Antiretroviral Drugs Linked to Heart Attacks in D:A:D
Study, but Overall Risk Remains Small
The latest analysis from the large European
D:A:D cohort, reported in the February
1, 2010 Journal of Infectious Diseases,
found that use of the antiretroviral drugs
(ddI, Videx), and abacavir
(Ziagen, also in the Epzicom
coformulation) was associated with a significantly
increased risk of myocardial
infarction (MI). The overall number
of heart attacks was small, however, and
the researchers said the findings should
be interpreted with caution given the potential
for confounding and the overall benefits
of HIV treatment.
2003, investigators with the Data Collection on Adverse
Events of Anti-HIV Drugs (D:A:D) study first reported
that use of combination antiretroviral therapy (ART)
was associated with a increased relative rate of myocardial
infarction, though the absolute risk was low.
that time, many researchers have attempted to tease
out whether -- and how much -- specific drugs raise
the risk of heart disease. Several studies have pointed
inhibitors, some of which can raise blood lipid
levels, a known cardiovascular risk factor.
the 2008 Conference on Retroviruses and Opportunistic
Infections, the D:A:D
team reported that patients taking abacavir or
didanosine within the past 6 months had a significantly
higher rate of myocardial infarction than those taking
reverse transcriptase inhibitors (NRTIs).
has continued to collect results, and the recently
published analysis includes 178,835 person-years of
data from 33,308 patients. The investigators assessed
the association between MI risk and cumulative (per
year) or recent (current or in the past 6 months)
use of 13 different antiretroviral agents that each
have available data reflecting more than 30,000 person-years
Statistical models for each drug were adjusted to
take into account various confounding factors, including
cardiovascular risk factors (such as older age, smoking,
diabetes, and obesity), calendar year, and use of
other antiretroviral agents.
178,835 person-years, a total of 580 patients
experienced an MI.
those with an MI, 91% were men, 60% were white,
the median age was 49 years, and 52% had HIV RNA
< 50 copies/mL.
the NRTI agents, recent exposure to abacavir (relative
risk [RR] 1.70 per year) or didanosine (RR 1.41
per year) were associated with significantly increased
risk of MI.
the earlier D:A:D analysis, there was a slight
association between cumulative abacavir use and
MI risk (RR 1.07 per year), but the difference
had marginal statistical significance.
was no association between MI risk and use of
(Viread, also in the Truvada
coformulations), zalcitabine (ddC, Hivid [now
(AZT; Retrovir), stavudine
(d4T, Zerit), or lamivudine
at the protease inhibitors, cumulative exposure
to indinavir (RR 1.12 per year) and lopinavir-ritonavir
(RR 1.13 per year) were associated with increased
was no association between MI risk and cumulative
exposure to nelfinavir
(Viracept) or saquinavir
increased risk associated with indinavir and lopinavir/ritonavir
was slightly reduced after adjusting for lipid
levels (to RR 1.08 and 1.09 per year, respectively).
was no association between MI risk and cumulative
exposure to the non-nucleoside reverse transcriptase
inhibitors (NNRTIs) nevirapine (Viramune) or efavirenz
in the earlier D:A:D analysis, the increased MI
risk was mainly seen in individuals with traditional
cardiovascular risk factors.
patients experiencing an MI, 18% had a high (>
20%) 10-year predicted heart disease risk and
30% had a moderate (10%-20%) risk.
"Of the drugs considered, only indinavir, lopinavir/ritonavir,
didanosine, and abacavir were associated with a significantly
increased risk of MI," the D:A:D investigators
concluded. "As with any observational study,
our findings must be interpreted with caution (given
the potential for confounding) and in the context
of the benefits that these drugs provide."
overall rate of MI remains relatively low in this
study, and any toxicities of antiretroviral drugs
must always be interpreted in the context of the benefits
that these drugs provide, but our findings do highlight
the need for studies to continue to examine the complications
associated with specific antiretroviral drugs,"
they continued in their discussion.
an accompanying editorial, Judith Aberg from New York
University School of Medicine and Heather Ribaudo
from Harvard School of Public Health discussed the
controversy over the link between ART and heart disease.
especially, has been the subject of conflicting
data, with several studies showing an increased
risk of cardiovascular events and others finding no
association. Unlike protease inhibitors, researchers
have not identified a biological mechanism to explain
a link between abacavir use and cardiovascular risk.
experts think the association may be attributable
to "channelling bias," or the tendency to
prescribe abacavir more often to patients with metabolic
syndrome, lipoatrophy, heart disease, or kidney disease
-- that is, those who are already at higher risk for
heart attacks. One recent study, for example, suggested
disease is an important confounder, since clinicians
tend to avoid giving tenofovir to patients with pre-existing
kidney disease or risk factors.
and Ribaudo cautioned against putting too much weight
on findings from observational cohort studies like
D:A:D, given the difficulty of teasing out confounding
the D:A:D investigators advise readers to interpret
their studies with caution, it remains unclear how
clinicians interpret statements of this sort,"
they wrote. "Certainly, the results of D:A:D
studies have become a rich source for marketing by
pharmaceutical companies, which has contributed, in
our opinion, to overemphasis of the results."
conclusion, they recommended, "More attention
should be given to the traditional factors that are
associated with the most risk (e.g., smoking, hypertension,
and obesity)" -- which, fortunately, are modifiable
with lifestyle changes and medication.
Copenhagen HIV Programme, University of Copenhagen,
Copenhagen, Denmark; Research Department of Infection
and Population Health and Centre for Sexual Health
and HIV Research, University College London, London,
UK; Division of Infectious Diseases and Hospital Epidemiology,
University Hospital Zurich, Zurich, Switzerland; HIV
Monitoring Foundation, Academic Medical Center, Amsterdam,
Netherlands; Columbia University and Harlem Hospital,
New York City, NY; Institut National de la Santé
et de la Recherche Médicale E0338 and U593,
Institut de Santé Publique, d'Epidémiologie
et de Développement, Université Victor
Segalen, Bordeaux, France; Centre Hospitalier Universitaire
Nice Hopital de l'Archet, Nice, France; Department
of Infectious Diseases, Centre Hospitalier Universitaire
Saint-Pierre Hospital, Brussels, Belgium; National
Centre in HIV Epidemiology and Clinical Research,
Sydney, Australia; Hospital San Paolo, University
of Milan, Milan, Italy.
Worm, C Sabin, R Weber, and others. Risk of Myocardial
Infarction in Patients with HIV Infection Exposed
to Specific Individual Antiretroviral Drugs from the
3 Major Drug Classes: The Data Collection on Adverse
Events of Anti-HIV Drugs (D:A:D) Study. Journal of
Infectious Diseases 201(3): 318-330 (Abstract).
February 1, 2010.
Aberg and H Ribaudo. Cardiac Risk: Not So Simple (Editorial
commentary). Journal of Infectious Diseases
201(3): 315-317. February 1, 2010.