START Antiretrovirals Early, 35-Country Trial Validates

Marcia Frellick

July 20, 2015

For asymptomatic HIV-infected patients with CD4 counts above 500 cells/mm3, starting antiretroviral therapy immediately after diagnosis cuts the risk of developing AIDS or other serious illnesses in half, according to one of the largest trials of HIV infection ever conducted.

The Strategic Timing of Antiretroviral Treatment, or START, trial completes the case for immediate treatment, said José Zuniga, PhD, MPH, president and chief executive officer of the International Association of Providers of AIDS Care (IAPAC) in Washington, DC.

And because thresholds for starting antiretrovirals vary by country and by organization, the START results have global implications.

The results, released today at the 8th International AIDS Society Conference in Vancouver, British Columbia, Canada, are published online in the New England Journal of Medicine to coincide with their presentation.

"START effectively ends the debate over when to initiate antiretroviral therapy," Dr Zuniga told Medscape Medical News. "We must move swiftly to implement these data in the public health setting. Failure to do so unjustly endangers the health and lives of millions, which is nothing short of a human rights violation."

START effectively ends the debate over when to initiate antiretroviral therapy. Dr José Zuniga

In the United States, antiretrovirals are recommended regardless of CD4 cell count. The World Health Organization recommends starting therapy at a CD4 count of 500 cells/mm3, whereas the United Kingdom and other countries use a threshold of 350 cells/mm3.

In 2009, 4685 HIV-infected people from 35 countries were enrolled in START, and were followed for 3 years. HIV-positive adults who had a CD4 count above 500 cells/mm3 were randomly assigned to immediate antiretrovirals or to delayed therapy until CD4 count fell to 350 cells/mm3 or the person developed AIDS or another condition that required treatment.

START Stopped Early

START was stopped in May after the data and safety monitoring board determined that the interim results supporting immediate treatment were conclusive. At that time, participants in the delayed treatment group were offered immediate therapy; there were no adverseeffects associated with this strategy.

The primary end point for the study was a composite of any serious AIDS-related event, serious non-AIDS-related event, or death from any cause.

That end point was met by 42 patients in the immediate group (1.8%; 0.60 events per 100 person-years) and 96 patients in the deferred group (4.1%; 1.38 events per 100 person-years), for a hazard ratio of 0.43 (95% confidence interval [CI], 0.30 - 0.62; P < .001).

The hazard ratio for serious AIDS-related events was 0.28 (95% CI, 0.15 - 0.50; P < .001) and for serious non-AIDS-related events was 0.61 (95% CI, 0.38 - 0.97; P = .04).

In fact, 68% of the patients who met the primary end point had a CD4 count above 500 cells/mm3, report START investigator Jens Lundgren, MD, from the University of Copenhagen in Denmark, and colleagues.

The team found no evidence that the benefit of immediate antiretrovirals differed by age, sex, race, region, CD4 count, viral load, or risk factors for serious disease.

The median age of the cohort was 36 years, and 27% of the patients were women. The median CD4 count was 651 cells/mm3, but some were as high as 2296 cells/mm3. The median HIV viral load was 12,759 copies/mL.

Lower CD4 Counts in Earlier Trials

Previous randomized studies enrolled patients with lower CD4 counts and compared immediate with delayed antiretrovirals when counts reached 250 or 200 cells/mm3. Those trials demonstrated that treatment should start before the CD4 count drops to 250 cells/mm3.

The START trial makes the case for starting treatment regardless of CD4 count, the investigators conclude.

"Now, of course, the challenge," Dr Lundgren told reporters attending a news conference Monday, "will be how we can get the 20 to 25 million people not on treatment on treatment."

Funding, Detection Threaten Progress

In an accompanying editorial, Salim Abdool Karim, MBChB, PhD, an infectious disease epidemiologist from the Centre for the AIDS Programme of Research in South Africa (CAPRISA), says that will be daunting.

"Most of the remaining remaining 20+ million HIV-positive people who need to initiate antiretrovirals are in countries in Africa that rank among the poorest in the world, with underdeveloped and underfunded health systems that are already strained," he explains.

A key challenge, he adds, is the high number of people who are not aware of their status, many of them avoiding testing or seeking care.

Global funding sources are also critical to using these data effectively.

"Without the more effective use of available funding and mobilization of additional resources, there is little prospect of a world rising to the challenge of ensuring that every HIV-positive person knows his or her HIV status, seeks care early, is started on antiretrovirals immediately, and is retained in care with viral suppression," he writes.

In advance of the release of the START results, the IAPAC launched Global HIV Policy Watch, which provides immediate access to published guidelines and recommendations containing HIV policies from 149 countries, representing approximately 90% of the people living with HIV around the world. A map on the website shows which countries support which strategies for antiretrovirals.

Findings such as those from the START trial will help move global policy forward, and closer to the UNAIDS 90-90-90 treatment target for ending AIDS by 2030, Dr Zuniga explained.

"We have the science behind us and the tools at our disposal to attain the 90-90-90 targets. But do we have the imagination and courage to make it happen," he asked, "or are we content to see millions of people continue to be HIV infected and die needlessly of AIDS-related complications?"

"That is the moral question hanging over our heads like a sword of Damocles as we gather in Vancouver this week," Dr Zuniga said.

This study was funded by the National Institutes of Health, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, Agence Nationale de Recherches sur le SIDA et les Hépatites Virales in France, the National Health and Medical Research Council in Australia, the National Research Foundation in Denmark, Bundesministerium für Bildung und Forschung in Germany, the European AIDS Treatment Network, the Medical Research Council in the United Kingdom as well as the National Institute for Health Research, the National Health Service, and the University of Minnesota. Antiretroviral drugs were donated to the central drug repository by AbbVie, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmith-Kline, Janssen Scientific Affairs, and Merck. Dr Zuniga has disclosed no relevant financial relationships.

8th International AIDS Society (IAS) Conference. Presented July 20, 2015.


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