Hepatitis C

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

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

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

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

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

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
6/9/2022 6

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

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

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

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

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

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

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

Virology…
 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

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
6/9/2022 19

6/9/2022 20
Source: The Polaris
Observatory HCV
Collaborators

Virology…
 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

Virology…
 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

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%).
6/9/2022 25

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

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

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

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

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

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

Patho…
 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

Patho…
 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

Patho…
 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

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

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

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

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

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

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

Clinical…
 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

Clinical…
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

Clinical…
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.
6/9/2022 46

6/9/2022 47
N Engl J Med 2021;384:1038-52. D

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

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

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

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

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

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

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

Dx…
6/9/2022 57
AASLD/IDSA and CDC

Dx…
6/9/2022 58
AASLD/IDSA and CDC

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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.
6/9/2022 81

6/9/2022 88
What made DAAs
Revolutionary?

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?

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

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

Tx…
Pretreatment Assessment
Cirrhosis assessment
Medication reconciliation
Potential drug-drug interaction assessment
Education
6/9/2022 97

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.
6/9/2022 98

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
6/9/2022 99

Simplified Treatment for Tx naïve
Adults with Compensated Cirrhosis
6/9/2022 100

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.
6/9/2022 102

How efficacious are HCV
Treatments?
6/9/2022 106

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
6/9/2022 113

Unique and Key Sub-Populations
6/9/2022 118

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
6/9/2022 119

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.
6/9/2022 121

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
6/9/2022 122

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.
6/9/2022 123

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
6/9/2022 124

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)
6/9/2022 129

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