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1 National Health Service Blood and Transplant, Cambridge Blood Centre, Cambridge, UK
2 Department of Obstetrics and Gynaecology, Komfo Anokye Teaching Hospital, Kumasi, Ghana
3 Division of Transfusion Medicine, Department of Haematology, University of Cambridge, Cambridge, UK
Correspondence
Daniel Candotti
dc241{at}cam.ac.uk
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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The GenBank/ENBL/DDBJ accession numbers for the sequences determined in this study are EF655914–EF655977 and EF661996–EF662052.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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). The age at which HBV infection occurs is one of the main factors that predispose to the acquisition and frequency of the chronic carriage status. Almost 90 % of infants born to HBV surface antigen- (HBsAg) and hepatitis B e antigen (HBeAg)-positive mothers and approximately 30 % of children infected before 6 years of age become chronic carriers, compared with less than 10 % of older children or adults (Hyams, 1995; Ip et al., 1989). Children may be infected horizontally in early childhood or perinatally from carrier mothers. Three mechanisms of HBV transmission from HBsAg-positive mothers to infants were suggested: (i) transplacental intrauterine transmission; (ii) transmission during delivery by contact with maternal infected fluids in the birth canal and (iii) postnatal transmission from mothers to infants during childcare or through breast feeding (Ghendon, 1987; Shepard et al., 2006).
Sub-Saharan Africa is an area of high endemicity in which more than 75 % of adults have been exposed to HBV, with an estimated 5–25 % being chronic carriers. The predominant route of HBV transmission is horizontal, most children being already infected by the age of five (Dumpis et al., 2001; Kew, 1996; Martinson et al., 1998). Maternofetal transmission seems to play a minor role in Africa, in contrast to what is observed in other high-prevalence endemic areas, such as south-east Asia, where maternofetal transmission is the dominant route of transmission (Zhang et al., 1998).
Here, a cross-sectional analysis of HBV serological and molecular parameters was conducted in Ghanaian pregnant women at delivery and in paired cord blood/newborn whole blood samples to investigate the part played by maternofetal transmission in the overall epidemiology and natural history of HBV genotype E infection in west Africa.
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METHODS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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Serological testing.
HBsAg was screened using a rapid test (1–2 IU ml–1 sensitivity) (Determine, Abbott Laboratories) and, in some cases, the Bioelisa HBsAg Colour kit (Biokit). HBeAg and anti-HBe were detected with Murex HBeAg/anti-HBe enzyme immunoassay (EIA) (Abbott-Murex). Antibodies against hepatitis B surface antigen (anti-HBs) were detected with Murex anti-HBs EIA and IgM anti-HBc antibodies with Murex anti-HBc IgM EIA (Murex Biotech).
HBV DNA detection.
Viral DNA was screened using a multiplex real-time quantitative PCR (qPCR) assay that simultaneously detected and identified HBV, human herpesvirus 8 and parvovirus B19 DNA (Candotti et al., 2006a). The 95 % and 50 % detection limits of this assay were 25 and 10 IU ml–1, respectively. HBV DNA was quantified by using a single-virus real-time qPCR assay (Allain et al., 2003).
HBV DNA-positive samples were confirmed using a hemi-nested PCR in the basic core promoter/precore region (BCP/PC) (Candotti et al., 2006b). A second nested-PCR was used to amplify a 1434 bp fragment including the whole preS/S gene. PSS2 (5'-ACATACTCTTTGGAAGGCKG-3'; positions 2761–2781) and PSS8 (5'-CGTCAGCAAACACTTGGC-3'; positions 1194–1177) were used in the first amplification round, and PSS9 (5'-GCCTCATTTTGYGGGTCA-3'; positions 2814–2831) and PSS5 (5'-AGCAAARCCCAAAAGACC-3'; positions 1022–1005) in the second round.
HBV cloning, sequencing and genotyping.
PreS/S amplicons were cloned using the TOPO TA cloning kit (Invitrogen). Sequences of BCP/PC and preS/S regions were obtained by direct sequencing of PCR products or by sequencing clones. The Ghanaian sequences were aligned with reference HBV genotypes A–H sequences using the CLUSTAL W software implemented in Mac Vector version 7.2 software (Accelrys), and the alignment was confirmed by visual inspection. Phylogenetic analysis was performed using the PAUP 4.0b10 software (Sinauer Associates) after exclusion of positions containing an alignment gap from pairwise sequence comparisons (Candotti et al., 2006b). Nucleotide distances were analysed by a neighbour-joining algorithm based on Kimura two-parameter distance estimation. To confirm the reliability of the phylogenetic trees, bootstrap resampling was performed for each analysis (1000 replicates). The GenBank accession numbers of the nucleotide sequences analysed in this study are EF655914–EF655977 (BCP/PC region) and EF661996–EF662052 (PreS/S region).
