Nursing Pharmacology:  Antiviral Drugs

• Antiretroviral Drugs Used in Treating HIV Infection

  • Development of Antiretroviral (anti-HIV) Drugs

    • The first antiretroviral drug approved for clinical use, zidovudine (AZT), was initially developed in anticipation of its efficacy as an anticancer chemotherapeutic drug.

      •  However, the zidovudine did not prove effective in that application.

      • About 10 years later in 1972 zidovudine was found to inhibit, in vitro, murine type C retrovirus.⁸ 

      • Following another approximately 10 year interval, zidovudine was found to exhibit in vitro inhibitory activity with respect to human immunodeficiency virus (HIV).

        • In that study, the antiviral effects of the thymidine analog, 3'-azido-3'-deoxythymidine (zidovudine, AZT), then known as BW A509U, were evaluated in a human T-cell line, H9.^9,10

          • Zidovudine blocked p24 gag protein expression in both human T-lymphotropic virus type III (HTLV-III) or lymphadenopathy-associated virus (LAV).¹⁰

            • Zidovudine was also found to inhibit cytopathic effects of HTLV-III_B, a viral isolate from a group of American patients and HLV-III/RF-II (an isolate from a Haitian patient).

            • Further, zidovudine completely inhibited viral replication as measured by reverse transcriptase production in normal human peripheral blood mononuclear cells exposed to HTLV-III_B.¹⁰

      • Shortly thereafter zidovudine was evaluated in clinical trials and based on a randomized trial reported in 1987 zidovudine was approved and marketed as an anti-HIV agent.¹

        • The approval of AZT (azidothymidine, zidovudine), a nucleoside reverse transcriptase inhibitor, was initially based on a 282 patient double-blind, placebo-controlled trial evaluating the effectiveness of oral drug.¹¹ 

          • Following zidovudine, other nucleoside analogues were evaluated for anti-retroviral reverse transcriptase inhibitor therapy.¹

      • Using viral enzyme (reverse transcriptase)-based assays, non-nucleoside reverse transcriptase inhibitors (nnRTIs) were also identified.

        • These agents when used therapeutically resulted in relatively rapid drug resistance probably as a result of intrinsically high mutation rates associated with retroviral replication.¹

      • Wei and collaborators used anti-retroviral experimental drugs, non-nucleoside reverse transcriptase inhibitors, to determine the lifespan of plasma virus and virus-producing cells.¹² 

        • Results indicated that plasma viral lifespan is short with a half-life of about two days.

        • Furthermore, wild-type virus in plasma is susceptible to replacement by drug-resistant mutational variants after about two weeks of drug administration.

        • This result suggested that HIV-1 viremia depends on continuous de novo viral infection and replication with rapid cell turnover.¹² 

        • Another class of antiretroviral drugs, the protease inhibitors, began to appear in 1989, with saquinavir being the first agent considered.¹  

          • Saquinavir was approved for clinical use (i.e. prescription use) in 1995.

          • Shortly thereafter, additional protease inhibitors ritonavir and indinavir were approved.¹

  Antiretroviral Drugs Approved in the United States¹ 

   

