Jpn. J. Infect. Dis., 55, 69-77, 2002

Review

Epidemiology and Clinical Aspects on Hepatitis C
Makoto Higuchi, Eiji Tanaka and Kendo Kiyosawa*Second Department of Internal Medicine, Shinshu University School of Medicine,
Asahi 3-1-1, Matsumoto, Nagano 390-8621, Japan(Received May 8, 2002. Accepted June 24, 2002)
CONTENTS:
1. Introduction
2. Serological and virologic tests for HCV infection
2-1. Serological tests
2-2. Virologic tests
3. Epidemiology
3-1. Worldwide
3-1-1. HCV carriers and HCV infection
3-1-2. Hepatocellular carcinoma (HCC)
3-2. Japan
3-2-1. HCV infection in Japan
3-2-2. Increasing HCC in Japan
3-2-3. Reason for the increase of HCC in Japan

4. Clinical characteristics
4-1. Natural course of hepatitis C
4-2. Extrahepatic manifestations
4-3. Antiviral treatment
4-3-1. Acute hepatitis C
4-3-2. Chronic hepatitis C
5. Prospects for the future

SUMMARY: Hepatitis C virus (HCV) infects an estimated 170 million persons worldwide, and 2 million persons
in Japan. HCV is a major cause of chronic liver diseases, especially hepatocarcinogenesis, and the number ofpatients with HCV-related hepatocellular carcinoma (HCC) is increasing worldwide as well as in Japan. Most
patients with acute hepatitis C develop chronic hepatitis. Spontaneous disappearance of HCV in patients with
type C chronic liver disease is uncommon, and it tends to progress to further advanced and more severe liverdisease, ultimately to HCC over a period of 30 years in most cases. Chronic liver disease due to HCV infection
is commonly associated with extrahepatic manifestation, for example cryoglobulinemia. Antiviral treatment for
HCV infection with interferon alone during 24 weeks was associated with a low rate (less than 10%) of sustained
virologic response (SVR), especially in patients infected with HCV genotype 1b and high HCV RNA concentration.
However, combination therapy of interferon and ribavirin raises the SVR rate. More recently, pegylated interferon
used for treatment of chronic hepatitis C resulted in a high SVR rate. These modalities of antiviral treatment will
reduce HCC occurrence. So far, there is no HCV vaccine in spite of many efforts.

1. Introduction

2. Serological and virologic tests for HCV infection

Hepatitis C virus (HCV) was discovered as a new viral
agent of non-A, non-B hepatitis virus in 1989 by researchersof Chiron Cooperation Group (1). They developed an antiHCV antibody assay system for diagnosis of HCV infection(2). This finding introduced HCV as a major causative agentof parenteral non-A, non-B hepatitis. Considerable progresshas been made regarding knowledge of hepatitis C in the past
decade. Hepatitis C is a major health problem not only inJapan but also in the world. It is well known that hepatitis C
develops to cirrhosis of the liver and hepatocellular carcinoma(HCC), which are uncontrollable and fatal diseases (3).
To date, many epidemiological observations of hepatitis C
worldwide has been reported. Thus, numerous data haveaccumulated and it has become easy to discuss the global
epidemiology of hepatitis C. In addition, numerous clinicalaspects including the natural course and treatment of hepatitis
C have been discussed in many papers. These make possible
a review of the epidemiology and clinical aspects of hepatitisC.

