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Journal of Clinical Microbiology, January 1998, p. 110-114, Vol.
36, No. 1
Past and Present Hepatitis G Virus Infections in
Areas Where Hepatitis C is Highly Endemic and Those Where It Is
Not Endemic
Eiji Tanaka,1,*
Michael Tacke,2 Masakazu Kobayashi,1
Yoshiyuki Nakatsuji,1 Kendo Kiyosawa,1
Susanne Schmolke,2 Alfred M. Engel,2
Georg Hess,2 and Harvey J. Alter3
Second Department of Internal Medicine, Shinshu University School
of Medicine, Matsumoto 390, Japan1; Boehringer Mannheim
GmbH, 82377 Penzberg, Germany2; and Department of
Transfusion Medicine, National Institutes of Health, Bethesda, Maryland
208923
Abstract:
We reported previously
on an area in Japan where over 30% of the inhabitants were positive
for Hepatitis C virus (HCV) antibody. In the present study, clinical
features of Hepatitis G virus (HGV) infection in this area of high
endemicity were compared to those in an area where HCV is not endemic.
A total of 400 individuals were selected randomly from those
who were medically screened for liver disease in 1993; 200 were
from the high-endemicity area, and the other 200 were from
the no-endemicity area. HGV RNA was measured by reverse transcription
and PCR with primers in the 5' noncoding region. Antibody to HGV
envelope protein E2 was measured by an enzyme-linked immunosorbent
assay. Prevalence of any HGV marker in the high-endemicity area
(32%) was significantly (P < 0.0001) higher than
that in the no-endemicity area (6%); similar differences, 32% versus
3% (P < 0.0001), had been observed for HCV markers
(HCV RNA and HCV antibody). In areas of both high and no endemicity,
HCV markers were significantly more prevalent in individuals with
any HGV marker than in those without HGV markers, and age-specific
prevalence of HGV markers was distributed similarly to that of any
HCV marker. Among possible routes of HGV transmission that were
analyzed, folk medicine was significant in the high-endemicity area,
but blood transfusion was the major route in the no-endemicity area.
The rate of accompanying viremia in HGV infection (15%) was significantly
lower than that in HCV infection (78%) (P < 0.0001).
In conclusion, HGV infection was highly prevalent in the area of
high HCV endemicity and was closely associated with HCV infection.
HGV seemed to be transmitted via the practice of folk medicine as
well as blood transfusion. HGV resulted in a chronic carrier state
less frequently than did HCV.
Introduction:
The GB virus C and the Hepatitis G virus (HGV) were identified
recently as possible causative agents of human viral hepatitis 12, 17). Molecular characterization of these
two agents has shown them to be closely related strains of the same
virus, and they are supposed to represent a new genus in the family
Flaviviridae (3). As the nomenclature of the new virus has not been settled, the term
HGV is used in this paper. HGV, like Hepatitis C virus (HCV), is
transmissible through blood transfusion and is associated with acute
and chronic infections (4, 5,
15, 22, 24).
Studies on HGV have depended on the measurement of HGV RNA in serum,
which reflects active HGV infection. Recently, an assay for antibody
to HGV envelope protein E2 (HGV-E2 antibody), which indicates recovery
from HGV infection, has been developed (6, 16,
18, 19). The combined use of these assays has
allowed for more comprehensive epidemiological studies of both past
and present HGV infection.
We previously reported on an area in which HCV is highly endemic,
where over 30% of the inhabitants were infected with HCV (10).
In that study, analyses of risk factors for HCV infection elucidated
inapparent modes of parenteral transmission, particularly folk medicine
procedures. In the present study, we determined the prevalence and
patterns of HGV infection in areas of high and low HCV endemicity
to compare the transmission patterns of these two common Flaviviridae
infections
Materials and Methods:
Patients. A total of 420 individuals over 18 years
old (62% of total inhabitants with corresponding ages) in an area
in which HCV infection was endemic were medically screened for liver
diseases in July 1993. Of those, the first 200 individuals
who prepared for screening were selected randomly for evaluation
in this study. Those subjects included 79 males and 121 females
aged 18 to 84 years (mean ± standard deviation
[SD], 56.3 ± 17.7 years). Medical screening
was also conducted in an area in which HCV was not endemic and which
is located near the high-endemicity area. Of 482 individuals
65% of total inhabitants with corresponding ages) who underwent
medical screening in the no-endemicity area, 200 individuals
were selected randomly for evaluation in the same manner as in the
high-endemicity area. These control subjects included 48 males
and 152 females aged 20 to 89 years (mean ± SD,
56.8 ± 13.4 years).
