From: National Institutes of Allergy and Infectious Diseases
1. What is the START study?
The START (“Strategic Timing of AntiRetroviral Treatment”) study is a randomized, controlled clinical trial designed to more clearly define the optimal time for HIV- infected individuals to begin antiretroviral therapy. The trial enrolled healthy, asymptomatic, HIV-infected people whose level of CD4+ T cells—a measure of immune system health—exceeded 500 cells per cubic millimeter (mm3). The primary objective was to determine whether taking antiretroviral therapy immediately would lead to a lower risk of AIDS, other serious illnesses or death compared to waiting until a person’s CD4+ T-cell count fell to 350 cells/mm3.
2. Who conducted the START trial?
The study is conducted by the International Network for Strategic Initiatives in Global HIV Trials (INSIGHT), which is led by principal investigator James D. Neaton, Ph.D., of the University of Minnesota. INSIGHT is funded by the National Institute of Allergy and Infectious Diseases (NIAID). The START protocol co-chairs are Abdel Babiker, Ph.D., of the Medical Research Council Clinical Trials Unit, London; Fred Gordin, M.D., of the Veterans Affairs Medical Center, Washington, D.C.; and Jens Lundgren, M.D., D.M.Sc., of the Copenhagen HIV Program.
3. Who funded the START trial?
NIAID is the primary funder of the START trial, with additional funds coming from other National Institutes of Health (NIH) institutes and centers as well as governmental organizations outside the United States. These other funders included:
- NIH Clinical Center
- National Cancer Institute National Heart, Lung, and Blood Institute
- Eunice Kennedy Shriver National Institute of Child Health and Human Development
- National Institute of Mental Health
- National Institute of Neurological Disorders and Stroke
- National Institute of Arthritis and Musculoskeletal and Skin Diseases
- National Agency for Research on AIDS and Viral Hepatitis (ANRS) (France)
- Australian National Health and Medical Research Council
- Federal Ministry of Education and Research (Germany)
- Danish National Research Foundation
- European AIDS Treatment Network
- Medical Research Council (United Kingdom)
- National Institute for Health Research, National Health Service (United Kingdom)
Study medication was donated by AbbVie, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline/ViiV Healthcare, Janssen Scientific Affairs and Merck Sharp & Dohme.
4. Who sponsored the study?
The University of Minnesota sponsored the study and worked closely with four international coordinating centers to implement and oversee the conduct of the trial. These coordinating centers were the Copenhagen HIV Program at the Rigshospitalet, University of Copenhagen, Denmark; the Kirby Institute at the University of New South Wales in Sydney; The Medical Research Council Clinical Trials Unit at University College London; and the Washington, D.C. Veterans Affairs Medical Center affiliated with The George Washington University in Washington, D.C.
5. Where was the START trial conducted?
The START study was conducted at 215 sites in 35 countries: Argentina, Australia, Austria, Belgium, Brazil, Chile, the Czech Republic, Denmark, Estonia, Finland, France, Germany, Greece, India, Ireland, Israel, Italy, Luxembourg, Malaysia, Mali, Mexico, Morocco, Nigeria, Norway, Peru, Poland, Portugal, South Africa, Spain, Sweden, Switzerland, Thailand, Uganda, the United Kingdom and the United States (including Puerto Rico).
6. Who participated in the START trial?
The START trial enrolled 4,685 HIV-infected men and women ages 18 years or older (median age of 36 years) who had CD4+ T-cell counts above 500 cells/mm3, no symptoms of HIV infection, and had never taken antiretroviral therapy. Twenty-seven percent of the participants are women, and approximately half are gay men.
7. When did the study begin?
The first participant was enrolled in April 2009, during the study’s pilot phase. The main study began in March 2011 and was scheduled to end in December 2016.
8. What was the study design?
Study participants were randomly assigned to either begin antiretroviral treatment immediately or delay starting treatment until either their CD4+ T-cell counts dropped to 350 cells/mm3 or they were diagnosed with an AIDS-defining illness.
Study clinicians selected the initial antiretroviral drug regimen for each participant from a pre-approved list of drugs based on the treatment guidelines of the U.S. Department of Health and Human Services. If the drug regimen subsequently needed to change during the course of the trial, clinicians could prescribe any licensed antiretroviral medication in accordance with their country’s national antiretroviral treatment guidelines.
Study participants had medical visits with study staff at one month, four months, and every four months thereafter. Study staff monitored participants closely for the development of AIDS, serious non-AIDS-related illness, and death from any cause. The serious non-AIDS conditions considered during the START study were major cardiovascular disease events, end-stage kidney disease, liver disease and non-AIDS-defining cancers. Participants were followed for an average of three years.
The study also assessed a number of secondary factors to comprehensively determine the risks and benefits of starting antiretroviral treatment early. These factors included undesirable effects on health, hospitalizations, quality of life, high-risk behaviors for transmitting HIV, and risk factors for serious non-AIDS conditions.
9. What is a data and safety monitoring board, and what was its role in the START study?
A data and safety monitoring board (DSMB) is an independent group composed of clinical research experts, statisticians, ethicists and community representatives that meets at regular intervals during a study to review data as it is gathered. Because the study team is blinded to interim study data, they are excluded from portions of meetings when data are presented. The DSMB alerts the study team if anything appears to compromise the safety of study participants, if there is compelling evidence of effectiveness, or if it becomes clear that the study cannot answer one of the questions it was designed to address.
The NIAID Division of AIDS (DAIDS) Multinational DSMB has regularly reviewed the data from the START study. After its 10th review in May 2015, the DSMB reported to the study leadership that the trial had answered the primary question it was designed to address.
