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.¹⁸  

      • 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.¹⁸

    • Dolutegravir (Tivicay)

    •  

      Dolutegravir (Tivicay)

    • Dolutegravir is the most recent and third example of a strand transfer integrase inhibitor drug for use in treating HIV-1 infection.¹⁵  

      • "Dolutegravir (Tivicay):  A Next Generation Integrase Inhibitor"¹⁶

        Attribution:  Wood BR,  Dolutegravir (Tivicay):  A Next Generation Integrase Inhibitor. https://www.youtube.com/watch?v=-utOC0EvS8g (1/2014) AETC National Coordinating Resource Center YouTube Channel:  https://www.youtube.com/channel/UCEZU7_BPxUSN75ekOz4Uskg

      • By contrast to elvitegravir, no boosting agent is required.

        • A single dose (50 mg/day) may be appropriate in treatment-naïve/integrase drug-naïve individuals.

          • Those patients receiving efavirenz, tipranavir + ritonavir combination treatment, fosamprenavir + ritonavir combination or rifampin may require two 50 mg doses of dolutegravir per day.

          • This higher dosage may also be appropriate in patients previously treated within integrase-inhibitor and in whom possible resistance to integrase inhibitors may be occurring.¹⁵

    • Dolutegravir (Tivicay) in the unboosted form is a recent example of an integrase strand transfer inhibitor, exhibiting extended plasma half-life (≈14 hours),  thus allowing for once a day dosing absent a requirement for pharmacokinetic boosting.¹²

      • In August 2013 dolutegravir received FDA approval and later that year, in November 2013 dolutegravir was approved by Health Canada. In early 2014 dolutegravir (Tivicay) was approved by the European Commission for use throughout the European Union.

      • Although dolutegravir is being evaluated for combination therapy with abacavir and lamivudine¹², dolutegravir has been shown to exhibit potent antiviral activity with good short-term tolerability.^11,12

    • Based on clinical trials involving treatment-naïve HIV-infected individuals, results with dolutegravir have been considered "impressive" when compared with, for example, nonnucleoside reverse transcriptase inhibitors (NNRTI, boosted protease inhibitors (PI) and raltegravir-containing protocols.

      • Furthermore, dolutegravir was found superior both to the combination treatment efavirenz + tenofovir + emtricitabine and to the protocol consisting of darunavir (Prezista) + ritonavir + tenofovir + emtricitabine in those patients who exhibited baseline HIV viral RNA loads >100,000 copies/mL.

    • Mutations and Resistance to Dolutegravir:

      • Locations of Integrase Gene Mutations and Resistance to the Antiretroviral Drug Dolutegravir⁹

        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

      • Many of the prominent mutations associated with the integrase strand inhibitor agents reduce dolutegravir sensitivity.⁶ 

        • These mutations include E92Q, G140S/A, and Q148H/R/K/; however, an exception is Q155H.

          • The Q155H (wild type glutamine substituted by histidine) retains in vitro susceptibility to dolutegravir.⁶   

        • In a clinical study involving 24 patients who exhibited raltegravir-resistant HIV-1 viral infection, about 75% of individuals on a 24 week, 50 mg 2X daily dolutegravir dose with an "optimized background regimen", achieved the endpoint of HIV-1 viral plasma levels of <50 copies/mL.^6,14  

          • However, if more than two integrase strand inhibitor-resistance mutations was initially present, virologic failure ensued.

            • Eligible subjects in this study had previously taken antiretroviral treatment (ART-experienced) and were HIV-1-infected adults (≥18 years of age) with a plasma HIV-1 viral RNA level of ≥ 1000 copies/mL with a genotypic and/or phenotypic resistance profile to integrase inhibitors (not including dolutegravir) along with documented resistance to ≥ 1 drug in each of 2 other approved antiretroviral drug classes such as nucleoside reverse transcriptase inhibitors (NRTIs), nonnucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs) and fusion-entry inhibitors.¹⁴  

            • The availability of ≥ 1 fully active anti-retroviral drug was encouraged or mandated depending on the cohort.

            • Exclusion criteria involved conditions or disorders which might interfere with study conduct such as pre-existing mental or physical issues or substance abuse disorders.

              • Other exclusion criteria included alanine aminotransferase levels  ≥ 5 times the upper limit of normal or lipase concentration ≥ 3 times the upper limit of normal.

              • Pregnant or breast-feeding women also were excluded from the study.

              • Patients were not enrolled if they were currently receiving or were about to receive efavirenz, navirapine, fosamprenavir/ritonavir or tipranavir/ritonavir.¹⁴

          • This study was considered preliminary with additional clinical data required for generalizable clinical conclusions.⁶ 

    • Pharmacokinetics:

      • As noted earlier, dolutegravir exhibits a half-life of ≈ 14 hours.⁶

        • Dolutegravir is metabolized principally by phase II glucuronidation (catalyzed by the UGT1A1 gene product, a glucuronosyltransferase¹) and with minor oxidative pathways catalyzed by the cytochrome P450 isoform CYP3A4 (8% of parent compound).^7,17

        • 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.

        • Given that dolutegravir is metabolized by both phase I and phase II (i.e. UGT1A1-coded glucuronosyltransferase and cytochrome P450 (i.e. CYP3A4), drug-drug interactions may be expected.⁷

          • For example, administration of dolutegravir with inducers of these metabolizing enzymes such as phenobarbital, carbamazepine, phenytoin, and St. John's wort may be inappropriate.

          • Another characteristic of dolutegravir is inhibition of an important organic anion transporter, OCT2, found in the kidney.

            •  

              Tubular Epithelial Cell²⁴

              Figure Attribution:  StraightHealthcare Ogranic Cation Transporter 2 (OCT2)  http://www.straighthealthcare.com/oct2-mate-illustration.html; http://www.straighthealthcare.com/index.html MATE = Multidrug And Toxin Extrusion proteins

            • Inhibition of this transporter may increase plasma concentration of drugs dependent on OCT2 including metformin.⁷

              • This transporter, OCT2 (Organic Cation Transporter 2) is expressed in the three segments of human renal proximal tubules as well is in small intestine.

                • OCT2 is localized in epithelial cell basolateral membranes as well as epithelial luminal membranes of trachea and bronchi.

                • However it is most prominently expressed in the kidney, although also expressed in lung, skin, brain, choroid plexus and placenta.^19-23

    • Adverse Effects:

      • Insomnia and headache represent the most common adverse reactions to dolutegravir administration.⁷  

        • Other reactions including hypersensitivity associated with rash and even organ dysfunction including hepatic damage have been described and could be life-threatening. Immediate cessation of drug administration without subsequent re-administration would be appropriate should such hypersensitivity reaction ensue.

        • "Fat redistribution" syndrome along with increases in serum aminotransferase enzyme levels have also been reported.⁷

    • Therapeutics:

      • A recommended INSTI-based protocol for HIV treatment in treatment-naïve patients is based on dolutegravir combination with abacavir and lamivudine (DTG/ABC/3TC)  ONLY in HLA-B*5701 negative individuals.⁹

      • 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