{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T15:39:39Z","timestamp":1791819579598,"version":"4.3.4"},"reference-count":35,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2021,2,24]],"date-time":"2021-02-24T00:00:00Z","timestamp":1614124800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,3,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>As morbidity due to viral coinfections declines among HIV-infected persons, changes in liver-related morbidity are anticipated. We examined data from the US Military HIV Natural History Study (NHS), a cohort of military beneficiaries, to evaluate incidence and risk factors associated with chronic liver enzyme elevation (cLEE) in HIV-monoinfected patients in the combination antiretroviral therapy (cART) era.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Participants who were hepatitis B virus and hepatitis C virus seronegative with follow-up after 1996 were included. We defined chronic liver enzyme elevation (cLEE) as alanine aminotransferase elevations \u22651.25 times the upper limit of normal on at least 2 visits, for a duration of \u22656 months within 2 years. We used multivariate Cox proportional hazards models to examine risk factors for cLEE.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Of 2779 participants, 309 (11%) met criteria for cLEE for an incidence of 1.28\/100 PYFU (1.28\u20131.29\/100 PYFU). In an adjusted model, cLEE was associated with Hispanic\/other ethnicity (reference Caucasian: hazard ratio [HR], 1.744; 95% CI, 1.270\u20132.395), non\u2013nucleoside reverse transcriptase inhibitor\u2013based cART (reference boosted protease inhibitors: HR, 2.232; 95% CI, 1.378\u20133.616), being cART na\u00efve (HR, 6.046; 95% CI, 3.686\u20139.915), or having cART interruptions (HR, 8.671; 95% CI, 4.651\u201316.164). African American race (HR, 0.669; 95% CI, 0.510\u20130.877) and integrase strand transfer inhibitor (INSTI)\u2013based cART (HR, 0.222; 95% CI, 0.104\u20130.474) were protective.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Our findings demonstrate that initiation and continued use of cART are protective against cLEE and support the hypothesis that HIV infection directly impacts the liver. INSTI-based regimens were protective and could be considered in persons with cLEE.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/ofid\/ofab076","type":"journal-article","created":{"date-parts":[[2021,2,24]],"date-time":"2021-02-24T11:59:08Z","timestamp":1614167948000},"source":"Crossref","is-referenced-by-count":9,"title":["Risk Factors Associated With Chronic Liver Enzyme Elevation in Persons With HIV Without Hepatitis B or C Coinfection in the Combination Antiretroviral Therapy Era"],"prefix":"10.1093","volume":"8","author":[{"given":"Shannon","family":"Wood","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, Madigan Army Medical Center, Tacoma, Washington, USA"},{"name":"Division of Infectious Diseases, Walter Reed National Military Medical Center, Bethesda, Maryland, USA"},{"name":"Infectious Diseases Clinical Research Program, Department of Preventive Medicine and Biostatistics, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA"},{"name":"Division of Infectious Diseases, Madigan Army Medical Center, Tacoma, Washington, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seung Hyun","family":"Won","sequence":"additional","affiliation":[{"name":"Infectious Diseases Clinical Research Program, Department of Preventive Medicine and Biostatistics, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA"},{"name":"The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hsing-Chuan","family":"Hsieh","sequence":"additional","affiliation":[{"name":"Infectious Diseases Clinical Research Program, Department of Preventive Medicine and Biostatistics, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA"},{"name":"The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9361-2991","authenticated-orcid":false,"given":"Tahaniyat","family":"Lalani","sequence":"additional","affiliation":[{"name":"Infectious Diseases Clinical Research Program, Department of Preventive Medicine and Biostatistics, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA"},{"name":"The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, Maryland, USA"},{"name":"Division of Infectious Diseases, Naval Medical Center Portsmouth, Portsmouth, Virginia, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karl","family":"Kronmann","sequence":"additional","affiliation":[{"name":"Infectious Diseases Clinical Research Program, Department of Preventive Medicine and Biostatistics, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA"},{"name":"Division of Infectious Diseases, Naval Medical Center Portsmouth, Portsmouth, Virginia, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan C","family":"Maves","sequence":"additional","affiliation":[{"name":"Infectious Diseases Clinical Research Program, Department of Preventive Medicine