NIH CONFERENCE

Pathogenesis, Natural History, Treatment, and Prevention

of Hepatitis C
Moderator: T. Jake Liang, MD; Discussants: Barbara Rehermann, MD; Leonard B. Seeff, MD;
and Jay H. Hoofnagle, MD

Approximately 4 million persons in the United States and edge will contribute to the development of an ef-
probably more than 100 million persons worldwide are fective vaccine and better therapies.
infected with hepatitis C virus. The virus has the unique Hepatitis C virus is a member of the Flaviviridae
ability to cause persistent infection in susceptible hosts
family, which includes the flaviviruses and pesti-
after parenteral or percutaneous transmission, and its un-
derlying mechanisms are not well understood. The immu-
viruses (2). There are at least 6 HCV genotypes and
nologic correlates of protection and viral clearance and more than 50 subtypes. The virion contains a posi-
the pathogenesis of liver injury are yet to be defined, but tive single-stranded RNA genome of 9.5 kilobases
recent studies suggest the importance of cell-mediated (Figure 1). The genome consists of 5⬘ and 3⬘ un-
immune responses. Although 70% to 80% of infected translated regions (5⬘UTR and 3⬘XR) that have
persons become chronic carriers, most have relatively mild little sequence variation among all genotypes and
disease with slow progression. However, chronic and pro- are important for translation of viral proteins and
gressive hepatitis C carries significant morbidity and mor-
replication of the virus. The viral genome encodes a
tality and is a major cause of cirrhosis, end-stage liver
large single polyprotein of about 3000 amino acids;
disease, and liver cancer. Development of an effective
hepatitis C virus vaccine is not imminent, but recent ad- the N-terminal one third harbors the structural pro-
vances in technology and basic knowledge of molecular teins, and the C-terminal two thirds contains the
virology and immunology have engendered novel ap- nonstructural proteins. The HCV structural proteins
proaches to the fundamental problems encountered in comprise the core protein and the two envelope
vaccine development. Current therapy for hepatitis C, al- glycoproteins E1 and E2. The nonstructural pro-
though effective in some patients, is problematic and still teins, including proteases (NS2/3 and NS3), helicase
evolving. Advances in modern biology and immunology (an enzyme that unwinds double-stranded nucleic
promise new therapies for this important disease.
acid) (NS3), and RNA-dependent RNA polymerase
(NS5B), perform various functions essential for the
viral life cycle (Table 1). Cleavage of structural pro-
Ann Intern Med. 2000;132:296-305. teins from the polyprotein is catalyzed by a host
For author affiliations and current addresses, see end of text. signal peptidase, whereas polyprotein cleavage in
the nonstructural region requires HCV-encoded

D r. T. Jake Liang (Liver Diseases Section, Na- proteases.

tional Institute of Diabetes and Digestive and Hepatitis C virus enters a susceptible host either
Kidney Diseases [NIDDK], National Institutes of directly, through needle inoculation or transfusion
Health [NIH], Bethesda, Maryland): The identifica- of contaminated blood products, or inadvertently,
tion of hepatitis C virus (HCV) as the cause of through breakage of a percutaneous barrier (as ex-
non-A, non-B hepatitis represents a technical tour emplified by sexual or perinatal transmission) (3).
de force of modern molecular medicine (1). Char- The virus then enters hepatocytes or other suscep-
acterization of the viral genome and the structures tible cells, probably through a unique surface mol-
and functions of viral gene products has led to a ecule or molecules, as the viral receptor (4). After
better understanding of the viral life cycle and the uptake, the virus uncoats and releases the genome
pathogenesis of HCV-associated disease. This knowl- to begin replication. The viral genome first serves as
the template for translation of the polyprotein. The
An edited summary of a Clinical Staff Conference held on 31 processed nonstructural proteins then form a com-
March 1999 at the National Institutes of Health in Bethesda, plex with the genome and initiate synthesis of the
Maryland.
Authors who wish to cite a section of the conference and negative strand, which in turn functions as the tem-
specifically indicate its author may use this example for the form plate for positive strand synthesis. The replication
of the reference: complex probably resides in a membranous com-
Rehermann B. Immunopathogenesis of hepatitis C. In: Liang
TJ, moderator. Pathogenesis, natural history, treatment, and partment in the cytoplasm, presumably derived from
prevention of hepatitis C. Ann Intern Med. 2000;132:297-299. the endoplasmic reticulum. The RNA replicative
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 Figure 1. Schematic diagram of the hepatitis C virus genome. The location of HCV genes, proposed functions of gene products, and the 5⬘ and 3⬘
untranslated regions (5⬘UTR and 3⬘XR) are shown. Numbering refers to nucleotide positions of genes.

