Research
Original Investigation
Pregnancy Incidence and Outcomes Among Women Receiving Preexposure Prophylaxis for HIV Prevention
A Randomized Clinical Trial Nelly R. Mugo, MBChB, M P H ;Ting Hong, MD, PhD; Connie Celum, MD, MPH; Deborah Donnell, PhD; Elizabeth A. Bukusi, MBChB, PhD; Grace JohnStew art, MD, PhD; Jonathan Wangisi, MBChB; Edwin Were, MBChB, MPH; Renee H effron, MPH, PhD; LynnT. M atthew s, MD, MPH; Susan M orrison, MD, MPH; Kenneth Ngure, PhD; Jared M. Baeten, MD, PhD; fo r th e Partners PrEP S tudy Team
gg Editorial page 349 IMPORTANCE Antiretroviral preexposure prophylaxis (PrEP), using te n ofo vir disoproxil
fum arate (TDF) and com bination e m tricita b in e /te n o fo vir disoproxil fum arate (FTC+TDF), is
[J Supplemental content at jam a.com
efficacious fo r prevention o f human im m unodeficiency 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 wom en using PrEP during
th e periconception period. DESIGN, SETTING, AND PARTICIPANTS Randomized trial among 1785 HIV-serodiscordant
heterosexual couples (the Partners PrEP Study) in which th e female partner was HIV uninfected th a t dem onstrated th a t PrEP was efficacious fo r HIV prevention, conducted between July 2 0 0 8 and June 2013 at 9 sites in Kenya and Uganda. INTERVENTIONS Daily oral TDF (n = 598), com bination FTC+TDF (n = 566), or placebo
(n = 621) through July 2011, when PrEP dem onstrated efficacy fo r HIV prevention. Thereafter, participants continued receiving active PrEP w ith o u t placebo. Pregnancy testing occurred m onthly and study m edication was discontinued when pregnancy was detected. MAIN OUTCOMES AND MEASURES Pregnancy incidence, birth outcom es (live births,
pregnancy loss, preterm birth, congenital anomalies), and infant grow th. RESULTS A to ta lo f4 3 1 pregnancies occurred. Pregnancy incidence was 10.0 per 100
person-years among wom en assigned placebo, 11.9 among those assigned TDF (incidence difference, 1.9; 95% Cl, -1.1 to 4.9 [P = .22 vs placebo]), and 8.8 among those assigned FTC+TDF (incidence difference, -1.3; 95% Cl, -4.1 to 1.5 [P = .39 vs placebo]). Before discontinuation o f the placebo treatm ent group in July 2011, the occurrence o f pregnancy loss (96 o f 288 pregnancies) was 42.5% for wom en receiving FTC+TDF compared w ith 32.3% fo r those receiving placebo (difference fo r FTC+TDF vs placebo, 10.2%; 95% Cl, -5.3% to 25.7%; P = .16) and was 27.7% fo r those receiving TDF alone (difference vs placebo, -4.6% ; 95% Cl, -18.1% to 8.9%; P = .46). A fte r July 2011, the frequency o f pregnancy loss (52 o f 143 pregnancies) was 37.5% fo r FTC+TDF and 36.7% fo r TDF alone (difference, 0.8% ; 95% Cl, -16.8% to 18.5%; P = .92). Occurrence o f preterm birth, congenital anomalies, and grow th throughout the first year o f life did not differ significantly fo r infants born to wom en who received PrEP vs placebo. CONCLUSIONS AND RELEVANCE Am ong HIV-serodiscordant heterosexual African couples,
differences in pregnancy incidence, b irth outcomes, and infant g ro w th were not statistically d iffe re n t fo r wom en receiving PrEP w ith TDF alone or com bination FTC+TDF compared w ith
Author Affiliations: Author
placebo at conception. Given th a t PrEP was discontinued when pregnancy was detected and
affiliations are listed at the end o f this article.
th a t CIs fo r the b irth outcom es were wide, d e finitive statem ents about th e safety o f PrEP in
Group Information: The Partners
th e periconception period cannot be made. These results should be discussed w ith HIV-uninfected wom en receiving PrEP w ho are considering becoming pregnant.
