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In May 2018, an unplanned interim evaluation of an NIH-funded observational surveillance study of birth outcomes among pregnant women receiving ART in Botswana revealed 4 NTDs among infants born to 426 women who were receiving a DTG-based regimen at or near the time of conception, yielding a prevalence of 0.94%. This raised concerns about possible teratogenic effects of DTG within the central nervous system. These data were updated in a planned analysis in 2019, which demonstrated a lower prevalence of 0.30%, and again in an April 2020 analysis, which showed 7 NTDs in 3591 deliveries with DTG exposure around the time of conception, for an even lower prevalence of 0.19% that is now statistically similar to the 0.11% rate among women receiving non–DTG-containing ART around the time of conception.[24-26]
It should be noted that almost all of the women for whom folate was prescribed started taking folate during, and not before, pregnancy, which is significant because there are ample data supporting that preconception use of folate reduces the incidence of NTDs in the general population.
This figure shows data from the Antiretroviral Pregnancy Registry on periconception ARV exposure and NTDs. As shown, through January 2019, there were more than 20,000 prospectively enrolled pregnancies with more than 20,000 birth outcomes, and 8546 of these had periconception ARV exposure. Overall, the NTD prevalence with periconception ARV exposure of 0.03% is consistent with the observed low NTD prevalence of 0.01% to 0.08% in most developed countries with folic acid fortification.
Notice that the number of exposures analyzable for the INSTI groups is much lower because these are newer agents, and it is, therefore, not possible to either rule out or confirm any NTD association.
Pregnancy outcomes after RAL exposure are available from several large data sources. First, the Merck Adverse Event Review and Reporting System (MARRS) aggregates data from clinical trials, market research programs, patient support programs, literature reports, and healthcare authorities. Through the end of May 2019, this included 961 prospective and 520 retrospective reports. Prevalence rates were calculated from prospective reports, almost all of which referenced the 400‑mg RAL tablet, and most of these reports were from the United States.
The second data source is the National Study of HIV in Pregnancy and Childhood (NSHPC), which collects data on pregnant women with HIV and on their infants and children who are seen for HIV care in the United Kingdom and Ireland.
And finally, the ANRS-French Perinatal Cohort (EPF) is a prospective, multicenter cohort that includes approximately 70% of pregnant women living with HIV in France.
Analysis of the MARRS data shows no evidence of an increase in the rate of spontaneous abortion, stillbirth, or congenital anomaly in pregnant women exposed to RAL vs a background population.[29-35] There were also no NTDs observed in prospective reports of RAL exposure at conception or during the first trimester as of early September 2019, although there was a single anencephaly case following second trimester RAL exposure that was deemed to be unrelated to RAL.
Since 2007, there have been 2 retrospective reports of NTDs with periconception RAL exposure in MARRS. One of these was a live birth with a myelomeningocele and one was a spontaneous abortion with evidence of an encephalocele. The estimated exposure to RAL among females ranging in age from 12-50 years through the end of May 2019 represents more than 300,000 patient-treatment years.
Additional surveillance evidence is also very reassuring, as no NTDs were reported from either NSHPC or EPF.[36,37]
Furthermore, no NTDs were reported among 765 periconception exposures to RAL in MARRS, NSHPC, and EPF, and therefore, these data are quite reassuring related to the risk of NTDs with RAL exposure.
This table shows several important modifiable risk factors for NTDs. As shown, maternal red blood cell folate < 500 nmol/L is associated with a 0.06% risk of an NTD, which is an approximately 4-fold increase in risk vs an RBC folate > 1000 nmol/L. In addition, the increase in risk of an NTD with maternal diabetes is 2-fold to 10-fold, with maternal obesity is 1.3-fold to 3.5-fold, with maternal hyperthermia is 2-fold, and with coadministration of certain other medications, specifically valproic acid, is 10-fold.
These background risk factors and the overall very low prevalence of NTDs highlight the difficulty of linking individual factors, including the use of specific ARVs, to an increase in risk.
This body of data has informed the current US Public Health Service perinatal guideline recommendations for use of DTG in pregnancy. As discussed, DTG is considered an alternative agent for women trying to conceive. For women who are pregnant, DTG is preferred throughout pregnancy and, in most cases, should be continued even when the woman presents for care in the first trimester. However, the woman should be carefully counseled about the benefits and potential risks of receiving DTG during early pregnancy.
Several considerations inform the current guidelines for continuing DTG during pregnancy. First, it should be noted that the background risk of NTDs is 0.07%, and data are insufficient to definitively rule out an increase in risk with other antiretroviral agents except for efavirenz. In addition, folate lowers the risk of NTDs and food in the United States is routinely fortified with folic acid. To date, there is not sufficient evidence to establish a link between DTG and impaired folate metabolism. Most NTDs occur by 6 weeks of gestation and thus the time period representing the greatest risk for NTDs is also the time period when many if not the majority of women do not yet know they are pregnant. Finally, changing ART in pregnancy, even in early pregnancy, may result in viral rebound because of adherence or tolerability issues. Therefore, the totality of this information should be considered when determining if a change in therapy is warranted.
