Effectiveness and impact of the hepatitis B vaccination program in preadolescents in Catalonia 21 years after its introduction

Hepatitis B is a viral disease of global importance. In Catalonia in the 1980s, the seroepidemiological pattern of HBV infection was low-intermediate. In 1990, the Expert Committee on Vaccinations of the Department of Health of the Generalitat of Catalonia evaluated the systematic introduction of hepatitis B vaccination in preadolescents, maintaining the vaccination of risk groups. The objective of this study was to estimate the effectiveness and impact of the systematic hepatitis B vaccination programme in preadolescents in Catalonia 21 years after its introduction. A retrospective cohort study was conducted, comparing the disease incidence in vaccinated and unvaccinated cohorts. Cases of hepatitis B were defined as those reported by the General Subdirectorate of Surveillance and Response to Public Health Emergencies between 2000 and 2014. The incidence rate was 2.5 per 100,000 persons in 1991 and 1.2 per 100,000 persons in 2014, a reduction of 52%. During the study period, 388 cases of hepatitis B infection were notified, of which three were classified as vaccine failures. Vaccine effectiveness was 99.30% (95% CI: 97.83–99.78) and the population prevented fraction in the cohorts of preadolescents studied was 64.56% (95% CI: 60.45–68.66). The effectiveness and impact of the hepatitis B vaccination program in preadolescents in Catalonia is high, with the consequent benefits for the population.     

Substantial decline in hepatitis B virus infections following vaccine introduction in Tajikistan

BackgroundTajikistan, considered highly endemic area for hepatitis B virus (HBV) in a pre-vaccine era, introduced hepatitis B vaccine in 2002 and reported ≥80% coverage with three doses of hepatitis B vaccine (HepB3) since 2004. However, the impact of vaccine introduction has not been assessed.MethodsWe tested residual serum specimens from a 2010 national serosurvey for vaccine-preventable diseases in Tajikistan and assessed the prevalence of HBV infection across groups defined based on the birth cohorts’ routine infant hepatitis B vaccination program implementation and HepB3 coverage achieved (≥80% versus <80%). Serosurvey participants were selected through stratified multi-stage cluster sampling among residents of all regions of Tajikistan aged 1–24 years. All specimens were tested for antibodies against HBV core antigen (anti-HBc) and those found positive were tested for HBV surface antigen (HBsAg). Seroprevalence and 95% confidence intervals were calculated and compared across subgroups using Satterthwaite-adjusted chi-square tests, accounting for the survey design and sampling weights.ResultsA total of 2188 samples were tested. Prevalence of HBV infection markers was lowest among cohorts with ≥80% HepB3 coverage (ages, 1–6 years): 2.1% (95% confidence interval, 1.1–4.3%) for anti-HBc, 0.4% (0.1–1.3%) for HBsAg, followed by 7.2% (4.1–12.4%) for anti-HBc and 2.1% (0.7–6.1%) for HBsAg among cohorts with <80% HepB3 coverage (ages, 7–8 years), by 12.0% (8.7–16.3%) for anti-HBc and 3.5% (2.2–5.6%) for HBsAg among children's cohorts not targeted for vaccination (ages, 9–14 years), and 28.9% (24.5–33.8%) for anti-HBc and 6.8% (4.5–10.1%) for HBsAg among unvaccinated adult cohorts (ages, 15–24 years). Differences across groups were significant (p < 0.001, chi-square) for both markers.ConclusionsThe present study demonstrates substantial impact of hepatitis B vaccine introduction on reducing HBV infections in Tajikistan. To achieve further progress in hepatitis B control, Tajikistan should maintain high routine coverage with hepatitis B vaccine, including birth dose.     

Trend in incidence of hepatitis B virus infection during a decade of universal childhood hepatitis B vaccination in Saudi Arabia

Since 1990, the national strategy to eliminate hepatitis B virus (HBV) infection in Saudi Arabia has included universal administration of HBV vaccine to all infants. From 1990 to 1995 this vaccine was also routinely administered to children at school entry. The prevalence of hepatitis B surface antigen (HBsAg) among children before this programme was reported to be 6.7%. The objective of this study was to describe the trend in incidence of HBV infection over a decade of surveillance following the introduction of this programme. From January 1990 to December 1999 a total of 30,784 cases of HBV infection (positive for HBsAg) were reported. The total number of HBV infections among children <15 years of age was 4180 cases, with a prevalence of 0.05%. The total number of HBV infections among adults was 26,604 cases, with a prevalence of 0.22%. The prevalence varied by region, ranging from 0.03% to 0.72% with a mean prevalence of 0.15%. There was a clear decline in incidence among children whereas the incidence in adults slightly rose, perhaps owing to population growth estimated to be 3.3% annually. This study showed that the universal childhood HBV vaccination programme had an enormous positive impact on HBsAg seroprevalence among children in Saudi Arabia.     

