Physical findings usually are not abnormal until portal hypertension or

decompensated liver disease develops. Signs in patients with

decompensated liver disease include the following:

HEPATITIS C

Update 11 jan, 2015

Author

Vinod K Dhawan, MD, FACP, FRCP(C), FIDSA Professor, Department

of Clinical Medicine, University of California, Los Angeles, David Geffen
School of Medicine; Chief, Division of Infectious Diseases, Rancho Los
Amigos National Rehabilitation Center

Chief Editor

BS Anand, MD Professor, Department of Internal Medicine, Division of

Gastroenterology, Baylor College of Medicine

practice Essentials
Hepatitis C is an infection caused by the hepatitis C virus (HCV) that
attacks the liver and leads to inflammation. The World Health Organization
(WHO) estimates that about 3% of the worlds population has been infected
with HCV and that there are more than 170 million chronic carriers who
are at risk of developing liver cirrhosis and/or liver cancer. The image
below depicts the HCV genome.

Hand signs: Palmar erythema, Dupuytren contracture, asterixis,

leukonychia, clubbing
Head signs: Icteric sclera, temporal muscle wasting, enlarged
parotid gland, 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
Other common extrahepatic manifestations include the following:

Cryoglobulinemia: Membranoproliferative glomerulonephritis

Idiopathic thrombocytopenic purpura

Lichen planus[4]

Keratoconjunctivitis sicca

Raynaud syndrome

Sjgren syndrome

Porphyria cutanea tarda

Necrotizing cutaneous vasculitis

Non-Hodgkin lymphoma
See Clinical Presentation for more detail.
Diagnosis

Hepatitis C viral genome.

Courtesy of Hepatitis Resource Network.
Essential update: FDA gives marketing approval for radiologic
application that evaluates severity of liver disease and clinical
outcomes
On December 17, 2014, the FDA gave marketing approval for the Hepatiq
radiologic image processing system. [1, 2] The software application uses
quantitative analysis of nuclear medicine liver-spleen images to determine
the severity of liver disease and to predict clinical outcomes. [2] The
developer notes that Hepatiq "automates the Quantitative Liver Spleen
Scan (QLSS) that has been proven to be an accurate predictor of clinical
outcomes
in
the
recently
concluded
HALT-C
[H epatitis
C A ntiviral L ong-term T reatment
against C irrhosis]
trial."[2] The
HALT-C trial was a multicenter, randomized controlled study that evaluated
whether long-term interferon would suppress HCV, prevent progression to
cirrhosis, prevent liver cancer, and reduce the need for liver transplantation.

General baseline studies in patients with suspected hepatitis C include the

following:

Initial symptoms of hepatitis C are often extrahepatic, most commonly

involving the joints, muscle, and skin. Examples include the following:

Myalgias
Pruritus
Sicca syndrome
Sensory neuropathy
Symptoms characteristic of complications from advanced or
decompensated liver disease are related to synthetic dysfunction and portal
hypertension, such as the following:
Mental status changes (hepatic encephalopathy)
Ankle edema and abdominal distention (ascites)
Hematemesis or melena (variceal bleeding)

Thyroid function studies

Screening tests for coinfection with HIV or hepatitis B virus
(HBV)
Screening for alcohol abuse, drug abuse, or depression
Tests for detecting hepatitis C virus (HCV) infection include the following:

Hepatitis C antibody testing: Enzyme immunoassays (EIAs),

rapid diagnostic tests (RDTs), and point-of-care tests (POCTs)
Recombinant immunoblot assay

Arthralgias
Paresthesias

Liver function tests, including alanine aminotransferase level

[3]

Signs and symptoms

Complete blood cell count with differential

Qualitative and quantitative assays for HCV RNA (based on

polymerase chain reaction [PCR] or transmission-mediated amplification
[TMA])
HCV genotyping
Serologic testing (essential mixed cryoglobulinemia is a
common finding)
Liver biopsy is not mandatory before treatment but may be helpful. Some
restrict it to the following situations:
The diagnosis is uncertain
Other coinfections or disease may be present
The patient has normal liver enzyme levels and no extrahepatic
manifestations
The patient is immunocompromised
See Workup for more detail.
Management
Treatment of acute hepatitis C has rapidly evolved
See Treatment and Medication for more detail.
Background

Hepatitis C is a worldwide problem. The hepatitis C virus (HCV) is a major

cause of both acute and chronic hepatitis. The World Health Organization
(WHO) estimates about 3% of the worlds population has been infected
with HCV and that there are more than 170 million chronic carriers who
are at risk of developing liver cirrhosis and/or liver cancer.

that at least 50% of hepatocytes may be infected with HCV in patients with
chronic hepatitis C.
RNA-dependent RNA polymerase, an enzyme critical in HCV replication,
lacks proofreading capabilities and generates a large number of mutant
viruses known as quasispecies. These represent minor molecular variations
with only 1-2% nucleotide heterogeneity. HCV quasispecies pose a major
challenge to immune-mediated control of HCV and may explain the
variable clinical course and the difficulties in vaccine development.

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.[5] This led to a mean prevalence of HCV
antibodies in persons in Egypt of 22%.

Etiology
Hepatitis C is caused by 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.

In the United States, the incidence of acute HCV infection has sharply
decreased during the past decade. Its prevalence remains high
(approximately 2.7 million Americans), however, because chronic hepatitis
C (CHC) infection develops in approximately 75% of patients after acute
infection.

The HCV genome consists of a single, open reading frame and 2

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).

According to the US Centers for Disease Control and Prevention (CDC), an

estimated 1.8% of the US population is positive for HCV antibodies.
Because 3 of 4 seropositive persons are also viremic, this corresponds to an
estimated 2.7 million people with active HCV infection nationwide.
Infection due to HCV accounts for 20% of all cases of acute hepatitis, an
estimated 30,000 new acute infections, and 8000-10,000 deaths each year
in the United States. HCV has rapidly surpassed HIV as a cause of death in
the US. An examination of nearly 22 million death records over 9 years
revealed an HCV mortality rate of 4.58 deaths per 100,000 people per year
and an HIV mortality rate of 4.16 deaths per 100,000 people. Almost 75%
of HCV deaths occurred among adults between the ages of 45 and 64.[6]
Medical care costs associated with the treatment of HCV infection in the
United States are estimated to be more than $600 million a year. Most
patients infected with HCV have chronic liver disease, which can progress
to cirrhosis andhepatocellular carcinoma (HCC). Chronic infection with
HCV is one of the most important causes of chronic liver disease (see the
image below) and, according to a report by Davis et al, the most common
indication for orthotopic liver transplantation (OLT) in the United States.[7]

Hepatitis C viral genome.

Courtesy of Hepatitis Resource Network.
Structural components include the core and 2 envelope proteins, E1 and E2.
Two regions of the E2 protein, designated hypervariable regions 1 and 2,
have an extremely high rate of mutation, thought 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.
The nonstructural components include NS2, NS3, NS4A, NS4B, NS5A,
NS5B, and p7, whose proteins function as helicase-, protease-, and RNAdependent RNA polymerase, although the exact function of p7 is unknown.
One region within NS5A is linked to an interferon (IFN) response and is
called the IFN sensitivitydetermining region. These enzymes are critical in
viral replication and are attractive targets for future antiviral therapy.

Hepatitis C. Causes of
chronic liver disease. Courtesy of the US Centers for Disease Control and
Prevention.
Most patients with acute and chronic infection are asymptomatic. Patients
and health care providers may detect no indications of the conditions for
long periods; however, chronic hepatitis C infection and chronic active
hepatitis are slowly progressive diseases and result in severe morbidity in
20-30% of infected persons. Astute observation and integration of findings
of extrahepatic symptoms, signs, and disease are often the first clues to
underlying HCV infection.[8]
Although acute hepatitis C virus (HCV) infection is usually mild, chronic
hepatitis results in at least 75% of patients. [9] (See Prognosis.) While liver
enzyme levels may be in the reference range, the presence of persistent
HCV-RNA levels discloses chronic infection. Biopsy samples of the liver
may reveal chronic liver disease in patients. Cirrhosis develops in 20-50%
of patients with chronic hepatitis C infection. Liver failure and
hepatocellular carcinoma can eventually result. Hepatocellular carcinoma
occurs in 11-19% of patients.
Pathophysiology
The cause of hepatitis C, HCV, is a spherical, enveloped, single-stranded
RNA virus belonging to the Flaviviridae family and Flavivirus genus. 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

HCV genomic analysis by means of arduous gene sequencing of many

viruses has led to the division of HCV into 6 genotypes based on
homology. Numerous subtypes have also been identified. Arabic numerals
denote the genotype, and lower-case letters denote the subtypes for lesser
homology within each genotype. [9]
Genotypes
Molecular differences between genotypes are relatively large, and they
have a difference of at least 30% at the nucleotide level. The major HCV
genotype worldwide is genotype 1, which accounts for 40-80% of all
isolates. Genotype 1 also may be associated with more severe liver disease
and a higher risk of HCC. Genotypes 1a and 1b are prevalent in the United
States, whereas in other countries, genotype 1a is less frequent. HCV
genotype 1, particularly 1b, does not respond to therapy as well as
genotypes 2 and 3. Genotype details are as follows:

