Two billion people alive today have ever been infected by the hepatitis B virus (HBV), leaving 350 million with chronic infection. 1 HBV infection can cause chronic hepatitis, cirrhosis, liver cancer, liver failure and death. Such HBV-related liver disease killed >520 000 people worldwide in 2000. 1 Universal infant HB immunization programs in some countries with high HBV endemicity have brought about profound reductions in carrier rates and declines in the rate of childhood hepatoma. 2
In Canada there are 250 000 people living with chronic hepatitis B infection, 3 including an estimated 40 000 in British Columbia (BC). There are ∼1000 reported cases of liver cancer in Canada every year, and the number has been rising steadily over the past two decades. 4
Although most of North America has low hepatitis B prevalence, BC is faced with particular challenges posed by injection drug use (accounting for 34% of acute HBV cases) and immigration. Almost 40 000 immigrants arrive in BC every year, and >90% settle in urban areas. 5 Many come from areas where hepatitis B is endemic, including 75% from Asia and the Pacific region and 10% from Africa and the Middle East.
BC had by far the highest rate of overall (acute and chronic) HBV infection in Canada at 15.1 per 100 000 in 1999, compared with the national average of 4.3 per 100 000. 6 In 1992 the problem was even greater. The overall HBV infection rate in BC was 33.7 per 100 000, compared with 9.9 in the rest of Canada, although differential rates of testing and reporting between BC and other parts of Canada may have accounted for some of this difference.
In response to this problem, BC became one of the first North American jurisdictions to introduce a school-based, preadolescent HB immunization program. 7 The program was introduced in 1992 to provide universal immunization for all Grade 6 students (children age 11 years). It was then enhanced by the introduction of a universal infant hepatitis B immunization program in January 2001.
All other provinces and territories of Canada have since joined in offering routine HB immunization to children and/or infants. An outstanding question, however, is how rapidly immunization programs can reduce the burden of reported HB infections in developed countries. This paper documents trends in the reported rate of acute HB since the onset of immunization efforts in 1992 and examines factors bearing on the rate of infection throughout this period of program implementation.
MATERIALS AND METHODS
Assessment of vaccine uptake
Public health nurses tracked vaccine uptake annually for every school within each health region. They counted all students who received a complete series of immunization as part of the Grade 6 program. These numbers were collated and compared with regional enrollment statistics to arrive at a final coverage statistic for each region and year. Because this was a population-based assessment, the movement of individual students into and out of the cohort after Grade 6 was not tracked.
Assessment of disease trends
Acute and newly diagnosed chronic HB infections are reportable in British Columbia by physicians and by biomedical laboratories. Reports made to local public health authorities are entered into an electronic public health information system (PHIS) and are collated for analysis at the British Columbia Centre for Disease Control. The national surveillance case definition for confirmed acute hepatitis B infection includes the presence of hepatitis B surface antigen combined with anti-hepatitis B core IgM antibody. Year-to-year trends were analyzed overall and by age group with the PHIS system.
Assessment of factors associated with acute hepatitis B infection in 12- to 20-year-olds
The main outcome of interest in our analyses was the rate of acute HB infection within specific cohorts. Analyses are therefore based on assessment of cohort incidence rates for reported acute HB infection rather than on individual level analyses.
For any given calendar year, vaccine-eligible cohorts were defined as those groups (determined by birth date) who were eligible to have received HB vaccine in the current or previous school year(s). Each such cohort was assigned a value for vaccine uptake based on eligibility and uptake data as described above.
Comparisons were made across health regions but also between urban and rural regions. Urban regions were defined as Vancouver and adjacent BC lower mainland municipalities and the capital (Victoria) district, comprising ∼60% of BC residents. 8 Other small BC cities and towns and all other regions were considered “rural” regions for the purpose of this analysis.
Basic frequencies, cross-tabulations and other descriptive statistics were performed with S-Plus (Insightful Corp., Seattle, WA). Likelihood ratio tests were used to establish whether a variable was associated with the rate of reported acute HB in a given cohort.
Poisson regression was applied to determine which variables were independently associated with the rate of acute HB infection. Starting with a null model, the final model was determined by a stepwise procedure. A step was based on the Akaike Information Criterion. 9 All possible interactions were considered provided that a hierarchical model was maintained.
The univariate analysis and the Poisson regression were limited to those age 12 to 20 years where age is calculated by report year minus birth year.
The Grade 6 HB immunization program was introduced in 1992. Immunization coverage in this program ranged between 90 and 93% of the overall eligible population for each year between 1993 and 2001. Within specific age strata and regions, the range of coverage was 80 to 97%.
The rate of acute HB as reported to the PHIS is depicted in Figure 1. The rate declined from 7 per 100 000 to just more than 2 per 100 000 during this one decade period. However, the rate in the cohort of adolescents and young adults who were eligible to have received vaccines since 1993 fell from 1.7 to 0 per 100 000 in 2001 (Fig. 2).
