Primary prevention model of liver cancer in rural China / 中华肿瘤杂志

Hepatocellular carcinoma (HCC) is the major histological type of primary liver cancer (PLC), and the etiology is relative clear. Chronic infection of hepatitis B virus (HBV) plays dominant roles, and high exposure to aflatoxins is an important co-factor. Qidong was one of the endemic area with high PLC incidence in rural China. The results from a series of etiological intervention studies on PLC in this area indicated that 1) the protective efficacy of neonatal HBV vaccination against PLC development under the age of 30 was 84% (95% CI 23%-97%); 2) the relative risk of liver cancer incidence decreased at least 4 folds in young adults aged <35 years with reducing aflatoxin exposures and cleaning drinking water. The prevention of HBV infection and the supplies of clean water and safe food with limited aflatoxins demonstrated as an effective primary prevention model of liver cancer in rural China.

Primary prevention by hepatitis B vaccine on liver cancer in high incidence area of China / 中华预防医学杂志

Objective@#Incidence of primary liver cancer (PLC) in China is mostly related to chronic infection of hepatitis B virus (HBV). Qidong was one of the endemic areas with high incidence of PLC in China before 2000. We conducted a series of studies regarding on PLC etiological prevention during the past decades to develop better primary prevention strategies for PLC.@*Methods@#Qidong Hepatitis B Intervention Study was conducted in 1983-1990. A total of 41 182 newborns were randomly assigned to vaccination group and 40 211 (97.64%) of them completed the three-dose, 5 µg-plasma-derived hepatitis B (HB) vaccination series at age 0, 1, 6 month. Among them, 28 988 participants received one-dose 10 µg recombinant HB booster vaccination at age 10-14 years. A total of 41 730 newborns were randomly assigned to the control group. When they were at age 10-14 years, 23 368 participants received the catch-up vaccination with three-dose, 10 µg-recombinant HB vaccine. Two cross-sectional HBV serology surveys were conducted in 1996-2000 and 2008-2012. Information on PLC incidence and mortality of chronic liver diseases were collected through cancer registry and vital statistics until December 31, 2016. Cox proportional hazard models were employed to compute hazard ratio (HR) of PLC and other liver diseases for the participants with neonatal HB vaccination or catch-up vaccination, and the protective efficacy was also calculated.@*Results@#During serologic survey in 1996-2000, a total of 22 689 participants in vaccination group and 12 395 participants in control group donated blood samples. The HBsAg seropositive rates in the vaccination group was 2.16% (491/22 689), which is significantly lower than that of control group (9.08%, 1 126/12 395) (χ2=896.61, P<0.001). During serologic survey in 2008-2012, a total of 17 386 participants in vaccination group and 18 060 participants in control group donated blood samples. The HBsAg seropositive rates in the vaccination group was 1.83% (319/17 386), which is still significantly lower than that of control group (6.77%,1 222/18 060) (χ2=518.05, P<0.001). By December 31, 2016, 4 cases of PLC in the vaccination group and 17 cases of PLC were identified in the vaccination and control group, respectively. The estimated efficacy of neonatal HB vaccination on HBsAg seroprevalence in childhood (at age 10-11 years), early adulthood (at age 19-28 years) and incidence rate of PLC at age below 33 years was 79% (95%CI: 76%-81%), 74% (95%CI: 71%-78%) and 79% (95%CI: 36%-93%), respectively. The estimated efficacy of three-dose, 10 µg-recombinant HB catch-up vaccination in early adulthood is 21% (95%CI: 11%-30%), which is significantly lower than that of neonatal HB vaccination.@*Conclusion@#HB vaccination to neonates/infants is crucial against chronic HBV infection in childhood through young adulthood, and subsequently reduced the risk of PLC in young adults.

Long-term efficacy of neonatal hepatitis B vaccination against chronic hepatitis B virus infection and chronic liver disease: a cross-sectional study based on Qidong Hepatitis B Intervention Study / 中华流行病学杂志

