Journal of Medical Virology 35212-215 (1991)

Prevention of Perinatal Transmission of Hepatitis B Virus (HBV): A Comparison of Two Prophylactic Schedules

Susan M. Wheeley, Paul T. Jackson, Elizabeth H. Boxall, Michael J. Tarlow, A. Rashid Gatrad, Janet Anderson, and Jeffrey Bissenden Department of Paediatrics and Child Health, University of Birmingham, East Birmingham Hospital (S.M. W., P.T.J., M.J.T.), Regional Virus Laboratory, East Birmingham Hospital (E.H.B.), and Dudley Road Hospital (J.B.), Birmingham, Manor Hospital, Walsall (A.R.G.), and New Cross Hospital, Wolverhampton (J.A.), England

Perinatal transmission of hepatitis B virus (HBV) from HBsAg carrier mothers who were HBeAg+, antiHBe+, or negative for both HBe markers, was interrupted using either 4 doses of vaccine, or one dose of hepatitis B immunoglobulin (HBIG) at birth, combined with 4 doses of vaccine. In those infants who received HBlG at birth, the antiHBs titre was significantly higher at 1 and 2 months old, but at 6 ,9 , and 18 months old, there was no significant difference.

Among the infants of carrier mothers who did not display HBeAg (i.e., were antiHBe+, or neg- ative for both HBe markers), a transient subclin- ical infection would have been expected in around 10% had there been no intervention. No evidence of such infection was detected, and no difference in outcome was found between the two treatment groups.

Amongst infants born to HBeAg+ carrier mothers, infection occurred in 1 out of 8 who had received HBlG and vaccine, and in 3 of 8 who had received vaccine only. The difference in outcome was not statistically significant, but the numbers analysed were small. The infections which oc- curred in spite of prophylaxis may be attribut- able to in utero infection, poor response to vaccine by the infant, or to the mother having a particularly high HBV-DNA level. HBlG given at birth to infants of HBeAg+ carrier mothers may enhance the protection of infants who are des- tined to be poor responders to vaccine.

KEY WORDS: hepatitis B virus (HBV), perina- tal transmission, hepatitis B im- munoglobulin (HBIG), vaccine

INTRODUCTION The challenge of interrupting perinatal transmission

of hepatitis B virus (HBV) has been taken up by many research groups [Beasley et al., 1983; Wong et al., 1984;

0 1991 WILEY-LISS, INC.

Maupas et al. 19811. Various prophylactic schedules involving use of hepatitis B specific immunoglobulin (HBIG) and or vaccine have been employed, but com- parison of efficacy has been complicated by the multi- plicity of regimes used, and the fact that the risk of perinatal infection varies with the maternal HBeAg status. It has been demonstrated that vaccine alone can protect the majority of neonates a t risk of HBV infec- tion [Wheeley et al., 19901: the main aim of this study was to assess the impact of the addition of HBIG to the prophylactic schedule and to investigate whether, and in what circumstances it confers any measurable ad- vantage. This study therefore compares two prophylac- tic schedules, identical but for the use of HBIG in one treatment group.

PATIENTS AND METHODS Screening for hepatitis B markers in pregnancy has

been routine in the West Midlands Region since 1974. About 140 pregnant women are identified as hepatitis B carriers each year (about 1 in 450 hospital confine- ments). For the purposes of this study, the pregnant HBV carrier having been identified, information on her estimated date of delivery (EDD) and HBeAg/antiHBe status, along with advice on precautions to be taken at delivery were sent out to her obstetrician. The respec- tive paediatrician was advised of the impending birth, and invited to enter the baby (with parental consent) into the study. Babies were grouped according to the mother’s ethnic origin and her HBeAgIantiHBe status and allocated sequentially, before birth, into treatment Group A (Four lOmcg. doses of vaccine (“HBVax,”

Accepted for publication June 18, 1991. Address reprint requests to Dr. S. Wheeley, Regional Virus

Laboratory, East Birmingham Hospital, Birmingham B9 5ST, England.

This study was conducted at the Regional Virus Laboratory, East Birmingham Hospital, and a t the Department of Paediatrics and Child Health, University of Birmingham (East Birmingham Hospital), England.

HBV Vaccine in Infants: Two Schedules Compared 213

TABLE I. Babies Born to Hepatitis B Carriers in the West Midlands in 1986 and 1987

Infants born to HBsAg carriers HBeAg+ HBeAg-/antiHBe- antiHBef Total Total population 34 40 197 271 Entered into study 30 33 109 172

Maternal HBe status

Data analysed on 16 23 62 101

Merck Sharp and Dohme) at birth, 1, 2, and 6 months old), or Group B (250IU HBIG at birth, combined with the same vaccine schedule as in treatment Group A).

