Lopinavir/ritonavir not linked to hepatotoxicity regardless of HCV status

Use of lopinavir/ritonavir (Kaletra) is not associated with significant liver toxicity even in patients coinfected with the hepatitis C virus (HCV), according to an American study published in the November 21, 2004 edition of AIDS.

Hepatotoxicity, indicated by elevation of the liver enzymes ALT and AST, is a potential treatment-limiting side effect of certain HIV medications. Liver toxicity is a particular concern for individuals with coexisting liver problems, including chronic hepatitis B or C. High-dose (1200 mg/day) ritonavir (Norvir) is more likely than other drugs in its class to cause severe hepatotoxicity (27% incidence in one previous study). However, the risk is substantially reduced when using lower doses to augment - or “boost” - blood concentrations of other protease inhibitors (PIs).

Noting that side effect rates observed in well-defined clinical trials tend to be lower than those seen under “real-world” conditions, Mark Sulkowski, MD, and colleagues examined the prevalence of drug-related hepatotoxicity in a cohort of 1,161 HIV-positive patients at an urban HIV clinic who were starting PI-based antiretroviral therapy for the first time. Regimens used included lopinavir boosted with 200 mg daily ritonavir (89 patients), unboosted indinavir (Crixivan) (100 patients), indinavir boosted with 200-400 mg daily ritonavir (94 patients), saquinavir (Invirase, Fortovase) plus 800 mg daily ritonavir (273 patients), and unboosted nelfinavir (Viracept) (605 patients); fewer than 1% of subjects were taking amprenavir (Agenerase), and atazanavir (Reyataz) and fosamprenavir (Lexiva, Telzir) were not yet available at the time of the study.

Patient demographic characteristics were similar among the groups taking the different regimens. About 75% were male, but there were more women (31%) in the nelfinavir group. Median age was about 37 years. About three-quarters were black and about one-quarter were white. About 37% overall were injection drug users, rising to 47% in the nelfinavir group. HCV seropositivity rates ranged from 39% in the saquinavir/ritonavir group to 49% in the nelfinavir group, while the overall HBV seroprevalence rate was 8-10%. HIV disease status varied more widely among the groups. Median CD4 cell count ranged from 76 to 309 cells/mm3, HIV viral load ranged from 3.5 to 5.0 log copies/mL, and 9-38% had undetectable HIV RNA (below 400 copies/mL).

Study data were collected for individuals receiving care between January 1996 and March 2003. All patients received regular liver enzyme monitoring, typically four weeks after starting therapy and then every 12 weeks. The researchers defined severe (grade 3 or 4) hepatotoxicity as a serum ALT or AST level more than five times the upper limit of the normal range if subjects had a normal baseline level, or at least a 3.6-fold increase if they had an elevated baseline level.

After beginning PI-based therapy, serum ALT and AST levels increased significantly in all treatment groups. However, the magnitude of increase was greater for subjects receiving saquinavir/ritonavir compared with other PI regimens (p Viramune) in their regimen developed severe liver toxicity, compared with 12.2% who included efavirenz (Sustiva, Stocrin) and 11.1% who included no NNRTIs.

HIV/HCV-coinfected patients were significantly more likely than HCV-negative subjects to develop any grade of hepatotoxicity (65% vs 35%; p

The researchers concluded that lopinavir/ritonavir is not associated with a significantly increased risk of hepatotoxicity in either HIV/HCV-coinfected or HIV-monoinfected individuals compared with nelfinavir, which does not require ritonavir boosting. “[A]ccordingly,” the study authors recommended, “other medication-related characteristics (e.g., efficacy, resistance, and non-hepatic adverse effects) should guide individual treatment decisions.”