Current HCV Treatment by Genotype Ira M. Jacobson, MD

Current HCV Treatment by Genotype Ira M. Jacobson, MD Director of Hepatology NYU School of Medicine

Objectives To understand the prevalence of HCV and distribution of HCV genotypes Describe the HCV lifecycle and how specific drugs target the HCV polypeptide sequence Explain circumstances where it is important to test for possible drug resistance Understand the landscape in regards to advances made in the evolution of treating HCV over the past 20+ years Understand the HCV genotypes and the drug regimens that work to eradicate HCV on each genotype

Distribution of Hepatitis C Genotypes Epidemiology of Infectious Diseases. Available at: http://ocw.jhsph.edu. Copyright John Hopkins Bloomberg School of Public Health. Creative Commons BY-NC-SA.

The HCV Life Cycle

T. Asselah. HCV Polypeptide Sequence

The HCV Polymerase (NS5B) The active site of the HCV polymerase is highly conserved Explains why sofosbuvir is the backbone of several regimens

What s Special About the Active Site of the HCV Polymerase? Feature Therapeutic Implication Highly conserved across genotypes Pangenotypic efficacy of potent inhibitors Low replicative fitness conferred by amino acid substitutions High resistance barrier

Where HCV Therapy Stands Now Interferon is gone in the U.S.; ribavirin not quite SVR in over 95% of patients Difficult to treat populations no longer difficult African-Americans HIV coinfected Cirrhosis Older age Renal failure and transplant Liver transplant Persons who use IV drugs (PWID) Confidence that SVR12 = cure Cost and access issues persist, but improving

Rising Cure Rates for Chronic HCV (GT1) 100% 80% Telaprevir or Boceprevir + PegIFN/RBV PR/SMV PR/SOF 80-90% IFN-Free DAA Combination Regimens >95% Cure Rate* 60% 40% IFN/RBV PegIFN/RBV 44% 70-80% 35% 20% IFN 16% 0% 1991 1998 2001 2011 2013 2014+ Year

The Evolution of HCV Therapy Ledipasvir + sofosbuvir (GT1) Telaprevir and boceprevir Daclatasvir: DCV+ASV (Japan) DCV+SOF (Europe) Simeprevir + sofosbuvir (GT1) Paritaprevir/rombitasvir/ dasabuvir ± RBV (GT1) DCV + SOF (GT3) (GT1 2016) Sofosbuvir + velpatasvir (all genotypes) Glecaprevir + Pibrentasvir (all genotypes) Interferon Era 2011 2013 2014 2015 2016 2017 1991- Curability of HCV without IFN Simeprevir, sofosbuvir with IFN (GT1) First approved IFN-free therapy: sofosbuvir + RBV (GT2,3) DAA: direct-acting antiviral; GT: genotype; IFN: interferon; PI: protease inhibitor; NI: nucleoside/nucleotide inhibitor; RBV: ribavirin; r: ritonavir. Grazoprevir+ Elbasvir (GT1,4) Sofosbuvir + Velpatasvir+ Voxilaprevir (all genotypes)

Approved Direct-Acting Antiviral Agents from Multiple Classes: Combination Regimens for HCV in 2017 Structural domain Nonstructural domain P 7 5 UTR Core E1 E2 NS2 NS4B NS3 NS5A NS5B 4A 3 UTR Protease Polymerase Ribavirin (RBV) NS3 Protease Inhibitors Simeprevir (SMV) Paritaprevir/ritonavir (PTV/r) Grazoprevir (GZR) Glecaprevir (GLE) Voxilaprevir (VOX) NS5A Replication Complex Inhibitors Daclatasvir (DCV) Ledipasvir (LDV) Ombitasvir (OMV) Elbasvir (EBV) Velpatasvir (VEL) Pibrentasvir (PIB) NS5B NUC Inhibitors Sofosbuvir (SOF) NS5B Non-NUC Inhibitors (NNI) Dasabuvir (DSV) previr = protease inhibitor; asvir = NS5A inhibitor; uvir = polymerase inhibitor Courtesy of Albert Min MD.