PrEP Study Team members are listed at the end the article. Corresponding Author: Jared M. Baeten, MD, PhD, Department
362
TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00557245
o f Global Health, University o f Washington, 325 Ninth Ave, Box 359927, Seattle, WA 98104
JAMA. 2014;312(4):362-371. doi:10.1001/jama.2014.8735
(j [email protected]).
jama.com
P re e x p o s u re P ro p h y la x is f o r H IV a n d P re g n a n c y O u tc o m e s
ntiretroviral preexposure prophylaxis (PrEP) as daily oral tenofovir disoproxil fumarate and coformulated em tricitabine/tenofovir disoproxil fumarate has been dem onstrated to be efficacious for the prevention of hum an im m u n o d e fic ie n c y v iru s (HIV) a c q u isitio n in d iv e rse populations.1’3 PrEP could be an im portant component of safer conception strategies for w om en at risk for HIV infection, in cluding those in HIV-serodiscordant couples (ie, in which only one member is HIV infected), particularly if the infected part ner is not eligible for antiretroviral treatm ent or is not willing or able to take it.4,5 Efforts to implement PrEP as a public health strategy for HIV prevention in heterosexual populations will be accompanied by PrEP exposure during conception and preg nancy, either inadvertently for women with unrecognized early pregnancy or intentionally as part of reducing HIV risk dur ing conception, and thus understanding the safety of PrEP in the periconception period is a priority. Tenofovir disoproxil fumarate and emtricitabine are preg nancy category B medications, w ith no evidence of terato genicity in animal experiments and in observational studies of humans.6 However, as with most medications, few data from controlled human studies in pregnancy are available. Renal and bone toxicity are known potential adverse effects of tenofo vir disoproxil fum arate in HIV-infected children and adults using tenofovir disoproxil fumarate as part of long-term com bination antiretroviral treatm ent.7'9 Observational studies of HIV-infected women using tenofovir disoproxil fumarate com pared w ith other antiretroviral agents during pregnancy have generally indicated safety, although some data suggest slight growth restriction in infants born to women using tenofovir disoproxil fum arate.10'12 To d a te , PrEP u se d u rin g c o n c e p tio n am o n g HIVuninfected women has not been studied systematically, to our knowledge. Within a randomized, placebo-controlled trial of PrEP for HIV prevention among HIV-serodiscordant couples, we assessed pregnancy incidence and outcom es for HIVuninfected women and growth and renal function during the first year of life for their infants.
A
O r ig in a l I n v e s tig a t io n
R e s e a rc h
emtricitabine/tenofovir disoproxil fumarate (200 mg/300 mg), or placebo. At m onthly follow-up visits for up to 36 months, participants received individualized adherence counseling, HIV testing, and a m onth’s supply of study medication. At enroll ment, HIV-infected partners did not m eet Kenyan or Ugan dan guidelines for initiation of antiretroviral therapy (gener ally, CD4 counts
Original Investigation
Pregnancy Incidence and Outcomes Among Women Receiving Preexposure Prophylaxis for HIV Prevention
A Randomized Clinical Trial Nelly R. Mugo, MBChB, M P H ;Ting Hong, MD, PhD; Connie Celum, MD, MPH; Deborah Donnell, PhD; Elizabeth A. Bukusi, MBChB, PhD; Grace JohnStew art, MD, PhD; Jonathan Wangisi, MBChB; Edwin Were, MBChB, MPH; Renee H effron, MPH, PhD; LynnT. M atthew s, MD, MPH; Susan M orrison, MD, MPH; Kenneth Ngure, PhD; Jared M. Baeten, MD, PhD; fo r th e Partners PrEP S tudy Team
gg Editorial page 349 IMPORTANCE Antiretroviral preexposure prophylaxis (PrEP), using te n ofo vir disoproxil
fum arate (TDF) and com bination e m tricita b in e /te n o fo vir disoproxil fum arate (FTC+TDF), is
[J Supplemental content at jam a.com
efficacious fo r prevention o f human im m unodeficiency 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 wom en using PrEP during
th e periconception period. DESIGN, SETTING, AND PARTICIPANTS Randomized trial among 1785 HIV-serodiscordant
heterosexual couples (the Partners PrEP Study) in which th e female partner was HIV uninfected th a t dem onstrated th a t PrEP was efficacious fo r HIV prevention, conducted between July 2 0 0 8 and June 2013 at 9 sites in Kenya and Uganda. INTERVENTIONS Daily oral TDF (n = 598), com bination FTC+TDF (n = 566), or placebo
(n = 621) through July 2011, when PrEP dem onstrated efficacy fo r HIV prevention. Thereafter, participants continued receiving active PrEP w ith o u t placebo. Pregnancy testing occurred m onthly and study m edication was discontinued when pregnancy was detected. MAIN OUTCOMES AND MEASURES Pregnancy incidence, birth outcom es (live births,
pregnancy loss, preterm birth, congenital anomalies), and infant grow th. RESULTS A to ta lo f4 3 1 pregnancies occurred. Pregnancy incidence was 10.0 per 100
