AMSTERDAM — The rate of neural tube defects in infants was seven times higher than expected when women with HIV were taking dolutegravir (Tivicay, GlaxoSmithKline) at the time of conception, according to the Tsepamo surveillance study.
But these numbers do not tell the whole story, said Rebecca Zash, MD, from the Beth Israel Deaconess Medical Center in Boston.
This finding comes from the Tsepamo study of 89,064 infants born in Botswana from August 2014 to May 2018. However, since that cutoff date, 170 babies have been born to women taking the drug during conception and none have such defects, Zash reported.
It is a hopeful sign, but it’s too soon to know whether the earlier signal was incorrect, she explained.
It is also too early to stop using the drug in all women of childbearing age. Instead, it is the job of the physician to “really bring it back to what the woman cares about,” she pointed out.
An unplanned analysis of preliminary data prompted the US Food and Drug Administration (FDA) and the Pharmacovigilance Risk Assessment Committee of the European Medicines Agency to issue safety alerts about the risk for neural tube defects with dolutegravir (Lancet. 2018;391:2296), as reported by Medscape Medical News.
Doctors must empower each woman to make her own decision after understanding how she feels about getting pregnant, her relationship status, and her birth control method, said Zash.
“People will see all these things very differently,” she told the audience here at the International AIDS Conference 2018, which spilled out into the hall where physicians and researchers sat cross-legged on the floor and watched the speakers on a television. “Beyond the data, that’s the crux.”
Capturing Birth Defects
The Tsepamo study was not initially designed to look at dolutegravir at all. Instead, it was meant to look at whether efavirenz (Sustiva, Bristol-Myers Squibb) — the first-line antiretroviral used in Botswana in 2014 — was associated with neural tube defects.
But when dolutegravir became the first-line treatment in Botswana in 2016, Zash and her colleagues added it to the study.
What they found surprised them.
“The rate of neural tube defects was one in 100 when we expected it to be one in 1000,” Zash reported.
Efavirenz use at the time of conception was also associated with a slightly elevated risk for the defect, as were antiretroviral regimens other than dolutegravir.
|Table. Neural Tube Defects in Infants Born in Botswana From August 2016 to May 2018|
|Type of Treatment||Births, n||Neural Tube Defects, n||Rate, %|
|At time of conception|
|None (HIV-negative women)||66,057||61||0.09%|
|Any other antiretroviral regimen||11,300||14||0.05%|
The fact that there were no cases of neural tube defects in babies born to women who started dolutegravir after conception suggests that it is “just as safe to start women on dolutegravir during pregnancy as it is to start women on efavirenz during pregnancy,” said Zash.
Since May 2018, none of the 170 babies born to women taking dolutegravir at the time of conception have neural tube defects, she reported. But even with these additional numbers, rates of the defects are still seven times higher with dolutegravir than with other regimens.
The study is ongoing and researchers expect to have data on another 1200 conceptions in women taking the drug by March 2019.
These details and the promise of a larger cohort to draw conclusions from drew praise from Wafaa El-Sadr, MD, from ICAP at Columbia University in New York City.
“The reason we’re all here is because there is concern,” she told Medscape Medical News. “I do think the signal is alarming, but I think we have to wait and see if this is a fluke, sort of just something random, or whether it is real. I was encouraged to hear that by March there will be enough births for these women who were exposed to dolutegravir to tell us one way or another.”
Public Policy, Personal Choice
Immediately after the safety alerts were issued, the FDA and other national health organizations changed their guidelines to recommend against the use of dolutegravir by women who might become pregnant.
Then, earlier this week, the World Health Organization (WHO) released an official update to their guidelines.
|Updates to the WHO Guidelines|
|Dolutegravir is safe to take after 8 weeks of pregnancy, when the risk for neural tube defects has passed.|
|Dolutegravir can be prescribed to women and adolescent girls of childbearing age if they are using “consistent contraception.”|
|Efavirenz can be used by women of childbearing age until the risk for neural tube defects has passed.|
|When developing national programs, countries should balance benefits and risks to the woman and her child, access to contraception, and other antiretroviral options available.|
Responses to the WHO update have been varied. The FDA, for instance, recommends a pregnancy test before a woman starts on dolutegravir and contraception use while taking dolutegravir. Other countries amended their guidelines to switch all women who might get pregnant to other formulations, according to a report published last week (Lancet. 2018;392:199).
These recommendations sparked protest at the conference, with African women decrying these sudden policy shifts as paternalistic. Women marched through the conference center, dancing, singing, and holding signs that read: “WHO, we want dolutegravir Now!,” “dolutegravir 4 All Women,” and “Trust HIV+ Women.”
Martha Akello, who has lived with HIV for close to a decade, has three children and doesn’t plan to have more. “Why should I be kept from taking dolutegravir?” she said to Medscape Medical News.
In parts of Africa, women are forcibly sterilized after testing positive for HIV, she told the audience. The requirement that women must be using some form of long-term birth control to take dolutegravir — which has a better safety profile and fewer adverse effects — smacks of old approaches that try to control women living with HIV “just because they want a better life.”
According to a modeling study presented during the same session, 25,000 South African women will die from AIDS-related complications over a 5-year period if they are required to take efavirenz instead of dolutegravir. However, if the early Botswana data are confirmed by additional data and women continue to take dolutegravir, 8000 children will likely die as a result of neural tube defects.
It’s an uncomfortable calculus, but one that the dolutegravir signal requires us to face, said Maggie Little, PhD, from Georgetown University in Washington, DC.
“The numbers alone will never tell us the answer,” she said. “It’s not like arithmetic is our moral guide here.”
Women make sacrifices for their children all the time, she pointed out. But there’s “a difference between a sacrifice a policy may impose on you and a sacrifice a woman may decide to make. Giving women access to dolutegravir only when they have agreed to long-term hormonal contraception is not robust choice.”
Just because women can become pregnant, they “should not be seen merely as reproductive vessels,” Little told the audience, to loud applause.
Akello says she agrees, adding that women want all the information and then a real ability to choose.
“What are the benefits, what are the risks, and then leave the choice to us,” she said. “Don’t pit us against our children, our unborn children, because many of us find them to be our motivation to live.”
The National Institutes of Health funds the Botswana surveillance project. Zash, El-Sadr, and Little have disclosed no relevant financial relationships.
International AIDS Conference 2018: Abstract TUSY15. Presented July 24, 2018.
By Heather Boerner