SVR and All-Cause Mortality in CHC Patients with Advanced Fibrosis 530 patients with all genotypes followed for a median of 8.4 years 10-Year Cumulative Occurrence Rate (%) 30 25 20 15 10 5 SVR patients 8.9 26.0 1.9 27.4 Non-SVR patients 5.1 21.8 2.1 29.9 Baseline factors significantly associated with all-cause mortality: Older age Genotype 3 (2-fold increase in mortality and HCC) Higher Ishak fibrosis score Diabetes Severe alcohol use 0 All-Cause Mortality Liver-Related Mortality or Liver Transplant HCC Liver Failure Van der Meer A, et al. JAMA. 2012; 308:2584 2593.

Cirrhosis Regression and Fibrosis Reduction Following SVR (any genotype) Cirrhosis Regression in 61% of Patients 100% 80% 15 Sample Liver Biopsy Pre-treatment (F4) Post-treatment (F3) 60% 40% 38 14 20% 0% Pre-treatment Post-treatment 7 2 F1 F2 F3 F4 Fibrosis Reduction After treatment, the area of fibrosis decreased in 34/38 (89%) of patients Post-treatment liver biopsies showed a significantly reduced area of fibrosis, with a median individual decrease of 71.8% Prospective study of patients with pre-treatment cirrhosis and an SVR with IFN-based therapy (enrolled in 2009-2010) to assess the impact of SVR on the full spectrum of histopathologic features of HCV-related cirrhosis. N=38, median f/u 67 months (range, 54-110 months). Adapted from D Ambrosio R, et al. Hepatology. 2012;56:532-543.

Evolution of Portal Pressure After DAA Therapy HVPG (mmhg) HVPG Absolute : -2.63 ± 0.38 mmhg; p<0.001 Relative : -23 ± 2.9% 30 20 16 12 10 6 Subclinical portal hypertension at BL HVPG 10 15 mmhg at BL Pronounced portal hypertension at BL Resolved 63% No progression Resolved 14% Regression 29% No progression No resolution Regression 5% Increase 20% 0 BL BL FU FU 13.1 ± 0.7 mmhg 10.4 ± 0.79 mmhg Earlier portal hypertension is more reversible than advanced PHT Mandorfer M, et al. EASL. 2016. Barcelona. #PS005.

Benefits of SVR Decreased liver mortality Decreased all-cause mortality Regression of fibrosis Improvement in portal pressures

Extra-hepatic Manifestations of HCV Infection Neuropsychiatric manifestations Thyroid dysfunction Mixed cryoglobulinemia Hematological disorders/ malignancies Type II diabetes Cardiovascular/ metabolic diseases Renal impairment Peripheral neuropathy Cacoub P, et al. Dig Liver Dis 2014; 46(Suppl 5):S165 S173; Negro F, et al. Gastroenterology 2015; 149:1345 1360; Englert Y, et al. Fertil Steril 2007; 88:607 11; Samuel DG & Rees IW. Frontline Gastroenterol2013; 4:249 254.

Treatment of HCV Is Associated with Reduced Risk for Type 2 Diabetes Mellitus Cumulative development rate of T2DM Japanese retrospective study: 2842 patients treated with IFN ± RBV were followed for a mean of 6.4 years 1 50 40 30 20 10 p<0.001 0 0 10 20 Follow up (years) Non-SVR (n = 1667) SVR (n = 1175) SVR was associated with a 66% reduction in the development of T2DM Patients without IFG and/or T2DM Spanish HCV chronic HCV cohort study: 1059 patients treated with IFN + RBV for 24/48 weeks 2 1.0 0.8 0.6 0.4 0.2 SVR Censored NR Censored P=0.0003 0.0 0 24 48 72 96 Follow-up (months) SVR reduces the risk of IFG and/or T2DM development 1.. Arase Y, et al. Hepatology 2009; 49:739 744; 2. Romero-Gomez M, et al. J Hepatol 2008; 47:721 727

Cumulative incidence (%) Treatment of HCV Is Associated with Reduced Risk for Cardiovascular Complications Large Taiwanese chronic HCV cohort study: 12,384 patients treated with pegifn/rbv and 24,768 untreated matched controls were followed up for a mean of 3.3 years and 3.2 years, respectively 2 1.5 1 0.5 Untreated cohort Treated cohort Ischemic stroke, p=0.001 0 0 1 2 3 4 5 6 7 8 Follow-up (years) Antiviral treatment was associated with a 38% lower risk for ischemic stroke Cumulative incidence (%) Antiviral treatment was associated with a 23% lower risk for ACS ACS, acute coronary syndrome. Hsu YC, et al. Gut 2015; 64:495 503. 3 2 1 Untreated cohort Treated cohort Acute coronary syndrome, p=0.027 0 0 1 2 3 4 5 6 7 8 Follow-up (years)

