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.¹⁴  

      • 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.¹⁴

    • Raltegravir (Isentress)

    • Raltegravir (Isentress)

    • Raltegravir is chemically a 1-N-alkyl-5-hydroxypyrimidinone, structural analogue of the di-keto acid class of agents and sharing their "β-hydroxy-ketone" structural feature.¹⁴ 

      • Compounds with this structural element exhibit metal-chelating capabilities, suggesting that integrase inhibitors may interact with divalent metals present at HIV-1 integrase catalytic sites¹⁴ , as described on the previous page and reference (13).

        • At a concentration of about 10 nM raltegravir, integrase catalytic activity is inhibited by about 50%, this describing the IC₅₀ for this drug.

          • Several double-blind, randomized, placebo-controlled clinical studies reported that to achieve 95% integrase activity inhibition requires about 30 nM raltegravir (IC₉₅ determined in 50% human serum).¹⁴ 

      • Clinical trial results suggest that administration of integrase strand inhibitor-based protocols  result in an initial more rapid decline of HIV-1 RNA when compared to other protocols.⁶  

        • The virologic response rate is, however, comparable after 48 to 96 weeks of treatment.⁶ 

    • Mutations and Resistance to Raltegravir:

      • Locations of Integrase Gene Mutations and Resistance to the Antiretroviral Drug Raltegravir⁸

        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

      • Mutations in the HIV integrase gene which significantly reduces sensitivity to raltegravir (25-to 50-fold sensitivity reduction, in vitro) have been identified.¹ 

        • Two such mutations involve the Q148 R/H/K or N155H sites, representing a transition from the wild type glutamate (Q) at codon 148 to either arginine (R), histidine (H) or lysine (K) in the first instance or a transition from the wild-type asparagine (N) to histidine (H) in the second case.^1,8,15   

        • Another important mutation site is located at codon 143 (Y143C/H/R) in which the wild-type tyrosine (Y) is replaced by either arginine (R), histidine (H), or cysteine (C).^1,8,15   

          • A clinical study suggested that almost 2/3 of patients exhibiting virologic treatment failure involving raltegravir combination protocols exhibited at least one of these primary resistance mutations.

          • High-level resistance may also develop from accumulation of secondary mutations which may extend from raltegravir in sensitivity to other integrase inhibitors.¹  

        • The above described amino acid substitutions conferring resistance to raltegravir appear localized in the vicinity of the HIV integrase catalytic (active) site.⁶ 

    • Pharmacokinetics:

      • Following oral dosing, raltegravir peak concentrations occur after 1-3 hours.¹ 

        • Elimination curves are biphasic with an initial t_½ (half-time) of about 1 hour with a longer terminal phase t_½ (half-time) lasting about 9 hours (range 7-12h).^1,16 

          •  

            Raltegravir Plasma Concentrations vs time Elimination Curve¹⁶

            Raltegravir elimination curve:  Plasma drug concentration, nM (Y-axis) plotted against time (X-axis, hours).16 Note the semilog Y-axis scale These curves were generated using various single dose administrations over a range of 10 mg to 1.6 g. Attribution: The above image corresponds to the insert in Figure 2, reference 16 (http://www.natap.org/2014/HIV/060914_01.htm)

        • Raltegravir exhibits variability in its pharmacokinetics.¹  

          • Furthermore, moderate to high-fat meals affects raltegravir bioavailability as described by area-under-the-curve (AUC) by as much as 2-fold.

          • On the other hand, a meal with reduced fat also affects area-under-the-curve (AUC), decreasing the value by about 50%.

