This document summarizes a seminar on the management of hepatitis C. It discusses the virology of hepatitis C virus and outlines guidelines for patient evaluation, counseling, and antiviral therapy. The summary focuses on the evolution of hepatitis C treatment from interferon-based regimens to highly effective all-oral direct-acting antiviral combination therapies that achieve over 95% cure rates.

2. MANAGEMENT OF HEPATITIS C
Speaker- Dr. Reshmi Harikumar Pillai
Guide - Dr. Neera Samar
RNT MEDICAL COLLEGE AND MB GOVT HOSPITAL
DEPARTMENT OF MEDICINE
SEMINAR

3. OVERVIEW
o Introduction
o Virology/Genome
o Guidelines
o Patient evaluation
o Counseling
o General Management
o Antiviral Therapy
o Special situation
o Summary

4. INTRODUCTION
oWHO- 71 million –global disease burden
o4,00,000 die each year
oIndia : 12-13 million anti-HCV positive patients
oAll ages ; highest between 20-39 years ; male predominance
oIncubation period : 15-160 days(mean 50)

5. VIROLOGY
o Linear single strand , positive sense , 9600 nucleotide RNA virus
o Previously labelled ‘non-A, non-B hepatitis’
o Genus Hepacivirus, Family Flaviviridae
o50-80nm size ; T1/2- 2.7 hours
oCirculates in low titre-103-107 virions/ml
oHigh replication rate – 1012virions/day

6. o 6 distinct major genotypes(and a minor genotype 7); >50 subtypes
within genotypes .
oGenotypes differ in responsiveness to antiviral therapy; but not in
pathogenicity/clinical progression .
oMost sensitive indicator of infection :HCV RNA (PCR/TMA)-in IU/ml;
detected within a few days of exposure and persist for the duration of
HCV infection

7. WORLDWIDEDISTRIBUTIONOFHCVGENOTYPE
o Globally, HCV genotype 1 is the most prevalent worldwide (49.1%), followed by
genotype 3 (17.9%), 4 (16.8%) and 2 (11.0%), while genotypes 5 and 6 are responsible
for the remaining < 5% . 1>3>4>2>5,6
o Most prevalent in India – Genotype 3

8. oTransmission : Percutaneous (transfusion/HD/occupational exposure)/
perinatal & sexual(5%)
oBreastfeeding –no increased risk
oRisk of Transfusion associated HCV : 1 in 2.3 million transfusion
oHCV infection by accidental needle puncture ~3%

9. ORGANISATION OF THE HEPATITIS C
VIRAL GENOME

11. NATURAL HISTORY OF DISEASE

12. LABORATORY PARAMETERS
oEpisodic aminotransferase elevation
oSerology : Anti-HCV(Non specificity can confound immunoassays for anti-HCV)
oAssays for HCV RNA(amplification techniques)---most sensitive ---GOLD STANDARD
oHCV RNA level is NOT a marker of disease severity; may predict relative
responsiveness to antiviral therapy
oDetermination of genotype
oOccasional finding : Autoantibody(anti LKM1)

14. GUIDELINES
o Released jointly by the AASLD(American association for the study of liver disease)
and the Infectious Disease Society of America(IDSA)-2014 guidelines
o European Association for the Study of Liver Disease(EASL)
o WHO – Guidelines regarding Screening and Treatment of HCV

15. PATIENT EVALUATION
o Assessment of the extent of liver Disease
o Assessment of viral and host factors –antiviral selection
-Viral genotype
-Stage of liver fibrosis
-History of antiviral treatment
-Renal function
-Concurrent medication
o Identification of comorbidities associated with HCV infection
o Test for HIV and HBV – common modes of transmission

16. COUNSELING
o Psychosocial issues:
-Counseling and screening for depression
-Substance use treatment/Psychiatric services
o Transmission risk
o Diet and behaviours
Avoid modifiable factors associated with accelerated liver disease: Alcohol use,
obesity, Insulin resistance and marijuana use.

