Guidelines Panel Responds to Abacavir Data
April 10, 2008
The Department of Health and Human Services (DHHS) HIV treatment guidelines panel has issued a response to recent negative findings about abacavir. Abacavir is an HIV drug sold as Ziagen and in the fixed dose combination pills Epzicom (with lamivudine/3TC) and Trizivir (with lamivudine/3TC + zidovudine/AZT). While acknowledging growing concerns about this widely used HIV drug, the panel stopped short of revising its recommendation of Epzicom as a preferred option for people taking HIV drugs for the first time.
The DHHS communication refers to two recent studies that have raised important questions about abacavir. The first was the analysis of the D:A:D study, first reported at CROI 2008 in February. Researchers looking at the D:A:D cohort found that people taking abacavir were about 1.9 times more likely to have a heart attack than those not on abacavir. The increased risk was greater for people who had other known risk factors for heart attack, like family history, diabetes and smoking.
As reported here, this finding came as a surprise. In contrast to protease inhibitors, which can increase cholesterol and triglycerides, there is no known biological explanation for the increased risk of heart attack with abacavir. While significant, the increased risk is also small, in absolute numbers. In the entire D:A:D study there was a .03% chance of heart attack per year. For people taking abacavir the rate was around .06%. That means if you followed 10,000 people for a year, 6 people taking abacavir would be expected to have a heart attack, compared to about 3 people overall.
It is important to point out that this increased risk associated with abacavir is much smaller than the risk found with cigarette smoking, poor diet and diabetes. The increased risk appeared to reverse once people had stopped taking abacavir for 6 months. This suggests that the effect is real, rather than a coincidental finding. It is also reassuring for anyone who has taken abacavir.
The second set back for abacavir came at the end of February 2008, when the AIDS Clinical Trail Group (ACTG) announced the decision to unblind almost half of the participants in ACTG 5202: a head-to-head study comparing Epzicom to Truvada (tenofovir + FTC), with either Sustiva (efavirenz) or Norvir (ritonavir)-boosted Reyataz (atazanavir).
The decision followed an early look at the results by a Data Safety Monitoring Board (DSMB), an independent group of scientists who periodically review data from ongoing studies to ensure the participants' safety. The DSMB found higher rates of treatment failure among people taking Epzicom who had started the study with HIV levels above 100,000 copies, referred to as the high viral load group. They also reported higher rates of moderate side effects for people in this group taking Epzicom. The DSMB decided to unblind the study participants who were in the high viral load group, and inform those taking Epzicom of the results. Importantly, they did not decide to stop the entire study, or unblind the lower viral load group.
The DHHS panel looked at these two sets of results and concluded they did not warrant changing the current recommendations. This decision was being watched closely, as these findings came closely after Epzicom had been added in January to the 'preferred' category for first line treatment.
While these results can not be ignored, they raise as many new questions as the answer. The analysis of the D:A:D study did not look at the components of Truvada, which is the most likely option for someone to switch to. GlaxoSmithKline (the maker of abacavir) released its own analysis of several studies, finding no increased risk of hear attack from taking abacavir. The lack of a solid biological explanation, confirmatory studies and information on Truvada make it challenging to know what exactly to do with the D:A:D results.
The same can be said of the decision to unblind the high viral load group in ACTG 5202. The DSMB looked at all of the results and saw enough of a difference to warrant taking action only in the high viral load group. The fact that they didn't decide to unblind the entire study is curious. While differences in treatment results in people with higher and lower viral levels have been seen in other studies, those differences have always gone away over time -- a fact that members of the DSMB should be well aware of. Their decision not to unblind the lower viral load group suggests that they saw something of interest in the lower viral load group, and that they felt justified allowing that part of the trial to go forward.
If you take abacavir, these results do not necessarily mean you should switch. Discuss the D:A:D findings with your doctor, especially if you have known risk factors for heart attack, like smoking, family history and diabetes. If you started aregimen with abacavir when you HIV levels were above 100,000 copies, extra vigilance might be warranted.
Some might question why the DHHS panel didn't change its recommendation to include Epzicom as a preferred option. It is fair to say that these two studies have raised important questions about abacavir. It is less clear however that Epzicom should be viewed less favorably than other options, specifically Truvada. Until more is understood about both of these studies, Project Inform supports the DHHS decision to detail the findings, and to counsel people living with HIV/AIDS and their doctors to consider all of the available research when making decisions on HIV treatment.
The full text of the DHHS communication is below.
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