This document provides an overview of Hepatitis C. It begins with an introduction stating that over 71 million people worldwide are chronically infected with HCV. It then covers the virology of HCV including its structure, genome, replication cycle, genotypes/quasispecies. The epidemiology section discusses the global prevalence and incidence. Pathogenesis outlines how HCV evades the immune system to cause chronic infection. Clinical features are separated into acute hepatitis C and chronic hepatitis C. Extrahepatic manifestations associated with HCV are also summarized.

1. Hepatitis C
Presenter:
Dr.Melaku Y.(IMR3)
Moderator:
Dr.Geda Lelisa (Internist,
Gastroenterologist and Hepatologist)
May,2022

2. Outline
Introduction
Virology
Epidemiology
Pathogenesis
Clinical Features
Diagnosis
Liver biopsy and Non-invasive assessment of
fibrosis
Natural History
Treatment
6/9/2022 2

3. Introduction
More than 71 million people worldwide are
chronically infected with HCV (WHO,2015)
399 000 Deaths from cirrhosis or hepatocellular
carcinoma caused by HCV infection.
HCV successfully evades the host immune
response in 50% to 90% of acutely infected
persons
Complications of HCV-related cirrhosis remain a
leading indication for LT in the USA and Europe.
6/9/2022 3

4. Introduction
6/9/2022 4
N Engl J Med 2019;380:2041-50

5. Introduction
6/9/2022 5
N Engl J Med 2019;380:2041-50

6. Virology
Structure:
 The HCV virion is an enveloped virus that is 50 nm in
diameter
 The 2 envelope proteins, E1 and E2, heterodimerize and
assemble into tetramers icosahedral symmetry
 The envelope proteins are anchored to a host cell–derived
lipid bilayer envelope membrane
 The nucleocapsid is believed to be composed of multiple
copies of the core protein and forms an internal icosahedral
viral coat
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7. 6/9/2022 7

8. Virology…
Genomic organization:
 HCV is a single-stranded positive-sense RNA virus that belongs to the
Flaviviridae family member of the genus Hepacivirus
 The genome of HCV contains approximately 9600 nucleotides with an
open reading frame (ORF)
 The HCV ORF is flanked upstream by a 5′ untranslated region (UTR)
that functions as an internal ribosome entry site and by a 3′ UTR that is
critical for initiation of new RNA strand synthesis.
 The 5′ and portions of the 3′ UTR are the most conserved regions of
the HCV genome.
6/9/2022 8

9. Virology…
Viral Replication and Life Cycle:
 HCV entry involves the attachment of envelope proteins E1
and E2 to cell surface molecules
 The expression and function of CD81 and human scavenger
receptor are essential for HCV entry into hepatocytes
 Once HCV attaches to the cell, endocytosis of the bound
virion is presumed to occur
 A pH drop in the vesicle causes conformational changes in
the glycoproteins.
6/9/2022 9

10. Virology…
Viral Replication and Life Cycle:
 11 viral proteins, including both structural and nonstructural
proteins
 HCV replication is catalyzed by the NS5B RNA-dependent
RNA polymerase (RdRp)
 The positive-strand genomic RNA serves as a template for
the synthesis of a negative-strand intermediate
 The negative-strand RNA serves as a template for
production of numerous strands of RNA of positive polarity
6/9/2022 10

11. Virology…
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12. 6/9/2022 12

13. 6/9/2022 13

14. Virology…
Viral Protein Function:
 E1 and E2 proteins:
Form highly glycosylated heterodimers and then tetramers that
are essential for viral assembly.
Mediate cell entry by binding to surface receptors.
Responsible for fusion between the host cell membrane and the
viral envelope.
They are targets of host antibodies.
The first 27 amino acids of E2 form hypervariable region 1
(HVR1)
6/9/2022 14

15. Virology…
Viral Protein Function:
P7 protein:
 Cleaved by ER signal peptidase and forms an ion
channel.
 This viroporin protein is essential for efficient
assembly and release of infectious virions but not
for cell entry.
6/9/2022 15