intermediate matures and interacts with the core interleukin-10) cytokines. In the context of class I
and envelope proteins to assemble into a virion. MHC molecules, CD8-positive cytotoxic T cells rec-
Although most of the replicative processes have not ognize HCV peptides that are synthesized and pro-
been defined, some nonstructural proteins clearly cessed in infected cells (Figure 2). This encounter
play critical roles in viral replication and productive can lead to lysis of virus-infected cells. Together
infection; these proteins are therefore the focus of with helper T cells, cytotoxic T lymphocytes may
antiviral development. also secrete cytokines, such as interferon-␥ and
tumor necrosis factor-␣, that inhibit replication and
gene expression of several viruses, such as hepatitis
Immunopathogenesis of Hepatitis C B virus, cytomegalovirus, and rotavirus (6 – 8).

Dr. Barbara Rehermann (Liver Diseases Section, Humoral Immune Response

NIDDK, NIH): Unlike other hepatitis viruses, the Hepatitis C virus can establish persistent infec-
hepatitis C virus is more likely to cause clinically tion despite an active humoral and cellular immune
inapparent, chronic infection in persons who are response that is generally targeted against all viral
otherwise considered immunocompetent. Thus, the proteins. The virus may escape from the humoral
virus is capable of circumventing an efficient im- immune response if the kinetics of infection and
mune response of the host. viral replication do not allow complete neutraliza-
tion of the virus by HCV-specific antibodies after
Components of Antiviral Immune Response primary infection. Although virus-specific antibodies
The mechanisms whereby HCV circumvents im- may interfere with viral entry into host cells and
mune response and establishes persistent infection opsonize the virus for elimination by macrophages,
are currently undefined. It is well known that the they cannot eliminate HCV from infected cells. In
specific immune response to any viral infection is
primed by macrophages and dendritic cells that
present viral proteins to B cells, helper T cells, and Table 1. Functions of Genetic Elements of Hepatitis
cytotoxic T cells (Figure 2). In many viral infections, C Virus*
B cells produce antibodies that can clear circulating
virus and protect from reinfection. For example, Genetic Element Function

antibodies against the hepatitis B virus surface an- Regulatory sequences

tigen are critical for viral clearance. Through spe- 5⬘UTR Internal ribosomal entry site for translation;
cific T-cell receptors on the cell surface, helper T 3⬘XR
replication
Translation and replication
cells recognize viral peptides that are derived from Viral proteins
phagocytosed and proteolytically cleaved HCV pro- Core
E1 and E2
Nucleocapsid; assembly
Envelope proteins; assembly and entry
teins and are presented in the context of class II p7 Assembly†
MHC molecules. NS2
NS3
NS2-3 protease
Serine protease, nucleotide triphosphatase, and
On activation of their specific T-cell receptors, RNA helicase
HCV-specific helper T cells assist with activation NS4A
NS4B
Cofactor for NS3 protease activity; replication†
Replication†
and differentiation of B cells as well as induction (5) NS5A Phosphoprotein; replication† and interferon
and stimulation of virus-specific cytotoxic T cells. NS5B
sensitivity sequence‡
RNA-dependent RNA polymerase
Most of these effects are mediated by different sets
of immunoregulatory Th1 (interferon-␥ and inter- * 3⬘XR ⫽ 3⬘ untranslated region; 5⬘UTR ⫽ 5⬘ untranslated region.
† A proposed function.
leukin-2) or Th2 (interleukin-4, interleukin-5, and ‡ This idea is controversial.

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 addition, HCV has a high mutation rate, especially sequences that are recognized most frequently and
in the hypervariable region of the envelope proteins vigorously by HCV-specific T cells vary little among
that can be recognized by neutralizing antibodies all the HCV genotypes. Furthermore, several of
(antibodies that can bind and eliminate virus) (9, these frequently recognized viral peptides bind with
10). Several studies have demonstrated that the hu- high affinity to many different class II MHC mole-
moral immune response can select HCV variants cules, suggesting that they can be efficiently pre-
with sequence changes that allow escape from anti- sented and recognized by patients with different
body recognition (11–14). However, recent studies MHC haplotypes (17, 20). Thus, these viral se-
in chimpanzees have suggested that HCV can cause quences could be explored for development of pre-
persistent infection in the absence of mutations in ventive or therapeutic vaccines against HCV.
