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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 91 No. 3 (February 1), 1998:
pp. 774-777
The Incidence and Natural Course of Transfusion-Associated GB Virus
C/Hepatitis G Virus Infection in a Cohort of Thalassemic Patients
By
Daniele Prati,
Alberto Zanella,
Patrizia Bosoni,
Paolo Rebulla,
Elena Farma,
Claudia De Mattei,
Carmen Capelli,
Fulvio Mozzi,
Domenico Gallisai,
Carmelo Magnano,
Caterina Melevendi, and
Girolamo Sirchia for
th e Cooleycare Cooperative Group
From Centro Trasfusionale e di Immunologia dei Trapianti, and
Divisione di Ematologia, IRCCS Ospedale Maggiore, Milan; Clinica
Pediatrica A. Filia, Università di Sassari, Sassari;
Divisione di Pediatria, Ospedale Garibaldi, Catania; and Divisione di
Pediatria, Ospedale Galliera, Genova, Italy.
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ABSTRACT |
To evaluate the risk of transmitting blood-borne GB virus
C/hepatitis G virus (GBV-C/HGV) and to define the natural course of
infection, we performed a prospective study in a cohort of multitransfused  -thalassemics during a 6-year follow-up period. We
analyzed serum samples of 150 patients collected at 3-year intervals
from 1990 to 1996. GBV-C/HGV RNA was determined by reverse transcriptase-polymerase chain reaction and antibodies to E2-protein by
an enzyme immunoassay. At baseline, 14.5% of patients had viremia and
18.5% anti-E2. None of the patients with anti-E2 in 1990 subsequently became viremic. Of the 100 GBV-C/HGV RNA ,
anti-E2 patients, 10 acquired infection during
follow-up, as indicated by positivity of GBV-C/HGV RNA (n = 2),
anti-E2 (n = 7), or both markers (n = 1) in 1996. The incidence
was 1.7 per 100 person-years (95% confidence interval [CI], 0.8 to
3). Since approximately 19,000 blood units were transfused to these
patients during follow-up, the risk of infection was 5.3 in 10,000 units (95% CI, 2 to 8.5). Six of 22 viremic patients cleared the virus
during follow-up; 4 of them became anti-E2+. Twelve of 28 patients lost anti-E2 reactivity during follow-up. In conclusion, more
than 25% of infections resolve within 6 years; the presence of anti-E2
seems to be protective against infection. Anti-E2 reactivity may
decrease with time.
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INTRODUCTION |
GB VIRUS C (GBV-C) is a recently
discovered RNA virus belonging to the Flaviviridae
family.1 Its genomic sequence is very similar to that of
another newly cloned viral agent, hepatitis G virus (HGV);2
hence, the two are currently considered different isolates of the same
virus.3 Specific viral RNA has been detected in patients
affected from hepatic and hematologic diseases, including fulminant,4 acute, and chronic non A-C
hepatitis,1,2,5 and aplastic anemia.1,6,7 The
evidence that GBV-C/HGV is a transfusion-transmissible
virus5,8 and that viremia is persistently present in 1% to
2% of repeat blood donors worldwide2,9,10 contributed to
some concern about the safety of the current blood supply. Therefore,
longitudinal surveys are deemed necessary to evaluate the risk of
acquiring blood-borne GBV-C/HGV and to better define the natural
history of transfusion-associated infection. Thus far, prospective
epidemiological and clinical investigations on GBV-C/HGV in blood
recipients have been hampered by two main difficulties. First, large
numbers of patients need to be repeatedly tested to reach reliable
conclusions. Second, the only available assay was the determination of
serum GBV-C/HGV RNA by reverse transcription-polymerase chain reaction
(RT-PCR), which could identify subjects with active viral replication,
but not those with past exposure to the virus.
To overcome these problems, we chose to base our study on multiply
transfused patients, such as homozygous -thalassemics, who represent
a very informative population because they have regularly received
blood transfusion every 2 to 4 weeks from early childhood. We analyzed
the sera collected in the period 1990-1996 from 150 patients at centers
of the Cooleycare Cooperative Group, where large numbers
of Italians with thalassemia are treated.11,12 In addition
to GBV-C/HGV RNA determination, we used a recently described
immunoassay to detect antibodies against the envelope protein E2 of
GBV-C/HGV (anti-E2), which seem to be useful markers for past exposure
to GBV-C/HGV.13,14
In this paper we report the current risk of acquiring blood-borne
GBV-C/HGV infection among transfusion-dependent -thalassemic patients of our country. Moreover, the virological, serological, and
biochemical features of transfusion-transmitted GBV-C/HGV infection are
prospectively described.
