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Al-Nimer MSM. Is COVID-19-induced liver injury different from other RNA viruses? World J Meta-Anal 2021; 9:108-127. [DOI: 10.13105/wjma.v9.i2.108] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2021] [Revised: 03/12/2021] [Accepted: 04/23/2021] [Indexed: 02/06/2023] Open
Abstract
Coronavirus disease 2019 is a pandemic disease caused by a novel RNA coronavirus, SARS coronavirus 2 (SARS-CoV-2), which is implicated in the respiratory system. SARS-CoV-2 also targets extrapulmonary systems, including the gastrointestinal tract, liver, central nervous system and others. SARS-CoV-2, like other RNA viruses, targets the liver and produces liver injury. This literature review showed that SARS-CoV-2-induced liver injury is different from other RNA viruses by a transient elevation of hepatic enzymes and does not progress to liver fibrosis or other unfavorable events. Moreover, SARS-CoV-2-induced liver injury usually occurs in the presence of risk factors, such as nonalcoholic liver fatty disease. This review highlights the important differences between RNA viruses inducing liver injury taking into consideration the clinical, biochemical, histopathological, postmortem findings and the chronicity of liver injury that ultimately leads to liver fibrosis and hepatocellular carcinoma.
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Affiliation(s)
- Marwan SM Al-Nimer
- Department of Clinical Pharmacy, Hawler Medical University, Erbil 44001, Iraq
- College of Medicine, University of Diyala, Baqubah 32001, Iraq
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Rachlis A, Clotet B, Baxter J, Murphy R, Lefebvre E. Safety, Tolerability, and Efficacy of Darunavir (TMC114) with Low-Dose Ritonavir in Treatment-Experienced, Hepatitis B or C Co-infected Patients in POWER 1 and 3. HIV CLINICAL TRIALS 2015; 8:213-20. [PMID: 17720661 DOI: 10.1310/hct0804-213] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
PURPOSE This subanalysis examines the safety and efficacy of darunavir with low-dose ritonavir (DRV/r) in hepatitis B or C virus (HBV or HCV) co-infected patients in POWER 1 and 3 trials. METHOD POWER 1 and 3 enrolled treatment-experienced, HIV-infected patients with > or =1 primary protease inhibitor (PI) mutation and HIV-1 RNA >1,000 copies/mL. All patients received an optimized background regimen plus either control PI (almost all ritonavir boosted) or one of four DRV/r doses (POWER 1) or DRV/r 600/100 mg bid (POWER 3). Patients with active HBV or HCV co-infection who did not require treatment for hepatitis were included. Safety parameters were evaluated. RESULTS Of 634 DRV/r and 63 control (97% ritonavir boosted) patients assessed, 13% and 16%, respectively, had active co-infection. In both groups, more patients with active co-infection than without co-infection had liver-related adverse events (AEs). These AEs were mainly asymptomatic liver transaminase elevations, although changes were slightly less in the DRV/r group (DRV/r, 13% vs. 8%; control PI, 20% vs. 12%). Only two patients (one per treatment arm) discontinued therapy due to grade 3 or 4 alanine and aspartate transaminase elevations. CONCLUSION DRV/r was generally well tolerated in treatment-experienced, HBV or HCV co-infected patients. No differences in liver-related AEs were observed between treatment groups.
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Affiliation(s)
- Anita Rachlis
- Division of Infectious Disease, Department of Medicine, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada.