the hypervariable region (15, 16). Thus, progression The cellular response against HCV could be in-
to persistent HCV infection is most likely a multi- terfered with in several ways. First, HCV elicits only
factorial process that depends on multiple aspects of a weak T-cell response in patients who develop
virus– host interaction. chronic infection (17, 21). In the blood of patients
with chronic hepatitis C, the frequency of cytotoxic
Cellular Immune Response T-cell precursors that are specific for individual
The cellular immune response probably plays an HCV peptides is much lower than the frequency of
important role in the outcome of HCV infection T cells that recognize an influenza virus peptide as
because of its ability to recognize and eliminate a recall antigen (22) or peptides of other viruses
virus from infected cells. Most studies have concen- that can be cleared, such as cytomegalovirus (23).
trated on the antigen-specific immune response that The reasons for this relative weakness of the cellu-
is mediated by CD4-positive helper T cells and lar immune response are not known. Certainly, gen-
CD8-positive cytotoxic T cells. eral immune tolerance or immunosuppression is not
Because chronic rather than acute infection is the cause of persistent HCV infection, because most
diagnosed in most patients, immunologic studies chronically infected patients display normal immune
have been performed on patients with persistent responses against other viral agents (22). The emer-
infection who could not clear HCV. Only a few gence of viral mutants or quasi-species with se-
studies have analyzed the cellular immune response quence variations in T-cell epitopes may contribute
during the acute phase of infection. These studies to the apparent ineffectiveness of cell-mediated im-
suggest that the strength and quality of both helper mune response (24 –26). There is also increasing
T-cell (17, 18) and cytotoxic T-cell responses (19) evidence that several HCV proteins, such as core
differ between patients who recover and those who (27), E2 (28), and NS5A (29), interfere with the
develop chronic infection. More important, the viral immune response. Furthermore, infected hepato-

Figure 2. Components of the antiviral immune response. Although the hepatocyte is depicted as the target cell of hepatitis C virus (HCV)–specific
immune response here, other cells, including dendritic cells and macrophages, are also important in antigen presentation to the immune system. CTL ⫽
cytotoxic T cell; IL ⫽ interleukin; MHC ⫽ major histocompatibility complex; TCR ⫽ T-cell receptor; Th ⫽ T helper; Th1 ⫽ helper T cells with a type 1 cytokine
profile; Th2 ⫽ helper T cells with a type 2 cytokine profile; TNF ⫽ tumor necrosis factor.

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 cytes, which lack co-stimulatory molecules, may be markedly protracted, spanning 20 to 40 years before
relatively inefficient in priming the immune system, the final outcome is reached. Moreover, the circum-
and the liver has been proposed as the major site stance of exposure (for example, transfusions, par-
where activated T cells are destroyed (30). Finally, enteral drug use, hemophilia, or hemodialysis) may
the cellular immune response is a double-edged itself be associated with reduced life expectancy,
sword. An immune response that is ineffective in thus competing with HCV for morbidity and mor-
clearing HCV infection may be more harmful to the tality.
liver, causing chronic inflammation, hepatocellular Strategies used to examine this issue have in-
injury, and, over several decades, liver fibrosis and cluded prospective transfusion-related studies that
cirrhosis. begin with acute hepatitis C; retrospective studies
Progression to persistent infection and the immu- that prospectively track persons with established
nologic mechanisms of liver injury are the conse- chronic hepatitis C; and a combination of the two—
quence of complicated interactions between the retrospective–prospective (nonconcurrent prospec-
virus and host. Identification of immunologic corre- tive) studies—that requires identification of a defin-
lates of viral clearance may contribute to the devel- itive acute hepatitis outbreak in the past, with
opment of an effective vaccine and better therapy subsequent patient recall followed by long-term pro-
for HCV infection. spective evaluation. The prospective study approach
describes the natural history of acute hepatitis C,
whereas the retrospective study delineates the nat-
Natural History of Hepatitis C ural history of chronic hepatitis C. Obstacles to the
first approach include the difficulty in identifying a
Dr. Leonard B. Seeff (Division of Digestive Dis- large study cohort with acute hepatitis C and the
eases and Nutrition, NIDDK, NIH): The natural time required to complete follow-up. The second
history of hepatitis C continues to be a controversial approach introduces the problem of selection bias—
issue because of the lack of clarification of long- namely, the focus on patients with already estab-
term outcome. Although it is widely accepted that lished chronic liver disease and the omission from
approximately 80% of persons who become infected analysis of persons who were infected earlier but
fail to clear the virus and progress to chronic infec- who spontaneously recovered or were not ill enough
tion, the uncertain extended outcome has prompted to consult a physician.