Data from the HCV high-endemicity area (Arahiro) were reported
previously (10), but the no-endemicity area (Sakaue)
was not involved in the previous study. In both areas the main source
of income is forestry, most people are middle class, Buddhism is
the predominant religion, and the lifestyle does not seem to differ
from that in other parts of Japan. Folk remedies in the areas of
high and no endemicity include acupuncture with needles and so-called
"Suidama" therapy, in which the skin is cut with knives (10).
Nonsterilized knives and needles had been used in the high-endemicity
area, but the use of sterilized instruments began after 1986 under
direction of the public health center. Use of nonsterilized tools
had not been noted in the no-endemicity area. Health screening and
blood sample collections were done in the same manner as reported
previously (10). Informed consent was obtained from each subject. Serum samples
were stored at 70°C ntil assayed.
Laboratory tests. Second-generation HCV antibody, Hepatitis
B surface (HBs) antigen, HBs antibody, and Hepatitis B core (HBc)
antibody were detected with commercially available enzyme-linked
immunosorbent assay kits (International Reagents Co., Kobe, Japan]
Alanine aminotransferase (ALT) (normal range, 7 to 45 IU/liter)
was measured on a multichannel autoanalyzer.
Measurement of HCV RNA in serum. RNA extraction and reverse
transcription (RT) were carried out in 100 µl of serum.
The serum HCV RNA was measured by a nested RT-PCR with primers targeting
the 5' noncoding region (14). Procedures to avoid
contamination of samples were implemented throughout the study (11).
In each PCR assay, two negative controls and one positive control
of 10 copies/ml were tested in addition to the samples of interest.
Measurement of HGV RNA in serum. HGV RNA in serum was detected
by nested RT-PCR using primers in the 5' noncoding region as described
previously (21). Briefly, total RNA was extracted
from 100-µl serum samples. After RT with Moloney murine leukemia
virus reverse transcriptase, the first 30 cycles and then the
second 30 cycles of PCR were performed (94°C for 1 min,
55°C for 1 min, and 72°C for 1 min). PCR products
were analyzed by gel electrophoresis with 3% agarose. In each PCR
assay, two negative controls and one positive control of 10 copies/ml
(15) were tested in addition to the samples of interest.
In the RT-PCR assays for HCV and HGV RNAs, all negative controls
were negative and all positive controls were positive.
Measurement of HGV-E2 antibody in serum. HGV-E2 antibody
was measured by an enzyme-linked immunosorbent assay described previously
(18, 19) in which recombinant
E2 protein was bound to a microtiter plate. After addition of diluted
serum samples, specifically bound antibodies against E2 protein
were detected with an anti-human immunoglobulin G conjugated with
peroxidase. Positive or negative results were judged as reported
previously (18, 19).
Statistical analysis. Statistical analyses were performed
with Student's t test, the chi-square test, and Fisher's
exact test. A significance level was set at a P value of
0.05.
Results:
Backgrounds and viral markers in areas of endemicity versus
areas of no endemicity. Clinical and virological features of
the 200 individuals in the high-endemicity area were compared
to those of the 200 individuals in the no-endemicity area (table
1). A history of folk remedies was significantly
more prevalent in the high-endemicity area than in the no-endemicity
area, while histories of surgery and blood transfusion were similar
in the two areas. Prevalence of HGV-related markers was significantly
higher in the area of endemicity than in the no-endemicity area,
as was observed for HCV-related markers. Prevalence of HBs antigen
did not differ between the two areas, but that of any Hepatitis
B virus (HBV) marker was significantly higher in the area of endemicity.
Of the 400 subjects, 75 (19%) were positive for HGV RNA
only, 4 (5%) were positive for both HGV RNA and HGV-E2 antibody,
and 64 (86%) were positive for HGV-E2 antibody only.
