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Hepatitis C Virus Infection: Natural History + Therapy

Hepatitis C Virus Infection: Natural History + Therapy. Brian L. Pearlman MD FACP Medical Director, Center for Hepatitis C Atlanta Medical Center, Atlanta, Georgia Adjunct Professor of Medicine, Medical College of Georgia Adjunct Professor of Medicine, Emory School of Medicine December, 2015.

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Hepatitis C Virus Infection: Natural History + Therapy

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  1. Hepatitis C Virus Infection:Natural History + Therapy Brian L. Pearlman MD FACP Medical Director, Center for Hepatitis C Atlanta Medical Center, Atlanta, Georgia Adjunct Professor of Medicine, Medical College of Georgia Adjunct Professor of Medicine, Emory School of Medicine December, 2015

  2. Disclosures • Gilead Sciences-contracted research; speaking and teaching • Merck-contracted research • Abbvie-contracted research; speaking and teaching • Johnson & Johnson-contracted research; speaking and teaching • Bristol Myers Squibb-contracted research

  3. Natural History

  4. Increased Mortality • Chronic HCV is associated with a 8- to 12-year reduction in overall life expectancy and reduced quality of life1 • Chronic HCV patients have significantly higher mortality rate • HR 1.53; (95% CI, 1.13-2.07)2 • HR 1.37; (95% CI, 1.31-1.47)3 • Death rate 12-fold higher than general population4 1 Ryder SD, et al. J Hepatology, 2007; 3 Butt AA, et al. Hepatology, 2009 2 Uto H, et al. Hepatology, 2009; 4 Mahajan R, et al. Clin Infect Dis 2014

  5. Age-adjusted HCV Mortality Surpasses that of HIV in the US, 1999-2007 Rate per 100,000 persons Ly K, et al. Ann Int Med, 2012

  6. Davis GL, et al. Gastroenterology, 2011

  7. Chronic HCV: Risk Factors for Progression • Older age at infection acquisition • Duration of infection • Gender • Coinfection • Alcohol • Obesity/NAFLD • Insulin Resistance • Genotype 3 • Cannabis McCombs J, JAMA Int Med 2014 Harrison S, Clin Gastro and Hep, 2008 Ishida, et al. Clin Gastro and Hepatol. 2007 Leandro et al., AASLD 2005; Hezode et al., Hepatol, 2005 Negro, et al., Hepatology, 2004; Soto, et al., J Hepatol, 1997; Adinolfi, et al. Hepatol, 2001;

  8. Progression to Cirrhosis Becomes Nonlinear with Age Age 31-40 yrs Age > 50 yrs Age 41-50 yrs Probability of Cirrhosis Age 21-30 yrs Age <21 yrs Duration (yrs) Poynard T, et al. J Hepatol. 2001;34:730-739.

  9. HCV/HIV Coinfection • HIV coinfection promotes accelerated hepatic fibrosis progression • In those who have progressed to cirrhosis, higher rates of liver failure and death are observed, relative to monoinfected HCV patients Sherman KE, Hepatology 2014 Macias J et al. Hepatology, 2009

  10. DISEASE PROGRESSION IN HEPATITIS C INFECTION 15-40% NEW INFECTION Infection Clears Spontaneously 55-85% Chronic Hepatitis Hepatocellular Carcinoma 20-25% 15-20 yrs 15%* 5-10 yrs Cirrhosis Variable Stable or Slow Progression Death Pearlman BL, South Med J, 2004 * 2% per year

  11. Therapy

  12. With Successful Therapy, Chronic Hepatitis C Infection Is ?? • 1) Nearly always permanently eradicated or cured • 2) Suppressible while on therapy but never curable • 3) Not suppressible or curable, but controllable • 4) Eliminated in the serum, but never eliminated intracellularly

  13. HCV is Curable- HIV & HBV Are Not HCV HBV HIV Proviral DNA Viral RNA Host cell ccc DNA Host DNA Nucleus HCV Sustained Virologic Response = Cure = Aviremia 12 weeks post-therapy

  14. 187 patients with SVR followed up to 14 years (mean 29 months)1 85 patients IFN or IFN/ribavirin 102 patients Peg-IFN/ribavirin No Relapse 1546patients with SVR followed up for five years2 IFN or Peg-IFN +/- ribavirin 19 patients (19/1546)= 1%Relapse 344 patients with SVR followed up to 18 years (mean 3.27 years)3 214 treated Peg/ribavirin No Relapse Residual liver RNA 1.7% 103 patients with SVR, followed up for up to 22 years4 IFN or Peg +/- ribavirin 3 patients = 1% Relapse Sustained Virologic Response (SVR):Has the Patient Been “Cured”? 1Formann, et al. Aliment Pharmacol Ther, 2005; 2Swain, et al. Gastroenterology, 2010 3Maylin, et al. Gastroenterology, 2008; 4Koh, et al. AASLD, 2010