divergent views. Clearly, some infected persons re-
cover completely; some remain HCV viremic with- Prospective Studies of Acute Hepatitis C
out biochemical evidence of liver damage; some Early studies focused on persons with transfu-
seem to have a static form of chronic hepatitis sion-associated hepatitis C (32–36). None of the
characterized by persistently elevated aminotransfer- studies had more than 14 years of follow-up, and
ase levels without overt symptoms or disease ad- none included a noninfected control group. Com-
vancement; some progress over a difficult-to-define posite analysis of these studies reveals that clinical
period to histologic fibrosis and cirrhosis; some have symptoms were identified in approximately 10% of
long-term stable cirrhosis identified only through patients, cirrhosis was found in about 20% (range,
liver biopsy; some have progressive cirrhosis that 8% to 24%), and hepatocellular carcinoma was
culminates in liver failure; and, finally, some de- rare. Liver disease appeared to be responsible for
velop hepatocellular carcinoma. The uncertainties death in approximately 3% of patients (range, 1.6%
lie in the relative frequencies and rates of develop- to 6.0%). These studies clearly identified liver-
ment of these various sequelae. Indeed, the major related morbidity and mortality but in generally
questions are whether progression is linear and modest frequencies. Their limitations, however,
whether advancement through these increasingly se- were the relatively small numbers of patients in-
vere manifestations is inevitable (31). cluded in each study and the short follow-up.
The only means of accurately defining outcome is
to conduct well-designed, long-term, prospective Retrospective Studies of Chronic Hepatitis
studies that begin with onset of acute HCV infec- In three important studies (37–39), a far bleaker
tion and follow participants over a sufficiently picture emerged. Despite the relatively short follow-
extended period. Such studies must use careful clin- up (4 to 11 years), these studies reported symptoms
ical, biochemical, serologic, and histologic assess- in far greater frequency, cirrhosis in a higher pro-
ment. However, there are numerous impediments to portion of patients (30% to 46%), a remarkably
accomplishing these aims. Onset of acute hepatitis high frequency of hepatocellular carcinoma (11% to
C is rarely recognized owing to lack of symptoms; 19% of patients), and a significantly high rate of
chronic HCV infection similarly is generally a silent liver-related death. Of note, a considerable number
condition; and the course of the disease is often of the patients in the U.S. study already had end-
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 tients with cirrhosis. These data are in accord with a
recent report from Germany showing that mortality
is increased in persons with chronic hepatitis C only
if they have cirrhosis (43).
The final study is an almost 50-year follow-up of
young military recruits on a U.S. Air Force base in
Wyoming, from whom blood samples were obtained
between 1948 and 1954 as part of a study of a
streptococcal infection outbreak (44). Among the
few persons found to be infected with HCV, less
Figure 3. Survival curves comparing patients with non-A, non-B than 20% have died or have liver disease.
transfusion-associated, predominantly type C hepatitis (solid line);
matched transfusion recipients without hepatitis (controls) (dashed
Taken together, these data suggest that approxi-
line); and the general U.S. population (dotted line). Survival of 100% mately 15% to 20% of persons who acquire HCV
is shown as 1 on the y axis.
infection progress to potentially serious end-stage
liver disease, the critical sequela being cirrhosis.
stage cirrhosis or hepatocellular carcinoma when The remainder are likely to die of causes other than
they were first seen (39). The impact of these re- liver disease.
sults must, however, be tempered by the fact that
they represent the worst-case scenario by focusing
only on persons with already well-established Therapy for Hepatitis C
chronic liver disease. Despite this “referral bias,”
the accrued data nevertheless underscore how seri- Dr. Jay H. Hoofnagle (Division of Digestive Dis-
ous the condition is once cirrhosis develops. eases and Nutrition and Liver Diseases Section,
NIDDK, NIH): The current recommendations for
Retrospective–Prospective Studies treatment of hepatitis C are based mainly on the
Three studies can be classified as retrospective– NIH Consensus Development Conference Panel on
prospective studies. The first, an ongoing study from Management of Hepatitis C that was formulated in
Ireland, involved an outbreak of acute hepatitis C in March 1997 (45). Although the recommendations
more than 50 000 young women who had received for therapy remain valid, the optimal regimen now
HCV-contaminated anti-D immunoglobulin (40). In requires modification.
