In patients with asymptomatic HIV infection with CD4+ count >500 cells/mm3, does immediate initiation of antiretroviral therapy (ART) reduce the risk of serious events or death compared to deferred initiation until the CD4+ is less than 350 cells/mm3?
In HIV-infected patients with CD4+ count >500 cells/mm3, early ART initiation reduces serious AIDS-related and non-AIDS-related complications compared with delayed ART.
The advent of three-drug antiretroviral therapy (ART) regimens in the 1990s have resulted in remarkable declines in morbidity and mortality among HIV-infected patients. In the early 2000s, therapy was withheld in HIV-infected patients without AIDS, given the toxicity of early potent ART and lack of evidence supporting early initiation in patients with relatively preserved CD4+ counts. Subsequently, randomized studies demonstrated AIDS-related morbidity and mortality benefit with early initiation of ART in patients with CD4+ counts <350. The evidence for initiating ART in patients with CD4+ counts >350 comes from the START and Temprano trials.
START randomized 4685 treatment-naive HIV-infected individuals with CD4+ counts >500 to start ART immediately (immediate-initiation arm) or to defer it until the CD4+ count decreases to 350 or until the development of AIDS (deferred-initiation arm). After a mean follow-up of three years, an interim analysis in May 2015 demonstrated that the composite endpoint of serious AIDS-related or non AIDS-related event (including all-cause mortality) was significantly reduced in the immediate-initiation arm compared to the deferred-initiation arm (0.60 vs. 1.38 events per 100 person-years), resulting in early termination of the deferred-initiation arm and offering ART to patients who were not receiving ART. In both arms, most primary events occurred when the CD4+ count was >500 (68% events). The immediate-initiation arm was associated with fewer serious AIDS (HR 0.28) or non-AIDS (HR 0.61) -related events. This study demonstrated that early initiation of ART is beneficial for nearly all HIV-infected patients, regardless of the CD4+ count, in reducing both serious AIDS-related and non-AIDS-related events.
As of November 2015, no guidelines have been published that reflect the results of this trial.
- Multicenter, multi-national RCT
- N=4,685 treatment-naive HIV-infected patients
- Immediate initiation of ART (n=2,326)
- Deferred initiation of ART (n=2,359)
- Setting: 215 centers in 35 countries
- Enrollment: 2009-2013
- Mean follow-up: 3.0 years
- Analysis: intention-to-treat
- Primary outcome: composite including serious serious AIDS-related event and serious non–AIDS-related event, including death from any cause.
- HIV-infected patients
- Age ≥18 years
- Antiretroviral treatment-naive
- No progression to AIDS
- Two CD4+ counts >500 cells/mm3, at least 2 weeks apart
- Pregnant or breastfeeding
- Diagnosis of AIDS
- Cardiovascular event within 6 months
- Dialysis within 6 months
- History of malignancy
- History of decompensated liver disease
- Current imprisonment or compulsory detention for physical or psychiatric disorder
- Mean age: 36 years
- Female: 26.8%
- White: 44.5%; Black: 30.1%; Latino or Hispanic: 13.6%; Asian: 8.3%
- Sexual transmission: 93.4%
- Median time since HIV diagnosis: 1.0 years
- Median CD4+ count: 651 cells/mm3
- Median HIV RNA: ~12,800 copies/mL
- Median CHD risk at 10 years: 1.9%
- Initial therapy: tenofovir (89%), emtricitabine (89% vs. 88%), efavirenz (73% vs. 51%)
- Randomized to immediate or delayed initiation of ART
- Patients in the immediate-initiation arm were started immediately on ART regardless of CD4 count upon enrollment
- Patients in the delayed-initiation arm were deferred ART until CD4+ count reached 350 cells/mm3 or progression to AIDS-related event or another condition that dictated use of ART (e.g., pregnancy)
- Followup at months 1, 4, and every 4 months afterwards
Comparisons are immediate-initiation vs. delayed-initiation of ART
- Composite end point of serious AIDS-related event, serious non-AIDS related event, or death from any cause
- 0.60 vs. 1.38 events per 100 person-years (HR 0.43; 95% CI 0.30-0.62; P<0.001)
- Serious AIDS related event
- Death from AIDS or any AIDS-defining illness, except nonfatal HSV and esophageal candidiasis
- 0.20 vs. 0.72 events per 100 person years (HR 0.28; 95% CI 0.15-0.50; P<0.001)
- Serious non-AIDS related event
- CV disease including MI, CVA or PCI, or death from CV disease; ESRD including dialysis or s/p renal transplant, or death from renal disease; decompensated liver disease or death from liver disease; non AIDS-defining malignancy, except BSS or SCC, or death from malignancy; and any death not attributable to AIDS
- 0.42 vs. 0.67 events per 100 person years (HR 0.61; 95% CI 0.38-0.97; P=0.04)
- Death from any cause
- 0.17 vs. 0.30 events per 100 person years (HR 0.58; 95% CI 0.28-1.17; P-0.13)
- 0.09 vs. 0.28 events per 100 person years (HR 0.29; 95% CI 0.12-0.73; P=0.008)
- Kaposi's Sarcoma
- 0.01 vs. 0.11 events per 100 person years (HR 0.09; 95% CI 0.01-0.71; P=0.02)
- Malignant lymphoma
- 0.04 vs. 0.14 events per 100 person years (HR 0.07; 95% CI 0.08-1.10; P=0.07)
- Symptomatic grade 4 event, according to the Division of AIDS (DAIDS) Table
- 1.06 vs. 1.05 events per 100 person years (HR 1.01; 95% CI 0.73-1.39; P=0.97)
- Bacterial infections
- 0.20 vs. 0.52 events per 100 person years (HR 0.38; 95% CI 0.20-0.70; P=0.002)
- Median CD4 count at ART initiation
- 651 vs. 408 cells/microL
- HIV Viral Load at initiation of ART
- 13,462 vs. 41,525 copies/mL
Across all subgroups (including age, gender, race, baseline CD4+, baseline HIV RNA, smoking status, and Framingham 10-year risk), hazard ratios consistently favored the immediate-initiation arm compared to delayed-initiation.
- Lower than anticipated rate of non-AIDS related serious events combined with early termination of deferred-ART arm resulted in low statistical power to quantify benefit.
- Mean follow-up of 3 years is a short period to assess risks and benefits of chronic ART
- ART medications were donated by AbbVie, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline/ViiV Healthcare, Janssen Scientific Affairs, and Merck.