Background: Long-acting (LA) injectable formulations of rilpivirine (RPV) and cabotegravir (CAB) are currently being evaluated for the treatment and prevention of HIV infection. It is possible that, following completion of the PrEP dosing regimen with an LA agent, participants may experience an extended period of exposure to declining antiretroviral concentrations. Individuals who acquire HIV infection during this period may be at risk of developing resistance to the agent. To mitigate this risk, the HPTN-083 Phase 2B/3 study of CAB LA PrEP is proposing to provide study participants with 12 months of oral PrEP to cover the LA PK tail. However, there is an urgent need to better define the PK tail for LA PrEP agents.
Methods: The MWRI-01 study was undertaken to characterize the safety, acceptability, pharmacokinetics (PK), and pharmacodynamic profile of RPV LA. Participants from the single dose (SD) phase of evaluation of RPV (600 mg and 1200 mg) were able to enroll in a multiple dose (MD) phase evaluation of RPV (1200 mg). This study design provided an opportunity to characterize the persistence of RPV in baseline plasma samples obtained from participants enrolled in the MD phase of the MWRI-01 study. The Lower Limit of Quantification for RPV was 0.5ng/mL. Multiple blanks were included in the PK assays to exclude the possibility of carryover contamination.
Results: Eight women and four men were enrolled in the MD phase of the study of whom 9/12 (75%) had participated in the SD phase of the study (Table 1). RPV was detected in baseline plasma samples all five female participants (Mean RPV concentration 4.8 ± 2.9 ng/mL) and 3/4 of the male participants (Mean RPV concentration 2.9 ± 1.6 ng/mL). The mean time interval between the SD and Baseline visit was 536 ± 182 and 591 ± 78 days respectively for the female and male participants.

SexSingle Dose (SD) of RPVPlasma RPV at 24 hours after SD RPV (ng/mL) Mean (± STD)Time (Days)between SD and Multiple Dose (MD) Baseline Visit Mean (± STD)Plasma RPV at MD Baseline Visit (ng/mL) Mean (± STD)
Male600 mg (N=2)20.9 (12.3)630 (100)0.8 (0.8)
 1200 mg (N=2)18.2 (3.7)553 (51)3.7 (1.1)
Female1200 mg (N=5)54.0 (12.1)536 (182)4.8 (2.9)
[Table 1 Summary of time interval between single dose RPV and baseline PK]

Conclusions: SD administration of RPV LA was associated with prolonged and declining PK exposure. These data have significant implications for the design of LA PrEP studies.