Nursing Pharmacology:  Antiviral Drugs

• Antiretroviral Drugs Used in Treating HIV Infection

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

    • Emtricitabine (Emtriva)1

    • As shown above, emtricitabine (Emtriva) is very closely chemically related to lamivudine (Epivir).¹ 

      • These drugs exhibit similar pharmacodynamic characteristics.

      • At least in vitro, emtricitabine appears about 10 times more active compared to lamivudine.

      • Emtricitabine following cell entry (passive diffusion) is initally phosphorylated by deoxycytidine kinase and ultimately other cellular kinases to the active drug form, emtricitabine 5'-triphosphate.

        • Accordingly, emtricitabine can be described as a "prodrug", requiring triphosphorylation to the active form.

      • Low toxicity associated with both emtricitabine and lamivudine is due to these agents limited tendency to bind  to human DNA polymerases (low affinity for human DNA polymerase).¹

    • Mutations and Resistance to Emtricitabine:

      • Resistance to the action of emtricitabine as a result of mutations in viral polymerase occurs by mechanism identical to that observed and described earlier for lamivudine.¹¹   

        • If emtricitabine is used as monotherapy, this resistance can develop within a few weeks, due to the single point mutation at position 184 of reverse transcriptase.¹¹ 

        • More recent studies have also noted that virological failure is more likely with lamivudine compared to emtricitabine when combined with other antiretroviral drugs.¹²  

          • Generally, lamivudine (Epivir) and emtricitabine (Emtriva) are viewed as interchangeable in "first-line" tenofovir/efavirenz and tenofovir/nevirapine combination antriretroviral therapy (cART; HAART).¹²  

        • Study conclusions indicated that emtricitabine in combination anti-retroviral treatment appeared associated with improved virological response compared to lamivudine.¹²  

        • Another similar study considering emtricitabine and lamivudine resistance profiles and tenofovir-containing protocols involved comparing the selection frequency of the codon 184 mutation in HIV-infected patients.¹³  

          • These patients had experienced virologic failure while receiving emtricitabine or lamivudine administered with tenofovir and either efavirenz or ritonavir-boosted protease inhibitor such as lopinavir or atazanavir.¹³  

        • Emtricitabine also exhibits a low level of resistance development when given in combination with efavirenz and didanosine.⁴

      • Pharmacokinetics:

        • Oral bioavailability of emtricitabine exceeds 90% with rapid absorption.¹  

          • This agent may be taken without regard to meals, although food may reduce the C_max, the area under the curve (AUC) is unaffected.

            • When compared to other nucleoside analog-type agents, emtricitabine exhibits a relatively slow systemic clearance with an elimination half-life (t_½) of about 9 hours.^1,11

    • Furthermore the estimated half-life of the active drug, emtricitabine-5'-triphosphate is even longer, up to 39 hours.

    • This extended half-life provides a pharmacokinetic reason supporting a single daily dosing.

    • With respect to excretion, emtricitabine is eliminated unchanged in the urine following glomerular filtration as well as active tubular secretion.

    • Dose reduction may be appropriate in individuals with creatinine clearance of < 50 mL/min.¹  Emtricitabine is also available as an oral solution which contains propylene glycol.⁷  

      • This formulation is contraindicated in pregnant women, young children, patients with hepatic or renal failure and in those individuals also taking metronidazole or disulfiram.⁷

    • Adverse Effects: 

      • Emtricitabine (Emtriva), similar to the other nucleoside analogues, exhibits toxicity potential as secondary to interaction with human mitochondrial DNA enzymes, for example mitochondrial DNA polymerases γ.¹¹  

        • Such interactions may result in myopathies and neuropathies and may cause of hepatic steatosis potentially leading to primary lactic acidosis syndrome.

        • In vitro studies demonstrated that emtricitabine 5'-triphosphate, the active intracellular form, did not appreciably influence either cellular or mitochondrial DNA polymerase enzymic function.

          • Comparing emtricitabine 5' triphosphate with the very similar agent lamivudine 5' triphosphate, Emtriva was about 20 times less active with respect to mitochondrial DNA polymerase (pol γ) inhibition.¹¹

        • Emtricitabine is considered one of the least toxic antiviral agents, much like lamivudine,  with relatively few substantially adverse reactions.¹  

          • However, emtricitabine may predispose to skin hyperpigmentation particularly in "sun-exposed" areas.

            • Skin hyperpigmentation was considered "very common:" (≥ 10%) in pediatric patients.¹⁵

          • Furthermore, since emtricitabine exhibits in vitro activity against hepatitis B virus (HBV) caution is appropriate when using this agent in those patients infected both with HIV and HBV and also more generally in regions with high HBV prevalence.

