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Seroprevalence of hepatitis B and factors potentially associated in a population-based study in Medellin, Colombia
Vaccine xxx (2017) xxx–xxx
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Seroprevalence of hepatitis B and factors potentially associated in a population-based study in Medellin, Colombia David A. Cadavid-Betancur a,b,⇑, Marta C. Ospina c, Doracelly Hincapié-Palacio a, Luz M. Bernal-Restrepo c, Seti Buitrago-Giraldo c, Olga Perez-Toro c, Eduardo Santacruz-Sanmartín d, Viviana Lenis-Ballesteros e, Rita Almanza-Payares d, Francisco J. Díaz f a
Group of Epidemiology, National School of Public Health, ‘Héctor Abad Gómez’ – University of Antioquia, Calle 62 # 52-29 Of. 226, Medellín, Colombia GIVET Research Group, Facultad de Ciencias Administrativas y Agropecuarias, Corporación Universitaria Lasallista, Caldas, Colombia Laboratory of Public Health of the Regional Secretariat of Health and Social Protection of Antioquia, Carrera 72a # 78b–141, tercer piso, Medellín, Colombia d Secretariat of Health, Calle 44 N 52 – 165 Centro Administrativo La Alpujarra, Medellín, Colombia e National School of Public Health, ‘Héctor Abad Gómez’ – University of Antioquia, Calle 62 # 52-29 Of. 226, Medellín, Colombia f Group of Inmunovirology, School of Medicine – University of Antioquia, Calle 62 #52-59, Medellín, Colombia b c
a r t i c l e
i n f o
Article history: Received 17 February 2017 Received in revised form 27 June 2017 Accepted 25 July 2017 Available online xxxx Keywords: Colombia Hepatitis B Sero-epidemiology Socioeconomic factors
a b s t r a c t The seroprevalence of hepatitis B (HB) and of potentially associated factors in Medellin, Colombia, were investigated 17 years after the start of universal vaccination. Biological and sociodemographic data from a population survey with a multistage random sampling were analyzed in 6–64 year old individuals. HB surface antigen, total HB core antibodies and HB surface antibodies, and in some cases IgM antibodies to HB core antigen, were tested in 2077 samples. Factors potentially associated with and natural, and vaccine immunity relative to susceptibility (absence of any marker) were analyzed using a multinomial logistic regression. The prevalence of serological patterns was: chronic infection 0.20% (95% CI 0.11– 0.71), vaccine immunity 25.10% (95% CI 21.72–28.83) and natural immunity 2.60% (95% CI 1.80–3.74). No markers were detected in 71.30% (95% CI 67.70–74.83) of the individuals and evidence of recent infection was not detected. Relative to the absence of markers, natural immunity was potentially associated with age (6–17 years and 41–64 years) and sleeping less than 6 hours, while vaccine immunity was associated with age (6–17 years), reporting vaccination against HB, belonging to high socioeconomic strata, home ownership and being obese, after adjusting for other variables. These results may be a population effect of mass vaccination. It is recommended to complete the vaccination schedule and to study in detail, persistence of antibodies and the role of obesity and socioeconomic strata in the vaccine immunity. Ó 2017 Elsevier Ltd. All rights reserved.
1. Introduction Hepatitis B (HB) is an infectious disease caused by hepatitis B virus (HBV) an agent characterized by its hepatotropism and capability to produce chronic infections and severe damages such as cirrhosis and liver cancer [1]. It is transmitted by direct or indirect contact with body fluids contaminated with the virus, especially blood and genital fluids, as well as by vertical transmission [1–3]. ⇑ Corresponding author at: Calle 62 # 52-29 Of. 226, Medellin, Colombia. E-mail addresses: [email protected] (D.A. Cadavid-Betancur), martha. [email protected] (M.C. Ospina), [email protected] (D. Hincapié-Palacio), [email protected] (L.M. Bernal-Restrepo), seti.buitrago@antioquia. gov.co (S. Buitrago-Giraldo), [email protected] (O. Perez-Toro), [email protected] (E. Santacruz-Sanmartín), [email protected] (V. Lenis-Ballesteros), [email protected] (R. Almanza-Payares), [email protected] (F.J. Díaz).
An estimated one third of the world population has been exposed to the virus and about 6% of those who become infected develop chronic infection [1]. Colombia is classified as a country with low endemicity and with a prevalence of the surface antigen (HBsAg) lower than 2% [1,4,5]. However, some Colombian regions are highly endemic such as the Amazon where that prevalence may reach 8.4% [6]. In Medellin, the incidence of HB has increased in recent years, from 2.14 per 100.000 individuals in 2006, 6.01 in 2009 and 10.40 in 2014 (Secretariat of Health of Medellin, 2015). Colombia introduced universal HB vaccination between 1992 and 1994 using a Cuban recombinant vaccine in a three-dose schedule (0–1–2 months) aimed at birth, to children under 5 years old in endemic settings and at groups with high risk. Later, since 2001 a four-dose schedule (0, 2, 4 and 6 months) was introduced
http://dx.doi.org/10.1016/j.vaccine.2017.07.084 0264-410X/Ó 2017 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Cadavid-Betancur DA et al. Seroprevalence of hepatitis B and factors potentially associated in a population-based study in Medellin, Colombia. Vaccine (2017), http://dx.doi.org/10.1016/j.vaccine.2017.07.084
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D.A. Cadavid-Betancur et al. / Vaccine xxx (2017) xxx–xxx
with routine vaccination, using an HB-containing pentavalent vaccine [7]. The main tool to assess the impact of vaccination and to analyze factors potentially associated with the serological patterns is population-based seroprevalence studies [8–12]. The aim of this study was to estimate the sero-prevalence of HB in Medellin and to identify factors potentially associated with immunity due to natural exposure and immunity by vaccination, relative to susceptibility (absence of any marker), 17 years after implementation of the HBV vaccination program, based on a random population survey in individuals 6–64 years old [13–15]. 2. Materials and methods A cross-sectional study was conducted to estimate the absence of markers, infection and immunity to HB and the potentially associated biological and socioeconomic factors. The data come from a population survey in Medellin in 2009. The sampling design includes a sample of 2400 individuals selected through a probabilistic multi-stage sampling representative by age, sex and area. Sampling was carried out in three stages of random sampling: neighborhood (in urban area) sector (in rural area) and home. One individual in each home was selected by simple random sampling [13]. The inclusion and exclusion criteria as well as the procedures used to collect information and blood samples in the original study were described previously [13,14]. The source of vaccination status was the immunization cards at the time of the household survey. This data was completed by telephone calls and consulting the vaccination database of the Secretary of Health when this was necessary. A questionnaire was used to record the vaccination card data including vaccine type, number of doses and date of administration of each dose. The samples were preserved and processed in the Public Health Laboratory of the Secretariat of Health and Social Protection of the Department of Antioquia [13,14]. Sera were initially processed for three serological markers: hepatitis B surface antigen (HBsAg), total antibodies to core antigen (anti-HBc) and antibodies against the surface antigen (anti-HBs). Samples testing positive for HBsAg and anti-HBc as well as those with isolated anti-HBc and negative anti-HBs were tested for IgM against core antigen (IgM anti-HBc) to differentiate between recent or ancient infection. The tests were performed using commercial immunoassays: HBsAg was processed by the sandwich ELISA technique (HBsAg Ultra HepanostikaÒ Biomerieux France); anti-HBs, anti-HBc and IgM anti-HBc, as well as the confirmation of HBsAg reactivity were carried out by electro-chemiluminescence (Cobas e 411) RocheÒ, Germany) following the manufacturer’s instruc-
tions. The individuals were classified in six serologic patterns as shown in Table 1. Potential associations were analyzed with biological variables (age, sex, previous vaccination, body mass index (BMI), medical or surgical procedures and use of immunosuppressive drugs during the previous month, self-perception of health throughout life) and with socioeconomic variables (socioeconomic strata, area of residence, education level, home ownership, leisure time, social security, effective sleeping time, and self-perception of problems at home within the last year). In the analysis, proportions and averages were weighed and their respective 95% confidence intervals were estimated. The inverse of the probability of being chosen and the weighing of variability at each stage of random sample were calculated. In the bivariate analysis (Supplementary Table 1S), the variables with p < 0.25 were selected as candidates to enter the multivariate model [16]. Assembling at least 10 results in the category with the lowest frequency of the dependent variable was also used as criterion [17]; consequently, no more than 6 or 7 variables were included in the models explored. A multinomial logistic regression model was used by the multinomial nature of the dependent variable, that is, to have natural immunity or vaccine immunity, taking as comparison group the absence of markers to HB. As is usual in this type of models the relative risk ratio (RRR) is computed relative to the base category. The RRR of an independent variable refers to the increase (RRR > 1) or decrease (RRR < 1) in risk of having natural or vaccine immunity relative to the absence of markers [18,19]. In this study, the multinomial logistic model, the RRR and their respective 95% confidence intervals were performed using STATA version 13.0 (StataCorp, College Station, TX). 3. Results Two thousand and seventy-seven samples (86.52%) were analyzed. No significant differences between participants and nonparticipants, by age group (p = 0.09) or by area or residence (p = 0.16) were found, but it was by sex (p = 0.01), which was adjusted with the correction factor [13,14]. The weighed proportions for the different HBV serological status are shown in Table 1. The greater proportion of individuals presented absence of any marker (71.30%), followed by immunity by vaccination (25.10%) and immunity by natural exposure (2.60%). No individuals with acute infection were detected. Chronic infection was present in 4 individuals for a 0.20% prevalence of HBsAg. Ancient infections without evidence of resolution (isolated antiHBc) were observed in 17 individuals (0.80%). Total prevalence of anti-HBc was 3.61%.
