Guomin Zhang

Prevention of Chronic Hepatitis B after 3 Decades of Escalating Vaccination Policy, China

China’s hepatitis B virus (HBV) prevention policy has been evaluated through nationally representative serologic surveys conducted in 1992 and 2006. We report results of a 2014 serologic survey and reanalysis of the 1992 and 2006 surveys in the context of program policy. The 2014 survey used a 2-stage sample strategy in which townships were selected from 160 longstanding, nationally representative, county-level disease surveillance points, and persons 1–29 years of age were invited to participate. The 2014 sample size was 31,713; the response rate was 83.3%. Compared with the 1992 pre–recombinant vaccine survey, HBV surface antigen prevalence declined 46% by 2006 and by 52% by 2014. Among children <5 years of age, the decline was 97%. China’s HBV prevention program, targeted toward interrupting perinatal transmission, has been highly successful and increasingly effective. However, this progress must be sustained for decades to come, and elimination of HBV transmission will require augmented strategies.

Loss of confidence in vaccines following media reports of infant deaths after hepatitis B vaccination in China

BACKGROUND China reduced hepatitis B virus (HBV) infection by 90% among children under 5 years old with safe and effective hepatitis B vaccines (HepB). In December 2013, this success was threatened by widespread media reports of infant deaths following HepB administration. Seventeen deaths and one case of anaphylactic shock following HBV vaccination had been reported. METHODS We conducted a telephone survey to measure parental confidence in HepB in eleven provinces at four points in time; reviewed maternal HBV status and use of HepB for newborns in birth hospitals in eight provinces before and after the event; and monitored coverage with hepatitis B vaccine and other programme vaccines in ten provinces. RESULTS HepB from the implicated company was suspended during the investigation, which showed that the deaths were not caused by HepB vaccination. Before the event, 85% respondents regarded domestic vaccines as safe, decreasing to 26.7% during the event. During the height of the crisis, 30% of parents reported being hesitant to vaccinate and 18.4% reported they would refuse HepB. Use of HepB in the monitored provinces decreased by 18.6%, from 53 653 doses the week before the event to 43 688 doses during the week that Biokangtai HepB was suspended. Use of HepB within the first day of life decreased by 10% among infants born to HBsAg-negative mothers, and by 6% among infants born to HBsAg-positive mothers. Vaccine refusal and HepB birth dose rates returned to baseline within 2 months; confidence increased, but remained below baseline. CONCLUSIONS The HBV vaccine event resulted in the suspension of a safe vaccine, which was associated with a decline of parental confidence, and refusal of vaccination. Suspension of a vaccine can lead to loss of confidence that is difficult to recover. Timely and credible investigation, accompanied by proactive outreach to stakeholders and the media, may help mitigate negative impact of future coincidental adverse events following immunization.

Cost-effectiveness analysis of a hepatitis B vaccination catch-up program among children in Shandong Province, China

Objective: The aim of the study was to estimate long-term cost‑effectiveness of a hepatitis B vaccination catch-up program among children born between 1994 and 2001 (when they were 8‑15 y old) in Shandong province, China, to provide information for nationwide evaluation and future policy making. Methods: We determined the cost-effectiveness of the catch-up program compared with the status quo (no catch-up program). We combined a Decision Tree model and a Markov model to simulate vaccination and clinical progression after hepatitis B virus (HBV) infection. Parameters in the models were from the literature, a field survey, program files, and the National Notifiable Disease Reporting System (NNDRS). The incremental cost‑effectiveness ratio (ICER) was used to compare the 2 alternative strategies. One-way sensitivity analysis, 2-way sensitivity analysis, and probability sensitivity analysis were used to assess parameter uncertainties. Results: The catch-up program was dominant compared with the status quo. Using a total of 5.53 million doses of vaccines, the catch-up program could prevent 21,865 cases of symptomatic acute hepatitis B, 3,088 carrier states with positive hepatitis B surface antigen (HBsAg), and 812 deaths due to HBV infection. The catch-up program could add 28,888 quality-adjusted life years (QALYs) and save

An economic analysis of adult hepatitis B vaccination in China.

192.01 million in the targeted population in the future. The models were robust, considering parameter uncertainties. Conclusion: The catch-up program in Shandong province among children born between 1994 and 2001 was ‘very cost-saving.’ It could save life years and reduce total future costs. Our study supported the desirability and impact of such a catch-up program throughout China.

