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Epidemic and Pandemic Use of Antivirals Introduction 15 September 2008 Frederick G. Hayden, M.D. University of Virginia Health System Charlottesville, Virginia, USA Antiviral Agents for Influenza Class/agent Brand name Route Symmetrel Flumadine PO PO NA inhibitors Zanamivir (GG167) Oseltamivir (GS4104) Peramivir (RWJ-270201)* Relenza Tamiflu Inhaled/IV* PO IV*/IM* Ribavirin Virazole Inhaled*/PO* /IV* M2 inhibitors Amantadine Rimantadine *Investigational Antivirals for Influenza: Overview • Effective for prophylaxis and early therapy – Useful in outbreak control – Rapid antiviral effect • Differing anti-influenza spectra – Amantadine/rimantadine: influenza A only – Oseltamivir/zanamivir: influenza A + B • Favorable PK characteristics – Treatment 2X/d; prophylaxis 1X/d – Few drug interactions • Differences in dosing routes, PK, tolerance, efficacy, and resistance profiles M2 Inhibitor Prophylaxis During Pandemic Influenza Protective efficacy Pandemic Influenza A illness Seroconversion 1968 H3N2 59-100% 28-52% 1977 H1N1 31-71% 19-39% Hayden. J Infect Dis 176:S56, 1997 Influenza Prevention In Households: PEP Antiviral (Study) No. Contacts (age) Oseltamivir 955 (Welliver et al, 2000) (13+ yr) Oseltamivir* 792 (Hayden et al, 2004) (1+ yr) Zanamivir* 837 (Hayden et al, 2000) (5+ yr) Zanamivir 1,291 (Monto et al, 2002) (5+ yr) *Index case given treatment Reduction in 2° influenza illness 89% 73% Reduction in influenza infection 49% 35% (Index +) 79% 62% 82% 59% Antiviral Treatment of Acute Influenza Outcome M2I ZNV OSEL Symptom relief Yes Yes Yes ? Yes Yes Decrease antibiotic use ? 28% 24-40% Decrease hospitalization ? ? ~50% ? ? Yes ~30% No Yes Complications reduction Treatment of viral complications Reduction in transmission ? = No placebo-controlled study or not reported Oseltamivir Treatment Effects in A(H5N1) Infection Virus Presumed clade 1 Presumed clade 2 Total Survivors/ Treated (%) Survivors/ Untreated (%) Pvalue 45/82 (55%) 6/26 (23%) 0.006 43/106 (41%) 1/30 (3%) < 0.001 88/188 (47%) 7/56 (12%) < 0.001 Adapted from Writing Committee of Second WHO Consultation on Human H5 Infections. N Engl J Med 358: 261, 2008 7 Resistance to M2 Inhibitors (S31N) in Community Isolates of A/H3N2, 2000-07 100 90 80 70 China Hong Kong Australia Japan Europe USA 60 % 50 40 30 20 10 0 2000/1 2001/2 2002/3 2003/4 2004/5 2005/6 2006/7 Bright et al. Lancet 2005, JAMA 2006; Klimov et al. CDC unpublished; Barr et al. Antiviral Res 2006; R Saito, Niigata Univ, unpublished Oseltamivir Resistance in H1N1 (H274Y) • Rare in community H1N1 isolates, 1996-2007 – 0 to <1% in most surveys – 2.2% in Japan in 2005-6 (but not in 2006-7 or early in 2007-8) • High prevalence in Europe and globally, 2007-8 – Patients without known oseltamivir use or exposure to those on drug – Generally no obvious epidemiologic links • Household contacts, several apparent clusters – Typical influenza illness; some fatalities • Efficient person-to-person transmission Oseltamivir Resistance in H1N1 Viruses Region Location No. isolates tested % resistant AMRO+ (17%) Canada USA 508 1026 26% 12% EURO+ (25%) France Norway 496 265 47% 67% WPRO+ (5%) China/HK Japan 666 1652 12% 3% AFRO* (85%) South Africa* Other* 107 20 100% 45% Worldwide 4Q07- 1Q08 2Q08-20Aug08 7528 788 16% 31% +4Q07- 1Q08 *2Q08-20Aug08 http://www.who.int/csr/disease/influenza/h1n1_table/en/index.html; 20 Aug 08 Antivirals for Seasonal, A(H5N1), and Pandemic Influenza: Efficacy, Resistance, and New Agents 15 September 2008 Frederick G. Hayden, M.D. University of Virginia Health System Charlottesville, Virginia, USA Do We Need New Anti-Influenza Agents? • Antiviral resistance – Global spread of