Recommendations for the Use of Antiretroviral Drugs During Pregnancy and Interventions to Reduce Perinatal HIV Transmission in the United States

Recommendations for Use of Antiretroviral Drugs During Pregnancy

Pregnant People With HIV Who Have Never Received Antiretroviral Drugs (Antiretroviral-Naive)

Antiretroviral (ARV) regimens designated by the Panel on Treatment of HIV During Pregnancy and Prevention of Perinatal Transmission (the Panel) as Preferred regimens for pregnant people who have never received antiretroviral drugs (ARV naive) include a dual-nucleoside reverse transcriptase inhibitor (NRTI) combination (abacavir plus lamivudine [3TC] or tenofovir disoproxil fumarate [TDF], or tenofovir alafenamide [TAF] plus emtricitabine [FTC] or 3TC) used with either the ritonavir-boosted protease inhibitor darunavir/ritonavir (DRV/r) or the integrase strand transfer inhibitor (INSTI) dolutegravir (DTG).

The NRTI components are Preferred because they are recommended for nonpregnant adults and have several advantages, including reassuring pharmacokinetic (PK) data and extensive experience with use in pregnancy, once-daily dosing, and less toxicity than zidovudine plus 3TC.^1-3 TDF and TAF with either 3TC or FTC are also active against hepatitis B virus.

DTG is Preferred because it is associated with higher rates of viral suppression, faster rates of viral load (VL) decline, greater tolerability, and a higher genetic barrier to drug resistance than other Preferred or Alternative agents.^4-6 For example, two randomized clinical trials that compared DTG plus two NRTIs to efavirenz (EFV) plus two NRTIs in antiretroviral therapy (ART)-naive women who initiated therapy during pregnancy found that DTG-based ART produced more rapid viral suppression than EFV-based ART, with a greater proportion of women reaching an undetectable VL (<50 copies/mL) at the time of delivery.^7,8 Higher rates of viral suppression did not translate into statistically significantly lower rates of observed vertical transmission with DTG compared with EFV; transmission rates were low with both regimens and the studies were not powered to detect small differences.^8-10 DTG is also Preferred for use in pregnant people with early (acute or recent) HIV infection without a history of prior use of long-acting cabotegravir (CAB-LA) as pre-exposure prophylaxis (PrEP). Ritonavir-boosted darunavir (DRV/r) is Preferred for pregnant people with early (acute or recent) infection with prior CAB-LA exposure pending genotype test results, see Early (Acute or Recent) HIV.

Ritonavir-boosted DRV is also a Preferred option because its efficacy in pregnancy is well documented; in a recent large observational study, viral suppression with DRV/r was not statistically significantly different than DTG.¹¹ Importantly, however, although the use of once-daily dosing for DRV/r is approved for nonpregnant adults, PK data do not support once-daily dosing in pregnancy¹²; therefore, twice daily dosing is recommended (see Darunavir). Detailed advantages and disadvantages of each of these medications in pregnancy, as well as of those in the Alternative, Insufficient Data, Not Recommended, and Not Recommended Except in Special Circumstances categories, are shown in Table 6. What to Start: Initial Antiretroviral Regimens During Pregnancy for People Who Are Antiretroviral-Naive.

Regimens Other Than Combination (Three-Drug) ART Are Not Recommended

Although the Adult and Adolescent Antiretroviral Guidelines recommend some two-drug ARV regimens for nonpregnant ARV-naive people in certain clinical circumstances, two-drug ARV regimens are not recommended for initiation of ART in ARV-naive pregnant people because of a lack of data in pregnancy.

ARV-Naive People Who Present in the Third Trimester

INSTIs have an important role when ART is initiated late in pregnancy, particularly for people who have high viral loads, because of the documented ability of DTG and raltegravir (RAL) to suppress viral load rapidly (a decrease of approximately 2 log₁₀ copies/mL occurs by Week 2 of therapy with these drugs).^13-17 Based on available data, the Panel recommends DTG-based regimens as Preferred and RAL-based regimens as Alternative when initiating ART during pregnancy. See Table 6.

