Changing epidemiology of hepatitis B in a U.S. community
Despite a reduction in newly acquired hepatitis B virus (HBV) infections since the mid-1980s, HBV remains an important cause of liver disease in the U.S. We report the prevalence of chronic HBV infection in a U.S. community and describe demographic and clinical characteristics. The Rochester Epidemiology Project records healthcare encounters of residents of Olmsted County, Minnesota. For all cases with a potential diagnosis of hepatitis B in this database, complete medical records were reviewed to identify subjects who met the inclusion criteria, i.e., a clinician diagnosis of chronic HBV infection and a laboratory record of positive hepatitis B surface antigen (HBsAg). There were 191 residents with chronic HBV infection in the community, consisting of 53% Asian, 29% African, 13% Caucasian, and 5% other or unknown race. The overall age- and sex-adjusted prevalence of HBV in this community was 0.15% in 2000. The race-specific prevalence was highest among Asians (2.1%), followed by African Americans (1.9%). The prevalence among Caucasians was 0.02%. Overall, 86% were born outside the U.S., 98% of whom were non-Caucasian. A total of 131 residents were tested for HBV replicative status, of whom 27% had viral replication. Of those tested for aminotransferases (n = 184), 28% had an abnormal value at least once. In a multivariable regression analysis, replicative status was the most influential (odds ratio [OR] = 5.98, P < .01) factor associated with abnormal aminotransferase values, followed by male gender (OR = 3.69) and age greater than 40 years (OR = 2.32 per decade). In conclusion, in this Midwestern community, chronic HBV infection was predominantly seen in immigrants from endemic parts of the world. (HEPATOLOGY 2004;39;811–816.)
According to the Centers for Disease Control and Prevention, the incidence of newly acquired hepatitis B virus (HBV) infection in the U.S. has declined steadily since the mid-1980s.1–3 This trend has been attributed to a number of public health interventions such as screening of pregnant women and vaccination of infants and adolescents, as well as safe injection practices in general.4 While reduction in the incidence of new infections is expected to reduce and eventually eliminate the pool of individuals for endogenous transmission, the prevalence of chronic hepatitis B has yet to show a decrease. Indeed, in a comparison of the second and third National Health and Nutrition Examination Surveys (NHANES), hepatitis B surface antigen (HBsAg) was found in 0.3% of the population from the former survey (NHANES II, 1976–1980) and in 0.4% of the latter (NHANES III, 1988–1994).5 While these figures may not appear strikingly high, the prevalence of HBV infection (HBsAg+) was approximately one-third of that of hepatitis C infections (HCV-RNA+) in the NHANES-III sample (1.3%). In both NHANES samples, however, there was wide variability in the prevalence of HBV by race and ethnicity. For example, the prevalence of antibodies against HBV core antigen (anti-HBc) was lowest among non-Hispanic Whites (2.6%), followed by Mexican-Americans (4.4%), and non-Hispanic Blacks (11.9%). Furthermore, as NHANES III included statistically valid samples only of Whites, Blacks, and Mexican Americans, the overall prevalence data do not address other racial groups, such as Asian-Pacific Islanders, in whom HBV infection is most commonly seen.
In this study, we analyzed the demographic and clinical characteristics of subjects with chronic HBV infection in Olmsted County, Minnesota. Our overall hypothesis was that the epidemiology of HBV in this Midwestern community is substantially influenced by prevalent cases immigrating from endemic countries. Our community has seen a strong influx of immigrants from Southeast Asia and Africa in recent years, so that the proportion of the population that is non-White doubled from 4.3% to 9.7% between 1990 and 2000.6, 7 The aims of this work included 1) identification of all prevalent cases diagnosed with chronic HBV infection in the community; 2) determining the prevalence of diagnosed chronic HBV infection in the community; and 3) describing the demographic and clinical characteristics of community residents with chronic HBV infection. We present data that provide a snapshot of the epidemiology of HBV in this Midwestern community in which chronic HBV infection is a disease predominantly of immigrants from endemic countries.
Materials and Methods
Population-based epidemiologic research can be conducted in Olmsted County because medical care is virtually self-contained within the community and there are only a limited number of healthcare providers that serve the population. For example, most specialty care (e.g., treatment for viral hepatitis or liver transplantation) is provided by the Mayo Clinic, which has maintained a common medical record system with its two affiliated hospitals for over 90 years.8 The diagnoses and surgical procedures recorded in these records are indexed in a computerized database. The Rochester Epidemiology Project (REP) indexes the medical records of other providers in the community, most notably the Olmsted Medical Center with its affiliated hospital.9 In this database, at least one healthcare encounter is recorded for 95% of County residents in any 3-year period. In addition, in Olmsted County serologic testing for viral hepatitis is performed only at Mayo Clinic laboratories, which allows convenient capture of all community residents with viral markers for HBV infection.
