- 學位論文
台灣C型肝炎病毒感染流行病學與健康風險評估
Epidemiology and Health Risk Assessment of Hepatitis C Virus Infection in Taiwan
摘要
本論文以四個子研究探討C型肝炎病毒感染在台灣地區的流行病學特性。第一部分評估C型肝炎病毒在社區的血清盛行率及地理分布差異，並以多層次分析模式探討地區特性及個人危險因子與C型肝炎病毒感染的相關。第二部份以追蹤研究方式，評估血清標記，包含血清C型肝炎病毒核糖核酸濃度(HCV RNA levels)、C型肝炎病毒基因型及丙胺酸轉胺酶(alanine aminotransferase, ALT)對C型肝炎病毒血清陽性者發生肝癌的預測性。第三部份除估計C型肝炎病毒感染對於肝硬化、肝癌死亡的影響，並系統性估計C型肝炎病毒對於肝外疾病(extrahepatic diseases)死亡的危險性。第四部份分析C型肝炎病毒血清病毒核糖核酸濃度對於腦血管疾病死亡風險是否存在劑量效應，以確立病毒感染與此肝外疾病的關聯性。 研究一、C型肝炎病毒血清盛行率的地理分布差異與決定因子 背景：居住在鄰近或相同地區的人共享環境，因此感染病毒的機會理當相似。C型肝炎病毒感染的個人危險因子常被探討，但環境特性卻鮮少被提及。本研究利用多層次分析方法，在考慮個人危險因子的條件下，評估地區特性：C型肝炎病毒核糖核酸血清陽性率及醫療資源，對於個人感染C型肝炎病毒風險之影響。方法：研究選取台灣地區7個鄉鎮共155個村里的居民共23,820人。研究個案進入研究時測量血清中抗C型肝炎病毒抗體，若此抗體為陽性則進一步檢驗血清中的C型肝炎病毒核糖核酸與C型肝炎病毒基因型。結果：C型肝炎病毒血清盛行率為5.5%，其中血清C型肝炎病毒抗體為陽性者中，有68.1%為C型肝炎病毒核糖核酸陽性。在社區中，以感染C型肝炎病毒第一基因型者為盛行。個人危險因子如年齡老化、女性、低教育程度及輸血經驗皆和病毒感染風險有關。透過多層次模式分析，在控制個人危險因子的條件之下，地區特性如C型肝炎病毒核糖核酸血清陽性率及醫療資源，對於病毒感染有重要的影響。C型肝炎病毒核糖核酸血清陽性率高的地區相對於陽性率低的地區，校正後的風險對比值為3.74 (95%信賴區間：2.50-5.19)；醫療資源有限相對於有適當醫療資源的地區校正後的風險對比值為1.90 (95%信賴區間：1.34-2.69)。結論：地區的特性和C型肝炎病毒感染的盛行有關聯。本研究結果顯示在社區中若要有效控制病毒的感染，必須有效分配醫療資源並且找出C型肝炎病毒抗體陽性且C型肝炎病毒核糖核酸血清陽性(即慢性感染)的個案，並且予以有效的治療及臨床處置。 研究二、C型肝炎病毒感染之血清標記對肝癌發生之預測性 背景：針對和C型肝炎病毒感染有關的肝癌發生，找出長期的預測因子能夠提供早期臨床處置的依據。本研究評估血清中的C型肝炎病毒核糖核酸濃度、C型肝炎病毒基因型別及丙胺酸轉胺酶對於C型肝炎病毒感染者未來發生肝癌之預測性。方法：自1991至2006年針對925名C型肝炎病毒抗體陽性，且年齡介於30至65歲的成年人作追蹤。研究個案血清中之C型肝炎病毒核糖核酸濃度、C型肝炎病毒基因型別及丙胺酸轉胺酶在納入研究時即已測量，研究世代之新發肝癌乃透過定期的健康檢查、癌症登記檔及死亡檔的連結做確立。結果：截至研究結束追蹤8,476人年，其中共有55名肝癌新發個案。研究個案血清中之C型肝炎病毒核糖核酸陰性、或血清中C型肝炎病毒量低，或血清中C型肝炎病毒量高之肝癌發生累積風險(cumulative risk)分別為1.1%，6.4%及14.7%；且三組之間達到統計上的顯著差異。血清中丙胺酸轉胺酶濃度對肝癌的累積風險，丙胺酸轉胺酶濃度持續等於或低於15 U/L者為1.7%，曾經高於15 U/L但未高於45 U/L者為4.2%；而追蹤過程中曾經高於45 U/L者為13.8%。而感染C型肝炎病毒第一基因型者相對於感染非第一基因型者有較高肝癌發生累積風險，分別為12.6%及4.5%。結論：血清中的C型肝炎病毒濃度高、感染C型肝炎病毒第一基因型及高濃度丙胺酸轉胺酶能預測C肝感染者之肝癌發生。 研究三、C型肝炎病毒對肝內及肝外疾病死亡率之風險 背景：C型肝炎病毒感染除了會導致肝臟疾病，亦可能增加罹患肝外疾病的風險。然而，C型肝炎病毒感染與肝內及肝外疾病死因的關聯卻鮮少被評估。方法：研究自1991年起追蹤台灣七鄉鎮社區30-65歲的成人至2008年底，研究個案為B型肝炎病毒表面抗原陰性者。研究個案之死亡資料以連結死亡登記檔取得，並依照國際疾病分類碼第九版(ICD-9)做死因之分類。結果：本研究共有19,636名B型肝炎病毒表面抗原陰性者納入分析，其中1,095人為C型肝炎病毒抗體陽性，另18,541人則為C型肝炎病毒抗體陰性。在C型肝炎病毒抗體陽性者中，有69.4%病毒核糖核酸陽性，表示病毒仍在持續複製，為慢性感染者。經過平均16.2年的追蹤，本研究世代共有2,394人死亡，死亡率為每十萬人年753.4人。將研究個案分成C型肝炎病毒抗體陰性、C型肝炎病毒抗體陽性但核醣核酸陰性、及C型肝炎病毒抗體陽性且核醣核酸陽性三組，全死因死亡率(每十萬人年)分別為708.8，741.0及1879.8；而肝臟相關疾病死亡率(每十萬人年)則分別為37.2，82.3，678.3。針對全死因、肝臟疾病死亡及肝外疾病死亡，校正年齡與性別的影響後，皆以C型肝炎病毒慢性感染者(即C型肝炎病毒抗體陽性且核糖核酸陽性者)的風險最高；而C型肝炎病毒感染對於肝外疾病的影響，包含腦血管及腎臟疾病的死亡。結論：慢性C型肝炎病毒感染者有較高風險死於肝內及肝外疾病。 研究四、C型肝炎病毒感染與腦血管疾病死亡之風險 背景：C型肝炎病毒感染和腦血管疾病的關聯在過去的文獻仍未有定論。本研究目的在評估慢性C型肝炎病毒感染與腦血管疾病死亡的相關。方法：研究自1991至2008年追蹤年齡介於30-65歲的成年人共23,665名。在研究收案時即針對個案做問卷訪視，並收取血液檢體做病毒學及生化相關檢驗。研究個案的死亡情形，由連結死亡登記檔確認。 結果：經過382,011人年的追蹤，共有255名研究個案死於腦血管疾病。C型肝炎病毒抗體陰性者累積風險是1.0%，而C型肝炎病毒抗體陽性者累積風險則為2.7%，兩組間並達統計顯著差異。在校正其他腦血管疾病相關的危險因子之後，C肝抗體陽性者相對於陰性者死於腦血管疾病的風險為2.11倍 (95%信賴區間：1.42-3.14)。若以血清C肝抗體陰性者為參考組，針對C肝抗體陽性血清中偵測不到核醣核酸者、C肝抗體陽性血清病毒量低，以及C肝抗體陽性血清病毒量高者，校正後的風險對比值為1.43 (95%信賴區間：0.63-3.23), 2.29 (95%信賴區間：1.38-3.82)和2.81 (95%信賴區間：1.25-6.35)，經過趨勢檢定之後，呈現劑量效應相關。而感染C型肝炎病毒的基因型別，則與腦血管疾病死亡無統計顯著相關。結論：C型肝炎病毒感染對於腦血管疾病有獨立於其他傳統危險因子的影響。 綜合本論文之研究顯示，C型肝炎病毒慢性感染者(C型肝炎血清抗體陽性且核糖核酸陽性)，除了有較高的肝癌發生風險之外，也有較高的死於肝臟相關疾病，甚至其他肝外疾病的可能性；而這群慢性感染者，在社區中扮演重要的病毒傳播角色，可能有較高的機會將病毒傳染給他人。因此，利用核糖核酸的檢驗，找出慢性C型肝炎病毒感染者，予以適當的臨床處置，對於疾病的控制，甚至病毒感染的控制，有相當的重要性。
