American Journal of Gastroenterology
C ?2008 by Am. Coll. of Gastroenterology
Published by Blackwell Publishing
Acute Hepatitis C: A Systematic Review
Sanaa M. Kamal, M.D., Ph.D.
Department of Gastroenterology and Liver Disease, Ain Shams Faculty of Medicine, Cairo, Egypt
INTRODUCTION: The annual incidence of acute hepatitis C virus (HCV) has fallen in recent years, primarily because of
effective blood screening efforts and increased education on the dangers of needle sharing.
However, hepatitis C infection is still relatively frequent in certain populations. Most patients infected
with HCV are unaware of their exposure and remain asymptomatic during the initial stages of the
infection, making early diagnosis during the acute phase (first 6 months after infection) unlikely.
While some of those infections will have a spontaneous resolution, the majority will progress to
chronic HCV. We scanned the literature for predictors of spontaneous resolution and treatment
during the acute stage of HCV to identify factors that would assist in treatment decision making.
METHODS: A medical literature search through MEDLINE was conducted using the keyword “acute hepatitis C”
with a variety of keywords focused on (a) epidemiology, (b) natural history and outcome, (c)
diagnosis, (d) mode of transmission, and (e) treatment.
RESULTS: There are no reliable predictors for spontaneous resolution of HCV infection and a significant
percentage of individuals exposed to HCV develop persistent infections that progress to chronic liver
disease. An intriguing approach is to treat acute HCV and prevent the development of chronic
hepatitis. Several clinical trials showed that treatment of hepatitis C infection during the acute
phase is associated with high sustained virological response (SVR) rates ranging between 75% and
100%. Although there is a prevailing consensus that intervention during the acute phase is
associated with improved viral eradication, relevant clinical questions have remained unanswered by
clinical trials. Optimization of therapy for acute hepatitis C infection and identification of predictors
of SVR represent a real challenge.
CONCLUSION:With more than 170 million chronic hepatitis C patients worldwide and an increase in the related
morbidity and mortality projected for the next decade, an improvement in our ability to diagnose
and treat patients with acute hepatitis C would have a significant impact on the prevalence of
chronic hepatitis and its associated complications particularly in countries with a high endemic
background of the infection.
(Am J Gastroenterol 2008;103:1283–1297)
Although hepatitis C virus (HCV) only accounts for a minor-
ity of cases of clinical acute hepatitis, it is a major cause of
chronic liver disease and liver transplantation in both devel-
oped and developing countries (1, 2). The global prevalence
of HCV is 3% with 170 million persons infected worldwide
(1–3). In the United States, nearly 2% of the population is in-
fected (4, 5). In Western Europe, a low prevalence (>0.1%)
is reported from the United Kingdom, Finland, and Germany
and higher prevalence rates >1% are reported from Italy and
in Eastern Europe (median 2%, range 0.4–4.9%) (1, 3, 6). In
To access a continuing medical education exam for this article, please visit
Asia, the prevalence of HCV ranges between 2% and 5%
(1, 2). Egypt has the highest prevalence of hepatitis C in the
world, reaching 13% of the population, equating to an esti-
mated 10 million anti-HCV-positive persons (8–10).
Acute HCV infection is typically defined as a new occur-
rence of viremia with conversion from an HCV-RNA neg-
ative to an HCV positive status. Acute HCV infection is
asymptomatic in the majority of cases (11–13). HCV-RNA
can be detected in the serum in almost all patients within
1–2 wk of exposure. Seroconversion is detected after 2–
6 months (window period) or later in certain risk groups,
making anti-HCV testing less reliable than HCV-RNA as-
sessments for early diagnosis of acute HCV (11–16). The
acute phase of infection is usually considered to be the first
6 months and this is the phase of infection in which spon-
taneous clearance is still possible (11). While 20–50% of
patients with acute hepatitis achieve spontaneous resolution,
between 50% and 80% of individuals develop chronic in-
fection (11–13). Approximately 20% of chronic hepatitis
C patients can be expected to develop cirrhosis; of these,
6% will decompensate to end-stage liver disease (ESLD)
and an additional 4% will develop hepatocellular carcinoma
METHODS OF THE REVIEW
Literature Search and Identification of Relevant Studies
The author identified relevant English-language articles per-
ing search terms were used to identify primary articles: acute
hepatitis and acute HCV with a variety of keywords focused
on (a) epidemiology, (b) natural history and/or outcome,
(c) transmission, (d) diagnosis, and (e) treatment of HCV
during the acute phase. Eligible studies were peer-reviewed
epidemiological and observational studies, prospective and
retrospective case-control or cohort studies, controlled and
uncontrolled randomized or nonrandomized trials, system-
atic reviews, and meta-analyses. Studies were assessed ac-
cording to their methodological soundness, independently of
the result. The bibliographies and references from the pri-
mary articles were then manually searched. When necessary,
ical trials was requested. Furthermore, experts in the field
were contacted for their knowledge of other relevant pub-
lished studies. Case reports and small case series reporting
on fewer than five patients were not included in the review in
an attempt to minimize potential reporting bias of uncharac-
teristic or nonrepresentative cases.
