Diagnosis, Management, and Treatment of Hepatitis C:
Marc G. Ghany,1Doris B. Strader,2David L. Thomas,3and Leonard B. Seeff4
This document has been approved by the AASLD, the
Infectious Diseases Society of America, and the American
College of Gastroenterology.
to establishing guidelines. They are based on the following:
(1) a formal review and analysis of the recently published
ber 2008); (2) the American College of Physicians’ Manual
for Assessing Health Practices and Designing Practice Guide-
Development and Use of Practice Guidelines and the
American Gastroenterological Association’s Policy State-
ment on the Use of Medical Practice Guidelines;2and (4)
the experience of the authors in regard to hepatitis C.
Intended for use by physicians, these recommenda-
apeutic and preventive aspects of care. They are intended
to be flexible, in contrast to standards of care, which are
inflexible policies to be followed in every case. Specific
recommendations are based on relevant published infor-
supporting recommendations, the Practice Guidelines
Committee of the AASLD requires a Class (reflecting
benefit versus risk) and Level (assessing strength or cer-
tainty) of Evidence to be assigned and reported with each
recommendation (Table 1, adapted from the American
College of Cardiology and the American Heart associa-
tion Practice Guidelines).3,4
The hepatitis C virus (HCV) is a major public health
problem and a leading cause of chronic liver disease.5An
estimated 180 million people are infected worldwide.6In
between the years 1999 and 2002 was 1.6%, equating to
about 4.1 million persons positive for antibody to hepa-
titis C (anti-HCV), 80% of whom are estimated to be
viremic.7Hepatitis C is the principal cause of death from
tation in the U.S.8Some calculations suggest that mortal-
ity related to HCV infection (death from liver failure or
hepatocellular carcinoma) will continue to increase over
provide clinicians with evidence-based approaches to the
prevention, diagnosis, and management of HCV infec-
Testing and Counseling
Testing. The optimal approach to detecting HCV
infection is to screen persons for a history of risk of expo-
an identifiable risk factor.10Currently, injection drug use
is the primary mode of HCV transmission in the U.S;
thus, all persons who use or have used illicit injection
drugs in the present or past, even if only once, as well as
intranasal drug users who share paraphernalia, should be
tested for HCV infection.7,11,12Individuals who have re-
ceived a blood or blood component transfusion or an
Abbreviations: AASLD, American Association for the Study of Liver Diseases;
ALT, alanine aminotransferase; ANC, absolute neutrophil count; anti-HCV, an-
tibody to HCV; AST, aspartate aminotransferase; CKD, chronic kidney disease;
CTP, Child-Turcotte-Pugh; EIA, enzyme immunoassay; ETR, end-of-treatment
response; EVR, early virological response; FDA, U.S. Food and Drug Administra-
tion; HCV, hepatitis C virus; HIV, human immunodeficiency virus; PCR, poly-
merase chain reaction; PEG, polyethylene glycol; RVR, rapid virological response;
SVR, sustained virological response; ULN, upper limit of normal.
From the1Liver Diseases Branch, National Institute of Diabetes and Digestive
and Kidney Diseases, National Institutes of Health, Department of Health and
Human Services, Bethesda, MD;
Fletcher Allen Health Care, University of Vermont College of Medicine, Burling-
ton, VT;3Infectious Disease, The Johns Hopkins University School of Medicine,
Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD.
Received November 21, 2008; accepted November 23, 2008.
Disclaimer Statement: The views expressed in these guidelines do not necessarily
represent the views of the Department of Health and Human Services, the National
Institutes of Health, the National Institute of Diabetes and Digestive and Kidney
Diseases, or the United States Government.
Address reprint requests to: Leonard B. Seeff, M.D., Liver Disease Research
Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Na-
tional Institutes of Health, Building 31, Room 9A27, Bethesda, MD 20892. E-
mail: email@example.com; fax: 301-480-7926.
Copyright © 2009 by the American Association for the Study of Liver Diseases.
Published online in Wiley InterScience (www.interscience.wiley.com).
have no financial relationships to declare. Dr. David Thomas was on the Advisory
Board of Merck, Sharpe and Dohme at the time of writing but has since resigned
from this position.
All American Association for the Study Liver Diseases (AASLD) Practice Guide-
12 months old, please visit www.aasld.org for an update in the material.