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MATERIALS AND METHODS |
Patients.
In 1989, centers of the Cooleycare program were invited to participate
in a prospective longitudinal survey aimed at assessing the risk of
blood-borne infections.12 Thirty-six centers agreed to
participate, and all 1,384 patients regularly receiving transfusions at
these centers were enrolled (716 males, 668 females; median age, 16 years; range, 0 to 45). For each patient, a serum sample collected in
December 1989-March 1990 (baseline sample) and a record including
demographic data and information on the transfusion regimen were sent
to Milan, where the reference laboratory of the Cooleycare group is
located. Additional samples of the same patients were collected at the
centers during the subsequent 6 years of follow-up, at 3-year intervals
(in 1992-1993 and in 1995-1996).
At the time of the present study, the samples of 1,001 subjects
completing the follow-up program were available in the repository. For
the purpose of this investigation, we decided to study a cohort of 150 patients attending 3 centers of the 26 which completed the program. The
3 participating centers were chosen according to the following
criteria: (1) being in charge of at least 30 patients each; (2) being
located in three different regions of the country (one each from
Northern, Central-Insular, and Southern Italy). The patients included
in the study were 81 males and 69 females, randomly selected, with a
median age at enrollment of 14 years (range, 1 to 30). Of them, 133 (88.7%) were positive for antibodies to hepatitis C virus (HCV) at
enrollment, and 1 (0.7%) acquired HCV infection during the study
period, as indicated by seroconversion; the remaining 16 (10.6%) were
persistently anti-HCV. All patients remained negative
for antibodies to human immunodeficiency virus throughout the
follow-up. The number of blood units transfused to the patient group
was measured on the basis of the Cooleycare database.11
Patients' sera were screened as follows: GBV-C/HGV RNA and anti-E2
were initially determined on samples collected in 1989-1990 and in
1995-1996. If a discrepancy of results was observed between the two
specimens, the sample collected in 1992-1993 was also examined. Liver
function tests, including levels of alanine
aminotransferase (ALT), aspartate aminotransferase (AST), and
 -glutamyl transpeptidase (GGT), were determined in the three
specimens.
Methods.
Enzyme immunoassays (EIAs) were used for anti-HCV (EIA-3; Ortho
Diagnostic Systems, Raritan, NJ) and anti-HIV (Murex, Dartford, UK)
determinations. A recombinant immunoblot assay (RIBA-3; Ortho Diagnostic Systems) was used to confirm anti-HCV reactivity. Liver function enzymes were determined using an Olympus AU510 analyzer (Eppendorf-Netheler, Hamburg, Germany). The patterns of ALT, AST, and
GGT were considered altered when the result was greater
than the upper reference limit (for ALT, 40 U/L in males,
30 U/L in females; for AST, 20 U/L in males, 18 U/L in females; for
GGT, 40 U/L in males, 21 U/L in females) in at least one of the three determinations.
Serum GBV-C/HGV-RNA was determined by RT-PCR using primers derived from
the 5 noncoding region (5-NCR) of the viral genome.10,15 Positive results were confirmed with primers specific for the nonstructural region 5a (NS5a). Only concordant results were
considered. In detail, RNA was extracted from 100 µL serum using the
Purescript RNA Isolation Kit (Gentra Systems Inc, Minneapolis, MN) and
resuspended in 20 µL of diethyl pyrocarbonate-treated water.
Complementary DNA (cDNA) synthesis was performed on 10 µL purified
RNA using 10 U of Moloney murine leukemia virus RT (BRL, Gaithersburg,
MD), 1 U of ribonuclease inhibitor (Promega, Madison, WI), 0.2 mmol/L deoxyribonucleoside triphosphates (Promega), and 1 µmol/L random hexamers (Pharmacia, Uppsala, Sweden) in commercial buffer for 30 minutes at 42°C. For the PCR, the Hepatitis G Virus-Primers and
Capture Probe Set and the PCR DIG Labeling Mix (Boehringer, Mannheim,
Germany), were used to obtain digoxigenin-labeled amplified products.
