| |
Dolutegravir in Pregnancy as Compared with
Current HIV Regimens in the United States
|
| |
| |
Download the PDF here
NEJM Sept 1 2022 Kunjal Patel, D.Sc., Yanling Huo, M.S., Jennifer Jao, M.D., Kathleen M. Powis, M.D., Paige L. Williams, Ph.D., Deborah Kacanek, Sc.D., Lynn M. Yee, M.D., Ellen G. Chadwick, M.D., Stephanie Shiau, Ph.D., Denise L. Jacobson, Ph.D., Sean S. Brummel, Ph.D., Leila Sultan-Beyer, M.D., Christian R. Kahlert, M.D., Rebecca Zash, M.D., and George R. Seage III, D.Sc.,* for the Pediatric HIV/AIDS
Cohort Study and the Swiss Mother and Child HIV Cohort Study
Abstract
Background
Data on the effectiveness and safety of dolutegravir-based antiretroviral therapy (ART) for human immunodeficiency virus type 1 (HIV-1) infection in pregnancy as compared with other ART regimens commonly used in the United States and Europe, particularly when initiated before conception, are limited.
Methods
We conducted a study involving pregnancies in persons with HIV-1 infection in the Pediatric HIV/AIDS Cohort Study whose initial ART in pregnancy included dolutegravir, atazanavir-ritonavir, darunavir-ritonavir, oral rilpivirine, raltegravir, or elvitegravir-cobicistat. Viral suppression at delivery and the risks of infants being born preterm, having low birth weight, and being small for gestational age were compared between each non-dolutegravir-based ART regimen and dolutegravir-based ART. Supplementary analyses that included participants in the Swiss Mother and Child HIV Cohort Study were conducted to improve the precision of our results.
Results
Of the pregnancies in the study, 120 were in participants who received dolutegravir, 464 in those who received atazanavir-ritonavir, 185 in those who received darunavir-ritonavir, 243 in those who received rilpivirine, 86 in those who received raltegravir, and 159 in those who received elvitegravir-cobicistat. The median age at conception was 29 years; 51% of the pregnancies were in participants who started ART before conception.
Viral suppression was present at delivery in 96.7% of the pregnancies in participants who received dolutegravir;corresponding percentages were 84.0% for atazanavir-ritonavir, 89.2% for raltegravir, and 89.8% for elvitegravir-cobicistat (adjusted risk differences vs. dolutegravir, -13.0 percentage points [95% confidence interval {CI}, -17.0 to -6.1], -17.0 percentage points [95% CI, -27.0 to -2.4], and -7.0 percentage points [95% CI, -13.3 to -0.0], respectively). The observed risks of preterm birth were 13.6 to 17.6%. Adjusted risks of infants being born preterm, having low birth weight, or being small for gestational age did not differ substantially between non-dolutegravir-based ART and dolutegravir. Results of supplementary analyses were similar.
Conclusions
Atazanavir-ritonavir and raltegravir were associated with less frequent viral suppression at delivery than dolutegravir. No clear differences in adverse birth outcomes were observed with dolutegravir-based ART as compared with non-dolutegravir-based ART, although samples were small. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and others.)
Viral Suppression at Delivery
The observed percentage of pregnancies in which viral suppression was present at delivery was 96.7% among participants who received dolutegravir; the corresponding percentages of pregnancies among participants who received other types of ART were 84.0% for atazanavir-ritonavir, 90.1% for darunavir-ritonavir, 89.2% for raltegravir, and 89.8% for elvitegravir-cobicistat (Table 2). In the analysis of oral rilpivirine as compared with dolutegravir, the percentage of pregnancies in which viral suppression was present at delivery was 96.8% among participants who received rilpivirine and 96.3% among those who received dolutegravir.
Model-based unadjusted and adjusted differences in the estimated probability of viral suppression at delivery are shown in Figure 2. In adjusted analyses, the estimated probability of viral suppression at delivery was lower among pregnancies in participants taking atazanavir-ritonavir than among those in participants taking dolutegravir (adjusted risk difference, -13.0 percentage points; 95% confidence interval [CI], -17.0 to -6.1); the probability of viral suppression at delivery was also lower with raltegravir than with dolutegravir (adjusted risk difference, -17.0 percentage points; 95% CI, -27.0 to -2.4) and lower with elvitegravir-cobicistat than with dolutegravir (adjusted risk difference, -7.0 percentage points; 95% CI, -13.3 to -0.0001).
