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Lenacapavir PrEP Shows Stable Pharmacokinetics and Minimal Infant Exposure During Pregnancy and Lactation
In a planned substudy of the phase 3 PURPOSE 1 trial, subcutaneous lenacapavir showed no statistically significant changes in drug exposure across pregnancy trimesters, and breastfed infants received only a small fraction of maternal drug levels, with a median infant-to-maternal plasma ratio of just 0.02 (IQR 0.01–0.05). Safety profiles were broadly comparable across treatment arms, and pregnancy loss rates were similar or lower in the lenacapavir group, supporting the drug’s potential suitability for use throughout pregnancy and the postpartum period.
What Was Studied
This substudy investigated HIV acquisition, safety, and pharmacokinetics of lenacapavir used as HIV pre-exposure prophylaxis (PrEP) in women who became pregnant or were lactating during the parent trial. The question was particularly urgent because pregnancy and lactation represent periods of heightened biological and social vulnerability to HIV acquisition, yet this population has historically been excluded from PrEP efficacy trials.
How It Was Studied
The PURPOSE 1 study was a randomised, double-blind, multicentre, active-controlled phase 3 trial enrolling cisgender adolescent girls and young women aged 16–25 years across multiple sites. Participants were assigned in a 2:2:1 ratio to receive subcutaneous lenacapavir every 26 weeks, daily oral emtricitabine-tenofovir alafenamide (F/TAF), or daily oral emtricitabine-tenofovir disoproxil fumarate (F/TDF). Those who became pregnant were invited to continue their assigned study drug within a pre-planned substudy after providing additional informed consent. The substudy included 487 participants who experienced one or more pregnancies (509 total pregnancies, 512 pregnancy outcomes, including three sets of twins), with a median age of 21 years. Lenacapavir concentrations were measured in maternal plasma, breastmilk, and breastfed infant plasma to characterise drug transfer and exposure.
What Was Observed
- Pharmacokinetics remained stable across pregnancy: Population pharmacokinetic modelling found no statistically significant differences in lenacapavir plasma exposure by trimester or during the postpartum period compared with non-pregnant participants, indicating that pregnancy does not meaningfully alter drug levels.
- Infant drug exposure via breastmilk was minimal: Although lenacapavir was detectable in breastmilk at a median breastmilk-to-plasma ratio of 0.52 (IQR 0.38–0.77) across 102 mother-infant pairs, the amount reaching the infant’s bloodstream was very small — a median breastfed-infant-to-maternal plasma ratio of only 0.02 (IQR 0.01–0.05) in 98 pairs.
- Pregnancy loss rates were similar or lower on lenacapavir: Pregnancy losses occurred in 31% (60/195) of outcomes in the lenacapavir group, compared with 41% (89/219) in the F/TAF group and 42% (41/98) in the F/TDF group. Livebirths were also numerically higher on lenacapavir at 66% (128/195) versus 54% and 57% in the oral comparator arms, though this substudy was not powered to draw formal comparative conclusions.
- Injection site reactions were common but mild: Among lenacapavir-treated pregnant participants, 33% (44/132) reported injection site reactions, but all were grade 1 or 2 in severity and none resulted in treatment discontinuation. Overall adverse event rates during pregnancy and postpartum were balanced across all three arms.
Why This Matters
Pregnant and lactating women face disproportionately elevated risk of HIV acquisition, yet they are frequently absent from the clinical trials that generate PrEP safety and dosing data. This substudy provides the first pharmacokinetic and safety characterisation of lenacapavir PrEP in this population, directly addressing an evidence gap that has constrained prescribing guidance. The finding of stable drug exposure during pregnancy and negligible infant plasma exposure during breastfeeding removes two major pharmacological uncertainties that would otherwise impede clinical use.
How to Read This Result
While the pharmacokinetic and safety signals are reassuring and the study design is high-quality, the substudy was not statistically powered to detect differences in HIV acquisition or pregnancy outcomes between arms, pregnancy outcome data relied partly on self-report, and entry after conception rather than before it introduces the possibility of selection bias.
Limitations
Participants entered the substudy only after becoming pregnant rather than at enrolment, which may have introduced selection bias by favouring women who remained willing and able to continue the assigned regimen. The substudy was not powered to formally compare HIV acquisition rates between treatment arms during pregnancy. Additionally, pregnancy outcomes — including losses — were determined in part through participant self-report rather than exclusively through clinical ascertainment, which may affect the precision of those estimates.