M2 inhibitor resistance in H3N2 > H1N1 – New emergence of oseltamivir-resistant H1N1 – Dual M2 and NAI resistance in IC hosts • Antiviral efficacy incomplete in H5N1 disease – Oseltamivir resistance emergence • Safety/efficacy ? in risk populations: infants < 1 yr, pregnancy, hospitalized, IC hosts • Lack of parenteral agents Viral Loads and Antiviral Treatments in Immunocompromised Host with Fatal Oseltamivir-Resistant H1N1 Illness Re-intubation Extubation Intubation • 67 yo male with CLL + recent chemoRx neutropenia • Fever, cough, SOB acute respiratory failure Oseltamivir resistance (H274Y) Amantadine resistance (L26F) Van der vries et al. NEJM 359:1074, 2008 Medical Needs for Anti-Influenza Antivirals • Greater antiviral efficacy greater clinical benefit • Safety and efficacy in special risk populations: infants < 1 yr, pregnancy, hospitalized, immuno-compromised • Reliable drug delivery in seriously ill patients • Manage antiviral resistance • Combinations Influenza Virus Replication and Sites for Antiviral Inhibition De Clercq. Nature Reviews- Drug Discovery 5:1015, 2006 Investigational Anti-Influenza Agents • Neuraminidase (NA) inhibitors - Zanamivir (IV), peramivir (IV/IM), A-315675 (oral) • Long-acting NA inhibitors (LANI) – CS8958/R-118958 (topical), Flunet (topical) • Conjugated sialidase- DAS181 (topical) • HA inhibitors- cyanovirin-N, sialyl-glycopolymer, arbidol • Polymerase inhibitors- ribavirin; viramidine; siRNA; T-705 • Protease inhibitors- aprotinin • Biologics- antibodies, interferons Investigational Agents in Clinical Development Agent Target Sponsor Route Development phase Zanamivir NA GSK IV Phase 1, 2a Peramivir NA Biocryst IV, IM Phase 2 CS8958 NA Sankyo, Biota Topical Phase 2 T-705 Polymerase Toyama Oral DAS181 HA receptor Nexbio Topical Phase 1 Phase 2 Neuraminidase Inhibitors Peramivir NA Inhibitor Resistance Profiles NA NA Susceptibility in the NAI assay (fold ) mutation type/ subtype Oselt Zana Peram A-315675 E119V A/N2 R (>50>1000) S (1) S (1) S (1-2) R292K A/N2 R (>1000) S (4-25) R (40-80) S (8-13) H274Y A/N1 R (>700) S (1) R (40-100) S (3) R152K B R (>30750) R (10-100) R (>400) R (150) Mishin et al. AAC 49:4516, 2005; Wetherall et al. AAC 41:742, 2003; Abed et al. Antiviral Res 77: 163, 2008 • IV zanamivir 600 mg or placebo twice daily X 5 days starting 4 hr before virus inoculation • Highly protective against experimental infection (14% vs 100%), virus shedding (0 vs 100%), and illness Pharmacokinetic Profiles of Intravenous and Intramuscular Peramivir Intravenous Intramuscular • Linear PK; prolonged plasma T1/2elim (18 – 20 hr) Kilpatrick JM, et al. Pharmacokinetics and Safety of Peramivir by Intramuscular Administration, Options for the Control of Influenza VI, Toronto, 2007 21 IM Peramivir: Time to Alleviation of Illness J Alexander, BioCryst Pharmaceuticals, unpublished data Long Acting Neuraminidase Inhibitors (LANI)- 2 Strategies CS-8958 FLUNET OMe O O CH3(CH2)6 O CO2H OH HN O HO HO OMe O R-125489 CO2H O HN HN O OH O N H HO HO NH2 NH OH HN O X N H O O NH HO O NH2 HN HN NH2 NH Pro-drug Clinical Dimer Preclinical COMMERCIAL IN CONFIDENCE O HN O O O HN OH NH2 NH 23 Yamashita et al. 43rd ICAAC, Abstract no. F-1830, 2003 • Double-blinded trial found that inhaled CS-8958 administered once only was not statistically different than standard oseltamivir regimen. T-705: Summary of Pre-Clinical Findings F N OH N CONH2 T-705 6-fluoro-3-hydroxy-2pyrazinecarboxamide Furuta et al. AAC 46:977, 2002; AAC 49:981, 2005 • Inhibitory for influenza A, B, C viruses: EC50s 0.01 - 0.5 µg/ml • Active against flavi, arena, bunya, picorna, alpha, and paramyxo viruses • Cytotoxicity for mammalian cell > 1,000 µg/ml • Triphosphate is inhibitor of influenza RNA polymerase. • Active orally in murine models T-705: In Vitro Activity vs Ribavirin IC50(μM) ± SD (A PR/8/34 H1N1 influenza) CC50(μM) ± SD (MDCK cells) T-705 1.0 ± 0.9 > 6,370 Ribavirin 31.6 ± 9.2 94.3 ± 47.6 Compound Furuta Y, et al. Antimicrob Agents Chemother. 