Factors May Explain Elevated Cardiovascular Risk in Patients Taking Abacavir|
studies presented last week at the 5th International AIDS Society Conference on
HIV Pathogenesis, Treatment and Prevention (IAS 2009) did not find a significant
association between abacavir use and increased risk of cardiovascular disease,
with one pointing to kidney disease as a confounding factor.|
potential link between abacavir (Ziagen,
also in the Epzicom and Trizivir
combination pills) and cardiovascular disease has been an ongoing topic of debate
since researchers with the large D:A:D study reported
at the 2008 Retrovirus conference that participants who took abacavir
or didanosine (ddI, Videx) had
a higher rate of heart attacks than those who used other nucleoside/nucleotide
reverse transcriptase inhibitors (NRTIs). Since then, several
subsequent studies have produced conflicting
further examine this association, Roger Bedimo and colleagues searched the U.S.
Veterans Administration's Clinical Case Registry to identify patients who had
experienced acute myocardial infarctions (MIs, heart attacks) or cerebrovascular
events (strokes) during the HAART era. This study was retrospective (looking back
in time) while the D:A:D analysis was prospective (following patients forward).
1996 and 2004, a total of 19,424 participants were assessed for an average of
about 4 years each, representing 76,376 person-years of follow-up. Almost all
were men, the median age was 46 years, and nearly one-third were smokers. They
were allocated into 4 categories based on the type of antiretroviral therapy they
received between 1996 and 2004:
Combination antiretroviral therapy (ART) including abacavir.|
ART including other NRTIs but not abacavir.|
that did not meet the definition of "highly active antiretroviral therapy,"
such as NRTI monotherapy or dual therapy.|
investigators looked for associations between abacavir use and MIs or strokes
and assessed the role of potential confounding factors not included in previous
studies. In particular, they examined the effect of hepatitis C virus (HCV) coinfection
and chronic kidney disease.
positive association between HCV and heart attacks in U.S. veterans has been reported
the 2008 International AIDS Conference and in a recent
journal article. In the present report, the investigators focused on kidney
disease, defined according to glomerular filtration rate (GFR; >90 considered
disease is a known risk factor for heart disease in the HIV negative general population.
HIV positive patients with kidney impairment are more likely to be prescribed
abacavir, since tenofovir (Viread,
also in the Truvada and Atripla
combination pills) a widely used alternative has been associated with kidney toxicity
in susceptible people.
A total of 278 acute MIs and 868 strokes were diagnosed during the study period.|
overall MI rate was 3.69 per 1000 person-years (PY).|
overall stroke rate was 11.68 per 1000 PY. |
who had MIs were significantly more likely to have traditional cardiovascular
risk factors including older age, diabetes, high blood pressure, and elevated
blood lipids, as well as hepatitis C and kidney disease.|
an unadjusted analysis, cumulative use of abacavir was associated with a borderline
significant increase in MI risk (hazard ratio [HR] 1.27; P = 0.056). |
of NRTI monotherapy or dual therapy was associated with a much greater increase
in MI risk (HR 1.44; P < 0.0001).|
use was also associated with a slight increase in the risk of stroke, which did
not reach statistical significance (HR 1.17; P = 0.081).|
coinfection was associated with a slight but non-significant increase in the risk
of both MI (HR 1.25; P = 0.075) and stroke (HR 1.12; P = 0.105).|
kidney disease (GFR < 60) increased the risk of MI by about 4-fold (HR 3.85;
P < 0.0001) and stroke by about 3-fold (HR 2.95; P = 0.002).|
mild kidney impairment (GFR 60-89) was associated with a less dramatic increase
in the risk of MI (HR 1.33; P < 0.048) and stroke (HR 1.28; P < 0.0001).|
adjusting for kidney disease and traditional risk factors, the links between abacavir
and MI or stroke no longer approached statistical significance.|
with serious kidney disease were about twice as likely to have used abacavir versus
tenofovir (12.29% vs 7.22%; approximately 10% had used both drugs or neither).|
our cohort, cumulative exposure to abacavir was associated with a modest, non-statistically
significant increase in acute MI and [cerebrovascular event] risks," the
researchers concluded. "The association of abacavir use with AMI was much
weaker after adjusting for traditional cardiovascular risk factors."
