Medical Pharmacology Chapter 36:  Antiviral Drugs

• Antiretroviral Drugs Used in Treating HIV Infection

  • →Integrase Strand Transfer Inhibitors (INSTI):

    • By way of review, HIV-1 replication depends on three enzymes: viral reverse transcriptase, protease and viral integrase.⁹  

      • Following interaction with host cells expressing surface CD4⁺ receptors and required co-receptors, HIV enters the cell and its single-stranded RNA genome is converted into a double-stranded form viral reverse transcriptase.

      • Integration of HIV-1 complementary DNA (complementary to the original HIV-1 RNA), utilizes HIV-1 integrase in promoting a two-step process.

        • (1) The first step involves excision of two nucleotides from the 3' ends of HIV-1 DNA.

        • (2) Subsequently, covalent insertion of HIV-1 viral genomic DNA into the host cell chromosome occurs.

      • Inhibition of the integrase enzyme results in viral complementary DNA circularization, a process catalyzed by host cell enzymes, as well as nuclear accumulation of 2-long terminal repeat (LTR) circles.

      • Stable integration of HIV-1 DNA into the host genome is therefore prevented by inhibition of viral integrase.

        • Consequently, viral latency within the host cell allowing HIV-1 replication and elaboration new virus is prevented.⁹

    • Elvitegravir (Viketa)

    •  

      Elvitegravir (Viketa)

    • Elvitegravir (Viketa) is a second example of the first-generation integrase inhibitors, following raltegravir.¹²   

      • Elvitegravir and raltegravir appear well-tolerated and potent in both treatment-naïve and treatment-experienced HIV-1 infected adults.

        • Raltegravir requires twice-daily dosing and may exhibit variable pharmacokinetic profiles.

      • By contrast, elvitegravir is typically taken with food and also requires pharmacokinetic boosting drugs.

        • These factors along with the possibility of cross-resistance between elvitegravir and raltegravir has suggested the need for new, unboosted integrase inhibitors with both once-daily dosing and a better resistance profile.¹² 

      • Chemically elvitegravir is a dihydroquinoline carboxylic acid compound.⁹  [chemical name: 6-(3-chloro-2-fluorobenzyl)-1-[(2S)-1-hydroxy-3-methylbutan-2-yl]-7-methoxy-4-oxo-1,4-dihydroxyquinoline-3-carboxylic acid]

        • This drug inhibits integrase associated with both HIV-1 and HIV-2.

        • In peripheral blood mononuclear cells elvitegravir-mediated integrase inhibition at the 90% level occurs at a concentration of about 1 nM (nanomolar).

          • In a serum-free test system, the concentration of elvitegravir required to inhibit viral integrase by 50% is approximately 0.2 nM.⁹

      • Elvitegravir is present in one of four recommended integrase strand transfer inhibitor (INSTI)-based protocols for antiretroviral treatment in antiretroviral treatment naïve patients.

        • One INSTI-based recommended protocol involves Raltegravir (RAL) is combined with tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) for this application, i.e. RAL/TDF/FTC.¹⁰

        • A second INSTI-based recommended protocol for treatment naïve patients is dolutegravir/abacavir/lamivudine (DTG/ABC/3TC) for use only in patients who are HLA-B*5701 negative.

          •  HLA refers to human leukocyte antigen genes and gene products.

            • These genes influence immune system response to viral and bacterial infections as well as directing antibody production against antigens or foreign substances.

              • HLA-B refers to an HLA subclass.²⁰  

                • Numerous versions of genes coding for the HLA-B antigen (over 2000) have been identified and products of the 5701 gene family have been found associated with abacavir hypersensitivity reactions.

                • Therefore, the HLA-B*5701 genotype is predictive of abacavir hypersensitivity at least in Western European populations.

                • These hypersensitivity reactions typically occur within the first month and a half of treatment may involve skin reactions, gastrointestinal symptoms and respiratory symptoms.

