Management of

Hepatitis C
By the
Gastroenterology Team
Outline
• Introduction
• Epidemiology
• Pathophysiology
• Aetiology
• Presentation
• Differential Diagnosis
• Work up
• Treatment
• Prognosis
• Conclusion
Introduction
• Hepatitis C is an infection caused by the hepatitis C virus (HCV)
that attacks the liver and leads to inflammation.
• The hepatitis C virus (HCV) is a major cause of both acute and
chronic hepatitis
• The World Health Organization (WHO) [1] estimates that about
50 million people globally have chronic hepatitis C, with
approximately 242,000 dying from this infection, primarily due
to cirrhosis and hepatocellular carcinoma (sixth most
commonly diagnosed malignancy and third leading cause of
cancer worldwide [2] ). Although direct-acting antiviral agents
cure over 95% of individuals infected with HCV, no effective
vaccine exists against hepatitis C.
Epidemiology
• The prevalence of HCV infection varies throughout
the world.
• For example, Frank et al reported in 2000 that
Egypt had the highest number of reported
infections, largely attributed to the use of
contaminated parenteral antischistosomal therapy.
• This led to a mean prevalence of 22% of HCV
antibodies in persons living in Egypt.
Epidemiology cont.
• In the United States, the incidence of acute HCV infection has
sharply decreased during the past decade, but its prevalence
remains high.
• According to US Centers for Disease Control and Prevention
(CDC) estimates, 2.7-3.9 million people (most of whom were
born from 1945 through 1965) in the United States have
chronic hepatitis C which develops in approximately 75% of
patients after acute infection.
• This virus is the most common blood-borne pathogen in the
United States [5] and a leading cause of morbidity and
mortality, primarily through the development of liver fibrosis
and cirrhosis; persons with chronic infection live an average
of 2 decades less than healthy persons.
Epidemiology cont.
• Worldwide, more than 170 million persons have hepatitis C virus
(HCV) infection, [28] of whom 71 million have chronic infection.
• The Eastern Mediterranean region and Europe have the highest
prevalence (2.3% and 1.5%, respectively), with other regions
having an estimated prevalence of 0.5%-1.0%.
• Jeddah City, Saudi Arabia, has a reported HCV prevalence of
0.38%.
•
• The prevalence rates in healthy blood donors are 0.01%-0.02% in
the United Kingdom and northern Europe, 1%-1.5% in southern
Europe, and 6.5% in parts of equatorial Africa. [30] Prevalence
rates as high as 22% are reported in Egypt and are attributed to
the use of parenteral antischistosomal therapy. [3]
Pathophysiology
• Hepatitis C virus (HCV) is a spherical, enveloped, single-stranded
RNA virus belonging to the family Flaviviridae, genus Flavivirus.
• Lauer and Walker reported that HCV is closely related to
hepatitis G, dengue, and yellow fever viruses.
• HCV can produce at least 10 trillion new viral particles each day.
•
• The HCV genome consists of a single, open reading frame and
two untranslated, highly conserved regions, 5'-UTR and 3'-UTR,
at both ends of the genome.
• The genome has approximately 9500 base pairs and encodes a
single polyprotein of 3011 amino acids that are processed into
10 structural and regulatory proteins (see the image below).
Pathophysiology cont.
The natural targets of HCV are hepatocytes and, possibly,
B lymphocytes. Viral clearance is associated with the
development and persistence of strong virus-specific
responses by cytotoxic T lymphocytes and helper T cells.

