LEAP Publications

Long-acting drugs and formulations for the treatment and prevention of HIV infection

Date: 
1/1/21
Citation: 

Flexner C, Owen A, Siccardi M, Swindells S. Long-acting drugs and formulations for the treatment and prevention of HIV infection. Int J Antimicrob Agents. 2021 Jan;57(1):106220. doi: 10.1016/j.ijantimicag.2020.106220. Epub 2020 Nov 6. PMID: 33166693; PMCID: PMC7790856.

Oral antiretroviral regimens are extremely effective at suppressing HIV with minimal toxicity. They offer the simplicity of once daily single-tablet dosing. However, long-acting regimens with infrequent dosing, for example weekly oral or long-acting (LA) parenterally administered agents, may be useful for treatment or prevention in circumstances where daily oral therapies are difficult to administer, and/or when adherence may be inadequate. In such circumstances, alternatives to oral therapy may be life-saving and reduce the transmission of infection to others.

    The Promise of Improved Adherence With Long-Acting Antiretroviral Therapy: What Are the Data?

    Date: 
    1/1/21
    Citation: 

    Scarsi KK, Swindells S. The Promise of Improved Adherence With Long-Acting Antiretroviral Therapy: What Are the Data? J Int Assoc Provid AIDS Care. 2021 Jan-Dec;20:23259582211009011. doi: 10.1177/23259582211009011. PMID: 33902356; PMCID: PMC8082990.

    For many chronic conditions, long-acting (LA) medication therapies have improved medication adherence compared to daily oral therapy, leading to improved clinical outcomes. The term LA has been used in drug delivery to describe applications for multiple routes of administration, including oral, topical and parenteral, which includes intravenous, intramuscular, subcutaneous injections, and implantable devices. Generally, it is proposed that to be considered a LA therapy, an oral drug should achieve at least once weekly dosing, an injection at least monthly, and an implant at least 6-monthly dosing.

      Prioritization of Anti‐SARS‐Cov‐2 Drug Repurposing Opportunities Based on Plasma and Target Site Concentrations Derived from their Established Human Pharmacokinetics

      Date: 
      10/1/20
      Citation: 

      Arshad U, Pertinez H, Box H, Tatham L, Rajoli RKR, Curley P, Neary M, Sharp J, Liptrott NJ, Valentijn A, David C, Rannard SP, O'Neill PM, Aljayyoussi G, Pennington SH, Ward SA, Hill A, Back DJ, Khoo SH, Bray PG, Biagini GA, Owen A. Prioritization of Anti-SARS-Cov-2 Drug Repurposing Opportunities Based on Plasma and Target Site Concentrations Derived from their Established Human Pharmacokinetics. Clin Pharmacol Ther. 2020 Oct;108(4):775-790. doi: 10.1002/cpt.1909. Epub 2020 Jun 14. Erratum in: Clin Pharmacol Ther. 2021 May;109(5):1362. PMID: 32438446; PMCID: PMC7280633.

      Coronavirus disease 2019 (COVID‐19) is an acute infectious respiratory disease caused by infection with the coronavirus subtype severe acute respiratory syndrome‐coronavirus 2 (SARS‐CoV‐2), first detected in Wuhan, China, in December 2019. There are currently no available treatments or chemopreventative options, but several are being explored preclinically and clinically. Most publications reporting in vitro activity have focused on 50% maximum effective concentrations and not considered the achievable concentrations in plasma or relevant compartments for COVID‐19, which may be an insufficiently robust indicator of antiviral activity because of marked differences in the slope of the concentration‐response curve between drugs.

        Predicting Pharmacokinetics of a Tenofovir Alafenamide Subcutaneous Implant Using Physiologically Based Pharmacokinetic Modelling

        Date: 
        7/22/20
        Citation: 

        Rajoli RKR, Demkovich ZR, Flexner C, Owen A, Siccardi M. Predicting Pharmacokinetics of a Tenofovir Alafenamide Subcutaneous Implant Using Physiologically Based Pharmacokinetic Modelling. Antimicrob Agents Chemother. 2020 Jul 22;64(8):e00155-20. doi: 10.1128/AAC.00155-20. PMID: 32423957; PMCID: PMC7526822.

        Long-acting (LA) administration using a subcutaneous (s.c.) implant presents opportunities to simplify administration of antiretroviral drugs, improve pharmacological profiles, and overcome suboptimal adherence associated with daily oral formulations. Tenofovir alafenamide (TAF) is a highly potent nucleoside reverse transcriptase inhibitor (NRTI) and an attractive agent for LA delivery, with a high potency and long intracellular half-life. The aim of this study was to predict minimum TAF doses required to achieve concentrations effective for HIV preexposure prophylaxis (PrEP).

          Addressing the global burden of hepatitis B virus while developing long-acting injectables for the prevention and treatment of HIV

          Date: 
          6/1/20
          Citation: 

          Bollinger RC, Thio CL, Sulkowski MS, McKenzie-White J, Thomas DL, Flexner C. Addressing the global burden of hepatitis B virus while developing long-acting injectables for the prevention and treatment of HIV. Lancet HIV. 2020 Jun;7(6):e443-e448. doi: 10.1016/S2352-3018(19)30342-X. Epub 2019 Dec 20. PMID: 31870675; PMCID: PMC7376366.

          Important progress has been achieved in the development of long-acting antiviral formulations for the prevention and treatment of HIV. Replacing daily oral regimens with long-acting ones, administered as infrequent injections or implantable devices, could greatly simplify and improve HIV prevention and treatment. The successful uptake of long-acting injectable formulations for treatment of schizophrenia, and the use of implantable formulations of contraceptive medications by millions of women, suggests that such formulations would be well accepted.

