Long-term use of HIV drugs is safe, does not raise risk of death, study shows

A large international study has provided persuasive evidence of the long-term safety of antiretroviral therapy. Writing in the online edition of AIDS, investigators from the EuroSIDA study report that prolonged use of antiretroviral therapy did not increase the risk of death from non-AIDS-related illnesses.

“The main finding of our study was that there was no evidence of an increase in the risk of any non-AIDS-related death with prolonged exposure to cART [combination antiretroviral therapy],” comment the authors. “The results are reassuring that so far prolonged use of cART does not appear to be leading to increased risk of death due to some previously identified cumulative effect, or a drug effect whereby there is a long induction period before disease appears.”

It is now well recognised that effective antiretroviral therapy has significantly improved the life expectancy of many patients with HIV.

However, all anti-HIV drugs can cause side-effects, and treatment with some has been linked to an increased risk of cardiovascular disease or kidney dysfunction. Whether prolonged treatment with antiretroviral therapy carries an increased risk of death from these and other diseases is currently unclear.

Therefore investigators from the EuroSIDA cohort study looked at the outcomes of approximately 12,000 patients who received potent combination antiretroviral therapy after 1996.

These patients were categorised according to the duration of treatment (under two years; two to three years; four to six years; six to eight years; and over eight years).

Overall mortality incidence was then calculated according to treatment exposure, as was the incidence of AIDS-related and non-AIDS-related deaths. The investigators adjusted their results to take into consideration factors known to independently affect prognosis including demographics, HIV risk group, co-infection status, CD4 cell count and viral load, and previous history of AIDS-related illnesses.

During 70,000 person years of follow-up, a total of 1297 patients died. A little over two-thirds of deaths (68%) were attributed to non-AIDS-related causes.

AIDS-related mortality accounted for 32% of all deaths. The investigators attributed 9% of deaths to non-AIDS-related infections, 14% to liver-related causes, 10% to non-AIDS-related cancers, 9% to cardiovascular causes, 7% to violence (including suicide) and 7% to other causes. In addition, 12% of non-AIDS-related mortality had an unknown cause.

Incidence of all-cause mortality was 18.3 per 1000 person years; AIDS-related mortality had an incidence of 5.85 deaths per 1000 person years; and the incidence of non-AIDS-related mortality was 12.5 per 1000 person years.

Further analysis showed that the incidence of all-cause mortality and AIDS-related mortality fell significantly as exposure to HIV therapy increased. However, the incidence of non-AIDS-related deaths remained broadly stable.

Each additional year of HIV therapy (after year two) was associated with a 5% reduction in the risk of all-cause mortality (p < 0.0001) and a 14% fall in the risk of AIDS-related deaths (p < 0.0001). The risk of non-AIDS-related deaths fell by 3% each year, a reduction that fell just short of significance (p = 0.06).

“Our analyses confirm the prolonged benefit of cART, with a 5% reduction in the overall risk of death per additional year on treatment, which was mostly attributed to a decrease in the risk of AIDS-related deaths.”

Prolonged use of antiretroviral therapy was also accompanied by a reduction in “the risk of liver-related death, violent, and unknown death.” The investigators speculate that the lower risk of violent death “could relate to stabilised health conditions, life-style changes or improvements in socio-economic status.”

However, longer duration of HIV therapy was accompanied by an increase in mortality attributed to non-AIDS-related cancers. The authors suggest this “may reflect aging of the HIV population…or improvement in cancer screening.”

They conclude: “It is clear that death due to accumulating treatment toxicities is a very uncommon event.”