Acute Hepatitis C Virus Infection - A Chronic Problem

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Hepatology. Author manuscript; available in PMC 2008 April 1.
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Hepatology. 2008 January ; 47(1): 321331.
Acute Hepatitis C Virus Infection: A Chronic Problem

Jason T. Blackard, M. Tarek Shata, Norah J. Shire, and Kenneth E. Sherman
From the Division of Digestive Diseases, University of Cincinnati College of Medicine, Cincinnati,
OH
Since the discovery of the hepatitis C virus (HCV) in the late 1980s, there has been an explosion
of information regarding its natural history, treatment, and replication cycle. Nonetheless, there
are still relatively few data regarding acute HCV infection. By convention, the term acute
hepatitis refers to the presence of clinical signs or symptoms of hepatitis for a period of 6
months or fewer after the presumed time of HCV exposure. Early studies of posttransfusion
patients who developed non-A, non-B hepatitis provide a clinical picture of early infection.1
Following the availability of specific serologic and virologic tests, most such patients were
shown to have acute HCV infection. After acute infection, HCV RNA may become detectable
in the serum/plasma in as little as 2 weeks (Fig. 1). Several weeks later, a high percentage of
patients experience an increase in serum aminotransferase levels consistent with the
development of acute hepatocellular injury. In the majority of cases, patients develop mild
constitutional symptoms, including abdominal pain, nausea, vomiting, anorexia, and fatigue.
During this acute infection, serum aminotransferases often peak below 1000 IU/mL and may
return to normal levels. A minority develops sufficient elevations in bilirubin to lead to overt
jaundice or the development of dark urine. Unless the clinical suspicion is high, few patients
will be tested for HCV RNA or HCV antibody seroconversion. However, in the majority
but not all of infected patients, HCV RNA persists, and a chronic disease state develops.
The reasons for the general lack of data regarding acute HCV infection are multifactorial and
include (1) the relatively high percentage of asymptomatic or unrecognized early infections,
(2) the lack of large-scale identification of chronic carriers in the general population who serve
as a reservoir for infection, and (3) the decreased number of acute infections that occur in
controlled clinical settings such as that of blood transfusions. These factors and the lack of
nonprimate animal models necessitate reliance on retrospective studies in chronic carriers, the
use of limited historical collections of banked sera, and the extrapolation of outcomes based
on small disease outbreaks in unique settings (for example, transmission from a physician to
a patient in the operating room setting or following parenteral exposure in healthcare workers).
Moreover, there exist only a limited number of population cohorts that continue to experience
high rates of HCV transmission (for example, Egypt); nonetheless, there is a growing body of
information regarding the clinical presentation, natural history, and treatment outcomes of
acute HCV infection.
In this article, we review the current information regarding our understanding of the
epidemiology, virology, and immunology of HCV with a particular emphasis on acute HCV
infection. In addition, we review recent data related to interferon-based treatment intervention
and propose an algorithm for the diagnosis and management of acute HCV infection.
Address reprint requests to: Kenneth E. Sherman, Gould Professor of Medicine, Division of Digestive Diseases, University of Cincinnati
College of Medicine, ML 0595, 231 Albert Sabin Way, Cincinnati, OH 45267-0595. E-mail: [email protected]; fax:
513-558-1744.
Potential conflict of interest: Nothing to report.
Blackard et al.
Page 2
Epidemiology and Natural History of HCV Infection

Data from the National Health and Nutrition Examination Survey estimated that more than 4.1
million people have evidence of HCV exposure, as measured by HCV antibody, in the United
States.2 This number may be even higher when homeless and incarcerated persons are taken
into account, as infection rates in these populations may exceed 40%36 and even 70% among
human immunodeficiency viruspositive (HIV+) urban poor.7 Overall, approximately 85% of
those with an acute infection will develop chronic disease,8 persistent viremia occurring at
least 6 months after initial exposure, with estimates ranging from 55% in the Irish anti-D
immune globulin cohort9 and 60% in a study of community-acquired HCV in the United
States10 to 90% in a single-source outbreak from contaminated clotting factors in Austria.11
Fortunately, HCV incidence has dropped nearly 10-fold in the United States since the 1980s,
12 largely because of improved screening of blood products, decreased injection drug use
(IDU), and safer sexual practices. However, HCV still poses a significant public health threat,
as most patients with an acute infection do not exhibit symptoms and therefore are unaware
that they are infected and remain capable of transmitting the virus to others.
