Integrating hepatotoxicity monitoring withpharmacogenetics in HIV and tuberculosis treatment: anarrative review
Main Article Content
Keywords
Hepatotoxicity; HIV infection; Tuberculosis; Coinfection; Pharmacogenetics
Abstract
Drug-induced hepatotoxicity represents a major clinical challenge in the management of patients with Human Immunodeficiency Virus (HIV), tuberculosis (TB), and HIV–TB coinfection, largely due to prolonged and combined therapeutic regimens that increase exposure to potentially hepatotoxic drugs. Early detection and appropriate classification of liver injury remain essential to prevent severe complications and treatment interruptions. This narrative review aims to examine the integration of hepatotoxicity monitoring with pharmacogenetic determinants in the context of HIV and tuberculosis therapy. Current evidence on the epidemiology, pathophysiological mechanisms, diagnostic approaches, and pharmacogenetic predictors of hepatotoxicity is summarized, with particular emphasis on genetic polymorphisms in drug-metabolizing enzymes such as N-acetyltransferase 2 (NAT2) and cytochrome P450 2B6 (CYP2B6), which influence susceptibility to liver injury associated with isoniazid and efavirenz. The available literature indicates that systematic biochemical monitoring, combined with pharmacogenetic information, may improve risk stratification, facilitate early detection of hepatotoxicity, and support more individualized therapeutic strategies. Integrating clinical assessment with pharmacogenetic data could therefore contribute to optimizing treatment safety and advancing personalized medicine approaches in populations affected by HIV and tuberculosis.
References
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[25] Zhao M, Ma J, Li M, Zhang Y, Jiang B, Zhao X, et al. Cytochrome P450 enzymes and drug metabolism in humans. International Journal of Molecular Sciences. 2021; 22: 12808.
[26] Hardi H, Fitrianti Z, Mahata LE, Louisa M. Pharmacogenetics in tuberculosis–HIV coinfected populations: a systematic review of genetic variants influencing antiretroviral and anti-tuberculosis drug response. Journal of Multidisciplinary Healthcare. 2025; 18: 7203–7218.
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[28] Calcagno A, Cusato J, Sekaggya-Wiltshire C, von Braun A, Motta I, Turyasingura G, et al. The influence of pharmacogenetic variants in HIV/tuberculosis coinfected patients in Uganda in the SOUTH Study. Clinical Pharmacology & Therapeutics. 2019; 106: 450–457.
[29] Mugusi S, Habtewold A, Ngaimisi E, Amogne W, Yimer G, Minzi O, et al. Impact of population and pharmacogenetic variations on efavirenz pharmacokinetics and immunologic outcomes during anti-tuberculosis co-therapy: a parallel prospective cohort study in two sub-Sahara African populations. Frontiers in Pharmacology. 2020; 11: 26.
[30] Cerrone M, Wang X, Neary M, Weaver C, Fedele S, Day-Weber I, et al. Pharmacokinetics of efavirenz 400 mg once daily coadministered with isoniazid and rifampicin in human immunodeficiency virus-infected individuals. Clinical Infectious Diseases. 2019; 68: 446–452.
[31] Covington N, Luetkemeyer AF, Imperial MZ, Dawson R, Cramer Y, Rosenkranz S, et al. Pharmacogenetics of plasma dolutegravir exposure during 1-month rifapentine/isoniazid treatment of latent tuberculosis. Pharmacogenetics and Genomics. 2025; 35: 140–144.
[32] Varadi M, Anyango S, Deshpande M, Nair S, Natassia C, Yordanova G, et al. AlphaFold protein structure database: massively expanding the structural coverage of protein-sequence space with high-accuracy models. Nucleic Acids Research. 2022; 50: D439–D444.
[33] Thomas L, Raju AP, Chaithra S, Kulavalli S, Varma M, Sanju SV, et al. Influence of N-acetyltransferase 2 polymorphisms and clinical variables on liver function profile of tuberculosis patients. Expert Review of Clinical Pharmacology. 2024; 17: 263–274.
