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Brief Reports Indian Pediatrics 2000;37: 882-886 |
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Seroconversion After Hepatitis B Vaccination in Children Receiving Cancer Chemotherapy |
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From the Departments of Pediatrics and Hepatology*, Post Graduate Institute of Medical Education and Research, Chandigarh 160 012, India. Reprint requests: Dr. R.K. Marwaha, Additional Professor and Incharge, Division of Hematology and Oncology, Advanced Pediatric Center, PGIMER, Chandigarhk 160 012, India.
E-mail: [email protected].in or
[email protected] Modern anticancer therapy, as used for children with malignancies, causes an immuno-suppressed state that renders the patients susceptible to infection by bacteria, fungi, viruses and protozoa(1). While the frequency of HbsAg is approximately 0.1% in the general population in the United States, it has been detected in 10-20% of children or adults with cancer(1). Immunosuppressive therapy may increase the risk of hepatitis as well as enhance the development of a chronic carrier state or reactivate HBV infection in an asymptomatic chronic carrier(2). As no effective treatment exists for a chronic carrier state, control of disease depends on prevention of transmission. Availability of a safe and effective vaccine has made this possible. But studies in patients with malignancies have shown impaired immune response to many vaccines including HBV(3-6). The poorer response may result from the intensity of chemotherapy, the timing of immunization, type of vaccine used or dosage and schedule of vaccination. Our study was designed to assess the immunogenicity and seroconversion after hepatitis B vaccination in children receiving cancer chemotherapy with double the conventional dose, in an accelerated (rapid) immunization schedule.
Forty-nine children admitted in the Hematology-Oncology Unit of Advanced Pediatric Center, PGIMER, Chandigarh were enrolled for the study. These children were diagnosed to have a malignant disorder and had opted for chemotherapy. The study period was from February 1998 to July 1999. All these patients were screened for Hepatitis-B infection status namely HbsAg, anti-HBs and anti-HBc. Patients who were positive for HbsAg, anti-HBs, and anti-HBc, who had received one or more doses of Hepatitis B vaccine in the past, who had coexisting congenital immunode-ficiency and who developed clinical jaundice during the study period were excluded from the study. The seronegative patients were adminis-tered four doses of recombinant Hepatitis-B vaccine (Enivac-HB) at 0, 1, 2 and 6 months. We administered twice the dose for healthy persons at each vaccination, i.e., children £10 years received 20 mcg (1ml) and children 10-14 years received 40 mcg (2ml), in accordance with recommendations made for patients on hemodialysis(7,8). Antibodies to HBsAg were determined by micro ELISA kits (MONOLISA) at 1, 2, 3, 6 and 7 months. Serum was stored at 20°C until assayed. A rise in the antibody titer above 10 mIU/ml was considered to be a positive response, as this antibody titer is regarded as protective against HBV infection. The significance of differences between the two cancer groups was evaluated by the chi-square test.
Of the 49 patients, 35 (71.4%) had hemato-logical malignancies namely acute leukemia or Non-Hodgkins Lymphoma (Group I). The remaining 14 (28.6%) cases had a variety of solid tumors (Group II). These patients were screened for the markers of hepatitis B infection (i.e., HbsAg, anti-HBs and anti-HBc). Of the patients screened 8 (16.3%) were positive for HbsAg, 3 (6.1%) were positive for anti-HBs and 1 (2%) was positive for anti-HBc. Overall, 12 (24.5%) patients were positive for any one of the three markers for HBV infection: 8 (22.9%) of the 35 in Group I and 4 (28.6%) of the 14 in Group II. The differences in sero-positivity between the two groups were not statistically significant. The seronegative patients received recombinant hepatitis B vaccine. Though 37 patients received the first dose of vaccine, 11 of them were lost on follow up and could not be sampled for seroconversion after vaccina-tion. Of the remaining 26 patients, 19 had hematological malignancies whilst 7 had a solid tumor. Blood samples obtained at 1 month and 2 months showed that none of these cases had protective anti-HBs titers of >10mIU/ml. One of the 26 patients defaulted and did not receive subsequent doses of vaccine. Five (20%) of the remaining 25 patients developed titres of >20mIU/ml a month after the 3rd dose of the vaccine. Of the five, three had a hematological malignancy whilst two had solid tumors. The difference in seroconversion rate was not significant statistically (p >0.05). At the sixth month, when