Top 10 Clinical Review


Respect for Raltegravir and the End of Grand Clinical Trials: A Top HIV Clinical Development of 2014

December 15, 2014

The U.S. AIDS Clinical Trials Group (ACTG) is known for its large comparative clinical trials that boast four-digit enrollment, dozens of sites, and great representation of women and minorities. However, with more super-awesome antiretrovirals than ever before, there is little juice left in battling them out in the clinical trial ring.

Almost certainly the last of this breed of study is A5257. In this trial, over 1,800 patients naive to therapy were randomized to tenofovir/emtricitabine plus one of three companion drugs: darunavir/ritonavir, atazanavir/ritonavir or raltegravir. That is, the three regimens not containing efavirenz considered to be preferred in the U.S. DHHS treatment guidelines at the time the study was designed. The trial was designed to be able to determine not just noninferiority but equivalence.

Beautifully, this open-label study laid bare what these regimens can do. Overall, raltegravir won the day, despite being cursed at birth to be a twice-a-day drug in a sea of once-dailies. In the pairwise comparisons, the raltegravir regimen beat the pants off of (i.e., was statistically better than) atazanavir/ritonavir, which suffered from excess toxicity compared to the other arms -- mostly, but not all, related to hypebilirubinemia. It was a much more even matchup for darunavir and raltegravir.

ITT off-ART = failure (SNAPSHOT)

The integrase inhibitor was kinder to bone density and lipids than the protease inhibitors. But, among those failing their regimen who had a resistance test, there was more resistance in the raltegravir arm, as expected.

There are certainly limitations to this study. Patients preferring to be on efavirenz were not entered and it was open label (thus avoiding extra pill and dosing burden). However, it again shows how well integrase inhibitors do in these studies -- even when they're dosed twice a day. Raltegravir's gain was atazanavir's loss: The hyperbilirubinemia caused by this protease inhibitor is often not a problem, but in some patients it does lead to icterus, which is unnecessary when alternatives like darunavir exist. Kidney stones and gallstones caused by crystallization of atazanavir and the drug-drug interaction with proton pump inhibitors further diminish its attractiveness relative to alternatives.

How we should extrapolate the findings from this study to the integrase inhibitors elvitegravir (Vitekta) and dolutegravir can be a topic of discussion over beers at an HIV conference. My guess is that doultegravir would perform just as well as raltegravir here, but with less resistance among the very few virologic failures, and that elvitegravir might be closer to darunavir in overall performance, due to low-level cobicistat-related adverse events. But it would take a big study to see if I am right -- a study the ACTG will not be doing.

What are some other top clinical developments of 2014? Read more of Dr. Wohl's picks.

David Alain Wohl, M.D., is an associate professor of medicine in the Division of Infectious Diseases at the University of North Carolina and site leader of the University of North Carolina AIDS Clinical Trials Unit at Chapel Hill.

Copyright © 2014 Remedy Health Media, LLC. All rights reserved.

This article was provided by TheBodyPRO.

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