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 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 Natural History 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, )2 HR 1.37; (95% CI, )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; Mahajan R, et al. Clin Infect Dis 2014 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 Davis GL, et al. Gastroenterology, 2011 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; Progression to Cirrhosis Becomes Nonlinear with Age
Age > 50 yrs Age yrs Age yrs Age yrs Age 50 years of age at the time of infection. During a second phase, occurring approximately 10 to 25 years after infection, there is a slow but steady increase in the rate of fibrosis progression. During the third phase, years 25 to 35 post-infection, the rate of progression is intermediate. Afterwards, there is a final phase >35 years post-infection in which the rate of progression becomes rapid in all age categories In a study by DSouza et al, infection for over 60 years caused cirrhosis in 71% of infected individuals References Marcellin P, Asselah T, Boyer N. Fibrosis and disease progression in hepatitis C. Hepatology. 2002;36:S47-S56. PoynardT, et al. J Hepatol. 2001;34: 8 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 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 Therapy With Successful Therapy, Chronic Hepatitis C Infection Is ??
1) Nearly always permanentlyeradicated 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 HCV is Curable- HIV & HBV Are Not
Proviral DNA Viral RNA Host cell ccc DNA Nucleus Host DNA HCV Sustained Virologic Response = Cure = Aviremia 12 weeks post-therapy Sustained Virologic Response (SVR): Has the Patient Been Cured?
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 1546 patients 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 1Formann, et al. Aliment Pharmacol Ther, 2005; 2Swain, et al. Gastroenterology, 2010 3Maylin, et al. Gastroenterology, 2008; 4Koh, et al. AASLD, 2010 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] = ); Development of liver-related morbidity/mortality (HR = 0.15, 95% CI = ); HCC (HR = 0.19, 95% CI = ) for SVR compared to NR. Morgan, TR, et al. Hepatology, 2010 Hazard Ratio for Death with SVR
SVR and Reduced Risk of All-Cause Mortality US VA Study: Treatment with Pegylated Interferon/Ribavirin HCV Genotype 1 0.30 No SVR SVR 0.25 P (log-rank) < 0.20 Cumulative Mortality 0.15 0.10 0.05 0.00 1 2 3 4 5 6 Years Genotype N SVR Hazard Ratio for Death with SVR P-value 1 12,166 35% 0.70 < 2 2904 72% 0.64 0.006 3 1794 62% 0.51 0.0002 Backus L, et al. Clin Gastroenterol Hepatol. 2011 16 16 The Importance of Sustained Virological Response
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 Pearlman B, Traub N. Clin Infect Dis. 2011; Backus L, et al. Clin Gastroenterol Hepatol. 2011; Van der Meer AJ, et al. JAMA, 2012. HCV-Infected Persons in the US: Estimated Ratesof Detection, Referral to Care and Cure
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 Multiple Classes of Direct-Acting Antiviral Agents
5UTR Core E1 E2 NS2 NS3 NS4B NS5A NS5B 3UTR p7 Polymerase NS5B Protease Ribavirin NS3 Protease Inhibitors NS5A Inhibitors 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 NUC, nucleotide analogue. *In routine use in U.S.; ( ) Obsolute in the U.S. HCV Direct Acting Antivirals: Relative Potencies + Barriers to Resistance
Drug Class Potency Barrier to Resistance Protease inhibitor 3-4+ 2-3+ Nucleotide/Nucleoside Polymerase inhibitor 2-4+ 4+ Non-nucleoside Polymerase inhibitor 1+ NS5a inhibitor 2+ SVR for Genotype 1-infected Treatment Nave (non-cirrhotic) Patients
