The New England Journal of Medicine August 27, 2015

Initiation of Antiretroviral Therapy in Early Asymptomatic HIV Infection

INSIGHT START Study Group (Lundgren JD, Babiker AG, Gordin F, et al.)

Bottom Line

In asymptomatic HIV-positive adults with CD4+ counts above 500 cells/mm³, immediate initiation of antiretroviral therapy significantly reduced the risk of serious AIDS-related and non-AIDS-related events compared to deferring therapy until CD4 counts fell to 350 cells/mm³.

Key Findings

1. Immediate ART initiation significantly reduced the composite primary end point (serious AIDS-related event, serious non-AIDS-related event, or death), which occurred in 42 patients (1.8%; 0.60 events per 100 person-years) compared to 96 patients in the deferred group (4.1%; 1.38 events per 100 person-years), yielding a hazard ratio of 0.43 (95% CI, 0.30 to 0.62; P<0.001).

2. The clinical benefit of early ART was driven by substantial reductions in both serious AIDS-related events (HR 0.28; 95% CI, 0.15 to 0.50; P<0.001) and serious non-AIDS-related events (HR 0.61; 95% CI, 0.38 to 0.97; P=0.04).

3. Overall mortality was numerically lower in the immediate-initiation group but did not reach statistical significance (HR 0.58; 95% CI, 0.28 to 1.17; P=0.13).

4. More than two thirds of the primary end points (68%) in the trial occurred while patients had a CD4+ count exceeding 500 cells/mm³.

5. Immediate ART was well tolerated, with similar risks of grade 4 adverse events in both groups; a composite measure including grade 4 events, unscheduled hospitalizations, and the primary endpoint still favored immediate treatment (HR 0.82; P=0.01).

Study Design

Design

RCT

Open-Label

Sample

4,685

Patients

Duration

3.0 yr

Median

Setting

Multicenter, global

Population Asymptomatic HIV-positive adults who were antiretroviral-naive with a CD4+ count of more than 500 cells/mm³.

Intervention Immediate initiation of combined antiretroviral therapy (ART) following randomization.

Comparator Deferred initiation of ART until the patient's CD4+ count declined to 350 cells/mm³, or until the development of an AIDS-defining condition or other clinical indication dictating ART use.

Outcome Composite of any serious AIDS-related event, serious non-AIDS-related event (cardiovascular disease, end-stage renal disease, liver disease, non-AIDS cancer), or death from any cause.

Study Limitations

• The open-label design could theoretically introduce bias into the reporting and ascertainment of subjective non-AIDS events, although primary endpoints were rigorously adjudicated.

• Because the trial was unblinded early (mean follow-up of 3.0 years) due to undeniable efficacy, the study was underpowered to assess very long-term ART toxicities or specific rare secondary outcomes like all-cause mortality.

• The early termination limited the ability to fully evaluate long-term medication adherence and the lifetime risk of developing viral resistance associated with decades of antiretroviral therapy.

Clinical Significance

The START trial provided definitive clinical endpoint data proving that immediate ART initiation benefits patients with early asymptomatic HIV. By demonstrating reductions in both AIDS and non-AIDS comorbidities, it decisively resolved the long-standing debate over the optimal timing for starting treatment, prompting a universal shift in global guidelines (including WHO) to a 'Treat All' strategy regardless of CD4 cell count.

Historical Context

Prior to the START trial, the optimal timing for initiating ART was highly controversial. While early observational data suggested benefits, concerns about long-term drug toxicities, pill burden, and viral resistance led guidelines to recommend deferring treatment until CD4 counts fell below specific thresholds (e.g., 350 or 500 cells/mm³). The START trial definitively settled this debate for individual patient health, directly complementing the concurrent HPTN 052 trial which established that early ART prevents HIV transmission to partners. Together, these landmark trials cemented the modern 'Test and Treat' era of HIV care.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

How does uncontrolled HIV viremia in early asymptomatic infection contribute to non-AIDS-related complications, such as cardiovascular disease, despite a high CD4 count?

Key Response

This tests the understanding of chronic immune activation and inflammation. Even with CD4 counts above 500, viral replication causes macrophage activation, endothelial dysfunction, and accelerated atherosclerosis, explaining why immediate ART reduces non-AIDS events like myocardial infarction.

