Chronic hepatitis B infection: A global disease requiring global strategies
Authors: George N. Ioannou
Journal: Hepatology (2013)

There has been a dramatic decline in the incidence of new hepatitis B virus (HBV) infections in the United States over the last 20 years.1 This was achieved partly through effective immunization. The immunization strategy in the U.S. has included for approximately the last 20 years the following components2: (1) routine vaccination of infants; (2) routine vaccination of adolescents who were not vaccinated as infants; (3) routine screening of pregnant women and appropriate postexposure immunoprophylaxis of infants born to hepatitis B surface antigen (HBsAg)-positive women; and (4) vaccination of adults at increased risk of infection. In addition to widespread vaccination, HBV transmission was reduced in the U.S. by limiting the exposure of susceptible persons to HBV by the following measures: (i) screening of donor blood and plasma derived products for HBsAg and viral inactivation procedures; (ii) adoption of safe sex practices; (iii) availability of needle exchange programs; and (iv) Implementation of universal precautions among laboratory and healthcare workers. These measures have reduced the incidence of new HBV infections in the U.S. and have led to a cohort of children and adolescents growing up with very high rates of immunity against HBV and very low rates of infection.3 Thus, if the U.S. was a "closed system," one would expect the prevalence of HBV infection in the U.S. to decline and be practically eradicated in the next few decades. This is unlikely to happen precisely because the U.S. is not a "closed system" due to the great impact of immigration. HBV is a truly global disease with an enormous worldwide reservoir of 350 million infected persons,4, 5 which far exceeds the worldwide reservoirs of HCV (∼150 million)6 and human immunodeficiency virus (HIV) (∼34 million).7 Two billion people, or one-third of the world's population, are estimated to have been exposed to HBV. Thus, while the incidence of new HBV infections has declined dramatically in the U.S., the prevalence of HBV has not changed much due to a dramatic increase in immigration into the U.S. from endemic (HBsAg-positive in ≥2%) and hyperendemic (HBsAg positive in ≥8%) countries over the last 50 years (Fig. 1). While in 1960 there were only 9.7 million foreign-born persons in the U.S. constituting 5.4% of the population, in 2010 there were 40.0 million foreign-born persons constituting 12.9% of the population (Fig. 1A).8 More important, foreign-born persons from endemic/hyperendemic countries constituted a negligible proportion of all foreign-born persons in 1960. However, by 2010 Asian and African countries with endemic or hyperendemic HBV were the countries of birth of 28% and 4%, respectively, of all foreign-born persons in the U.S. (Fig. 1B-D). Several studies have used estimates of HBV prevalence in the country or region of origin of foreign-born persons living in the U.S. together with estimates of their numbers to calculate how many foreign-born U.S. residents might be expected to have HBV infection. Weinbaum et al.9 estimated that out of 35,689,467 foreign-born U.S. residents in 2005, 939,416 (or 2.6%) had chronic HBV; Kowdley et al.10 estimated that out of 38,433,860 foreign-born U.S. residents in 2009, 1,324,693 had chronic HBV in 2009. These calculations critically depend on estimates of HBV infection prevalence in the country of origin, which may be inaccurate, and on the assumption that immigrants to the U.S. have a similar prevalence of HBV as that of their entire country of origin, which may be untrue. Nonetheless, these staggering estimates of foreign-born U.S. residents with HBV far exceed the number of U.S.-born residents with HBV estimated at 229,000-534,000.9 Thus, foreign-born persons from endemic and hyperendemic countries now constitute the majority of HBV-infected patients in the U.S. Looking at incidence rather than prevalence, and using similar methods based on estimates of HBV in the country of origin, Mitchell et al.11 calculated another thought-provoking statistic: U.S.-acquired new HBV infections had declined to 3,700 in 2006, while the estimated number of foreign-born persons with HBV infection who immigrated to the U.S. ("newly imported infections") in 2006 was 62,000: nearly 17 times the U.S.