  15. SVR Improves Outcomes in Patients with HCV-associated Cirrhosis 13.9% 11% 9.1% Rates of liver-related Complications (%) 6.8% 1.4% 1.4% 0.7% 0.7% Decomp. Xplant HCC Hep-death AHR death/liver transplantation (HR = 0.17, 95% confidence interval [CI] = 0.06-0.46); Development of liver-related morbidity/mortality (HR = 0.15, 95% CI = 0.06-0.38); HCC (HR = 0.19, 95% CI = 0.04-0.80) for SVR compared to NR. Morgan, TR, et al. Hepatology, 2010

  16. SVR and Reduced Risk of All-Cause MortalityUS VA Study: Treatment with Pegylated Interferon/Ribavirin HCV Genotype 1 No SVR SVR 0.30 0.25 P (log-rank) < 0.0001 0.20 0.15 Cumulative Mortality 0.10 0.05 0.00 0 1 2 3 4 5 6 Years Backus L, et al. Clin Gastroenterol Hepatol. 2011

  17. The Importance of Sustained Virological Response Pearlman B, Traub N. Clin Infect Dis. 2011; Backus L, et al. Clin Gastroenterol Hepatol. 2011; Van der Meer AJ, et al. JAMA, 2012. Tantamount to cure Associated with improvement in liver histology (inflammation, fibrosis) Less frequent liver-related complications Reduced risk of decompensation Reduced risk of hepatocellular carcinoma Reduced liver-related mortality Reduced all-cause mortality

  18. HCV-Infected Persons in the US: Estimated Rates of Detection, Referral to Care and Cure 3.2 M X1000 persons 50% 32-38% 20-23% 7-11% 5-6% Infected Diagnosed Referred HCV RNA Treated ‘Cure’ to care test Holmberg S, N Engl J Med 2013; 368: 1859

  19. Multiple Classes of Direct-Acting Antiviral Agents Core E1 E2 NS2 NS3 NS4B NS5A NS5B • 3’UTR • 5’UTR p7 • Polymerase • NS5B • Protease Ribavirin NS3Protease Inhibitors NS5AInhibitors Nucleoside/nucleotide Polymerase Inhibitors Non-Nucleoside Polymerase Inhibitors (Telaprevir) (Boceprevir)Simeprevir* Paritaprevir* Grazaprevir Asunaprevir Sovaprevir ACH-2684 GS-9857 Ledipasvir* Ombitasvir* Daclatasvir* Elbasvir Velpatasvir MK-8042 ACH-3102 (Odalasvir) Samatasvir • Sofosbuvir* • MK-3682 • ACH-3422 • AL-335 • Dasabuvir* • Beclabuvir • GS-9669 • TMC647055 *In routine use in U.S.; ( ) Obsolute in the U.S.

  20. HCV Direct Acting Antivirals: Relative Potencies + Barriers to Resistance

  21. SVR for Genotype 1-infected Treatment Naïve (non-cirrhotic) Patients 99% 70% 45% Sustained Virologic Response (%) 30% 10% IFN IFN/RBV PEG/RBV PEG/RBV/PI Poly/NS5a Type of Therapy IFN=standard interferon; RBV=ribavirin; PEG=peginterferon; PI=protease inhibitor; Poly=polymerase inhibitor; NS5a=NS5a inhibitor

  22. Phase III Studies of Sofosbuvir + Ledipasvir (NS5a inhibitor) FDC Wk 12 Wk 24 SVR12, % SOF/LDV (n = 214) ION-1[1,2]Treatment-naiveHCV GT1; cirrhosis in 15% to 17% per arm (N = 865) SOF/LDV + RBV (n = 217) SOF/LDV (n = 217) SOF/LDV + RBV (n = 217) Wk 12 Wk 24 SOF/LDV (n = 109) ION-2[3]Treatment-experienced HCV GT1; 20% cirrhotics(N = 440) SOF/LDV + RBV (n = 111) SOF/LDV (n = 109) SOF/LDV + RBV (n = 111) ION-1,2: No difference in outcomes according to cirrhosis status, type of treatment failure 1. Mangia A, et al. EASL 2014. Abstract O164. 2. Afdhal N, et al. N Engl J Med. 2014;370:1889-1983. 3. Afdhal N, et al. N Engl J Med. 2014;370:1483-1493.

  23. Phase III Study of SOF/LDV (Ledipasavir) ± RBV for 8-12 Wks in Treatment-Naive Noncirrhotic Genotype 1 Patients Wk 8 Wk 12 SVR12, % SOF/LDV (n = 215) Treatment-naive, noncirrhotic pts with HCV GT1(N = 647) SOF/LDV + RBV (n = 216) SOF/LDV (n = 216) Kowdley KV, et al. N Engl J Med. 2014;3701879-1888.

