Hepatitis C : Complete Overview and Recent Updates 2019 Introduction, Classification, Clinical features, Staging, Investigation, Management Guidelines, Drugs, Updates 2019 Heaptobiliary disorder Sheila Sherlok Harrison

1. Hepatitis C :
Approach and
Management
GUIDE : DR CHANDRASHEKHAR KACHAPUR
STUDENT : CHETAN K GANTEPPANAVAR

2. Epidemiology
 Population prevalence : 2 – 3% of the
world ’ s population
 170 million individuals : risk of cirrhosis
 One of the top 10 causes of death due
to infectious diseases

3.  Hepatitis c accounted for the vast majority of
non - A, non - B post - transfusion hepatitis
before screening of hepatitis was started
 Most common reason for a hepatology
consultation
 Single leading indication for liver
transplantation in Europe and north America

4. Epidemiology

5. Transmission
 Parenterally - m.c intravenous drug use
 Permucosally
 Vertically

6. HCV Virus
 Enveloped RNA virus
 Family flaviviridae
 Structural proteins are encoded at the 5 ′ end of the genome
 Non - structural elements are downstream of this region
 Two glycoprotein products, E1 or gp35 and E2 or gp70 are seen
on the viral envelope

7.  E1 and E2 are important antigenic sites
 Variability may be important in persistence of infection and
immunopathogenesis
 RNA - dependent RNA polymerase
 Closely related, but different, nucleotide sequences, ‘quasispecies’
in infected persons
 Non – structural region of the HCV genome is divided into regions
NS2 to NS5

8.  NS2/NS3 encodes a protease with
cleavage activity
 NS3 has helicase activity with replication
function
 NS4a is a cofactor for protease
 NS5b is a viral RNA - dependent RNA
polymerase

9. HCV genome organization
and poly-protein processing

10. Genotypes
 6 genotypes
1. Genotpes 1 to 6
 >100 of subtypes

11. Pathology
 15 - 40 % acute illness resolving completely
 Mechanism of hepatitis is Unknown
 Lymphocytes are seen in liver parenchyma

12. Immune escpae
 E2 and NS3 interfere with IFN - induced double -
stranded - RNA - activated protein kinase and allow
HCV to replicate
 Retinoic - acid - inducible gene I
 Ifn regulatory factor 3 pathway

13. Diagnostic tests
 Anti – HCV : detection of the viral antigen is difficult.
 Serum HCV RNA : 10 – 15 IU/mL . No direct correlation with
activity or progression of the disease. Change of 1 log value
are normal during HCV course
 Genotyping : Type 6 is prevalent in South East Asia, Asian
Americans and Asian Australians. Type 3 : Faster
progression. Type 1b : Faster HCC
 Response to treatment is influenced by the infecting
genotype. HCV 1 is least pathogenic.

14. Genotypes in INDIA
 Genotype 3 : 60%
 Genotype 1 : 30%
 Genotype 4 : 6%
 Genotype 2,6 : 4%

15. Acute hepatitis C
 Typically unrecognized
 Incubation period : 2 – 12 weeks (average 7weeks)
 HCV RNA becomes positive within 2 weeks of exposure
 Anti - HCV positive within 8 – 10 weeks of exposure
 Female gender , acute severe hepatitis and jaundice :
faster viral clearance

16. MANAGEMENT
SPECIFIC
ANTIVIRALS
SUPPORTIVE
TREATMENT
IFN – a PEG – IFN –a
+
RIBAVARIN
NO RESPONSE IN
2- 4 MONTHS
• DONOT WAIT AND WATCH
• START TREATMENT
IMMEDIATELY
• ASYMPTOMATIC ARE PREFERRED
• NO ROLE OF PROPHYLACTIC IFN
AFTER NEEDLE PRICK
• STARTING TREATMENT OF 1
YEAR HAS UNSATISFACTORY
OUTCOME