2Division of Gastroenterology/Hepatology,
organ transplant before 1992 should also be tested. With
the introduction of sensitive tests to screen blood donors
for HCV antibodies in 1992, transfusion-transmission of
before 1987, after which time, viral inactivation procedures
were implemented.14Similarly, individuals with unex-
plained elevations of the aminotransferase levels (alanine
hemodialysis, children born to HCV-infected mothers, or
should be tested for the presence of HCV infection.15-17
Other potential sources of HCV transmission include
exposure to an infected sexual partner or multiple sexual
partners, exposure among health care workers to HCV-
contaminated blood and blood products, and tattoo-
ing.12,15,18-23The prevalence of HCV infection is
consistently higher among persons with multiple sexual
partners, whereas sexual transmission of HCV between
it is prudent to counsel HCV-infected persons to notify
low19that many authorities do not advise the use of bar-
of index HCV cases test positive for anti-HCV. There is
no need for HCV-infected persons to limit ordinary
household activities except for those that might result in
blood exposure, such as sharing a razor or toothbrush.
The hepatitis C virus is not transmitted by hugging, kiss-
ing, sharing of eating utensils or breastfeeding.
Folk medicine practices, including acupuncture and
ritual scarification, as well as body piercing, tattooing and
commercial barbering are potential modes for transmis-
sion of HCV infection when performed without appro-
priate infection control measures.24-28Transmission of
HCV infection by body piercing is, however, rare and
many HCV infected persons who have undergone body
piercing acquired their infection by other means.23,29-33
Therefore, there is no need to routinely test persons who
have received tattoos or undergone piercings in the ab-
sence of other risk factors, particularly if these procedures
have taken place in licensed establishments. Because
HCV infection, recognition of infection requires risk fac-
tor screening, which should be done whenever it is possi-
ble to link with appropriate HCV testing and
Table 2 outlines the list of persons who should be
such as those with a history of injection drug use or per-
sons with hemophilia, the prevalence of HCV is high
(?90%). For other groups (recipients of blood transfu-
sions prior to 1992), the prevalence is moderate (?10%).
partners of HCV-infected persons), the prevalence is low
(1% to 5%).
Table 1. Grading System for Recommendations
Class I Conditions for which there is evidence and/or general
agreement that a given diagnostic evaluation procedure
or treatment is beneficial, useful, and effective.
Conditions for which there is conflicting evidence and/or a
divergence of opinion about the usefulness/efficacy of
a diagnostic evaluation, procedure or treatment.
Weight of evidence/opinion is in favor of
Usefulness/efficacy is less well established by evidence/
Conditions for which there is evidence and/or general
agreement that a diagnostic evaluation, procedure/
treatment is not useful/effective and in some cases
may be harmful.
Level of EvidenceDescription
Level A Data derived from multiple randomized clinical trials
Data derived from a single randomized trial, or
Only consensus opinion of experts, case studies, or
Table 2. Persons for Whom HCV Screening is
● Persons who have injected illicit drugs in the recent and remote past,
including those who injected only once and do not consider themselves to
be drug users.
● Persons with conditions associated with a high prevalence of HCV infection
? Persons with HIV infection
? Persons with hemophilia who received clotting factor concentrates prior
? Persons who have ever been on hemodialysis
? Persons with unexplained abnormal aminotransferase levels
● Prior recipients of transfusions or organ transplants prior to July 1992
? Persons who were notified that they had received blood from a donor
who later tested positive for HCV infection
? Persons who received a transfusion of blood or blood products
? Persons who received an organ transplant
● Children born to HCV-infected mothers
● Health care, emergency medical and public safety workers after a needle
stick injury or mucosal exposure to HCV-positive blood
● Current sexual partners of HCV-infected persons*
Table adapted from “Recommendations for prevention and control of hepatitis
C virus (HCV) infection and HCV-related chronic disease.” Centers for Disease
Control and Prevention. MMWR Recomm Rep 1998;47(RR-19):1-39.
*Although the prevalence of infection is low, a negative test in the partner
provides reassurance, making testing of sexual partners of benefit in clinical
1336 GHANY ET AL. HEPATOLOGY, April 2009
1. As part of a comprehensive health evaluation, all
persons should be screened for behaviors that place
them at high risk for HCV infection. (Class I, level B).
