Nursing Pharmacology:  Antiviral Drugs

• Antiretroviral Drugs Used in Treating HIV Infection

  • →Integrase Strand Transfer Inhibitors (INSTI):

    • By way of review, HIV-1 replication depends on three enzymes: viral reverse transcriptase, protease and viral integrase.⁹  

      • Following interaction with host cells expressing surface CD4⁺ receptors and required co-receptors, HIV enters the cell and its single-stranded RNA genome is converted into a double-stranded form viral reverse transcriptase.

      • Integration of HIV-1 complementary DNA (complementary to the original HIV-1 RNA), utilizes HIV-1 integrase in promoting a two-step process.

        • (1) The first step involves excision of two nucleotides from the 3' ends of HIV-1 DNA.

        • (2) Subsequently, covalent insertion of HIV-1 viral genomic DNA into the host cell chromosome occurs.

      • Inhibition of the integrase enzyme results in viral complementary DNA circularization, a process catalyzed by host cell enzymes, as well as nuclear accumulation of 2-long terminal repeat (LTR) circles.

      • Stable integration of HIV-1 DNA into the host genome is therefore prevented by inhibition of viral integrase.

        • Consequently, viral latency within the host cell allowing HIV-1 replication and elaboration new virus is prevented.⁹

    • Elvitegravir (Viketa)

    • Elvitegravir (Viketa) is a second example of the first-generation integrase inhibitors, following raltegravir.¹²   

      • Elvitegravir and raltegravir appear well-tolerated and potent in both treatment-naïve and treatment-experienced HIV-1 infected adults.

        • Raltegravir requires twice-daily dosing and may exhibit variable pharmacokinetic profiles.

      • By contrast, elvitegravir is typically taken with food and also requires pharmacokinetic boosting drugs.

        • These factors along with the possibility of cross-resistance between elvitegravir and raltegravir has suggested the need for new, unboosted integrase inhibitors with both once-daily dosing and a better resistance profile.¹² 

      • • This drug inhibits integrase associated with both HIV-1 and HIV-2.

        • In peripheral blood mononuclear cells elvitegravir-mediated integrase inhibition at the 90% level occurs at low concentration.

      • Elvitegravir is present in one of four recommended integrase strand transfer inhibitor (INSTI)-based protocols for antiretroviral treatment in antiretroviral treatment naïve patients.

        • One INSTI-based recommended protocol involves Raltegravir (RAL) is combined with tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) for this application, i.e. RAL/TDF/FTC.¹⁰

        • A second INSTI-based recommended protocol for treatment naïve patients is dolutegravir/abacavir/lamivudine (DTG/ABC/3TC) for use only in patients who are HLA-B*5701 negative.

        • A third recommended INSTI-based protocol for HIV treatment in treatment-naïve patients is also based on dolutegravir (DTG) but in combination with tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC).¹⁰ 

        • A fourth recommended INSTI-based protocol for HIV treatment in treatment-naïve patients is based on elvitegravir (EVG) in combination with cobicistat (c) with tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC), i.e. (EVG/c/TDF/FTC).¹⁰   

          • This combination is recommended only in patients with pre-antiretroviral treatment creatinine clearance >70ml/min¹⁰  

      • A fifth NON-INSTI-based recommended protocol for HIV treatment in treatment-naïve patients is based on darunavir/ritonavir (HIV protease inhibitors) (DRV/r) in combination with tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC).⁹

    • Elvitegravir is available as a fixed-dose combination tablet containing elvitegravir, and tenofovir disoproxil fumarate, emtricitabine and cobicistat.

    • Several clinical trial studies have compared elvitegravir-based protocols with other anti-HIV retroviral therapies.

      • Results from this extended study to week 96 supported conclusions of both long-term safety and lasting efficacy of the elvitegravir-based protocol.¹⁸

    • Mutations and Resistance to Elvitegravir:

      • Drug resistance to elvitegravir-based protocols appear similar to that observed with efavirenz-based regimens.⁶

      • Elvitegravir is considered an antiretroviral drug exhibiting clinical effectiveness in both treatment-naïve and-experienced HIV-1 infected individuals.¹⁴ 

        • In some patients failing elvitegravir-containing protocols as well as in in vitro studies, mutations in viral integrase appear responsible for diminished raltegravir sensitivity.

          • Accordingly, for those HIV-infected individuals exhibiting virologic failure on either elvitegravir or raltegravir integrase strand inhibitors (INSTI)-based regimens, generally overlapping resistance profiles occur.¹⁴

    • Pharmacokinetics:

      • Single oral dosing of elvitegravir (100, 200, 400 or 800 mg) to healthy subjects results in maximal plasma concentration (C_max) of 108 ng/ml, 160 ng/ml, 264 ng/ml and 455 ng/ml respectively, with an uncertainty in these values of about 30%.¹⁶ 

        • These levels were obtained from 1.3-2.5 hours following dosing.

        • Oral administration with food extends boosted elvitegravir C_max  to about 4-4.5 hours post-dosing, consistent with relatively slow absorption.

