Table:

Summary of new antiretroviral-based HIV prevention products and studies in women, including pregnant and breastfeeding populations (either ongoing or completed)

	Status of PrEP research in cisgender women	Inclusion of pregnant or breastfeeding women in study
Vaginal rings and gels
Dapivirine ring	MTN-029/IPM 039 phase 1, open-label study⁵² assessed the presence of dapivirine in blood, breast milk, and cervicovaginal fluid when delivered via a vaginal ring used continuously for 14 days	The study enrolled 16 healthy, women without HIV at least 6 weeks post partum, who were lactating but not breastfeeding, at two US sites
Dapivirine ring	MTN-043 (B-PROTECTED; NCT04140266) phase 3b, is evaluating safety in breastfeeding mother-infant pairs using dapivirine vaginal rings or tenofovir disoproxil fumarate plus emtricitabine in Malawi, South Africa, Uganda, and Zimbabwe	200 healthy, breastfeeding women without HIV and their healthy infants between 6–12 weeks old
Dapivirine ring	MTN-042 (DELIVER; NCT03965923) phase 3b, is evaluating maternal and infant safety in dapivirine vaginal rings or oral tenofovir disoproxil fumarate plus emtricitabine in pregnant women and their infants; cohort 1 accrual completed in April, 2021; recruitment of pregnant women in Malawi, South Africa, Uganda, and Zimbabwe is ongoing for another cohort	750 healthy, women without HIV who are 18–40 years old, pregnant with a single fetus
Dapivirine ring	Phase 3b open label extensions: MTN 025/H0PE⁵³ and DREAM (IPM 032)⁵⁴	22 pregnancies in DREAM (IPM 032); 53 pregnancies in MTN-025/HOPE; no congenital anomalies reported, no new safety signals with respect to available pregnancy outcome data in either study
Dapivirine ring	Phase 3 Ring Trial⁵⁵ assessed safety and efficacy in South Africa and Uganda	Pregnant and breastfeeding populations excluded; incident pregnancies reported to be the same in both groups
Dapivirine ring	Phase 3 MTN-020/ASPIRE trial⁵⁶ assessed safety and efficacy	No differences noted in pregnancy incidence or outcome in 169 incident pregnancies⁵⁷
Dapivirine ring	Phase 2a clinical trial (REACH; MTN-034)⁵⁸ enrolled 247 girls and young women in Kenya, South Africa, Uganda, and Zambia to evaluate safety and adherence to vaginal ring with dapivirine and oral PrEP in a crossover trial where they can choose either product or neither	Data among pregnant and breastfeeding populations are not anticipated from this trial due to pending data in MTN-042 and MTN-043
Vaginal tenofovir 1% gel^59,60	MTN-008^52,59,61 phase 1 study of daily tenofovir 1% vaginal gel use in term and near-term pregnancy appears to be safe and produces low serum drug concentrations;^59,60 the MTN-008 lactation cohort evaluated pharmacokinetics, pharmacodynamics, safety, and adherence profiles associated with 7 days of 1% tenofovir vaginal gel use^59,60	Pregnancy cohort randomly assigned (2:1) 98 healthy pregnant women for tenofovir or placebo gel for pharmacokinetic sampling; lactation cohort included 17 HIV-1-seronegative breastfeeding mother-infant pairs
Vaginal tenofovir 1% gel^59,60	MTN-002 phase 1 study, maternal serum drug concentrations were determined and fetal cord blood, amniotic fluid, placental tissue, and endometrial tissue specimens were collected	16 healthy pregnant women scheduled for caesarean delivery who received a single application of tenofovir gel preoperatively⁶¹
Implants and injectable long-acting formulations
Long-acting cabotegravir (integrase inhibitor)	HPTN 084 phase 3 study,^62,63 evaluated safety and efficacy of long-acting injectable cabotegravir in cisgender women (completed in 2021) in Botswana, Kenya, South Africa, Uganda, and Zimbabwe	14 pregnancies to date reported on in the long-acting cabotegravir group;^41,64 open label extension to include pregnant women
Implants and injectable long-acting formulations	Islatravir in a small removable implant could provide PrEP for more than 1 year^58,65	Data among pregnant and breastfeeding populations are not anticipated from ongoing or planned studies