17. Chronic Hep C
 HCV RNA > 6 months in serum
 Asymptomatic and go unnoticed
 Usually serum ALT is abnormal after 12 months of infection ( 2x to 8x )
 10-20 % develop cirrhosis in next 20 years
 Younger the age lesser the cirrhosis
1. 2% infected before the age of 20 developed cirrhosis over a 20 - year
period
2. 6% of those infected between 31 and 40 years,
3. 37% infected between the age of 41 and 50 years 63% infected after
the age of 50

18.  Progressive disease results in worse lab values :
1. AST > ALT
2. Low Serum albumin
3. Prolonged PT
4. Low platelet count
5. Low level of auto antibodies
6. Positive for LKM-1 antibodies

20. Extrahepatic manifestations
 Autoimmune Hepatitis,
 Cryoglobulinaemia,
 Vasculitis,
 Lichen Planus,
 Porphyria Cutanea Tarda,
 Lymphocytic Sialoadenitis And
 Membranous Glomerulonephritis
 Non - Hodgkin ’ S Lymphoma
 Insulin resistance and T2DM

21. Microscopy
 Mild portal tract
inflammation
 Lymphoid
aggregates or
follicles
 Mild periportal
piecemeal necrosis
 Parenchymal
steatosis,
 Apoptosis and mild
lobular inflammation
 Portal fibrosis or
portal – central
fibrosis
 Bridging necrosis -
rarely
 Granulomas - rarely

22. Management - Approach
 HCV RNA in serum
 Anti HCV antibodies
 Liver enzymes
 PT
 Bilirubin levels
 HCV Genotyping
 HBsAg
 HIV
 Anti Smooth muscle antibody
 Anti LKM antibodies

23. Liver biposy
 Not mandatory for all
 Unique extra information is available with biopsy like grading
of fibrosis and necroinflammation
 Calculation of fibrosis
1. AST/Platelet ration Index ( APRI ) : 80 -90% accuracy
2. Transient elastography ( Fibroscan )
Normal = 4-6 kilo-pascals
Cirrhosis = 12 – 14 kilo pascals

24.  The Enhanced Liver Fibrosis Panel
 Fibrotest
 Ultrasound Microbubble Hepatic Transit Times (HTT)
 Two tests show concordance : avoid biopsy
 Two tests show discordance : do biopsy

25. Indications for treatment
 All patients
 Psychiatry patients may worsen with
IFN treatment
 In cirrhotics : Avoid IFN : Plan for
transplant

26. Peg IFN – a ( ONCE A WEEK )
&
RIBAVARIN ( DAILY )
Peg IFN – a
1. Half life : 3 – 8 hours
2. Peak Sr Conc : 7 – 12 hour after
injection
3. Cleared from blood : < 24 hours
RIBAVARIN
1. Guanosine analogue
2. Inhibition of
guanyltransferase and
methytransferase capping
enzymes
3. Induce mutation affecting
HCV replication
4. <65kg : 800mg
5. 65-85kg : 1000mg
6. >85kg : 1200mg

27.  PEG IFN a : 180 microgm/week
 Genotype 1
1. 48 week therapy
2. < 75 kg : 1000 mg
3. >75kg : 1200 mg
 Genotype 2 and 3
1. 24 week therapy
2. 800mg / day

28. Response to IFN + Ribavirin
 > 40% SVR in genotype 1 and 4
 > 80% SVR in genotype 2 and 3
 In hep B the response of increase in ALT after
therapy is good response and it is reverse in
case of hep C.

29.  SVR of > 24 week is considered as
good sign.
 It is accepted as an equivalent for viral
cure
 Genotype 1 : Total duration of 48
weeks of PegIFN + Ribavirin
 Genotype 2 and 3 : 24 week of therapy

30. Ribavirin
 Most common adverse effect is hemolysis.
 Reduction of Hb% upto 2-3 gm% is seen
 Reduction of haematocrit upto 10%
 Risk of usage in patients with stroke / CAD / Hemoglinopathies.
 Increase in anemia on ribavirin usage, Epo can be supplemented
 Reduction of dose of ribavirin upto 60% of planned dose is
acceptable

31. PegIFN types
pegIFN alpha 2a pegIFN alpha 2b
40 kilodalton
molecule
12 kilodalton
molecule
Dose is weight
independent
Dose is weight
dependent
180 microgram /
week
+
800 mg Ribavirin
1.5 microgram / kg
/ week
+
1000 mg Ribavirin
• BETTER TOLERABLE
• GOOD COMPLIANCE

