The START (Strategic Timing of AntiRetroviral Treatment) trial enrolled 4,685 HIV-positive adults beginning in 2009 and randomized them to start ART immediately, with a CD4 count above 500 cells/mm3, or to wait until it had dropped below 350. An independent data and safety monitoring board (DSMB) reviewed the interim results and recommended that the results be released early because the data overwhelmingly support early ART. Participants in the early ART arm had a 53 percent lower risk of an AIDS-related illness, serious non-AIDS illness, or death compared to those who deferred ART.
START was a controversial study—not because the question wasn’t important or because the study was poorly designed. Instead, many experts, especially in the U.S., felt that observational studies like NA-ACCORD, data supporting the prevention benefits of ART, and the reduction in inflammation and immune activation associated with ART already provided sufficient justification for starting treatment regardless of CD4 count. They argued that by the time the expensive START study was completed, guidelines and practice would have evolved, and universal treatment would have already become the standard of care. They raised the possibility that START would be inconclusive, since in people with high CD4 counts and low risk for opportunistic infections, the potential long-term benefits of early therapy couldn’t be assessed within the time frame of the study. I was one of those skeptics, arguing that while in a world of unlimited resources it would be nice to have such a trial, there were better ways to spend our limited research dollars.
Both the DHHS and the IAS-USA guidelines panels agreed, recommending ART for all. Those recommendations were equally controversial, since they were not based on data from randomized, controlled clinical trials and were made while START was still enrolling. The criticisms on both sides of the Atlantic were loud and sometimes ugly, but with time the controversy in the U.S. subsided. Clinicians and their patients came to accept the idea that HIV infection should be treated after diagnosis. For the last few years it has been rare to hear a “When to Start” lecture at any HIV update conference since the question was felt to have been answered.
Now along come the early results of the START trial, which confirm current U.S. practice and treatment guidelines. Surprise: Treating a chronic, progressive disease that causes immunosuppression and inflammation with safe and effective drugs is good for you! Cynicism aside, these are important results, even if they come too late to affect guidelines and practice in the U.S. Few expected such a dramatic result, dramatic enough to cause the study to be stopped early. Besides providing a surprisingly definitive result and vindicating U.S. guidelines panels, these data will have tremendous importance globally, where most countries have not jumped on the American universal therapy bandwagon.
There will undoubtedly be a steady stream of additional data from START substudies over the coming years. As with the earlier SMART trial of CD4-guided treatment interruption, a study that some experts also thought was ill-advised, there is more we can learn from START. Although I was a naysayer, I’m glad to have the SMART data to support the guidelines I contributed to, as well as my own clinical practice. More importantly, I’m optimistic about the influence these data will have on the treatment of HIV infection globally.
EDITOR’S NOTE: For another great summary plus Q&A about the START study, including an excellent community perspective by Simon Collins, go to i-base.info/i-base-qa-on-the-start-study-results.
JOEL GALLANT is Medical Director of Specialty Services at Southwest CARE Center in Santa Fe, New Mexico, adjunct professor of medicine at the Johns Hopkins School of Medicine, and clinical professor of medicine at the University of New Mexico. He treats patients and conducts clinical trials on the treatment of HIV infection. He is Immediate Past-Chair of the HIV Medicine Association and is on the Board of Directors of the IAS-USA. He is a member of the IAS-USA Antiretroviral Guidelines panel and the IDSA/HIVMA HIV Primary Care Guidelines panel. He authored 100 Questions and Answers about HIV and AIDS and has an interactive question and answer blog at hivforum.tumblr.com.