Medical Pharmacology Chapter 36:  Antiviral Drugs

• Antiretroviral Drugs Used in Treating HIV Infection

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

    • Efavirenz (Sustiva)

      •  

        Efavirenz

         

         

      • Efavirenz: Molecular Modeling¹⁵

        Attribution: Weiss M Weiner J Carey M Shaliba E Efavirenz:  A non-nucleoside reverse transcriptase inhibitor https://www.youtube.com/watch?v=GKuXxn1gqkY (4/2010) Jweiner070790 YouTube Channel:  https://www.youtube.com/channel/UCpkrLoEEK1gk6VzZjD2ECLw

       

    • Efavirenz (Sustiva) has been described as potent antiretroviral drug, highly active with respect to HIV-1 inhibtion.¹ 

      • The concentration of efavirenz required to inhibit HIV-1 replication is of the order of 10^-8 to 10^-9 M (molar) (IC₅₀, inhibitory constant for 50% inhibition, K_i)

        • Accordingly, up to 95% replication inhibition is obtained at 1.5 mM (1.5 x 10^-3 M).⁴ 

          • When used in combination with indinavir a mean reduction in plasma HIV RNA of about 2 log (100 fold) along with an increase in CD4⁺ T cell counts of about 100 cells/mm³ has been noted.⁴   

            • However, use of efavirenz in combination with indinavir decreases indinavir concentration, as described by area under the curve (AUC) by about one third.

      • Efavirenz is ineffective inhibiting HIV-2 or other retroviruses.¹ 

    • Mutations and Resistance to Efavirenz (Sustiva)

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

         

        Efavirenz⁸

        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

      • Efavirenz resistance commonly follows a mutation at codon 103 of HIV-1 reverse transcriptase.¹ 

        • This mutation involves a change from the wild type lysine amino acid to an asparagine (K103N) or serine (K103S) amino acid.⁸ 

          • Note that the K103N mutation occurs by a single nucleotide substitution (AAA → AAC or AAT).^12,13

        • The K103N mutation is described as non-polymorphic and is observed in patients receiving nevirapine as well as efavirenz.¹⁰

          • Efavirenz efficacy in the presence of this one mutation is reduced by about 20 fold.

            • For comparison, this mutation reduces nevirapine antiretroviral activity by about 50 fold.¹⁰

        • The K103N mutation appears sufficient to prevent the HIV-1 antiretroviral effects of efavirenz.¹¹

        • K103S is described as a non-polymorphic two base-pair mutation emerging by efavirenz or nevirapine selection pressure.¹⁰  

          • AAA → AGT, AGC represents an example two-base pair change requirement.¹³

          • Patients exhibiting this mutation usually had previously acquired the K103N mutation.

            • The K103S mutation is categorized as conferring "intermediate to high-level resistance" to efavirenz and nevirapine.

              • Since K103S represents a two base pair change from the wild type form, patients with K103S is viewed as more likely to exhibit K103N which is just a one base pair change from the wild type.¹⁰

        • In addition to the K103N mutation, the Y181C mutation is also sufficient to result in virologic treatment failure.¹

    • Pharmacokinetics

      • Efavirenz (Sustiva) is well absorbed from the G.I. tract with peak plasma levels noted about five hours after administration.¹  

        • The oral bioavailability is about 45%. A high-fat meal increases bioavailability, as measured by area under the curve (AUC),  by about 22 %.⁷  

          • Accordingly, this drug is preferably administered on an empty stomach.

        • The half-life for efavirenz is unusually long, approximately 2 days.⁷  

          • Efavirenz is extensively bound to plasma albumin (~99%) and CSF (cerebrospinal fluid) levels correspond to about 0.75% of the plasma drug concentration.^1,7   

          • Despite relatively low CSF drug penetration, many highly significant adverse reactions to efavirenz administration are central nervous system in nature.¹

      • Efavirenz is metabolized using the hepatic cytochrome P450 oxidative metabolizing system.⁶  

        • Efavirenz is a substrate mainly for the cytochrome P450 enzyme isoforms CYP2B6 and CYP3A4 isoforms.

          • Efavirenz is classified as a moderate inhibitor of other cytochrome P450 isoforms including CYP2C9, CYP2C19, and CYP3A4.

            • Efavirenz induces CYP2B6 and CYP3A4 synthesis.⁶

          • Efavirenz is not subject to renal excretion to any appreciable extent and as a result no dose adjustment is typically required in renal failure.^6,1  

          • Clearance of efavirenz, slow enough to allow once daily dosing, may be further slowed in certain individuals with the 516G→T and the 983C→T CYP2B6 genotype, which is a common polymorphism in individuals of African and Japanese ancestry.^1,14

            •  

              Genetic Polymorphisms:  CYP2B6 (G526T)¹⁴

              CYP2B6 allelic variants were associated with higher efavirenz plasma levels during HIV therapy.  Inter-individual variations in metabolism might partially explain susceptibility to efavirenz CNS side effects.

        • Since the antiretroviral protease inhibitors are also substrates for CYP3A4, dosage adjustments are likely required.

          • Efavirenz reduces plasma concentrations of several central nervous system drugs including phenytoin, phenobarbital and carbamazepine.¹ 

          • Efavirenz decreases rifabutin area-under-the- curve (AUC) by about 40%.