Transmission of Acute HCV Infection
It is believed that HCV can be acquired or transmitted via any blood-borne route. High-risk
settings include IDU and the transfusion of unscreened blood and blood products. Other
possible but less well characterized risk exposures include tattoos and piercings, needle sticks,
and unsafe/traumatic sexual practices. Historically, sexual transmission has been considered a
relatively inefficient route for HCV transmission. For instance, in a recent study of sexual
transmission among monogamous couples in Italy, only 3 persons contracted HCV among 770
partners of persons with a chronic HCV infection who were observed during a 10-year period.
13 Another cross-sectional analysis detected a 2.5% risk of spousal HCV transmission.14
Despite the relatively small risk of sexual transmission of HCV, coinfection with HIV may
potentially increase this risk. For instance, the Swiss HIV Cohort Study calculated an HCV
incidence rate of 6.4 per 1000 person years (PY) among HIV+ subjects who were HCV-seronegative at the baseline.15 In contrast, the national rate in Switzerland is 04 cases per 100,000
PY. Factors increasing the risk of acute HCV infection included a history of IDU and unsafe
sex. However, the association between unsafe sex and HCV seroconversion was not
statistically significant in those with HIV transmission from heterosexual sex but was only
among men who have sex with men (MSM). In a related study of acute HCV among HIV+
MSM, 29 cases were detected in a 3.5-year study period.16 All patients reported unprotected
anal sex, whereas 6 described sexual practices with mucosal trauma. Forty-one percent had
concomitant sexually transmitted diseases, although none reported IDU. Another study
detected incident HCV infection in 11 of 308 HIV+ MSM during a 5-year follow-up.17 A
detailed behavioral questionnaire revealed that fisting was the only significant predictor of
acute HCV infection. Furthermore, an analysis of the HIV+ French PRIMO Cohort followed
379 subjects without HCV at the baseline for at least 18 months. Six subjects seroconverted,
yielding an HCV incidence rate of 4.3 per 1000 PY.18 Four were male, and all reported highrisk, unprotected anal sex. Another analysis reported a statistically significant trend toward
increasing HCV seroconversion, from 0.2 per 1000 PY in 1997 to 4.5 per 1000 PY in 2002 in
HIV+ MSM in the United Kingdom.19 This trend was exaggerated (from 0.69.3 per 1000
PY) in those who received an HCV test because of elevated liver enzymes.
Collectively, these data suggest that HIV could mediate the risk of HCV transmission,
particularly among MSM. There is mechanistic plausibility to support this hypothesis as well.
For example, HCV viral loads are significantly elevated among individuals coinfected with
HIV,2022 whereas the viral half-life may also be prolonged.23 Furthermore, HCV RNA has
Blackard et al.
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been detected at higher rates in the semen from HIV/HCV-coinfected men24 versus HCVmonoinfected men.25 The practices of unprotected and traumatic anal sex increase the chance
of semen-to-blood or blood-to-blood transmission, whereas concomitant sexually transmitted
infections may further facilitate this process. These explanations may also help explain why
similar effects of HIV on HCV transmission and acquisition are not generally observed in
females.26
Natural History of Acute HCV
Most patients with newly acquired HCV do not exhibit symptoms of infection within the first
6 months. A prospective evaluation of 179 HCV antibodynegative injection drug users
identified 62 seroconverters, yielding an incidence rate of 27.2 cases per 100 PY.27 Of the 40
cases with available follow-up data, 8 cleared the infection. None of the patients exhibited any
clinical symptoms that would warrant medical attention. Symptomatic patients may exhibit
jaundice but more often will complain of fatigue, nausea, abdominal pain, or flulike symptoms.