person-years among wom en assigned placebo, 11.9 among those assigned TDF (incidence difference, 1.9; 95% Cl, -1.1 to 4.9 [P = .22 vs placebo]), and 8.8 among those assigned FTC+TDF (incidence difference, -1.3; 95% Cl, -4.1 to 1.5 [P = .39 vs placebo]). Before discontinuation o f the placebo treatm ent group in July 2011, the occurrence o f pregnancy loss (96 o f 288 pregnancies) was 42.5% for wom en receiving FTC+TDF compared w ith 32.3% fo r those receiving placebo (difference fo r FTC+TDF vs placebo, 10.2%; 95% Cl, -5.3% to 25.7%; P = .16) and was 27.7% fo r those receiving TDF alone (difference vs placebo, -4.6% ; 95% Cl, -18.1% to 8.9%; P = .46). A fte r July 2011, the frequency o f pregnancy loss (52 o f 143 pregnancies) was 37.5% fo r FTC+TDF and 36.7% fo r TDF alone (difference, 0.8% ; 95% Cl, -16.8% to 18.5%; P = .92). Occurrence o f preterm birth, congenital anomalies, and grow th throughout the first year o f life did not differ significantly fo r infants born to wom en who received PrEP vs placebo. CONCLUSIONS AND RELEVANCE Am ong HIV-serodiscordant heterosexual African couples,
differences in pregnancy incidence, b irth outcomes, and infant g ro w th were not statistically d iffe re n t fo r wom en receiving PrEP w ith TDF alone or com bination FTC+TDF compared w ith
Author Affiliations: Author
placebo at conception. Given th a t PrEP was discontinued when pregnancy was detected and
affiliations are listed at the end o f this article.
th a t CIs fo r the b irth outcom es were wide, d e finitive statem ents about th e safety o f PrEP in
Group Information: The Partners
th e periconception period cannot be made. These results should be discussed w ith HIV-uninfected wom en receiving PrEP w ho are considering becoming pregnant.
PrEP Study Team members are listed at the end the article. Corresponding Author: Jared M. Baeten, MD, PhD, Department
362
TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00557245
o f Global Health, University o f Washington, 325 Ninth Ave, Box 359927, Seattle, WA 98104
JAMA. 2014;312(4):362-371. doi:10.1001/jama.2014.8735
(j [email protected]).
jama.com
P re e x p o s u re P ro p h y la x is f o r H IV a n d P re g n a n c y O u tc o m e s
ntiretroviral preexposure prophylaxis (PrEP) as daily oral tenofovir disoproxil fumarate and coformulated em tricitabine/tenofovir disoproxil fumarate has been dem onstrated to be efficacious for the prevention of hum an im m u n o d e fic ie n c y v iru s (HIV) a c q u isitio n in d iv e rse populations.1’3 PrEP could be an im portant component of safer conception strategies for w om en at risk for HIV infection, in cluding those in HIV-serodiscordant couples (ie, in which only one member is HIV infected), particularly if the infected part ner is not eligible for antiretroviral treatm ent or is not willing or able to take it.4,5 Efforts to implement PrEP as a public health strategy for HIV prevention in heterosexual populations will be accompanied by PrEP exposure during conception and preg nancy, either inadvertently for women with unrecognized early pregnancy or intentionally as part of reducing HIV risk dur ing conception, and thus understanding the safety of PrEP in the periconception period is a priority. Tenofovir disoproxil fumarate and emtricitabine are preg nancy category B medications, w ith no evidence of terato genicity in animal experiments and in observational studies of humans.6 However, as with most medications, few data from controlled human studies in pregnancy are available. Renal and bone toxicity are known potential adverse effects of tenofo vir disoproxil fum arate in HIV-infected children and adults using tenofovir disoproxil fumarate as part of long-term com bination antiretroviral treatm ent.7'9 Observational studies of HIV-infected women using tenofovir disoproxil fumarate com pared w ith other antiretroviral agents during pregnancy have generally indicated safety, although some data suggest slight growth restriction in infants born to women using tenofovir disoproxil fum arate.10'12 To d a te , PrEP u se d u rin g c o n c e p tio n am o n g HIVuninfected women has not been studied systematically, to our knowledge. Within a randomized, placebo-controlled trial of PrEP for HIV prevention among HIV-serodiscordant couples, we assessed pregnancy incidence and outcom es for HIVuninfected women and growth and renal function during the first year of life for their infants.
A
O r ig in a l I n v e s tig a t io n
R e s e a rc h
emtricitabine/tenofovir disoproxil fumarate (200 mg/300 mg), or placebo. At m onthly follow-up visits for up to 36 months, participants received individualized adherence counseling, HIV testing, and a m onth’s supply of study medication. At enroll ment, HIV-infected partners did not m eet Kenyan or Ugan dan guidelines for initiation of antiretroviral therapy (gener ally, CD4 counts
