MELBOURNE, Australia — The use of pre-exposure prophylaxis (PrEP) during the periconceptual period does not affect a woman's ability to become pregnant, and it does not appear to adversely affect fetal outcomes, new research from the Partners PrEP Study shows.
However, on average, women in the study who were receiving PrEP were pregnant for only about 35 days, so the findings do not indicate what effect prophylaxis with antiretroviral therapy has if used throughout a pregnancy, said Jared Baeten, MD, PhD, professor of global health and medicine and adjunct associate professor of epidemiology at the University of Washington in Seattle.
"This is the very first information to assess the safety of PrEP when used in women who are becoming pregnant, and we found no effect on the frequency of pregnancies between women on PrEP and women on placebo," he told Medscape Medical News.
Results from the Partners PrEP pregnancy study were published online July 20 in JAMA to coincide with the 20th International AIDS Conference; first results were presented at the 2011 meeting.
When the Partners PrEP Study was launched in 2008, heterosexual HIV-serodiscordant couples were randomized to monotherapy with tenofovir disoproxil fumarate, combination therapy with emtricitabine plus tenofovir, or placebo.
None of the women were infected with HIV, but they received antiretroviral prophylaxis to prevent transmission from their partner.
Placebo Group Halted
In 2011, the data safety and monitoring board ordered trial investigators to terminate the placebo group because the therapies were shown to be effective in preventing HIV.
At the 2011 meeting of the International AIDS Society, Dr. Baeten reported efficacy results from the initial stages of the Partner PrEP Study, which were later published in the New England Journal of Medicine (2012;367:399-410).
In the pregnancy study, Dr. Baeten and colleagues followed 1785 HIV-serodiscordant couples to the end of 2012.
There were 431 pregnancies during the study — 288 before discontinuation of the placebo group and 143 after discontinuation. The pregnancy incidence rates in the PrEP groups were similar before and after the discontinuation of the placebo group.
Table. Pregnancy Outcomes
|Outcomes||Placebo Group||Monotherapy Group||Combination Group|
|Pregnancies per 100 person-years||10.0||11.9||8.8|
|Rate of pregnancy loss||32.2%||27.7%||42.5%|
|Pregnancies per 100 person-years||—||9.4||12.7|
|Rate of pregnancy loss||—||36.7%||37.5%|
|Pregnancies per 100 person-years||—||10.9||10.4|
|Rate of pregnancy loss||—||30.8%||40.0%|
The rate pregnancy loss of about one-third observed in the study population is considered a normal rate around the world, and simply reflects the fact that study participants were monitored every month using a highly sensitive urine test to detect early pregnancy, Dr. Baeten explained. "We detected very, very early pregnancy," he said. "We did this so that we could minimize the duration of time on PrEP if a woman became pregnant."
There were no significant adverse associations between the monotherapy and combination groups for birth outcomes, infant growth, or renal function.
However, the investigators note that for some outcomes, including pregnancy loss, preterm birth, congenital anomalies, and infant mortality, the 95% confidence intervals were wide. In fact, for pregnancy loss, the 95% confidence interval ranged from –5.3% (protective) to 25.7% (harmful).
Because of this, no definitive statement about the safety of PrEP in the periconceptual period can be made, the investigators conclude.
"But PrEP offers an additional option to decrease the risk of HIV transmission in women who might become or who want to get pregnant and who may have an HIV-positive partner," Dr. Baeten explained. Still, "unprotected sex should be limited to times when the female partner is most likely to be fertile."
Newer antiretroviral regimens are associated with a low risk for adverse events, and there is psychological benefit in knowing that the risk of transmitting HIV to a partner is reduced with PrEP, Bradley Mathers, MD, and David Cooper, MD, both from the University of New South Wales in Sydney, Australia, state in an accompanying editorial.
Nevertheless, they worry that there might be a "signal" suggesting potential harm because pregnancy loss did appear to be higher with the combination PrEP regimen.
"Tenofovir and emtricitabine are both category B drugs," they point out. Drugs are classified as such when animal reproduction studies have failed to demonstrate a risk to the fetus, but there are no good studies demonstrating a null effect in pregnant women.
They also caution that although women in this study were not exposed to the nucleosides for longer than 6 weeks into the pregnancy, in the real world, exposure to these drugs might be longer.
"The conservative clinician's choice in this difficult decision of a possible harm signal for pregnancy outcomes will be to target antiretrovirals to the HIV-infected partner, especially men in a heterosexual relationship, and to reserve PrEP for women who may have other unprotected exposures outside the primary relationship," they write.
However, "clinicians also have a responsibility to ensure patients are equipped to make informed decisions about how they manage risk and to choose the combination of prevention methods that suit their individual circumstances, values, and preferences," Drs. Mathers and Cooper note.
This study was funded by the Bill and Melinda Gates Foundation. Study medication was donated by Gilead Sciences. Dr. Baeten has disclosed no relevant financial relationships. Dr. Cooper reports receiving honoraria and grant support for clinical trials from Gilead Sciences.
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Cite this: Antiretrovirals Before Pregnancy Appear to Be Safe - Medscape - Aug 07, 2014.