![]() 21 22 TFV-DP inhibits HIV-1 replication through incorporation into viral DNA by HIV reverse transcriptase, resulting in DNA chain-termination. Residual TFV is slowly released from cells into plasma for renal elimination by a combination of glomerular filtration and active tubular secretion. TFV is then phosphorylated by intracellular kinases to the active metabolite tenofovir diphosphate (TFV-DP). 20 Following penetration of TAF into the cells and hydrolysis of the isopropyl ester, the TFV-Ala conjugate is formed eventually releasing free TFV. In peripheral blood mononuclear cells (PBMCs), this is performed by the serine protease cathepsin A and in hepatocytes, by carboxyesterase 1. 19 TAF enters the cell via OATP1B1 and OATP1B3-mediated transport and is subject to ester hydrolysis. This protocol focuses on the study of tenofovir alafenamide (TAF), a phosphonamidate prodrug of the HIV-1 nucleotide reverse transcriptase inhibitor TAF. Furthermore, products that have fewer renal and bone mineral density side effects are also desirable given that TDF/FTC oral PrEP has been shown to decrease creatinine clearance and lower bone density. An effective, low-cost, method of HIV prevention that overcomes adherence challenges is needed. 14 Unless adherence improves, many women and men using oral TDF/FTC will remain unprotected. Pharmacological models suggest that while an individual only needs 2–3 doses per week of oral TDF/FTC to successfully prevent HIV infection via receptive anal intercourse, 6–7 doses per week are needed to successfully prevent HIV infection via receptive vaginal intercourse, because drug concentrations in the lower female genital tract after oral administration are 10 times lower than those found in the colorectal mucosa. These formulations along with the implant under study offer specific adherence advantages over daily oral PrEP. the Dapivirine ring 12 and possibly long-acting injectable ARVs, 13 are poised to be accessible soon. 7–10 Other novel long-acting PrEP agents and innovative delivery systems such as ARV containing intravaginal rings, viz. 11 Although daily oral PrEP has been shown to be consistently effective in men who have sex with men and transgender women globally, 5 6 results have been inconsistent in African women, most likely due to varying adherence. Since antiretrovirals (ARVs) were first shown by the CAPRISA 004 trial 4 in 2010 to prevent sexual transmission of HIV, the HIV prevention landscape has been transformed, principally through oral tenofovir (TFV)-containing pre-exposure prophylaxis (PrEP) 5–10 or through early ARV therapy initiation in HIV-positive individuals (treatment as prevention). 2 3 Despite their greater vulnerability, young women have limited access to non-user-dependent prevention options to reduce their risk for HIV acquisition. 1 Young women in this region are particularly vulnerable and acquire HIV infection 3–5 years earlier than their male peers. 1 Adolescent girls and young women in sub-Saharan Africa account for approximately 25% of all new HIV infections globally. Safety will be assessed by calculating the percentage change in creatinine clearance from baseline at weeks 4, 12, 24, 36, 72, 96 and 120, compared with the percentage change in the control group.ĭespite the global decline in HIV infections by 23% since 2010, the number of people who acquire HIV each year remains unacceptably high. ![]() The phase II component (Group 4) will assess extended safety, PK, tolerability and acceptability of the implant in 490 at risk women, randomised in a 1:1 ratio to the TAF implant and placebo tablet or to the placebo implant and an oral pre-exposure prophylaxis tablet. Data from this phase I trial will be used to determine the dosing, implant location and implant replacement interval for the phase II trial. The phase I trial (n=60) will assess the safety of one implant inserted in six participants (Group 1), followed by dose escalation components (Groups 2 and 3) assessing the safety, tolerability and PK of one to four TAF 110 mg implants releasing between 0.25 mg and 1 mg daily in 54 healthy women at low risk for HIV infection. Methods and analysis CAPRISA 018 is a phase I/II trial to evaluate the safety, acceptability, tolerability and pharmacokinetics (PKs) of a TAF free base subdermal silicone implant containing 110 mg of TAF with an anticipated 0.25 mg/day release rate. ![]()
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