並列摘要
This dissertation included four studies to investigate the prevalence of HCV infection and risk of hepatic/extrahepatic diseases associated with HCV infection. Study 1: Geographical Variation and Determinants Associated with Anti-HCV Seroprevalence Background and Aims: Residents living in the same area may share similar likelihood to acquire infections. The risk factors for infection with hepatitis C virus (HCV) may be classified as individual and community risk factors. Individual risk factors of HCV infection have been extensively investigated whereas the community risk factors have been rarely evaluated. The aim of this epidemiological study was to explore the community risk factors, such as high HCV RNA positive rate and limited medical resources in a residential area, and the personal risk of HCV infection. Methods: This study enrolled 23,820 residents living in 155 villages in Taiwan to explore both individual and community risk factors for HCV infection. Antibodies against HCV (anti-HCV), HCV RNA and HCV genotype in serum samples were determined by enzyme immunoassay, polymerase chain reaction, and melting curve analysis, respectively. Results: The overall anti-HCV seroprevalence was 5.5%, HCV RNA was detectable in 68.1% of the seropositives of anti-HCV, and genotype 1 was the most prevalent genotype (54.6%). Personal risk factors for the seropositivity of anti-HCV included older ages, female gender, low educational level, and history of blood transfusion. Based on the multilevel analysis, persons living in villages with high HCV RNA-seropositive rates and limited health care resources had an increased seroprevalence of anti-HCV after adjustment for individual risk factors. The multivariate-adjusted odds ratio (95% confidence interval) was 3.74 (2.70-5.19) for high (versus low) seropositive rate of HCV RNA, and 1.90 (1.34-2.69) for limited (versus adequate) health care resource. Conclusions: This study suggests the community risk factors contribute significantly in the variation of anti-HCV seroprevalence. It implies both the adequacy of health care resources and the treatment of patients seropositive for HCV RNA will prevent individual residents from acquisition of HCV infection from the community. Study 2: Hepatitis C Seromarkers and Subsequent Risk of Hepatocellular Carcinoma Background and Aims: Hepatitis C virus (HCV) contributes to one-third of hepatocellular carcinoma cases worldwide. Long-term predictors for HCV-related hepatocellular carcinoma are essential