• In most infected people, viremia persists and is

accompanied by variable degrees of hepatic
inflammation and fibrosis.
• Findings from studies suggest that at least 50% of
hepatocytes may be infected with HCV in patients with
chronic hepatitis C
Pathophysiology
• The proteolytic cleavage of the virus results in two structural
envelope glycoproteins (E1 and E2) and a core protein.
• Two regions of the E2 protein, designated hypervariable
regions 1 and 2, have an extremely high rate of mutation,
believed to result from selective pressure by virus-specific
antibodies.
• The envelope protein E2 also contains the binding site for CD-
81, a tetraspanin receptor expressed on hepatocytes and B
lymphocytes that acts as a receptor or coreceptor for HCV. HCV
core protein is an important risk factor in the development of
liver disease; it can modulate several signaling pathways
affecting cell cycle regulation, cell growth promotion, cell
proliferation, apoptosis, oxidative stress, and lipid metabolism.
Aetiology
• Transfusion of blood contaminated with hepatitis C virus
(HCV) was once a leading means of HCV transmission.
• Since 1992, however, the screening of donated blood for
HCV antibody sharply reduced the risk of transfusion-
associated HCV infection.
• With the advent of more advanced screening tests for
HCV such as polymerase chain reaction (PCR), the risk is
considered to be less than 1 per 2 million units
transfused.
• The newer assays have decreased the window after
infection to 1-2 weeks.
Aetiology cont.
• Transmission of HCV to healthcare workers may
occur via needle-stick injuries or other occupational
exposures. Needle-stick injuries in the healthcare
setting result in a 3% risk of HCV transmission.
• Persons who inject illicit drugs with nonsterile
needles are at the highest risk for HCV infection.
• In developed countries, most of the new HCV
infections are reported in injection drug users
(IDUs).
Aetiology cont.
• HCV may be transmitted via sexual transmission.
• However, studies of heterosexual couples with
discordant serostatus have shown that such
transmission is extremely inefficient.
• A higher rate of HCV transmission is noted in men
who have sex with men (MSM), particularly those
who practice unprotected anal intercourse and
have infection with the human immunodeficiency
virus (HIV).
Aetiology cont
• HCV may also be transmitted via tattooing, sharing
razors, and acupuncture.
• The use of disposable needles for acupuncture, now
the standard practice in the United States, should
eliminate this transmission route.
• Maternal-fetal HCV transmission may occur at a rate
of approximately 4%–5%. [21]
• Breastfeeding is not associated with transmission.
[22] Casual household contact and contact with the
saliva of those infected are inefficient modes of
transmission
Presentation-History
• Acute hepatitis C virus (HCV) infection becomes
chronic in 70% of patients, which represents a high
rate of chronicity for a viral infection.
• Most patients with chronic hepatitis C are
asymptomatic or may have nonspecific symptoms
such as fatigue or malaise in the absence of hepatic
synthetic dysfunction.
• Patients with decompensated cirrhosis from HCV
infection frequently have symptoms typically
observed in other patients with decompensated liver
disease, such as sleep inversion and pruritus.
Presentation
History cont
• Symptoms characteristic of complications from advanced or
decompensated liver disease are related to synthetic dysfunction
and portal hypertension.
• These include mental status changes (hepatic encephalopathy),
ankle edema and abdominal distention (ascites), and hematemesis
or melena (variceal bleeding).
•
• Symptoms often first develop as clinical findings of extrahepatic
manifestations of HCV and most commonly involve the joints,
muscle, and skin.
• In a large study of the extrahepatic manifestations of HCV, 74% of
medical workers with HCV infection demonstrated extrahepatic
manifestations, of which the following were the most common [48] :
Presentation
History cont
Arthralgias (23%)
Paresthesias (17%)
Myalgias (15%)
Pruritus (15%)
• Sicca syndrome (11%
Presentation
Physical Examination
• Most patients with hepatitis C virus (HCV) infection
do not have abnormal physical examination findings
until they develop portal hypertension or
decompensated liver disease.
• One exception is patients with extrahepatic
manifestations of HCV infection, such as porphyria
cutanea tarda or necrotizing vasculitis.
• Signs in patients with decompensated liver disease
include the following:
Presentation
Physical Examination cont
• Hand signs: Palmar erythema, Dupuytren contracture,
asterixis, leukonychia, clubbing
• Head signs: Icteric sclera, temporal muscle wasting, enlarged
parotid, cyanosis
• Fetor hepaticus
• Gynecomastia, small testes
• Abdominal signs: Paraumbilical hernia, ascites, caput
medusae, hepatosplenomegaly, abdominal bruit
• Ankle edema
• Scant body hair
• Skin signs: Spider nevi, petechiae, excoriations due to pruritus
Differential Diagnosis
Autoimmune Hepatitis

•
• Cholangitis
•
•
• Viral Hepatitis
Workup
• Please note that guidelines for the current
diagnostic workup and management of hepatitis C
(HCV) infection continue to evolve rapidly.
Clinicians are advised to refer frequently to HCV
Guidance: Recommendations for Testing,
Managing, and Treating Hepatitis C, the most
recent recommendations of the American
Association for the Study of Liver Diseases (AASLD)
and Infectious Diseases Society of America (IDSA).
Other resources can also be found at the IDSA
website
Workup cont
AASLD/IDSA guidelines
The AASLD/IDSA recommend the following for one-
time HCV testing [52] :

