The impact of immigration and vaccination in reducing the incidence of hepatitis B in Catalonia (Spain)

The Hepatitis B virus (HBV) infection is a major cause of liver disease and liver cancer worldwide according to the World Health Organization. Following acute HBV infection, 15% of infected healthy adults and up to 90% of infected infants become chronic carriers and have an increased risk of cirrhosis and primary hepatocellular carcinoma. HBV is carried in the blood and other body fluid [1], including saliva, tears, semen and vaginal secretions, and person-to-person transmission is possible by various means, depending on the epidemiologic pattern within a geographic area [2]. In areas of high endemicity, the most common routes of infection are vertical mother-child transmission and horizontal transmission between children, particularly siblings. In areas of intermediate or low endemicity, such as Catalonia (Spain), the predominant modes of infection are sexual contact and intravenous drug use. Currently, hepatitis B is considered a major health problem, not only by health professionals, but also by many areas of society, especially sufferers [3] and the elevated health costs of the disease have been highlighted [4].

Safe, effective vaccines have been available to prevent hepatitis B virus infection since 1981 and the cost-effectiveness of hepatitis B vaccination programmes is well documented [5]. Recently, some recommendations on the identification and management of persons with chronic hepatitis B virus infection have been proposed [6, 7], but vaccination is regarded as the best strategy to diminish the disease burden. In Catalonia, hepatitis B vaccination programmes began in 1984 with a vaccine obtained from human plasma that was expensive and had limited availability. Vaccination was carried out in groups at risk of suffering the disease due to lifestyles or work exposure and in newborns of mothers who were carriers of the virus, in accordance with the recommendations in place at that time. Unfortunately, this strategy had a limited impact on the incidence and long-term consequences of the disease, and highlighted the need for a strategy of universal vaccination in order to successfully prevent the disease. The availability of an effective, safe and cheaper vaccine obtained by genetic recombination opened the way for mass vaccination programmes to protect the whole population [8]. In December 1990, the Department of Health of Catalonia, after analyzing the available data on the impact obtained in terms of vaccination coverage and reduction of disease incidence with the vaccination programmes aimed at risk groups, decided to adopt a strategy of universal vaccination of preadolescents in schools, in addition to the vaccination of newborns from infected mothers and high risk groups [9]. In 2002, the Department of Health introduced the vaccination of newborns at 2, 4, and 6 months without abandoning the vaccination of preadolescents, which was of proven benefit [10]. This strategy, maintained until the first cohort of infants reached the age at which they could have been offered the preadolescent programme, seems to be the most comprehensive approach [1].

Infectious disease models have been proposed to estimate the burden of hepatitis B infection, and the impact of vaccination [11, 12], in order to develop disease control strategies [13, 14].

The aim of this study was to investigate the relationship between the reduction in acute hepatitis B incidence and the universal vaccination programme of preadolescents in Catalonia, taking population changes into account, and to construct a model to forecast the future incidence of cases that permits the best preventive strategy to be adopted.

Model gam1 shows whether the trend of the variables was linear or not. Reporting of hepatitis B cases decreased over time until 2001, as indicated by the estimated smoothing coefficient of the variable year and its graphic representation (Figure 1A). From 2001 to 2004, there was an increase in the incidence of hepatitis B infection.

In the adjusted GLM models (glm.nb1 and glm.nb2 in Table 1) the incidence was higher in all age groups (age) for children under 12 years (p <0.001) but was less pronounced for people aged > 59 years (p = 0.015).

The percentage of vaccination was significant (p <0.001) in the glm.nb1 model; the higher the rate of vaccination, the lower the incidence. In model gam1, vaccination coverage (vac) was introduced non-parametrically s(vac) and was significant (p <0.001). The trend was nonlinear and negative (Figure 1B), i.e., vaccination reduced cases of hepatitis B, and the greatest slope at the origin more clearly separates the vaccinated groups (with lower incidence) from unvaccinated groups. Model glm.nb2 , which collected the categorization of vaccination coverage and the rate of immigration, can be considered as an alternative model to model glm.nb1 (p <0.05), as confirmed by the ANOVA test, meaning there were no significant differences between models glm.nb1 and glm.nb2.