          • However, no food requirements are associated with raltegravir administration has clinical trials evaluating efficacy were performed without such restrictions and also initial antiviral effects were maximal and all concentrations noted following 400 mg twice-daily administration.¹  

        • Raltegravir elimination proceeds via phase II metabolism, specifically by glucuronidation catalyzed by the UGT1A1 gene product, a glucuronosyltransferase.¹

          • 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.¹⁷

        • Since raltegravir is a UGT1A1 substrate, raltegravir levels may be affected by drug-drug interactions that describe either UGT1A1 inhibition or induction (higher levels).¹  

          • For example, atazanivir, described as a "moderate" UGT1A1 inhibitor, increases raltegravir levels, as assessed by area-under-the-curve (AUC), increasing AUC by about 55%.

          • Another drug, tenofovir increases AUC by about 50%.

          • Raltegravir itself does not appear to be an important enzyme inducer or inhibitor, at least in vitro, thus exhibiting minimal effects on the pharmacokinetics of concurrently administered agents.¹

    • Adverse Effects:

      • Raltegravir usually exhibits limited clinical toxicity.¹ 

        • Among the most common complaints, exceeding those reported by placebo recipients, following raltegravir administration include:

          • Headache

          • Nausea

          • Fatigue

          • Asthenia (weakness or reduced energy).

        • Worsening of depression has also been reported.¹  

        • Changes in certain enzyme levels have also been documented including:⁷

          • Pancreatic amylase

          • Creatine kinase (with rhabdomyolysis)

          • Serum aminotransferases⁷

        • More severe, even life-threatening and fatal skin reactions have been described and include:⁷

          • Stevens-Johnson syndrome

          • Toxic epidermal necrolysis

          • Hypersensitivity reactions. ⁷

      • Common adverse effects of the anti-retroviral drugs for HIV considered more broadly have been described.¹⁸ 

      • A detailed clinical trial comparing raltegravir and efavirenz also has presented raltegravir adverse effects in detail.¹⁹

    • Therapeutics:

      • 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

       

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

        • →In one recommended protocol Raltegravir (RAL) is combined with tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) for this application, i.e. RAL/TDF/FTC.⁹

        • 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).⁹

        • 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).⁹  

          • This combination is recommended only in patients with pre-antiretroviral treatment creatinine clearance >70ml/min.⁹

      • 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

      • A study comparing raltegravir-based drug protocol with an efavirenz-based regimen was important in establishing both effectiveness and safety of raltegravir for treating HIV treatment-naïve patients.²¹

        • The context of the study was the evaluation of raltegravir with respect to both safety and efficacy compared to efavirenz as part of combination antiretroviral treatment for treatment-naïve patients.²¹

          • Previously, raltegravir along with "optimized background therapy" had been shown effective as well as well-tolerated in treatment-experienced patients exhibiting multidrug-resistant HIV-1 infection.²¹

        • Patients recruited from 67 study sites across five continents were selected based on several eligibility factors:²¹  

          • (1) patients had been infected with HIV-1, exhibiting viral RNA serum concentrations of >5000 viral RNA copies/ml.

          • (2) Patients exhibited no baseline resistance to tenofovir disoproxil fumarate, efavirenz or emtricitabine.

        • The principal endpoint was attainment of viral RNA concentrations of <50 viral RNA copies/ml at week 48.

        • Nearly 600 patients were enrolled with 281 individuals receiving a raltegravir-based protocol and 282 individuals receiving an efavirenz-based regimen.²¹  

          • In both the  raltegravir and efavirenz protocols, the primary drug was combined with tenofovir and emtricitabine.

          • Most patients (53%) prior to treatment initiation had >100,000 viral RNA copies/ml and about 47% of patients exhibited CD4⁺ T cell counts of <200 cells/µl.

            • Time course of increase (from baseline) of CD4+ T cell counts following initiation of Raltegravir-based and Efavirenz-based anti-HIV-1 therapy²¹

              Attribution:  This figure corresponds to Figure 4 in reference 21 (Lennox JL DeJesus E Lazzarin A Pollard RB Madruga JVR Berger DS Zhao J Xu X Williams-Diaz A Rodgers AJ Barnard RJO Miller MD DiNubile MJ Ngyen B-Y Leavitt R Sklar P, for the STARTMRK investigators Safety and efficacy of raltegravir-based versus efavirenz-based combination therapy in treatment naïve patients with HIV-1 infection:  a multicentre, double-blind randomised controlled trial. Lancet 374:  796-806 2009. http://www.ncbi.nlm.nih.gov/pubmed/19647866)

          • 86.1% of patients in the raltegravir group and 81.9% of patients in the efavirenz group achieved the primary endpoint (i.e. <50 viral RNA copies/ml).

