START (HIV) trial

START (HIV) trial
Name	START
Other names	Strategic Timing of Antiretroviral Treatment
Phase	Randomized controlled trial
Status	Completed
Start date	2009
Completion date	2015
Locations	Global
Principal investigator	International Network for Strategic Initiatives in Global HIV Trials

Contents

START (HIV) trial The START trial was a randomized, international clinical study that compared immediate versus deferred antiretroviral therapy for adults with asymptomatic human immunodeficiency virus infection and CD4+ cell counts above 500 cells/μL. The trial enrolled participants across multiple continents and sought to inform treatment guidelines issued by organizations such as the World Health Organization, the Centers for Disease Control and Prevention, and the European AIDS Clinical Society. Results influenced policies advocated by groups including the United Nations, the Joint United Nations Programme on HIV/AIDS, and national agencies like the National Institutes of Health.

Background

The START trial was initiated against a backdrop of evolving evidence from observational cohorts such as those reported by investigators associated with the Multicenter AIDS Cohort Study, the Women’s Interagency HIV Study, and regional consortia like the EuroSIDA study. Debates during the 1990s and 2000s involved stakeholders from the International AIDS Society, the British HIV Association, and the French National Agency for Research on AIDS and Viral Hepatitis over when to initiate therapy first pioneered in trials like those conducted by the Collaborative HIV Seroincidence Study. Earlier randomized trials and policy statements by the Public Health Agency of Canada and the Australian Department of Health had left open questions about optimal timing, which START aimed to resolve alongside contemporaneous trials such as the TEMPRANO study in Côte d’Ivoire and observational analyses from the Istituto Superiore di Sanità in Italy.

START was designed as a randomized, open-label, multicenter trial coordinated by networks linked to the National Institute of Allergy and Infectious Diseases, the University College London, and the Fred Hutchinson Cancer Research Center. Adult participants were enrolled at sites in regions represented by institutions such as St. Mary’s Hospital (London), The Rockefeller University Hospital, and the University of Cape Town. Randomization compared immediate initiation of antiretroviral therapy versus deferral until CD4+ counts declined to thresholds recommended in documents from the European Centre for Disease Prevention and Control and the World Health Organization. The protocol incorporated standardized outcome measures used by trials like SMART (study), laboratory monitoring similar to practices at Mayo Clinic, and endpoint adjudication by panels drawing expertise from the Royal College of Physicians and the Infectious Diseases Society of America. Data management and statistical analysis followed methods recommended in guidance from the Cochrane Collaboration and the CONSORT statement, with oversight from independent monitoring boards including members from the Wellcome Trust and the Bill & Melinda Gates Foundation.

Primary results demonstrated that immediate antiretroviral therapy reduced the risk of serious AIDS-related events and serious non-AIDS events relative to deferred therapy, echoing outcome themes from trials like TEMPRANO and analyses from the D:A:D Study. Findings were presented at conferences including the Conference on Retroviruses and Opportunistic Infections and the International AIDS Conference, and published in journals that engage editorial leadership connected to institutions such as the New England Journal of Medicine and The Lancet. The trial reported efficacy across diverse populations recruited from centers such as Massachusetts General Hospital, Groote Schuur Hospital, and Hospital Clínic de Barcelona. Subgroup analyses referenced demographic cohorts represented in the China CDC, the Brazilian Ministry of Health, and the South African Medical Research Council.

Safety monitoring identified patterns of adverse events consistent with contemporary antiretroviral regimens supplied under formularies similar to those used by the National Health Service (England), the Medicare (US), and programmatic procurement by the Global Fund to Fight AIDS, Tuberculosis and Malaria. Serious adverse events and laboratory abnormalities were adjudicated with frameworks used by the European Medicines Agency and the Food and Drug Administration. The trial compared incidence rates of events such as cardiovascular outcomes highlighted in cohorts like the Framingham Heart Study and renal outcomes monitored in registries analogous to those managed by the United Network for Organ Sharing. Safety data informed prescribing considerations referenced by professional bodies including the American College of Physicians and the International Antiviral Society–USA.

Results from START contributed to guideline revisions by the World Health Organization, accelerated recommendations from the United States Department of Health and Human Services, and influenced national policies in countries represented by the Ministry of Health (Brazil), the South African Department of Health, and the Indian Council of Medical Research. The evidence supported "treat all" strategies promoted by the Joint United Nations Programme on HIV/AIDS and underpinned investments by funders such as the Global Fund and the President's Emergency Plan for AIDS Relief. Implementation influences were observed in programs operating through partners like Clinton Health Access Initiative and the Partners In Health network, and informed economic and modeling work by groups such as the Institute for Health Metrics and Evaluation.

Critiques of the trial echoed concerns raised in methodological debates involving the Cochrane Collaboration and the CONSORT group about open-label designs, and mirrored discussions in health policy forums such as the World Bank and the Organisation for Economic Co-operation and Development. Limitations included generalizability to settings with differing comorbidity burdens observed in registries from the Global Burden of Disease Study and to resource-constrained delivery platforms assessed by the United Nations Development Programme. Questions remained about long-term outcomes beyond trial follow-up intervals tracked in cohorts like the Swiss HIV Cohort Study and the Australian HIV Observational Database.

Category:Clinical trials in HIV