Recommendations Regarding the Use of Dolutegravir in Adults and Adolescents with HIV who are Pregnant or of Child-Bearing Potential

Date: May 30, 2018

A National Institutes of Health (NIH)-funded observational surveillance study of birth outcomes among pregnant women on antiretroviral therapy (ART) in Botswana identified neural tube defects (NTDs) in four infants born to 426 women who initiated a dolutegravir (DTG)-based regimen prior to pregnancy, and who were still receiving it at the time of conception.¹ This study is ongoing, and more data from approximately 600 additional births among pregnant women who have been using a DTG-based regimen from conception are expected in the next 9 months. Importantly, the same study presented data on women who initiated ART during the first trimester of pregnancy, and no NTDs were identified in the infants of the 116 women who initiated a DTG-based regimen in the first trimester or in 396 women who initiated an efavirenz (EFV)-based regimen.² In the upcoming months, data from this study and other investigations will provide more information about the safety of DTG for infants exposed in utero.

The Department of Health and Human Services (HHS) Antiretroviral Guidelines Panels* are issuing these recommendations to elaborate on our previous statement of May 18, 2018³ and to support the related Food and Drug Administration (FDA) Drug Safety Communication.⁴

For treatment of adults and adolescents with HIV who are pregnant or of child-bearing potential, we recommend the following:

• For individuals not known to be pregnant, documentation of a negative pregnancy test is recommended prior to initiating DTG.
• Those who are currently receiving DTG as a component of their ART or who wish to be started on DTG should be counseled about the potential risk of NTDs when DTG is taken near the time of conception. NTDs occur within the first 28 days after conception or 6 weeks from the last menstrual period.
• Those who are pregnant, taking DTG, and within 8 weeks from last menstrual period should discuss the risks and benefits of their current regimens with their health care providers. If there are other good options to replace DTG, then switching to a non-DTG ART regimen is recommended (see Table 2).
• Those who are pregnant and 8 weeks or greater from last menstrual period may initiate or continue DTG-based regimens. Discontinuing DTG-based regimens is unlikely to confer any benefits after the neural tube has formed, and medication changes during pregnancy could increase the risk of viremia and transmission of HIV to the infant.
• Currently, it is not clear if DTG is the only integrase strand transfer inhibitor (INSTI) with the potential to cause NTDs, or if other INSTIs also carry this risk (i.e., a class effect). Although there have been no reports of NTDs associated with taking DTG or other INSTIs near the time of conception in the prospective portion of the U.S. Antiretroviral Pregnancy Registry, the Registry is based on voluntary reporting and the number of reported INSTI exposures near the time of conception is relatively small.
• The Panels encourage all providers to prospectively report the pregnancy exposures of individuals with HIV receiving ART to the Antiretroviral Pregnancy Registry.
• For additional guidance, please contact the Perinatal HIV/AIDS Hotline at (888) 448-8765.

Table 1 below provides recommendations for the use of DTG in pregnant individuals and in those individuals who may become pregnant based on antiretroviral (ARV) history and various clinical scenarios. The decision of whether or not to initiate or continue to prescribe DTG should be made by the provider and the patient, after taking into account the potential risk of DTG to the fetus and the benefit of DTG for maintaining viral suppression. Table 2 provides recommendations on alternative ARV drugs when DTG cannot be used.

Table 1: Recommendations Regarding Use of Dolutegravir in Adults and Adolescents with HIV who are Pregnant or of Child-Bearing Potential