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Di Biagio A, Nicolini LA, Lorenzini P, Puoti M, Antinori A, Cozzi-Lepri A, Gori A, Vecchiet J, Mussini C, Andreoni M, Viscoli C, d'Arminio Monforte A, For The Icona Foundation Study Group. Liver enzyme elevation during darunavir-based antiretroviral treatment in HIV-1-infected patients with or without hepatitis C coinfection: data from the ICONA foundation cohort. HIV CLINICAL TRIALS 2014; 15:151-60. [PMID: 25143024 DOI: 10.1310/hct1504-151] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
OBJECTIVES To investigate differences in liver enzyme elevation (LEE) between HIV-infected patients with and without HCV coinfection who start a darunavir/ritonavir-containing regimen. METHODS HIV-infected patients enrolled in the Italian Cohort of Naïve to Antiretrovirals (ICONA) Foundation Study were included if they started darunavir/ritonavir for the first time. Patients were classified as not HCV coinfected, HCV active coinfected (HCV RNA positive), and HCV nonactive coinfected (HCV-Ab positive/HCV RNA negative). Time to LEE endpoint was defined using the ACTG toxicity scale, based on changes relative to baseline. Kaplan-Meier was used to estimate 1-year and 2-year probability of LEE. The incidence rate ratios (IRRs) of LEEs were estimated until the last follow-up (intention-to-treat analysis [ITT]) and up to darunavir/ritonavir discontinuation (on-treatment analysis [OT]). RESULTS Overall, 703 patients were included. Ninety-one were HCV-Ab positive; of those, 68 (9.7%) had active HCV coinfection. In 879 person-years of follow-up, 101 LEEs occurred (ITT). No severe hepatotoxicity event was registered in active HCV coinfected patients. HCV active coinfection was predictive of LEE in the overall population (OT: adjusted incidence rate ratio (IRR), 2.25; 95% CI, 0.70-7.24; P = .17; ITT: adjusted IRR, 3.62; 95% CI, 1.67-7.83; P < .001) and in naïve patients (OT: adjusted IRR, 6.29; 95% CI, 2.54-15.55; P = .00; ITT: adjusted IRR, 3.87; 95% CI, 0.99-15.16; P = .05). CONCLUSIONS No grade 3-4 LEEs occurred in HCV active coinfected patients. HCV active coinfected patients experienced low grade LEEs more frequently than HCV-Ab negative patients. Darunavir/ritonavir seems to be safe whatever the HCV status, when liver enzymes are carefully monitored.
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Affiliation(s)
- Antonio Di Biagio
- Clinica Malattie Infettive, IRCCS Azienda Ospedaliera Universitaria San Martino-IST, Genova, Italy
| | - Laura Ambra Nicolini
- Clinica Malattie Infettive, IRCCS Azienda Ospedaliera Universitaria San Martino-IST, Genova, Italy
| | | | - Massimo Puoti
- Malattie Infettive Azienda Ospedaliera Niguarda Ca' Grande, Milano, Italy
| | | | | | - Andrea Gori
- Malattie Infettive Azienda Ospedaliera Universitaria San Gerardo, Monza, Italy
| | - Jacopo Vecchiet
- Clinica Malattie Infettive Università di Chieti, Chieti, Italy
| | | | - Massimo Andreoni
- Clinica Malattie Infettive Università di Tor Vergata, Roma, Italy
| | - Claudio Viscoli
- Clinica Malattie Infettive, IRCCS Azienda Ospedaliera Universitaria San Martino-IST, Genova, Italy
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Mikl J, Sulkowski MS, Benhamou Y, Dieterich D, Pol S, Rockstroh J, Robinson PA, Ranga M, Stern JO. Hepatic profile analyses of tipranavir in Phase II and III clinical trials. BMC Infect Dis 2009; 9:203. [PMID: 20003457 PMCID: PMC2803791 DOI: 10.1186/1471-2334-9-203] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2009] [Accepted: 12/14/2009] [Indexed: 11/17/2022] Open
Abstract
Background The risk and course of serum transaminase elevations (TEs) and clinical hepatic serious adverse event (SAE) development in ritonavir-boosted tipranavir (TPV/r) 500/200 mg BID recipients, who also received additional combination antiretroviral treatment agents in clinical trials (TPV/r-based cART), was determined. Methods Aggregated transaminase and hepatic SAE data through 96 weeks of TPV/r-based cART from five Phase IIb/III trials were analyzed. Patients were categorized by the presence or absence of underlying liver disease (+LD or -LD). Kaplan-Meier (K-M) probability estimates for time-to-first US National Institutes of Health, Division of AIDS (DAIDS) Grade 3/4 TE and clinical hepatic SAE were determined and clinical actions/outcomes evaluated. Risk factors for DAIDS Grade 3/4 TE were identified through multivariate Cox regression statistical modeling. Results Grade 