Jury Still Out on Neural Tube Defects From Dolutegravir

Heather Boerner

November 06, 2018

GLASGOW — Ever since four infants with neural tube defects were born to women in Botswana who were using dolutegravir at conception, researchers and surveillance experts have been scrambling to see if their cohorts confirm or disprove the signal.

Now, at HIV Drug Therapy 2018, four posters add to data from the Tsepamo surveillance cohort in Botswana, previously reported by Medscape Medical News, but it is still too soon to confirm or disprove the signal, investigators say.

Researchers presented data from a Canadian cohort and from small groups of women taking dolutegravir (Tivicay, GlaxoSmithKline) early in their pregnancies in Frankfurt and in Eastern and Central European countries. And Gilead Sciences presented global data from their databases on bictegravir and elvitegravir.

So far, "we do not see an association," said Deborah Money, MD, from the University of British Columbia in Vancouver, Canada, who presented data from the Canadian Perinatal HIV Surveillance Program.

But that doesn't mean the signal isn't real. The only way we'll know that is with more data, she explained.

"Our numbers aren't huge," said Money, noting that only 2423 women were using antiretrovirals during their first trimester in the province. "But we wanted to put these data out there."

"We've submitted the study for publication so people can start doing a combined analysis of all the cohorts" around the world, not just one from Africa, she reported.

Scanning for Signals

The Canadian Perinatal HIV Surveillance Program started decades ago as a means to track mother-to-child transmission. Now it is a clearing house for data on women, the medications they use to control their HIV, adverse effects, and birth outcomes.

When the Tsepamo signal emerged, the first thing researchers did was to start searching their data, not just for neural tube defects in women taking dolutegravir during conception, but for all women taking any antiretroviral in the first trimester.

"We were a little frightened that we would find things that we hadn't realized. It was possible they were happening in different cities or different clinics and maybe we hadn't put all the stories together," Money said. "We were relieved that we didn't see anything."

Of the 2423 women taking antiretrovirals during their first trimester, 75 were taking dolutegravir. That subset of women gave birth to four infants with nonchromosomal anomalies — two in the urinary system, one in the circulatory system, and one in the musculoskeletal system — but none involved the neural tubes.

Although there were more anomalies in children born to women taking integrase inhibitors — 10 of 169, or 5.9% — that wasn't any different, statistically, than for women on other regimens.

The data from the other three cohorts presented at the meeting create a fuller picture.

Table. Neural Tube Defects in Infants in Tsepamo and the Four New Cohorts
Treatments in the Cohorts Births, n Neural Tube Defects, n Rate, %
  None (HIV-negative women) 66,057 61 0.09
  Dolutegravir at time of conception 4 4 0.94
  Dolutegravir after conception 2812 0 0.00
  Dolutegravir any time during pregnancy 75 0 0.00
  Dolutegravir any time during pregnancy 1 0 0.00
Eastern and Central Europe      
  Dolutegravir any time during pregnancy 28 0 0.00
Gilead Global      
  Bictegravir or elvitegravir any time during pregnancy 650 1 0.00

We did see "a wee signal from elvitegravir," Money reported, although not in the neural tubes. "We'll have to keep an eye on that."

But even with that, the rate of neural tube defects was only 0.13% for Canadian women taking elvitegravir during pregnancy — far below the Tsepamo rate of 0.94%.

Gilead Sciences conducted a review of their information — a combination of clinical trial data, spontaneous postmarket reports, and literature review — and turned up one case of neural tube defects in an infant born to a woman taking elvitegravir in the first 48 days of pregnancy.

In this system of spontaneous reporting, there is no way to truly rule in or rule out an effect of a drug in pregnancy.

Of course, a handful of pregnancies here and there "aren't enough to provide any reassurance" that the signal is not borne out, said Rebecca Zash, MD, from Beth Israel Deaconess Medical Center in Boston, who was involved with the Tsepamo cohort.

For one thing, not all the data specify that the women were on dolutegravir during the critical first 28 days of pregnancy. After that, the neural tubes close and the risk passes. And the numbers are too small to provide the power necessary to draw conclusions. Although folic acid supplementation can obviate the risk, its use by the women is not always documented.

The spontaneous reports from Gilead are particularly difficult to decipher. "Ask any busy clinician how often they report," she said.

"In this system of spontaneous reporting, there is no way to truly rule in or rule out an effect of a drug in pregnancy," she told Medscape Medical News.

More Data Needed

This is not an argument against reporting data that do exist. Instead, it points to a need for better surveillance of pregnant women across the board, Zash said.

Money said she agrees. As one of the most senior doctors in her team at a referral clinic in Vancouver, she's always the one "who drags behind the curve," prescribing old antibiotics, old hypertension medicines, and older HIV regimens with a bit more clinical experience behind them.

"Everyone rolls their eyes at me," she said, but she was not surprised by the neural tube signal. "I was waiting for this to happen. I was hoping I was wrong," she explained.

Money said she leans toward boosted protease inhibitors, which "are not cool, but they work beautifully" in women who are well monitored and adherent.

Such defensive medicine is necessary because of the lack of clinical data on pregnant women, she said, noting how few of the trials presented at the meeting disaggregated data for women or included enough women to power thoughtful clinical decisions.

The predominance of men in HIV studies occurs even though women often having poorer virologic outcomes with "any of these combinations."

At a session dedicated to women, clinicians went through case studies and asked which medication should be prescribed to the woman described in the scenario. Repeatedly, the answer was a best guess, combined with, "we don't really have the answer."

Money said she lays out all the data for her patients, tells them what she knows — a fair bit, not very much, or nothing at all — and lets them choose.

"When you present that, most women don't want the "drug that has no data in pregnancy," Money said.

Money and Zash have disclosed no relevant financial relationships.

HIV Drug Therapy 2018: Abstracts P001 (Canada), P002 (Frankfurt), P004 (Eastern Europe), and P030 (Gilead). Presented October 28, 2018.

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