Table 1 Distribution of the study population by HBV serological status. Statusa
Susceptibility Vaccine immunity Naturally acquired immunity Isolated anti-HBc (old infection with unclear resolution) Chronic infection Acute infection Total
HBsAg
AntiHBc
IgM antiHBc
+ + + +
+ +
+
95% confidence interval
Non-weighed frequency
Anti-HBs (10 mUI mL)
Weighed prevalenceb
Standard error
Lower
Upper
+ +
71.30 25.10 2.60 0.80
1.81 1.82 0.51 0.31
67.70 21.72 1.80 0.40
74.83 28.83 3.74 1.61
1568 422 66 17
0.20 0.00 100
0.11
0.11
0.71
4 0 2077
a Status names were adapted from Centers for Diseases Control and Prevention ‘‘Interpretation of Hepatitis B Serologic Test Results”, and to determine the cut-off to antiHBs was adapted from Huzly et al., 2008 [22,23]. Nevertheless, ‘‘Susceptibility” should not be equated to lack of immunity as explained in detail in the discussion. b Prevalence estimated taking in account the complex design.
Please cite this article in press as: Cadavid-Betancur DA et al. Seroprevalence of hepatitis B and factors potentially associated in a population-based study in Medellin, Colombia. Vaccine (2017), http://dx.doi.org/10.1016/j.vaccine.2017.07.084
D.A. Cadavid-Betancur et al. / Vaccine xxx (2017) xxx–xxx
The prevalence of absence of markers and immunity due to natural infection and isolated anti-HBc were significantly lower in the group of 6–17 years of age compared with the group of 18–40 years; conversely, immunity due to vaccination was higher in the 6–17 year group (Table 2). Immunity due to natural infection was higher in the group of 41–64 years. No significant differences in the serological pattern were detected by area and sex. The proportions of obese and overweight individuals were significantly higher in individuals with absence of markers, immune by natural exposure and in those with isolated anti-HBc compared to individuals immune by vaccination. The proportion of absence of markers was significantly higher in those who reported no vaccination against HB compared with those who reported vaccination. The four HBV carriers detected were aged 29, 59, and 64 years old (two individuals); two lived in urban and two in rural areas. These carriers primarily had a low socioeconomic status, sleeping less than seven hours a day and benefiting of social security. Analyzing the states of immunity, absence of markers and infection by birth cohort a trend towards decreased absence of markers, chronic infection and immunity due to natural exposure as well as an increased immunity by vaccination was observed as of the beginning in 1992 (Fig. 1). This increase in the proportion of vaccine immunity by cohort is detailed in Fig. 2, in relation to the number of vaccine doses. Vaccination against HB was reported in 203 (9.81%) individuals studied. Vaccination data was obtained from immunization cards consulted by telephone calls (n = 106), surveys (n = 55) and social security databases (n = 42). Only in 137 individuals were the number of doses documented in detail; of these, 58 (42.33%) had one or two doses, 28 (48.31%) of which were born after 1992, when universal vaccination began. On the other hand, in the remaining 79 (57.71%) individuals in whom the vaccination schedule was completed, the concentration of anti-HBs tended to decrease slightly with the time that elapsed between the last dose of vaccine applied and the serological survey. Anti-HBs < 10 mIU/ml was observed in 44 (55.72%) of those with three or more doses (Fig. 3). In the adjusted multivariate model, the probability of being immune by natural exposure relative to the absence of markers was higher in individuals aged 41–64 years (RRR 3.52; 95% CI 1.62–7.70) and was lower in those 6–17 years old (RRR 0.01; 95% CI 0.00–0.03) in comparison to those 18–40 years old and in those with less than 6 h of effective sleep per day (RRR 0.21; 95% CI 0.06– 0.79) in comparison to sleep 6–7 h per day, after adjusting for other variables including age and BMI (Table 3). The probability of being immune through vaccination relative to the absence of markers increased in those 6–17 years old (RRR 4.48; 95% CI 3.12–7.18), in individuals vaccinated against HB versus those who were not (RRR 2.00; 95% CI 1.02–3.92), in those in high versus low socioeconomic status (RRR 2.08; 95% CI 1.16–3.72) and those living in their own home versus those living in rented lodgings (RRR 1.56; 95% CI 1.01–2.41). Conversely, it was noted that vaccine immunity decreased in those who were obese versus those who had a normal BMI (RRR 0.40; 95% CI 0.17–0.95).
4. Discussion This study provides valuable information on the prevalence of HB and its potentially associated factors in a broad age range (6– 64 years). The procedures used for sampling, data collection and handling of blood specimens make it possible to draw reliable inferences at the population level.
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4.1. Endemicity This study demonstrated a low endemicity of HB in the population studied, with a prevalence of 0.20% (95% CI 0.11–0.71) for HBsAg and 3.61% (95% CI 2.82–4.41) for anti-HBc. The very low prevalence of these markers in people born after the beginning of mass vaccination (Fig. 2) may be an effect of this program, that in turn limits the transmission to susceptible contacts [20,21]. 4.2. Susceptibility The weighed prevalence of the susceptibility (absence of any serological markers) was 71.30% (95% CI 67.70–74.83); disaggregating this data by birth cohort, a tendency to reduced absence of markers was observed as of the beginning of 1992–1994, after the start of universal vaccination (Fig. 1). The absence of markers was higher than 80% in individuals 18 years or older (Table 2), that is mainly attributable to the fact of not having been included in the mass vaccination campaign. However, the absence of markers was also considerably higher in those 18 years or less (53.21%, 95% CI 46.53–59.70), which does not necessarily indicate lack of immunity in this group; in keeping with the usual standards [22,23], they were classified here as ‘‘susceptible” (Table 1), although most of them probably had immunological memory that would protect them in case of exposure to HBV (see below). 4.3. Vaccine immunity In this study, immunity by vaccination was detected in just a quarter of the population studied, although in the group aged 6– 17 years, this pattern reached 46.80%, thus about three and four times higher than in the 18–40 (15.50%) and 41–64 (11.24%) year-old groups, respectively (Supplementary Fig. 1S). We identified two factors that could have negatively influenced the achievement or persistence of such immunity: the high frequency of individuals with incomplete vaccination schedules among those who had such data and the decline of the anti-HB titer in the years following the primary vaccination. Of the 137 individuals with detailed immunization data, 58 (42.33%) had received only one or two doses. On the other hand, the trend towards a decrease in the titer of anti-HBs with the time that elapsed since the last dose (Fig. 3) argue in favor of a gradual loss of antibodies below the 10 mIU/mL limit. The prevalence of vaccine immunity estimated in this study is reliable given the high sensitivity and specificity of the tests used (>98.8% for HBsAg, 98% for anti-HBs [23,24] and 99.6% for antiHBc according to the manufacturer), but the data from the vaccine history, obtained only in about 10% of the individuals, are limited. Further studies are needed to understand factors that influence the low frequency of vaccine immunity and monitor the persistence of antibodies in this population. Although the duration of immunity conferred by the vaccine has not been definitively established, several studies in populations vaccinated more than 20 years earlier demonstrate the persistence of immunity despite the decreased levels of anti-HBs below 10 mIU/mL. This is demonstrated by the strong and rapid response to a booster dose characteristic of an anamnestic response [21]. The longest follow-up study published to date [25] shows the persistence of immune memory for up to 30 years. Moreover, anti-HBs is not a complete assessment of the immunity conferred by the vaccine, since cellular immunity response and memory is not evaluated in that test. Cellular immunity plays an important role, perhaps more decisive than the humoral response, in protection against HBV [1]. In the multinomial adjusted model among those younger than 18 years reporting vaccination against HB, high socioeconomic sta-
Please cite this article in press as: Cadavid-Betancur DA et al. Seroprevalence of hepatitis B and factors potentially associated in a population-based study in Medellin, Colombia. Vaccine (2017), http://dx.doi.org/10.1016/j.vaccine.2017.07.084
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Variables and categories
Age (years)
Gender Area of residence Hepatitis B vaccination Recent vaccination (any vaccine) Body-mass index (BMI)
Socioeconomic strata Medical procedures one month before serological test Home ownership Immunosuppressive drug use Disease one month before serological test Immunosuppressive disease Self-reported health status Effective sleep time
Education level Social security status Problems at home in the last year a b c
6–17 18–40a 41–64 Male Femalea Urbana Rural Reported Unreporteda Yes Noa Normala Overweight Obesity High (4, 5 and 6)a Low (1, 2 and 3) Yes Noa Own Rented or similara Yes Noa Yes Noa Yes Noa Good to very gooda Fair to poor <6 h 6–7 ha >7 h Complete elementary or highera None Insured Not-insureda Yes No
Susceptibilityc
Vaccine immunity
PP [95%CI] 53.21 81.39 79.86 69.22 73.42 71.13 76.22 53.22 73.90 69.69 75.71 68.03 74.21 84.02 64.60 72.52 75.61 71.12 67.90 76.01 45.61 71.80 69.10 75.61 70.79 68.90 71.40 72.30 79.60 72.05 69.49 73.72 62.82 70.64 76.25 73.26 70.73
[46.53–59.70] [76.81–85.33] [73.79–84.81] [63.42–74.53] [68.72–77.53] [67.13–74.78] [71.74–80.24] [41.33–64.83] [70.03–77.48] [65.20–73.70] [67.81–82.22] [62.94–72.73] [68.01–79.63] [74.53–90.45] [53.22–74.52] [68.51–76.28] [57.72–87.52] [67.27–74.71] [63.19–72.32] [69.91–81.30] [24.52–68.43] [68.07–75.32] [64.58–73.34] [69.70–80.70] [53.80–83.36] [64.31–73.10] [67.68–74.90] [60.11–81.91] [70.11–86.79] [63.30–79.41] [64.61–73.71] [69.42–77.60] [53.70–71.29] [66.63–74.33] [66.14–84.01] [67.46–78.39] [66.26–74.90]
Reference category for the difference of proportions. PP: Proportion of prevalence. 95% CI: 95% confidence interval. Prevalence estimated taking into account the complex design. Absence of any serological marker.