View this table :
table 1
|
table
1. Comparison of clinical and virological
characteristics between individuals in high-and no-endemicity areas |
|
Age-specific prevalence. Age-specific prevalences of hepatitis
viruses in the high-endemicity and no-endemicity areas are shown
in Fig. 1. Individuals who had a marker indicating
the existence of viremia were defined as having ongoing infection,
the presence of HBs antigen was defined as indicating HBV infection,
the presence of HCV RNA was defined as indicating HCV infection,
and the presence of HGV RNA was defined as indicating HGV infection.
On the other hand, individuals who had antibody in the absence of
viremia were considered to have resolved or past infection. Age-specific
prevalences of total infection (viremia plus antibody) were similar
for HBV, HCV, and HGV in the high-endemicity area. The prevalence
was around 10% in groups under 50 years old and around 40%
in groups over 50 years old. This difference in distribution between
groups under and over 50 was statistically significant (chi-square
test) for each hepatitis virus: 10% versus 42% for HBV (P < 0.0001),
8% versus 42% for HCV (P < 0.0001), and 10%
versus 41% for HGV (P < 0.0001). In the no-endemicity
area, the prevalence did not differ between the two age groups for
either HBV, HCV, or HGV.
Fig
1
|
FIG. 1. Age-specific
prevalences of HBV, HCV, and HGV infections in high-endemicity
and no-endemicity areas. Prevalence of exposure is indicated
by both filled and open bars and reflects a positive
test for at least one viral marker (HBs antigen, HBs
antibody, and/or HBc antibody for HBV; HCV RNA and/or
HCV antibody for HCV; and HGV RNA and/or HGV-E2 antibody
for HGV). Filled bars indicate a positive test for a
marker of viremia (HBs antigen for HBV, HCV RNA for
HCV, and HGV RNA for HGV).
|
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Current versus past infection. To analyze the proportion
of present HGV infections to total HGV infections, cases in the
high- and no-endemicity areas were combined, because the proportions
were similar in each area for each hepatitis virus (6% versus 5%
for HBV, 79% versus 60% for HCV, and 14% versus 17% for HGV, respectively).
The overall percentage of current (to total) infections (15%, 11/75)
was significantly higher for HGV than for HBV (6%, 6/106 [P = 0.04 by
the chi-square test]) but significantly lower than for HCV (78%,
53/68 [P < 0.0001]).
HGV-infected versus noninfected groups. Clinical and virological
features were compared between groups with and without HGV infection
(including past and present infections) in the high- and low-endemicity
areas (table 2). A history of exposure to folk
remedies was more frequent in HGV-positive subjects than in HGV-negative
subjects in the high-endemicity rea but not in the no-endemicity
area. In contrast, a history of blood transfusion was significantly
more common among HGV-positive subjects than among HGV-negative
subjects in the no-endemicity area. The prevalence of HBV-related
markers did not differ between he two groups, while that of HCV-related
markers was significantly higher in the HGV-positive group.
table 2
|
table
2. Comparison of clinical and virological
characteristics between individuals with and without
any HGV marker in high- and no-endemicity areas |
|
In the high-endemicity area, HGV infection (past and present) was
significantly more common (P = 0.0233 by Fisher's
exact test) in individuals exposed to folk remedies before 1986 (44%,
37/82) than in those exposed after 1986 (11%, 1/9). Similarly,
HCV infection was significantly more common (P = 0.0160 by
Fisher's exact test) in individuals exposed before 1986 (48%,
39/82) than in those exposed after 1986 (11%, 1/9). Thus, HGV
or HCV infection was less common in individuals who were exposed
to folk remedies after the use of sterilized tools was adopted in
1986.
Mean levels of ALT in serum were compared according to the status
of HCV and HGV RNAs (table 3). The mean level
was significantly higher in those with HCV and HGV RNAs and those
with HCV RNA alone than in those without HCV or HGV RNA. Other comparisons
among the four groups were not statistically significant, including
the comparison between those with HGV RNA alone and those without
HCV or HGV RNA.
table 3
|
table
3. Comparison of mean ALT levels in serum
according to the status of HGV and HCV RNAs |
|
Discussion:
We previously reported that there was a small outbreak of community-acquired,
non-A, non-B acute hepatitis among adults in the Arahiro area between
1981 and 1982. Subsequent study (10)
showed that the outbreak was due to HCV infection spread mainly
via folk remedies in which nonsterilized needles and knives were
used. Age-specific prevalence of HCV antibody showed that inhabitants
who were infected were predominantly over 40 years old when
screened in 1986. By 1993 (present study), a high prevalence
was found only in those over 50 years old, suggesting a cohort
effect and indicating that the outbreak of HCV infection had already
ceased n the Arahiro area following the adoption of sterilized tools
in the practice of folk remedies.