2. Persons who are at risk should be tested for the
presence of HCV infection (Table 2) (Class I, level B).
Counseling. Good clinical practice dictates that per-
sons found to be HCV-infected are counseled regarding
prevention of spread of the virus to others. Because expo-
sure to infected blood is the primary mode of transmis-
sion, it is essential to inform HCV-infected individuals
that precautions should be taken to avoid the possibility
of exposing others to contact with their blood. This is
particularly important for injection drug users who are
the leading source of HCV infection, because their trans-
infected implements. Table 3 outlines the measures to
avoid HCV transmission.
3. Persons infected with HCV should be counseled
on how to avoid HCV transmission to others, as in-
dicated in Table 3 (Class I, level C)
Two classes of assays are used in the diagnosis and
management of HCV infection: serologic assays that de-
molecular assays that detect viral nucleic acid. These as-
says have no role in the assessment of disease severity or
Tests that detect anti-HCV are
used both to screen for and to diagnose HCV infection.
number of immunoassays. Two enzyme immunoassays
(EIAs) are approved by the U.S. Food and Drug Admin-
istration (FDA) for clinical use, Abbott HCV EIA 2.0
(Abbott Laboratories, Abbott Park, IL) and ORTHO?
HCV Version 3.0 ELISA (Ortho-Clinical Diagnostics,
Raritan, NJ), as well as one enhanced chemiluminescence
immunoassay (CIA) VITROS? Anti-HCV assay, (Or-
tho-Clinical Diagnostics, Raritan, NJ). The specificity of
current EIAs for anti-HCV is greater than 99%.34False
positive results are more likely to occur when testing is
performed among populations where the prevalence of
hepatitis C is low. False negative results may occur in the
setting of severe immunosuppression such as infection
with HIV, solid organ transplant recipients, hypo- or ag-
gammaglobulinemia or in patients on hemodialysis.35-37
3.0 SIA (Chiron Corporation, Emeryville, CA) is also
FDA approved. This assay was originally developed as a
third generation EIA results that exceed particular signal/
cutoff ratios (e.g., ?3.8 for the above mentioned Or-
tho and Abbott EIA tests). Given the widespread
availability of nucleic acid testing, the role for RIBA test-
ing in HCV diagnosis and management has all but disap-
The list of commercial assays
available for the detection (qualitative assays) or quantifi-
cation (quantitative assays) of HCV RNA is shown in
Tables 4 and 5. Historically, qualitative assays have been
Table 3. Measures to Avoid Transmission of HCV
● HCV-infected persons should be counseled to avoid sharing toothbrushes
and dental or shaving equipment, and be cautioned to cover any bleeding
wound in order to prevent contact of their blood with others
● Persons should be counseled to stop using illicit drugs. Those who continue
to inject drugs should be counseled to avoid reusing or sharing syringes,
needles, water, cotton or other paraphernalia; to clean the injection site with
a new alcohol swab; and to dispose of syringes and needles after one use
in a safe, puncture-proof container
● HCV-infected persons should be advised to not donate blood, body organs,
other tissue or semen
● HCV-infected persons should be counseled that the risk of sexual
transmission is low, and that the infection itself is not a reason to change
sexual practices ( i.e., those in long-term relationships need not start using
barrier precautions and others should always practice “safer” sex)
Table adapted from “Recommendations for prevention and control of hepatitis
C virus (HCV) infection and HCV-related chronic disease.” Centers for Disease
Control and Prevention. MMWR Recomm Rep 1998;47(RR-19):1-39.