16. Virology…
Viral
Protein
Function
NS2 Complexes with NS3 to form a cysteine protease
NS3  Functions as serine protease
portion of the NS3 protein functions as a helicase
NS4A complexes with NS3 and functions to stabilize the protease and
helicase
NS4B Membranous Web formation
NS5A Essential for viral replication and is believed to provide an RNA-
binding site within the replication complex
NS5B RNA dependent RNA Polymerase
6/9/2022 16

17. Virology…
Genotypes and Quasispecies:
 HCV has an inherently high mutational rate that results in
considerable heterogeneity throughout the genome.
 This high mutational rate is in part a consequence of the RdRp
of HCV, which lacks 3′- to 5′-exonuclease proofreading ability
 An average of one error occurs for every 104 to 105
nucleotides copied.
 This phenomenon is favored by a high viral turnover rate; 1010
to 1012 virions are produced per day.
6/9/2022 17

18. Virology…
Genotypes and Quasispecies:
 Nucleotide sequencing has shown variation of up to
34% between genotypes
 The most conserved region (5′ UTR) has a maximum
nucleotide sequence divergence of 9%
 The sequences cluster into 7 major genotypes 60% to
70% and
 More than 67 subtypes within these major genotypes,
with sequence similarities of 77% to 80%.
6/9/2022 18

19. Virology…
Genotype Geographic Distribution
1a USA,Europe
1b USA,Europe
1c USA,Europe
2 USA
3 Europe,USA
4 Middle East,Egypt,Central Africa
5 South Africa, Europe(France and Belgium),Middle East(Lebanon and
Syria)
6 Predominantly in Asia
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20. 6/9/2022 20
Source: The Polaris
Observatory HCV
Collaborators

21. Virology…
6/9/2022 21

22. Virology…
Genotypes and Quasispecies:
 Quasispecies are closely related, yet heterogeneous, sequences of HCV
RNA within a single infected person that result from mutations that
occur during viral replication
 The rate of nucleotide changes varies significantly among the different
regions of the viral genome
 The highest proportion of mutations are found in the E1 and E2
regions, particularly in HVR1
 The development of quasispecies may be one mechanism by which the
virus escapes the host’s immune response and establishes persistent
infection.
6/9/2022 22

23. 6/9/2022 23

24. Virology…
Genotypes and Quasispecies:
 In acute disease, patients in whom genetic variation in
the HVR1 region develops after antibody
seroconversion progress to chronic disease
 Quasispecies formation results from antibody-mediated
immune pressure
 An increased number of quasispecies has also been
associated with more rapid progression to cirrhosis and
the development of HCC
6/9/2022 24

25. Epidemiology
Incidence and Prevalence:
 The worldwide prevalence of HCV infection, based on
detection of HCV RNA in serum, is estimated to be 1%,
with more than 71 million people infected chronically.
 The highest seroprevalence in different age groups shifted
from 35 to 44 years (2.5%) to 55 to 64 years in 2005 (2.7%)
 The prevalence is higher in males (2.1%) than in females
(1.1%), and in African Americans (3%) than in whites
(1.5%).
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26. 6/9/2022 26

27. 6/9/2022 27

28. 6/9/2022 28

29. Epi…
Worldwide, 3 different epidemiologic patterns of
HCV infection have emerged:
Previous exposure through health care with a peak
prevalence in older persons
Exposure through injection drug use, the major risk
factor since data first became available in about 1960,
with a peak prevalence among middle-aged persons;
and
Ongoing high levels of infection in areas where high
rates of infection occur in all age groups.
6/9/2022 29

30. Epi…
Transmission:
Percutaneous transmission
 Blood transfusion
 Needlestick inocculation
Non Percutaneous transmission
 Sexual contact
 Perinatal exposure
Sporadic HCV infection
6/9/2022 30