          • With respect to HIV antiretroviral protease inhibitors, some drugs reduce plasma concentrations while others elevate plasma levels.¹

            • Agents exhibiting decreased  plasma levels following efavirenz administration include saquinavir, indinavir and amprinavir.

            • By contrast, protease inhibitors associated with higher plasma concentrations following efavirenz include ritonavir and nelfinavir.¹  

          • Agents that, as a result of induction of cytochrome P450 isoforms associated with efavirenz metabolism (CYP2B6 and CYP3A4), such as carbamazepine, phenytoin or phenobarbital, should not be used as efavirenz clearance would likely be increased.

          • Similar to nevirapine, efavirenz reduces methadone plasma levels and can induce acute opioid withdrawal.⁶

          • Efavirenz doses may require adjustment when the drug is co-administered with voriconazole but apparently no adjustment is required when coadministered with fluconazole.⁶

    • Adverse Effects

      •  The two major classes of efavirenz (Sustiva) toxicities relate to the central nervous system (CNS) and reproduction (teratogenicity).⁶  

        • One view concerning efavirenz use in pregnancy is that, since efavirenz is the the only antiretroviral agent clearly teratogenic in primates, the drug should not be administered during pregnancy or to women attempting conception or in sexually active women not using contraception.

        • Efavirenz administration may cause neural tube defects in the newborn.⁶  

        • Because neural tube defects occurs only during the first 5-6 weeks of pregnancy, an alternate view is that efavirenz-based protocols may be initiated in pregnant women after the initial eight week gestation period.¹⁶ 

      • Perhaps the more prominent efavirenz adverse effect involves the central nervous system since about 50% of patients exhibit some CNS/psychiatric side effects.

        • However, <5% of patients discontinued efavirenz because of CNS adverse effects.

        • The range of adverse effects reported includes dizziness, diminished concentration, dream abnormalities, dysphoria and insomnia.

        • Efavirenz, when first administered, may predispose to depression, hallucinations and/or mania; however, these effects tend to abate within the first month of therapy.

      • Miscellaneous side effects include:⁷

        • Nausea and vomiting

        • Crystalluria

        • Increases in liver enzyme values

        • Increases in total serum cholesterol on the order of 10%-20%.

        • Skin rash may occur early in efavirenz treatment with a frequency of about 30% of patients.⁷  

          • This rash tends to be mild to moderate and usually resolves without the need to discontinue efavirenz treatment.⁷

          • "Maculo-papular drug rash due to efavirenz"¹⁷ 

    • Therapeutics

      • Efavirenz (Sustiva) has been until recently classified as a preferred agent useful in beginning antiretroviral protocol treatment.⁶  

        • This agent, when combined with other drugs, provides long-lasting suppression of HIV-1 viral replication.

        • However, efavirenz administration may result in central nervous system adverse effects.

          • Up to 50% of patients receiving efavirenz may experience CNS adverse effects, particularly during the initial weeks of treatment.⁶  

            • Such adverse effects include:

              • Insomnia,

              • Dizziness and

              • Poor concentration.

            • Less frequently, the following more serious side effects have been reported:

              • Hallucinations

              • Depression

              • Psychosis and

              • Suicidality

            • For these reasons efavirenz may be inappropriate for use in patients diagnosed with pre-existing psychiatric conditions.⁶  

        • Recently (2015) efavirenz has been moved from the "Recommended" to the "Alternative" category due to adverse effects found both in clinical trial and clinical practice.⁹  

          • Most of the concern is due to CNS-related toxicities as described above and the possible relationship between suicidality and efavirenz administration.

          • This change in status applies to initial combination protocols for the antiretroviral drug naïve patient and is a revision to the May 1, 2014 HIV-1 Treatment Guideline, noted in the April 8, 2015 publication.⁹

        • Efavirenz (Sustiva) was the first antiretroviral drug FDA-approved for once-daily dosing.¹  

          • The rapid development of resistance to the antiretroviral effects of efavirenz in monotherapy has led to its use as part of multidrug protocols.

          • Efavirenz has been widely used (developed world) due to convenience, effectiveness and tolerability, although this agent is now classifed in the Alternative" regimen category as noted earlier.¹

            • One popular combined agent involves efavirenz coformulated with tenofovir and emtricitabine (Atripla).

              •  

                Atripla (Efavirenz, Emtricitabine, and Tenofovir)

                The long half-life of efavirenz is very important in this combination treatment should suboptimal adherence to medication is noted in a patient.18   Should doses be missed, the long-half life of efavirenz assures its presence; however, the other agents in this combination are no longer active due to their shorter half-lives.  As a result, during periods of missed doses, the patient is on essentially efavirenz monotherapy and susceptible to inactivating mutations.18

              • Efavirenz-containing multidrug protocols may provide the best long-term clinical responses.

            • Until recently, efavirenz along with two nucleoside reverse transcriptase inhibitors was categorized as a “Preferred” regimen in the treatment-naïve individual.⁹  

              • Efavirenz in the generic version has been used increasingly as part of treatment regimens in "resource-poor" countries due to relatively better toxicity profiles when compared to nevirapine.

                • Also, efavirenz may be combined with rifampin for management of tuberculosis.¹