Genotype 1a occurs in 50-60% of patients in the United States

Genotype 1b occurs in 15-20% of patients in the United States;
this type is most prevalent in Europe, Turkey, and Japan
Genotype 1c occurs in less than 1% of patients in the United
States
Genotypes 2a, 2b, and 2c occur in 10-15% of patients in the
United States; these subtypes are widely distributed and are most
responsive to medication

Genotypes 3a and 3b occur in 4-6% of patients in the United

States; these subtypes are most prevalent in India, Pakistan, Thailand,
Australia, and Scotland

Genotype 4 occurs in less than 5% of patients in the United

States; it is most prevalent in the Middle East and Africa

Genotype 5 occurs in less than 5% of patients in the United

States; it is most prevalent in South Africa

Genotype 6 occurs in less than 5% of patients in the United

States; it is most prevalent in Southeast Asia, particularly Hong Kong and
Macao
Within a region, a specific genotype may also be associated with a specific mode
of transmission, such as genotype 3 among persons in Scotland who abuse
intravenous drugs.
Transmission
Transfusion of blood contaminated with HCV was once an important source of
transmission. Since 1990, however, the screening of donated blood for
HCV antibody has decreased the risk of transfusion-associated HCV
infection to less than 1 case in 103,000 transfused units. With the use of
more sensitive assays, such as polymerase chain reaction (PCR), Stramer et
al reported that the risk of acquiring HCV from blood transfusions is
estimated to be 1 in 230,000 donations. [10] The newer assays have decreased
the window after infection to 1-2 weeks.
Persons who inject illegal drugs with nonsterile needles or who snort cocaine
with shared straws are at highest risk for HCV infection. In developed
countries, most new HCV infections are related to intravenous drug abuse
(IVDA).
Transmission of HCV to health care workers may occur via needle-stick injuries
or other occupational exposures. Needle-stick injuries in the health care
setting result in a 3% risk of HCV transmission. According to Rischitelli et
al, however, the prevalence of HCV infection among health care workers is
similar to that of the general population. [11] Nosocomial patient-to-patient
transmission may occur by means of a contaminated colonoscope, via
dialysis, or during surgery, including organ transplantation before 1992.
HCV may also be transmitted via tattooing, sharing razors, and acupuncture. The
use of disposable needles for acupuncture, which has become standard
practice in the United States, eliminates this transmission route.
Yeung et al reported that uncommon routes of transmission of HCV, which affect
less than 5% of the individuals at risk, include high-risk sexual activity and
maternal-fetal transmission.[12] Coinfection with human immunodeficiency
virus (HIV) type 1 appears to increase the risk of both sexual and maternalfetal transmission of HCV. Casual household contact and contact with the
saliva of those infected are inefficient modes of transmission. No risk
factors are identified in approximately 10% of cases.
Epidemiology
United States statistics
Hepatitis C is the major cause of chronic hepatitis in the United States. HCV
infections account for 20% of all cases of acute hepatitis and for more than
40% of all referrals to active liver clinics.

15,000 in 1999. According to Kim, this number is expected to increase in

the future because of the current large pool of undiagnosed patients with
chronic infection.[15]
International statistics
Worldwide, more than 170 million persons have hepatitis C virus (HCV)
infection.[16] 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. Prevalence rates as high as 22% are
reported in Egypt and are attributed to the use of parenteral
antischistosomal therapy.
Race-, sex-, and age-related differences in incidence
In the United States, HCV infection is more common among minority
populations, such as black and Hispanic persons, than other populations, in
association with lower economic status and educational levels. In addition,
in the United States, genotype 1 is more prevalent in blacks than in other
racial groups.
No sex preponderance occurs with HCV infection. In the third National
Health and Nutrition Examination Survey, neither sex nor racial-ethnic
group was independently associated with HCV infection. [13]
In the United States, 65% of persons with HCV infection are aged 30-49
years. Those who acquire the infection at a younger age have a somewhat
better prognosis than those who are infected later in life. Infection is
uncommon in persons aged 20 years and younger and is more prevalent in
persons older than 40 years. [17, 18] Data suggest an association between age
and transmission route, such as nonsterile medical procedures, including
vaccination and parenteral drug treatment. [19]
Prognosis
Infection with HCV is self-limited in only a small minority of infected
persons. Chronic infection develops in 70-80% of patients infected with
HCV.[9] Cirrhosis develops within 20 years of disease onset in 20% of
persons with chronic infection.[20] The onset of chronic hepatitis C infection
early in life often leads to less serious consequences. [21, 22] Hepatitis B virus
(HBV) coinfection, iron overload, and alpha 1-antitrypsin deficiency may
promote the progression of chronic HCV infection to HCV-related
cirrhosis.[23, 24]
Two studies of compensated cirrhosis in the United States and Europe
showed that decompensation occurred in 20% of patients and that HCC
occurred in approximately 10% of patients. [25, 26] The survival rate at 5 and
10 years was 89% and 79%, respectively. HCC develops in 1-4% of
patients with cirrhosis each year after an average of 30 years.
The risk of cirrhosis and HCC doubles in patients who acquired HCV
infection via transfusion. [27] Progression to HCC is more common in the
presence of cirrhosis, alcoholism, and HBV coinfection.
Bellentani et al[28] and Hourigan et al[29] reported that the rate and likelihood
of progression is influenced by alcohol use, immunosuppression, sex, iron
status, concomitant hepatitis, and age of acquisition (see the image below).

Alter et al reported that HCV infections account for approximately 30,000 new
infections and 8000-10,000 deaths each year in the United States.[13] Of new
infections, 60% occur in intravenous drug users; less than 20% of new
cases are acquired through sexual exposure; and 10% are due to other
causes, including occupational or perinatal exposure and hemodialysis.
The overall prevalence of anti-HCV antibodies in the United States is 1.8% of
the population. Approximately 74% of these individuals are positive for
HCV RNA, meaning that active viral replication continues to occur. Thus,
an estimated 3.9 million persons are infected with HCV and 2.7 million
persons in the United States have chronic infection. [13] Genotype 1a occurs
in 57% of patients; genotype 1b occurs in 17%.
From 1989-1993, the occurrence of HCV to approximately 28,000 new cases per
year, reflecting an 80% decrease. Decreased transfusion-associated disease
and a dramatic decrease in intravenous drug use accounted for this change.
El-Serag et al reported that HCV is largely responsible for the increase in the
incidence of HCC in the United States during the final decades of the 20th
century.[14] In the United States, the number of deaths due to HCV-related
complications increased from fewer than 10,000 in 1992 to just fewer than

Natural history of hepatitis C

virus infection.
In an observational study of Veterans Affairs (VA) HCV clinical registry
data from 128,769 patients, McCombs et al found that those who achieved
an undetectable HCV viral load had a decreased risk of subsequent liver
morbidity and death.[30, 31]Viral load suppression reduced the risk for future
liver events by 27% (eg, compensated/decompensated cirrhosis,
hepatocellular carcinoma, or liver-related hospitalization), as well as
reduced the risk of death by 45%, relative to patients who did not achieve
viral load suppression. [30, 31] Additionally, patient race/ethnicity and HCV
genotypes affected the risk of future liver events and death. The risk for all
liver events and death was higher in white patients relative to black
patients, and those with HCV genotype 3 had a higher risk for all study

outcomes compared with patients who had HCV genotype 2 (lowest risk)
or 1.[30, 31]

Chronic hepatitis C has a strong association with pruritus. Indeed, some

authorities believe that all patients with unexplained pruritus should be
investigated for HCV infection. [37]
Physical Examination
Most patients with 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:

Patient Education
Patients with hepatitis C should be advised to abstain from alcohol use.
Optimally, patients should use barrier protection during sexual intercourse.
[32]

Patients with hepatitis C should not donate blood or organs. One exception
is in patients with HCV who require liver transplantation. Arenas et al
showed that liver transplant recipients who received liver grafts from HCVpositive donors had 5-year survival rates comparable to recipients who
received grafts from HCV-negative donors. [33] Given the shortage of organs
and the long waiting list, this strategy has proven safe and effective.
In August 2012, the Centers for Disease Control and Prevention (CDC)
expanded their existing, risk-based testing guidelines to recommend a 1time blood test for hepatitis C virus (HCV) infection in baby boomersthe
generation born between 1945 and 1965, who account for approximately
three fourths of all chronic HCV infections in the United Stateswithout
prior ascertainment of HCV risk (seeRecommendations for the
Identification of Chronic Hepatitis C Virus Infection Among Persons Born
During 19451965).[34] One-time HCV testing in this population could
identify nearly 808,600 additional people with chronic infection. All
individuals identified with HCV should be screened and/or managed for
alcohol abuse, followed by referral to preventative and/or treatment
services, as appropriate.
History
Acute hepatitis C (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 infection 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.

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
Other common extrahepatic manifestations include the following:

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).

