First START Results Show Early HIV Treatments Reduces Risk of Illness and Death

Long-awaited interim findings from the START trial have shown that people with HIV who were randomly assigned to start antiretroviral therapy (ART) while their CD4 count was above 500 cells/mm³ had a 53% lower risk of AIDS-related and non-AIDS illnesses and deaths compared to those who waited until their count fell below 350 cells/mm³, according to an announcement today from the National Institute of Allergy and Infectious Diseases.

It is well known that starting ART before extensive immune system damage occurs leads to reduced illness and death. A growing number of experts -- and current U.S. treatment guidelines -- recommend that all people diagnosed with HIV should start ART immediately, both for the sake of their own health and to prevent transmission. But others have expressed concern that the benefits of very early treatment may not outweigh the risks, which could include longer exposure to toxic therapies and evolution of drug-resistant virus. Observational studies have suggested that early treatment is associated with better outcomes, but until now the optimal timing of early ART has not previously been confirmed by randomized, controlled studies.

The INSIGHT START trial enrolled more than 4600 HIV-positive participants in 35 countries with CD4 counts above 500 cells/mm³. They were randomly assigned to start ART immediately or remain off treatment until their CD4 count reached 350 cells/mm³.

Started in 2011, the study was scheduled to conclude in 2016, but results were released early after an interim review showed that people who started ART early had about half the risk of progressing to a combined endpoint of AIDS-related events, serious non-AIDS events (such as cancer or major cardiovascular, kidney, or liver disease), or death.

"We now have clear-cut proof that it is of significantly greater health benefit to an HIV-infected person to start antiretroviral therapy sooner rather than later,” said NIAID Director Anthony Fauci.

"Some have worried that the CDC's focus on test-and-treat could be coercive of people living with HIV to start antiretroviral treatment early, more to protect others than to benefit themselves," explained Project Inform's Director of Research Advocacy David Evans. "Hopefully this will reassure them that the benefits to early treatment are available to those taking the medication no matter their sexual choices."

"Every person living with HIV should have immediate access to life-saving antiretroviral therapy," said UNAIDS Executive Director Michel Sidibé, commenting on today's announcement. "Delaying access to HIV treatment under any pretext is denying the right to health...This is a further demonstration of the importance of science and research that enables an evidence-based, people-centered response to HIV that leaves no one behind."

Below is an edited excerpt from NIAID press release describing the START findings in more detail.

Starting Antiretroviral Treatment Early Improves Outcomes for
HIV-Infected Individuals

NIH-Funded Trial Results Likely Will Impact Global Treatment Guidelines

May 27, 2015 -- A major international randomized clinical trial has found that HIV-infected individuals have a considerably lower risk of developing AIDS or other serious illnesses if they start taking antiretroviral drugs sooner, when their CD4+ T-cell count -- a key measure of immune system health -- is higher, instead of waiting until the CD4+ cell count drops to lower levels. Together with data from previous studies showing that antiretroviral treatment reduced the risk of HIV transmission to uninfected sexual partners, these findings support offering treatment to everyone with HIV.

The new finding is from the Strategic Timing of AntiRetroviral Treatment (START) study, the first large-scale randomized clinical trial to establish that earlier antiretroviral treatment benefits all HIV-infected individuals. The National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, provided primary funding for the START trial. Though the study was expected to conclude at the end of 2016, an interim review of the study data by an independent data and safety monitoring board (DSMB) recommended that results be released early.

"We now have clear-cut proof that it is of significantly greater health benefit to an HIV-infected person to start antiretroviral therapy sooner rather than later," said NIAID Director Anthony S. Fauci, MD. "Moreover, early therapy conveys a double benefit, not only improving the health of individuals but at the same time, by lowering their viral load, reducing the risk they will transmit HIV to others. These findings have global implications for the treatment of HIV."

"This is an important milestone in HIV research," said Jens Lundgren, MD, of the University of Copenhagen and one of the co-chairs of the START study. "We now have strong evidence that early treatment is beneficial to the HIV-positive person. These results support treating everyone irrespective of CD4+ T-cell count."

