Featured news from NHIVNA
HIV-related news from NAM
D:A:D study – long-term use of darunavir/ritonavir modestly increases the risk of cardiovascular disease
Michael Carter, 2017-03-08 07:10:00
Long-term use of
the protease inhibitor darunavir/ritonavir modestly increases the risk of
cardiovascular disease, according to data from the ongoing D:A:D study
presented to the recent Conference on Retroviruses and Opportunistic Infections
(CROI 2017). Investigators identified an independent association between
cumulative use of the drug over five years and heart attack and stroke.
The development of
protease inhibitors represented a major breakthrough in antiretroviral therapy.
However, a large body of research, including analyses from the D:A:D study, shows
that cumulative treatment with first-generation protease inhibitors –
indinavir, nelfinavir, saquinavr and full-dose ritonavir – increases the risk
of cardiovascular disease. A possible explanation for the association is the
increases in blood lipids caused by these drugs.
improvements in treatment and care, many people with HIV are now living well
into old age. Diseases normally associated with ageing – including
cardiovascular disease – are now an important cause of serious illness and
death in people with HIV. Prevention of these diseases is now a priority of
HIV care and it is important to establish which anti-HIV drugs are
independently associated with increased cardiovascular risk. It is unknown if
cumulative therapy with the protease inhibitors in current use, especially
darunavir/ritonavir and atazanavir/ritonavir, is associated with an increased
risk of cardiovascular disease.
the D:A:D study therefore designed an observational study to see if therapy
with darunavir/ritonavir or atazanavir/ritonavir is independently associated
with the risk of cardiovascular disease.
disease was defined as myocardial infarction (heart attack), stroke, sudden cardiac
death or invasive cardiovascular procedures such as coronary bypass,
angioplasty or carotid endarterectomy (unblocking of the carotid artery).
received care between early 2009 and early 2016 were eligible for inclusion.
Incidence of cardiovascular disease was stratified by cumulative (five year)
treatment with darunavir/ritonavir and atazanavir/ritonavir. The investigators
performed a series of statistical analyses to assess the independent
associations between use of these drugs and cardiovascular disease risk,
adjusting for potential confounders.
population consisted of 35,711 people. The median age was 44 years, 74% were
male, 48% were white and 46% were in the men who have sex with men risk group. A large proportion (38%)
was assessed as having a 5% or greater risk of a cardiovascular event, with 5%
having a 10% or greater risk of cardiovascular disease.
followed for a median of seven years. During this time 1157 (3%) people
experienced a cardiovascular event, an incidence rate of 5.3 per 1000
person-years of follow-up. The most common events was angioplasty (n = 459),
followed by stroke (n = 379), heart attack (n = 354), bypass (n = 93) and
unblocking of the carotid artery (n = 15).
with atazanavir/ritonavir was associated with a cardiovascular disease
incidence of 6.68 per 1000 person-years of follow-up, with use of
darunavir/ritonavir associated with an incidence of 13.67 per 1000
for potential confounders including CD4 cell count, BMI, kidney disease,
dyslipidaemia and diabetes, there was no association between long-term use of
atazanavir/ritonavir and cardiovascular disease (IRR = 1.01; 95% CI,
0.88-1.16). However, an independent and significant relationship was present
for darunavir/ritonavir (IRR = 1.53; 95% CI, 1.28-1.84).
were essentially unchanged after adjustment for bilirubin levels.
darunavir/ritonavir therapy showed that cumulative five-year use of the drug
independently increased the risk of heart attack (IRR = 1.51; 95% CI,
1.13-2.02) and stroke (IRR = 1.49; 95% CI, 1.08-2.07). Associations were
unchanged after taking into account whether darunavir/ritonavir was used in the
first ever protease inhibitor-containing regimen and baseline cardiovascular
do not believe their results are definitive. They acknowledge that there could
be unmeasured confounding factors and that their findings are limited by the
observational design of their study.
conclude that cumulative therapy with darunavir/ritonavir was associated with a
small, but gradually increasing risk of cardiovascular disease per five years
of therapy. They call for further research to identify the factors underlying