Statistical analysis.
Analyses were carried out using the SPSS software. Categorical variables were compared using Fisher's exact test and, for continuous variables, the non-parametric Mann–Whitney test. All values shown were derived from the results of a two-tailed test. P<0.05 was considered statistically significant.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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). HBsAg was detected in 174 plasmas and confirmed by EIA in 173 (12.6 % of total). Age ranged between 15 and 48 years (median: 27 years) and no difference in age distribution was observed between HBV carriers and non-carriers. All mothers were negative for anti-HIV and none had been vaccinated against HBV or had received antiviral treatment.
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, Table 1). The 46 HBsAg-negative/HBV DNA-positive plasmas were retested for HBsAg by EIA with a 0.2 IU ml–1 sensitive test (Biokit). Twenty-six of these plasmas were EIA-reactive, increasing the number of HBsAg-positive samples to 199 and the prevalence to 14.5 %. Of these 46 samples, 20 were HBV DNA-positive/HBsAg-negative, indicating a 1.5 % prevalence of occult HBV infection (Table 1). Surface antigen and viral DNA were associated in 187 samples (13.7 %). Twelve samples (0.9 %) were confirmed HBsAg-positive and HBV DNA-negative. The overall prevalence of markers of HBV chronic infection was 16.0 %. Plasma viral load (median 51.8 IU ml–1) followed a biphasic distribution, with 183 samples (88.4 %) having HBV DNA levels below 1x104 IU ml–1 (Fig. 2).
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Identification and frequency of HBV maternofetal transmission
In order to assess transmission by pregnant women carrying HBsAg and/or HBV DNA, the presence of HBV DNA was investigated in paired plasmas from cord blood collected at delivery and/or newborn whole blood samples collected approximately 2 weeks after birth (Fig. 1, Table 2). Confirmed HBV DNA was repeatedly detected in 17 paired samples from 204 available cord blood and/or newborn samples. The prevalence of HBV DNA in cord blood/newborn samples was therefore 17/1353 or 1.3 %. In only one case, both cord blood and newborn samples were available and both carried HBV DNA (pair 1449). In the others, either cord blood (n=12) or newborn (n=4) samples were available. Fifteen cases of apparent maternofetal transmission were found in women carrying both HBsAg and HBV DNA. In two cases, transmission from HBsAg-positive/HBV DNA-negative women was found in the newborn sample (1237B and 1350B) (Table 2). To verify the apparent absence of detectable viral DNA in these two women (1237M and 1350M), nucleic acids were extracted from 500 µl (instead of 200 µl) of plasma and nested-PCR confirmed that HBV DNA was present with a viral load <10 IU ml–1. No viral DNA was detected in cord blood or newborn samples from 20 women carrying occult HBV infection (Table 2).
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). None of the cord blood plasmas contained IgM anti-HBc. HBsAg and HBeAg were present in 7 and 10 of the 13 cord blood plasmas, respectively.
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demonstrates close genetic relationship, but not identity, between maternal and cord blood/newborn sequences from 11 of the 14 pairs. Identical consensus sequences were found in two pairs (1648M/1648C and 1660M/1660C). Relatively high genetic distance between pregnant woman and cord blood was observed in pair 2075. Within the group of sequences studied, the genetic diversity observed within each pair or triplet ranged between 0 and 0.15 %. In contrast, a 1.0 % genetic diversity was observed between samples 2075M and 2075C. The overall inter-sample genetic diversity was 1.1 % (range: 0.0–2.1 %).
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). The maternal and cord blood quasispecies were not distinguishable and the intra-quasispecies diversity was 0.88 % (range: 0.0–1.8 %). Two clusters of sequences were apparent, representing 71 % (5 and 6 clones from maternal and cord blood samples, respectively) and 29 % (clones 2075M-3, 2075M-9 and 2075C-2) of the clone sequences, respectively. The apparent divergence between the consensus sequences 2075M and 2075C seemed to result from a complex population of variants, present in both maternal and cord blood plasmas, rather than from a minor variant having infected the fetus.
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When stratified according to the type of sample tested, the apparent frequency of transmission from cord blood was 9.5 % (13/137 samples), while it was 4.7 % from newborn samples (5/107) (P=0.23).