          • Elvitegravir absorption appears unaffected by gastrointestinal pH very ability but is lowered in the presence of antacids (presumably due to drug association with di-trivalent cations).¹⁶ 

      • Metabolism of elvitegravir occurs mainly in liver and intestine and is dependent on the cytochrome P450 microsomal drug metabolizing system.¹⁶ 

        • Cytochrome P450 CYP3A isozymes are mainly responsible.

          • In view of the role of CYP3A4, increasing elvitegravir effects may be obtained by coadministration with CYP3A4 inhibitors.

            • For example, "pharmacokinetic boosting" occurs with coadministering of ritonavir or cobicistat along with elvitegravir.

              • Cobicistat and low-dose ritonavir examples of CYP3A4 inhibitors.

              • Elvitegravir coadministered with cobicistat appears to provide improved adverse-effect profiles relative to elvitegravir administration with ritonavir.

                • Additionally, this combination provides both high systemic levels and extended elimination half-life (t_½) which allows for once-daily dosing.

                  • Boosting can extend elvitegravir half-life to about 9 hours.⁶

                • Since cobicistat exhibits no anti-retroviral activity, the concern of induced protease inhibitor resistance due to the use of low-dose ritonavir with elvitegravir is eliminated.¹⁶ 

      • UGT1A1 is the gene UDP glucuronosyltransferase 1 family, polypeptide A1.

        • The gene product is  the enzyme UDP-glucuronosyltransferase which catalyzes transformation of drugs, hormones, steroids etc. into more water-soluble forms amenable to excretion.¹⁵

    • Adverse Effects:

      • The principal side effect in elvitegravir-based coformulated drug (stribild) is a likely non-pathologic, reversible increase in serum creatinine levels.¹³  

        • This increase in creatinine appears to be attributable to the cobicistat component in the formulation, since cobicistat inhibits renal tubular creatinine secretion.

        • Elvitegravir-based treatment, i.e. treatment with stribild is appropriate and recommended for treatment-naïve HIV-1 infected individuals with an apparent glomerular filtration rate >70 mL/min.

          • Other side effects include rash and diarrhea but generally stribild is considered well tolerated.¹³

    • Therapeutics:

      • A recommended INSTI-based protocol for HIV treatment in treatment-naïve patients is based on elvitegravir (EVG) in combination with cobicistat (c) with tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC), i.e. (, stribild, EVG/c/TDF/FTC).¹⁰   

        • This combination is recommended only in patients with pre-antiretroviral treatment creatinine clearance >70ml/min¹⁰  

      • Stribild¹⁹

        Attribution:  Wood BR Stribild (The Quad Pill) https://www.youtube.com/watch?v=aLAZ7m-_rlI (5/2014) HIV/AIDS (CDC) YouTube Channel:  https://www.cdc.gov/hiv/basics/whatishiv.html

      •  

        Stribild Forumation

         

      • Abbreviations:  Antiretroviral Drugs, Combinations, and Classifications⁹

        3TC = lamivudine	ABC = abacavir	ARV = antiretroviral	ATV/c = cobicistat-boosted atazanavir	ATV/r = ritonavir-boosted atazanavir ear
        DRV/r= ritonavir-boosted darunavir	DTG = dolutegravir	EFV = efavirenz	EVG/c/TDF/FTC = elvitegravir/cobicistat/tenofovir DF/emtricitabine	FTC = emtricitabine
        LPV/r = ritonavir-boosted lopinavir	RAL = raltegravir	RPV =rilpivirine	RTV = ritonavir	TDF = tenofovir disoproxil fumarate
        INSTI = integrase strand transfer inhibitor	NNRTI = nonnucleoside reverse transcriptase inhibitor	NRTI = nucleoside reverse transcriptase inhibitor	PI = protease inhibitor	CrCl = creatinine clearance

       

 