<p><b>OBJECTIVE</b>To evaluate the long-term protection efficacy of neonatal hepatitis B vaccination on chronic hepatitis B (CHB) and liver fibrosis and cirrhosis in adults.</p><p><b>METHODS</b>From January to October, 2013, a cross-sectional study was conducted among the participants from Qidong Hepatitis B Intervention Study (QHBIS), who were selected through stratified random sampling. The detections of serum alanine aminotransferase (ALT), HBsAg, anti-HBs, anti-HBc, HBeAg, and anti-HBe were conducted and ultrasonography on liver, gallbladder and spleen was performed for them. The positive rates of each serologic markers, the prevalence of active CHB and liver fibrosis and cirrhosis were calculated, the gender specific differences between vaccination group and control group were compared with Chi-square test.</p><p><b>RESULTS</b>A total of 4 421 participants aged (25.59±1.84) years in vaccination group and 3 880 participants aged (26.61±2.24) years in control group were surveyed. The positive rates of HBsAg, anti-HBs, anti-HBc, HBeAg and anti-HBe were 2.38%, 37.73%, 3.78%, 0.57% and 2.15% in vaccination group, and 9.02%, 29.41%, 16.83%, 2.73% and 8.87% in control group, respectively, the differences between two groups were statistically significant (all P<0.05). The prevalence of active CHB and liver fibrosis and cirrhosis were 0.45% and 0.16% in vaccination group, 1.29% and 0.39% in control group, the differences between two groups were statistically significant (P<0.05). The active CHB prevalence was lower in females than in males in both vaccination group and control group (P<0.05). The liver fibrosis and cirrhosis prevalence was lower in females than in males in control group (P<0.05); whereas, no statistical significant difference in liver fibrosis & cirrhosis prevalence between males and females was found in vaccination group (P>0.05).</p><p><b>CONCLUSIONS</b>Protection conferred by neonatal hepatitis B vaccination could last to marrying age. The gender specific difference in protection efficacy needs further study.</p>

HBsAg seroprevalence in students for college entrance examination from 2006 to 2014 in Qidong of Jiangsu Province / 临床肝胆病杂志

ObjectiveTo investigate the HBsAg seroprevalence in the young generation in Qidong of Jiangsu Province, China. MethodsA total of 15 534 students for college entrance examination from 2006 to 2014 were randomly selected from three secondary schools in Qidong as student group. Some of them had hepatitis B vaccination at birth. A total of 1208 adults who had their routine checkups in our hospital from 2007 to 2013 were selected as adult group. It was confirmed that all of them did not have hepatitis B vaccination at birth. Serum HBsAg levels of the two groups were measured using enzyme-linked immunosorbent assay and the seroprevalence was analyzed. Comparison of data between the two groups was made by chi-square test. Results In the 9 years from 2007 to 2013, the seroprevalence rates of HBsAg in the student group were 4.2%(75/1794), 4.3%(77/1797), 4.4%(82/1858), 4.3%(82/1903), 3.4%(56/1627), 2.6%(46/1768), 1.6%(29/1778), 1.6%(27/1642), and 1.8%(24/1367), respectively. The mean HBsAg seroprevalence of the student group was 32%(498/15534), significantly lower compared with 7.1% (86/1208) of the adult group (χ2= 59.986, P＜0.001). In both of the student group and the adult group, the males had a significantly higher HBsAg seroprevalence than the females (χ2=10.521, P=0001; χ2=8.452, P=0.004) and the values were 3.7%(266/7236) vs 2.8%(229/8298) and 8.8%(66/750) vs 4.4%(20/458), respectively. Among male subjects, the HBsAg seroprevalence of the adult group was 2.4 times that of the student group; among female subjects, the HBsAg seroprevalence of the adult group was 1.6 times that of the student group. ConclusionIn the recent 9 years from 2006 to 2014, the HBsAg seroprevalence in students for college entrance examination declined continuously. The goal set by the World Health Organization Western Pacific Region in 2010 had been achieved ahead of the schedule that the HBsAg seroprevalence should be controlled below 2% in children aged less than 5.

HBsAg seroprevalence in students for college entrance examination from 2006 to 2014 in Qidong of Jiangsu Province / 临床肝胆病杂志

ObjectiveTo investigate the HBsAg seroprevalence in the young generation in Qidong of Jiangsu Province, China. MethodsA total of 15 534 students for college entrance examination from 2006 to 2014 were randomly selected from three secondary schools in Qidong as student group. Some of them had hepatitis B vaccination at birth. A total of 1208 adults who had their routine checkups in our hospital from 2007 to 2013 were selected as adult group. It was confirmed that all of them did not have hepatitis B vaccination at birth. Serum HBsAg levels of the two groups were measured using enzyme-linked immunosorbent assay and the seroprevalence was analyzed. Comparison of data between the two groups was made by chi-square test. Results In the 9 years from 2007 to 2013, the seroprevalence rates of HBsAg in the student group were 4.2%(75/1794), 4.3%(77/1797), 4.4%(82/1858), 4.3%(82/1903), 3.4%(56/1627), 2.6%(46/1768), 1.6%(29/1778), 1.6%(27/1642), and 1.8%(24/1367), respectively. The mean HBsAg seroprevalence of the student group was 32%(498/15534), significantly lower compared with 7.1% (86/1208) of the adult group (χ2= 59.986, P＜0.001). In both of the student group and the adult group, the males had a significantly higher HBsAg seroprevalence than the females (χ2=10.521, P=0001; χ2=8.452, P=0.004) and the values were 3.7%(266/7236) vs 2.8%(229/8298) and 8.8%(66/750) vs 4.4%(20/458), respectively. Among male subjects, the HBsAg seroprevalence of the adult group was 2.4 times that of the student group; among female subjects, the HBsAg seroprevalence of the adult group was 1.6 times that of the student group. ConclusionIn the recent 9 years from 2006 to 2014, the HBsAg seroprevalence in students for college entrance examination declined continuously. The goal set by the World Health Organization Western Pacific Region in 2010 had been achieved ahead of the schedule that the HBsAg seroprevalence should be controlled below 2% in children aged less than 5.

