770 
Exposure to ART and the Risk of Liver-related Death: Is there an Association? Results from the D:A:D Study
Rainer Weber*1, C Sabin2, N Friis-Mĝller3, A D'Arminio Monforte4, P Reiss5, W El-Sadr6, F Dabis7, M Law8, C Pradier9, S De Wit10, and on behalf of the D:A:D Study Group
1SHCS, Univ Hosp Zürich, Switzerland; 2Royal Free Ctr for HIV Med, Royal Free and Univ Coll, London, UK; 3Copenhagen HIV Prgm, Hvidovre, Denmark; 4ICONA, L Sacco Hosp, Univ of Milan, Italy; 5HIV Monitoring Fndn, Academic Med Ctr, Univ of Amsterdam, The Netherlands; 6CPCRA, Columbia Univ, Harlem Hosp, New York, NY, US; 7Bordeaux Univ Hosp, INSERM U593, France; 8Australian HIV Observational Database, Natl Ctr in HIV Epidemiology and Clin Res, Sydney; 9Nice Cohort, CHU Nice Hosp de l'Archet, France; and 10Ctr Hosp Univ St Pierre, Brussels, Belgium
Background: Whether
extended exposure to combination ART (cART) is associated with impaired liver function
and liver-related death is a concern, particularly in those co-infected with
hepatitis B virus (HBV) or C virus (HCV). We assessed the association between
exposure to cART and the risk of liver-related death.
Methods: In the
D:A:D collaboration, we prospectively followed more than 23,400 persons for
more than 76,893 person-years. Liver-related death rates (/100 person-years)
were calculated according by years of cART exposure. Relative rates (RR) for
factors associated with liver-related death were estimated using multivariable
Poisson regression (age and hepatitis-status fitted as time-updated; info on
alcohol use not available).
Results: Of the
total, 1248 (5.3%) persons died (1.6/100 person-years), 183 (15%) from
liver-related causes. Among those with liver-related death, 16.9% had active
HBV (s/e antigen+, or DNA+) and 66.1% HCV (antibody+
or RNA+); 7.1% had both; 97.3% had been exposed to cART for a median
of 3.3 years. The most frequently reported immediate causes of liver-related
death were hepatic failure (n = 124),
bleeding (38), infection in patients with end stage-liver disease (21 bacterial;
8 opportunistic), and hepatocellular carcinoma (17). Independent predictors of liver-related
death were lower baseline CD4 count (RR 1.18 [1.11 to 1.27] per 2-fold lower),
older age (1.34 [1.23 to 1.47]/5 years older), intravenous drug use (2.49 [1.46
to 4.24]), HCV (7.30 [4.23 to 12.61]) and active HBV (3.66 [2.31 to 5.80])
infections. The crude incidence rates of liver-related death did not vary by
duration of cART exposure (table, left column). A model adjusting for the risk
factors above (including the CD4 at study entry), suggested a trend with >4
years exposure to cART (central column, test for trend fitting cART exposure as
a continuous variable, p = 0.23).
Further adjustment for the latest CD4 count (as a time-updated variable)
strengthened the relationship (right column, p = 0.03). Stratification by HCV status revealed no significant
relationship with cART exposure and liver-related death in either HCV
or HCV+ patients.
Conclusions: No
strong association was found between exposure to cART for as long as 7 years
and the rate of liver-related death. When controlling for the beneficial effect
that cART has on the CD4 count, there was some evidence of an association
suggesting an increased risk of liver-related death with extended cART use.
However, the main risk factors for liver-related death were low CD4 counts,
chronic co-infection with HBV/HCV and age. Additional follow-up will further
inform whether cART (or components hereof) affects the risk of liver-related
death.
|
