Continued surveillance needed to improve ART safety for pregnant women

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Despite prospective cohort trials not producing evidence of an increased risk of neural tube defects (NTDs) with dolutegravir (DTG), elvitegravir and raltegravir, or bictegravir, continued surveillance studies with DTG and other contemporary antiretroviral therapies, including provider reporting of pregnancy outcomes, are needed to further evaluate the safety of ART during pregnancy.

The reduction in morbidity and mortality with combination antiretroviral therapy (cART) in the past two decades has positively changed the outlook for pregnancy and extended life expectancy in mothers with HIV. According to E Kelly Hester, associate clinical professor in the department of pharmacy practice at Auburn University Harrison School of Pharmacy and Celeste Caulder, associate clinical professor in the department of clinical pharmacy and outcomes sciences at the University of South Carolina College of Pharmacy, women being treated effectively with cART during pregnancy has reduced vertical transmission to 1% or less in the US and Europe and close to zero when virologically suppressed prior to conception and throughout the pregnancy. Women with HIV have the same reproductive desires as women without HIV infection. Therefore, in order to lower the risk of unplanned pregnancies and mother-to-child-transmission (MTCT), it is important to routinely discuss reproductive plans with women of childbearing potential.

Among women with HIV who are pregnant or planning to conceive, important considerations include the therapeutic efficacy of the individual antiretrovirals (ARVs) in pregnancy, teratogenicity, and potential for poor tolerability. Information that patients can use to make decisions about the safe use of medications in pregnancy is based on results from preliminary animal studies, pregnancy registries, clinical trials, and reported experience. The Antiretroviral Pregnancy Registry (APR) represents a prospective, observational study of pregnancy outcomes related to ARV exposure in utero. Pregnancy cases are evaluated with the intention of identifying teratogenicity signals with exposure. In order to ascertain the risk of birth defects with a given ARV medication, the APR requires use of the individual therapy in at least 200 pregnancies. Studies have generally found similar rates of birth defects from ARV exposure during the first and later trimesters, indicating that early ARV use is not associated with an increased risk of birth defects.

In a prospective cohort study in Quebec, Canada, pregnant women with HIV who received care between 1998 and 2015 and were exposed to antiretroviral therapy (ART) during their first trimester did not have an increased risk of major congenital malformations compared with women who were untreated. The results of a US prospective cohort study from 2007 to 2012 evaluating outcomes in first trimester ARV exposure of children noted no association between congenital anomalies and specific ARV medications, drug classes, or combination therapies.

Many studies that evaluate the association between birth defects and ARV exposure do not evaluate the use of folate during the first trimester. The risk of neural tube defects (NTDs) is reduced with maternal folic acid supplementation of at least 400 mcg/d during periconception. Therefore, it is recommended that women contemplating pregnancy begin folate supplementation, as the greatest fetal risk is during the first 28 days post conception.

Dolutegravir (DTG) was approved in 2013. The results of animal studies in clinical development indicated no teratogenicity in pregnancy. However, in May 2018, the World Health Organisation (WHO) released a statement highlighting a potential safety signal with DTG noted in a preliminary unplanned analysis of an ongoing observational pregnancy surveillance study in Botswana. The study aim was to compare the prevalence of NTDs in children following exposure to DTG with other ARV regimens at conception.

Of 426 women taking DTG at conception, there were 4 cases of NTDs. This birth defect rate (0.94%) was much higher than that observed with exposure to other ARVs (14 of 11,300 exposures; 0.12%) at conception when evaluating data from 88,755 births.13,14 There were no cases of NTDs in women who started DTG during pregnancy (n = 2812). Data on pregnancy outcomes through March 2019 have recently been further analysed. Updated data now indicate 5 cases (5/1683; 0.30%) of NTDs among children exposed to DTG from conception and 1 NTD case (1/3,840; 0.03%) when DTG was started in pregnancy. Comparatively, 15 NTD cases (15/14,792; 0.10%) were observed in children born to women receiving non-DTG regimens during conception, 3 cases (3/7959; 0.04%) with exposure to efavirenz from conception, and 70 cases (70/89,372; 0.08%) in pregnancies of HIV-uninfected women (no ART).