Analysis of association of hepatitis B virus infection and family history of hepatocellular carcinoma with age at primary liver cancer / 国际肿瘤学杂志

Objective To explore the relationship of hepatitis B virus surface antigen(HBsAg)infec-tion and family history of hepatocellular carcinoma(HCC)with age at primary liver cancer. Methods Totally 1 359 cases of primary liver cancer were enrolled. Their data of sex,HBsAg status and family history informa-tions of liver cancer were analyzed on the associations with diagnosis age. Results Of the 1 359 cases,1 053 were males and 306 were females,their average age at diagnosis was(54. 02 ± 10. 47)years(20-84 years). For HBsAg positive cases,the average age at diagnosis was 51. 99,significantly younger than that of HBsAg negative cases(61. 23),t = 13. 51,P = 0. 000. Cases with family history of HCC were diagnosed at a signifi-cantly earlier age than those without family history(52. 53 vs 55. 23,t = 4. 389,P = 0. 000). In HBsAg posi-tive cases,the average age at diagnosis showed a significant difference not only between males and females (51. 18 vs 54. 89,t = 5. 353,P = 0. 000),but also between cases with family history and cases without family history(51. 33 vs 52. 62,t = 2. 233,P = 0. 026). In HBsAg negative cases,the average age at diagnosis of males and females were 60. 83 and 62. 45 respectively(t = 1. 126,P = 0. 261). The average age at diagnosis of cases with family history and cases without family history were 59. 58 and 61. 92 respectively(t = 1. 728,P =0. 085),both showed no significant difference. Conclusion Cases of primary liver cancer with positive-HBsAg are diagnosed averagely 9. 24 years younger than those with negative-HBsAg in Qidong. Sex and family history of HCC significantly advance hepatocarcinogenesis only in HBsAg positive individuals,not in HBsAg negative individuals.

Family history of liver cancer increases the risk of liver cancer incidence: a 20-year prospective cohort study in Qidong, China / 中华肝脏病杂志

<p><b>OBJECTIVE</b>To evaluate whether first-degree family history of liver cancer plays a role in liver cancer incidence by prospective evaluation of a patient cohort in Qidong, China over a 20-year period.</p><p><b>METHODS</b>In May 1992, 708 hepatitis B surface antigen (HBsAg) carriers and 730 HBsAg-negadve controls from Qidong city were enrolled for participation in a prospective cohort study ending in November 2012.Follow-up was carried out every 6 to 12 months, and evaluations included serum assays to measure concentrations of alpha fetoprotein (AFP), HBsAg and alanine aminotransferase (ALT), as well as abdominal ultrasound to assess liver disease.The relationship between baseline (study entry) information of patients with first-degree family history of liver cancer and liver cancer incidence during the two decades of study was statistically assessed.</p><p><b>RESULTS</b>There were 172 newly diagnosed liver cancer cases in the cohort during 25 753 person-years (py) of follow-up, representing an incidence of 667.88/100 000 py.The incidence rates of liver cancer among participants with or without liver cancer family history were 1 244.36/100 000 py and 509.70/100 000 py respectively, and the between-group difference reached the threshold for statistical significance (P less than 0.01, Relative Risk (RR):2.44, 95% Confidence Interval (CI):1.80-3.31).The incidence rates of liver cancer among participants who had a sibling with liver cancer and participants who had a parent with liver cancer were not significantly different (P > 0.05), but the liver cancer incidence among participants who had a mother with liver cancer was significantly higher than that of participants who had a father with liver cancer (P < 0.05, RR:1.86, 95% CI:1.03-3.36). Among the participants with liver cancer family history, 56.52% (39/69) were diagnosed before 50 years old, and this rate was significantly higher than that of participants without a family history of liver cancer (40.78%, 42/103, P less than 0.05).The incidence rate of liver cancer among the participants who were family history-positive and HBsAg-positive was significantly higher than that of participants who were family history-negative but HBsAg-positive (P < 0.01, RR:1.75, 95% CI:1.29-2.38), and was 59.59 times higher than for participants who were family history-negative and HBsAgnegative.Subgroup analysis of liver cancer incidence among participants who were family history-positive but HBsAg-negative and participants who were family history-negative and HBsAg-negative produced anRR of 2.60, but there was no statistically significant difference between the two subgroups (P > 0.05).At the study's end, the incidence rates of liver cancer for the different subgroups were 32.21% for the family history-positive and HBsAgpositive participants, 19.80% for the family history-negative and HBsAg-positive participants, 1.71% for the family history-positive and HBsAg-negative participants, and 0.65% for the family history-negative and HBsAg-negative participants.</p><p><b>CONCLUSION</b>First-degree family history of liver cancer is a risk factor of liver cancer in Chinese patients from Qidong, and exhibits synergism with HBsAg-positivity for incidence of liver cancer.</p>