31. Pathogenesis
Determinants of persistence of HCV include:
 Inadequate induction of the innate immune response
 Insufficient induction or maintenance of an adaptive
immune response
 The production of viral quasispecies and
 The induction of immunologic tolerance or
exhaustion.
6/9/2022 31

32. Patho…
 Chronic hepatitis develops in 50% to 90% of persons with
acute HCV infection
 In the minority of patients in whom acute HCV resolves
spontaneously
 This response can be detected up to 20 years after
resolution of infection
 Immune response is essential in preventing viral
persistence, in those without viral clearance the immune
response mediates hepatic cell destruction and fibrosis.
6/9/2022 32

33. Patho…
Viral Mechanisms:
In chronically infected patients, the pathogenesis
of liver damage is largely immune mediated.
In a small subset of immunocompromised HCV-
infected patients a syndrome termed fibrosing
cholestatic hepatitis develops
The majority of patients with HCV infection have
a variable immune response
6/9/2022 33

34. Patho…
Immune-Mediated Mechanisms:
 HCV infection elicits an immune response involves both
innate and adaptive immunity
 The innate response includes natural killer (NK) cell
activation and cellular antiviral mechanisms triggered by
PAMPs recognized by the cell
 These processes can lead to apoptosis of infected cells
within the first few hours of infection
 NK cells, as the effector cells of the innate immune system,
also produce TNF-β and IFN-α
6/9/2022 34

35. Patho…
Immune-Mediated Mechanisms:
 NK cell function is slowed because of production of cytokines are
interrupted when the HCV E2 protein binds its cellular receptor
CD81
 PAMPs activate several cellular processes, including the JAK-STAT
(Janus kinase‒signal transducer and activator of transcription)
proteins pathway and Toll-like receptor-3
 NS3/4 protease
 Degrades TRIF, an essential intermediate in this pathway, and
 Cleaves IFN promoter stimulator-1, an intermediate in the signaling
cascade, to block activation of IFN when retinoic inducible gene-1
binds viral intermediates.
6/9/2022 35

36. Patho…
Immune-Mediated Mechanisms:
 NS5A and E2 both can disrupt protein kinase R
function to suppress translation, thereby allowing viral
replication to continue.
 NS5A inhibits 2′-5′-oligoadenylate synthetase, which is
expressed in response to HCV infection and leads to
HCV RNA degradation.
 Taken together, HCV is able to disrupt the innate
immune response at several levels, thereby establishing
chronicity of infection.
6/9/2022 36

37. Patho…
Immune-Mediated Mechanisms:
 Cellular immune response plays a pivotal role in the
pathogenesis of HCV infection, the importance of the
humoral immune response is less clear
 Antibodies to viral proteins are produced and do not appear
to correlate with the stage of infection or immune reactivity
 Administration of high-titer HCV-enriched or HCV-specific
Ig has little effect on viral levels or persistence in humans.
 Both the virus and the immune response probably play a
role in the development of hepatocellular injury.
6/9/2022 37

38. Clinical Features
Acute Hepatitis C :
 HCV accounts for an estimated 20% of cases of acute hepatitis
 Within 7 to 21 days after viral transmission, HCV RNA becomes
detectable in serum
 HCV RNA levels rise rapidly in serum, followed by a delayed
increase in serum ALT levels 4 to 12 weeks, indicative of hepatic
injury
 Serum ALT levels frequently reach values more than 10x, with
concomitant rises in the serum bilirubin level in some inidividuals
6/9/2022 38

39. Clinical…
6/9/2022 39
www.cdc.gov/hepatitis/Resources/Professionals/Traini
ng/Serology/training.htm

40. Clinical…
Acute Hepatitis C :
 Commonly reported symptoms include fatigue, nausea, abdominal pain,
loss of appetite, mild fever, itching, and myalgia
 Jaundice, which is the most specific liver-related symptom, develops in
50% to 84% of patients with clinically overt acute HCV infection
 Clinical course apparent and the more severe when acute HCV
infection occurs in patients who drink large amounts of alcohol or have
coinfection with HBV or HIV
 Age and gender clearly influence the risk of chronicity, with younger
and female patients having the lowest rates of chronicity.
6/9/2022 40