and Biostatistics, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA"},{"name":"Division of Infectious Diseases, Naval Medical Center San Diego, San Diego, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregory","family":"Utz","sequence":"additional","affiliation":[{"name":"Infectious Diseases Clinical Research Program, Department of Preventive Medicine and Biostatistics, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA"},{"name":"Division of Infectious Diseases, Naval Medical Center San Diego, San Diego, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina","family":"Schofield","sequence":"additional","affiliation":[{"name":"Infectious Diseases Clinical Research Program, Department of Preventive Medicine and Biostatistics, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA"},{"name":"Division of Infectious Diseases, Madigan Army Medical Center, Tacoma, Washington, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rhonda E","family":"Colombo","sequence":"additional","affiliation":[{"name":"Infectious Diseases Clinical Research Program, Department of Preventive Medicine and Biostatistics, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA"},{"name":"The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, Maryland, USA"},{"name":"Division of Infectious Diseases, Madigan Army Medical Center, Tacoma, Washington, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason F","family":"Okulicz","sequence":"additional","affiliation":[{"name":"Infectious Diseases Clinical Research Program, Department of Preventive Medicine and Biostatistics, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA"},{"name":"Infectious Disease Service, San Antonio Military Medical Center, San Antonio, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason","family":"Blaylock","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, Walter Reed National Military Medical Center, Bethesda, Maryland, USA"},{"name":"Infectious Diseases Clinical Research Program, Department of Preventive Medicine and Biostatistics, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5114-1669","authenticated-orcid":false,"given":"Brian K","family":"Agan","sequence":"additional","affiliation":[{"name":"Infectious Diseases Clinical Research Program, Department of Preventive Medicine and Biostatistics, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA"},{"name":"The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anuradha","family":"Ganesan","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, Walter Reed National Military Medical Center, Bethesda, Maryland, USA"},{"name":"Infectious Diseases Clinical Research Program, Department of Preventive Medicine and Biostatistics, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA"},{"name":"The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,2,24]]},"reference":[{"key":"2021031212390345800_CIT0001","doi-asserted-by":"crossref","first-page":"e81355","DOI":"10.1371\/journal.pone.0081355","article-title":"Closing the gap: increases in life expectancy among treated HIV-positive individuals in the United States and Canada","volume":"8","author":"Samji","year":"2013","journal-title":"PLoS One"},{"key":"2021031212390345800_CIT0002","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1097\/01.qai.0000233310.90484.16","article-title":"Mortality in the highly active antiretroviral therapy era: changing causes of death and disease in the HIV Outpatient Study","volume":"43","author":"Palella","year":"2006","journal-title":"J Acquir Immune Defic Syndr"},{"key":"2021031212390345800_CIT0003","doi-asserted-by":"crossref","first-page":"209","DOI":"10.5501\/wjv.v4.i3.209","article-title":"Non-AIDS definings malignancies among human immunodeficiency virus-positive subjects: epidemiology and outcome after two decades of HAART era","volume":"4","author":"Brugnaro","year":"2015","journal-title":"World J Virol"},{"key":"2021031212390345800_CIT0004","doi-asserted-by":"crossref","first-page":"1002","DOI":"10.1016\/j.cgh.2010.08.024","article-title":"Liver disease in the HIV-infected individual","volume":"8","author":"Price","year":"2010","journal-title":"Clin Gastroenterol Hepatol"},{"key":"2021031212390345800_CIT0005","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1016\/j.cld.2018.12.011","article-title":"Liver disease in human immunodeficiency virus infection","volume":"23","author":"Oikonomou","year":"2019","journal-title":"Clin Liver Dis"},{"key":"2021031212390345800_CIT0006","doi-asserted-by":"crossref","first-page":"1375","DOI":"10.1007\/s10620-007-9999-6","article-title":"The prevalence and risk factors for abnormal liver enzymes in HIV-positive patients without hepatitis B or C coinfections","volume":"53","author":"Sterling","year":"2008","journal-title":"Dig Dis Sci"},{"key":"2021031212390345800_CIT0007","doi-asserted-by":"crossref","first-page":"1267","DOI":"10.1097\/QAD.0000000000002233","article-title":"Clinical significance of elevated liver transaminases