Pregnancy not nevirapine associated with risk of hepatotoxicity in large cohort comparison
Polly Clayden, HIV i-Base
There is some uncertainty about the association between nevirapine, pregnancy and hepatotoxicity in HIV-positive women.
In a concise communication, published in the November 27 2009 edition of AIDS, David Ouyang and investigators from two large American multicentre cohorts, the Women and Infants Transmission Study (WITS) and the International Maternal Paediatric Adolescent Clinical Trials (IMPAACT) protocol P1025, showed findings from a study to estimate whether this association differs by pregnancy status in HIV-positive women.
The study compared pregnant women in WITS and IMPAACT to a non-pregnant reference group from the Women Interagency HIV Study (WIHS).
Cox proportional hazard models were used to investigate the association between nevirapine use and any liver enzyme elevation (LEE, grade 1-4) and severe LEE (grade 3-4). Potential confounders included pregnancy status.
The analysis included a total of 2050 HIV-positive women receiving HAART of which 60% were pregnant.
Pregnant women in this analysis were younger than non-pregnant, mean age 27.99 vs 35.96, p<0.001. They had higher CD4, lower viral loads and had been HIV-positive for a shorter duration of time. They also had less chronic hepatitis and were more likely to be both ART and nevirapine naive. A similar proportion of pregnant and non-pregnant women had been exposed to nevirapine, with a greater proportion of non-pregnant women having CD4 >=250 cells/mm3. See Table 1.
Table 1. CD4 cell count of women receiving NVP by pregnancy status
Overall the investigators found pregnant women were significantly more likely than non-pregnant women to develop any LEE, 14.2 vs 9.1% respectively, p=0.0001. They also had a higher rate of severe LEE, 1.2 vs 0.6%, although this difference did not reach statistical significance.
Multivariate analysis found pregnancy to be significantly associated with any LEE, RR 4.7 (95% CI, 3.39-6.53, p<0.01 and with severe LEE, RR 3.8 (95% CI, 1.3-11.1). However, nevirapine was not significantly associated with any LEE, RR 1.17 (95% CI, 0.8-1.7) or severe LEE, RR 1.78 (95% CI 0.4-7.82) and this was regardless of pregnancy status. The investigators noted that due to concerns in the literature about nevirapine exposure at higher CD4 counts, these variables were included in the multivariate models despite not being significant in univariate analysis and they continued to demonstrate no association with LEE.
Thee investigators wrote: While we support close monitoring for clinical or laboratory evidence of hepatotoxicity with any ART regimen, our results challenge the notion that NVP is uniquely associated with hepatotoxicity during pregnancy.
It seems likely that pregnancy does not increase the risk of nevirapine-related toxicity at CD4 counts below 250 cells/mm3 and is therefore safe to prescribe in pregnancy in accordance with current guidelines.
However, it gets more complicated with regard to safety of nevirapine in pregnant women with CD4 counts greater than 250 cells/mm3, and this study, along with others, is not showing any signal or nevirapine-associated toxicity in pregnancy.
It is also notable that expert panel reviews for new WHO guidance did not confirm an increase of serious adverse events and concluded that the benefits of using nevirapine in this situation outweigh the risks of not initiating ART (see our review of WHO guideline revisions).
Given the temporary pregnancy related immunodeficiency in addition to any HIV-related immunodeficiency it certainly seems sensible to re-run these analyses at higher CD4 counts – eg 400 cells/mm3.
Ouyang et al. Increased risk of hepatotoxicity in HIV-infected pregnant women receiving antiretroviral therapy independent of nevirapine exposure. AIDS 2009, 23:2425-2430.