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. 2020 Apr 6:21:100303.
doi: 10.1016/j.eclinm.2020.100303. eCollection 2020 Apr.

Safety and tolerability of injectable Rilpivirine LA in HPTN 076: A phase 2 HIV pre-exposure prophylaxis study in women

L G Bekker  1 , S Li  2 , S Pathak  2 , E E Tolley  3 , M A Marzinke  4 , J E Justman  5 , N M Mgodi  6 , M Chirenje  6 , S Swaminathan  7 , A Adeyeye  8 , J Farrior  3 , C W Hendrix  4 , E Piwowar-Manning  4 , P Richardson  4 , S H Eshelman  4 , H Redinger  2 , P Williams  9 , N D Sista  3 ; HPTN 076 Study Team
Affiliations

Safety and tolerability of injectable Rilpivirine LA in HPTN 076: A phase 2 HIV pre-exposure prophylaxis study in women

L G Bekker et al. EClinicalMedicine. .

Abstract

Background: Daily oral TDF/FTC is protective against HIV infection when used for pre-exposure prophylaxis (PrEP). However, daily adherence to oral PrEP is difficult for many; therefore, finding alternative PrEP strategies remains a priority. HPTN 076 evaluated the long-acting injectable form of rilpivirine (RPV), known as RPV LA for safety, pharmacokinetics and acceptability.

Methods: HPTN 076 (NTC 02165202) was a phase 2, double-blind, 2:1 randomized trial comparing the safety of 1200mg RPV LA (LA) to placebo (P). The study included a 28-day oral run-in phase of daily, self- administered oral RPV (25 mg), with directly observed oral dosing about six times. Of 136 enrolled sexually active, HIV-uninfected, low HIV-risk African (100) and US (36) adult women, injectable product was administered in two gluteal, intramuscular (IM) injections once every eight weeks to 122 participants following the oral run-in phase. A maximum of six injection time points occurred over a 48-week period. Acceptability, safety, tolerability and pharmacokinetic (PK) data were collected throughout the study. This paper includes primary endpoint data collected up to the week 52 post enrollment.

Findings: The median age of the enrolled population was 31 years (IQR: 25,38), median weight 75 kg (IQR: 64, 89), median body mass index (BMI) 30 (IQR: 27, 35), 46% married, 94% Black and 60% unemployed. A total of 122 (80 LA, 42 P) women received at least one injection and 98 (64 LA, 34 P) received all six injections. During the injection phase, three women withdrew from the study (2 LA, 1 P) and 16 women discontinued study product (10 LA, 6 P). Fourteen women (11 LA and 3 P) discontinued oral study product and did not enter the injection phase. Study product discontinuations were not significantly different between the two arms throughout. Of the product discontinuations in the injection phase, 8% in LA and 5% in P arm were due to adverse events (AEs), including one randomized to the P arm with prolonged QTc interval on EKG. The proportion of women who experienced Grade 2 or higher AEs during the injection phase as the primary outcome was not significantly different between the two arms [73.8%, 95% CI: (63.2%, 82.1%) for LA and 73.8%, 95% CI: (58.9%, 84.7%), p>0.99]. Transient Grade ≥2 liver abnormalities occurred in 14% of women in the LA arm compared with 12% in P arm. Three LA women (4%) developed Grade 3 injection site reactions compared with none in P arm. In participants who received at least 1 injection, the geometric mean of overall RPV trough concentrations (Ctrough) was 62.2 ng/mL. In participants who received all six injections, the geometric mean of CTrough through the injection phase and after the last injection were 72.8 ng/mL and 100.9 ng/mL, respectively. At week 52 (eight weeks after last injection), the geometric mean of RPV Ctrough was 75.0 ng/mL. At the last injection visit (Week 44), 80 % of women who answered acceptability questions strongly agreed that they would think about using- and 68% that they would definitely use a PrEP injectable in the future.

Interpretation: RPV LA IM injections every eight weeks in African and US women were safe and acceptable. Overall, despite more injection site reactions and pain in the participants receiving RPV LA the injections were well tolerated. Data from this study support the further development of injectable PrEP agents.

Keywords: RPV LA as Pre exposure prophylaxis.

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Conflict of interest statement

Linda-Gail Bekker serves on advisory boards and has received honoraria from Merck, GSK and Gilead. She has also been recipient of donated antivirals for clinical trials from Gilead. Craig W. Hendrix reports grants from NIH during the conduct of the study. He also reports grants from Gilead, ViiV/GSK, the Gates Foundation, and Merck, as well as personal fees and non-financial support from Merck, non-financial support from Gilead outside the submitted work. In addition, he has a patent US 10, 092, 509 B2 issued to Johns Hopkins University. Mark Marzinke reports grants from NIH during the conduct of the study and grants from NIH and ViiV/GSK outside the submitted work. Peter Williams reports other support from Johnson & Johnson, outside the submitted work.

Figures

Fig 1
Fig. 1
Schema of the HPTN 076 study.
Fig 2
Fig. 2
Consort diagram for HPTN 076.
Fig 3
Fig. 3
Plasma RPV concentration by visit among the participants who received at least one injection (top panel) and among the participants who received all six injections (bottom panel). Small dots represent individual participants’ RPV concentrations, big dots represent the geometric means connected by solid lines between visits, and shaded area represent the 90% prediction intervals. PA-IC90 (12.5ng/mL) is protein-adjusted concentration required for 90% viral inhibition.
Fig 4a
Fig. 4a
Participants’ likes and dislikes of an injectable PrEP product at baseline.
Fig 4b
Fig. 4b
Recommendations for injectable changes, by arm, at week 28.
See this image and copyright information in PMC

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