MEXICO CITY — Children born to women on HIV therapy that contained dolutegravir (Tivicay, Dovato) at conception had a small risk of neural tube defects versus children born to women on other antiretroviral (ART) regimens, a researcher reported here.
In the Tsepamo study, in 1,683 deliveries among women taking dolutegravir, five neural-tube defects were diagnosed (0.30% of deliveries) compared with 15 neural-tube defects among 14,792 deliveries in which the mother was treated for HIV-infection with any non-dolutegravir ART (0.10%), stated Rebecca Zash, MD, of the Beth Israel Deaconess Medical Center/Harvard Medical School in Boston, at the International AIDS Society (IAS) Conference on HIV Science.
“The prevalence of neural-tube defects was higher in association with dolutegravir treatment at conception than with non-dolutegravir ART at conception … or with other types of ART exposure” for a difference of 0.20 percentage points (95% CI 0.01-0.59), Zash and colleagues reported simultaneously in the New England Journal of Medicine.
At an IAS press conference, Zash said the difference translated to three babies per 1,000 deliveries with neural-tube defects for mothers taking dolutegravir versus one baby per 1,000 deliveries with neural tube defects among mothers taking other, non-dolutegravir ART.
The authors also reported that major structural anomalies were observed in 0.95% of babies born to women on dolutegravir versus 0.68% of women who were on non-dolutegravir ART, which was not statistically significant (0.27 percentage point difference, 95% CI -0.13 to 0.87).
Zash said the study was triggered by reports in 2018 that the risk of neural tube defects in Botswana were as high as 0.94% — one in 100 — which was concerning as dolutegravir-based therapy was on the verge of being rolled out across sub-Saharan Africa and elsewhere. She added that the results show that the risk is not as great as once was feared.
IAS press conference moderator Anton Pozniak, MD, PhD, noted that “the signal we saw for dolutegravir and neural tube defects is not as great as we saw earlier. There is still a small risk but the benefits of dolutegravir for the health of the mother may outweigh the risk to the child.”
“The original signal was concerning enough to put on hold the rolling out of dolutegravir-based therapy, but these new studies indicate that it may be safe to proceed with dolutegravir administration,” Pozniak, IAS president and international scientific chair, told MedPage Today.
The study was conducted in Botswana, the first African nation to switch from ART with efavirenz (Sustiva) to dolutegravir, which has become the treatment of choice because it has a higher barrier to resistance, fewer adverse side effects, and more effective virus suppression.
In 2018, Zash’s group reported that among 426 infants born to HIV-positive women who had been taking dolutegravir-based ART from the time of conception, four (0.94%) had a neural tube defect. In comparison, neural tube defects occurred in 14 (0.12%) of 11,300 infants born to women who had been exposed to any non-dolutegravir ART from the time of conception, zero of 2,812 infants born to women who had been exposed to dolutegravir treatment that was started in pregnancy, and 61 (0.09%) of 66,057 infants born to HIV-uninfected women.
The data prompted the Botswana Ministry of Health and Wellness to expand surveillance for neural-tube defects in selected non-Tsepamo [study] health facilities and issue government warnings regarding use of dolutegravir in pregnancy, explained Vasavi Thomas, PharmD, MPH, of the CDC in Atlanta, and colleagues in a New England Journal of Medicine correspondence appearing in the same issue as the study by Zash and colleagues.
The data also prompted Zash’s group and colleagues to expanded their study to include other hospitals and clinics in Botswana to get a larger picture of the risk of neural tube defects in the babies of women with HIV-infection on dolutegravir. The expansion covered more than 70% of births in the country, instead of 45% that were included in the first reports of neural tube defects.
The current study was conducted from August 2014 through March 2019, and surveillance captured 119,477 deliveries of which 99.6% had an infant surface examination that could be evaluated; 98 neural-tube defects were identified (0.08% of deliveries).
The authors noted that from May 2018, when the signal regarding neural-tube defects was first reported, until March 2019, one additional neural-tube defect was identified in a delivery in which the mother was taking dolutegravir-based ART at conception (1/1,257, 0.08%) versus one neural-tube defect in all other groups with any ART exposure at conception (1/3,492, 0.03%), none in the group with efavirenz exposure at conception (0/2,172), one in the group with dolutegravir treatment started during pregnancy (1/1,028, 0.10%), and nine in the group of HIV-uninfected women (9/23,315, 0.04%).
There were a total of 16 major external structural malformations, including presumed holoprosencephaly, omphalocele, gastroschisis, club foot, and upper-limb defects. While the prevalence of major external structural malformations did not differ substantially in other exposure groups, “More surveillance is required to interpret these findings,” the authors stated.
“Although much lower than we reported [in 2018], neural tube defects in babies exposed to dolutegravir at the time of conception is still significantly higher than the other comparison groups, but the absolute difference is still very small,” Zash said. “While there may be a risk, this risk is small when weighed against the large potential benefits of dolutegravir.”
Study limitations included its observational nature and the fact that differences in preconception folate levels or genetic predisposition could have results in unmeasured confounding. “Folate deficiency is a well-known risk factor for neural-tube defects,” Zash’s group said.
Zash added that there is a lack of studies that evaluated other HIV drugs in regard to neural tube defects, and that more pregnancy safety data is needed, especially in economically disadvantaged countries.
Stay on Dolutegravir
In a second IAS report, Fernanda Fernandes Fonseca, MD, a technical advisor in the area of sexually transmitted diseases for the Ministry of Health of Brazil in Brazilia, reported that her country conducted an investigation of dolutegravir and raltegravir (Isentress) and their possible ties to neural tube defects. Fonseca’s group followed 1,468 pregnant women with HIV in the 6 months after the 2018 report from Zash and colleagues.
Fonseca and colleagues found that 382 women were exposed to dolutegravir and 1,086 women to efavirenz or raltegravir. Women taking dolutegravir ART had a more recent HIV diagnosis, had lower CD4 cell counts, and were less likely to have viral suppression, the authors reported.
However, they found cases of neural tube defects among the women on dolutegravir, and no neural tube defects among babies delivered by women who were being treated with the other ART.
“When we first heard of the possible problem, we told all women on dolutegravir to change their treatment,” Fonseca told MedPage Today. “We think that some women may have been harmed by having to switch to another agent. We are now studying if we did cause harm with this change. We now think dolutegravir can be used with very small risk.”
Thomas and colleagues agreed that “the magnitude of the risk of neural-tube defects associated with dolutegravir exposure at the time of conception remains less than 1%, which is consistent with findings from the Tsepamo study and important in individual decision making regarding ART options.”
They conducted the surveillance study in selected non-Tsepamo health facilities and reported three confirmed or probable neural-tube defects, with one neural-tube defect seen among 152 deliveries in which the mother had been taking dolutegravir at conception (prevalence 0.66%, 95% CI 0.02-3.69).
The study was funded by the NIH. Zash and a co-author disclosed support from the NIH and the Eunice Kennedy Shriver National Institute of Child Health and Human Development.
The study by Thomas’ group was supported by the U.S. President’s Emergency Plan for AIDS Relief (PEPFAR) through the CDC.