Briefly, 10 µL of cDNA was amplified in a 9600 thermal cycler
(Perkin-Elmer, Emeryville, CA) according to the following protocol: 40 cycles at 94°C for 30 seconds, 55°C for 30 seconds, 72°C for 30 seconds. The reaction buffer contained 10 pmol of each primer (NCR
primer 1 and 2 for 5-NCR or NS5a primer 1 and 2 for NS5a region), 0.2 mmol/L Labeling Mix; 2.5 U of Expand High Fidelity DNA polymerase
[Boehringer] in commercial buffer (50 µL reaction volume). The
labeled PCR products were analyzed by hybridization to 5-NCR or NS5a
Capture Probes (Boehringer), using an EIA system (PCR ELISA;
Boehringer). Probes are biotin-labeled to allow immobilization of
hybrids to a streptavidin-coated microtiter plate surface. The bound
hybrids were detected by anti-digoxigenin peroxidase conjugate and a
colorimetric substrate. Results were interpreted according to the
manufacturer's instructions.
Antibodies to the E2-protein of GBV-C/HGV were detected by a two-step
sandwich enzyme immunoassay, the µPLATE Anti-HGenv
(Boehringer).13 Ten-microliter serum samples
or controls were diluted in 200 µL of sample buffer. Twenty
microliters of the diluted sample was added to streptavidin-coated
microtiter wells, together with 80 µL of incubation solution,
consisting of biotinylated mouse antibody linked to GBV-C/HGV-E2
antigen. The microplate was incubated at room temperature for 2 hours,
and 100 µL of a solution containing peroxidase-conjugated anti-human
IgG antibody was added. After incubation for 1 hour at room temperature
and the addition of 100 µL of ABTS chromogen substrate, the optical
density was measured at 405 nm within 10 minutes. All the incubation
steps were performed using a shaker. Results were interpreted according
to the manufacturer's instruction. As recommended, reactive samples
were submitted to a confirmatory test procedure, in which the
incubation solution did not contain the GBV-C/HGV-E2 antigen.
Statistical analysis.
The incidence of infection was expressed as the number of new
infections per 100 person-years. The risk of acquiring infection was
computed by the ratio between the number of seroconverting patients
and the total number of red blood cell (RBC) units transfused to the
patient cohort during the study period. The upper bound of 95%
confidence interval (CI) of incidence and risk was calculated. The
chi-squared test was used to compare proportions. The Student's t-test was used when appropriate. A P value of less
than .05 was considered statistically significant.
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RESULTS |
The results of GBV-C/HGV RNA and anti-E2 determination observed at the
baseline and at the end of the 6-year follow-up period are reported in
Table 1. In 1989-1990, 22 patients (14.5%)
were GBV-C/HGV RNA+, and 28 (18.5%) had detectable anti-E2
reactivity, accounting for an overall prevalence of infection of 33%.
View this table:
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Table 1.
Results of GBV-C/HGV RNA and Anti-E2 Determination
Observed at the Baseline and at the End of the Six-Year Follow-up
Period in 150 Homozygous -Thalassemic Patients
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Of the 100 GBV-C/HGV RNA and anti-E2 patients, 10 acquired GBV-C/HGV infection during the 6 years of follow-up, as
documented by either conversion to viremia (2 subjects; age at
enrollment, 3 and 19 years), to anti-E2 (7 subjects; median age, 15;
range, 6 to 21 years), or to both markers (1 subject, age 17 years) in the sample collected in 1995-1996. The analysis of the samples collected in 1992-1993 showed a concomitant positivity for GBV-C/HGV RNA and anti-E2 in one of the seroconverting patients. The incidence of
GBV-C/HGV infection was 1.7 per 100 person-years (95% CI, 0.8 to 3).
Since approximately 19,000 RBC units were administered to the GBV-C/HGV
RNA and anti-E2 patients during the study period, the
risk of blood-borne GBV-C/HGV infection was 5.3 in 10,000 units (95%
CI, 2 to 8.5).
Sixteen of the 22 patients with active infection at the baseline (73%)
remained viremic throughout the study period. Two of them developed
concomitant anti-E2 reactivity between 1993 and 1996. The remaining 6 GBV-C/HGV RNA+ patients (27%) became nonviremic during
follow-up; in 4 of them, the appearance of anti-E2 accompanied the
clearance of viremia.