kidney disease may be a contributor to the observed association of abacavir and
acute MIs, they suggested. Discussing these findings, Bedimo noted that observational
studies that showed a link between abacavir and MIs (including D:A:D and SMART)
included all patients without regard for kidney function, and abacavir was more
likely to be used by patients with kidney disease. In contrast, controlled studies
that excluded people with chronic kidney disease (including
STEAL, ALLRT, and a GlaxoSmithKline analysis of more than 50 abacavir trials)
did not see an association.
North Texas Healthcare System, Dallas, TX; University of Texas Southwestern Medical
Center, Dallas, TX; University of Alabama at Birmingham, Birmingham, AL; University
of Pennsylvania, Philadelphia, PA.
the same session, E. Martinez presented results from a retrospective analysis
of data from the Spanish
BICOMBO study, in which 335 patients with suppressed viral load were randomly
assigned to switch to either the abacavir/lamivudine (Epzicom) or tenofovir/emtricitabine
(Truvada) combination pill, while staying on the same NNRTI or protease inhibitor.
(80%) were men and the median age was 43 years. The median Framingham cardiovascular
risk score was 4.4, but it was slightly higher among abacavir recipients compared
with tenofovir recipients (5.5 vs 3.8).
present analysis included a subset of 80 patients, 46 taking Epzicom and 34 taking
Truvada. The investigators measured several blood biomarkers associated with increased
inflammation (high-sensitivity C-reactive protein [hsCRP], monocyte chemottractant
protein-1, osteoprotegrin, adiponectin, interleukin-6 [IL-6], IL-10, and tumor
necrosis factor-alpha [TNF-alpha]), blood vessel dysfunction (ICAM-1, VCAM-1,
selectin E and P, insulin), and coagulation (D-dimer).Results
baseline, there were no significant differences in biomarker levels between patients
taking abacavir and those taking tenofovir. |
48 weeks, changes in biomarker levels were small.|
biomarker changes were similar in patients taking abacavir and tenofovir.|
largest albeit not statistically significant differences were in adiponectin (P
= 0.12), selectin E (P = 0.13), selectin P (P = 0.33), and insulin (P = 0.69),
all of which increased considerably in the tenofovir arm while decreasing or increasing
only slightly in the abacavir arm.|
otherwise healthy, virologically suppressed HIV-infected patients from the BICOMBO
study, the researchers concluded, "the initiation of [abacavir/lamivudine]
did not lead to significant changes after 48 weeks in markers of inflammation,
endothelial dysfunction, insulin resistance or hypercoagulability as compared
with the initiation of [tenofovir/emtricitabine]."
results, they added, "argue against the involvement of [abacavir] in any
of these mechanisms and therefore e do not explain the higher risk of MI associated
with recent [abacavir] use in some cohort studies."
Clinic-IDIBAPS, University of Barcelona, Barcelona, Spain; Hospital de Bellvitge,
L'Hospitalet de Llobregat, Spain; Hospital General Universitario de Elche, Elche,
Martinez, M Larrousse, I Perez, and others. No evidence for recent abacavir/lamivudine
use in promoting inflammation, endothelial dysfunction, hypercoagulability, or
insulin resistance in virologically suppressed HIV-infected patients: a substudy
of the BICOMBO randomized clinical trial (ISRCTN61891868). 5th International AIDS
Society Conference on HIV Pathogenesis, Treatment, and Prevention (IAS 2009).
July 19-22, 2009. Cape Town, South Africa. Abstract MoAb203. (Abstract).
A Westfall, H Drechsler, and others. Abacavir use and risk of acute myocardial
infarction and cerebrovascular disease in the HAART era. 5th International AIDS
Society Conference on HIV Pathogenesis, Treatment, and Prevention (IAS 2009).
July 19-22, 2009. Cape Town, South Africa. Abstract MOAB202. (Abstract).