[34] Araujo-Mariz C, Albuquerque MFP, Lopes EP, Ximenes RAA, Lacerda HR, Miranda-Filho DB, et al. Hepatotoxicity during TB treatment in people with HIV/AIDS related to NAT2 polymorphisms in Pernambuco, Northeast Brazil. Annals of Hepatology. 2020; 19: 153–160.
[35] Sundell J, Bienvenu E, Janzén D, Birgersson S, Äbelö A, Ashton M. Model-based assessment of variability in isoniazid pharmacokinetics and metabolism in patients co-infected with tuberculosis and HIV: implications for a novel dosing strategy. Clinical Pharmacology & Therapeutics. 2020; 108: 73–80.
[36] Kasamatsu A, Miyahara R, Yoneoka D, Toyo-Oka L, Chiyasirinroje B, Imsanguan W, et al. One-year mortality of tuberculosis patients on isoniazid-based treatment and its association with rapid acetylator NAT2 genotypes. International Journal of Infectious Diseases. 2025; 155: 107895.
[37] Kengo A, Gausi K, Nabisere R, Musaazi J, Buzibye A, Omali D, et al. Unexpectedly low drug exposures among Ugandan patients with TB and HIV receiving high-dose rifampicin. Antimicrobial Agents and Chemotherapy. 2023; 67: e0043123.
[38] Saukkonen JJ, Duarte R, Munsiff SS, Winston CA, Mammen MJ, Abubakar I, et al. Updates on the treatment of drug-susceptible and drug-resistant tuberculosis: an official ATS/CDC/ERS/IDSA clinical practice guideline. American Journal of Respiratory and Critical Care Medicine. 2025; 211: 15–33.
[39] Enimil A, Antwi S, Yang H, Dompreh A, Alghamdi WA, Gillani FS, et al. Effect of first-line antituberculosis therapy on nevirapine pharmacokinetics in children younger than three years old. Antimicrobial Agents and Chemotherapy. 2019; 63: e00839-19.
[40] Chaivichacharn P, Avihingsanon A, Manosuthi W, Ubolyam S, Tongkobpetch S, Shotelersuk V, et al. Dosage optimization of efavirenz based on a population pharmacokinetic–pharmacogenetic model of HIV-infected patients in Thailand. Clinical Therapeutics. 2020; 42: 1234–1245.
[41] Gausi K, Wiesner L, Norman J, Wallis CL, Onyango-Makumbi C, Chipato T, et al. Pharmacokinetics and drug–drug interactions of isoniazid and efavirenz in pregnant women living with HIV in high TB incidence settings: importance of genotyping. Clinical Pharmacology & Therapeutics. 2021; 109: 1034–1044.
[42] Dutra CA, Teixeira RLDF, Lopes MQP, Silva VM, Suffys PN, Carvalho RS, et al. Determination of NAT2 genotypes in a cohort of patients with suspected TB in the state of Rio de Janeiro. Pharmaceutics. 2024; 16: 917.
[43] Cheng F, Jiang XG, Zheng SL, Wu T, Zhang Q, Ye XC, et al. N-acetyltransferase 2 genetic polymorphisms and anti-tuberculosis drug-induced liver injury: a correlation study. Frontiers in Pharmacology. 2023; 14: 1171353.
[44] Sundell J, Bienvenu E, Åbelö A, Ashton M. Effect of efavirenz-based ART on the pharmacokinetics of rifampicin and its primary metabolite in patients coinfected with TB and HIV. Journal of Antimicrobial Chemotherapy. 2021; 76: 2950–2957.
[2] Andrade RJ, Chalasani N, Björnsson ES, Suzuki A, Kullak-Ublick GA, Watkins PB, et al. Drug-induced liver injury. Nature Reviews Disease Primers. 2019; 5: 58.
[3] Wang Y, Xie W. Drug-induced liver injury: an overview and update. Gastroenterology & Endoscopy. 2023; 1: 102–109.
[4] Suzuki A, Chen M. Epidemiology and risk determinants of drug-induced liver injury: current knowledge and future research needs. Liver International. 2025; 45: e16146.
