A so
S of
H
de
res
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len
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th
(H
ne
he
pr
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inf
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ne
ach
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intended to assist physicians and other health care
workers in arriving at reasoned patient care decisions,2
are designed to be flexible rather than rigidly inflex-
ibl
th
cas
ph
sta
lin
soc
rel
wh
no
jec
be
HC
rec
fre
co
an
ch
son
rec
pa
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wh
can
for
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an
rec
co
co
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asp
for therapy. All candidates for antiviral therapy should
be tested for HCV RNA with a quantitative amplifi-
GASTROENTEROLOGY 2006;130:225–230
e universally applied “standards of care.” Although
ese recommendations should be followed in most
es, management decisions are left to the individual
ysician and health care worker based on the circum-
cation assay and should be tested for HCV genotype.
Patients in whom antiviral therapy is being considered
are candidates for liver biopsy, the gold standard for
merican Gastroenterological As
tatement on the Management
epatitis C accounts for a sizable proportion of
cases of chronic liver disease, liver disease
aths, and cases of hepatocellular carcinoma and rep-
ents the most common indication for liver trans-
ntation. Projections based on the current preva-
ce of infection and anticipated rates of progression
ggest that the morbidity and mortality, as well as
e medical care costs attributable to hepatitis C virus
CV) infection, will escalate alarmingly during the
xt 2 decades.
The substantial clinical and economic impact of
patitis C focuses attention on the critical need to
event and control HCV infection. Public health
asures, changes in behavior to avoid blood-borne
ections, and screening of donated blood and organs
HCV have reduced dramatically the frequency of
w infections, and substantial progress has been
ieved in antiviral therapy for hepatitis C. Applied
ectively, contemporary antiviral therapy can pre-
nt chronic infection in almost all persons with acute
patitis C and can cure chronic liver disease associ-
d with HCV infection in as many as half of patients
th compensated, HCV-associated liver disease. In
ort, hepatitis C is an important public health prob-
whose consequences can be reduced by appropri-
application of antiviral therapy. Because the de-
nd for management of chronic hepatitis C has
reased so considerably over the past decade, the
erican Gastroenterological Association developed a
hnical review1 and this medical position statement.
This medical position statement, which contains
actice guidelines intended for physicians, nurse
actitioners, physician assistants, and other health
e workers who participate in the care of patients
th hepatitis C, includes suggestions for preferable
proaches to the management of persons with hepa-
is C. These guidelines, which are recommendations
nces of the individual patient. As in previous guide-
es issued by the American Gastroenterological As-
ciation Medical Position
Hepatitis C
iation, specific recommendations are based on
evant published information.
Screening
Routine screening of all asymptomatic adults,
o have a low prior probability of HCV infection, is
t recommended. Among high-risk groups (eg, in-
tion drug users, persons who received a transfusion
fore 1992 [when donor screening for antibody to
V was introduced], persons with hemophilia who
eived clotting factors before 1987, persons with
quent percutaneous exposures, immigrants from
untries with a high prevalence of HCV infection,
d persons with clinical or biochemical evidence for
ronic liver disease, even among asymptomatic per-
s), diagnostic testing for HCV infection has been
ommended by the US Public Health Service, expert
nels, and professional medical specialty societies.
ouses of persons with chronic hepatitis C are also
didates for HCV serologic testing. Persons in
om the diagnosis of hepatitis C is established are
didates for hepatitis A and hepatitis B vaccines.
Pretreatment Diagnostic Evaluation
of Patients With Chronic
Hepatitis C
Persons with a reactive enzyme immunoassay
antibody to HCV, the presence of HCV RNA, and
mpensated liver disease are potential candidates for
tiviral therapy. Currently, antiviral therapy is not
ommended routinely for patients with hepatic de-
mpensation; patients with a history of severe, un-
ntrolled psychiatric disorder; and/or patients with
ere hematologic cytopenias.