Characterization of viral and host factors of transmitting women
The main factors associated with HBV vertical transmission previously described were HBeAg and viral load. The median HBV DNA load in the transmitting women's plasmas was 1.7x107 IU ml–1, with values ranging between <10 and 3.6x108 IU ml–1. As shown in Fig. 1, a significant correlation was observed between maternal viral load >1x104 IU ml–1 (high) and detectable HBV DNA in cord blood and/or newborn blood (P=0.0008). However, 6 out of 17 transmitting women carried a viral load lower than 1x104 IU ml–1 (low) and three below 10 IU ml–1.
All maternal samples from transmitting women contained IgG anti-HBc and two samples (2769M and 1975M) were reactive for IgM anti-HBc. Anti-HBs was not detected. In contrast, two plasmas from 74 unselected HBsAg-positive, non-transmitting women (viral loads ranging between <10 and 3.6x108 IU ml–1) were weakly anti-HBs reactive (2.7 %). Eleven (65 %) transmitting women samples were reactive for HBeAg, five (29 %) were anti-HBe reactive, and one (6 %) contained neither HBeAg nor anti-HBe (Table 3). In contrast, in 71 HBsAg-positive/non-transmitting women, the prevalence of HBeAg and anti-HBe was 14 % (10/71) and 86 % (61/71), respectively. HBeAg was significantly associated with high viral load (P<0.0001) in transmitting and non-transmitting groups and as well as with HBV transmission (P<0.0001).
In order to examine whether transmission was associated with known mutations affecting viral replication in the maternal strains, the nucleotide sequences of the BCP and PC regions were analysed and compared with sequences obtained from 27 non-transmitting women (8 with high and 19 with low viral load). Within the transmitter group, paired mutations 1762T and 1764A were associated in samples 1928M (viral load 4.3x107 IU ml–1) and 2075M (viral load <10 IU ml–1) (Table 4). Sequence ambiguities in sample 2075M indicated the simultaneous presence of wild-type and variants, while all cord blood clones carried the 1762T/1764A double mutation. At the BCP and pre-core initiation site, no distinctive pattern of mutation was observed. However, paired 1762T/1764A mutations and 1764A/T mutations alone were observed in three high viral load samples (4.8x104–1.1x106 IU ml–1) and four low viral load samples (<10–7.8x102 IU ml–1), respectively. Mutant 1809T was identified in 10 samples (2.1x102–1.2x107 IU ml–1) and mutant 1809A in one sample (7.8x102 IU ml–1).
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). Among the low viral load groups, none of the six transmitted strains from HBeAg-negative/anti-HBe-positive women and 15/19 (79 %) of the non-transmitted strains had the 1896A stop codon mutation (P=0.0041).
In summary, the relative risk of maternofetal transmission associated with high viral load (
104 IU ml–1) compared with low viral load in pregnant women was 2.41 (95 % confidence interval: 1.09–5.35; P=0.048). A relative risk of transmission of 11.5 (95 % confidence interval: 1.68–79.2; P=0.00038) was associated with the presence of wild-type precore sequences at position 1896, irrespective of viral load and HBeAg/anti-HBe status. Since no transmission was observed from 15 women infected with 1896 mutant virus with viral load <104 IU ml–1, the relative risk of transmission was very low.
The amino acid sequences deduced from preS/S nucleotide sequences were analysed and the mean divergence rates within the pre-S1, pre-S2 and S regions were 1.5 % (range: 0–4.2 %), 3.4 % (range: 0–12.7 %) and 0.85 % (range: 0–2.2 %) in the transmitting group (n=16), compared with 3.1 % (range: 0–7.6 %), 5.3 % (range: 0–14.9 %) and 1.8 % (range: 0–5.3 %) in the non-transmitting group (n=17), respectively. The intra-group amino acid divergence observed in transmitted strains was significantly lower than that in non-transmitted strains over the whole S gene (P<0.0001). In addition, one non-transmitting sample (7.8x102 IU ml–1) showed a deletion including the major part of the PreS1 region, and three others (viral load 5.7x102, 4.0x105 and 1.1x106 IU ml–1) had 4–7 amino acid deletions in the PreS2.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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, Table 1), the bimodal distribution of viral load, the predominance of genotype E and the high frequency of ‘occult’ HBV were consistent with those previously reported among the mostly male blood-donor population from the same area (male-to-female ratio >3) (Allain et al., 2003; Candotti et al., 2006b; Owusu-Ofori et al., 2005). Equally consistent with previously reported data was the presence of rare cases (0.9 %) of HBsAg with undetectable levels of HBV DNA (Kuhns et al., 2004). Overall, the characteristics of chronic HBV infection in Ghanaian pregnant women or blood donor (80 % males) adult populations were similar, irrespective of age or gender.
