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.¹⁴  

      • 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.¹⁴

    • Raltegravir (Isentress)

    • Mutations and Resistance to Raltegravir:

      • Mutations in the HIV integrase gene which significantly reduces sensitivity to raltegravir (25-to 50-fold sensitivity reduction, in vitro) have been identified.¹ 

    • Pharmacokinetics:

      • Following oral dosing, raltegravir peak concentrations occur after 1-3 hours.¹ 

        • Elimination curves are biphasic with an initial t_½ (half-time) of about 1 hour with a longer terminal phase t_½ (half-time) lasting about 9 hours (range 7-12h).^1,16 

        • Raltegravir exhibits variability in its pharmacokinetics.¹  

          • Furthermore, moderate to high-fat meals affects raltegravir bioavailability as described by area-under-the-curve (AUC) by as much as 2-fold.

          • On the other hand, a meal with reduced fat also affects area-under-the-curve (AUC), decreasing the value by about 50%.

          • However, no food requirements are associated with raltegravir administration has clinical trials evaluating efficacy were performed without such restrictions and also initial antiviral effects were maximal and all concentrations noted following 400 mg twice-daily administration.¹  

        • Raltegravir elimination proceeds via phase II metabolism, specifically by glucuronidation catalyzed by the UGT1A1 gene product, a glucuronosyltransferase.¹

          • Phase II Metabolism: Features

            Phase II characteristics: Parent drug participates in conjugation reactions that form covalent linkage between a parent compound functional group and Glucuronic acid Sulfate Glutathione Amino acids Acetate Conjugates are highly polar, and generally biologically inactive.  One exception to this rule is a morphine metabolite, morphine glucuronide which is a more potent analgesic compared to the parent compound.  Conjugates tend to be rapidly excreted in the urine. High molecular weight conjugates  are more likely excreted in the bile. The conjugate bond may be cleaved by intestinal flora with the parent compound released back to the systemic circulation.  This process, "enterohepatic recirculation" results in delayed parent drug elimination and a prolongation of drug effects.

    • Adverse Effects:

      • Raltegravir usually exhibits limited clinical toxicity.¹ 

        • Among the most common complaints, exceeding those reported by placebo recipients, following raltegravir administration include:

          • Headache

          • Nausea

          • Fatigue

          • Asthenia (weakness or reduced energy).

        • Worsening of depression has also been reported.¹  

        • Changes in certain enzyme levels have also been documented including:⁷

          • Pancreatic amylase

          • Creatine kinase (with rhabdomyolysis)

          • Serum aminotransferases⁷

        • More severe, even life-threatening and fatal skin reactions have been described and include:⁷

          • Stevens-Johnson syndrome

          • Toxic epidermal necrolysis

          • Hypersensitivity reactions. ⁷

      • Common adverse effects of the anti-retroviral drugs for HIV considered more broadly have been described.¹⁸ 

      • A detailed clinical trial comparing raltegravir and efavirenz also has presented raltegravir adverse effects in detail.¹⁹

    • Therapeutics:

      • 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

       

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

        • →In one recommended protocol Raltegravir (RAL) is combined with tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) for this application, i.e. RAL/TDF/FTC.⁹

        • 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).⁹

        • 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).⁹  

          • This combination is recommended only in patients with pre-antiretroviral treatment creatinine clearance >70ml/min.⁹

      • 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

       