Table 4. FDA Approved Qualitative Assays for Detection of HCV RNA
Assay and ManufacturerMethod
Lower Limit of
Amplicor HCV v2.0 (Roche Molecular Systems)
Cobas Amplicor HCV v2.0 (Roche Molecular Systems)
Ampliscreen (Roche Molecular Systems)
Versant HCV RNA Qualitative Assay, (Siemens Healthcare Diagnostics)
Procleix HIV-1/HCV Assay (Chiron Corporation)
Diagnosis and monitoring
Diagnosis and monitoring
Diagnosis and monitoring
Abbreviations: RT-PCR, reverse transcription polymerase chain reaction; TMA, transcription-mediated amplification
HEPATOLOGY, Vol. 49, No. 4, 2009 GHANY ET AL. 1337
more sensitive than quantitative assays. With the recent
based assays and transcription-mediated amplification
(TMA) assays, with sensitivities of 10-50 IU/mL, there is
no longer need for qualitative assays.42,43A highly sensi-
tive assay with this lower limit of detection is considered
appropriate for monitoring during therapy. All currently
available assays have excellent specificity, in the range of
98% to 99%. In 1997, the World Health Organization
nucleic acid technology,44and the IU rather than viral
copies is now the preferred unit to report test results.44,45
For monitoring purposes, it is important to use the same
laboratory test before and during therapy.
Genotyping Assays. Genotyping is useful in epide-
miological studies and in clinical management for pre-
dicting the likelihood of response and determining the
optimal duration of therapy. The hepatitis C virus can be
classified into at least 6 major genotypes (genotypes 1 to
6) based on a sequence divergence of 30% among iso-
mon in the U.S., followed by genotypes 2 and 3. Less
common genotypes (genotypes 4-6) are beginning to be
observed more frequently because of the growing cultural
diversity within the United States.47Several commercial
assays are available to determine HCV genotypes using
direct sequence analysis of the 5? non-coding region, that
include Trugene 5?NC HCV Genotyping kit (Siemens
Healthcare Diagnostics Division, Tarrytown, NY), re-
verse hybridization analysis using genotype specific oligo-
nucleotide probes located in the 5? non-coding region,
INNO-LiPa HCV II, (Innogenetics, Ghent, Belgium),
and Versant HCV Genotyping Assay 2.0 (Siemens
Healthcare Diagnostics Division, Tarrytown, NY). In-
correct typing among the major genotypes is rare (?3%)
and mixed genotypes occur but are uncommon. Occa-
sionally (?5%), tested samples cannot be genotyped.
This usually results from low viral levels, issues with the
PCR amplification step of the assay, or extreme nucleo-
tide variability within the HCV genome.48
Diagnosis of Acute and Chronic HCV
Infection and Interpretation of Assays
The diagnosis of acute or chronic HCV infection gen-
(anti-HCV) and for HCV RNA. A sensitive quantitative
also provides information on the level of virus which is
helpful in management.
The differentiation of acute from chronic HCV infec-
tion depends on the clinical presentation: namely the
presence of symptoms or jaundice, and whether or not
there was a prior history of ALT elevation and its dura-
tion. After acute exposure, HCV RNA is usually detected
early as 2 weeks following exposure whereas anti-HCV is
generally not detectable before 8-12 weeks. These two
markers of HCV infection may be present in varying per-
mutations, requiring careful analysis for interpretation
Table 5. Available Assays for Quantification of HCV in Serum/Plasma
Assay (Manufacturer) Method
Amplicor HCV Monitor
(Roche Molecular Systems)
Cobas Amplicor HCV Monitor V2.0
(Roche Molecular Systems)
Versant HCV RNA 3.0 Assay (bDNA)
(Siemens Health Care Diagnostics)
LCx HCV RNA-Quantitative Assay
(National Genetics Institute)
Cobas Taqman HCV Test
(Roche Molecular Systems)
Manual RT-PCR0.9 copies/mL 600-500,000Yes
Semi-automated RT-PCR 2.7 copies/mL 600-500,000Yes
Semi-automated bDNA signal amplification5.2 copies/mL615-7,700,000Yes
Semi-automated RT-PCR 3.8 copies/mL25-2,630,000 No
Semi-automated RT-PCR3.4 copies/mL 30-1,470,000 No
Semi-automated real-time PCR 43-69,000,000 Yes
Semi-automated RT-PCR 12-100,000,000No
Table 6. Interpretation of HCV Assays
Anti-HCV HCV RNAInterpretation
PositivePositiveAcute or chronic HCV depending on the
Resolution of HCV; Acute HCV during
period of low-level viremia.