Cryoglobulinemia: Membranoproliferative glomerulonephritis

Idiopathic thrombocytopenic purpura
Lichen

Walter

Reed

planus[4] (see

Army

the

Medical

images

below)

Lichen planus. Courtesy of

Center
Dermatology.

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. [35] The
most
commonly
occurring
extrahepatic
manifestations were as follows:

Arthralgias (23%)
Paresthesias (17%)

Courtesy

Myalgias (15%)

of

Walter

Reed

Army

Lichen planus (oral lesions).

Medical Center Dermatology.

Pruritus (15%)
Sicca syndrome (11%)
In addition, sensory neuropathy has been reported as an extrahepatic
manifestation in 9% of patients with HCV infection. [36] Risk factors for
manifestations of extrahepatic chronic hepatitis C infection include
advanced age, female sex, and liver fibrosis.
Patients also present with symptoms that are less specific and are often
unaccompanied by discrete dermatologic findings. Pruritus and urticaria are
examples of less specific clues to underlying HCV infection in the
appropriate setting (eg, posttransfusion, organ transplantation, surgery,
intravenous drug use, injury of the nasal mucosa from snorting cocaine
through shared straws).
Patients with ongoing pathology associated with chronic hepatitis C that
eventually results in organ failure can present with symptoms and signs in
the skin. Pruritus, dryness, palmar erythema, and yellowing of the eyes and
skin are examples of less specific findings in patients with end-stage liver
disease with cirrhosis; these findings provide clues that lead to further
evaluation of the underlying causes. Patients with the mucosa-associated
lymphoma tumors (MALT) syndrome itself tend to have bowel symptoms.

Lichen planus (volar wrist). Courtesy of

Walter Reed Army Medical Center Dermatology.
Keratoconjunctivitis sicca
Raynaud syndrome
Sjogren syndrome

Identification of Chronic Hepatitis C Virus Infection Among Persons Born

During 19451965).[34]

Porphyria cutanea tarda

Necrotizing cutaneous vasculitis

One-time HCV testing in this population could identify nearly 808,600

additional people with chronic infection. All individuals identified with
HCV should be screened and/or managed for alcohol abuse, followed by
referral to preventive and/or treatment services, as appropriate.[34]

Non-Hodgkin lymphoma
Approximately 10-15% of affected patients have symptoms such as
weakness, arthralgias, and purpura; these are often related to vasculitis. The
precise pathogenesis of these extrahepatic complications has not been
determined, although most are the clinical expression of autoimmune
phenomena

In June 2013, The US Preventive Services Task Force also updated its 2004
HCV screening and treatment recommendations, advocating a 1-time
screening for all persons born between 1945 and 1965. The new
recommendation arose from the fact that a lack of universal blood
screening for the virus prior to 1992 placed persons born between the mid1940s and mid-1960s at increased risk of exposure to HCV.[40, 41,
42]
Screening for HCV in the emergency department (ED) has been found to
be feasible, albeit costly.[43, 44]

Differential Diagnoses

Autoimmune Hepatitis
Cholangitis

Hepatitis C Antibody Test

Hepatitis, Viral

Anti-HCV EIAs include second- and third-generation EIAs. These assays

are 97% specific but cannot distinguish acute from chronic infection. The
most recent third-generation EIA detects antibodies against core protein
and nonstructural proteins 3, 4, and 5 and can yield positive results an
average of 8 weeks after the onset of infection.

Approach Considerations
Serologic screening for hepatitis C virus (HCV) involves an enzyme
immunoassay (EIA). These assays are 97% specific but cannot distinguish
acute from chronic infection. A rapid antibody test for HCV is available.
The recombinant immunoblot assay is used to confirm HCV infection.

False-negative results for the presence of HCV antibody can occur in

persons with compromised immune systems, such as those with HIV type 1
infection, renal failure, or HCV-associated essential mixed
cryoglobulinemia. False-positive EIA results can occur; the likelihood of a
false-positive result is greater in persons without risk factors and in those
without signs of liver disease, such as blood donors or health care workers.

A meta-analysis comparing point-of-care screening tests (POCTs) with

rapid diagnostic tests (RDTs) indicated that POCTs are highly accurate for
diagnosing hepatitis C.[38, 39] POCTs do not require special equipment or
electricity and are more robust than RDTs at high temperatures; thus, they
may enable expanded screening.

The FDA has approved OraQuick HCV Rapid Antibody Test, which can be
used for persons at risk for hepatitis or for those with signs or symptoms of
hepatitis. The test strip can be used with a sample collected from a
fingerstick or venipuncture whole blood.[45]

Health care personnel who sustain a needle-stick injury involving an HCVinfected patient should undergo polymerase chain reaction (PCR) testing
for HCV immediately and then every 2 months for 6 months. If HCV
infection is diagnosed, therapy can be instituted.

Recombinant Immunoblot Assay

The recombinant immunoblot assay is used to confirm HCV infection. A
positive immunoblot assay result is defined as the detection of antibodies
against 2 or more antigens and an indeterminate assay result defined as the
detection of antibodies against a single antigen.

Other baseline studies include the following:

Complete blood cell count (CBC) with differential

A positive immunoblot assay result followed by 2 or more instances of

undetectable HCV RNA suggests HCV infection has resolved. A positive
anti-HCV immunoassay result followed by a negative immunoblot assay
result represents a false-positive immunoassay, and no further testing is
required.

Liver function tests, including alanine aminotransferase (ALT)

level
Thyroid function studies
HCV genotyping as an aid for guiding treatment
Quantitative HCV RNA assay

The recombinant immunoblot assay has limited usefulness in clinical

practice.

Screening tests for coinfection with HIV or hepatitis B virus

(HBV)

Qualitative and Quantitative Assays for HCV RNA

Screening for alcohol abuse, drug abuse, and/or depression

The CBC demonstrates thrombocytopenia in approximately 10% of
patients. Low thyroxine levels are found in approximately 10% of patients,
as well. Stress testing may be necessary in appropriate patients. An
ophthalmologic examination may also be necessary.
A diagnostic algorithm for the evaluation of hepatitis C is shown in the
following image.

Qualitative assays can be used to test for HCV RNA. HCV RNA can be
detected in blood using amplification techniques such as PCR or
transcription-mediated amplification (TMA). The FDA has approved the
following 2 PCR-based tests for qualitative HCV RNA detection:

Diagnostic

algorithm

for

hepatitis C virus infection.

In August 2012, the Centers for Disease Control and Prevention (CDC)
expanded their existing, risk-based testing guidelines to recommend a 1time blood test for hepatitis C virus (HCV) infection in baby boomersthe
generation born between 1945 and 1965, who account for approximately
three fourths of all chronic HCV infections in the United Stateswithout
prior ascertainment of HCV risk (seeRecommendations for the

Cobas Amplicor Hepatitis C Virus Test, version 2.0 (Roche

Molecular Systems): PCR with a lower limit of detection of 50 IU/mL
Versant HCV RNA Qualitative Assay (Bayer HealthCare): TMA
with a lower limit of detection of 9.6 IU/mL
Quantitative assays ascertain HCV RNA quantity in blood, using signal
amplification (branched DNA [bDNA] assay) or target amplification
techniques (PCR, TMA). Reverse transcriptase PCR (RT-PCR) is more
sensitive than bDNA testing. The HCV RNA level in blood helps predict
the likelihood of a response to treatment, and the change in HCV RNA
level can also be used to monitor response.
The same quantitative test should be used throughout therapy to avoid
confusion, and results should be reported in international units (IU) to
standardize data. The only FDA-approved quantitative test is Versant HCV
RNA, version 3.0 (Bayer HealthCare). It is based on bDNA technology and
has a dynamic range of 615-7,700,000 IU/mL.
HCV Genotyping

Genotyping is helpful for predicting the likelihood of response and duration

of treatment. Patients with genotypes 1 and 4 are generally treated longer
than genotypes.

are useful for assessing improvements in histologic findings in studies but

are impractical for clinical use because of interobserver disagreement.
The METAVIR score was developed by the French METAVIR Cooperative
Study Group and reported by Bedossa and Poynard in 1996; it is frequently
used in European trials. This score consists of a 3-point activity scale and
4-point fibrosis score, with good agreement among pathologists. In the
United States, many pathologists use a scale described by Batts and
Ludwig in 1995, which consists of an activity grade (0-4) and a fibrosis
stage (0-4).

Genotyping can be performed by direct sequence analysis, reverse

hybridization to genotype-specific oligonucleotide probes, or restriction
fragment length polymorphisms (RFLPs).
In June 2013, the FDA approved the Abbott RealTime HCV Genotype II
test, which, by analyzing a sample of an infected patients blood plasma or
serum, can differentiate HCV genotypes 1, 1a, 1b, 2, 3, 4, and 5. This new
test is approved for use in adult, non-immunocompromised patients with
known chronic HCV infection but has not been approved for diagnostic use
or as a screening test for HCV genetic material. FDA approval was based
partly on a comparison of the test's accuracy with that of a validated genesequencing method. [46, 47]

Noninvasive methods of assessing hepatic fibrosis are in development.