In a study with a surprisingly high rate of symptoms (68%), Santantonio et al.28 noted jaundice
in 57% and alanine aminotransferase (ALT) levels greater than 20 times the upper limit of
normal in 73%.28 Seventy-three of the 203 subjects (36%) had spontaneous viral clearance
80% within 3 months of disease onset. Although symptomatic infection was not associated
with clearance in this study, it has nonetheless been postulated that symptomatic patients have
a higher rate of spontaneous clearance than asymptomatic patients. For instance, Gerlach et al.
29 observed a spontaneous clearance rate of 52% (24 of 46) in symptomatic acute HCV
infected patients with HIV, but clearance was not evident in any asymptomatic patients in that
study. Likewise, a retrospective analysis from a non-HIV clinic population reported symptoms
in 26 of 28 acute HCV cases.30 The authors observed spontaneous clearance in 25% (7 of 28)
of subjects, all of whom were symptomatic. Interestingly, this study included 4 patients, each
with 2 distinct instances of acute HCV; each infection was symptomatic, and each was cleared.
However, in another small study of 9 HIV+ men with acute HCV, of whom 7 were symptomatic,
2 had spontaneous clearance, 3 responded to interferon-based treatment, and 4 developed a
chronic infection.31 Similarly, among incarcerated injection drug users, McGovern and
colleagues32 detected 21 cases of acute HCV infection. Of 17 individuals observed for more
than 6 months, 8 spontaneously cleared the virus (6 of 13 patients with symptoms and 2 of 4
patients without symptoms). One patient had de novo HCV reinfection through IDU after
spontaneous clearance and normalization of the liver enzyme, as demonstrated by sequence
analysis. Although the initial infection caused jaundice, the patient remained asymptomatic
during the second infection, and this was consistent with the increased likelihood of
spontaneous clearance during symptomatic acute infection.
Several studies have shown that a wide spectrum of clinical, virologic, and immunologic
outcomes may be exhibited after exposure, even during common source outbreaks.9,33,34 This
suggests complex interactions among various factors that result in self-limiting acute infection
versus chronic infection (Table 1).
HCV Diversity
Hepatitis C viral replication is extremely robust, producing an estimated 10 trillion viral
particles per day.35 A hallmark of RNA viruses is their extreme genetic diversity. The
nonstructural 5B protein of HCV is an RNA-dependent RNA polymerase that lacks a
proofreading mechanism. Thus, mutations within the HCV genome are generated at a rate of
approximately 1 mutation per genome per replication cycle. This results in a population of
distinct but closely related viral variants, termed the viral quasispecies, that exist within a single
individual.
Blackard et al.
Page 4
Given the diverse nature of HCV, it has been suggested that the emergence of particular viral
variants may permit HCV to circumvent the host immune response and maintain persistent
infection.3640 Moreover, several studies have explored potential associations between
immunologic selection pressure and clinical outcome in vivo. For instance, Ray et al.38
investigated viral diversity in 5 individuals who spontaneously cleared viremia and 10
individuals with persistent viremia. Persistent viremia was associated with a higher
hypervariable region 1 (HVR1) nonsynonymous/synonymous rate ratio, a lower E1 nonsynonymous/synonymous rate ratio, higher quasispecies complexity, and fewer positively
charged residues in HVR1. Spontaneous clearers also differed from individuals with persistent
viremia at 8 amino acid positions, although no residues were completely predictive of clinical
outcome. Farci et al.39 similarly examined viral diversity among 12 patients with different
clinical outcomes. Acute resolving hepatitis was associated with relative stasis of the viral
quasispecies, whereas progressing hepatitis correlated with HCV evolution, particularly in
HVR1.
Innate Immunity to HCV Infection
An acute viral infection triggers the activation of several antiviral effectors in mammalian cells.
