On May 18, 2018, the U.S. Food and Drug Administration and the World Health Organization announced that cases of neural tube defects have been reported in babies of women with HIV who were on treatment with dolutegravir at the time of conception and during early pregnancy. The information comes from an unplanned interim analysis of an observational study (the Tsepamo Study) of ART (dolutegravir/TDF/FTC or efavirenz/TDF/FTC) in pregnant women in Botswana.
Initial data from this study, presented last year at IAS, reported that in women who started ART during pregnancy there were no congenital abnormalities seen in the 116 babies born to those who started dolutegravir/TDF/FTC during the first trimester and 1 birth defect among the babies of 396 women who started efavirenz/TDF/FTC in the first trimester. There were no differences in adverse birth defects in the larger numbers of women in the two groups who started ART later in pregnancy.
The new data from the Tsepamo Study show that 0.9% of babies (4 of 426 babies) who were exposed to dolutegravir had neural tube defects compared with 0.1% of babies (14 of 11,173) who were exposed to other HIV medicines during pregnancy. The neural tube defects were reported only in babies of women who were taking dolutegravir at the time of conception--there were no reported neural tube defects among more than 2,500 babies born to women who began taking dolutegravir after conception.
Previous studies of dolutegravir use among pregnant women did not show concern for abnormal fetal development, and animal studies of dolutegravir (and other integrase inhibitors) during pregnancy have not shown fetal neural tube defects. Women who are currently pregnant and included in the Tsepamo Study will be followed through delivery to gain more information about the safety of dolutegravir in pregnancy.
Until more data are available, the FDA advises that:
- Health care professionals should weigh the benefits and the risks of dolutegravir when prescribing antiretroviral medicines to women of childbearing age. Alternative antiretroviral medicines should be considered. Discuss the relative risks and benefits of appropriate alternative antiretroviral therapies.
- If the decision is made to use dolutegravir in women of childbearing age, health care professionals should reinforce the importance of consistent use of effective birth control.
- Perform pregnancy testing before initiating a dolutegravir-containing regimen in women of childbearing age to exclude pregnancy.
And the CDC added an interim recommendation that dolutegravir should not be used for postexposure prophylaxis (PEP) for:
- Nonpregnant women of childbearing potential who are sexually active or have been sexually assaulted and who are not using an effective birth control method.
- Pregnant women early in pregnancy, since the risk of an unborn infant developing a neural tube defect is increased during the first 28 days.
Clinical Bottom Line
Pending availability of additional data, it would be prudent to avoid the use of dolutegravir (either in ART or PEP) regimens for women who are planning pregnancy or may become pregnant (note that this applies to cis-gender women and also to trans men who may be planning pregnancy). For pregnant women who are taking dolutegravir, there is no need to stop dolutegravir.
In the United States, dolutegravir is marketed as Tivicay and is present in the coformulations Triumeq and Juluca.
- Centers for Disease Control and Prevention. Interim statement regarding potential fetal harm from exposure to dolutegravir--implications for HIV post-exposure prophylaxis (PEP). May 2018.
- FDA Drug Safety Communication: FDA to evaluate potential risk of neural tube birth defects with HIV medicine dolutegravir (Juluca, Tivicay, Triumeq). May 18, 2018.
- World Health Organization. Statement on DTG. May 18, 2018; Geneva.
- Zash R, Jacobson D, Mayondi G, et al. Dolutegravir / tenofovir / emtricitabine (DTG/TDF/FTC) started in pregnancy is as safe as efavirenz / tenofovir / emtricitabine (EFV/TDF/FTC) in nationwide birth outcomes surveillance in Botswana. In: Program and abstracts of the 9th IAS Conference on HIV Science; July 23-26, 2017; Paris. Abstract MOAX0202LB.