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

OBJECTIVES: Whilst several antiretroviral drugs (ARVs), 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:: D:A:D participants were followed until the first of ESLD (variceal bleeding, hepatic encephalopathy, hepatorenal syndrome or liver transplantation), HCC (histology or alpha-fetoprotein plus imaging), death, 6 months after last visit or 1/2/2014. Associations between ESLD/HCC and cumulative use of individual ARVs 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%CI 0.90-1.12]) with a 62.6% one-year mortality rate. After adjustment, cumulative (per 5 years) exposure to d4T (relative rate 1.46 [95%CI 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 amongst 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.