This innate antiviral response is an early host defense mechanism that occurs prior to adaptive
immune responses.41 The recent discovery of pathogen-associated molecular patterns that are
recognized by specific toll-like receptors have dramatically advanced our understanding of the
innate host response to viral infection.42 For example, HCV RNA contains pathogenassociated molecular pattern motifs43,44 that could bind to toll-like receptor 3 at the cell
surface and intracellularly through retinoic acidinducible gene 1 to induce type I interferons
(interferon alpha and interferon beta) in hepatocytes.43,45 Type I interferons regulate the
antigen-processing machinery through the induction of immunoproteasome subunits, their
incorporation into the proteasome complex, and the generation of an immunoproteasomedependent CD8 T cell epitope.46 Moreover, type I interferons activate the expression of more
than 300 interferon-stimulated genes that also have antiviral functions. The best characterized
include the RNA-dependent protein kinase (PKR), 25-oligoadenylate synthetase, RNase L,
adenosine deaminase (adenosine deaminase, RNA-specific), and the Mx protein GTPases.
It is generally thought that only a minority of hepatocytes are infected with HCV.47
Nonetheless, the gene products secreted by this small number of infected cells can produce a
transient antiviral state in neighboring uninfected cells. Although such a scenario would limit
the potential replicative space within the liver, it is rare that this innate antiviral response
completely eradicates the virus as the majority of persons exposed to HCV develop a chronic
infection. Thus, the ability of HCV to antagonize these antiviral responses is crucial to viral
persistence. Several HCV proteins, including core, E2, nonstructural 3/4A, and nonstructural
5A proteins, have been implicated in the inhibition of interferon-inducible genes and/or key
components of interferon signaling pathways via multiple mechanisms.48 Thus, HCV can both
trigger and control the hepatic response to infection (Fig. 1).
Role of Natural Killer (NK) Cells

NK cells are the major effector cells of the innate immune system and play an important role
in the activation and maintenance of subsequent adaptive immune responses. The antiviral role
of NK cells during HCV infection has been demonstrated by the induction of an HCVassociated, perforin/granzyme-dependent lysis of human hepatoma cells by cytokine-activated
NK cells.49 The ligation of CD81 (a potential receptor for HCV) on NK cells inhibits interferon
gamma production and results in decreased anti-HCV activity. In addition, antibodies to
interferon gamma or interferon gamma receptors abolish the anti-HCV activity of NK cells.
50 Furthermore, genes encoding an inhibitory NK cell receptor (killer cell immunoglobulin-
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Page 5
like receptor, two domains, long cytoplasmic tail, 3) and its human leukocyte antigen C group
1 ligand directly influence the resolution of HCV infection,51 and this suggests that inhibitory
NK cell interactions are important determinants of antiviral immunity and that diminished
inhibitory responses confer protection against HCV.
Humoral Immune Responses

Humoral immune responses are generated against multiple HCV proteins, but the correlation
of a single specific immune response with recovery from an acute infection has not been clearly
established. Two HVRs (HVR1 and HVR2) in the E2 envelope glycoprotein have been
identified.52,53 At least 1 study has suggested that the early appearance of HVR1 antibodies
is associated with an acute self-limiting HCV infection.54 Additionally, mutations within
certain regions, especially the E2 HVR, have been associated with the emergence of virus
resistance to neutralization and the persistence of infection.55 Recently, discordance between
the level of neutralizing anti-HCV antibodies and clearance of viremia has been reported.56
In fact, there exists a subpopulation of individuals exposed to HCV that clear the virus without
the induction of anti-HCV antibodies; therefore, the only surrogate markers for HCV exposure
in such persons are HCV-specific cell-mediated immune responses.5763
Role of CD4 T Cells

A growing body of evidence indicates that the spontaneous clearance of HCV is associated
with a strong HCV-specific CD4+ T cell response.56,64,65 A number of studies have indicated
that successful cellular immune responses in recovered patients appear to be multispecific and
sustained, with CD4+ T cells playing major roles.6673 The role of CD4+ T cells in acute HCV
infection has been examined by depletion studies in chimpanzees, in which the loss of CD4+
T cells resulted in persistent infection.74 CD4+ T cell levels also appear to be important during
acute HCV infection, as the level of CD4+ T cell proliferative responses is associated with viral
clearance,65,75,76 whereas the loss of such responses often results in the recurrence of viremia.