Following approval by Mayo's Institutional Review Board, we used the REP database to identify all Olmsted County residents with any diagnosis of hepatitis B. In addition, we screened records at the hepatitis serology laboratories to identify local residents who had ever tested positive for HBsAg.
For the potential cases thus identified, we reviewed their complete (inpatient and outpatient) medical records in the community to verify the following eligibility criteria: The subject 1) was seen by a healthcare provider and was given a diagnosis of chronic HBV infection at any time between 1994 and 2000; 2) had a verifiable record of having tested positive for HBsAg; and 3) was a resident of Olmsted County in 2000. The 1994–2000 time frame for the case ascertainment was chosen because complete electronic data were available for the REP and hepatitis serology laboratory databases for that period of time.
During the study period, the following techniques were used for detection of hepatitis B markers in our clinical laboratories. HBsAg was detected by the Abbott (Abbott Park, IL) EIA method (AUSZYME®), HBeAg and anti-HBe by the DiaSorin (Stillwater, MN) EIA method (ETI-EBK Plus® and ETI-AB-EBK Plus®, respectively), and HBV DNA by the Digene's (Gaithersburg, MD) Hybrid Capture II® assay. Aminotransferase levels (AST and ALT) were measured by standard laboratory methods using a Roche Hitachi 747-200 Chemistry Analyzer (Roche Diagnostics, Indianapolis, IN).
In patients who met the eligibility criteria, detailed demographic, clinical, and laboratory data were collected by reviewing all medical records in the community using a standard data form. Because of the racial and ethnic difference in hepatitis B prevalence in general, we collected information about race, ethnicity, and place of birth. In subjects who had been born outside the U.S., the country of origin was also noted. Clinical data including viral replication status, hepatic decompensation, hepatocellular carcinoma, and specific antiviral treatment were also recorded.
Since the denominator population is known, we were able to calculate the prevalence of known hepatitis B in the community. In this calculation, the entire population of Olmsted County was considered to be at risk, and was stratified by age, gender, and race according to Census 2000 data for the county.10 In order to obtain some sense of variability, it was assumed that, given a fixed number of persons, the number of prevalent cases follows a Poisson distribution.11 This allowed for the estimation of standard errors, calculation of 95% confidence intervals (95% CI), and comparison of the prevalence estimates across, age, gender, and racial categories. The overall prevalence rate was age- and sex-adjusted to the population structure of the United States in 2000.
Standard methods were used for descriptive analyses of the demographic and clinical characteristics of the prevalent cases, including the chi-square and Kruskal-Wallis tests for comparison among groups. Multivariable logistic regression analysis was performed to identify factors associated with an abnormal transaminase level. Explanatory variables included age, gender, race, immigrant status, and viral replication status. After examining the full model (all explanatory variables considered), we constructed the final model by the backward elimination method. Odds ratios (OR) and 95% CI were obtained.
One hundred ninety-one residents in the community met the inclusion criteria for the study, e.g., had at least one healthcare encounter with a diagnosis of chronic HBV infection with a verifiable record of positive serum HBsAg between 1994 and 2000 and resided in Olmsted County in 2000. The overall racial composition of these individuals included 53% Asian, 29% African, 13% Caucasian, and 5% other or unknown race (Table 1).
Table 1. Prevalence of Documented Chronic HBV Infection by Race in Olmsted County, Minnesota, in 2000
|n (denominator population)||112,255||3,330||5,346||3,346||124,277|
|Age-specific prevalence (per 100,000)|
|Gender-specific prevalence (per 100,000)|
|Age- and gender-adjusted prevalence|
| Per 100,000||22||1,863||2,123||350||152|
| [95% confidence interval]||[13–30]||[1,249–2,476]||[1,668–2,578]||[84–615]||[130–174]|
Based on the 2000 census of the county, the overall age- and sex-adjusted prevalence of known chronic HBV infection in Olmsted County was 0.2% (152 per 100,000, 95% CI 130–174). Race-specific prevalence was highest among Asians (2.1%), followed by Africans (1.9%), other (0.4%), and Caucasian (0.02%). Age-specific prevalence was the highest among Asians over 50 years of age (3.1%) and was generally lower among people less than 30 years than their older counterparts. Overall, HBV was more common among men than women (Table 1). The pattern of age-specific prevalence of HBV was different across racial groups in that among Whites and Asians the prevalence increased with age, whereas among Africans and others the prevalence peaked in the 30–49-year group and then decreased (P < .05 for interactions between race and age groups, Poisson regression model). There was no difference in gender-specific prevalence across the racial categories.