Model-based unadjusted and adjusted differences in the estimated probability of viral suppression at delivery are shown in Figure 2. In adjusted analyses, the estimated probability of viral suppression at delivery was lower among pregnancies in participants taking atazanavir-ritonavir than among those in participants taking dolutegravir (adjusted risk difference, -13.0 percentage points; 95% confidence interval [CI], -17.0 to -6.1); the probability of viral suppression at delivery was also lower with raltegravir than with dolutegravir (adjusted risk difference, -17.0 percentage points; 95% CI, -27.0 to -2.4) and lower with elvitegravir-cobicistat than with dolutegravir (adjusted risk difference, -7.0 percentage points; 95% CI, -13.3 to -0.0001).
Among pregnancies in participants who conceived while taking ART, the probability of viral suppression at delivery was lower with raltegravir than with dolutegravir (86.0% vs. 96.0%; risk difference, -10.0 percentage points; 95% CI, -22.0 to 1.9) and was higher with rilpivirine than with dolutegravir (99.6% vs. 92.3%; risk difference, 7.3 percentage points; 95% CI, 4.1 to 20.9) (Table S5). Among pregnancies in participants who started ART during pregnancy, the percentages in which viral suppression was present at delivery were lower among participants who started taking a PI-based regimen than among those who started taking dolutegravir (risk difference, -21.2 percentage points [95% CI, -26.9 to -16.0] for atazanavir-ritonavir and -14.0 percentage points [95% CI, -23.1 to -5.7] for darunavir-ritonavir). In addition, the percentages of pregnancies in which viral suppression was present at delivery were lower among participants who started taking rilpivirine, raltegravir, or elvitegravir-cobicistat during pregnancy than among participants who started taking dolutegravir during pregnancy (risk difference, -7.5 percentage points [95% CI, -13.7 to -1.9] for rilpivirine, -7.4 percentage points [95% CI, -18.3 to -3.1] for raltegravir, and -14.2 [95% CI, -24.5 to -6.0] for elvitegravir-cobicistat) (Table S5).
Adverse Birth Outcomes
The observed risks of infants being born preterm, having low birth weight, and being small for gestational age ranged from 13.6% to 17.6%, from 11.9% to 16.7%, and from 9.1% to 12.5%, respectively, across different initial ART regimens in pregnancy (Table 2). The observed risks of the composite of any adverse birth outcome and any severe adverse birth outcome ranged from 22.6% to 27.9% and from 0% to 4.2%, respectively, across initial ART regimens in pregnancy. Across all ART regimens, 20 very preterm births occurred, and in 15 of these births the infants had very low birth weight. No neonatal deaths occurred. Four instances of perinatal HIV transmission occurred - two in pregnancies in participants who were taking atazanavir-ritonavir, one in a pregnancy in a participant taking rilpivirine, and one in a pregnancy in a participant taking elvitegravir-cobicistat. (Additional data on perinatal HIV transmission are provided in Table S6.) Among the 95 infants born to participants who conceived while taking dolutegravir or received dolutegravir in the first trimester, 3 had major congenital anomalies reported: 1 case of syndactyly and 2 cases of polydactyly.
Model-based unadjusted and adjusted differences in the risk of adverse birth outcomes are shown in Figure 3. Adjusted risks of preterm birth were lower for all evaluated non-dolutegravir-based ART regimens than for dolutegravir, with risk differences ranging from -3.8 percentage points (elvitegravir-cobicistat vs. dolutegravir) to -7.6 percentage points (rilpivirine vs. dolutegravir); however, the variability around these estimated differences was large for all comparisons with dolutegravir, ranging from large decreases (risk differences as low as -18.8 percentage points, for atazanavir-ritonavir vs. dolutegravir) to large increases (risk differences as high as 8.8 percentage points, for raltegravir vs. dolutegravir). We also did not observe clear differences between any of the ART regimens and dolutegravir with respect to the other adverse birth outcomes.
We found no apparent patterns of differences in observed risks of adverse birth outcomes between any non-dolutegravir-based ART and dolutegravir stratified according to timing of ART initiation in pregnancy (Table S5). However, the observed risks of any adverse birth outcome were higher among participants who started taking dolutegravir, oral rilpivirine, raltegravir, or elvitegravir-cobicistat during pregnancy than among participants who conceived while taking those drugs.
|
|
| |
| |
|
|
|
