bla g 1, in sensitized individuals has been linked to a greater risk of hospitalization and unscheduled medical visits for asthma. This was not found to be the case for other common indoor allergens, such as dust mite and cat dander.⁸

However, it is not only exposure to high cockroach allergen levels that puts African Americans at risk. African Americans living in low-income urban areas may also be more likely than whites living in low-income urban areas to become sensitized to cockroach allergen.^7,80 This suggests a gene-environment interaction that may be unique to African Americans. Moreover, cockroach sensitization may occur early in life.^81,82

While successful cockroach avoidance measures and environmental control may be challenging, such measures have been shown to decrease rates of asthma morbidity.⁸³

OBESITY

Obesity has been linked to an ever-growing list of diseases, one of which is asthma. Obesity is not a unique challenge for African Americans, but recent data from the US Centers for Disease Control and Prevention show that African Americans have a 51% higher prevalence of obesity compared with whites.⁸⁴

Obesity is a risk factor for greater asthma morbidity and is a significant challenge in the African American community. The rise in obesity rates has paralleled the rise in asthma in recent decades. The higher one’s body mass index, the higher one’s risk of asthma.⁸⁵ This association appears to be stronger in people without concurrent atopic disease.⁸⁶ Obesity has also been associated with a poorer response to inhaled corticosteroids and a higher risk of asthma exacerbations.⁸⁷ Interestingly, significant weight loss has been associated with improvements in both asthma control and lung function.^88,89

The underlying pathogenic mechanisms have not been completely elucidated, and they are likely multiple.

Adipokines (cytokines secreted by adipocytes) have been implicated. Two of the most extensively studied adipokines are leptin and adiponectin. Leptin production is increased in obesity, and it has inflammatory effects on both the innate and adaptive immune systems.⁹⁰ The opposite is true for adiponectin, which may have anti-inflammatory properties and which decreases as the body mass index increases.⁹⁰ The precise role these molecules may have in lung disease is undergoing further investigation.

Mechanical alterations in lung function may also contribute. Obese people have a lower functional residual capacity and expiratory reserve volume. Breathing with a lower-volume functional residual capacity results in decreased airway diameter and contributes to increased airway resistance.⁹⁰ The decreased airway diameter may alter the contractile properties of airway smooth muscle and lead to increased airway responsiveness.⁹⁰ These differences are in addition to the lower mean values of common spirometry indices such as the FEV₁ and FVC, found in nonasthmatic African Americans compared with whites.⁹¹

Data suggest these differences are primarily due to anthropometric factors, with nutritional and environmental factors playing a less significant role.⁹² On this basis, the American Thoracic Society recommends applying race-specific reference standards for use with spirometry in order to accurately gauge lung function in African Americans.

APPROPRIATE CARE AND EDUCATION

The cause of greater asthma prevalence and severity among African Americans is multifactorial. It is likely that a number of factors work together, rather than separately, in influencing the development of asthma and its course.

Some risk factors are avoidable, and it is important to identify and ameliorate them. Others are not preventable, but knowledge of them may provide more specific management strategies and may lead to new therapies in the future.

While more work is needed to further unravel the complex risk factors associated with asthma, ensuring that higher-risk patients are provided the appropriate care and the knowledge to help control their disease is a necessary step in improving the disparities in asthma care outcomes.

The last several decades have seen a dramatic surge in the prevalence of asthma. In 2009, there were an estimated 17.5 million adults and almost 7.1 million children with asthma in the United States,¹ up from 9.5 million adults and slightly more than 5 million children in 1995.²

Multiple factors contribute to these disparities, including genetics, socioeconomic factors, cultural factors, health maintenance behaviors, provider-patient communication, air quality, and obesity.

GENETICS: 70% OF DESTINY?

The trend towards personalized medicine has spurred extensive research into the genetics of asthma. Studies in twins and familial aggregation studies suggest genetics plays a significant role, with estimates of the heritability of asthma as high as 70%.^4,5 More than 100 candidate genes have been shown to be associated with asthma and atopy, 30 of them in five or more independent studies.⁶

Researchers face many challenges when investigating the genetics involved in asthma for a particular race. Race is both a biologic and a social construct and, as such, is a poor substitute for genetics. Race constitutes not only genetic differences in individuals, but also the behaviors, beliefs, and experiences that vary among races.

