Recent Publications

Long-acting combination anti-HIV drug suspension enhances and sustains higher drug levels in lymph node cells than in blood cells and plasma

Date: 
3/27/17
Citation: 

Kraft JC, McConnachie LA, Koehn J, et al. Long-acting combination anti-HIV drug suspension enhances and sustains higher drug levels in lymph node cells than in blood cells and plasma. AIDS. 2017;31(6):765-770. doi:10.1097/QAD.0000000000001405. PMID: 28099191; PMCID: PMC5345888.

Objective:
To determine if a combination of anti-HIV drugs-tenofovir (TFV), lopinavir (LPV), and ritonavir (RTV)-in a lipid-stabilized nanosuspension (called TLC-ART101) could enhance and sustain intracellular drug levels and exposures in lymph node and blood cells above those in plasma.

Design:
Four macaques were given a single dose of TLC-ART101 subcutaneously. Drug concentrations in plasma and mononuclear cells of the blood (PBMCs) and lymph nodes (LNMCs) were analyzed using a validated combination LC-MS/MS assay.

Health Topics: 
HIV

    Systems Approach to Targeted and Long-acting HIV/AIDS Therapy

    Date: 
    12/5/15
    Citation: 

    Ho RJ, Yu J, Li B, et al. Systems Approach to targeted and long-acting HIV/AIDS therapy. Drug Deliv Transl Res. 2015;5(6):531-539. doi:10.1007/s13346-015-0254-y. PMID: 26315144; PMCID: PMC4826474.

    ABSTRACT
    Medication adherence and insufficient drug levels are central to HIV/AIDS disease progression. Recently, Fletcher et al. confirmed that HIV patients on oral antiretroviral therapy had lower intracellular drug concentrations in lymph nodes than in blood. For instance, in the same patient, multiple lymph node drug concentrations were as much as 99 % lower than in blood. This study built upon our previous finding that HIV patients taking oral indinavir had 3-fold lower mononuclear cell drug concentrations in lymph nodes than in blood. As a result, an association between insufficient lymph node drug concentrations in cells and persistent viral replication has now been validated. Lymph node cells, particularly CD4 T lymphocytes, host HIV infection and persistence; CD4 T cell depletion in blood correlates with AIDS progression. With established drug targets to overcome drug insufficiency in lymphoid cells and tissues, we have developed and employed a "Systems Approach" to engineer multi-drug-incorporated particles for HIV treatment.
     
    Health Topics: 
    HIV

      A long-acting formulation of the integrase inhibitor raltegravir protects humanized BLT mice from repeated high-dose vaginal HIV challenges

      Date: 
      3/21/16
      Citation: 

      Kovarova M, Swanson MD, Sanchez RI, et al. A long-acting formulation of the integrase inhibitor raltegravir protects humanized BLT mice from repeated high-dose vaginal HIV challenges. J Antimicrob Chemother. 2016 Jun;71(6):1586-96. doi: 10.1093/jac/dkw042. Epub 2016 Mar 21. PMID: 27002074; PMCID: PMC4867102.

      Objectives:
      Pre-exposure prophylaxis (PrEP) using antiretroviral drugs (ARVs) has been shown to reduce HIV transmission in people at high risk of HIV infection. Adherence to PrEP strongly correlates with the level of HIV protection. Long-acting injectable ARVs provide sustained systemic drug exposures over many weeks and can improve adherence due to infrequent parenteral administration. Here, we evaluated a new long-acting formulation of raltegravir for prevention of vaginal HIV transmission.

      Health Topics: 
      HIV
      LA/ER Injectable Therapy

        Antiretroviral Drugs-Loaded Nanoparticles Fabricated by Dispersion Polymerization with Potential for HIV/AIDS Treatment

        Date: 
        3/20/16
        Citation: 

        Ogunwuyi O, Kumari N, Smith KA, et al. Antiretroviral Drugs-Loaded Nanoparticles Fabricated by Dispersion Polymerization with Potential for HIV/AIDS Treatment. Infect Dis (Auckl). 2016;9:21-32. Published 2016 Mar 20. doi:10.4137/IDRT.S38108. PMID: 27013886; PMCID: PMC4803317.

