Nursing Pharmacology:  Antiviral Drugs

• Antiretroviral Drugs Used in Treating HIV Infection

• • →Entry Inhibitors: The drug enfuvirtide, derived from gp41, binds to gp41 in a way that prevents the structural change needed for fusion (see previous page).

     Another drug, maraviroc, inhibits viral entry by binding to one of the chemokine HIV co-receptors, CCR5, thus inhibiting interaction with gp120 and inhibiting fusion initiation.¹

    • In 2007 the US FDA approved the first member of a new group of antiretroviral drugs used for treating HIV-1 infection.²  

      • This agent, Maraviroc (Selzentry, Celsentri) acts by interfering with the interaction between HIV-1 gp120 protein and the chemokine co-receptor CCR5.

      • Maraviroc was FDA approved for use in those patients experiencing virologic failure secondary to resistance to other antiviral medications.² 

      •  

        HIV Entry and Locations of Different Entry Inhibitor Sites of Action⁸

        "A schematic illustration of HIV entry in the steps presented by different entry inhibitors. "HIV entry can be divided into 3 discrete steps: Attachment of the viral glycoprotein (gp120) to the CD4 receptor, followed by subtle conformational changes in gp120 which expose structural elements on the v3 loop that bind to co-receptor, either CCR5 or CXCR4. This induces a structural rearrangement in gp41 which inserts a hydrophobic fusion peptide region into the target cell membrane. This brings the virus and cell membrane in close apposition to initiate fusion and ultimately entry of the virus into the target cell. HIV entry inhibitors can be thought of as 3 distinct subclasses, each targeting one of the 3 previous steps."

    • Studies about 30 years ago identified the CD4 receptor as the principal target for HIV-1 binding to CD4⁺ cells.

      • Experiments using hybrid mouse cells expressing human CD4⁺ indicated that CD4⁺ binding by itself is insufficient to cause viral entry.

      • Subsequently, two co-receptors were discovered.

        • These co-receptors were CCR5 (C-C chemokine Receptor type 5)and CXCR4 and were chemokine receptors which were also necessary for viral entry, along with the CD4⁺ receptor.

          • CCR5 is associated with naturally occurring ligands:

            • These HIV-1 co-receptors, CXCR4 and CCR5, are part of the G protein-coupled receptor superfamily described in earlier sections.⁶ 

              • CCR5 is considered an especially important therapeutic target since genetic absence of surface expression of this protein confers nearly complete resistance to HIV-1 infection.⁷

  • Maraviroc (Selzentry, Celsentri) Pharmacology

    • Introduction: 

      • Maraviroc inhibits association between gp120, HIV outer envelope protein, and the CCR5 chemokine receptor.⁸ 

        • Maraviroc activity is limited to those HIV strains expressing CCR5 and therefore exhibits no activity against those HIV strains which are either CXCR4 expressing or which express both CCR5 and CXCR4 co-receptors.

        • As a result of this focused mechanism of action, Maraviroc has the advantage of retaining antiretroviral efficacy even when HIV strains exhibit resistance to other antiretroviral drugs.⁸ 

    • Drug Resistance:²

      • Resistance to the antiretroviral activity of Maraviroc appears to occur in either of two mechanisms.²

      • The first mechanism involves a change in tropism such that the HIV-1 strain becomes able to use the CXCR4 chemokine co-receptor.

        • The second mechanism allows HIV-1 to continue to use the CCR5 co-receptor even though it is being blocked by Maraviroc.

        • Of these two mechanisms of resistance development, the change in tropism may be of particular clinical concern since virus that can use the CXCR4 co-receptor may be associated with a more rapid decline in CD4⁺ lymphocyte count and disease progression.¹⁰ 

        • However, the main mechanism of Maraviroc resistance is likely the ability of HIV-1 to use Maraviroc-associated CCR5 co-receptors.

        • In this setting increasing concentrations of Maraviroc does not result in increased viral inhibition. Intrinsic resistance to Maraviroc appears limited and cross-resistance with the fusion inhibitor enfuvirtide has not been observed.²  

  • Pharmacokinetics:⁹

    • The dose-dependent oral bioavailability of Maraviroc is about 20%-30%.

      • Food decreases bioavailability as much as 50% in this agent exhibits protein binding in human plasma in the range of about 75%.

    • The P450 microsomal metabolizing system is responsible for biotransformation and supports Maraviroc elimination with a half-life of about 10 hours.

      • The P450 isozyme primarily implicated in elimination is CYP3A4.² 

    • Pharmakokinetics of Maraviroc may be affected by agents that inhibit CYP3A.

      • For example, itraconozole, lopinavir, lopinavir plus ratonavir, ratonavir, saquinavir and ataznavir increase maximal plasma concentration of Maraviroc as well as increasing the area under the curve (AUC).²

  • Clinical/Therapeutic Uses:⁹  

    • Maraviroc (Selzentry, Celsentri) is FDA approved for use in HIV-infected patients (adults) whose HIV infection consists mainly of the CCR5-tropic virus.

    • The addition of Maraviroc to patients receiving optimal, typically multidrug antiviral treatment but with documented multidrug resistant HIV-1 appears clinically beneficial.