The clinical disease—the phenotype—is the product of the interaction of genes and these differing behaviors and exposures. Genetics can affect how environmental factors found in association with socioeconomic factors relate to asthma morbidity and mortality.

For example, as we will discuss below, African Americans are more likely than whites to be sensitized to cockroach allergen, even after controlling for socioeconomic variables that may be associated with greater exposure.⁷ High-level exposure to cockroach allergen in sensitized children has been associated with poor asthma outcomes.⁸ This suggests that a genetic difference may exist between African Americans and whites with respect to the potential to develop cockroach sensitization, and this difference may be of particular importance for those African Americans living in areas with higher levels of cockroach exposure.

Two polymorphisms

Two polymorphisms have garnered attention for their influence on African Americans with asthma:

TheADRB2gene. This gene codes for the beta-2 adrenergic receptor and resides at chromosome 5q13.⁹ The receptor is found on several types of cells in the lung, including airway smooth muscle and epithelial cells, and is responsible for the salutary effects of inhaled beta-2 agonists such as albuterol (eg, Proventil).

Allelic polymorphisms of this gene are clinically relevant. The substitution of arginine (Arg) for glycine (Gly) at codon 16 of this gene is responsible for differences in response to short-acting beta-2 agonists. The allelic frequency of Arg16 is lower in white Americans (39.3%) than in African Americans (49.2%), and thus African Americans are more likely to be homozygous for Arg16 (ie, to have the Arg/Arg genotype).¹⁰

People who are homozygous for Arg16 who use albuterol on a regular basis are at higher risk of untoward asthma outcomes.¹¹ This is important, for several reasons. In general, adherence to inhaled corticosteroids is poor (not only in African Americans),¹² and patients who do not take their inhaled corticosteroids as they should may rely on short-acting beta-2 agonists more frequently. Furthermore, African Americans may have a poorer response to the repeated doses of albuterol that are typically given in the emergency department and in the hospital for severe asthma exacerbations.¹³ Additionally, data suggest that Arg/Arg individuals have more frequent exacerbations independent of beta-agonist use,¹⁴ although curiously, patients who are homozygous for Arg16 have a greater benefit from single doses of short-acting beta-2 agonists than those who are Gly16 homozygous.¹⁵

TheCD14gene. An interesting relationship between innate immunity and asthma has recently been described. Polymorphisms of CD14, which codes for a receptor for endotoxin, have been uncovered. The single-nucleotide polymorphism variant thymine (T) at position −260 has been found in greater frequency in whites than in African Americans, who are more likely to have the cytosine (C) allele.¹⁶ An association between the CC genotype and atopy has been reported,¹⁶ although this has not been consistent.¹⁷

A possible explanation for these inconsistencies may lie in complex gene-environment interactions. The amount of endotoxin exposure may play a role in phenotypic expression. Individuals with the CC genotype were at lower risk of developing atopy when exposed to high levels of endotoxin; however, when exposed to lower levels of endotoxin, the CC genotype was associated with a higher risk of atopy.¹⁸ Nonfarm homes in westernized countries tend to have lower levels of endotoxin than farm homes, even in low-income urban areas.¹⁹ This implies that individuals with the CC allele, who are more likely to be African American, would be at greater risk for atopy in the United States. Greater knowledge of these types of gene-environment interactions may lead to improved understanding of the observations that have generated controversy concerning the “hygiene hypothesis.”

The details of how microbial exposure can influence the human immune response to antigen exposure are still being elucidated.²⁰

These examples highlight not only the importance of genetics in the development of asthma, but also the role genes play in variation of treatment response and subsequent risk of morbidity and death. An understanding of these genetic differences among patients is clearly important for moving towards personalized treatment strategies for asthma.

A developing strategy to assess the differences in asthma prevalence, severity, and response to treatment between racial groups is the use of ancestry-informative markers (AIMs).

