December 18, 2018
Debates about the role of abacavir (Ziagen, ABC) in the development of cardiovascular disease in persons living with HIV have raged for over a decade, and a kind of stalemate has been achieved between those who are and are not convinced of a link. What has been missing has been a plausible biological mechanism by which ABC would increase the risk of heart attacks and stroke. At the 2018 Conference on Retroviruses and Opportunistic Infections (CROI), data were presented that may finally solve this "how"dunit.
A collaborative from Ireland and the United Kingdom looked at participants in a Gilead-sponsored trial that randomized 556 patients with suppressed viremia on an ABC/lamivudine or 3TC (Epzicom, Kivexa)-containing regimen to either continue this regimen or switch their nucleosides to emtricitabine/tenofovir alafenamide (Descovy, F/TAF).
The investigators performed intensive platelet function examinations on fresh blood samples taken from a subset of 61 participants (29 of whom were switched to F/TAF) at one of four sites in Dublin or London. Platelet aggregation provoked by different agonists was assessed, and significant inter-arm differences were observed, indicating a greater tendency for platelets to aggregate within people who remained on ABC/3TC.
Also examined was glycoprotein VI (GPVI), a collagen receptor on platelets that can trigger activation. Both platelet surface expression of GPVI in the 61 substudy participants and levels of soluble GPVI in the total cohort of 556 were looked at. It is a complicated bit of cell biology, but low levels of soluble GPVI are thought to be associated with coronary artery events and, thus, are not good. Those who switched from ABC/3TC to F/TAF saw an increase in expression and mean soluble GPVI over time -- suggesting "an inherent defect in participants on ABC" that was reversible with a switch.
The presented data on platelet activity may be the most convincing we will ever see implicating ABC in cardiovascular disease. Other studies, including one from a UK team also presented at CROI, likewise hone in on ABC and its effects on the complex biology of the platelet.
It should be noted that both studies were funded by Gilead (presumably through unrestricted grants), have yet to be published, and involve small numbers of participants. But, industry-independent clinical cohorts with large sample sizes have continued to publish associations between exposure to ABC and cardiovascular disease. For instance, at this same CROI, the venerable Swiss Cohort Study found an independent association between treatment with ABC and non-calcified coronary plaque.
With the dawn of dolutegravir+3TC, as well as TAF, the sun may be fading on ABC. Tolerance for the shadow of doubt cast on a medication is proportional to the drug's usefulness. As the treatment of HIV has evolved to include fitter agents, many of our older medications, including ABC, are becoming less relevant. Few patients need to be on ABC, and there are alternatives that, on par, are probably better tolerated and safer.
|Top 10 Clinical Developments of 2018|
|1. GEMINI and the Rise of Two-Drug HIV Therapy|
|2. Debate Over Dolutegravir in Early Pregnancy|
|3. Integrase Inhibitors and Weight Gain|
|4. PrEP and the Decline in New HIV Diagnoses|
|5. On-Demand Prevention in France|
|6. Bictegravir Has Finally Arrived|
|7. Abacavir, Platelets, and a Cardiovascular Verdict|
|8. African-American Men and HIV Treatment Outcomes|
|9. The Long-Acting Bandwagon|
|10. Designing HIV-Resistant People|
David Alain Wohl, M.D., is a professor of medicine in the Division of Infectious Diseases at the University of North Carolina (UNC). He is site leader of the UNC AIDS Clinical Trials Unit at Chapel Hill, director of the North Carolina AIDS Education and Training Center (AETC), and co-director of HIV services for the North Carolina state prison system. In 2014, he became co-director of the UNC-Duke Clinical RM Ebola Response Consortium.
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