The initial search retrieved 2,002 articles at the title review
level, of which 154 articles were considered by the author
to contain relevant data on acute hepatitis C. Of these, 101
articles were eligible for full review, representing 20 clinical
of acute HCV.
Acute Hepatitis C Epidemiology and Geographic
Because most acute HCV patients remain undiagnosed and
able, little is known about the epidemiology of acute HCV.
Robust epidemiological data are available only for those
patients who progress to chronic infection, develop symp-
toms, and/or seek treatment. A precise estimation of the in-
cidence of HCV infection is difficult to determine because
most acute infections are asymptomatic and surveillance and
reporting systems are inadequate in many countries (1, 17,
18). Because direct measurement of HCV incidence is diffi-
cult, estimation of incidence from available prevalence data
is a more practical approach for estimating incidence on a
(1, 2). However, what we do know is that there are both geo-
graphic and temporal differences in the rates of acute HCV
INCIDENCE OF HCV IN DIFFERENT GEOGRAPHIC
REGIONS. The epidemiology of acute HCV has changed
during the past decade, particularly in western countries. In
the United States, the incidence of acute HCV has declined
among the general population, different age groups, gen-
ders, and ethnic populations since 1989 (1–5, 18, 19). The
incidence of HCV dropped in the United States from 130
per 100,000 in the 1980s to 0.2 per 100,000 in 2005 with
40,000 acute HCV cases reported per year (18, 19). In Italy,
the surveillance system for acute viral hepatitis showed that
the incidence (number of cases per 100,000 population) of
hepatitis C decreased from 5 in 1985 to 1 in 1991 (7). The
incidence of HCV infection is even lower in Northern Eu-
rope, Germany, the United Kingdom, and the Netherlands
(1, 2, 6). HCV accounts for 10% and 8% of acute hepatitis
cases in China and Japan, respectively (20, 21). In hyper-
endemic areas in Taiwan and Japan, the incidence rates of
HCV infection were 110 per 10,000 and 28–36 per 10,000
persons, respectively (21, 22). The incidence is much higher
in African countries and in Egypt in particular. In Egypt, the
incidence rates of HCV were found to range from 0.8 per
1,000 person-years to 6.8 per 1,000 depending on the back-
ground prevalence (23–25). HCV accounts for 31% of acute
viral hepatitis cases in Egypt (23).
age, gender, racial, and ethnic distributions are scarce. How-
ever, the published data show some variations in different
geographical areas. In the United States and Western Eu-
rope, most acute HCV infections occur in adults 30–49 yr
old, and acute HCV seems extremely rare in children (4,
17, 18, 26). In the Far East, the mean age of individuals
with acute HCV is 50 yr (21). In Egypt, high rates of in-
fection are observed in all age groups including young indi-
viduals, indicating an ongoing high risk for acquiring HCV
infection (23–25). More than 60% of acute HCV infections
are in persons below the age of 25 yr. High incidence rates
(14.1 per 1,000 person-years) have been detected in Egyp-
tian children younger than 10 yr of age living in households
with an anti-HCV-positive parent (23, 25). This high inci-
dence in young persons could lead to future increases in
chronic disease in these individuals and persistence of the
high magnitude of the burden of HCV-related chronic dis-
ease in Egypt. The prevalence of acute HCV in both gen-
ders is controversial. While some studies showed higher
HCV incidence among men (17–18, 21), other population-
based surveys (7, 27) showed slightly higher rates in women
Acute Hepatitis C1285
Modes of Transmission: Changing
Patterns in the West and East
Several modes of transmission of HCV are well documented
and widely accepted; others are less well defined and require
HCV transmission differ between developed and developing
countries. Socioeconomic differences are likely to explain
much of the geographic variability.
BLOOD TRANSFUSION. Percutaneous inoculation via
transfusion is very efficient in transmitting HCV infection.
Transfusion-associated cases occurred prior to routine donor
screening in blood banks with second and third generation
enzyme immunoassays, a procedure that resulted in a sharp
decline in transfusion-associated HCV transmission (28). As
of 2001, the risk of HCV infection from a unit of transfused
blood is less than one per million transfused units. However,
the risk of HCV transmission through blood has not been
fully eliminated in some developing countries that lack the
resources to implement adequate donor screening and con-
tinue to use commercial donors to supplement their blood
supplies (29). In such countries, blood transfusion still ac-
counts for some percentage of acute HCV cases.
