Continued Follow-Up of Phambili Phase 2b Randomized HIV-1 Vaccine Trial Participants Supports Increased HIV-1 Acquisition among Vaccinated Men

Abstract

Background: The Phase 2b double-blinded, randomized Phambili/HVTN 503 trial evaluated safety and efficacy of the MRK Ad5 gag/pol/nef subtype B HIV-1 preventive vaccine vs placebo in sexually active HIV-1 seronegative participants in South Africa. Enrollment and vaccinations stopped and participants were unblinded but continued follow-up when the Step study evaluating the same vaccine in the Americas, Caribbean, and Australia was unblinded for non-efficacy. Final Phambili analyses found more HIV-1 infections amongst vaccine than placebo recipients, impelling the HVTN 503-S recall study.

Methods: HVTN 503-S sought to enroll all 695 HIV-1 uninfected Phambili participants, provide HIV testing, risk reduction counseling, physical examination, risk behavior assessment and treatment assignment recall. After adding HVTN 503-S data, HIV-1 infection hazard ratios (HR vaccine vs. placebo) were estimated by Cox models.

Results: Of the 695 eligible, 465 (67%) enrolled with 230 from the vaccine group and 235 from the placebo group. 38% of the 184 Phambili dropouts were enrolled. Enrollment did not differ by treatment group, gender, or baseline HSV-2. With the additional 1286 person years of 503-S follow-up, the estimated HR over Phambili and HVTN 503-S follow-up was 1.52 (95% CI 1.08-2.15, p = 0.02, 82 vaccine/54 placebo infections). The HR was significant for men (HR = 2.75, 95% CI 1.49, 5.06, p = 0.001) but not for women (HR = 1.12, 95% CI 0.73, 1.72, p = 0.62).

Conclusion: The additional follow-up from HVTN 503-S supported the Phambili finding of increased HIV-1 acquisition among vaccinated men and strengthened the evidence of lack of vaccine effect among women.

Trial registration: clinicaltrials.gov NCT00413725 SA National Health Research Database DOH-27-0207-1539.

Conflict of interest statement

Competing Interests: The authors have read the journal's policy and the authors of this manuscript have the following competing interests: MA is employed by the National Institute of Allergy and Infectious Diseases (NIAID), the study sponsor. All authors are current recipients of NIAID funding, and this publication is a result of activities funded by NIAID. MA was not involved with the process of funding these awards, nor in their administration or scientific aspects, and, in accordance with NIAID policies, is deferred from decisions regarding funding of coauthors for a requisite period. This study was also partly funded by Merck and Co Inc. Michael Robertson is an employee of and owns stock in Merck Research Laboratories. There are no patents, products in development or marketed products to declare. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials, as detailed online in the guide for authors.

Figures

Fig 1. Cumulative HIV-1 incidence curves for vaccine and placebo groups for Phambili and Phambili + HVTN 503-S follow-up; Phambili + HVTN 503-S curves are based on all MITT Phambili participants (n = 800) with updated HIV-1 status for the subset of participants enrolled in HVTN 503-S (n = 465).

Fig 2. Cumulative HIV-1 incidence curves for vaccine and placebo groups for Phambili and Phambili + HVTN 503-S follow-up by gender.