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2-Hydroxypropyl-β-cyclodextrin-enhanced pharmacokinetics of cabotegravir from a nanofluidic implant for HIV pre-exposure prophylaxis.

ABSTRACT: Preexposure prophylaxis (PrEP) with antiretrovirals (ARV) can prevent human immunodeficiency virus (HIV) transmission, but its efficacy is highly dependent on strict patient adherence to daily dosing regimen. Long-acting (LA) ARV formulations or delivery systems that reduce dosing frequency may increase adherence and thus PrEP efficacy. While cabotegravir (CAB) long-acting injectable (CAB LA), an integrase strand transfer inhibitor (INSTI), reduces dosing frequency to bimonthly injections, variable pharmacokinetics (PK) between patients and various adverse reactions necessitate improvement in delivery methods. Here we developed a subcutaneously implantable nanofluidic device for the sustained delivery of CAB formulated with 2-hydroxypropyl-β-cyclodextrin (βCAB) and examined the pharmacokinetics (PK) in Sprague-Dawley rats for 3 months in comparison to CAB. Our study demonstrated βCAB treatment group maintained clinically-relevant plasma CAB concentrations 2 times above the protein-adjusted concentration that inhibits viral replication by 90% (2 × PA-IC₉₀) and drug penetration into tissues relevant to HIV-1 transmission. Further, we successfully fitted plasma CAB concentrations into a PK model (R² = 0.9999) and determined CAB apparent elimination half-life of 47 days. Overall, our data shows the potential of sustained release of βCAB via a nanofluidic implant for long-term PrEP delivery, warranting further investigation for efficacy against HIV infections.

SUBMITTER: Pons-Faudoa FP

PROVIDER: S-EPMC8591786 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Pre-exposure prophylaxis (PrEP) has emerged as a promising strategy for preventing the transmission of HIV. Although only one formulation is currently approved for PrEP, research into both new compounds and new delivery systems for PrEP regimens offer intriguing challenges from the perspective of pharmacokinetic and pharmacodynamic modeling. This review aims to provide an overview the current modeling landscape for HIV PrEP, focused on PK/PD and QSP models relating to antiretroviral agents. Both current PrEP treatments and new compounds that show promise as PrEP agents are highlighted, as well as models of uncommon administration routes, predictions based on models of mechanism of action and viral dynamics, and issues related to adherence to therapy. The spread of human immunodeficiency virus (HIV) remains one of the foremost global health concerns. In the absence of a vaccine, other prophylactic strategies have been developed to prevent HIV transmission. One approach, known as pre-exposure prophylaxis (PrEP), allows HIV-negative individuals who are at high risk of exposure to the virus, be it through an HIV-positive sexual partner or through the shared use of drug injection equipment, to substantially reduce the risk of developing an HIV infection. PrEP is a relatively recent approach to combating the HIV epidemic, with the only currently approved treatment being Truvada, a daily oral antiretroviral (ARV) therapy initially indicated in the treatment of active HIV-1 infections, but approved for HIV PrEP in 2012. Although PrEP therapy has consistently demonstrated high efficacy in preventing HIV infection, this efficacy is dependent on patient adherence to the prescribed treatment regimen. This can present a significant problem in low- and middle-income countries, which may lack the infrastructure to provide sufficient access to PrEP medication to maintain daily dosing regimens. Furthermore, while the conventional approach has generally been to advocate for continuous administration akin to regimens used for viral suppression in infected patients, there has been some discussion of whether a better treatment paradigm might be to push for PrEP therapy primarily during those known periods of heightened exposure risk, while relying on post-exposure prophylaxis regimens to prevent infection after unanticipated exposures during low-risk periods. These considerations have led to a push for the development of long-duration and on-demand PrEP formulations, including subdermal and subcutaneous implants, slow-release intramuscular depot injections, vaginal and rectal antimicrobial gels, and intravaginal rings and dissolving films. PrEP therapy is a quickly evolving field, with a variety of antiretroviral compounds and formulations under investigation. This review aims to report on notable drugs and formulations from a pharmacokinetic/pharmacodynamic (PK/PD) modeling perspective. Given the nature of PrEP as a preventive therapy designed for long-term use, clinical trials for PrEP therapies can last for months or even years, particularly in the case of long-duration formulations. Furthermore, in contrast to antiretroviral trials in infected patients, pharmacodynamic endpoints in PrEP therapies are difficult to quantify, as the primary endpoint for efficacy is generally the rate of seroconversion. Computational modeling approaches offer flexible and powerful tools to provide insight into drug behavior in clinical settings, and can ultimately reduce the time, expense, and patient burden incurred in the development of PrEP therapies.

Project description:Detection of HIV infection may be challenging in persons using long-acting cabotegravir (CAB-LA) pre-exposure prophylaxis (PrEP) due to viral suppression and reduced/delayed antibody production. We evaluated two point-of-care tests for detecting HIV infection in persons who received CAB-LA in the HPTN 083 trial. Samples were obtained from 12 participants who received CAB-LA and had delayed detection of HIV infection using HIV rapid tests and an antigen/antibody test (52 plasma samples; 18 dried blood spot [DBS] samples). Plasma samples were tested with the Xpert HIV-1 Viral Load XC test (Xpert VL-XC); DBS samples were tested with the total nucleic acid Xpert HIV-1 Qual XC test (Xpert Qual-XC). Results from these assays were compared to results from three reference, laboratory-based, plasma RNA assays (Aptima HIV-1 Qualitative assay [Aptima Qual]; Aptima HIV-1 Quant DX Assay [Aptima Quant]; cobas HIV-1/HIV-2 Qualitative Test [cobas]). HIV RNA was detected with all four plasma assays for all samples with viral loads (VLs) ≥ 200 copies/mL; the number of samples with VLs < 200 copies/mL with HIV RNA detected was: Xpert VL-XC: 19/26 (73.1%); Aptima Qual: 17/26 (65.4%); Aptima Quant: 17/26 (65.4%); and cobas: 12/21 (57.1%). The Xpert Qual-XC assay was positive for all DBS samples with VLs ≥ 200 copies/mL and 1/10 DBS with VLs < 200 copies/mL. The performance of the Xpert VL-XC assay was comparable to the reference assays for detecting HIV infection in these cases. The Xpert Qual-XC assay was less sensitive than plasma-based HIV RNA assays for detecting HIV in the setting of CAB-LA PrEP.ImportanceHIV RNA assays can detect HIV infections earlier than HIV rapid tests or Ag/Ab tests in persons using CAB-LA PrEP. Earlier HIV diagnosis could allow for earlier treatment initiation and reduced risk of INSTI resistance. POC tests may help detect HIV infection before CAB-LA administration and may be more accessible than laboratory-based assays in some settings. In this study, the POC Xpert VL-XC assay detected HIV RNA in most samples from individuals who received CAB-LA PrEP and had delayed detection of HIV infection with HIV rapid tests and an Ag/Ab test. The performance of this assay was similar to laboratory-based HIV RNA assays in this cohort. The POC Xpert Qual-XC assay detects both HIV RNA and DNA, with a higher viral load cutoff for RNA detection. This assay was negative for most lower viral load samples and did not offer an advantage for HIV screening in persons using CAB-LA PrEP.

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2-Hydroxypropyl-β-cyclodextrin-enhanced pharmacokinetics of cabotegravir from a nanofluidic implant for HIV pre-exposure prophylaxis.

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