The mean (±SD) age of the 191 subjects was 34.1 ± 14.9 years and 58% were male. On average, Caucasian residents with hepatitis B were older than their non-Caucasian counterparts (Table 2). Overall, 86% of those with chronic HBV infection (n = 164) had been born outside the United States. The vast majority of non-Caucasian residents were immigrants, including 91% of Africans, 99% of Asians, and 100% of those of other/unknown race. The country of origin of the immigrants was as follows: Somalia (26%), Vietnam (18%), Cambodia (18%), China (10%), Laos (8%), all other countries (16%), and unspecified (5%). There was no significant difference in gender ratios across race or immigrant status.
Table 2. Comparison of Characteristics of Olmsted County, MN, Residents With Chronic HBV Infection by Race in 2000
|HBeAg or DNA+||25%||10%||35%||25%|
Diagnostic investigations performed in our patients included AST (94%), ALT (78%), total bilirubin (84%), albumin (54%), HBeAg (66%), anti-HBe (65%), and HBV-DNA (40%). Of those who had AST or ALT tested (n = 184, 94%), 53 (28%) had an abnormal value at least once. Of the remaining 131 residents who did not have abnormal transaminase values, 69 (38% of 184) had two or more normal values over observation times longer than 6 months. A total of 15 (8%) underwent a liver biopsy, which showed histologic features that were considered diagnostic (n = 1) or consistent (n = 9) with hepatitis B. Four patients (2%) were HIV positive and another four (2%) had hepatitis C, in addition to hepatitis B.
A total of 131 residents were tested for HBV replicative status, by either HBeAg (n = 126) and/or HBV-DNA (n = 76). Of these, 36 (27%) had evidence of viral replication, being positive for either HBeAg or HBV-DNA. Patients with replicative disease were mostly under 40 years of age (92%, mean age = 25.6 ± 14.0 years). A higher proportion of Asians (39%) had replicative disease than whites (23%) or Africans (8%) (P < .01). Only two patients (2.8% of 71 who were tested for both HBeAg and HBV-DNA) had a profile consistent with the so-called precore variant (HBV-DNA+, HBeAg-, and anti-HBe+).
Further analyses were performed to explore associations between demographic factors, abnormal transaminase values, and HBV replicative status. Patients with replicative disease were more likely to have abnormal transaminase than those with nonreplicative disease (50% vs. 17%, P < .01). In fact, in the multivariable logistic regression analysis, replicative status was the most influential factor (OR = 5.98, P < .01) associated with abnormal transaminase values (Table 3). After adjusting for replication status and multiplicity of laboratory values, age beyond 40 years (OR = 2.32 per decade) and male gender (OR = 3.69) were significant. By contrast, race and immigrant status appeared to have no impact on transaminase values.
Table 3. Factors Associated With Abnormal Transaminase Levels Among Olmsted County, MN, Residents With Chronic HBV Infection in 2000
|Age|| || || || |
| Age less than 20||1.43||0.52–3.96||—|| |
| Age 40 or older||2.38||1.43–3.98||2.32||1.43–3.78|
| Ages 20–39 (reference)||1||—||1|| |
|Race|| || || || |
| Black||0.77||0.14–4.15||—|| |
| Asian||0.69||0.12–3.85||—|| |
| Other race||1.64||0.15–18.05||—|| |
| White (reference)||1||—||1|| |
|Replication status|| || || || |
| Unknown status||2.20||0.85–5.66||—|| |
| Nonreplicative (reference)||1||—||1|| |
|Multiple lab data*||0.37||0.16–0.85||0.29||0.13–0.63|
As of 2000, only 8 of the 191 patients had ever received antiviral therapy, which was exclusively with lamivudine. To date, 17 patients (9%) have experienced complications of chronic hepatitis B, including ascites (n = 6, 3%), variceal bleeding (n = 4, 2%), hepatic encephalopathy (n = 1, 0.5%), and hepatocellular carcinoma (n = 12, 6%). Hepatocellular carcinoma was seen in all race groups (2 Caucasian, 1 African, 8 Asian, and 1 other). Two of the patients with carcinoma were diagnosed because of symptoms, whereas hepatocellular carcinoma was found in the course of screening or initial diagnostic investigation in the remaining 10 patients.
Our data show that chronic HBV infection in this Midwestern community was predominantly a condition of immigrants from endemic countries. According to data from the Bureau of Citizenship and Immigration Service, the fastest-growing immigrant populations in the past two decades have been from Central and South America, Asia, and Africa.12 Many of these countries are endemic to hepatitis B, with a population prevalence greater than 8%.13, 14 Thus, the observation made in this study may not be unique to this community and, on a national scale, the influx of prevalent cases from endemic countries may be an important element in hepatitis B epidemiology currently and in the foreseeable future.