Model glm.nb2 shows that when the vaccination coverage was > 70% there was a two-fold higher reduction in incidence compared with vaccination coverages < 70% (Table 1). The opposite occurred with the percentage of immigration (model gam1 ). The percentage of immigration showed a non-linear but positive trend (Figure 1C). The slope was steeper from a rate of 15% indicating that the greater the percentage of immigration, the greater the incidence. Groups with an immigration rate between 5% and 10% or between 10% and 15% did not have a greater incidence than when the percentage is < 5% (p = 0.307 and p = 0.587, respectively), while for a percentage of immigration of >15%, the increase in incidence was significantly higher than in groups with a percentage of immigration of<5% (p <0.001) (Table 1).

We identified the presence of four outliers, corresponding to the <12 years age group in 1998, 2001 and 2002, in whom the incidence was higher than estimated, and adolescents aged 12-18 years in 2000, with zero incidence. The residuals of the adjusted model were considered valid, and this model was proposed to explain and forecast the reported incidence of the disease.

Figure 2 panel (c) shows the temporal distribution of hepatitis B infection according to gender in the 19- 49 years age group (all ages group), which had the highest incidence, varying from > 8 x10^-5 person-years in males and 3 x10^-5 person-years in females in 1992 and 1993 to 1.8 x 10^-5 person-years in males and 0.65 x10^-5 person-years in females in 2001. However, from 2001 onwards, the incidence increased in males aged 19-49 years, reaching 6.7 x10^-5 person-years in 2006, with a slight increase in females in the same age group to nearly 1.5 x10^-5 person-years. The rate observed in the 19-34 years age group [Figure 2 panel (a)] declined until 2001 and then, despite the increase in vaccination coverage, rose again. The distribution of cases in the 35-49 years age [Figure 2, panel (b)] was similar from 2001 onwards, to the observed 19-34 years group. The proportion of immigrants increased over time (green line) and the increase was much greater from the year 2000 onwards.

The male/female ratio in incidence rates fluctuated between 3 and 4 x10^-5 person-years, except in 2003, when six cases were reported in males aged 19-49 years for each case reported in women of the same age. The rates were less than for the total population, passing from 4 x 10^-5 person-years in males and 2 x10^-5 person-years in females in 1992 to 1.2 in males and 0.5 in females in 2001; in 2007 the rates rose to 3 x 10^-5 person-years in males and 0.8 x10^-5 person-years in females. The male/female ratio increased over time, from 2 reported cases reported in males for each case in females in 1992 to almost 4 reported cases in males for each case in females in 2007.

Incidence rates for children aged < 12 years were below 2 x10^-5 person-years and there were 4 cases, all immigrants, in the last year, 2007. As vaccination coverages rose in the 12-18 years age group, the reported incidence rate fell until 1995 and remained low (<1 x10^-5 person-years) until 2007.

The significance of the percentage of vaccination was greater for model gam2* than for model glm.nb3* (p = 0.009 and p = 0.05, respectively), and the trend remained negative and nonlinear (Figure 1E). The percentage of immigration was significant in both models (p <0.01) and the trend remained positive and nonlinear (Figure 1F). The inclusion of gender in the models allowed a better fit, and the estimated coefficients of the variable gender in both models were similar and significant (p <0.01 and p <0.001 respectively, Table 2).

The residuals for the GLM and GAM models for the period 2000-2007 (eq. 1, 4, 2 and 5, respectively) were also considered correct. Interactions between gender and other covariates (age, and/or year, vac or immigration) were not significant.

The percentage of cases that occurred in immigrants during the 2005-2007 period decreased with age; 91% in immigrant children aged < 12 years, 82% in immigrants aged 12-18 years, 61% in young adults and only 14.5% in immigrants aged > 50 years. As shown in Figure 3, this means that the ratio between the incidence rate in immigrants and in indigenous persons was higher in children aged < 12 years (ratio = 77.2, rate of 3.86 x10^-5 person-years in immigrant children compared to 0.05 x10^-5 person-years in indigenous children) and in people aged 12- 18 years (ratio = 23.19, rate of 3.7 x10^-5 person-years compared to 0.2 x10^-5 person-years in indigenous children).

Figure 4 shows the distribution of the incidence in immigrants according to gender and age group for the period 2005-2007. The incidence rate for male immigrants was > 5 in all age groups except the > 59 years age group. In people aged < 18 years, the origin (born in Spain or outside) was known in 18 of the 21 cases (86%). In immigrant girls, the incidence rate was around 2.36 x10^-5 person-years and in boys it was more than double, at 5.3 x10^-5 person-years (p <0.001). The incidence in indigenous children aged < 19 years was <0.2 person-years in both males and females, but was 5.55 x10^-5 person-years in immigrant males aged < 19 years, much higher than the nearly 2 x10^-5 person-years in immigrant females of the same age (p <0.001).

