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Original Investigation |

Pregnancy Incidence and Outcomes Among Women Receiving Preexposure Prophylaxis for HIV Prevention:  A Randomized Clinical Trial

Nelly R. Mugo, MBChB, MPH1,2,3; Ting Hong, MD, PhD1; Connie Celum, MD, MPH1,4,5; Deborah Donnell, PhD1,6; Elizabeth A. Bukusi, MBChB, PhD1,7,8; Grace John-Stewart, MD, PhD1,4,5,9; Jonathan Wangisi, MBChB10; Edwin Were, MBChB, MPH11; Renee Heffron, MPH, PhD1; Lynn T. Matthews, MD, MPH12,13; Susan Morrison, MD, MPH1; Kenneth Ngure, PhD14; Jared M. Baeten, MD, PhD1,4,5; for the Partners PrEP Study Team
[+] Author Affiliations
1Department of Global Health, University of Washington, Seattle
2Centre for Clinical Research Kenya Medical Research Institute, Nairobi, Kenya
3Department of Obstetrics and Gynaecology, Kenyatta National Hospital, Nairobi, Kenya
4Department of Medicine, University of Washington, Seattle
5Department of Epidemiology, University of Washington, Seattle
6Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
7Department of Obstetrics and Gynecology, University of Washington, Seattle
8Centre for Microbiology Research, Kenya Medical Research Institute, Nairobi, Kenya
9Department of Pediatrics, University of Washington, Seattle
10The AIDS Support Organization (TASO), Kampala, Uganda
11Department of Reproductive Health, Moi University, Eldoret, Kenya
12Division of Infectious Disease, Massachusetts General Hospital, Boston
13Center for Global Health, Massachusetts General Hospital, Boston
14Jomo Kenyatta University of Agriculture and Technology, Nairobi, Kenya
JAMA. 2014;312(4):362-371. doi:10.1001/jama.2014.8735.
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Importance  Antiretroviral preexposure prophylaxis (PrEP), using tenofovir disoproxil fumarate (TDF) and combination emtricitabine/tenofovir disoproxil fumarate (FTC+TDF), is efficacious for prevention of human immunodeficiency virus (HIV) acquisition. PrEP could reduce periconception HIV risk, but the effect on pregnancy outcomes is not well defined.

Objective  To assess pregnancy incidence and outcomes among women using PrEP during the periconception period.

Design, Setting, and Participants  Randomized trial among 1785 HIV-serodiscordant heterosexual couples (the Partners PrEP Study) in which the female partner was HIV uninfected that demonstrated that PrEP was efficacious for HIV prevention, conducted between July 2008 and June 2013 at 9 sites in Kenya and Uganda.

Interventions  Daily oral TDF (n = 598), combination FTC+TDF (n = 566), or placebo (n = 621) through July 2011, when PrEP demonstrated efficacy for HIV prevention. Thereafter, participants continued receiving active PrEP without placebo. Pregnancy testing occurred monthly and study medication was discontinued when pregnancy was detected.

Main Outcomes and Measures  Pregnancy incidence, birth outcomes (live births, pregnancy loss, preterm birth, congenital anomalies), and infant growth.

Results  A total of 431 pregnancies occurred. Pregnancy incidence was 10.0 per 100 person-years among women assigned placebo, 11.9 among those assigned TDF (incidence difference, 1.9; 95% CI, −1.1 to 4.9 [P = .22 vs placebo]), and 8.8 among those assigned FTC+TDF (incidence difference, −1.3; 95% CI, −4.1 to 1.5 [P = .39 vs placebo]). Before discontinuation of the placebo treatment group in July 2011, the occurrence of pregnancy loss (96 of 288 pregnancies) was 42.5% for women receiving FTC+TDF compared with 32.3% for those receiving placebo (difference for FTC+TDF vs placebo, 10.2%; 95% CI, −5.3% to 25.7%; P = .16) and was 27.7% for those receiving TDF alone (difference vs placebo, −4.6%; 95% CI, −18.1% to 8.9%; P = .46). After July 2011, the frequency of pregnancy loss (52 of 143 pregnancies) was 37.5% for FTC+TDF and 36.7% for TDF alone (difference, 0.8%; 95% CI, −16.8% to 18.5%; P = .92). Occurrence of preterm birth, congenital anomalies, and growth throughout the first year of life did not differ significantly for infants born to women who received PrEP vs placebo.

Conclusions and Relevance  Among HIV-serodiscordant heterosexual African couples, differences in pregnancy incidence, birth outcomes, and infant growth were not statistically different for women receiving PrEP with TDF alone or combination FTC+TDF compared with placebo at conception. Given that PrEP was discontinued when pregnancy was detected and that CIs for the birth outcomes were wide, definitive statements about the safety of PrEP in the periconception period cannot be made. These results should be discussed with HIV-uninfected women receiving PrEP who are considering becoming pregnant.

Trial Registration  clinicaltrials.gov Identifier: NCT00557245

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Figure 1.
Randomization and Follow-up for the Primary Analysis Cohort

Pregnancies detected before discontinuation of the trial’s placebo group in July 2011. HIV-uninfected women (1785) were randomized in a 1:1:1 fashion to daily oral tenofovir disoproxil fumarate, combination emtricitabine/tenofovir disoproxil fumarate, or placebo and followed for up to 36 months, through July 2011. Cumulative retention for women is detailed: denominators indicate women eligible for follow-up through different periods up to 36 months from enrollment and numerators note those completing such follow-up. Four women contributed no follow-up: 3 randomized to tenofovir disoproxil fumarate and 1 to emtricitabine/tenofovir disoproxil fumarate. One hundred ninety-four live-born infants were followed up with scheduled visits within the first month of life and then quarterly. Per-visit retention is provided, with denominators referring to infants eligible to have attended the visit (ie, excluding infants who died) and numerators referring to infants who attended the visit.

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Figure 2.
Infant Sex- and Age-Adjusted z Scores for Weight, Length, and Head Circumference, by Randomization Group

Box plots depict median (horizontal line), interquartile range (box), and range (whiskers); also shown is number of infants who attended the visit and had growth parameters recorded. Comparisons for active preexposure prophylaxis vs placebo, using 2-sample t tests, were significant as follows. For infant weight, tenofovir disoproxil fumarate was significant (P<.05) at months 6, 9, and 12; emtricitabine/tenofovir disoproxil fumarate at month 12. For infant length, emtricitabine/tenofovir disoproxil fumarate was significant at month 3. No comparisons were significant for head circumference.

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