a follow-up report 17 years later, three quarters of
the women were symptomatic, mainly with fatigue; Indications for Therapy
serum enzyme values were normal in more than Therapy for hepatitis C is clearly indicated in
40% of patients; and, most important, liver biopsies patients 18 to 60 years of age who have persistently
revealed fibrosis, which was mostly mild in 51% but abnormal alanine aminotransferase levels, HCV
represented cirrhosis in 2%. This surprising result RNA in serum, and evidence on liver biopsy of
has been attributed to the fact that these were chronic hepatitis with either fibrosis or moderate
young, healthy, nondrinking women, who seem to be degrees of inflammatory activity (45). Patients with
at less risk than older, alcohol-imbibing men (31). decompensated cirrhosis and those with persistently
The second study followed persons from several normal aminotransferase levels and mild hepatitis
early transfusion-related studies in whom acute hep- should not be treated outside of clinical trials.
atitis C had developed (41). Patients with acute
hepatitis in these studies were combined and com- Optimal Therapeutic Regimen
pared with a matched group of controls who did not The NIH Consensus Panel stated that the opti-
undergo transfusion and did not have cirrhosis so mal therapeutic regimen for hepatitis C was inter-
that morbidity and mortality could be studied long- feron-␣ given subcutaneously in a dose of 3 million
term. Analysis at 18 years (41) and 23 years (42) U three times weekly for 12 months with assessment
revealed no difference between the two cohorts with of aminotransferase levels and HCV RNA at 3
respect to overall mortality but showed a slight and months to allow early discontinuation in patients
slowly increasing difference in liver-related mortality who do not respond (45). Two years later, these
(Figure 3). Follow-up for morbidity in living pa- recommendations clearly require modification in re-
tients revealed that one fourth seemed to have had sponse to results of studies on combination therapy
spontaneous resolution; in the remainder, viremia with interferon-␣ and ribavirin.
persisted, and only half of these patients had ac- Ribavirin is an oral nucleoside analogue with a
companying aminotransferase elevations. Liver bi- broad spectrum of activity against both RNA and
opsies revealed cirrhosis in 15% of patients; clinical DNA viruses. When used alone as therapy for hep-
symptoms were confined almost exclusively to pa- atitis C, ribavirin decreases aminotransferase levels
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 Despite the impressive results obtained with
combination therapy, the real issue is whether pa-
tients in whom sustained virologic response is
achieved are likely to have relapse months or years
later. Insufficient time has elapsed to evaluate the
durability of virologic responses after combination
therapy, but long-term follow-up after treatment
with interferon alone indicates that most patients
who fulfill the criteria for a sustained virologic re-
sponse remain negative for HCV RNA, have nor-
mal serum aminotransferase levels, and have no
symptoms of liver disease 5 to 12 years after treat-
ment (53, 54).
Figure 4. Rates of virologic response in patients with chronic
hepatitis C treated with interferon-␣ for 24 weeks (IFN 24 wk) or 48 Factors That Predict Response to Therapy
weeks (IFN 48 wk) or interferon-␣ plus ribavirin for 24 weeks (IFN
and RBV 24 wk) or 48 weeks (IFN and RBV 48 wk). The total height of Retrospective analyses of the two studies for fea-
the bars represents the end-of-treatment response rate; the white portion
represents the sustained response rate. Data are shown for 1744 patients tures that produced a response have identified sev-
(the number in each treatment group is given in parentheses) from two eral factors important for recommending therapy
large prospective clinical trials (49, 51). Numbers at the top of the bars
represent exact percentages. (49, 51). The host factors of young age, female sex,
and lesser degrees of fibrosis on liver biopsy corre-
lated with a greater likelihood of a sustained re-
and improves hepatic histologic findings in 30% to sponse. Even more significant were the viral fea-
50% of patients (46 – 48). However, HCV RNA lev- tures of genotype and HCV RNA level. The
els do not decrease, and relapses occur in almost all sustained response rate among patients with geno-
patients soon after treatment is stopped. types 2 and 3 was twice as high as that among
Results of three multicenter randomized, con- patients with genotype 1 (the number of patients
trolled trials comparing combination therapy with with genotypes 4, 5, and 6 were too few to analyze
interferon and ribavirin with interferon-␣ alone separately) (Figure 5). In patients with genotype 2
were recently published (49 –51). The similarity of or 3, a 24-week course was as effective as a 48-week
design, monitoring, end points, and analysis of these course of combination therapy; two thirds of these
trials allows presentation of combined results. A patients had a sustained response. In contrast, the
total of 1744 previously untreated patients were en- response rate among patients with genotype 1 was
rolled in two large trials (49, 51). Patients were significantly higher with 48 weeks of therapy than
randomly assigned to receive interferon-␣ alone or with 24 weeks (30% compared with 17%).
combination therapy for 24 or 48 weeks. The pri-
mary end point was lack of detectable HCV RNA
in serum 6 months after stopping therapy (sustained
virologic response). Biochemical (normal amino-
transferase levels) and histologic responses (im-
provements in liver histologic findings) were also
analyzed.