                • Abacavir hypersensitivity reactions may be fatal.²⁰

        • A third recommended INSTI-based protocol for HIV treatment in treatment-naïve patients is also based on dolutegravir (DTG) but in combination with tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC).¹⁰ 

        • →A fourth recommended INSTI-based protocol for HIV treatment in treatment-naïve patients is based on elvitegravir (EVG) in combination with cobicistat (c) with tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC), i.e. (EVG/c/TDF/FTC).¹⁰   

          • This combination is recommended only in patients with pre-antiretroviral treatment creatinine clearance >70ml/min¹⁰  

      • A fifth NON-INSTI-based recommended protocol for HIV treatment in treatment-naïve patients is based on darunavir/ritonavir (HIV protease inhibitors) (DRV/r) in combination with tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC).⁹

       

    • Elvitegravir is available as a fixed-dose combination tablet containing elvitegravir, and tenofovir disoproxil fumarate, emtricitabine and cobicistat.

      • The trade name for this combination tablet is stribild.

    • Several clinical trial studies have compared elvitegravir-based protocols with other anti-HIV retroviral therapies.

      • For example, in one study elvitegravir, co-formulated with cobicistat, emtricitabine and tenofovir disoproxil fumarate (EVG/COBI/ FTC/PDF, single tablet) was compared with standard of care coformulation of efavirenz, emtricitabine and tenofovir disoproxil fumarate (EFV/FTC/TDF).

        • This study, a phase 3 trial, evaluated antiretroviral treatment-naïve individuals seen in North America outpatient clinics. Patients were randomly assigned to either EVG/COBI/FTC/TDF or EFV/FTC/TDF plus matching placebo.

        • With respect to patient trial eligibility, patient HIV RNA plasma concentrations had to equal or exceed 5000 viral RNA copies/mL and patients needed to exhibit susceptibility to efavirenz, tenofovir, and emtricitabine.

        • The principal endpoint was HIV RNA concentrations <50 copies/mL at week 48. 700 patients were selected for the trial, split about evenly between the two groups.

        • Combination treatment based on elvitegravir was found non-inferior to that based on efavirenz.

          • For example, about 86% of patients in either treatment group met the endpoint requirement of HIV RNA concentration <50 viral RNA copies/mL and the proportion of patients needing to discontinue drugs due to adverse effects was similar between groups, between 4% and 5%.

      • The virologic success rates, comparing EVG/COBI/FTC/TDF and EFV/FTC/TDF protocols, described above at week 48 were essentially the same when evaluated at week 96.¹⁸

        • Regimen discontinuation secondary to adverse effects remained low, about 6%.

        • Also similar were changes in serum creatinine at the 96 week point compared to week 48.

        • Results from this extended study to week 96 supported conclusions of both long-term safety and lasting efficacy of the elvitegravir-based protocol.¹⁸

          •  

            Comparison of Stribild (VG/COBI/FTC/TDF) and Atripla (EFV/FTC/TDF) at Week 48 and Week 96¹⁸

            In the above figure virologic success (<50 viral RNA copies/mL) appears similar in both the week 48 and week 96 time point. 18 Virologic failure in the above figure consists of three categories the first being HIV-1 concentrations ≥ 50 HIV-1 viral RNA copies/mL.18 Virologic failure also includes both drug discontinuation due to lack of clinical effectiveness or drug discontinuation for other reasons including, for example, consent withdrawal and lost to follow-up. STB is the abbreviation for stribild which is the elvitegravir-based multidrug formulation; ATR is the abbreviation for atripla, which is the efavirenz-based multidrug formulation.18 Attribution:  The figure above corresponds to Figure 1 of reference 18. (Zolopa A Sax PE DeJusus E Mills A Cohen C Wohl D Gallant JE Liu HC Plummer A White KL Cheng AK Rhee MS Szwarcberg J for the GS-US-236-0102 Study Team.  A randomized double-blind comparison of coformulated elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate versus efavirenz/emtricitabine/tenofovir disoproxil fumarate for initial treatment of HIV-1 infection:  analysis of week 96 results.  J Acquir Immune Defic Syndr 63:  96-100, 2013. http://www.ncbi.nlm.nih.gov/pubmed/23392460

    • Mutations and Resistance to Elvitegravir:

      • Drug resistance to elvitegravir-based protocols appear similar to that observed with efavirenz-based regimens.⁶

      • Elvitegravir is considered a relatively new antiretroviral drug exhibiting clinical effectiveness in both treatment-naïve and-experienced HIV-1 infected individuals.¹⁴ 

        • In some patients failing elvitegravir-containing protocols as well as in in vitro studies, mutations in viral integrase appear responsible for diminished raltegravir sensitivity.