Current serum assays are directed at measuring breakdown products of
extracellular matrix constituents (eg, glycoproteins, propeptides) and their
regulatory enzymes (eg, lysyl oxidase, lysyl hydroxylase, propyl
hydroxylase).

Two other genotype tests are available, although neither has been approved
by the FDA. They are as follows:

Radiographic Tests
A liver stiffness test (FibroScan) is available as a noninvasive method of
staging liver disease in persons with chronic hepatitis C. Obesity, female
sex, operator experience, and age older than 52 may give invalid results.
Falsely high estimates of liver fibrosis have also been reported with acute
inflammation and recent food intake.

Trugene HCV 5'NC Genotyping kit (Visible Genetics; Toronto,

Canada): Based on direct sequencing followed by comparison with a
reference sequence database
Line Probe Assay (Inno LiPA HCVII, Innogenetics; Ghent,
Belgium): Based on reverse hybridization of PCR amplicon on a
nitrocellulose strip coated with genotype-specific oligonucleotide probes
In addition to HCV genotype, a growing body of research indicates that
patient genetics play a role in response to treatment. The single-nucleotide
polymorphism (SNP) rs12979860, located near the IL28B gene on
chromosome 19, which encodes type III interferon, is associated with more
than a 2-fold difference in the rate of sustained virologic response to
antiviral treatment with pegylated interferon and ribavirin. This SNP can be
detected by PCR and is an independent predictor of sustained virologic
response regardless of HCV genotype. [48]

Approach Considerations
Patients with acute hepatitis C virus (HCV) infection appear to have an
excellent chance of responding to 6 months of standard therapy with
interferon (IFN). Because spontaneous resolution is common, no definitive
timing of therapy initiation can be recommended; however, waiting 2-4
months after the onset of illness seems reasonable.
In August 2014, the Infectious Diseases Society of America and the
American Associations for the Study of Liver Diseases, in collaboration
with the International Antiviral Society-USA, released a new section to
their online guidelines (hcvguidelines.org) to cover information on when to
begin therapy and in which patients with chronic hepatitis C virus (HCV)
infection.[50] The new section is intended to aid clinicians in prioritizing
treatment to patients who will benefit most.

Serologic Testing
Della Rossa et al reported that cryoglobulins are found in as many as 50%
of persons with HCV infection. [49] HCV is the primary cause of essential
mixedcryoglobulinemia (ie, type 2 cryoglobulinemia); as many as 90% of
affected persons have HCV viremia. Cryoprecipitates usually contain large
amounts of HCV antigens and antibodies. Vasculitis, arterial hypertension,
purpura, lichen planus, arthralgias, and low thyroxine levels were
associated with titers positive for cryoglobulin.
Other common serologic findings in patients with chronic HCV infection
include one or more of the following:

Antinuclear antibody (ANA; 41%)

Rheumatoid factor (38%)
Anticardiolipin antibody (27%)
Antithyroid antibody (13%)
Antismooth muscle antibody (9%)
Liver Biopsy
Liver biopsy is not considered mandatory before the initiation of treatment,
but it may be helpful for assessing the activity and severity of HCV-related
liver disease. However, some experts recommend biopsy only in the
following situations:

The diagnosis is uncertain

Other coinfections or disease may be present
The patient being considered for treatment has normal liver
enzyme levels and no extrahepatic manifestations
The patient is immunocompromised
Histologic Findings
Lymphocytic infiltration, moderate degrees of inflammation and necrosis,
and portal or bridging fibrosis are noted. Regenerative nodules are seen in
patients with cirrhosis. Some patients also may have findings indicative of
HCC.
Most pathologists give separate measurements of disease activity (grade)
and fibrosis (stage). Many scoring systems are used, including the Ishak (6point scale) and the Knodell histologic activity index (18-point score); both

The guidelines propose 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 include the
following[50] :

Patients with advanced fibrosis, those with compensated

cirrhosis, liver transplant recipients, and those with severe extraheptic
hepatitis are to be given the highest priority for treatment

Based on available resources, patients at high risk for liverrelated 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 (e.g., men who have high-risk sex with men,
active injection drug users, incarcerated persons, and those on
hemodialysis)
Treatment of chronic HCV infection has 2 goals. The first is to achieve
sustained eradication of HCV (ie, sustained virologic response [SVR]),
which is defined as the persistent absence of HCV RNA in serum 6 months
or more after completing antiviral treatment. The second goal is to prevent
progression to cirrhosis, hepatocellular carcinoma (HCC), and
decompensated liver disease requiring liver transplantation.
Antiviral therapy for chronic hepatitis C should be determined on a case-bycase basis. However, treatment is widely recommended for patients with
elevated serum alanine aminotransferase (ALT) levels who meet the
following criteria[6] :

Age greater 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/mm3, serum creatinine < 1.5 mg/dL)

Willingness to be treated and to adhere to treatment

requirements
No contraindications for treatment
A further criterion is liver biopsy findings consistent with a diagnosis of
chronic hepatitis. However, a pretreatment liver biopsy is not mandatory. It
may be helpful in certain situations, such as in patients with normal
transaminase levels, particularly those with a history of alcohol
dependence, in whom little correlation may exist between liver enzyme
levels and histologic findings.
Patients with normal liver enzyme levels and minimal histologic damage
noted on liver biopsy may elect to defer treatment until more effective and
less toxic medications become available, whereas patients with more
advanced liver injury may prefer to initiate treatment sooner. Patients
should be informed that the treatment of HCV infection in the setting of
normal liver enzyme levels remains controversial.
Viral load suppression reduces risk of hepatitis C liver morbidity and
mortality. In an observational study of Veterans Affairs (VA) HCV clinical
registry data from 128,769 patients that spanned more than a decade,
researchers found that those who achieved an undetectable HCV viral load
had a decreased risk of subsequent liver morbidity and death. [51, 52] Viral
load suppression reduced the risk for future liver events by 27% (eg,
compensated/decompensated cirrhosis, hepatocellular carcinoma, or liverrelated hospitalization) as well as reduced the risk of death by 45%, relative
to patients who did not achieve viral load suppression. Among the entire
study population, only 24% had been treated previously for HCV; of these
patients, only 16% (4% of all patients) achieved an undetectable viral load.
[51, 52]

Patient race/ethnicity and HCV genotypes also affected the risk of future
liver events and death. The risk for all liver events and death was higher in
white patients relative to black patients, and those with HCV genotype 3
had a higher risk for all study outcomes compared with patients who had
HCV genotype 2 (lowest risk) or 1.[51, 52]
The treatment of hepatitis C has evolved over the years. Initial studies used
IFN monotherapy. Subsequently, combination of ribavirin and IFN or of
IFN to which polyethylene glycol (PEG) molecules have been added (ie,
PEG-IFN) were used.
Protease inhibitors have emerged as a third feature of combination therapy.
The first protease inhibitor indicated for use in HCV infection, boceprevir
(Victrelis), was approved by the FDA in May 2011 followed by approval of
telaprevir. However these two protease inhibitors are not recommended due
to the more recent availability of more effective options. A third protease
inhibitor, simeprevir (Olysio), was approved in November 2013 and is
recommended as a part of combination therapy for chronic hepatitis C
infection.
Most recently, HCV NS5B polymerase inhibitor sofosbuvir (Sovaldi) was
shown to result in suppression of HCV replication and has emerged as an
important component of currently recommended regimens. In November
2014, the FDA approved an all oral regimen of simeprevir plus sofosbuvir
for treatment-nave or treatment-experienced patients.[53] The treatment
duration is 12 weeks for patients without cirrhosis and 24 weeks for those
with cirrhosis.

IFN monotherapy in acute hepatitis C

Although the short courses of standard IFN monotherapy introduced in the
1980s by Hoofnagle et al,[54] Davis et al,[7] and Di Bisceglie et al[55] 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. IFN
monotherapy may play a role in the treatment of acute HCV infection.
Jaeckel et al reported that treatment with IFN alfa-2b prevented chronic
infection in 98% of a group of 44 German patients with acute hepatitis C.
[56]
In this study, patients received 5 million U/day of IFN alfa-2b
subcutaneously for 4 weeks and then 3 times per week for another 20
weeks; the IFN alfa-2b was well tolerated in all patients but one. [56] Because
spontaneous resolution is common, no definitive timing of therapy can be
recommended; however, waiting 2-4 months after the onset of illness seems
reasonable.
PEG-IFN monotherapy
Several reports have documented improved SVR with PEG-IFN
monotherapy. In a randomized study of patients with chronic hepatitis C,
Zeuzem et al found that PEG-IFN alfa-2a at 180 mcg subcutaneously
administered once per week was associated with a higher rate of virologic
response than IFN alfa-2a at 6 million U subcutaneously administered 3
times per week for 12 weeks followed by 3 million U 3 times per week for
36 weeks.[57] Findings were 69% versus 28% at week 48 of therapy and
39% versus 19% at week 72 of therapy.[57]
In a controlled trial of persons with cirrhosis, Heathcote and colleagues
reported an SVR rate of 30% after 48 weeks of therapy with PEG-IFN alfa2a, compared with 8% for patients treated with standard IFN alfa. Adverse
effects were not significantly higher with the pegylated product.[58]
Interferons and Ribavirin
A major advance in the treatment of chronic hepatitis C was the addition of
the oral nucleoside analogue ribavirin to the IFN regimen. As reported in
the landmark 1998 studies by McHutchison et al [59] and Poynard et al,
[60]
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 6month course of therapy.
PEG-IFN therapy with ribavirin
As with IFN alfa, 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 3 landmark trials: Manns et al from 2001, [61] Fried et al from
2002,[62] and Hadziyannis et al from 2004.[63]
Manns et al reported a significantly higher SVR rate in patients given
higher-dose PEG-IFN alfa-2b plus ribavirin than in patients given lowerdose PEG-IFN alfa-2b plus ribavirin or given IFN alfa-2b plus ribavirin.
[61]
Adverse-effect profiles in the 3 treatment groups were similar.
Secondary analyses identified body weight and HCV RNA viral load less
than 1 million copies per milliliter as important predictors of SVR. (See the
image below.)