17. GENERAL MANAGEMENT
o ANTIVIRAL TREATMENT = CORNERSTONE
o Symptom Management:
o Dose adjustments of medications
o Vaccination: Pneumococcal vaccination , Hepatitis A/B
o Advanced liver fibrosis / cirrhosis: Signs of liver failure/ esophageal varices/HCC

18. ANTIVIRAL THERAPY
o Goals of Therapy
o Indications
o Regimen Selection

19. Goals of Therapy
oEradicate HCV RNA :Predicted by attainment of a sustained virological response(SVR):
oUndetectable RNA level 12 weeks following the completion of Therapy
oSVR- 97-100% chance of being HCV RNA negative during long term follow up
oAntiviral Therapy:
Improves survival/ Complication free survival / Slows Progression / Reversal of fibrosis

23. INDICATIONS
oAll patients with chronic HCV infection (detectable HCV RNA over a 6 month period,
with or without elevated ALT)
oException : Those with short life expectancies
oAny stage of fibrosis; highest priority for advanced fibrosis [METAVIR stage 3]/
cirrhosis [METAVIR stage 4]

24. oRETREATMENT RECOMMENDED
Relapsers, partial responders, or nonresponders after a previous course of
interferon-based therapy or prior direct-acting antiviral therapy
oSCREENING FOR HBV -MANDATORY
HBV reactivation occurs in those receiving DAA in patients with HBV/HCV
coinfection

25. REGIMEN SELECTION
o INDIVIDUALISED : Varies by Genotype/ Patient factors- cirrhosis , treatment history
oMonitor serum HCV RNA levels- Pretreatment / During treatment / after treatment

26. ACUTE HEPATITIS C
Same directly acting agents as that used in chronic infection
Choice: Delay 12-16weeks  spontaneous recovery
Acute Hepatitis C is not rapidly progressive
EASL Guidelines : Genotype appropriate DAA Regimen
Sofosbuvir + one of the approved without Ribavirin x 8weeks
NS5A Inhibitors
Extend to 12 weeks 1)HIV Coinfection
2)HCV RNA level > 1 million IU/ml

28. CHRONIC HEPATITIS C
oThe Interferon Era(1991-2011)
oFirst Generation Protease Inhibitors(2011-2013)
oContemporary Direct acting Antiviral combination Therapy (2013-)
oFuture Direct acting antiviral combination therapy(2017-)
o6 ALL ORAL , HIGHLY EFFECTIVE,LOW RESISTANCE,WELL TOLERATED SHORT
DURATION(12 WEEKS) COMBINATION REGIMENS

29. The Interferon Era(1991-2011)
IFN alpha – first given as s/c injection thrice weekly x 6 months  SVR <10%
X 12 MONTHS~SVR 20%
+ RIBAVIRIN  SVR-55% (IFN + RIBAVIRIN = SYNERGISTIC)
40% SVR in genotypes 1 ,4 ; 80% in genotypes 3,4

30. MECHANISM OF ACTION OF INTERFERON:
-Activation of JAKSTAT signal transduction pathwayelaboration of genes / protein
products that have antiviral properties
-90% virological response is achieved within 12 weeks of therapy
-SVR12(Current standard)=24 week SVR(previous standard)=CURE
Genetic changes in the virus explains differences in treatment responsiveness
GENOTYPE DURATION SVR
1 48 WEEKS 40-45%
2,3 24 WEEKS 80%

31. PEG IFN
-Longer half life-prolonged conc-once weekly dosing
-2 PEG IFN – PEG IFN alpha2b , PEG IFN aplpha 2a
-Duration: Genotype1-48 weeks; Genotype 2,3- 24 weeks
RIBAVIRIN DOSAGE:
Genotype 1 : <75kg- 1000mg ; >75kg- 1200mg
Genotype 2,3 : 800mg
Linear
12kD
Large vol of
distbn
Dose – 1.5mcg/kg
Branched
Larger
30kD
Small vol of
distbn
Dose -180mcg

32. MECHANISM OF ACTION OF RIBAVIRIN
-Reduction of HCV replication
-Inhibits host IMP dehydrogenase activity
-Induction of virological mutational catastrophe
-Enhancement of IFN medicated gene expression
-Immunomodulation

