Role of Dolutegravir/Lamivudine in the Management of Pregnant People Living with HIV-1: A Narrative Review

Abstract

Lowering viral load during pregnancy is regarded as the most important method of reducing human immunodeficiency virus 1 (HIV-1) vertical transmission risk, and minimizing fetal exposure to drugs is a guiding principle during pregnancy. Dolutegravir/lamivudine (DTG/3TC) has demonstrated high efficacy, a high barrier to resistance, and a good safety profile in non-pregnant individuals; however, DTG/3TC is not recommended by perinatal HIV treatment guidelines for initial therapy in pregnant people living with HIV-1 because of limited data on use of the 2-drug regimen during pregnancy. Efficacy and pharmacokinetic data from pregnant individuals using DTG and/or 3TC are reviewed and used to extrapolate anticipated DTG/3TC efficacy in pregnancy. There are robust data on the use of DTG- and 3TC-containing combination regimens, which are recommended by perinatal HIV treatment guidelines during pregnancy, supporting their well-established efficacy and safety in pregnant people living with HIV-1. Updated data from the Tsepamo and Eswatini surveillance studies (> 14,000 DTG exposures from conception) indicate no increased risk of neural tube defects with DTG. Pharmacokinetic data for DTG and 3TC indicate that exposures in pregnancy are within the therapeutically effective range seen in non-pregnant adults. Two studies evaluated DTG/3TC during pregnancy and both reported high virologic suppression rates [HIV-1 ribonucleic acid (RNA) < 50 copies/mL at delivery: 97% (30/31) overall], no events of vertical transmission, and no new safety signals, consistent with the use of DTG-based 3-drug regimens in pregnancy. The use of DTG/3TC during pregnancy is anticipated to be comparably effective and well tolerated for both parental health and prevention of vertical transmission with fetal exposure to fewer antiretrovirals compared with 3- or 4-drug regimens. These considerations are relevant when evaluating use of DTG/3TC in people living with HIV-1 who are pregnant or considering pregnancy in clinical practice and in perinatal HIV treatment guidelines.Video abstract available for this article. Supplementary file1 (MP4 319,147 KB).

Keywords: Antiretroviral therapy; Dolutegravir/lamivudine; HIV-1; Integrase strand transfer inhibitor; Pregnancy; Vertical transmission.

Fig. 1

Efficacy of DTG-based 3DRs in pregnant people living with human immunodeficiency virus 1 (HIV-1). 3DR 3-drug regimen, 3TC lamivudine, ART antiretroviral therapy, DTG dolutegravir, EFV efavirenz, FTC emtricitabine, NR not reported, TAF tenofovir alafenamide, TDF tenofovir disoproxil fumarate. ^aParticipants were naive to ART with the following exceptions: ≤ 14 days of ART during current pregnancy, previous use of TDF or TDF/FTC for pre-exposure prophylaxis, or use of ART during previous pregnancies (last dose ≥ 6 months ago)^bOf 617 liveborn infants, 561 had at least 1 HIV test result available; N not reported for each treatment group

Fig. 2

Prevalence of birth defects by earliest trimester of exposure to ART (APR through July 31, 2023). 3TC lamivudine, APR Antiretroviral Pregnancy Registry, ART antiretroviral therapy, DTG dolutegravir, MACDP Metropolitan Atlanta Congenital Defects Program, TBDR Texas Birth Defects Registry. ^aBlue dotted line upper 95% CI for MACDP, 2.8%^bRed dotted line upper 95% CI for TBDR, 4.2%

Fig. 3

Summary of the safety profiles of DTG and 3TC during pregnancy. 3TC lamivudine, ABC abacavir, APR Antiretroviral Pregnancy Registry, ART antiretroviral therapy, DTG dolutegravir, EFV efavirenz, MACDP Metropolitan Atlanta Congenital Defects Program, NTD neural tube defect, TBDR Texas Birth Defects Registry. ^a2.72, 2.92, and 4.17 per 100 live births from MACDP, APR, and TBDR, respectively^bPregnant individuals were from Russia and Spain^cIncluded data from the DolPHIN-1, DolPHIN-2, ADVANCE, NAMSAL, and IMPAACT 2010 (VESTED) clinical trials. DolPHIN-1 and DolPHIN-2 were conducted in South Africa and Uganda, ADVANCE in South Africa, and NAMSAL in Cameroon. IMPAACT 2010 (VESTED) was implemented at 22 sites across North and South America, Asia, and sub-Saharan Africa

Fig. 4

a DTG plasma concentration–time profiles in pregnant versus postpartum/non-pregnant people living with HIV-1, and b PK parameters of DTG in pregnant versus non-pregnant adults. AUC area under the plasma concentration–time curve, C₂₄ observed plasma concentration at 24 h, Cmin minimum observed plasma concentration, CV coefficient of variation, DTG dolutegravir, NR not reported, PA-IC₉₀ protein-adjusted 90% inhibitory concentration, PK pharmacokinetics. ^aData are median (IQR)^bData are geometric mean (range)^cData are geometric mean (%CV)

Fig. 5

a 3TC plasma concentration–time profiles in pregnant versus postpartum/non-pregnant people living with HIV-1, and b PK parameters of 3TC in pregnant versus non-pregnant adults. 3TC lamivudine, AUC area under the plasma concentration–time curve, PI prediction interval, PK pharmacokinetics. ^aData are geometric least squares mean (95% CI)^bData are median^cData are mean (SD)

Fig. 6

Efficacy of DTG/3TC in pregnant people living with HIV-1. 3TC lamivudine, ABC abacavir, ART antiretroviral therapy, DTG dolutegravir, FTC emtricitabine, TDF tenofovir disoproxil fumarate. ^a1 participant naive to ART had HIV-1 RNA 53 copies/mL at delivery^b1 participant had HIV-1 RNA 35 copies/mL at delivery, and 2 had HIV-1 RNA > 1500 copies/mL at delivery^c3/11 participants in the DTG/3TC group and 4/13 in the DTG + ABC/3TC or DTG + TDF/FTC group were naive to ART^dParticipants were naive to ART and initiated DTG/3TC between 14 and 28 weeks of gestation