Risk of Acute Liver Injury With Antiretroviral Therapy by Viral Hepatitis Status

Abstract

Background: The risk of hepatotoxicity with antiretroviral therapy (ART) remains unknown. We determined the comparative risk of acute liver injury (ALI) for antiretroviral drugs, classes, and regimens, by viral hepatitis status.

Methods: We followed a cohort of 10 083 human immunodeficiency virus (HIV)-infected persons in Kaiser Permanente Northern California (n = 2099) from 2004 to 2010 and the Veterans Aging Cohort Study (n = 7984) from 2004 to 2012. Within the first year of ART, we determined occurrence of (1) liver aminotransferases >200 U/L and (2) severe ALI (coagulopathy with hyperbilirubinemia). We used Cox regression to determine hazard ratios (HRs) with 95% confidence intervals (CIs) of endpoints among initiators of nucleos(t)ide analogue combinations, antiretroviral classes, and ART regimens, all stratified by viral hepatitis status.

Results: Liver aminotransferases >200 U/L developed in 206 (2%) persons and occurred more frequently among HIV/viral hepatitis-coinfected than HIV-monoinfected persons (116.1 vs 20.7 events/1000 person-years; P < .001). No evidence of differential risk was found between initiators of abacavir/lamivudine versus tenofovir/emtricitabine among coinfected (HR, 0.68; 95% CI, .29-1.57) or HIV-monoinfected (HR, 1.19; 95% CI, .47-2.97) groups. Coinfected patients had a higher risk of aminotransferases >200 U/L after initiation with a protease inhibitor than nonnucleoside reverse-transcriptase inhibitor (HR, 2.01; 95% CI, 1.36-2.96). Severe ALI (30 events; 0.3%) occurred more frequently in coinfected persons (15.9 vs 3.1 events/1000 person-years; P < .001) but was too uncommon to evaluate in adjusted analyses.

Conclusions: Within the year after ART initiation, aminotransferase elevations were infrequently observed and rarely led to severe ALI. Protease inhibitor use was associated with a higher risk of aminotransferase elevations among viral hepatitis-coinfected patients.

Keywords: HIV; antiretroviral; drug-induced liver injury; hepatotoxicity.

Figure 1.

Selection of patients into the study from Kaiser Permanente Northern California and the Veterans Aging Cohort Study. ^aIndex Date is the earliest qualifying date the antiretroviral therapy was dispensed in an outpatient setting on or after January 1, 2004. ^bSevere acute liver injury is defined as total bilirubin >2 times the upper limit of normal and an international normalized ratio (INR) ≥1.5 in an inpatient or outpatient setting. ^cAcute liver injury is defined as (1) inpatient or outpatient alanine aminotransferase or aspartate aminotransferase >200 U/L; (2) a total bilirubin >2 times the upper limit of normal and an INR ≥1.5 in an inpatient or outpatient setting; or (3) inpatient INR ≥1.5 and either hepatic encephalopathy or liver transplantation in the absence of chronic liver disease. KPNC, Kaiser Permanente Northern California; VACS, Veterans Aging Cohort Study.

Figure 2.

Comparative risk of liver aminotransferase levels >200 U/L among users of different nucleoside reverse-transcriptase inhibitor (NRTI) combinations (Model A), antiretroviral classes (Model B), and antiretroviral regimens (Model C). ^a“Other” includes regimens with <2 NRTIs or alternative NRTI combinations than those listed. ^bEach model adjusted for baseline alanine aminotransferase >40 U/L, calendar year of antiretroviral therapy initiation, and data source. ^cOther refers to regimens with none or >1 of the listed antiretroviral class. ABC, abacavir; ATV/r, boosted atazanvir; DRV/r, boosted darunavir; EFV, efavirenz; FTC, emtricitabine; INSTI, integrase inhibitor; LPV/r, boosted lopinavir; PI, protease inhibitor; TDF, tenofovir; ZDV, zidovudine; 3TC, lamivudine.