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Journal of Clinical Microbiology, July 1999, p. 2333-2336, Vol. 37, No. 7
Liver Unit,
Received 26 October 1998/Returned for modification 4 February
1999/Accepted 15 March 1999
Hepatitis G virus (HGV) RNA was detected in 18 of 133 pregnant
women from Tanzania without known risk factors for HGV infection and in
7 of 18 children born to HGV RNA-positive mothers. Molecular evidence
of mother-to-infant transmission was obtained only for three of seven
children. HGV RNA was also detected in 4 of 42 children born to
non-HGV-infected women. Thus, mechanisms other than materno-filial may
play an important role in HGV transmission during early childhood.
Infection with hepatitis G virus
(HGV) (12), or GB virus C (20), is frequently
detected in persons exposed to blood-borne infections and in patients
with liver diseases (2, 6, 9, 11-13, 17, 20). Worldwide,
the prevalence of HGV infection in blood donors ranges from 0.9 to 10%
(12, 13, 17, 20, 21). However, little information is
available about the epidemiologic characteristics of HGV infection on
the African continent (2, 23).
Transmission of HGV by blood transfusion has already been demonstrated
(18), and a role of the sexual route in the spread of HGV
has also been suggested (6, 11, 21). Mother-to-infant transmission of HGV, which has been confirmed at the molecular level in
a single case (7), has been previously described (5, 24). In all these reports, HGV-infected mothers were coinfected with hepatitis C virus (HCV) or human immunodeficiency virus (HIV).
We analyzed the presence of HGV RNA in 133 pregnant women from Tanzania
and in 15 of the 18 children born to HGV-infected mothers. Samples from
the remaining three children were not available due to migration (two
cases) or death (one case). The presence of HGV RNA was tested for at 5 and 18 months of age in 11 children, at 5 months in 2, and at 18 months
in 2, since only these samples were available. Forty-two children born
to randomly selected HGV RNA-negative mothers were also tested for the
presence of HGV RNA at the same ages. The demographic and geographical
characteristics of the area of Ifakara (Tanzania) studied have been
previously described (14). The prevalence of infection with
hepatitis B virus, HCV, and hepatitis E virus and the risk for
mother-to-infant transmission of hepatitis viruses, as well as the
prevalence of antibodies to HIV, have been reported elsewhere
(15).
Specific amplification of the NS3 region of HGV by reverse
transcription-PCR, HGV RNA titration, and sequencing and phylogenetic analysis of HGV were performed as previously reported (8, 11, 13,
17).
Differences between groups were analyzed by use of the chi-square test
and the Fisher's exact test for categorical variables and the
Mann-Whitney U test for quantitative variables.
HGV RNA was detected in 18 of the 133 women (13.5%) analyzed.
Hepatitis B surface antigen was detected in 8 mothers, antibodies to
HCV were found in 2, and antibodies to HIV were found in 1. The titer
of HGV RNA in infected mothers varied between 102 and
106 genome equivalents per ml, but it was similar in women
who transmitted the infection to their children and in those who did
not (P, 0.8).
At 5 months of age, HGV RNA was detected in 4 of 13 infants (31%) born
to HGV RNA-positive mothers and in 2 of 42 infants (5%) born to HGV
RNA-negative mothers (odds ratio, 6.5; 95% confidence interval, 0.8 to
76.2; Fisher's exact test; P, 0.04). At 18 months, HGV RNA
was detected in 5 of 13 babies (38.5%) and in 2 of 42 babies (5%)
born to HGV RNA-positive and HGV RNA-negative women, respectively (odds
ratio, 8.1; 95% confidence interval, 1.1 to 90.4; Fisher's exact
test; P, 0.02).
Among children born to HGV RNA-positive mothers, HGV RNA remained
detectable at 18 months of age in two of the four infants who were
positive for HGV RNA at 5 months. No sample was available for retesting
from the remaining two children. HGV RNA became detectable at 18 months
of age in three children who had tested negative for HGV RNA at 5 months. One of these three children had received a blood transfusion,
and another was hospitalized on several occasions before HGV RNA was
detected. In the remaining children, no risk factors could be identified.
Among children born to HGV RNA-negative mothers, the two children with
detectable HGV RNA at 5 months became negative at 18 months, whereas
HGV RNA became detectable at 18 months in two children negative for HGV
RNA at 5 months. It should be noted that the detection of a humoral
immune response against HGV usually implies the clearance of HGV RNA
from sera (22).
The genetic heterogeneity of HGV was analyzed by direct sequence
analysis of 31 HGV RNA-positive samples from mothers and children (Fig.
1). Pairwise comparison between samples
showed a close relationship in three mother-child pairs. The genetic heterogeneity ranged from 97 to 100% similarity in these three groups
of samples (black bars in Fig. 1) and from 70 to 94% similarity in the
remaining samples (white bars in Fig. 1). The observed intersubject NS3
sequence heterogeneity is similar to that described previously (8,
16).