Hepatitis B virus infection in northern Uganda: Impact of pentavalent hepatitis B vaccination

Chronic hepatitis B virus infection (CHBI) is effectively prevented by vaccination starting at birth. Beginning in 2002 Uganda adopted a policy of providing the pentavalent hepatitis B vaccine starting at 6 weeks of age. However, there is concern that this delay may leave the infant vulnerable to infection during the first 6 weeks of life. We assessed whether vaccination at 6 weeks was an effective strategy by HBV serologic study. Of 656 persons tested for HBV, 9.4% were chronically infected; among children aged 5–9 years the prevalence was 7.6%. Of all tested, 73 were born (i.e., aged ≤4 years) after the introduction of the pentavalent vaccine; none were infected with HBV (p = 0.003). In this study, vaccination with the pentavalent vaccine at 6 weeks did not result in CHBI, but rather provides an opportunity to prevent mother-to-infant transmission of HBV infection where there is no access to birth-dose vaccine.     

Prevalence of hepatitis B markers in the population of catalonia (Spain). Rationale for universal vaccination of adolescents

The prevalence of hepatitis B markers was determined in a representative sample of the general population of Catalonia (Spain). HBsAg was found in 0.5% of children (less than 15 years of age) and in 1.7% of adults (more than 15 years of age), and anti HBs in 1.6% and 18%, respecitvely. Age-specific prevalence for both markers showed a low risk for hepatitis B before puberty, and a progressive rise since adolescence, suggesting that perinatal transmission and horizontal transmission in children are relatively uncommon in Spain. Prevalence of hepatitis B markers was significantly higher among subjects with low education level, residing in an urban area and born outside Catalonia, but in the stratified analysis, a statistical significant difference was only maintained in the prevalence of HBV markers between those who live in urban and rural areas, and between those who were born outside Catalonia and in Catalonia. These data may be used as a basis for a strategy of hepatitis B prevention in Spain which include universal vaccination of adolescents, passive-active immunization of newborns to HBsAg positive mothers and vaccination of susceptible adults subjects from high-risk groups.Preventive Medicine Unit.Liver Unit.Corresponding author.     

Probabilistic cost-effectiveness analysis of the long-term effect of universal hepatitis B vaccination: An experience from Taiwan with high hepatitis B virus infection and Hepatitis B e Antigen positive prevalence

Aim

To assess cost-effectiveness of hepatitis B virus (HBV) vaccination strategies from health care payer and societal perspectives, focusing on the long-term effect, in Taiwan where prevalence of HBV and Hepatitis B e Antigen (HBeAg) is high.

Methods

A decision analysis was performed to compare total costs and effectiveness between two vaccination strategies: universal vaccination and no-vaccination. The Markov process was defined as a series of states including acute HBV infection, asymptomatic carrier, chronic hepatitis, compensated and decompensated liver cirrhosis, hepatoma, and death. Direct and indirect costs were also imputed based on estimates. The incremental cost-effectiveness ratio (ICER) per life-year gained and quality-adjusted life years gained were calculated at a 3% discount rate. By assigning a series of specific distributions to each parameter, a probabilistic cost-effective analysis using Monte Carlo simulation was conducted to yield 5000 ICER replicates.

Results

The effectiveness of a universal vaccination program for reducing hepatocellular carcinoma cases and deaths was approximately 86%. The average life years gained per subject as a result of such a universal vaccination was 3.9. The vaccination program dominated over a no-vaccination program (less cost and more effectiveness).

Conclusions

A universal vaccination program against hepatitis B infection is not only effective for reducing long-term sequelae but is also a cost-saving primary preventive strategy, which supports a universal infant immunization in endemic area with high prevalence of HBV and HBeAg.     

