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Pregnancy incidence and correlates during the HVTN 503 Phambili HIV vaccine trial conducted among South African women.

ABSTRACT: HIV prevention trials are increasingly being conducted in sub-Saharan Africa. Women at risk for HIV are also at risk of pregnancy. To maximize safety, women agree to avoid pregnancy during trials, yet pregnancies occur. Using data from the HVTN 503/"Phambili" vaccine trial, we report pregnancy incidence during and after the vaccination period and identify factors, measured at screening, associated with incident pregnancy.To enrol in the trial, women agreed and were supported to avoid pregnancy until 1 month after their third and final vaccination ("vaccination period"), corresponding to the first 7 months of follow-up. Unsterilized women, pooled across study arms, were analyzed. Poisson regression compared pregnancy rates during and after the vaccination period. Cox proportional hazards regression identified associations with first pregnancy.Among 352 women (median age 23 yrs; median follow-up 1.5 yrs), pregnancy incidence was 9.6/100 women-years overall and 6.8/100 w-yrs and 11.3/100 w-yrs during and after the vaccination period, respectively [Rate Ratio = 0.60 (0.32-1.14), p = 0.10]. In multivariable analysis, pregnancy was reduced among women who: enrolled at sites providing contraception on-site [HR = 0.43, 95% CI (0.22-0.86)]; entered the trial as injectable contraceptive users [HR = 0.37 (0.21-0.67)] or as consistent condom users (trend) [HR = 0.54 (0.28-1.04)]. Compared with women with a single partner of HIV-unknown status, pregnancy rates were increased among women with: a single partner whose status was HIV-negative [HR = 2.34(1.16-4.73)] and; 2 partners both of HIV-unknown status [HR = 4.42(1.59-12.29)]. Women with 2 more of these risk factors: marijuana use, heavy drinking, or use of either during sex, had increased pregnancy incidence [HR = 2.66 (1.24-5.72)].It is possible to screen South African women for pregnancy risk at trial entry. Providing injectable contraception for free on-site and supporting consistent condom use may reduce incident pregnancy. Screening should determine the substance use, partnering, and HIV status of both members of the couple for both pregnancy and HIV prevention.SA National Health Research Database DOH-27-0207-1539; Clinicaltrials.gov NCT00413725.

SUBMITTER: Latka MH

PROVIDER: S-EPMC3331975 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Pregnancy incidence and correlates during the HVTN 503 Phambili HIV vaccine trial conducted among South African women.

Latka Mary H MH Fielding Katherine K Gray Glenda E GE Bekker Linda-Gail LG Nchabeleng Maphoshane M Mlisana Koleka K Nielson Tanya T Roux Surita S Mkhize Baningi B Mathebula Matsontso M Naicker Nivashnee N de Bruyn Guy G Kublin James J Churchyard Gavin J GJ

PloS one 20120419 4

<h4>Background</h4>HIV prevention trials are increasingly being conducted in sub-Saharan Africa. Women at risk for HIV are also at risk of pregnancy. To maximize safety, women agree to avoid pregnancy during trials, yet pregnancies occur. Using data from the HVTN 503/"Phambili" vaccine trial, we report pregnancy incidence during and after the vaccination period and identify factors, measured at screening, associated with incident pregnancy.<h4>Methods</h4>To enrol in the trial, women agreed and ...[more]

