As
effective antiretroviral therapy has extended the lives of people with HIV/AIDS,
there is growing concern about long-term drug-elated toxicities. With regard to
increased cardiovascular disease risk, protease
inhibitors (PIs) have taken most of the blame, but some studies have found
an association with drugs in other classes.
The thymidine analogs, a subset
of nucleoside
reverse transcriptase inhibitors (NRTIs) that includes AZT
(zidovudine, Retrovir) and d4T
(stavudine, Zerit) have been linked to several long-term side effects including
lipoatrophy (peripheral fat loss). Some data have shown an association with abnormal
blood fat levels (dyslipidemia) and insulin resistance, both known risk factors
for heart disease.
To explore this connection, researchers with the large
D:A:D (Data Collection on Adverse Events of Anti-HIV Drugs) study assessed the
association between various NRTIs used as part of combination therapy and risk
of myocardial infarction (MI, or heart attack). Results were reported in a poster
presented at the 15th Conference on Retroviruses and Opportunistic Infections
this week in Boston.
D:A:D, begun in 1999, is a large ongoing collaboration
of 11 prospective cohorts in North America, Europe, and Australia that has collected
data on more than 33,000 patients. As
previously reported, antiretroviral therapy overall, and PI use in particular,
were associated with an increase risk of MIs.
In the present analysis,
the investigators set out to assess the effect of cumulative, recent (current
or within the past 6 months), and past (> 6 months ago) use of AZT, d4T, abacavir
(Ziagen; also in the Trizivir
and Epzicom combination pills),
ddI (didanosine, Videx), and 3TC
(lamivudine, Epivir). Emtricitabine
(Emtriva) and the sole nucleotide reverse transcriptase inhibitor, tenofovir
(Viread) (both combined in the Truvada
and Atripla combination pills)
were not included since they came on the market relatively late.
Results
•
A large majority - 89% -- of the total 157,912
person-years of follow-up included in the present analysis was spent on NRTI(s).
•
During this period, 517 individuals experienced
heart attacks.
•
98% of the MIs occurred among patients exposed
to 1 or more NRTIs.
•
Neither cumulative nor recent use of the 2
thymidine analogs (AZT and d4T) nor 3TC were associated with increased risk of
MI.
•
However, cumulative use of abacavir and ddI
were both significantly associated with an excess heart attack risk:
•
abacavir: relative risk per year of use 1.14
(95% CI 1.08-1.21; P < 0.01);
•
ddI: relative risk per year of use 1.06 (95%
CI 1.01-1.12; P = 0.03).
•
In a model focusing on recent use, use of
abacavir and ddI within the past 6 months -- but not cumulative use - predicted
an increased risk of MI (relative risk per year of use 1.90 and 1.49, respectively;
both P < 0.01).
•
In other models, recent use of these 2 drugs
-- but not past use -- predicted elevated MI risk.
•
Rates of MI per 1000 person-years for patients
with recent use versus no recent use, stratified by level of Framingham cardiovascular
risk, were as follows:
•
Abacavir:
•
Low risk: 3.3 vs 1.2;
•
Medium risk: 9.8 vs 7.1;
•
High risk: 31.3 vs 11.2.
•
ddI:
•
Low risk: 2.1 vs 1.5;
•
Medium risk: 9.1 vs 7.5;
•
High risk: 20.8 vs 14.9.
•
The elevated risk of MI associated with recent
abacavir or ddI use was seen regardless of duration of use.
•
The increased risk remained after adjusting
for HIV viral load, CD4 cell count, elevated blood lipids, and other metabolic
factors.
•
Preferential use of abacavir or ddI by patients
with pre-existing elevated cardiovascular risk ("channeling") did not
appear to explain the findings.
Conclusion
Based
on these results, the D:A:D researchers concluded that, "Thymidine analogs
were not associated with risk of MI." But, they continued, "Unexpectedly,
recent use of abacavir and ddI were associated with increased risk of MI, by 90%
and 49%, respectively."
"The excess risks of MI associated with
abacavir and ddI use were most pronounced -- in absolute terms -- in patients
with high underlying cardiovascular risk," they added. "Although it
is impossible to rule out bias as an explanation, if these associations are causal,
the unknown biological mechanism(s) appears reversible upon cessation of these
drugs."
The latter finding - that elevated MI risk did not continue
after patients stopped the drugs - is in contrast with use of PIs, which seems
to confer a persistent increase in risk. While PI risk is thought to be related
to elevated blood lipids that promote atherosclerosis, abacavir and ddI appear
to be associated with a short-term effect, perhaps related to inflammation, though
the biological mechanism is not clear at this time.
Based on these findings,
abacavir manufacturer GlaxoSmithKline conducted a retrospective review of 54 past
clinical trials of the drug. They reported at a community meeting prior to the
conference that they did not find an increased MI risk, with rates of 1.7 and
2.4 per 1000 person-years, respectively, in abacavir-exposed versus non-exposed
patients; the company said further analysis is ongoing.
Given the alarming
nature of the study findings, the D:A:D Steering Committee issued a statement
putting the results in context.
"To
give an estimate of the magnitude of the increase risk of heart attacks associated
with the use of these drugs, the 1.9 fold (90%) increased risk associated with
use of abacavir compares with a 2-3 fold increased risk of heart attack associated
with current cigarette smoking," they wrote.
However,
they noted that the increased risk was concentrated in patients with other cardiovascular
risk factors, including older age, smoking, diabetes, and high cholesterol, underling
the need to tailor antiretroviral therapy on an individual basis - and to manage
modifiable lifestyle factors that increase heart disease risk.
"The
authors of this study recommend patients receiving abacavir or ddI should consult
their doctor, and discuss whether a modification of their anti-HIV drug regimen
is appropriate," they wrote. "Patients should NOT stop any drug without
prior discussion with their doctor."
Univ
Coll London and Royal Free Hosp, UK; Univ of Copenhagen, Denmark; Univ Hosp Zurich,
Switzerland; Colombia Univ, New York, NY; Academic Med Ctr, Amsterdam, The Netherlands;
Inst for Publ Hlth, Epi and Devt, Univ Victor Segalen Bordeaux 2, France; St Pierre
Univ Hosp, Brussels, Belgium; Univ of New South Wales, Sydney, Australia; and
Rigshospitalet, Copenhagen, Denmark
02/08/08
Sources C
Sabin, S Worm R Weber, and others (D:A:D Study Group). Do Thymidine Analogues,
Abacavir, Didanosine and Lamivudine Contribute to the Risk of Myocardial Infarction?
The D:A:D Study. 15th Conference on Retroviruses and Opportunistic Infections.
Boston, MA. February 3-6, 2008. Abstract 957c.
D:A:D Steering Committee.
Position Statement by the D:A:D Steering Committee.
D:A:D
NRTI Analysis Shows Abacavir (Ziagen) and ddI (Videx) Boost Cardiovascular Risk
As
effective antiretroviral therapy has extended the lives of people with 