Effectiveness of prevention of mother-to-child transmission practice in three provinces of Southern China

BACKGROUND AND OBJECTIVE With the universal infant hepatitis B vaccination (HepB) program, China has made remarkable achievements to prevent and control hepatitis B. In order to further reduce hepatitis B virus (HBV) infection, the Chinese government is considering implementing a widespread adult HBV vaccination campaign. We performed an economic analysis of two different adult HepB vaccination strategies for 21-59-years-olds: vaccination without screening and screening-based vaccination. METHODS Cost-benefit analyses were conducted. All 21-59-year-olds were divided into two groups: young adults (ages 21-39) and middle-aged adults (ages 40-59). Costs and benefits were estimated using the direct cost and societal (direct and indirect costs) perspectives. All costs and benefits were adjusted to 2014 US dollars, where future values were discounted at a 3% annual rate. We calculated benefit-cost ratios (BCRs) of the two vaccination strategies for the two different age groups. Sensitivity analyses varied key parameters within plausible ranges. RESULTS Among young adults, the direct and societal BCRs for a vaccination campaign with no screening would be 1.06 and 1.42; with a screening-based vaccination campaign, the model estimated the direct and societal BCRs would be 1.19 and 1.73. Among middle-aged adults, the direct and societal BCRs for a vaccination campaign without screening would be 0.59 and 0.59; with a screening-based vaccination campaign, the model estimated the direct and societal BCRs would be 0.68 and 0.73. CONCLUSION The results of our study support a HepB vaccination campaign for young adults. Additionally, a vaccination campaign with screening appeared to provide greater value than a vaccination without screening.

Economic evaluation on infant hepatitis B vaccination combined with immunoglobulin in China, 2013.

Vaccination in prevention mother-to-child transmission (PMTCT) of hepatitis B has been recommended since plasma-derived hepatitis B vaccines became available in China in 1986; however, less study evaluated practice effectiveness of PMTCT systematically. We conducted a prospective survey to evaluate the effectiveness of PMTCT practices in 3 provinces of southern China. We selected prefectures with low timely birth dose coverage in Yunnan, Guangxi, and Hunan provinces. Infants born to HBsAg positive mothers were evaluated at 7–12 months of age. We tested hepatitis B virus (HBV) surface antigen (HBsAg) and HBV e antigen (HBeAg) of mothers and tested HBsAg of infants born to HBsAg positive mothers using Enzyme-linked Immunosorbent Assay (ELISA) at provincial CDC laboratories. We used logistic regression analysis to analyze the risk factors for HBV infection. Among 3,094 infants born to HBsAg positive mothers, 172 were positive for HBsAg (5.6%). HBeAg status of pregnant women, timely birth dose (TBD) of hepatitis B vaccine were major predictors for HBV infection of infants. PMTCT practices greatly reduced the prevalence of HBsAg among infants born to HBsAg positive mothers China. However, the effectiveness of strategies used in PMTCT varied. HBsAg screening for pregnant women, monitoring of infants born to HBsAg positive mother should be enhanced to evaluate the effectiveness of program.

Post-vaccination serologic testing of infants born to hepatitis B surface antigen positive mothers in 4 provinces of China

Hepatitis B virus (HBV) infection was highly endemic before the introduction of hepatitis B vaccine (HepB) in China, with HBV surface antigen (HBsAg) prevalence being 9.75% in the general population in 1992. HBsAg prevalence among children <4 years old (9.67%) was nearly the same as the prevalence among adults, which means transmission during birth and early childhood was the predominant mode of HBV transmission in China. Ninety percent of newborns infected with HBV would become chronic carriers, leading to a substantial disease burden of chronic liver disease. China has made substantial progress in reducing HBV mother-to-child transmission (MTCT), but challenges remain. In 1992, HepB was first recommended by the Ministry of Health (MOH) for routine vaccination of infants, with the first dose to be administered within 24 hours of birth and subsequent doses at ages 1 and 6 months. In 2002, China integrated HepB into the Expanded Progamme on Immunization (EPI), with the government providing free 5mg/0.5ml/dosage HepB for all infants. In 2011, China changed the HepB dosage form to 10mg/0.5ml/dosage to improve vaccine immunogenicity. Joint HBV immune prophylaxis with HepB vaccine and hepatitis B immunoglobulin (HBIG) after birth could generally interrupt HBV MTCT, and it is recommended by the World Health Organization (WHO), the World Gastroenterology Organization (WGO), and the US Centers for Disease Control and Prevention (CDC). At the end of 2010, China implemented a program for preventing mother-to-child transmission (PMTCT) of HIV, syphilis, and hepatitis B, where all children born to HBsAg positive mothers could receive free 100IU HBIG at birth. Economic analysis of universal infant hepatitis B vaccination has been carried out by several studies in China. However, previous studies were focused on the economic analysis of 5mg vaccine used in China. Most of the previous studies did not include screening for pregnant women and HBIG injection. Some of these studies also did not include costs for adverse events following immunization (AEFI) and productivity losses due to HBVrelated diseases. The objective of this study is to provide an updated and comprehensive economic evaluation of infant HepB vaccination with 10ug vaccine and HBIG. Results from this study will be important and useful for making future policy decisions regarding HepB vaccination.