Early acute HCV infection; chronic HCV
in setting of immunosuppressed
state; false positive HCV RNA test
Absence of HCV infection
1338GHANY ET AL. HEPATOLOGY, April 2009
One pattern is the identification of both anti-HCV
and HCV RNA in a person with recent elevation of the
ALT value. This scenario is consistent with either acute
HCV infection when there is a recent known risk expo-
sure, with exacerbation of chronic HCV infection, or
with an acute hepatitis of another etiology in a patient
with chronic HCV infection. Another pattern is the de-
tection of anti-HCV but with a negative test for HCV
RNA. This may represent acute HCV infection during a
period of transient clearance of HCV RNA, a false posi-
tive or negative result or, more commonly, recovery from
HCV infection. Re-testing for HCV RNA 4-6 months
later is recommended to confirm the resolution of HCV
infection. The reverse scenario — a negative anti-HCV
test but a positive result for HCV RNA — is compatible
with the early stage of acute infection prior to the devel-
an immunosuppressed individual. Alternatively, it may
represent a false positive HCV RNA result. In all circum-
stances, re-testing for anti-HCV and HCV RNA in 4-6
raised ALT values but the tests for anti-HCV and HCV
RNA are negative, both acute and chronic hepatitis C
may be excluded and another diagnosis should be consid-
ered. Antibody testing should be repeated in 4-6 months
for confirmation purposes.
4. Patients suspected of having acute or chronic
HCV infection should first be tested for anti-HCV
(Class I, Level B.)
5. HCV RNA testing should be performed in:
a) Patients with a positive anti-HCV test (Class I,
b) Patients for whom antiviral treatment is being
considered, using a sensitive quantitative assay (Class
I, Level A)
c) Patients with unexplained liver disease whose
anti-HCV test is negative and who are immunocom-
promised or suspected of having acute HCV infection
(Class I, Level B).
6. HCV genotyping should be performed in all
HCV-infected persons prior to interferon-based treat-
ment in order to plan for the dose and duration of
therapy and to estimate the likelihood of response
(Class I, Level A)
Utility of the Liver Biopsy and Noninvasive
Tests of Fibrosis
There are three primary reasons for performing a liver
biopsy: it provides helpful information on the current
status of the liver injury, it identifies features useful in the
decision to embark on therapy, and it may reveal ad-
vanced fibrosis or cirrhosis that necessitates surveillance
varices. The biopsy is assessed for grade and stage of the
liver injury, but also provides information on other histo-
logical features that might have a bearing on liver disease
progression.49The grade defines the extent of necroin-
flammatory activity, while the stage establishes the extent
of fibrosis or the presence of cirrhosis. Several scoring
French METAVIR, the Batts-Ludwig, the International
Association for the Study of the Liver (IASL) and the
mon non-HCV conditions that might affect disease pro-
gression and possibly impede treatment response are
steatosis49,55,56and excess hepatocellular iron.57Identify-
ing either of these two features does not preclude initiat-
ing treatment, but their presence provides additional
information regarding the likelihood of response to treat-
The liver biopsy has been widely regarded as the “gold
standard” for defining the liver disease status, but it has
drawbacks that have prompted questions about its val-
ue.61,62The procedure is not without risks (including
pain, bleeding and perforation of other organs),63,64it is
Table 7. Comparison of Scoring Systems for Histological Stage
Fibrous portal expansion
Periportal fibrotic expansion
Fibrous expansion of some portal areas with or without short fibrous
Fibrous expansion of most portal areas with or without short fibrous
Fibrous expansion of most portal areas with occasional portal to
Fibrous expansion of most portal areas with marked bridging (portal
to portal and portal to central)
Marked bridging (portal to portal and portal to central) with
occasional nodules (incomplete cirrhosis)
2Moderate fibrosis Rare bridges or septaePeriportal septae 1
Porto-central septae3 Severe fibrosis Numerous bridges or
HEPATOLOGY, Vol. 49, No. 4, 2009GHANY ET AL.1339
interpreting the histopathology, it adds cost to medical
care, and it is anxiety-provoking for the implicated per-
son. Thus, efforts are underway to seek alternative means
of establishing information on the extent of fibrosis by
focusing on noninvasive blood marker panels.66These
markers are useful for establishing the two ends of the
fibrosis spectrum (minimal fibrosis and cirrhosis) but are
less helpful in assessing the mid-ranges of fibrosis or for
tracking fibrosis progression.66The recently developed
transient elastography that uses ultrasound and low fre-
quency elastic waves to measure liver elasticity67has im-