Of the 28 patients with anti-E2 reactivity at the baseline evaluation,
none developed GBV-C/HGV infection during follow-up; 12 (43%) became
anti-E2 negative. Six of them lost reactivity between 1990 and 1993, the remaining 6 between 1993 and 1996.
Patients with GBV-C/HGV viremia were younger (age, 10 ± 5 years)
than the patients with anti-E2 reactivity (16 ± 6 years, P < .005) and than those negative for both markers
(15 ± 6 years, P < .005). The prevalence of HCV
infection was 76% in patients with GBV-C/HGV viremia, and 92% in
those GBV-C/HGV RNA and anti E2 (P = .056).
The patterns of ALT, AST, and GGT were altered in 20%, 68%, and 28%
of the GBV-C/HGV RNA+ patients, as compared with 25%,
61%, and 35% of those GBV-C/HGV RNA, without
significant associations.
During the study period, 7 of the 150 patients received interferon-
treatment for chronic HCV infection, at a dose of 3 to 6 MU thrice
weekly for 3 to 12 months. Five were persistently GBV-C/HGV RNA and
anti-E2, and 2 remained anti-E2+ throughout
the follow-up.
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DISCUSSION |
GBV-C/HGV is a transfusion transmissible agent, which is endemic among
the blood donor population worldwide.2,8-10
In this article we report the results of a multicenter, prospective
study performed in a large cohort of transfusion-dependent -thalassemic patients, to evaluate the risk of acquiring blood-borne GBV-C/HGV in 1990-1996, and to describe the natural course of infection. At the baseline evaluation in 1989-1990, the frequency of
GBV-C/HGV viremia was 14.5%, a figure not dissimilar to that reported
by others in transfusion recipients who underwent cardiac surgery.8 Considering also the subjects with anti-E2
reactivity, the prevalence of infection increased to 33%, which is
remarkably lower than the 90% observed for HCV in the same population
of -thalassemic patients. This finding was unexpected, because the prevalence rate of GBV-C/HGV viremia in the blood donors of our area is
higher than that of HCV (1.5% v 0.7%).10,16
Moreover, during the 6-year follow-up period we observed that the
incidence of GBV-C/HGV infection was approximately 1.7 per 100 person-years, which accounts for a risk of infection of 5.3 per 10,000 transfused blood units. The latter is about 10-fold lower than that
recently estimated, using GBV-C/HGV RNA as the only marker of
infection, among first-time blood recipients from Taiwan.8
As discussed below, the natural course of GBV-C/HGV infection provides
a useful background for the interpretation of these data.
Whether the presence of specific anti-E2 antibodies has a protective
role against GBV-C/HGV infection is still an open question, as pointed
out by Tacke et al13 in a recent report describing the
immunoassay used in this study. At the baseline investigation, we found
that the presence of viral RNA and anti-E2 antibodies was mutually
exclusive, as already described by others.13,17 Moreover,
we observed that none of the 28 patients with detectable anti-E2
reactivity became GBV-C/HGV RNA positive in the following 6 years,
although during this time they received several thousands of blood
units unscreened for GBV-C/HGV. These results apparently suggest that
anti-E2+ patients are protected against GBV-C/HGV
infection. However, definitive conclusions on this issue can not be
drawn given the low conversion to viremia rate of patients lacking
antibody. In addition, it remains to be elucidated whether the
protective immunity observed in our series is actually caused by the
anti-E2 antibodies, or by other humoral and/or cellular
factors. More than 25% of the GBV-C/HGV RNA+ subjects
cleared the virus during a 6-year period, which indicates that, at
least in some individuals, GBV-C/HGV infection may have a natural
progression toward recovery. This is also supported by the evidence
that viremic patients were younger than those with anti-E2 reactivity.