2-1. Serological tests
Cloning of the HCV genome and sequence analysis has
led to the development of antigens and synthetic peptides thathave been successfully used in immunoassays to detect antibodies to HCV. Though the sensitivity and specificity of thefirst generation assay (anti-C100-3) was not significantly high(2,4), they increased in the second and third generation
enzyme immunoassays (5). Especially, the third generation
assay which detects mixtures of antibodies directed to various
HCV epitopes (core[C22-3], NS3[C299], and NS5) has a highsensitivity. The specificity of currently available enzyme
immunoassays for anti-HCV is almost 100% (6).
2-2. Virologic tests
Sensitive tests for HCV RNA based on reverse transcriptase
polymerase chain reaction (RT-PCR) or other nucleic acidamplification techniques can be used during the window
period in acute HCV infection (7). Quantitative assays of HCV
RNA can be performed by end-point dilutions of RT-PCR
assays, competitive RT-PCR assays, or one of the commercial
tests, such as the AMPLICOR Monitor (Roche Diagnostics,
Branchburg, N.J., USA) or the QUANTIPLEX or branched
DNA (bDNA) assay (Chiron Corporation, Emeryville, Calif.,*Corresponding author: Tel: +81-263-37-2632, Fax: +81-263-329412, E-mail: kkiyosa@hsp.me.shinshu-u.ac.jp
69risk of HCV infection in developed countries. The introduction in 1989 and 1992 of improved blood-screening tests
by the detection of anti-HCV antibodies has dramaticallydecreased the risk of transfusion-associated HCV infection(15). The current risk of contracting the disease from bloodin developed countries is very low, with the residual risk
resulting from blood donations that occur in the interval
between infection and the development of detectable antibodies (the so-called ‘window period’). However, the nucleic
acid amplification test (NAT) based on PCR assay has been
introduced to screen HCV RNA, hepatitis B virus (HBV)DNA, and human immunodeficiency virus 1 (HIV-1) RNA,and has resulted in very rare infection. In the U.S., it has beenreported that among voluntary blood donors, blood transfusion, intranasal cocaine use, intravenous drug use, andear-piercing in men are risk factors for HCV infection (16).
3-1-2. Hepatocellular carcinoma (HCC)
An epidemiological survey conducted in 1985 revealed
approximately 320,000 deaths due to HCC worldwide. This
number is expected to have reached more than 400,000 atpresent, of which >80% are confined to Asia and Africa.
According to the Gann Monographs on Cancer Research, No.
47, restricted to males, Hong Kong is at the top of the list
with 29 deaths as a result of HCC per 100,000 population
annually, followed by 24.5 in Singapore and 19 in Japan (17).
Of the seven major industrialized nations, Japan stands out
with 19 HCC/100,000 population annually, in comparison
with 11 in Italy, 9 in France, 6 in nonwhite Americans (2 inwhite Americans), 4 in Germany, and 2.5 in Canada. HCC isfrequently associated with chronic HCV and HBV infection,and both viruses are believed to be causative factors in a large
percentage of cases. In geographic regions where HCV andHBV are endemic, such as in Africa, Asia, and Mediterranean
regions, HCC is common. In geographic regions where HCV
and HBV are not endemic, such as North America and North
Europe, HCC is uncommon.
A high prevalence of anti-HCV has been observed inpatients with HBsAg-negative HCC in Italy (70 to 79%),
Spain (77%), and Japan (75 to 90%). A relatively high prevalence has been observed in France (57%), Florida, U.S. (48%),and a low prevalence in Germany (16%), India (9%),USA). These quantitative tests may have utility in determining
indications of antiviral therapy and in monitoring viral loadin patients undergoing antiviral therapy (6).
Immunoassay using monoclonal antibodies for the detectionof the core antigen of HCV have been developed with theclaim of sensitivities comparable to those of nucleic acidamplification systems (8,9).
HCV genotypes are distributed differently depending on
geography and etiology. HCV genotype is not useful forthe assessment of prognosis but is useful for therapeutic
management, since it is one of the predictors of sustained
response by interferon treatment. Most methods for HCV
genotyping are based on the amplification of subgenomic viralfragment by PCR. HCV types can also be determined byserological methods, which are simpler to use but are slightly
less sensitive and specific (10).
3. Epidemiology
3-1. Worldwide
3-1-1. HCV carriers and HCV infection
The global prevalence of HCV carriers is estimated toaverage 3%, ranging from 0.1 to 10% or more in different
countries (11). In Europe, the overall prevalence is 1% with anorth-south gradient, ranging from 0.5% in northern countries
to 2% in Mediterranean countries. Recent studies have shownhigh prevalence in Eastern Europe, ranging from 0.7% to 5%.
In Asia, Mongolia, Vietnam, Myanmar, and China show highprevalence. In Africa, high prevalence is seen in central region
countries and Egypt (12). In North America, the prevalenceis relatively low. In South America, high prevalence is seenin Brazil (13). The highest prevalence (10% or more) is seenin Mongolia, Egypt, Tanzania, Guinea, and Cameroon as shownin Fig. 1 (11,14). There are reasons for the high prevalence of
HCV carriers in each of these regions. For example, in Egypt,
the use of parenteral antischistosomal therapy is thought tohave contributed to a prevalence of HCV spreading by 22%(12). There are 170 million chronic HCV carriers throughout
the world, of whom an estimated 2 million are in Japan, 2.7
million in the United State (U.S.), 5 million in Western Europe.
Until relatively recently, blood transfusion posed a major

