Use of antiretroviral therapy and risk of end-stage liver disease and hepatocellular carcinoma in HIV-positive persons

L. Ryom, J.D. Lundgren, S. De Wit, H. Kovari, P. Reiss, M. Law, W. El-Sadr, A.D. Monforte, A. Mocroft, C. Smith, E. Fontas, F. Dabis, A. Phillips, C. Sabin, Ferran Torres

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46 Citations (Scopus)


Objectives: 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. Design: Prospective cohort study. Methods: 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. Results: 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. Conclusion: 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. © Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.
Original languageEnglish
Pages (from-to)1731-1743
Number of pages13
JournalAIDS (London, England)
Issue number11
Publication statusPublished - Jul 2016


  • (fos)amprenavir
  • d-drugs
  • end-stage liver disease
  • hepatocellular carcinoma
  • hepatotoxicity
  • HIV
  • tenofovir
  • alpha fetoprotein
  • didanosine
  • emtricitabine
  • fosamprenavir
  • nevirapine
  • stavudine
  • antiretrovirus agent
  • adult
  • Article
  • CD4 lymphocyte count
  • cohort analysis
  • drug exposure
  • end stage liver disease
  • esophagus varices bleeding
  • female
  • follow up
  • hepatic encephalopathy
  • hepatorenal syndrome
  • highly active antiretroviral therapy
  • human
  • Human immunodeficiency virus infected patient
  • Human immunodeficiency virus infection
  • liver cell carcinoma
  • liver histology
  • liver transplantation
  • major clinical study
  • male
  • mortality
  • priority journal
  • prognosis
  • prospective study
  • sensitivity analysis
  • survival
  • chemically induced
  • complication
  • liver tumor
  • middle aged
  • risk assessment
  • Adult
  • Anti-Retroviral Agents
  • Carcinoma, Hepatocellular
  • End Stage Liver Disease
  • Female
  • HIV Infections
  • Humans
  • Liver Neoplasms
  • Male
  • Middle Aged
  • Prospective Studies
  • Risk Assessment


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