Serious liver toxicity appears to be no more frequent among Thai patients starting antiretroviral therapy when compared to their Western counterparts, according to a review of 692 patients who took part in clinical trials in the country. However, the study also revealed high rates of liver toxicity in nevirapine-treated patients, and the authors suggest that agents with higher rates of liver toxicity should be avoided where monitoring capability is limited. The study is published in the October 17th edition of AIDS (now available online).
Three hundred and fifty of the 692 received triple combination therapy (215 with a non-nucleoside reverse transcriptase inhibitor, 135 with a protease inhibitor). The remainder received dual nucleoside analogue therapy. Five of the studies were organised by the HIV-Netherlands Australia Thailand Research Collaboration (HIV NAT). The remainder were drug company sponsored studies evaluating either dual NNRTI therapy with nevirapine and/or efavirenz (200 patients) or d4T/3TC/atazanavir (n=31) versus d4T/3TC/efavirenz (15).
Liver function tests were carried out at baseline, and weeks 4, 8, 12, 24, 36 and 48. Severe hepatotoxicity was defined as an ALT elevation of at least five times the upper limit of normal and an increase of at least 100 U/l above baseline. The incidence of severe liver toxicity was 6.1 cases per 100 person years of treatment, but was substantially higher among nevirapine-treated patients (18.5) and patients who received nevirapine and efavirenz together (44.4).
In comparison, an Italian study reported earlier this year found an overall rate of 4.2 cases per 100 person years in a cohort where NNRTI-based therapy was under-represented compared to the Thai study and the definition of severe hepatotoxicity was stricter (ACTG grade 4, or 10 x ULN).
Another cohort study that used the same measure of incidence, conducted among nevirapine treated patients in Spain, found an incidence of 13.1 cases per 100 person years of treatment (Martinez), whilst a Dutch cohort study found an incidence of 6.3 cases per 100 person years, using the stricter grade 4 definition (Wit).
The HIV NAT cohort study found that hepatitis co-infection and NNRTI-containing therapy were both predictors of severe liver toxicity by multivariate analysis. Hepatitis B coinfection carried a relative risk of severe hepatotoxicity of 3.20, HCV coinfection a relative risk of 3.00 and an NNRTI-containing regimen a relative risk of 9.75. The combination of hepatitis coinfection and nevirapine treatment carried the highest risk (RR 57.4 for hepatitis B and 72.2 for hepatitis C).
Although a total of 40 patients experienced severe hepatotoxicity, all were still taking their original assigned regimen after 48 weeks follow-up. Temporary treatment modification according to the protocol of the individual study took place in each case, and ALT levels in these patients had declined close to normal levels by week 48
The authors suggest that despite encouraging findings on the comparability of Thai and Western patients, “development of standardized antiretroviral therapy protocols should consider potential hepatoxicity, and agents with higher rates may be best avoided in settings where monitoring capabilities are limited.”
Nevirapine is widely prescribed in resource-limited settings, in part because the drug is available as part of multiple fixed dose combinations. It is one of the cornerstones of regimens recommended for use in the developing world by the World Health Organisation. In Europe and North America, monitoring for liver toxicity is recommended every 14 days for the first two months of treatment. To date, little information is available on the incidence of serious liver toxicity in nevirapine-treated patients in resource-limited settings outside clinical trials.
Further information on this website
Hepatitis not HAART causing serious liver toxicity in HIV patients – news story March 10 2003
Nevirapine - key research - summary of key studies
HIV & AIDS Treatment in Practice # 2 - Nevirapine-based fixed dose combination ARVs - a review of the use of nevirapine-based therapy in resource-limited settings, April 2003.
References
Law WP et al. Risk of severe hepatotoxicity associated with antiretroviral therapy in the HIV-NAT Cohort, Thailand, 1996-2001. AIDS 17: 2191-2199, 2003.
Martinez E et al. Hepatotoxicity in HIV-1-infected patients receiving nevirapine-containing antiretroviral therapy. AIDS. 2001 Jul 6;15(10):1261-8.
Wit FW et al. Incidence of and risk factors for severe hepatotoxicity associated with antiretroviral combination therapy. J Infect Dis 186: 23-31, 2003.