Elevation of alanine aminotransferase (ALT) and
artate aminotransferase levels is not a requirement
© 2006 by the American Gastroenterological Association
0016-5085/06/$32.00
doi:10.1053/j.gastro.2005.11.011
de
ten
tie
ME
his
me
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to
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by
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th
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226 AMERICAN GASTROENTEROLOGICAL ASSOCIATION GASTROENTEROLOGY Vol. 130, No. 1
termining histologic grade and stage, unless the po-
tial for complications is unacceptably high. For pa-
nts with moderate to severe fibrosis (Ishak stage �3,
TAVIR stage �F2; please see technical review1 for
tologic scoring systems), antiviral therapy is recom-
nded uniformly. For patients with milder histologic
ease, progression may be sufficiently slow to justify
nitoring without imminent therapeutic intervention
a proportion of these patients (see Treatment Recom-
ndations). For patients with genotypes 2 and 3, the
elihood of response is so high that the benefits of
atment may outweigh the importance of histologic
siderations; therefore, some authorities forego a base-
e liver biopsy in patients with genotypes 2 and 3. Data
support routine ultrasonography for localization of the
er before liver biopsy are insufficient to justify man-
ting prebiopsy ultrasonography in all cases and for all
ctitioners regardless of levels of skill and experience.
Treatment of Chronic Hepatitis C
The current standard of care for the treatment
previously untreated patients with chronic hepatitis
is combination pegylated interferon (PEG-IFN) alfa
subcutaneous injection once a week and oral riba-
in daily. For patients with contraindications to
avirin but who have indications for antiviral ther-
y, PEG-IFN represents the best available treatment.
Two PEG-IFN alfa preparations are available: (1)
G-IFN alfa-2b, administered at a weight-based,
-�g/kg dose, and (2) PEG IFN alfa-2a, adminis-
ed at a fixed, 180-�g dose. Randomized controlled
als (RCTs) have shown that combination PEG-IFN
a and ribavirin therapy can achieve a sustained
ologic response (SVR) in 54%–56% of patients:
%–52% of patients with genotype 1 and 76%–84%
those with genotypes 2 and 3. Whether one of these
G-IFN/ribavirin regimens or weight-based modifi-
ions of the 2 regimens will prove to be superior is
e subject of ongoing trials. Predictors of response to
erapy in these large RCTs are displayed in Table 1.
The results of a single, large RCT support a recom-
ndation that patients with genotype 1 require 48
eks of therapy with higher daily doses of ribavirin
00–1200 mg, depending on weight �75 or �75
) (some clinicians may wish to adhere to the Food
d Drug Administration–approved 800 mg daily
se of ribavirin when used with PEG-IFN alfa-2b,
ecially in patients who weigh �65 kg), while
tients with the more treatment-favorable genotypes
nd 3 can be treated for only 24 weeks and with only
0 mg of ribavirin daily. Moreover, 12 weeks of
his
da
his
erapy suffices in patients with genotypes 2 and 3 in
om HCV RNA levels are undetectable at week 4. In
e group of patients with genotypes 2 and 3, patients
th genotype 2 are more likely than those with
notype 3 to achieve an SVR; for patients with
notype 3 who have high levels of HCV RNA or
vanced fibrosis on liver biopsy, many authorities
ommend treatment for 48 weeks. Pending addi-
nal data, in patients with genotypes 2 and 3, cli-
ians may wish to consider higher doses of ribavirin
a longer duration of therapy on an individual basis,
ing into account considerations such as high viral
el, cirrhosis, or delayed response to therapy. For
tients with genotype 4, 48 weeks of treatment with
G-IFN alfa plus full-dose (1000–1200 mg) ribavi-
is recommended. The potential added benefit of a
oader range (800–1400 mg) of ribavirin weight-
sed dosing as part of combination therapy with
G-IFN is currently being studied.