INJECTING DRUG USERS. The number of cases of acute
hepatitis C among injection drug users has recently declined
mentation of harm reduction policies, syringe exchange pro-
grams, counseling of injecting drug users (IDUs) regarding
Figure 1. Sources of acute hepatitis C infection by geographic region.
protection from infection, and changing injecting behavior
(30, 31). However, both incidence and prevalence of HCV
infection remain high among new young drug injectors (19,
32, 33) since IDU is recognized as the risk factor in about
55% of the acute HCV cases reported in developed countries
and in developing and transitional countries with high IDU
prevalence such as Eastern Europe and Central and South
Asia (34). Lower prevalence rates of IDU are reported from
the Middle East and Africa (34) where IDU does not rep-
resent the major risk factor for acute HCV. Engagement in
unsafe injection practices such as syringe sharing, sharing of
injection equipment, engaging in sexual relationships with
other IDUs increase the risk of HCV transmission (19, 28,
of acute HCV cases.
SEXUAL TRANSMISSION. Sexual transmission of HCV
has been controversial. Some case-control studies identified
some well-documented instances of acute hepatitis C occur-
ring after a defined sexual exposure (7, 18, 19, 35, 36). The
rates of sexual transmission of HCV vary substantially be-
reported cases of acute hepatitis C in the United States, a
history of sexual contact with a person infected with HCV
can be elicited in approximately 15–20% of cases (18, 19).
Studies showed that HCV sexual transmission increases with
the recent outbreaks of acute HCV in men who have sex with
reflects a predisposition to HCV secondary to HIV status
per se, or whether this reflects differences in the behavior
of HIV-positive versus HIV-negative MSM, or possibly in-
creased screening in HIV-positive MSM (38–40). The inter-
studies are therefore needed to investigate the impact of HIV
status on HCV transmission.
In Egypt, relatively higher rates of sexual transmission
have been reported and reflect the higher background preva-
lence in this country. In rural Egypt, sexual transmission be-
tween monogamous spouses (41) ranged between 3 and 34%
(95% CI 0–49%). Acute HCV is associated with a high tem-
poral risk of transmission of HCV to sexual partners. Sexual
transmission was confirmed by phylogenetic analysis in 15%
of sexual partners of individuals with acute HCV (42).
Taken together, although some cases of acute HCV have
been related to sexual transmission, the degree to which sex-
ual transmission is difficult to confirm given that partners
might have other risk factors for HCV transmission such as
IDU. Phylogenetic analysis to identify genetic relatedness of
HCV viral isolates in partners is required to confirm sexual
tis C are limited by the potential of the confounding variable
of IDU or shared items such as razors and other items among
sexual partners. Large studies directed at evaluating HCV-
infected persons with multiple sexual partners are needed for
accurate estimates of sexual transmission.
NOSOCOMIAL TRANSMISSION. Nosocomial transmis-
sion of HCV is becoming rare in the west but is considered
a major risk factor that accounts for a significant percent-
age of the new cases of HCV in developing countries with
high endemic backgrounds. Hemodialysis has been shown
in several studies to be associated with the emergence of
acute HCV (43–46). The high incidence and prevalence of
HCV among dialysis patients can be attributed to several
risk factors, including the number of blood transfusions, lack
of adherence to infection control practices in dialysis units,
pitalizations and surgery, which increases their opportunities
for exposure to nosocomial infections (18). The frequency
of new HCV infections varies according to countries and
(43–46) and 40 and 85% in some developing countries (47,
48). The rate of seroconversion among hemodialysis patients
In developing countries, HCV infection has been associ-
ated with health-care-related procedures performed by tradi-
tional healers and folk medicine practices, acupuncture, tat-
tooing, body piercing, and commercial barbering. Informal
that may be associated with HCV transmission such as in-
jections, dentistry, wound treatment, circumcision, excision,
and scarification (52, 53). In rural Egypt, about 50% of de-
liveries are attended by traditional birth assistants (54). Lack
of appropriate cleaning and disinfection of equipment used
in these procedures contribute to HCV transmission and the
emergence of new HCV cases.
important occupational hazard for health-care workers. The
risk of occupational HCV transmission increases with deep
injuries and after procedures involving hollow-bore needles
(55). In longitudinal studies, attempts have been made to
assess the risk of infection associated with occupational ex-
posures to HCV in the health-care setting. In these studies,
transmission rates ranged from 0 to 10.3% (55–57). The sub-
stantial variation in transmission rates can be explained by
differences in implementation of infection control policies
and occupational infection surveillance systems in different
countries. In the United States and Europe, acute HCV due
to occupational exposure to HCV in the health-care setting
is rare due to the strict implementation of universal precau-
tions to prevent the spread of HCV in health facilities and
health-care settings (i.e., safety-engineered needle devices,
such as IV catheters and blood-drawing devices), together
with other preventive measures and education (55–57). In
developing countries, health-care workers are at increased
risk for transmission following a needlestick or sharp injury
from a source patient known to be infected with HCV (58,
59). In Egypt, the country with the highest prevalence of
HCV worldwide, occupational transmission among health-
care workers through needlesticks and sharp injuries con-
tributes to new HCV cases given that needlestick-prevention
devices are not yet adopted in most hospitals and health-care
units in addition to inadequate compliance with universal,
standard precautions in some health facilities (59).
