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Professor of HIV
Queen Mary, University of London
Lead for HIV Research
Barts Health NHS Trust
The Royal London Hospital
London, United Kingdom
Chloe Orkin, MBChB, FRCP, MD, has disclosed that she has received funds for research support, consulting fees, and fees for non-CME/CE services from Gilead Sciences, GlaxoSmithKline, Janssen, MSD, and ViiV Healthcare.
As is well known, pregnant people are systematically excluded from clinical trials of novel HIV therapies due to the potential risk to the fetus. Although this is most definitely a significant concern, this exclusion results in substantial delays before data become available concerning the use of a new agent in pregnant or breastfeeding people. Indeed, it takes an average of 6 years after approval of a new ART agent before the first data in pregnant people becomes available, and an average of 8 years for data in breastfeeding people. Moreover, the initial data are on pharmacokinetics, rather than on safety and efficacy.
Consequently, when these drugs are prescribed to people who conceive, we typically know almost nothing about the risks to the fetus or to them. In pregnancy, a variety of physiologic changes can alter the pharmacokinetics and pharmacodynamics of some drugs, most commonly increasing drug clearance and decreasing exposure—so the drugs may work less well. Without data on these effects, pregnant people are at risk of harmful interventions, inadequate treatment, and/or failed prevention of maternal disease. In turn, these data deficiencies raise important ethical concerns for healthcare providers committed to providing the best possible care for our patients, by providing equitable protection from drug-related risks, equitable access to effective medications, and equitable respect for pregnant women’s own health, not just for fetal and child outcomes.
Update on Neural Tube Defects (NTDs) With ARV Exposure in the Tsepamo Study, Botswana
One of the most eagerly anticipated presentations at AIDS 2020 was the latest analysis of the Tsepamo cohort that captured another year of data for the cohort of women enrolled into this very large ongoing surveillance programme in Botswana.
In May 2018, the Tsepamo study unexpectedly identified an association between dolutegravir (DTG) use at conception and NTDs. The prevalence of NTDs in neonates exposed to DTG at conception was significantly higher than that seen with exposure to efavirenz (EFV) (0.9% vs 0.1%, respectively). A subsequent update from Tsepamo, using an expanded dataset collected through March 2019, was presented at IAS 2019 and showed a lower prevalence of NTDs associated with DTG exposure at conception (0.3% vs 0.1% with EFV), but the 0.2% (95% CI: 0.01-0.59) difference remained statistically significant.
At AIDS 2020, Rebecca Zash, MD, reported that an additional 39,200 births were recorded between March 2019 and April 2020, bringing the total to 158,244 deliveries. Out of 28 new NTDs, 2 were associated with exposure to DTG at conception and 1 was associated with exposure to DTG in pregnancy. Among women receiving DTG at conception, the prevalence of NTDs has decreased to 0.19% (7 NTDs out of 3591 deliveries). The prevalence of NTDs among women receiving other ART at conception was 0.1%, and the 0.09% (95% CI: -0.03% to 0.30%) difference is no longer statistically significant.
Virologic Suppression and Mother-to-Child Transmission Rates With DTG vs EFV in Pregnancy
Given the paucity of data on efficacy and safety of DTG use in pregnancy, Sumbul Fatima Asif, MD, presented the results of a meta-analysis of 5 recent randomised controlled trials studying pregnant women, comparing the safety and efficacy of DTG vs EFV. A total of 1074 pregnant women took part in the DolPHIN-1 and DolPHIN-2, IMPAACT 2010, ADVANCE, and NAMSAL studies. NAMSAL and ADVANCE enrolled women at conception, whereas IMPAACT 2010 and the DolPHIN studies enrolled women beyond the second trimester.
Although the safety profiles were similar, more women receiving DTG experienced viral suppression. However, there was no statistically significant difference in the rates of mother-to-child HIV transmission with DTG-based vs EFV-based ART (1% vs 0%, respectively; P = .17). All 5 cases of mother-to-child HIV transmission were in the DTG arms of the studies (2 cases in IMPAACT 2010 and 3 cases in DolPHIN-2).
These 2 presentations add important new details to our understanding of the safety and efficacy of DTG use at conception and in pregnancy, 7 years after it was first approved by the FDA. Its safety and its efficacy in preventing mother-to-child HIV transmission both appear to be comparable to the safety and efficacy of other widely used ART regimens, especially EFV-based therapy. In Tsepamo, exposure to DTG around conception in this cohort of women who did not receive folate supplementation was associated with a slight but nonsignificant increased risk of NTDs compared with other ARVs.
In the words of Rebecca Zash, with whom I entirely agree: “Women are not a niche population; to maintain gender equity requires pregnancy safety data. If we don’t include women in trials, we are not protecting women.”
What are your thoughts about enrolling pregnant women or women wishing to conceive on clinical trials of novel ART agents? Have you read the latest guidance document from the Pregnancy and HIV/AIDS: Seeking Equitable Study (PHASES) Project? Join the discussion by posting a comment and share your experiences of treating women who wish to conceive.