Hepatitis B virus infection and vaccine-induced immunity in Madrid (Spain)

ObjectiveTo estimate the prevalence of hepatitis B virus (HBV) infection and vaccine-induced immunity in the region of Madrid, and to analyze their evolution over time.MethodsAn observational, analytical, cross-sectional study was carried out in the population aged 16–80 years between 2008 and 2009. This was the last of four seroprevalence surveys in the region of Madrid. The prevalence of HBV infection and vaccine-induced immunity was estimated using multivariate logistic models and were compared with the prevalences in the 1989, 1993 and 1999 surveys.ResultsIn the population aged 16–80 years, the prevalence of HBV infection was 11.0% (95% CI: 9.8–12.3) and that of chronic infection was 0.7% (95% CI: 0.5–1.1). The prevalence of vaccine-induced immunity in the population aged 16–20 years was 73.0% (95% CI: 70.0–76.0). Compared with previous surveys, there was a decrease in the prevalence of HBV infection.ConclusionsBased on the prevalence of chronic infection (<1%), Madrid is a region with low HBV endemicity. Preventive strategies against HBV should especially target the immigrant population.     

Hepatitis B vaccination of relatives of hepatitis B virus DNA positive carriers: An experience with plasma-derived vaccine

We assessed in a western population the efficacy of a plasma-derived hepatitis B vaccine in relatives of highly infectious hepatitis B virus (HBV) carriers. A consecutive group of 103 HbsAg, anti-HBs and anti-HBc negative household relatives of 45 HBV-DNA positive chronic carriers received a 5 pg dose of plasma-derived vaccine at 0, 1, 2 and 12 months. Protective levels of immunity developed in 101 subjects (97.8%) 3 months after boosting. Low responders to the vaccine were mostly found among parents and spouses of carriers, whilst offspring and siblings were usually high responders. The main discriminant in predicting a good response was age below 12 years. Hyporesponsiveness did not occur in family clusters. No major HBV events occurred among immunized relatives patients. Hepatitis B vaccine is safe and effective in immunizing relatives of HBV carriers while no genetic conditioning of the immune response is evident among them.Corresponding author.     

A reduction in chronic hepatitis B virus infection prevalence among children in Vietnam demonstrates the importance of vaccination

Background

Vietnam has high endemic hepatitis B virus infection with >8% of adults estimated to have chronic infection. Hepatitis B vaccine was first introduced in the national childhood immunization program in 1997 in high-risk areas, expanded nationwide in 2002, and included birth dose vaccination in 2003. This survey aimed to assess the impact of Vietnam's vaccination programme by estimating the prevalence of hepatitis B surface antigen (HBsAg) among children born during 2000–2008.

Methods

This nationally representative cross-sectional survey sampled children based on a stratified three-stage cluster design. Demographic and vaccination data were collected along with a whole blood specimen that was collected and interpreted in the field with a point-of-care HBsAg test.

Results

A total of 6,949 children were included in the survey analyses. The overall HBsAg prevalence among surveyed children was 2.70% (95% confidence interval (CI): 2.20–3.30). However, HBsAg prevalence was significantly higher among children born in 2000–2003 (3.64%) compared to children born 2007–2008 (1.64%) (prevalence ratio (PR: 2.22, CI 1.55–3.18)). Among all children included in the survey, unadjusted HBsAg prevalence among children with ≥3 doses of hepatitis B vaccine including a birth dose (1.75%) was significantly lower than among children with ≥3 doses of hepatitis B vaccine but lacked a birth dose (2.98%) (PR: 1.71, CI: 1.00–2.91) and significantly lower than among unvaccinated children (3.47%) (PR: 1.99, CI: 1.15–3.45). Infants receiving hepatitis B vaccine >7 days after birth had significantly higher HBsAg prevalence (3.20%) than those vaccinated 0-1 day after birth (1.52%) (PR: 2.09, CI: 1.27–3.46).

Conclusion

Childhood chronic HBV infection prevalence has been markedly reduced in Vietnam due to vaccination. Further strengthening of timely birth dose vaccination will be important for reducing chronic HBV infection prevalence of under 5 children to <1%, a national and Western Pacific regional hepatitis B control goal.     