Combined results of these two studies are shown
in Figure 4. In patients given interferon alone, the
end-of-treatment response rates were the same after
both 24 and 48 weeks (29%), but rates of sustained
response were higher with the longer course of ther-
apy. This supports the previous recommendation
that interferon as monotherapy should be given for
12 rather than 6 months (45, 52). Both the end-of-
treatment and sustained response rates were higher
with combination therapy than with interferon Figure 5. Rates of sustained virologic response in patients with
chronic hepatitis C treated with interferon-␣ for 24 weeks (IFN 24
alone. Most important, rates of sustained response wk) or 48 weeks (IFN 48 wk) or interferon-␣ plus ribavirin for 24
were higher with combination therapy, and 48 weeks (IFN and RBV 24 wk) or 48 weeks (IFN and RBV 48 wk), by
weeks of treatment (41%) was superior to 24 weeks viral genotype. The white bars represent patients with genotype 1 and the
few patients with genotypes 4, 5, and 6; the striped bars represent patients
(33%). Similar differences were reported for bio- with genotypes 2 and 3. Data are shown for 1744 patients (the number in
chemical responses and histologic improvement 6 each treatment group is given in parentheses) from two large prospective
clinical trials (49, 51). Numbers at the top of the bars represent exact per-
months after stopping therapy. centages.

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 Table 2. Major Side Effects of Combination Therapy with pared with 20% of patients receiving combination
Interferon-␣ and Ribavirin
therapy. Furthermore, ribavirin is known to cause
Common side effects usually caused by interferon-␣
fetal abnormalities and should not be used in pa-
Fatigue, malaise, myalgias, headache, poor appetite tients (both men and women) who cannot practice
Depression, irritability, anxiety, emotional lability
Difficulty concentrating, forgetfulness, sleeplessness
adequate birth control during therapy and for at
Bone marrow suppression, thrombocytopenia, neutropenia least 6 months thereafter.
Common side effects usually caused by ribavirin
Contraindications to combination therapy include
Hemolysis, hemoglobin decrease of 20 to 40 g/L hemolysis, anemia, bone marrow suppression, coro-
Gastrointestinal upset
Nasal congestion, sore throat, cough, dyspnea
nary and cerebrovascular disease, neuropsychiatric
Pruritus, skin rash conditions, active alcohol or substance abuse, renal
Uncommon, serious side effects
insufficiency or transplantation, and autoimmune
Bacterial infections disease. In some of these situations, interferon
Induction of autoantibodies and autoimmune disease
Severe depression, psychosis, disorientation, suicide
monotherapy can be used instead.
Relapse in alcohol or substance abuse
Seizures Special Patients and Populations
Vision or hearing loss, tinnitus
Acute renal or heart failure Most therapeutic trials have focused on typical
Fetal loss or fetal abnormalities
patients with chronic hepatitis C. Scant information
is available for patient groups who do not fit the
standard profile, including children; elderly persons;
In both studies, patients with higher initial HCV patients with acute hepatitis C who have normal
RNA levels (ⱖ2 million copies/mL) had a lower aminotransferase levels, severe extrahepatic mani-
response rate than those with lower levels, indepen- festations, HIV co-infection, active alcohol or sub-
dent of genotype. Among patients with genotype 1 stance abuse, or renal disease; patients who have
and low levels of HCV RNA (⬍2 million copies/ had solid organ transplantation; patients receiving
mL), the response rate for a 24-week course of cancer chemotherapy or immunosuppressive agents;
combination therapy was the same as that for a and patients in prisons or public institutions.