Lenacapavir	Lenacapavir is a long-acting HIV-1 capsid inhibitor being tested as an injectable PrEP option administered every 6 months; the Women’s HIV Prevention Study (NCT04994509) will evaluate the efficacy of lenacapavir and tenofovir alafenamide plus emtricitabine (which are used together in some groups and separately in other groups) for PrEP in adolescent girls and young women at risk of HIV infection in the USA and South Africa	Participants who become pregnant after being randomly assigned can remain on the study after a reconsent process in which they will be informed of the benefits and risks of continuing to receive the study drug and possible birth outcomes for the child and information on lactation (GS-US-412–5624)
Oral formulations of antiretrovirals for HIV treatment as PrEP
Tenofovir alafenamide and emtricitabine	Phase 1 study of pharmacokinetic and pharmacodynamics and safety study in cisgender women (NCT02904369)	Pharmacokinetic study in pregnant and post-partum women in South Africa planned for 2022 (NCT04937881)
Oral islatravir (MK-8591) once monthly as PrEP	Phase 3 study of oral islatravir in the USA and sub-Saharan Africa including 4500 cisgender, non-pregnant, and breastfeeding women, at high risk for HIV-1 infection; the study will compare oral islatravir taken once a month with tenofovir disoproxil fumarate plus emtricitabine, taken once per day (NCT04644029)	Data among pregnant and breastfeeding populations are not anticipated from ongoing or planned studies
Raltegravir with or without lamivudine to protect from HIV infection (Raltegravir-PrEP)	Phase 4 open-label study determining ex-vivo protection for genital tissue, randomised pharmacokinetic and pharmacodynamics trial randomised according to gender (NCT03205566)	Data among pregnant and breastfeeding populations are not anticipated from ongoing or planned studies
Other novel approaches in the pipeline
Vaginal films	FAME-04:⁶⁶ phase 1 study showed vaginal films to be safe and well tolerated; 78 non-pregnant women without HIV were included	Data among pregnant and breastfeeding populations are not anticipated from ongoing or planned studies
Patches	Emerging formulation strategies for skin permeation are poised to open transdermal drug delivery allowing the development of new patch technologies to deliver antiretroviral drugs that were previously incapable of transdermal delivery⁶⁷	Data among pregnant and breastfeeding populations are not anticipated from ongoing or planned studies
Vaginal insert⁵⁸	Topical inserts deliver drugs to the portal of viral entry (ie, the genital mucosa), with low systemic exposure, and therefore could be safer and have fewer side-effects than systemic PrEP agents; topical inserts include CONRAD’s tenofovir alafenamide fumarate plus elvitegravir insert, and a tenofovir disoproxil fumarate plus emtricitabine insert; Population Council and PATH’s griffithsin plus carrageenan fast-dissolve insert; Osel’s MucoCept lactobacillus vaginal tablet; prototype extended-release elvitegravir osmotic insert, evaluated pre-clinically by CONRAD⁵⁸	Data among pregnant and breastfeeding populations are not anticipated from ongoing or planned studies
Multipurpose products that might incorporate contraception, HIV, or sexually transmitted infection prevention agents in a single product	Early phase 2 trials of pharmacokinetics, safety, and vaginal bleeding in 90-day use of dapivirine plus levonorgestrel ring⁶⁸	Data among pregnant and breastfeeding populations are not anticipated from ongoing or planned studies

We searched PubMed, ClinicalTrials.gov, and HIV trial network protocols to review ongoing or completed studies on new PrEP agents in cisgender women. We identified 14 ongoing or complete PrEP trials of novel agents in cisgender women, and six phase 1–3 clinical trials and open-label extensions in pregnant and breastfeeding populations. Here we summarise new antiretroviral-based HIV prevention products and studies that are either ongoing or completed in women and pregnant and breastfeeding populations. PrEP=pre-exposure prophylaxis.