[5] Meintjes G, Maartens G. HIV-associated tuberculosis. The New England Journal of Medicine. 2024; 391: 343–355.
[6] Dhillon P. How to write a good scientific review article. The FEBS Journal. 2022; 289: 3592–3602.
[7] Skat-Rørdam J, Lykkesfeldt J, Gluud LL, Tveden-Nyborg P. Mechanisms of drug induced liver injury. Cellular and Molecular Life Sciences. 2025; 82: 213.
[8] Kumar A, Patel R, Kumar S, Kumar R. Antituberculosis drugs-induced hepatotoxicity: an update. Tropical Gastroenterology. 2024; 45: 125–133.
[9] Daly AK. Genetics of drug-induced liver injury: current knowledge and future prospects. Clinical and Translational Science. 2023; 16: 37–42.
[10] Nyangwara V, Waja Z, Thelingwani R, Osman R, Pretorius Z, Majoro K, et al. Incidence and associated risk factors of antituberculosis drug-induced liver injury among TB patients. BMC Infectious Diseases. 2025; 25: 1400.
[11] Bekker LG, Beyrer C, Mgodi N, Lewin SR, Delany-Moretlwe S, Taiwo B, et al. HIV infection. Nature Reviews Disease Primers. 2023; 9: 42.
[12] Mohammed O, Alemayehu E, Bisetegn H, Tilahun M, Gedefie A, Ebrahim E, et al. Prevalence of hepatotoxicity among HIV-infected patients in Ethiopia: a systematic review and meta-analysis. BMC Infectious Diseases. 2022; 22: 826.
[13] NIH. LiverTox: clinical and research information on drug-induced liver injury. National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK): Bethesda (MD). 2019.
[14] Andrade RJ, Chalasani N, Björnsson ES, Suzuki A, Kullak-Ublick GA, Watkins PB, et al. EASL clinical practice guidelines: drug-induced liver injury. Journal of Hepatology. 2019; 70: 1222–1261.
[15] Yimer G, Gry M, Amogne W, Makonnen E, Habtewold A, Petros Z, et al. Evaluation of patterns of liver toxicity in patients on antiretroviral and anti-tuberculosis drugs: a prospective four arm observational study in Ethiopian patients. PLOS ONE. 2014; 9: e94271.
[16] Division of AIDS (DAIDS); National Institute of Allergy and Infectious Diseases; National Institutes of Health. Division of AIDS (DAIDS) table for grading the severity of adult and pediatric adverse events. 2017. Available at: https://rsc.niaid.nih.gov/ (Accessed: 17 December 2025).
[17] CIOMS/RUCAM scale 2025. Roussel Uclaf Causality Assessment Method (RUCAM). 2025. Available at: https://www.rccc.eu/scores/RUCAM.html (Accessed: 17 December 2025).
[18] Gandhi RT, Bedimo R, Hoy JF, Landovitz RJ, Smith DM, Eaton EF, et al. Antiretroviral drugs for treatment and prevention of HIV infection in adults: 2022 recommendations of the International Antiviral Society—USA Panel. JAMA. 2023; 329: 63–84.
[19] Trajman A, Campbell JR, Kunor T, Ruslami R, Amanullah F, Behr MA, et al. Tuberculosis. The Lancet. 2025; 405: 850–866.
[20] Klindt C, Fuchs A, Behnke K, Dröge C, Eberhardt KA, Orth HC, et al. Genetic and clinical risk factors for anti-tuberculosis drug-induced liver injury: insights from a prospective cohort study in central Ethiopia. Infection. 2025; 53: 2833–2846.
[21] HIV.gov Clinical Guidelines. Guidelines for the use of antiretroviral agents in adults and adolescents with HIV. 2025. Available at: https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-and-adolescent-arv/virologic-failure?view=full (Accessed: 17 December 2025).
[22] Montepiedra G, Aaron L, Theron G, McCarthy K, Bradford S, Chipato T, et al. Hepatotoxicity among people living with HIV and receiving isoniazid preventive therapy in pregnancy and postpartum: the role of antiretroviral regimen and pharmacogenetics. Clinical Infectious Diseases. 2026; 82: e156–e164.