          • Resistance associated mutations identified by cell-based selection include T66I, E92Q, S147G and Q148R/K, reflecting threonine to isoleucine, glutamate to glutamine, serine to glycine and glutamine to arginine/lysine substitutions respectively.

            • Additional resistance-conferring mutations have been identified in patients exhibiting virologic failure associated with elvitegravir-based protocols. These additional mutations include T66A/K, E92G, T97A, Q148H and N155H, corresponding to threonine to alanine/lysine, glutamate to glycine, threonine to alanine, glutamine to histidine and asparagine to histidine transitions respectively.¹⁴  

        • The most frequently clinically observed integrase mutations (E92Q, Q148R and N155H) correlated with the greatest decrease in elvitegravir susceptibility.¹⁴

        • Molecular structural analysis suggested that both elvitegravir and raltegravir are similar with respect to integrase active site binding.

          • Accordingly, for those HIV-infected individuals exhibiting virologic failure on either elvitegravir or raltegravir integrase strand inhibitors (INSTI)-based regimens, generally overlapping resistance profiles occur.¹⁴

          •  

            Locations of Major Elvitegravir Mutations in Relations to the Integrase Enzyme Active Site¹⁴

            "Proximal location of EVG primary INSTI RAMs in a homology model of the HIV-1 IN active site. Amino acid residues of HIV-1 IN were substituted in a crystal structure model of PFV IN with bound EVG and its cognate DNA substrate (PDB accession number 3L2U) . The protein backbone in a ribbon representation is shown in green. The viral DNA substrate sugar-phosphate backbone and nitrogenous bases are shown in brown and blue, respectively. Residues associated with primary EVG RAMs are shown as light blue spheres, and Mg2+ ions are shown as pink spheres. Elvitegravir (EVG) is labeled and shown as yellow spheres. White labels indicate HIV-1 IN residue numbers and mutations." Attribution: This image and legend correspond to FIG 4 from reference 14.  It is recommended that the reader consult the original work for detailed analysis of INSTI-integrase mutational analysis. Abram ME Hluhanich RM Boodman DD Andreatta KN Margot NA Ye L Niedziela-Majka A Barnes TL Novikov N Chen X Svarovakaia ES McColl DJ White KL Miller MD.  Impact of primary elvitegravir Resistance-mutations in HIV-1 integrase on drug susceptibility and viral replication fitness. Antimicrobial Agents and Chemotherapy 57(6): 2654-2663 June 2013. (http://aac.asm.org/content/57/6/2654.short; http://www.ncbi.nlm.nih.gov/pubmed/23529738)

         

      • Locations of Integrase Gene Mutations and Resistance to the Antiretroviral Drug Elvitegravir⁸

        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

    • Pharmacokinetics:

      • Single oral dosing of elvitegravir (100, 200, 400 or 800 mg) to healthy subjects results in maximal plasma concentration (C_max) of 108 ng/ml, 160 ng/ml, 264 ng/ml and 455 ng/ml respectively, with an uncertainty in these values of about 30%.¹⁶ 

        • These levels were obtained from 1.3-2.5 hours following dosing.

        • Oral administration with food extends boosted elvitegravir C_max  to about 4-4.5 hours post-dosing, consistent with relatively slow absorption.

          • Elvitegravir absorption appears unaffected by gastrointestinal pH very ability but is lowered in the presence of antacids (presumably due to drug association with di-trivalent cations).¹⁶ 

      • Metabolism of elvitegravir occurs mainly in liver and intestine and is dependent on the cytochrome P450 microsomal drug metabolizing system.¹⁶ 

        • Cytochrome P450 CYP3A isozymes are mainly responsible.

          • In view of the role of CYP3A4, increasing elvitegravir effects may be obtained by coadministration with CYP3A4 inhibitors.

            • For example, "pharmacokinetic boosting" occurs with coadministering of ritonavir or cobicistat along with elvitegravir.

              • Cobicistat and low-dose ritonavir examples of CYP3A4 inhibitors.

              • Elvitegravir coadministered with cobicistat appears to provide improved adverse-effect profiles relative to elvitegravir administration with ritonavir.

                • Additionally, this combination provides both high systemic levels and extended elimination half-life (t_½) which allows for once-daily dosing.