Further evaluation of the 4 NTD cases with DTG expo¬sure in the original analysis revealed the women were not taking folate supplementation at conception and their past medical history did not include risk factors for NTDs, such as diabetes or epilepsy. When the safety of DTG-based regimens (n = 1729) and efavirenz-based regimens (n = 4593) started during pregnancy were compared in the Botswana surveillance study between 2016 and 2017, the prevalence rates of adverse pregnancy outcomes (preterm birth, stillbirth, and small for gestational age) were similar between groups (33.2% and 35.0%, respectively). In this study period, 32% of women began DTG-based regimens after conception.

Recently, other prospective cohort studies have evaluated the safety of DTG and other integrase strand transfer inhibitors (INSTIs) early in pregnancy in real-world settings (Table 2). In these studies, the majority of the women were taking INSTIs before their first trimester. Neonatal outcomes following prenatal and first-trimester exposure to DTG were analysed in 2 large prospective pregnancy registries: Antiretroviral Pregnancy Registry and the European Pregnancy and Pediatric Cohort Collaboration.17 No cases of NTDs were observed in over 300 pregnancies.

Data from other cohort studies in the US, Canada, Sweden, and France reported similar results following preconception and first trimester use of DTG. In a Canadian Perinatal HIV Surveillance Program representing 23 Canadian HIV centers, there were 3 cases of NTDs in women taking ART other than DTG, which was a similar rate (0.13%) to the Botswana data.

Surveillance studies of congenital anomalies associated with the use of elvitegravir (EVG) and raltegravir (RAL) early in pregnancy were also analysed to determine if there were safety signals within the INSTI class. The greatest use during conception was with RAL, but no reports of NTDs were identified in over 800 cases. Cases reviewed for RAL use from the Merck safety database resulted in no cases of NTD with prospective data, as well; however, there were 3 cases (1 of which was during periconception) from among retrospective data. Gilead reviewed its Global Safety Database for EVG and bictegravir (BIC)-containing regimens for pregnancy outcomes. There were no reports of NTDs from prospective data from 155 reported pregnancies using EVG and 18 pregnancies using BIC, including preconception and first trimester use.

Following the release of the original Botswana surveillance data in 2018, HIV guidelines were updated regarding the use of DTG in women of childbearing potential and pregnancy. However, recently the WHO released updated recommendations for the preferential use of DTG in all populations, including pregnancy and women of childbearing potential, based on the body of evidence to date. In light of the updated Botswana information, other HIV guidelines may soon revise their guidance, but at this time the following are recommended prior to use of DTG in women of childbearing potential: a pregnancy test, determination of their desire to become pregnant, and a discussion of the risks and benefits of conceiving on DTG therapy. DTG should be avoided in patients during the first trimester of pregnancy and in women who are of childbearing potential who desire to become pregnant or who are not consistently using effective contraception. In susceptible patients, RAL is the INSTI with the most early-pregnancy data and could be used. DTG appears safe after the first trimester and may be used at that time.

In reality, prevention of MTCT in women who are highly treatment-experienced with multiclass ARV resistance (such as women vertically infected) may require use of INSTIs, such as DTG and BIC. Currently, in light of the limited safety data with BIC in pregnancy and its structural similarity to DTG, the same concerns exist and treatment is not recommended.

The NTDs observed in the Botswana study may represent folate deficiency, but ongoing surveillance is necessary to determine the association. Other prospective cohort trials have not produced evidence of an increased risk of NTDs with DTG, EVG, RAL, or BIC. Analysis of these cohort studies revealed no NTDs or clustering of congenital malformations associated with the use of DTG or other INSTIs in early pregnancy. Continued surveillance studies with DTG and other contemporary antiretroviral therapies, including provider reporting of pregnancy outcomes to the APR, are needed to further evaluate the safety of ART during pregnancy.

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