48-week course (32% and 33%). Nevertheless, the The role of combination therapy for patients pre-
variability of quantitative assays for HCV RNA and viously treated with interferon-␣ is also not re-
spontaneous fluctuations in levels over time make it solved. In a study of 24 weeks of re-treatment in
difficult to use this factor to recommend therapy or 345 patients who had had relapse, the sustained
its duration. response rate was 49% for combination therapy
In both studies, all patients with a sustained re- compared with only 5% for interferon re-treatment
sponse to combination therapy became negative for (50). These findings support use of combination
HCV RNA before 24 weeks. These findings suggest therapy in patients who have had relapse, but they
that patients who remain positive for HCV RNA did not address whether a 48-week course might be
after 24 weeks of treatment are unlikely to benefit preferable to a 24-week course, especially among
from further therapy and that the “3-month stop- patients with genotype 1 or high levels of HCV
rule” of interferon monotherapy should be replaced RNA.
by a “6-month stop-rule” when combination therapy Recommendations for patients who do not re-
is being used. spond to interferon are also difficult. True non-
responders have a low rate of response to combi-
Side Effects nation therapy, but some sustained responses have
The side effects of combination therapy include been reported (55).
those of both interferon and ribavirin (Table 2). The major challenge is how to increase the rate
Ribavirin causes dose-related hemolysis and anemia, of sustained response to antiviral therapy. Ap-
and prolonged treatment can cause pruritus, nasal proaches being evaluated include use of different
congestion, and cough. Most side effects are mild to types of interferon (56), daily interferon dosing (57),
moderate, transient, and reversible; they can be higher doses and induction regimens (57), and long-
managed with counseling, dosage adjustment, or acting pegylated interferons (58). Long-term, con-
specific treatment. tinuous interferon or ribavirin therapy is an option,
Severe side effects are more frequent with com- particularly in patients with extrahepatic manifesta-
bination therapy. In two recent trials, dose reduc- tions, those with marked fibrosis on liver biopsy, or
tions were required in 13% of patients receiving those who are at high risk for hepatocellular carci-
interferon alone compared with 17% of those re- noma (59 – 63).
ceiving combination therapy for 48 weeks (49, 51). The current recommendations for treatment are
Similarly, early discontinuation of 48-week therapy summarized in Table 3. The greatest need in hep-
was required in 8% of interferon recipients com- atitis C therapy is better and safer antiviral agents.
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 Table 3. Current Recommendations for Treatment gous or heterologous strain of HCV resulted in
of Hepatitis C
reinfection, suggesting an absence of protective im-
Course 24 to 48 weeks of interferon-␣ and ribavirin
munity after natural infection (14, 67).
Dosage Interferon, 3 million U three times weekly, and ribavirin, On the more optimistic side, infected persons can
1000 mg/d, for patients who weigh less than 75 kg
(165 lb) or ribavirin, 1200 mg/d, for those who weigh
develop neutralizing antibodies (12), and 15% to
75 kg or more. 25% of infected humans and 60% to 70% of in-
Monitoring Regular visits to assess symptoms, blood counts, and
serum aminotransferase levels; after 24 weeks,
fected chimpanzees ultimately recover from HCV
patients should be tested for HCV RNA by using a infection (66, 68). In addition, recent studies show
sensitive method.
Decision point Therapy should be discontinued at 24 weeks for
that a vigorous multispecific cellular immune re-
patients with genotype 2 or 3. In patients with sponse is implicated in viral clearance (17, 18, 69).
genotype 1, therapy should be stopped if HCV RNA
test results are positive and should be continued for a
This response involves both helper and cytotoxic T
full 48 weeks if HCV RNA test results are negative at lymphocytes, particularly of the Th1 type.
24 weeks.
Follow-up Serum aminotransferase levels should be monitored and
The ideal HCV vaccine should elicit high-titer,
testing for HCV RNA should be done at least 6 long-lasting, and broadly directed antienvelope anti-
months after stopping therapy.
bodies that recognize conserved epitopes and neu-
tralize against all HCV isolates. The vaccine should
also be capable of inducing a vigorous, multispecific
Advances in knowledge of the genomic structure, cellular immune response that includes both helper
structural biology, viral life cycle, and replicative and cytotoxic T lymphocytes. In particular, con-
strategy of HCV will aid in the development of served T-cell epitopes in the core, NS3, and NS4
potent antiviral agents. Particularly attractive targets regions should be targeted. Finally, because the Th1
for therapy are the enzymatic activities of the non- response is important in viral clearance, a vaccine
structural polypeptides, including the helicase, pro- candidate should direct a predominantly Th1 re-
tease, and RNA polymerase. sponse.