                  • Boosting can extend elvitegravir half-life to about 9 hours.⁶

                • Since cobicistat exhibits no anti-retroviral activity, the concern of induced protease inhibitor resistance due to the use of low-dose ritonavir with elvitegravir is eliminated.¹⁶ 

            • More specifically, elvitegravir metabolism occurs mainly through CYP-mediated (cytochrome P450 microsomal metabolizing system) aromatic and aliphatic hydroxylation and/or primary secondary glucuronidation (phase II).¹⁶   

              • Absent the boosting agent, two primary metabolites have been identified.

                • One, M1 (GS-9202) as a result of CYP3A4 metabolism, appear nearly totally inhibited if the elvitegravir is coadministered with ritonavir or cobicistat.

                • The second, M4 (GS-9200) is a metabolite produced by phase II metabolism dependent on uridine diphosphate glucuronosyltransferase (UGT) 1A1/3.

                • Elvitegravir metabolism by this mechanism is not affected by boosting.

                  • Both M1 and M4 metabolites are much less potent (10 to about 40-fold) as antiviral agents compared to the parent compound and therefore do not add to elvitegravir antiretroviral efficacy.¹⁶ 

         

      • Phase II Metabolism: Features

        Phase II characteristics: Parent drug participates in conjugation reactions that form covalent linkage between a parent compound functional group and Glucuronic acid Sulfate Glutathione Amino acids Acetate Conjugates are highly polar, and generally biologically inactive.  One exception to this rule is a morphine metabolite, morphine glucuronide which is a more potent analgesic compared to the parent compound.  Conjugates tend to be rapidly excreted in the urine. High molecular weight conjugates  are more likely excreted in the bile. The conjugate bond may be cleaved by intestinal flora with the parent compound released back to the systemic circulation.  This process, "enterohepatic recirculation" results in delayed parent drug elimination and a prolongation of drug effects.

      • UGT1A1 is the gene UDP glucuronosyltransferase 1 family, polypeptide A1.

        • The gene product is  the enzyme UDP-glucuronosyltransferase which catalyzes transformation of drugs, hormones, steroids etc. into more water-soluble forms amenable to excretion.¹⁵

    • Adverse Effects:

      • The principal side effect in elvitegravir-based coformulated drug (stribild) is a likely non-pathologic, reversible increase in serum creatinine levels.¹³  

        • This increase in creatinine appears to be attributable to the cobicistat component in the formulation, since cobicistat inhibits renal tubular creatinine secretion.

        • Elvitegravir-based treatment, i.e. treatment with stribild is appropriate and recommended for treatment-naïve HIV-1 infected individuals with an apparent glomerular filtration rate >70 mL/min.

          • Other side effects include rash and diarrhea but generally stribild is considered well tolerated.¹³

    • Therapeutics:

      • A recommended INSTI-based protocol for HIV treatment in treatment-naïve patients is based on elvitegravir (EVG) in combination with cobicistat (c) with tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC), i.e. (, stribild, EVG/c/TDF/FTC).¹⁰   

        • This combination is recommended only in patients with pre-antiretroviral treatment creatinine clearance >70ml/min¹⁰  

      • Stribild¹⁹

        Attribution:  Wood BR Stribild (The Quad Pill) https://www.youtube.com/watch?v=aLAZ7m-_rlI (5/2014) HIV/AIDS (CDC) YouTube Channel:  https://www.cdc.gov/hiv/basics/whatishiv.html

      •  

        Stribild Forumation

         

      • Abbreviations:  Antiretroviral Drugs, Combinations, and Classifications⁹

        3TC = lamivudine	ABC = abacavir	ARV = antiretroviral	ATV/c = cobicistat-boosted atazanavir	ATV/r = ritonavir-boosted atazanavir ear
        DRV/r= ritonavir-boosted darunavir	DTG = dolutegravir	EFV = efavirenz	EVG/c/TDF/FTC = elvitegravir/cobicistat/tenofovir DF/emtricitabine	FTC = emtricitabine
        LPV/r = ritonavir-boosted lopinavir	RAL = raltegravir	RPV =rilpivirine	RTV = ritonavir	TDF = tenofovir disoproxil fumarate
        INSTI = integrase strand transfer inhibitor	NNRTI = nonnucleoside reverse transcriptase inhibitor	NRTI = nucleoside reverse transcriptase inhibitor	PI = protease inhibitor	CrCl = creatinine clearance