32. Treatment of genotype 1
and 4
 Until 2013 the only treatment available was PegIFN and
Ribavirin
 However, with the introduction of protease inhibitors, the
treatment of HCV found many new turns and paths
 PI’s are contraindicated if age < 18 years

33. DROP IN THE LEVEL OF HCV RNA AT 12 WEEKS
<2 LOG 10
OF EVR
2 LOG 10
OF EVR
UNDETECT
ABLE HCV
RNA
NEGLIGIBLE
SVR
66% SVR >80% SVR

34. 1ST GENERATION Protease
Inhibitors
 NS3-4A serine protease inhibitors
 Boceprevir
 Telaprevir
 Introduced in 2011 for both previously failed treatment
and untreated patients
 Never to be used alone

35. Triple therapy with PI’s
Protease inhibitor + PegIFN-a + Ribavirin
Response to treatment at week 4 and 12
Start Dual therapy with PegIFN + Ribavirin
SVR : Telaprevir = 79 %
SVR : Boceprevir = 59 – 66 %
Telaprevir > Boceprevir in overall SVR rates
and tolerability

36. Genotype 1 : naïve = PegIFN + Ribavirin + Boceprevir
Boceprevir 800mg 1-1-1
with food
HCV RNA Undetectable at
week 8 and 24
If HCV detected at week 4
4 week DT + 44week of TT
NO HCV detected
4 week dual therapy(DT) +
24 week triple therapy(TT)
Detectable HCV at 8week
and Undetectable at 24
week
36 week of therapy
4 week DT + 32 week of
TT
Followed by Dt for 12
week total of 48 week
Cirrhosis with HCV absent
at 8 and 24 week
Triple therapy
4week DT + 44 week TT
48 week total

37. Telaprevir 750 mg 1-1-
1 with fatty food
HCV RNA
Undetectable at week
4 and 12
TT for 12 week
DT for 12 week
24 week total
Detectable HCV at
week 4 and 12
TT for 12 week
DT for 36 week
48 weeks total
Cirrhosis with HCV
absent
TT 12 week
DT for 36 week
48 week total

38. Terminate the treatment if :
 HCV RNA detectable in serum of > 100
IU / ml at 24 week with Boceprevir
 HCV RNA detectable in serum of >
1000 IU / ml at 24 week with Telaprevir

39. Genotype 1 : Prior experienced treatment
Boceprevir 800mg 1-1-1
with food
HCV RNA Undetectable
at week 8 and 24
If HCV detected at week
4
4 week DT + 44week of
TT
4 week dual therapy(DT)
+ 32 week triple
therapy(TT)
36 week total
Detectable HCV at 8
week and Undetectable
at 24 week
36 week of therapy
4 week DT + 32 week of
TT
Followed by DT for 12
week total of 48 week
Cirrhosis with HCV
absent at 8 and 24 week
4week DT +44 week TT
48 week therapy

40. Telaprevir 750 mg 1-
1-1 with fatty food
Prior Relapse
Similar to naïve
patient
Partial / Null
responder
TT for 12 week
DT for 36 week
48 weeks total

41. TELAPREVIR : Adverse effects
 Rashes : Maculopapular
 Rectal burning sensation
 Nausea
 Anemia
 Vomiting and diarrhoea

42. BOCEPREVIR : Adverse
effects
 Anemia, leucopenia, thrombocytopenia
 Fatigue
 Nausea
 Vomiting
 Headache

43. Simeprevir
 Particularly for Genotype 1
 Regimen similar to the 1st gen Protease
inhibitors

44. Sofosbuvir : Polymerase inhibitor
Sofusbuvir
Genotype 1, 4 , 6
Sofosbuvir + Peg
IFN + Ribavirin for
12 week
Genotype 2
RBV + Sofosbuvir
12 week
Genotype 3
RBV + Sofosbuvir
24 week