AIMs are single-nucleotide polymorphisms that occur in varying allelic frequencies between ancestral groups, eg, continental Africans or European whites.²¹ AIMs provide an estimate of an individual’s proportion of ancestry—ie, of how “African” an African American is genetically.

African ancestry, determined using AIMs, was found to be associated with asthma in people living on the Caribbean coast of Colombia.²² However, one study found that AIMs could not predict an individual’s response to inhaled corticosteroids.²³

Further research is necessary to find a technique to determine how groups of individuals can be characterized more precisely and managed more appropriately.

SOCIOECONOMIC FACTORS

African Americans living in low-income urban areas have an even greater prevalence of asthma and a greater risk of asthma-related morbidity and death than African Americans overall.^3,24,25 Urban areas typically have a high proportion of residents living at or below the poverty level, and minorities often constitute a substantial proportion of the population in these areas. Evidence suggests that both African American race and lower socioeconomic status are independent risk factors for asthma prevalence, morbidity, and death.^3,25

To provide better care for African Americans living in low-income urban areas, it is important to understand the factors that may be contributing to the higher morbidity and mortality rates in low-income urban areas.

Inadequate follow-up

Proper and routine follow-up for evaluation of asthma symptoms is essential for appropriate management. The Expert Panel Report 3 (EPR-3) of the National Education and Prevention Program Guidelines for the Diagnosis and Management of Asthma,²⁶ published in 2007, recommends that patients be seen at least every 6 months if they have been experiencing good control. While gaining control, patients should be seen every 2 to 6 weeks.²⁶

Despite these recommendations, numerous studies have suggested that African Americans do not receive adequate follow-up. Children who are poor, are nonwhite or Hispanic, or are underinsured are more likely to lack routine health care²⁷ and, more specifically, routine asthma care.²⁸ Low-income patients are also more likely to receive care in a large hospital-run clinic or neighborhood clinic,^27,28 where continuity of care may be less than ideal.²⁹ Even among patients enrolled in Medicaid or Medicare, African American children with a primary care provider have fewer asthma visits compared with white Medicaid-insured children.³⁰

Insufficient follow-up care contributes to greater asthma morbidity, resulting in, for example, more emergency department visits for asthma in African Americans.^27,31,32

Suboptimal care

Data also suggest that the quality of care that residents of low-income urban areas receive is often suboptimal. Many people living in low-income urban areas are not provided with the knowledge and tools to treat asthma exacerbations at home.³³ African Americans are also less likely to be seen by an asthma specialist^31,34 as recommended for those with moderate or severe asthma.²⁶

The EPR-3 guidelines also stress the importance of inhaled corticosteroids as the preferred therapy for all patients with persistent asthma. Even after controlling for the number of primary care visits, insurance status, and disease severity, African Americans are less likely to receive a prescription for inhaled corticosteroids, or they receive the same dosage of inhaled corticosteroids in the face of more severe disease.^31,33,35,36

The reasons for these differences in treatment are not fully understood but are likely multiple. Lack of access to an asthma specialist and financial or formulary constraints are some of the potential barriers to optimal asthma care outcomes.

Misdiagnosis in the acute setting may also be a source of less-than-ideal care, as patients seen in emergency departments may be misdiagnosed with viral infection or bronchitis.

African Americans may report different symptoms than whites

Intriguing studies suggest that African Americans report different symptoms while describing asthma exacerbations.

In one study, compared with whites, African Americans were less likely to report nocturnal symptoms, dyspnea, or chest pain during exacerbations.³⁷ In another study, when given a methacholine challenge that induced a significant drop in forced expiratory volume in 1 second (FEV₁), African Americans with asthma were more likely to complain of upper airway symptoms as opposed to lower airway symptoms, compared with white patients.³⁸

The symptoms that African Americans describe, such as having a tight throat or voice, are not typically regarded as related to asthma; for this reason, such descriptions may be an obstacle to correct diagnosis, management, and follow-up.

Asthma care providers should be aware of these observations to ensure that their patients are managed appropriately.