41. Clinical…
Acute Hepatitis C :
 Other factors that may play a role include the
 Source of infection and size of inoculum
Immune status of the host
The patient’s race
 The rate of spontaneous clearance is higher in symptomatic
patients
 Single nucleotide polymorphisms (SNPs) close to the IFN
lambda-3, or interleukin 28B, gene (IFN-λ3, IL28B) have
been found to be associated with the outcome of acute
hepatitis C.
6/9/2022 41

42. Clinical…
Chronic Hepatitis C:
 Serum ALT levels are usually elevated in patients with chronic HCV
infection
 The ALT level may remain normal for prolonged periods of time in about
20% of cases, although transient elevations occur even in these cases
 Persistently normal ALT levels are more common in women, and such
cases typically are associated with lower serum HCV RNA levels
 Most patients with chronic hepatitis C are asymptomatic before the onset of
advanced hepatic fibrosis
 Patients often complain of nonspecific symptoms such as fatigue, vague
abdominal pain, or depression, and they consistently score lower than HCV
negative in HRQOL
6/9/2022 42

43. Clinical…
Extrahepatic Manifestations:
 Types 2 and 3 cryoglobulinemia,
 Characterized by polyclonal IgG plus monoclonal IgM and polyclonal IgG plus
polyclonal IgM, respectively
 Among HCV-infected patients, 19% to 50% have cryoglobulins in serum
 Clinical manifestations of cryoglobulinemia are reported in only 5% to 10% of
these patients
 Symptoms and signs include fatigue, arthralgias, arthritis, purpura, Raynaud
phenomenon, vasculitis, peripheral neuropathy, and nephropathy
 The diagnosis is clear when a rheumatoid factor is detected, cryoglobulins are
present, and complement levels are low in serum
6/9/2022 43

44. Clinical…
Extrahepatic Manifestations:
 Treatment of the underlying HCV infection should be
considered in patients with symptomatic
cryoglobulinemia.
 Consensus guidelines recommend treatment of
extrahepatic manifestations with IFN-free DAA
regimens
 In addition,monoclonal antibody therapy targeting B
cells (anti-CD20 therapy with rituximab) has been
shown to be useful for HCV-related cryoglobulinemia,
6/9/2022 44

45. Clinical…
Extrahepatic Manifestations:
Patients with vasculitis due to HCV infection may
benefit from low-dose interleukin-2 therapy
Type 2 cryoglobulinemia evolves into lymphoma
over time in 8% to 10% of patients
HCV shows lymphotropism and may facilitate the
development and selection of abnormal B-cell
clones by chronic stimulation of the immune
system.
6/9/2022 45

46. Clinical…
Extrahepatic Manifestations:
Seropositivity for autoantibodies
ANA with a titer greater than 1:40 in 9%,
ASMA with a titer greater than 1:40 in 20%,
LKM abs in 6%
The diagnosis of an autoimmune condition in a
patient with HCV infection can never be based
on serology alone.
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47. 6/9/2022 47
N Engl J Med 2021;384:1038-52. D

48. 6/9/2022 48

49. Clinical…
6/9/2022 49

50. Diagnosis
Indirect Assays
Direct Assays
Genotype Testing
6/9/2022 50

51. Dx…
Indirect Assays:
 EIAs detect antibodies against different HCV antigens
 The third-generation EIAs detect antibodies against HCV
core, NS3, NS4, and NS5 antigens as early as 7 to 8 weeks
after infection
 Despite ongoing viral replication, serologic test results can
be negative in patients who are on hemodialysis or are
immunocompromised
 Instead, patients who are anti-HCV positive should undergo
HCV RNA testing to determine if they have active viremia
or have cleared the infection.
6/9/2022 51