Resident

A newly diagnosed asymptomatic HIV patient with a CD4 count of 650 cells per mm3 is hesitant to start ART immediately due to fear of side effects. Based on the START trial, how would you counsel this patient regarding the risks of deferring therapy?

Key Response

Residents need to apply trial data to patient counseling. Deferring therapy increases the risk of both AIDS-defining illnesses and non-AIDS-related events (such as cardiovascular events and non-AIDS malignancies). The START trial definitively showed that the clinical benefits of early treatment strongly outweigh the risks of ART toxicity.

Fellow

The START trial demonstrated a reduction in both AIDS and non-AIDS events with immediate ART. However, what are the implications of early ART initiation on the latent HIV reservoir, and how does this inform current cure research strategies?

Key Response

Fellows should connect clinical trials to translational concepts. Early ART limits the size and genetic diversity of the latent viral reservoir. While early ART alone does not eradicate the virus, minimizing the reservoir size is considered a crucial prerequisite for functional cure or eradication strategies being tested in ongoing trials.

Attending

The START trial shifted the paradigm to universal treatment regardless of CD4 count. In an era of test-and-treat models, what are the practical systemic and individual barriers that still prevent the realization of the START trial morbidity benefits in real-world populations?

Key Response

Attendings must consider systems-level implementation. While the trial established biological efficacy, real-world effectiveness is hampered by structural barriers like linkage to care, retention, medication adherence, stigma, and psychiatric comorbidities, which require multidisciplinary care models to overcome.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

The START trial was stopped early by the DSMB due to a clear demonstration of efficacy. How does early trial termination for benefit potentially overestimate the true treatment effect, and how might this affect the long-term safety data regarding prolonged ART exposure?

Key Response

PhDs focus on methodology. Stopping early for benefit can lead to random high bias, where the effect size is exaggerated at the time of the interim analysis. Furthermore, truncating the deferred arm limits the ability to collect long-term comparative data on cumulative drug toxicities, which is a key consideration for lifelong therapy.

Journal Editor

In an unblinded strategy trial like START, how might differential follow-up, patient dropout, or ascertainment bias regarding subjective non-AIDS endpoints skew the composite primary outcome, and how should reviewers assess the robustness of these endpoints?

Key Response

Editors must look for biases. In unblinded trials, patients in the deferred arm might feel neglected, leading to higher dropout rates or less frequent reporting of symptoms. Reviewers should look for blinded end-point adjudication committees (which START used) to mitigate the risks of ascertainment bias.

Guideline Committee

How did the results of the START trial, alongside the TEMPRANO trial, specifically influence the DHHS and WHO HIV treatment guidelines regarding the strength of recommendation and level of evidence for ART initiation in patients with CD4 counts >500 cells per mm3?

Key Response

The START trial provided the definitive Grade AI evidence that shifted WHO and DHHS guidelines from treating based on CD4 thresholds to recommending ART for all HIV-infected individuals regardless of CD4 count (Treat All). This unified global guidelines, eliminating the previous CD4 >500 deferral recommendation.

Clinical Landscape

Noteworthy Related Trials

2006

SMART Trial

n = 5,472 · NEJM

Tested

Episodic ART (stopping when CD4 > 400, restarting when < 250)

Population

HIV-infected adults with CD4 > 350

Comparator

Continuous ART

Endpoint

Opportunistic disease or death from any cause

Key result: Episodic ART significantly increased the risk of opportunistic disease or death compared to continuous ART.

2011

HPTN 052

n = 1,763 · NEJM

Tested

Early ART initiation (CD4 350-550)

Population

HIV-serodiscordant couples

Comparator

Delayed ART initiation (CD4 < 250 or AIDS-defining illness)

Endpoint

Linked HIV transmission and HIV-related clinical events

Key result: Early ART reduced HIV transmission by 96% and decreased HIV-related clinical events in the infected partner.

2015

TEMPRANO ANRS 12136

n = 2,056 · NEJM

Tested

Early ART initiation (CD4 > 500) and/or 6 months of isoniazid preventive therapy

Population

HIV-1 infected adults in Ivory Coast with high CD4 counts

Comparator

Deferred ART (WHO criteria) and/or no IPT

Endpoint

Severe HIV morbidity, non-HIV morbidity, or death

Key result: Early ART and IPT independently reduced the risk of severe HIV-related illness or death compared to deferred treatment.

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