INTRAFAMILIAL EXPOSURE. The role of intrafamilial
HCV transmission is still controversial. However, several
studies reported HCV spread in families with HCV-infected
index cases. An Italian study (60) demonstrated an overall
rate of HCV infection of 2.3% in offsprings of HCV posi-
tive individuals and the risk was significantly higher when
the index case was female. In rural Egypt, intrafamilial HCV
where living in a house with an infected family member is a
risk factor for HCV transmission. Analysis of data collected
for contracting anti-HCV than children whose parents did
Taken together, IDU and to less extent sexual transmission
represent the main risks for acute HCV in western countries.
The picture is different in developing countries, in which
Acute Hepatitis C 1287
ferent set of risk factors for HCV. Nosocomial and iatrogenic
transmission, occupational exposure, sexual and intrafamil-
ial transmission in addition to IDU contribute to acute HCV
cases in developing countries. Accurate risk factor assess-
ment is essential for education targeted at risk reduction in
culturally diverse populations.
Clinical Presentation and Diagnosis of Acute Hepatitis C:
Cracking the Code of Early Detection
tic criteria for acute HCV. A series of clinical features gen-
erally leads to a suspicion of acute HCV infection (13, 15).
These “characteristics” include exposure to HCV during the
previous 2–12 wk, development of symptoms, particularly
jaundice, in a previously healthy individual, and an acute in-
crease in alanine aminotransferase (ALT) levels to more than
10–20 times the upper limit of normal (with or without an
tectable HCV-RNA 1–2 wk postexposure (11–16). Hepatitis
C-specific antibodies (seroconversion) are detected 6–8 wk
toms (11, 13, 15). Acute HCV infection produces a wide
range of clinical presentations from asymptomatic to icteric
illnesses similar to other forms of acute viral hepatitis. Flu-
like symptoms, fever, jaundice, dark urine, fatigue, nausea,
reported in symptomatic patients with acute HCV (11, 61).
Acute HCV can be severe and prolonged, but is rarely ful-
minant (11, 13, 61). Symptoms, if they occur, develop 6–8
wk after exposure and may last for 3–12 wk in self-limited
acute HCV and subside as ALT and HCV levels fall (10, 13,
asymptomatic and difficult to identify. Diagnosis of asymp-
tomatic cases requires routine screening of those individuals
who are in at-risk groups, have a history of exposure, or have
abnormal liver function tests.
Natural History and Outcome of Acute Hepatitis C
HCV infection maybe self-limiting and can spontaneously
resolve before proceeding beyond the acute phase, or may
persist, leading to chronic infection. Estimates of sponta-
neous resolution range from 10 to 60%; conversely, 43 to
86% of cases are thought to progress to chronic infections
(2, 11, 13, 61–64). Although these estimates vary widely, a
general rule of thumb is that 20–40% of patients with acute
HCV experience spontaneous resolution (11, 15, 61, 64–67).
HCV-RNA clearance within 3 months of disease onset (11,
13, 15, 35, 36). Detectable HCV-RNA beyond 6 months af-
ter infection is usually associated with chronic evolution (11,
36, 60, 61). However, establishing just who may resolve be-
fore reaching the chronic phase has proved difficult because
so few cases are actually detected. Predicting whether acute
and is associated with higher response rates.
Can Spontaneous Resolution
of Acute HCV Infection Be Predicted?
Although no reliable predictors for spontaneous resolution
have been identified, several clinical features have been as-
sociated with spontaneous viral clearance in patients with
acute HCV. Patients less than 40 yr of age are more likely
to undergo spontaneous resolution (11, 63, 65–67). Interest-
ingly, children with HCV infection have a 75–100% chance
of spontaneous resolution (25, 26). Self-limiting disease is
also significantly more common in women than men (40%
vs 19%, P < 0.01) (13, 27, 63, 67). Several studies have
identified symptomatic disease, particularly jaundice, as a
predictor of spontaneous viral clearance, presumably reflect-
ing a more effective host immune response that is capable of
eradicating the virus by killing infected hepatocytes and that
is responsible for clinical manifestations (11, 12, 61, 63–67).
HIV (38–40) or Schistosoma mansoni infection are far less
likely to spontaneously clear HCV than those without (68,
69). Additionally, patients with weakened immune systems,
progression to chronic infection (70).
Several studies demonstrated that cellular immune re-
HCV. Clearance of HCV is associated with the development
in blood and liver (65, 68–74) that, in some cases, can be
maintained for years after recovery from acute disease (74).
to mount such a response or may have inadequate production
Incomplete control of viral replication by CD8+ T cells in
mutants (73, 75).
