Anti-HIV therapy based on the non-nucleoside (NNRTI) nevirapine (Viramune) is associated with an increased incidence of serious liver toxicities in HIV-positive pregnant women with a CD4 cell count above 250 cells/mm3, according to a study published in the July 1st edition of the Journal of Acquired Immune Deficiency Syndromes. The study was designed to compared the safety and efficacy of HAART regimens based on either the NNRTI nevirapine or the protease inhibitor nelfinavir (Viracept) in HIV-positive pregnant women, however the study was stopped early because of a higher than expected incidence of serious side-effects in the nevirapine arm.
Although the study investigators conclude that nevirapine-based HAART is associated with an increased incidence of severe liver toxicities in women with a CD4 cell count above 250 cells/mm3, they stress that their findings do not suggest that nevirapine use has similar dangers when a single dose is used to prevent mother-to-baby transmission of HIV.
The findinds lend further weight to advice issued by nevirapine's manufacturer, Boehringer Ingleheim, which warned of an increased risk of hepatotoxicity in women with a CD4 cell count above 250 cells/mm3.
A total of 38 HIV-positive women, who had never taken anti-HIV treatment before, were recruited to the US Pediatric AIDS Clinical Trials Group 1022 study. All the women were in their tenth to 30th week of pregnancy, and 17 were randomised to receive nevirapine and 21 to receive nelfinavir. The study medication was provided in combination with the nucleoside analogues 3TC and AZT. Because nevirapine is known to be potentially toxic to the liver, women were excluded from entry to the study if they had abnormal liver function at baseline or were infected with hepatitis B or hepatitis C.
Recruitment to the study was stopped early because of a greater than expected incidence of severe liver side-effects in the nevirapine arm of the trial, and because the manufacturers of nevirapine issued new prescribing information recommending caution if prescribing the drug to women with a CD4 cell count above 250 cells/mm3.
The study investigators performed an unscheduled intent-to-treat analysis of their data. Just under three quarters of the women recruited to the study had a CD4 cell count above 250 cells/mm3, and all had asymptomatic HIV.
Toxicity led one of the 21 patients (5%) randomised to receive nelfinavir to stop treatment, and five of the 17 women taking nevirapine (29%). The woman taking nelfinavir who stopped treatment had a CD4 cell count below 250 cells/mm3, however all of the women ceasing nevirapine therapy because of toxicity had a CD4 cell count above 250 cells/mm3. The woman taking nelfinavir experienced her severe side-effects after six weeks of treatment, and the severe toxicities in the nevirapine arm occurred between weeks two and 26 of treatment.
Nevirapine severe side-effects
One woman taking nevirapine developed Stevens-Johnson syndrome, two woman experienced an increase in their ALTs accompanied by non-specific symptoms suggestive of hepatitis, another woman’s ALT’s increased without symptoms, and the fifth woman experienced liver failure and died.
The woman who died was a 33 year old African-American who entered the study during the 29th week of pregnancy. She was negative for both hepatitis B and hepatitis C at baseline, at which point her ALT levels were normal and AST levels just above the normal range. He CD4 cell count on entry to the study was 330 cells/mm3. Four weeks into the study she developed a transient facial rash, accompanied by increased liver function tests. Six days later she developed fever and malaise and both her ALTs and ASTs had increased further. All anti-HIV medication was stopped, the women was admitted to hospital and had a caesarean delivery. Three days later she developed multi-organ failure and died. A post-mortem examination showed that the woman had liver failure caused by nevirapine treatment.
”We observed greater than expected toxicity associated with nevirapine during the first phase of this randomized trial. All of the adverse events in the nevirapine group occurred among women with an entry CD4 cell count greater than 250 cells/mm3. The hepatic necrosis seen on liver biopsy from the subject who died is consistent with drug-induced hepatic toxicity”, comment the investigators.
The investigators note that both gender and immunological status seem to be associated with the incidence of liver toxicities in individuals taking nevirapine. In men, a CD4 cell count above 400 cells/mm3 is associated with a higher risk of liver problems in patients taking nevirapine, however in women a CD4 cell count of 250 cells/mm3 is the trigger for an increased incidence of liver problems. “There appears to be an interaction between gender and immunologic status as risk factors for rash-associated hepatic toxicity with nevirapine”, comment the investigators. They add, however, that although “the exact mechanism for nevirapine-associated hepatic toxicity is not understood, an immune-mediated hypersensitivity component is postulated.”
The investigators are keen to emphasise that this study has no bearing on the safety of single-dose nevirapine to prevent mother-to-baby transmission of HIV. Nor should their findings imply, they add, that women who are taking nevirapine-based HAART without problems should discontinue their treatment.
Further information on this website
Nevirapine - overview
HIV and women - booklet in the information for HIV-positive people series (pdf)
New warning about nevirapine liver toxicities issued by manufacturer - news story
Hitti J et al. Maternal toxicity with continuous nevirapine in pregnancy: results from PACTG 1022. Journal of Acquired Immune Deficiency Syndromes 36: 772-776, 2004.