For all individuals aged 18 years or older, one-time,

routine, opt-out HCV testing
For all individuals aged younger than 18 years who
have an elevated risk of HCV infection due their
activities, exposures, or conditions
• For each pregnancy as part of routine prenatal care
Workup cont.
The AASLD/IDSA recommend the following for initial HCV testing and followup [10] :
•
• Initial HCV testing: HCV-antibody test with reflex HCV RNA polymerase chain reaction
(PCR); if the result is positive, confirm current infection with a sensitive HCV-RNA test.
• Positive HCV-antibody test with negative HCV RNA by PCR: Inform patients they do not
have evidence of current (active) HCV infection but are not protected from reinfection.
• Negative HCV-antibody test but had HCV exposure within last 6 months: Test for HCV
RNA or followup testing for HCV antibody 6 months or longer after exposure; consider
testing for HCV RNA for immunocompromised individuals.
• Risk of reinfection after previous spontaneous or treatment-related viral clearance:
Obtain HCV-RNA testing (because an HCV-antibody test is expected to be positive).
• Before initiation of antiviral therapy: Obtain quantitative HCV-RNA testing to document
baseline viral load.
• Selection of the most appropriate antiviral regimen: Consider HCV genotype testing for
guidance in those in whom treatment recommendations may alter
Work up cont
WHO guidelines
• The World Health Organization (WHO) recommends nucleic acid
testing for qualitative or quantitative HCV RNA detection as well as for
test of cure at 12 or 24 weeks following antiviral treatment
completion.
• In areas with limited resources, the WHO suggests using the
aminotransferase/platelet ratio index (APRI) or the fibrosis-4 (FIB-4)
score for evaluating hepatic fibrosis rather than other noninvasive
tests that require more resources (eg, elastography, FibroTest), as
follows :
•
• APRI = [(AST (IU/L)/AST_ULN (IU/L))×100]/platelet count (10 9 /L)
• FIB-4= age (years) × AST (IU/L)/platelet count (10 9)/L × [ALT
(IU/L)1/2]
Work up cont
Other baseline studies include the following [10] :
•
• Complete blood cell (CBC) count with differential
• International normalized ratio (INR)
• Liver function tests, including levels of ALT and AST, alkaline
phosphatase, albumin, and total and direct bilirubin
• Calculated glomerular filtration rate (eGFR)
• Thyroid function studies
•
• Screening tests for coinfection with human
immunodeficiency virus ( HIV) or hepatitis B virus (HBV)
Workup
• Screening for alcohol abuse, drug abuse, and/or
depression
• Hepatitis B virus (HBV) testing with hepatitis B
surface antigen (HBsAg) (to identify coinfection), as
well as hepatitis B surface antibody (anti-HBs) and
antibody against hepatitis B core antigen (anti-HBc)
(for evidence of previous infection)
• Serum pregnancy testing in women of childbearing
age before initiating a treatment regimen that
includes ribavirin or that includes direct-acting
antiviral agents (DAAs) without ribavirin
Treatment
• Please note that the guidelines for the current diagnostic workup
and management of hepatitis C (HCV) infection continue to
rapidly evolve.
• Clinicians are advised to refer frequently to HCV Guidance:
Recommendations for Testing, Managing, and Treating Hepatitis
C for the most recent recommendations of the American
Association for the Study of Liver Diseases (AASLD) and Infectious
Diseases Society of America (IDSA).
•
• The treatment goal of HCV-infected individuals is the reduction of
all-cause mortality and hepatic-associated morbidity (eg, end-
stage liver disease, hepatocellular carcinoma) as achieved by
virologic cure, with sustained virologic response.
Treatment cont
• Spontaneous resolution of acute HCV infection may
occur in 15% to 50% of patients.
• Monitoring for spontaneous clearance for a minimum
of 6 months before initiating treatment is therefore
recommended.
• Patients with acute HCV infection appear to have an
excellent chance of responding to 6 months of
standard therapy with interferon (IFN).
• However, IFN-sparing regimens are safer and are
currently recommended for the treatment of acute
HCV infection as with chronic HCV infection.
Treatment cont
• Hepatitis C has become a curable disease with the
use of antiviral agents (>95%).
• Treatment for chronic HCV is based on guidelines
from the Infectious Diseases Society of America
(IDSA) and the American Associations for the Study
of Liver Diseases (AASLD), in collaboration with the
International Antiviral Society-USA (IAS-USA).
• These guidelines are updated often.
Treatment cont
• Hepatitis C has become a curable disease with the use of
antiviral agents (>95%). [1] Treatment for chronic HCV is based
on guidelines from the Infectious Diseases Society of America
(IDSA) and the American Associations for the Study of Liver
Diseases (AASLD), in collaboration with the International
Antiviral Society-USA (IAS-USA).
• These guidelines are updated often.
•
• The AASLD/IDSA guidelines previously proposed that because
all patients cannot receive treatment immediately upon the
approval of new agents, priority should be given to those with
the most urgent need. The recommendations included the
following [36] :
Treatment cont.
Patients with advanced fibrosis, those with compensated cirrhosis, liver
transplant recipients, and those with severe extrahepatic complications
are to be given the highest priority for treatment.
•
• Based on available resources, patients at high risk for liver-related
complications and severe extrahepatic hepatitis C complications
should be given high priority for treatment.
•
• Treatment decisions should balance the anticipated reduction in
transmission versus the likelihood of reinfection in patients whose risk
of HCV transmission is high and in whom HCV treatment may result in
a reduction in transmission (eg, men who have high-risk sex with
men, active injection drug users, incarcerated persons, and those on
hemodialysis).
Treatment cont.
• Antiviral therapy for chronic hepatitis C should be determined on a case-
by-case basis.
• However, treatment is widely recommended for patients with elevated
serum alanine aminotransferase (ALT) levels who meet the following
criteria [7] :
•
• Age older than 18 years
• Positive HCV antibody and serum HCV RNA test results
• Compensated liver disease (eg, no hepatic encephalopathy or ascites)
• Acceptable hematologic and biochemical indices (hemoglobin at least 13
g/dL for men and 12 g/dL for women; neutrophil count >1500/mm 3,
serum creatinine < 1.5 mg/dL)
• Willingness to be treated and to adhere to treatment requirements
• No contraindications for treatment
Treatment cont.
Interferons and Pegylated Interferons
• The two most frequently used recombinant interferon
(IFN) preparations in clinical trials have been IFN alfa-
2b (Intron-A) and IFN alfa-2a (Roferon-A), which differ
from each other by only a single amino acid residue.
• IFN alfacon-1 (Infergen), or consensus IFN, is a
genetically engineered compound synthesized by
combining the most common amino acid sequences
from all 12 naturally occurring IFNs. Roferon-A was
discontinued from the market in 2007 and Infergen
was discontinued from the market in 2013.
Treatment cont
IFN monotherapy in acute hepatitis C
• Although the short courses of standard IFN
monotherapy introduced in the 1980s by Hoofnagle
et al, Davis et al, and Di Bisceglie et al led to
sustained improvement in liver disease and loss of
virus in less than 10% of patients, these therapies
were the first to cure chronic viral hepatitis.
Treatment cont
Interferons and Ribavirin
•
• A major advance in the treatment of chronic hepatitis C was the
addition of the oral nucleoside analogue ribavirin to the
interferon (IFN) regimen.
• As reported in the landmark 1998 studies by McHutchison et al
and Poynard et al, IFN alfa-2b and ribavirin combination therapy
for 6-12 months resulted in sustained eradication rates of 30%-
40%.
• However, patients with HCV genotype 1 who were treated for
12 months had a much less favorable response than patients
infected with genotypes 2 and 3 who received a 6-month course
of therapy.
Treatment cont
PEG-IFN therapy with ribavirin
• The addition of ribavirin to PEG-IFN heralded a new
era in the treatment of chronic HCV.
• The benefits of combination therapy were
documented in three landmark trials: Manns et al
in 2001, [88] Fried et al in 2002, [89] and
Hadziyannis et al in 2004. [90]
Treatment cont
Direct-Acting Antiviral Agents (DAAs)
• Relatively recently, several antiviral agents have been developed to
specifically target various sites of hepatitis C (HCV) viral replication.
• Similar to the antiretroviral drugs, these agents have been
approved by the FDA in various combinations to interrupt HCV
replication at different sites, with reported 90%-95% sustained
virologic response (SVR) rates in treated patients versus 40%-55% in
those completing treatment with dual-therapy pegylated interferon
(PEG-IFN) plus ribavirin.
• However, clinicians should be aware that baseline resistance-
associated substitutions (RASs) may impair treatment response to
direct-acting antiviral agents (DAAs), particularly baseline NS5A
resistance in DAA-naïve HCV patients.
Treatment cont
Currently available agents and their target sites are
outlined below.

