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

Gowda, Charitha; Newcomb, Craig; Liu, Qing; Carbonari, Dena M.; Forde, Kimberly A.; Goldberg, David S.; Reddy, K. Rajender; Roy, Jason; Marks, Amy R.; Schneider, Jennifer L.; Kostman, Jay R.; Tate, Janet P.; Lim, Joseph K.; Justice, Amy C.; Goetz, Matthew Bidwell; Corley, Douglas A.; Re, Vincent Lo

doi:10.1093/ofid/ofx012

Cited by 7 publications

(4 citation statements)

References 37 publications

(51 reference statements)

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“…17 months), however, makes it difficult to impute LEE exclusively to the toxicity of underlying ART, but may suggest a mechanism of additive effects of multiple factors, wich add up over time, and that may be more or less fauvored by the concomitant ART. Of note, LEE incidence rate in our work was lower than those reported in the past, 21,41,48,49 suggesting a more hepatic friendly profile of the newer therapies, togeter with reduction of hepatic comorbidities such as hepatitis coinfection. 50 Indeed, besides initial ART, the stronger predictors of LEE resulted HBV or HCV coinfections, in accordance with previous studies.…”

Section: Discussioncontrasting

confidence: 51%

“…7,[18][19][20] Moreover, few data about INSTI tolerability are available in the population of PLWHIV co-infected with HBV or HCV, especially in comparison with other classes of antiretroviral agents. 21,22 The aim of the present study is to compare the incidence of LEE events in PLWHIV in first line antiretroviral therapy with different class agents, and identify the possible predictors of LEE.…”

Section: Introductionmentioning

confidence: 99%

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Incidence and risk factors for liver enzyme elevation among naive HIV-1-infected patients receiving ART in the ICONA cohort

Taramasso

Lorenzini

Biagio

et al. 2019

Journal of Antimicrobial Chemotherapy

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Objectives To evaluate the incidence and risk factors for liver enzyme elevations (LEE) in patients initiating first-line ART in the ICONA prospective observational cohort, between June 2009 and December 2017. Patients and methods In total, 6575 ART-naive patients were selected, initiating two NRTIs with the third drug being a boosted PI (n=2436; 37.0%), an NNRTI (n=2384; 36.3%) or an integrase strand transfer inhibitor (INSTI) (n=1755; 26.7%). HBV surface antigen and HCV RNA were detected in 3.9% and 5.8% of the study population. Inverse probability weighted Cox regression analysis was used to calculate the HRs, according to first-line regimen, for LEE, defined as ALT or AST increases of ≥2.5× upper limit of normal (ULN) for patients with normal baseline values or ≥2.5× baseline for patients with higher baseline values. Results One hundred and eighty-three LEE occurred over 20722 patient-years of follow-up. After adjusting for the main confounders, the risk of LEE halved with INSTIs compared with NNRTIs (HR 0.46, 95% CI 0.25–0.86), with a significant reduction in the raltegravir group (HR 0.11, 95% CI 0.02–0.84 using the NNRTI class as reference). HRs for LEE were significantly higher in subjects with HBV or HCV coinfection, in patients with poorly controlled HIV infection and in those who acquired HIV through homosexual transmission. Conclusions In our study, INSTI use almost halved the risk of LEE compared with other regimens. This finding could be particularly important for choosing ART in patients with risk factors for liver toxicity such as HCV and HBV coinfections.

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Section: Discussioncontrasting

confidence: 51%

Section: Introductionmentioning

confidence: 99%

Incidence and risk factors for liver enzyme elevation among naive HIV-1-infected patients receiving ART in the ICONA cohort

Taramasso

Lorenzini

Biagio

et al. 2019

Journal of Antimicrobial Chemotherapy

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“…Antimicrobial medications represented 64% of the medications from groups 1 and 2 with the highest rates of severe ALI. Antifungal and older antiretroviral medications have been particularly implicated as hepatotoxic . This is consistent with our findings.…”

Section: Discussionsupporting

confidence: 93%

Severe Acute Liver Injury After Hepatotoxic Medication Initiation in Real-World Data

