Hepatitis C is a major global public health problem that infects approximately 180 million people worldwide. It is a leading cause of liver disease and death, with more than 350,000-500,000 people dying each year from hepatitis C related liver disease. The virus predominantly causes chronic infection in 70-85% of cases and can lead to cirrhosis, liver failure, and hepatocellular carcinoma over time if left untreated. New direct acting antiviral regimens have revolutionized treatment and now offer cure rates over 95% with shorter, better tolerated courses of therapy.

1. Hepatitis C
Dr Avatar Verma
MD Resident
CMSTH

2. Global Burden of Hepatitis C
•Hepatitis C is major public health problem worldwide
•About 180 million people are infected with hepatitis C virus
•It account for 3 percent of global population
•3-4 million people become infected with HCV annually
•About 25 million people are infected in Europe
•HCV prevalence 5 times exceeds HIV prevalence

3. Global Burden of Hepatitis C
•More then 350 000-500 000 people die every year from Hepatitis C
related end-stage liver disease (cirrhoses, HCC, liver failure)
•Hepatitis C infection is top priority problem in many African countries (as
high as 14.5% in Egypt ) and Asian countries ie. India (1.5%), Japan
(1.2%), Malaysia (2.3%), and Philipines (2.3%)

4. • Hepatitis C virus before its identification was labeled “non-A, non-B
hepatitis,”
• Linear, single-strand, positive-sense, 9600-nucleotide RNA virus
• Only member of the genus Hepacivirus in the family Flaviviridae
• Genome contains a single, large open reading frame (gene) that
codes for virus polyprotein of ~3000 amino acids, which is cleaved
after translation to yield 10 viral proteins

8. • At least six distinct major genotypes (and a minor genotype 7), as
well as >50 subtypes within genotypes, of HCV have been identified
by nucleotide sequencing
• Genotypes differ from one another in sequence homology by ≥30%,
and subtypes differ by approximately 20%
• Because divergence of HCV isolates within a genotype or subtype
and within the same host may vary insufficiently to define a distinct
genotype, these intragenotypic differences are referred to as
quasispecies
• The genotypic and quasispecies diversity of HCV, resulting from its
high mutation rate, interferes with effective humoral immunity
• Neutralizing antibodies to HCV have been demonstrated, but they
tend to be short lived, and HCV infection does not induce lasting
immunity against reinfection with different virus isolates or even the
same virus isolate

9. • Thus, neither heterologous nor homologous immunity appears to
develop commonly after acute HCV infection
• Some HCV genotypes are distributed worldwide, whereas others are
more geographically confined
• In addition, differences exist among genotypes in responsiveness to
antiviral therapy but not in pathogenicity or clinical progression
(except for genotype 3, in which hepatic steatosis and clinical
progression are more likely)

11. HCV genotype distribution

12. Pathogenesis
• The virus replicates mainly in the hepatocytes of the liver, where it
is estimated that daily each infected cell produces approximately
fifty virions (virus particles)
• The virus may also replicate in peripheral blood mononuclear cells,
potentially accounting for the high levels of immunological
disorders found in chronically infected HCV patients

13. • To enter the host cell, HCV E2 and E1 proteins recognize and bond
with the CD81 receptors present on the surface of hepatocytes and
lymphocytes
• HCV enters cell through endocytosis
• In the cytoplasm, the messenger RNA then undergoes translation,
and polyproteins are processed;
• HCV RNA then replicates, after which the new viral 'RNA's are
packaged and transported to the surface of the host cell so that they
can disseminate and complete a new cycle

16. Transmission routes of HCV
Transfussion of infected blood or its products, using nonsterile syringes,
needles and medical instruments, transplantation of infected donor organs
or tissues, occupational exposure with infected blood
Parenteral
Risk of sexual transmission of HCV is very low. In monogamous partners
about 2%. The risk is higher among persons having multiple sexual partners
about 4-6% (commercial sex workers, men who have sex with men etc.)
Sexual
Mother to child
Chance of Vertical transmission of HCV is about 5-7 %. The risk is
increased if HCV viral load in mother’s blood is high
HCV is not transmitted by air, droplets, vectors or from animals.

