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Biodegradable TAF Implants Protect
6 of 6 Macaques From Vaginal SHIV
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HIVR4P Virtual, January 27-28 and February 3-4, 2021
Mark Mascolini
Biodegradable tenofovir alafenamide (TAF) implants delivering a total dose of 0.7 mg daily yielded high tenofovir-diphosphate (TFV-DP) levels in peripheral blood mononuclear cells (PBMCs) and protected 6 of 6 macaques from vaginal SHIV infection through 6 weeks of twice-weekly low-dose SHIV challenges [1]. But protection from SHIV came at the cost of "marked deep dermal necrosis" at 8 of 12 implant sites.
To overcome inconsistent adherence to daily preexposure prophylaxis (PrEP) pills, researchers are studying novel oral antiretrovirals, injectable agents, intravaginal rings, and implants. This study by Centers for Disease Control and Prevention (CDC) researchers assessed protection from vaginal SHIV challenge with thin-film polymer implants releasing TAF, a potent tenofovir prodrug that provides high and prolonged PBMC levels of TFV-DP, the active form of TAF. (SHIV, or simian HIV, combines genetic elements of simian immunodeficiency virus [SIV] and HIV.) Oral emtricitabine/TAF at 22/1.5 mg/kg proved 91% to 100% effective in protecting macaques from vaginal or rectal SHIV [2,3]. Single-agent oral TAF at a dose of 1.5 mg/kg protected macaques from SHIV with 58% to 83% efficacy. The CDC researchers believe the threshold for high protection probably lies above 350 fmol/1 million cells.
Compatible with current contraceptive trocar applicators, polycaprolactone (PCL) implants passively release core biofluids through the PCL membrane at a constant rate. They are biocompatible and biodegradable and can be retrieved if necessary. In TAF implant studies in macaques, low-dose (0.17/d) TAF maintained a median TFV-DP level of 378.5 fmol/1 million cells over 8 weeks; mid-dose (0.35 mg/d) TAF yielded median TFV-DP levels of 868.5 fmol/1 million cells through 11 weeks; and high-dose (0.7 mg/d) TAF yielded median TFV-DP levels of 1619 fmol/1 million cells through 20 weeks.
In 3 female pigtailed macaques mid-dose (0.35 mg/d) TAF implants placed subcutaneously in the right arm yielded a median TFV-DP concentration of 3870 fmol/1 million cells in right axillary lymph nodes versus 307.8 fmol/1 million cells in left axillary nodes and 50.7 fmol/1 million cells in vaginal lymphocytes.
In the efficacy study 6 pigtailed macaques received 2 mid-dose TAF implants, 1 in each arm, to yield a total release rate of 0.7 mg/d. Researchers exposed the animals to a low dose of SHIV162p3 twice weekly for 6 weeks. They collected blood twice weekly to check for SHIV infection and to monitor drug levels. And they compared SHIV infection outcomes with 2 real-time macaque controls without TAF implants and 6 historical controls. The investigators removed the implants 1 week after the last SHIV challenge.
Through 6 weeks of vaginal SHIV challenge, an additional no-challenge week with the implant in place, and 15 weeks after that with no implant and no challenges, all 6 implanted macaques remained free of SHIV infection. In contrast, 7 of 8 control macaques (with no implant) became infected by week 5 (P = 0.0037 versus 6 TAF-implanted macaques).
During the 6 weeks with implants in place, TFV-DP exposure in PBMCs remained high (median 1519 fmol/1 million cells). After implant removal at week 7, TFV-DP levels dropped steadily and reached an undetectable level at week 13. The researchers calculated TFV-DP half-life at 7.1 days.
Of the 12 implant sites (1 in each arm of each macaque), only 1 had minimal adverse skin reactions observed during the 6 weeks of challenge. However, hematoxylin and eosin staining showed "marked deep dermal necrosis" at week 7 in 8 of 12 skin biopsies.
The CDC investigators noted that two previous studies of PCL TAF implants in macaques disagreed on whether those implants had a pathological impact, as they did in this study. The researchers called for dose-ranging efficacy studies to define the lowest TAF level that provides full protection with subcutaneous single-agent TAF formulations. They proposed that "improved delivery platforms for TAF that maintain high TFV-DP levels while reducing local toxicity have the potential to provide long-acting protection against vaginal HIV infection."
References
1. Massud I, Nishiura K, Ruone S, et al. High protection against vaginal SHIV infection in macaques by a biodegradable implant releasing tenofovir alafenamide. HIVR4P (HIV Research for Prevention) Virtual, January 27-28 and February 3-4, 2021. Abstract OA02.01.
2. Massud I, Mitchell J, Babusis D, et al. Chemoprophylaxis with oral emtricitabine and tenofovir alafenamide combination protects macaques from rectal simian/human immunodeficiency virus infection. J Infect Dis. 2016;214:1058-62. doi: 10.1093/infdis/jiw312.
3. Massud I, Cong ME, Ruone S, et al. Efficacy of oral tenofovir alafenamide/emtricitabine combination or single-agent tenofovir alafenamide against vaginal simian human immunodeficiency virus infection in macaques. J Infect Dis. 2019;220:1826-1833. doi: 10.1093/infdis/jiz383.
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