Randomized trial of stopping or continuing ART among postpartum women with pre-ART CD4 ≥ 400 cells/mm3

Abstract

Background: Health benefits of postpartum antiretroviral therapy (ART) for human immunodeficiency virus (HIV) positive women with high CD4+ T-counts have not been assessed in randomized trials.

Methods: Asymptomatic, HIV-positive, non-breastfeeding women with pre-ART CD4+ T-cell counts ≥ 400 cells/mm3 started on ART during pregnancy were randomized up to 42 days after delivery to continue or discontinue ART. Lopinavir/ritonavir plus tenofovir/emtricitabine was the preferred ART regimen. The sample size was selected to provide 88% power to detect a 50% reduction from an annualized primary event rate of 2.07%. A post-hoc analysis evaluated HIV/AIDS-related and World Health Organization (WHO) Stage 2 and 3 events. All analyses were intent to treat.

Results: 1652 women from 52 sites in Argentina, Botswana, Brazil, China, Haiti, Peru, Thailand and the US were enrolled (1/2010-11/2014). Median age was 28 years and major racial categories were Black African (28%), Asian (25%) White (15%). Median entry CD4 count was 696 cells/mm3 (IQR 575-869), median ART exposure prior to delivery was 19 weeks (IQR 13-24) and 94% had entry HIV-1 RNA < 1000 copies/ml. After a median follow-up of 2.3 years, the primary composite endpoint rate was significantly lower than expected, and not significantly different between arms (continue arm 0.21 /100 person years(py); discontinue 0.31/100 py, Hazard ratio (HR) 0.68, 95% CI: 0.19, 2.40). WHO Stage 2 and 3 events were significantly reduced with continued ART (2.08/100 py vs. 4.36/100 py in the discontinue arm; HR 0.48, 95%CI: 0.33, 0.70). Toxicity rates did not differ significantly between arms. Among women randomized to continue ART, 189/827 (23%) had virologic failure; of the 155 with resistance testing, 103 (66%) failed without resistance to their current regimen, suggesting non-adherence.

Conclusions: Overall, serious clinical events were rare among young HIV-positive post-partum women with high CD4 cell counts. Continued ART was safe and was associated with a halving of the rate of WHO 2/3 conditions. Virologic failure rates were high, underscoring the urgent need to improve adherence in this population.

Trial registration: ClinicalTrials.gov NCT00955968.

Conflict of interest statement

Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: LM is a member of PlosMed editorial board. WA receives research grants and contracts from Merck and Glaxo SMithKline; moneys to University of Colorado Denver(UCD). Spouse and UCD receive royalties from Merck for intellectual property. AC owned stock in Bristol-Myers Squibb. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Figures

Fig 1. CONSORT Flow Diagram.

Fig 2. Survival Curves for the Primary and Secondary Endpoints.

A) Composite endpoint of the first AIDS-defining illness, serious non-AIDS defining cardiovascular, renal or hepatic event or death. B) Composite endpoint of the first WHO 2 or 3 event. C) Composite of first grade 3 or 4 sign or symptom, or grade 2,3, or 4 hematology or chemistry event. D) Composite of the first grade 3 or 4 sign or symptom, or hematology or chemistry event.

Fig 3. CD4 Cell Counts Over time (Median, 10th and 90th percentile, and the proportion <350 cells/mm).

The median CD4 cell counts in the continue (green) and discontinue (red) arms are show at each follow-up visit. The proportion with a CD4 count below 350 cells/mm3 are shown across the top of the figure at each timepoint.