-acquired number. These studies suggest that the single most important measure to identify HBV-infected persons in the U.S. is to screen foreign-born persons from endemic or hyperendemic countries. Since 2008, the Centers for Disease Control and Prevention (CDC) has recommended HBsAg testing for all persons born in countries or regions with HBsAg prevalence of ≥2% (as well as men who have sex with men, injection-drug users, HIV-positive persons and household, needle-sharing or sex contacts of HBV-positive persons), referral of infected persons to care, and referral of close contacts for testing or vaccination.5 This was, in fact, an appropriate expansion of a previous CDC recommendation from 2005 to test persons from countries or regions with HBsAg prevalence ≥8%.12 It is important to note that although there are many countries with estimated HBsAg prevalence ≥2% (notably most Asian countries except Japan, most African countries, and some Eastern European countries), the majority of foreign-born persons with HBV in the U.S. were born in a small group of countries in East and Southeast Asia: China, Korea, the Philippines, Vietnam, Laos, and Cambodia.10 These countries have both high numbers of immigrants to the U.S. as well as high prevalence of HBsAg. It is equally important to point out that foreign-born Hispanics, who constitute the majority of foreign-born persons in the U.S., have an overall very low prevalence of HBsAg, well below 2% (except those from a selected small group of countries, e.g., Dominican Republic, Haiti, and Guatemala). This is especially true of foreign-born Mexican Americans, the single largest group of foreign-born persons in the U.S., who actually had a lower prevalence of HBsAg (0.026%) in nationally representative surveys than U.S.-born Americans (0.17%).3 It is unclear whether the 2008 CDC recommendations for screening and referral of foreign-born ethnic/racial groups from endemic and hyperendemic countries are followed. The Institute of Medicine estimates that up to 65% of persons living with HBV infection are unaware they are infected.13 In this issue of Hepatology, Hu et al. used data from the 2009-2010 Racial and Ethnic Approaches to Community Health (REACH US), Risk Factor Survey to investigate HBV testing and access to care among racial and ethnic minorities in the U.S.14 The REACH US Risk Factor Survey was conducted by the CDC in order to gather health-related information from 28 selected minority communities across the U.S. The survey consists of a questionnaire that was completed by 53,896 minority persons including 21,683 (40%) African Americans, 16,484 (31%) Hispanics, 9,972 (19%) Asian/Pacific Islanders (APIs), and 5,757 (11%) American Indian / Alaska Natives (AI/AN). The questionnaire included a dedicated "hepatitis" section. Overall, 39% reported having been tested for HBV with little difference between the highest group (42.5% among APIs) and the lowest group (35.5% among Hispanics). There was also little difference between foreign-born (40.3%) and U.S.-born (38.8%) respondents in the proportion who reported having been tested for HBV, with the exception of foreign-born APIs who reported being tested more frequently than U.S.-born APIs (48% versus 31%). The most striking finding is that persons with high risk for HBV (APIs and foreign-born) were reporting screening rates rather similar to persons with very low risk for HBV (Hispanics and U.S.-born), suggesting that providers are not aware of the great underlying differences in HBV risk or the CDC recommendations for screening. However, these results are difficult to interpret because self-reported results on HBV screening may be very inaccurate. In addition, we do not know about risk factors such as injection drug use, high-risk sexual behavior, or country of origin of foreign-born persons that determine whether screening for HBV is recommended. Among those who reported being tested, foreign-born persons reported higher rates of infection than U.S.-born persons (9.3% versus 4.2%), and APIs higher rates (13.5%) than Blacks (5%), Hispanics (5.4%) or AI/AN (4.3%), as expected. However, self-report is again a very serious limitation. These self-reported rates are many times higher than comparable rates of measured HBsAg-positive rates: for example, only 0.73% of blacks and 0.05% of Hispanics were HBsAg-positive in NHANES 1999-2008.3 Among those who reported having HBV infection, only 33% reported currently seeing a physician for HBV, with higher rates for foreign-born than U.S.