In the Dolutegravir in Pregnant HIV Women and Their Neonates (DolPHIN 2) study, 268 ART-naive women in Uganda and South Africa were randomized to receive DTG plus two NRTIs or EFV plus two NRTIs at a minimum of 28 weeks gestational age (median: 31 weeks). At delivery, women in the DTG arm were significantly more likely to achieve VLs of <50 copies/mL (74.1% vs. 42.7%; adjusted risk ratio 1.64 [1.31–2.06], P < 0.0001) than women in the EFV arm, with a faster time to reach VL <50 copies/ml (4.1 vs. 12.1 weeks).⁷ The International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) 1081 trial randomized 408 ART-naive women in South America, Africa, Thailand, and the United States who presented late in pregnancy (20 to <37 weeks gestation) to receive RAL plus two NRTIs or EFV plus two NRTIs. Among 307 women in the primary efficacy analysis, 84% in the EFV group and 94% in the RAL group achieved a VL of <200 copies/mL at or near delivery (absolute difference 10%; 95% confidence interval, 3% to 18%; P = 0.0015); the difference primarily occurred among women enrolling later in pregnancy (interaction P = 0.040). The median time to achieve a VL of <200 copies/mL was 8 days for women who received RAL-based ART and 15 days for women who received EFV-based ART. The decline in viral load was greater in the women who received RAL than in those who received EFV at 2, 4, and 6 weeks after initiation.¹⁸ Although RAL and DTG are likely to be similarly effective in reducing viral load rapidly, DTG is Preferred and RAL is Alternative because RAL requires twice-daily dosing and has a lower barrier to development of drug resistance than DTG (see Adult and Adolescent Antiretroviral Guidelines).

References

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2. Brooks K, Pinilla M, Shapiro D, et al. Pharmacokinetics of tenofovir alafenamide 25 mg with PK boosters during pregnancy and postpartum. Presented at: Workshop on Clinical Pharmacology of HIV, Hepatitis, and Other Antiviral Drugs; 2019. Noordwijk, Netherlands.
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8. Lockman S, Brummel SS, Ziemba L, et al. Efficacy and safety of dolutegravir with emtricitabine and tenofovir alafenamide fumarate or tenofovir disoproxil fumarate, and efavirenz, emtricitabine, and tenofovir disoproxil fumarate HIV antiretroviral therapy regimens started in pregnancy (IMPAACT 2010/VESTED): a multicentre, open-label, randomised, controlled, phase 3 trial. Lancet. 2021;397(10281):1276-1292. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33812487.
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10. Malaba TR, Nakatudde I, Kintu K, et al. 72 weeks post-partum follow-up of dolutegravir versus efavirenz initiated in late pregnancy (DolPHIN-2): an open-label, randomised controlled study. Lancet HIV. 2022;9(8):e534-e543. Available at: https://www.ncbi.nlm.nih.gov/pubmed/35905752.
11. Patel K, Huo Y, Jao J, et al. Dolutegravir in pregnancy as compared with current HIV regimens in the United States. N Engl J Med. 2022;387(9):799-809. Available at: https://www.ncbi.nlm.nih.gov/pubmed/36053505.
12. Schalkwijk S, Ter Heine R, Colbers A, et al. Evaluating darunavir/ritonavir dosing regimens for HIV-positive pregnant women using semi-mechanistic pharmacokinetic modelling. J Antimicrob Chemother. 2019;74(5):1348-1356. Available at: https://www.ncbi.nlm.nih.gov/pubmed/30715324.
13. Grinsztejn B, Nguyen BY, Katlama C, et al. Safety and efficacy of the HIV-1 integrase inhibitor raltegravir (MK-0518) in treatment-experienced patients with multidrug-resistant virus: a phase II randomised controlled trial. Lancet. 2007;369(9569):1261-1269. Available at: http://www.ncbi.nlm.nih.gov/pubmed/17434401.
14. Papendorp SG, van den Berk GE. Preoperative use of raltegravir-containing regimen as induction therapy: very rapid decline of HIV-1 viral load. AIDS. 2009;23(6):739. Available at: http://www.ncbi.nlm.nih.gov/pubmed/19279447.
15. Pinnetti C, Baroncelli S, Villani P, et al. Rapid HIV-RNA decline following addition of raltegravir and tenofovir to ongoing highly active antiretroviral therapy in a woman presenting with high-level HIV viraemia at week 38 of pregnancy. J Antimicrob Chemother. 2010;65(9):2050-2052. Available at: http://www.ncbi.nlm.nih.gov/pubmed/20630894.
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17. Waitt C, Orrell C, Walimbwa S, et al. Safety and pharmacokinetics of dolutegravir in pregnant mothers with HIV infection and their neonates: a randomised trial (DolPHIN-1 study). PLoS Med. 2019;16(9):e1002895. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31539371.
18. Joao EC, Morrison RL, Shapiro DE, et al. Raltegravir versus efavirenz in antiretroviral-naive pregnant women living with HIV (NICHD P1081): an open-label, randomised, controlled, phase 4 trial. Lancet HIV. 2020;7(5):e322-e331. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32386720.