By Liz Highleyman

Abacavir (Ziagen)

The 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 results.

Veteran's Study

To 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).

Between 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.
	Combination ART including other NRTIs but not abacavir.
	ART that did not meet the definition of "highly active antiretroviral therapy," such as NRTI monotherapy or dual therapy.
	No ART.

The 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.

A positive association between HCV and heart attacks in U.S. veterans has been reported previously at 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 normal).

Kidney 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.

Results

	A total of 278 acute MIs and 868 strokes were diagnosed during the study period.
	The overall MI rate was 3.69 per 1000 person-years (PY).
	The overall stroke rate was 11.68 per 1000 PY.
	Patients 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.
	In 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).
	Use of NRTI monotherapy or dual therapy was associated with a much greater increase in MI risk (HR 1.44; P < 0.0001).
	Abacavir 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).
	HCV 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).
	Serious 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).
	Even 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).
	After adjusting for kidney disease and traditional risk factors, the links between abacavir and MI or stroke no longer approached statistical significance.
	Patients 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).

Chronic 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.

VA 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.

BICOMBO Study

Most participants (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).

The 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).

	At baseline, there were no significant differences in biomarker levels between patients taking abacavir and those taking tenofovir.
	After 48 weeks, changes in biomarker levels were small.
	Overall, biomarker changes were similar in patients taking abacavir and tenofovir.
	The 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.

"In 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]."

The 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."

Hospital Clinic-IDIBAPS, University of Barcelona, Barcelona, Spain; Hospital de Bellvitge, L'Hospitalet de Llobregat, Spain; Hospital General Universitario de Elche, Elche, Spain.

7/28/09

References

E 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).

R Bedimo, 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).

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