Some virological factors have been associated with spon-
taneous resolution. Farci et al. (76, 77) showed that acute
resolving hepatitis was associated with homogeneity of the
HCV quasispecies, whereas progressing hepatitis correlated
with genetic diversity, presumably reflecting greater immune
pressure during acute spontaneous clearance. Similarly, a
reduction in genetic diversity leading to an increasingly
homogeneous viral population was a consistent feature as-
sociated with viral clearance in sustained responders. No as-
sociation between HCV-RNA levels and spontaneous reso-
lution of HCV infection has been established. Similarly, no
relationship between genotype and self-limited disease has
been confirmed elsewhere.
Natural History and Clinical Presentation of Acute HCV
Infection in Special Patient Populations
HEMODIALYSIS PATIENTS. Data on the natural history
and clinical outcomes of acute HCV in end-stage renal dis-
course of disease in such patients is crucial, however, to de-
veloping indications for therapy. The available data suggest
that acute HCV infection among this patient group is usu-
ally asymptomatic and rarely recognized (43, 44, 50). Some
hemodialysis patients may have delayed seroconversion and
others may not develop hepatitis C antibodies despite the
presence of viremia; thus, polymerase chain reaction (PCR)
is necessary for diagnosis of these cases. The rates of sponta-
neous resolution in hemodialysis patients range between 20
and 34% and are thus similar to rates reported in nonuremic
patients in analyses of community-acquired HCV (63, 64).
develop chronic HCV viremia may have significant liver dis-
ease and severe chronic hepatitis on liver biopsy despite nor-
mal liver enzymes (49, 51).
ical presentation and course of acute HCV infection in HIV-
infected patients. Coinfection with HCV is seen in 15–30%
of the HIV-infected population of the United States (18, 79).
Acute hepatitis C is mostly asymptomatic (11, 38). Diagno-
sis is made when investigating causes of unexplained liver
enzyme elevation in an HIV-coinfected patient (40). Com-
pared with HIV-uninfected patients, HIV-infected patients
have higher HCV viral loads (80, 81), lower rates of spon-
taneous HCV clearance (40, 80), and sometimes accelerated
liver disease in those who fail to clear the virus (80). HCV
antibody may remain negative for up to 6 months and occa-
sionally for longer periods. When serum HCV antibody is
negative, serum HCV-RNA is a useful diagnostic tool that
may aid in the prompt diagnosis of acute HCV infection
Treatment of Acute Hepatitis C
is controversial given the variable rates of spontaneous reso-
lution and the absence of symptoms in many patients. There
with acute HCV such as the high rate of chronic evolution
and the lack of reliable predictive factors for the outcome of
acute infection. Compared with acute HCV, chronic HCV is
associated with a worsening prognosis, the need for more in-
tensive treatment with pegylated interferon (PEG-IFN) and
ribavirin, longer treatment duration, and a decline in suc-
cessful treatment outcomes. Conversely, intervention during
the acute phase is associated with improved viral eradica-
tion using a monotherapy regimen that is better tolerated,
less expensive, more convenient, and shorter than the cur-
From the public health standpoint, early diagnosis and treat-
ment in at-risk populations helps to reduce the risk of HCV
Evolution of Acute Hepatitis C Treatment
Several clinical trials addressed the optimal treatment regi-
men and showed significant improvement in the rate of sus-
tained virologic response (SVR) rates with interferon (IFN)-
based therapies compared with no treatment (82).
CLINICAL TRIALS USING CONVENTIONAL INTER-
were uncontrolled investigations in small patient groups,
often employing biochemical endpoints. They were gener-
ally open-label studies using IFN α-2b at a dose of 3 MU
three times weekly for variable durations. Overall, SVR rates
ranged between 32 and 100% (83–89). However, the diverse
enrollment criteria, small number of subjects, heterogeneity
of the patients, lack of controls, different types and doses of
IFNα, differences in the definition of response, and lack of
results of such trials difficult to interpret given that 20–40%
of patients with acute HCV may resolve spontaneously (11,
Adopting an early aggressive approach to therapy, patients
with acute HCV were treated with IFN alfa-2b at a daily
dose of 5 MU for 4 wk and then 5 MU three times weekly
for a further 20 wk. The SVR rate was 98% with almost no