in HIV-infected patients","volume":"33","author":"Cai","year":"2019","journal-title":"AIDS"},{"key":"2021031212390345800_CIT0008","doi-asserted-by":"crossref","first-page":"502","DOI":"10.1086\/649922","article-title":"Incidence and risk factors for chronic elevation of alanine aminotransferase levels in HIV-infected persons without hepatitis B or C virus co-infection","volume":"50","author":"Kovari","year":"2010","journal-title":"Clin Infect Dis"},{"key":"2021031212390345800_CIT0009","doi-asserted-by":"crossref","first-page":"1522","DOI":"10.1080\/09540121.2016.1191603","article-title":"Non-viral liver disease burden in HIV-monoinfected individuals: a longitudinal observational retrospective cohort study","volume":"28","author":"Shur","year":"2016","journal-title":"AIDS Care"},{"key":"2021031212390345800_CIT0010","doi-asserted-by":"crossref","first-page":"436","DOI":"10.1002\/hep.22665","article-title":"Liver damage underlying unexplained transaminase elevation in human immunodeficiency virus-1 mono-infected patients on antiretroviral therapy","volume":"49","author":"Ingiliz","year":"2009","journal-title":"Hepatology"},{"key":"2021031212390345800_CIT0011","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1053\/j.gastro.2008.10.052","article-title":"Elevated serum alanine aminotransferase and gamma-glutamyltransferase and mortality in the United States population","volume":"136","author":"Ruhl","year":"2009","journal-title":"Gastroenterology"},{"key":"2021031212390345800_CIT0012","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1093\/milmed\/usy430","article-title":"The US Military HIV Natural History Study: informing military HIV care and policy for over 30 years","volume":"184","author":"Agan","year":"2019","journal-title":"Mil Med"},{"key":"2021031212390345800_CIT0013","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.cld.2014.09.001","article-title":"Chronic liver disease in the human immunodeficiency virus patient","volume":"19","author":"Acharya","year":"2015","journal-title":"Clin Liver Dis"},{"key":"2021031212390345800_CIT0014","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1111\/acer.12975","article-title":"Characterizing the association between alcohol and HIV virologic failure in a military cohort on antiretroviral therapy","volume":"40","author":"Deiss","year":"2016","journal-title":"Alcohol Clin Exp Res"},{"key":"2021031212390345800_CIT0015","doi-asserted-by":"crossref","first-page":"782","DOI":"10.1053\/j.gastro.2013.06.057","article-title":"Simple noninvasive systems predict long-term outcomes of patients with nonalcoholic fatty liver disease","volume":"145","author":"Angulo","year":"2013","journal-title":"Gastroenterology"},{"key":"2021031212390345800_CIT0016","doi-asserted-by":"crossref","first-page":"1104","DOI":"10.1016\/j.cgh.2009.05.033","article-title":"Comparison of noninvasive markers of fibrosis in patients with nonalcoholic fatty liver disease","volume":"7","author":"Shah","year":"2009","journal-title":"Clin Gastroenterol Hepatol"},{"key":"2021031212390345800_CIT0017","doi-asserted-by":"crossref","first-page":"1317","DOI":"10.1002\/hep.21178","article-title":"Development of a simple noninvasive index to predict significant fibrosis in patients with HIV\/HCV coinfection","volume":"43","author":"Sterling","year":"2006","journal-title":"Hepatology"},{"key":"2021031212390345800_CIT0018","doi-asserted-by":"crossref","first-page":"1735","DOI":"10.1097\/00002030-199814000-00004","article-title":"Adverse effects of reverse transcriptase inhibitors: mitochondrial toxicity as common pathway","volume":"12","author":"Brinkman","year":"1998","journal-title":"AIDS"},{"key":"2021031212390345800_CIT0019","doi-asserted-by":"crossref","first-page":"288","DOI":"10.5144\/0256-4947.2016.288","article-title":"Elevated alanine aminotransferase levels in HIV-infected persons without hepatitis B or C virus coinfection","volume":"36","author":"Alghamdi","year":"2016","journal-title":"Ann Saudi Med"},{"key":"2021031212390345800_CIT0020","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1186\/1743-422X-6-181","article-title":"Correlation between HIV viral load and aminotransferases as liver damage markers in HIV infected naive patients: a concordance cross-sectional study","volume":"6","author":"Mata-Mar\u00edn","year":"2009","journal-title":"Virol J"},{"key":"2021031212390345800_CIT0021","doi-asserted-by":"crossref","first-page":"674","DOI":"10.1093\/cid\/ciq199","article-title":"HIV mono-infection is associated with FIB-4 - a noninvasive index of liver fibrosis - in women","volume":"52","author":"Blackard","year":"2011","journal-title":"Clin Infect Dis"},{"key":"2021031212390345800_CIT0022","doi-asserted-by":"crossref","first-page":"e202","DOI":"10.1111\/j.1365-2893.2011.01529.x","article-title":"The association of HIV viral load with indirect markers of liver injury","volume":"19","author":"Forrester","year":"2012","journal-title":"J Viral