HGV-E2 antibody has been reported as a marker of recovery from
HGV infection, based on observations that HGV RNA and HGV-E2 antibody
are generally mutually exclusive and that clearance of HGV RNA generally
coincides with the appearance of HGV-E2 antibody (6, 16, 18). Our results showing
that only 5% of individuals with any HGV marker were positive for
both HGV RNA and HGV-E2 antibody further support the previous observations.
Tacke et al. (18) reported that 2.5% of healthy
blood donors were positive for HGV RNA and that 9% were positive
for HGV-E2 antibody. Similarly, Dille et al. (6) reported that 1% of donors were positive for HGV RNA and that 3%
were positive for HGV-E2 antibody. Our data in the no-endemicity
area were similar, showing a 1% prevalence of HGV RNA and a 5% prevalence
of HGV-E2 antibody. Thus, in an area of low HCV endemicity in Japan,
the rates of HGV infection are similar to those in Western nations.
When we previously compared HCV and HGV infections in the high-endemicity
area by testing HCV and HGV RNAs (23), the prevalence of HGV infection (5%) appeared much lower than
that of HCV infection (34%). However, with the advent of the HGV-E2
antibody assay, it became obvious that prevalence of both past and
present HGV infection (32%) was as high as that of HCV (32%) or
HBV (32%) infection in the high-endemicity area. The prevalence
of total infection (past and present infections) for each virus
was significantly higher in the high-endemicity area than in the
no-endemicity area.However, the proportions of the infections that
were active (viremic) were similar in the low- and high-endemicity
areas for each virus. The overall proportions of subjects who were
antigenic or viremic were 6% for HBV, 15% for HGV, and 78% for HCV.
Seventy to 85% of patients with acute HCV infection become chronic
HCV carriers (1, 2, 20) and usually maintain the carrier state
for long periods afterwards (7, 9, 20). Although several reports have shown
that HGV can cause a chronic carrier state (4, 5,13, 15), the frequency with which it occurs and the rate by which it is
maintained has not been clarified sufficiently. Our data suggest
that the rate of persistence does not differ between areas with
different prevalences of HGV infection, and it is higher than that
of HBV but markedly lower than that of HCV.
HGV infection was closely associated with HCV infection both in
areas of endemicity and in areas of no endemicity; individuals with
total (past plus present) HGV infections had high prevalences of
HCV markers and similar patterns of age-specific prevalence. Among
possible routes of HGV transmission, folk remedies were significant
in the area of endemicity, but blood transfusion was most significant
in the no-endemicity area; similar trends were observed in our previous
study of HCV transmission (10). Thus, our results
indicate that HGV is transmissible not only by blood transfusion
but also by folk remedies such as acupuncture and cutting of the
skin with nonsterilized knives and that HGV infection had spread
in parallel with HCV in the area of high HCV endemicity.
ALT levels of individuals with active HCV infection did not differ
among those with and without concurrent HGV infection. Further,
individuals with active HGV infection alone tended to exhibit normal
or very-low-level elevations of ALT. These results are consistent
with the findings of previous studies (4, 5, 8, 13, 21) that suggested a minimum-pathogenic-effect
HGV.
Aknowledgements:
This research was supported in part by a grant-in-aid from the
Ministry of Health and Welfare in Japan and in part by a grant-in-aid
from the Ministry of Education, Science, Sports and Culture (no.
09670529).
We thank members of the South Kiso hepatitis study group for assistance
at the medical screenings performed in the Arahiro and Sakaue areas.
We also thank Kafumi Todoriki for technical assistance.
FootNotes:
* Corresponding author. Mailing
address: Second Department of Internal Medicine, Shinshu University
School of Medicine, 3-1-1 Asahi, Matsumoto 390, Japan. Phone:
81-263-37-2634. Fax: 81-263-32-9412. E-mail: etanaka@gipac.shinshu-u.ac.jp.
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Copyright © 1998, American Society for Microbiology. All rights
reserved.
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