During the two-year period of January 1986 to December 1987, 271 HBsAg carrier women gave birth in the West Midlands: 64.2% were of Asian ethnic origin (i.e., from Pakistan, Bangladesh, or India), 14.8% Caucasian, 13.3% Oriental, and 7.7% Negro. One hundred and seventy-two offspring of these women were born at collaborating centres and offered entry into the study.

Laboratory Methods Laboratory tests for hepatitis B markers were iden-

tical to those described previously [Wheeley et al., 19903. The quantitative estimation of HBV-DNA was measured using Abbott Genostics (Abbott Laborato- ries, Chicago, IL) [Kuhns et al., 19841.

Statistical Methods The geometric mean titre has been used as a sum-

mary measure of antibody titres. The Wilcoxon Rank test and Fishers exact test have been used as indicated in the text.

RESULTS Information adequate to allow inclusion in the final

analysis (i.e., on adherence to the immunisation sched- ule, age at immunisation, and serial blood samples) was received on 101 babies (Table I). The proportion of babies from each ethnic group was the same as in the total population.

Antibody Titres Geometric mean antibody titres for the two treat-

ment groups are represented in Figure 1. At 1 and 2 months old, the antibody titre was significantly higher in treatment Group B (infants who had received HBIG at birth) (P = <<< 0.001 at 1 month: P = <<< 0.001 at 2 months). However, a t 6,9, and 18 months old there was no statistically significant difference in antibody titre between the two groups (P = 0.22 at 6 months: P = 0.24 at 9 months: P = 0.33 at 18 months Wilcoxon Rank test).

Outcome in Babies Born to HBeAg+ Mothers (Table 11)

Treatment group A (vaccine only). Eight infants completed the course, four becoming immune, three becoming HBsAg+, and one remaining negative for all markers of HBV.

antlHB8 titre (mlulml) too00

6 9 1 I ~ I I I I ~ I I

1 2

Legend age In month8

- Treatmen1 group A + Treatment group B

I

Fig. 1. Geometric mean anti-HBs titres in immunised infants

Treatment group B. One of the 8 infants in this group became HBsAg-t , all the others became immune. A statistically significant difference in outcome be- tween treatment groups A and B was not demonstrated (P = 0.14: Fisher’s test of exact probability), but the numbers of infants born to HBeAg+ mothers was small. It was noted that two further babies enrolled in Group A (but excluded from final analysis as they each attended over one month late for their third vaccina- tions) were known to have become HBsAg+.

Outcome in Babies Born to HBeAg-/antiHBe- Mothers

No difference in the proportion of babies becoming immune was observed in babies born to these mothers. No evidence of hepatitis B infection was seen in any infant in this category.

Treatmentgroup A (vaccine only). One infant in this group failed to respond to four doses of vaccine, but responded well, and became immune, following a fifth dose given at 2 years old.

Treatment group B. All 12 infants became im- mune.

Outcome in Babies Born to AntiHBe+ Mothers Again, no difference in the proportion of babies

becoming immune in treatment groups A and B was observed, and there was no evidence of HBsAg infection in any infant in this category.

214

TABLE 11. Outcome in Immunised Babies

Wheeley et al.

Maternal HBe status HBeAgf HBeAg-/antiHBe- antiHBe+

Treatment Immune 4 Group A Poor responder 1 (vaccine) Hepatitis B carrier 3

Group A total 8

10 32 1 0 0 0

11 32

Treatment Immune 7 12 29 Group B Poor responder 0 0 1 (HBIG & Hepatitis B carrier 1 0 0 vaccine) Group B total 8 12 30

Overall total analysed 16 23 62

Treatment group A (vaccine only). All 32 infants became immune to hepatitis B following immunisation.

Treatment group B. Twenty-nine out of 30 infants became immune, the thirtieth having produced only a low antibody titre at six months old, after which time he was lost to follow up.

HBV-DNA. Limited facilities were available for measurement of serum HBV-DNA and testing was therefore confined to HBeAg+ mothers. The results are shown in Table 111, which relates maternal HBV-DNA to outcome in the baby.

DISCUSSION

The worldwide eradication of hepatitis B virus infec- tion is a distant goal, there being around 300,000,000 individuals carrying the virus [Maynard et al., 19881. While eradication of the organism from an infected person remains a challenge to clinicians, the advent of vaccine has meant that containment of the virus by preventing its spread is a real possibility.

Neonates born to HBV carrier mothers run a sub- stantial risk of becoming infected if they do not receive immunoprophylaxis [Hwang et al., 1985; Boxall, 19861 however the optimal preventive therapy has yet to be established. HBIG was the first prophylactic agent available, and where available, it has continued to be used in combination with vaccine. However, the supply of HBIG is not unlimited, and in many third world countries, is not be available at all.

In this study we set out to examine the impact of the addition ofa single dose of HBIG to a 4 dose vaccination schedule. Our main finding was that during the first 2 months antibody titres were significantly greater in treatment Group B, but in the long term, active re- sponse to vaccine was unaffected by the addition of HBIG.