99% 70% 45% Sustained Virologic Response (%) 30% 10% IFN IFN/RBVPEG/RBVPEG/RBV/PI Poly/NS5a Type of Therapy IFN=standard interferon; RBV=ribavirin; PEG=peginterferon; PI=protease inhibitor; Poly=polymerase inhibitor; NS5a=NS5a inhibitor Phase III Studies of Sofosbuvir + Ledipasvir (NS5a inhibitor) FDC
Wk 12 Wk 24 SVR12, % 99 97 98 SOF/LDV (n = 214) ION-1[1,2] Treatment-naive HCV 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 94 96 99 ION-2[3] Treatment-experiencedHCV GT1; 20% cirrhotics (N = 440) GT, genotype; FDC, fixed-dose combination; HCV, hepatitis C virus; RBV, ribavirin; SOF/LDV, sofosbuvir/ledipasvir; SVR, sustained virologic response. SOF/LDV (n = 109) 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 Abstract O Afdhal N, et al. N Engl J Med. 2014;370: Afdhal N, et al. N Engl J Med. 2014;370: Treatment-naive, noncirrhotic pts with HCV GT1 (N = 647)
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) 94 93 95 Treatment-naive, noncirrhotic pts with HCV GT1 (N = 647) SOF/LDV + RBV (n = 216) SOF/LDV (n = 216) GT, genotype; FDC, fixed-dose combination; HCV, hepatitis C virus; RBV, ribavirin; SOF/LDV, sofosbuvir/ledipasvir; SVR, sustained virologic response; Tx, treatment. Kowdley KV, et al. N Engl J Med. 2014; Progressive Improvement in SVR: Whites vs African Americans
99 100 75 62 52 Sustained Virologic response (%) 32 19 16 12 2 IFN IFN/RBV PEG/RBVPEG/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 HCV-HIV Coinfection SVR: Genotype 1; 12 weeks Therapy
96% 97% 94% Sustained Virologic Response (percentage) n= n= n=168 Naggie S, et al. NEJM 2015; Sulkowski M, et al. JAMA 2015; Wyles DL, et al. NEJM 2015 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 Adverse Effects of Current Therapies
Headache Nausea Fatigue Insomnia Diarrhea Ribavirin-containing regimens only Pruritus Rash Hemolytic Anemia Leukopenia AE, adverse effect; PegIFN/RBV, peginterferon/ribavirin. Real-World U.S. Registry Data: Genotype 1 Infection
93% 96% %97% %96% Sustained Response Rate (%) 1 Backus, et al. AASLD 2015, abst. 3763; 2 Terrault, et al. AASLD 2015, abst. 895; 3 Curry, et al. AASLD 2015, abst. 1108, AASLD/IDSA Recommendations for HCV Genotype 2 or 3 Treatment-Nave Patients
Peginterferon + RBV x 12 wks Sofosbuvir 400 mg/d + RBV x 12 wks (16 wks F4) Interferon-ineligible Sofosbuvir 400 mg/d + Daclatasvir 60 mgx 12 wks (24 wks F4) AASLD/IDSA, American Association for the Study of Liver Diseases/Infectious Diseases Society of America; HCV, hepatitis C virus; IFN, interferon; PEG, peginterferon; RBV, ribavirin. Alternative: Sofosbuvir 400 mg/d + RBV x 24 wks AASLD/IDSA treatment recommendations 2015:RBV=ribavirin. No Longer Special Populations
African Americans Genotype 1 Infection Hispanics HIV Coinfection Compensated Cirrhosis Null responders to Peginterferon/Ribavirin Peginterferon/Ribavirin/Protease inhibitor failure Special Populations Remaining
Decompensated Cirrhosis Genotype 3 Infection Renal Insufficiency Direct Acting Antiviral Therapy Failure Grazoprevir + Elbasvir in Stage 4/5 Renal Insufficiency: GT-1
99.1% 94.3% Subjects: 76% on hemodialysis 6% cirrhotic 80% treatment nave 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/ /122 Modified full analysis Full analysis Roth D, et al. Lancet, 2015 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) 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 HCV Global Therapy 150 million infected worldwide estimate with 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 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