10. What are the results of the START study, and why are they being announced now?
During a scheduled interim review of study data that had accrued through March 13, 2015, the DSMB found compelling evidence that the benefits of starting antiretroviral treatment immediately at CD4+ cell counts above 500 cells/mm3 outweigh the risks. Specifically, the DSMB found that over an average follow-up of three years, the risk of AIDS, other serious illnesses or death was reduced by 53 percent among those in the early treatment group compared to those in the deferred treatment group. In its review, the DSMB found 41 instances of AIDS, serious non-AIDS illness or death among those enrolled in the study’s early treatment group compared to 86 such events in the deferred treatment group. These results indicate that starting anti-HIV treatment soon after diagnosis of HIV infection protects people’s health. These findings are likely to affect many countries’ guidelines for when to start treatment for HIV infection.
The DSMB recommended that treatment be offered to all participants in the deferred treatment group who had not yet begun therapy. The DSMB also recommended that the study results immediately be communicated to study participants and investigators, clinicians, policy-makers, and the World Health Organization (WHO), and that the study team continue follow-up of participants. The DSMB reported its findings in May 2015 and NIAID, the trial’s primary funder, concurred with the DSMB’s recommendations. For more information about the DSMB, please see question 9 above.
11. What specific data led to the DSMB’s conclusion that the study’s primary question had been answered??
The interim analysis reviewed by the DSMB showed the following:
Early treatment reduced the risk of the combination of serious AIDS-related illness, serious non-AIDS-related illness and death by more than half compared to deferring treatment. Early treatment reduced the risk of serious AIDS-related and non-AIDS-related illnesses, but had a greater effect on reducing the risk of AIDS-related illnesses. The most common AIDS-related illnesses among study participants were pulmonary tuberculosis, Kaposi’s sarcoma, and non-Hodgkins lymphoma. The most common serious non-AIDS-related illnesses were cancer, heart attack, and deaths attributed to causes other than AIDS or serious non-AIDS events. The benefits of early treatment were observed across geographic regions. The benefits of early treatment were similar for the 2,530 participants from low- and middle-income countries and the 2,155 participants from high-income countries.
12. Why was it important to conduct the START study?
At the time the START study was designed, some observational and epidemiological data and data from non-randomized trials suggested that the risk of illness and death for people with HIV infection might be lower for those who began anti-HIV treatment earlier, at higher CD4+ T-cell counts. While data from randomized controlled clinical trials existed to support starting anti-HIV treatment when CD4+ T-cell counts fell below 350 cells/mm3, there was no randomized controlled trial results to guide decisions on whether or not to start treatment at higher CD4+ thresholds where the risk of clinical disease was very low. A randomized, controlled trial was necessary to evaluate the risks and benefits of starting anti-HIV therapy at CD4+ T-cell counts above 500 cells/mm3.
The START study gained added importance when a NIAID clinical trial that ended in 2011, HPTN 052, found that taking antiretroviral therapy dramatically reduces the chance of transmitting the virus from HIV-infected individuals to uninfected sexual partners. This result indicated that starting treatment soon after HIV diagnosis confers a benefit to uninfected sexual partners, but the risk-benefit ratio of early therapy for the infected individual remained unclear.
13. What sub-studies are being conducted in connection with the START trial?
Seven sub-studies are being conducted in connection with the START trial. They are focused on genomics, neurology, arterial elasticity (a measure of cardiovascular disease), lung disease, bone density, liver disease and informed consent.
- The genomics sub-study aims to expand scientists’ understanding of how to optimize an HIV-infected person’s treatment regimen based on a set of genetic characteristics known to influence HIV treatment outcomes.
- The purpose of the neurology sub-study is to determine whether neurocognitive function is better in HIV-infected people who start treatment with a CD4+ cell count greater than 500 cells/mm3 than in those who defer treatment until their CD4+ cell count drops below 350 cells/mm3.
- The informed consent sub-study aims to evaluate START study participants’ understanding of study information and satisfaction with the informed consent process after receiving information from one of two types of consent forms: a standard form and a concise form. This sub-study is complete.
- The purpose of the arterial elasticity sub-study is to determine if vascular function (a measure of early cardiovascular disease) is better in those who start therapy early.
- The purpose of the lung disease sub-study is to determine if lung function is better if HIV treatment is started earlier rather than deferred.
- The purpose of the bone density sub-study is to determine the effect on bone mineral density (how strong the bones are) of early versus deferred therapy.
- The purpose of the liver disease sub-study is to determine if liver fibrosis (scarring) happens less if HIV infection is treated earlier rather than deferred.
14. What are current U.S. and global guidelines for when to start antiretroviral therapy for HIV infection?
Current WHO HIV treatment guidelines recommend that HIV-infected individuals begin antiretroviral therapy when CD4+ cell counts fall to 500 cells/mm3 or less. Please see When to start ART for more information.
Since February 2013, the U.S. Department of Health and Human Services has recommended antiretroviral therapy for all adults and adolescents with HIV infection, regardless of CD4+ T-cell count, but only the recommendation for those with CD4+ T-cell counts less than 350 cells/mm3 was based on evidence from randomized controlled trials. NIAID-funded research contributed to the development of this recommendation. Visit Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescentsfor more information.
For more information about the START trial, please see the related news release, Starting Antiretroviral Treatment Early Improves Outcomes for HIV-Infected Individualsds, visit ClinicalTrials.gov and use study identifier NCT00867048, or see NIAID’s HIV/AIDS webpage.