Isolated anti-HBc
Chronic infection
PP [95%CI]
Naturally acquired immunity PP [95%CI]
PP [95%CI]
PP [95%CI]
46.83 [40.32–53.51] 15.50 [11.91–20.03] 11.24 [7.43–16.84] 26.71 [21.66–32.54] 23.54 [19.55–28.16] 25.43 [21.84–29.35] 19.70 [16.18–23.99] 45.22 [33.61–57.34] 22.33 [19.03–26.01] 27.40 [23.42–31.92] 19.41 [13.83–26.91] 29.85 [25.23–34.83] 19.6 [14.93–25.45] 10.91 [5.54–20.60] 33.42 [23.46–45.27] 23.62 [20.02–27.53] 18.53 [8.01–37.02] 25.45 [22.00–29.21] 28.73 [24.34–33.54] 20.21 [15.11–26.51] 50.22 [28.03–72.44] 24.60 [21.27–28.48] 27.51 [23.32–32.23] 20.53 [15.76–26.49] 23.61 [12.28–40.77] 27.62 [23.22–32.52] 25.50 [22.12–29.12] 21.24 [12.44–33.93] 17.80 [11.03–27.52] 20.81 [14.82–28.53] 28.00 [23.79–32.78] 23.01 [19.31–27.29] 32.61 [24.81–41.63] 25.80 [22.16–29.88] 20.60 [13.31–30.50] 24.30 [19.30–30.31] 25.40 [21.41–29.81]
0.01 2.09 6.70 3.06 2.21 2.61 3.20 0.75 2.94 3.91 2.11 1.91 4.80 1.65 2.08 2.81 6.04 2.51 2.51 2.86 4.27 2.63 2.52 2.70 5.70 2.80 2.40 3.80 1.71 5.42 1.91 2.50 2.90 2.70 2.21 1.51 3.01
0.01 0.78 1.90 0.90 0.71 0.81 0.88 0.81 0.83 1.00 0.31 0.21 0.92 3.50 0 0.93 0 0.80 0.83 0.71 0 0.82 0.74 0.91 0 0.62 0.61 1.96 0 1.82 0.60 0.70 1.21 0.74 1.14 1.03 0.73
0 0.30 0.40 0.20 0.22 0.21 0.10 0 0.20 0.01 0.76 0.20 0.41 0.11 0 0.20 0 0.22 0.23 0.21 0 0.25 0.23 0.35 0 0.26 0.19 0.80 0.89 0 0.20 0.17 0.56 0.22 0 0.03 0.33
[0.00–0.04] [1.24–3.90] [4.11–10.89] [1.75–5.29] [1.38–3.78] [1.74–3.85] [2.12–5.03] [0.11–5.00] [2.07–4.12] [2.33–6.64] [1.24–3.64] [1.17–3.25] [2.63–8.90] [0.67–4.29] [0.81–5.14] [1.91–3.80] [1.52–20.50] [1.71–3.71] [1.56–4.00] [1.61–5.05] [0.71–21.30] [1.84–3.74] [1.53–4.23] [1.51–4.81] [1.45–20.24] [1.72–4.52] [1.65–3.63] [1.52–9.69] [0.71–4.50] [2.86–10.27] [1.18–3.21] [1.69–4.01] [1.41–5.80] [1.88–3.99] [0.52–9.33] [0.61–3.62] [2.00–4.41]
[0.00–0.06] [0.36–1.91] [0.71–5.05] [0.34–2.66] [0.35–1.67] [0.41–1.64] [0.41–1.91] [0.14–5.40] [0.40–1.79] [0.43–2.11] [0.14–0.98] [0.03–0.96] [0.21–4.33] [1.30–8.80] [0.58–1.91] [0.44–1.63] [0.30–2.21] [0.36–2.05] [0.42–1.61] [0.35–2.02] [0.31–2.38] [0.22–1.52] [0.32–1.41] [0.58–6.90] [0.79–4.78] [0.22–1.74] [0.31–1.53] [0.25–5.96] [0.34–1.64] [0.20–7.01] [0.33–3.45] [0.38–1.70]
[0.04–1.67] [0.13–2.28] [0.03–1.36] [0.03–1.20] [0.05–0.87] [0.02–0.80] [0.61–0.87] [0.00–0.02] [0.20–2.56] [0.02–1.16] [0.10–2.45] [0.01–0.43] [0.11–0.90] [0.10–0.83] [0.03–1.06] [0.03–1.6] [0.11–0.71] [0.02–1.08] [0.13–1.76] [0.16–1.04] [0.01–0.80] [0.11–4.50] [0.10–5.54] [0.11–0.90] [0.01–0.81] [0.16–3.20] [0.10–0.80] [0.01–0.28] [0.11–1.01]
D.A. Cadavid-Betancur et al. / Vaccine xxx (2017) xxx–xxx
Please cite this article in press as: Cadavid-Betancur DA et al. Seroprevalence of hepatitis B and factors potentially associated in a population-based study in Medellin, Colombia. Vaccine (2017), http://dx.doi.org/10.1016/j.vaccine.2017.07.084
Table 2 Distribution of the weighed prevalence of HBV serological status according to the variables studied. Medellin, 2009.b
D.A. Cadavid-Betancur et al. / Vaccine xxx (2017) xxx–xxx
5
Fig. 1. Weighed prevalence of susceptibility (absence of serological markers), immunity and infection (HBsAg carriers and isolated anti-HBc) to HBV according to year of birth. Medellín, 2009.
Fig. 2. Proportion of immunity due to vaccination against HBV and number of doses of vaccine given according to year of birth. Medellín, 2009; (n = 2077).
tus and possessing their own housing were identified as variables potentially associated with vaccine immunity (Table 3). Different studies have reported the positive association of being younger and vaccinated against HB with immunity in the population [8,26]. It is an expected consequence of the implementation of the vaccination program [27,28], as cohorts born between 6 and 17 years before initiation of universal vaccination should have greater access to vaccination. In a study conducted in Medellin in 1998 in individuals 1– 14 years old, seropositivity to anti-HBs was higher in individuals of high compared to low socioeconomic strata [26]. Accordingly, in this study, in the population aged 6–64 years, the possibility of
being immune through vaccination was significantly higher in the upper stratum compared to the lower stratum (RRR 2.08, 95% CI 1.16–3.72), which could also be related to access to vaccination. However, neither of these two studies were designed to be representative of socioeconomic strata and the samples were mainly from lower strata. This study found that obesity decreased the possibility of being immune by vaccination (RRR 0.40; 95% CI = 0.17–0.95). According to previous reports, obesity could have negative effects on humoral and cellular immune systems, by affecting T and B cell populations [29,30]. Particularly in HB, obesity may reduce the response to vaccination and contribute to the development of carcinomas in
Please cite this article in press as: Cadavid-Betancur DA et al. Seroprevalence of hepatitis B and factors potentially associated in a population-based study in Medellin, Colombia. Vaccine (2017), http://dx.doi.org/10.1016/j.vaccine.2017.07.084
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D.A. Cadavid-Betancur et al. / Vaccine xxx (2017) xxx–xxx
Fig. 3. Antibody titers against HBV surface antigen (anti-HBs) in individuals with three or more doses of vaccine based on the time between application of the last dose and serologic assessment. Medellin, 2009; (n = 79); Spearman’s Rho: 0.10.
