The ongoing and deepening controversy surrounding abacavir was one of the main stories at this year's International AIDS Conference. The "late breaker" sessions, often the venue for the most interesting research data, included four full presentations debating two important questions about this widely used HIV drug. While it's fair to say that controversy remains, Project Inform can't help but note a growing cloud of questions surrounding this important HIV treatment.
Abacavir is sold alone as Ziagen and in the fixed-dose combination pills Epzicom (with emtricitabine/FTC) and Trizivir (with zidovudine/AZT + emtricitabine/FTC). Approved in 1999, abacavir is generally considered among the most potent NRTIs, or nucleoside/nucleotide reverse transcriptase inhibitors.
Until recently, concern over hypersensitivity reactions or HSR has held back the wider use of abacavir. The recent success using a simple genetic test called HLA screening to successfully predict a person's risk of abacavir HSR has allayed many people's fears. This led the Federal Guidelines panel to upgrade Epzicom from an alternative to a preferred first line treatment in early 2008.
A short time after the Guidelines upgraded Epzicom, trouble began brewing. At the Conference on Retroviruses and Opportunistic Infections (CROI) in February, researchers combed through the D:A:D study and found an increased risk of heart attack -- called myocardial infarction or MI -- in people taking abacavir. Overall the risk was about 2 times higher, but it grew substantially when people had more pre-existing cardiovascular risk factors, like being overweight, smoking and having a family history of heart disease. Remarkably, this increased risk appeared to be reversed when people had stopped taking abacavir for 6 months.
In Mexico City, another set of researchers reported on data from the SMART study and found very similar results. SMART enrolled over 5,000 people worldwide who were randomly assigned to take HIV treatment continuously (the viral suppression or VS arm) or to start and stop treatment based on their CD4 counts (the drug conservation or DC arm). As reported here, SMART was stopped early when researchers noted a higher rate of all-cause death, as well as heart and kidney disease among people in the DC arm.
To better understand the results from D:A:D, researchers examined the SMART data and looked at everyone who took HIV drugs during the study. They found almost exactly the same increased risk of MI among those on abacavir that was found in the D:A:D. They looked at 4 definitions for heart disease and found higher rates for all 4 in people taking abacavir.
GlaxoSmithKline, who makes abacavir (and Epzicom and Trizivir), presented an analysis of a group of other studies, called a meta analysis. Overall they looked at results from 54 studies, involving around 15,000 people who took either abacavir or another NRTI. GSK's pooled analysis found low rates of heart attack across the studies, with no differences among people taking abacavir or other NRTIs.
The other debate was whether Epzicom works as well as Truvada for people with high viral loads (>100,000). In February investigators working on the AIDS Clinical Trials Group's (ACTG) 5202 announced that early analysis of their data showed higher rates of virologic failure among people taking Epzicom than Truvada. These data were presented publically for the first time in Mexico City.
ACTG 5202 compares 4 HIV drug regimens. Participants are randomly assigned to take either Truvada or Epzicom with either Sustiva (efavirenz) or boosted Reyataz (atazanavir). The study's Data Safety and Monitoring Board (DSMB) -- an independent group of scientists who get an early look at study results to ensure that no harm is done to its participants -- found higher rates of virologic breakthrough among people taking Epzicom, who had high viral loads before the study. The DSMB decided to "unblind" that group, and tell everyone what they were taking. The study remains blinded and unchanged for people with low viral loads.
Overall there were 57 virologic failures among people taking Epzicom compared to 26 for those on Truvada. People on Epzicom were 2.3 times more likely to experience loss of virologic control than those taking Truvada. Looking deeper, they examined 4 definitions of virologic failure and found higher rates for Epzicom regardless of definition. Data also suggested higher rates of adverse events (side effects) for people taking Epzicom.
GSK presented their analysis of 6 studies to see if the same thing was seen. These studies included almost 3,000 people taking HIV treatment for the first time. Using the same criteria as ACTG 5202, GSK's team found no differences in virologic failure rates for people with high vs. low viral loads.
The ongoing controversy surrounding abacavir is certainly fueled by these results. Jules Levin, a prominent AIDS activist from the National AIDS Treatment Advocacy Project (NATAP), told Project Inform that he is unconvinced by these negative findings, "but the damage is already done."
When the D:A:D results came out earlier this year, they perplexed most people. There was no known biological explanation for this increased risk. In fact, the study's designers were looking to see if Retrovir (zidovudine/AZT) or Zerit (stavudine/d4T) increased the risk of MI. While not definitive, the fact that a second study -- looked at by a second set of researchers and presented at a major scientific conference -- found the same thing greatly strengthens the power of the observation.
Most of the doctors, researchers and activists we spoke with feel that SMART's confirmation of the D:A:D raises serious issues for using abacavir, particularly by people at high risk for heart disease. The 5202 story is less clear. The finding itself is troubling. If it is independently confirmed by others, it could spell more trouble for abacavir. It is noteworthy that the DSMB did not unblind the whole study, meaning that whatever they saw among people with lower viral loads, they didn't see danger in letting the trial go forward.
Along with tenofovir (sold alone as Viread and in the fixed-dose combinations Truvada [with emtricitabine/FTC] and Atripla [Truvada + Sustiva]), abacavir is considered by most to be one of the most potent NRTIs. These negative study results are likely to raise more questions about when and how to use it.
A final note: during the 5202 session, the presenter mentioned, as an aside, that one person died in the study likely because they were put back on abacavir after an HSR, called re-challenge. With almost 10 years of experience using abacavir there's no reason this should happen, especially in an ACTG trial. Whatever the truth about abacavir and heart disease or high viral loads, there's no controversy over re-challenging. If a person has an HSR, or even a suspected HSR, they should never take abacavir again. While an initial HSR is unpleasant and often non-fatal, the reaction from a re-challenge with abacavir is drastically worse and is often fatal. It is crucial, even with HLA testing, that doctors and people with HIV be vigilant about abacavir HSR.