3/4 TEs occurred in 144/1299 (11.1%) patients; 123/144 (85%) of these were asymptomatic; 84% of these patients only temporarily interrupted treatment or continued, with transaminase levels returning to Grade ≤ 2. At 96 weeks of study treatment, the incidence of Grade 3/4 TEs was higher among the +LD (16.8%) than among the -LD (10.1%) patients. K-M analysis revealed an incremental risk for developing DAIDS Grade 3/4 TEs; risk was greatest through 24 weeks (6.1%), and decreasing thereafter (>24-48 weeks: 3.4%, >48 weeks-72 weeks: 2.0%, >72-96 weeks: 2.2%), and higher in +LD than -LD patients at each 24-week interval. Treatment with TPV/r, co-infection with hepatitis B and/or C, DAIDS grade >1 TE and CD4+ > 200 cells/mm3 at baseline were found to be independent risk factors for development of DAIDS Grade 3/4 TE; the hazard ratios (HR) were 2.8, 2.0, 2.1 and 1.5, respectively. Four of the 144 (2.7%) patients with Grade 3/4 TEs developed hepatic SAEs; overall, 14/1299 (1.1%) patients had hepatic SAEs including six with hepatic failure (0.5%). The K-M risk of developing hepatic SAEs through 96 weeks was 1.4%; highest risk was observed during the first 24 weeks and decreased thereafter; the risk was similar between +LD and -LD patients for the first 24 weeks (0.6% and 0.5%, respectively) and was higher for +LD patients, thereafter. Conclusion Through 96 weeks of TPV/r-based cART, DAIDS Grade 3/4 TEs and hepatic SAEs occurred in approximately 11% and 1% of TPV/r patients, respectively; most (84%) had no significant clinical implications and were managed without permanent treatment discontinuation. Among the 14 patients with hepatic SAE, 6 experienced hepatic failure (0.5%); these patients had profound immunosuppression and the rate appears higher among hepatitis co-infected patients. The overall probability of experiencing a hepatic SAE in this patient cohort was 1.4% through 96 weeks of treatment. Independent risk factors for DAIDS Grade 3/4 TEs include TPV/r treatment, co-infection with hepatitis B and/or C, DAIDS grade >1 TE and CD4+ > 200 cells/mm3 at baseline. Trial registration US-NIH Trial registration number: NCT00144170
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Affiliation(s)
- Jaromir Mikl
- SUNY at Albany, School of Public Health, Rensselaer NY, USA.
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Bansi L, Turner J, Gilson R, Post F, Gazzard B, Leen C, Anderson J, Porter K, Hill T, Fisher M, Ainsworth J, Pillay D, Johnson M, Winston A, Orkin C, Easterbrook P, Phillips A, Sabin C, UK Collaborative HIV Cohort Study. Is 1 alanine transaminase >200 IU enough to define an alanine transaminase flare in HIV-infected populations? A new definition derived from a large cohort study. J Acquir Immune Defic Syndr 2009; 52:391-6. [PMID: 19553826 DOI: 10.1097/qai.0b013e3181ab73cc] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
OBJECTIVES Recent studies have suggested that highly active antiretroviral therapy may lead to rises in alanine transaminase (ALT) among HIV-infected patients. However, the definition of an ALT flare is arbitrary and the extent to which such increases represent normal fluctuations has not been explored. METHODS Using data from untreated, hepatitis B virus/hepatitis C virus-negative, HIV-infected patients, we derived a definition for an ALT flare by exploring a series of ALT thresholds (from 100 to 200 IU/L). The resulting definition (2 consecutive ALTs > 200 measured >2 weeks apart) was applied to all patients in the UK Collaborative HIV Cohort (CHIC) Study, and Poisson regression was used to identify factors associated with ALT flares. RESULTS Five hundred and twenty six of 12,206 eligible patients (4.3%) had > or =1 ALT flare, resulting in a total of 615 episodes of ALT flares. The overall rate of an ALT flare was 1.19 (95% confidence interval: 1.10 to 1.28) per 100 person-years. Higher risk of ALT flare was associated with lower CD4 counts, detectable viral loads, being under follow-up in earlier calendar years, prior clinical AIDS, receipt of nevirapine either with didanosine/stavudine or without didanosine/stavudine, receipt of ritonavir, detectable anti-hepatitis C virus, and detectable hepatitis B surface antigen. CONCLUSIONS Associations between known risk factors may be under/over estimated if using single values, that is, 1 ALT > 200, to define ALT flares. We recommend studies to use a more stringent measure and suggest our derived definition of an ALT flare.