A recent study modeled the risk vs benefit of DTG use in women of childbearing potential in South Africa.[40,41] According to the model, although the use of DTG exclusively vs EFV exclusively results in 1 more NTD per every 1000 women of childbearing potential initiating ART, it also results in 3 more women alive, 13 more men without HIV because of prevention of sexual transmission, and 3 fewer mother-to-child HIV transmissions. With DTG used only in combination with contraception vs use of EFV only, no NTDs are seen, and it results in 1 more woman alive, 5 more men without HIV due to sexual transmission, and no mother-to-child HIV transmissions.
A separate modeling study of averted disability adjusted life-years (DALYs) for different ART policies showed that the largest number of averted DALYs is predicted with use of tenofovir DF, 3TC, and DTG in all people receiving ART.
Investigators also noted in this analysis that reducing unintended pregnancies in women using DTG effectively eliminates NTD concerns. Of importance, there needs to be high coverage of effective contraception methods, and reducing unintended pregnancy is an important goal of integrating family planning services into HIV care.
Therefore, these data demonstrate the importance of considering the big picture when determining the best course of action for ART in women of childbearing age, including preventing unintended pregnancies, the health of the mother, and prevention of transmission to uninfected partners.
Considering this larger picture, data demonstrate that INSTIs lower HIV-1 RNA more rapidly than other ART drug classes, which may have particular applications for women who present later in pregnancy and those with high HIV-1 RNA.
The DolPHIN-2 study was a randomized phase III trial comparing DTG-based therapy vs EFV-based therapy initiated during pregnancy at ≥ 28 weeks of gestation. The study demonstrated a faster time to HIV-1 RNA < 50 copies/mL with DTG vs EFV and that, overall, significantly more women in the DTG group vs the EFV group had an undetectable HIV-1 RNA at delivery (73.8% vs 42.6%; P < .0001). Significantly higher rates of HIV-1 RNA < 50 copies/mL were also observed with DTG-based vs EFV-based ART across multiple subgroups analyzed, including by baseline HIV-1 RNA, baseline CD4+ cell count, and gestational age when ART was initiated.
Regarding safety, there were 3 infant HIV transmissions in the DTG arm and none in the EFV arm. Maternal creatinine increase from baseline was significantly higher with DTG vs EFV (6.2 μmol/L with DTG vs 1.8 μmol/L with EFV; P < .0001). There were 3 stillbirths in the DTG arm vs 1 in the EFV arm, but they were all deemed unrelated or not likely related to either ART or immune reconstitution syndrome.
The median gestational age at delivery was similar in the 2 treatment arms as was the proportion of infants who were born prematurely. In terms of serious adverse events, there were no significant differences between the DTG-based and EFV-based arms, and infant deaths in both arms were considered to be unrelated or not likely related to ART or immune reconstitution inflammatory syndrome.
Another recent study that examined the efficacy and safety of an INSTI when initiated during pregnancy was NICHD P1081. This was a randomized phase IV trial of RAL-based vs EFV-based ART initiated at 20 to < 37 weeks of gestation. A similar proportion of patients remained on their assigned ARV regimen through delivery in both groups.
This study showed that RAL-based ART was superior to EFV-based ART in terms of virologic efficacy, with 94% vs 84% of patients, respectively, achieving HIV-1 RNA < 200 copies/mL at delivery. When stratified by gestational week of ART initiation, the greatest benefit of the RAL-based regimen was seen for those women who started later in pregnancy (93% vs 71% of patients receiving RAL-based vs EFV-based ART achieved HIV-1 RNA < 200 copies/mL at delivery), which is consistent with a more rapid viral suppression with RAL vs EFV.
Finally, grade ≥ 3 adverse events were not different between study arms for either women or their infants.
In terms of other outcomes, the median time to reaching HIV-1 RNA < 200 copies/mL was 8 days with RAL vs almost double that—15 days—with EFV. Overall, there was a significant difference between RAL-based and EFV-based ART in rapid and sustained virologic response in women who remained on study drug throughout delivery. Indeed, 92% vs 64% of women, respectively, achieved this endpoint (P < .001).
Birth outcomes, including stillbirths, preterm deliveries, and infant HIV infections, were not statistically different between the 2 treatment arms.
To summarize, the data presented in these 2 studies demonstrate that both DTG and RAL are important drugs in the ARV armamentarium during pregnancy, especially for women who may present later in pregnancy and with higher HIV-1 RNA.
The IMPAACT 2010 study was a randomized, open-label phase III trial that examined the safety and efficacy of DTG vs EFV and TDF vs TAF in pregnant women with HIV at 14-28 weeks of gestation.
The study found that neonatal death was more frequent with EFV/FTC/TDF vs either DTG plus FTC/TAF or DTG plus FTC/TDF. Two infants were diagnosed with HIV in the DTG plus FTC/TAF arm, and 1 infant was diagnosed with HIV in the DTG plus FTC/TDF arm.
Regarding virologic efficacy, significantly more women achieved HIV-1 RNA < 200 copies/mL in the DTG-based arms vs the EFV-based arm in the intention-to-treat population (97.5% vs 91.0%, respectively; P = .005). This was also true for the per protocol population, with 97.5% and 91.4% (P = .008) of women, respectively, achieving this endpoint.
Regarding adverse pregnancy outcomes, there was a significantly lower risk of any adverse pregnancy outcome in the DTG plus FTC/TAF group vs the other 2 groups. There was also a significantly lower risk of preterm delivery with DTG plus FTC/TAF vs EFV/FTC/TDF.