Hepat"},{"key":"2021031212390345800_CIT0023","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1186\/1471-2334-10-116","article-title":"Prevalence and risk factors for significant liver fibrosis among HIV-monoinfected patients","volume":"10","author":"DallaPiazza","year":"2010","journal-title":"BMC Infect Dis"},{"key":"2021031212390345800_CIT0024","doi-asserted-by":"crossref","first-page":"1387","DOI":"10.1002\/hep.20466","article-title":"Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity","volume":"40","author":"Browning","year":"2004","journal-title":"Hepatology"},{"key":"2021031212390345800_CIT0025","doi-asserted-by":"crossref","first-page":"464","DOI":"10.1097\/QAI.0b013e318198a88a","article-title":"Nonalcoholic fatty liver disease among HIV-infected persons","volume":"50","author":"Crum-Cianflone","year":"2009","journal-title":"J Acquir Immune Defic Syndr"},{"key":"2021031212390345800_CIT0026","doi-asserted-by":"crossref","first-page":"1943","DOI":"10.1086\/497608","article-title":"Histological findings and clinical characteristics associated with hepatic steatosis in patients coinfected with HIV and hepatitis C virus","volume":"192","author":"Marks","year":"2005","journal-title":"J Infect Dis"},{"key":"2021031212390345800_CIT0027","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1055\/s-2003-39948","article-title":"Toxicity of non-nucleoside analogue reverse transcriptase inhibitors","volume":"23","author":"Kontorinis","year":"2003","journal-title":"Semin Liver Dis"},{"key":"2021031212390345800_CIT0028","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1093\/jac\/dkl524","article-title":"Liver toxicity induced by non-nucleoside reverse transcriptase inhibitors","volume":"59","author":"Rivero","year":"2007","journal-title":"J Antimicrob Chemother"},{"key":"2021031212390345800_CIT0029","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1053\/jhep.2002.30319","article-title":"Hepatotoxicity associated with nevirapine or efavirenz-containing antiretroviral therapy: role of hepatitis C and B infections","volume":"35","author":"Sulkowski","year":"2002","journal-title":"Hepatology"},{"key":"2021031212390345800_CIT0030","doi-asserted-by":"crossref","first-page":"3295","DOI":"10.1093\/jac\/dkz353","article-title":"Incidence and risk factors for liver enzyme elevation among naive HIV-1-infected patients receiving ART in the ICONA cohort","volume":"74","author":"Taramasso","year":"2019","journal-title":"J Antimicrob Chemother"},{"key":"2021031212390345800_CIT0031","doi-asserted-by":"crossref","first-page":"e25484","DOI":"10.1002\/jia2.25484","article-title":"Weight gain among treatment-na\u00efve persons with HIV starting integrase inhibitors compared to non-nucleoside reverse transcriptase inhibitors or protease inhibitors in a large observational cohort in the United States and Canada","volume":"23","author":"Bourgi","year":"2020","journal-title":"J Int AIDS Soc"},{"key":"2021031212390345800_CIT0032","doi-asserted-by":"crossref","first-page":"909","DOI":"10.1111\/jgh.12861","article-title":"Association of weight gain since age 20 with non-alcoholic fatty liver disease in normal weight individuals","volume":"30","author":"Kimura","year":"2015","journal-title":"J Gastroenterol Hepatol"},{"key":"2021031212390345800_CIT0033","volume-title":"Modern Epidemiology","author":"Rothman","year":"1998"},{"key":"2021031212390345800_CIT0034","doi-asserted-by":"crossref","first-page":"e2127","DOI":"10.1097\/MD.0000000000002127","article-title":"Liver fibrosis in HIV patients receiving a modern cART: which factors play a role?","volume":"94","author":"Mohr","year":"2015","journal-title":"Medicine (Baltimore)"},{"key":"2021031212390345800_CIT0035","doi-asserted-by":"crossref","first-page":"e263","DOI":"10.1093\/milmed\/usy318","article-title":"Age, race, and at-risk drinking in an HIV-infected U.S. military cohort","volume":"184","author":"Byrne","year":"2019","journal-title":"Mil Med"}],"container-title":["Open Forum Infectious Diseases"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/ofid\/advance-article-pdf\/doi\/10.1093\/ofid\/ofab076\/36351266\/ofab076.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/ofid\/article-pdf\/8\/3\/ofab076\/36583495\/ofab076.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/ofid\/article-pdf\/8\/3\/ofab076\/36583495\/ofab076.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,3,12]],"date-time":"2021-03-12T12:39:39Z","timestamp":1615552779000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/ofid\/article\/doi\/10.1093\/ofid\/ofab076\/6149076"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,2,24]]},"references-count":35,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2021,3,1]]}},"URL":"https:\/\/doi.org\/10.1093\/ofid\/ofab076","relation":{},"ISSN":["2328-8957"],"issn-type":[{"value":"2328-8957","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2021,3,1]]},"published":{"date-parts":[[2021,2,24]]},"article-number":"ofab076"}}