infected individuals [1,31]. Although this effect was reported since 1985, with the application of plasma-derived HB vaccine [32], the mechanism is still unclear. In a study conducted in the USA in 2010 it was proposed that the length of the needle used for the application of the vaccine in obese adolescents could explain the lower response because the vaccine could have been deposited in the adipose tissue instead of in the muscle [33]. On the other hand, it is possible that obesity boosts liver damage and increases the risk of mortality in chronic HB since obese people are more likely to develop metabolic syndromes and fatty liver, which can lead to cirrhosis, liver cancer and death [34–36]. In any case, caution is required in interpreting the effect of obesity on vaccine immune response since it is not possible to establish the presence of obesity before the time of vaccination due to the cross-sectional design of this study. 4.4. Naturally acquired immunity Immunity from natural exposure was also relative to the absence of markers in multinomial regression, showing a positive association with age in individuals between 41 and 64 years, whereas individuals between 6 and 17 years and sleeping less than 6 h per day were inversely associated. Few studies have specifically reported an association between immunity acquired by natural exposure to HBV and age; a study conducted in Australia among intravenous drug users reported an increase in the probability of being immune by natural exposure with age [2]. In our study in the general population, this potential association may be due to more opportunities of exposure to the virus in the older, unvaccinated population. Other studies relating the presence of anti-HBc with age do not discriminate between individuals immune by natural infection and chronically infected. In a study in four regions of Colombia, Alvarado-Mora et al., reported an increased prevalence of antiHBc with age [6]. Also in other regions, it was observed that the prevalence of anti-HBc increased exponentially with age as occurred in a population-based study conducted in China in 2006, and another study performed in Amsterdam in 2004 [8,37]. In our study individuals who slept less than six hours had potentially a lower chance of being immune from natural exposure in comparison to those who slept 6–7 h per day and presented absence of markers (RRR 0.21, 95% CI 0.06–0.79), after adjusting
for other variables, including age and BMI, which might confuse this relationship although it is possible that this finding was the result of residual confounding by an additional, uncontrolled factor. The effect of the sleep time on the immune response to HB vaccination has been addressed in some studies, but no study has addressed its effects on the outcome of natural exposure to HBV. It has been postulated that acute or chronic sleep disturbances may be related to the risk of infectious diseases due to interference with immunological processes [38,39]. The effect of the duration of daily sleep on the immune response to HB vaccination has been addressed in some studies, but no study has addressed its effects on the outcome of natural exposure to HBV. In a study involving 125 women between 40 and 60 years of age, Prather et al., reported that sleeping less than 6 h a day confers a significant risk of not achieving vaccine protection against HBV, an effect independent of age, sex and BMI [10]. In a study in Beijing-China in 2009 and 2010, increased frequency of insomnia in patients diagnosed with chronic liver disease including HB, compared with a control group [40] was also reported. Additional studies are needed to understand the potential mechanisms underlying the relationship between sleep time and the development of both, natural and vaccine immunity to HBV, using standardized techniques to measure the amount and quality of sleep. This study is limited by the lack of data related to other important variables in the transmission of HB that were not included in the original survey such as occupational exposure, sexual risk behavior, intravenous drug use, performing tattoos, and piercings. Given the controversy over the usefulness of the booster dose in the routine schedule and the available data on the duration of vaccine immunity [41], additional vaccine doses are not indicated in this population. Instead, we recommend to set up mechanisms to complete the vaccination in children under five years and increase the coverage by overcoming the barriers present in the organization of the health service system. It is necessary to identify individuals with incomplete schemes as well as mechanisms reminding them of further scheduled doses and encouraging vaccination with strategies in agreement with the culture practices of the population and to increase health promotion policies aimed at improving living conditions, since other aspects besides vaccination practices, such as socioeconomic strata and obesity, could influence vaccine immunity.
Please cite this article in press as: Cadavid-Betancur DA et al. Seroprevalence of hepatitis B and factors potentially associated in a population-based study in Medellin, Colombia. Vaccine (2017), http://dx.doi.org/10.1016/j.vaccine.2017.07.084
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D.A. Cadavid-Betancur et al. / Vaccine xxx (2017) xxx–xxx Table 3 Multinomial logistic regression models for HBV serologic status. Medellín, 2009. Crude model
Natural immunity/susceptibility┼ Age group (years) 6–17 18–40 41–64 HBV vaccination reported No Yes Effective sleeping time (h) <6 6–7 >7 Body mass index (according to WHO) Normal Overweight Obesity Socioeconomic strata Low High Home ownership Rented or similar Own
Adjusted model
RRR
95%CI [SE]
RRR
95%CI [SE]
0.01*** 1 3.23**
0.00–0.03 [0.01]
0.00–0.03 [0.01]
1.39–7.52 [1.39]
0.01*** 1 3.52**
0.05–2.75 [0.01]
1 0.70
1 0.36 0.29 1 0.37*
0.08–1.00 [0.18]
1.62–7.70 [1.40]
0.09–5.29 [0.71] *
0.14–0.94 [0.18]
0.21 1 0.44
0.17–1.14 [0.21]
1 2.36 0.67
0.98–5.68 [1.05] 0.21–2.21 [0.41]
1 1.31 0.34
0.57–3.02 [0.56] 0.10–1.14 [0.21]
1 0.81
0.29–2.28 [0.43]
1 0.56
0.18–1.73 [0.32]
1 1.00
0.45–2.22 [0.41]
1 0.94
0.43–2.03 [0.37]
0.06–0.79 [0.02]
┼
Vaccine immunity/Susceptibility Age group (years) 6–17 18–40 41–64 HBV vaccination reported No Yes Effective sleeping time (h) <6 6–7 >7 Body mass index (according to WHO) Normal Overweight Obese Socioeconomic strata Low High Home ownership Rented or similar Own
4.63*** 1 0.74 1 2.82*** 1.40 1 0.78
0.42–1.31 [0.22]
4.48*** 1 0.804
1.66–4.78 [0.76]
1 2.00*
3.24–6.61 [0.84]
0.86–2.26 [0.34]
3.12–7.18 [0.90] 0.43–1.50 [0.26]
1.02–3.92 [0.69]
0.41–1.48 [0.26]
1.12 1 1.17
0.55–2.30 [0.41]
1 0.60* 0.30**
0.41–0.89 [0.12] 0.14–0.64 [0.12]
1 0.87 0.40*
0.52–1.44 [0.22] 0.17–0.95 [0.18]
1 1.59
0.92–2.74 [0.44]
1 2.08*
1.16–3.72 [0.62]
1 1.59*
1.04–2.42 [0.34]
1 1.56*
1.01–2.41 [0.34]
0.71–1.95 [0.30]
RRR: relative risk ratio estimated taking into account the complex design. CI: 95% confidence interval. SE: standard error. * p < 0.05. ** p < 0.01. *** p < 0.001. ┼ Reference category for the dependent variable. Absence of any serological marker.
Acknowledgement This study was supported by the Colombian Science, Technology and Innovation Administrative Department [Colciencias], the Fund for Teaching Support of the National School of Public Health, the Sustainability Strategy 2013-2014 and 2015-2016 for the Epidemiology and Immunovirology Research Groups of University of Antioquia, the Secretariat of Health of Medellin, and the Public Health Laboratory of the Secretariat of Health and Social Protection of Antioquia. Thanks to Dr. Anne-Lise Haenni, Université de Paris, Diderot, for her linguistic correction of the manuscript.
quia in session 107 of August 14, 2014; it was classified as ‘‘study of minimal risk” because it used secondary data. The study followed the national ethical rules for research with human beings (Resolution 8430 of 1993 of the Ministry of Health of Colombia); it was also in agreement with the Declaration of Helsinki guidelines. In children, informed consent was obtained and signed by parents or legal guardians. Chronically infected individuals and their cohabitants were studied in agreement with the guidelines of the Ministry of Health of Colombia; these patients were referred to the Secretariat of Health of Medellin for further studies and management.
Ethical considerations Conflicts of interests The project was reviewed and approved by the Ethics Committee of the National School of Public Health of the University of Antio-
The authors declare no conflict of interest.
Please cite this article in press as: Cadavid-Betancur DA et al. Seroprevalence of hepatitis B and factors potentially associated in a population-based study in Medellin, Colombia. Vaccine (2017), http://dx.doi.org/10.1016/j.vaccine.2017.07.084
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Appendix A. Supplementary material Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.vaccine.2017.07. 084.