Interferons and Pegylated Interferons

The 2 most frequently used recombinant 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.
The addition of propylene glycol (PEG) molecules to IFN has led to the
development of long-lasting IFNs that have better sustained absorption, a
slower rate of clearance, and a longer half-life than unmodified IFN, which
permits more convenient once-weekly dosing. The FDA has approved
PEG-IFNs for the treatment of chronic hepatitis C.
Two PEG-IFN preparations are available. PEG-IFN alfa-2b (PEG-Intron)
consists of IFN alfa-2b attached to a single 12-kd PEG chain; it is excreted
by the kidneys. PEG-IFN alfa-2a (Pegasys) consists of IFN alfa-2a attached
to a 40-kd branched PEG molecule; it is metabolized predominantly by the
liver.

Pegylated interferon alfa-2b

plus ribavirin therapy for chronic hepatitis C.
Fried at al found that patients who received PEG-IFN alfa-2a plus ribavirin
had a significantly higher SVR rate than patients who received IFN alfa-2b
plus ribavirin (56% vs 44%) or PEG-IFN alfa-2a alone (56% vs 29%).
[62]
The SVR rates for patients with HCV genotype 1 were 46%, 36%, and
21%, respectively, for the 3 regimens.
Hadziyannis et al reported that in patients infected with HCV genotype 1,
48 weeks of treatment was statistically superior to 24 weeks, and standarddose ribavirin was statistically superior to low-dose ribavirin. [63] In this
study, 1311 persons were randomized to PEG-IFN alfa-2a at 180 mcg/wk

for 24 or 48 weeks plus a low dose (800 mg/day) or standard weight-based

dose (1000 or 1200 mg/day) of ribavirin.[63] In patients with HCV genotypes
2 or 3, there were no statistically significant differences in SVR rates in the
4 treatment groups.
In a study of ribavirin in combination with either PEG-IFN alfa-2b or PEGIFN alfa-2a for the treatment of chronic HCV infection, Ascione et al
reported a higher SVR rate with PEG-IFN alfa-2a than with PEG-IFN alfa2b (68% versus 54.4%).[64] SVR rates were not statistically different in
patients with a baseline HCV RNA of 500,000 IU/mL or less or in those
with cirrhosis. [64]
In a similar trial, Rumi et al reported that treatment with ribavirin plus
PEG-IFN alfa-2a resulted in a significantly higher SVR rate than ribavirin
plus PEG-IFN alfa-2b. The 2 regimens showed a similar safety profile.[65]
In a study of patients coinfected with HCV and HIV with compensated
cirrhosis, Mira et al found that SVR to PEG-IFN plus ribavirin significantly
reduced the incidence of liver-related decompensations and overall
mortality.[66] The probability of hepatic decompensation was 0% at 1 year
and 4% at 3 years for SVR patients, compared with 15% and 32%,
respectively, for non-SVR patients. The probability of overall mortality was
0% at 1 year and 4% at 3 years for SVR patients, compared with 12% and
20%, respectively, for non-SVR patients.
In conclusion, treatment with PEG-IFN alfa-2a and ribavirin may be
individualized by genotype. Patients with HCV genotype 1 require
treatment for 48 weeks and a standard dose of ribavirin; those with HCV
genotype 2 or 3 seem to be adequately treated with a low dose of ribavirin
for 24 weeks.[67]
Response to therapy of HCV genotype 1 (i.e. achievement of SVR) can
now be predicted by identifying the single neoceotide polymorphisms
(SNPs) located in the region of interleukin (IL)-28B gene through genomewide association studies. Patients with CC genotype of the IL-28B have
much more favorable response as compared to CT or TT genotypr (70% vs
25-30%). Testing for IL-28B genotype is thus a useful tool in the
managemet of patients.[68]
Adverse effects
Adverse effects are common with IFN and ribavirin combination therapy.
Approximately 75% of patients experience one or more of adverse effects.
Adverse effects of IFN include the following:

Hematologic complications (ie, neutropenia, thrombocytopenia)

Neuropsychiatric complications (ie, memory and concentration
disturbances, visual disturbances, headaches, depression, irritability)
Flu-like symptoms
Metabolic complications (ie, hypothyroidism, hyperthyroidism,
low-grade fever)
Gastrointestinal complications (ie, nausea, vomiting, weight
loss)
Dermatologic complications (ie, alopecia)
Pulmonary complications (ie, interstitial fibrosis)
Adverse effects of ribavirin include the following:
Hematologic complications (ie, hemolytic anemia)
Reproductive complications (ie, birth defects)
Metabolic complications (ie, gout)
Because of the risk of reproductive complications from ribavirin,
recommend that patients and their spouses not become pregnant while
either is on therapy and for 6 months after the completion of treatment.
Growth factors, such as granulocyte-stimulating factor (GSF) and
erythropoietin, are frequently used to counteract the adverse hematologic
effects of IFN and ribavirin, respectively. Despite the encouraging early
results reported by Afdhal et al[69] and Van Thiel et al,[70] cost-effectiveness
data supporting the routine use of these agents as a means of avoiding IFN
and ribavirin dose reductions are insufficient.
In November 2012, the US Food and Drug Administration (FDA) approved
eltrombopag (Promacta), an oral thrombopoietin agonist, for treatment of
thrombocytopenia in patients with chronic hepatitis C to allow the initiation

and maintenance of IFN-based therapy. The approval was based on results

from the phase 3 E ltrombopag to I N itiate and Maintain
Interferon A ntiviral Treatment toB enefit Subjects with Hepatitis C
related L iver Diseas E (ENABLE) 1 and 2 trials, which showed
eltrombopag significantly reduced the time to the first IFN dose reduction
compared with placebo.[71, 72]
Because of this, a significant improvement in virologic response was
observed in the eltrombopag group compared with placebo. These
randomized, double-blind, placebo-controlled, multicenter studies
collectively enrolled 1521 patients with platelet counts less than
75,000/mcL. ENABLE 1 utilized PEG-IFN alfa-2a plus ribavirin for
antiviral treatment and ENABLE 2 utilized PEG-IFN alfa-2b plus ribavirin.
In patients who are at risk of depression or who develop depression during
treatment, any antidepressant is better than none. Because available
evidence suggests that all antidepressants will have an effect, Schaefer et al
reported that treatment must be individualized on the basis of adverse effect
profile, drug-to-drug interactions, and general considerations (eg, speed of
onset, efficacy). [73]
Fatigue is common in patients with chronic hepatitis C but is poorly
associated with biochemical parameters. Sustained response is
accompanied by substantial improvement of fatigue. [74]
Protease and Polymerase Inhibitors
Protease inhibitors
Despite the improved results achieved with the addition of ribavirin to
PEG-IFN, the current available therapies for chronic HCV infection are
effective in fewer than 50% of patients with HCV genotype 1. A new class
of direct-acting antiviral agents (DAAs) has revolutionized the treatment of
HCV genotype 1 infection. These drugs target specific enzymes involved in
viral replication. The addition of these new protease inhibitors to pegylated
interferon and ribavirin is becoming the new standard of care for the
treatment of chronic HCV infection.
Boceprevir (Victrelis) and telaprevir (Incivek) are HCV NS3/4A protease
inhibitors and were approved by the US Food and Drug Administration
(FDA) in May 2011. However, treatment with either of these agents is no
longer recommended because of higher efficacy with regimens that contain
sofosbuvir or simeprevir. In August 2014, Vertex Pharmaceuticals
announced they will discontinue the sale and distribution of telaprevir in
the United States by October 2014.
A third HCV NS3/4A protease inhibitor, simeprevir (Olysio), was approved
in November 2013. Each of these is indicated for treatment of chronic HCV
genotype 1 infection in combination with PEG-IFN alfa and ribavirin in
adults with compensated liver disease, including cirrhosis, who are
previously untreated or who have failed previous interferon and ribavirin
therapy. In November 2014, the FDA approved an all-oral regimen of
simeprevir plus sofosbuvir for treatment-nave or treatment-experienced
patients; the duration of treatment is 12 weeks for patients without cirrhosis
and 24 weeks for those with cirrhosis.[53]
The approval for simeprevir plus sofosbuvir was based on the COSMOS
study, an open-label, randomized phase II clinical trial. [53] For all patients
(treatment-nave and treatment-experienced, with or without cirrhosis),
93% achieved a sustained virologic response at treatment week 12 (SVR12)
after 12 weeks of treatment, and 97% achieved SVR12 after 24 weeks of
treatment.[53]
The QUEST 1 and QUEST 2 phase 3 trials assessed efficacy of simeprevir
in 785 adult, treatment-nave patients with chronic HCV genotype 1.
Results showed that 80% and 81% of patients treated with simeprevir (plus
peginterferon alfa and ribavirin) achieved SVR12 compared with the
peginterferon alfa and ribavirin control groups (50%).[75]
In the PROMISE study, 393 patients who had previous relapse after
completing HCV treatment with pegylated interferon and ribavirin, were
randomized to receive either 150 mg of once-daily simeprevir for 12 weeks
plus pegylated interferon and ribavirin for 24 or 48 weeks based on
response guided treatment criteria (simeprevir group) or pegylated
interferon and ribavirin alone for 48 weeks (control group). In this study,
the SVR12 was 79% in the simeprevir treatment group compared with 37%
with peginterferon and ribavirin alone.[75]
The presence of the Q80K HCV GT1a polymorphism (commonly found in
GT1a patients in the United States) at baseline had a substantial impact on

