13 There is difficulty discerning and dissecting out the number of individual factors that may contribute collectively to liver damage

in patients receiving antiretroviral therapy. Several drugs are combined in a given HAART regimen making difficult the attribution of hepatotoxicity to a particular drug. Moreover, HIV-infected patients may be receiving concurrent medications with potential for liver toxicity as well, such as antimycobacterial drugs, lipid-lowering agents, antifungals, antibiotics, and anticonvulsants. It is also difficult to make comparisons among reported cohorts, because individuals often differ on the factors predisposing to elevations of liver enzymes, like the presence/absence of concurrent viral hepatitis. Biochemical, pharmacokinetic/dynamic, and pathological correlations ICG-001 of HAART hepatotoxicity have been poorly characterized, which makes it often difficult to determine the true incidence of drug-induced liver injury. In many instances, the hepatotoxic potential of a drug has been recognized only after post-marketing experience with the drug. Chronic viral hepatitis has been consistently reported to increase the risk of severe HAART hepatotoxicity (relative risk = 2.1).14 There is an estimated 2.7-fold to 5-fold increased risk of severe alanine aminotransferase (ALT) elevation on HAART with hepatitis C virus (HCV) coinfection.15-17

Chronic hepatitis B virus (HBV) infection appears to also carry a higher risk, with a 9.2 hazard risk of grade 4 liver enzyme elevations reported in one study.17 The same authors Romidepsin concentration also observed that discontinuing lamivudine, an antiretroviral also active against HBV, was a factor associated with aminotransferase elevation in HIV/HBV-coinfected patients (hazard risk = 6.8 for grade 4 liver toxicity).17 The presence of underlying liver inflammation as reflected by elevated ALT at baseline has been also identified as a risk factor for HAART liver toxicity.16, 17 Isolated

studies have identified additional host factors including older age, female sex, thrombocytopenia, renal insufficiency, high HIV RNA levels, increased body mass index, and non-black ethnicity.15-18 Aside from host factors, several individual antiretrovirals or classes have been independently Parvulin associated with HAART hepatotoxicity, such as nevirapine, protease inhibitors, high doses of ritonavir (≥600 mg/day), and prolonged zidovudine or stavudine exposure.14, 17, 18 Alcohol use and concurrent hepatotoxic medications are additional factors identified.15, 16, 18 Lastly, an increase in CD4 cell counts of >50 cells/mm3 after HAART initiation was associated with almost two-fold increased risk of severe ALT elevation in one study.14 Other risk factors individual to each pathogenic mechanism are covered within its corresponding section. A major challenge for mechanistic classifications is that the pathogenesis of drug hepatotoxicity is poorly understood in many instances.