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Antiretroviral drug activity and potential for pre-exposure prophylaxis against COVID-19 and HIV infection.

ABSTRACT: COVID-19 is the disease caused by SARS-CoV-2 which has led to 2,643,000 deaths worldwide, a number which is rapidly increasing. Urgent studies to identify new antiviral drugs, repurpose existing drugs, or identify drugs that can target the overactive immune response are ongoing. Antiretroviral drugs (ARVs) have been tested in past human coronavirus infections, and also against SARS-CoV-2, but a trial of lopinavir and ritonavir failed to show any clinical benefit in COVID-19. However, there is limited data as to the course of COVID-19 in people living with HIV, with some studies showing a decreased mortality for those taking certain ARV regimens. We hypothesized that ARVs other than lopinavir and ritonavir might be responsible for some protection against the progression of COVID-19. Here, we used chemoinformatic analyses to predict which ARVs would bind and potentially inhibit the SARS-CoV-2 main protease (Mpro) or RNA-dependent-RNA-polymerase (RdRp) enzymes in silico. The drugs predicted to bind the SARS-CoV-2 Mpro included the protease inhibitors atazanavir and indinavir. The ARVs predicted to bind the catalytic site of the RdRp included Nucleoside Reverse Transcriptase Inhibitors, abacavir, emtricitabine, zidovudine, and tenofovir. Existing or new combinations of antiretroviral drugs could potentially prevent or ameliorate the course of COVID-19 if shown to inhibit SARS-CoV-2 in vitro and in clinical trials. Further studies are needed to establish the activity of ARVs for treatment or prevention of SARS-CoV-2 infection .Communicated by Ramaswamy H. Sarma.

SUBMITTER: Copertino DC

PROVIDER: S-EPMC8448789 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature

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Antiretroviral drug activity and potential for pre-exposure prophylaxis against COVID-19 and HIV infection.

Copertino Dennis C DC Casado Lima Bruno C BC Duarte Rodrigo R R RRR Powell Timothy R TR Ormsby Christopher E CE Wilkin Timothy T Gulick Roy M RM de Mulder Rougvie Miguel M Nixon Douglas F DF

Journal of biomolecular structure & dynamics 20210318 16

COVID-19 is the disease caused by SARS-CoV-2 which has led to 2,643,000 deaths worldwide, a number which is rapidly increasing. Urgent studies to identify new antiviral drugs, repurpose existing drugs, or identify drugs that can target the overactive immune response are ongoing. Antiretroviral drugs (ARVs) have been tested in past human coronavirus infections, and also against SARS-CoV-2, but a trial of lopinavir and ritonavir failed to show any clinical benefit in COVID-19. However, there is li ...[more]

PMID: 33734021

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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.

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Antiretroviral drug activity and potential for pre-exposure prophylaxis against COVID-19 and HIV infection.

Publications

Antiretroviral drug activity and potential for pre-exposure prophylaxis against COVID-19 and HIV infection.

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