Global epidemiology of hepatitis B virus infection: new estimates of age-specific HBsAg seroprevalence and endemicity

Objective

Chronic hepatitis B virus infection is one of the most serious infections and a major risk factor for deaths from cirrhosis and liver cancer. We estimate age-, sex- and region-specific prevalence of chronic HBV infection and calculate the absolute number of persons being chronically infected.

Methods

A systematic review of the literature for studies reporting HBV infection was conducted and worldwide HBsAg seroprevalence data was collected over a 27-year period (1980–2007). Based on observed data, age-specific prevalence and endemicity were estimated on a global level and for all world regions for 1990 and 2005 using an empirical Bayesian hierarchical model.

Findings

From 1990 to 2005, the prevalence of chronic HBV infection decreased in most regions. This was particularly evident in Central sub-Saharan Africa, Tropical and Central Latin America, South East Asia and Central Europe. Despite this decrease in prevalence, the absolute number of HBsAg positive persons increased from 223 million in 1990 to 240 million in 2005. Age-specific prevalence varied by geographical region with highest endemicity levels in sub-Saharan Africa and prevalence below 2% in regions such as Tropical and Central Latin America, North America and Western Europe. Asian regions showed distinct prevalence patterns with lower intermediate prevalence in South Asia, but up to 8.6% HBsAg prevalence in East Asia. Strong declines were seen in South East Asian children.

Conclusion

Declines in HBV infection prevalence may be related to expanded immunization. The increasing overall number of individuals being chronically infected with HBV, and the widespread global differences in HBV prevalence call for targeted approaches to tackle HBV-related mortality and morbidity. HBV infection prevalence data are needed at country and sub-national level to estimate disease burden and guide health and vaccine policy.     

Seroepidemiology of varicella-zoster virus infection in Catalonia (Spain). Rationale for universal vaccination programmes

With the aim of designing a strategy for vaccination against varicella-zoster virus (VZV), the results of a seroepidemiological survey on VZV infection carried out in a sample of the population of Catalonia are presented. Representative samples from schoolchildren (30 schools) and adults (97 municipal areas) were obtained by random cluster sampling. In the study, 883 children and 1253 adults were included. Age, gender, place of birth, place of residence, educational level and occupation were investigated in the study subjects. An ELISA test was used to measure varicella antibodies. The prevalence of varicella antibodies increased with age, being 85% in the 5-9 years age group, 92% in the 10-14 years age group, 94% in the 15-34 years age group and almost 100% in people over 35. No association was found between sociodemographic variables studied and prevalence levels of antibodies. These results suggest that the best vaccination strategy in Catalonia would be to add a temporary vaccination programme of pre-adolescents at 12 years to routine vaccination at 15 months.     

Seroprevalence of hepatitis B virus infection markers among children in Ukraine, 2017

BackgroundBefore hepatitis B vaccine (HepB) introduction, level of endemicity of hepatitis B virus (HBV) in Ukraine was estimated as intermediate but the prevalence of HBV infection markers has not been measured in population-based serosurveys. Coverage with 3 doses of HepB, introduced in 2002, was 92%-98% during 2004–2007 but declined to 21%-48% during 2010–2016. To obtain data on HBV prevalence among children born after HepB introduction, we tested specimens from a serosurvey conducted in Ukraine in 2017, following circulating vaccine-derived poliovirus outbreak in 2015, among birth cohorts eligible for polio immunization response.MethodsThe serosurvey was conducted in Zakarpattya, Sumy, and Odessa provinces, and Kyiv City, targeting 2006–2015 birth cohorts. One-stage cluster sampling in the provinces and stratified simple random sampling in Kyiv were used for participant selection. All participants were tested for antibodies against HBV core antigen (anti-HBc). Anti-HBc-positive children were tested for HBV surface antigen (HBsAg). We also obtained information on HepB vaccination status for all children.ResultsOf 4,596 children tested, 81 (1.8%) were anti-HBc-positive and eight (0.2%) were HBsAg-positive. HBsAg prevalence was 0.7% (95% confidence interval, 0.3%-1.4%) in Zakarpattya, 0.1% (0.0%-0.4%) in Sumy, 0% (0.0%-03%) in Odessa, and 0.1% (0.0%-0.8%) in Kyiv. Across survey sites, the proportion of recipients of ≥ 3 HepB doses was 53%-80% in the 2006–2009 cohort and 28%-59% in the 2010–2015 cohort.ConclusionHBV prevalence among children in surveyed regions of Ukraine in 2017 was low, including in Zakarpattya—the only site above the 0.5% European Regional target for HBsAg seroprevalence. However, HepB vaccination was suboptimal, particularly among children born after 2009, resulting in large numbers of unvaccinated or incompletely vaccinated children at risk of future HBV infection. HepB coverage should be increased to further reduce HBV transmission among children in Ukraine and achieve regional and global hepatitis B control/elimination targets.     

