e Oral or topical daily administration of antiretroviral (ARV) drugs to HIV-1-negative individuals in vulnerable populations is a promising strategy for HIV-1 prevention. Adherence to the dosing regimen has emerged as a critical factor determining efficacy outcomes of clinical trials. Because adherence to therapy is inversely related to the dosing period, sustained release or long-acting ARV formulations hold significant promise for increasing the effectiveness of HIV-1 preexposure prophylaxis (PrEP) by reducing dosing frequency. A novel, subdermal implant delivering the potent prodrug tenofovir alafenamide (TAF) with controlled, sustained, zero-order (linear) release characteristics is described. A candidate device delivering TAF at 0.92 mg day ؊1 in vitro was evaluated in beagle dogs over 40 days for pharmacokinetics and preliminary safety. No adverse events related to treatment with the test article were noted during the course of the study, and no significant, unusual abnormalities were observed. The implant maintained a low systemic exposure to TAF (median, 0.85 ng ml ؊1 ; interquartile range [IQR], 0.60 to 1.50 ng ml ؊1 ) and tenofovir (TFV; median, 15.0 ng ml ؊1 ; IQR, 8.8 to 23.3 ng ml ؊1 ), the product of in vivo TAF hydrolysis. High concentrations (median, 512 fmol/10 6 cells over the first 35 days) of the pharmacologically active metabolite, TFV diphosphate, were observed in peripheral blood mononuclear cells at levels over 30 times higher than those associated with HIV-1 PrEP efficacy in humans. Our report on the first sustained-release nucleoside reverse transcriptase inhibitor (NRTI) for systemic delivery demonstrates a successful proof of principle and holds significant promise as a candidate for HIV-1 prophylaxis in vulnerable populations. O ral or topical daily administration of antiretroviral (ARV) drugs to HIV-1-negative individuals in vulnerable populations is a promising strategy for HIV-1 prevention, but clinical outcomes have varied widely (1-3). Adherence to frequent dosing is burdensome to the user and has emerged as a key factor in explaining the heterogeneous efficacy outcomes of HIV-1 preexposure prophylaxis (PrEP) clinical trials (4-7). It is well established across different delivery methods that adherence to therapy is inversely related with the dosing period (8-11). Sustained-release or long-acting ARV formulations hold significant promise as a means of reducing dosing frequency, thereby increasing the effectiveness of HIV-1 PrEP.Long-acting preexposure prophylaxis (LA-PrEP) is an alternative regimen to daily dosing designed to mitigate the abovedescribed adherence challenges (12, 13). LA-PrEP has been based primarily on ARV nanoparticles for parenteral administration as injections (12,14). Dosing intervals of 1 month or longer for injectable, long-acting, nanomilled formulations of the integrase strand-transfer inhibitor cabotegravir (GSK1265744) and the nonnucleoside reverse transcriptase inhibitor (NNRTI) rilpivirine are undergoing clinical evaluation as possible regimens for H...
Recent clinical trials have demonstrated that pre-exposure prophylaxis (PrEP) may prevent HIV infection in a significant number of HIV-1 negative individuals in venerable populations; however, trial efficacy has been highly variable, with notable successes and failures. Poor adherence to PrEP regimens has been implicated as a primary factor in determining efficacy of these trials. With the exception of CAPRISA 004 where use of a pericoital tenofovir gel led to a 39% reduction in HIV infection, all successful PrEP regimens to date have used the disoproxil fumarate ester prodrug of tenofovir (TDF) alone or in combination with emtricitabine (FTC). A sustained-release, intravaginal ring (IVR) formulation of TDF holds promise for improving adherence and, thus, increasing the effectiveness of PrEP. Here, a novel IVR delivering TDF with sustained zero-order release characteristics that may be controlled over nearly two orders of magnitude is described. Pod-IVRs containing 1-10 pods delivering TDF at 0.01 – 10 mg d−1 were fabricated and their release characteristics evaluated in vitro. The pod-IVRs stabilized TDF against hydrolytic degradation both in storage and during in vitro release experiments. Successful translation of the TDF pod-IVR from laboratory evaluation to large-scale clinical trials requires the ability to manufacture the devices at low cost and in high quantity. Methods for manufacturing and scale-up were developed and applied to pilot-scale production of TDF pod-IVRs that maintained the IVR’s release characteristics while significantly decreasing the variability in release rate observed between pod-IVRs. This pod-IVR enables for the first time the dose-ranging clinical studies that are required to optimize topical TDF PrEP in terms of efficacy and safety.