17. Acute HCV
Asymptomatic
75%
Without Jaundice
Jaundice
recovery
10%? ? ?
Chronic Infection
70-85%
Recovery
50%-52%
Symptomatic
25%
recovery
15-30%
Natural History

18. Natural history of Hepatitis C
Acute HCV Infection
60-85 % Persistent infection15-40%
Recovery
20-40%
cirrhoses
4-5%
HCC

19. Why HCV infection is predominantly chronic?
• HCV has ability to “escape” immune response of the host
• HCV is characterized by rapid and permanent changes in its
antigenic structure; antigenic structure changes occur multiple times
per minute variability of this virus makes T and B lymphocytes
unable to identify and respond to these permanently changed
antigens
• Antigenic variations of HCV in the same host is called
(quasispecies), number of such quasispecies reaches about 1010 –
1011 per day
• Due to variability of HCV “Time competition” between new
antigenic strains and the speed of neutralizing antibodies develops

20. Clinical Manifestations
• Incubation period: 15–160 days (mean, 7 weeks)
• Constitutional symptoms of anorexia, nausea and vomiting, fatigue,
malaise, arthralgias, myalgias, headache, photophobia, pharyngitis, cough,
and coryza may precede the onset of jaundice by 1–2 weeks
• Dark urine and clay-colored stools may be noticed by the patient from 1–5
days before the onset of clinical jaundice

21. • With the onset of clinical jaundice, the constitutional prodromal
symptoms usually diminish, but in some patients, mild weight loss
(2.5–5 kg) is common and may continue during the entire icteric phase
• The liver becomes enlarged and tender and may be associated with
right upper quadrant pain and discomfort
• Infrequently, patients present with a cholestatic picture, suggesting
extrahepatic biliary obstruction
• Splenomegaly and cervical adenopathy are present in 10–20% of
patients with acute hepatitis
• Rarely, a few spider angiomas appear during the icteric phase and
disappear during convalescence
• During the recovery phase, constitutional symptoms disappear, but
usually some liver enlargement and abnormalities in liver biochemical
tests are still evident

22. • The duration of the posticteric phase is variable, ranging from 2–12
weeks, and is usually more prolonged
• Complete clinical and biochemical recovery is to be expected 3–4
months after the onset of jaundice in three-quarters of
uncomplicated cases
• Hepatitis C is self limited in only ~15%
• Chronic hepatitis is generally present as fatigue otherwwise are
assymptomatic and slowly progressive well compensated untill
signs of decompensation occurs

23. Laboratory Features
• Complete Blood count
 Transient neutropenia and lymphopenia followed by lymphocytosis
• Deranged liver function test
 Increased transaminase mostly ALT
 Increase in both conjugated and uncojugated bilirubin fractions
 Mild increase in ALP and γ globulin
 Raised PT

24. • During acute phase, antibodies to smooth muscle and other cell
constituents may be present, and low titers of RF, nuclear antibody, and
heterophile antibody can also be found
• Antibodies to LKM may occur; however, the species of LKM is
different from LKM characteristic of autoimmune hepatitis type 2
• The presence of anti-HCV supports a diagnosis of acute hepatitis C
• Occasionally, testing for HCV RNA or repeat anti-HCV testing later
during the illness is necessary to establish the diagnosis
• Anti-HCV supports and HCV RNA testing establishes the diagnosis of
hepatitis C

25. Interpretation of HCV Assays
Anti HCV HCV RNA Interpretation
Positive Positive Acute or chronic HCV depending on the clinical context
Positive Negative Resolution of HCV; Acute HCV during period of low-level
viremia.
Negative Positive Early acute HCV infection; chronic HCV in setting of
immunosuppressed state; false positive HCV RNA test
Negative Negative Absence of HCV infection
25