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Seroprevalence of hepatitis B and factors potentially associated in a population-based study in Medellin, Colombia David A. Cadavid-Betancur a,b,⇑, Marta C. Ospina c, Doracelly Hincapié-Palacio a, Luz M. Bernal-Restrepo c, Seti Buitrago-Giraldo c, Olga Perez-Toro c, Eduardo Santacruz-Sanmartín d, Viviana Lenis-Ballesteros e, Rita Almanza-Payares d, Francisco J. Díaz f a
Group of Epidemiology, National School of Public Health, ‘Héctor Abad Gómez’ – University of Antioquia, Calle 62 # 52-29 Of. 226, Medellín, Colombia GIVET Research Group, Facultad de Ciencias Administrativas y Agropecuarias, Corporación Universitaria Lasallista, Caldas, Colombia Laboratory of Public Health of the Regional Secretariat of Health and Social Protection of Antioquia, Carrera 72a # 78b–141, tercer piso, Medellín, Colombia d Secretariat of Health, Calle 44 N 52 – 165 Centro Administrativo La Alpujarra, Medellín, Colombia e National School of Public Health, ‘Héctor Abad Gómez’ – University of Antioquia, Calle 62 # 52-29 Of. 226, Medellín, Colombia f Group of Inmunovirology, School of Medicine – University of Antioquia, Calle 62 #52-59, Medellín, Colombia b c
a r t i c l e
i n f o
Article history: Received 17 February 2017 Received in revised form 27 June 2017 Accepted 25 July 2017 Available online xxxx Keywords: Colombia Hepatitis B Sero-epidemiology Socioeconomic factors
a b s t r a c t The seroprevalence of hepatitis B (HB) and of potentially associated factors in Medellin, Colombia, were investigated 17 years after the start of universal vaccination. Biological and sociodemographic data from a population survey with a multistage random sampling were analyzed in 6–64 year old individuals. HB surface antigen, total HB core antibodies and HB surface antibodies, and in some cases IgM antibodies to HB core antigen, were tested in 2077 samples. Factors potentially associated with and natural, and vaccine immunity relative to susceptibility (absence of any marker) were analyzed using a multinomial logistic regression. The prevalence of serological patterns was: chronic infection 0.20% (95% CI 0.11– 0.71), vaccine immunity 25.10% (95% CI 21.72–28.83) and natural immunity 2.60% (95% CI 1.80–3.74). No markers were detected in 71.30% (95% CI 67.70–74.83) of the individuals and evidence of recent infection was not detected. Relative to the absence of markers, natural immunity was potentially associated with age (6–17 years and 41–64 years) and sleeping less than 6 hours, while vaccine immunity was associated with age (6–17 years), reporting vaccination against HB, belonging to high socioeconomic strata, home ownership and being obese, after adjusting for other variables. These results may be a population effect of mass vaccination. It is recommended to complete the vaccination schedule and to study in detail, persistence of antibodies and the role of obesity and socioeconomic strata in the vaccine immunity. Ó 2017 Elsevier Ltd. All rights reserved.
1. Introduction Hepatitis B (HB) is an infectious disease caused by hepatitis B virus (HBV) an agent characterized by its hepatotropism and capability to produce chronic infections and severe damages such as cirrhosis and liver cancer [1]. It is transmitted by direct or indirect contact with body fluids contaminated with the virus, especially blood and genital fluids, as well as by vertical transmission [1–3]. ⇑ Corresponding author at: Calle 62 # 52-29 Of. 226, Medellin, Colombia. E-mail addresses: [email protected] (D.A. Cadavid-Betancur), martha. [email protected] (M.C. Ospina), [email protected] (D. Hincapié-Palacio), [email protected] (L.M. Bernal-Restrepo), seti.buitrago@antioquia. gov.co (S. Buitrago-Giraldo), [email protected] (O. Perez-Toro), [email protected] (E. Santacruz-Sanmartín), [email protected] (V. Lenis-Ballesteros), [email protected] (R. Almanza-Payares), [email protected] (F.J. Díaz).
An estimated one third of the world population has been exposed to the virus and about 6% of those who become infected develop chronic infection [1]. Colombia is classified as a country with low endemicity and with a prevalence of the surface antigen (HBsAg) lower than 2% [1,4,5]. However, some Colombian regions are highly endemic such as the Amazon where that prevalence may reach 8.4% [6]. In Medellin, the incidence of HB has increased in recent years, from 2.14 per 100.000 individuals in 2006, 6.01 in 2009 and 10.40 in 2014 (Secretariat of Health of Medellin, 2015). Colombia introduced universal HB vaccination between 1992 and 1994 using a Cuban recombinant vaccine in a three-dose schedule (0–1–2 months) aimed at birth, to children under 5 years old in endemic settings and at groups with high risk. Later, since 2001 a four-dose schedule (0, 2, 4 and 6 months) was introduced
http://dx.doi.org/10.1016/j.vaccine.2017.07.084 0264-410X/Ó 2017 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Cadavid-Betancur DA et al. Seroprevalence of hepatitis B and factors potentially associated in a population-based study in Medellin, Colombia. Vaccine (2017), http://dx.doi.org/10.1016/j.vaccine.2017.07.084
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D.A. Cadavid-Betancur et al. / Vaccine xxx (2017) xxx–xxx
with routine vaccination, using an HB-containing pentavalent vaccine [7]. The main tool to assess the impact of vaccination and to analyze factors potentially associated with the serological patterns is population-based seroprevalence studies [8–12]. The aim of this study was to estimate the sero-prevalence of HB in Medellin and to identify factors potentially associated with immunity due to natural exposure and immunity by vaccination, relative to susceptibility (absence of any marker), 17 years after implementation of the HBV vaccination program, based on a random population survey in individuals 6–64 years old [13–15]. 2. Materials and methods A cross-sectional study was conducted to estimate the absence of markers, infection and immunity to HB and the potentially associated biological and socioeconomic factors. The data come from a population survey in Medellin in 2009. The sampling design includes a sample of 2400 individuals selected through a probabilistic multi-stage sampling representative by age, sex and area. Sampling was carried out in three stages of random sampling: neighborhood (in urban area) sector (in rural area) and home. One individual in each home was selected by simple random sampling [13]. The inclusion and exclusion criteria as well as the procedures used to collect information and blood samples in the original study were described previously [13,14]. The source of vaccination status was the immunization cards at the time of the household survey. This data was completed by telephone calls and consulting the vaccination database of the Secretary of Health when this was necessary. A questionnaire was used to record the vaccination card data including vaccine type, number of doses and date of administration of each dose. The samples were preserved and processed in the Public Health Laboratory of the Secretariat of Health and Social Protection of the Department of Antioquia [13,14]. Sera were initially processed for three serological markers: hepatitis B surface antigen (HBsAg), total antibodies to core antigen (anti-HBc) and antibodies against the surface antigen (anti-HBs). Samples testing positive for HBsAg and anti-HBc as well as those with isolated anti-HBc and negative anti-HBs were tested for IgM against core antigen (IgM anti-HBc) to differentiate between recent or ancient infection. The tests were performed using commercial immunoassays: HBsAg was processed by the sandwich ELISA technique (HBsAg Ultra HepanostikaÒ Biomerieux France); anti-HBs, anti-HBc and IgM anti-HBc, as well as the confirmation of HBsAg reactivity were carried out by electro-chemiluminescence (Cobas e 411) RocheÒ, Germany) following the manufacturer’s instruc-
tions. The individuals were classified in six serologic patterns as shown in Table 1. Potential associations were analyzed with biological variables (age, sex, previous vaccination, body mass index (BMI), medical or surgical procedures and use of immunosuppressive drugs during the previous month, self-perception of health throughout life) and with socioeconomic variables (socioeconomic strata, area of residence, education level, home ownership, leisure time, social security, effective sleeping time, and self-perception of problems at home within the last year). In the analysis, proportions and averages were weighed and their respective 95% confidence intervals were estimated. The inverse of the probability of being chosen and the weighing of variability at each stage of random sample were calculated. In the bivariate analysis (Supplementary Table 1S), the variables with p < 0.25 were selected as candidates to enter the multivariate model [16]. Assembling at least 10 results in the category with the lowest frequency of the dependent variable was also used as criterion [17]; consequently, no more than 6 or 7 variables were included in the models explored. A multinomial logistic regression model was used by the multinomial nature of the dependent variable, that is, to have natural immunity or vaccine immunity, taking as comparison group the absence of markers to HB. As is usual in this type of models the relative risk ratio (RRR) is computed relative to the base category. The RRR of an independent variable refers to the increase (RRR > 1) or decrease (RRR < 1) in risk of having natural or vaccine immunity relative to the absence of markers [18,19]. In this study, the multinomial logistic model, the RRR and their respective 95% confidence intervals were performed using STATA version 13.0 (StataCorp, College Station, TX). 3. Results Two thousand and seventy-seven samples (86.52%) were analyzed. No significant differences between participants and nonparticipants, by age group (p = 0.09) or by area or residence (p = 0.16) were found, but it was by sex (p = 0.01), which was adjusted with the correction factor [13,14]. The weighed proportions for the different HBV serological status are shown in Table 1. The greater proportion of individuals presented absence of any marker (71.30%), followed by immunity by vaccination (25.10%) and immunity by natural exposure (2.60%). No individuals with acute infection were detected. Chronic infection was present in 4 individuals for a 0.20% prevalence of HBsAg. Ancient infections without evidence of resolution (isolated antiHBc) were observed in 17 individuals (0.80%). Total prevalence of anti-HBc was 3.61%.