Several approaches have been used to develop an
HCV vaccine. The classic approach of developing
Vaccine Development live attenuated viral strain is hindered by the lack of
convenient experimental systems. The initial effort
Dr. T. Jake Liang (Liver Diseases Section, by Choo and coworkers (70) was directed toward
NIDDK, NIH): Because HCV infection has major generating recombinant HCV envelope proteins as
public health implications, the development of an a subunit-based vaccine, but success was limited
effective vaccine is of paramount importance. How- (71). Immunization of chimpanzees with the subunit
ever, such an effort is not without daunting challenges. vaccine resulted in partial and transient protection
First, the virus exists as a quasi-species because of a against low-dose challenge of a homologous, but not
high rate of mutation in the hypervariable region of heterologous, strain. Genetic vaccination has engen-
the envelope proteins (9, 10). Second, the hypervari- dered enthusiasm and holds great promise for in-
able region is a major site of antienvelope antibody duction of broadly directed humoral and cellular
response and contains a principal neutralization immune response (72); however, preliminary exper-
epitope (11, 13, 64). Third, antibody responses to iments in chimpanzees demonstrated that DNA im-
the envelope proteins develop slowly and achieve munization with HCV gene constructs may not be
only modest titers during primary infection (65). particularly immunogenic. Furthermore, the devel-
Consequently, neutralizing antibodies may emerge opment of chimeric viruses expressing HCV gene
too late to prevent chronic infection. In addition, products is attractive, but safety and regulatory is-
antienvelope antibodies tend to be short-lived, dis- sues may surface with implementation (73). An al-
appearing gradually after viral clearance (65). ternative approach relies on the synthesis and pro-
Fourth, immunologic correlates of protection and duction of viruslike particles (74). In contrast to the
disease progression have not been clearly defined. recombinant subunit-based vaccine, the structural
These problems are further complicated by a lack of proteins of HCV-like particles are presented in a
a convenient infectious tissue culture system for native, virion-like conformation and may therefore
testing neutralizing antibodies or passage of atten- be superior in eliciting a protective immune re-
uated viral strains. In addition, the only infectious sponse. In addition, HCV-like particles, as a partic-
animal model is the chimpanzee, an endangered ular antigen, may elicit a cytotoxic T-cell response
species that is difficult to study; in addition, the (75–77), which plays a critical role in viral clearance.
course of HCV infection in the chimpanzee is not Given the complexity of immune responses
necessarily representative of that in humans (66). against HCV infection and the lack of convenient
Experiments have demonstrated that challenge of experimental model systems, completely elucidating
apparently recovered chimpanzees with a homolo- the variables and correlates of protective immunity,
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 viral clearance, and disease progression will be chal- infectious clone for hepatitis C virus. J Virol. 1999;73:3317-25.
17. Diepolder HM, Gerlach JT, Zachoval R, Hoffmann RM, Jung MC,
lenging. Nevertheless, development of an effective Wierenga EA, et al. Immunodominant CD4⫹ T-cell epitope within non-
HCV vaccine requires a thorough understanding of structural protein 3 in acute hepatitis C virus infection. J Virol. 1997;71:
6011-9.
these issues. The final product may have to incor- 18. Missale G, Bertoni R, Lamonaca V, Valli A, Massari M, Mori C, et al.
Different clinical behaviors of acute hepatitis C virus infection are associated
porate multiple components that target various as- with different vigor of the anti-viral cell-mediated immune response. J Clin
pects of protective immunity. Finally, attainment of Invest. 1996;98:706-14.
19. Chang KM, Gruener NH, Southwood S, Sidney J, Pape GR, Chisari FV,
sterilizing immunity may not be necessary as long as et al. Identification of HLA-A3 and -B7-restricted CTL response to hepatitis C
the vaccine-induced immunity is effective in prevent- virus in patients with acute and chronic hepatitis C. J Immunol. 1999;162:
1156-64.
ing chronic infection. 20. Lamonaca V, Missale G, Urbani S, Pilli M, Boni C, Mori C, et al.
Conserved hepatitis C virus sequences are highly immunogenic for CD4(⫹)
T cells: implications for vaccine development. Hepatology. 1999;30:1088-98.
From the National Institutes of Health, Bethesda, Maryland. 21. Cooper S, Erickson AL, Adams EJ, Kansopon J, Weiner AJ, Chien DY,
et al. Analysis of a successful immune response against hepatitis C virus.
Requests for Single Reprints: T. Jake Liang, MD, Liver Diseases Immunity. 1999;10:439-49.
Section, National Institute of Diabetes and Digestive and Kidney 22. Rehermann B, Chang KM, McHutchison JG, Kokka R, Houghton M,
Diseases, National Institutes of Health, 10 Center Drive, Room Chisari FV. Quantitative analysis of the peripheral blood cytotoxic T lympho-
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9B16, Bethesda, MD 20892-1800.
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Nutrition, National Institute of Diabetes and Digestive and Kid- Impaired induction of cytotoxic T lymphocytes by antagonism of a weak
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