28. Complications
• Hepatitis C is less severe during the acute phase than hepatitis B and
is more likely to be anicteric
• Chronic hepatitis is more likely in older age, longer duration of
infection, advanced histologic stage and grade, more complex
quasispecies diversity, increased hepatic iron, concomitant other
liver disorders (alcoholic liver disease, chronic hepatitis B,
hemochromatosis, α1 antitrypsin deficiency, and steatohepatitis),
HIV infection, and obesity
• Cirrhosis (20% within 10–20 years of acute illness) accelerated by
concomitant HIV infection, other causes of liver disease, excessive
alcohol use, and hepatic steatosis

29. • Hepatocellular carcinoma in cirrhotic patients with hepatitis C is
1−4%, in patients who have had HCV infection for 30 years or more
• EMC (Essential mixed cryoglobulinemia) is an immune-complex
disease that can complicate chronic hepatitis C and is part of a
spectrum of B cell lymphoproliferative disorders
• Cutaneous vasculitis and membranoproliferative glomerulonephritis
as well as lymphoproliferative disorders such as B-cell lymphoma
and unexplained monoclonal gammopathy

30. • Sjogren’s syndrome, lichen planus, porphyria cutanea tarda, type 2
diabetes mellitus, and the metabolic syndrome (including insulin
resistance and steatohepatitis)

31. Definition of responses
• Rapid virological response (RVR)
– HCV RNA negative at treatment week 4 by a sensitive PCR based
quantitative assay
• Early virological response (EVR)
– ≥2 log reduction in HCV RNA level compared to baseline HCV RNA
level (partial EVR) or HCV RNA negative at treatment week 12
(complete EVR)
• End-of-treatment response (ETR)
– HCV RNA negative by a sensitive test at the end of treatment
31

32. • Sustained virological response (SVR)
– HCV RNA is undetectable at the end of treatment and remains
undetectable 24 weeks after completion of treatment
• Breakthrough
– On-treatment presence of detectable HCV RNA on 2 consecutive
serum tests conducted after a previous on-treatment serum test
showed an undetectable level of HCV RNA
• Relapsers
– Virological response occurred; the patient became HCV RNA
undetectable, and remained negative through the end of treatment,
but relapse occurred after discontinuation of treatment.
32

33. • Nonresponder
– Patient who never achieved an undetectable of HCV RNA during or
at the end of treatment.
• Null responder
– Failure to decrease HCV RNA by 2 logs after 12 week of therapy
• Partial responder
– Two log decrease in HCV RNA but still HCV RNA positive at
week 24
• Slow responder
– During treatment, the HCV RNA shows a decline, but does not
become negative until after 12 weeks of treatment
33

34. Virologic responses during a 48-week course of antiviral therapy in patients with
hepatitis C, genotype 1 or 4 (for genotypes 2 or 3, the course would be 24 weeks).
34

35. Treatment
• SVR= Cure
• Till 2001 to 2011 standard of care dual therapy with PEG-Interferon
+ Ribavirin
• In 2011 DAA (direct acting antiviral) were introduced Telaprevir
and Boceprevir
• Direct-acting antivirals (DAAs), are medications targeted at specific
steps within the HCV life cycle
• DAAs are molecules that target specific nonstructural proteins of the
virus and results in disruption of viral replication and infection

36. HCV Life Cycle and DAA Targets
Adapted from Manns MP, et al. 2007
Transport
and release
(+) RNA
Translation and
polyprotein
processing RNA replication
Virion
assembly
NS3/4A protease
inhibitors
NS5B polymerase
inhibitors
NS5A inhibitors
“Previr’s”
Boceprevir, Telaprevir, Simeprevir, Faldaprevir
“Buvir’s”
Sofosbuvir, Deleobuvir
“Asvir’s”
Daclatasvir, Ledipasvir
DAA
Uncoating
Receptor binding

