Drug therapy for pregnant women is always a balancing act between the benefits that can be achieved through maternal treatment and the harm possibly caused to the unborn child. Lynne Meryl Mofenson (Elizabeth Glaser Pediatric AIDS Foundation, Silver Spring, MD, USA), presented the most recent research on treatments for pregnant women with antiretroviral agents at CROI 2019 in Seattle, Washington, on March 6, 2019.
Of the 32 antiretroviral drugs (ARV) approved for adults, only Zidovudine (also known as azidothymidine or AZT) is specifically approved for use in pregnancy to prevent perinatal transmission. In most cases, the approval states that "use in pregnancy should only occur if the potential benefit outweighs the potential risk.'' Of the 32 ARVs approved, 26 experienced a significant delay between FDA approval and the availability of pregnancy data, an average of 6 years (1 - 12 years). For 5 substances, in particular, the newer drugs, there are no data available on their use during pregnancy.
The greatest risk of serious defects is not in women who start taking medication during pregnancy, but in women who become pregnant under therapy because the teratogenic risk is highest in the first weeks of pregnancy. However, most studies do not distinguish between preconception and first-trimester intake.
The molecular basis of a teratogenic effect by a drug is known only in very few cases. In most cases, teratogenic substances were only detected in clinical or epidemiological studies, such as thalidomide or valproic acid. Animal experiments are also not meaningful, because animals often react differently than humans. No negative effect could be seen with thalidomide in studies in rats and mice, while only in rabbits a teratogenic effect was detected. Therefore, the FDA today demands corresponding investigations in at least 2 animal species.
Although substances that are known today as teratogenic in humans also show teratogenic effects in mice, rats or rabbits, there is "no absolute certainty that negative results in studies of substances in these species definitely mean that no teratogenic effects occur in humans either," says Mofenson. "Accordingly, it cannot be said that a teratogenic agent in animals is necessarily teratogenic in humans in therapeutic doses."For example, efavirenz triggers CNS defects in monkeys, but not in humans.
In an observational study in Botswana, a quarter of over 47,000 pregnant women were exposed to HIV. Among HIV-infected mothers, premature birth, deficiency birth, stillbirth or neonatal death were more frequent than among non-HIV-infected mothers (39 vs. 29%). It is against this background that the impact of ART must be seen. The lowest rate (36%) of premature, deficient, stillbirth or neonatal death was in mothers who had taken a combination of tenofovir (TDF), emtricitabine (FTC) and efavirenz (EFV). For women treated with TDF-FTC and nevirapine (NVP), the rate was 42%, NVP, AZT, and lamivudine (3-TC) 47%, TDF-FTC, and lopinavir-ritonavir (TDF-FTC-LPV-R) 48% and the combination of ZDV-3TC-LPV-R 45%. Under ART, birth complications in HIV-positive women are therefore not comparable with those in HIV-negative mothers. However, EFV-based regimes appear to be more secure than NVP- or LPV-r-based combinations.
According to recent data from Botswana, the rate of birth complications does not differ between EFV and Dolutegravir(DTG)-based regimes. Once again it was confirmed that HIV-positive women already have more birth complications than HIV-negative mothers. "EFV- and DTG-based regimes thus appear to be equivalent in terms of birth complications," concludes Mofenson.
In a meta-analysis, the question was investigated whether the preterm birth rate differed if ART began before conception or only during pregnancy. The risk of preterm birth was significantly higher (RR 1.20) if the women had started ART before conception.
Since 1990, the Antiretroviral Pregnancy Register (APR) has collected prospective, voluntary and anonymous data on women and their children who have received ART during pregnancy. This should enable early warnings of teratogenic effects to be given and the risk of birth complications to be assessed in comparison with the general population. Currently, 151 antiretroviral substances (52 branded preparations and 89 generics) are included. But "A register is only as good as it is reported to," Mofenson emphasized. It is important that all caregivers of pregnant women with HIV take part.
The prevalence of birth defects, when exposed to ART in the first trimester, was 2.7% between 1 January 1989 and 31 July 2018, similar to the prevalence in the normal population.
The Botswana study in April 2018 found that 4 cases of neural tube defects had occurred in a group of 426 newborns whose mothers had dolutegravir-containing ART at the time of conception. This corresponds to an incidence of 0.9% compared to an expected background incidence of 0.1% in newborns whose mothers took other ARVs at the time of conception. Therefore, it is currently recommended in Germany, for example, to exclude pregnancy before treatment with DTG and to use an effective contraceptive method during therapy.
Other data have so far confirmed no further neural tube defects with pre-conceptional DTG use, although they all originated from countries with high incomes and folic acid supplementation as well as from a few patients.
Mofenson hopes that better data from the Botswana study will be available by mid-year, which can be combined with data from the Antiretroviral Pregnancy Register (APR). She also pointed out that the risk for neural tube defects is not zero even without taking medication and that the risk under DTG intake - should it be confirmed - is also relatively low. One could possibly expect an increase from 1:1000 in the general population to 7:1000.
Mofenson LM. Update on antiretroviral drugs and birth defects. CROI 2019, Seattle, Washington, March 5, 209, Abstract 59. http://www.croiconference.org/sessions/update-antiretroviral-drugs-and-birth-defects