Treatment of HCV Is Associated with Reduced Risk for End Stage Renal Disease Large Taiwanese prospective chronic HCV cohort study: 12,384 patients treated with pegifn/rbv and 24,768 untreated matched controls were followed up for a mean of 3.3 years and 3.2 years, respectively Cumulative incidence (%) 1.5 1.2 0.9 0.6 0.3 Untreated cohort Treated cohort End-stage renal disease, p<0.001 Hsu YC, et al. Gut 2015; 64:495 503; 0 0 1 2 3 4 5 6 7 8 Follow-up (years)

Benefits of SVR Reduced risk of the development of type 2 DM Reduced risk of cardiovascular complications Reduced risk of development of renal disease

Classes of Medications Used for HCV Treatment NS3-4A Protease Inhibitors ( Previr ) NS5A Inhibitors ( Asvir ) NS5B Inhibitors: ( Buvir ) Other Nucleoside Analogues Non-Nucleoside Analogues Grazoprevir Daclatasvir Sofosbuvir Dasabuvir Ribavirin Paritaprevir Elbasvir Simeprevir Glecaprevir Voxilaprevir Ledipasvir Ombitasvir Velpatasvir Combination Therapies Trade Name Glecaprevir / Pibrentasvir Mavyret Grazeprevir/Elbasvir Zepatier Paritaprevir/Ombitasvir/Dasabuvir Viekira XR Sofosbuvir/Ledipasvir Harvoni Sofosbuvir/Velpatasvir Epclusa Sofosbuvir/Velpatasvir/Voxilaprevir Vosevi

Genotype 1 Regimens Updated September 2017 http://www.hivguidelines.org/hcvinfection/treatment-with-daa

Recommended and Alternative Regimens for GT1 Without Cirrhosis No Distinction Between Naïve & IFN-Experienced Recommended Alternative Nucleotide No nucleotide GLE/PIB LDV/SOF SOF + VEL DCV + SOF SMV + SOF GZR/EB R OBV/PTV/RT V + DSV GT1a 8 wks (8 wks if HCV RNA<6M IU/ml, non- AA, no HIV) 12 wks 16 wks + RBV + RBV GT1b 8 wks (8 wks if HCV RNA<6M IU/ml, non- AA, no HIV) 12 wks If NS5A RAVs present (GT1a only) http://www.hivguidelines.org/hcv-infection/treatment-with-daa Accessed 9/17

Recommended and Alternative Regimens for GT1a with Compensated Cirrhosis Recommended Alternative Nucleotide No nucleotide GLE/PI B LDV/SO F SOF + VEL DCV + SOF SMV + SOF GZR/EBR OBV/PTV/RT V + DSV GT1a - Naive - PR exp + RBV or 24 wks w/o RBV 24 wks ± RBV 24 wks ± RBV 24 wks ± RBV* 24 wks ± RBV* 16 wks + RBV 16 wks + RBV 24 wks + RBV 24 wks + RBV *Not w/q80k If NS5A RAVs present. http://www.hivguidelines.org/hcv-infection/treatment-with-daa. Accessed 9/17

Recommended and Alternative Regimens for GT1b with Compensated Cirrhosis Recommended Alternative Nucleotide No nucleotide GLE/PI B LDV/SO F SOF + VEL DCV + SOF SMV + SOF GZR/EBR OBV/PTV/RT V + DSV GT1b - Naive 24 wks ± RBV 24 wks ± RBV* - PR exp + RBV or 24 wks 24 wks ± RBV 24 wks ± RBV* *Not w/q80k If NS5A RAVs present. http://www.hivguidelines.org/hcv-infection/treatment-with-daa. Accessed 9/17

