Medicine+Wellness: The Quad

When drugmakers Gilead and Bristol-Myers Squibb agreed to collaborate to create a three-drugs-in-one pill, Atripla was born. The holy grail of treating HIV with just one pill a day soon became a treatment of choice when starting patients on their first anti-HIV regimen. However, Atripla was not for everyone. Some patients could not tolerate the side effects of the efavirenz component, which gave some patients sleep problems, like uncomfortably vivid dreams or daytime drowsiness. Other patients were already resistant to efavirenz, since in some populations over 10% of transmitted HIV carries the efavirenz resistance mutation. Now it looks like the next all-in-one pill is on the way. Researchers presented data in February at the annual Conference on Retroviruses and Opportunistic Infections on a combination drug containing tenofovir plus emtricitabine (Truvada) combined with elvitegravir (a new integrase inhibitor) and cobicistat (a booster) -- since nicknamed the Quad. Note that this pill contains an integrase inhibitor instead of a nonnucleoside reverse transcriptase inhibitor, like efavirenz, so it will work when there is resistance. These drugs are all made by Gilead, which licensed elvitegravir from a Japanese company in 2005 for further development. Gilead then discovered that elvitegravir needed to be boosted with ritonavir to achieve effective blood levels, just like most protease inhibitors. So Gilead created cobicistat, which blocks a metabolic enzyme pathway in the liver similar to ritonavir. The CROI presentation was a Phase II trial comparing the Quad to Atripla in treatment-naive patients. The study showed that 90% of the Quad patients and 83% of the Atripla patients achieved viral loads below 50 at the 24-week point. This difference was not statistically significant. The study size of only 71 patients did not allow for formal efficacy comparisons, but the Quad did statistically meet the criteria for noninferiority. There were no significant differences in side effects between the two groups, other than the specific side effects of efavirenz mentioned above. Larger, Phase III trials are now just beginning. In an interesting and logical move, Gilead ran a parallel study comparing cobicistat to ritonavir as boosters in a standard combination of Reyataz plus Truvada. At 24 weeks 84% of patients on cobicistat had undetectable viral loads compared to 86% for those on ritonavir. Researchers had hoped that cobicistat might be better tolerated than ritonavir, but there were no significant differences in side effects, specifically nausea or diarrhea, or changes in blood lipids. Finally, researchers in the two studies had some concern that cobicistat might reduce kidney function, since the drug seemed to cause a small increase in creatinine. Further kidney clearance studies have shown, fortunately, that the kidney function remains intact, and the creatinine elevations are caused by cobicistat slightly slowing creatinine excretion by the kidney without impairment of total kidney function. It was a bright new day when the first all-in-one pill came out. It will be an even brighter day when I can tell my patients that we have a second option. Bowers is an HIV specialist and is board-certified in family medicine. He is in private practice in New York City. Learn more about him on his professional website.