dropouts or adverse events despite the high dose of daily in-
terferon and the extended duration of treatment. Although
Jaeckel et al. (84) achieved high efficacy rates using conven-
with high doses of IFN during the first 4 wk of therapy repre-
sents significant inconvenience to patients with a high prob-
ability of adverse events and noncompliance particularly in
CLINICAL TRIALS USING PEGYLATED INTERFER-
ONS. Pegylation of the IFN alfa (PEG-IFNα) molecule was
a major advance in the treatment of chronic HCV due to
the higher SVR rates induced by PEG-IFNα. Furthermore,
PEG-IFNα helped to reduce the number of outpatient visits
and improved patient compliance due to the lower admin-
istration frequency (90). Subsequently, several randomized
and nonrandomized clinical trials were conducted to assess
the efficacy and safety of PEG-IFNα in acute HCV. The ma-
jor modes of transmission of HCV in these trials were IV
drug use, needle stick injuries, medical procedures, or sex-
ual contact with known HCV positive partners. The SVR
rates with treatment of 12–24 wk with PEG-IFN alfa-2b
monotherapy ranged between 71 and 95% (91–98) (Table 1)
depending on the populations treated, HCV genotypes, onset
of therapy, and compliance to therapy. These SVR rates are
Acute Hepatitis C 1289
Table 1. Summary of Studies Evaluating Interferon-Based Therapy in Patients With Acute Hepatitis C Virus Infection
Studies using conventional IFNα
Vogel et al. (83)
IFN alfa-2b 10
of ALT 18–43
Jaeckel et al. (84)
1 (61)2/3 (27) 4 (0)
Induction IFN alfa-2b
5 MU/day for 4 wk
followed by IFN
alfa-2b 5 MU tiw
89 days from
Nomura et al. (85)
Early intervention: IFN
IFN) 6 MU/day IM
Late intervention: IFN
IFN) 6 MU/day IM
8 wk from onset
Pimstone et al. (87) Non-R
Induction IFN alfa-2b
5 MU/day for 12 wk
followed by IFN
alfa-2b 3 MU tiw
Delwaide et al. (89) Non-R
1 (12) 2/3 (5)4 (1)
IFN alfa-2b 5 MU/day
Mean, 110 ± 44 8 wk
Studies using PEG-IFNα
Rocca et al. (86)
Piercing (6%) Sexual (19%)
1 (50)2/3 (38)
and/or IFN alfa-
2b ± RBV
Gerlach et al. (65)
1a (24)1b (40)2/3 (32)4 (4)
IFN alfa 3–5 MU tiw
IFN alfa 3–5 MU tiw
PEG-IFN α-2a 80–100
PEG-IFN α-2a 80–100
µg/week + RBV
from onset of
1/2 (50) 4/4 (100)
Table 1. Continued
Studies using PEG-IFNα
Kamal et al. (92)
sharp injuries or
PEG-IFN α-2a 180
µg/week ± RBV
PEG-IFN α-2b 1.5
12 wk from onset
of symptoms or
Santantonio et al. (91) Non-R
12 wk from onset
Broers et al. (88)
100 ± 82 days from
symptoms or 63
± 53 days from
the first HCV
Wiegand et al. (93)
Others (8%) Unknown (17%)
2/3 (22) 4 (1) not
76 days after
Kamal et al. (94)
2/3 (8)4 (58)
31/141 (22)§ PEG-IFNα-2b 1.5
8 wk from onset
12 wk from onset 20 wk from onset
40/43 (93) 33/43 (77)
De Rosa et al. (96)
Mean 33.6 days,
range 0–116 days
Acute Hepatitis C1291
Table 1. Continued
Studies using PEG-IFNα
Kamal et al. (95)
29/131 (22) PEG-IFNα-2b 1.5
PEG-IFN α-2b 1.5
PEG-IFN α-2b 1.5
12 wk 24 wk
28/34 (82) 31/34 (91)
Corey et al. (66)
Non-R 24 and 15
1.33 µg/kg per
(180 µg weekly)
21 days (range
30.7 ± 12 wk
Calleri et al. (97)
Surgery (6%)Sexual (5%)
Needle sticks (7%)Unknown (13%)
De Rosa et al. (98)
µg/kg per week
Studies in HIV patients with acute hepatitis C
Vogel et al. (101)
Vogel et al. (102)
2/3 (1) 4 (20)
24 wk 48 wk
Dominguez et al. (99) Non-R 25
2 (28) 4 (44)1 + 4 (4)
Table 1. Continued
Studies in HIV patients with acute hepatitis C
Serpaggi et al. (103)
and/or IFN alfa-2b ± RBV
Gilleece Y et al. (100) Non-R 27
µg/kg per week
Studies on treatment of dialysis patients with acute hepatitis C
Griveas I et al. (44)
µg per week
HCV = hepatitis C virus; IFN = interferon; IM = intramuscular; NA = not available; Non-R = nonrandomized; PCR = polymerase chain reaction; MU = million units; PEG-IFN = pegylated interferon; R = randomized; RBV = ribavirin;
RT = reverse transcription; SVR = sustained virologic response; LLOQ = lower limit of quantification; tiw = three times weekly; TMA = transcription-mediated amplification, MSM = men having sex with men.
∗Patients receiving combination (PEG-IFN alfa-2a/2b and RBV) therapy.
†Patients receiving monotherapy (PEG-IFN 2a/2b) only.
‡Patient (N = 1) with nosocomial infection started treatment at week 20.
§Treatment arm only; N = 141 patients.
Treatment arm only; N = 131 patients.
#LLOQ not provided.
ωNumber of patients.
ment of acute HCV monoinfection, as no significant differ-
ence was detected between the PEG-IFNα monotherapy and
PEG-IFNα and ribavirin combination regimens for the over-
all cohort SVR rates (92). So far, no study has shown a ben-
efit for combination therapy with interferon plus ribavirin.