Therapy is indicated for previously untreated pa-
nts with chronic hepatitis C, circulating HCV
A, elevated aminotransferase levels, evidence on
er biopsy of moderate to severe hepatitis grade and
ge (METAVIR stage �F2, Ishak stage �3, septal
bridging fibrosis), and compensated liver disease.
Patients with milder histologic changes (META-
R stage F1, Ishak stage �3) (and normal serum
inotransferase activity; see following text) appear to
pond as well as patients with more advanced his-
ogic changes; such patients can be counseled about
e reduced risk of disease progression but still can be
ered therapy. If a decision is made to defer therapy
patients with mild disease, periodic laboratory and
ble 1. Predictors of Response to PEG-IFN Plus Ribavirin
Therapy in RCTs Conducted in Previously
Untreated, Immunocompetent Patients With
Compensated Chronic Hepatitis C
n-genotype 1
HCV RNA levels
ence of cirrhosis/bridging fibrosis
ration of therapy (for genotype 1)
40 years or younger
hter body weight
nblack ethnicity
erence
ence of steatosis on liver biopsy
TE. Non-genotype 1 is the most influential predictor of response to
ndard of care therapy with combination PEG-IFN plus ribavirin. The
tive weighting of variables analyzed in RCTs of PEG-IFN/ribavirin
bination therapy is presented in the technical review.1
tologic monitoring should be pursued; however,
ta to support a recommendation on the frequency of
tologic monitoring are wanting.
co
un
tiv
pa
car
co
mu
oth
RN
tit
sp
HC
is
EV
go
dis
Po
ab
be
ach
res
sp
ap
lim
RN
sho
mo
mo
tro
sti
thy
Ta
ace
dr
nia
Fo
fic
lat
it
ne
tat
of
HC
ing
in
va
cie
do
pe
pr
tio
lev
pa
no
ap
mi
pa
log
wh
In
Ta
Re
F
M
E
A
H
R
D
S
V
W
S
H
P
I
I
Re
H
C
P
S
R
G
N
D
T
January 2006 AMERICAN GASTROENTEROLOGICAL ASSOCIATION 227
Current contraindications to therapy include de-
mpensated cirrhosis (see following text), pregnancy,
controlled depression or severe mental illness, ac-
e substance abuse in the absence of concurrent
rticipation in a drug treatment program, advanced
diac or pulmonary disease, severe cytopenias, poorly
ntrolled diabetes, retinopathy, seizure disorders, im-
nosuppressive treatment, autoimmune diseases, or
er inadequately controlled comorbid conditions.
Monitoring Response to Antiviral Therapy
Baseline and 12-week monitoring of HCV
A levels should be performed with the same quan-
ative amplification assay. An early virologic re-
onse (EVR), defined as a �2-log10 reduction in
V RNA levels during the first 12 weeks of therapy,
a valuable clinical milestone. In the absence of an
R, the likelihood of an SVR is 0–3%. If the only
al of therapy is to achieve an SVR, therapy can be
continued after 12 weeks if an EVR is not achieved.
tentially, histologic benefit can accrue even in the
sence of an SVR; therefore, some authorities treat
yond 12 weeks even in patients who have not
ieved an EVR. For documentation of a virologic
ponse at the end of therapy (end-of-treatment re-
onse) or an SVR �6 months after completing ther-
y, a more sensitive quantitative assay with a lower
it of �50 IU/mL, if available, or a qualitative HCV
A assay is recommended.
Clinical and virologic monitoring during therapy
uld be conducted at intervals ranging from once a
nth to once every 3 months. Frequent hematologic
nitoring is necessary to identify marked anemia, neu-
penia, and thrombocytopenia; monitoring of thyroid-
mulating hormone level is indicated to identify hypo-
roidism or hyperthyroidism.
Management of Side Effects of Antiviral
Therapy
Side effects of antiviral therapy are listed in
ble 2.
