134-138 Data with thiazolidinediones (pioglitazone, troglitazone, and rosiglitazone) for the treatment of NASH are more robust.139-142 However, it is unclear whether a thiazolidinedione-associated increase in adiposity and weight gain would ultimately limit its benefits.133 In addition, long-term toxicities of these agents include a potential for cardiovascular events and fracture

risk. Therefore, we need more information regarding the efficacy and safety of these agents before recommendations for safe use can be made. Available information points toward didanosine as the antiretroviral agent linked to cases of noncirrhotic portal hypertension, which should discourage use of this agent.100, 109 With the continued decrease GDC-0449 clinical trial in its use, this complication should fade away and disappear over time. A conclusion which may be drawn from these cases of nodular regenerative hyperplasia is the need to obtain image studies, and in selected cases, also liver biopsy for diagnosis when HIV-infected patients have persistent and unexplained liver enzyme elevation while on HAART. Strategies for the management of noncirrhotic portal hypertension include placement of transjugular intrahepatic portosystemic shunt (TIPS) and liver transplant.143, 144 Anticoagulant

therapy with low-molecular-weight heparin is a more specific treatment for this entity which has been recently reported.145 HAART hepatotoxicity complicates the management of HIV-infected patients, increases medical costs, alters the prescription patterns, and has an impact on official treatment recommendations. Several mechanisms of liver Staurosporine toxicity in patients receiving HAART have been recognized. Although infrequent, HAART-related liver damage may have devastating consequences.

Among clinical syndromes of HAART liver toxicity, hypersensitivity reactions and lactic acidosis are recognized as acute events with potential to evolve MCE into fatal cases, whereas there are other syndromes not as well characterized but of equal concern as possible long-term liver complications. Among the latter, HAART-related NASH, liver fibrosis, portal hypertension, and nodular regenerative hyperplasia are discussed. Prevention is the best strategy to minimize the cases of hepatotoxicity and includes recognition of antiretrovirals’ liver safety profile and of susceptible hosts. Management of hepatotoxic events includes discontinuation of suspected culprits and changes in HAART regimens as well as identification of mechanisms involved and treatment of specific disorders. NOTE: Definition of boxed warning as it is found in the Code of Federal Regulations Title 21, Volume 4 (chapter 1, subchapter c): (1) Boxed warning. Certain contraindications or serious warnings, particularly those that may lead to death or serious injury, may be required by the FDA to be presented in a box.