Hepatitis Alert: Management of Patients With HCV Who Have Achieved SVR This program is supported by educational grants from AbbVie, Gilead Sciences, and Merck

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Faculty Ira M. Jacobson, MD Paul Y. Kwo, MD Professor of Medicine Director of Hepatology Department of Medicine NYU School of Medicine New York, New York Paul Y. Kwo, MD Professor of Medicine Director of Hepatology Stanford University School of Medicine Palo Alto, California

Faculty Disclosure Information Ira M. Jacobson, MD, has disclosed that he has received consulting fees from AbbVie, Bristol‐Myers Squibb, Gilead Sciences, Intercept, Janssen, Merck, and Trek; fees for non‐CME/CE services from Gilead Sciences, Intercept, and Merck; and funds for research support from Gilead Sciences and Merck. Paul Y. Kwo, MD, has disclosed that he has received consulting fees from AbbVie, Bristol-Myers Squibb, Gilead Sciences, and Merck, and has received funds for research support from AbbVie and Gilead Sciences.

Program Overview Long-term Outcomes After SVR Post-SVR Monitoring of HCV RNA Post-SVR Monitoring for HCC Management of Varices Additional Considerations HCC, hepatocellular carcinoma; SVR, sustained virologic response.

Current All-Oral Therapies Highly Effective PR/SIM PR/SOF DAA Therapy 100 95+ TPV or BCV + PR 90 80 70+ PegIFN/ RBV (PR) 60 IFN/RBV 50 SVR (%) 40 40 Standard IFN 20 BCV, beclabuvir; DAA, direct-acting antiviral; IFN, interferon; pegIFN, peginterferon; PR, peginterferon/ribavirin; RBV, ribavirin; SIM, simeprevir; SOF, sofosbuvir; TPV, tipranavir. References Friedman RM, et al. Hepat Res Treat. 2010;323926. James JS. AIDS Treat News. 1998;19:7. Tan SL, et al. Nat Rev Drug Discov. 2002;1:867-881. Yau AH, et al. Can J Gastroenterol Hepatol. 2014;28:445-451. McHutchison JG, et al. N Engl J Med. 1998;339:1485-1492. Poynard T, et al. Lancet. 1998;352:1426-1432. Fried MW, et al. N Engl J Med. 2002;347:975-982. Manns MP, et al. Lancet. 2001;358:958-965. Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416. Poordad F, et al. N Engl J Med. 2011;364:1195-1206. Lawitz E, et al. N Engl J Med. 2013;368:1878-1887. Afdhal N, et al. N Engl J Med. 2014;370:1889-1898. Kwo P, et al. EASL 2015. Abstract LB14. Zeuzem S, et al. Ann Intern Med. 2015;163:1-13. Feld JJ, et al. N Engl J Med. 2015;373:2599-2607. Foster GR, et al. N Engl J Med. 2015;373:2608-2617. 15 1991 1998 2001 2011 2013 2018 With all the pts who will be cured, how much care do the cured need? Slide credit: clinicaloptions.com References in slidenotes

Long-term Outcomes After SVR

Benefits of Achieving SVR Decreased transmission Improved clinical outcomes Extrahepatic ↓ All-cause mortality ↑ QoL ↓ Malignancy ↓ Diabetes ↓ CVD ↓ Renal ↑ Neurocognitive Hepatic ↓ Cirrhosis ↓ Decompensation ↓ HCC ↓ Transplantation CVD, cardiovascular; HCC, hepatocellular carcinoma; QoL, quality of life; SVR, sustained virologic response. Smith-Palmer J, et al. BMC Infect Dis. 2015;15:19. Negro F, et al. Gastroenterology. 2015;149:1345-1360. George SL, et al. Hepatology. 2009;49:729-738. Slide credit: clinicaloptions.com

SVR and Mortality: IFN Era Long-term follow-up study of pts with chronic HCV infection and advanced fibrosis or cirrhosis (N = 530 treated 1990-2003; median follow-up: 8.4 yrs)[1] 10-Yr Cumulative Incidence 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 SVR also reduces all-cause mortality even in absence of cirrhosis[2] 50 SVR No SVR 40 27.4 30 26.0 Pts (%) 21.8 20 8.9 10 5.1 1.9 CVD, cardiovascular; HCC, hepatocellular carcinoma; IFN, interferon; SVR, sustained virologic response. HCC All-Cause Mortality Liver-Related Mortality 1. van der Meer AJ, et al. JAMA. 2012;308:2584-2593. 2. Backus LI, et al. Clin Gastroenterol Hepatol. 2011;9:509-516. Slide credit: clinicaloptions.com