Flu-like side effects of IFN can be managed with
taminophen or nonsteroidal anti-inflammatory
ugs, sleep-promoting agents can be used for insom-
, and antidepressants can be used for depression.
r management of neutropenia, dose reduction suf-
es, and the addition of granulocyte colony-stimu-
ing factor is generally not recommended, although
may be considered in individual cases of severe
utropenia.
Ribavirin is contraindicated in pregnancy, necessi-
ing strict precautions and contraception in women
th
tra
de
childbearing age and their sexual partners and in
V-infected men with female partners of childbear-
age. Treatment with ribavirin should be avoided
patients with ischemic cardiovascular and cerebro-
scular disease and in patients with renal insuffi-
ncy. If anemia occurs, options include ribavirin
se reduction or the addition of erythropoietin.
Approach to Other Patient Populations
Normal aminotransferase activity. Patients with
rsistently normal ALT levels generally do not
ogress histologically, while responses to combina-
n antiviral therapy in patients with normal ALT
els are indistinguishable from response rates in
tients with elevated ALT activity. Patients with
rmal ALT activity are candidates for antiviral ther-
y or for monitoring without intervention, as deter-
ned on an individual basis and as influenced by
tient factors such as motivation, genotype, histo-
ic activity, and fibrosis.
Cirrhosis. Patients with compensated cirrhosis
o can tolerate therapy are candidates for treatment.
patients with decompensated cirrhosis, antiviral
ble 2. Side Effects of Antiviral Therapy
lated to IFN
lu-like symptoms
arrow suppression (especially leukopenia and
thrombocytopenia)
motional effects (irritability, difficulty concentrating, memory
disturbances, depression)
utoimmune disorders (especially thyroiditis)
air loss
ash
iarrhea
leep disorders
isual disorders (rarely retinal hemorrhages, especially in diabetic
patients and hypertensive patients)
eight loss
eizures
earing loss
ancreatitis
nterstitial pneumonitis
njection site reactions
lated to ribavirin
emolytic anemia
hest congestion, dry cough, and dyspnea
ruritus
inus disorders
ash
out
ausea
iarrhea
eratogenicity
erapy is not recommended; instead, referral for liver
nsplantation is indicated. Although patients with
compensated cirrhosis are not routine candidates for
IF
he
do
wi
th
ou
ter
in
en
th
a r
th
ho
is
pa
eff
IF
pa
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a r
plu
IF
rib
to
ou
me
fre
Ex
low
ba
fac
th
sh
div
no
no
da
cal
sp
lim
dis
era
th
ass
an
ati
tri
ma
ad
SV
aft
de
me
acu
aft
sp
ma
ter
PE
to
rib
ab
he
ini
ad
lis
lik
en
au
mo
wo
me
me
rev
jun
ran
fol
reg
an
clu
vir
an
alc
he
con
est
pr
un
th
cu
ma
th
rib
228 AMERICAN GASTROENTEROLOGICAL ASSOCIATION GASTROENTEROLOGY Vol. 130, No. 1
N-based antiviral therapy, attempts to eradicate
patitis C viremia with progressively escalated, low-
se antiviral therapy before transplantation have met
th limited, early success; however, data supporting
is approach are insufficient to justify its adoption
tside of clinical trials conducted at established cen-
s by experienced investigators.
Previous relapsers and nonresponders. Patients
whom HCV RNA is undetectable during and at the
d of therapy but reappears again after completion of
erapy (relapsers) are likely to respond and experience
elapse again with a subsequent course of the same
erapy. The chance of achieving an SVR in relapsers,
wever, may be as high as 40%–50% if re-treatment
pursued with more effective therapy. If this group of
tients is to be re-treated, ideally, a different, more
ective regimen should be used. Therapy with PEG-
N and ribavirin should be strongly considered for
tients who experienced a relapse after a course of
ndard IFN/ribavirin combination therapy, while a
ger duration of therapy in patients who experienced
elapse after 12 months of treatment with PEG-IFN
s ribavirin is of unproven efficacy.