NS3/4 targeting protease inhibitors

Simeprevir
Paritaprevir
Grazoprevir
• Glecaprevir
Treatment contact.
NS5B targeting polymerase inhibitors

Nucleotide: Sofosbuvir
Non-nucleotide: Dasabuvir
NS5A targeting agents

Ledipasvir
Ombitasvir
Elbasvir
Prognosis
• Infection with hepatitis C virus (HCV) is self-limited in 15% to
50% of patients.
• In a review of HCV infection, it was reported that chronic
infection developed in 70-80% of patients.
• Cirrhosis develops within 20 years of disease onset in 20% of
persons with chronic infection.
• The onset of chronic hepatitis C infection early in life often
leads to less serious consequences. Hepatitis B virus (HBV)
coinfection, iron overload, and alpha 1-antitrypsin deficiency
may promote the progression of chronic HCV infection to HCV-
related cirrhosis. The INSIGHT Study reported the three most
common comorbidities with HCV across 9 Asia-Pacific countries
were cirrhosis, hypertension, and diabetes. [2]
Conclusion
• Hepatitis C is an infection caused by the hepatitis C
virus (HCV) that attacks the liver and leads to
inflammation.
• The hepatitis C virus (HCV) is a major cause of both
acute and chronic hepatitis
• Infection with hepatitis C virus (HCV) is self-limited
in 15% to 50% of patients.
• In a review of HCV infection, it was reported that
chronic infection developed in 70-80% of patients.
THANKS
• THANK YOU FOR LISTENING
References
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