2005;49:981-986. Effect of a T-705 Treatment in Mice Exposed to Lethal A/Duck/N/1525/81 (H5N1) Virus Control T-705, 300 mg/kg * * 100 * * * *P < .01 relative to control * 80 Survival (%) T-705, 600 mg/kg * * 60 40 20 0 4 12 24 48 60 Delay before starting treatment following viral exposure, hours Sidwell RW, et al. Antimicrob Agent Chemother. 2007;51:845-851. Pharmacokinetics of Oral T-705 – Mainly excreted as T705M1 in urine • Single doses up to 1,600 mg or multiple up to 400 mg tid for 7 days well tolerated 90 mg (n=6) 200 mg (n=6) 100 T-705 Plasma Concentration (μg/mL) • Bioavailability > 97% in mouse • Rapid absorption in humans (Tmax < 1 hr) • Plasma T1/2elim from 1.3 to 3.9 hr 30 mg (n=6) 400 mg (n=6) 800 mg (n=6) 1600 mg (n=6) 10 1 0.1 0.01 0.001 0 3 6 9 12 15 18 21 24 Time after dose (hr) Single oral doses of T-705 over a range of 30 to 1600 mg Toyama Chemical Co, unpublished Molecular Model of DAS181 (Fludase®) • Fusion construct with catalytic domain of A. viscosus sialidase and an epitheliumanchoring domain (human amphiregulin) – Active against both α2,6and α2,3-linked sialic Malakhov et al. AAC 50:1470, 2006 acid receptors Preclinical Features of DAS181 • Inhibitory for range of influenza A and B viruses – In vitro EC90 values: 1-14 nM – Epithelial tag increases activity 5-30 fold – Pretreatment (24 hr) effective • Intranasal dosing shows – Prophylactic and therapeutic activities in mice – Antiviral effects with reduced inflammatory responses in ferrets Malakhov et al. Antimicrob Agent Chemother 50:1470, 2006 Effect of DAS181 on S. pneumo Binding to Human Airway Epithelium (HAE) Cells • DAS181 treatment had no significant effect on adherence. Nicholls et al. J Antimicrob Chemother 62:426, 2008 DAS181 Treatment in Mice with H5N1 • Dose of 1 mg/kg/d for 7-8 d • Inoculum of 3 MLD50 • Time-totreatment effects on survival and lung titers on day 3 and 6. Belser et al. JID 196:1439, 2007 Potential Role of Combination Antiviral Therapy in Influenza Treatment • Combinations evaluated in animal models – Amantadine + interferon – M2 inhibitors + ribavirin – M2 inhibitors + oseltamivir – Oseltamivir + ribavirin • Combinations evaluated in humans – Oral rimantadine + nebulized zanamivir • Future considerations – Dual NAIs – Triple therapy: M2 inhibitor + ribavirin (or other transcriptase inhibitor) + IFN-α or NAI – Inclusion of other novel agents Ong and Hayden. J Infect Dis 196:181, 2007; Hayden FG. Antivir Res 71:372, 2006 CASG* Trial of Nebulized Zanamivir + Rimantadine in Hospitalized Adults Measure Zanamivir + Rimantadine P value Rimantadine alone No or mild cough, day 3 15/16 (94%) 11/20 (55%) .01 4.7 ± 2.3 5.2 ± 2.3 .52 0 3 ND Days of hospitalization Frequency of rimantadine resistance *CASG = Collaborative Antiviral Study Group. Ison et al. Antiviral Ther. 2003;8:183-190. Survival of mice inoculated with rg VN-1203/04 – Amantadine susceptible Combination therapy 1 0.75 AM 30 0.5 AM 15 OS 10 0.25 AS 1.5 Control 0 0 5 10 OS 1 15 Days after inoculation 20 Survival distribution function Survival distribution function Single-drug therapy 1 AM 30 + OS 10 0.75 AM 15 + OS 10 0.5 0.25 Control 0 0 5 10 15 20 Days after inoculation Ilyushina et al. Antiviral Therapy 12;363, 2007 39 • Comparison of monotherapy with i.p. zanamivir (ZNV), celecoxib, mesalazine, or gemfibrizol to triple regimen of ZNV + celecoxib + mesalazine in mice – High inoculum of A/Vietnam/1194/04 (103 