Torgersen,

Mezochow,

Newcomb

et al. 2024

JAMA Intern Med

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ImportanceCurrent approaches to classify the hepatotoxic potential of medications are based on cumulative case reports of acute liver injury (ALI), which do not consider the size of the exposed population. There is little evidence from real-world data (data relating to patient health status and/or the delivery of health care routinely collected from sources outside of a research setting) on incidence rates of severe ALI after initiation of medications, accounting for duration of exposure.ObjectiveTo identify the most potentially hepatotoxic medications based on real-world incidence rates of severe ALI and to examine how these rates compare with categorization based on case reports.Design, Setting, and ParticipantsThis series of cohort studies obtained data from the US Department of Veterans Affairs on persons without preexisting liver or biliary disease who initiated a suspected hepatotoxic medication in the outpatient setting between October 1, 2000, and September 30, 2021. Data were analyzed from June 2020 to November 2023.ExposuresOutpatient initiation of any one of 194 medications with 4 or more published reports of hepatotoxicity.Main Outcomes and MeasuresHospitalization for severe ALI, defined by either inpatient: (1) alanine aminotransferase level greater than 120 U/L plus total bilirubin level greater than 2.0 mg/dL or (2) international normalized ratio of 1.5 or higher plus total bilirubin level greater than 2.0 mg/dL recorded within the first 2 days of admission. Acute or chronic liver or biliary disease diagnosis recorded during follow-up or as a discharge diagnosis of a hospitalization for severe ALI resulted in censoring. This study calculated age- and sex-adjusted incidence rates of severe ALI and compared observed rates with hepatotoxicity categories based on cumulative published case reports.ResultsThe study included 7 899 888 patients across 194 medication cohorts (mean [SD] age, 64.4 [16.4] years, 7 305 558 males [92.5%], 4 354 136 individuals [55.1%] had polypharmacy). Incidence rates of severe ALI ranged from 0 events per 10 000 person-years (candesartan, minocycline) to 86.4 events per 10 000 person-years (stavudine). Seven medications (stavudine, erlotinib, lenalidomide or thalidomide, chlorpromazine, metronidazole, prochlorperazine, and isoniazid) exhibited rates of 10.0 or more events per 10 000 person-years, and 10 (moxifloxacin, azathioprine, levofloxacin, clarithromycin, ketoconazole, fluconazole, captopril, amoxicillin-clavulanate, sulfamethoxazole-trimethoprim, and ciprofloxacin) had rates between 5.0 and 9.9 events per 10 000 person-years. Of these 17 medications with the highest observed rates of severe ALI, 11 (64%) were not included in the highest hepatotoxicity category when based on case reports.Conclusions and RelevanceIn this study, incidence rates of severe ALI using real-world data identified the most potentially hepatotoxic medications and can serve as a tool to investigate hepatotoxicity safety signals obtained from case reports. Case report counts did not accurately reflect the observed rates of severe ALI after medication initiation.

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“…Acute liver injury (ALI), also known as acute liver failure, is caused by various factors, including drug stimulation [ 1 ], viral infection [ 2 ], alcohol consumption [ 3 ], and chemical toxins [ 4 ]. It is associated with severe impairment or liver function loss.…”

Section: Introductionmentioning

confidence: 99%

Role of liensinine in sensitivity of activated macrophages to ferroptosis and in acute liver injury

Li,

Huang,

et al. 2023

Cell Death Discov.

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Acute liver injury (ALI) is an acute inflammatory liver disease with a high mortality rate. Alternatively, activated macrophages (AAMs) have been linked to the inflammation and recovery of ALI. However, the mechanism underlying AAM death in ALI has not been studied sufficiently. We used liensinine (Lie) as a drug of choice after screening a library of small-molecule monomers with 1488 compounds from traditional Chinese remedies. In ALI, we evaluated the potential therapeutic effects and underlying mechanisms of action of the drug in ALI and found that it effectively inhibited RSL3-induced ferroptosis in AAM. Lie significantly reduced lipid peroxidation in RSL3-generated AAM. It also improved the survival rate of LPS/D-GalN-treated mice, reduced serum transaminase activity, suppressed inflammatory factor production, and may have lowered AAM ferroptosis in ALI. Lie also inhibited ferritinophagy and blocked Fe2+ synthesis. Following combined treatment with RSL3 and Lie, super-resolution microscopy revealed a close correlation between ferritin and LC3-positive vesicles in the AAM. The co-localization of ferritin and LC3 with LAMP1 was significantly reduced. These findings suggest that Lie may ameliorate ALI by inhibiting ferritinophagy and enhancing AMM resistance to ferroptosis by inhibiting autophagosome-lysosome fusion. Therefore, Lie may be used as a potential therapeutic agent for patients with ALI.

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

Cited by 7 publications

References 37 publications

Incidence and risk factors for liver enzyme elevation among naive HIV-1-infected patients receiving ART in the ICONA cohort

Incidence and risk factors for liver enzyme elevation among naive HIV-1-infected patients receiving ART in the ICONA cohort

Severe Acute Liver Injury After Hepatotoxic Medication Initiation in Real-World Data

Role of liensinine in sensitivity of activated macrophages to ferroptosis and in acute liver injury

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