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 AIDSinfo:  Guidelines for the Use of Antriretroviral Agents in HIV-1-Infected Adults and Adolescents https://aidsinfo.nih.gov/guidelines (2015) Hicks C Gulick RM Raltegravir:  The First HIV Type 1 Integrase Inhibitor. Clin Infect Disease Apr. 1; 48(7):  931-939 2009. http://www-ncbi-nlm-nih-gov.proxy.kumc.edu:2048/pubmed/19231980. Huzuda D and the Merck Integrase Inhibitor Team (Inhibitors of HIV-1 Integrase:  From the Bench to the Bedside, and Back Again) https://www.youtube.com/watch?v=HZBEq8ZBR4g, 21 February, 2009; uploaded Dec. 22, 2009. PommierY Hohnson AA Marchand C Integrase Inhibitors to Treat HIV/AIDS Nature Review (Drug Discovery) 4:  235-248 March 2005 (http://discover.nci.nih.gov/pommier/2005.Pommier.nrd.pdf) Hopur:  "Structure active relationship of elvitegravir and raltegravir.  Benzyl group in a hydrophobic pocket and a triad to chelate the two Mg2+ ions." https://commons.wikimedia.org/wiki/File:SAR_of_elvitegravir_and_raltegravir.png 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 HIV Drug Resistance Data Base (Stanford University):  Integrase Inhibitor Resistance Notes (3/2014), http://hivdb.stanford.edu/DR/INIResiNote.html Iwamoto MWenning LA Petryy AS Laethem m De Smet M Kost JT Merschman SA Strohmaier KM Ramael S Lasseter KC Stone JA Gottesdiener KM Wagner JA Safety, Tolerability and Pharmacokinetics of Raltegravir After Single and Multiple Doses in Healthy Subjects. Clinical Pharmacology & Therapeutics 83:(2), 293-299,  February 2008. (http://www.natap.org/2014/HIV/060914_01.htm) 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 Reust CE Common Adverse Effects of Antiretroviral Therapy for HIV Disease.  American Family Physician 83(12):  1443-1451 June 15, 2011. Lennox JL deJusus E Berger DS Lazzarin A Pollard RB Madruga JVR Zhao J Wan H Gilbert CL Teppler H Rodgers AJ Barnard RJO Miller MD CiNubil MJ Nguyen B-Y Leavitt R Sklar P for the STARTMRK Investigators Raltegravir Versus Efavirenz Regiments in Treatment-Naive HIV-1-Infected Patients:  96-Week Efficacy, Durability, Subgroup, Safety, and Metabolic Analyses. J Acquir Immune Defic Syndrom 55:  39-48 2010. Test ID:  HLA57-HLA-B 5701 Genotype, Abacavir Hypersensitvity Mayo Clinic, Mayo Medical Laboratories. http://www.mayomedicallaboratories.com/test-catalog/Clinical+and+Interpretive/89346 Lennox JL DeJesus E Lazzarin A Pollard RB Madruga JVR Berger DS Zhao J Xu X Williams-Diaz A Rodgers AJ Barnard RJO Miller MD DiNubile MJ Ngyen B-Y Leavitt R Sklar P, for the STARTMRK investigators Safety and efficacy of raltegravir-based versus efavirenz-based combination therapy in treatment naïve patients with HIV-1 infection:  a multicentre, double-blind randomised controlled trial. Lancet 374:  796-806 2009.http://www.ncbi.nlm.nih.gov/pubmed/19647866 Rockstroh JK DeJesus E Lennox JL Yazdanpanah Y Saag MS Wan H Rodgers AJ Walker ML Miller M DiNubile MJ Nguyen B-Y Teppler H Leavitt R Sklar for the STARTMRK Investigators Durable efficacy and safety of raltegravir versus efavirenz when combined with tenofovir/emtricitabine in treatment-naïve HIV-1-infected patients:  Final 5-year results from STARTMRK  J Acquir Immune Defic Syndr 63(1) 77-85 May 1, 2013. http://www.ncbi.nlm.nih.gov/pubmed/23412015 Comparisons of effects of atazanavir, raltegravir or darunavir with FTC/tenofovir on biomarkers of systemic inflammation, macrophage and T cell activation:  ACTG" AIDS Clinical Trials Group. Kelesidis T Tran TTT McComsey GA Brown TT Moser C Ribaudo HJ Rothenberg J Yang OO Stein JH Currier JS Abstract WEAB0106LB, IAS 2014, July 23, 2014. https://www.youtube.com/watch?v=8314xSodP2E

 

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