As with any vaccine-preventable disease, hepatitis B vaccination programmes should be reviewed according to the evolution of the disease, and surveillance data are crucial to enable correct assessments of the situation [1].

The results of our study are consistent with those for hepatitis A, which showed that the estimates of GLM using negative binomial distribution were better [19]. In addition, GAM permitted estimation of non-linear trends of continuous variables as year, vac and immigrant. The incidence of hepatitis B fell from 1992 to 2000, and has since increased non-linearly, being much higher in groups with a high percentage of immigration and falling when vaccination coverages are higher.

The results also coincide in the case of categorical variables in the GLM models. Poisson or negative binomial regression can cause problems in estimating the coefficients due to the low incidence of cases. This is a limitation of the model that was solved by aggregation into age groups, and not introducing it as a continuous variable. An alternative would have been to adjust using models for count data with Poisson distribution with many zeros (ZIP) or negative binomial (ZINB) [20].

With respect to the predictions, future studies could simulate the predictions of future incidence rates with vaccination strategies other than those proposed in this study. This could allow evaluation of these strategies and the detection of atypical incidence rates other than the estimated pattern.

The use of two data sets (1992-2007) and (2000-2007, which included the category male/female, has advantages and disadvantages. Using the (1992-2007) database has the advantage of a 16-year historical record in which the estimated coefficient of the variable year is significant. This is one possible explanation of why the estimates are better using this database. In the second case, the use of the (2000-2007) database supposes a historical record of only eight years. The positive aspect is that the clearly-differentiated incidence rates in males and females can be estimated. However, the estimated coefficient of the variable year is not significant in this period in the models with the lower AIC (glm.nb3 y gam2). As the number of observations is reduced, the number of degrees of freedom and, therefore, the estimates, are worse.

La Torre et al. [12], applied jointpoint regression and estimated that the incidence decreased in all groups, and highlighted the importance of analyzing the changes in disease incidence in the evaluation of vaccination policies.

The increased incidence in men aged 19-49 years from 2001 onwards obtained in the present study with the overall rate increasing from 2.16 in 2000 to 5.74 in 2007(x10^-5 person-years) respectively, coincides with the mass influx of immigrants to Catalonia with rose from 5.6% in 2000 to 22.7% in 2007 [15]; in this same period, the incidence in men aged 19-34 years increased from 2.9 in 2000 to 5.3 in 2007 (x10^-5 person-years) and in men aged 35-49 years from 1.4 in 2000 to 7.5 in 2007 (x10^-5 person-years). These results differ from those obtained in the USA [21, 22], where the incidence rate of hepatitis B has decreased steadily in all age groups, from 6.3 x 10^-5 person-years in 1992 to 1.5 x10^-5 person-years in 2007. In that country, although progress has been made in reducing disparities in incidence of new infections rates among non-Hispanic blacks have declined, the incidence rates remain more than twofold higher than those among other ethnic population and the rate in elderly immigrants is much lower than in young adults, although the number of elderly immigrants is very low. Several authors have already analyzed the relationship between the incidence of hepatitis B and immigration, showing that there is a positive relationship between both [23, 24].

In 1992, the rate in females in Catalonia was 2 x10^-5 person-years, which fell to 0.45 x10^-5 person-years in 2000 and remained fairly stable in the remainder of the study period. In the USA [22] the rate fell from 7.34 in males and 5.01 in females (x10^-5 person-years) in 1992 to 3.6 and 2.09 x 10^-5 person-years, in males and females, respectively, in 2000 and 1.85 in males and 1.15 in females (x10^-5 person-years) in 2007, while in Germany, rates fell from 1.96 x10^-5 person-years in 2001 to 0.89 x10^-5 person-years in 2006 and 0.6 x10^-5 person-years in 2007.

In people aged 12-18 years, the incidence was zero in 2000 and less than one case per year, later. No gender differences in the incidence were detected in indigenous children of vaccination age or in children aged < 12 years, with very low or zero rates. The rates in indigenous women and people aged < 18 years were less than 1x10^-5 person-years, as a result of the vaccination programs implemented. In contrast, in immigrants and other age groups, the reported incidence was more than two-fold higher for men than for women.