77 Moreover, it has also been shown that patients who clear the infection respond to higher
numbers of HCV epitopes in comparison with chronically infected patients.66,78
Cytokines are also important for the clearance or persistence of viremia. For instance, a
vigorous HCV-specific type 1 helper T cell CD4+ response, particularly against nonstructural
proteins, is associated with viral clearance65 or a successful response to therapy.76,7982 In
fact, the lack of type 1 helper T effector cells within the first months of acute HCV is a predictor
of viral persistence and could thus serve as a criterion for selecting candidates for early antiviral
treatment.65 The cause of dysfunctional CD4+ T cells in chronic HCV infection is not clear.
However, exhaustion from continuous T cell stimulation,83 the induction of T-cell anergy,
84 the induction of T regulatory cells that inhibit the immune responses,85,86 and the
suppression of immune responses by HCV proteins48,8793 represent several intriguing
hypotheses. Without sufficient HCV-specific CD4 help, HCV-specific CD8+ T cell and
heterologous neutralizing antibody responses may develop but fail to clear viremia.56
Role of CD8 T Cells

CD8 T cells could respond to HCV viral infection through 2 main mechanisms: the killing of
infected hepatocytes or the secretion of antiviral cytokines. In comparison with CD4+ T cells,
the role of CD8+ T cells in an acute HCV infection is less well defined because their detection
during an acute infection coincides with viral clearance in some94,95 but not all studies.96
The reason for this discrepancy is not clear; however, most studies have used peripheral blood
lymphocytes stimulated with selected epitopes previously identified or predicted from protein
sequences. Therefore, this approach may not adequately evaluate the local intrahepatic immune
responses to naturally processed HCV peptides. A comprehensive analysis of the CD8
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responses using overlapping peptides covering the entire HCV genome has revealed multiple
unpredicted epitopes that stimulate CD8-specific T cells even in chronically HCV-infected
patients.97 Moreover, differences also exist between intrahepatic T cell responses and those
in the peripheral blood.98100 However, strong, multispecific interferon gammaproducing,
HCV-specific CD8+ T cells are one of the characteristic features of patients who recover from
an acute HCV infection.66,68,69,72,101114 In a chronic HCV infection, although the
frequencies of HCV-specific CD8+ T cells may be normal, the cells exhibit a dysfunctional or
stunned phenotype.66,100,115,116 Recent data indicate that most HCV-specific CD8+ T cells
express the inhibitory receptor programmed death 1 (PD-1) at the time of acute infection.
117 Interestingly, levels of PD-1 decline in patients with a resolved HCV infection but remain
high during viral persistence.117 The high expression of PD-1 is associated with dysfunctional
CD8+ T cells and may partially explain the defective phenotypes of CD8+ T cells reported in
chronically HCV-infected patients. Blocking the PD-1/programmed death ligand 1 interaction
improved the functional activity of HCV-specific CD8+ T cells and restored CD8 function in
vitro.118 Supporting data for the role of PD-1 expression in chronic HCV infection has been
recently published with chimpanzees models.119 However, there are also data suggesting that
most intrahepatic CD8+ T cells are toleragenic and express PD-1.120 One of the evasion
mechanisms used by HCV to escape immune responses, especially CD8 responses, is the
development of viral escape mutants.121 Finally, a significant correlation has been
demonstrated between the number of lobular CD8+ T cells and ALT levels, suggesting a
prominent role for T cellmediated cytotoxicity in the genesis of hepatocellular damage.122
Treatment of Acute HCV Infection

Treatment decisions related to acute HCV infection must be considered in light of the natural
history of the disease process. Although early treatment may increase the likelihood of
improved treatment outcome, this must be balanced against the possibility that spontaneous
clearance during the acute phase of infection could render treatment interventions needless and
potentially harmful. Therefore, treatment paradigms must effectively balance these outcomes
and lead to optimal patient selection without significant loss of treatment efficacy.