DAA Therapy and Risk of Mortality ANRS HEPATHER: multicenter observational cohort study assessing short-term effects of DAAs on mortality in pts with HCV (N = 9295) Median follow-up: 24 mos DAA treatment associated with decreased risk of death vs no DAA treatment All-Cause Mortality 1.00 DAA+ (n = 6460)* 0.98 0.96 DAA- (n = 2835)† DAA, direct-acting antiviral. Effect of DAAs quantified with weighted Cox proportional hazards models adjusted for confounding via IPTW. IPTW scores derived from covariates associated with DAA, including age, sex, cirrhosis, and treatment experience. Survival Probability 0.94 0.92 HR: 0.65 (95% CI: 0.45-0.95; P = .0258) 0.90 5 10 15 20 25 30 Mos *8482 person-yrs. †10040 person-yrs. Slide credit: clinicaloptions.com Carrat F, et al. AASLD 2017. Abstract LB-28.

Post-SVR Monitoring of HCV RNA When Does Virologic Victory Become Closure? SVR, sustained virologic response.

Recommendations on HCV RNA Follow-up After SVR Organization Recommendation AASLD/IDSA Additional testing can be considered at ≥ 24 wks post treatment for pts with ALT increases to > ULN EASL Noncirrhotics should be tested for ALT and HCV RNA at 48 wks post treatment and discharged if ALT normal and HCV RNA negative Note that HCV antibody tests will remain positive for most after cure and need not be repeated Reinfection can occur AASLD, Association for the Study of Liver Diseases; ALT, alanine aminotransferase; EASL, European Association for the Study of the Liver; ULN, upper limit of normal. Slide credit: clinicaloptions.com AASLD/IDSA Guidelines. September 2017. EASL Guidelines. 2016.

Late Relapse Beyond SVR12 With DAA Therapy Risk of late relapse very low, but can happen Analysis of recurrent viremia after SVR12 in 11 SOF ± LDV phase III trials n = 2992 SVR24 5/12 with late relapse 7/12 reinfected N = 3004 SVR12 Phylogenetic analyses n = 12 (< 1%) No SVR24 DAA, direct-acting antiviral; LDV, ledipasvir; SOF, sofosbuvir; SVR, sustained virologic response. Slide credit: clinicaloptions.com Sarrazin C, et al. Clin Infect Dis. 2017;64:44-52.

Post-SVR Monitoring for HCC Which Patients Need It? HCC, hepatocellular carcinoma; SVR, sustained virologic response.

SVR and HCC Risk: IFN Era Meta-analysis of studies assessing HCC development in HCV pts following SVR through February 2012 Outcome All Pts (n = 25,497) Pts With Advanced Fibrosis* (n = 2649) SVR No SVR Developed HCC, %/PY 0.33 1.67 1.05 3.30 Adjusted HR (95% CI) 0.24 (0.18-0.31) 0.23 (0.16-0.35) *METAVIR score of F3/F4 or Ishak score of 4-6. HCC, hepatocellular carcinoma; IFN, interferon; PY, patient-years; SVR, sustained virologic response. Slide credit: clinicaloptions.com Morgan RL, et al. Ann Int Med. 2013;158:329-337.

DAA Therapy and HCC Risk Retrospective cohort study assessing the relationship between SVR and de novo HCC risk in pts with HCV in the VA system receiving antiviral therapy 1999-2015 (N = 62,354) Mean follow-up: 6.1 yrs SVR with DAA regimen associated with 71% decrease in de novo HCC risk Regimen HCC/100 PY aHR IFN only SVR No SVR 0.28 1.07 0.32 DAA + IFN 0.6 1.73 0.48 DAA only 0.92 5.2 0.29 DAA-Induced SVR and HCC Incidence 1.00 No cirrhosis with SVR No cirrhosis with no SVR Cirrhosis with SVR Cirrhosis with no SVR 0.95 Probability Free From HCC Diagnosis aHR, adjusted HR; DAA, direct-acting antiviral; HCC, hepatocellular carcinoma; IFN, interferon; PY, patient-years; SVR, sustained virologic response; VA, Veterans Affairs. 0.90 0.85 1 2 Yrs After Start of HCV Treatment Slide credit: clinicaloptions.com Ioannou G, et al. AASLD 2017. Abstract 142.

