Dolutegravir During Conception/Pregnancy: Evolving Data and Recommendations

In May 2018, an unplanned interim evaluation of the Tsepamo study, an NIH-funded, observational surveillance study of birth outcomes among pregnant women receiving ART in Botswana, revealed 4 infants with neural tube defects (NTDs) born to 426 women who were receiving dolutegravir (DTG) at the time of conception, corresponding to a prevalence of 0.94% vs 0.12% in women receiving non-DTG–based ART at conception. This observation led the DHHS Panel on Treatment of Pregnant Women With HIV Infection and Prevention of Perinatal Transmission to advise avoiding the use of DTG in women trying to conceive or already in the first trimester of pregnancy. We have learned much since this first report, and I would like to share those data with you, along with my thoughts on how they affect practice.

Accumulating Data on the Use of DTG in Pregnancy
Two updated analyses of the Tsepamo study have now been performed since the first unplanned analysis that caused much alarm. In an updated analysis in May 2019, the NTD prevalence among infants born to 1683 women receiving DTG was revised downward to 0.30%, but remained higher than other exposure groups. Indeed, the NTD prevalence was 0.10% for infants born to 14,792 mothers who were receiving non-DTG–based ART and 0.04% for infants born to 7959 women receiving efavirenz (EFV)-based ART. By comparison, the prevalence of NTDs was 0.08% among 89,372 infants born to mothers without HIV. The most recent update presented at the AIDS 2020 virtual meeting revealed 2 additional infants with NTDs from April 1, 2019, through April 30, 2020, resulting in an overall NTD prevalence of 0.19% for infants exposed to DTG during conception vs 0.11% for infants exposed to non-DTG ART during conception.

Three additional studies have added information on the potential risk of NTDs for infants born to women exposed to DTG at conception and included assessments of NTDs in stillbirths and terminations. The first study included additional surveillance data from 22 sites in Botswana that were not included in the Tsepamo study and reported an NTD prevalence (confirmed or probable) of 0.66% (1 case; n = 152) in infants born to women exposed to DTG at conception, no NTDs (n = 381) in infants born to women exposed to other ARVs, and 0.09% (2 cases; n = 2328) in infants born to women without HIV. The second study included prospective data on the prevalence of central nervous system defects from the Antiretroviral Pregnancy Registry. Of note, most data (~ 75%) come from countries requiring folate fortification for food, which is known to reduce the NTD risk substantially. Nevertheless, this study found an NTD prevalence of 0.4% (n = 248) in infants born to mothers with periconception DTG exposure vs no NTDs in 485 infants born to mothers with periconception exposure to elvitegravir or raltegravir (RAL). The third study, a retrospective study of women with periconception ARV drug exposure in a national cohort in Brazil, showed no NTDs among 384 pregnancies in which infants were exposed to DTG or among 1109 pregnancies in which infants were exposed to EFV or RAL.

How Should Providers Interpret These Data?
Overall, we should be reassured. The observed NTD prevalence among infants born to women with DTG exposure at conception has continued to decline in the Tsepamo study. Although the rate is still numerically higher for infants exposed at conception to DTG vs those receiving any non-DTG-based regimen, the difference is small and not statistically significant. In addition, the potential risk must be balanced by a careful consideration of the benefits of DTG. DTG is currently part of recommended initial regimens for adults and adolescents living with HIV with an A1 rating by the DHHS, denoting both a strong recommendation and a strong base of evidence for the recommendation. DTG has a high barrier to resistance, can be given as part of a 1-pill once-daily regimen, and is well tolerated. Because of these features, it may be considered in regimens for patients with rapid initiation of ART immediately after diagnosis and before resistance test results are available. In the context of pregnancy, it also has the advantage of lowering HIV-1 RNA more rapidly than other classes of ARV agents. All of these considerations have led the DHHS Panel on Treatment of Pregnant Women With HIV Infection and Prevention of Perinatal Transmission to update guidelines to now recommend DTG as apreferred (ARV) drug in women who are trying to conceive and throughout pregnancy.

In our practices, we must be mindful that the potential risk of NTDs with DTG, the benefits of DTG-containing regimens, and the risks and benefits of alternative regimens should be discussed with women who may initiate ART during the first trimester or who are planning to become pregnant. Key features of counseling include:

1. In the United States, the background risk of NTDs in the general population is 0.07% (7/10,000 pregnancies), corresponding to 3000 pregnancies affected each year. With the exception of EFV, there are not enough data to determine the risk of NTDs with periconception use of any of the other currently available ARV drugs in the United States.
2. Folic acid is known to lower the risk of NTDs in the general population and the United States Public Health Service recommends that all pregnant women and women who might conceive take at least 400 mcg of folic acid daily. Unlike in Botswana, food in the United States is routinely fortified with folate, which can decrease NTD prevalence by one half. However, studies to date have not established a link between the use of DTG and impaired folate metabolism, and there is currently no evidence that folate supplementation prevents the NTDs that are potentially associated with the use of DTG. Nevertheless, women with HIV who are pregnant or are considering pregnancy should receive the recommended dose of folate to minimize their risk of NTDs, regardless of ARV regimen.
3. Most NTDs occur early in pregnancy before the neural tube closes at approximately 6 weeks after the last menstrual period, often before a woman realizes she is pregnant. In most cases, the Panel recommends continuation of DTG for pregnant women who are receiving DTG and present to care during the first trimester due to the small risk of NTDs, and data show that changes in ART during pregnancy can lead to viral rebound that increase the risk of perinatal HIV transmission and with possible implications on development of resistance.
4. Data have not shown an increase in the risk of NTDs in infants born to women who initiated DTG during pregnancy.
5. All cases of ARV drug exposure during pregnancy should be reported to the Antiretroviral Pregnancy Registry.
6. Before, during, and after pregnancy, clinicians and patients should discuss future childbearing desires and plans, the potential risks and benefits of conceiving while receiving specific ARV medications, including DTG, and contraceptive options to prevent unintended pregnancy.

Your Thoughts?
How have the latest data on DTG affected the way in which you provide care for women with HIV of childbearing age? Please join the conversation and share your experiences in the comments box.