Highly active antiretroviral therapy (HAART) reduces the risk of liver-related death by 68%, although infection with both HIV and hepatitis C virus (HCV) increases the risk of liver-related mortality more than ten-fold compared with individuals infected with HIV alone, according to data from the Brescia HIV Liver Cohort (BRHILCO) presented to the Second International Workshop on HIV and Hepatitis Coinfection, held in Amsterdam last week. Even though Professor Massimo Puoti and colleagues also found that HAART-related life-threatening liver toxicity increased the risk of liver-related mortality almost six-fold, 96% of all liver-related deaths occurred in individuals coinfected with HIV/HCV.
In order to identify risk factors associated with liver-related mortality, all HIV-positive individuals who enrolled at the University of Brescia HIV between first of September 1997 and first of April 1998 were included in the Brescia HIV Liver Cohort. At baseline, CD4 cell count, HIV viral load and hepatitis antibodies, as well as a complete medical history and alcohol consumption were assessed, and patients were followed-up at least every three months until the first of April 2004. Anti-HIV and anti-HBV and anti-HCV treatment was given as per current guidelines.
The investigators defined liver-related mortality as a death due to cirrhosis (C on the Child-Pugh classification scale) and/or hepatorenal syndrome and/or bleeding of oesophageal varices and/or hepatic coma, in the absence of opportunistic infections. They defined HAART-related life threatening liver toxicity was defined as ALT and/or AST increase after initiation of a new HAART regime by >10x the upper limit of normal or >7.5x the upper limit of normal in patients whose ALT/AST were abnormal at baseline.
A total of 812 patients were enrolled in BRHILCO, 70% of whom were male, with a median age of 34 years, and of whom 57% had a history of injecting drug use. At baseline, the cohort's median CD4 count was 305 cells/mm3, although 37% had a CD4 count <200 cells/mm3, and 25% had a CD4 count between 200 - 350 cells/mm3. A total of 60% of the cohort were coinfected with HCV, and 8% were coinfected with HBV. A history of alcohol abuse was found in 15% of the cohort, although only 5% were active alcohol abusers. Just over 43.5% (n=354) began HAART before enrolment in the cohort; another 43% (n=349) started HAART during follow-up, and just under 13.5% (n= 109) did not take HAART at any time.
At the end of the study, 98% of the cohort were available for assessment, with 19 patients (2%) lost to follow-up, having left the Brescia area. In total, 129 deaths occurred over 4650 person-years of follow-up. This led to a mortality rate of 2.77 per 100 person-years (95% CI 2.3-3.25 per 100 person-years). A total of 37% (n=48) deaths were AIDS-related; 36% (n=46) were liver-related, and a further 27% (n=35) of death were due to other causes, including suicide, drug overdoses, trauma and cardiovascular disease.
Of the 44 liver-related deaths analysed, 96% (n=42) were coinfected with HCV and in 36% (n=16) coinfection with HCV was the only risk factor for liver injury.
Independent risk factors for liver-related mortality by Cox's proportional hazard model were as follows:
- HCV infection (Hazard Ratio, 10.35; p = 0.0024),
- HBV infection (HR, 2.7; p=0.0025),
- alcohol abuse (HR, 2.7; p=0.0017),
- HAART-related life-threatening liver toxicity (HR, 5.8; p<0.0001), and
- HAART initiation at CD4 < 350/mm3 (HR, 4.6; p<0.0001).
Even after adjusting for hepatitis virus coinfection and alcohol abuse, use of HAART was independently protective of liver-related mortality (HR, 0.32; p=0.0068) as was a CD4 nadir >350 (HR, 0.20; p=0.0088).
Professor Puoti concluded that liver-related mortality "was the second highest cause of death in our cohort." He suggested that optimised management of HBV, HCV coinfections, alcohol abuse "are mandatory" to prevent liver-related mortality, and that the maintenance of high CD4 counts by HAART may be necessary in those with these risk factors. However, he added that although his data suggests starting HAART in coinfected patients when CD4 counts are above 350 cells/mm3 it needed to be balanced with HAART-related toxicity, since the prevention and treatment of HAART-related liver related death is also crucial.