Why the Dolutegravir Pregnancy Warning Is Important -- and What We Should Do Now

Last week, in response to newly available surveillance data, multiple agencies issued a warning about the HIV integrase inhibitor dolutegravir (DTG) and pregnancy. The warnings cite an increased risk of neural tube defects in babies born to women who became pregnant while receiving the drug.

From the U.S. Department of Health and Human Services:

The concern stems from a preliminary unscheduled analysis of an ongoing NIH-funded birth surveillance study in Botswana, which has reported an increased risk of neural tube defects among infants of women who became pregnant while taking DTG-based regimens. The study reported 4 cases of neural tube defects out of 426 infants born to women who became pregnant while taking DTG-based regimens. This rate of approximately 0.9% compares to a 0.1% risk of neural tube defects among infants born to women taking non-DTG-based regimens at the time of conception.

The U.S. Food and Drug Administration, World Health Organization, United States President's Emergency Plan for AIDS Relief (PEPFAR), and European Medicines Agency issued similar statements.

There are several reasons why this warning is important -- and why the best treatment for women with HIV who want children remains an open question.

Since its FDA approval in 2013, dolutegravir has emerged as one of our best antiretroviral agents. It's highly potent, well tolerated, has few drug interactions, and a high resistance barrier -- meaning that even patients with poor adherence rarely if ever develop resistance to the drug.

Related: FDA to Evaluate Potential Risk of Neural Tube Birth Defects With HIV Medicine Dolutegravir (Juluca, Tivicay, Triumeq)

Not surprisingly, DTG-based treatments are now listed among recommended initial options in all HIV treatment guidelines. In a massive shift away from TDF/FTC/EFV, the tenofovir-lamivudine-dolutegravir single-pill regimen -- or "TLD" -- is increasingly becoming the default therapy in multiple countries throughout the world.

Based on the widespread and growing use of DTG-based regimens globally, these data on the potential risks of becoming pregnant while receiving DTG have immediate and broad clinical relevance.

This is the case despite the fact that this is a preliminary, early warning signal -- one that ideally will either be confirmed or refuted with additional data. According to the PEPFAR statement, the Botswana surveillance study will include an additional 600 more births from pregnant women who were using DTG at time of conception.

So as we await further information, what should we do now?

  • Women with HIV who wish to become pregnant and currently are receiving dolutegravir should be switched to a regimen with a more well-defined safety record in pregnancy. My personal preference would be for tenofovir DF/FTC plus either EFV or raltegravir. Note that neither is a perfect choice -- EFV has its own ambiguous history in this context, and raltegravir is also an integrase inhibitor. What if this is a class effect? Bottom line -- there is simply not enough systematically collected information on the safety of any HIV regimen taken at the time of conception.
  • Women with HIV who are not interested in having children, but are of childbearing age, should be counseled about this new information. If they choose to be on a DTG-containing regimen, regular use of reliable contraception should be strongly encouraged. For the record, there is very limited information to date about bictegravir.
  • Women who become pregnant while on dolutegravir need to talk with their HIV providers about what to do. This is a tricky clinical scenario, and the one that triggered the safety warning. Although the exposure during conception has already occurred, it would not surprise me if on hearing of these data, women and their care providers would choose to switch to a non-dolutegravir containing regimen.
  • Women starting HIV therapy during pregnancy (that is, after conception) should be treated with a regimen listed in established guidelines. In our clinic currently, this is typically TDF/FTC plus raltegravir. Note that the early data on DTG in this setting are encouraging, as these women started ART after the risk period for neural tube abnormalities; the PEPFAR statement indicates that there are now "more than 2,500 women who began taking DTG after the time of conception" with no reported cases of neural tube defects.
  • Reporting pregnancy outcomes to the Antiretroviral Pregnancy Registry remains an important clinician task. These data are critical to gathering further information about safe ART during pregnancy.

One final point -- it's been clear ever since suppressive ART during pregnancy became standard of care that we could eliminate the risk of HIV transmission to the newborn.

But with that staggering success comes a responsibility -- and that is to determine the safest treatment for the uninfected baby.

And while I've made fun of the "more research is needed" cliche that academics often bring out when reviewing studies or writing grants, here is one research agenda -- the safety of HIV treatment during pregnancy -- where further research is absolutely critical.

[Note from TheBodyPRO: This article was originally published by NEJM Journal Watch on May 20, 2018. We have cross-posted it with their permission.]