The predominant route of HBV transmission in sub-Saharan Africa has been reported to be horizontal, and most children are already infected by age 5 (Dumpis et al., 2001; Kew, 1996; Martinson et al., 1998). This is consistent with the repeated observation that <20 % of HBV-infected young adults in Ghana are carrying a high viral load (this study and Allain et al., 2003). However, the part of maternofetal transmission in the overall epidemiology of HBV genotype E has not been evaluated. This study provided evidence of HBV DNA in cord blood or newborn samples or both (Table 2, Fig. 2), strongly suggesting maternofetal HBV transmission. The low nucleotide sequence divergence observed in 10 out of 12 pregnant women/cord blood pairs excluded cross-contamination from maternal blood (Fig. 3). The likelihood of cross-contamination was even lower in pregnant women with low viral load, reinforcing the fact that they transmitted HBV. Identical sequences, however, were observed in 1648M/1648C and 1660M/1660C pairs in association with high maternal viral load (>107 IU ml–1), but HBsAg, which does not usually cross the placental barrier (Roingeard et al., 1993; Vranckx et al., 1999), was found, while it was undetectable in cord blood or newborn samples from non-transmitting women (Table 3). In samples 2075M and 2075C, the apparent discrepancy in the consensus sequences between maternal and fetal samples was subsequently explained by the heterogeneity of the maternal quasispecies, which was reflected in the cord blood when clones were sequenced (Fig. 4).
The overall 8.3 % (17/204) HBV maternofetal transmission rate observed in Ghana was similar to the 7 % rate reported from Senegal in infants at birth, but was higher than previously reported in other studies from sub-Saharan Africa investigating HBV infection in 6–9-months-old infants (Menendez et al., 1999; Roingeard et al., 1993). The Senegalese study also showed that when HBsAg-positive newborns were followed up at 6–7 months, approximately half of them became HBsAg-negative and did not develop antibodies against HBV antigens, reducing the estimated rate of transmission from 7 to 3.2 % (Roingeard et al., 1993). In the present study, the HBV DNA prevalence in cord blood at delivery (8.8 %) was higher than in 2 week-old newborns (4.7 %), but not significantly. Several potential explanations can be offered to account for this discrepancy: (i) the sensitivity of HBV DNA detection in whole blood might be lower than in plasma, affecting detection in samples generally containing low viral load; (ii) a proportion of HBV DNA detected in cord blood might be non-infectious and rapidly cleared after birth and (iii) although we have not found evidence that contamination from maternal blood occurred at sampling, it is certainly more likely to occur in cord blood than in newborn samples.
According to the data collected in this study, the findings that (i) the distribution of high/low viral load in pregnant women is 12/88 %, (ii) the vertical transmission rate is 3 % with low maternal viral load and 46 % with high viral load (Fig. 1 and see below), (iii) all cases of maternofetal transmission lead to chronic infection and (iv) the prevalence of HBsAg by age 15–20 is 15 %, indicate that the proportion of chronic HBV infections related to maternofetal transmission would be approximately 8 % or accounting for 1.2 % of the overall 15 % prevalence of HBsAg. This is consistent with the estimation derived from this study and the previously reported horizontal transmission as preferred route of HBV infection in Africa (Dumpis et al., 2001; Kew, 1996; Martinson et al., 1998).
Multiple risk factors potentially influencing HBV genotype E maternofetal transmission have been identified in chronically infected pregnant women: viral load, HBV serological profile, duration of chronic infection, genotype and mutations in the BCP/PC or S regions (Cacciola et al., 2002; Xu et al., 2006). Three groups of HBV carriers were initially identified among the Ghanaian pregnant women according to their HBsAg/HBV DNA status (Table 2): HBsAg-positive/viral DNA 10 IU ml–1, HBsAg-positive/viral DNA <10 IU ml–1, and HBsAg-negative/viral DNA 10 IU ml–1. HBV transmission rates of 8.7 % (15/172) and 16.7 % (2/12) were observed in the first and second group, respectively, while no evidence of transmission was found within the third group. The lack of infection in the third group might be in part related to the presence of low-level anti-HBs in 37 % of these women (data not shown). When HBV-carrier pregnant women were stratified according to high or low plasma viral load, transmission rates of 45.8 % (11/24) and 3.3 % (6/180) were found, respectively (Fig. 2). These results confirmed that the risk of maternofetal transmission of HBV is positively related to maternal viral load, as suggested by others in different epidemiological settings, but also clearly indicate that transmission can occur in pregnant women carrying a low or very low viral load (Burk et al., 1994; Greenfield et al., 1986; Ip et al., 1989; Wang et al., 2003; Xu et al., 2002; Zhang et al., 1998).
