The use of the nevirapine (Viramune) by women with a low body mass index (BMI) should be discouraged, according to a study published in the March 15th edition of The Journal of Infectious Diseases which found that women with a BMI below 18.5 who received the drug were significantly more likely to develop severe liver side-effects.
Liver toxicities are a well established side-effect of nevirapine, and the use of the drug is not recommended in men with a pre-treatment CD4 cell count above 400 cells/mm3 and in women with a pre-treatment CD4 cell count above 250 cells/mm3.
Investigators wishes to determine the risk factors and symptoms associated with the emergence of grade three or grade four elevations in ALT or AST levels during the first twelve weeks of antiretroviral therapy. The study population consisted of treatment naïve South African men and non-pregnant women with a viral load above 5,000 copies/ml and a CD4 cell count above 200 cells/mm3. All patients were screened for hepatitis B virus prior to entry to the study, and those who developed liver toxicities were retrospectively tested for hepatitis C virus.
Individuals were randomised to receive either FTC or 3TC with d4T and either nevirapine or efavirenz. A total of 468 individuals were recruited to the study between August 1999 and February 2000, and they were equally randomisation was equal between the nevirapine and efavirenz arms.
In total 66 (14%) patients developed severe hepatotoxicity, with the frequency of severe liver toxicity being 17% in the nevirapine arm and 0% in the efavirenz arm (p
The occurrence of severe liver toxicity was equal between nevirapine patients randomised to receive FTC and 3TC.
Clinical symptoms occurred in 83% of patients prior to the diagnosis of hepatotoxicity. Symptoms included nausea, vomiting, fever, malaise, rash, diarrhoea, jaundice and abdominal pain. Rash was significantly associated with the occurrence of severe liver toxicity (p = 0.01).
In multiple regression analysis, the investigators identified female sex, BMI below 18.5, serum albumin levels below 35g/l, mean corpuscular volume above 85fl, viral load below 20,000 copies/ml, lactate dehydrogenase below 164IU/l and AST below 75IU/l as being independent and significant risk factors for the emergence of severe liver side-effects in the first twelve weeks of nevirapine treatment.
Women with a BMI below 18.5 had a 50% probability of experiencing severe hepatotoxicity, however the probability for women with a BMI above 18.5 was 17%. For men with a BMI below 18.5 the probability of developing severe liver toxicities was 15% and 7% for men with a BMI above 18.5.
Two women died as a result of the severe liver toxicities they developed during the study. Both had normal ALT and AST levels at baseline and neither had hepatitis coinfection.
ALT/AST levels returned to grade two level or lower within a median of 37 days in patients who continued taking nevirapine and in 19 days in patients who stopped treatment.
“Our data demonstrate a high risk (17%) of early hepatotoxicity associated with the use of nevirapine. The specific study population, which consisted mainly of African women with relatively high baseline CD4 cell counts (mean 398 cells/mm3), may have increased the likelihood of hepatotoxicity. These observations are important, because nevirapine is commonly used as a component in first-line therapy, in resource limited settings, especially in women”, write the investigators.
The investigators note that a low BMI was an independent risk factor for the development of severe liver toxicities amongst women taking nevirapine. They believe that a low BMI could leave to over-exposure to nevirapine, which triggers toxicity.
Doctors should avoid treating women with a BMI below 18.5 with nevirapine, conclude the investigators and should conduct weekly monitoring of ALT/AST levels to spot the early signs of liver toxicity during the initial weeks of treatment with the drug when it is used. Rash, nausea, or fever during the first twelve weeks of nevirapine treatment should trigger closer monitoring.
Sanne I et al. Severe hepatotoxicity associated with nevirapine use in HIV-infected subjects. J Infect Dis 191: 825 – 829, 2005.