Long-term exposure to combination antiretroviral therapy and risk of death from specific causes: no evidence for any previously unidentified increased risk due to antiretroviral therapy

Despite the known substantial benefits of combination antiretroviral therapy (cART), cumulative adverse effects could still limit the overall long-term treatment benefit. Therefore we investigated changes in the rate of death with increasing exposure to cART. A total of 12 069 patients were followed from baseline, which was defined as the time of starting cART or enrolment into EuroSIDA whichever occurred later, until death or 6 months after last follow-up visit. Incidence rates of death were calculated per 1000 person-years of follow-up (PYFU) and stratified by time of exposure to cART (≥3 antiretrovirals): less than 2, 2-3.99, 4-5.99, 6-7.99 and more than 8 years. Duration of cART exposure was the cumulative time actually receiving cART. Poisson regression models were fitted for each cause of death separately. A total of 1297 patients died during 70,613 PYFU [incidence rate 18.3 per 1000 PYFU, 95% confidence interval (CI) 17.4-19.4], 413 due to AIDS (5.85, 95% CI 5.28-6.41) and 884 due to non-AIDS-related cause (12.5, 95% CI 11.7-13.3). After adjustment for confounding variables, including baseline CD4 cell count and HIV RNA, there was a significant decrease in the rate of all-cause and AIDS-related death between 2 and 3.99 years and longer exposure time. In the first 2 years on cART the risk of non-AIDS death was significantly lower, but no significant difference in the rate of non-AIDS-related deaths between 2 and 3.99 years and longer exposure to cART was observed. In conclusion, we found no evidence of an increased risk of both all-cause and non-AIDS-related deaths with long-term cumulative cART exposure.