Clinical Syndromes and Consequences of Antiretroviral-Related Hepatotoxicity

Department of Internal Medicine, Wake Forest University Health Sciences, Winston Salem, NC 27157, USA.
Hepatology (Impact Factor: 11.19). 09/2010; 52(3):1143-55. DOI: 10.1002/hep.23716
Source: PubMed

ABSTRACT Highly active antiretroviral therapy (HAART)-related hepatotoxicity complicates the management of patients infected with human immunodeficiency virus (HIV), increases medical costs, alters the prescription patterns, and affects the guideline recommendations. Among the clinical consequences derived from HAART-related liver toxicity, hypersensitivity reactions and lactic acidosis are recognized as acute events with potential to evolve into fatal cases, whereas there seems to be other syndromes not as well characterized but of equal concern as possible long-term liver complications. Belonging to the latter category of syndrome, HAART-related nonalcoholic steatohepatitis, liver fibrosis, portal hypertension, and nodular regenerative hyperplasia are discussed in this review. Updated information on liver toxicity of current antiretroviral drugs, including the most recently licensed, is provided. Management and prevention of liver toxicity among HIV-infected patients treated with HAART are reviewed as well.

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    • "Among the indirect mechanisms, the most important is based on an impaired T-cell response to HCV [4], which can be only partially reverted by antiretroviral treatment [2]; in fact, end-stage liver disease actually represents the leading cause of mortality among HIV-positive patients, regardless of the use of ART [5]. Moreover, HIV itself and certain antiretrovirals may contribute to liver disease by inducing the metabolic syndrome [6]. In addition, HIV infection of the gastrointestinal tract amplifies microbial translocation which can stimulate hepatocytes, Kupffer cells (KCs), and hepatic stellate cells (HSC) to produce pro-inflammatory cytokines and chemokines. "
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    ABSTRACT: In HIV/HCV co-infected patients, HIV-1 gp120 activates human hepatic stellate cells (HSCs) which play a key role in fibrosis pathogenesis. It is still unclear whether pro-fibrogenic effects are more attributable to X4 or R5 strains in vivo. To assess if HIV-1 X4 or R5 variants are associated with a different progression of fibrosis. A total of 105 HIV/HCV co-infected patients were submitted to gp120 sequencing on proviral DNA and classified as X4 or R5 based on g2p (20% false positive rate). The fibrosis evolution was retrospectively determined by means of APRI and FIB-4 scores at 3-month intervals from the first anti-HCV-positive test. The association of co-receptor tropism with increased fibrosis scores was evaluated by linear mixed models. X4 variants were found in 41 patients (39%). The median observation period was similar in X4 and R5 patients (17 years). No difference was observed between the two groups of patients, except for nadir CD4 which was lower in X4 compared to R5 (percentage, p=0.005, and absolute number, p=0.005). X4 and R5 patients did not significantly differ for FIB-4 and APRI score over time (p=0.5, and p=0.1, respectively). No association between HCV-RNA levels over time and co-receptor tropism was noted (p=0.9). Conversely, a significant correlation of fibrosis scores with gamma-glutamyl transferase levels, lower current CD4 count, HIV viremia and use of antiretrovirals was observed. This retrospective analysis of fibrosis evolution did not support the evidence of a differing pro-fibrogenic activity for X4 and R5 HIV-1 variants in HIV/HCV co-infected patients.
    Journal of clinical virology: the official publication of the Pan American Society for Clinical Virology 01/2014; 59(3). DOI:10.1016/j.jcv.2013.12.009 · 3.47 Impact Factor
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    • "In this sense, the study of Guaraldi et al. (2008) suggested that NAFLD is common in HIV patients who have traditional risk factors but this study also highlights that treatment with NRTIs is also an important independent risk factor, increasing up to 11% the risk of developing hepatic impairment for each year of use [60]. Some protease inhibitors are also hepatotoxic, in particular full-dose ritonavir and tipranavir [61]. However, the generalized use of only boosting concentrations of ritonavir prevents the liver toxicity. "
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    ABSTRACT: Highly active antiretroviral therapy (HAART) has considerably improved the prognosis of HIV-infected patients. However, prolonged use of HAART has been related to long-term adverse events that can compromise patient health such as HIV-associated lipodystrophy syndrome (HALS) and nonalcoholic fatty liver disease (NAFLD). There is consistent evidence for a central role of mitochondrial dysfunction in these pathologies. Nucleotide reverse transcriptase inhibitors (NRTIs) have been described to be mainly responsible for mitochondrial dysfunction in adipose tissue and liver although nonnucleoside transcriptase inhibitors (NNRTIs) or protease inhibitors (PIs) have also showed mitochondrial toxicity, which is a major concern for the selection and the long-term adherence to a particular therapy. Several mechanisms explain these deleterious effects of HAART on mitochondria, and evidence points to other mechanisms beyond the "Pol- γ hypothesis." HIV infection has also direct effects on mitochondria. In addition to the negative effects described for HIV itself and/or HAART on mitochondria, HIV-infected patients are more prone to develop a premature aging and, therefore, to present an increased oxidative state that could lead to the development of these metabolic disturbances observed in HIV-infected patients.
    Oxidative Medicine and Cellular Longevity 07/2013; 2013:493413. DOI:10.1155/2013/493413 · 3.36 Impact Factor
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    • "Nevirapine-based HAART induces a faster liver fibrosis in those co-infected with hepatitis C (Macias et al. 2004), most likely due to a hypersensitivity reaction. In addition, some RTIs can have deleterious effects in the liver due to mitochondrial toxicities, which will not be discussed here due to a lack of correlation with metabolic side effects [reviewed in (Nunez 2010)]. However, HIV PIs are known to induce components of the metabolic syndrome, and hepatic alterations have been subsequently found to be at the core. "
    Recent Translational Research in HIV/AIDS, 11/2011; , ISBN: 978-953-307-719-2
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