As in chronic infection, all current acute HCV treatment paradigms are interferon-based.
Mechanistically, issues related to both viral evolution and immune response must be considered
in the context of interferon use. Several studies now suggest that quasispecies diversity is an
independent predictor of HCV treatment response. For instance, Chambers et al.123 noted that
an early treatment response to pegylated interferon alpha 2a and ribavirin (RBV) was associated
with lower baseline HCV RNA complexity in the envelope coding region, although this was
not the exclusive predictor of sustained viral response (SVR). Among subjects with advanced
liver disease, the treatment response was also reduced in subjects with increased baseline
quasispecies complexity.124 Shire et al.125 examined the relationship between baseline and
early viral selection pressures in HCV-monoinfected and HIV/HCV-coinfected subjects with
hemophilia who were treated with pegylated interferon plus weight-based RBV. Lower
baseline quasispecies complexity was associated with SVR. At the end of the phase 1 decline
in HCV viremia, subjects whose decrease was greater than 90% also had a strong trend toward
lower baseline complexity. The presence of HIV coinfection further mediated changes in the
complexity over time. Thus, low pretreatment quasispecies complexity may predict the
pegylated interferon response. These data do not, however, permit the ascertainment of the
latest time following acute exposure at which HCV infection can be treated with maximum
effect.
Multiple clinical trials report the arbitrary selection of start times for treatment intervention
after the recognition of HCV infection. However, because of the variability among treatment
regimens, current clinical recommendations are derived from diverse population cohorts with
Blackard et al.
Page 7

data extrapolated to individual patients. Jaeckel et al.126 described the treatment response
among 44 German patients with acute HCV. Patients had known or suspected exposure within
4 months, as documented by HCV seroconversion or a serum ALT greater than 20 times the
upper limit of normal with evidence of previously normal ALT for 1 year. Patients were treated
with interferon alpha 2b at a dose of 5 MU per day for 4 weeks followed by 5 MU 3 times per
week for 20 weeks. Sixty-eight percent met the first entry criteria for documented
seroconversion; 61% were infected with HCV genotype 1. Fully 98% of the subjects achieved
SVR. Subsequently, another German study evaluated a 24-week course of pegylated interferon
alpha 2b.127 The overall SVR was 71%, although an 89% SVR rate was achieved among
subjects classified as adherent with prescribed therapy. A third German experience by Gerlach
et al.29 included 60 patients with acute HCV by either seroconversion or acute hepatitis with
ALT greater than 10 times the upper limit of normal. There was no randomization or fixed
time for treatment intervention, and patients were offered the most effective therapy at the time
of diagnosis. Fifty-two percent spontaneously cleared HCV RNA less than 12 weeks after
diagnosis. Only 26 subjects were treated with an interferon-based regimen; 12 had therapy
started more than 6 months after the diagnosis of acute HCV. Twenty received pegylated
interferon, and half of those had coadministration of RBV. Viral clearance was observed in 21
of 26 (81%) treated subjects, leading to SVR. Kamal et al.81 described 54 patients screened
after either the first positive HCV RNA or the onset of symptoms. Laboratory studies were
performed for 12 weeks, and then HCV RNApositive subjects were offered interferon-based
therapy [either pegylated interferon alpha 2a (180 g/week) RBV (800 mg/day) or pegylated
interferon alpha 2b (1.5 g/kg/week) weight-based RBV]. Only 4 subjects cleared the virus
during the 12-week period without treatment. Ten subjects refused therapy, and 1 of these
cleared at week 14. All subjects had either genotype 1 or 4, with a slight genotype 4
predominance. Among the treated subjects, 33 of 40 (82.5%) achieved SVR. There was a
nonstatistically significant advantage to subjects treated with regimens containing RBV.