proved the ability to define the extent of fibrosis without
a liver biopsy, particularly when combined with other
noninvasive markers.68However, it is not yet ready to
replace the liver biopsy since it is not FDA approved, the
failure rate is higher in obese patients, and there is now
evidence that the transient elastography score can be un-
expectedly increased in persons with acute hepatitis who
have high necroinflammatory activity but no or minimal
A liver biopsy may be unnecessary in persons with ge-
notypes 2 and 3 HCV infection, since more than 80% of
them achieve a sustained virlogical response (SVR) to
standard-of-care treatment. There is, however, an ongo-
ing debate about whether a biopsy is warranted for per-
sons infected with HCV, genotype 1, whose response to
is whether there is need for a liver biopsy in persons in-
fected with the other less common genotypes (4 through
Thus, although the liver biopsy was previously re-
garded as routine for defining the fibrosis stage in persons
with genotype 1 infection,62the issue is now in a state of
flux and possible transition. Supporters of a biopsy cite
apy and are therefore willing to withhold or delay treat-
ment if liver histology displays minimal to moderate
fibrosis stage ?2 (Table 7), especially if the infection is
known to have been long-standing. These individuals are
regarded as having slowly progressive liver disease that
may not be responsible for their ultimate demise74-76
However, treatment is advised for those with more ad-
ever, that while information obtained from a biopsy is
useful, the procedure is not mandatory for deciding on
treatment. If performed and treatment is withheld, a
common strategy is to repeat the liver biopsy 4 to 5 years
of disease progression.77
The earlier views that persons with genotype 1 infec-
tion and persistently normal aminotransferase values did
not require a liver biopsy because they were believed to
have minimal liver disease, and that treatment may actu-
ally be harmful, are no longer valid.78It is now apparent
that as many as a quarter of such individuals have signif-
levels.82-84Therefore, the decision to perform a liver bi-
opsy should be based on whether treatment is being con-
sidered, taking into account the estimated duration of
the platelet count), the viral genotype, and the patient’s
treated. If the biopsy is not performed and treatment not
undertaken, the patient should continue to be monitored
at least annually and a biopsy performed if the amino-
transferase values become abnormal and other indicators
of progressing liver disease become apparent.
7. A liver biopsy should be considered in patients
with chronic hepatitis C infection if the patient and
health care provider wish information regarding fi-
brosis stage for prognostic purposes or to make a
decision regarding treatment (Class IIa, Level B)
8. Currently available noninvasive tests may be
useful in defining the presence or absence of advanced
fibrosis in persons with chronic hepatitis C infection,
but should not replace the liver biopsy in routine
clinical practice (Class IIb, Level C).
Initial Treatment of HCV Infection
Justification for Treatment. Natural history studies
indicate that 55% to 85% of individuals who develop
taneous resolution is more common among infected in-
fants and young women than among persons who are
older when they develop acute hepatitis.86Chronic HCV
infection has relevance for the infected persons as well as
for their contacts: the former are at risk for progression to
cirrhosis and/or HCC, the latter are at risk of acquiring
the infection through exposure to the virus. The risk of
developing cirrhosis ranges from 5% to 25% over periods
of 25 to 30 years.87,88Prospective studies of women and
years report low rates of cirrhosis, 1% to 3%.75,89-92Ret-
ities document higher rates of cirrhosis, 20% to 25%, but
1340 GHANY ET AL.HEPATOLOGY, April 2009
age, who are obese, who are immunosuppressed (e.g.,
HIV co-infected), and who consume more than 50g of
alcohol per day, although the precise quantity of alcohol
sons with HCV-related cirrhosis are at risk for the devel-
opment of hepatic decompensation (30% over 10 years)
Identifying individuals at risk for developing progres-
to assess the degree of fibrosis on liver biopsy, using a
validated staging system such as the Ishak, IASL, Metavir
or Batts-Ludwig staging systems.94,96,100Persons with no
or minimal fibrosis (Ishak stage 0-2; Metavir, IASL and
Batts-Ludwig stage 0-1) have a low risk for liver-related
complications and liver-related death (over the next 10 to
20 years). However, the presence of bridging fibrosis (for
example Metavir stage 3, Table 7) is an important predic-
tor of future progression to cirrhosis and therefore an
indication for treatment.101
Infection with HCV can also cause extrahepatic dis-
eases including mixed cryoglobulinemia, types II and III.
