May 20th, 2018

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 OrganizationUnited 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.

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.

10 Responses to “Why the Dolutegravir Pregnancy Warning Is Important — and What We Should Do Now”

  1. Gillian Arsenault says:

    On the topic of what to do next, WHO mentions in their advisory that taking folic acid is important in helping to prevent neural tube defects: “WHO recommends that women take daily supplements of folic acid before conception and during pregnancy to help prevent neural tube defects.” (from http://i-base.info/htb/34133 )

    Also, based on this recent case report of reversible lower extremity numbness that cleared when dolutegravir was stopped ( AIDS: July 17th, 2017 – Volume 31 – Issue 11 – p 1645–1646 ) in combination with the possibility that inadequate B12 activity may be a factor in neural tube defects ( https://nyaspubs.onlinelibrary.wiley.com/doi/pdf/10.1111/nyas.13574 ), I wonder if dolutegravir could have an effect on the metabolism of not just folic acid, but also other B vitamins, particularly B12?

    Is there any information about the B vitamin status of these moms – and, for those taking supplements, their methylation capacity – and were any differences found between the moms whose babies were affected compared to the other moms?

    If we don’t yet have enough information on this particular group of moms on their risk factors for having babies with neural tube defects to guide us, what about doing a formal decision analysis on potential risk factor reductions that could be bundled with dolutegravir? (A google scholar search on “neural tube defects” risk factors review gives an idea of the range of environmental and genetic risk factors identified to date.) Such a decision analysis could provide interim guidance in the current setting of major uncertainty.

    Simple things like providing dolutegravir bundled with prenatal-type supplements that included methylated B vitamins for any patient who could get pregnant – a cheap & cheerful low-risk intervention – might turn out to be a robust strategy and something we could do now.

  2. Carlos Zala says:

    Great advice. Thank you Paul

  3. Agnes Cha says:

    Just curious, why would you not opt for a boosted PI based regimen? At our practice we end up using ATV/r very often because of its safety data.
    Thanks for always providing us readers with your insight.

    • Paul Sax says:

      Good question! We’ve moved away from boosted PIs at our hospital, mostly due to GI tolerability issues. Some studies have linked them to premature birth and/or low birth weight. And my collaborators strongly believe in the safety of EFV, ironically (given where we started with this drug).

      Paul

  4. Eduardo Orlando says:

    Dear Paul. Thanks for your always brightening posts. We received the same orientations from the NIH here (Brazil). But I have a question, not responded yet. In case of sexual violence, our guideline suggests TDF/3TC/DTG as first option. You think we should maintain this schedule? The day after pills are enough to assure this use? Thanks again.

  5. Sylvain Meylan says:

    Thanks, very useful as always.

  6. Mehri McKellar says:

    Hi Paul

    So now the big question is what we do next. I follow about 100 female patients here in Durham, NC, and many are on dolutegravir. Do you think the best approach is to call them stat (at least those <50 years old and without IUDs?), let them know about the new warning and switch them to Atripla or 3 pills with Isentress HD? Should I wait until their next appointment? Are we jumping the gun given that there were only 4 patients – albeit with devastating outcomes. This has the potential to create a lot of panic among my female patient population.

    Thanks for your blog as always.
    Mehri McKellar
    Duke University

  7. Mark Drapkin says:

    Thank you as always, Paul. What about PEP, both occupational and non-occupational? We’ve been using Truvada/DTG. Substitute raltegravir, either regular twice daily or HD once daily, for women of childbearing age?

  8. Wanjiku says:

    I told my doctor am expecting but he said DTG is okay with pregnancy. I was given on my 3month. Does this have n negative effects on the featus? Kindly advise.

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HIV Information: Author Paul Sax, M.D.

Paul E. Sax, MD

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