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Affiliation(s)
- Loveleen Bansi
- Research Department of Infection and Population Health, University College London Medical School, London, UK.
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Puoti M, Nasta P, Gatti F, Matti A, Prestini K, Biasi L, Carosi G. HIV-related liver disease: ARV drugs, coinfection, and other risk factors. ACTA ACUST UNITED AC 2009; 8:30-42. [PMID: 19211929 DOI: 10.1177/1545109708330906] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Highly-active antiretroviral therapy (HAART) has proven remarkably effective for prolonging the life of patients with human immunodeficiency virus (HIV). However, while most HAART agents are safe, many have the potential to cause liver toxicity. Physicians must therefore consider the possibility of drug-induced liver injury in the management of HIV-infected patients, especially those with certain risk factors such as coinfection with hepatitis B virus (HBV) or hepatitis C virus (HCV), female gender, alcohol abuse, older age, or obesity. Understanding how, when, and why drug-related liver damage occurs is key to managing these patients safely and effectively. Knowledge of HAART-related liver effects will help ensure that patients receive the most benefit with the least toxicity from any given drug regimen. As more information about the mechanisms of drug related liver injury is known, clinicians will be better able to tailor therapies to suit individual situations, resulting in greater patient safety and outcomes.
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Affiliation(s)
- Massimo Puoti
- Department of Infectious and Tropical Diseases, University of Brescia, AO Spedali Civili, Brescia, Italy.
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Abstract
Antiretroviral therapy (ART) for HIV infection frequently has been associated with elevated liver enzyme levels. Determining the cause of elevated liver enzyme levels in patients who have HIV is difficult because ART usually consists of three different drugs, patients may be taking additional hepatotoxic medications and patients who have HIV often suffer from other liver diseases. Several agents, however, are recognized as having noteworthy and specific patterns of toxicity. This article reviews the different HIV drug classes, incidence of elevated liver enzyme values by class and by individual drug, risk factors, specific toxicities, and possible mechanisms of injury.
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Affiliation(s)
- Mamta K Jain
- University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-9113, USA.
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Chihrin S, Antoniou T, Raboud J, Shen S, Govan V, Fletcher D, Rachlis A, Kovacs C, Crouzat F, Tilley D, Chang B, Saskin R, Loutfy MR. Risk factors for grade 3-4 liver enzyme elevation in HIV and hepatitis C coinfected patients on combination antiretroviral therapy. AIDS Patient Care STDS 2007; 21:469-78. [PMID: 17651028 DOI: 10.1089/apc.2006.0113] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Although coinfection with hepatitis C (HCV) is an established risk factor for hepatotoxicity in HIV-positive patients receiving combination antiretroviral therapy (cART), specific variables that may be predictive of severe hepatotoxicity among co-infected patients receiving cART remain poorly defined. A retrospective cohort study of HIV/HCV coinfected adults from two HIV treatment centers covering the period between December 1998 and December 2003 was conducted to address this question. The primary endpoint of the study was the occurrence of grade 3 or 4 elevation of serum alanine aminotransferase (ALT) during follow-up and the primary predictors of interest were specific antiretrovirals. One hundred five coinfected patients receiving cART for a median of 70 months (interquartile range [IQR], 37, 83) were included in the analysis. Twenty-three (22%) patients developed a grade 3 or 4 increase in serum ALT at least once in follow-up. In univariate analysis, current receipt of lopinavir/ritonavir (LPV/r) (odds ratio [OR] 3.09, 95% confidence interval [CI] 1.14-8.34, p = 0.03), baseline ALT (OR 1.01, 95% CI 1.00-1.02, p = 0.004), and current use of boosting ritonavir (OR 2.84, 95% CI 1.16-7.00, p = 0.02) were significantly associated with a grade 3 or 4 increase in serum ALT, although most patients receiving boosting ritonavir were on lopinavir/ritonavir based regimens. Patients receiving LPV/r had been previously exposed to significantly more antiretrovirals (p < 0.0001), protease inhibitors (p < 0.0001), and nucleoside analogues (p = 0.0009) compared to the rest of the cohort. Further research to better clarify risk factors for hepatotoxicity in coinfected patients is warranted given the challenges in treating this population.
