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
“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.
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).
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
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.
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.
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.”
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