Moreover, one patient showed a concomitant positivity of anti-E2 and
GBV-C/HGV RNA before achieving a complete suppression of viral
replication. This provides the experimental evidence that a time
overlap may exist between anti-E2 seroconversion and seronegativity for
viral RNA, as recently hypothesized by others.13,14,17
Interestingly, we found that two of the six patients who cleared the
virus during the study period did not develop detectable humoral
response to the E2 region. In these cases, GBV-C/HGV RNA and/or
anti-E2 antibodies could be present at titers that are below the limit
of detection of the tests used for this investigation. Alternatively,
neutralizing antibodies might recognize viral antigens not included in
the current anti-E2 assay. According to the latter hypothesis, the
sequence studies performed so far indicate that significant genetic
diversity exists between different isolates of GBV-C/HGV.18
Another striking finding of our study was that more than one third of
the patients who were anti-E2+ at the baseline evaluation
in 1989-1990 lost anti-E2 reactivity during the study period. Moreover,
we observed that the age of GBV-C/HGV RNA and anti-E2
thalassemics was similar to that of anti-E2+ subjects, and
that the former patients were older than those with active infection.
Taken together, these data seem to indicate that a proportion of
patients with past, resolved GBV-C/HGV infection test negative for both
markers. The relatively low incidence rate observed in our
investigation could be justified considering that these subjects might
still have a protective immunity against reinfection. In the light of
these considerations, our estimate of the current risk of
transfusion-associated GBV-C/HGV infection applies only to chronic
transfusion-dependent patients, and not necessarily to first-time
recipients of blood transfusion.
We found that the presence of active GBV-C/HGV infection does not
significantly contribute to hepatocellular injury in patients affected
from homozygous -thalassemia. This adds more data to the growing
literature indicating that GBV-C/HGV does not cause classic hepatitis
in most cases.3,8-10,19 In our opinion, the evidence that
GBV-C/HGV is not a major cause of chronic liver disease should not lead
to exclude a potential pathogenetic role of this agent in inducing
clinical disease in transfusion recipients. In fact, it should be taken
into account that GBV-C/HGV sequences have been identified in patients
with life-threatening conditions.1,4,6,7 In addition, some
viral agents which generally cause mild, self-limiting infections in
healthy individuals, may sometimes induce serious sequelae in blood
recipients with compromised immune response or abnormal
hematopoiesis.20-22
In conclusion, GBV-C/HGV infection is epidemic among
transfusion-dependent thalassemic patients of our country. In some
individuals, viral replication may be spontaneously suppressed, even
after several years of chronic infection. The clearance of viremia
generally parallels the appearance of anti-E2 antibodies, which seem to have a protective role against reinfection. However, anti-E2 reactivity may decrease with time. Further studies are needed to better define the
possible interplay between viral and host factors in determining the
outcome of infection, and to explore the potential role of GBV-C/HGV in
inducing extrahepatic manifestations in infected blood recipients.
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FOOTNOTES |
Submitted June 19, 1997;
accepted November 14, 1997.
A list of members of the Cooleycare Cooperative Group appears in the
Acknowledgment.
Supported in part by a grant from the Italian National Institute of
Health ("Progetto Sangue," Istituto Superiore di Sanità).
Address reprint requests to Daniele Prati, MD, Centro Trasfusionale e
di Immunologia dei Trapianti, IRCCS Ospedale Maggiore, Via Francesco
Sforza, 35, 20122 Milano, Italy.
The publication costs of this article were defrayed in part by page
charge payment. This article must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. section 1734 solely
to indicate this fact.
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ACKNOWLEDGMENT |
The complete list of the members participating in the Cooleycare
Cooperative Group is given below:
M. Alessi (Catania); M.G. Batzella (S. Gavino Monreale); P. Bellavita
(Bergamo); G. Bertrand (Sassari); F. Betto (Rho); A. Biolchini
(Iglesias); C. Borgna (Verona); S. Calò (Magenta); A. Cambosu, A. Carta (Oristano); E. Cichella (Rovigo); V. Cilla (Matera); E. Corvaglia
(Casarano); D. Costantino (Locri); C. De Rosa (Napoli); F. Di Gregorio
(Catania); P. Di Paola (Palermo); D. Gallisai (Sassari); G. Girelli
(Roma); M. Lendini (Olbia); R. Longhi (Como); C. Magnano (Catania); G. Malfitano (Agrigento); A. Mangiagli (Siracusa); A. Meo (Messina); W. Monguzzi (Monza); S. Montin (Monselice); A. Rasore-Quartino, C. Melevendi (Genova); P. Rizzone Favacchio (Ragusa); F. Schettini (Bari);
G. Sciorelli (Monza); A. Zanella (Milano).
| |
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Cornu P:
Human parvovirus and thalassemia.
J Infect
13:45,
1986[Medline]
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Abstract
Introduction
Abstract