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Affiliation(s)
- S Chihrin
- Maple Leaf Medical Clinic, Toronto, Ontario, Canada
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Cicconi P, Cozzi-Lepri A, Phillips A, Puoti M, Antonucci G, Manconi PE, Tositti G, Colangeli V, Lichtner M, Monforte AD. Is the increased risk of liver enzyme elevation in patients co-infected with HIV and hepatitis virus greater in those taking antiretroviral therapy? AIDS 2007; 21:599-606. [PMID: 17314522 DOI: 10.1097/qad.0b013e328013db9c] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
OBJECTIVES To investigate if the risk of liver enzyme elevation (LEE) in HIV/hepatitis B or C (HBV, HCV) co-infection is altered by HAART (two or more drugs). METHODS Analysis comprised HIV-positive patients in the ICoNA study without acute hepatitis who had >or= 1 positive HCV antibody test and > 1 positive HBV surface antigen test. LEE was defined as > 5x baseline alanine aminotransferase (ALT) or > 3.5x baseline if the baseline was > 40 IU/l. Analysis used Poisson regression with generalized estimating equation correction to examine HBV or HCV co-infection, use of HAART, baseline ALT and demographics as LEE predictors. RESULTS Of the 5272 patients, 47.6% were co-infected with HCV/HBV; 29.9% were female and 39% were intravenous drug users. There were 275 episodes of LEE during 18 259 person-years follow up. Taking HAART did not significantly increase risk of LEE [adjusted relative risk (RR), 1.19; 95% confidence interval (CI), 0.81-1.75; P = 0.37]. Co-infection increased the risk of LEE (adjusted RR, 5.07; 95% CI, 3.47-7.48; P < 0.001), with no significant differences if taking HAART (adjusted RR, 4.99; 95% CI, 3.38-7.37) or not (adjusted RR, 6.02; 95% CI, 2.02-17.98) (P = 0.74 for interaction). Females were at lower risk of LEE than males (adjusted RR, 0.59; 95% CI, 0.42-0.83; P = 0.02). CONCLUSIONS HIV and HBV/HCV co-infection per se is associated with increased risk of LEE that is not modified by HAART. The recommendation for caution in HAART use in co-infected patients, simply based on a high rate of LEE in people on therapy, may be questionable.
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Affiliation(s)
- Paola Cicconi
- Clinic of Infectious Diseases and Tropical Medicine University of Milan, Milan, Italy.
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Abstract
PURPOSE OF REVIEW To summarize the pertinent case reports, case series and clinical studies that described clinical, histological, epidemiological and mechanistic features of drug-induced liver disease in 2005. RECENT FINDINGS Acetaminophen, highly active antiretroviral therapy and drugs for tuberculosis retained their preeminent position as the most commonly reported agents causing drug-induced liver disease, with acetaminophen continuing to be the leading cause of acute liver failure in the USA. While the frequency of drug-induced liver disease remains low, a large case-series of acute drug-induced liver disease from Spain and Sweden supported the observation that acute hepatocellular jaundice from a drug is associated with death or the need for transplant in at least 10% (known as Hy's Law). With respect to using potentially hepatotoxic medications in patients with underlying liver disease, statins and second-generation thiazolidinediones were shown to be safe when used in patients with elevated baseline alanine aminotransferase or aspartate aminotransferase levels. SUMMARY Drug-induced liver disease remains an important cause of acute liver failure, and research efforts by the National Institutes of Health and others are underway to better determine the risk factors and other host susceptibilities that will allow for the safer use of drugs in the future.
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Affiliation(s)
- James H Lewis
- Division of Gastroenterology, Georgetown University Medical Center, Washington DC 20007, USA.
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