[23] Nicoletti P, Aithal GP, Bjornsson ES, Andrade RJ, Sawle A, Arrese M, et al. Association of liver injury from specific drugs, or groups of drugs, with polymorphisms in HLA and other genes in a genome-wide association study. Gastroenterology. 2017; 152: 1078–1089.
[24] U.S. Food and Drug Administration (FDA). For healthcare professionals | FDA’s examples of drugs that interact with CYP enzymes and transporter systems. 2025. Available at: https://www.fda.gov/drugs/drug-interactions-labeling/healthcare-professionals-fdas-examples-drugs-interact-cyp-enzymes-and-transporter-systems#table%201 (Accessed: 17 December 2025).
[25] Zhao M, Ma J, Li M, Zhang Y, Jiang B, Zhao X, et al. Cytochrome P450 enzymes and drug metabolism in humans. International Journal of Molecular Sciences. 2021; 22: 12808.
[26] Hardi H, Fitrianti Z, Mahata LE, Louisa M. Pharmacogenetics in tuberculosis–HIV coinfected populations: a systematic review of genetic variants influencing antiretroviral and anti-tuberculosis drug response. Journal of Multidisciplinary Healthcare. 2025; 18: 7203–7218.
[27] Gutiérrez-Virgen JE, Piña-Pozas M, Hernández-Tobías EA, Taja-Chayeb L, López-González ML, Meraz-Ríos MA, et al. NAT2 global landscape: genetic diversity and acetylation statuses from a systematic review. PLOS ONE. 2023; 18: e0283726.
[28] Calcagno A, Cusato J, Sekaggya-Wiltshire C, von Braun A, Motta I, Turyasingura G, et al. The influence of pharmacogenetic variants in HIV/tuberculosis coinfected patients in Uganda in the SOUTH Study. Clinical Pharmacology & Therapeutics. 2019; 106: 450–457.
[29] Mugusi S, Habtewold A, Ngaimisi E, Amogne W, Yimer G, Minzi O, et al. Impact of population and pharmacogenetic variations on efavirenz pharmacokinetics and immunologic outcomes during anti-tuberculosis co-therapy: a parallel prospective cohort study in two sub-Sahara African populations. Frontiers in Pharmacology. 2020; 11: 26.
[30] Cerrone M, Wang X, Neary M, Weaver C, Fedele S, Day-Weber I, et al. Pharmacokinetics of efavirenz 400 mg once daily coadministered with isoniazid and rifampicin in human immunodeficiency virus-infected individuals. Clinical Infectious Diseases. 2019; 68: 446–452.
[31] Covington N, Luetkemeyer AF, Imperial MZ, Dawson R, Cramer Y, Rosenkranz S, et al. Pharmacogenetics of plasma dolutegravir exposure during 1-month rifapentine/isoniazid treatment of latent tuberculosis. Pharmacogenetics and Genomics. 2025; 35: 140–144.
[32] Varadi M, Anyango S, Deshpande M, Nair S, Natassia C, Yordanova G, et al. AlphaFold protein structure database: massively expanding the structural coverage of protein-sequence space with high-accuracy models. Nucleic Acids Research. 2022; 50: D439–D444.
[33] Thomas L, Raju AP, Chaithra S, Kulavalli S, Varma M, Sanju SV, et al. Influence of N-acetyltransferase 2 polymorphisms and clinical variables on liver function profile of tuberculosis patients. Expert Review of Clinical Pharmacology. 2024; 17: 263–274.
[34] Araujo-Mariz C, Albuquerque MFP, Lopes EP, Ximenes RAA, Lacerda HR, Miranda-Filho DB, et al. Hepatotoxicity during TB treatment in people with HIV/AIDS related to NAT2 polymorphisms in Pernambuco, Northeast Brazil. Annals of Hepatology. 2020; 19: 153–160.