for early intervention. Serum HCV RNA and alanine aminotransferase (ALT) levels and HCV genotype were assessed for their predictability of hepatocellular carcinoma risk. Methods: A prospective cohort of 925 participants positive for antibodies against HCV and aged 30-65 years were recruited and followed from 1991 to 2006. Serum HCV RNA and ALT levels and HCV genotypes at enrollment and during follow-up were examined. Newly-developed hepatocellular carcinoma was identified by health examination and computerized linkage with national cancer registration and death certification profiles. Multivariate-adjusted hazard ratios with 95% confidence intervals were estimated by Cox regression models. Results: There were 55 newly-developed hepatocellular carcinoma cases during 8,476 person-years of follow-up, giving an incidence rate of 648.9 per 100,000 person-years. The cumulative hepatocellular carcinoma risk increased from 1.1% for HCV RNA seronegatives, 6.4% for low HCV RNA levels, to 14.7% for high HCV RNA levels (p<0.001). The cumulative risk also increased with elevated serum ALT levels from 1.7% for persistently ≤15 U/L, 4.2% for ever >15 U/L but never >45 U/L, to 13.8% for ALT ever >45 U/L (p<0.001). HCV genotype 1 was associated with a higher cumulative hepatocellular carcinoma risk (12.6%) than HCV genotype non-1 (4.5%, p<0.001). Conclusions: Elevated serum levels of HCV RNA and ALT and HCV genotype 1 infection are independent risk predictors of hepatocellular carcinoma. These findings have strong implications for the management of chronic hepatitis C. Study 3: Hepatitis C Virus Infection Associated with Hepatic and Extrahepatic Mortality Background and Aims: Hepatitis C virus (HCV) infection is associated with hepatic and extrahepatic disease. However, it has rarely been examined the risk of all causes of death systematically after HCV infection, including those with persistent HCV infection. Methods: The R.E.V.E.A.L.-HCV cohort enrolled 23,820 adults aged 30-65 years old in community during 1991-1992. The seromarkers including HBsAg, anti-HCV, and serum HCV RNA were tested at study entry. The vital status was followed by computerized linkage with national death registration system from 1991-2008 via matching each participant’s name, identification number, and birthday and the specific causes of death were categorized according to ICD9. The mortality rate was calculated by the number of specific-cause of death divided by the person-years of follow-up. The Cox’s proportional hazards model was utilized to estimate the hazard ratios with 95% confidence intervals. Results: A total of 19,636 HBsAg seronegatives (18,541 anti-HCV seronegatives and 1,095 anti-HCV seropositives) included in this study. Among anti-HCV seropositives, 69.4% were positive for HCV RNA. There were 2394 deaths occurred