Indeed, symptomatic cryoglobulinemia is an indication
for HCV antiviral therapy regardless of the stage of liver
disease. (See section on Treatment of Patients with Kid-
Treatment Objectives and Outcomes. The goal of
therapy is to prevent complications and death from HCV
infection. Because of the slow evolution of chronic HCV
onstrate that therapy prevents complications of liver dis-
ease. Accordingly, treatment responses are defined by a
surrogate virological parameter rather than a clinical end-
point. Short-term outcomes can be measured biochemi-
cally (normalization of serum ALT levels), virologically
(absence of HCV RNA from serum by a sensitive PCR-
based assay), and histologically (?2 point improvement
in necroinflammatory score with no worsening in fibrosis
score).71,72Several types of virological responses may oc-
cur, labeled according to their timing relative to treat-
ment. The most important is the sustained virological
response (SVR), defined as the absence of HCV RNA
from serum by a sensitive PCR assay 24 weeks following
discontinuation of therapy (Table 8, Fig. 1). This is gen-
erally regarded as a “virological cure,” although liver can-
cer has been identified years later, especially if cirrhosis
existed at the time of achieving an SVR.102
Undetectable virus at the end of either a 24-week or
48-week course of therapy is referred to as an end-of-
treatment response (ETR). An ETR does not accurately
A rapid virological response (RVR), defined as unde-
tectable HCV RNA at week 4 of treatment, using a sen-
sitive test with a lower limit of detection of 50 IU/mL,
predicts a high likelihood of achieving an SVR.103,104An
early virological response (EVR) is defined as a ?2 log
reduction or complete absence of serum HCV RNA at
ure to achieve an EVR is the most accurate predictor of
not achieving an SVR.72,105-107Monitoring viral kinetics
is thus useful for predicting whether or not an SVR is
likely to develop.
Virological breakthrough refers to the reappearance of
HCV RNA while still on therapy, while virological re-
lapse is the reappearance of HCV RNA in serum after
treatment is discontinued and an ETR was documented.
Persons who fail to suppress serum HCV RNA by at least
2 logs after 24 weeks of therapy are null responders, while
Table 8. Virological Responses During Therapy and Definitions
Virological Response DefinitionClinical Utility
Rapid virological response (RVR)HCV RNA negative at treatment week 4 by a sensitive PCR-
based quantitative assay
May allow shortening of course for genotypes
2&3 and possibly genotype 1 with low viral
Predicts lack of SVREarly virological response (EVR)
? 2 log reduction in HCV RNA level compared to baseline HCV
RNA level (partial EVR) or HCV RNA negative at treatment
week 12 (complete EVR)
HCV RNA negative by a sensitive test at the end of 24 or 48
weeks of treatment
HCV RNA negative 24 weeks after cessation of treatment
End-of-treatment response (ETR)
Sustained virological response (SVR) Best predictor of a long-term response to
Reappearance of HCV RNA in serum while still on therapy
Reappearance of HCV RNA in serum after therapy is
Failure to clear HCV RNA from serum after 24 weeks of therapy
Failure to decrease HCV RNA by ? 2 logs after 24 week of
Two log decrease in HCV RNA but still HCV RNA positive at
HEPATOLOGY, Vol. 49, No. 4, 2009 GHANY ET AL. 1341
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1374GHANY ET AL. HEPATOLOGY, April 2009
In the practice guideline “Diagnosis, Management, and Treatment of Hepatitis C: An Update ”
(HEPATOLOGY 2009:49 (4): 1335-1374; DOI: 10.1002/hep.22759), two errors have been corrected
in the online version.
1. The Treatment Objectives and Outcomes section contained an error which has been
corrected to read: “Short-term outcomes can be measured biochemically
(normalization of serum ALT levels), virologically (absence of HCV RNA from serum
by a sensitive PCR based assay), and histologically (>2 point improvement in
necroinflammatory score with no worsening in fibrosis score).71,72
2. In Table 11, the following sentence has been deleted from the second bullet:
“Candidates should be abstinent for a minimum period of 6 months.”