Table 1 Distribution of the study population by HBV serological status. Statusa
Susceptibility Vaccine immunity Naturally acquired immunity Isolated anti-HBc (old infection with unclear resolution) Chronic infection Acute infection Total
HBsAg
AntiHBc
IgM antiHBc
+ + + +
+ +
+
95% confidence interval
Non-weighed frequency
Anti-HBs (10 mUI mL)
Weighed prevalenceb
Standard error
Lower
Upper
+ +
71.30 25.10 2.60 0.80
1.81 1.82 0.51 0.31
67.70 21.72 1.80 0.40
74.83 28.83 3.74 1.61
1568 422 66 17
0.20 0.00 100
0.11
0.11
0.71
4 0 2077
a Status names were adapted from Centers for Diseases Control and Prevention ‘‘Interpretation of Hepatitis B Serologic Test Results”, and to determine the cut-off to antiHBs was adapted from Huzly et al., 2008 [22,23]. Nevertheless, ‘‘Susceptibility” should not be equated to lack of immunity as explained in detail in the discussion. b Prevalence estimated taking in account the complex design.
Please cite this article in press as: Cadavid-Betancur DA et al. Seroprevalence of hepatitis B and factors potentially associated in a population-based study in Medellin, Colombia. Vaccine (2017), http://dx.doi.org/10.1016/j.vaccine.2017.07.084
D.A. Cadavid-Betancur et al. / Vaccine xxx (2017) xxx–xxx
The prevalence of absence of markers and immunity due to natural infection and isolated anti-HBc were significantly lower in the group of 6–17 years of age compared with the group of 18–40 years; conversely, immunity due to vaccination was higher in the 6–17 year group (Table 2). Immunity due to natural infection was higher in the group of 41–64 years. No significant differences in the serological pattern were detected by area and sex. The proportions of obese and overweight individuals were significantly higher in individuals with absence of markers, immune by natural exposure and in those with isolated anti-HBc compared to individuals immune by vaccination. The proportion of absence of markers was significantly higher in those who reported no vaccination against HB compared with those who reported vaccination. The four HBV carriers detected were aged 29, 59, and 64 years old (two individuals); two lived in urban and two in rural areas. These carriers primarily had a low socioeconomic status, sleeping less than seven hours a day and benefiting of social security. Analyzing the states of immunity, absence of markers and infection by birth cohort a trend towards decreased absence of markers, chronic infection and immunity due to natural exposure as well as an increased immunity by vaccination was observed as of the beginning in 1992 (Fig. 1). This increase in the proportion of vaccine immunity by cohort is detailed in Fig. 2, in relation to the number of vaccine doses. Vaccination against HB was reported in 203 (9.81%) individuals studied. Vaccination data was obtained from immunization cards consulted by telephone calls (n = 106), surveys (n = 55) and social security databases (n = 42). Only in 137 individuals were the number of doses documented in detail; of these, 58 (42.33%) had one or two doses, 28 (48.31%) of which were born after 1992, when universal vaccination began. On the other hand, in the remaining 79 (57.71%) individuals in whom the vaccination schedule was completed, the concentration of anti-HBs tended to decrease slightly with the time that elapsed between the last dose of vaccine applied and the serological survey. Anti-HBs < 10 mIU/ml was observed in 44 (55.72%) of those with three or more doses (Fig. 3). In the adjusted multivariate model, the probability of being immune by natural exposure relative to the absence of markers was higher in individuals aged 41–64 years (RRR 3.52; 95% CI 1.62–7.70) and was lower in those 6–17 years old (RRR 0.01; 95% CI 0.00–0.03) in comparison to those 18–40 years old and in those with less than 6 h of effective sleep per day (RRR 0.21; 95% CI 0.06– 0.79) in comparison to sleep 6–7 h per day, after adjusting for other variables including age and BMI (Table 3). The probability of being immune through vaccination relative to the absence of markers increased in those 6–17 years old (RRR 4.48; 95% CI 3.12–7.18), in individuals vaccinated against HB versus those who were not (RRR 2.00; 95% CI 1.02–3.92), in those in high versus low socioeconomic status (RRR 2.08; 95% CI 1.16–3.72) and those living in their own home versus those living in rented lodgings (RRR 1.56; 95% CI 1.01–2.41). Conversely, it was noted that vaccine immunity decreased in those who were obese versus those who had a normal BMI (RRR 0.40; 95% CI 0.17–0.95).
4. Discussion This study provides valuable information on the prevalence of HB and its potentially associated factors in a broad age range (6– 64 years). The procedures used for sampling, data collection and handling of blood specimens make it possible to draw reliable inferences at the population level.
3
4.1. Endemicity This study demonstrated a low endemicity of HB in the population studied, with a prevalence of 0.20% (95% CI 0.11–0.71) for HBsAg and 3.61% (95% CI 2.82–4.41) for anti-HBc. The very low prevalence of these markers in people born after the beginning of mass vaccination (Fig. 2) may be an effect of this program, that in turn limits the transmission to susceptible contacts [20,21]. 4.2. Susceptibility The weighed prevalence of the susceptibility (absence of any serological markers) was 71.30% (95% CI 67.70–74.83); disaggregating this data by birth cohort, a tendency to reduced absence of markers was observed as of the beginning of 1992–1994, after the start of universal vaccination (Fig. 1). The absence of markers was higher than 80% in individuals 18 years or older (Table 2), that is mainly attributable to the fact of not having been included in the mass vaccination campaign. However, the absence of markers was also considerably higher in those 18 years or less (53.21%, 95% CI 46.53–59.70), which does not necessarily indicate lack of immunity in this group; in keeping with the usual standards [22,23], they were classified here as ‘‘susceptible” (Table 1), although most of them probably had immunological memory that would protect them in case of exposure to HBV (see below). 4.3. Vaccine immunity In this study, immunity by vaccination was detected in just a quarter of the population studied, although in the group aged 6– 17 years, this pattern reached 46.80%, thus about three and four times higher than in the 18–40 (15.50%) and 41–64 (11.24%) year-old groups, respectively (Supplementary Fig. 1S). We identified two factors that could have negatively influenced the achievement or persistence of such immunity: the high frequency of individuals with incomplete vaccination schedules among those who had such data and the decline of the anti-HB titer in the years following the primary vaccination. Of the 137 individuals with detailed immunization data, 58 (42.33%) had received only one or two doses. On the other hand, the trend towards a decrease in the titer of anti-HBs with the time that elapsed since the last dose (Fig. 3) argue in favor of a gradual loss of antibodies below the 10 mIU/mL limit. The prevalence of vaccine immunity estimated in this study is reliable given the high sensitivity and specificity of the tests used (>98.8% for HBsAg, 98% for anti-HBs [23,24] and 99.6% for antiHBc according to the manufacturer), but the data from the vaccine history, obtained only in about 10% of the individuals, are limited. Further studies are needed to understand factors that influence the low frequency of vaccine immunity and monitor the persistence of antibodies in this population. Although the duration of immunity conferred by the vaccine has not been definitively established, several studies in populations vaccinated more than 20 years earlier demonstrate the persistence of immunity despite the decreased levels of anti-HBs below 10 mIU/mL. This is demonstrated by the strong and rapid response to a booster dose characteristic of an anamnestic response [21]. The longest follow-up study published to date [25] shows the persistence of immune memory for up to 30 years. Moreover, anti-HBs is not a complete assessment of the immunity conferred by the vaccine, since cellular immunity response and memory is not evaluated in that test. Cellular immunity plays an important role, perhaps more decisive than the humoral response, in protection against HBV [1]. In the multinomial adjusted model among those younger than 18 years reporting vaccination against HB, high socioeconomic sta-
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Variables and categories
Age (years)
Gender Area of residence Hepatitis B vaccination Recent vaccination (any vaccine) Body-mass index (BMI)
Socioeconomic strata Medical procedures one month before serological test Home ownership Immunosuppressive drug use Disease one month before serological test Immunosuppressive disease Self-reported health status Effective sleep time
Education level Social security status Problems at home in the last year a b c
6–17 18–40a 41–64 Male Femalea Urbana Rural Reported Unreporteda Yes Noa Normala Overweight Obesity High (4, 5 and 6)a Low (1, 2 and 3) Yes Noa Own Rented or similara Yes Noa Yes Noa Yes Noa Good to very gooda Fair to poor <6 h 6–7 ha >7 h Complete elementary or highera None Insured Not-insureda Yes No
Susceptibilityc
Vaccine immunity
PP [95%CI] 53.21 81.39 79.86 69.22 73.42 71.13 76.22 53.22 73.90 69.69 75.71 68.03 74.21 84.02 64.60 72.52 75.61 71.12 67.90 76.01 45.61 71.80 69.10 75.61 70.79 68.90 71.40 72.30 79.60 72.05 69.49 73.72 62.82 70.64 76.25 73.26 70.73
[46.53–59.70] [76.81–85.33] [73.79–84.81] [63.42–74.53] [68.72–77.53] [67.13–74.78] [71.74–80.24] [41.33–64.83] [70.03–77.48] [65.20–73.70] [67.81–82.22] [62.94–72.73] [68.01–79.63] [74.53–90.45] [53.22–74.52] [68.51–76.28] [57.72–87.52] [67.27–74.71] [63.19–72.32] [69.91–81.30] [24.52–68.43] [68.07–75.32] [64.58–73.34] [69.70–80.70] [53.80–83.36] [64.31–73.10] [67.68–74.90] [60.11–81.91] [70.11–86.79] [63.30–79.41] [64.61–73.71] [69.42–77.60] [53.70–71.29] [66.63–74.33] [66.14–84.01] [67.46–78.39] [66.26–74.90]
Reference category for the difference of proportions. PP: Proportion of prevalence. 95% CI: 95% confidence interval. Prevalence estimated taking into account the complex design. Absence of any serological marker.
