title: Use of antiretroviral therapy and risk of end-stage liver disease and hepatocellular carcinoma in HIV-positive persons.
abstract: Although several antiretroviral drugs, including the d-drugs stavudine (d4T) and didanosine (ddI), may cause biomarker-defined hepatotoxicity, their association with clinically defined end-stage liver disease (ESLD) and hepatocellular carcinoma (HCC) remains unknown.
  
  
  
  Prospective cohort study.
  
  
  
  Data collection on adverse events of anti-HIV drugs study (D:A:D) participants were followed until the first of ESLD (variceal bleeding, hepatic encephalopathy, hepatorenal syndrome or liver transplantation), HCC (histology or α-fetoprotein along with imaging), death, 6 months after last visit or 1 February 2014. Associations between ESLD/HCC and cumulative use of individual antiretrovirals were investigated using Poisson regression adjusting for potential confounders.
  
  
  
  During a median follow-up of 8.4 years, 319 ESLD/HCC cases occurred [incidence 1.01/1000 person-years (95% confidence interval 0.90-1.12)] with a 1-year mortality rate of 62.6%. After adjustment, cumulative (per 5 years) exposure to d4T [relative rate 1.46 (95% confidence interval 1.20-1.77)], ddI [1.32 (1.07-1.63)], tenofovir [TDF, 1.46 (1.11-1.93)] and (fos)amprenavir [APV; 1.47 (1.01-2.15)] was associated with increased ESLD/HCC rates. Longer exposure to emtricitabine [0.51 (0.32-0.83)] and nevirapine [0.76 (0.58-0.98)] were associated with lower ESLD/HCC rates. The ddI/d4T-associated increased ESLD/HCC rate only started to decline 6 years after cessation.
  
  
  
  Cumulative use of d4T, ddI, TDF and APV were independently associated with increased ESLD/HCC rates, and intensified monitoring of liver function should hence be considered among all individuals exposed for longer time periods. The use of d-drugs should furthermore be avoided, where there are alternatives available, and focus should be put on those with longer-term d-drugs exposure who remain at increased ESLD/HCC risk. The unexpected, and viral hepatitis-independent, TDF association calls for further investigations.
authors.affiliation: aDepartment of Infectious Diseases, CHIP, Section 8632, Finsenscentret, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark bDepartment of Infectious Diseases, CHU Saint-Pierre, Brussels, Belgium cDivision of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, University of Zurich, Switzerland dDivision of Infectious Diseases and Department of Global Health, Academic Medical Center, University of Amsterdam, and the HIV Monitoring Foundation, Amsterdam The Netherlands eThe Kirby Institute, UNSW, Sydney, Australia fICAP-Columbia University and Harlem Hospital, New York, USA gDipartimento di Scienze della Salute, Clinica di Malattie Infectitive e Tropicali, Azienda Ospedaliera-Polo Universitario San Paolo, Milan, Italy hResearch Department of Infection and Population Health, UCL, London, UK iDepartment of Public Health, Nice University Hospital, Nice, France jUniversité Bordeaux Segalen, INSERM U 897 kEpidemiologie-Biostatistique, CHU de Bordeaux, France.
authors.forename: Lene
authors.initials: L
authors.lastname: Ryom
authors.forename: Jens Dilling
authors.initials: JD
authors.lastname: Lundgren
authors.forename: Stéphane
authors.initials: S
authors.lastname: De Wit
authors.forename: Helen
authors.initials: H
authors.lastname: Kovari
authors.forename: Peter
authors.initials: P
authors.lastname: Reiss
authors.forename: Matthew
authors.initials: M
authors.lastname: Law
authors.forename: Wafa
authors.initials: W
authors.lastname: El-Sadr
authors.forename: Antonella D'Arminio
authors.initials: AD
authors.lastname: Monforte
authors.forename: Amanda
authors.initials: A
authors.lastname: Mocroft
authors.forename: Colette
authors.initials: C
authors.lastname: Smith
authors.forename: Eric
authors.initials: E
authors.lastname: Fontas
authors.forename: Francois
authors.initials: F
authors.lastname: Dabis
authors.forename: Andrew
authors.initials: A
authors.lastname: Phillips
authors.forename: Caroline
authors.initials: C
authors.lastname: Sabin
mesh_terms: D000328:Adult; D044966:Anti-Retroviral Agents / Q000009:adverse effects* / Q000627:therapeutic use*; D006528:Carcinoma, Hepatocellular / Q000139:chemically induced / Q000453:epidemiology*; D058625:End Stage Liver Disease / Q000139:chemically induced / Q000453:epidemiology*; D005260:Female; D015658:HIV Infections / Q000150:complications* / Q000188:drug therapy*; D006801:Humans; D008113:Liver Neoplasms / Q000139:chemically induced / Q000453:epidemiology*; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D018570:Risk Assessment
chemical_list: D044966:Anti-Retroviral Agents