Lack of social support

Living in a low-income urban area presents many challenges that can interfere with proper asthma control.

Asthma diagnosis, management, and morbidity are affected by family support.³⁹ Patients with asthma who lack sufficient financial support for treatment, who lack adequate psychological support, and who have more major life stressors are at higher risk of untoward outcomes. Disruption and dysfunction of the family and the supports available have been associated with greater asthma morbidity.^40–42 Unfortunately, these types of stressors are all too common in families living in low-income urban areas.^43–45

Multiple stressors that can occur more often in low-income urban areas, including exposure to violent crime, have also been linked to greater asthma morbidity.^45–47

POOR PHYSICIAN-PATIENT COMMUNICATION

A consistent theme in focus groups of African Americans living in inner-city areas is the perception that health care providers are not effectively communicating and taking the time to listen to their concerns.^48,49 Respondents believed they had better insight into their illness than their providers, and for this reason were better able to manage their disease.

The importance of an optimal provider-patient relationship was highlighted by a prospective cohort study in which Medicaid children receiving care at physician’s offices with the highest cultural competency scores were more adherent with their asthma controller medications.⁵⁰

MEDICATION ADHERENCE RATES ARE DISTURBINGLY LOW

Rates of medication adherence for chronic diseases is disturbingly low, and may be even worse for pulmonary diseases.⁵¹ Reported rates of adherence to asthma medications among all patients range from 50% to 60%.^52,53 Several studies showed that African Americans have a lower rate of adherence than do whites,^53–55 even after adjusting for multiple socioeconomic variables.⁵⁶

Many explanations have been proposed for this discrepancy, and all likely play a role in particular environments. For example, the incidence of crime in the surrounding area was inversely related to medication adherence after adjusting for socioeconomic factors.⁵⁷ African Americans may have more concern about side effects associated with inhaled corticosteroid use and may be less likely to understand how these drugs work.^52,53 A poor provider-patient relationship has also been cited as a barrier to adherence.^55,57 Finally, physicians are more likely to underestimate asthma severity in an African American patient than in a white patient.⁵⁸

Taking the time to ensure that patients truly understand all aspects of their disease and establishing a health care environment that is culturally appropriate may have a significant impact in patients with asthma.

ENVIRONMENTAL EXPOSURES

Air quality contributes to the greater asthma morbidity observed in urban residents, including African Americans. While poor outdoor air quality has not been clearly linked to a higher incidence of asthma, it has been associated with greater asthma morbidity. Poor air quality may affect individuals of all races, but with respect to ambient pollutants such as particulate matter and diesel exhaust, outdoor air quality is worse in urban environments where greater proportions of people of low socioeconomic status reside.^59,60

The most extensively studied components of air pollution are ozone, sulfur dioxide, and particulate matter. These pollutants have been associated with a higher rate of emergency department visits,^61,62 worse asthma symptoms,^63,64 and higher exhaled nitric oxide levels.⁶⁵

Tobacco smoke

Despite the substantial success of smoking cessation efforts nationwide, exposure to tobacco smoke continues to be common and is a significant risk factor for poor asthma control. Recent data suggest that African Americans and whites have a similar prevalence of smoking,⁶⁶ but a study found a very high prevalence in low-income African Americans.⁶⁷

Active smoking has been associated with worse asthma control and a higher risk of death.⁶⁸ People with asthma who smoke are less likely to improve in their lung function and symptom scores when treated with short courses of oral glucocorticoids compared with both nonsmokers and former smokers.⁶⁹

Secondhand smoke hurts too. Many children living in low-income urban areas are exposed to secondhand smoke or environmental tobacco smoke.^70,71 Passive exposure in children has been associated with worse asthma outcomes, and data suggest such exposure may be a cause of asthma.^68,72–74

Environmental tobacco smoke has also been implicated in gene-environment interactions. Patients who are either homozygous or heterozygous for the Arg allele at codon 16 of the ADRB2 gene (discussed above) had significantly lower FEV₁ and forced vital capacity (FVC) values when exposed to passive tobacco smoke. This difference was not seen in people who were not exposed.⁷⁵