52. Dx…
Direct Assay:
 Quantitative, highly sensitive, “real-time” HCV RNA tests represent
the state of the art for determining HCV viremia in antiHCV–
positive persons
 The lower limit of detection of most assays varies from 10 to 15
international units (IU)/mL
 Transcription-mediated amplification is also extremely sensitive, but
available assays are not quantitative in the lower dynamic range of
the test:
 Positivity within 1 to 3 weeks after acute infection and
 Detection of low-level residual infection during antiviral therapy.
6/9/2022 52

53. Dx…
Direct Assay…
Although conversion to a standard IU/mL
concentration attempted to resolve such
discrepancies, results are still variable
Reported conversion factors vary from 0.9
copies/mL to 5.2 copies/mL per IU/mL
For this reason, the same laboratory and assay
are recommended during antiviral treatment
monitoring
6/9/2022 53

54. Dx…
Direct Assay:
A cheaper and faster alternative to nucleic acid
testing for HCV RNA to confirm HCV viremia is
the HCV core antigen assay.
The assay cannot be used to monitor response to
antiviral therapy and make decisions regarding
therapy
 If viremia needs just to be confirmed, however,
HCV core antigen testing is a reasonable
alternative to HCV RNA testing
6/9/2022 54

55. Dx…
HCV genotype:
 Some DAA regimens are only recommended for certain
HCV genotypes and subtypes.
 HCV genotyping can be accomplished by several
methods.
 The most accurate approach uses PCR methodology
and direct sequencing of the NS5B or E1 region
 HCV genotyping can be performed by evaluating type-
specific antibodies (90% concordance in
immunocompetent patients).
6/9/2022 55

56. Dx…
HCV genotype:
 Testing can also be accomplished with
reverse hybridization to genotype-specific probes,
restriction fragment length polymorphism analysis, or
 PCR amplification of the 5′ noncoding region of the HCV
genome.
 These tests have 92% to 96% concordance with the correct
genotype; genotype 1 is identified with the highest accuracy.
 A line-probe assay (INNO-LiPA) using genotype-specific
probes for reverse transcription of the 5′ portion of the HCV
genome is the most popular commercial assay for HCV
genotyping.
6/9/2022 56

57. Dx…
6/9/2022 57
AASLD/IDSA and CDC

58. Dx…
6/9/2022 58
AASLD/IDSA and CDC

59. Dx…
6/9/2022 59
https://ww
w.hcvguidel
ines.org/ref
erences/cd
c-2013

60. Non Invasive Assesment of Fibrosis
Assessment of the degree of liver injury is
recommended in all patients with HCV infection.
For many years, this assessment was performed by
percutaneous liver biopsy but noninvasive
methods are now used for initial assessment of
liver fibrosis stage
Several histologic scoring systems have been used
to quantify hepatic injury into discrete grades of
inflammation and stages of fibrosis.
6/9/2022 60

61. Non Invasive…
 The first system used was the Histology Activity
Index described by Knodell and colleagues.
periportal inflammation and necrosis (graded as 0 to 10),
 lobular inflammation and necrosis (0 to 4),
portal inflammation (0 to 4),
fibrosis (0 to 4).
 This scoring system combines inflammation and
fibrosis into one score.
6/9/2022 61

62. Non Invasive…
Scheuer created a simplified scoring system
that separates grade of inflammation from
stage of fibrosis:
portal inflammation and interface hepatitis (0 to 4),
lobular activity (0 to 4), and
 fibrosis stage (0 to 4).
6/9/2022 62

63. Non Invasive…
The Ishak system is a modification of Knodell’s
system
 Ishak’s fibrosis scores range from 0 to 6
1 or 2( portal fibrotic expansion)
3 or 4( bridging fibrosis)
5 or 6 (cirrhosis)
The higher number of stages of fibrosis has made
the Ishak system popular for scoring progression
of fibrosis in clinical trials.
6/9/2022 63

