This document summarizes recent trends in the management of chronic hepatitis C. It discusses the prevalence and genotypes of HCV, the natural history of infection, milestones in treatment including newer direct-acting antiviral drugs, treatment guidelines, and considerations for special populations like those with HIV or renal co-infection. New all-oral interferon-free regimens have high efficacy rates over short durations with improved safety profiles compared to previous interferon-based therapies. Guidelines now recommend treatment for all patients except those with short life expectancy.

1. RECENT TRENDS IN
MANAGEMENT OF CHRONIC
HEPATITIS C
Surg Lt Cdr Abhish Mohan
Moderator: Col P K Sharma

2. References
• AASLD 2016
• EASL 2016
• INASL 2016

3. Introduction
• Prevalence 0.5-1.5%
• Genotypes: 6
– Most Common-1; 3 in India
• 60-80% Chronicity
• MC Cause of Liver Transplantation
• Rapidly evolving treatment options

4. Natural history of HCV
Natural history of chronic hepatitis B and C; Imperial J
World J Gastroenterol 1999

5. MILESTONES
1989
Identification of
Hep C
2002-2011
Peg IFN+ RBV
2011
Telapravir
Bocepravir
2013
SOFOSBUVIR
2014-2016
DASABUVIR
DACLATASVIR
VELPATASVIR
OMBITASVIR
ELBASVIR
PARITAPREVIR
GRAZOPREVIR

6. Screening
• One time testing
– Persons born between 1945-1965
– Risk behaviours
– Risk exposures
– Others
• HIV infection
• Unexplained CLD
• Solid organ donors

7. Diagnosis
• Anti- HCV antibodies
• HCV RNA
• Immune deficient subset
• HCV Core Ag
• Sensitivity- 93% Specificity- 99%
• Ref: Hep C Virus Core Ag Testing: Role in Diag,
monitoring
&Management: Hans Tillmann World J Gastroenterol
2014 Jun

8. Treatment Indication
• All pts with HCV infection except
– Patients with short life expectancy
• Priority
– Advanced fibrosis
(Metavir F3)
– Compensated cirrhosis
(Metavir F4)
– Liver transplantation
– Severe extrahepatic HCV

9. Pretreatment Assessment
• Detailed history and physical examination
• Baseline tests
• Viral Coinfections
• Other Causes
• Serum HCV RNA and Genotype
• Detection Of Liver Fibrosis and Cirrhosis
– Liver Biopsy
– Noninvasive Markers
• Biomarker panels
• Elastography
– Fibroscan

10. Transient Elastography

11. Non Invasive Scores
SCORE VARIABLES SIGBIFICANT FIBROSIS
SENSITIVITY SPECIFICITY
CIRRHOSIS
SENSITIVITY SPECIFICITY
APRI AST, Platelet 81 95 77 94
FIB 4 Age,AST,ALT, Platelet 64 79 90 92
FIBRO
TEST
Age, Sex, Se
Haptoglobulin, A2
macroglobulin,GGT,
Bilirubin, Apolip A1
92 96 85 81
HEPASC
ORE
Age, Sex, A2
macroglobulin,GGT,
Bilirubin, Hyaluronic
acid
66 79 72 86

12. Liver biopsy

13. HCV THERAPY-Response
• Sustained virological response(SVR)
Undetectable HCV RNA in the blood after end of HCV treatment, either at
12 week(SVR12) or 24 weeks(SVR24)
• Rapid virological response
Undetectable HCV RNA in blood at 4 weeks of treatment
• Early Virological response
Undetectable HCV RNA in blood at 4 weeks of treatment
• Delayed virological response
More than 2 log reductions of HCV RNA but detectable HCV RNA at week 12
and undetectable RNA at week 24.

14. Need for Newer Drugs
• 20-50% of patients treated with IFN based
regimes did not achieve SVR
• Side effect Profile
• Duration
• Genetic variations

15. Treatment of Chronic HCV
Peginterferon and Ribavirin
0
20
40
60
80
100
1-4 2-3
Genotype
SustainedVirologic
Response(%)
PegIFN-2a/RBV
PegIFN-2b/RBV
Fried MW, et al. N Eng J Med. 2002;347:975-982. Manns MP, et al. Lancet 2001;358:958-965.