Subsequently, Kamal et al. evaluated the optimization of the treatment duration and time of
initiation in 2 randomized treatment trials. Among 102 subjects randomized to receive
pegylated interferon alpha 2b for 8, 12, or 24 weeks, the highest rate of response was observed
in the 24-week arm (91.2%). Although stratification by genotype led to relatively small subsets
(only 1516 subjects per arm), 88% of genotype 1 subjects who were treated for 24 weeks
achieved SVR. Excellent results were reported for shorter therapy in genotype 2 and 3 subjects;
however, each treatment arm contained only 2 or 3 subjects, and this limited interpretation.
Genotype 4 was nearly as common as genotype 1 and had the highest response (100% SVR)
in the 24-week treatment group.128 In a second study, Kamal et al.129 followed patients for
8 weeks after the identification of acute HCV. Subjects were then randomized to receive
pegylated interferon alpha 2b, beginning at 8, 12, or 20 weeks, and they underwent a 12-week
treatment regimen. SVR was higher for subjects with shorter waiting times.
Reports of acute HCV within the United States are limited. The largest experience involves a
retrospective analysis of clinical practices reported by Corey et al.30 Acute HCV was
diagnosed in 24 patients; 15 received interferon-based therapy. All treated patients cleared the
virus on therapy, and all but 1 (93%) achieved SVR; 5 of 6 patients not offered therapy remained
viremic. A similar study by Rahman et al.130 included 7 patients who were treated with an
interferon-based regimen; 6 of 7 achieved SVR. Interestingly, the only patient to not achieve
SVR did not receive RBV; however, the authors noted that this patient was also an African
American male with poor prognostic likelihood of viral clearance, obscuring potential
conclusions regarding the cause of treatment failure.
As mentioned previously, patients with acute HCV infection in the setting of HIV coinfection
represent a unique and increasingly important subset of this disease process.19 A prospective
evaluation for liver function test abnormalities and HCV antibody seroconversion was
performed every 3 months in an HIV clinic in Great Britain. Fifty acute HCV infections were
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Page 8
identified and confirmed with HCV RNA testing, and this was followed every 4 weeks with
HCV RNA quantitative assays. After 12 weeks of positive HCV RNAs, patients were offered
therapy with pegylated interferon and weight-based RBV. During the 12-week window, 12 of
50 (24%) cleared HCV RNA and remained aviremic. Eleven subjects declined therapy, and
all progressed to chronic HCV infection. The remaining 25 were treated for 24 weeks. SVR
was 59% among the treated patients, and this is clearly lower than reports during HCV
monoinfection. All treatment failures occurred among patients with HCV genotype 1 and
relatively low CD4 counts (median: 276 cells/mm3). However, better response rates were
reported among 11 acutely infected German patients, with 10 having SVR.131 Ten patients
with genotype 4 HCV and HIV were treated in France following a suspected common source
sexually transmitted infection cluster. Treatment was provided within a mean time of 49 days
from the onset of acute hepatitis, and a variety of interferon-based regimens were used. No
patient achieved SVR.132 Finally, 9 acute HCV infections were identified in HIV-infected
patients in California.31 Only 4 were treated with pegylated interferon and RBV; 3 achieved
SVR. Among 5 untreated patients, 2 demonstrated spontaneous clearance, and 3 developed
chronic liver disease.
