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Background: Long-acting (LA) injectable formulations of antiretroviral agents are being developed for HIV-1 prevention. The MWRI-01 Phase 1 study was undertaken to characterize the safety, acceptability, pharmacokinetic (PK), and pharmacodynamic (PD) profile of LA rilpivirine (RPV). Single dose (SD) data have previously been reported (McGowan I et al. Lancet HIV 2016). We now present data on the multiple dose (MD) phase of the study.
Methods: HIV-1 uninfected participants received three intramuscular doses of 1200 mg LA RPV at 2 month intervals. We collected plasma, genital/rectal fluids, and tissue (rectal (RT), cervical (CT), and vaginal (VT)) before and after exposure to LA RPV for assessment of PK and PD (ex vivo biopsy challenge with HIV-1). Clade B (HIV-1BaL) and Clade C (G147-1) viruses were used separately in the explant challenge model. The primary study objective was to characterize product safety and the analysis included all enrolled participants.
Results: We enrolled 8 women and 4 men. There were 195 adverse events reported, of which 193 (99%) were Grade 1 (71%) or Grade 2 (28%) and the majority were related to injection site discomfort. Table 1 provides the PK values (geometric mean; 90% Cl) for each compartment 56 days after dosing.


 PlasmaRTVTCT
 WomenMenWomenMenWomenWomen
Dose 139 (33-45)29 (17-40)46 (34-53)29 (17-40)22 (14-29)28 (23-33)
Dose 359 (45-73)40 (30-51)61(52-70)40 (30-51)40 (28-52)44 (22-66)
[Table 1: PK Data 56 Days After Injection (ng/mL)]


We found significant suppression of viral replication in RT for both Clade B (p< 0.05) and Clade C (p< 0∙0001) viruses at all time points in RT. In contrast, viral suppression was only seen in CT at Day 56 after the first dose of LA-RPV and at no time point for VT.
Conclusions: : MD administration of LA RPV was safe and well tolerated. As with our previous SD data, we saw prolonged suppression of viral replication in RT following exposure to LA RPV. Interestingly, despite modest accumulation of plasma RPV over time, there was minimal evidence of viral suppression in CT or VT.