Nursing Pharmacology:  Antiviral Drugs

• Antiretroviral Drugs Used in Treating HIV Infection

  • →Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (continued):

    • Lamivudine (3TC, Epivir)1

      • Lamivudine (Epivir), a cytidine analog which inhibits reverse transcriptase, shows activity against HIV-1, HIV-2, and hepatitis B virus (HBV).¹ 

        • Upon entering the cell, lamivudine, a prodrug similar to zidovudine and stavudine, must be converted to the triphosphate form to exhibit antiretroviral activity.

        • Lamivudine exhibits relatively low host toxicity probably because of its low tendency to associate with human DNA polymerases (low affinity).¹

      • Mutations and Lamivudine Resistance:¹

        • Two mutational sites have been identified in the reverse transcriptase gene associated with resistance to lamivudine.¹  

          • Lamivudine may also be administered to treat hepatitis B infection (HBV).

            • Up to 90% of HIV/HBV co-infected patients exhibit lamivudine resistance after about four years of therapy.¹

              • For individuals receiving lamivudine to manage HIV + HBV co-infection, lamivudine discontinuation may induce a hepatitis flare.⁷

      • Pharmacokinetics:^1,7

        • Lamivudine exhibits oral bioavailability of >80%, not influenced by food.^1,7  

          • Serum half-life of the parent, prodrug, lamivudine is about 2.5 hours although the intracellular half-life of the active, triphosphorylated drug is about 11-14 hours.⁷

          • Lamivudine is mainly eliminated, about 70%, unchanged in the urine.^1,7,13

            • Renal elimination is at least in part due to active tubular secretion.¹³

            • Dosage adjustment may be appropriate if creatine clearance drops below 50mL/min.^1,13

              • Half-life of lamivudine with normal renal function was estimated at about hours, rising to 22 hours in patients with end-stage renal disease.¹³

          • Lamivudine is an antiretroviral agent recommended for use in pregnant patients.⁷

      • Adverse Effects:

        • Lamivudine has relatively few significant adverse effects and is considered among the least toxic antiviral agents.¹ 

          • However, neutropenia, nausea and headache may occur at doses higher than that recommended.

          • As noted earlier, lamivudine exhibits antiviral activity against hepatitis B, reducing plasma HBV DNA levels.

          • In HIV patients co-infected with HBV or in areas in which HBV is endemic, abrupt lamivudine discontinuation may induce rebound HBV replication with worsening hepatitis.¹  

          • Mild adverse effects, however infrequent, include dizziness, fatigue, insomnia, gastrointestinal issues, dry mouth and headache.⁷ 

            • Bioavailability of lamivudine is increased if coadministered with trimethoprim-sulfamethoxazole (Bactrim).

            • Additionally, lamivudine and zalcitabine inhibit intracellular phosphorylation of each other; accordingly, concurrent use should be avoided.⁷

      • Therapeutics:

        • Lamivudine has been approved for treating HIV in both adults and children (≥ 3 months of age).¹ 

          • When used in monotherapy, lamivudine-resistance develops following an initial up to 90% reduction in plasma HIV-1RNA levels, typically observed within two weeks.

            • Reduction in plasma HIV-1 RNA and 52 weeks following lamivudine + zidovudine combination exceeds results obtained with zidovudine alone.

            • Combination of lamivudine with zidovudine or stavudine also is effective in promoting substantial decline in viral load (at 24 weeks), using zidovudine or stavudine monotherapy for comparison.

            • Lamivudine is effective in combination with other antiretroviral drugs and represents a common or "backbone" component of contemporary therapy.

              • Lamivudine efficacy and safety are important considerations.¹ 

          • Lamivudine (or the chemically related agent emtricitabine) is considered a "backbone" agent in many, nearly all, currently endorsed antiretroviral protocols.⁶ 

            • Lamivudine is available coformulated with abacavir, with zidovudine or with the combination abacavir and zidovudine.

            • Emtricitabine is available in several fixed-dose combinations with other antiretroviral agents.

              • These other drugs include tenofovir, efavirenz, rilpivirine, and elvitegravir.⁶

          •  

            Lamivudine (Epivir) Formulation Examples

             

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. HIV Overview:  The HIV Life Cycle, Education Materials, AIDSinfo, NIH http://aidsinfo.nih.gov/education-materials/fact-sheets/19/73/the-hiv-life-cycle 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 Perry CM Faulds D Lamivudine:  A Review of its Antiviral Activity, Pharmacokinetic Properties and Therapeutic Efficacy in the Management of HIV Infection.  Drugs 53(4):  667-68- 1997. http://www.ncbi.nlm.nih.gov/pubmed/9098665 Wainberg MA Miller MD Quan Y Salomon H Mulato AS Lamy PD Margot NA Anton KE Cherrington JM In vitro selection and charactization of HIV-1 with reduced susceptibility to PMPA.  Antiviral Therapy 4:  87-94 1999. http://www.ncbi.nlm.nih.gov/pubmed/10682153 (second sourced from reference 1) Larder BA Kemp SD Harrigan PR Potential Mechanism for Sustained Antiretroviral Efficacy of AZT-3TC Combination Therapy. Science, New Series, 269(5334) pp 696-699, Aug. 4, 1995. http://www.ncbi.nlm.nih.gov/pubmed/7542804 (second sourced from reference 1) Jayasekara D Aweeka FT Rodriguez R Kalayjian RC Humphreys MH Gambertoglio JB Antiviral Therapy for HIV Patients with Renal Insufficiency JAIDS, Journal of Acquied Immune Deficiency Syndromes 21:  384-395 1999. http://www.ncbi.nlm.nih.gov/pubmed/10458619  (second sourced from reference 1)

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