Based on reference 11.

Fig. 1. Hepatitis C virus (HCV) prevalence in the world.

70

the recent decade. Fifty years ago in Japan there were several
characteristic backgrounds regarding its social and medical
conditions (25,26).
3-2-2. Increasing HCC in JapanThe recent increase in the incidence of HCC is ascribed topoor socioeconomic conditions intrinsic to Japan in the moredistant past (25,26). Although it is unprecedented in otherindustrialized countries, a similar increase in HCC may well
be expected where hepatitis virus infections prevail. A
remarkable trend of HCC in Japan is its development preferentially in males in the most productive middle ages of theirlives. Figure 2 shows annual deaths due to HCC in Japan
stratified by distinct age groups. It has increased sharply since1975 and continues to do so at present. In 1997, approximately
32,000 patients died due to HCC in Japan. Most of them (about90%) were infected with HCV (25). For each and every year,
the groups below 69 years of age account for the majority. Of
the deaths due to malignancies in individuals in their 50s,
HCC is the most prevalent cause after stomach cancer.
3-2-3. Reason for the increase of HCC in Japan
We can say that the increase of HCC in Japan depends on
the spread of HCV infection. Therefore, we should refer tothe way of HCV infection is spread in our country. The historyof HCV infection in Japan can be traced back more than 100
years to the Edo era. HCV has spread explosively since theend of World War II, which can be submitted by evidence.
Nomura et al. (27) compared incidence rates of HCC between
the Japanese who emigrated to Hawaii in early 1900 andage-matched Japanese controls who had stayed in Japan.

Bangladesh (8%), Taiwan (10 to 23%), Hong Kong (7%),
and South Africa (16%) (18).
Recently, several reports have indicated an increase in therate of HCC in developed countries. The changes in the numberof patients with HCC per 100,000 population are 2.1 to 4.0
during a period of 11 years in Australia (19), 7.5 to 10.2 during
16 years in France (males) (20), 4.8 to 10.9 during 25 years
in Italy (21), 1.9 to 7.6 during 21 years in Sweden (22), 1.4 to
2.4 during 15 years among the general population in the U.S.
(23), and 2.3 to 7.0 during 3 years in veterans infected with
HCV in the U.S. (24). Unfortunately, none of the reports
regarding the U.S., Sweden, or France included virologic data
which could have shed light on the possible roles of the hepatitis
viruses in this rise in appearance of HCC incidence. However,a spread of HCV infection should be considered as the mostimportant factor in increasing HCC rates in these countries
as seen in Japan (25).
3-2. Japan
3-2-1. HCV infection in JapanThe average prevalence of HCV carriers in Japan is about
2%, with the number estimated at 2 million. According to thestudy of Yoshizawa (25), the age-specific prevalence of antiHCV among blood donors are <0.5%, 0.5-1%, 1-2%, 2-3%,
3- 4%, and >4% in individuals <34 years, 35-44 years, 45-54
years, 55-59 years, 60-64 years, and >65 years, respectively.
There is a clear increase with age in the prevalence of antiHCV, reaching its highest rate in individuals >70 years at
7%. This indicates that HCV infection was relatively common
in the generation over 45 years old and has seen a decrease in

Adopted from reference 26 with permission of the publisher.