• Nucleoside/Nucleotide Reverse Transcriptase Inhibitors^1,7

  Zidovudine (Retrovir,ZDV,AZT)
  	Adverse Effects:7  Asthenia (Weakness, reduced energy/strength), insomnia, headache, nausea, neutropenia (reduced number of circulating neutrophils; causes other than medication includes autoimmune disorders, cancer, radiation and others), macrocytic anemia (this is a type of anemia in which erythrocytes (red blood cells) are increased in volume but reduced in number of with reduced hemoglobin content per cell) Miscellaneous:7   Zidovudine should note be administered with concurrent use of stavudine or myelosupressive agents such as ribavirin or ganciclovir.
  Didanosine (Videx, DdI, dideoxyinosine)
  	Adverse Effects:7  Hyperuricemia (elevated uric acid blood levels; upper end of normal is 6 mg/dL for women and 6.8 mg/dL for men), nausea, diarrhea, pancreatitis (pancreatic inflammation, either acute or chronic; may be caused by drugs trauma, autoimmune disease, et al.), peripheral neuropathy. Miscellaneous:7 Didanosine should note be given  with other drugs that may cause neuropathy. Examples of such agents include stavudine, isoniazid, zalcitabine, ribavirin or alcohol. Didanosine should also not be administered with tenofovir.
  Stavudine (Zerit, d4T, didehydrodeothymidine)
  	Adverse Effects:7   Peripheral neuropathy, lipodystrophy (refers to abnormalities in body fat, including distribution; this class of agents, the nucleoside reverse transcriptase inhibitors is most associated with lipdystrophy compared to other classes of HIV antiretroviral drugs), pancreatitis (pancreatic inflammation, either acute or chronic; may be caused by drugs trauma, autoimmune disease, et al.), rarely neuromuscular weakness. Miscellaneous7 :  Concurrent stavudine admininistration with zidovudine or neuropathic agents such as ddI, zalcitabine, isoniazid should be avoided.
  Lamivudine (3TC)
  	Adverse Effects:7  Fatigue, vertigo, nausea, headache Miscellaneous:7   Should not be administered with zalcitabine (ddC, dideoxycytidine)
  Abacavir (Ziagen)
  	Adverse Effects:7 Hypersensitivity reaction, rash, nausea Miscellaneous:7 Alcohol should be avoided FDA bulletin (March 2015) approvided both lamivudine (Epivir) and abacavir sulfate (ziagen) labelling for once-dailing dosing in pediatric patients 3 months of age and older in combination with other antirretroviral drugs for HIV-1 infection treatment. (see: http://content.govdelivery.com/accounts/USFDA/bulletins/fa3e70 Abacavir is used in combination with other antiretroviral agents.
  Tenofovir (tenofovir disoproxil fumarate, Viread)
  	Adverse Effects:7 Nausea, diarrhea, vomiting, renal insufficiency, headache Miscellaneous:7 Should not be administered along with atazanvir, probenecid or didanosine. Nucleotide reverse transcriptase inhibitor class member
  Emtricitabine (Emtriva, formerly Coviracil)
  	Adverse Effects:7 Nausea, diarrhea, headache, weakness with reduced energy (asthenia), skin hyperpigmentation (<2%) Miscellaneous:7 Cross drug resistance with lamivudine13; should not be administered together with lamivudine. In oral preparation, disulfiram and metonidazole  should be avoided.

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 189, Human Immunodeficiency Virus Disease:  AIDS and Related Disorders, 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. 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. McLeod GX Hammer SM Zidovudine:  Five Years Later Annals of Internal Medicine 117:  487-501 1992. Cinatl, jr J Cinatl J Rabenau H Ebener U Kornhuber B Doerr HW Increased HIV-1 production in chronically infected H9 cells grown in protein-free medium.  Arch Virol 125:  327-330, 1992.(http://www.ncbi.nlm.nih.gov/pubmed/1642559) Mitsuya H Weinhold KJ Furman PA St. Clair MH Nusinoff Lehrman S Gallo RC Bolognesi D Barry DW Broder S 3'-azido-3'-deoxythymidine (BW A509U):  An antiviral agent that inhibits the infectivity and cytopathic effect of T-lymphotropic virus type III/lymphadenopathy-associated virus in vitro. Proc Natl Acad Sci USA 82:  7096-7100, October 1985. (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC391317/) Fischl MA Richman DD Grieco MH Gottlieb MS Volberding PA Laskin OL Leedom JM Groopman JE Mildvan D Schooley RT Jackson GG Durack DT King D and The AZT Collaborative Working Group. N Engl J Med 317:  185-191 July 23, 1987. (http://www.ncbi.nlm.nih.gov/pubmed/3299089) Wei X Ghosh SK Taylor ME JohnsonVA Emini EA Deutsch P Lifson JD Bonhoeffer S Nowak MA Hahn BH Saag MS Shaw GM Viral dynamics in human immunodeficiency virus type 1 infection.  Nature 373:  6510):  117-122 1995 (http://www.ncbi.nlm.nih.gov/pubmed/7529365)  Coffey S Emtricitabine (Emttiva) HIV InSite UCSF Updated 2013:  http://hivinsite.ucsf.edu/InSite?page=ar-01-08#S3.5.1X HIV Resistance:  The Intersection of HIV Treatment and Prevention, June 3, 2010; Ryan White Program TARGET Center; https://www.youtube.com/watch?v=Oe4sFA-BJM8

 

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