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, M.D. "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, M.D., 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, Ph.D., 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, D.C. coordinated the work of the 215 START sites.
 

For more information about the START trial, see the below Questions and Answers or visit ClinicalTrials.gov using study identifier NCT00867048

Question & Answer: 

The START HIV Treatment Study

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.

    Who conducted the START trial?

    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.

        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.

          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 & Co.

              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.

                  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).

                      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.

                          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.

                            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.

                            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.

                            What are the results of the START study?

                            Starting antiretroviral therapy early prevents a combination of outcomes that includes AIDS events (such as AIDS-related cancer) and serious non-AIDS events (major cardiovascular, renal and liver disease, non-AIDS cancer, and death not attributable to AIDS).  According to a new analysis of data 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, rates of both serious AIDS and serious non-AIDS events were significantly reduced with early therapy. Furthermore, other potentially life threatening events and unscheduled hospitalizations for reasons other than AIDS that were assessed to measure the safety of early treatment did not differ between the immediate and deferred antiretroviral therapy groups.

                            The study measured a combination of outcomes that included serious AIDS events, serious non-AIDS events, and death. Based on new data and analysis, the study now reports risk of developing serious AIDS, serious non-AIDS, or death was reduced by 57 percent among those in the early treatment group, compared to those in the deferred group. This reduction was seen regardless of age, sex, baseline CD4+ cell counts, geographic region or country income level. 

                            Although the median age of study participants was 36 – a relatively young group of participants – the most common events observed in the study were non-AIDS events that typically affect older individuals. The two most common individual serious non-AIDS events in the immediate and deferred groups were cardiovascular disease (12 and 14 participants with events, respectively) and non-AIDS-defining cancer (9 and 18 participants with events, respectively). Most of the tuberculosis occurred among participants at study sites in Africa (16 of 26 events), where both TB and HIV/AIDS are endemic.

                            To evaluate the safety of early treatment, potentially life-threatening symptomatic events not attributable to AIDS and unscheduled hospitalizations for reasons other than AIDS were assessed in both treatment groups. These events occurred more often than serious AIDS and serious AIDS-related events, and rates were similar in the two groups. When these events were combined with the serious AIDS and serious non-AIDS events, as an overall measure of clinical benefit for early treatment, the rate was 18 percent lower in the early treatment group, compared to the deferred treatment group. 

                            Why were results from the START study announced in May 2015?

                            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.

                            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.

                              Why have the results from START changed since the initial release in May 2015?

                              When the DSMB recommended that early treatment be offered to all study participants, their recommendation was based on data that had accrued through March 13, 2015. The study team was subsequently able to analyze additional data that had been collected through May 26, the day prior to NIAID's public announcement of the DSMB's recommendation. Analysis of this additional data has allowed the study team to draw additional conclusions beyond those reported in May.

                                  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.

                                  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.

                                  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 Adolescents for more information.

                                  For more information about the START trial, please see the related news release, Starting Antiretroviral Treatment Early Improves Outcomes for HIV-Infected Individuals, visit ClinicalTrials.gov and use study identifier NCT00867048, or see NIAID’s HIV/AIDS webpage.

                                  Content last reviewed on May 27, 2015