the efficacy of simeprevir. In the pooled trials, the differences in SVR12

rates in GT1a patients with the Q80K polymorphism were not statistically
significant between the treatment (58%) and control (55%) groups. In
HPC3007, the SVR12 rates for those with the Q80K polymorphism were
47% in the treatment group and 30% in the control group.
Newer approaches to hepatitis C therapy involve treatment with 2 directacting antiviral agents. In a preliminary study a combination of NS5A
replication complex inhibitor daclatasvir (60 mg once daily) and the NS3
protease inhibitor asunaprevir (600 mg twice daily) resulted in a sustained
virologic response in patients with HCV genotype 1 infection who had not
responded to prior therapy with peginterferon and ribavirin. [76]
Polymerase inhibitors
HCV NS5B polymerase plays an essential role in HCV replication.
Sofosbuvir (Sovaldi) is a NS5B polymerase inhibitor that results in
suppression of HCV replication and life cycle. Sofosbuvir was approved by
the FDA in December 2013 for treatment of CHC infection genotypes 1, 2,
3, and 4 as part of a combination antiviral regimen, including those with
hepatocellular carcinoma meeting Milan criteria (awaiting liver
transplantation) to prevent HCV recurrence and those with HCV/HIV-1 coinfection.
Sofosbuvir treatment regimens and duration are dependent on both viral
genotype and patient population. Patients with genotype 1 or 4 are treated
with sofosbuvir plus peginterferon alfa and ribavirin for 12 weeks. Those
with genotype 2 or 3 are part of an all oral drug regimen consisting of
sofosbuvir plus ribavirin for 12 or 24 weeks respectively.
Approval for sofosbuvir was supported by data from several Phase 3
studies that evaluated 12 or 16 weeks of treatment with the drug combined
with either ribavirin or ribavirin plus peginterferon alfa. Three of these
studies evaluated sofosbuvir plus ribavirin in genotype 2 or 3 patients who
were either treatment-nave,[77] treatment-experienced[78] or peginterferon
intolerant, ineligible or unwilling.[78] The fourth study evaluated sofosbuvir
in combination with peginterferon/ribavirin in treatment-nave patients with
genotypes 1, 4, 5 or 6.[77]
In these studies, sofosbuvir-based therapy was found to be superior to
historical controls [77] or to placebo,[78] or noninferior to currently available
treatment options[77] based on the proportion of patients who had a sustained
virologic response 12 weeks after completing therapy (SVR12). Patients
who achieve SVR12 are considered cured of HCV. Trial participants taking
sofosbuvir-based therapy achieved SVR12 rates of 50-90%.
During the FDAs review, data from two additional Phase 3 studies were
added to the NDA as a result of the Breakthrough Designation status. In the
first study, patients with genotype 3 HCV infection were treated with
sofosbuvir and ribavirin for 24 weeks. Eighty-four percent of patients in
this trial achieved SVR12.[79] The second study evaluated sofosbuvir and
ribavirin for 12 weeks in patients with genotype 2 HCV infection coinfected with HIV-1.[80]
In all Phase 3 studies, no viral resistance to sofosbuvir was detected among
patients who relapsed following completion of therapy.
Harvoni is a combination oral product containing ledipasvir, an NS5A
protein inhibitor, and sofosbuvir that was approved by the FDA in October
2014 for HCV genotype 1. It is administered once daily and does not need
to be administered with interferon or ribavirin. Studies showed a high,
sustained virologic response (94-99%) in all treatment groups (ie,
treatment-nave or experienced, and with or without cirrhosis). [81, 82, 83]
This fixed-dose combination drug demonstrated efficacy in refractory
cirrhotic hepatitis C. In a study of 154 patients with cirrhotic chronic HCV
infection who had failed previous protease inhibitorbased therapy,
treatment with the fixed-dose combination of ledipasvir and sofosbuvir
(Harvoni) with or without ribavirin led to sustained viral response in the
majority of patients.[84, 85]
Study subjects received either ledipasvir and sofosbuvir plus placebo for 24
weeks or placebo for 12 weeks followed by edipasvir and sofosbuvir plus
ribavirin for 12 weeks. Sustained viral response 12 weeks after treatment
was seen in 96% of the 24-week combination group and 97% of the 12week combination plus ribavirin group. Three patients in the 12-week
group and two patients in the 24-week group experienced relapses.[84, 85]

Current treatment recommendations for chronic hepatitis C infection

(American Association for the Study of Liver Diseases [AASLD] and
the Infectious Disease Society of America [ISDA])[50]
Treatment-nave patients:

Genotype 1: sofosbuvir (SOF) 400mg daily with PEG

IFN/RBV (weight-based, 1000 to 1200mg daily) for 12 weeks or
simeprevir (SMV) 150mg with PEG IFN/RBV for 12 weeks followed by
another 12 weeks of PEG IFN/RBV; an alternative for IFN-ineligible
patients is combination SOF, SMV, and RBV for 12 weeks.

Genotype 2: SOF 400mg daily with RBV (weight-based, 1000

to 1200mg daily) for 12 weeks.

Genotype 3: SOF 400mg daily with RBV (weight-based, 1000

to 1200mg daily) for 24 weeks (an alternative is SOF with PEG
IFN/RBV for 12 weeks).

Genotypes 4: Daily sofosbuvir (400 mg) and weight-based RBV

(1000 mg [< 75 kg] to 1200 mg [75 kg]) plus weekly PEG for 12 weeks
is recommended for IFN-eligible. Alternatively, Daily simeprevir (150
mg) for 12 weeks and weight-based RBV (1000 mg [< 75 kg] to 1200
mg [75 kg]) plus weekly PEG for 24 to 48 weeks.

For IFN-ineligible patients, daily sofosbuvir (400 mg) plus

weight-based RBV (1000 mg [< 75 kg] to 1200 mg [75 kg]) for 24
weeks is recommended.

Genotype 5 to 6: Daily sofosbuvir (400 mg) and weight-based

RBV (1000 mg [< 75 kg] to 1200 mg [75 kg]) plus weekly PEG for 12
weeks is recommended for IFN-eligible persons. Alternatively, Daily
weight-based RBV (1000 mg [< 75 kg] to 1200 mg [75 kg]) plus
weekly PEG for 48 weeks is an acceptable regimen.
Patients with prior PEG IFN/RBV treatment failure:

