CROI 2019 Results From 2 Randomized Trials Evaluating INSTI-Based ART Initiation During Pregnancy: Implications for HIV Care in France

Karine Lacombe, MD, PhD

Sorbonne University
Head, Infectious Diseases Department
St Antoine Hospital, AP-HP
Paris, France

Karine Lacombe, MD, PhD, has no relevant conflicts of interest to report.

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Released: July 18, 2019

Pregnancy and ART for Women Living With HIV
Pregnancy is a key period in a woman’s life. Challenges around maternal well-being and newborn health are all the more important when the mother is living with HIV. With enhanced quality of life and increasing life expectancy in good health resulting from the enormous progress made in combating HIV and its consequencies, the chance that women living with HIV, including those perinatally infected, will become pregnant during their childbearing years is particularly high. A key pregnancy concern for women living with HIV relates to the efficacy and tolerability of ART, both at the time of conception and throughout gestation. Of paramount importance is the prevention of mother-to-child HIV transmission during pregnancy and delivery. When one of my patients comes to my outpatient clinic to share the good news of her pregnancy, my ultimate goal is to prescribe the right HIV treatment with optimal efficacy and tolerability to protect the baby from any risk of HIV acquisition while also assuring the mother a comfortable pregnancy.

In the current era of ART, many of these patients start pregnancy while receiving an INSTI-based regimen, which has become the cornerstone of recommended ART in recent years. Evidence of drug efficacy and safety during pregnancy has until now been gathered mainly through observational cohorts, due to the long-standing contention that it would be unethical to design a clinical trial with pregnant women. What do the available data from such studies tell us about INSTI safety during pregnancy? Elvitegravir is not recommended during pregnancy because suboptimal plasma concentrations during the second and third trimesters may lead to virologic failure. Regarding dolutegravir use and pregnancy, interim results from an ongoing birth surveillance study in Botswana (Tsepamo study) reported an increased risk of neural tube defects among infants whose mothers became pregnant while receiving dolutegravir-based ART (0.67% of 596 births), prompting concerns about the use of dolutegravir in women of childbearing age who may become pregnant and in early pregnancy. However, follow-up data involving over 1600 births among pregnant women receiving dolutegravir-based ART from conception demonstrated a much lower rate of neural tube defects, 3 per 1000 deliveries vs 1 per 1000 deliveries with non-dolutegravir ART use at the time of conception. It is also important to note that in the same study, there was no evidence of neural tube defects among infants born to mothers who initiated dolutegravir-based ART during pregnancy.

Data on raltegravir collected in observational settings have been, to date, reassuring from a clinical point of view, for both maternal and fetal health. In many guidelines, raltegravir is now considered a suitable option or as an alternative to efavirenz or darunavir in this setting.

CROI 2019: New Data on INSTI Use During Pregnancy
Previous findings on raltegravir safety and efficacy during pregnancy are further supported by new data reported at CROI 2019 from the NICHD P1081 trial, an international multicenter randomized clinical study conducted in Argentina, Brazil, South Africa, Tanzania, Thailand, and the United States. This trial compared the efficacy, safety, and tolerability of efavirenz vs raltegravir, each in combination with zidovudine and lamivudine, initiated between 20 and 37 weeks of gestation in 408 treatment-naive pregnant women. The results are very interesting and in line with the intrinsic characteristics of raltegravir as an INSTI: The very rapid viral load decline associated with the drug class translated here to a significantly higher viral suppression rate at the time of delivery in women who started raltegravir-based treatment after 28 weeks of pregnancy (93%) compared with an efavirenz-containing regimen (71%). However, in mothers who started treatment earlier in pregnancy (20-27 weeks), the rates of viral suppression at the time of delivery were similar between arms ( 96% and 97%, respectively). Tolerability was overall not an issue, but the number of mother-to-child HIV transmissions was higher with efavirenz (6 of 184 births) than with raltegravir (1 of 190), although this difference was not statistically significant. Of note, the study was not powered to show a potential statistical difference for that outcome.

In addition, new data reported at CROI 2019 from the randomized DolPHIN-2 trial comparing dolutegravir-based vs efavirenz-based ART initiated during pregnancy confirm previous reports on the safety and efficacy of dolutegravir when initiated during pregnancy. In this study, 268 pregnant women living with HIV were randomized to either drug, each in combination with 2 NRTIs, at ≥ 28 weeks of gestation. Similar to the NICHD P1081 trial, the rate of viral suppression at the time of delivery was notably higher in the dolutegravir arm vs the efavirenz arm, at 73.8% vs 42.6%, respectively (P < .0001). There was no difference in frequency of congential anomolies among infants in the 2 maternal treatment groups.

Considerations for HIV Treatment During Pregnancy in France
What do we learn from these important contributions to the field that could be translated into our everyday practice in France? These are the first randomized trials that really show how much we would gain in terms of efficacy and safety in favoring INSTIs as treatment of choice when initiating ART during the second or third trimesters of pregnancy, at least compared with efavirenz. The French guidelines are generally in line with the overall European recommendations. Most women (76%) living with HIV in France are already receiving HIV treatment when they become pregnant. When an INSTI is part of the ART regimen, it can be continued if it is raltegravir but should be modified if it is dolutegravir or elvitegravir. The use of efavirenz has been rapidly declining during recent years in France, and if a woman becomes pregnant while receiving efavirenz, it is currently recommended that the regimen be changed. However, these recommendations may change in the future with consideration of emerging data, including these studies presented at CROI 2019.

Join the Discussion
What did you take away from the findings of these 2 trials? Join the discussion by posting a comment below. For more details on this and other key studies from CROI 2019, download and review CCO’s summary slidesets, listen to audio from a series of postconference Webinars, and participate in CCO’s CME/CE-certified Expert Analysis module featuring even more studies from CROI 2019.

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