        Highly active antiretroviral (ARV) therapy (HAART) for chronic suppression of HIV replication has revolutionized the treatment of HIV/AIDS. HAART is no panacea; treatments must be maintained for life. Although great progress has been made in ARV therapy, HIV continues to replicate in anatomical and intracellular sites where ARV drugs have restricted access.

        Health Topics: 
        HIV

          Strengths, Weaknesses, Opportunities and Challenges for Long Acting Injectable Therapies: Insights for applications in HIV therapy

          Date: 
          8/1/16
          Citation: 

          Owen A, Rannard S. Strengths, weaknesses, opportunities and challenges for long acting injectable therapies: Insights for applications in HIV therapy. Adv Drug Deliv Rev. 2016;103:144-156. doi:10.1016/j.addr.2016.02.003. PMID: 26916628; PMCID: PMC4935562.

          Many terms have been utilised to describe the LA approach and standardisation would be beneficial.  Ultimately, definitions will depend upon specific indications and routes of delivery.  This review focuses upon the critical importance of potency in achieving the LA outcome for injectable formulations and explores established and emerging technologies that have been employed across indications.

          Health Topics: 
          HIV
          LA/ER Injectable Therapy

            Long-acting HIV Drugs Advanced to Overcome Adherence Challenge

            Date: 
            4/7/14
            Citation: 

            Dolgin E. Long-acting HIV Drugs Advanced to Overcome Adherence Challenge Nat Med. 2014 Apr 7;20(4):323-4. PMID: 24710366.

            The results from a particular drug trial presented here last month at the annual Conference on Retroviruses and Opportunistic Infections (CROI) may not have seemed particularly noteworthy. It simply showed that two pills performed as well as another combination of medicines. But the antiretroviral agents tested in the trial were not your ordinary drugs.

            Health Topics: 
            HIV

              Long-acting injectable antiretrovirals for HIV treatment and prevention

              Date: 
              11/15/13
              Citation: 

              Spreen WR, Margolis DA, & Pottage JC Jr. Long-acting injectable antiretrovirals for HIV treatment and prevention. Curr Opin HIV AIDS. 2013 Nov;8(6):565-71. PMID: 24100877; PMCID: PMC3815009.

              Investigational long-acting injectable nanoformulations of rilpivirine and GSK1265744 are clinical-stage development candidates. 

              Health Topics: 
              HIV

                Physiologically Based Pharmacokinetic Modelling to Inform Development of Intramuscular Long-Acting Nanoformulations for HIV

                Citation: 

                Rajoli RK, Back DJ, Rannard S, et al. Physiologically Based Pharmacokinetic Modelling to Inform Development of Intramuscular Long-Acting Nanoformulations for HIV. Clin Pharmacokinet. 2015;54(6):639-650. doi:10.1007/s40262-014-0227-1. PMID: 25523214; PMCID: PMC4450126.

                These data may help inform the target product profiles for LA antiretroviral reformulation strategies.

                Health Topics: 
                HIV
                LA/ER Injectable Therapy

                  Regulatory challenges in developing long-acting antiretrovirals for treatment and prevention of HIV infection

                  Date: 
                  7/1/15
                  Citation: 

                  Arya V, Au S, Belew Y, Miele P, Struble K. Regulatory challenges in developing long-acting antiretrovirals for treatment and prevention of HIV infection. Curr Opin HIV AIDS. 2015 Jul;10(4):278-81. doi: 10.1097/COH.0000000000000163. PMID: 26049954.

                  Despite advances in drug development that have reduced ARV dosing to once daily, suboptimal drug adherence remains an obstacle to successful HIV treatment. Further, large randomized trials of once daily oral ARVs for preexposure prophylaxis (PrEP) have shown that drug adherence correlates strongly with prophylactic effect and study outcomes. Thus, the prospect of developing long-acting ARVs, which may mitigate drug adherence issues, has attracted considerable attention lately.

                  Health Topics: 
                  HIV

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