PROJECT SUMMARY/ ABSTRACT
Long‐acting injectables for antiretroviral therapy (ART) or pre‐exposure prophylaxis (PrEP) are the most
exciting recent advance in HIV medicine. The roll‐out of cabotegravir long‐acting (CAB LA) PrEP will be
expanded massively globally with the WHO advising this PrEP option in late July 2022. For any new PrEP
tool, determining the best way to avert failures is key, especially with CAB LA PrEP which can fail with
integrase inhibitor mutations, with implications for future management. The trials demonstrating that CAB LA
was superior to oral PrEP across populations employed single plasma levels of CAB as exposure metrics to
adjudicate failures. However, half of the breakthroughs in the trials were not explained by plasma CAB levels,
especially with on‐time injections, likely because of limitations of plasma levels. Drugs delivered via injection
elute from depot compartments at variable rates over time, making long‐term metrics of exposure important.
Our UCSF group has been working on long‐acting exposure metrics of antiretrovirals (ARVs) in hair
samples (which are easy to collect, store and ship) during the first iteration and first renewal of this R01 grant.
We have been highly productive over this R01 to date (publishing 72 papers), demonstrating important uses of
hair levels in the fields of HIV treatment, prevention, over the perinatal period, and in low‐income countries.
As PrEP is revolutionized with the availability (e.g. CAB) and promise (e.g. lenacapavir) of LA agents, drug
levels will play a critical role in determining the onset of protection, adjudicating failures, and assessing risks
with discontinuation; this renewal seeks to contribute to this important field. As an exploratory objective, we
will also develop an antibody to CAB to create a point‐of‐care urine assay, as we have with tenofovir.
This proposal will leverage three important trials to explore key knowledge gaps that will arise in the
next phase of LA PrEP. The Sustainable East Africa Research in Community Health (SEARCH) Sapphire trial is
evaluating a number of interventions to prevent and treat HIV, including the provision of CAB LA to 600 at‐
risk individuals across 10 communities in East Africa (Aim 1). The Botswana Harvard AIDS Institute
Partnership will launch a new study to provide women in the immediate postpartum period CAB LA PrEP
and follow mothers and their infants for 96 weeks, evaluating incident HIV and resistance, as well as the
pharmacokinetics (PK) of CAB and its transfer during breastfeeding (Aim 2). The PURPOSE 1 and 2 trials
(Gilead) will study lenacapavir LA (a new capsid inhibitor given every 6 months as a subcutaneous injection)
for PrEP in diverse populations and will incorporate hair collection in their open‐label extension phases. All 3
trials will collect hair and plasma for drug levels, and track robust outcomes, to allow us to 1) investigate hair
levels as predictors of failure; 2) determine maternal to infant transfer of CAB; and 3) assess contributors to PK
variability to LA PrEP in diverse populations. The overarching goal of this renewal is to develop highly
predictive biologic PK measures to optimize LA PrEP and to inform public health interventions in prevention.