摘要:我國自1984年開始實施全國新生兒B型肝炎疫苗接種計畫,使B型肝炎帶原率由15-20%,降至1%以下。然而接種疫苗後仍感染慢性B型肝炎,甚或發生肝癌,猛暴性肝炎之病例仍有所見。我們過去研究也發現,母親為B型肝炎帶原之0-10歲兒童,母親為HBsAg(+)/HBeAg(+)者,所生子女帶原率為9.26%,明顯高於HBsAg(+)/HBeAg(-)之母親所生子女,其帶原率約0.28-0.29%,可見B型肝炎在台灣尚未徹底根除的主因在母子傳染,為了進一步降低B型肝炎帶原率,針對高危險群做B肝防治乃必要之措施。本研究目的,在以多中心合作之方式,持續進行台灣預防母嬰B肝感染研究群的高危險孕產婦篩檢,並選用更安全的抗病毒藥物韋立得Tenofovir alafenamide (TAF),進行臨床試驗。TAF與TDF在體內同樣轉換為有效抗病毒成份tenofovir,其降低B肝病毒量之效果兩者相當,但TAF對於腎臟及骨骼的安全性更高。本研究將繼續進行多中心臨床試驗,將在懷孕20-32週篩檢B型肝炎帶原孕婦,病毒量大於106 IU/mL者,自懷孕26-30週(第二~三孕期) 起投與每日TAF 25 mg治療,至生產完0-2週止;另有不接受藥物治療者為對照組;所生之子女均接受例行之HBIG及三劑B型肝炎疫苗,以評估降低母嬰傳染率之效果及安全性。並將追蹤使用TDF或未服藥之個案,了解此綜合預防對策之執行效果及實際執行之困難點。此外,我們將以跨院多中心合作共預計收集大約3000位健康無癌症的個案,年齡層從0-40歲(每一年齡層約60-100人),其中0-6歲收案涵蓋北中南東部地區,徵得其本人或家長同意後抽血檢查B型肝炎表面抗原,依不同年齡層分組得出B型肝炎表面抗原盛行率以及自然感染率,除比較不同年齡層之差異外,並同時回顧過去的研究材料,比較疫苗施種前、以及施種後5年、10年、15年、20年、25年、30年、以及35年之血清流行病學變化,由於目前台灣孕產婦平均年齡為31歲,因此此次調查將涵蓋疫苗世代之孕產婦所生之下一代兒童。本研究將會在這3000位受試者中,依照年齡分布,隨機篩選出B型肝炎表面抗原呈陰性者共300位,了解是否有HBsAg(-)/HBV DNA(+)之潛隱性感染者,以了解疫苗世代非帶原者中,潛隱性感染是否為重要之問題;另外,受試者若B型肝炎表面抗原呈陽性者,將進行母子之B型肝炎病毒突變檢測,了解這些帶原的受試者中,其B型肝炎病毒突變株是否較以前有所不同,且進一步詢問這些受試者的疫苗接種史,並將轉介帶原者至肝膽胃腸科醫師追蹤其病程。B型和C型病毒的重要傳染途徑包括輸血、醫療行為或注射。而對於洗腎患者,由於醫護人員會時常接觸到病人的血液,因此不只醫護人員會暴露在感染B、C型肝炎病毒的高風險,對於其他非慢性肝炎的洗腎患者,若是醫護人員沒有嚴謹的無菌操作,則有可能造成急性B型或是C型肝炎的感染。因此目前的血液透析中心,都會有針對慢性B型及C型肝炎的患者,有專門的機器和區域來進行血液透析。然而過去相關的發生率,由於缺乏一個很嚴謹的調查,所以並沒有很確切的證據來支持這樣的作法。此外,當藥物已經可以有效的治癒洗腎患者的C型肝炎感染,讓病患在隔離區接受血液透析,或是要移至非感染區接受血液透析,目前並沒有實質的證據,哪一種作法會影響急性C型肝炎的發生率是,也因此是此項研究計畫的重點之一。我們將以前瞻性研究探討這幾項重要的問題。我們會納入從醫學中心,地區醫院,區域醫院,以及洗腎中心合併慢性B型或C型的洗腎患者,並分析相關病毒因子。對於非慢性肝炎的患者,我們將每年檢測其血清中的 IgG-HCV, HBsAg, anti-HBs, 以及anti-HBc,來評估急性B型和C型肝炎的發生率。此外,當C型肝炎病毒被清除24週後,我們會將病患挪至一般區接受血液透析,也將藉此探討是否會影響一般區急性C型肝炎的發生率。而對於慢性B型肝炎的患者,我們也希望藉由控制病毒的複製來探討是否能降低急性B型肝炎的發生率。
Abstract: Since the implementation of universal vaccination in 1984, the chronic HBV carrier rate in our general population reduced from 15-20%, down to < 1% in the post-vaccination population. However, even receiving full vaccine protection, cases of chronic HBV carrier, even hepatocellular carcinoma and fulminant hepatitis still exist.We well continue our clinical trial in using Tenofovir alafenamide fumarate (TAF) to reduce mother-to-infant transmission. TAF, a novel prodrug of tenofovir with 89% lower plasma concentration compared to TDF, demonstrated similar high rates of virologic suppression, and has better renal and bone safety profiles. We will continue to screen pregnant women HBsAg and HBeAg positive mothers, for those with high HBV viral load (>106 IU/mL) and are willing to participate in the study, they will receive TAF 25 mg daily starting from 2nd~3rd trimester until postpartum. The newborn babies