Liver Toxicity of Antiretroviral Drugs

Jones, Mitchell L.; Núñez, Marina

doi:10.1055/s-0032-1316472

Cited by 58 publications

(37 citation statements)

References 81 publications

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“…Side effects have been reported to be associated with different classes of anti-HIV drugs, including nucleoside reverse transcriptase inhibitors, non-nucleoside analogue reverse transcriptase inhibitors, and HIV protease inhibitors [69].…”

Section: Anti-hiv Drugsmentioning

confidence: 99%

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Endoplasmic Reticulum Stress in Drug- and Environmental Toxicant-Induced Liver Toxicity

Chen

Melchior

Guo

2014

Journal of Environmental Science and Health, Part C

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Liver injury resulting from exposure to drugs and environmental chemicals is a major health problem. Endoplasmic reticulum stress (ER stress) is considered to be an important factor in a wide range of diseases, such as cancer, neurological and cardiovascular disease, diabetes, and inflammatory diseases. The role of ER stress in drug-induced and environmental toxicant-induced liver toxicity has been underestimated in the past; emerging evidence indicates that ER stress makes a substantial contribution to the pathogenesis of drug-induced liver toxicity. In this review, we summarize current knowledge on drugs and environmental toxicants that trigger ER stress in liver and on the underlying molecular mechanisms. We also discuss experimental approaches for ER stress studies.

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Section: Anti-hiv Drugsmentioning

confidence: 99%

“…Although generally considered safe, some evidence indicates that efavirenz disrupts lipid metabolism [70] and induces liver fibrosis [69,71]. An in vitro study demonstrated that a battery of ER stress markers was induced when primary human hepatocytes and Hep3B cells were exposed to clinically relevant concentrations of efavirenz [72,73].…”

Section: Efavirenzmentioning

confidence: 99%

Endoplasmic Reticulum Stress in Drug- and Environmental Toxicant-Induced Liver Toxicity

Chen

Melchior

Guo

2014

Journal of Environmental Science and Health, Part C

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“…On the other hand, antiretroviral (ARV) treatment-associated hepatotoxicity is of increasing concern in the management of patients with HIV/AIDS ( Jones and Nunez, 2012;Reisler et al, 2003;Turkova et al, 2009;Ugiagbe et al, 2012;Walker, 2007).…”

Section: Introductionmentioning

confidence: 99%

Genome-Wide Association and Replication Study of Hepatotoxicity Induced by Antiretrovirals Alone or with Concomitant Anti-Tuberculosis Drugs

Petros

Lee

Takahashi

et al. 2017

OMICS: A Journal of Integrative Biology

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Drug-induced hepatotoxicity (DIH) is a common adverse event that is associated with both antiretroviral (ARV) and anti-tuberculosis drugs (ATD). Moreover, the genetic variations predisposing ARV-and ARV-ATDinduced liver toxicity in African populations are not well investigated, despite the two diseases being the major global health problems in sub-Saharan Africa. We performed a genome-wide association study (GWAS) and replication study to identify the genetic variants linked to the risk of developing DIH due to ARV drugs alone, and ARV-ATD co-treatment in Ethiopian HIV-positive patients. Treatment-naïve newly diagnosed HIV patients (n = 719) with or without tuberculosis (TB) co-infection were enrolled prospectively and received efavirenz-based ARV therapy with or without rifampicin-based short course ATD, respectively. Whole-genome genotyping was performed by using the Illumina Omni Express Exome Bead Chip genotyping array with 951,117 single nucleotide polymorphisms (SNPs) on a total of 41 cases of DIH, and 452 people without DIH (treatment tolerants). The replication study was carried out for 100 SNPs with the lowest p-values (top SNPs) by using an independent cohort consisting of 18 DIH cases and 208 treatment tolerants. We identified a missense SNP rs199650082 (2756G/A, R919Q, p = 1.4 · 10 -6 , odds ratio [OR] = 18.2, 95% confidence interval [CI] = 7.1-46.9) in an endoplasmic reticulum to the nucleus signaling-1 (ERN1) gene on chromosome 17 to be associated with DIH in the ARV-only cohort. In the ARV-ATD co-treatment groups, rs4842407, a long intergenic noncoding RNAs (lincRNAs) transcript variant on chromosome 12, was associated with DIH ( p = 5.3 · 10 -7, OR = 5.4, 95% CI = 2.8-10.3). These genetic variants that are putatively associated with DIH due to ARV drugs alone and ARV-ATD co-treatment establish a foundation for future personalized medicine in people with HIV and TB and call for larger studies in independent populations.

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“…However, these studies focused on risks associated with individual antiretrovirals used in the early ART era and did not stratify results by viral hepatitis status [6, 7, 11–15]. Analyses that evaluate antiretroviral-associated hepatotoxicity in clinical practice settings are important to ensure the safety of these medications among HIV-infected individuals, particularly those with viral hepatitis coinfection.…”

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confidence: 99%

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

Gowda

Newcomb

Liu

et al. 2017

Open Forum Infectious Diseases

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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.

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Liver Toxicity of Antiretroviral Drugs

Cited by 58 publications

References 81 publications

Endoplasmic Reticulum Stress in Drug- and Environmental Toxicant-Induced Liver Toxicity

Endoplasmic Reticulum Stress in Drug- and Environmental Toxicant-Induced Liver Toxicity

Genome-Wide Association and Replication Study of Hepatotoxicity Induced by Antiretrovirals Alone or with Concomitant Anti-Tuberculosis Drugs

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

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