Considerations in the rationale, design and methods of the Strategic Timing of AntiRetroviral Treatment (START) study

Abstract

Background: Untreated human immunodeficiency virus (HIV) infection is characterized by progressive depletion of CD4+ T lymphocyte (CD4) count leading to the development of opportunistic diseases (acquired immunodeficiency syndrome (AIDS)), and more recent data suggest that HIV is also associated with an increased risk of serious non-AIDS (SNA) diseases including cardiovascular, renal, and liver diseases and non-AIDS-defining cancers. Although combination antiretroviral treatment (ART) has resulted in a substantial decrease in morbidity and mortality in persons with HIV infection, viral eradication is not feasible with currently available drugs. The optimal time to start ART for asymptomatic HIV infection is controversial and remains one of the key unanswered questions in the clinical management of HIV-infected individuals.

Purpose: In this article, we outline the rationale and methods of the Strategic Timing of AntiRetroviral Treatment (START) study, an ongoing multicenter international trial designed to assess the risks and benefits of initiating ART earlier than is currently practiced. We also describe some of the challenges encountered in the design and implementation of the study and how these challenges were addressed.

Methods: A total of 4000 study participants who are HIV type 1 (HIV-1) infected, ART naïve with CD4 count > 500 cells/µL are to be randomly allocated in a 1:1 ratio to start ART immediately (early ART) or defer treatment until CD4 count is <350 cells/µL (deferred ART) and followed for a minimum of 3 years. The primary outcome is time to AIDS, SNA, or death. The study had a pilot phase to establish feasibility of accrual, which was set as the enrollment of at least 900 participants in the first year.

Results: Challenges encountered in the design and implementation of the study included the limited amount of data on the risk of a major component of the primary endpoint (SNA) in the study population, changes in treatment guidelines when the pilot phase was well underway, and the complexities of conducting the trial in a geographically wide population with diverse regulatory requirements. With the successful completion of the pilot phase, more than 1000 participants from 100 sites in 23 countries have been enrolled. The study will expand to include 237 sites in 36 countries to reach the target accrual of 4000 participants.

Conclusions: START is addressing one of the most important questions in the clinical management of ART. The randomization provided a platform for the conduct of several substudies aimed at increasing our understanding of HIV disease and the effects of antiretroviral therapy beyond the primary question of the trial. The lessons learned from its design and implementation will hopefully be of use to future publicly funded international trials.

Figure A1

Standardized residuals for the standard mixed linear model and the extended model for square root CD4 before initiation of ART (15,274 participants in CASCADE). CD4: CD4+ T lymphocyte; ART: antiretroviral treatment; CASCADE: Concerted Action for HIV SeroConversion and AIDS in Europe.

Figure A2

Distribution of “true” square root CD4 at seroconversion (15,274 participants in CASCADE). CD4: CD4+ T lymphocyte; CASCADE: Concerted Action for HIV SeroCon-version and AIDS in Europe.

Figure A3

Distribution of the slope of square root CD4 before ART initiation (15,274 participants in CASCADE). CD4: CD4+ T lymphocyte; ART: antiretroviral treatment; CASCADE: Concerted Action for HIV SeroConversion and AIDS in Europe.

Figure A4

Kaplan–Meier plots for time to initiation of ART. ART: antiretroviral treatment; CD4: CD4+ T lymphocyte.

Figure A5

Median “true” CD4 count during follow-up according to ART deferral strategy. CD4: CD4+ T lymphocyte; ART: antiretroviral treatment.

Figure B1

Cumulative probability of reaching the primary endpoint according to three different strategies for deferring ART compared to immediate ART and no ART. ART: antiretroviral treatment; CD4: CD4+ T lymphocyte.

Figure B2

Cumulative probability of reaching the primary endpoint by treatment group compared to no ART. ART: antiretroviral treatment.

Figure 1

Trial schema. HIV-1: human immunodeficiency virus type 1; ART: antiretroviral treatment; CD4: CD4+ T lymphocyte; AIDS: acquired immunodeficiency syndrome.

Figure 2

Median projected CD4 cell count during follow-up. CD4: CD4+ T lymphocyte; ART: antiretroviral treatment.

Figure 3

Kaplan–Meier's plot for projected time from randomization to ART initiation in the deferred ART group under two scenarios about the CD4 count cutoff below which ART is initiated: 350, 400, and 450 cells/μL for 70%, 20%, and 10% of the participants, respectively (deferred ART group); 350 cells/μL for all participants. ART: antiretroviral treatment; CD4: CD4+ T lymphocyte.

Figure 4

START CCs and participating countries (numbers in parentheses refer to participating sites). CC: Coordinating Center; ICC: International Coordinating Center.

Figure 5

Cumulative enrollment (left axis) and cumulate number of enrolling sites (right axis) up to December 31, 2010.