Nursing Pharmacology:  Antiviral Drugs

• Antiretroviral Drugs Used in Treating HIV Infection

  • →Non-nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NNRTI): (continued)

    • Etravirine (Intelence)

      • Etravirine (Intelence) inhibits HIV-1 replication at low concentration.

      • As with other members of the NNRTI antiretroviral drug class, etravirine does not show inhibitory activity against HIV-2.

      • An important and unique aspect of etravirine pharmacology is that the drug inhibits reverse transcriptase otherwise resistant to other NNRTI drugs.

        • Multiple mutations appear required to confer etravirine drug resistance with virologic failure.

    • Mutations and Resistance to Etravirine (Intelence)

      • Although a number of mutations have been identified in HIV-1 reverse transcriptase that can limit or eliminate sensitivity to etravirine's antiretroviral efficacy, several mutations appear particularly effective in conferring resistance.⁸ 

      •  

        Non-Nucleoside Reverse Transcriptase Inhibitor Resistance (NNRTI)¹²

        Attribution: Wood BR, NNRTI Resistance https://www.youtube.com/watch?v=mcHWUMvYubs (5/2014) HIV/AIDS (CDC) YouTube Channel:  https://www.cdc.gov/hiv/basics/whatishiv.html

    • Pharmacokinetics

      • Etravirine (Intelence) is administered orally and is then rapidly absorbed.^1,7  

        • Highest plasma concentration occurs about three hours following administration.

        • Administration of etravirine with food results in increased Area Under the Curve (AUC) levels and as a result of etravirine should be administered with a meal.

      • Etravirine is eliminated from the body utilizing the cytochrome P450 microsomal metabolizing system.^1,7

        •  of pharmacokinetic-related drug interactions occur because etravirine not only induces CYP3A4 but also inhibits CYP2C9 and CYP2C19.^1,7

          • For example, within the antiretroviral drug category, etravirine decreases efavirenz and dolutegravir serum levels while increasing fosamprenavir serum levels.

          • Another example involves antifungal drugs in which, etravirine administration on one hand, reduces itraconozole and ketoconazole levels and on the other increasees voriconazole levels.

      • Unmetabolized etravirine is not found in the urine.

        • Elimination t_1/2 for etravirine is about 40 hours, allowing for twice-daily dosing.

          • This dose frequency is an example of how newer drugs have dramatically reduced the extent of "pill burdens" when compared with older formulations.¹

    • Adverse Effects

      • The most frequently observed adverse effects associated with etravirine administration include rash, diarrhea and nausea.⁷ 

        • Rash is typically self-resolving within about two weeks.

          • The rash is rarely severe.⁷   

        • In at least one clinical trial involving an etravirine + darunavir combination protocol, rash was the only side effect that appeared more common with etravirine when compared with placebo.¹ 

          • In that instance rash was observed within several weeks following treatment initiation and lasted about two weeks.

          • About 2% of patients in this study discontinued etravirine as a consequence of rash.¹

            • However, more serious rash such as Stevens-Johnson syndrome and toxic epidermal necrolysis has been described.¹  

      • Etravirine was not associated with either neuropsychiatric or hepatic adverse effects, relative to placebo administration.¹  

        • However, laboratory anomalies following etravirine administration may include increases in serum cholesterol, triglyceride, anhepatic transaminase levels.

          • Glucose levels may also be elevated.⁷  

          • Increases in transaminase levels appear more likely in patients with either hepatitis B or hepatitis C co-infection.⁷  

      • As noted earlier, since etravirine induces CYP3A4 as well as glucuronosyltransferases and inhibits CYP2C9 and CYP2C19 pharmacokinetic-drug interactions are expectable.¹  

        • Some combinations do not require etravirine dose adjustments.¹  

          • Examples of these combinations include darunavir + ritonavir, lopinavir + ritonavir, and saquinavir + ritonavir.

          • By contrast the dose of maraviroc likely requires adjustment if used in combination with etravirine.

          • Furthermore, etravirine, pending better information concerning possible dose adjustment requirements, probably should not be administered with tipranavir + ritonavir fosamprenavir + ritonavir or atazanavir + ritonavir.

          • Finally, etravirine should not be combined with efavirenz, delavirdine, or nevirapine.

          • At present using two NNRTI-class drugs in combination is not recommended for any treatment protocol.⁹ 

    • Therapeutics

      • Etravirine (Intelence) is not in the recommended category for antiretroviral-naïve patients as a result of insufficient clinical data.⁹   

        • As a consequence this agent is approved for administration only in "treatment-experienced" HIV-infected adult patients.¹  

          • In treatment-experienced patients with baseline therapy of a darunavir + ritonavir combination, adding etravirine increase the percentage of patients achieving a plasma HIV-RNA reference level of <50 copies/cc as determined at week 48 of treatment.

            • Patients receiving etravirine along with the other agents exhibited improved mean CD4⁺ T cell counts, also determined at week 48.

          • Week 48 virologic responsiveness appear dependent on the extent of baseline etravirine-resistance mutations.¹ 

      • With respect to initial combination protocols in the antiretroviral-naïve patient, five regimens have been described.⁹   

        • Four of the five are based on integrase strand transfer inhibitors and one protocol is based on a ritonavir-boosted protease inhibitor.⁹ 

        • The details of these recommended protocols will be described in the section on integrase strand transfer inhibitor drugs.

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) DNA Codon Table https://en.wikipedia.org/wiki/DNA_codon_table Yanakakis LJ Bumpus NN Biotransformation of the Antiretroviral Drug Etravirine:  Metabolite Identification, Reaction Phenotyping and Characterization of Autoinduction of Cytochrome P450-Dependent Metabolism.  Drug Metabolism and Disposition. 40(4) 803-814, April 2012. http://dmd.aspetjournals.org/content/40/4/803.full Wood BR NNRTI Resistance https://www.youtube.com/watch?v=mcHWUMvYubs

 

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