References

Flexner C Antiretroviral Agents and Treatment of HIV Infection, Chapter 59  in Goodman & Gilman's The Pharmacological Basis of Therapeutics, 12th edition (Brunton LL Chabner BA Knollmann BC, eds; Brunton LL, ed; Blumenthal DK  Murri N Hilal-Dandan R, assoc eds, Knollmann BC, consulting ed, on-line edition) The McGraw-Hill Companies, 2011. Fauci AS Lane HC Chapter 226, Human Immunodeficiency Virus Disease:  AIDS and Related Disorders, in Harrison's Online   (Kasper DL Fauci AS Hauser SL Longo DL Jameson JL Loscalzo J, Eds.),  Harrison's Principles of Internal Medicine, 19th edition, The McGraw-Hill Companies, Inc. 2015 (on-line edition) Longo DL Fauci AS  188, The Human Retroviruses, in Harrison's Online   (Dan L. Longo, Anthony S. Fauci, Dennis L. Kasper, Stephen L. Hauser, J. Larry Jameson, Joseph Loscalzo, Eds.),  Harrison's Principles of Internal Medicine, 18th edition, The McGraw-Hill Companies, Inc. 2012. Woster PM Chapter 43:  Antiviral Agents and Protease Inhibitors in Foye's Principles of Medicinal Chemistry 6e, Lemke, TL Williams DA, eds; Roche VG Zito SW, asst eds) Wolters Kluwer|Lippincott Williams & Wilkins 1214, 2008. HIV Overview:  The HIV Life Cycle, Education Materials, AIDSinfo, NIH http://aidsinfo.nih.gov/education-materials/fact-sheets/19/73/the-hiv-life-cycle Tsibris AMN Hirsch MS Chapter 130 Antiretroviral Therapy for Human Immunodeficiency Virus Infection in Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases, 8e (Bennett JE Bolin R Blaser, eds) Elsevier, Inc/Saunders 2015, online version. Safrin S Chapter 49:  Antiviral Agents:  Antiretroviral Agents in Basic & Clinical Pharmacology 13e (Katzung BG Trevor AJ, eds) 2015, online edition. Wensing AM Calvez V Gunthard JF Johnson VA Paredes R Pillay D Shafer RW Richman DD Special Contribution:  2014 Update of the Drug Resistance Multations in HIV-1 Topics in Antivral Medicine 22(3)  June/July 2014, https://www.iasusa.org/sites/default/files/tam/22-3-642.pdf Evering TH Markowitz M HIV-1 Integrase Inhibitors PRN Notebook 13 1-9, June 2008 http://www.prn.org/index.php/management/article/integrase_inhibitors_raltegravir_elvitegravir_hiv_disease_478 AIDSinfo:  Guidelines for the Use of Antriretroviral Agents in HIV-1-Infected Adults and Adolescents https://aidsinfo.nih.gov/guidelines (2015) HIV Drug Resistance Data Base (Stanford University):  Integrase Inhibitor Resistance Notes (3/2014), http://hivdb.stanford.edu/DR/INIResiNote.html Cahn P Pazniak AL Mingrone H Shuldyakov A Crites C Andrade-Villanueva JF Richmond G Buendia CB Fourie J Ramgopal M Hagins D Felizarta F Madruga J Reuter T Newman T Small CB Lombaard J Brinsztejn B Dorey D Underwood M Griffith S Min S on behalf of the extended SAILING Study Team. Dolutegravir versus raltegravir in antiretroviral-experienced, integrase-inhibitor-naive adults with HIV:  week 48 results from the randomised, double-blind, non-inferiority SAILING study. The Lancet, published online July 3, 2013. Katz MH Zolopa AR HIV Infection & AIDS, Chapter 31 in Current Medical Diagnosis & Treatment 2015 (Papadakis MA McPhee SJ Rabow MW, eds), 54th edition, McGraw-Hill Education, 2015. Abram ME Hluhanich RM Boodman DD Andreatta KN Margot NA Ye L Niedziela-Majka A Barnes TL Novikov N Chen X Svarovakaia ES McColl DJ White KL Miller MD.  Impact of primary elvitegravir Resistance-mutations in HIV-1 integrase on drug susceptibility and viral replication fitness. Antimicrobial Agents and Chemotherapy 57(6): 2654-2663 June 2013. (http://aac.asm.org/content/57/6/2654.short; http://www.ncbi.nlm.nih.gov/pubmed/23529738) NCBI:  Gene-UGT1A1 UDP glucuronosyltransferase 1 family, polypeptide A1 [Homo sapiens (human)] Gene ID: 54658 (updated 30-Aug-2015) http://www.ncbi.nlm.nih.gov/gene/54658 Ramanathan S Mathias AA German P Kearney BP Clinical pharmacokinetic and pharmacodynamic profile of the HIV integrase inhibitor elvitegravir.  Clin Pharmacokinet 50(4):  229-244, 2011. http://www.ncbi.nlm.nih.gov/pubmed/21348537 Sax PE DeJusus E Mills Zolopa A Cohen C Wohl D Gallant JE Liu HC Zhong L Yale K White K Kearney BP Szwarcberg J Quirk E Cheng AK, for the GS-US-236-0102 study team.  Co-formulated evitegravir, cobicistat, emtricitabine, and tenofovir versus co-formulated efavirenz, emtricitabine, and tenofovir for initial treatment of HIV-1 infection:  a randomised, double-blind, phase 3 trial, analysis of results after 48 weeks.  Lancet 379:  2439-2448, 2012. http://www.ncbi.nlm.nih.gov/pubmed/22748591 Zolopa A Sax PE DeJusus E Mills A Cohen C Wohl D Gallant JE Liu HC Plummer A White KL Cheng AK Rhee MS Szwarcberg J for the GS-US-236-0102 Study Team.  A randomized double-blind comparison of coformulated elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate versus efavirenz/emtricitabine/tenofovir disoproxil fumarate for initial treatment of HIV-1 infection:  analysis of week 96 results.  J Acquir Immune Defic Syndr 63:  96-100, 2013. http://www.ncbi.nlm.nih.gov/pubmed/23392460. Wood BR, Medical Director, NW AETC ECHO, Assistant Professor of Medicine, University of Washington. Stribild (aka The Quad Pill)https://www.youtube.com/watch?v=aLAZ7m-_rlI

 

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