45. Response
 40 – 50 % virological response with combination
therapy
 Studies have concluded that optimum dose of
ribavarin is 10.6mg/kg/day with response of
1. 48 % for genotype 1
2. 88% for genotype 2 and 3
 In genotype 1 : response less than 2 log 10 after 12
weeks of therapy : DISCONTINUE THERAPY
 Patients who are HCV RNA - positive at 6 months of
therapy, should stop therapy

46.  There may be benefit in prolonging therapy to 72
weeks in slow responders,
1. Negative PCR after 24 weeks of
2. More than 2 log 10 decline at 12 weeks
 The response to treatment of genotype 4 is
intermediate between genotype 1 and 2 or 3.
 There are limited published data on treatment
outcome in patients with genotype 5.

47. RESPONSES and DEFINITION

49. Side effects – IFN alpha
 Flu like symptoms
 Seizure
 Acute psychosis
 autoimmune diseases
 Bacterial infections
 Hyperthyroidism and
thyroiditis
 Proteinuria
 Cardiomyopathy
 IFN antibodies
 Neuroretinitis
 ILD
 Sarcoidosis

50.  Haemolytic anaemia,
 Myalgia,
 Hyperuricaemia,
 Dyspepsia,
 Monitored for
haemoglobin,
leucocytes and
platelets, AST, ALT,
albumin, bilirubin every
4 weeks.
 Uric acid and thyroid
function at 1 to 3 -
monthly intervals.
 Risk of teratogenicity,
need for contraception
up to 6 months after
completing treatment.
Side effects – Ribavarin

51. Depression
 20 – 40 % of cases
 Moderate severity
 First 4 – 8 weeks
 SSRI are DOC
 Dose modification needed in presence of
anemia and cirrhosis
 Epo and G-CSF are needed in severe cases

52. Non Responders
 Start with never antivirals
 Response is poor with success rates of 20%
 Genotype 2 & 3 > Genotype 1 has better response

55. Retreatment trials
 EPIC and HALT – C : some response to retreatment of patients
with advanced fibrosis or cirrhosis treated with PEG - IFN - α and
RBV.
 EPIC3 and HALT - C have not shown a definite benefit of low -
dose IFN in non – responders
 HALT - C trial did not show a difference in primary clinical
outcomes.
 EPIC3 trial : maintenance IFN therapy : may delay progression of
portal hypertension and variceal bleeding in a subset of patients

56. PEG - IFN plus RBV
Non - responders or relapses to either standard IFN plus
RBV or PEG - IFN monotherapy. PEG - IFN plus RBV
retreatment
Less value if low SVR inprevious full course of PEG - IFN
plus RBV.
Treatment should be stopped if no early viral response
with re - treatment

57. Drugs
 Aug 2011 : Boceprevir and Telaprevir
 Nov 2013 : Simeprevir
 Dec 2013 : Sofusbuvir
 Oct 2014 : Ledipasvir/Sofosbuvir
 Nov 2014 : Simepravir/Sofosbuvir
 Dec 2014 : Ombitasvir / paritaprevir / ritonavir
 Dec 2014 : Dasabuvir
 July 2015 : Daclatasvir
 Jan 2016 : Sofosbuvir / Velpatasvir

58. Protease inhibitors
 Boceprevir
 Telaprevir
 Simeprevir
 Aritaprevir

59. NS5A inhibitors
 Odalasvir
 Ombitasvir
 Ravidasvir
 Samatasvir
 Velpatasvir
 Daclatasvir : all genotypes, 60mg OD,
 Elbasvir
 Ledipasvir : HCV 1 and 4, 90mg OD,

60. NS5B inhibitors
 Beclabuvir
 Dasabuvir
 Deleobuvir
 Filibuvir
 Radalbuvir
 Setrobuvir
 Sofosbuvir : Genotypes 1 -6 , 400mg OD, Renal
excretion

61. Newer drugs
 Genotype 1, 4, 5, 6 : Sofosbuvir + Ledipasvir :
12 week orally
 Genotype 2, 3 : Sofosbuvir monotherapy
 Genotype 3 : Daclatasvir