64. Non Invasive…
The METAVIR scoring system is the most
popular in practice.
Inflammation is graded from 0 to 4(none, mild,
moderate, and severe), and
 Fibrosis is staged from 0 to 4
 Portal fibrotic expansion(1);
Portal fibrosis with septa formation(2)
Bridging fibrosis(3)
Cirrhosis(4)
6/9/2022 64

65. Non Invasive…
6/9/2022 65

66. Non Invasive…
 Examination of liver biopsy specimens is still considered the gold
standard for establishing the grade of inflammation and stage of
fibrosis, limitations of liver biopsy include:
 Associated morbidity
 Cost;
Poor patient acceptance;
 Intraobserver and interobserver variability
 Inaccuracy in the interpretation of findings,
Sampling error
6/9/2022 66

67. Non Invasive…
6/9/2022 67

68. Non Invasive…
6/9/2022 68

69. Non Invasive…
 The AST-to-platelet ratio index (APRI) is used primarily to
diagnose or exclude cirrhosis.
 In an initial evaluation, 81% of cirrhotic patients were
accurately excluded with an APRI score of 0.5 or less
 Transient elastography (FibroScan) to assess liver stiffness,
which correlates with the amount of hepatic fibrosis.
 Combining transient elastography with serum markers
increases the accuracy of predicting fibrosis and cirrhosis
6/9/2022 69

70. Non Invasive…
6/9/2022 70

71. Non Invasive…
6/9/2022 71

72. Non Invasive…
 In patients undergoing initial assessment of chronic
hepatitis C. determination of the stage of liver fibrosis,
either by liver biopsy or noninvasive methods, is
recommended
 Liver biopsy is not required when cirrhosis is already
suggested by clinical findings
 It is also not indicated following successful antiviral
therapy, although histology generally improves
significantly over time following eradication of HCV
6/9/2022 72

73. Non Invasive…
6/9/2022 73
Diagnostic algorithm for investigating the presence of cirrhosis in
patients with chronic liver disease.

74. Natural History
 Chronic hepatitis C can cause continuous liver damage, resulting in
liver cirrhosis and subsequently HCC
 Most liver-related symptoms are restricted to patients with advanced
cirrhosis
 The most feared complication of chronic HCV infection is liver-
related mortality due to decompensated liver cirrhosis or
development of HCC
 In a meta-analysis, cirrhosis developed on average in 16% of
patients within 20 years after the onset of HCV infection
 Cirrhosis was attributable to HCV infection in 27% of cases
6/9/2022 74

75. Natural hx…
 Age is one of the most important risk factors for fibrosis progression
in chronic HCV infection
 A longer duration of infection has also been associated with a higher
stage of liver fibrosis
 Overall, the development of HCV related cirrhosis seems to be a
dynamic process that accelerates exponentially with increasing age
 The mechanisms by which progression of fibrosis accelerates with
aging are not well defined.
 Changes in the regenerative capacity of the liver,
 Alterations in the immune system, and
 Telomere shortening may play roles.
6/9/2022 75

76. Natural hx…
Female gender seems to be protective, and
fibrosis progression is much faster in HCV-
infected men
 Genetic factors also play a role in the
development of cirrhosis
Histologic activity and the frequency of
cirrhosis are lower in African Americans than
in Caucasians.
6/9/2022 76

77. Natural hx…
Elevated serum ALT levels during chronic
hepatitis C are associated with an increased risk
of liver fibrosis progression.
 Lower progression rates of fibrosis are reported
in patients with normal serum ALT levels
Accelerated disease progression in patients
infected with HCV genotype 3
6/9/2022 77

78. Natural hx…
 Flares of hepatitis seem to occur more frequently in HCV genotype
2 infection and may result in a more severe course of liver disease.
 Viral load is not related to the degree of liver damage or fibrosis.
 Hepatic steatosis is a histologic hallmark of chronic hepatitis C.
 Several studies have shown that steatosis is linked to the stage of
liver fibrosis in patients with chronic HCV infection
 The strongest association exists between HCV genotype 3 infection
and steatosis
6/9/2022 78

