Search Results (9)

Rilpivirine (RPV, R278474) was highlighted in 2005, two years after the death of Dr. Paul Janssen, as the ideal non-nucleoside reverse transcriptase inhibitor (NNRTI) to treat HIV infections. For this purpose, it was subsequently combined with tenofovir disoproxil fumarate (TDF), tenofovir alafenamide (TAF), darunavir (boosted with ritonavir or cobicistat) or dolutegravir. Its wide-spread use is thanks to its combination with cabotegravir (CAB) in the form of a long-acting intramuscular injection once per month (QM), later twice per month (Q2M), for the treatment of adults, later extended to adolescents and pregnant women, with HIV infections. The long-acting CAB plus RPV should not be administered in patients treated with rifampicin or rifabutin, patients with virological failure or patients with resistance to CAB or RPV, or patients with hepatitis B virus (HBV) infection. Long-acting CAB+RPV may lead to pain at the site of injection which would diminish over time. Full article

Treatment as Prevention (TasP) and Pre-Exposure Prophylaxis (PrEP) are both widely recognized as essential biomedical tools to control HIV/AIDS. TasP calls for the immediate initiation of fully subsidized and supported antiretroviral therapy (ART) following HIV diagnosis. TasP effectively prevents progression to AIDS, and premature AIDS-related deaths among people living with HIV (PLWH), and simultaneously renders HIV non-transmissible, thus preventing onward HIV transmission. In addition, PrEP has proven effective against HIV transmission among high-risk individuals who are adherent to the regimen. PrEP traditionally consists of two antiretrovirals given orally as one pill daily: originally, tenofovir-DF plus emtricitabine (TDF-FTC), and later, tenofovir-AF (TAF) plus FTC (more recently, other options have become available, including long-acting parenteral formulations; however, these are still of limited availability). Over the last two decades, the province of British Columbia has rolled out TasP among all PLWH, and starting in 2018, PrEP was added as a strategy to reach individuals most at risk of acquiring HIV to further accelerate progress in addressing HIV/AIDS as a public health threat. Our “generalized TasP + focused PrEP” program proved to be synergistic (or multiplicative) as it relates to reducing the HIV effective reproduction number (${\mathrm{R}}_{\mathrm{e}}$). TasP lowers HIV incidence by reducing the pool of individuals able to transmit HIV, which is dependent on the extent of community plasma viral load (pVL) suppression. Meanwhile, PrEP reduces the number of potential new infections among those most susceptible to acquiring HIV in the community, independent of viral load suppression among PLWH. Our results strongly support widespread implementation of the combination of “generalized TasP + focused PrEP” strategy and underscore the importance of long-term monitoring of ${\mathrm{R}}_{\mathrm{e}}$ at a programmatic level to identify opportunities for optimizing TasP and PrEP programs. This approach aligns with the United Nations goal of “Ending HIV/AIDS as a pandemic by 2030”, both in Canada and globally. Full article

Pre-exposure prophylaxis (PrEP) with a weekly oral regimen of antiretroviral drugs could be a suitable preventative option for individuals who struggle with daily PrEP or prefer not to use long-acting injectables. We assessed in macaques the efficacy of weekly oral tenofovir alafenamide (TAF) at doses of 13.7 or 27.4 mg/kg. Macaques received weekly oral TAF for six weeks and were exposed twice-weekly to SHIV vaginally or rectally on day 3 and 6 after each dose. Median TFV-DP levels in PBMCs following the 13.7 mg/kg dose were 3110 and 1137 fmols/10⁶ cells on day 3 and 6, respectively. With the 27.4 mg/kg dose, TFV-DP levels were increased (~2-fold) on day 3 and 6 (6095 and 3290 fmols/10⁶ cells, respectively). Both TAF doses (13.7 and 27.4 mg/kg) conferred high efficacy (94.1% and 93.9%, respectively) against vaginal SHIV infection. Efficacy of the 27.4 mg/kg dose against rectal SHIV infection was 80.7%. We estimate that macaque doses of 13.7 and 27.4 mg/kg are equivalent to approximately 230 and 450 mg of TAF in humans, respectively. Our findings demonstrate the effectiveness of a weekly oral PrEP regimen and suggest that a clinically achievable oral TAF dose could be a promising option for non-daily PrEP. Full article