PMID: 22532824

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Project description:BackgroundThe HVTN 503/Phambili study, which assessed the efficacy of the Merck Ad5 gag/pol/nef subtype B HIV-1 preventive vaccine in South Africa, was stopped when futility criteria in the Step study (assessing the same vaccine in the Americas, Caribbean, and Australia) were met. Here we report long-term follow-up data.MethodsHVTN 503/Phambili was a double-blind, placebo-controlled, randomised trial that recruited HIV-1 uninfected, sexually active adults aged 18-35 years from five sites in South Africa. Eligible participants were randomly assigned (1:1) by computer-generated random numbers to either vaccine or placebo, stratified by site and sex. Cox proportional hazards models were used to estimate HIV-1 infection in the modified intention-to-treat cohort, all of whom were unmasked early in follow-up. The trial is registered with ClinicalTrials.gov, number NCT00413725 and the South African National Health Research Database, number DOH-27-0207-1539.FindingsBetween Jan 24, 2007, and Sept 19, 2007, 801 participants (26·7%) of a planned 3000 were randomly assigned (400 to vaccine, 401 to placebo); 216 (27%) received only one injection, 529 (66%) received only two injections, and 56 (7%) received three injections. At a median follow-up of 42 months (IQR 31-42), 63 vaccine recipients (16%) had HIV-1 infection compared with 37 placebo recipients (9%; adjusted HR 1·70, 95% CI 1·13-2·55; p=0·01). Risk for HIV-1 infection did not differ according to the number of vaccinations received, sex, circumcision, or adenovirus type 5 (Ad5) serostatus. Differences in risk behaviour at baseline or during the study, or annualised dropout rate (7·7% [95% CI 6·2-9·5] for vaccine recipients vs 8·8% [7·1-10·7] for placebo recipients; p=0·40) are unlikely explanations for the increased rate of HIV-1 infections seen in vaccine recipients.InterpretationThe increased risk of HIV-1 acquisition in vaccine recipients, irrespective of number of doses received, warrants further investigation to understand the biological mechanism. We caution against further use of the Ad5 vector for HIV vaccines.FundingNational Institute of Allergy and Infectious Diseases, Merck, and South African Medical Research Council.

Project description:BackgroundThe MRKAd5 HIV-1 gag/pol/nef subtype B vaccine was designed to elicit T-cell-mediated immune responses capable of providing complete or partial protection from HIV-1 infection or a decrease in viral load after acquisition. We aim to assess the safety and efficacy of the vaccine in South Africa, where the major circulating clade is subtype C.MethodsWe did a phase 2b double-blind, randomised test-of-concept study in sexually active HIV-1 seronegative participants at five sites in South Africa. Randomisation was by a computer-generated random number sequence. The vaccine and placebo were given by intramuscular injection on a 0, 1, 6 month schedule. Our coprimary endpoints were a vaccine-induced reduction in HIV-1 acquisition and viral-load setpoint. These endpoints were assessed independently in the modified intention-to-treat (MITT) cohort with two-tailed significance tests stratified by sex. We assessed immunogenicity by interferon-? ELISPOT in peripheral-blood mononuclear cells. After the lack of efficacy of the MRKAd5 HIV-1 vaccine in the Step study, enrolment and vaccination in our study was halted, treatment allocations were unmasked, and follow-up continued. This study is registered with the South Africa National Health Research Database, number DOH-27-0207-1539, and ClinicalTrials.gov, number NCT00413725.Findings801 of a scheduled 3000 participants, of whom 360 (45%) were women, were randomly assigned to receive either vaccine or placebo. 445 participants (56%) had adenovirus serotype 5 (Ad5) titres greater than 200, and 129 men (29%) were circumcised. 34 MITT participants in the vaccine group were diagnosed with HIV-1 (incidence rate 4·54 per 100 person-years) and 28 in the placebo group (3·70 per 100 person-years). There was no evidence of vaccine efficacy; the hazard ratio adjusted for sex was 1·25 (95% CI 0·76-2·05). Vaccine efficacy did not differ by Ad5 titre, sex, age, herpes simplex virus type 2 status, or circumcision. The geometric mean viral-load setpoint was 20,483 copies per mL (n=33) in the vaccine group and 34,032 copies per mL (n=28) in the placebo group (p=0·39). The vaccine elicited interferon-?-secreting T cells that recognised both clade B (89%) and C (77%) antigens.InterpretationThe MRKAd5 HIV-1 vaccine did not prevent HIV-1 infection or lower viral-load setpoint; however, stopping our trial early probably compromised our ability to draw conclusions. The high incidence rates noted in South Africa highlight the crucial need for intensified efforts to develop an efficacious vaccine.FundingThe US National Institute of Allergy and Infectious Disease and Merck and Co Inc.

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Pregnancy incidence and correlates during the HVTN 503 Phambili HIV vaccine trial conducted among South African women.

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Pregnancy incidence and correlates during the HVTN 503 Phambili HIV vaccine trial conducted among South African women.

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