            •  

              Time for patients to achieve <50 copies of HIV-1 RNA/ml²¹

              Attribution:  This figure corresponds to Figure 3 in reference 21 (Lennox JL DeJesus E Lazzarin A Pollard RB Madruga JVR Berger DS Zhao J Xu X Williams-Diaz A Rodgers AJ Barnard RJO Miller MD DiNubile MJ Ngyen B-Y Leavitt R Sklar P, for the STARTMRK investigators Safety and efficacy of raltegravir-based versus efavirenz-based combination therapy in treatment naïve patients with HIV-1 infection:  a multicentre, double-blind randomised controlled trial. Lancet 374:  796-806 2009. http://www.ncbi.nlm.nih.gov/pubmed/19647866)

            • Furthermore, fewer drug-related clinical adverse occurrences were noted in the raltegravir group compared to the efavirenz group.

            • Drug-related serious clinical adverse events were noted in <2% of patients in each group.²¹  

        • The authors concluded that raltegravir-based combination treatment exhibited both potent and rapid antiretroviral drug action comparable to that noted with efavirenz at week 48.

          • Also, raltegravir was described as a well-tolerated alternative to efavirenz in combination anti-HIV-1 protocols administered to treatment naïve individuals.²¹

      • The full five-year STARTMRK study evaluating both safety and efficacy of raltegravir versus efavirenz-based protocols in treatment-naïve HIV-1-infected individuals has recently been completed and results published.

        • Final results indicated that in combination therapy with tenofovir/emtricitabine in treatment-naïve patients evaluated at week 240, viral RNA suppression rates and increases in CD4⁺ T cell counts were both higher in raltegravir compared to efavirenz-receiving individuals.

          •  

            "CD4 cell count increments by treatment group"²²

            Attribution:  The above figure corresponds to part of Figure 2B from reference 22 (Rockstroh JK DeJesus E Lennox JL Yazdanpanah Y Saag MS Wan H Rodgers AJ Walker ML Miller M DiNubile MJ Nguyen B-Y Teppler H Leavitt R Sklar for the STARTMRK Investigators Durable efficacy and safety of raltegravir versus efavirenz when combined with tenofovir/emtricitabine in treatment-naïve HIV-1-infected patients:  Final 5-year results from STARTMRK  J Acquir Immune Defic Syndr 63(1) 77-85 May 1, 2013. http://www.ncbi.nlm.nih.gov/pubmed/23412015)

        • Furthermore, fewer patients presented with neuropsychiatric and drug-related adverse events were found in the raltegravir study arm compared to the efavirenz group.

        • Considering both virologic and immunologic outcomes after 240 weeks, raltegravir/tenofovir/emtricitabine combination treatment appeared to exhibit higher efficacy when compared with the efavirenz/tenofovir/emtricitabine protocol.

         

      • Biomarkers:

        • Comparison of atazanavir, raltegravir or darunavir with FTC/tenofovir on Biomarkers of systemic inflammation²³

          Kelesidis T Tran TTT McComsey GA Brown TT Moser C Ribaudo HJ Rothenberg J Yang OO Stein JH Currier JS  "Comparisons of effects of atazanavir, raltegravir or darunavir with FTC/tenofovir on biomarkers of systemic inflammation, macrophage and T cell activation:  ACTG" AIDS Clinical Trials Group https://www.youtube.com/watch?v=8314xSodP2E (7/2014) International AIDS Conference https://www.youtube.com/channel/UCBBhpWA2uqSzk2lfFig-7JQ