Medical Pharmacology Chapter 36:  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, in the nanomolar range.

        • The concentration of etravirine required to inhibit HIV-1 reverse transcriptase by 50% (IC₅₀) is approximately 2.5 nanomolar (nM).

      • 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.

        • For example, etravirine is not affected by the K103N mutation or by K103N/Y181C mutation pair, which mediates resistance to efavirenz, nevirapine and delaviridine.

        • 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 

        • As described below, these mutations occur at amino acid 100, 101, and 181.⁸  

          • There are numerous other sites where mutations have been identified, including amino acid at 90, 98, 106, 138, 179, 190 and 230.

        • At site 100 the wild type amino acid leucine is substituted by an isoleucine.

        • At amino acid 101, a lysine is replaced by glutamate, histidine, or proline.

        • At amino acid 181, the wild type amino acid tyrosine is replaced by either cysteine, isoleucine, or valine.⁸

        • Other studies suggest that the glycine to alanine mutation at site 190 is also an important resistant muation.⁶

      • A concern and possible limitation of etravirine resistance investigations is that many studies consider etravirine resistance in patients also receiving darunavir, a possible confounding factor.¹

      • Locations of HIV Reverse Transcriptase Gene Mutations and Resistance to the Antiretroviral Drug

         

        Etraverine⁸

        Amino acid abbreviations: A:  Alanine C:  Cysteine D:  Aspartate E:  Glutamate F:  Phenylalanine G:  Glycine H:  Histidine I:  isoleucine K:  Lysine L:  Leucine	M:  Methionine N:  Asparagine P:  Proline Q:  Glutamine R:  Arginine S:  Serine T:  Threonine V:  Valine W:  Tryptophan Y:  Tyrosine

      •  

        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

        • As noted earlier for other agents, certain enzyme isoforms of cytochrome P450 are more important than others in metabolizing certain drugs.

          • In this case, three cytochrome P450 isoforms appear most important: CYP3A4, CYP2C9, and CYP2C19.

            • Metabolism by these agents results in methyl-and dimethyl-hydroxylated metabolites.¹  

              •  

                Etravirine Metabolism¹¹

                The above represents a proposed model for etravirine metabolism Note both phase I metabolism (cytochrome P450) and Phase II metabolism (conjugation reactions) involvement in this proposed mechanism. Attribution:  This figure corresponds to a slightly modified Fig. 10 in reference 11 (http://dmd.aspetjournals.org/content/40/4/803.full)

        • A variety 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.