Sequential samples from the two children showing the persistence of HGV
RNA in serum were studied. Three nucleotide changes between isolates
were detected in one child, and no nucleotide substitutions were
detected in the other. Thus, the rate of nucleotide substitution in the
NS3 region observed in this study is also in agreement with previous
observations (8).
Phylogenetic reconstruction of the 31 isolates showed that three
clusters of sequences (corresponding to the three mother-infant pairs
mentioned above) had 100% bootstrap values (Fig.
2). None of the remaining clusters
reached an 80% bootstrap value. Analysis of isolates from the
remaining four children born to HGV RNA-positive mothers showed that
their sequences were unique, and the level of sequence divergence
between isolates from these children and isolates from their mothers
was similar to that observed among isolates in the whole series
analyzed. These data suggest that materno-filial transmission of HGV
did not occur in these four cases.
0095-1137/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
Molecular Evidence of Mother-to-Infant Transmission
of Hepatitis G Virus among Women without Known Risk Factors for
Parenteral Infections
ABSTRACT
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FIG. 1.
Distribution of nucleotide similarities within HGV
sequences. For this analysis, the percentage of nucleotide distances
was rounded off to the nearest percentage, and the total number of
pairwise comparisons (y axis) with a given similarity was
represented as a histogram. Each sequence was compared to every other
sequence. Black bars represent the percent similarity among
mother-child pairs (7, 11, and 14) in which vertical transmission
occurred.
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FIG. 2.
Neighbor-joining tree for the HGV NS3 region. GB virus C
(GBV-C) (20) was used as an outgroup to root the tree.
Branch lengths are drawn to scale. The scale bar corresponds to 1%
nucleotide sequence divergence. Numbers in italics represent bootstrap
proportions in support of the adjacent node based on 100 resampling
iterations. Only bootstrap values greater than 80% are shown. Boxes
represent mother-child pairs for which phylogenetic analysis supports
vertical transmission, and asterisks denote mother-child pairs for
which mother-to-infant transmission is not supported. (Different
numbers of asterisks correspond to different mother-child pairs.) For
isolates from children born to HGV RNA-positive (C) and -negative (CN)
mothers (M), the sample time points in months after birth are shown
after the subject numbers.
Four of 42 children born to HGV RNA-negative women had detectable HGV RNA in serum, suggesting that HGV may spread through mechanisms other than vertical transmission. HGV RNA has been isolated from saliva (1) and semen (19); therefore, crowding might facilitate horizontal transmission of the virus.
In the three instances of documented vertical transmission analyzed here, the NS3 sequences in isolates obtained from children 5 months after birth differed from those of the maternal HGV isolates in 2, 5, and 5 nucleotides. In spite of being in equilibrium, an RNA viral population exists as a distribution of mutant genomes termed quasispecies (10). Viral genetic variability is generated mainly through random mutational events, but changes in the consensus sequence will be dictated by environmental selective forces, by the stochastic generation of mutants more fit than their parental counterpart, or by random sampling events (bottleneck transmission [3]), which often produce a population with a genetic composition different from that of the parental population (3, 4). Our data suggest that random sampling events during intersubject viral transmission can modify the distribution of variants in the HGV quasispecies population.
In conclusion, our study shows that the prevalence of HGV RNA among a population of pregnant women from Tanzania without known risk factors for parenterally or sexually transmitted infections is remarkably high. HGV can be transmitted from infected mothers to their children, as demonstrated at the molecular level, but mechanisms other than vertical transmission may also play a role in HGV infection in young children.
Nucleotide sequence accession numbers. HGV sequences have been submitted to GenBank under accession no. AF099442 to AF099472.
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ACKNOWLEDGMENTS |
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M.G.-B. was supported by Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS). This work was supported in part by grants from CICYT (SAF 97-0103), FIS (99/0277), Generalitat de Catalunya, the Spanish Agency for International Cooperation, and the UNDP/World Bank/WHO Special Program for Research and Training in Tropical Diseases. The Ifakara Health Research and Development Centre and the St. Francis Designated District Hospital receive major core funding from the Swiss Agency for Development and Cooperation.
We thank the parents and guardians of all study children. We are also grateful to the staff of the Ifakara Health Research and Development Centre and the St. Francis Designated District Hospital. We thank M. A. Martínez for valuable discussions during preparation of the manuscript.
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FOOTNOTES |
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* Corresponding author. Mailing address: Liver Unit, Department of Medicine, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clinic, Barcelona, Spain. Phone: 34-93-227-54-00. Fax: 34-93-451-52-72. E-mail: JCSAIZ{at}MEDICINA.UB.ES.
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Journal of Clinical Microbiology, July 1999, p. 2333-2336, Vol. 37, No. 7
0095-1137/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
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