37. Recommended Assessments Prior to Starting
Antiviral Therapy
• Staging of hepatic fibrosis is essential prior to HCV treatment
• Following laboratory tests are recommended within 12 weeks prior
to starting antiviral therapy:
 Complete blood count (CBC)
 INR
 Hepatic function panel (albumin, total and direct bilirubin, alanine
aminotransferase, aspartate aminotransferase, and alkaline
phosphatase levels)
 Calculated glomerular filtration rate (GFR)
 Thyroid-stimulating hormone (TSH) if IFN is used

38. • The following laboratory testing is recommended at any time prior
to starting antiviral therapy:
 HCV genotype and subtype
 Quantitative HCV RNA (HCV viral load)
• Patients scheduled to receive an HCV NS3 protease inhibitor
(previr) assessed for history of decompensated liver disease and for
severity of liver disease using CTP score.
• Patients with current or prior history of decompensated liver
disease or with a current CTP score of 7 or greater should NOT
receive treatment with regimens that contain NS3 protease
inhibitors due to lack of safety data
• Similarly, CTP score of 5 or 6, who cannot be closely monitored for
during treatment, should not receive paritaprevir/ritonavir

39. • All patients initiating HCV DAA therapy should be assessed for
HBV coinfection with HBsAg, anti-HBs, anti-HBc and for
resistance-associated variants (RAV)

40. Treatment regimens
EASL 2016

41. PATIENTS WITH DECOMPENSATED
CIRRHOSIS
• Patients with HCV genotype 1 or 4 infection who have
decompensated cirrhosis (moderate or severe hepatic impairment;
CTP class B or C) who may or may not be candidates for liver
transplantation, including those with hepatocellular carcinoma
 Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400
mg) with low initial dose of ribavirin (600 mg, increased as
tolerated) for 12 weeks
 Daily fixed-dose combination of sofosbuvir (400 mg)/velpatasvir
(100 mg) with weight-based ribavirin| for 12 weeks
 Daily daclatasvir (60 mg) plus sofosbuvir (400 mg) with low initial
dose of ribavirin (600 mg, increased as tolerated) for 12 weeks

42. • Genotype 1 or 4 patients with decompensated cirrhosis who are
ribavirin Ineligible or prior sofosbuvir-based treatment has failed
 Daily fixed-dose combination of sofosbuvir (400 mg)/velpatasvir
(100 mg) for 24 weeks
 Daily daclatasvir (60 mg) plus sofosbuvir (400 mg) for 24 weeks
 Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400
mg) for 24 weeks

43. • HCV genotype 1 or 4 infection who have decompensated cirrhosis
or prior sofosbuvir-based treatment has failed
 Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400
mg) with low initial dose of ribavirin (600 mg, increased as
tolerated) for 24 weeks
 Daily fixed-dose combination of sofosbuvir (400 mg)/velpatasvir
(100 mg) with weight-based ribavirin|| for 24 weeks

44. • HCV genotype 2 or 3 infection who have decompensated cirrhosis
(moderate or severe hepatic impairment; CTP class B or C) and who
may or may not be candidates for liver transplantation, including
those with hepatocellular carcinoma
 Daily fixed-dose combination sofosbuvir (400 mg)/velpatasvir (100
mg) with weight-based ribavirin for 12 weeks
 Daily daclatasvir (60 mg*) plus sofosbuvir (400 mg) with low initial
dose of ribavirin (600 mg, increased as tolerated) for 12 weeks

45. • In patients with renal impairment
• For patients with mild to moderate renal impairment (CrCl 30
mL/min-80 mL/min), No dosage adjustment is required when
using
 Daclatasvir (60mg*),
 Fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400
mg), Sofosbuvir (400mg)/velpatasvir (100mg), or paritaprevir (150
mg)/ritonavir (100 mg)/ombitasvir (25 mg) with twice-daily dosed
dasabuvir (250 mg), simeprevir (150 mg), or sofosbuvir (400 mg)
to treat or retreat HCV infection in patients with appropriate
genotypes