    • Maraviroc with darunavir/ritonavir Combination Therapy:  Analysis¹⁴

      Attribution:  Stellbrink HJ Pulik P Szlavic J Murphy D Lazzarin A Portilla J Rinehart A Le Fevre E Fang A Valluri S Mukwaya G Heera J Maraviroc (MVC) Once Daily with Darunavir/Ritonavir (DRV/r) Compared to Tenofovir/Emtricitabine (TDF/FTC) With DRV/r:  48 Week Results from MODERN (Study A4001095) https://www.youtube.com/watch?v=JMMqkXx4YrU (7/2014) International AIDS Conference YouTube Channel:  https://www.youtube.com/channel/UCBBhpWA2uqSzk2lfFig-7JQ

    • Noting that Maraviroc adminstration results in limited to no therapeutic effectiveness in those patients whose HIV-1 strain exhibits CXCR4 or dual/mixed CCR5 + CXCR4 chemokine co-receptors, Maraviroc cost-effectiveness may be limited due to the need for phenotype testing.⁹

References

Wang F Kieff E Medical Viriology, Chapter 177 Section 11:  Viral Diseases:  General Considerations (in Harrison's Principles of Internal Medicine, 18th edition, Longo DF Fauci AS Kasper DL Hauser SL Jameson JL Loscalzo J, eds) McGraw-Hill, New York, 2012, pp 1432-1433. MacArthur RD Novak RM Maraviron: The first of a new class of antiretroviral agents Clinical infectious Diseases 47(2) (July 15, 2008) pp 236-241. Steve Dewhurst, Ph.D., Structure of the CC-chemokine, RANTES, (c) University of Rochester and Stephen Dewhurst, 1999 Swaminathan J and MSD staff (European Bioinformatics Institute) http://en.wikipedia.org/wiki/CCL5#mediaviewer/File:PDB_1eqt_EBI.jpg . Splettstoesser T CCR5+membrane http://en.wikipedia.org/wiki/CCR5#mediaviewer/File:CCR5+membrane1.png Tilakaratne N Sexton PM G-protein-coupled receptor protein interactions:  basis for new concepts on receptor structure and function.  Clin Exp Pharmacol Physiol 32:  979-987, 2005. Samson M Libert F Doranz BJ Rucker J Liesnard C Farber CM Saragosti S Lapoumeroulie C Cognaux J Forceille C Muyldermans G Verhofstede C Burtonboy G Georges M Imai T Rana S yi Y Smyth RJ Collman RG Doms RW Vassart G Parmentier M Resistance to HIV-1 infection in caucasian individual bearing mutant alleles of the CCR-5 chemokine receptor gene Nature 382(6593) 722-725, 1996. Lu K Gulick RM (Based on a presentation at PRN by Roy M. Gulick, MD, MPH New antiretrovirals for the treatment of HIV;  the view in 2006.  The PRN Notebook 11(2) October 2006. The figure corresponds to Figure 2 in this reference and was derived by the authors from an original image by Robert W. Doms, MD, Ph.D. The figure in on this page has been slightly modified from its original form in reference 8. Flexner C Chapter 59.  Antiretroviral Agents and Treatment of HIV Infection (in Goodman & Gilman's The Pharmacological Basis of Therapeutics, 12 e, Brunton LL Chabner BA Knollmann BC, eds) The McGraw-Hill Companies, Inc, 2011. Shankarappa R Margolick JB Gange SJ Rodrigo AG Upchurch D Farzadegan H Gupta P Rinaldo CR Learn GH He X Huang X-L Mullins JI Consistent viral evolutional changes associated with the progression of human immunodeficiency virus type 1 infection. Journal of Virology 73(12) 10489-10502, Dec 1999. Vetrivel U Sankar P Nagarajan Nk Subramanian G Peptidomimetics based inhibitor design for HIV-1 gp120 attachment protein. J Proteomics Bioinform 2:481-484 2009.http://omicsonline.org/ArchiveJPB/2009/November/03/JPB2.481.php?aid=1412 Saven J CCR5:  HIV binding and Maraviroc inhibtion (For CHEM 251:  Biochemistry, Spring 2014, Video by Zachary Goldsmith), University of Pennsylvania, 2014. https://www.youtube.com/watch?v=4gwIRiwcqUU Tan Q Zhu Y Li J Chen Z Han GW Kufareva I Li T Ma L Fenalti G Li J Zhang W Xie X Yang H Jiang H Cherezov V Liu H Stevens RC Zhao Q Beili W Science 341 20 September 2013 1387-1390. Stellbrink HJ Pulik P Szlavic J Murphy D Lazzarin A Portilla J Rinehart A Le Fevre E Fang A Valluri S Mukwaya G Heera J Maraviroc (MVC) Once Daily with Darunavir/Ritonavir (DRV/r) Compared to Tenofovir/Emtricitabine (TDF/FTC) With DRV/r:  480Week Results from MODERN (Study A4001095) International AIDS Conferences:  July 29, 2014. https://www.youtube.com/watch?v=JMMqkXx4YrU

 

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