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Professor of Medicine and Epidemiology
University of North Carolina School of Medicine
Director, AIDS Clinical Trials Unit
University of North Carolina
Chapel Hill, North Carolina
Joseph J. Eron, Jr., MD, has disclosed that he has received funds for research support from Gilead Sciences, Janssen, and ViiV Healthcare; and has received consulting fees from Gilead Sciences, Janssen, Merk, Trio Health, and ViiV Healthcare.
The case: A 33-year-old woman with HIV is referred to us for consultation. She has lived with HIV for at least 5 years, and her HIV-1 RNA is suppressed on therapy with elvitegravir (EVG)/cobicistat (COBI)/emtricitabine (FTC)/tenofovir alafenamide (TAF) for 4 years with an HIV-1 RNA <40 copies/mL (not detected) and CD4+ cell count of 542 cells/mm3. She is in a long-term relationship with a man without HIV, and they want to start a family.
What treatment regimen should we recommend? Here’s my answer based on how our understanding has evolved up to the most-recent data presented at IDWeek 2021.
In May 2018, regulatory agencies in the United States and the European Union received a stunning finding. In the Tsepamo study, in Botswana, investigating antiretroviral therapy (ART) safety in pregnant women and women of childbearing potential, dolutegravir (DTG) use was associated with 4 neural tube defects (NTDs) in 426 women who became pregnant while on therapy, which translated to a risk of 0.9%.
This result was in contrast to other ART regimens where NTDs were seen only 0.1% of the time, and, ironically, with efavirenz-based therapy that had a risk of 0.04%. This result was in stark contrast to previously presented data from the Tsepamo study, which demonstrated the safety of DTG treatment started during pregnancy.
The 2018 Tsepamo NTD results led to a swift change in recommendations for the use of DTG in women of childbearing potential and very early pregnancy, beginning a robust discussion about informed consent and women’s choice given the perceived risks with DTG.
Reassurance of Safety
Additional data from the Tsepamo study have been shared each subsequent year, demonstrating a declining risk of NTD with each analysis. The data presented at AIDS 2020 showed the risk of NTDs had declined to approximately 0.2%, which was not statistically different from the risk to women who were on other ART regimens at the time of conception. Efavirenz-based regimens in use at the time of conception still bore the lowest risk.
These data and data from other cohort studies resulted in substantial updates to the US Department of Health and Human Services perinatal treatment guidelines:
The Panel on Treatment of Pregnant Women with HIV Infection and Prevention of Perinatal Transmission (the Panel) recommends dolutegravir (DTG) as a Preferred antiretroviral (ARV) drug throughout pregnancy and now also recommends DTG as a Preferred ARV for women who are trying to conceive. This decision was based on updated data showing that the increased risk of neural tube defects (NTDs) associated with the use of DTG is very small and the advantages of DTG which include once-daily dosing, being generally well tolerated, and producing rapid, durable viral load suppression, which is important for maternal health and the prevention of perinatal HIV transmission.
New data from IDWeek 2021 from the Antiretroviral Pregnancy Registry support this recommendation. This international prospective cohort study included more than 21,000 pregnancies in which women with HIV were exposed to ART. In this analysis, periconception exposure to DTG was associated with a birth-defect prevalence of 3.4% with a single NTD (0.21% prevalence). This overall rate was similar to the rate of birth defects with any prenatal ARV use (2.85%). The overall rates of birth defects with exposure to DTG prenatally and during any trimester was 4.1%, which is similar to estimates in the general population.
Case and Conclusions
Given the accumulation of data and the updated Perinatal HIV Guidelines, DTG-based therapy would be one of the preferred therapies for this woman as she tries to conceive a child. It has advantages over raltegravir, including a high barrier to resistance and once-daily dosing. EVG/COBI/FTC/TAF is not recommended, owing to a decrease in EVG levels during pregnancy, so continuing her current therapy is not a recommended option.
At this point, treatment guidelines support tenofovir disoproxil fumarate (TDF)/FTC as the partner nucleos(t)ide reverse transcriptase inhibitor combination with DTG. TAF is recommended as an alternative therapy, but we could make an argument for continuing TAF in our patient given she is currently tolerating, and being successfully treated with, a TAF-based regimen. Recently published data from the IMPAACT 2010/VESTED trial support this approach, showing that—at delivery—DTG-containing regimens exhibited superior virologic efficacy with significantly fewer women experiencing preterm delivery. Neonatal mortality was also reduced. I expect the Perinatal Guidelines may soon incorporate these data.
What do you think about using DTG in women who are trying to conceive or who are pregnant? Join the discussion by posting a comment. For more details on this and other key HIV issues from IDWeek 2021, review more CCO Conference Coverage, including Capsule summary slidesets, video recaps with expert faculty, and other ClinicalThought commentaries highlighting US and global perspectives.