16. Simple Regimen
Short duration, simple,
straightforward stopping
rules
Ideal HCV Regimen
Pan-Genotypic
Regimen can be used
across all genotypes
Highly Effective
High efficacy in
traditionally challenging
populations (ie, poor IFN
sensitivity, cirrhosis)
Safe and Tolerable
Few or easily manageable
adverse effects
All Oral
PegIFN/RBV replaced with
alternate backbone with
low chance of resistance
Easy Dosing
Once daily, low pill
burden

17. HCV Life Cycle and DAA Targets
Ref: Manns MP, et al. Nat Rev Drug Discov. 2007;6:991-
1000.
Receptor binding
and endocytosis
Fusion
and
uncoating
Transport
and release
(+) RNA
Translation
and
polyprotein
processing
RNA replication
Virion
assembly
Membranous
web
ER lumen
LD
LD
ER lumen
LD
NS3/4 protease
inhibitors
NS5B polymerase
inhibitors
Nucleoside/nucleotide
Nonnucleoside
*Block replication complex formation, assembly
NS5A* inhibitors

18. Classes of DAA

19. Currently Available DAA Combinations
Combi
nation
Protease
Inhibitors
Polymerase Inhibitors
Nucleotide Non-nucl
NS5A
Inhibitors
Genotype India
1 Sofosbuvir Ledipasvir 1,4,5,6 YES
2 Sofosbuvir Velpatasvir ALL Likely in
2017
3 Sofosbuvir Daclatasvir ALL YES
4 Paritaprevir/
Ritonavir
Dasabuvir Ombitasvir 1,4,5,6 NO
5 Grazoprevir Elbasvir 1,4,5,6 NO
6 Simeprevir Sofosbuvir 1 NO

20. AASLD Guidelines 2016
Combination Regime GT 1 2 3 4 5,6
Sofosbuvir + Ribavarin
Sofosbuvir/Ledipasvir
Sofosbuvir/Velpatasvir
Ombitasvir/Paritaprevir/ritonavir/da
sabuvir
Ombitasvir/Paritaprevir/ritonavir
Grazoprevir/elbasvir
Sofosbuvir/Daclatasvir
Sofosbuvir/Simeprevir

21. INASL Guidelines 2016
Combination Regime GT 1 2 3 4 5,6
Sofosbuvir + Ribavarin
Sofosbuvir/Ledipasvir
Sofosbuvir/Daclatasvir
Sofosbuvir/Prg INF/RBV

22. Is Ribavirin Required for Pts With
Cirrhosis?
• Integrated analysis of > 500 pts with cirrhosis treated with LDV/SOF ± RBV
• Treatment-experienced pts had previously received HCV PI
• Although NS5A resistance not measured, RBV overcomes shorter treatment
duration in patients with HCV cirrhosis and prior treatment failure
SVR12, % Total
(N = 513)
Treatment Naive
(n = 161)
Treatment Experienced
(n = 352)
Overall 96 98 95
12 wks ± RBV 95 97 94
24 wks ± RBV 98 99 98
Without RBV 95 96 95
With RBV 97 99 96
12 wks without RBV 92 96 90
12 wks with RBV 96 98 96
24 wks without RBV 98 97 98
24 wks with RBV 100 100 100

23. HCV/HIV Coinfection
• Same recommendations as in HCV-monoinfected pts
• Consider drug–drug interactions
Daclatasvir 30mg/d with CYP3A4 inh
90mg/d with inducers
Ledipasvir Avoid with Tenofovir in
Cr Cl <60ml/min or along with RTV boosted Pis
Avoid with Elvitegravir/Cobicistat comb therapy
Velpatasvir Avoid with NVP, EFV and Ertravirine
Sofosbuvir Not rec with Tipranavir

24. HBV co-infection
• Same regimens as HCV monoinfected patients.
• Concurrent HBV therapy
– If Hep B replicates at significant levels before,during
or after therapy.

25. Renal Impairment
• If CrCl > 30 mL/min
– IFN and RBV free DAA as per GT
• If CrCl < 30 mL/min
– AASLD
• 2,3,5,6: IFN + low dose RBV
• 1,4: Elbasvir + Grazoprevir
– INASL
• IFN eligible: IFN + low dose RBV
• IFN ineligible: Low dose SOF(200mg/d) and full dose DCV
• Post renal
– IFN- not recommended
– DAA as per GT

26. Acute HCV Infection
• Monitor HCV RNA for spontaneous
clearance for 12- 16 weeks
• Treatment
– As per GT for 8- 12 weeks

27. Resource Constrained Scenario
• Simplified Testing
– HCV RNA at baseline and at 12 weeks
– Viral load, GT and Fibrosis assessment
• Not mandatory in noncirrhotic treatment naive
• Simplified Treatment
– No Cirrhosis
• 90% of the treatment eligible population
• DCV/SOF x 12 weeks
• Close Monitoring
– SVR 12 and virological failure

28. Follow up
• SVR Achieved
– No Significant fibrosisas if never infected
– Advanced Fibrosis
• HCC Screening 6 monthly USG
• Baseline endoscopy if Cirrhosis present
• SVR Not achieved
– Disease progression assessment every 6-12m
– Advanced Fibrosis
• HCC Screening 6 monthly USG
• Baseline endoscopy if Cirrhosis present
– Evaluation for retreatment

29. In the Horizon

30. THANK YOU