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Review
. 2021 Jun;37(6):409-420.
doi: 10.1089/AID.2021.0028.

Tenofovir Alafenamide for HIV Prevention: Review of the Proceedings from the Gates Foundation Long-Acting TAF Product Development Meeting

Joseph W Romano  1 , Marc M Baum  2 , Zach R Demkovich  3 , Frank Diana  4 , Charles Dobard  5 , Paul L Feldman  6 , J Gerardo Garcia-Lerma  5 , Alessandro Grattoni  7 , Manjula Gunawardana  2 , Duy-Khiet Ho  8 , Thomas J Hope  9 , Ivana Massud  5 , Mark Milad  10 , John A Moss  2 , Fernanda P Pons-Faudoa  7 , Shane Roller  6 , Ariane van der Straten  11   12 , Selvi Srinivasan  8 , Ronald S Veazey  13 , Doris Zane  14
Affiliations
Review

Tenofovir Alafenamide for HIV Prevention: Review of the Proceedings from the Gates Foundation Long-Acting TAF Product Development Meeting

Joseph W Romano et al. AIDS Res Hum Retroviruses. 2021 Jun.

Abstract

The ability to successfully develop a safe and effective vaccine for the prevention of HIV infection has proven challenging. Consequently, alternative approaches to HIV infection prevention have been pursued, and there have been a number of successes with differing levels of efficacy. At present, only two oral preexposure prophylaxis (PrEP) products are available, Truvada and Descovy. Descovy is a newer product not yet indicated in individuals at risk of HIV-1 infection from receptive vaginal sex, because it still needs to be evaluated in this population. A topical dapivirine vaginal ring is currently under regulatory review, and a long-acting (LA) injectable cabotegravir product shows strong promise. Although demonstrably effective, daily oral PrEP presents adherence challenges for many users, particularly adolescent girls and young women, key target populations. This limitation has triggered development efforts in LA HIV prevention options. This article reviews efforts supported by the Bill & Melinda Gates Foundation, as well as similar work by other groups, to identify and develop optimal LA HIV prevention products. Specifically, this article is a summary review of a meeting convened by the foundation in early 2020 that focused on the development of LA products designed for extended delivery of tenofovir alafenamide (TAF) for HIV prevention. The review broadly serves as technical guidance for preclinical development of LA HIV prevention products. The meeting examined the technical feasibility of multiple delivery technologies, in vivo pharmacokinetics, and safety of subcutaneous (SC) delivery of TAF in animal models. Ultimately, the foundation concluded that there are technologies available for long-term delivery of TAF. However, because of potentially limited efficacy and possible toxicity issues with SC delivery, the foundation will not continue investing in the development of LA, SC delivery of TAF products for HIV prevention.

Keywords: HIV PrEP; TAF; long-acting.

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Conflict of interest statement

I.M. and J.G.G-L. are named in U.S. Government patents or patent applications on methods of HIV prevention by chemoprophylaxis; J.W.R., M.M.B., Z.R.D., F.D., C.D., P.L.F., A.G., M.G., D.-K.H., T.J.H., M.M., J.A.M., F.P.P.-F., S.R., A.v.d.S., S.S., R.S.V., D.Z. all declare no conflict of interests.

Figures

FIG. 1.
FIG. 1.
The plasma PKs were characterized for the homopolymer drugamer depots with a benzyl carbamate linker, p(Benzyl-TAFMA) with 54.5 drug wt% TAF, or an alkyl carbamate linker, p(Alkyl-TAFMA) with 73 drug wt% TAF. The polymers were formulated in DMSO at the polymer concentration of 625 and 465 mg/mL, respectively. The final dosing volume was 20 μL that corresponded to the 6.77 mg TAF/mouse. Plasma was collected at designated time points (4 h, 1, 3, 6, 9, 12, 16, 20, 25, 30, 40, 50, and 60 days). LC-MS/MS measurements of TFV and TAF were performed with isotope-labeled standards. All animal procedures and handling were performed with the approval of the Institutional Animal Care and Use Committee and kept in accordance with federal and state policies on animal research at the University of Washington. Female BALB/cJ mice, aged 6–8 weeks at time of experiments, were obtained from Jackson Laboratory (Bar Harbor, ME). n = 3 mice per data points. Blue circle: plasma TFV from the p(benzyl-TAFMA), green diamond: plasma TFV from p(alkyl-TAFMA), and red square: plasma TAF from p(alkyl-TAFMA). No TAF was measurable in the p(benzyl-TAFMA) depot. Dash lines are logarithmic trendlines. DMSO, dimethyl sulfoxide; LC-MS, liquid chromatography-mass spectrometry; TAF, tenofovir alafenamide; TFV, tenofovir.
FIG. 2.
FIG. 2.
The osmotic mini-pump is placed in the subdermal space. Interstitial fluid flows consistently and predictably through the semipermeable membrane into the osmotic engine compartment that contains NaCl tablets. Mixing of the salt with fluid causes expansion of the osmotic engine compartment that pushes a piston resulting in formulated drug being expelled through the diffusion moderator into the SC space where drug is absorbed into the systemic circulation. NaCl, sodium chloride; SC, subcutaneous.
FIG. 3.
FIG. 3.
(A) Scanning electron microscopy image of the surface of the nanofluidic membrane, showing the inlet of the slit-nanochannels and the dense channel array. (B) Nanofluidic implant displaying the two loading and venting ports with self-sealing septa (top) and the nanochannel membrane (pink) assembled within the titanium drug reservoir (bottom).
FIG. 4.
FIG. 4.
Stage 1, scab, slight erythema; stage 2, slight swelling at dose site, scab, slight edema; stage 3, mild-to-moderate edema, scab, swelling, ocular discharge, emesis; stage 4, macroscopic descriptions of swelling and/or firmness in the interscapular implant sites, no expressible fluid; stage 5, slight swelling, emesis, red-tinged material at dose site and yellow discharge; mild edema, mild erythema.
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References

    1. Van Damme L, Corneli A, Ahmed K, et al. : Preexposure prophylaxis for HIV infection in African women. N Engl J Med 2012;367:411–422 - PMC - PubMed
    1. Marrazzo J, Ramjee G, Richardson BA, et al. : Tenofovir based preexposure prophylaxis for HIV infection among African women. N Engl J Med 2015;372:509–518 - PMC - PubMed
    1. Markowitz K, Frank I, Grant RM, et al. : Safety and tolerability of long acting cabotegravir injection in HIV uninfected men (ÉCLAIR): A multi-centered, double blind, randomized, placebo controlled, phase 2A trial. Lancet HIV 2017;4:e331–e340 - PubMed
    1. Swindells S, Abdrade-Villanueva JF, Richmond GJ, et al. : Long-acting cabotegravir and rilpivirine for maintenance of HIV suppression. N Engl J Med 2020;382:1112–1123 - PubMed
    1. Baeten JM, Phillips TP, Brown ER, et al. : Use of a vaginal ring containing dapivirine for HIV-1 prevention in women. N Engl J Med 2016;375:2121–2132 - PMC - PubMed

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