JAIDS Journal of Acquired Immune Deficiency Syndromes:
Letters to the Editor
Division of Antiviral Drug Products, US Food and Drug Administration, Rockville, MD
This letter represents the opinion of the authors and not necessarily that of the US Food and Drug Administration.
To the Editor:
Although Stern et al. 1 from Boehringer Ingelheim (BI) Pharmaceuticals, the manufacturer of nevirapine, imply that their supplement publication entitled “A comprehensive hepatic safety analysis of nevirapine in different populations of HIV infected patients” is a comprehensive review of hepatoxicity associated with nevirapine use, this publication describes hepatic adverse events in only a subset of patients in the BI Viramune Hepatic Safety Project (VHSP). They present only the patients with asymptomatic increases in hepatic transaminases >5 times the upper limit of normal (>5× ULN). Data are not shown on the other 2 subsets that make up the totality of the VHSP analysis, i.e., patients with rash-associated hepatic events and other symptomatic hepatic events. Furthermore, the BI authors couple the results of these subset analyses of VHSP’s asymptomatic patients with a retrospective database compilation of other antiretroviral observational cohorts to state in their abstract conclusion, “analyses . . . demonstrated no significant differences in the rate of serious hepatic events among antiretroviral regimens.” We are concerned that BI’s less than comprehensive compilation of the available data may mislead the reader into thinking that there is no increased risk of hepatotoxicity associated with nevirapine use. In this letter, we would like to address a few issues regarding the data analyses from all 3 subsets of the VHSP so that a comprehensive hepatic safety assessment of nevirapine may be possible.
We first discuss the analysis of the patient subset with asymptomatic aspartate aminotransferase (AST)/alanine aminotransferase (ALT) increases. The patient cohort described in this publication included 1731 patients from 9 controlled studies of nevirapine that were analyzed as part of BI’s VHSP. According to Stern et al., 1 the incidence of asymptomatic increases in AST/ALT >5× ULN was similar in the nevirapine group (5.8%) and in the control group (5.5%). It is important to point out, however, that these results were largely driven by one trial, BI 1090. This one study, which enrolled primarily men (79%) with an average baseline CD4 count of 107 cells/mm 3, accounted for 1121 (68%) of the total controlled database. 2 When the results were analyzed without including patients from BI 1090, the rate of asymptomatic increases in AST/ALT >5× ULN was significantly (P < 0.01) higher in the nevirapine group (5.9%) compared to the control group (2.9%). 1 Different study populations and risk factors probably account for the differential rates of nevirapine toxicity in these controlled studies. The rate of hepatic events was higher in trials enrolling more women and in study populations with higher CD4 counts.
Next, although the authors did not include the results from other patient subsets (i.e., symptomatic hepatic events), these results have been reviewed by the US Food and Drug Administration as part of BI’s Labeling Supplemental application and have been presented in the last several years at scientific meetings. 3–5 A total of 285 patients (11% of all nevirapine recipients in controlled and uncontrolled trials included in the VHSP) had hepatic adverse events associated with nevirapine use. In the BI analysis, symptomatic hepatic adverse events were divided into 2 categories: rash-associated hepatic events and other symptomatic events. Rash-associated events occurred in 57 subjects (2.2%) receiving nevirapine and other symptomatic hepatic events occurred in 68 subjects (2.7%) receiving nevirapine; when the analysis was limited to controlled trials, more subjects receiving nevirapine than receiving controls had either rash-associated or other symptomatic hepatic events (P < 0.01 for both comparisons). 4 The risk of rash-associated hepatic adverse events was 3-fold higher in women than in men. A rash-associated hepatic event was also associated with a higher CD4 count. In the noncomparative trial FTC-302, which enrolled 384 patients, of whom 59% were female, 2 women receiving nevirapine who had CD4 counts >400 μL died from fulminant hepatic failure. 6 The increased risk of hepatic adverse events for women included in BI’s VHSP was observed at lower CD4 counts than for men. When the risk of rash-associated hepatic events in women with CD4 counts <250 cells/mm 3 was compared to those with CD4 counts of ≥250, the risk ratio was 9.8. When the risk of rash-associated events was compared in men with CD4 counts <400 cells/mm 3 to those with counts of ≥400, the risk ratio was 6.4. In these symptomatic patient subsets (not included in the BI publication), there was a significantly higher risk of hepatotoxicity associated with nevirapine use, particularly in women and in patients with higher CD4 counts.
Health care providers caring for HIV-infected patients must be aware of the risks associated with nevirapine use and should not be misled by this publication of a subset analysis. This is particularly important in light of reports of hepatic failure leading to liver transplantation and death, including deaths in pregnant and nonpregnant women receiving nevirapine. 6–8 Viramune’s manufacturer, BI, has recently described the significantly higher risk of nevirapine hepatotoxicity in women and in patients with higher CD4 counts in the nevirapine package insert. 9 Hepatic transaminases should be followed closely in all patients receiving nevirapine, and nevirapine should be permanently discontinued in all patients who develop hepatitis while receiving nevirapine. 9
Melisse Sloas Baylor, MD
1. Stern JO, Robinson PA, Love J, et. al. A comprehensive hepatic safety analysis of nevirapine in different populations of HIV infected patients. J Acquir Immune Defic Syndr
. 2003;34(suppl 1):S21–33.
2. Haverkos H. Medical Officer’s Review. U.S. Food and Drug Administration Supplemental New Drug Application 20-636/SE-017. April 11, 2002.
3. Baylor M. Medical Officer’s Review. U.S. Food and Drug Administration Labeling Supplement (Changes Being Effected) to New Drug Application 20-636/S-020. July 10, 2003.
4. Imperiale SM, Stern JO, Love JT, et al. The VIRAMUNE Nevirapine Hepatic Safety Project: analysis of symptomatic hepatic events. Paper presented at: 4th
International Workshop on Adverse Events and Lipodystrophy in HIV. September 22–25, 2002; San Diego, CA. Abstract 87.
5. Stern JO, Love JT, Robinson PA, et al. Hepatic safety of nevirapine: results of the Boehringer Ingelheim Viramune Hepatic Safety Project. Paper presented at: XIV International AIDS Conference; July 7–12, 2002; Barcelona, Spain. Abstract LBOr15.
7. Boxwell D, Haverkos H, Struble K, et al. Serious adverse events attributed to nevirapine regimens for postexposure prophylaxis after HIV exposure: worldwide, 1997-2000. MMWR Morb Mortal Wkly Rep.
8. Lyons F, Hopkins S, McGeary A, et. al. Nevirapine tolerability in HIV-1 infected women in pregnancy: a word of caution. Paper presented at: International AIDS Society; July 13–16, 2003; Paris. Abstract LB27.
9. Viramune [package insert]. Boehringer-Ingelheim Pharmaceuticals, Inc, Ridgefield, CT; revised December 22, 2003.
© 2004 Lippincott Williams & Wilkins, Inc.