In this community, the overall age- and sex-adjusted prevalence of known HBsAg prevalence was 0.15%, approximately one-third of the national average of 0.42% reported from the NHANES III samples. The NHANES study was based on screening of all study participants, whereas this study only included community residents who had clinical indications to be tested for and were given a diagnosis of chronic HBV infection. Although NHANES did not have representative samples of Asians or foreign-born residents, our data suggest that many Olmsted County residents who have the infection are yet to be diagnosed.
The contrast in the prevalence between the White and non-White populations is striking in that chronic HBV infection was ∼100 times more common among the latter than the former. We also saw differences in the pattern of age-specific prevalence of chronic HBV infection in that the prevalences were higher among 30–49-year-olds for African and other races. While there may be important biologic mechanisms behind this observation, we suspect this simply reflects the fact that the two latter racial groups represent more recent immigrants. As people with chronic hepatitis B typically develop liver-related morbidities in their fifth decade and later, those who were able to immigrate in their 50s and older may represent a healthier (lower prevalence) subgroup of the originating population.
Given the strong association between race and chronic HBV infection prevalence, it is likely that focused screening, e.g., among non-White residents, may uncover a substantial number of individuals with heretofore-undiagnosed hepatitis B. This is especially important for recent immigrants, whose access to healthcare tends to be limited.6, 7, 15 Screening in these residents for HBV is important not only for identifying those at risk of developing long-term consequences of chronic HBV infection, particularly hepatocellular carcinoma, but also for developing opportunities to vaccinate susceptible contacts to prevent further transmission.
There were intriguing differences in clinical characteristics across racial categories. For example, non-White patients were younger than Whites, whereas Asians had a higher likelihood of being in a replicative phase of HBV infection. This may reflect differences in the epidemiology of HBV infection, such as mode of transmission (perinatal vs. adulthood) or viral characteristics (genotypes, HBe-negative variants) in these groups and do not necessarily represent biologic differences among races. Indeed, in our multivariable analysis looking for factors associated with abnormal transaminase levels, race was not an important factor, once viral replication, age (over 40 years), and male gender were taken into account.
There are limitations to this study. First, a large proportion of our patients did not undergo appropriate evaluation or follow-up subsequent to their diagnosis, limiting our ability to understand our patients' status and natural history in detail. Only approximately one-half underwent what would be viewed by hepatologists as adequate evaluation for chronic hepatitis B infection, such as HBeAg or HBV-DNA status or biochemical parameters of hepatic synthetic function, which may be attributable to the fact that the majority of these unselected patients from the community were seen by generalists, and not referred for specialty consultation, and that the majority of patients had normal hepatic enzyme levels. Second, even among those with an abnormal transaminase level, only a minority underwent a liver biopsy or antiviral treatment. A similar trend was seen in our previous study of community residents with hepatitis C.16 Hepatic decompensation was relatively uncommon among this population of community residents. However, 6% of our prevalent cases had hepatocellular carcinoma initially or during subsequent follow-up. Given that many of our patients have had HBV infection presumably from early childhood, it is likely that the proportion with carcinoma will increase over time.
Finally, it may be worthwhile to comment briefly on the generalizability of our data. This community still consists of a relatively small proportion of non-Caucasian subjects, with ∼90% of the population being Whites. While this tends to reduce the overall prevalence of HBV measured in this community, it is likely that the main findings in this study hold true in most parts of the country, i.e., that chronic HBV infection is very common among recent immigrants from endemic countries and that it is probable that many patients in the community have not yet been diagnosed, One peculiar aspect of our population was that the majority of Africans with HBV were immigrants themselves from Somalia, so these data will not be generalizable to the majority of native-born African-Americans in the U.S. Second, Olmsted County is different from most communities in that healthcare delivery is concentrated to a few providers, including the Mayo Clinic, from which hepatology expertise is readily available. While this has no impact on the epidemiology of HBV per se, the observation that only a minority of patients underwent complete evaluation, treatment, and regular follow-up suggests that the situation may be worse in other communities.
In conclusion, in this community, chronic HBV infection was predominantly seen in immigrants of non-White race from endemic parts of the world. Based on these data, it is likely that targeted screening of a high-risk population will be effective in identifying subjects who may be at a risk of complications of long-term HBV infection such as hepatocellular carcinoma, as well as susceptible individuals who are at risk of transmission and thus most likely to benefit from vaccination.