Pregnancy incidence and outcomes among women receiving preexposure prophylaxis for HIV prevention: a randomized clinical trial

Abstract

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.

Figures

Figure 1. Randomization and follow-up for the primary analysis cohort (i.e., prior to discontinuation of the trial’s placebo group in July 2011), including retention of HIV uninfected women during follow-up and visit attendance of infants during the first 12 months after birth

1785 HIV uninfected women 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. 194 live-born infants were followed 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 (i.e., excluding infants who died) and numerators referring to infants who attended the visit.

Figure 2. Infant growth: sex- and age-adjusted Z-scores for A) weight, B) length, and C) head circumference, by randomization group

Box plots depict median (central line), interquartile range (box), and range (whiskers); numbers below each box indicate the number of subjects who attended the visit and who had growth parameters recorded. P-value comparisons are each active PrEP group versus placebo, using two sample t-tests for the comparisons.

Figure 2. Infant growth: sex- and age-adjusted Z-scores for A) weight, B) length, and C) head circumference, by randomization group

Box plots depict median (central line), interquartile range (box), and range (whiskers); numbers below each box indicate the number of subjects who attended the visit and who had growth parameters recorded. P-value comparisons are each active PrEP group versus placebo, using two sample t-tests for the comparisons.

Figure 2. Infant growth: sex- and age-adjusted Z-scores for A) weight, B) length, and C) head circumference, by randomization group

Box plots depict median (central line), interquartile range (box), and range (whiskers); numbers below each box indicate the number of subjects who attended the visit and who had growth parameters recorded. P-value comparisons are each active PrEP group versus placebo, using two sample t-tests for the comparisons.

Figure 3. Serum creatinine levels in infants, by randomization group

Box plots depict median (central line), interquartile range (box), and range (whiskers); numbers below each box indicate the number of subjects. P-value comparisons are each active PrEP group versus placebo, using two sample t-tests for the comparisons.