Economic evaluation of universal newborn hepatitis B vaccination in China

Objective

To estimate the long-term cost-effectiveness of universal newborn hepatitis B vaccination in China, an area of high endemicity.

Method

A decision tree was used to describe perinatal hepatitis B virus (HBV) transmission, early infection and impact of vaccination. A Markov model based on 1-year cycles was used to simulate these impacts for the lifetime of a cohort of 10,000,000 infants born in 2002 in China. We compared both cost and health outcomes for two strategies: universal newborn vaccination comprising a timely birth dose (HepB1) with a three-dose vaccination (HepB3) compared with no vaccination. Univariate and probabilistic sensitivity analyses using Monte Carlo simulations were performed to test parameter uncertainty.

Results

Over the cohort's lifetime, 79,966 chronic infections, 37,553 cases of hepatocellular carcinoma (HCC) and 130,796 HBV related deaths would be prevented by universal infant vaccination. The prevalence of HBV infection is reduced by 76%. Over 743,000 life-years and 620,000 quality adjusted life years (QALYs) would be gained and there would be monetary benefits of more than 1 billion US dollars in medical care costs and lost productivity avoided.

Conclusion

The newborn vaccination programme for Hepatitis B in China both gains QALYs and saves medical care costs. It is important to ensure that timely and comprehensive vaccination programmes continue.     

城、郊新生儿乙型肝炎疫苗免疫情况调查

目的　了解乙型肝炎疫苗的免疫后效果。方法　于 1997年 9～ 12月在北京、武汉、哈尔滨、上海、成都、兰州和长春 7个城市 ,采用整群随机抽样方法抽取 3～ 4岁年龄组儿童 2 180人进行调查。结果　 1993～ 1994年新生儿乙型肝炎疫苗全程接种率城区为 91.10 % ,明显高于郊区的 84.71%。HBsAg阳性率降至1.5 6% ,抗 -HBs阳性率平均为 70 .5 0 %。城区儿童HBsAg阳性率0 .2 8% ,郊区儿童HBsAg阳性率为2 .17% ,说明免疫儿童中HBsAg阳性者的主要来源在郊区。 结论　上述表明 ,我国乙型肝炎疫苗免疫效果显著 ,但在郊区 ,疫苗免疫效果还不够理想。     

Epidemiological serosurvey of Hepatitis B in China—Declining HBV prevalence due to Hepatitis B vaccination

Objective

To determine the prevalence of hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (anti-HBs), and hepatitis B core anti-body (anti-HBc) in a representative population in China 14 years after introduction of hepatitis B vaccination of infants.

Methods

National serosurvey, with participants selected by multi-stage random sampling. Demographics and hepatitis B vaccination history collected by questionnaire and review of vaccination records, and serum tested for HBsAg, antibody to anti-HBc and anti-HBs by ELISA.

Findings

The weighted prevalences of HBsAg, anti-HBs and anti-HBc for Chinese population aged 1–59 years were 7.2%, 50.1%, 34.1%, respectively. HBsAg prevalence was greatly diminished among those age <15 years compared to that found in the 1992 national serosurvey, and among children age <5 years was only 1.0% (90% reduction). Reduced HBsAg prevalence was strongly associated with vaccination among all age groups. HBsAg risk in adults was associated with male sex, Western region, and certain ethnic groups and occupations while risk in children included birth at home or smaller hospitals, older age, and certain ethnic groups (Zhuang and other).

Conclusions

China has already reached the national goal of reducing HBsAg prevalence to less than 1% among children under 5 years and has prevented an estimated 16–20 million HBV carriers through hepatitis B vaccination of infants. Immunization program should be further strengthened to reach those remaining at highest risk.     

