July 12, 2004
It is well known that HIV-infected patients with hepatitis C virus (HCV) are at greater risk of antiretroviral-induced hepatotoxicity. Some studies suggest that they may have a less robust immunologic response as well. Less clear are the relative risks of individual agents, with the possible exception of the idiosyncratic increase in liver toxicity caused by nevirapine (NVP, Viramune) in women with CD4+ cell counts >250 or men with CD4+ cell counts >400. This systematic review of several industry-sponsored studies of lopinavir/ritonavir (LPV/r, Kaletra) provides some estimate of the relative risk of the hepatotoxicity of this agent.
Eight clinical trials were reviewed for safety, tolerability and efficacy data at 48 weeks, including studies in both treatment-naive and treatment-experienced subjects. The basis for this comparison was 132 patients with chronic HCV and/or hepatitis B (HBV) infection, and 687 without. A similar analysis was done on a smaller group of patients (11 with hepatitis, 89 without) at 5 years in the treatment-naive 720 study of stavudine (d4T, Zerit), lamivudine (3TC, Epivir) and lopinavir/ritonavir.
Not surprisingly, grade 3 elevations (more than 5 times the upper limit of normal) in alanine transaminase (ALT) and aspartate transaminase (AST) were more common in those with HBV and/or HCV coinfection than those without, a finding consistent with analyses of other antiretroviral regimens. Aside from these increases, however, there were no differences between groups with regards to adverse event, treatment discontinuation, rates of HIV-RNA suppression or deaths. Immunologic recovery, as measured by CD4+ cell count, was also similar for the 2 groups. The 5-year analysis of the 720 study also showed no difference in time to loss of virologic response or CD4+ cell recovery between the 2 groups, although the study numbers here were clearly much smaller.
There are two important limitations to these analyses. First, as is the case with most clinical trials, patients with severe hepatic impairment (who are at greatest risk for hepatic decompensation due to antiretroviral therapy) were excluded from participation. Second, HCV and HBV infection were grouped together, even though the clinical course and treatment for the 2 viruses are markedly different. Nonetheless, the results provide reassuring data that, exclusive of transaminase elevation, short-term outcomes of lopinavir/ritonavir-based treatment in clinically stable patients are similar in those who do and do not have HCV and/or HBV. Of note, data presented at the 11th Conference on Retroviruses and Opportunistic Infections from the randomized, prospective 863 study comparing lopinavir/ritonavir and nelfinavir (NFV, Viracept)1 demonstrated similarly low rates of grade 3/4 liver function test abnormalities, as well as equal CD4+ cell increases.