No increased risk of non-AIDS deaths from cumulative use of ART in EuroSIDA cohort
Nathan Geffen, Centre for Social Science Research, UCT
Two ongoing concerns for HIV positive people on ART are (1) whether long-term side effects shorten life-expectancy? and (2) is premature ageing related to either ART or HIV?
While both short and medium term outcomes have so far been very good, data for these questions requires following large numbers of patients over many years. Since it is impossible to have randomised control groups, the interpretation of cohort results also needs to consider numerous confounding variables.
The second question is a particular focus for current research. But a new analysis from the EuroSIDA cohort comes close to answering the first. In an article published in the 21 January 2012 edition of AIDS, there was no evidence in this huge cohort that the risk of death, all-cause or AIDS, increased with length of time on ART. 
EuroSIDA is one of the largest prospective observational ART cohorts. It includes nearly 17,000 patients from Europe, Israel and Argentina. This cohort’s researchers previously have published important papers showing the benefits of ART on life expectancy. The authors explain that this is the first study “to look into the association of non-AIDS deaths with duration of time spent on combination antiretroviral therapy (cART) and with a long-term perspective of exposure to treatment. 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.”
Just over 12,000 patients were followed from baseline, defined as the time of starting ART or enrolment into EuroSIDA after 1996. Three quarters of the cohort is male. About 40% acquired HIV homosexually, 22% from IDU and 30% heterosexually. Interestingly, nearly 60% of the cohort are current or previous smokers and smoking status was unknown in more than 20%. At baseline about 21% were confirmed hepatitis C positive and about 53% were confirmed negative. About 10% had confirmed hypertension and just over 2% confirmed diabetes.
The researchers calculated incidence rates of death, AIDS-related and non-AIDS-related, per 1000 person-years of follow-up stratified by time of exposure to cART (< 2 years, 2 to 3.99 years; 4 to 5.99 years; 6 to 7.99 years and > 8 years).
During 70,613 person years of follow-up, a total of 1,297 patients died. AIDS caused 413 and non-AIDS diseases caused 884 deaths. Incidence rates per 1,000 years of follow-up were 18.3 overall (95% CI: 17.4-19.4), 5.85 for AIDS deaths (95% CI: 5.28-6.41) and 12.5 for non-AIDS deaths (95% CI: 11.7-13.3).
For the non-AIDS related deaths, 121 were due to infections, 182 due to liver-disease, 125 due to cancer, 122 due to cardiovascular disease, 90 due to violence (including suicide) and 91 due to other causes.
The main analysis compared mortality over the predefined periods on ART. The researchers used 2 to 3.99 years on ART as reference. In a multivariate analysis controlling for sex, ethnic origin, region of Europe, hepatitis B and C status, diabetes, hypertension, smoking, viral load, CD4 cell count, prior AIDS and age, they found the following incidence rate ratios of all-cause, AIDS-related and non-AIDS related deaths (see Table 1).
|Time on ART||all-cause death||AIDS deaths only||non-AIDS deaths only|
|< 2 years||1.02
|> 8 years||0.69
Longer time on ART was associated with a reduction in the risk of liver-related death, violent, and unknown deaths. But longer time on ART was also associated with an increase in mortality attributed to non-AIDS-related cancers. The researchers suggest this “may reflect ageing of the HIV population, as the effect was no longer present after adjustment for time updated age …”
This article is reassuring for people who are recently diagnosed, who have access to modern ARVs and a medical history that is uncomplicated by coinfections or prior drug resistance. It is important that there is no signal of additional risk from treatment that is otherwise stable and effective.
The risk of premature ageing is the focus for research into immune activation and inflammation. It is also dependent on HIV negative controls to understand the impact of residual inflammation in people suppressed on HAART. In an editorial in Current Opinion Infect Diseases, Martin Fisher and Vanessa Cooper suggest caution over links between HIV or ART and ageing. They conclude, “Although undoubtedly there are higher rates of comorbidities in the HIV-positive population […] Further research is needed to explore the mechanisms by which HIV/HAART may contribute to age-related diseases, the contribution of other important and potentially modifiable risk factors including smoking, alcohol and drug use, and the role of comorbid disease.” 
- Kowalska JD et al. for EuroSIDA. 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. AIDS 26:315-323. (28 January 2012). Free full text online.
- Fisher M and Cooper V. 2012. HIV and ageing: premature ageing or premature conclusions? Curr Opin Infect Dis 25:1-3. Free full text online.