Treatment of DAA Failures: The 2017 Regimens Approved in the US

Treatment of Genotype 1 DAA Failures Genotype Previous Regimen Treatment Duration GLE/PIB 1a, 1b NS5a without prior treatment with an NS3/4A PI GLE/PIB 1a, 1b NS3/4A PI without prior treatment with an NS5A 16 weeks 12 weeks SOF/VEL/VOX 1a,1b NS5A inhibitor 12 weeks SOF/VEL/VOX 1a Sofosbuvir without an NS5A inhibitor 12 weeks http://www.hivguidelines.org/hcv-infection/treatment-with-daa Accessed 9/17

Genotype 2

Recommended Regimens for GT2, Naive without and with Compensated Cirrhosis GLE/PI B SOF + VEL DCV + SOF Noncirrhotic 8 wks Cirrhotic *Not w/q80k If NS5A RAVs present. http://www.hivguidelines.org/hcv-infection/treatment-with-daa. Accessed 9/17

Recommended Regimens for GT2, Treatment Experienced without and with Compensated Cirrhosis Previous Regimen Treatment Duration (No cirrhosis) Treatment Duration (cirrhosis) GLE/PIB PEG/RBV +/- SOF 8 weeks 12 weeks SOF/VEL/VOX NS5A inhibitor 12 weeks 12 weeks SOF/VEL/VOX Sofosbuvir without an NS5A inhibitor 12 weeks 12 weeks http://www.hivguidelines.org/hcv-infection/treatment-with-daa Accessed 9/17

Genotype 3

Recommended Regimens for GT3, Naive without and with Compensated Cirrhosis GLE/PI B SOF + VEL DCV + SOF Noncirrhotic 8 wks Cirrhotic 24 wks *Not w/q80k If NS5A RAVs present. http://www.hivguidelines.org/hcv-infection/treatment-with-daa. Accessed 9/17

Recommended Regimens for GT3, Treatment Experienced without and with Compensated Cirrhosis Previous Regimen Treatment Duration (No cirrhosis) Treatment Duration (cirrhosis) GLE/PIB PEG/RBV +/- SOF 16 weeks 16 weeks SOF/VEL/VOX NS5A inhibitor 12 weeks 12 weeks SOF/VEL/VOX Sofosbuvir without an NS5A inhibitor DAC/SOF PEG/RBV 12 weeks 12 weeks 12 weeks DAC/SOF/RBV PEG/RBV 24 weeks http://www.hivguidelines.org/hcv-infection/treatment-with-daa Accessed 9/17

Decompensated Cirrhosis

SOLAR-1: LDV/SOF + RBV in Decompensated Cirrhotics: Genotypes 1 and 4, Childs-Pugh B and C LDV/SOF + RBV 12 Weeks LDV/SOF + RBV 24 Weeks 100 80 87 89 87 89 86 90 SVR12 (%) 60 40 20 0 45/52 42/47 Overall 26/30 24/27 19/22 18/20 CPT B CPT C Charlton M, et al. Gastroenterology. 2015;149:649-659.

ASTRAL-4: SOF/VEL FDC for Treatment of HCV in Patients with Decompensated Liver Disease SVR24 rates (%) 100 80 83 94 96 88 88 94 85 100 100 86 60 50 50 40 20 0 75/ 90 82/ 87 79/ 90 60/ 68 65/ 68 Safety d/c due to AE 3%; death 3% (9) AE more frequent with RBV Fatigue (29%); nausea (23%); HA (22%); anemia (13%; 31% in RBV arm) 67/ 71 7/ 14 11/ 13 6/ 12 G2: 4/4 G4: 4/4 G2: 4/4 G4: 2/2 Overall G1 G3 G2, 4, 6 BT - 1 1 - - - Relapse 1 1 2 7 5 1 3 LTFU 1-1 1-1 Death 3 2 2 2 2 - G2: 4/4 G4: 2/2 G6: 1/1-1 1 - - - 6 1 4 - - - - - - - - - 1-1 - - 1 Charlton MR, et al. AASLD. 2015. San Francisco. #LB-13; O Leary J, et al. EASL. 2016. Barcelona. #SAT-169. RBV dose: Hb <10 = 23%; Hb <8.5 = 7% RBV decreased in 37% and d/c in 17% Bili <3 x ULN

What Therapy Should Be Used for Decompensated Cirrhotics? 1. Only regimens containing an NS5A inhibitor and polymerase inhibitor should be used for decompensated cirrhotic patients 2. Protease inhibitors should not be used in decompensated cirrhotics because they accumulate to potentially toxic levels 3. Decompensated cirrhotics can be safely treated at a transplant center or in close coordination with a transplant center 4. Decompensated cirrhotics should not be treated in the primary care setting 1 http://www.fda.gov/drugs/drugsafety/ucm468634.htm; 2 hcvguidelines.org. Feb 24; 3 2016. EASL Recommendations. J Hepatol. 2016.