Fig. 2. Yearly death due to liver cancer between 1960 and 1997 in Japan.

71period in which there are no symptoms. Acute infection leads
to chronic infection in the majority of patients (around 80%),and spontaneous resolution of chronic hepatitis C which has
been established once is rare (30).
Regarding the natural course of HCV carriers, we publishedan article entitled “Interrelationship of blood transfusion, nonA, non-B hepatitis and hepatocellular carcinoma: analysis bydetection of antibody to hepatitis C virus” in 1990 (3). Thisis the first report which provided the natural history of HCV
carriers and the pathogenesis of HCC. Thus, this article has
been the second most highly referenced article in the area ofhepatology since 1981 to 2000 as described by Di Bisceglie(31). We found that the mean interval between blood transfusion (the presumed source of HCV infection) and diagnosis
of HCC was about 30 years, whereas those with cirrhosis but
no HCC were on average only 21.2 years and those withchronic hepatitis only 10 years from transfusion. This observation has subsequently been confirmed by several investigators
in Japan and other countries. One of them has been made in the
U.S. Tong et al. (32) showed that the mean interval after bloodtransfusion for patients with chronic HCV infection to chronic
hepatitis was 13.7 years, more severe chronic hepatitis 18.4
years, cirrhosis 20.6 years, and HCC 28.3 years. Surprisingly,
our and Tong’s results (3,32) are coincident as shown in Fig.
3. Presently, though these observations are retrospective analysis, it has been generally accepted that the interval between
initial HCV infection and the development of cirrhosis and
HCC are 20 years and 30 years, respectively.
The prevalence of the development to cirrhosis and HCCfrom the HCV carrier state remains controversial, because of
the lack of long term prospective follow-up study. Seeff et al.
(33) traced 568 patients who developed posttransfusion nonA, non-B hepatitis (presumed hepatitis C mostly) in the 1970s
and found that their overall mortality after an average 18year follow-up was 51%, not different from that in matchedtransfused patients who had not developed hepatitis. In
further follow-up study at 25 years (34), they reported thatthe all-cause mortality approximately 25 years after acutehepatitis C is high but is no different between cases (67%)
and controls (65%). When they followed 90 patients whodeveloped hepatitis C, 34 patients (38%) revealed viremia withchronic hepatitis C, 35 patients (39%) with viremia without
chronic hepatitis, and 15 patients (17%) with anti-HCV positive

