Copyright © 1998, American Society for Microbiology
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,
2MASAKAZU KOBAYASHI,
1YOSHIYUKI NAKATSUJI,
1KENDO KIYOSAWA,
1SUSANNE SCHMOLKE,
2ALFRED M. ENGEL,
2GEORG HESS,
2AND
HARVEY J. ALTER
3Second Department of Internal Medicine, Shinshu University School of Medicine, Matsumoto 390, Japan
1; Boehringer
Mannheim GmbH, 82377 Penzberg, Germany
2; and Department of Transfusion Medicine, National Institutes of
Health, Bethesda, Maryland 20892
3Received 14 July 1997/Returned for modification 22 September 1997/Accepted 8 October 1997
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.
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
en-velope protein E2 (HGV-E2 antibody), which indicates
recov-ery from HGV infection, has been developed (6, 16, 18, 19).
The combined use of these assays has allowed for more
com-prehensive 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
transmis-sion, 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 indi-viduals 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 (mean6standard deviation [SD], 56.3617.7 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 (mean6SD, 56.8613.4 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 270°C until assayed.
Laboratory tests.Second-generation HCV antibody, hepatitis B surface (HBs) antigen, HBs antibody, and hepatitis B core (HBc) antibody were detected with
* 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.
110
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commercially available enzyme-linked immunosorbent assay kits (International Reagents Co., Kobe, Japan).
Alanine aminotransferase (ALT) (normal range, 7 to 45 IU/liter) was mea-sured on a multichannel autoanalyzer.
Measurement of HCV RNA in serum.RNA extraction and reverse transcrip-tion (RT) were carried out in 100ml of serum. The serum HCV RNA was measured by a nested RT-PCR with primers targeting the 59noncoding region (14). Procedures to avoid contamination of samples were implemented through-out 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 59noncoding region as described previously (21). Briefly, total RNA was extracted from 100-ml 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
ver-sus 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
(Ta-ble 1). A history of folk remedies was significantly more
prev-alent 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
sub-jects, 75 (19%) were positive for HGV RNA and/or HGV-E2
antibody, 7 (9%) 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.
Age-specific prevalence.
Age-specific prevalences of
hepati-tis 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.
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
5
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
viro-logical features were compared between groups with and
with-out 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
area 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
mark-ers did not differ between the two groups, while that of
HCV-related markers was significantly higher in the HGV-positive
group.
In the high-endemicity area, HGV infection (past and
present) was significantly more common (P
5
0.0233 by
Fish-er’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
5
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.
[image:2.612.49.290.90.287.2]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 1. Comparison of clinical and virological characteristics
between individuals in high- and no-endemicity areas
Characteristic
No. (%) of patients in area of:
P
High endemicity
(n5200) No endemicity(n5200)
History of:
Surgical operation
50 (25.0)
45 (22.5)
.
0.2
Blood transfusion
14 (7.0)
20 (10.0)
.
0.2
Folk remedy
91 (45.5)
54 (27.0)
0.0001
HBs antigen
4 (2.0)
2 (1.0)
.
0.2
aHBs antibody
50 (25.0)
36 (18.0)
0.0884
HBc antibody
54 (27.0)
38 (19.0)
0.0573
Any HBV marker
64 (32.0)
42 (21.0)
0.0127
HCV RNA
50 (25.0)
3 (1.5)
,
0.0001
HCV antibody
64 (32.0)
5 (2.5)
,
0.0001
Any HCV marker
64 (32.0)
5 (2.5)
,
0.0001
HGV RNA
9 (4.5)
2 (1.0)
0.0323
HGV-E2 antibody
58 (29.0)
10 (5.0)
,
0.0001
Any HGV marker
63 (31.5)
12 (6.0)
,
0.0001
aObtained by Fisher’s exact test; all other P values were obtained by the
chi-square test.
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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
anti-body showed that inhabitants who were infected were
predom-inantly 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 in 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
recov-ery 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
show-ing 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
persis-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).on May 15, 2020 by guest
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[image:3.612.98.502.68.401.2]tence 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
transmis-sion, 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
infec-tion. 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
stud-ies (4, 5, 8, 13, 21) that suggested a minimum-pathogenic-effect
HGV.
ACKNOWLEDGMENTS
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.
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TABLE 2. Comparison of clinical and virological characteristics
between individuals with and without any HGV marker in high- and
no-endemicity areas
Characteristica
No. (%) of patients with any HGV markerb
P
Positive Negative
High-endemicity area
cHistory of surgical operation
17 (27.0)
33 (24.1)
.
0.2
History of blood transfusion
5 (7.9)
9 (6.6)
.
0.2
History of folk remedies
38 (60.3)
53 (38.7)
0.0043
HBs antigen
0 (0.0)
4 (2.9)
.
0.2
dAny HBV marker
23 (36.5)
41 (29.9)
.
0.2
HCV RNA
34 (54.0)
16 (11.7)
,
0.0001
Any HCV marker
41 (65.1)
22 (16.1)
,
0.0001
No-endemicity area
eHistory of surgical operation
3 (25.0)
42 (22.3)
.
0.2
History of blood transfusion
4 (33.3)
16 (8.5)
0.0055
History of folk remedies
3 (25.0)
51 (27.1)
.
0.2
HBs antigen
0 (0.0)
3 (1.6)
.
0.2
dAny HBV marker
5 (41.7)
37 (19.7)
0.0698
HCV RNA
2 (16.7)
1 (0.5)
0.0096
dAny HCV marker
3 (25.0)
2 (1.1)
0.0016
daAny HBV marker, positive for HBs antigen, HBs antibody, and/or HBc
antibody; any HCV marker, positive for HCV RNA and/or HCV antibody.
bAny HGV marker, positive for HGV RNA and/or HGV-E2 antibody. cTotal positive, 63; total negative, 137.
dObtained by Fisher’s exact test; all other P values were obtained by the
chi-square test.
eTotal positive, 12; total negative, 188.
TABLE 3. Comparison of mean ALT levels in serum according to
the status of HGV and HCV RNAs
Viral marker statusa No.
positive Mean ALT levelSD (IU/liter)6
HGV RNA alone
4
20.5
6
8.3
HCV RNA alone
46
33.4
6
29.0
Both HGV and HCV RNAs
7
52.7
6
63.9
Neither HGV nor HCV RNA
343
16.8
6
10.9
aStatistical analyses by Student’s t test: HCV RNA alone versus neither HGV
nor HCV RNA, P,0.0001; both HGV and HCV RNAs versus neither HGV nor HCV RNA, P,0.0001. Other comparisons among the four groups were not significant.
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[image:4.612.49.289.626.692.2]virus-like sequences associated with human hepatitis virus. Nat. Med. 1:564– 569.
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