Renal Failure

Treatment of patients with renal impairment No dose adjustment is required in patients with mild, moderate or severe renal impairment, including dialysis with the following regimens: GLE/PIB GRZ/ELB SVR rates similar to non-renal failure patients Sofosbuvir containing regimens should not be used in patients with a GFR < 30 Mavyret PI 2017 Zepatier PI 2016,

Paradigm of HCV Therapy for Renal Failure Patients Past: Difficult to use interferon + ribavirin in renal failure Renal transplantation historically withheld for HCV+ patients with hepatic fibrosis ( we won t transplant till HCV cured ) Concern about progression of fibrosis post-transplant Present Effective and safe DAA therapy available for renal failure patients Non-renal transplant candidates should be offered treatment If wait list is much shorter for an HCV+ kidney, may be better to proceed with transplant and treat the HCV after transplant Future Transplant HCV- patients with HCV+ kidneys? Being studied

HCV Therapy: Almost at the Summit But Still Climbing The Quest: Pangenotypic regimens that cover resistant variants associated with first generation NS5A and protease inhibitors

Second Generation Combination Pangenotypic Regimens Protease Inhibitor NS5A Inhibitor Nucleotide Polymerase Inhibitor FDA Status Glecaprevir Pibrentasvir Approved GS-9857 Velpatasvir Sofosbuvir Approved Grazoprevir Ruzasvir Uprifosbuvir Under study

SUMMARY OF GLE/PIB STUDIES STUDY Genotype C/NC TN/TE Duration (wks) SVR Endurance-1 1 NC TN/TE 8 99% Surveyor-2 2 NC TN/TE 8 98% 4 NC TN/TE 8 93% 5 NC TN/TE 8 100% 5 NC TN/TE 12 100% 6 NC TN/TE 8 100% 6 NC TN/TE 12 100% Expedition 1 1,2,4,5,6 C TN/TE 12 99-100% Endurance 3 3 NC TN 8, 12 95%, 95% Surveyor 2 Pt 3 3 C/NC TN/TE 12, 16 98%, 96% Magellan 1 1 C/NC TE PI 12, NS5A 16 92%, 94% C-cirrhosis, NC-non-cirrhosis, TN- treatment-naïve, TE-treatment experienced Mavyret PI 2017

SUMMARY OF SOF/VEL/VOX STUDIES: All treatments 12 weeks STUDY Genotype NC/C TN/TE SVR Polaris 1 1 NC/C TE with NS5A 97% 2 NC/C TE with NS5A 100% 3 NC/C TE with NS5A 95% 4 NC/C TE with NS5A 91% 5 NC/C TE with NS5A 100% 6 NC/C TE with NS5A 100% Polaris 4 1 NC/C TE without prior NS5A 96% 2 NC/C TE without prior NS5A 100% 3 NC/C TE without prior NS5A 96% C-cirrhosis, NC-non-cirrhosis, TN- treatment-naïve, TE-treatment experienced Vosevi PI 2017

Summary We are now in an era of highly effective interferon free treatment Historically difficult to treat patients are no longer considered difficult to treat HIV coinfected patients have similar efficacy, must be mindful of drug-drug interactions PWID should be treated with appropriate avaliable expertise in addiction medicine w/harm reduction There is significant fibrosis regression, reduction in liver complications, and all-cause mortality post-svr There is no justification for withholding treatment from HCV infected patients regardless of degree of fibrosis Post-SVR patients with advanced fibrosis or cirrhosis must be monitored for liver cancer

On Line Treatment Guideline Links NYS DOH http://www.hivguidelines.org/hcv-infection/treatmentwith-daa/#tab_0 AASLD/IDSA http://www.hcvguidelines.org