'Time to Lay to Rest' Fears About Dolutegravir Birth Defects

Mitchel L. Zoler, PhD

July 08, 2020

The longer researchers have looked for evidence of neural tube defects linked with dolutegravir treatment of HIV at the time of conception the fewer incident cases they've found.

The newest data, based on 3,591 deliveries among women in Botswana infected by HIV and treated with dolutegravir at the time of conception during a little more than 5.5 years through April 2020, showed that dolutegravir use at conception linked with 7 cases of neonatal neural tube defects (NTDs), a 0.19% rate that exceeded comparator rates by about 1 in every 1,000 deliveries, far below the 0.94% rate initially found and that raised a red flag 2 years ago (New Engl J Med. 2018 Sep 6;379[10]:979-81). "The prevalence of NTDs among infants born to women on dolutegravir at conception may be stabilizing at approximately 2 per 1,000," said Rebecca Zash, MD, during the virtual meeting of the International AIDS conference.

"This small absolute risk for neural tube defects is far outweighed by the potential benefits from dolutegravir" for better tolerability than alternative drugs and fewer drug–drug interactions. "This should allow for broader use of dolutegravir in women," added Dr. Zash, an HIV specialist at Beth Israel Deaconess Medical Center and codirector of the Placental Scientific Working Group of the Harvard University Center for AIDS Research, both in Boston.

"What this has taught us is that women are not a niche population" of people infected with HIV, but rather constitute about half of HIV patients worldwide. "Maintaining gender equity in HIV treatment requires safety data for treatments during pregnancy," she said during a press briefing.

The new findings mean that it's "time to lay to rest" concerns about neural tube defects in infants born to women treated with dolutegravir, "given the incredible benefits of dolutegravir," commented Monica Gandhi, MD, professor of medicine and associate chief of the division of HIV, infectious disease, and global medicine at the University of California, San Francisco. Another benefit from removing any caveats about use of dolutegravir in women who could become pregnant is that it would simplify treatment recommendations and make dolutegravir the unqualified first-line agent for treating HIV infection, Dr. Gandhi said during the briefing. "It's super reassuring to have these data, as the incidence of NTDs goes down and down," she added.

Following the alarm raised by initial findings from the Tsepamo study in 2018, Dr. Zash and associates first updated their data through March 2019, when they reported a revised cumulative NTD incidence rate of 0.3% (New Engl J Med. 2019 Aug 29;381[9]:827-40). The Tsepamo study began by following the pregnancy outcomes of women at eight Botswana sites during August 2014–July 2018, representing 45% of the country's deliveries. This expanded to 18 sites and 72% of deliveries during July-–September 2018, and then starting in September 2019 the scope slightly reduced to 16 Botswana sites with 70% of the nation's deliveries.

Folate supplementation to women who might conceive is vital, but remains spotty in Botswana. "Folate supplementation is a no-brainer, but has had really slow adoption in many countries," Dr. Zash said. "Folate supplementation, especially in food so that everyone gets it, will reduce NTDs by half." The two most recent cases of infants born with a NTD to mothers who had been on dolutegravir at conception occurred in mothers who had received no folate supplementation, Dr. Zash reported.

The most recent HIV treatment guidelines for adults from the Department of Health & Human Services, which date from late 2019, designated dolutegravir plus lamivudine as a first-line regimen for most, but flagged it as an "alternative" antiretroviral drug when treating women who have childbearing potential and are either trying to conceive or are sexually active but not using contraception.

The study had no commercial funding. Dr. Zash has been a researcher in studies funded by CytoDyn, Fulcrum, and Gilead . Dr. Gandhi had no commercial disclosures.

This article originally appeared on MDEdge.com.

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