            • The concern is that with abrupt emtricitabine discontinuation, by analogy to observations with lamivudine, may lead to HBV replication rebound with worsening hepatitis.¹ 

        • Overall the most common adverse effects following emtricitabine administration include insomnia, nausea, headache, and rash.⁷ 

          • Some occurrence of hyperpigmentation (palms or soles) has also been reported at an overall frequency of about 3% although more frequently noted in African Americans (up to 13%).⁷ 

          • Hyperpigmentation in HIV-Infected Patients Receiving Emtriva¹⁴

    • Therapeutics:

      • Emtricitabine (Emtriva) is used in combination with tenofovir, either alone in the two drug protocol or in combination with efavirenz, rilpivirine, or elvitegravir plus cobicistat which is a boosting agent.⁷ 

      • Tenofovir and emtricitabine in combination has been suggested as:⁷ 

        • Pre-exposure prophylaxis with the intent of reducing HIV infection in men who have sex with men

        • In heterosexually active individuals and

        • In those who inject drugs.⁷   

      • Emtricitabine is a recommended agent, as part of a multidrug protocol, for initial treatment of HIV in antiretroviral drug-naïve patients.¹⁶ 

        • At this time (2015), there are five recommended regimens for antiretroviral therapy in antiretroviral drug-naïve individuals.¹⁶

          • For the regimens involve "integrase strand transfer inhibitor"-based protocols and one ritonavir-boosted protease inhibitor-based protocol.

            • Integrase strand transfer inhibitor-based regimens include:

              • (1) Dolutegravir/abacavir/lamivudine (DTG/ABC/3TC for those patients who are HLA-B *5701 negative.

              • (2) Dolutegravir plus tenofovir disoproxil fumarate/emtricitabine.

              • (3) Elvitegravir/cobicistat/tenofovir disoproxil fumarate/emtricitabine [restricted for patients with creatinine clearance >70 mL/min prior to antiretroviral therapy].

              • (4) Raltegravir with tenofovir disoproxil fumarate/emtricitabine.

            • The single ritonovir-boosted protease inhibitor protocol involves combination of darunavir/ritonavir with tenofovir disoproxil fumarate/emtricitabine.¹⁶

      •  

        Emtricitabine (Emtriva) 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. 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 Gallant JE Gerondelis PZ Wainberg MA Shulman NS Haubrich RH St Clain M Lanier ER Hellmann NS Richman DD Nucleoside and nucleotide analogue reverse transcriptase inhibitors:  a clinical review of antiretroviral resistance.  Antiviral Therapy 8:  489-506, 2003 http://www.intmedpress.com/journals/avt/abstract.cfm?id=1027&pid=88; http://www.ncbi.nlm.nih.gov/pubmed/14760883. (second sourced from reference 1 above) Hervey PS Perry CM Abacavir:  A Review of its Clinical Potential In Patients with HIV Infection. Drugs 60(2)  447-479 August, 2000. http://www.ncbi.nlm.nih.gov/pubmed/10983741 (second sourced from reference 1). Saag MS Emtricitabine, a New Antiretroviral Agent with Activity against HIV and Hepatitis B Virus:  Reviews of Anti-Infective Agents.  Clin infect Dis 42:  126-131 2006. http://www.ncbi.nlm.nih.gov/pubmed/16323102 Rokx C Fibriani A van de Vijer D Verbon A Schutten M Gras Luuk Rijnders Bart KA More virological failure with lamivudine than emtricitabine in efavirenz and nevirapin regiments in the Dutch nationwide HIV Cohort. Abstracts of the HIV Drug Therapy Glasgow Congress 2014.  Journal of the International AIDS Society 17(Suppl 3): 1949l 2014. http://www.jiasociety.org/index.php/jias/article/view/19491/html Marcelin AG Charpentier C Wirden M Landman R Valantin MA Simon A Katlama C Yeni P Descamps D Aubron-Olivier  C Calvez V Resistance profiles of emtricitabine and lamivudine in tenofovir-containing regimens.  J Antiimicrob Chemother 67:  1475-1478 2012. http://www.ncbi.nlm.nih.gov/pubmed/22371439 Levin J; Rashbaum B reported this poster at IAS at IAS-Rio (July 2005) Capital Medical Associates, P.C., Washington DC "Evaluation of Hyperpigmentation in HIV-Infected Patients Receiving Emtricitabine (FTC,Emtriva) http://www.natap.org/2005/ias/ias_34.htm Emtricitabine, Gilead Sciences, revised November 2012 http://www.gilead.com/~/media/Files/pdfs/medicines/hiv/emtriva/emtriva_pi.pdf AIDSinfo:  Guidelines for the Use of Antriretroviral Agents in HIV-1-Infected Adults and Adolescents https://aidsinfo.nih.gov/guidelines (2015)

 

Disclaimer

This Web-based pharmacology and disease-based integrated teaching site is based on reference materials, that are believed reliable and consistent with standards accepted at the time of development. Possibility of human error and on-going research and development in medical sciences do not allow assurance that the information contained herein is in every respect accurate or complete. Users should confirm the information contained herein with other sources. This site should only be considered as a teaching aid for undergraduate and graduate biomedical education and is intended only as a teaching site. Information contained here should not be used for patient management and should not be used as a substitute for consultation with practicing medical professionals. Users of this website should check the product information sheet included in the package of any drug they plan to administer to be certain that the information contained in this site is accurate and that changes have not been made in the recommended dose or in the contraindications for administration.  Advertisements that appear on this site are not reviewed for content accuracy and it is the responsibility of users of this website to make individual assessments concerning this information.  Medical or other information  thus obtained should not be used as a substitute for consultation with practicing medical or scientific or other professionals.