[35] Sundell J, Bienvenu E, Janzén D, Birgersson S, Äbelö A, Ashton M. Model-based assessment of variability in isoniazid pharmacokinetics and metabolism in patients co-infected with tuberculosis and HIV: implications for a novel dosing strategy. Clinical Pharmacology & Therapeutics. 2020; 108: 73–80.
[36] Kasamatsu A, Miyahara R, Yoneoka D, Toyo-Oka L, Chiyasirinroje B, Imsanguan W, et al. One-year mortality of tuberculosis patients on isoniazid-based treatment and its association with rapid acetylator NAT2 genotypes. International Journal of Infectious Diseases. 2025; 155: 107895.
[37] Kengo A, Gausi K, Nabisere R, Musaazi J, Buzibye A, Omali D, et al. Unexpectedly low drug exposures among Ugandan patients with TB and HIV receiving high-dose rifampicin. Antimicrobial Agents and Chemotherapy. 2023; 67: e0043123.
[38] Saukkonen JJ, Duarte R, Munsiff SS, Winston CA, Mammen MJ, Abubakar I, et al. Updates on the treatment of drug-susceptible and drug-resistant tuberculosis: an official ATS/CDC/ERS/IDSA clinical practice guideline. American Journal of Respiratory and Critical Care Medicine. 2025; 211: 15–33.
[39] Enimil A, Antwi S, Yang H, Dompreh A, Alghamdi WA, Gillani FS, et al. Effect of first-line antituberculosis therapy on nevirapine pharmacokinetics in children younger than three years old. Antimicrobial Agents and Chemotherapy. 2019; 63: e00839-19.
[40] Chaivichacharn P, Avihingsanon A, Manosuthi W, Ubolyam S, Tongkobpetch S, Shotelersuk V, et al. Dosage optimization of efavirenz based on a population pharmacokinetic–pharmacogenetic model of HIV-infected patients in Thailand. Clinical Therapeutics. 2020; 42: 1234–1245.
[41] Gausi K, Wiesner L, Norman J, Wallis CL, Onyango-Makumbi C, Chipato T, et al. Pharmacokinetics and drug–drug interactions of isoniazid and efavirenz in pregnant women living with HIV in high TB incidence settings: importance of genotyping. Clinical Pharmacology & Therapeutics. 2021; 109: 1034–1044.
[42] Dutra CA, Teixeira RLDF, Lopes MQP, Silva VM, Suffys PN, Carvalho RS, et al. Determination of NAT2 genotypes in a cohort of patients with suspected TB in the state of Rio de Janeiro. Pharmaceutics. 2024; 16: 917.
[43] Cheng F, Jiang XG, Zheng SL, Wu T, Zhang Q, Ye XC, et al. N-acetyltransferase 2 genetic polymorphisms and anti-tuberculosis drug-induced liver injury: a correlation study. Frontiers in Pharmacology. 2023; 14: 1171353.
[44] Sundell J, Bienvenu E, Åbelö A, Ashton M. Effect of efavirenz-based ART on the pharmacokinetics of rifampicin and its primary metabolite in patients coinfected with TB and HIV. Journal of Antimicrobial Chemotherapy. 2021; 76: 2950–2957.
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Jun 18, 2026
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Integrating hepatotoxicity monitoring withpharmacogenetics in HIV and tuberculosis treatment: anarrative review. (2026). Journal of Renal and Hepatic Disorders, 10(1), 4-13. https://doi.org/10.63268/jrenhp.v10i1.259
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Review Hepatology
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Author Biographies
Yair Lara-Blanco , Faculty of Medicine and Psychology, Autonomous University of Baja California, 22424 Tijuana, BC, Mexico
Department of Medicine, Faculty of Medicine and Psychology
José R. Chavez-Méndez , Faculty of Health Sciences “Valle de las Palmas”, Autonomous University of Baja California, 22260 Tijuana, BC, Mexico
Faculty of Health Sciences Valle de las Palmas
Full-time Professor
Genaro Rodríguez-Uribe, Faculty of Medicine and Psychology, Autonomous University of Baja California, 22424 Tijuana, BC, Mexico
Department of Medicine, Faculty of Medicine and Psychology
Full-time Professor