            Pharmacogenetic interactions between antiretroviral drugs and vaginally-administered hormonal contraceptives

            Date: 
            4/1/20
            Citation: 

            Haas DW, Cramer YS, Godfrey C, Rosenkranz SL, Aweeka F, Berzins B, Coombs R, Coughlin K, Moran LE, Gingrich D, Zorrilla CD, Baker P, Cohn SE, Scarsi KK; AIDS Clinical Trials Group A5316 Study Team. Pharmacogenetic interactions between antiretroviral drugs and vaginally administered hormonal contraceptives. Pharmacogenet Genomics. 2020 Apr;30(3):45-53. doi: 10.1097/FPC.0000000000000396. PMID: 32106141; PMCID: PMC7398416.

            It is important that women of reproductive potential who are living with HIV be provided with effective contraceptive options. Unfortunately, drug-drug interactions between some antiretroviral therapies (ART) and hormonal contraceptives hinder available options for effective family planning. Efavirenz-containing ART significantly lowers plasma exposure to progestin contraceptives given orally or via subdermal implant, which may reduce hormonal contraception effectiveness. HIV protease inhibitors that are combined with ritonavir increase progestin exposure, but may decrease estrogen exposure.

              Long-acting implants to treat and prevent HIV infection

              Date: 
              1/1/20
              Citation: 

              Weld ED, Flexner C. Long-acting implants to treat and prevent HIV infection. Curr Opin HIV AIDS. 2020 Jan;15(1):33-41. doi: 10.1097/COH.0000000000000591. PMID: 31764198; PMCID: PMC7050620.

              Great advances over the past three decades have led to the development and optimization of antiretrovirals that are highly potent, safe, and well tolerated. There is, however, no currently available ARV drug or formulation with a dosing frequency less than once daily. Nonadherence to daily oral medication remains the most significant barrier to long-term suppression of HIV replication and prevention of the emergence of drug-resistant virus.

                Modelling the intradermal delivery of microneedle array patches for long-acting antiretrovirals using PBPK

                Date: 
                11/1/19
                Citation: 

                Rajoli RKR, Flexner C, Chiong J, Owen A, Donnelly RF, Larrañeta E, Siccardi M. Modelling the intradermal delivery of microneedle array patches for long-acting antiretrovirals using PBPK. Eur J Pharm Biopharm. 2019 Nov;144:101-109. doi: 10.1016/j.ejpb.2019.09.011. Epub 2019 Sep 13. PMID: 31525446; PMCID: PMC6917207.

                Abstract

                Introduction: Existing HIV therapy using oral antiretrovirals (ARVs) can result in pill fatigue and sub-optimal adherence. Microneedle array patches (MAPs) offer non-invasive, blood-free and painless drug delivery, and may improve patient adherence. The objective of this study was to develop a novel physiologically-based pharmacokinetic (PBPK) model to simulate the systemic pharmacokinetics of cabotegravir and rilpivirine MAPs using the intradermal route.

                  Long-acting or extended-release antiretroviral products for HIV treatment and prevention in infants, children, adolescents, and pregnant and breastfeeding women: knowledge gaps and research priorities

                  Date: 
                  8/1/19
                  Citation: 

                  Nachman S, Townsend CL, Abrams EJ, Archary M, Capparelli E, Clayden P, Lockman S, Jean-Philippe P, Mayer K, Mirochnick M, McKenzie-White J, Struble K, Watts H, Flexner C. Long-acting or extended-release antiretroviral products for HIV treatment and prevention in infants, children, adolescents, and pregnant and breastfeeding women: knowledge gaps and research priorities. Lancet HIV. 2019 Aug;6(8):e552-e558. doi: 10.1016/S2352-3018(19)30147-X. Epub 2019 Jul 12. PMID: 31307946; PMCID: PMC7152795.

                  In 2017, an estimated 10·1 million women and 1·8 million children younger than 15 years worldwide were living with HIV.1 Women continue to account for a disproportionate percentage of new HIV infections among adults (aged 15 years and older) in sub-Saharan Africa: this population represented 59% of the 18 million new adult HIV infections in 2017. Meanwhile, the number of adolescents (aged 10–19 as defined by WHO) living with HIV has increased.2 Daily oral antiretroviral therapy (ART) has had a substantial impact on treatment and prevention of HIV, but inadequate or incomplete adherence, leading to treatment failure and drug resistance, are major obstacles.

                    Predicting Drug–Drug Interactions Between Rifampicin and Long-Acting Cabotegravir and Rilpivirine Using Physiologically Based Pharmacokinetic Modeling

                    Date: 
                    5/5/19
                    Citation: 

                    Rajoli RKR, Curley P, Chiong J, Back D, Flexner C, Owen A, Siccardi M. Predicting Drug-Drug Interactions Between Rifampicin and Long-Acting Cabotegravir and Rilpivirine Using Physiologically Based Pharmacokinetic Modeling. J Infect Dis. 2019 May 5;219(11):1735-1742. doi: 10.1093/infdis/jiy726. PMID: 30566691; PMCID: PMC6500558.

                    Tuberculosis (TB) and human immunodeficiency virus (HIV) are global epidemics, and individuals who are HIV infected are at high risk of acquiring TB. In 2016, an estimated 1 million individuals infected with TB were coinfected with HIV, and TB was the leading infectious cause of death in HIV-infected patients. Since the commencement of the global epidemic of HIV, 25% of the 39 million HIV-infected individuals have died due to TB coinfection. HIV accelerates the usual slow progression of TB infection, leading to a significantly higher mortality. Appropriate treatment and care of TB patients with HIV can reduce the risk of mortality and improve survival.

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