33. ADVERSE EFFECTS OF INTERFERON:
o Dose dependent side effects
o Flu like symptoms, hematological toxicity, elevated transaminases, nausea, fatigue,
psychiatric sequelae
ADVERSE EFFECTS OF RIBAVIRIN:
o Hemolysis – Reduction in hemoglobin by 2-3g/Hct by5-10%
o Nasal and chest congestion/pruritis/gout
o Contraindications: Anaemia/Hemoglobinopathy/CAD/CVA/CKD/pregnancy

35. First Generation Protease Inhibitors(2011-
2013)
oHCV RNA Genome Single polyprotein
oProtease – NS3/4A –serine protease activity
oTelaprevir/ Boceprevir + PEG IFN + Ribavirin = for Genotype 1
oResistance with monotherapy

37. oADR:
Telaprevir: Maculopapular pruritic rash , rectal burning , dysgeusia,
nausea, diarrhea, fatigue , anemia
Boceprevir: anemia, neutropenia, thrombocytopenia,

38. DISADVANTAGE:
-High pill burden
-q8H dosing with food
-Metabolised by CYP3A4-multiple interactions
-Triple drug protease inhibitor therapy – amplified intolerability
-RAS(resistance associated substitution)/RAV(resistance associated
variation)responsible for protease inhibitor nonresponders

39. Contemporary Direct acting Antiviral
combination Therapy (2013-)
6 therapeutic regimens--all oral-- IFN –free -- >95% SVR -- simple dosing--low pill
burden--resistance—8-12 weeks—pangenotypic efficacy
3 classes:
-NS3/4 protease inhibitors(cleave HCV polyprotein into structural and nonstructural
proteins)-Grazoprevir,Paritaprevir
-NS5B nucleoside and nonnucleoside polymerase inhibitors(interfere with RNA
dependent RNAP- a Replicase)-Sofosbuvir,Dasabuvir
- NS5A inhibitors(interfere with a membrane associated phosphoprotein essential to
the HCV RNA replication complex)-Daclatasvir,Elbasvir,Velpatasvir,Ombitasvir

42. SIMEPREVIR:
Second generation protease inhibitor for genotype 1
Once daily dosing, not response guided therapy
Numerous drug-drug interactions
ADR: photosensitivity, rash, mild hyperbilirubinemia
Reduced efficacy= HCV NS3 polymorphism Q80K –necessitates genetic testing and
disqualificationof 30%
Simeprevir 150mg + Sofosbuvir 200mg x 12weeks  97% SVR12 -treatment
naiive/experienced w/o cirrhosis
88% SVR12 t/t naiive / 79% SVR12
t/t refractory with cirrhosis

43. SOFOSBUVIR
1ST non protease inhibitor DAA
High potency/pangenotypic activity/barrier to resistance/min. interactions
Used in combination with protease inhibitor / NS5A inhibitor x 8 weeks upto 24 weeks
ADR: Fatigue , insomnia, headache, nausea

44. SOFOSBUVIR / LEPIDASVIR:
SOF 400mg + NS5A inhibitor Lepidasvir 90mg
Once daily, single pill (FDC)
Effective for genotypes 1,4,5,6
Treatment naiive non cirrhotics/cirrhotics  97% SVR12
Cirrhotic non responders to IFN based therapy  86% SVR12 (12 weeks) v/s 100%
SVR12 (24 weeks)
Renal safety-not known
Extremely effective against post transplant HCV
C/I Amiodarone/beta blocker(Bradyacardia) ; P gp inducers(reduced activity)

45. SOFOSBUVIR AND DACLATASVIR
SOF 400mg + DACLA 60mg once daily x 12-24 weeks
Genotypes 12,3,4 + 5,6(EASL)
SVR12 rates for 12 weeks :-98% -genotype 1 ,92%-genotype 2, 89% genotype 3
Addition of Ribavirin in noncirrhotics- no benefit
Cirrhotics: Child A , B – 93% SVR12; Child C-56% SVR12
Well tolerated(fatigue, headache, nausea)
C/I Amiodarone/beta blocker(Bradycardia)
Interactions with CYP3A, OATP1B1 and 1B3 , BCP, P-gp

