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Finally, we move on to 2 studies that looked at pregnancy outcomes following ART. Remember that it is critical to monitor birth defects among infants born to women with exposure to ARV agents during pregnancy to prospectively assess the safety of these agents.
Before continuing, please take a moment to answer the following question.
Preliminary data in May 2018 from the Tsepamo trial in Botswana showed an elevated risk of neural tube defects of approximately 1% of patients among 426 women receiving DTG at periconception and during their first trimester during the DTG rollout in sub-Saharan Africa.28 This prompted an FDA alert calling for closer monitoring for birth abnormalities among pregnant women receiving DTG and women receiving DTG who might become pregnant.29
The objective for the APR study was to assess pregnancy and neonatal outcomes from pregnancies reported to this database involving infants exposed to DTG.30,31 The APR contains data on 21,861 pregnancies involving ARV exposure and is current to January 2021, so it is fairly contemporary and up to date. The study included infants with exposure to DTG at conception or in utero (N = 1010), and the data were reported as the earliest DTG use, whether at periconception (exposure from 2 weeks before conception through no more than 28 days after conception by an estimated 6-week gestational age), later in the first trimester (after 6-week estimated gestational age), or second or third trimester (exposure beginning after the first trimester ended, or greater than 12-week estimated gestational age).
The prevalence of birth defects in any trimester with prenatal DTG was consistent with the prevalence in the general population, reported by the Metropolitan Atlantic Congenital Defects Program as 2.72 (95% CI: 2.68-2.76) and by the Texas Birth Defect Registry as 4.17 (95% CI: 4.15-4.19).30 These prevalence rates are also comparable to the prevalence of birth defects with any prenatal ARV exposure reporting to the APR (2.85; 95% CI: 2.63-3.09).
These very encouraging data contributed to the decision to revise the DHHS guideline recommendations for use of DTG in HIV in June 2021.32 Updated data from the Tsepamo study, presented at AIDS 2020, showed a decreased prevalence of neural tube defects among infants born to women receiving DTG at conception, with a rate of 0.19% (95% CI: 0.09-0.40).33 With these cumulative data, the Panel on Treatment of Pregnant Women With HIV Infection and Prevention of Perinatal Transmission now recommends DTG as a preferred ARV drug throughout pregnancy and also recommends DTG as the preferred ARV drug for women who are trying to conceive.32 This decision was based on the updated data showing a decrease in neural tube defects, and this rate is regarded as very small.
Combined with the advantages of DTG—once-daily dosing, high tolerability, and rapid, durable virologic suppression—this update of the safety data and guideline recommendations represents an important moment for maternal health and prevention of perinatal HIV transmission. I was at the International AIDS Conference in 2018, in Amsterdam, and there was a lot of activism among stakeholders, particularly for women in sub-Saharan Africa, saying “do not take away our DTG, it is an important agent.” And so here in the United States, the DHHS now supports DTG for women planning for conception or during pregnancy.
Next, we will discuss the newer integrase inhibitor, CAB. There are limited data on the safety of CAB and RPV in pregnancy. This report assessed pregnancy outcomes and pharmacokinetic tail data among women with HIV who became pregnant after receiving at least 1 dose of CAB plus RPV, either oral or long-acting, during participation in the phase II and III trials.34 Upon confirmation of a pregnancy, CAB plus RPV was discontinued and the participant switched to an alternative regimen, with long-term follow-up for 52 weeks post last injection for safety and quarterly pharmacokinetic evaluation.
As of March 31, 2021, 26 pregnancies had occurred, followed by 11 live births—10 in the long-acting arm and 1 in the oral regimen arm—8 elective abortions, 7 spontaneous abortions, and no stillbirths.34 All women with subsequent live births remained virologically suppressed from conception through pregnancy and postpartum or the last available HIV-1 RNA assessment following switching to alternative ART.
Among those women discontinuing CAB plus RPV due to pregnancy, their plasma concentrations of CAB and RPV during pregnancy were within the range observed in nonpregnant women.34,35
Following the switch to alternative ARVs, concentrations of CAB and/or RPV in the pharmacokinetic tail may have been affected in 3 participants, due to inhibition from switching to DRV (participant #3), metabolic induction from EFV (participant #5), and by receiving oral RPV after switching from long-acting RPV (participant #10).34,35
We anticipate more data on the safety of these long-acting agents as we look again at pregnancies longitudinally in these trials. As I mentioned earlier, as pregnancy data from the PrEP monotherapy studies emerges, including HPTN 084 with women, we will get more information on the safety of CAB in pregnancy.
So far, in the very limited numbers coming out of the phase II and III licensing trials for use of these long-acting agents in ART, CAB appears to be safe.