Whole-gene analysis of two groups of hepatitis B virus C/D inter-genotype recombinant strains isolated in Tibet, China

OBJECTIVE To evaluate prenatal maternal hepatitis B virus (HBV) screening and post-vaccination hepatitis B surface antigen (HBsAg) and antibody to hepatitis B surface antigen (anti-HBs) status and titers of babies born to HBsAg positive mothers, and to provide evidence for development of standard postvaccination serologic testing (PVST) strategies for babies born to HBsAg positive mothers in China. METHODS In 2014, we conducted a baseline survey of HBV mother to child transmission (MTCT) interruption strategy implementation and PVST for babies born to HBsAg positive mothers after received 3 doses of hepatitis B vaccine (HepB) in 8 counties in 4 Provinces. Bivariate analysis and multivariable analyses modeled statistically significant predictor variables associated with infant HBsAg, anti-HBs positive, anti-HBs titer. RESULTS Among the 1563 infants born to HBsAg positive mothers, 1025 (65.6%) maternal-infant pairs were enrolled in PVST after receiving 3 doses of HepB. 38 infants tested HBsAg positive for an HBsAg positive rate of 3.7%. Maternal hepatitis B e antigen (HBeAg) status and age of infant were significantly associated with infant HBsAg positivity. A total of 932 infants were anti-HBs positive when tested at 7-24months of age, yielding an anti-HBs positivity rate of 90.9%. Maternal HBeAg status was the factor associated with infant anti-HBs status. Amount of antigen of HepB and infants age were most associated with anti-HBs titers. PVST performed 1-2months after the 3rd dose of HepB was associated with the highest anti-HBs level and the anti-HBs Geometric Mean Concentration (GMC) decreased as the PVST intervals prolonged. CONCLUSIONS In China, perinatal HBV transmission is approaching the theoretical minimum possible with the current strategy of HepB coupled with HBIG administration for HBV-exposed newborns. PVST of infants born to an HBsAg positive mother is an essential strategy to ensure full protection for vaccine non-responders and appropriate medical care for those infected.

The impact of expanded program on immunization with live attenuated and inactivated Hepatitis A vaccines in China, 2004–2016

Tibet is a highly hepatitis B virus (HBV) endemic area. Two types of C/D recombinant HBV are commonly isolated in Tibet and have been previously described. In an effort to better understand the molecular characteristic of these C/D recombinant strains from Tibet, we undertook a multistage random sampling project to collect HBsAg positive samples. Molecular epidemiological and bio-informational technologies were used to analyze the characteristics of the sequences found in this study. There were 60 samples enrolled in the survey, and we obtained 19 whole-genome sequences. 19 samples were all C/D recombinant, and could be divided into two sub-types named C/D1 and C/D2 according to the differences in the location of the recombinant breakpoint. The recombination breakpoint of the 10 strains belonging to the C/D1 sub-type was located at nt750, while the 9 stains belonging to C/D2 had their recombination break point at nt1530. According to whole-genome sequence analysis, the 19 identified strains belong to genotype C, but the nucleotide distance was more than 5% between the 19 strains and sub-genotypes C1 to C15. The distance between C/D1with C2 was 5.8±2.1%, while the distance between C/D2 with C2 was 6.4±2.1%. The parental strain was most likely sub-genotype C2. C/D1 strains were all collected in the middle and northern areas of Tibet including Lhasa, Linzhi and Ali, while C/D2 was predominant in Shannan in southern Tibet. This indicates that the two recombinant genotypes are regionally distributed in Tibet. These results provide important information for the study of special HBV recombination events, gene features, virus evolution, and the control and prevention policy of HBV in Tibet.

Comparison of hepatitis E virus seroprevalence between HBsAg-positive population and healthy controls in Shandong province, China

INTRODUCTION Since 2008, two types of hepatitis A (HepA) vaccines were integrated into the expanded program on immunization (EPI) in China. Children were given either one dose of live attenuated HepA (L-HepA) or two doses of inactivated HepA (I-HepA), depending on geographic regions. We sought to evaluate the impact of the EPI on HepA incidence in China. METHODS We reviewed the epidemiology of HepA during 2004-2016 from National Notifiable Disease Reporting System (NNDRS). We collected data of L-HepA and I-HepA coverage from Children Immunization Information Management System (CIIMS). Based on the regions where two types of HepA vaccines were used, the coverage and incidence of HepA were compared over time. RESULTS In 2008-2016, the HepA vaccine coverage was 98.8% among target children, with 99.6% in I-HepA region and 98.7% in L-HepA region. HepA incidence declined by 78.0% and 82.3% in L-HepA region and I-HepA region, respectively, without significant difference. Dramatic decline were seen in all age groups of both regions. CONCLUSION The study suggests that the EPI, with high coverage for both I-HepA and L-HepA, had positive impact on HepA incidence in China.