69. Genotype 1 (AASLD – 2016)
 Non cirrhotics
1. SOFOSBUVIR + LEDIPASVIR (12 WEEK)
2. Sofosbuvir + Daclatasvir (12 week)
3. Sofosbuvir + Simeprevir (12 week)
4. Elbasvir + Grazoprevir (12 week)
5. Paritaprevir + Ombitasvir + Dasabuvir + Ribavirin (12 week)
 Cirrhotics
1. SOFOSBUVIR + LEDIPASVIR (12 WEEK)
2. Sofosbuvir + Daclatasvir +/- Ribavirin (24 week)
3. Sofosbuvir + Simeprevir +/- Ribavirin (24 week)
4. Elbasvir + Grazoprevir (12 week)
5. Paritaprevir + Ombitasvir + Dasabuvir + Ribavirin (24 week)

70. Genotype 2
 Non cirrhotics
1. SOFOSBUVIR + DACLATASVIR (12 WEEK)
2. Sofosbuvir + Ribavirin (12 week)
 Cirrhotics
1. SOFOSBUVIR + DACLATASVIR (24 WEEK)
2. Sofosbuvir + Ribavirin (16 – 24 week)

71. Genotype 3
 Non cirrhotics
1. SOFOSBUVIR + DACLATASVIR (12 WEEK)
2. Sofosbuvir + Ribavirin + PegIFN (12 week)
3. Sofosbuvir + Ribavirin (12 week)
 Cirrhotics
1. SOFOSBUVIR + DACLATASVIR +/- RIBAVIRIN (12
WEEK)
2. Sofosbuvir + Ribavirin + PegIFN (12 week)

72. Genotype 4
 Non cirrhotics
1. SOFOSBUVIR + LEDIPASVIR (12 WEEK)
2. Sofosbuvir + Ribavirin + PegIFN (12 week)
3. Elbasvir + Grazoprevir (12 week)
4. Paritaprevir + Ombitasvir + Dasabuvir + Ribavirin (12 week)
 Cirrhotics
1. SOFOSBUVIR + LEDIPASVIR (12 WEEK)
2. Sofosbuvir + Ribavirin + PegIFN (12 week)
3. Elbasvir + Grazoprevir (12 week)
4. Paritaprevir + Ombitasvir + Dasabuvir + Ribavirin (12 week)

73. Genotype 5 / 6
 Non cirrhotics
1. SOFOSBUVIR + LEDIPASVIR (12 WEEK)
2. Sofosbuvir + Ribavirin + PegIFN (12 week)
 Cirrhotics
1. SOFOSBUVIR + LEDIPASVIR (12 WEEK)
2. Sofosbuvir + Ribavirin + PegIFN (12 week)

74. DRUG INTERACTIONS
 Sofusbivir
1. Amiodarone : serious bradycardia
 Daclatasvir
1. CYP450 Inducers : Increase dose from 90mg to higher
2. CYP450 Inhibitors : Reduce dose to 30mg

75. Cost of HCV Treatment ?

76. Cost  Boceprevir : Rs 70000 / week
 Telaprevir : Rs 2,66,000 / week
Drug Dollars INR
Simeprevir Per 150mg Capsule $790 51,000
28 Days Simeprevir $22120 14,40,000
12-week Supply Of Simeprevir $66360 43,21,064
Simeprevir When Used With A Total Of 24-
weeks Of Peginterferon Plus Ribavirin
$85,000 55,34,817
Simeprevir Plus Sofosbuvir For 12 Week $150000 97,67,325

77. Wholesale acquisition cost (WAC)
for LEDIPASVIR-SOFOSBUVIR
Drug Dollar INR
Per Pill $1125 73,254
8-week course of
therapy
$63000 41,02,276
12-week course of
therapy
$94000 61,20,857
24-week course of
therapy
$189000 1,23,06,829

79. VACCINE

81. References
 Sherlock’s Diseases Of The Liver And Biliary System
 Harrison's Principles Of Internal Medicine
 AASLD Guidelines 2016
 EASL Guidelines 2017
 Preventive And Social Medicine By Park
 Nelson’s Text Book Of Paediatrics
 Text Book Of Microbiology By Apurba Shastry
 Medguideindia.com - Internet