For nonresponders to a previous course of standard
N monotherapy, re-treatment with PEG-IFN plus
avirin can increase the frequency of responsiveness
approximately 20%; for nonresponders to a previ-
s course of standard IFN plus ribavirin, re-treat-
nt with PEG-IFN plus ribavirin can increase the
quency of responsiveness to approximately 10%.
pectations for responsiveness to re-treatment are
er in patients with genotype 1, cirrhosis, high
seline HCV RNA levels, and black ethnicity. Such
tors, in addition to a patient’s tolerance to previous
erapy and severity of underlying liver disease,
ould be taken into consideration when making in-
idualized decisions about the re-treatment of prior
nresponders.
Given the difficulty of clearing hepatitis C viremia,
nresponder patients have been considered as candi-
tes for long-term maintenance therapy. Hypotheti-
ly, maintenance IFN alfa therapy in prior nonre-
onders might retard the progression of fibrosis and
it the progression of cirrhosis to end-stage liver
ease and hepatocellular carcinoma. Therefore, sev-
l large, multicenter RCTs of long-term (2–4 years)
erapy with low-dose PEG-IFN are in progress to
ess the effect of maintenance therapy on histologic
d clinical end points in patients with chronic hep-
tis C and advanced fibrosis. The results of these
als will be required before recommendations can be
de for chronic maintenance therapy in those with
are
plu
sp
vanced histologic fibrosis who fail to achieve an
R.
Acute hepatitis C. The risk of HCV infection
er an accidental needlestick is sufficiently low to
lay antiviral therapy until HCV infection is docu-
nted virologically and biochemically. Patients with
te hepatitis C are candidates for antiviral therapy
er a period of observation to allow for potential
ontaneous clearance. Case series have focused pri-
rily on IFN or PEG-IFN monotherapy adminis-
ed for 12–24 weeks. Although combination IFN or
G-IFN/ribavirin has not been shown to be superior
IFN monotherapy, conventional doses of PEG-IFN/
avirin combination therapy may represent a reason-
le approach to treatment of patients with acute
patitis C. In fact, the optimal regimen, dose, time to
tiate therapy, duration of therapy, or benefit of
ding ribavirin to IFN therapy has not been estab-
hed, and the infrequency of acute hepatitis C will
ely confound the prospective comparison of differ-
t treatment regimens. Based on available data, most
thorities would initiate treatment no later than 2–3
nths after presentation with acute hepatitis and
uld extend therapy for at least 24 weeks.
Injection drug or alcohol use. Therapy is recom-
nded for recovered drug users, including those on
thadone maintenance, and, based on a case-by-case
iew, for active drug users, especially when in con-
ction with drug treatment programs. Additional
domized trials will be required to evaluate the
lowing: the safest and most effective treatment
imens; the levels of and factors favoring compli-
ce; the risk of recidivism; side effect profiles, in-
ding the risk of depression; and the effect of anti-
al therapy on methadone requirements.
Abstinence should be recommended before and during
tiviral treatment in alcoholic persons, and treatment of
ohol abuse should be linked with efforts to treat
patitis C in alcoholic patients. A safe level of alcohol
sumption in patients with hepatitis C has not been
ablished.
Hematologic disorders. The therapeutic ap-
oach in this group of patients may depend on the
derlying hematologic disorder. For example, in
alassemic patients, primary therapy should be fo-
sed on reducing iron overload. Chronic hepatitis C
y be treated with PEG-IFN plus ribavirin, al-
ough data supporting the safety and efficacy of
avirin, at full or reduced doses, in these populations
limited, because registration trials of PEG-IFN
s ribavirin excluded patients with these disorders
ecifically. In patients with a genetic predisposition
to
pr
ma
vid
ab
are
tio
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log
ma
tre
3 y
co
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an
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pa
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for
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