HCV was associated with fewer adverse events compared
with chronic HCV. This might be explained by the use of a
single agent and the shorter duration of treatment.
Taken together, recent data demonstrate that PEG-IFNα-
2b monotherapy in acute hepatitis C induces high SVR rates
and is well tolerated. PEG-IFNα monotherapy represents a
viable alternative to aggressive induction therapy with con-
ventional IFN and results in similar response rates without
the associated complications.
Treatment of Acute HCV in Special Populations
TREATMENT OF ACUTE HEPATITIS C IN HIV-
COINFECTED PATIENTS. Few studies evaluated PEG-
IFN α-based therapy in HIV-coinfected patients with acute
HCV infection (98–101). In a French study, a 71% SVR
rate was achieved with combination therapy of PEG-IFN α
(180 µg/week) and ribavirin (800 mg/day) for 24 wk (99).
In another study from Germany, an overall SVR rate of 91%
was achieved in coinfected patients treated with either IFNα,
PEG-IFNα monotherapy, or PEG-IFNα and ribavirin ther-
apy (100) (Table 1). Other studies (100–102) showed 59–
61% overall SVR rates in HIV-positive patients with sexu-
ally transmitted acute HCV treated with PEG-IFNα or PEG-
IFNα combined with ribavirin. Higher treatment response
rates were observed in patients treated for over 48 wk com-
pared with 24 wk (99). Patients infected with HCV genotype
nia, anemia, and depression. These data suggest that SVR
rates in HIV-positive patients with acute HCV infection are
lower than in HIV-negative subjects. HIV patients with acute
HCV might require longer more aggressive therapy and the
addition of ribavirin might be necessary. Further investiga-
tion is warranted to evaluate the efficacy and safety of acute
optimal components and duration of therapy.
TREATMENT OF ACUTE HCV IN PATIENTS RECEIV-
ING HEMODIALYSIS. HCV is an increasingly recognized
infection in patients on dialysis because it may increase mor-
bidity and mortality after kidney transplantation. It is thus
important to identify effective and safe antiviral agents for
this group of patients. However, the literature on the efficacy
and safety of IFN-based regimens in acute HCV in dialysis
trials utilized conventional IFNα or PEG-IFNα given that
ribavirin may be dangerous in dialysis patients, because it is
Acute Hepatitis C1293
associated with hemolytic anemia and many dialysis patients
are already anemic.
In one study (102), 23 hemodialysis patients with proven
acute HCV were treated with either a low dose of IFNα (3
MU three times per week) for 12 months or a high dose
(5 MU three times per week, preceded by a daily induction
dose) for 6 months. The SVR rate was 38% in lower doses
received PEG-IFNα2 in a dose of 135 µg, 3 months after the
to therapy. The optimal treatment of hepatitis C in dialysis
patients remains to be established.
CHALLENGES IN TREATING ACUTE HEPATITIS C.
clearance rates, and IFN-based therapy is associated with
both adverse events and significant cost. The optimization
of acute HCV therapy is thus critical to ensure that SVR
rates are maximized and chronic infection is prevented with-
out exposing the patient to an unnecessarily long and costly
treatment regimen with its associated adverse events. Given
that most acute HCV cases are asymptomatic and that, as a
clinical entity, acute HCV is not commonly seen in clinical
practice, particularly in western countries, there is a paucity
of large, multicenter, well-designed, randomized, controlled
ment of this disease. Until recently, the onset and duration of
of therapy as well as determinants of SVR.
TREATED? The appropriate timing of IFN-based therapy
in acute hepatitis has not been accurately determined. This
is because clinical trials enrolling well-characterized cohorts
with known time of infection and conversion from HCV-
negative to HCV-positive status are necessary to address this
issue. The exact onset of infection could be determined in
some incidents, such as needle-stick injuries, after unsafe
medical procedures, or after unprotected sexual contact
with an HCV positive partner. However, in many cases
the actual time of HCV infection is difficult to determine.
