{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T21:45:23Z","timestamp":1791582323530,"version":"4.3.4"},"reference-count":0,"publisher":"Oxford University Press (OUP)","license":[{"start":{"date-parts":[[2026,3,6]],"date-time":"2026-03-06T00:00:00Z","timestamp":1772755200000},"content-version":"am","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Hepatotoxicity is frequent in the standard-of-care regimen for drug-susceptible tuberculosis, yet the association of each companion drug with hepatotoxicity has not been fully characterized. We examined the association between hepatotoxicity and the pharmacokinetics of rifampin and its companion drugs in standard therapy, as well as N-acetyltransferase 2 (NAT2) genotype.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We evaluated HIRIF trial participants who were randomized to receive rifampin 10, 15, or 20 mg\/kg\/day during the intensive phase of tuberculosis treatment. We fitted Cox proportional hazards models to identify risk factors for grade 2 or higher (grade 2+) alanine transaminase (ALT) or aspartate transaminase (AST) elevation, and considered pharmacokinetic exposure of each antituberculosis drug and NAT2 genotype as potential covariates.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Among 168 participants with pharmacokinetic data, neither rifampin dose nor exposure were associated with the risk of grade 2+ ALT or AST elevation. Higher pyrazinamide exposure (hazard ratio [HR] 1.85 for every 50 mg*h\/L AUC0-6h increase), higher isoniazid exposure (HR 1.40 for every 5 mg*h\/L AUC0-6h increase), and among a subset with known NAT2 genotype, slow NAT2 acetylator status (HR 9.32 relative to fast, n=90) were associated with grade 2+ ALT or AST elevation in univariable analysis. In multivariable analysis, only pyrazinamide exposure was associated with hepatotoxicity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>While higher pyrazinamide and isoniazid exposures and slow NAT2 acetylator status were each associated with increased hepatotoxicity, only pyrazinamide exposure was associated when considering pharmacokinetic variables together. Rifampin exposure was not associated with hepatotoxicity, supporting further evaluation of doses up to 20 mg\/kg\/day in a larger trial.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/cid\/ciag141","type":"journal-article","created":{"date-parts":[[2026,3,4]],"date-time":"2026-03-04T12:48:58Z","timestamp":1772628538000},"source":"Crossref","is-referenced-by-count":2,"title":["Pharmacokinetic and pharmacogenomic predictors of hepatotoxicity in the HIRIF trial for drug-susceptible tuberculosis"],"prefix":"10.1093","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2581-349X","authenticated-orcid":false,"given":"Eunsol","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Bioengineering and Therapeutic Sciences, University of California , San Francisco, San Francisco, California ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0365-5841","authenticated-orcid":false,"given":"Pieter","family":"Van Brantegem","sequence":"additional","affiliation":[{"name":"Department of Bioengineering and Therapeutic Sciences, University of California , San Francisco, San Francisco, California ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9002-7052","authenticated-orcid":false,"given":"Charles A","family":"Peloquin","sequence":"additional","affiliation":[{"name":"College of Pharmacy and Emerging Pathogens Institute, University of Florida , Gainesville, Florida ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8431-5517","authenticated-orcid":false,"given":"Meredith B","family":"Brooks","sequence":"additional","affiliation":[{"name":"Department of Global Health, Boston University School of Public Health , Boston, Massachusetts ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia M","family":"Coit","sequence":"additional","affiliation":[{"name":"Department of Global Health and Social Medicine, Harvard Medical School , Boston, Massachusetts ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dante","family":"Vargas V\u00e1squez","sequence":"additional","affiliation":[{"name":"Hospital Nacional Hip\u00f3lito Unanue , Lima ,","place":["Peru"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Epifanio","family":"S\u00e1nchez Garavito","sequence":"additional","affiliation":[{"name":"Hospital Nacional Sergio Bernales , Lima ,","place":["Peru"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8932-0489","authenticated-orcid":false,"given":"Roger I","family":"Calder\u00f3n","sequence":"additional","affiliation":[{"name":"Advanced Research and Health , Lima ,","place":["Peru"]},{"name":"Facultad de Medicina Humana, Universidad de San Mart\u00edn de Porres , Lima ,","place":["Peru"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7633-8401","authenticated-orcid":false,"given":"Judith","family":"Jim\u00e9nez","sequence":"additional","affiliation":[{"name":"Socios En Salud Sucursal Peru , Lima ,","place":["Peru"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen","family":"Tintaya","sequence":"additional","affiliation":[{"name":"Socios En Salud Sucursal Peru , Lima ,","place":["Peru"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6444-8627","authenticated-orcid":false,"given":"Dalicxa","family":"Garcia","sequence":"additional","affiliation":[{"name":"Socios En Salud Sucursal Peru , Lima ,","place":["Peru"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elna","family":"Osso","sequence":"additional","affiliation":[{"name":"Department of Global Health and Social Medicine, Harvard Medical School , Boston, Massachusetts ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0516-6080","authenticated-orcid":false,"given":"Elizabeth A","family":"Mackay","sequence":"additional","affiliation":[{"name":"Department of Clinical Infection, Microbiology, and Immunology, University of Liverpool , Liverpool ,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6687-0012","authenticated-orcid":false,"given":"Gareth","family":"Platt","sequence":"additional","affiliation":[{"name":"Department of Clinical Infection, Microbiology, and Immunology, University of Liverpool , Liverpool ,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1363-3985","authenticated-orcid":false,"given":"Leonid","family":"Lecca","sequence":"additional","affiliation":[{"name":"Department of Global Health and Social Medicine, Harvard Medical School , Boston, Massachusetts ,","place":["USA"]},{"name":"Socios En Salud Sucursal Peru , Lima ,","place":["Peru"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Radojka M","family":"Savic","sequence":"additional","affiliation":[{"name":"Department of Bioengineering and Therapeutic Sciences, University of California , San Francisco, San Francisco, California ,","place":["USA"]},{"name":"UCSF Center for Tuberculosis, Institute for Global Health Sciences, University of California , San Francisco, San Francisco, California ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3819-490X","authenticated-orcid":false,"given":"Geraint R","family":"Davies","sequence":"additional","affiliation":[{"name":"Department of Clinical Infection, Microbiology, and Immunology, University of Liverpool , Liverpool ,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carole D","family":"Mitnick","sequence":"additional","affiliation":[{"name":"Department of Global Health and Social Medicine, Harvard Medical School , Boston, Massachusetts ,","place":["USA"]},{"name":"Division of Global Health Equity, Brigham and Women's Hospital , Boston, Massachusetts ,","place":["USA"]},{"name":"Partners In Health , Boston, Massachusetts ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1438-0692","authenticated-orcid":false,"given":"Gustavo 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