Older drugs, including the deoxynucleotides (e.g., didanosine and stavudine), were highly injurious, often leading to mitochondrial injury and oxidative stress (OS). Many of these agents are still in use. Risk of mitochondrial injury can be categorized by agent: didanosine (2′,3′-dideoxyinosine or ddI) > stavudine (d4T) > zidovudine (ZDV or AZT) ≫> tenofovir (TFV or tenofovir disoproxil fumarate Ferroptosis targets [TDF]); lamivudine (Lam

or 3TC); emtricitabine (FTC); and abacavir (ABC). Furthermore, there is some evidence that prolonged exposure to agents such as ddI (didanosine) may be associated with the development of noncirrhotic PH.[9] Vispo et al. have proposed a two-hit model that leads to increased risk among patients with a specific genetic predisposition.[10]

Drug-related hypersensitivity injury to the liver represents another mechanism of injury with a unique pattern of histology. It is noted in 5%-8% of all patients exposed to abacavir, but, in the setting of human leukocyte antigen (HLA)-B*5701, has a prevalence SB203580 manufacturer of 45%. HLA testing and avoidance of abacavir in patients with HLA-B*5701 prevents development of this type of hepatotoxicity. Similarly, nevirapine-mediated hypersensitivity reactions occur in 5%-7% of exposed persons, but are very frequent in those with low body mass index (BMI), high CD4 count and with HLA DRB1*0101. The NIH has created a U.S. network to study drug hepatotoxicity, including toxicity associated http://www.selleck.co.jp/products/Staurosporine.html with antiretroviral agents. In the NIH Drug-Induced Liver Injury Network database, the majority of HIV patients

enrolled are men. Their age is higher than non-HIV-infected patients in the database. Fifty-seven percent had hepatocellular injury and 43% had mixed or cholestatic injuries reported. Acute hepatitis E infection can mimic drug-induced liver injury and must be considered in the differential diagnosis.[11] Antiretroviral therapy is currently recommended by several U.S. agencies for all HIV-infected persons (http://aidsinfo.nih.gov/guidelines).[12] ART used to be indicated only for persons with lower CD4+ lymphocyte count (e.g., <350/mm3). However, there is accumulating evidence of a survival benefit for taking ART at essentially all CD4+ lymphocyte counts.[13] An even greater urgency for antiretroviral therapy is emphasized for persons with HBV or HCV coinfection, given accumulating data that ART might attenuate the progression of liver fibrosis. In one recent study, a cohort of 638 coinfected adults receiving care at the Johns Hopkins HIV clinic between July 1993 and August 2011, persons receiving effective antiretroviral therapy had 73% fewer clinical events than those not on ART.[14] Special emphasis is also given to providing ART to other special patient groups, such as pregnant women and persons with HIV-infected nephropathy. This “special” emphasis might override factors that would weigh against using antiretroviral therapy, such as poor anticipated adherence.