Thus, in most clinical trials, therapy was initiated at various
time points ranging between 1 and 24 months from the
appearance of symptoms, the first positive HCV-PCR, or at
seroconversion. A randomized, controlled study showed that
treatment of acute HCV infection within 8 wk of exposure
yielded higher rates of SVR (87%) compared with the
SVR rates (40%) achieved when therapy is delayed 112
months after exposure (84). In another study of acute HCV,
patients were randomized to begin PEG-IFN 8, 12, or 20
wk after recognition of infection. A greater proportion of
those who started treatment 8 or 12 wk after recognition
achieved sustained viral suppression compared with those
who started it 20 wk later (93). In studies in which treatment
SHOULDACUTE HCV PATIENTS BE
was initiated within 8–12 wk, the SVR rates ranged between
71 and 100% (83–85, 89, 90, 93, 95, 96) (Table 1). Thus,
there is a growing consensus that delaying treatment 3–4
months after the onset of infection is a reasonable strategy
that gives every opportunity for patients to spontaneously
clear the virus through HCV-specific T-cell activity, without
jeopardizing treatment outcomes in those who will fail to
HOW LONG SHOULD ACUTE HEPATITIS C PATIENTS
as clinical trials have evaluated variable durations of conven-
tional IFN treatment or PEG-IFN (ranging from 4 to 48 wk)
for sufficiently long enough periods to rule out late relapse
(63, 81–87, 89–96). In patients in whom spontaneous res-
olution does not occur 3 months after infection, 12–24 wk
of treatment has been shown to be effective and well toler-
ated in various clinical trials, and appears to provide the best
SVR rates. Recently, four clinical trials showed that 12 wk
of therapy may be sufficient for the treatment of acute HCV,
particularly in nongenotype 1 patients (92, 93, 95, 96). PEG-
IFN for 12 wk to treat hepatitis C has a compliance that is
much higher, particularly in IDUs, than that reported with a
24-wk regimen. Adverse effects are minimal and follow-up
of patients treated for 12 wk did not show an increase in re-
lapse rates compared with those treated for 24 wk. Further
studies are required to identify factors for individualizing the
duration of therapy in acute HCV infection.
WHO IS LIKELY TO ACHIEVE SVR? To date, the predic-
fied and further research is required. Recent data have shown
some factors that might be considered when individualiz-
ing therapy for acute HCV infection. Several studies suggest
spond better to treatment (81, 83, 91–96). Virological factors
such as HCV nongenotype 1, low baseline viral load, and
rapid virological response (undetectable serum HCV-RNA
or a >2 log10decrease at week 4) are probably associated
with favorable treatment outcome (94, 97). HIV-coinfected
patients may need combination therapy and require it for a
longer duration. These data can be used as a platform for
further research to optimize therapeutic options for patients
with acute HCV, and to define optimal therapeutic outcomes
in acute hepatitis. In addition, research to better describe pa-
tients who do or do not respond by evaluating the impact
of factors such as gender, ethnicity, obesity, mode of trans-
mission, HCV genotypes, and viral kinetics on response to
therapy is needed. Another challenge is how to manage pa-
tients who relapse or who do not respond to therapy during
the acute phase.
Figure 2. Proposed clinical algorithm for management of acute hepatitis C.
CAN ACUTE HCV THERAPY BE INDIVIDUALIZED?
In an effort to improve rates of sustained response to
interferon-based therapy for chronic hepatitis C, various
strategies have been adopted for tailoring drug doses and
on-treatment response to meet the needs of individual pa-
tients. A similar approach might be necessary to optimize
acute hepatitis C treatment. Some studies showed that acute
1 have higher rates of SVR (92–96). In one study (95), SVR
was achieved in 60% and 88% of genotype 1 patients and in
93% and 100% of genotype 4 patients after 12 and 24 wk
of treatment, respectively. Rapid virological response (unde-
levels after 4 wk of therapy) was predictive of SVR (95, 98).
patients with acute hepatitis C. If a patient appears likely not
to have spontaneous resolution of infection, then a decision
to treat needs to be individualized according to a variety of
factors that could influence outcome such as baseline clin-
ical condition, ethnic background, likelihood of adherence,
genotype, and IDU history. However, more clinical trials are
needed to clarify the impact of different pretreatment crite-
ria and on-treatment viral kinetics on determining the onset
and duration of an IFN-based regimen in the setting of acute
CONCLUSIONS AND FUTURE PROSPECTS
Acute HCV is not a commonly encountered clinical entity
due to its mostly asymptomatic nature and variable rates of
spontaneous resolution. However, acute HCV represents an
important window in the time course of this infection during
which medical intervention is greeted with a high degree of
acute HCV infection is shown in Figure 2. In the absence of
contraindications to therapy, patients with acute HCV should
be considered eligible for therapeutic intervention. The SVR
rates in the acute setting far exceed those attained in pa-
tients with chronic HCV. For this reason, early intervention
may be the best opportunity to attain viral eradication. An
8- to 12-wk window of “watchful waiting” between expo-
sure to HCV and initiation of therapy is important to al-
low for the possibility of spontaneous resolution. Patients
might be treated for 12 or 24 wk; however, further research
is warranted to identify individuals eligible for the shorter
From a public health standpoint, health-care systems
should adopt strategies to identify individuals at high risk for
HCV infection and provide opportunities for education and
behavior modification. In developing countries with a high
endemic background of HCV infection, surveillance pro-
grams, and efforts to increase awareness, improve diagnosis,
and facilitate treatment of acute HCV will have far-reaching
rent disease management and health outcome strategies are
Reprint requests and correspondence: Dr. Sanaa M. Kamal, De-
partment of Gastroenterology and Liver Diseases, Ain Shams Uni-
versity, 22 Al Ahram Street, Cairo, Egypt.
Received July 14, 2007; accepted December 12, 2007.
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CONFLICT OF INTEREST
The author declared no potential conflict of interest.