A Prospective Study of the Relationship between Hepatitis B Virus Markers and Primary Liver Cancer / 天津医药

Objective:To study the relationship between hepatitis B surface antigen(HBsAg)and the primary liver cancer (PLC).Methods:A 20-year prospective follow-up study was performed continuously in Qidong on a cohort of 515 HBsAg positive male patients aged 20-60 years old.The markers of hepatitis B virus,HBsAg,HBsAb,HBeAg,HBeAb and HBcAb (HBVM 1,2,3,4,5)were detected at the first time of the follow-up.Results:The PLC incidence of the whole cohort was 1340.90/100 000 person years(PY).The middle age of the PLC diagnosis was 43 with an average survival of 15 months.The PLC incidence was significantly higher in 41-50 age group than that of other age groups(P＜0.05).The three major HBVM patterns were 15,135 and 145 in the cohort with percentages of 38.83%(200/515),15.92%(82/515)and 44.08%(227/515)respective1y.The PLC incidences of these three patterns were 1 433.69/100 000 PY,2 284.71/100 000 PY,984.10/100 000 PY respectively,showing a significant difference between 135 and 145(P＜0.01).The percentages of 15,135 and 145 were 39.64%(44/111),23.42%(26/111)and 35.14%(39/111)in PLC patients respectively,showing a significant difference between 15 and 135(P＜0.01).The liver cirrhosis mortality of those three patterns were 195.50/100 000 PY,966.61/100 000 PY and 277.57/100 000 PY respectively,showing the significant differences between 135 and other two patterns(P＜0.01).Conclusion:HBsAg carriers were high risk population of PLC.The regular following-up is helpful on early diagnosis and treatment of PLC in those people,and can prolong the survival time.It was found that 135 had higher PLC risk than other HBVM patterns,suggesting a relationship between HBV duplication and PLC.The anti-virus treatment may delay or remove the occurring of PLC.

Mutations in hepatitis B virus genome involved in immunoprophylaxis failure against vertical transmission / 中华微生物学和免疫学杂志

Objective To determine the factors responsible for failed postnatal immunoprophylaxis for hepatitis B virus(HBV) in Qidong, China. Methods Eleven children who developed into chronic HBV infection after receiving HBIG and HBV recombinant vaccines were recruited into the study. Eleven paired mothers with chronic hepatitis and other 6 mothers whose children successfully generated anti-HBs after im-munoprophylaxis were included as the control in the study. Full-length HBV DNA was amplified through ser-um sample by PCR method and underwent cloning and sequencing. HBV DNA level was quantified by real-time PCR. Results The mean levels of HBV DNA in mothers who had HBV DNA positive children and healthy children were ( 1.2 ×107± 3.1 × 106 ) copies/ml and ( 1.6× 107±8.8×106 ) copies/ml, respec-tively. There was no significant difference between the groups (P >0.05). Meanwhile, viral load in chil-dren was unrelated to that in their mothers (r2 =0.2429). In 11 HBV DNA positive children, 4(36.4% ) demonstrated amino acid substitutions in HBsAg "a" determinant region with 6 different types, I.e. T125A, I126T, Q129H, M133V, D144V and G145A. All of the mothers showed the wild-type sequence in "a" epitope, indicating surface escape mutants were not acquired from the initial infection, but developed under the immune pressure. The mutation rates after immunoprophylaxis for preS1, preS2, S, X, preC/C and P genes were 0.38%, 0. 22%, 0.27%, 0.17%, 0.11%, and 0.11%, respectively, nt2999-3157 in preS1, nt529-677 in S, nt1955-2016 in C, nt923-1001 and nt2489-2602 in P genes were among the hottest muta-tional spots throughout the HBV genome. Conclusion HBV mutation may occur in all the open readingframes after passive and active immunoprophylaxis. In addition to S gene, HBV preS and P genes could alsoassociate with the escape mutants.