HBe status and genotype are two additional factors associated with viral load and frequency of vertical transmission. Despite similar high prevalence of HBV chronic carriers (Maddrey, 2000), the rate of maternofetal infection in east Asia, particularly China, was estimated to range between 10 and 88 % (Ip et al., 1989; Zhang et al., 1998, 2004), compared with 8 % or less in the present and other studies conducted in sub-Saharan Africa (Kew et al., 1987; Menendez et al., 1999; Roingeard et al., 1993). This difference can be largely attributed to the natural history of HBV infection of genotype B and C, as in south-east Asia where infected individuals carry HBeAg and high viral load in age groups that include most women of gestational age (Chu et al., 2002; Kao et al., 2002). In contrast, in sub-Saharan Africa, whether infected with HBV genotype A1 or E, seroconversion to anti-HBe occurs before age 15 or 16, with the consequence that most women of gestational age carry anti-HBe (Candotti et al., 2006b).
Using highly sensitive molecular assays, HBV transmission was detected in three cord blood and three newborn samples from six women with low HBV DNA load, five of them <20 IU ml–1 (Table 3). It is possible that certain viral genetic features might influence the ability of genotype E HBV to be vertically transmitted. While the presence of the e antigen and of strains with wild-type nucleotide at position 1896 in transmitting women with high viral load was expected, the fact that all strains from transmitting low-viral-load women were wild-type at codon 28 despite the presence of anti-HBe was intriguing (Table 4). This feature is unlikely to affect infectivity of the strain per se, but permits the production of HBeAg, a protein related to HBV tolerance, that might play a role either in the migration of the virus through the placenta or in establishing infection in the fetus (Chen et al., 2005). Should the capacity to produce the e antigen play a significant role in establishing HBV infection, low viral load strains wild-type at the 1896 nucleotide might be given an infectivity advantage that constitutes a significant risk factor. This feature is reinforced by the comparison of genetic differences between sequences of transmitting and non-transmitting women infected with HBV genotype E irrespective of viral load. The frequency of amino acid substitutions across preS1, preS2 and S regions of viruses associated with transmission was significantly lower than that of viruses from the non-transmitting group. In addition, it is to a large extent the absence of a mutation at nucleotide 1896 in strains from transmitting women with low viral load that made significant the difference between transmitted and non-transmitted strains at this location (P=0.0034) (Table 4). As a single risk factor, wild-type at nucleotide 1896 was considerably more predictive of transmission (relative risk: 11.5) than viral load (relative risk: 2.4).
One proposed route of maternofetal HBV transmission is transplacental transfusion or leakage of maternal blood into the fetal circulation (Lin et al., 1987; Ohto et al., 1987; Xu et al., 2002). Mother-to-fetus transfer of nucleated cells and DNA may occurs during the second trimester, but is mostly seen during the third trimester of gestation, and is precipitated by trauma associated with labour, particularly in threatened preterm labour (Ohto et al., 1987; Petit et al., 1997; Xu et al., 2002). Maternal nucleated cells and DNA have been detected in the fetal circulation at a fractional concentration ranging between 10–5 and 10–2 of nucleated fetal blood cells and cord plasma DNA (Lo et al., 2000; Petit et al., 1997). Variable amounts of maternal blood, containing low levels of infectious virus, might be sufficient to determine fetal infection. Reported cases of transfusion-transmitted HBV infections have been examined as an analogous situation. Occult HBV infection, characterized by a viral load below 500 IU ml–1 viral DNA in anti-HBc-positive donations, were shown to be infectious in approximately 50 % of the few cases recently reported (Gerlich, 2006; Inaba et al., 2005), whereas it was found to be non-infectious below 100 IU ml–1 (Dow et al., 2001). Maternofetal infection occurring close to delivery might also explain the low level of HBV DNA consistently detected in cord blood and newborn whole blood samples, and the lack of detectable anti-HBc IgM in the cord blood.
This study has provided evidence that maternofetal transmission of HBV is relatively rare in a genotype E prevalent area of west Africa. Although maternal viral load remains the main risk factor for transmission, pregnant women with low viral load (<1x104 IU ml–1), even below 20 IU ml–1, might transmit, particularly if the strains remain wild-type in the BCP/PC as well as the pre-S/S regions. Irrespective of viral load, the absence of the position 1896 stop codon was the highest predictor of transmission, suggesting a role of HBe antigen in the maternofetal route of HBV genotype E infection.
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ACKNOWLEDGEMENTS |
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Received 19 April 2007;
accepted 21 June 2007.
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