Current treatment options for patients infected with hepatitis B virus (HBV) are suboptimal, because the approved drugs rarely induce cure due to the persistence of the viral DNA genome in the nucleus of infected hepatocytes, and are associated with either severe side effects (pegylated interferon-alpha) or require life-long administration (nucleos(t)ide analogs). We report here the evaluation of the safety and therapeutic efficacy of a novel, humanized antibody (hzVSF) in the woodchuck model of HBV infection. hzVSF has been shown to act as a viral entry inhibitor, most likely by suppressing vimentin-mediated endocytosis of virions. Targeting the increased vimentin expression on liver cells by hzVSF after infection with HBV or woodchuck hepatitis virus (WHV) was demonstrated initially. Thereafter, hzVSF safety was assessed in eight woodchucks naïve for WHV infection. Antiviral efficacy of hzVSF was evaluated subsequently in 24 chronic WHV carrier woodchucks by monotreatment with three ascending doses and in combination with tenofovir alafenamide fumarate (TAF). Consistent with the proposed blocking of WHV reinfection, intravenous hzVSF administration for 12 weeks resulted in a modest but transient reduction of viral replication and associated liver inflammation. In combination with oral TAF dosing, the antiviral effect of hzVSF was enhanced and sustained in half of the woodchucks with an antibody response to viral proteins. Thus, hzVSF safely but modestly alters chronic WHV infection in woodchucks; however, as a combination partner to TAF, its antiviral efficacy is markedly increased. The results of this preclinical study support future evaluation of this novel anti-HBV drug in patients. Full article

Long-acting (LA) HIV pre-exposure prophylaxis (PrEP) can mitigate challenges of adhering to daily or on-demand regimens of antiretrovirals (ARVs). We are developing a subcutaneous implant comprising polycaprolactone (PCL) for sustained delivery of ARVs for PrEP. Here we use tenofovir alafenamide (TAF) as a model drug. Previously, we demonstrated that the release rates of drugs are controlled by the implant surface area and wall thickness, and the molecular weight (MW) of PCL. Here, we further advance the implant design and tailor the release rates of TAF and the mechanical integrity of the implant through unique polymer blend formulations. In vitro release of TAF from the implant exhibited zero-order release kinetics for ~120 days. TAF release rates were readily controlled via the MW of the polymer blend, with PCL formulations of higher MW releasing the drug faster than implants with lower MW PCL. Use of polymer MW to tune drug release rates is partly explained by PCL crystallinity, as higher PCL crystalline material is often associated with a slower release rate. Moreover, results showed the ability to tailor mechanical properties via PCL blends. Blending PCL offers an effective approach for tuning the ARV release rates, implant duration, and integrity, and ultimately the biodegradation profiles of the implant. Full article

A critical need exists to develop diverse biomedical strategies for the widespread use of HIV Pre-Exposure Prophylaxis (HIV PrEP). This manuscript describes a subcutaneous reservoir-style implant for long-acting delivery of tenofovir alafenamide (TAF) for HIV PrEP. We detail key parameters of the TAF formulation that affect implant performance, including TAF ionization form, the selection of excipient and the exposure to aqueous conditions. Both in-vitro studies and shelf stability tests demonstrate enhanced performance for TAF freebase (TAF_FB) in this long-acting implant platform, as TAF_FB maintains higher chemical stability than the TAF hemifumarate salt (TAF_HF). We also examined the hydrolytic degradation profiles of various formulations of TAF and identified inflection points for the onset of the accelerated drug hydrolysis within the implant using a two-line model. The compositions of unstable formulations are characterized by liquid chromatography-mass spectrometry (LC-MS) and are correlated to predominant products of the TAF hydrolytic pathways. The hydrolysis rate of TAF is affected by pH and water content in the implant microenvironment. We further demonstrate the ability to substantially delay the degradation of TAF by reducing the rates of drug release and thus lowering the water ingress rate. Using this approach, we achieved sustained release of TAF_FB formulations over 240 days and maintained > 93% TAF purity under simulated physiological conditions. The opportunities for optimization of TAF formulations in this biodegradable implant supports further advancement of strategies to address long-acting HIV PrEP. Full article