Isolated anti-HBc
Chronic infection
PP [95%CI]
Naturally acquired immunity PP [95%CI]
PP [95%CI]
PP [95%CI]
46.83 [40.32–53.51] 15.50 [11.91–20.03] 11.24 [7.43–16.84] 26.71 [21.66–32.54] 23.54 [19.55–28.16] 25.43 [21.84–29.35] 19.70 [16.18–23.99] 45.22 [33.61–57.34] 22.33 [19.03–26.01] 27.40 [23.42–31.92] 19.41 [13.83–26.91] 29.85 [25.23–34.83] 19.6 [14.93–25.45] 10.91 [5.54–20.60] 33.42 [23.46–45.27] 23.62 [20.02–27.53] 18.53 [8.01–37.02] 25.45 [22.00–29.21] 28.73 [24.34–33.54] 20.21 [15.11–26.51] 50.22 [28.03–72.44] 24.60 [21.27–28.48] 27.51 [23.32–32.23] 20.53 [15.76–26.49] 23.61 [12.28–40.77] 27.62 [23.22–32.52] 25.50 [22.12–29.12] 21.24 [12.44–33.93] 17.80 [11.03–27.52] 20.81 [14.82–28.53] 28.00 [23.79–32.78] 23.01 [19.31–27.29] 32.61 [24.81–41.63] 25.80 [22.16–29.88] 20.60 [13.31–30.50] 24.30 [19.30–30.31] 25.40 [21.41–29.81]
0.01 2.09 6.70 3.06 2.21 2.61 3.20 0.75 2.94 3.91 2.11 1.91 4.80 1.65 2.08 2.81 6.04 2.51 2.51 2.86 4.27 2.63 2.52 2.70 5.70 2.80 2.40 3.80 1.71 5.42 1.91 2.50 2.90 2.70 2.21 1.51 3.01
0.01 0.78 1.90 0.90 0.71 0.81 0.88 0.81 0.83 1.00 0.31 0.21 0.92 3.50 0 0.93 0 0.80 0.83 0.71 0 0.82 0.74 0.91 0 0.62 0.61 1.96 0 1.82 0.60 0.70 1.21 0.74 1.14 1.03 0.73
0 0.30 0.40 0.20 0.22 0.21 0.10 0 0.20 0.01 0.76 0.20 0.41 0.11 0 0.20 0 0.22 0.23 0.21 0 0.25 0.23 0.35 0 0.26 0.19 0.80 0.89 0 0.20 0.17 0.56 0.22 0 0.03 0.33
[0.00–0.04] [1.24–3.90] [4.11–10.89] [1.75–5.29] [1.38–3.78] [1.74–3.85] [2.12–5.03] [0.11–5.00] [2.07–4.12] [2.33–6.64] [1.24–3.64] [1.17–3.25] [2.63–8.90] [0.67–4.29] [0.81–5.14] [1.91–3.80] [1.52–20.50] [1.71–3.71] [1.56–4.00] [1.61–5.05] [0.71–21.30] [1.84–3.74] [1.53–4.23] [1.51–4.81] [1.45–20.24] [1.72–4.52] [1.65–3.63] [1.52–9.69] [0.71–4.50] [2.86–10.27] [1.18–3.21] [1.69–4.01] [1.41–5.80] [1.88–3.99] [0.52–9.33] [0.61–3.62] [2.00–4.41]
[0.00–0.06] [0.36–1.91] [0.71–5.05] [0.34–2.66] [0.35–1.67] [0.41–1.64] [0.41–1.91] [0.14–5.40] [0.40–1.79] [0.43–2.11] [0.14–0.98] [0.03–0.96] [0.21–4.33] [1.30–8.80] [0.58–1.91] [0.44–1.63] [0.30–2.21] [0.36–2.05] [0.42–1.61] [0.35–2.02] [0.31–2.38] [0.22–1.52] [0.32–1.41] [0.58–6.90] [0.79–4.78] [0.22–1.74] [0.31–1.53] [0.25–5.96] [0.34–1.64] [0.20–7.01] [0.33–3.45] [0.38–1.70]
[0.04–1.67] [0.13–2.28] [0.03–1.36] [0.03–1.20] [0.05–0.87] [0.02–0.80] [0.61–0.87] [0.00–0.02] [0.20–2.56] [0.02–1.16] [0.10–2.45] [0.01–0.43] [0.11–0.90] [0.10–0.83] [0.03–1.06] [0.03–1.6] [0.11–0.71] [0.02–1.08] [0.13–1.76] [0.16–1.04] [0.01–0.80] [0.11–4.50] [0.10–5.54] [0.11–0.90] [0.01–0.81] [0.16–3.20] [0.10–0.80] [0.01–0.28] [0.11–1.01]
D.A. Cadavid-Betancur et al. / Vaccine xxx (2017) xxx–xxx
Please cite this article in press as: Cadavid-Betancur DA et al. Seroprevalence of hepatitis B and factors potentially associated in a population-based study in Medellin, Colombia. Vaccine (2017), http://dx.doi.org/10.1016/j.vaccine.2017.07.084
Table 2 Distribution of the weighed prevalence of HBV serological status according to the variables studied. Medellin, 2009.b
D.A. Cadavid-Betancur et al. / Vaccine xxx (2017) xxx–xxx
5
Fig. 1. Weighed prevalence of susceptibility (absence of serological markers), immunity and infection (HBsAg carriers and isolated anti-HBc) to HBV according to year of birth. Medellín, 2009.
Fig. 2. Proportion of immunity due to vaccination against HBV and number of doses of vaccine given according to year of birth. Medellín, 2009; (n = 2077).
tus and possessing their own housing were identified as variables potentially associated with vaccine immunity (Table 3). Different studies have reported the positive association of being younger and vaccinated against HB with immunity in the population [8,26]. It is an expected consequence of the implementation of the vaccination program [27,28], as cohorts born between 6 and 17 years before initiation of universal vaccination should have greater access to vaccination. In a study conducted in Medellin in 1998 in individuals 1– 14 years old, seropositivity to anti-HBs was higher in individuals of high compared to low socioeconomic strata [26]. Accordingly, in this study, in the population aged 6–64 years, the possibility of
being immune through vaccination was significantly higher in the upper stratum compared to the lower stratum (RRR 2.08, 95% CI 1.16–3.72), which could also be related to access to vaccination. However, neither of these two studies were designed to be representative of socioeconomic strata and the samples were mainly from lower strata. This study found that obesity decreased the possibility of being immune by vaccination (RRR 0.40; 95% CI = 0.17–0.95). According to previous reports, obesity could have negative effects on humoral and cellular immune systems, by affecting T and B cell populations [29,30]. Particularly in HB, obesity may reduce the response to vaccination and contribute to the development of carcinomas in
Please cite this article in press as: Cadavid-Betancur DA et al. Seroprevalence of hepatitis B and factors potentially associated in a population-based study in Medellin, Colombia. Vaccine (2017), http://dx.doi.org/10.1016/j.vaccine.2017.07.084
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D.A. Cadavid-Betancur et al. / Vaccine xxx (2017) xxx–xxx
Fig. 3. Antibody titers against HBV surface antigen (anti-HBs) in individuals with three or more doses of vaccine based on the time between application of the last dose and serologic assessment. Medellin, 2009; (n = 79); Spearman’s Rho: 0.10.