Within the subgroups of infants (those born to HBeAg+, HBeAg-/antiHBe-, antiHBe+ mothers) no statistically significant difference in outcome between treatment groups A and B was demonstrated. Among babies born to HBeAgS mothers, 4 of 8 of those receiving vaccine alone became immune. Although the number of infants in this category was small, the finding is consistent with our previous results using vaccine alone [Wheeley et al., 19901 when immunity

was achieved in 15 out of 21 (71%) of infants born to HBeAg+ mothers (P = 0.26 Fishers exact test).

Of the 4 infants from groups A and B (all born to HBeAg+ mothers) who were not protected by immu- noprophylaxis, 3 were HBsAg+ at 1 month old, raising the likelihood of in utero infection. The fourth (from treatment Group A, vaccine only) was negative for both HBsAg and surface antibody (antiHBs) at 1 and 2 months old, but was HBsAg+ at 6 months old. It may be that this child was destined to be a poor responder to vaccine, and as he failed to mount a detectable antibody response, he remained at risk of infection from his HBeAg+ mother in the postnatal period. There is evidence that poor response to vaccine may be geneti- cally determined [Nepom et al., 1989; Chiou et al., 1988; Alper et al., 19891, but potentially poor respond- ers are not routinely identified. It may be that the addition of HBIG to the prophylactic regime for all infants born to HBeAg+ mothers is the only way of ensuring immunity during the early months of life for poor responders.

Without intervention, an infection rate of about 10% would be expected amongst infants born to antiHBe+ mothers [Polakoff et al., 19881. Such infections are generally subclinical, and only rarely to result in chronic carriage (although antibody to hepatitis B core antigen (antiHBc) is detectable long term). Occasion- ally, in somewhere between 1 in 5000 [Polakoff et al., 19881 and 1 in 1000 cases (Boxall EH, unpublished data) the infection will be clinically apparent, and the infant will become seriously ill with acute hepatitis B [Moroni et al., 1982; Sacher et al., 19861. In this study, no evidence of HBV infection was detected amongst the infants of antiHBe+ mothers.

The relationship between maternal serum HBV- DNA levels and infection in the neonate has been examined. Our data are insufficient to allow firm conclusions to be drawn but it has been noted that there is a tendency for the mothers of the Group A children who became infected to have higher HBV DNA levels than the mothers of the babies who became immune (Table 111). The same pattern of results was reported by Ip et al. [19891 in a study using the same HBV-DNA assay, and is also consistent with findings from previ- ous work of our own in which an alternative HBV-DNA assay was used [Boxall et al., 19911.

HBV Vaccine in Infants: Two Schedules Compared 215

TABLE 111. HBV-DNA Levels in HBeAg+ Mothers and Outcome in Infants Treatment Group A Case no.

249 266 356 274 233 173 293 245

Maternal Outcome Treatment Maternal HBV-DNA in infant Group B HBV-DNA

Case no. 478.8 pg/ml HBsAg+ 251 465.4 pg/ml 109.2 pg/ml HBsAg+ 288 160.4 pg/ml 105.8 pg/ml Immune 244 133.8 pg/ml 97.9 pg/ml HBsAg+ 309 127.0 pg/ml

Immune 301 2.6 pg/ml 94.8 pg/ml 6.4 pg/ml 0 pg/ml Immune 169 insufficient serum

insufficient serum Immune 227 insufficient serum

* 193 0 pg/ml

*Poor response to vaccine-immune after 5th dose.

The major difficulty encountered in running this multi-centre study was the fact that frequent visits to a hospital out-patients department were required for immunisations and the taking of blood samples. This represented a considerable workload for the paediatri- cians concerned, and logistic difficulties for the parents, the majority of whom did not have English as a first language. Strict compliance with the immunisation schedule presented major practical difficulties, and led to a large number of babies failing to complete the treatment schedule. From a practical point of view, if immunisation against HBV could be integrated with the usual community based paediatric immunisation programme for all infants a t risk of perinatal infection, better coverage could be achieved.

ACKNOWLEDGMENTS This project was supported by Merck Sharp and

Dohme who supplied vaccine, by the West Midlands Regional Research Committee, and by the Birmingham Children’s Hospital Centenary Fund. We thank the families of all those infants who took part in the study, as well as all the paediatric staff who cared for them, and in particular Dr. B. Macnamara, George Eliot Hospital, Nuneaton; Dr. I. Haines, Bromsgrove Hospi- tal; Dr. N. Fraser, County Hospital, Hereford; Dr. F. Leyland, Wordesley Hospital, Stourbridge; Dr. P. Man- field, Good Hope Hospital, Birmingham; Dr. J. Par- tridge, Warwick Hospital; Dr. M. Addy, General Hos- pital, Burton on Trent; Dr. P. Cully and Dr. J. Insley, Birmingham Maternity Hospital; Dr. B. Wharton, Sor- rento Maternity Hospital; and Dr. M. Watkinson, Mar- ston Green Hospital.

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