Awaiting a Long-Acting PrEP Dosage Form

Topical microbicides delivered in vaginal rings are less toxic than oral dosage forms. These products achieve sufficient antiretroviral concentrations at the cervix to prevent HIV transmission through the vagina without a high serum burden. Vaginal rings encourage the near-absolute adherence necessary to avoid resistance-induced treatment failure and have less social stigma than oral antiretroviral dosage forms as well.

Dapivirine is a topical microbicide in the non-nucleoside-based reverse transcriptase inhibitor drug class. Researchers were reporting on dapivirine in vaginal rings, gels, and films as of early 2016.¹ The International Partnership for Microbicides, developer of a dapivirine ring product, will seek multinational regulatory approval in 2017 and expect product availability in 2018.²

The New England Journal of Medicine published a study (“ASPIRE”) in its December 1, 2016 issue supporting the use of vaginal rings for antiretroviral delivery.³

This phase 3, randomized, double-blind, placebo-controlled trial assessed the efficacy of a 25 mg dapivirine monthly vaginal ring in African women between the ages of 18 and 45. Patients were not pregnant, HIV-negative, and sexually active. Site providers counseled patients on proper device insertion and removal, HIV risk reduction, and the importance of maintaining placement for the entire month.

The study investigators measured adherence with serum and residual ring dapivirine levels. The device must be in place for at least 8 hours prior to measurement for serum drug levels to reach the benchmark (95 pg per mL). However, this method alone overestimates adherence because a patient needs to place the ring only 8 or more hours before the visit to achieve sufficient serum levels. The investigators added the second method a year into the 3 year-long trial period to relieve these concerns. The study sites determined patients to be adherent if the rings had less than 23.5 mg of dapivirine remaining. These methods assure patients do not remove and re-insert the vaginal rings between visits.

Most patients (82%) were adherent to the vaginal ring in this trial. HIV protection had a positive association with extensive vaginal ring adherence. This finding is unsurprising and supported by a litany of previous research.

Adherence increased during the first 12 months of use and remained consistent for at least 24 months. HIV incidence mirrored this trend.

Active arm patients under 21 years old had particularly low adherence and were at increased risk of contracting HIV than their age cohort in the placebo group. This young cohort has social reasons for high HIV risk (eg low HIV diagnosis and treatment and low contraceptive use) and biological reasons. Increased risky behavior because of the protective effects of the product may have driven this heightened risk. The vaginal ring may not provide adequate protection because of differences in the reproductive tract of young patients.

Moodley et al noted sharing of study product to be a considerable detriment to adherence. Patients received one of 5 study medications (tenofovir, emtricitabine/tenofovir (Truvada), and placebo products) and returned medications with incorrect patient identifiers and even products from a different treatment arm. Patients shared oral products because they considered the tenofovir products to be as-needed products. Patients shared the gel products (the most commonly shared dosage form) because the products increased sexual pleasure. Patients are less likely to share a vaginal ring because they cannot split it between friends and/or family members. Color coding products can reduce accidental sharing of products within a household. However, this effort is less important for vaginal rings because they are single-use products.⁴

The safety profile of the dapivirine ring product in the ASPIRE study was similar to the placebo and the findings of “The Ring Study” (the sister phase 3 trial by the International Partnership for Microbicides). Patients experienced abnormal uterine bleeding and pelvic discomfort or pain consistent with vaginal ring use. Active arm patients infected with HIV during use did not experience an increased risk of medication resistance.²

The probable counseling points for an antiretroviral vaginal ring upon market entry would combine the placement and removal advice of existing contraceptive vaginal rings with the safety and efficacy counseling of non-nucleoside inhibitors. For example, patients can insert Nuvaring while sitting, standing, or lying down and remove it with a single fingered hooking motion or with a two-fingered grasping motion. Patients can rinse and reinsert Nuvaring if accidentally expelled during sex or bowel movements.⁵ Prompt re-insertion may be critical with a dapivirine vaginal ring because the cervical tissue concentration drops rapidly after ring removal.⁶

Nuvaring is stored in a refrigerator prior to dispensing at room temperature (stable for up to 4 months). Patients should avoid exposing the product to sunlight and temperatures over 30 degrees Celsius prior to use. Nuvaring’s rubbery nature is from ethylene vinylacetate copolymers and a prospective dapivirine ring may include cellulose derivatives, polyvinyl alcohol, or povidone.⁵ Akil et al. found combined dapivirine with maraviroc or tenofovir products retain their purity for up to a year in these polymers without damaging the typical vaginal microflora.⁷ This exceeds the necessary stability for monthly use. Irritation and damaged microflora can increase the transmission of sexually transmitted infections including HIV.

The long-acting dapivirine vaginal ring may avoid the need for daily oral antiretroviral medication in uninfected women seeking HIV pre-exposure prophylaxis. A vaginal ring is a convenient (once monthly) and discreet prophylactic that may improve adherence and uptake of pre-exposure prophylaxis.

References

• Dapivirine. AIDSinfo website. https://aidsinfo.nih.gov/drugs/523/dapivirine/0/patient Updated March 13, 2016. Accessed December 20, 2016.
• Dapivirine Ring: Phase 3 results. International Partnership for microbicides. http://www.ipmglobal.org/our-work/our-products/dapivirine-ring/phase-iii-results Accessed December 20, 2016.
• Baeten JM, Palanee PT, Brown ER, et al. Use of a vaginal ring containing dapivirine for HIV-1 prevention in women. NEJM. 2016; 375(22):2121—2132.
• Moodley J, Naidoo S, Moodley J, Ramjee G. Sharing of investigational drug among participants in the Voice Trial. AIDS Behav. 2016; 20(11):2709—2714. .
• Nuvaring ® [package insert]. Whitehouse Station, NJ. Merck & Co., Inc.; 2016.
• Chen BA, Panther L, Marzinke MA, et al. Phase 1 safety, pharmacokinetics, and pharmacodynamics of dapivirine and maraviroc vaginal rings: a double-blind randomized trial. J Acquir Immune Defic Syndr. 2015; 70(3):242—249.
• Akil A, Agashe H, Dezzutti CS, et al. Formulation and characterization of polymeric films containing combinations of antiretrovirals (ARVs) for HIV prevention. Pharm Res. 2015; 32(2): 458—468. doi:10.1007/s11095-014-1474-4.