Intriguingly enough, the incidence of HCC in Japaneseimmigrants in Hawaii remained unchanged, both for males
and females, from 1960 through 1987. In contrast, the incidenceof HCC increased sharply in control male and female Japanese
who remained in the same districts from where the residents
in Hawaii had emigrated. The etiology was different. HBV
infection accounted for 62.5% of male HCC cases in the
Hawaii immigrants, and so was much more frequent than forthe 2.8% of the control Japanese who had remained in theirmotherland. As mentioned earlier, HCV is by far the mostfrequent cause of HCC in the Japanese residents who served
as controls.
It is known that the birth date of patients with chronic hepatitis and those with liver cirrhosis in Japan peaks within thedecade from 1920 to 1930 (26). The Japanese who were born
during this decade reached adulthood some 20 years later in
1940-1950, when drastic changes in the society were occurringin Japan around the end of World War II, 1945, and the periodof rapid reconstruction which followed. During this time,
tuberculosis and peptic ulcer prevailed as a result of malnutrition, which had been treated surgically needing blood transfusion. As most donors at that time were paid professionals, theoccurrence of posttransfusion hepatitis was observed in almost
half of the recipients. The blood from the paid donors wascalled yellow blood, indicating that it was contaminated byhepatitis agents. In addition, because of the confused social
background in those years, methamphetamine was habitually
injected intravenously by certain subpopulations, who shared
used syringes repeatedly (25).
Although the overall prevalence of HCV infection in thegeneral population in Japan is relatively low (about 2%), HCV
is highly endemic in some towns and villages (28). These
restricted areas of high prevalence may be responsible forthe spread of HCV infection. These outbreaks of hepatitis
occurred mainly from 1955 to 1980. By far the most frequentcause of hepatitis in these endemics has been identified as
HCV infection (29). Recently, 20-40 years since then, theseareas emerged with the highest incidence of HCC, which ismost likely ascribable to the HCV spread decades ago. The
way in which HCV was transmitted widely, but neverthelessremained restricted to these areas, is a matter of conjecture.
The overuse of intravenous injections of analgesics, antipyretics,
and nutritive agents became a popular medical practicenationwide. It is not hard to conceive that disposable needles
and syringes were used more than once in some instances
and that the disinfection of medical equipment as not always
satisfactory. They would have been efficient vehicles for thetransmission of HCV. We cannot ignore the inappropriate
medical practices of past decades.
These were recognized as the major routes for HCV transmission in Japan, which is now taking a heavy toll after 30
years or more.
4. Clinical characteristics
4-1. Natural course of hepatitis C
HCV infection is infrequently diagnosed during the acutephase of infection. Clinical manifestations can occur, usually
within 4 to 8 weeks after exposure to HCV. However, mostpatients with acute hepatitis C show either no symptoms or
only mild symptoms. Fulminant hepatitis is very rare in casesof hepatitis C. Jaundice, malaise, and nausea have been documented as symptoms of acute hepatitis in type A, B, and E,
but not C. The infection becomes chronic in most cases, andchronic infection is typically characterized by a prolonged

Fig. 3. Comparison of intervals from blood transfusion to diagnosis oftype C chronic hepatitis, cirrhosis and hepatocellular carcinoma(HCC) between United States (reference 31) and Japan (reference 3).

72related HCC acquired the HBV infection as newborn infants(mainly via vertical transmission from their HBV carriermothers). In contrast, most patients with HCV-related HCC
acquired type C acute hepatitis as adults through horizontaltransmission of HCV. Although there have been reports of
HBsAg-positive HCC in children, HBV-related cirrhosis
usually develops in patients in their 40s and HCC in their
50s. The concentration of HBsAg and HBV-DNA decrease inserum as HCC progresses. Type C hepatitis typically becomeschronic following an acute episode experienced when patientsare in their 30s, and progresses to cirrhosis when they are in
their 50s (about 20 years from onset) and HCC 10 years later(about 30 years from onset). HCV-RNA concentration in serum
persists at high level in these patients.
As synergistic factors in occurrence of HCV-related HCC,HBV co-infection (38), alcohol intake (39), and aflatoxin
ingestion (40) should be considered. HIV-1 co-infection is
also considered (41).
4-2. Extrahepatic manifestations
There are many important extrahepatic manifestations of
HCV infection (42). Most of them are associated with
autoimmune or lymphoproliferative states and may be related
to the possibility that HCV is able to replicate in lymphoidcells (43). Cryoglobulins can be found in 50% or more ofpatients with hepatitis C. Cryoprecipitates usually contain large
amounts of HCV antigens and antibodies. Only a small fraction of affected persons (less than 15%) have symptomatic
disease. Vasculitis, arthralgia and purpura are included as
symptoms. The most severe cases associated with membranoproliferative glomerulonephritis, as well as involvement of
the nerves and brain. Presently, it is well known that HCV isthe chief cause of essential mixed cryoglobulinemia. Other
diseases, including lichen planus (44), Sjogren’s syndrome(45), and porphyria cutanea tarda (46), have been linked to
HCV infection. However, a definite pathophysiological roleof HCV has been difficult to establish.
4-3. Antiviral treatment
In 1989, Davis et al. (47) and Di Bisceglie et al. (48)

