Predictors of antiretroviral-related hepatotoxicity in the Adult AIDS Clinical Trial Group (1989-1999)

HIV antiretroviral therapy (ART)-related hepatotoxicity is a significant clinical problem, resulting in severe elevations of liver enzymes and, potentially, liver failure and death. We retrospectively determined baseline clinical predictors of severe hepatotoxicity (SH; serum aminotransferases or total bilirubin > 5 times and > 2.5 times the upper limit of normal [ULN], respectively) among 8851 subjects enrolled in 16 Adult AIDS Clinical Trial Group studies from October 1989 to June 1999. Subjects were divided into the following treatment categories: single nucleoside reverse transcriptase inhibitors (NRTIs), multiple NRTIs, normucleoside reverse transcriptase inhibitors (NNRTls) combined with NRTIs, and the protease inhibitor (PI) indinavir (IDV) combined with NRTIs. SH occurred in 824 (9.3%) subjects, in 613 (6.92%) in the first 6 months and in another 211(2.38%) in the subsequent 6 months of study ART. Consistent with other reports, baseline elevation in serum aminotransferases was a significant risk factor for SH for all regimens. Risk factors not previously identified included concomitant hepatotoxic medications, thrombocytopenia, and renal insufficiency. Hepatitis C virus coinfection was associated with an increased risk of SH (odds ratio [OR] = 2.7; P < 0.003). In conclusion, this study identified known and previously unreported risk factors for severe hepatotoxicity that should be considered before the initiation of ART.