ART history	Clinical Scenario	Recommendations/Comments
ARV-naive or On ART (but not on DTG) and contemplating switching to a DTG-based regimen	Pregnant, less than 8 weeks from last menstrual period (LMP)	Do not initiate a DTG-based regimen (see Table 2 for alternatives to DTG).
	Pregnant, 8 weeks or longer from LMP	If an individual is ARV-naive, use DTG or another ARV drug (see Table 2). If an individual is currently on a non-DTG regimen, continue current regimen or switch to DTG or another option (see Table 2).
	Those who desire pregnancy or who are not using effective contraception	Do not initiate a DTG-based regimen (see Table 2 for alternatives to DTG). Refer to preconception counseling section of the Perinatal Guidelines for guidance.
	Those who do not desire pregnancy and who are using effective contraception	DTG can be considered as part of an ARV regimen. Pregnancy testing is recommended prior to initiation of DTG. Discuss the potential of DTG to the fetus and the effective use of contraception.
Currently receiving DTG	Pregnant, less than 8 weeks from LMP	Switch DTG to an alternative option (see Table 2) or continue DTG after weighing the risks and benefits of a DTG-containing regimen and alternative options. Do not stop DTG without replacing it with another effective ARV drug. Discuss the potential risk of DTG to the fetus, and explain that switching regimens after the neural tube has formed is unlikely to confer benefits. ARV history, current and prior resistance profiles, safety for the patient and the fetus, tolerance, and drug interaction potential should be taken into account when determining the optimal alternative to DTG.
	Pregnant, 8 weeks or longer from LMP	DTG can be continued. Neural tube defects occur in first 4 weeks after conception or 6 weeks from LMP.
	Those who desire pregnancy or who are not using effective contraception and have effective treatment options other than DTG	Switch to an alternative to DTG (see Table 2 for alternative options). Do not stop DTG without replacing it with another effective ARV drug. Discuss the potential risk of DTG to the fetus. Refer to preconception counseling section of the Perinatal Guidelines for guidance. ART history, current and prior resistance profiles, safety for the patient and the fetus, tolerance, and drug interaction potential should be taken into account when determining the optimal alternative to DTG.
	Those who desire pregnancy or who are not using effective contraception and have drug-resistant HIV and are using DTG as part of a salvage regimen, with no other effective ART options	Continue DTG. Discuss the potential risks of DTG to the fetus and the risks of viremia rebound if DTG is discontinued, including potential transmission of HIV to the fetus, so that an informed decision can be made.
	Those who do not desire pregnancy and who are using effective contraception	DTG can be continued. Discuss the potential risks of DTG to the fetus and the effective use of contraception.

 

Table 2: Alternatives to Dolutegravir in Adults and Adolescents with HIV who are Pregnant or of Child-Bearing Potential

• ARV history, current and past resistance profiles, safety for the patient and the fetus, tolerance, and drug interaction potential should be taken into account when determining the optimal alternative to DTG.
• Elvitegravir/cobicistat should not be used during pregnancy, due to concerns about adequate drug levels and risk of viral breakthrough.
• There are currently little data on the use of cobicistat, tenofovir alafenamide, or bictegravir-containing regimens during pregnancy.

ARV Drug Class	ARV	Considerations
INSTI	Raltegravir (RAL)	Before pregnancy, dose at 1200 mg (as two 600-mg tablets) once daily or 400 mg BID. During pregnancy, dose at 400 mg BID. Dose separately from iron supplement. Note: At this time, it is not known if the potential effect of DTG on the fetus is specific to DTG or whether it represents an INSTI class effect. This uncertainty should be acknowledged and discussed with the patient.
Protease inhibitor (PI)	Atazanavir/ ritonavir (ATV/RTV)	ATV concentration may be affected by acid-lowering agents; careful attention should be paid to this interaction in those taking or needing acid-lowering therapy during pregnancy.
	Darunavir/ ritonavir (DRV/RTV)	Before pregnancy (if there is no known PI resistance), dose at DRV/RTV 800 mg/100 mg once daily or DRV/RTV 600 mg/100 mg BID. During pregnancy, dose at DRV/RTV 600 mg/100 mg BID.
Non-nucleoside reverse transcriptase inhibitors (NNRTI)a	Efavirenz (EFV)	Primate studies have raised concerns about birth defects, but these defects have not been seen in human studies. Based on extensive experience in pregnancy, EFV is considered to be safe to use. Screen and monitor for antepartum depression.
	Rilpivirine (RPV)	For ARV-naive individuals, use of rilpivirine is not recommended if HIV RNA >100,000 copies/mL or CD4 count <200 cells/mm3. Do not use with proton pump inhibitor; stagger dosing with H2 blocker.
a NNRTIs are considered “Alternatives” to PIs and INSTIs during pregnancy (see the Perinatal Guidelines).

For detailed descriptions of the advantages and disadvantages of each of these regimens, please see Table 8 of the Adult and Adolescent Antiretroviral Guidelines. Please also consult the Perinatal Guidelines for more specific recommendations during pregnancy.

The Panels emphasize that these are interim recommendations based on limited data. Additional information is being collected to provide a more complete understanding of the risk/benefit profile of DTG for individuals who are pregnant or are of childbearing potential. These recommendations will be updated as needed as more data become available.

The NIH Office of AIDS Research Advisory Council (OARAC) will review the proposed changes to the HIV/AIDS treatment and prevention guidelines at the earliest opportunity.

* The Panel on Antiretroviral Guidelines for Adults and Adolescents, the Panel on Antiretroviral Therapy and Medical Management of Children Living with HIV, and the Panel on Treatment of Pregnant Women Living with HIV and Prevention of Perinatal Transmission are working groups of the OARAC.

References

1. World Health Organization. Potential safety issue affecting women living with HIV using dolutegravir at the time of conception. Geneva, Switzerland. May 18, 2018.
2. Zash, R. Jacobson D., 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. 9th IAS 2017 Paris, France.
3. https://www.fda.gov/Drugs/DrugSafety/ucm608112.htm