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AMSTERDAM -- There was a significant increase in the prevalence of neural tube defects among women with HIV who took dolutegravir (Tivicay) at conception compared with other non-dolutegravir-based antiretroviral therapy (ART), including efavirenz (Sustiva), a researcher here said.

There were four instances of neural tube defects out of 426 infants, but the prevalence among this group (0.94%, 95% CI 0.37%-2.4%) was higher than among women on non-dolutegravir-based therapy at conception (0.12%, 95% CI 0.07%-0.21%), reported Rebecca Zash, MD, of Beth Israel Deaconess Medical Center in Boston.

Moreover, prevalence of birth defects was higher among women taking dolutegravir compared with efavirenz (0.05%, 95% CI 0.02%-0.15%).

Data from this interim unplanned late-breaking analysis was presented at a press conference at the , and covered in correspondence published simultaneously in the .

The study authors were asked to provide preliminary data for the for outcomes related to women who started dolutegravir prior to pregnancy, they said. Ultimately, this data sparked warnings from the FDA, the European Medicines Agency, and the WHO about dolutegravir and its link to birth defects.

Myron Cohen, MD, of the University of North Carolina at Chapel Hill, who was not affiliated with the research, emphasized the need for additional research on this topic.

"Given the importance of this agent for treatment of HIV, careful study of more women who have documented exposure to this agent at the time of conception is urgent," he told 木瓜直播. "Public policy has already pushed providers away from this drug for women of child bearing age. The real issue to prove or disprove this risk as quickly as possible."

Recently, the WHO released , including a programmatic algorithm indicating that women can continue to take dolutegravir as long as they have access to "consistent and reliable contraception."

"Many people interpreted this as the WHO and others saying women shouldn't be on dolutegravir, but the WHO recent guidelines update make it clear that ... this should not be a one-size-fits-all approach," Zash said. "The question is how do we make that a reality on the ground and get people the contraceptive access they need that can allow them to make an informed choice with data out there that's very preliminary."

Zash added that this study started in 2014 when dolutegravir "wasn't even being used in Botswana." She said that the study was originally designed to evaluate ART regimens for birth defects, and they were mainly interested in neural tube defects related to efavirenz (which was part of first-line ART therapy in Botswana at the time). In mid-2016, Botswana switched its first-line ART therapy from an efavirenz-based regimen to a dolutegravir-based regimen, "becoming the first country to do so for all adults and pregnant women," Zash said.

The Tspemo study took place at eight of the largest maternity wards in Botswana, comprising about 45% of total births in the country. Zash said that when an abnormality was noted in an infant, trained midwives contacted research assistants involved in the study who asked the mothers to consent to a photograph of the abnormality. This was then reviewed by medical experts in the U.S.

Researchers identified 86 neural tube defects in 88,755 births (0.10%, 95% CI 0.08%-0.12%), including 42 meningocele/myelomeningocele, 30 anencephaly and 13 encephalocele. Of these, 57% had photos and 43% had descriptions.

There were 14 neural tube defects out of 11,300 for non-dolutegravir-based therapy at conception and three of 5,787 for efavirenz-based ART at conception. For HIV-uninfected women, there were 61 neural tube defects out of 5,624 (0.05%, 95% CI 0.02%-0.16%).

Interestingly, there were no instances of birth defects for 2,812 women starting dolutegravir during pregnancy. Zash added that in data on 170 additional births collected since May 2018, there have been no instances of birth defects for women on dolutegravir at conception (updated prevalence 0.67%, 95% CI 0.26%-1.7%).

Weighing Risks and Benefits

An in NEJM by Sonja A. Rasmussen, MD, of the CDC, and colleagues cited the "complicated" decisions about treatment of HIV-infected pregnant women -- but because pregnant women are nearly always excluded from clinical trials, there is nearly always insufficient information about treatment decisions.

"Treatment decisions during pregnancy will continue to be a balancing act that should be informed by available data and expert input," the editorialists wrote. "However, shifting the default from exclusion of pregnant women to a careful consideration of benefits and risks can ensure that pregnant women and their fetuses receive the care they need."

Linda-Gail Bekker, MBChB, PhD, of the Desmond Tutu HIV Centre in Cape Town, South Africa and president, International AIDS Society, who moderated the press conference, but was not involved in the research, emphasized the importance of involving the patient in the discussion about treatment, including a discussion of different therapies.

"Hearing from women at these conferences, they want to be included in the decision-making. We're going to have to script that for healthcare workers on the front lines and I think that's rapidly being done at the moment," she told 木瓜直播.

Zash said that the next planned analysis of the data will be March 2019. She added that whether the safety signal is ultimately confirmed or refuted, this data has "highlighted the need for better access to contraception, better patient-centered care in areas of high HIV prevalence and better systems to study the safety of ART in pregnancy."