宁波市实施乙型肝炎疫苗计划免疫后儿童乙型肝炎病毒血清流行病学研究

目的了解宁波市实施乙型肝炎疫苗(乙肝疫苗)计划免疫7年后,儿童乙型肝炎病毒(HBV)感染及免疫状况.方法采用整群分层抽样法调查1982～1995年出生儿童血清HBsAg和抗-HBs阳性率(RIA法).结果①1992～1995年出生的免疫人群HBsAg阳性率为2.66%,比未免疫人群(10.95%)下降了75.71%(χ2=22.91,P＜0.0001);②免疫人群抗-HBs阳性率达65.95%,显著高于未免疫人群的41.03%(χ2=113.67,P＜0.0001);③在计划免疫后的第5～7年起显现了免疫人群HBsAg阳性率升高和抗-HBs阳性率下降的迹象.结论宁波市实施乙肝疫苗计划免疫7年后,儿童对HBV已呈现出高免疫、低感染的特征;但需进一步研究计划免疫4～5年后,免疫人群HBsAg阳性率升高、抗-HBs阳性率下降的现象和乙肝疫苗加强免疫的适时问题.     

广西地区乙型肝炎病毒无症状携带者乙型肝炎病毒前C区突变分析

目的 调查广西地区乙型肝炎病毒（HBV）无症状携带者HBV前C区基因突变株的流行情况。方法 用套式聚合酶链反应（PCR)对77例广西南部，北部地区人群HBV无症状携带者血清HBV前C区进行扩增，阳性者用直接测序法进行序列分析。结果 39例HBsAg无症状携带者血清HBVDNA阳性，阳性率为50.7%(39/77)，突变株出现率为22.1%(17/77)。南部地区阳性率为55.6%(20/36)，其中6份标本出现突变株，占30%，常见的突变类型是nt1858位发生点突变（T→C),只有一份标本在nt1896发生点突变（G→A），导致终止密码产生，该标本同时伴有nt1837点突变（A→G）；北部地区阳性率为46.3%(19/41)，其中有11份标本出现突变株，占57.9%,常见的突变类型是ny1896位发生点突变（G→A），这些标本中有4份同时在nt1846发生点突变（A→T），2份同时在nt1862发生点突变（G→T)；标本734分别在nt1856,1858发生点突变（C→T，T→C）。结论 广西地区HBV无症状携带者HBV前C区突变株的流行率居全国中等水平，广西南部，北部是否存在主要突变类型不同值得进一步研究。     

Search for hepatitis delta virus (HDV) infection in hepatitis C patients in north-eastern Poland. Comparison with anti-HDV prevalence in chronic hepatitis B

Hepatitis C virus and hepatitis D virus have been shown to suppress HBsAg synthesis. Thus it is possible that HDV infection occurs despite the lack of detectable HBsAg. The aim of our study was to (a) determine the prevalence of HDV infection in patients with chronic hepatitis C (b) compare it with the prevalence of HDV infection in HBsAg positive patients with hepatitis B. The study group consisted of 51 chronic hepatitis C patients, 30 HIV infected drug addicts (27 of them were also positive for anti-HCV) and 102 hepatitis B patients. The participants were tested for anti-HDV, anti-HCV and HBsAg. All anti-HCV positive patients were negative for anti-HDV. Four individuals with anti-HDV belonged to hepatitis B group and constituted 3.9% of all HBsAg positive subjects. We conclude that (a) there is currently no evidence of HDV infection among HCV infected patients in our region (b) hepatitis delta infection is rare in north-eastern Poland.     

隐匿性乙型肝炎病毒感染流行现状及其临床和公共卫生学意义

乙型肝炎(乙肝)病毒(HIV)感染是严重的全球性公共卫生问题.多数HBV感染没有明显临床症状.HBsAg阳性和病毒血症是HBV感染的主要证据.     

Reduction in hepatitis B virus seroprevalence among U.S.-born children of foreign-born Asian parents—Benefit of universal infant hepatitis B vaccination

We demonstrate that after implementation of recommendations for universal infant hepatitis B vaccination, HBV infection prevalence among children of foreign-born Asian parents in Georgia declined dramatically; horizontal transmission of infection within households has occurred infrequently; and the vast majority of infants and children have received the recommended hepatitis B vaccinations. These results provide evidence of the success of the hepatitis B infant vaccination program and highlight its potential impact on reducing chronic HBV infection morbidity and mortality among U.S. populations at high risk.