HIV

Recent developments of nanotherapeutics for targeted and long-acting, combination HIV chemotherapy

Date: 
8/14/18
Citation: 

Gao Y, Kraft JC, Yu D, Ho RJY.  Recent developments of nanotherapeutics for targeted and long-acting, combination HIV chemotherapy. Eur J Pharm Biopharm. 2019 May;138:75-91. doi: 10.1016/j.ejpb.2018.04.014. Epub 2018 Apr 17. PMID: 29678735; PMCID: PMC6482852.

Combination antiretroviral therapy (cART) given orally has transformed HIV from a terminal illness to a manageable chronic disease. Yet despite the recent development of newer and more potent drugs for cART and suppression of virus in blood to undetectable levels, residual virus remains in tissues.

Health Topics: 
HIV
LA/ER Injectable Therapy

    Mechanism-based pharmacokinetic (MBPK) models describe the complex plasma kinetics of three antiretrovirals delivered by a long-acting anti-HIV drug combination nanoparticle formulation.

    Date: 
    2/12/18
    Citation: 

    Kraft JC, Treuting PM, Ho RJY. Mechanism-based pharmacokinetic (MBPK) models describe the complex plasma kinetics of three antiretrovirals delivered by a long-acting anti-HIV drug combination nanoparticle formulation. J Control Release. 2018 Apr 10;275:229-241. doi: 10.1016/j.jconrel.2018.02.003. Epub 2018 Feb 10. PMID: 29432823; PMCID: PMC5878144.

    Existing oral antiretroviral (ARV) agents have been shown in human studies to exhibit limited lymph node penetration and lymphatic drug insufficiency. As lymph nodes are a reservoir of HIV, it is critical to deliver and sustain effective levels of ARV combinations in these tissues. To overcome lymph node drug insufficiency of oral combination ARV therapy (cART), we developed and reported a long-acting and lymphocyte-targeting injectable that contains three ARVs-hydrophobic lopinavir (LPV) and ritonavir (RTV), and hydrophilic tenofovir (TFV)-stabilized by lipid excipients in a nanosuspension.

    Health Topics: 
    HIV
    LA/ER Injectable Therapy

      Translation of combination nanodrugs into nanomedicines: lessons learned and future outlook

      Date: 
      1/10/18
      Citation: 

      Mu Q, Yu J, McConnachie LA Kraft JC, Gao Y, Gulati GK, Ho RJY. Translation of combination nanodrugs into nanomedicines: lessons learned and future outlook. J Drug Target. Jun-Jul 2018;26(5-6):435-447. doi: 10.1080/1061186X.2017.1419363. Epub 2018 Jan 10. PMID: 29285948; PMCID: PMC6205718.

      For the past two decades, the number of research publications on single-agent nanoformulations has grown exponentially. However, formulations advancing to pre-clinical and clinical evaluations that lead to therapeutic products has been limited.

      Health Topics: 
      HIV

        Indocyanine green nanoparticles undergo selective lymphatic uptake, distribution and retention and enable detailed mapping of lymph vessels, nodes and abnormalities

        Date: 
        2/12/18
        Citation: 

        Kraft JC, Treuting PM, Ho RJY. Indocyanine green nanoparticles undergo selective lymphatic uptake, distribution and retention and enable detailed mapping of lymph vessels, nodes and abnormalities. J Drug Target. 2018 Jun-Jul;26(5-6):494-504. doi: 10.1080/1061186X.2018.1433681. Epub 2018 Feb 12. PMID: 29388438 PMCID: PMC6205717

        The distributed network of lymph vessels and nodes in the body, with its complex architecture and physiology, presents a major challenge for whole-body lymphatic-targeted drug delivery. To gather physiological and pathological information of the lymphatics, near-infrared (NIR) fluorescence imaging of NIR fluorophores is used in clinical practice due to its tissue-penetrating optical radiation (700-900 nm) that safely provides real-time high-resolution in vivo images. 

        Health Topics: 
        HIV

          Long-acting profile of 4 drugs in 1 anti-HIV nanosuspension in nonhuman primates for 5 weeks after a single subcutaneous injection

          Date: 
          7/15/18
          Citation: 

          McConnachie LA, Kinman LM, Koehn J, et al. Long-acting profile of 4 drugs in 1 anti-HIV nanosuspension in nonhuman primates for 5 weeks after a single subcutaneous injection. J Pharm Sci. 2018 Jul;107(7):1787-1790. doi: 10.1016/j.xphs.2018.03.005. Epub 2018 Mar 13. PMID: 29548975; PMCID: PMC6954863.

          Daily oral antiretroviral therapy regimens produce limited drug exposure in tissues where residual HIV persists and suffer from poor patient adherence and disparate drug kinetics, which all negatively impact outcomes. To address this, we developed a tissue- and cell-targeted long-acting 4-in-1 nanosuspension composed of lopinavir (LPV), ritonavir, tenofovir (TFV), and lamivudine (3TC). In 4 macaques dosed subcutaneously, drug levels over 5 weeks in plasma, lymph node mononuclear cells (LNMCs), and peripheral blood mononuclear cells (PBMCs) were analyzed by liquid chromatography-tandem mass spectrometry. 

          Health Topics: 
          HIV

            Long-acting formulations for the treatment of latent tuberculous infection: opportunities and challenges

            Date: 
            2/15/18
            Citation: 

            Swindells S, Siccardi M, Barrett SE, et al. Long-acting formulations for the treatment of latent tuberculous infection: opportunities and challenges. Int J Tuberc Lung Dis. 2018 Feb 1; 22(2): 125–132. PMID: 29506608; PMCID: PMC6103451.

            Long-acting/extended-release drug formulations have proved very successful in diverse areas of medicine, including contraception, psychiatry and, most recently, human immunodeficiency virus (HIV) disease. Though challenging, application of this technology to anti-tuberculosis treatment could have substantial impact. 

            Health Topics: 
            HIV
            LA/ER Injectable Therapy
            Tuberculosis

              Development of an oral once-weekly drug delivery system for HIV antiretroviral therapy

              Date: 
              1/9/18
              Citation: 

              Kirtane AR, Abouzid O, Minahan D, et al. Development of an oral once-weekly drug delivery system for HIV antiretroviral therapy. Nat Commun. 2018;9(1):2. Published 2018 Jan 9. doi:10.1038/s41467-017-02294-6. PMID: 29317618; PMCID: PMC5760734.

              The efficacy of antiretroviral therapy is significantly compromised by medication non-adherence. Long-acting enteral systems that can ease the burden of daily adherence have not yet been developed.

              Health Topics: 
              HIV
              LA/ER Oral Therapy

                From in silico hit to long-acting late-stage preclinical candidate to combat HIV-1 infection

                Date: 
                12/26/17
                Citation: 

                Kudalkar SN, Beloor J, Quijano E, et al. From in silico hit to long-acting late-stage preclinical candidate to combat HIV-1 infection [published correction appears in Proc Natl Acad Sci U S A. 2018 Mar 12;:]. Proc Natl Acad Sci U S A. 2018;115(4):E802-E811. doi:10.1073/pnas.1717932115. PMID: 29279368; PMCID: PMC5789948.

                Nonnucleoside reverse transcriptase inhibitors (NNRTIs) that target the viral polymerase have been a key component of the current HIV-1 combination drug regimens; however, these issues hamper them. Thus, the development of novel more effective NNRTIs as anti-HIV-1 agents with fewer long-term liabilities, efficacy on new drug-resistant HIV-1 strains, and less frequent dosing is crucial.

                Health Topics: 
                HIV

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