The START study, which opened widely in March 2011, was conducted by the International Network for Strategic Initiatives in Global HIV Trials (INSIGHT) at 215 sites in 35 countries. The trial enrolled 4,685 HIV-infected men and women ages 18 and older, with a median age of 36. Participants had never taken antiretroviral therapy and were enrolled with CD4+ cell counts in the normal range -- above 500 cells per cubic millimeter (cells/mm³). Approximately half of the study participants were randomized to initiate antiretroviral treatment immediately (early treatment), and the other half were randomized to defer treatment until their CD4+ cell count declined to 350 cells/mm³. On average, participants in the study were followed for three years.

The study measured a combination of outcomes that included serious AIDS events (such as AIDS-related cancer), serious non-AIDS events (major cardiovascular, renal and liver disease and cancer), and death. Based on data from March 2015, the DSMB found 41 instances of AIDS, serious non-AIDS events or death among those enrolled in the study’s early treatment group compared to 86 events in the deferred treatment group. The DSMB’s interim analysis found risk of developing serious illness or death was reduced by 53 percent among those in the early treatment group, compared to those in the deferred group.

Rates of serious AIDS-related events and serious non-AIDS-related events were both lower in the early treatment group than the deferred treatment group. The risk reduction was more pronounced for the AIDS-related events. Findings were consistent across geographic regions, and the benefits of early treatment were similar for participants from low- and middle-income countries and participants from high-income countries.

"The study was rigorous and the results are clear," said INSIGHT principal investigator James D. Neaton, PhD, a professor of biostatistics at the University of Minnesota, Minneapolis. "The definitive findings from a randomized trial like START are likely to influence how care is delivered to millions of HIV-positive individuals around the world." The University of Minnesota served as the trial’s regulatory sponsor and statistical and data management center.

Prior to the START trial, there was no randomized controlled trial evidence to guide initiating treatment for individuals with higher CD4+ cell counts. Previous evidence to support early treatment among HIV-positive people with CD4+ cell counts above 350 was limited to data from non-randomized trials or observational cohort studies, and on expert opinion.

START is the first large-scale randomized clinical trial to offer concrete scientific evidence to support the current U.S. HIV treatment guidelines, which recommend that all asymptomatic HIV-infected individuals take antiretrovirals, regardless of CD4+ cell count. Current World Health Organization HIV treatment guidelines recommend that HIV-infected individuals begin antiretroviral therapy when CD4+ cell counts fall to 500 cells/mm³ or less.

In light of the DSMB findings, study investigators are informing all participants of the interim results. Participants will be offered treatment if they are not already on antiretroviral therapy, and they will continue to be followed through 2016.

The HIV medicines used in the trial are approved medications donated by AbbVie, Inc., Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline/ViiV Healthcare, Janssen Scientific Affairs, LLC, and Merck Sharp & Dohme Corp.

In addition to NIAID, funding for the START trial came from other NIH entities, including the National Cancer Institute; the National Heart, Lung and Blood Institute; the National Institute of Mental Health; the National Institute of Neurological Disorders and Stroke; the Eunice Kennedy Shriver National Institute of Child Health and Human Development; the NIH Clinical Center; and the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Funding was also provided by the National Agency for Research on AIDS and Viral Hepatitis (ANRS) in France, the Federal Ministry of Education and Research in Germany, the European AIDS Treatment Network and government organizations based in Australia, Denmark, and the United Kingdom.

The Medical Research Council Clinical Trials Unit at University College London; the Copenhagen HIV Program at the Rigshospitalet, University of Copenhagen in Denmark; the Kirby Institute at the University of New South Wales in Sydney, Australia; and the Veterans Affairs Medical Center affiliated with George Washington University in Washington, DC, coordinated the work of the 215 START sites.

5/27/15

Sources

NIAID. Starting Antiretroviral Treatment Early Improves Outcomes for
HIV-Infected Individuals. Press release. May 27, 2015.

UNAIDS. UNAIDS welcomes further evidence that starting antiretroviral therapy early saves lives. Press release. May 27, 2015.