Factors associated with acute hepatitis B infection in 12–20-year-olds
Table 1 illustrates the variation in rates by vaccine uptake, urban vs. rural region of residence, gender, age and year of reporting. On univariate analysis urban residence and membership in a cohort not eligible for vaccination were significantly associated with higher rates of reported acute HB. Female subjects tended to have a higher rate of the disease, but this was not statistically significant. The rate of reported acute HB increases with age with a noticeable jump at age 17 years.
In the final Poisson regression model, the rate of reported acute HB infection was significantly associated with calendar year, urban region and lower vaccine uptake. There was an interaction between region and vaccine uptake such that higher vaccine uptake appeared more protective in rural than urban regions (Table 2). In rural communities vaccine conferred a 49-fold reduction (95% confidence interval, 5.4, 435) in risk of reported acute HB while in urban regions, vaccine conferred a still significant 6.4-fold risk reduction (95% confidence interval, 2.8, 14.7).
Significant declines in acute HB infection rates have been observed in BC during the past 10 years. However, the rate in the cohort of adolescents and young adults who were eligible to have received vaccines since 1993 fell from 1.7 to 0.0 per 100 000 in 2001. The cohort eligible for immunization during the 10-year period was ∼500 000, so that a rate of 0.0 per 100 000 in 2001 suggests that person-to-person HB transmission within this age group has been eliminated. No further acute HB was reported in this age group during 2002.
The decline was not easily discerned during the early years of the program. Because immunization was being offered only to the age 11 years cohort each year, progressive coverage of the entire adolescent group was gradual. Further, adolescents are unlikely to be at high risk of HBV acquisition until several years after their 11th birthday. Hence, their immunity would be unlikely to have an early effect on rates.
Twelve- to 21-year-olds accounted for only 5% of reported acute infections in 1993. Yet the virtual elimination of reported acute HB infections in this group has been accompanied by a >50% decline in the rate in the overall population. The decline from 7 to 2 per 100 000 between 1992 and 2001 is similar to that reported from Italy after 10 years of infant and adolescent programs (5.2 to 2 per 100 000 between 1990 and 2000). 10 It is implausible that this overall reduction in BC is the result of a reduction in carrier rates or duration of chronic infection brought about by adolescent or recently introduced infant programs. Rather the decline in reported acute HB outside of the 12- to 21-year age group may be explained by concurrent immunization programs for injection drug users and men who have sex with men, increased awareness of HB and of modes of transmission in families with carriers and by immunization of family and other close contacts of acute and chronically infected persons. In addition widespread implementation of WHO/Enhanced Program of Immunization recommendations for universal HB immunization programs during the last decade in countries from which many BC immigrants originate may be reducing the pool of susceptible immigrants to the province.
Lower rates of acute HB in vaccine-eligible cohorts are expected because of the known 85 to 95% protective efficacy against acute infection of available vaccines among vaccinated children. 11 The crude rates of reported acute HB were lower in rural than in urban areas, and the results of the Poisson regression suggest that for any given level of vaccine coverage, the risk of acute HB remains higher in urban than in rural regions. A higher level of risk for urban residents because of higher HB virus carrier rates in the urban population is the most likely explanation and has face validity, based in part on historic patterns of immigrant settlement in BC that have favored urban areas. Carrier prevalence rates were not measured, so they could not be adjusted for in the model. However, the PHIS tracks the reported rate of chronic HB infection. The cumulative rate of reported chronic HB infection during the 10-year study period was 107 per 100 000 in urban vs. 6.3 per 100 000 in rural regions.
This study has several limitations. First, because it was population-based, tracking of students entering or leaving a region after immunization coverage had been assessed at Grade 6 was not possible. However, given that BC initiated this program before other North American jurisdictions, student migration would be expected to result in a net increase in unimmunized students, generating a conservative bias. Second, acute hepatitis B cases were assessed by passive surveillance. Cost of laboratory reporting is not an obstacle to testing in the BC universally funded health care system, and laboratory reporting to public health has been assessed as highly complete during the study period. However, some acute cases may not coming to the attention of the reporting system if patients were not tested. There was no change to the patterns or practice of testing in this cohort during the study period. As with the rest of the population, 12- to 20-year-olds would be tested for HBV if they had symptoms or signs compatible with acute viral hepatitis or complicating syndromes. Therefore, even if some cases could have been missed, the observed change in trend is most likely a reliable barometer of reduced risk and morbidity in this group.
British Columbia is experiencing historic declines in the rate of acute HB infection among vaccine-eligible cohorts and in the general population. Although vaccine coverage is having a large impact on the burden of disease generally, a lower HB carrier rate in rural regions is the most likely reason for an apparently higher level of program effectiveness in those areas.
We thank Cristina Lindsay for assistance with literature retrieval and Dr. David Scheifele for manuscript review.
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