Some Key Questions With SVR and HCC Pts with what stage(s) of fibrosis may be at increased risk for HCC following SVR? Are pts with < F3 fibrosis at risk? Is there a typical time course for when HCC develops among at- risk pts following SVR? How long should HCC surveillance continue? HCC, hepatocellular carcinoma; SVR, sustained virologic response. Slide credit: clinicaloptions.com

Pretreatment Fibrosis Stage and HCC in Pts Achieving SVR: Retrospective Japanese Study Retrospective cohort study of de novo HCC incidence in Japanese pts achieving SVR on IFN therapy Median follow-up: 4.8 yrs Fibrosis Stage n HCC, n (%) Cumulative HCC, % 5 Yrs 10 Yrs 15 Yrs F0 53 0 (0) F1 187 1 (0.5) 0.7 F2 193 13 (6.7) 3.5 14.7 17.2 F3 78 11 (14.1) 3.7 12.7 30.5 F4 51 6 (11.8) 11.7 22.8 All 562 31 (5.5) 3.1 10.1 15.9 Cumulative Incidence of HCC 100 SVR (n = 562) No SVR (n = 351) 80 60 Pts (%) 42.3 40 35.5 HCC, hepatocellular carcinoma; IFN, interferon; SVR, sustained virologic response. 15.9 20 15.8 10.1 3.1 5 10 15 Yrs Slide credit: clinicaloptions.com Yamashita N, et al. J Gastroenterol. 2014;49:1504-1513.

Cumulative Incidence of HCC (%) Fibrosis Stage and Incidence of HCC in Pts Achieving SVR: Retrospective US VA Study Retrospective cohort study of de novo HCC incidence in pts achieving SVR on IFN- based therapy in VA Healthcare System 1999-2010 (N = 10,738) 25 Cumulative Incidence of HCC Incidence of HCC Following SVR Baseline Status n HCC, n Annual Incidence, % Cirrhosis High APRI* No 6832 11 0.055 Yes 2358 31 0.476 584 9 0.526 964 49 1.997 Cirrhosis negative Cirrhosis positive 20 15 Cumulative Incidence of HCC (%) Annual incidence rate, %: Cirrhosis 1.393 No cirrhosis 0.159 10 HCC, hepatocellular carcinoma; SVR, sustained virologic response. 5 1 2 3 4 5 6 7 8 Yrs After SVR *> 2.0. Slide credit: clinicaloptions.com El-Serag HB, et al. Hepatology. 2016;64:130-137.

Recommendations for HCC Screening After SVR Organization Recommendations F0-F2 F3-F4 AASLD/IDSA Follow-up same as for those never infected with HCV Ultrasound surveillance every 6 mos EASL None AASLD, American Association for the Study of Liver Diseases; EASL, European Association for the Study of Liver Diseases; HCC, hepatocellular carcinoma; IDSA, Infectious Diseases Society of America; SVR, sustained virologic response. Slide credit: clinicaloptions.com AASLD/IDSA Guidelines. September 2017. EASL Guidelines. 2016.

Surveillance and Management of Varices After SVR SVR, sustained virologic response.

Recommendations for Surveillance and Management of Varices After SVR Organization Recommendations Noncirrhotics Cirrhotics AASLD/IDSA and EASL No specific recommendations Endoscopy to screen for varices Pts with varices should be managed as indicated AASLD, American Association for the Study of Liver Diseases; EASL, European Association for the Study of the Liver; IDSA, Infectious Diseases Society of America; SVR, sustained virologic response. Slide credit: clinicaloptions.com AASLD/IDSA Guidelines. September 2017. EASL Guidelines. 2016.

Endoscopic Surveillance for Varices Following SVR Study of de novo esophageal varices in pts with HCV and compensated cirrhosis (N = 218) Pts underwent endoscopic surveillance for varices every 3 yrs; median follow- up: 11.4 yrs Incidence of Varices 100 80 HVPG fell to < 10 mm Hg in 4/4 pts with HVPG > 10 mm Hg before treatment 60 de Novo Varices (%) 39 40 32 HVPG, hepatic venous pressure gradient; SVR, sustained virologic response. 20 n/N = 0/34 45/115 22/69 SVR Untreated Nonresponders Slide credit: clinicaloptions.com Bruno S, et al. Hepatology. 2010;51:2069-2076.

Impact of SVR on Portal Hypertension Study of 48 wks of SOF + RBV for cirrhotic pts with portal hypertension (N = 50) SVR12: 72% (n/N = 33/46) HVPG Reduction in Pts With Baseline HVPG ≥ 12 mm Hg Who Achieved SVR12 and Completed 48-Wk Follow-up (n = 9*) -10 -20 -30 HVPG Change (%) -40 Baseline MELD -50 < 10 ≥ 10 HVPG, hepatic venous pressure gradient; RBV, ribavirin; SOF, sofosbuvir; SVR, sustained virologic response. -60 -70 *n = 8 pts with > 20% decrease. Slide credit: clinicaloptions.com Afdhal N, et al. J Viral Hepat. 2017;24:823-831.