the fourth dose of the vaccine was due, two cases failed to keep their appointment. Samples obtained from the remaining 23 patients at 6 months showed that only 2 (8.7%) had protective titres. Both these patients had a solid tumour. None of the patients with a hematological malignancy had a positive protective titer. At the 7th month, two more patients were lost to follow-up. Of the remaining 21 patients, six (28.6%) had anti-HBs titre of >10mIU/ml. Three of these patients had developed protective titers for the first time whilst the titers had risen in the other 3 cases (Table I ). The seroconversion rates in children with hemato-logical malignancies and in those with solid tumors are depicted in Table II. The differences are not statistically significant (p >0.05). Side effects of the vaccine were observed after 7 of the 96 doses of vaccination administered altogether. These were of a minor nature and consisted of soreness and short lasting moderate grade fever. Table I - Anti-HBs Titre in Patients with Atleast One Positive Seroconversion
RB - Retinoblastoma, NHL - Non Hodgkins Lymphoma, ALL - Acute Lymphoblastic Leukemia, AML - Acute Myeloid Leukemia, RMS - Rhabdomyosarcoma, NB - Neuroblastoma, X-Lost to Follow up, - = Antibody titer <10 mIU/ml. Table II - Comparison of Seroconversion Rates Between the Two Cancer Groups
* p
vlaue >0.05, not significant
In our initial screening, one fourth (24.5%) of pediatric cancer patients were positive for any one of the three markers of HBV infection. This is comparable with a previous study done in Turkey(9). This seroprevalence rate is much higher than the reported HBsAg carrier rate of about 4% in the general population. However, in comparison to the reported prevalence of HBV infection in high-risk categories like thalassemics (72%), hemodialysis patients (42%) and hemophiliacs (24%), a prevalence of 24.5% in pediatric cancer patients is not surprising(10). Our data showed that only 28.6% subjects had mounted an antibody response reaching protective vlaue of >10mIU/ml after four double doses of recombinant hepatitis B vaccine. The observations are similar to an earlier report(5) where only a third (32%) of the pediatric cancer patients on chemotherapy mounted a protective response with the number of responders being similar in hematological and solid malignancies. Moreover, in all patients with acute leukemia, antibody titers were low and vanished during the course of intensive therapy(5).Antibody response rates in our study were similar in both hematological and solid malignancies. The apparent difference of 60% in solid tumors vis-a-vis 18.8% in acute leukemia did not attain statistical significance and is probably a reflection of the small sample size. In contrast to these findings, Hovi et al.(6) showed that after 3 doses of plasma derived vaccine, 67% patients receiving cancer chemotherapy had protective anti-HBs titres compared with 97% of those not receiving chemotherapy. The observations in our study document that some patients lose their protective titers during the course of intensive therapy. Two children with acute leukemia who had attained protective antibody titer at 3 months became seronegative at 6 months, probably because of the immunosuppressive effect of ongoing chemotherapy. The proportion of patients, who attained protective antibody titers (28.6%) in our study was lower in comparison to the observations of 32% (5) and 67% (6) made earlier. The possible reasons for the differences may be: (i) genetic/racial factors, (ii) associated malnutrition, (iii) other local environmental factors, and (iv) administration of the vaccine simultaneously with chemotherapy. No major adverse effects of vaccination were observed by us. Local soreness and fever were docu-mented after 7 of the 96 doses of vaccine administered. Based on our experience, we recommend that all pediatric cancer patients should be screened for hepatitis B infection prior to initiating chemotherapy. Since a third of the pediatric cancer patients on chemotherapy develop protective antibodies, hepatitis B vaccination should be administered to all children who are treated for pediatric malig-nancies. The benefits of protecting a third of the patients would definitely outweigh the costs of managing morbidity associated with HBV related disease. Contributors: RKM and MR coordinated the study (particularly its design and interpretation) and drafted the paper. RKM will act as the guarantor for the paper. YKC and AT participated in the data collection and also helped in drafting the paper. Funding: The study received financial support from M/s Panacea Biotec who supplied the doses of hepatitis B vaccine and provided the kits for antibody titers. Competing interest: None stated.
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