HIV-1 is a chronic disease managed by strictly adhering to daily antiretroviral therapy (ART). However, not all people living with HIV-1 have access to ART, and those with access may not adhere to treatment regimens increasing viral load and disease progression. Here, a subcutaneous nanofluidic implant was used as a long-acting (LA) drug delivery platform to address these issues. The device was loaded with tenofovir alafenamide (TAF) and implanted in treatment-naïve simian HIV (SHIV)-positive nonhuman primates (NHP) for a month. We monitored intracellular tenofovir-diphosphate (TFV-DP) concentration in the target cells, peripheral blood mononuclear cells (PBMC). The concentrations of TFV-DP were maintained at a median of 391.0 fmol/10⁶ cells (IQR, 243.0 to 509.0 fmol/10⁶ cells) for the duration of the study. Further, we achieved drug penetration into lymphatic tissues, known for persistent HIV-1 replication. Moreover, we observed a first-phase viral load decay of −1.14 ± 0.81 log₁₀ copies/mL (95% CI, −0.30 to −2.23 log₁₀ copies/mL), similar to −1.08 log₁₀ copies/mL decay observed in humans. Thus, LA TAF delivered from our nanofluidic implant had similar effects as oral TAF dosing with a lower dose, with potential as a platform for LA ART. Full article

Long-acting (LA) HIV pre-exposure prophylaxis (PrEP) offers the potential to improve adherence by lowering the burden of daily or on-demand regimens of antiretroviral (ARV) drugs. This paper details the fabrication and in vitro performance of a subcutaneous and trocar-compatible implant for the LA delivery of tenofovir alafenamide (TAF). The reservoir-style implant comprises an extruded tube of a biodegradable polymer, poly(ε-caprolactone) (PCL), filled with a formulation of TAF and castor oil excipient. Parameters that affect the daily release rates of TAF are described, including the surface area of the implant, the thickness of the PCL tube walls (between 45 and 200 µm), and the properties of the PCL (e.g., crystallinity). In vitro studies show a linear relationship between daily release rates and surface area, demonstrating a membrane-controlled release mechanism from extruded PCL tubes. Release rates of TAF from the implant are inversely proportional to the wall thickness, with release rates between approximately 0.91 and 0.15 mg/day for 45 and 200 µm, respectively. The sustained release of TAF at 0.28 ± 0.06 mg/day over the course of 180 days in vitro was achieved. Progress in the development of this implant platform addresses the need for new biomedical approaches to the LA delivery of ARV drugs. Full article

Tenofovir alafenamide (TAF) is an effective nucleotide reverse transcriptase inhibitor that is used in the treatment of HIV-1 and HBV. Currently, it is being investigated for HIV prophylaxis. Oral TAF regimens require daily intake, which hampers adherence and increases the possibility of viral resistance. Long-acting formulations would significantly reduce this problem. Therefore, the aim of this study was to develop a transdermal patch containing TAF and investigate its performance in vitro through human epidermis. Two types of TAF patches were manufactured. Transparent patches were prepared using acrylate adhesive (DURO-TAK 87-2516), and suspension patches were prepared using silicone (BIO-PSA 7-4301) and polyisobutylene (DURO-TAK 87-6908) adhesives. In vitro permeation studies were performed while using vertical Franz diffusion cells for seven days. An optimized silicone-based patch was characterized for its adhesive properties and tested for skin irritation. The acrylate-based patches, comprising 2% w/w TAF and a combination of chemical enhancers, showed a maximum flux of 0.60 ± 0.09 µg/cm²/h. However, the silicone-based patch comprising of 15% w/w TAF showed the highest permeation (7.24 ± 0.47 μg/cm²/h). This study demonstrates the feasibility of developing silicone-based transdermal patches that can deliver a therapeutically relevant dose of TAF for the control of HIV and HBV infections. Full article