  24. Progressive Improvement in SVR:Whites vs African Americans 100 99 75 62 52 Sustained Virologic response (%) 32 19 16 12 2 IFN IFN/RBV PEG/RBV PEG/RBV/PI Poly/NS5a IFN=interferon; RBV=ribavirin; PEG=peginterferon PI=protease inhibitor; Poly=polymerase inhibitor; NS5a=NS5a inhibitor Modified from Pearlman BL. Clin Infect Dis. 2006; Jacobson IM, et al. N Engl J Med, 2011; Afdhal N, et al. N Engl J Med, 2014

  25. HCV-HIV Coinfection SVR: Genotype 1; 12 weeks Therapy 96% 97% 94% Sustained Virologic Response (percentage) n=327 n=31 n=168 Naggie S, et al. NEJM 2015; Sulkowski M, et al. JAMA 2015; Wyles DL, et al. NEJM 2015

  26. Genotype ONE Therapy 2015: Duration 8-24 weeks • HARVONI sofosbuvir/ledipasvir = nucleotide polymerase inhibitor/NS5a inhibitor • VIEKIRA PAK (often combined with Ribavirin) paritaprevir/ombitasvir/dasabuvir/(ritonavir)= protease inhibitor/NS5a inhibitor/non-nucleotide polymerase inhibitor/(booster) • OLYSIO/SOVALDI (aka “Sim-Sof”) simeprevir/sofosbuvir = protease inhibitor/ nucleotide polymerase inhibitor

  27. Adverse Effects of Current Therapies • Headache • Nausea • Fatigue • Insomnia • Diarrhea • Ribavirin-containing regimens only • Pruritus • Rash • Hemolytic Anemia • Leukopenia

  28. Real-World U.S. Registry Data: Genotype 1 Infection 93% 96% 97% 97% 95% 96% Sustained Response Rate (%) 1 2 3 1 Backus, et al. AASLD 2015, abst. 3763; 2 Terrault, et al. AASLD 2015, abst. 895; 3 Curry, et al. AASLD 2015, abst. 1108,

  29. AASLD/IDSA Recommendations for HCV Genotype 2 or 3 Treatment-Naïve Patients Genotype 2 Patients Peginterferon + RBV x 12 wks Sofosbuvir 400 mg/d + RBV x 12 wks(16 wksF4) Interferon-ineligible Sofosbuvir400 mg/d + Daclatasvir60 mg x 12 wks(24 wksF4) Alternative: Sofosbuvir400 mg/d + RBV x 24 wks AASLD/IDSA treatment recommendations 2015: www.hcvguidelines.org; RBV=ribavirin.

  30. No Longer Special Populations African Americans Genotype 1 Infection Hispanics HIV Coinfection Compensated Cirrhosis Null responders to Peginterferon/Ribavirin Peginterferon/Ribavirin/Protease inhibitor failure

  31. Special Populations Remaining Decompensated Cirrhosis Genotype 3 Infection Renal Insufficiency Direct Acting Antiviral Therapy Failure

  32. Grazoprevir + Elbasvir in Stage 4/5 Renal Insufficiency: GT-1 99.1% 94.3% Subjects: 76% on hemodialysis 6% cirrhotic 80% treatment naïve 52% genotype 1a 46% African American Adverse Events: 17.1% headache 15.3% nausea 9.9% fatigue 6.3% insomnia 5.4% dizziness 5.4% diarrhea Sustained Virologic Response (%) 115/116115/122 Modified full analysis Full analysis Roth D, et al. Lancet, 2015

  33. The Future: Triplet Regimens • Nucleoside/nucleotide polymerase inhbibitor + second generation NS5a inhibitor + second generation protease inhibitor • Pangenotypic • No Ribavirin • One pill, once daily • High genetic barrier to resistance • Shorter durations (? 6 weeks)

  34. Cost-Effectiveness of Current HCV Therapies • $24,921 and $25,405 per QALY gained for Viekira Pak and Harvoni, respectively (1) • Less than $50,000 per QALY gained for Harvoni (2) • Harvoni cost-effective if less than $780/day; currently $1100/day AWP (3) • Treatment of patients with moderate fibrosis (Stage 2 of 4) $37,300 per QALY gained (4) 1 Rein DB, et al. Clin Infect Dis 2015; 2 Tice JA, et al. JAMA Int Med 2015; 3 Najafzadeh M, et al. Ann Int Med 2015; 4 Leidner AJ, et al. Hepatology 2015

  35. HCV Global Therapy • 150 million infected worldwide estimate with ¾ of whom living in middle-income countries in poorest populations • Cost dominates the debate to treat • Price reductions in poorest countries (eg. India and Egypt); yet, China, 10 million infected with no cost reductions • Testing/treating early will benefit countries economically by reducing burden of disease and retaining healthy workforce

  36. Conclusions • HCV progresses to cirrhosis over 20 years in about 20-30% of patients, but this rate can be accelerated by cofactors • HCV infection is curable, and therapy has evolved rapidly; cure rates exceed 90% even in many populations that heretofore had been difficult to treat • Some populations remain difficult to treat with currently available therapies • Near future therapies pangenotypic and of shorter duration • Therapy is cost-effective yet cost still barrier

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