LD50) – Therapy initiated at 48 hrs post-inoculation – No survival benefit of early therapy (4 hrs) with single agents except ZNV Zheng et al. PNAS, on line 6/2008 Antiviral + Immunomodulator Therapy for H5N1 in Mice • survival with ZNV + celecoxib + mesalazine • 2/8 surviving mice in triple therapy group had detectable titers at day 21. Influenza Antivirals: Future Directions • Goal: Rapid inhibition of influenza viral replication at all affected sites • Near-term: parenteral NAIs – IV zanamivir or IV/IM peramivir • Next: antiviral combinations – NAI plus M2 inhibitors, polymerase inhibitor (T-705 or ribavirin), or neutralizing antibodies • Longer-term: – Antivirals with immunomodulators – Host function-targeted agents Forthcoming Book from ASM Press • Third edition • Updates 2002 version • Available first quarter 2009 44 Back-up Slides • Pre-clinical assessment of arbidol toxicity and antiviral activity – Ethyl-6-bromo-4-[(dimethylamino)-methyl]-5hydroxy-1-methyl-2-[(phenylthio)methyl]-indole3-carboxylate hydrochloride monohydrate – Previous reports of activity for influenza, hepatitis B and C viruses Shi et al. Arch Virol 152:1447, 2007 • Influenza testing by CPE inhibition in MDCK cells • Arbidol causes overt cytotoxicity at >16 ug/ml • Broad spectrum; narrow therapeutic index Shi et al. Arch Virol 152:1447, 2007 In Vivo Activity of Arbidol • Murine model of A/PR/8/34(H1N1) • Drugs by oral gavage X 6 d starting 24 hr previrus • Up to ~3 log10 lung virus titers • LD50 of 314 mg/kg/d for arbidol • Narrow TI Shi et al. Arch Virol 152:1447, 2007 • Kinetic analysis of NA (sialidase) activity – Whole virus suspensions of isolates from 2007-8 and prior seasons • Vm (reflecting enzyme activity) similar in susceptible and resistant isolates from 2007-8 but both ~3X than in earlier H1N1 viruses • Km (reflects substrate affinity) ~2X in susceptible H1N1 from 2007-8 than earlier; intermediate for oseltamivir-resistant isolates Rameix-Welti et al. PLoS Pathogens 4:e1000103, 2008 Growth of H1N1 Viruses from 2007-8 in MDCK SIAT-1 Cells • Replication of oseltamivirresistant H1N1 (H274Y) isolates not impaired in vitro compared to susceptible H1N1 viruses from 2007-8 or earlier. Rameix-Welti et al. PLoS Pathogens 4:e1000103, 2008 S R S R NA Gene Phylogeny • NA substitutions found in majority of H1N1 from 20078 include 3 near catalytic site (222, 249, 344). • NA affinity for substrate and NAIs may have altered HA-NA balance to fitness ? Rameix-Welti et al. PLoS Pathogens 4:e1000103, 2008 Clinical Experience Suggests No Role for Corticosteroids in A(H5N1) Treatment •Vietnam Survival Steroid Rx No steroids Pvalue Hanoia 12/29 (41%) 29/38 (76%) 0.008 Published casesb 3/19 (16%) 10/15 (66%) 0.007 a Cao T, Liem NT. N Engl J Med 2008; 358: 261 b Emerg Infect Dis 2005; 11: 201; N Engl J Med 2004; 350: 1179; N Engl J Med 2006; 355: 2186-94. Convalescent Plasma Therapy in H5N1 Disease • Case report of 31 yo male who presented with 4 day Hx of fever, cough, and sputum – CXR on day 6 showed LLL pneumonia – Tracheal aspirate + H5N1 by RT-PCR and culture – Oseltamivir 150 mg bid started day 9 of illness but progressive bilateral pneumonia – Convalescent plasma infusions from H5 survivor (200 ml X 3) on days 12-13 • Plasma neutralizing ab titer of 1:80 – Hospital discharge on day 30 Zhou et al. NEJM 357:1450, 2007 Convalescent Plasma Therapy in H5N1 Disease • Relative contributions of exogenous plasma, endogenous immune responses, and oseltamivir ? Zhou et al. NEJM 357:1450, 2007 • H5N1 hyperinduces COX-2 and proinflammatory cytokine RNAs in macrophages but not type 2 alveolar epi cells, compared to H1N1. • COX-2 expressed in epithelial cells of autopsy lung tissue of H5N1 patients