without viremia. Thirty-five percent of 20 posttransfusion
hepatitis C patients biopsied for biochemically defined chronic
hepatitis displayed cirrhosis, representing 17% of all thoseoriginally HCV-infected. Another retrospective prospective
follow-up survey of women infected with HCV throughcontaminated lots of anti-D immune globulin used in Ireland
in 1977 and 1978 was completed (35). Seventeen years later,
only 2% of 376 women infected in this way had cirrhosis
demonstrable on liver biopsy. This suggests that young and/or healthy women at the time infection rarely develop severe
liver disease such as cirrhosis from chronic hepatitis C. These
two groups’ studies (33-35) showing a relatively benign
outcome are in contrast with our (3) and Tong’s (32) results
showing progressive disease in spite of slow progression.
The frequency of HCC development among patients withchronic liver disease, particularly cirrhosis, was determinedby many research groups. An incidence of HCC in patientswith cirrhosis has been found to occur at a rate of 7%/year or
12.5%/3 years in Japan, and 3%/year in Italy. Ikeda et al.
(36), Toranomon Hospital, in Tokyo followed 795 consecutive
patients with cirrhosis for up to 17 years and analyzed thecumulative rate of HCC development. It was 19.4%, 44.3%,
and 58.2% at the end of the fifth, tenth, and fifteenth years,
respectively, in 349 patients with type C cirrhosis. In contrast,
it was 14.2%, 27.2%, and 27.2% at the end of the fifth, tenth,and fifteenth years, respectively, in 190 patients with type B
cirrhosis. According to Gentilini et al. (37) in Italy reported
similar study. It was 4.6%, 24.0%, and 56.2% at the end of
the fifth, tenth, and fifteenth years, respectively, in patientswith type C cirrhosis. In type B cirrhosis, it was 6.5%, 23.4%,
and 31.9% at the end of the fifth, tenth, and fifteenth years,
respectively. In both Japan and Italy, the HCC occurrence rateincreased steadily over time in patients with HCV-related
cirrhosis, and the HCC occurrence rate of patients with HBV
was noticeably lower than those of patients with HCV.
The clinical course of patients with type C and type B
hepatitis, from initial infection of HCV and HBV to HCC, iscompared and shown in Fig. 4. Most patients with HBV-

Fig. 4. Clinical course and evolution of disease after hepatitis B virus (HBV) and hepatitis C virus (HCV) infection andsynergic cofactors for progression.

73

Two large, prospective trials from the U. S. (61) and Europe(62) demonstrated that the combination of interferon alfa andribavirin significantly increases the percentage of previously
untreated patients who have a sustained virologic response,from 16% to 40%. Both studies showed that in patients
infected with HCV genotype 2 or 3 and in those with low
viral loads before treatment, the response was maximal after
24 weeks of treatment, whereas patients infected with type 1
and those with a high viral load before treatment required acourse of 48 weeks for an optimal outcome. These findings
led to a recommendation that the duration of treatment should
be based on the HCV genotype and the pretreatment viralload.
More recently, peginterferon has used in treatment ofpatients with chronic hepatitis C (51). Peginterferons are given
only once a week, and the individual dose is calculated
according to patient’s weight. These introduce more sustained
serum levels of interferon, and consistently induce a higher
rate of response than conventional interferons. Presently,
peginterferons are replacing the standard formulations (6365).
It is expected that the rate of sustained complete remission(SCR) will be over 30% with these new modalities in patientswith HCV type 1b and high concentration of HCV RNA inserum.
Changes in antiviral treatment for chronic hepatitis C andthe estimated rate of sustained virologic response at 24 weeks
after the discontinuation of antiviral treatment are summarized in Table 1.
There are many side effects of treatment with interferon
and ribavirin as shown in Table 2. Among them, flu-like
symptoms, headache, fatigue, fever, anorexia are temporary.
Depression, suicide, and autoimmune phenomena such as
thyroiditis, interstitial pneumonia are serious. Hemolytic
anemia, with an expected hemoglobin decrease of 10 to 30
g/L, is a ubiquitous side effect of ribavirin that reverses withcessation of therapy. Dose adjustment of ribavirin may benecessary in patients with excessive decreases in hematocrit.
We should pay more attention these side effects during antiviral treatment

