Abacavir Not Associated with Inflammation in 2 Large U.S. HIV Cohorts

		SUMMARY: Patients who took the NRTI abacavir (Ziagen, also in the Trizivir and Epzicom combination pills) did not show elevated levels of biomarkers of inflammation and cardiovascular risk, according to an analysis of HIV positive men in the large MACS cohort and women in the WIHS cohort, as reported in the July 17, 2010 issue of AIDS. These findings add to a conflicting body of evidence about the link between abacavir and cardiovascular disease.

By Liz Highleyman

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Inflammation, its role in disease progression, and its contribution to non-AIDS conditions such as cardiovascular disease has become a hot topic in HIV research over the past few years.

At the 2008 Conference on Retroviruses and Opportunistic Infections researchers studying the large D:A:D cohort reported that HIV positive people who recently used abacavir were more likely to experience heart attacks. Since that time, analyses of other observational studies and randomized clinical trials have produced conflicting data, with some seeing a similar association between abacavir and cardiovascular diseases and others finding no such link.

Since cardiovascular disease has been associated with biomarkers of inflammation, coagulation (blood clotting), and endothelial (blood vessel) dysfunction in numerous studies including the SMART treatment interruption trial, investigators have also looked at whether abacavir use might be association with biomarker changes; some suspected that inflammation might be related to low-level abacavir hypersensitivity reactions. But here too, findings have been inconsistent.

In the most recent analysis, Frank Palella from Northwestern University and colleagues with the Multicenter AIDS Cohort Study (MACS) and Women's Interagency HIV Study (WIHS) assessed associations between abacavir use and systemic, or whole body, inflammation.

This nested case-control study included 180 pairs of participants from MACS, a long-running cohort of gay and bisexual men in 4 U.S. cities (Baltimore, Chicago, Pittsburgh and Los Angeles), and 328 pairs of women from WIHS, a cohort of HIV positive and at-risk women in several U.S. cities. Each demographically matched pair included 1 HIV positive individual who took abacavir as part of an antiretroviral therapy (ART) regimen and 1 who was not exposed to the drug. Nearly half the participants smoked and more than one third were coinfected with hepatitis C.

The researchers measured levels of high-sensitivity C-reactive protein (hsCRP, an inflammation biomarker), interleukin-6 (IL-6, a pro-inflammatory cytokine), and D-dimer (a by-product of coagulation) in blood samples taken before and after initiation of combination ART; some participants had previously used nucleoside/nucleotide reverse transcriptase inhibitor (NRTI) monotherapy or dual therapy.

Results

	Regardless of abacavir use, hsCRP levels rose and D-dimer levels fell on average after starting ART.
	CRP increases -- indicating greater inflammation -- were seen overall (+28 mcg/mL), as well as in the MACS men (+28 mcg/mL) and WIHS women (+29 mcg/mL) considered separately.
	D-dimer decreases -- suggesting reduced coagulation -- were -27%, -31%, and -24%, respectively.
	IL-6 levels decreased on average among the MACS men, but did not change in the WIHS women.
	Despite biomarker level changes after starting ART, average levels of each biomarker were within generally accepted "normal" ranges for healthy adults both before and after treatment initiation.
	In an adjusted analysis, no significant differences in biomarker levels were observed after starting ART between participants who used abacavir and those who remained unexposed to the drug.
	Decreases in D-dimer and IL-6 were significantly correlated with HIV viral load reductions.
	Associations between abacavir use and average biomarker levels were affected by suboptimal use of NRTIs before combination ART.
	Kidney dysfunction was equally likely among abacavir recipients and unexposed patients.

Based on these findings, the researchers concluded, "Abacavir use was not associated with plasma elevations in hsCRP, IL-6, and D-dimer."

"Mechanisms other than increased systemic inflammation may account for abacavir's reported association with increased cardiovascular disease," they added. "HAART-associated reductions in D-dimer and IL-6 were apparent regardless of abacavir use and were correlated with HIV RNA reductions."

"This work should not be interpreted as either refuting or supporting hypotheses suggesting associations between recent use of abacavir (or any other ART for that matter) and cardiovascular disease in general or specific cardiovascular disease endpoints," they elaborated in their discussion. "We did not undertake evaluations of use of abacavir and cardiovascular disease nor the assessment of plasma biomarker levels in relationship to specific clinical events."

However, they continued, "our work does suggest that, if recent abacavir use is indeed associated with increase risk for adverse cardiovascular events, system inflammation is not likely the sole or primary means by which its effects are mediated."

The authors also acknowledged that while their finding of D-dimer and IL-6 decreases after starting ART agrees with other research indicating that HIV suppression is associated with reduced inflammation, they could not explain the observed increase in CRP.

Investigator affiliations: Division of Infectious Diseases, Northwestern University Feinberg School of Medicine, Chicago, IL; Johns Hopkins University, Baltimore, MD; Albert Einstein College of Medicine, New York, NY; Rush University Medical Center, Chicago, IL; University of Vermont, Burlington, VT; George Washington University, Washington, DC.

7/13/10

Reference
FJ Palella, SJ Gange, L Benning, and others. Inflammatory biomarkers and abacavir use in the Women's Interagency HIV Study and the Multicenter AIDS Cohort Study. AIDS 24(11): 1657-1665 (Abstract). July 17, 2010.