infected individuals [1,31]. Although this effect was reported since 1985, with the application of plasma-derived HB vaccine [32], the mechanism is still unclear. In a study conducted in the USA in 2010 it was proposed that the length of the needle used for the application of the vaccine in obese adolescents could explain the lower response because the vaccine could have been deposited in the adipose tissue instead of in the muscle [33]. On the other hand, it is possible that obesity boosts liver damage and increases the risk of mortality in chronic HB since obese people are more likely to develop metabolic syndromes and fatty liver, which can lead to cirrhosis, liver cancer and death [34–36]. In any case, caution is required in interpreting the effect of obesity on vaccine immune response since it is not possible to establish the presence of obesity before the time of vaccination due to the cross-sectional design of this study. 4.4. Naturally acquired immunity Immunity from natural exposure was also relative to the absence of markers in multinomial regression, showing a positive association with age in individuals between 41 and 64 years, whereas individuals between 6 and 17 years and sleeping less than 6 h per day were inversely associated. Few studies have specifically reported an association between immunity acquired by natural exposure to HBV and age; a study conducted in Australia among intravenous drug users reported an increase in the probability of being immune by natural exposure with age [2]. In our study in the general population, this potential association may be due to more opportunities of exposure to the virus in the older, unvaccinated population. Other studies relating the presence of anti-HBc with age do not discriminate between individuals immune by natural infection and chronically infected. In a study in four regions of Colombia, Alvarado-Mora et al., reported an increased prevalence of antiHBc with age [6]. Also in other regions, it was observed that the prevalence of anti-HBc increased exponentially with age as occurred in a population-based study conducted in China in 2006, and another study performed in Amsterdam in 2004 [8,37]. In our study individuals who slept less than six hours had potentially a lower chance of being immune from natural exposure in comparison to those who slept 6–7 h per day and presented absence of markers (RRR 0.21, 95% CI 0.06–0.79), after adjusting
for other variables, including age and BMI, which might confuse this relationship although it is possible that this finding was the result of residual confounding by an additional, uncontrolled factor. The effect of the sleep time on the immune response to HB vaccination has been addressed in some studies, but no study has addressed its effects on the outcome of natural exposure to HBV. It has been postulated that acute or chronic sleep disturbances may be related to the risk of infectious diseases due to interference with immunological processes [38,39]. The effect of the duration of daily sleep on the immune response to HB vaccination has been addressed in some studies, but no study has addressed its effects on the outcome of natural exposure to HBV. In a study involving 125 women between 40 and 60 years of age, Prather et al., reported that sleeping less than 6 h a day confers a significant risk of not achieving vaccine protection against HBV, an effect independent of age, sex and BMI [10]. In a study in Beijing-China in 2009 and 2010, increased frequency of insomnia in patients diagnosed with chronic liver disease including HB, compared with a control group [40] was also reported. Additional studies are needed to understand the potential mechanisms underlying the relationship between sleep time and the development of both, natural and vaccine immunity to HBV, using standardized techniques to measure the amount and quality of sleep. This study is limited by the lack of data related to other important variables in the transmission of HB that were not included in the original survey such as occupational exposure, sexual risk behavior, intravenous drug use, performing tattoos, and piercings. Given the controversy over the usefulness of the booster dose in the routine schedule and the available data on the duration of vaccine immunity [41], additional vaccine doses are not indicated in this population. Instead, we recommend to set up mechanisms to complete the vaccination in children under five years and increase the coverage by overcoming the barriers present in the organization of the health service system. It is necessary to identify individuals with incomplete schemes as well as mechanisms reminding them of further scheduled doses and encouraging vaccination with strategies in agreement with the culture practices of the population and to increase health promotion policies aimed at improving living conditions, since other aspects besides vaccination practices, such as socioeconomic strata and obesity, could influence vaccine immunity.
Please cite this article in press as: Cadavid-Betancur DA et al. Seroprevalence of hepatitis B and factors potentially associated in a population-based study in Medellin, Colombia. Vaccine (2017), http://dx.doi.org/10.1016/j.vaccine.2017.07.084
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D.A. Cadavid-Betancur et al. / Vaccine xxx (2017) xxx–xxx Table 3 Multinomial logistic regression models for HBV serologic status. Medellín, 2009. Crude model
Natural immunity/susceptibility┼ Age group (years) 6–17 18–40 41–64 HBV vaccination reported No Yes Effective sleeping time (h) <6 6–7 >7 Body mass index (according to WHO) Normal Overweight Obesity Socioeconomic strata Low High Home ownership Rented or similar Own
Adjusted model
RRR
95%CI [SE]
RRR
95%CI [SE]
0.01*** 1 3.23**
0.00–0.03 [0.01]
0.00–0.03 [0.01]
1.39–7.52 [1.39]
0.01*** 1 3.52**
0.05–2.75 [0.01]
1 0.70
1 0.36 0.29 1 0.37*
0.08–1.00 [0.18]
1.62–7.70 [1.40]
0.09–5.29 [0.71] *
0.14–0.94 [0.18]
0.21 1 0.44
0.17–1.14 [0.21]
1 2.36 0.67
0.98–5.68 [1.05] 0.21–2.21 [0.41]
1 1.31 0.34
0.57–3.02 [0.56] 0.10–1.14 [0.21]
1 0.81
0.29–2.28 [0.43]
1 0.56
0.18–1.73 [0.32]
1 1.00
0.45–2.22 [0.41]
1 0.94
0.43–2.03 [0.37]
0.06–0.79 [0.02]
┼
Vaccine immunity/Susceptibility Age group (years) 6–17 18–40 41–64 HBV vaccination reported No Yes Effective sleeping time (h) <6 6–7 >7 Body mass index (according to WHO) Normal Overweight Obese Socioeconomic strata Low High Home ownership Rented or similar Own
4.63*** 1 0.74 1 2.82*** 1.40 1 0.78
0.42–1.31 [0.22]
4.48*** 1 0.804
1.66–4.78 [0.76]
1 2.00*
3.24–6.61 [0.84]
0.86–2.26 [0.34]
3.12–7.18 [0.90] 0.43–1.50 [0.26]
1.02–3.92 [0.69]
0.41–1.48 [0.26]
1.12 1 1.17
0.55–2.30 [0.41]
1 0.60* 0.30**
0.41–0.89 [0.12] 0.14–0.64 [0.12]
1 0.87 0.40*
0.52–1.44 [0.22] 0.17–0.95 [0.18]
1 1.59
0.92–2.74 [0.44]
1 2.08*
1.16–3.72 [0.62]
1 1.59*
1.04–2.42 [0.34]
1 1.56*
1.01–2.41 [0.34]
0.71–1.95 [0.30]
RRR: relative risk ratio estimated taking into account the complex design. CI: 95% confidence interval. SE: standard error. * p < 0.05. ** p < 0.01. *** p < 0.001. ┼ Reference category for the dependent variable. Absence of any serological marker.
Acknowledgement This study was supported by the Colombian Science, Technology and Innovation Administrative Department [Colciencias], the Fund for Teaching Support of the National School of Public Health, the Sustainability Strategy 2013-2014 and 2015-2016 for the Epidemiology and Immunovirology Research Groups of University of Antioquia, the Secretariat of Health of Medellin, and the Public Health Laboratory of the Secretariat of Health and Social Protection of Antioquia. Thanks to Dr. Anne-Lise Haenni, Université de Paris, Diderot, for her linguistic correction of the manuscript.
quia in session 107 of August 14, 2014; it was classified as ‘‘study of minimal risk” because it used secondary data. The study followed the national ethical rules for research with human beings (Resolution 8430 of 1993 of the Ministry of Health of Colombia); it was also in agreement with the Declaration of Helsinki guidelines. In children, informed consent was obtained and signed by parents or legal guardians. Chronically infected individuals and their cohabitants were studied in agreement with the guidelines of the Ministry of Health of Colombia; these patients were referred to the Secretariat of Health of Medellin for further studies and management.
Ethical considerations Conflicts of interests The project was reviewed and approved by the Ethics Committee of the National School of Public Health of the University of Antio-
The authors declare no conflict of interest.
Please cite this article in press as: Cadavid-Betancur DA et al. Seroprevalence of hepatitis B and factors potentially associated in a population-based study in Medellin, Colombia. Vaccine (2017), http://dx.doi.org/10.1016/j.vaccine.2017.07.084
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D.A. Cadavid-Betancur et al. / Vaccine xxx (2017) xxx–xxx
Appendix A. Supplementary material Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.vaccine.2017.07. 084.
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Please cite this article in press as: Cadavid-Betancur DA et al. Seroprevalence of hepatitis B and factors potentially associated in a population-based study in Medellin, Colombia. Vaccine (2017), http://dx.doi.org/10.1016/j.vaccine.2017.07.084