title: Antiretroviral Drugs and Risk of Chronic Alanine Aminotransferase Elevation in Human Immunodeficiency Virus (HIV)-Monoinfected Persons: The Data Collection on Adverse Events of Anti-HIV Drugs Study.
abstract: Background.  Although human immunodeficiency virus (HIV)-positive persons on antiretroviral therapy (ART) frequently have chronic liver enzyme elevation (cLEE), the underlying cause is often unclear. Methods.  Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) Study participants without chronic viral hepatitis were observed to the earliest of cLEE (elevated aminotransferase ≥6 months), death, last follow-up, or January 2, 2014. Antiretroviral treatment exposure was categorized as follows: no exposure and ongoing short- and long-term exposure (<2 or ≥2 years) after initiation. Association between development of cLEE and ART exposure was investigated using Poisson regression. Results.  Among 21 485 participants observed for 105 413 person-years (PY), 6368 developed cLEE (incidence 6.04/100 PY; 95% confidence interval [CI], 5.89-6.19). Chronic liver enzyme elevation was associated with short-and long-term exposure to didanosine (<2 years rate ratio [RR] = 1.29, 95% CI, 1.11-1.49; >2 years RR = 1.26, 95% CI, 1.13-1.41); stavudine (<2 years RR = 1.51, 95% CI, 1.26-1.81; >2 years RR = 1.17, 95% CI, 1.03-1.32), and tenofovir disoproxil fumarate (<2 years RR = 1.55, 95% CI, 1.40-1.72; >2 years RR = 1.18, 95% CI, 1.05-1.32), but only short-term exposure to nevirapine (<2 years RR = 1.44, 95% CI, 1.29-1.61), efavirenz (<2 years RR = 1.14, 95% CI, 1.03-1.26), emtricitabine (<2 years RR = 1.18, 95% CI, 1.04-1.33), and atazanavir (<2 years RR = 1.20, 95% CI, 1.04-1.38). Chronic liver enzyme elevation was not associated with use of lamivudine, abacavir, and other protease inhibitors. Mortality did not differ between participants with and without cLEE. Conclusions.  Although didanosine, stavudine, nevirapine, and efavirenz have been described to be hepatotoxic, we additionally observed a consistent association between tenofovir and cLEE emerging within the first 2 years after drug initiation. This novel tenofovir-cLEE signal should be further investigated.
authors.affiliation: Division of Infectious Diseases and Hospital Epidemiology , University Hospital Zurich , Switzerland.
authors.forename: Helen
authors.initials: H
authors.lastname: Kovari
authors.affiliation: Research Department of Infection and Population Health , University College London , United Kingdom.
authors.forename: Caroline A
authors.initials: CA
authors.lastname: Sabin
authors.affiliation: Division of Infectious Diseases and Hospital Epidemiology , University Hospital Zurich , Switzerland.
authors.forename: Bruno
authors.initials: B
authors.lastname: Ledergerber
authors.affiliation: CHIP, Department of Infectious Diseases , Rigshospitalet, University of Copenhagen , København , Denmark.
authors.forename: Lene
authors.initials: L
authors.lastname: Ryom
authors.affiliation: Division of Infectious Diseases and Department of Global Health , Academic Medical Center, University of Amsterdam , Netherlands.
authors.forename: Peter
authors.initials: P
authors.lastname: Reiss
authors.affiliation: The Kirby Institute for Infection and Immunity in Society , University of New South Wales , Sydney , Australia.
authors.forename: Matthew
authors.initials: M
authors.lastname: Law
authors.affiliation: Department of Public Health , Nice University Hospital , France.
authors.forename: Christian
authors.initials: C
authors.lastname: Pradier
authors.affiliation: Université Bordeaux, ISPED, Centre INSERM U897-Epidémiologie-Biostatistique France.
authors.forename: Francois
authors.initials: F
authors.lastname: Dabis
authors.affiliation: Department of Health Sciences , San Paolo University Hospital , Milan , Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: d'Arminio Monforte
authors.affiliation: Research Department of Infection and Population Health , University College London , United Kingdom.
authors.forename: Colette
authors.initials: C
authors.lastname: Smith
authors.affiliation: Department of Infectious Diseases , St. Pierre University Hospital , Brussels , Belgium.
authors.forename: Stephane
authors.initials: S
authors.lastname: de Wit
authors.affiliation: CHIP, Department of Infectious Diseases , Rigshospitalet, University of Copenhagen , København , Denmark.
authors.forename: Ole
authors.initials: O
authors.lastname: Kirk
authors.affiliation: CHIP, Department of Infectious Diseases , Rigshospitalet, University of Copenhagen , København , Denmark.
authors.forename: Jens D
authors.initials: JD
authors.lastname: Lundgren
authors.affiliation: Division of Infectious Diseases and Hospital Epidemiology , University Hospital Zurich , Switzerland.
authors.forename: Rainer
authors.initials: R
authors.lastname: Weber
keywords: HIV; alanine aminotransferase; antiretroviral therapy; hepatotoxicity; liver disease