46. Creatinine clearance [crcl] <30 ml/min) or end-stage renal disease
(ESRD) for whom treatment has been elected before kidney
transplantation:
• Genotype 1a, or 1b, or 4
 Daily fixed-dose combination of elbasvir (50 mg)/grazoprevir
(100mg) for 12 weeks
• Genotype 1b
 Daily fixed-dose combination of paritaprevir (150 mg)/ritonavir (100
mg)/ombitasvir (25 mg) plus twice-daily dosed dasabuvir (250 mg)
for 12 weeks
• Genotype 2, 3, 5, or 6
 PEG-IFN and dose-adjusted ribavirin (200 mg daily)

47. HIV coinfection
• Daclatasvir requires dose adjustment with ritonavir-boosted atazanavir (a
decrease to 30 mg daily) and efavirenz or etravirine (an increase to 90 mg
daily)
• Elbasvir/grazoprevir and Simeprevir should be used with antiretroviral drugs
with which it does not have clinically significant interactions: abacavir,
emtricitabine, enfuvirtide, lamivudine, maraviroc, raltegravir, dolutegravir,
rilpivirine, and tenofovir
• Daily fixed-dose combination of Sofosbuvir/Velpatasvir (100 mg) or
Ledipasvir (90 mg)/Sofosbuvir (400 mg) can be used with most
antiretrovirals, but not efavirenz or etravirine
• Tenofovir alafenamide (TAF) may be an alternative to TDF treatment for
patients who take cobicistat or ritonavir as part of their antiretroviral therapy

48. Recommended Follow-up for Patients Who
Achieve a Sustained Virologic Response (SVR)
• For patients who do not have advanced fibrosis (ie, those with Metavir
stage F0-F2), recommended follow-up is the same as if they were never
infected with HCV
• In such cases, a quantitative HCV RNA assay rather than an anti-HCV
serology test is recommended to test for HCV recurrence or reinfection
• Surveillance for hepatocellular carcinoma with twice-yearly ultrasound
examination is recommended for patients with advanced fibrosis (ie,
Metavir stage F3 or F4) who achieve an SVR

49. • A baseline endoscopy is recommended to screen for varices if cirrhosis
is present. Patients in whom varices are found should be treated and
followed up as indicated
• Assessment of other causes of liver disease is recommended for
patients who develop persistently abnormal liver tests after achieving
an SVR

50. Concomitant HBV infection
• For HBsAg+ patients who are not already on HBV suppressive
therapy, monitoring of HBV DNA levels during and immediately
after DAA therapy for HCV is recommended and antiviral treatment
for HBV should be given if treatment criteria for HBV are met

51. Liver transplantation
• Recommended for patients with end stage cirrhosis
• Chronic hepatitis C and alcoholic liver disease are the most
common indications for liver transplantation, accounting for
over 40%
• Recurrence of hepatitis C virus (HCV) following orthotopic
liver transplantation (OLT) occurs in more than 95 percent of
patients

52. PATIENTS WHO DEVELOP RECURRENT
HCV INFECTION POST-LIVER
TRANSPLANTATION
• Genotype 1 or 4 Infection in the Allograft, Including Those with
Compensated Cirrhosis
 Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400
mg) with weight-based ribavirin for 12 or Daily daclatasvir (60 mg)
plus sofosbuvir (400 mg) with low initial dose of ribavirin (600 mg,
increased as tolerated) for 12 weeks
• Decompensated cirrhosis
• Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400
mg) with low initial dose of ribavirin (600 mg, increased as
tolerated) for 12 weeks

53. • Genotype 2 or 3 Infection in the Allograft, Including Those with
Compensated Cirrhosis
 Daily daclatasvir (60 mg) plus sofosbuvir (400 mg), with low initial
dose of ribavirin (600 mg, increased as tolerated) for 12 weeks or
Daily sofosbuvir (400 mg) and weight-based ribavirin for 24 weeks
• Decompensated cirrhosis
 Daily sofosbuvir (400 mg) and ribavirin (initial dose 600 mg/day,
increased monthly by 200 mg/day as tolerated to weight-based dose)
for 24 weeks