79. Natural hx…
 Mild to moderately increased hepatic iron stores are associated with
more advanced liver fibrosis.
 Excessive alcohol consumption is clearly an independent major
cause of cirrhosis
 Coffee consumption has been reported to have a beneficial effect on
overall mortality from HCV infection in population-based studies,
 Freedman and colleagues have also shown that
 Greater coffee consumption correlates with a lower stage of liver
fibrosis, reduced fibrosis progression,
 Less steatosis and insulin resistance,
 Lower serum ALT levels;
 Best outcomes occur in persons who drink 3 or more cups per day
6/9/2022 79

80. Natural hx…
HCC:
 chronic hepatitis C is responsible for approximately 25% of cases of
HCC worldwide, with particularly high prevalence rates in East Asia
 In contrast to chronic hepatitis B, HCC due to HCV usually does not
develop in noncirrhotic livers
 The risk is much higher in patients with cirrhosis, with a rate of
1.4% to 4.9% per year.
 The overall 5-year risk of HCC has been reported to be as high as
7% to 30% in patients with HCV-related cirrhosis.
6/9/2022 80

81. Natural hx…
 HCC is frequently the first clinical complication of HCV related
cirrhosis and often occurs before hepatic decompensation becomes
evident.
 Risk factors for the development of HCC in patients with chronic
HCV infection are similar to those associated with the development
of cirrhosis.
 older age
 and male gender and
 substantial alcohol consumption are well-established risk factors.
 Type 2 diabetes mellitus has been identified as an important
independent risk factor.
 Coinfection with HBV
 Genetic factors also contribute to the development of HCC.
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82. Natural hx…
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83. Natural hx…
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84. Treatment
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85. Treatment
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86. Tx…
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87. Tx…
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88. 6/9/2022 88
What made DAAs
Revolutionary?

89. Tx…
 All oral
 IFN-free
 Highly efficacious (>95%
SVR)
 Well tolerated
 High barriers to
resistance,
 Simple dosing,
 Low pill burdens,
 Treatment durations as
brief as 8–12 weeks,
 Pangenotypic efficacy
6/9/2022 89
What made DAAS Revolutionary?

90. Treatment
6/9/2022 90

91. 6/9/2022 91

92. Tx…
6/9/2022 92

93. Tx…
6/9/2022 93

94. Tx…
Factors affecting drug selection:
HCV genotype
Prior treatment experience
Presence of cirrhosis and severity of liver disease
Potential for drug–drug interactions
Renal function
Presence of baseline resistance-associated variants
(RAVs)
6/9/2022 94

95. Simplified Treatment for Tx naïve
Adults without Cirrhosis
6/9/2022 95

96. Tx…
6/9/2022 96

97. Tx…
Pretreatment Assessment
Cirrhosis assessment
Medication reconciliation
Potential drug-drug interaction assessment
Education
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98. Tx…
Pretreatment laboratory testing:
 Within 6 months of initiating treatment:
 Complete blood count (CBC)
 Hepatic function panel (ie, albumin, total and direct bilirubin, alanine
aminotransferase [ALT], aspartate aminotransferase [AST])
 Calculated glomerular filtration rate (eGFR)
 Any time prior to starting antiviral therapy:
 Quantitative HCV RNA (HCV viral load)
 HIV antigen/antibody test
 Hepatitis B surface antigen
 Before initiating antiviral therapy:
 Serum pregnancy testing and counseling about pregnancy risks of HCV
medication should be offered to women of childbearing age.
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99. Tx…
Recommended Regimens
Glecaprevir (300 mg) / pibrentasvir (120
mg) to be taken with food for a duration of 8
weeks
Sofosbuvir (400 mg) / velpatasvir (100 mg) for
a duration of 12 weeks
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100. Simplified Treatment for Tx naïve
Adults with Compensated Cirrhosis
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101. Tx…
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102. Tx…
Recommended Regimens
 Genotype 1-6:
 Glecaprevir (300 mg) / pibrentasvir (120 mg) to be taken with food for
a duration of 8 weeks
 Genotype 1, 2, 4, 5, or 6
 Sofosbuvir (400 mg) / velpatasvir (100 mg) for a duration of 12 weeks
 Patients with genotype 3 require baseline NS5A resistance-associated
substitution (RAS) testing.
 Those without Y93H can be treated with 12 weeks of
sofosbuvir/velpatasvir.
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103. Tx…
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104. Tx…
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105. 6/9/2022 105