Additional Considerations

Does Regression of Cirrhosis Have an Impact on Long-term Outcomes? Cohort study of cirrhotic pts with HCV who underwent IFN-based treatment from 1988-2001 (N = 96; median follow-up: 118 mos; SVR12: 41%) n = 18 (19%) had regression from F4 to F0-2 (n = 17 had SVR) Outcome, n (%) SVR P Value Cirrhosis Regression No Yes Overall deaths 17 (27.9) 4 (11.4) .075 20 (25.6) 1 (5.6) .110 Liver-related death/transplantation 19 (31.1) 3 (8.6) .012 22 (28.2) .010 Liver-related event 23 (37.7) .009 27 (34.6) .002 Hepatocellular carcinoma 14 (23.3) .097 17 (22.1) .036 Variceal bleeding 6 (9.8) 1 (2.9) .42 7 (9) .34 Ascites 10 (23.3) .004 10 (16.9) .197 Spontaneous bacterial peritonitis 2 (4.8) .5 2 (3.4) 1.0 Hepatic encephalopathy 7 (16.7) .018 7 (12.1) .33 IFN, interferon; SVR, sustained virologic response. 10-yr survival: 100% with regression of cirrhosis; 74% without regression of cirrhosis Slide credit: clinicaloptions.com Mallet V, et al. Ann Int Med. 2008;149:399-403.

How Accurate Is Transient Elastography to Monitor for Regression of Cirrhosis After SVR? 33 pts with HCV and biopsy-proven cirrhosis who achieved SVR after IFN based therapy FibroScan and biopsy ~ 60 mos post SVR Biopsy 20 pts regressed (≤ F3) 13 pts had persistent cirrhosis (F4) FibroScan HV, hepatic veins; IFN, interferon; SVR, sustained virologic response; TE, transient elastography. 19 (95%) pts regressed (TE < 12 kPa) 5 (38%) pts regressed (TE < 12 kPa) Diagnostic accuracy of TE for diagnosing post-SVR cirrhosis: 61% sensitivity, 95% specificity Regression of Fibroscan scores to “sub-cirrhotic” levels does not ensure true cirrhosis regression Slide credit: clinicaloptions.com D’Ambrosio R, et al. J Hepatol. 2013;59:251-256.

AASLD/IDSA Recommendations on Monitoring Fibrosis Regression in Pts Achieving SVR Risk of HCC in pts with advanced pretreatment fibrosis who demonstrate regression to minimal fibrosis post treatment is not known Such pts should continue to be monitored for HCC regularly No recommendations for routine assessment for regression in liver fibrosis after achieving SVR AASLD, American Association for the Study of Liver Diseases; HCC, hepatocellular carcinoma; IDSA, Infectious Diseases Society of America; SVR, sustained virologic response. Slide credit: clinicaloptions.com AASLD/IDSA Guidelines. September 2017.

Additional Considerations for Maintaining Liver Wellness After SVR Key Points and Recommendations Reinfection risk Pts who inject drugs and those with high-risk sexual exposure at greatest HCV reinfection risk Recommendations: for pts with ongoing risk for HCV infection Counsel and educate on risk reduction Test HCV RNA annually Alcohol use Alcohol use associated with liver fibrosis progression and HCC risk with chronic HCV infection; less evidence in post-SVR setting Recommendations: Counsel avoidance of significant alcohol use in all pts and abstinence for pts with advanced liver fibrosis or cirrhosis Obesity Fatty liver disease can cause fibrosis/cirrhosis; diabetes associated with unfavorable liver-related outcomes Counsel lifestyle modifications, glycemic control HCC, hepatocellular carcinoma; SVR, sustained virologic response. AASLD/IDSA Guidelines. September 2017. Jacobson IM, et al. Gastroenterology. 2017;152:1578-1587. Slide credit: clinicaloptions.com

Conclusions SVR associated with myriad clinical benefits Mandatory to continue HCC surveillance post SVR in pts with F3/F4 fibrosis; ultrasound every 6 mos Consider assessing AFP levels as well for these pts Less evidence to support continued screening of F0-F2 but remains a theoretical concern Indefinite screening for varices not warranted if varices absent at baseline: 1 more exam after SVR? Surveillance of small varices if no other liver disease present requires further study but advisable Large varices require ongoing management and surveillance Routine monitoring for fibrosis regression not the standard of care; further studies may change this For pts with ongoing risk for HCV infection after SVR, counsel and test HCV RNA annually AFP, alpha-fetoprotein; HCC, hepatocellular carcinoma; SVR, sustained virologic response. Slide credit: clinicaloptions.com

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