The male-female ratio doubled over the study period, unlike the results in the USA [22] and Germany [25]. In the USA, the male-female ratio increased slightly, from 1.5 in 1992 to 1.8 in 2006, and in Germany, it rose from 1.91 in 2001 to 2.2 in 2008. This may be explained by the increased incidence in immigrants, a group containing a large proportion of men of working age. The statistical models used show that the incidence of cases increased due to immigration, especially in groups with > 15% of immigrants.

Although the impact of disease prevention measures and the maintenance of high vaccination coverages are important, this impact may be offset by an increase in cases in adult immigrants. The proportion of immigrants aged >50 years is still low, which could explain the low incidence of acute hepatitis B in this population compared to younger ages. Therefore, as suggested by the distribution of cases in other countries [22, 25], the incidence may increase in these groups. For this reason, vaccination strategies for risk groups, including travellers to countries with high or intermediate prevalence of chronic Hepatitis B virus infection should be reinforced [26, 27]. This recommendations should also be applicable to susceptible immigrants (children and adolescents) coming from countries with high or intermediate prevalence where hepatitis B vaccination programmes have still not been launched or where coverages are still very low [28].

In countries like the USA, Germany and Italy, incidence rates have declined in all age groups. In Germany, the rate for males decreased from 2.8 x10^-5 person-years in 2001 to 1.2 x10^-5 person-years in 2007, while in the USA [22] the rate fell from 3.6 and 2.09 (x 10^-5 person-years) in 2000 to 1.85 and 1.15 (x10^-5 person-years in 2007 in males and females, respectively. In Catalonia, the rate increased from 1.3 x 10^-5 person-years in 2001 to 2.9 x10^-5 person-years in 2007. However, it should be noted that, in Germany, the percentage of immigrants has remained constant at around 9% since 1995 [25]. In the USA the percentage of immigrants increased from 10.4% in 2000 to 12.6% in 2007 [29]. However, in Catalonia, the rise was much higher, from 4.1% in 2000 to 15.7% in 2007.

This study was conducted using routine surveillance data. It would probably be useful to focus more-closely on immigrants and risk groups to obtain a better understanding of the situation of hepatitis B virus infection in order to design strategies to increase vaccination coverages [21, 30].

In addition to the protection afforded to individuals in avoiding the risk of chronic liver diseases such as cirrhosis and hepatocellular carcinoma [31], a strategy focused not only on universal vaccination of infants or preadolescents but on risk groups, and immigrants should be considered because it takes into account the substantial indirect effects of vaccination, as avoiding new infections avoid the cases transmitted by them [32].

A possible limitation of this study is the underdetection of cases in the immigrant population. The attendance of health services is free in Catalonia for all people (indigenous and immigrants), but we do not know if there are differences in the attendance to medical services for acute hepatitis B. So, we cannot rule out some underdetection of cases in immigrant population. In order to improve our estimates we would need to improve the surveillance of acute hepatitis B disease and to know what level of completeness of reporting we have for immigrant and indigenous population.

With respect to the quality of the proposed forecasts, the randomness in the incidence pattern of the disease is much lower than in males, making it much easier to predict the temporal disease evolution. However, the randomness in the incidence is greater in males, depending, amongst other factors, on age and disease outbreaks, and therefore it is more difficult to predict its future evolution. The observed incidence was lower than the confidence intervals of the predictions, indicating a change in the pattern of the evolution of the disease.

Future research might concentrate on extending the proposed models to include the spatial-temporal distribution of the disease, as we have done for hepatitis A [33]. Likewise, Pearce and Dorling [34] studied a period of rapid social, economic and political changes in which differences in life expectancy between men and women had a clear geographical dependence. It is essential that future studies have access to more reliable information on immigration and that they can recover missing data whenever possible, in order to detect disease outbreaks earlier and adjust the vaccination strategy to these situations.

In conclusion, the results of the models used in this study confirm that the overall incidence of hepatitis B has declined in Catalonia due to the universal vaccination of preadolescents, but that the incidence has increased in male immigrants. Given the seriousness of hepatitis B virus infection for individuals and for the community, universal vaccination programmes should be continued and measures to increase vaccination of risk groups and immigrants, should be reinforced.