106. How efficacious are HCV
Treatments?
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107. Tx…
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108. 6/9/2022 108

109. 6/9/2022 109

110. Tx…
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111. Tx…
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AASLD/IDSA

112. Tx…
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113. Tx…
Drug-Drug Interactions:
 Amiodarone, which can cause severe bradycardia with
sofosbuvir containing regimens
 Strong cytochrome P450 inducers
 Statins, which can increase to toxic levels with protease
inhibitor regimens
 Ethinyl estradiol–containing OCPs and certain
chemotherapy medications that may also be increased by
protease inhibitors
 Proton-pump inhibitors that may reduce the absorption of
certain NS5A inhibitors
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114. Tx…
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115. Tx…
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116. Tx…
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117. Tx…
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118. Unique and Key Sub-Populations
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119. Tx…
HIV/HCV co-infection
The success rate and tolerance of DAA therapy
for persons co infected infected with HIV and
HCV are identical to those of HCV mono
infected persons
The only special considerations required in
HIV/HCV co-infected persons are drug–drug
interactions of HCV DAA and antiretroviral
therapy regimens
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120. Tx…
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121. Tx…
HBV/HCV
 Co-infection Hepatitis C typically suppresses hepatitis B replication
in patients who are co-infected.
 Patients who are HBsAg-positive should be treated with an HBV-
directed DAA (entecavir or tenofovir) during and after HCV
treatment.
 Patients who are HBsAg negative but HBc Ab-positive have less
than 1% risk for HBVr, which can occur years after HCV treatment
 These patients should be routinely monitored for HBVr for at least
24 weeks after completion of HCV treatment and if liver test results
become abnormal thereafter.
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122. Tx…
Decompensated cirrhosis
Interferon-based treatments and protease
inhibitors are contraindicated
Candidacy for liver transplant must be
assessed
Drug options for patients with decompensated
cirrhosis are sofosbuvir– velpatasvir or
sofosbuvir–ledipasvir
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123. Tx…
Decompensated cirrhosis
 For treatment-naive patients with decompensated
cirrhosis a 12-week course of sofosbuvir–ledipasvir or
sofosbuvir–velpatasvir plus weight-based ribavirin
results in cure in more than 85% of cases
 For noncandidates for ribavirin, sofosbuvir–velpatasvir
or sofosbuvir–ledipasvir can be used for 24 weeks
without ribavirin.
 For patients with decompensated cirrhosis who are
experienced with either sofosbuvir or an NS5A
inhibitor, sofosbuvir–velpatasvir or sofosbuvir–
ledipasvir plus ribavirin for 24 weeks.
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124. Tx…
HCV and Renal Impairment
No dose adjustment for GFR ≥ 30
The fixed-dose combination of
Glecaprevir and pibrentasvir
and
Grazoprevir and elbasvir(for 1b)are the preferred
choices in patients with eGFR <30 ml/min/1.73 m2
The risks and benefits of treatment before
transplant must be individualized
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126. Tx…
Pregnancy:
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127. Tx…
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128. Tx…
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129. References
 Sleisenger and Fordtrans’ Gastrointestinal and Liver
Disease(11th edition)
 AASLD/IDSA,2021
 Harrison’s Principles of Internal Medicine(20th edition)
 Practical Gastroenterology and Hepatology(2nd edition)
 Uptodate,2018
 Lancet 2019; 394: 1451–66
 WHO Guidelines For The Care and Treatment Of
Persons Diagnosed With Chronic Hepatitis C
Virus(2018)
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130. Thank You!!!
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