are given with HBIG and HBV vaccines. We will also follow-up the mother-children pairs for those who received maternal TDF treatment for safety and outcomes.In addition, we will evaluate the population impact of the HBV mass vaccination program 35 years after its initiation. Seroprevalence of HBsAg positivity will be analyzed aged 0-40 years in the greater Taipei metropolitan area, the same area where the baseline and previous follow-up seroepidemiologic studies were done. We plan to enroll 3000 subjects < 40 years of age, about 60-100 subjects at each age. Of the 3000 subjects, we will also randomly selected 300 cases negative for HBsAg and teste for occult HBV infection, to evaluate the impact of vaccination on the seroprevalence of occult HBV infection. For those positive for HBsAg, we will analyze the HBV mutant rates of the index cases and mothers, to evaluate the impact of mass vaccination to the emergence of HBV mutants.The transmission routes for viral hepatitis B and C include blood transfusion, medical procedures or injection. Thus nosocomial infection of HBV or HCV is not uncommon in hemodialysis patients, who may expose to the contaminated medical instruments easily and frequently.There exist several strategies to reduce the nosocomial transmission of HBV or HCV in the hemodialysis units in Taiwan. For example, it is advised to use isolation of HBV or HCV-infected patients and dedicated dialysis machines for them. However, the evidence to support these strategies remains limited. Furthermore, when chronic hepatitis C patients achieving sustained virological response (SVR12 or 24), the optimal management of these IgG-HCV-positive patients with undetectable virus is still a challenge. We wil address these important issues by conducting a prospective cohort study. Hemodialysis patients from medical centers, regional hospitals, district hospitals, and clinics will be enrolled, and their viral profiles will be evaluated. Serum IgG-HCV, HBsAg, anti-HBs, and anti-HBc will be determined annually in dialysis patients without chronic viral hepatitis infection, whereas seroconversion of these biomarkers will be defined as acute C and acute B, respectively. We will further explore (1) whether IgG-HCV seroconversion rate is affected after the implantation of reimbursed HCV treatment and (2) moving HCV-cured patients from the isolated area and dedicated machines to the clean area with shared machines. In the meantime, we will examine the actual incidence rates of acute hepatitis B and whether it is affected by the introduction of antiviral treatment.