On the basis of the available (albeit insufficient) data, several conclusions may be drawn. First,
the optimal timing to initiate treatment remains unclear. Different definitions of decision trees
used in clinical trials contribute to some of this confusion because some studies define the
estimated time from acute exposure, whereas others define the starting point as seroconversion
or acute hepatitis, using arbitrary serum aminotransferase criteria. The only study to
prospectively evaluate this issue used 12 weeks of therapy, although the same group reported
better efficacy with 24 weeks of therapy in another cohort. These inconsistencies argue for a
formal definition to be used in future prospective trials (Fig. 2). Although the first HCV RNA
positive result may be useful, in unsuspected, community-acquired cases, clinical findings are
often used to reach an eventual diagnosis. It is reasonable to suggest that treatment should be
considered at least 12 weeks after seroconversion or acute hepatitis. In the future, increased
availability of more sensitive HCV assays (for example, transcription-mediated amplification)
may require reassessment of this algorithm because of the potential for earlier diagnosis. The
latest time at which the treatment of acute infection may be initiated has not been precisely
defined; however, the data support the concept that earlier treatment may be more effective
than later treatment. Although excellent responses have been observed with standard interferon,
clinical experience suggests that the use of once weekly agents improves adherence and is
preferred.133 Therefore, pegylated interferon use is recommended. Second, the need for RBV
with an interferon-based treatment remains controversial. European experts suggest that RBV
use is unnecessary on the basis of excellent response rates observed with monotherapy.63
However, response rates have not been as high in the United States. The extrapolation of data
from the treatment of chronically HCV-infected patients would support RBV use in the United
States. Pending further data, a dose of 800 mg of RBV per day combined with pegylated
interferon seems ideal, although patients with poor response characteristics may require
weight-based dosing regimens. Treatment durations of 24 weeks have been shown to be more
effective in genotype 1 patients in 1 prospective trial; therefore, this treatment cycle should be
used in HCV-monoinfected patients because excellent overall responses have been observed.
These recommendations are similar to those promulgated by the American Association for the
Study of Liver Diseases,134 although that body felt that RBV use should be individualized.
Finally, patients with HIV/HCV coinfection seem to have poorer outcomes following acute
HCV infection. At this time, there are no data to support either longer treatment durations or
higher doses of interferon products, and no specific recommendations can be made.
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Conclusions
Acute HCV infection remains a significant clinical problem because of the difficulty of early
case recognition and the inability to predict the risk of clearance versus chronicity of infection
with a high degree of accuracy during early infection. Research focused on either virologic or
immunologic events that signal spontaneous clearance should be vigorously pursued.
Similarly, a lack of large, randomized clinical trials limits our ability to make informed
treatment decisions and leads to the development of treatment paradigms that are often
vigorously defended by their proponents yet poorly supported by the data available. Studies
of timing, duration, and dose are needed. However, these studies are difficult to perform, and
investment is often tempered by the rapid evolution of agents used in more common chronic
infection scenarios. Therefore, it seems likely that existing regimens will dominate the acute
HCV scene for several years to come.
Acknowledgements
Supported in part by a National Institute of Diabetes and Digestive and Kidney Diseases K24 award (DK 070528-01)
to K.E.S. and by a National Institute on Drug Abuse R21 award (DA022148-01) to J.T.B.
Abbreviations
Ab
antibody
ALT
alanine aminotransferase
HCV
hepatitis C virus
HIV
human immunodeficiency virus
HVR
hypervariable region
IDU
injection drug use
ISC
interferon secreting cell
MSM
men who have sex with men
NK
natural killer
PCR
polymerase chain reaction
PD-1
programmed death 1
PEG-IFN
pegylated interferon
PY
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Page 10
person years
RBV
ribavirin
SVR
sustained viral response
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Fig. 1.
Natural history of HCV infection (upper panel) and immunologic responses to HCV infection
(lower panel): () HCV RNA, (- - -) cellular response, and ( ) ALT. ALT indicates alanine
aminotransferase; HCV, hepatitis C virus; ISC, interferon secreting cell; NK, natural killer;
and PD-1, programmed death 1.

Blackard et al.
Page 19

Fig. 2.
Proposed algorithm for the diagnosis and treatment of an acute HCV infection. Ab indicates
antibody; ALT, alanine aminotransferase; HCV, hepatitis C virus; PCR, polymerase chain
reaction; PEG-IFN, pegylated interferon; and RBV, ribavirin.

Blackard et al.
Page 20
Table 1
Factors Potentially Associated with the Clearance or Persistence of an Acute HCV Infection
Type of exposure
Size of inoculum/HCV viral load
Gender
Age
Prior HCV exposure
Prior exposure to interferon therapy
HCV genotype
Quasispecies diversity/complexity
Other coinfections
Immunologic response
Innate immune response: viral evasion
Neutralizing antibody response: viral epitope recognition or escape
CD8+ cytotoxic T lymphocyte response: viral epitope recognition or escape


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