P reexposure prophylaxis (PrEP) using FDA-approved antiretroviral (ARV) drugs holds significant promise as a strategy in the prevention of HIV infection. By analogy to highly active antiretroviral therapy (HAART), a combination of ARV agents likely is essential for optimally effective HIV PrEP (1, 2). Multiple HIV PrEP clinical trials have demonstrated that vaginal and oral ARV regimens based on the nucleoside reverse transcriptase inhibitor (NRTI) tenofovir (TFV) can be effective in susceptible men, women, and partners of HIV-infected individuals (3-9), but other studies based on analogous drug regimens were unsuccessful at reducing the rates of HIV acquisition (10-12). A critical factor driving success in these trials appears to involve sustaining high adherence to frequent dosing (13).Adherence to therapy was found to be inversely related to dosing periods across different delivery methods (14-17). Topical delivery of ARV drugs using intravaginal rings (IVRs) is believed to improve adherence (18) while maintaining sustained mucosal microbicide levels independently of coitus and daily dosing (19). A recent phase 3, randomized, double-blind, placebo-controlled trial involving 2,629 African women evaluating a monthly IVR delivering the nonnucleoside HIV-1 reverse transcriptase inhibitor dapivirine (DPV) showed that this dosing modality can be effective at preventing HIV-1 infection (20). Overall, the incidence of HIV-1 infection in the DPV group was lower by 37% than that in the placebo group, following the exclusion of data from two sites that exhibited lower-than-expected protocol and product adherence. The efficacy of HIV-1 prevention was as high as 61% among women 25 years of age or older. However, the delivery of two or more ARV drugs by the use of conventional IVR designs, such as the DPV IVR, involves significant technological and manufacturing hurdles. To meet these challenges, we have developed a novel IVR technology, the pod-IVR (19,21), that enables rapid development of devices capable of delivering multiple agents over a wide range of target delivery rates and levels of aqueous solubility (22)(23)(24)(25).Here, we report on the pharmacokinetics (PK) and preliminary local safety in an ovine model of a pod-IVR delivering the prodrug TFV disoproxil fumarate (TDF) in combination with maraviroc (MVC), an entry inhibitor/antagonist of chemokine receptor CCR5. Steady-state drug levels for both ARV agents in cervicovaginal fluids (CVFs) were sustained over the 28-day study with corresponding vaginal tissue (VT) concentrations above the levels required for putative efficacy in preventing HIV infection.
Topical preexposure prophylaxis (PrEP) against HIV has been marginally successful in recent clinical trials with low adherence rates being a primary factor for failure. Controlled, sustained release of antiretroviral (ARV) drugs may help overcome these low adherence rates if the product is protective for extended periods of time. The oral combination of tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) is currently the only FDA-approved ARV drug for HIV PrEP. A novel pod-intravaginal ring (IVR) delivering TDF and FTC at independently controlled rates was evaluated for efficacy at preventing SHIV162p3 infection in a rigorous, repeat low-dose vaginal exposure model using normally cycling female pigtailed macaques. Six macaques received pod-IVRs containing TDF (65 mg) and FTC (68 mg) every two weeks, and weekly vaginal exposures to 50 TCID50 of SHIV162p3 began one week after the first pod-IVR insertion. All pod-IVR-treated macaques were fully protected throughout the study (P = 0.0002, Log-rank test), whereas all control animals became infected with a median of 4 exposures to infection. The topical, sustained release of TDF and FTC from the pod-IVR maintained protective drug levels in macaques over four months of virus exposures. This novel and versatile delivery system has the capacity to deliver and maintain protective levels of multiple drugs and the protection observed here warrants clinical evaluation of this pod-IVR design.
Globally, women bear an uneven burden for sexual HIV acquisition. Results from two clinical trials evaluating intravaginal rings (IVRs) delivering the antiretroviral agent dapivirine have shown that protection from HIV infection can be achieved with this modality, but high adherence is essential. Multipurpose prevention technologies (MPTs) can potentially increase product adherence by offering protection against multiple vaginally transmitted infections and unintended pregnancy. Here we describe a coitally independent, long-acting pod-IVR MPT that could potentially prevent HIV and HSV infection as well as unintended pregnancy. The pharmacokinetics of MPT pod-IVRs delivering tenofovir alafenamide hemifumarate (TAF2) to prevent HIV, acyclovir (ACV) to prevent HSV, and etonogestrel (ENG) in combination with ethinyl estradiol (EE), FDA-approved hormonal contraceptives, were evaluated in pigtailed macaques (N = 6) over 35 days. Pod IVRs were exchanged at 14 days with the only modification being lower ENG release rates in the second IVR. Plasma progesterone was monitored weekly to determine the effect of ENG/EE on menstrual cycle. The mean in vivo release rates (mg d-1) for the two formulations over 30 days ranged as follows: TAF2 0.35–0.40; ACV 0.56–0.70; EE 0.03–0.08; ENG (high releasing) 0.63; and ENG (low releasing) 0.05. Mean peak progesterone levels were 4.4 ± 1.8 ng mL-1 prior to IVR insertion and 0.075 ± 0.064 ng mL-1 for 5 weeks after insertion, suggesting that systemic EE/ENG levels were sufficient to suppress menstruation. The TAF2 and ACV release rates and resulting vaginal tissue drug concentrations (medians: TFV, 2.4 ng mg-1; ACV, 0.2 ng mg-1) may be sufficient to protect against HIV and HSV infection, respectively. This proof of principle study demonstrates that MPT-pod IVRs could serve as a potent biomedical prevention tool to protect women’s sexual and reproductive health and may increase adherence to HIV PrEP even among younger high-risk populations.
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