-born (42% versus 24%), API than other racial groups (41% versus 19%-34%), and those with insurance than those without insurance (36% versus 21%). Assuming that persons with self-reported HBV truly had chronic HBV infection, these rates of physician follow-up for HBV are low among all racial/ethnic groups. The results reported by Hu et al. suggest that screening efforts need to be more targeted in accordance with CDC recommendations. Not all racial/ethnic "minorities" need to be screened and providers as well as communities need to be better educated. Specifically, Hispanics, who constitute the vast majority of foreign-born persons currently living in the U.S., have a very low prevalence of HBsAg and do not need to be routinely screened for HBV (with the possible exception of those born in Haiti, the Dominican Republic, Guatemala, and Jamaica). Instead, interventions are needed to reach out to, screen, vaccinate, and potentially treat foreign-born persons from East and Southeast Asia and Africa. In response to the Institute of Medicine recommendations, the Viral Hepatitis Action Plan was drafted by the Department of Health and Human Services, a 76-page document that proposes actions to improve viral hepatitis diagnosis, prevention, treatment, and care.15 Of particular relevance was the commitment to "provide resources for the expansion of community-based programs that provide hepatitis B screening, testing, and vaccination services that target foreign-born populations." Community-based programs that bring together the API community, healthcare systems, local government, and public health agencies can perform efficient, culturally appropriate outreach. Such innovative examples include the San Francisco Hep B Free campaign,16 the BfreeNYC campaign in New York City,17 and Stanford University's Jade Ribbon Campaign,18 which have enhanced HBV testing and provided treatment for patients who tested positive. These campaigns may serve as models that could be replicated in other appropriate cities or counties with large API communities, as in fact has already happened in the case of Hep B Free campaigns in Santa Clara County, Alameda County, San Mateo, San Diego, and Philadelphia. Universal screening and vaccination in refugee and immigrant health centers can also efficiently reach foreign-born U.S. residents and should ideally be linked to free or low-cost treatment options for patients who test positive. Foreign-born persons who apply for (adjustment of status to) permanent residency are required to have a "Report of Medical Examination and Vaccination Record" form (I-693) completed by a registered civil surgeon and submitted to the U.S. Citizenship and Immigration Services (USCIS). The aim is to establish absence of specific health conditions that make the applicant inadmissible to the U.S. on public health grounds (including tuberculosis, syphilis, and leprosy, but not HIV since 2010) and the presence of "age-appropriate" vaccinations. Although HBV is listed among the conditions requiring evidence of vaccination, it is not required in adults seeking permanent residency since in the U.S. routine vaccination of infants and catch-up vaccination of adolescents is recommended. Thus, a 25-year-old applicant from China or Vietnam is required to have diphtheria, tetanus, and pertussis vaccination but not HBV vaccination. I think that testing for HBV and providing evidence of vaccination should become a requirement for all applicants for permanent residency irrespective of age. This could be implemented within the existing forms, regulations, and infrastructure of the USCIS and is probably the most efficient way to implement universal screening and vaccination of new, foreign-born persons legally immigrating to the U.S. (although it would not of course affect undocumented immigrants or those who have already obtained permanent residency). It would be of great benefit to U.S. immigrants themselves and their communities, as well as to U.S.-born citizens. Testing positive for HBV should not be grounds for inadmissibility to the U.S. Finally, the face of HBV in the U.S. in the next few decades depends as much on vaccination practices in endemic and hyperendemic countries as it does on actions taken within the U.S. In 1992 the World Health Organization recommended that all countries include HBV vaccination in their routine infant immunization programs. The number of countries with a universal infant HBV vaccination policy increased from 31 in 1992 to 116 in 20002 to 179 out of 215 countries in 2010.4 Global HBV vaccine coverage is estimated at 75% and has reached 91% in the Western Pacific Region and 89% in the American Region but is only 52% in the Southeast Asian Region.19, 20 Thus, despite the availability of an effective vaccine for 30 years a significant proportion the world's children remain at risk for HBV infection, particularly in endemic countries. The cornerstone of HBV control will remain universal vaccination. HBV will continue to be a major problem in the U.S. as long as there is an influx of HBV-infected cases from countries without effective universal vaccination. George N. Ioannou, BMBCh, M.S.1-3 1Research and Development Veterans Affairs Puget Sound Health Care System Seattle, WA 2Division of Gastroenterology Department of Medicine Veterans Affairs Puget Sound Health Care System Seattle, WA 3Division of Gastroenterology Department of Medicine University of Washington Seattle, WA