Liver toxicity in HIV-infected patients receiving novel second-generation nonnucleoside reverse transcriptase inhibitors etravirine and rilpivirine.

There are few data on the hepatic safety profile of the novel second-generation nonnucleoside reverse transcriptase inhibitors etravirine and rilpivirine. Previous extensive studies including other drugs of the same class, nevirapine and efavirenz, have shown an incidence of liver toxicity of 3-20%, higher in the case of nevirapine. The pathogenic mechanisms involved are related to hypersensitivity, as described with nevirapine, impaired metabolism and therefore increased drug levels, and direct toxic effects with production of toxic metabolites. Hepatitis C coinfection seems to be the most important factor for toxicity, especially in the case of advanced liver fibrosis. Etravirine showed a similar rate of liver toxicity to placebo in regulatory studies, but this seems to be lower in the clinical setting, as has been observed in the Expanded Access Program and in cohort studies including HCV/HIV-coinfected patients with different degrees of fibrosis. Also, rilpivirine showed a low rate of liver toxicity, similar to the comparator efavirenz in development studies, even in coinfected patients. Both second-generation nonnucleoside reverse transcriptase inhibitors are rarely associated to hypersensitivity reactions, and drug metabolism is not severely altered in the case of HCV coinfection, at least in the absence of severe fibrosis. Also, both drugs are weak hepatic cell inducers. Therefore, clinical and pathogenic data suggest that both etravirine and rilpivirine are safe to be used in the clinical setting, including patients with liver abnormalities at baseline.