Genotype 1: SOF 400mg daily, SMV 150mg daily, and RBV

(1000 to 1200mg daily) for 12 weeks (an alternative is SOF for 12
weeks with PEG IFN/RBV for 12 to 24 weeks or SMV 150mg for 12
weeks with PEG IFN/RBV for 48 weeks).
Genotype 2: SOF 400mg daily with RBV (weight-based, 1000
to 1200mg daily) for 12 weeks (an alternative is SOF 400mg daily with
PEG IFN/RBV [weight-based, 1000 to 1200mg daily] for 12 weeks).
Genotype 3: SOF 400mg daily with RBV (weight-based, 1000
to 1200mg daily) for 24 weeks (an alternative is SOF 400mg daily with
PEG IFN/RBV [weight-based, 1000 to 1200mg daily] for 12 weeks).
Genotypes 4 to 6: SOF 400mg daily with PEG IFN/RBV
(weight-based, 1000 to 1200mg daily) for 12 weeks.
Patients with genotype 1 and prior TVR or BOC protease
inhibitor failure: SOF for 12 weeks with PEG IFN/RBV for 12 to 24
weeks.
HIV-HCV Coinfection
The older therapy of HIV coinfected patients with PEG IFN/RBV and firstgeneration protease inhibitors has been replaced by SOF-based regimens.
The PHOTON-1 study evaluated sofosbuvir and ribavirin for 12 weeks in
patients with genotype 2 HCV infection co-infected with HIV-1 and for 24
weeks in patients with genotypes 1 or 3 HCV co-infected with HIV-1. Trial
participants achieved SVR12 rates of 76-92%.[80]
Current recommendations are very similar in HIV-HCV coinfected patients
to those for HCV monoinfected patients. For treatment-nave patients and
prior relapsers: in genotype 1, first-line therapy is SOF with PEG IFN/RBV
for 12 weeks (or SOF with RBV for 24 weeks in IFN-ineligible or
unwilling patients); in genotype 2, SOF with RBV for 12 weeks (consider
16 weeks in cirrhotics); in genotype 3, SOF with RBV for 24 weeks; in
genotype 4, SOF with PEG IFN/RBV for 12 weeks.
For treatment-experienced patients (partial and null responders): in
genotype 1, prior PEG IFN/RBV nonrespondersSOF, SMV (only with
ART drugs with which SMV does not have drug-drug interactions), and
RBV; for BOC or TVR nonrespondersSOF plus PEG IFN/RBV for 12
weeks; in genotypes 2, 3, and 4, the same regimens as in treatment-nave
patients.
Hepatitis C and B Coinfection
Coinfection with HCV and hepatitis B virus (HBV), in the absence of HIV
infection, is relatively uncommon in the United States, and optimal
treatment regimens have not been established. However, 2 important

studies are worth mentioning. Villa et al reported that 9 million U of

standard IFN 3 times weekly for 3 months could clear HCV in 31% of
patients with HCV-HBV coinfection. [86] Liu et al used standard IFN and
ribavirin and discovered that sustained HCV eradication was achieved at
rates comparable to those in patients with HCV alone and, interestingly, up
to 21% of their patients lost the hepatitis B surface antigen. [87]

Patients with Normal Liver Enzyme levels

The treatment for these patients remains controversial, because previous
studies have demonstrated that they frequently have mild liver disease, do
not tolerate therapy, or can develop new elevations in liver chemistry
parameters after starting treatment. Liver biopsy can be valuable in these
cases. Hui et al reported that ALT levels and histologic findings are not well
correlated and patients can have advanced fibrosis or cirrhosis in the
presence of normal liver enzyme levels. [97]

Given the superior efficacy of PEG-IFN over standard IFN, Liu et al

subsequently conducted a multicenter study using PEG-IFN and ribavirin
in HVC-HBC coinfected patients. This regimen proved equally effective in
patients with HCV monoinfection and in those with chronic HCV-HBV
infection.[88]

Jacobson et al reported that sustained HCV eradication rates in patients

with HCV infection and normal ALT values were comparable to those in
patients with elevated liver enzyme levels. [98] However, the authors used
both high-dose (5 million U) and low-dose (3 million U) IFN with ribavirin
in their study, and only 1 patient had cirrhosis. [98]

Interferon Response in Specific Populations

Several small studies have reported a lower response rate to IFN alfa in
black patients with chronic hepatitis C infection than in white patients. The
increased prevalence of infection with HCV genotype 1, which is
associated with a lower response rate than other genotypes, has been
suggested as the cause.

In addition, Jacobson et al did not investigate the role of previous alcohol

use on liver injury, although all patients abstained from alcohol for at least
12 months. Future trials will most likely evaluate PEG-IFN with ribavirin
in this cohort of patients, and the hope is they will adjust for confounders,
such as alcohol use.

However, in a study that enrolled equal proportions of black and nonHispanic white patients with chronic hepatitis from HCV genotype 1, Muir
et al reported that the SVR rate was significantly higher among nonHispanic white patients (52%) than among black patients (19%) after
treatment with PEG-IFN alfa-2b and ribavirin for 48 weeks. [89] Multivariate
analyses examining sociodemographic and clinical characteristics found
that black race was the only variable significantly associated with the
difference in response rates.

Patients Using Alcohol or Injection Drugs

In 1998, Wiley et al reported that significant alcohol use (>40 g alcohol/d
in women and >60 g of alcohol/day in men for >5 y) in HCV-infected
patients resulted in a twofold to threefold greater risk of liver cirrhosis and
decompensated liver disease. In addition, cirrhosis developed more rapidly
in alcohol users.[99]Because of the risk that alcohol use poses for rapid liver
fibrosis, hepatoma, and deleterious effects on treatment response, complete
alcohol abstinence is recommended during treatment.

Hepburn et al analyzed data from 661 patients in 2 multicenter trials and

found that compared with white patients, Asians were more likely to
respond to treatment, and Hispanics and blacks were less likely to respond.
[90]
The role of ethnicity in predicting successful viral eradication emerged
after multiple logistic regression analyses adjusted for factors known to
impact outcome (eg, genotype).

Practice guidelines from the American Association for the Study of Liver
Diseases recommend that HCV treatment not be withheld from patients
who use illicit drugs or are on a methadone maintenance program, provided
they are willing to maintain close monitoring, including practicing
contraception.[100] However, the guidelines note that "it is important to
consider the individual issues that may affect the risks and benefits of
treatment of HCV infection in persons who use illicit drugs, rather than to
make categorical recommendations." [91]

Nonresponse or Relapse
For patients who do not achieve an SVR after a full course of PEG-IFN
plus ribavirin, retreatment is recommended with regimens listed above.
Patients who do not respond to antiviral therapy and who have advanced
fibrosis should be screened for hepatocellular carcinoma (HCC) and varices
and should be evaluated for liver transplantation if they are appropriate
candidates. Patients with mild fibrosis should be monitored without
treatment.[91]

The complexity of HCV treatment in these patients is aided by a

multidisciplinary team approach composed of physicians, nurses, and
substance abuse and mental health professionals.
Deterrence/Prevention

Hayashi and Kasahara noted that exposure to IFN, irrespective of HCV

eradication status, was associated with a reduced incidence of HCC. [92] An
important randomized study by Kubo et al, first conducted in 1996 with
follow-up in 2002, also demonstrated that the administration of IFN to
patients undergoing liver resection for HCC was associated with reduced
tumor recurrence and improved survival.[93] Although IFN may have a role
in reducing the incidence of HCC, it remains unclear as to which subgroup
of HCV patients are most likely to benefit.

Currently, no products are available to prevent HCV infection. The

development of immunoprophylaxis for this disease is proving difficult; an
effective neutralizing immune response has not been demonstrated.

The aim of treating decompensated cirrhotic patients is to achieve sustained

viral eradication before liver transplantation in an attempt to prevent
recurrent HCV infection. However, this intervention is not recommended
outside of clinical trials because the risks of treatment can outweigh the
benefits.[94] Although viral titers may decrease during treatment and
possibly diminish the severity of recurrent HCV infection, complications
and successful eradication are less likely in patients with more advanced
liver disease.[95]

In an ongoing prospective study of prevention of HCV infection in

injection-drug users, researchers recommended 6 measures that can be used
to prevent the spread of hepatitis C[101, 102] :

Patients with hepatitis C should be advised to abstain from alcohol use;

they should also be advised to use barrier protection during sexual
intercourse. Screening high-risk patients and initiating appropriate
treatment may decrease the prevalence of cirrhosis and HCC.

Recurrence after liver transplantation

Recurrent HCV infection is universal after liver transplantation, can lead to
cirrhosis in 30% of patients within 5 years, and is emerging as the most
common cause of retransplantation in the United States. [96] IFN is
contraindicated after organ transplantation because of its high risk of
precipitating rejection, in part due to upregulation of the human leukocyte
antigen (HLA) system by IFN. Liver transplantation is a possible
exception, however, as allograft rejection is uncommon in liver transplant
recipients with recurrent HCV infection who are treated with IFN-based
therapies.
SOF-based therapy is now recommended for patients with recurrent
hepatitis C after liver transplantation; first-line regimens are as follows: for
genotype 1, SOF plus SMV with or without RBV for 12 to 24 weeks; for
genotypes 2 and 3, SOF plus RBV for 24 weeks

Reducing risk from shared ancillary drug preparation

equipment, such as containers, rinse water, and filters, in addition to
shared syringes
Using a new rapid test at the point of care that offers results in
20 minutes can detect infection before seroconversion occurs and,
combined with counseling, can help to stem transmission
Addressing social and relational contexts of injecting can
encourage uninfected individuals to take precautions when injecting
drugs with infected sex partners
Encouraging "taking a break" from injecting drugs
Developing models to guide delivery of new prevention
strategies, including already-available approaches such as increasing
syringe availability and future strategies such as direct-acting antivirals
that can be used prophylactically, as well as vaccines
Combining interventions in synergistic ways, such as needle
exchange and methadone maintenance programs
Consultations and Long-Term Monitoring

10

Consultation with a gastroenterologist and hepatologist is recommended in

the treatment of HCV infection. Consultation with a psychiatrist may be
helpful before and during treatment in patients at risk of depression or other
psychiatric illnesses. Consultation with a surgeon may be necessary for
patients in whom hepatic resection for HCC or liver transplantation is being
considered.

