1. Hepatitis Alert: Management of Patients With HCV Who Have Achieved SVR
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3. 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

4. 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.

5. 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.

6. 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;
James JS. AIDS Treat News. 1998;19:7.
Tan SL, et al. Nat Rev Drug Discov. 2002;1:
Yau AH, et al. Can J Gastroenterol Hepatol. 2014;28:
McHutchison JG, et al. N Engl J Med. 1998;339:
Poynard T, et al. Lancet. 1998;352:
Fried MW, et al. N Engl J Med. 2002;347:
Manns MP, et al. Lancet. 2001;358:
Jacobson IM, et al. N Engl J Med. 2011;364:
Poordad F, et al. N Engl J Med. 2011;364:
Lawitz E, et al. N Engl J Med. 2013;368:
Afdhal N, et al. N Engl J Med. 2014;370:
Kwo P, et al. EASL Abstract LB14.
Zeuzem S, et al. Ann Intern Med. 2015;163:1-13.
Feld JJ, et al. N Engl J Med. 2015;373:
Foster GR, et al. N Engl J Med. 2015;373: 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

7. Long-term Outcomes After SVR

8. 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: George SL, et al. Hepatology. 2009;49:
Slide credit: clinicaloptions.com

9. SVR and Mortality: IFN Era
Long-term follow-up study of pts with chronic HCV infection and advanced fibrosis or cirrhosis (N = 530 treated ; 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: Backus LI, et al. Clin Gastroenterol Hepatol. 2011;9:
Slide credit: clinicaloptions.com

10. 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: ; 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 Abstract LB-28.

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

12. 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 EASL Guidelines

13. 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.

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

15. 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 ( )
0.23 ( )
*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:

16. 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 (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
0.32
DAA + IFN
0.48
DAA only
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 Abstract 142.

17. 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

18. 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:

19. 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 (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:

20. 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 EASL Guidelines

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

22. 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 EASL Guidelines

23. 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/ / /69
SVR
Untreated
Nonresponders
Slide credit: clinicaloptions.com
Bruno S, et al. Hepatology. 2010;51:

24. 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:

25. Additional Considerations

26. Does Regression of Cirrhosis Have an Impact on Long-term Outcomes?
Cohort study of cirrhotic pts with HCV who underwent IFN-based treatment from (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:

27. 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:

28. 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.

29. 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 Jacobson IM, et al. Gastroenterology. 2017;152:
Slide credit: clinicaloptions.com

30. 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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