Nevirapine Liver Toxicity not Linked to Gender or Higher CD4 Counts in 2 Studies

By Liz Highleyman

Several previous trials and reports of "real world" use have indicated that treatment-naive patients taking nevirapine (Viramune) may develop liver toxicity (hepatotoxicity). Based on past data, women appear to be at higher risk than men, as do individuals with higher CD4 cell counts (above 250 cells/mm3 for women and above 400 cells/mm3 for men).

However, 2 studies presented at the 46th ICAAC, held last week in San Francisco, found that these groups were not more prone to develop nevirapine-related liver problems.

Study 1

In the first presentation, German researchers reported on the incidence of nevirapine-associated liver toxicity determined via a retrospective review of medical records of patients starting nevirapine between 1996 and 2005 at a single center in Munich.

The mean observation time was 21 months. Liver toxicity was defined as an alanine transaminase (ALT) elevation of more than 5 times the upper limit of normal (x ULN), or Grade 3-4, at the latest measurement. The researchers assessed the role of potential risk factors including gender, CD4 count, hepatitis B or C coinfection (HBV, HCV), and baseline ALT.

Results

507 patients started on nevirapine during the study period, of whom 22% were women.

13% of patients were coinfected with hepatitis B or C.

17% of patients had an elevated baseline ALT above 1.25 x ULN.

40% of women had CD4 cell counts greater than 250 cells/mm3 and 27% of men had CD4 counts above 400 cells/mm3.

Liver toxicity was observed in 4.6% of patients overall, and 7.5% discontinued therapy due to elevated liver enzymes.

Among women with CD4 counts above 250 cells/mm3, 5.6% experienced a Grade 3-4 ALT elevations, compared to 6.3% of women with lower CD4 counts.

Among men with CD4 counts above 400 cells/mm3, 6.5% developed liver toxicity, compared with 3.4% of men with lower CD4 counts

Grade 3-4 elevations of GGT (another liver enzyme) were seen in 10.4% of patients.

In a multivariate analysis, the only independent risk factors for ALT greater than 5 x ULN were:

- coinfection with hepatitis B or C (OR 3.9; 95% CI 1.6-11.6);
- baseline ALT elevation (OR 4.8; 95% CI 1.8-12.2).

Gender and CD4 count were not significantly associated with increased risk of liver toxicity.

Conclusion

"In this cohort of 507 HIV patients on nevirapine, hepatotoxicity defined by an ALT elevation [greater than] 5 x ULN occurred in 5% of patients," the researchers concluded. "We identified hepatitis B/C and a baseline ALT elevation as independent risk factors, but not female gender or a high CD4 count."

Study 2

In the second study, Spanish researchers aimed to determine the risk of liver toxicity when virologically suppressed patients switched to nevirapine. They performed a meta-analysis of all randomized studies in which virologically suppressed individuals changed to a regimen containing nevirapine and had at least 3 months of follow-up.

CD4 counts were classified as "high" if they were above 250 cells/mm3 in women or above 400 cells/mm3 in men. Hepatotoxicity was defined as ALT or aspartate transaminase (AST) elevations above 200 U/L if levels were normal at baseline, or a 3-fold or greater increase if levels were abnormal at baseline, within the first 3 months after starting nevirapine.

Results

4 studies with a total of 410 patients were included.

133 patients were classified into the low CD4 group and 277 into the high CD4 group.

The risk of hepatotoxicity was 2% in the low CD4 group and 4% in the high CD4 group, but the different did not reach statistical significance (OR 1.46; P = 0.54).

The overall odds ratio (OR) for hepatotoxicity or skin rash was 1.17 (P = 0.68).

The risk of hepatotoxicity at any moment during the evolution of therapy was similar in the high CD4 and low CD4 groups, with a combined hazard ratio of 0.85 (P = 0.80).

The only factor associated with increased risk of hepatotoxicity was elevated baseline transaminase levels (P = 0.08).

2 patients (1%) in the high CD4 group developed symptomatic hepatitis; no patients died.

Conclusion

In contrast with treatment-naive patients, the researchers concluded, "virologically suppressed patients do not have a higher risk of hepatotoxicity or rash when stratified by gender and CD4 count."

During the discussion of these studies at the conference, it was noted that it took clinical trials of thousands of patients before the influence of gender and CD4 count on nevirapine toxicity was recognized; it was not apparent in early trials that led to the drug's approval. The 2 recent studies (which included about 500 and 400 subjects, respectively) may not have been large enough to see the same effects, and careful monitoring is still needed when starting nevirapine.

MUC Res., Munich, Germany; HIV Res. and Clinical Care Ctr., Munich, Germany.

Hospital Clinic, Barcelona, Spain.

10/03/06

References

E Wolf, C Koegl, T Theobald, and others. Nevirapine-Associated Hepatotoxicity: No Increased Risk for Females or High CD4 Count in a Single-Centre HIV Cohort. 46th ICAAC. San Francisco, CA. September 27-30, 2006. Abstract H-1063.

E De Lazzari, A Leon, J A Arniaz, and others. Risk of Hepatotoxicity in Virologically Suppressed HIV Patients Switching to Nevirapine According to Gender and CD4 Count. 46th ICAAC. San Francisco, CA. September 27-30, 2006. Abstract H-1064.

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