reported the successful treatment of chronic hepatitis C withinterferon alfa at same time but independently. However, thevery high rates of relapse frequently necessitated retreatment.
Several kinds of interferons are used, but all appear to have
similar efficacy. Recently, combination therapy with interferon and ribavirin has markedly improved clinical outcomes,
though less than half of those with HCV infection can be
expected to have a favorable response to the agents that are
currently available (49,50). More recently, attachment ofpolyethylene glycol to interferon (pegylated interferon, socalled peginterferon) has been used for treatment for chronic
hepatitis C (51,52). Large clinical trials are under evaluationin the U. S. as well as in Japan.
4-3-1. Acute hepatitis C
As acute hepatitis C has a tendency to become chronic hepatitis, it should be considered to treat it with antiviral agents.
Several preliminary results suggest that early treatment, evenwith interferon alone, has a high rate of efficacy (53,54).
Jaeckel et al. (55) sought to determine whether treatment
during the acute phase could prevent the development ofchronic infection on 44 patients who had acute hepatitis C.
At the end of both therapy and follow-up, 43 patients (98%)
had undetectable levels of HCV RNA in serum and normal
serum alanine aminotransferase levels. They concluded thatearly treatment with interferon alfa 2b alone (5 million U per
day for the first 4 weeks, followed by a dose of 5 million
U three times a week for another 20 weeks) prevents thedevelopment of chronic HCV infection in most patients. Thus,
it is recommended that acute hepatitis C be treated withinterferon at the early phase of this disease.
4-3-2. Chronic hepatitis C
As described above, since chronic hepatitis C and cirrhosis
have a tendency to develop into HCC, the most important
aim of antiviral therapy to chronic hepatitis C is to preventthe occurrence of HCC. Thus, all patients with chronic HCV
infection are candidates for antiviral therapy. There are many
reports that show significant reduction of the occurrenceof HCC among patients who achieved complete response(virological and biochemical response) by interferon therapy.
These reports came from mostly Japanese investigators (5660). Though about 30% of patients treated with standard
interferon therapy showed complete response, interferon
monotherapy has limitations in a large segment of patients
especially in cases with HCV genotype 1b, high HCV RNA
titer, and severe fibrosis.

5. Prospects for the future
Infection with HCV is now the most frequent cause ofchronic hepatitis, cirrhosis, and HCC in Japan as well as

Table 1. Changes in antiviral treatment for chronic hepatitis C and estimated sustained virologic
response (SVR) assessed at 24 weeks after treatment
Age and Antiviral treatment

HCV 1b and High HCV RNA

1990-1997
IFN aloneStandard (24 weeks)Long term (48 weeks)
1998Combination of IFN & RIB
Standard (24 weeks)Long term (48 weeks)
2001PEG-IFN alone
Standard (48 weeks)
Combination of PEG-IFN & RIB

HCV non-1b and/or low HCV RNA

<10%
50%

50-60%

20%
30%

70%
70%

20%
45%

IFN: interferon, RIB: ribavirin, PEG-IFN: pegylated-interferon

74

Table 2. Adverse events of antiviral treatment
Frequency

Interferon

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Ribavirin

Very Common

Flu-like symptoms
Headache
Fatigue
Fever
Thrombocytopenia

Hemolysis
NauseaCommonAnorexia
Insomnia
Alopecia
Depression
Irritability
Diarrhea
Leukocytopenia
Autoimmune phenomena
Thyroid abnormality
Exanthema
Interstitial pneumonia

AnemiaLeukocytopenia
Nasal congestion
Itching

Rare

Diabetes mellitus
Paranoia
SuicidePolyneuropathy
Retinopathy

Goutworldwide. The estimated number of chronically infected
HCV persons in the world is 170 million. These facts indicatethat the prevention of HCV infection and the treatment of
HCV carriers are very urgent problems. Despite recent progress,
efforts to develop more effective therapies continue. As well,the establishment of an effective HCV vaccine in the near
future is highly desirable.
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