Chronic Hepatitis C

At week 12 of treatment, the patient should be evaluated for an early

virologic response by repeating the quantitative HCV RNA and IFNassociated thyroid dysfunction screening. If the HCV RNA level is
undetectable or if a greater than 2-log-fold reduction in HCV RNA level is
present, therapy should be continued because, according to Fried et al, up
to 65% of patients go on to develop an SVR.[62]

See content below for specific treatment regimens and duration

Conversely, if an early virologic response is not present, treatment should

be stopped, because the chance of developing a sustained response of HCV
eradication is less than 3%. Poynard et al reported that the one exception is
in the context of clinical trials or treatment of recurrent HCV infection in
liver transplant recipients[103] ; improved fibrosis scores have been reported
in patients in whom the virus has not been eradicated, thus identifying a
subgroup of patients who may benefit from maintenance therapy.

Indicated for treatment of chronic hepatitis C genotype 1 infection as a

component of a combination antiviral treatment regimen
150 mg PO qDay in combination with peginterferon alfa and ribavirin, or
in combination with simeprevir

Combination with peginterferon alfa and ribavirin

Treatment-nave and prior relapsed patients (including those

with cirrhosis): 12 weeks of treatment with simeprevir, peginterferon alfa,
and ribavirin FOLLOWED by an additional 12 weeks of peginterferon
alfa and ribavirin (total treatment duration of 24 wk)
All prior nonresponders (including partial and null-responders
and those with cirrhosis): 12 weeks of treatment with simeprevir,
peginterferon alfa, and ribavirin FOLLOWED by an additional 36 weeks
of peginterferon alfa and ribavirin (total treatment duration of 48 wk)

The HCV RNA level should be rechecked 6 months after the completion of
treatment; if HCV RNA is detectable, the patient has had a relapse of
disease and an alternative treatment should therefore be considered. If HCV
RNA is undetectable and test results remain negative, the patient has
developed an SVR.

Simeprevir (Olysio)

Simeprevir inhibits HCV NS3/4A protease needed for proteolytic cleavage

of the HCV-encoded polyprotein into mature forms. It is indicated for
chronic hepatitis C genotype 1a infection in combination with
peginterferon alfa and ribavirin, or as an all-oral regimen in combination
with sofosbuvir.

Patients with HCV infection should be monitored closely for adverse

effects as well as response to therapy. Tests to help monitor drug toxicity
include the following:

Complete blood count with differential

HCV Polymerase Inhibitors

Renal function testing

Class Summary

Liver function tests (including alanine aminotransferase [ALT]

HCV NS5B polymerase plays an essential role in HCV replication.

level)
Thyrotropin level
While measurement of ALT levels is useful for monitoring the effectiveness
of therapy for HCV infection, ALT levels can fluctuate. Consequently, a
single value in the reference range does not rule out active infection,
progressive liver disease, or cirrhosis. ALT normalization with therapy is
not proof of cure.

View full drug information

tablet

Chronic Hepatitis C

Patients with cirrhosis should be screened for HCC and esophageal varices.
They should also be monitored for the development of decompensated liver
disease. Vaccination against hepatitis A virus (HAV) and HBV before or
after completing HCV treatment has been recommended. [104] Patients should
be offered vaccination for HAV and HBV before they develop
decompensated liver disease, after which they may be less likely to mount
an immune response.

Indicated for treatment of chronic hepatitis C (CHC) infection as a

component of a combination antiviral regimen for patients with HCV
mono-infection and HCV/HIV-1 coinfection
Treatment regimen and duration are dependent on both viral genotype and
patient population
Genotype 1 or 4: 400 mg PO qDay plus ribavirin and peginterferon alfa for
12 weeks; may consider sofosbuvir plus ribavirin for 24 weeks in genotype
1 patients ineligible to receive peg-interferon-based regimen

Medication Summary
The addition of HCV protease and polymerase inhibitors to the
combination of PEG-IFN alfa and ribavirin has become the new standard of
care for the treatment of chronic HCV infection. Regimens that use these
new agents significantly improve sustained virologic response rates in
patients with genotype 1 HCV infection and, often, they also allow shorter
treatment durations.

Genotype 2: 400 mg PO qDay plus ribavirin for 12 weeks

Sofosbuvir is an oral NS5B polymerase inhibitor that was FDA-approved

for HCV genotypes 1, 2, 3, and 4. The combination of ledipasvir/sofosbuvir
is the first oral regimen without INF and ribavirin approved by the FDA for
HCV.

Sofosbuvir (Sovaldi)

Genotype 3: 400 mg PO qDay plus ribavirin for 24 weeks

Sofosbuvir is a NS5B polymerase inhibitor that results in suppression of

HCV replication and interrupts HCV life cycle. It is indicated for treatment
of CHC infection genotypes 1, 2, 3, and 4 as part of a combination antiviral
regimen, including those with hepatocellular carcinoma meeting Milan
criteria (awaiting liver transplantation) to prevent HCV recurrence and
those with HCV/HIV-1 co-infection.

HCV Protease Inhibitors

Class Summary
These agents interfere with HCV replication by inhibiting a key viral
enzyme, NS3/4A serine protease.

View full drug information

View full drug information

blet

capsule

400mg

150mg

90mg/400mg

11

Hepatitis C
Indicated for adults with chronic hepatitis C (CHC) genotype 1 infection
1 tablet (90mg/400mg) PO qDay
Treatment duration

PEG-IFN consists of IFN alfa-2b attached to a single 12-kd PEG chain. It

is excreted by the kidneys. PEG-IFN has sustained absorption, a slower rate
of clearance, and a longer half-life than unmodified IFN, which permits
more convenient once-weekly dosing and significantly improves quality of
life for patients. The adult dose is 1.5 mcg/kg SC.
View full drug information

Treatment-nave with or without cirrhosis: 12 weeks

Treatment-experienced without cirrhosis: 12 weeks

Pegylated interferon alfa-2a (Pegasys)

Treatment-experienced with cirrhosis: 24 weeks

Note: 8 weeks can be considered in treatment-nave patients
without cirrhosis who have pretreatment HCV RNA <6 million IU/mL

Ledipasvir/sofosbuvir (Harvoni)

PEG-IFN alfa-2a consists of IFN alfa-2a attached to a 40-kd branched PEG

molecule. It is predominantly metabolized by the liver. The adult dosage is
180 mcg/kg SC once weekly.
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Ribavirin (Rebetol, Virazole, Copegus, Moderiba, Ribasphere)

Ledipasvir inhibits HCV NS5A protein, which is required for viral

replication. Sofosbuvir is an inhibitor of HCV NS5B RNA-dependent
polymerase. The oral combination is indicated for adults with chronic
hepatitis C genotype 1 infection. Duration of therapy ranges from 8 to 24
weeks and depends on if the patient is treatment-nave or experienced, and
if cirrhosis is evident.
Interferons and ribavirin
Class Summary
Interferons are naturally produced proteins with antiviral, antitumoral, and
immunomodulatory actions. Interferons alfa, beta, and gamma may be
given topically, systemically, and intralesionally. Interferons are
immunomodulators that may shorten the clinical course, prevent
complications, prevent latent and/or subsequent recurrences, decrease
transmission, and eliminate established latency.

Ribavirin is an antiviral nucleoside analogue. Its chemical name is Dribofuranosyl-1H-1,2,4-triazole-3-carboxamide. Given alone, ribavirin has
little effect on the course of hepatitis C. Given with IFN, it significantly
augments the rate of sustained virologic response. The adult dosage is 10.6
mg/kg orally once daily or in 2 divided doses.
Thrombopoietin-Receptor Agonists
Class Summary
These agents directly stimulate bone marrow platelet production to provide
stable platelet counts to allow therapy with interferons.
View full drug information
Eltrombopag (Promacta)

View full drug information

njectable solution

6 million International Units/mL (3.8mL vial)

10 million International Units/mL (3.2mL vial)
hronic Hepatitis C

Oral thrombopoietin (TPO) receptor agonist. Interacts with transmembrane

domain of human TPO receptor and induces megakaryocyte proliferation
and differentiation from bone marrow progenitor cells. Indicated for
treatment of thrombocytopenia in patients with chronic hepatitis C to allow
the initiation and maintenance of interferon-based therapy.

3 million U IM/SC 3 times/wk for16 wk

If ALT normalized after 16 wk, continue treatment for 18-24 mo
If ALT not normalized or high levels of HCV RNA after 16 wk, consider
discontinuing treatment
Acute Hepatitis C
5 million U SC/IM qd for 4 wk, then 3 times/wk for 20 wk
If severe adverse reactions develop reduce dose by 50% or temporarily
withhold until adverse reactions abate
If intolerance persists discontinue permanently

Interferon alfa-2b (Intron-A)

IFN alfa-2b is a protein product manufactured by recombinant DNA

technology. The adult dosage is 3 million units subcutaneously (SC) 3
times weekly. Modulation of host immune response by IFN may play an
important role in the treatment of viral diseases.
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Peginterferon alfa-2b (PEG-Intron, Sylatron)

12