Cockroach allergen

The type and condition of a person’s housing also plays a role in asthma-related morbidity and death. Across several socioeconomic levels, it has been suggested that African Americans have poorer-quality housing compared with whites.⁷⁶ Some of the conditions found in low-quality houses, such as interruptions in heat, plumbing leaks, and the presence of rodents, have been associated with a higher prevalence of asthma in the household.⁷⁷

Cockroach allergen exposure and sensitization is a major contributor to asthma morbidity in African Americans, particularly those living in poorer urban areas where cockroach allergen may be the most common indoor allergen.⁸ Living in older housing in urban areas is associated with higher exposure to cockroach allergen, and with subsequent sensitization.^78,79 Exposure to high levels of the major cockroach allergen, Bla g 1, in sensitized individuals has been linked to a greater risk of hospitalization and unscheduled medical visits for asthma. This was not found to be the case for other common indoor allergens, such as dust mite and cat dander.⁸

However, it is not only exposure to high cockroach allergen levels that puts African Americans at risk. African Americans living in low-income urban areas may also be more likely than whites living in low-income urban areas to become sensitized to cockroach allergen.^7,80 This suggests a gene-environment interaction that may be unique to African Americans. Moreover, cockroach sensitization may occur early in life.^81,82

While successful cockroach avoidance measures and environmental control may be challenging, such measures have been shown to decrease rates of asthma morbidity.⁸³

OBESITY

Obesity has been linked to an ever-growing list of diseases, one of which is asthma. Obesity is not a unique challenge for African Americans, but recent data from the US Centers for Disease Control and Prevention show that African Americans have a 51% higher prevalence of obesity compared with whites.⁸⁴

Obesity is a risk factor for greater asthma morbidity and is a significant challenge in the African American community. The rise in obesity rates has paralleled the rise in asthma in recent decades. The higher one’s body mass index, the higher one’s risk of asthma.⁸⁵ This association appears to be stronger in people without concurrent atopic disease.⁸⁶ Obesity has also been associated with a poorer response to inhaled corticosteroids and a higher risk of asthma exacerbations.⁸⁷ Interestingly, significant weight loss has been associated with improvements in both asthma control and lung function.^88,89

The underlying pathogenic mechanisms have not been completely elucidated, and they are likely multiple.

Adipokines (cytokines secreted by adipocytes) have been implicated. Two of the most extensively studied adipokines are leptin and adiponectin. Leptin production is increased in obesity, and it has inflammatory effects on both the innate and adaptive immune systems.⁹⁰ The opposite is true for adiponectin, which may have anti-inflammatory properties and which decreases as the body mass index increases.⁹⁰ The precise role these molecules may have in lung disease is undergoing further investigation.

Mechanical alterations in lung function may also contribute. Obese people have a lower functional residual capacity and expiratory reserve volume. Breathing with a lower-volume functional residual capacity results in decreased airway diameter and contributes to increased airway resistance.⁹⁰ The decreased airway diameter may alter the contractile properties of airway smooth muscle and lead to increased airway responsiveness.⁹⁰ These differences are in addition to the lower mean values of common spirometry indices such as the FEV₁ and FVC, found in nonasthmatic African Americans compared with whites.⁹¹

Data suggest these differences are primarily due to anthropometric factors, with nutritional and environmental factors playing a less significant role.⁹² On this basis, the American Thoracic Society recommends applying race-specific reference standards for use with spirometry in order to accurately gauge lung function in African Americans.

APPROPRIATE CARE AND EDUCATION

The cause of greater asthma prevalence and severity among African Americans is multifactorial. It is likely that a number of factors work together, rather than separately, in influencing the development of asthma and its course.

Some risk factors are avoidable, and it is important to identify and ameliorate them. Others are not preventable, but knowledge of them may provide more specific management strategies and may lead to new therapies in the future.

While more work is needed to further unravel the complex risk factors associated with asthma, ensuring that higher-risk patients are provided the appropriate care and the knowledge to help control their disease is a necessary step in improving the disparities in asthma care outcomes.