46. SOFOSBUVIR AND VELPATASVIR.
Velpatasvir 100mg(pangenotypic NS5A inhibitor) + Sofosbuvir 400mg single pill
Addition of Ribavirin –decompensated cases
Genotypes 1,2,4,5 -99% SVR12
Genotypes 3 -95% SVR12
Baseline NS5A RASs – no impact on responsiveness
ADR: mild headache, nausea, fatigue
C/I Amiodarone/beta blocker(Bradycardia)
CYP3A inducers, P-gp inducers(reduces plasma drug levels)

50. Future Direct acting antiviral combination
therapy(2017-)
-Investigative protease inhibitor + Polymerase/NS5A inhibitor  97% SVR12
Voxilaprevir Sofosbuvir/Velpatasvir
- Sofosbuvir +NS5A inhibitor (Odalasvir) x 6 weeks  100% SVR12 –Genotype 1
- Odalasvir + Protease Inhibitor Simeprevir + Polymerase inhibitor (AL 335) 
100% SVR12 –Genotype 1
- Protease Inhibitor ABT-493 + NS5A inhibitor ABT-530 X 8 WEEKS  100% SVR12 –
1,2,3(noncirrrhotic)
X 12 weeks  100% SVR12 –3(noncirrrhotic),4,5,6

51. SPECIAL SITUATION
o HCV + CRF : 7.5% HCV prevalence in CKD
o HCV +HBV : Similar SVR rates. Screening for HBV is a must  disease flare
o HCV +HIV : SVR similar to monoinfection. Drug interaction between DAAs and ARV
medication
o TB + HCV : Screen for active TB and treat before commencing therapy for HCV.
Monitor LFT --- higher incidence of antimicrobial induced hepatotoxicity

52. AVAILABLE TREATMENT OPTIONS
o FIXED DOSE : SOFOSBUVIR + LEDIPASVIR X 8 WEEKS
o Effective for all genotypes except 2,3/NO baseline RAS testing
o Genotype 2,3: Single Pill SOFOSBUVIR + VELPATASVIR X 12 WEEKS

53. LET’S SUMMARISE…….
REGIMEN
TYPE
CATEGORY OF PATIENTS REGIMEN RECOMMENDED DURATION
I WITHOUT CIRRHOSIS SOFOSBUVIR 400mg + DACLATASVIR 60mg 12 WEEKS
II COMPENSATED CIRRHOSIS(CHILD-PUGH A) SOFOSBUVIR 400mg + VELPATASVIR 100mg 12 WEEKS
III DECOMPENSATED CIRRHOSIS(CHILD-PUGH
B AND C)
(FDC)SOFOSBUVIR 400
mg+VELPATASVIR100mg+ RIBAVIRIN
RIBAVIRN INTOLERANT :
SOFOSBUVIR400mg+VELPATASVIR100mg
12 WEEKS
24 WEEKS
MANAGEMENT OF TREATMENT NAÏVE PATIENTS

54. DRUG DOSAGE RECOMMENDATION
NAME OF DRUG DOSAGE
SOFOSBUVIR 400mg ONCE DAILY
DACLATASVIR 60mg ONCE DAILY
SOFOSBUVIR+VELPATASVIR SOF 400mg + VEL 100mg ONCE DAILY
RIBAVIRIN 800-1200mg

55. PROPHYLAXIS
oHep C vaccination not feasible: Genotype and quasispecies heterogeneity , rapid
evasion of neutralizing antibodies by rapidly mutating virus
oBehaviour changes and precautions to limit exposure

56. National Viral Hepatitis Control
Programme
oEarly diagnosis and treatment
o Provision of free qualitative and quantitative testing
o Main Objective : Provision of free DAA
o Screening of high risk patients
o Aim: - Reduce deaths due to HCV by 2/3 in the next decade and eliminate HCV by
2030

57. REFERENCES
1.Harrison’s Principles of Internal Medicine
2.Medicine Update 2020
3.Schiff’s Diseases of the Liver

58. THANKYOU 