in this cohort during an average of 16.2 year follow-up, giving an overall mortality rate of 753.4 per 100,000 person-years. The all cause mortality was 708.8 for anti-HCV seronegative, 741.0 for HCV RNA seronegatives, and 1879.8 per 100,000 person-years for HCV RNA seropositives. The liver-related mortalitywas 37.2, 82.3, 678.3 per 100,000 person-years for anti-HCV seronegatives, HCV RNA seronegatives, and HCV RNA seropositives, respectively. Participants with detectable HCV RNA had increased risk for extrahepatic diseases with trend (p<0.001), including deaths from cerebrovascular and renal diseases. Conclusion: Chronic hepatitis C patients had elevated risk for all-cause, liver-related, and extrahepatic diseases. Study 4: Chronic Hepatitis C Virus Infection and Cerebrovascular Disease Background and Aims: The association between hepatitis C virus (HCV) infection and cerebrovascular disease remains controversial. This study aimed to assess the risk of lethal cerebrovascular diseases associated with chronic HCV infection. Methods: In this community-based prospective cohort study, 23,665 residents (aged 30-65years) were enrolled in 1991-1992. They were personally interviewed using structuredquestionnaires and provided blood samples for various serological and biochemical tests at study entry. Serum HCV RNA level and HCV genotype were tested for participants seropositive for antibodies against HCV (anti-HCV). Deaths from cerebrovascular disease during follow-up were ascertained by computerized linkage with National Death Certification profiles from 1991 to 2008 (ICD-9: 430-438). Multivariate-adjusted hazard ratio (HR) with 95% confidence interval (CI) was estimated for each risk predictor. Results: There were 255 cerebrovascular deaths during 382,011 person-years of follow-up. The cumulative risk of cerebrovascular deaths were 1.0% and 2.7% for seronegatives and seropositives of anti-HCV, respectively (p<0.001). The HR (95% CI) of cerebrovascular death was 2.11 (1.42-3.14) for anti-HCV seropositives after adjustment for several conventional risk factors of cerebrovascular disease. Compared with participants seronegative for anti-HCV as the referent, the multivariate-adjusted HR (95% CI) was 1.43 (0.63-3.23), 2.29 (1.38-3.82) and 2.81 (1.25-6.35), respectively, for anti-HCV-seropositive participants with undetectable, low and high serum levels of HCV RNA (p<0.001 for trend). However, no significant association was found between HCV genotype and cerebrovascular death. Conclusions: Chronic HCV infection is an independent risk predictor of cerebrovascular deaths showing a biological gradient of cerebrovascular mortality with increasing serum HCV RNA level. In summary, HCV infection was prevalent and high HCV RNA positive rate in a community increased personal risk of HCV infection in that area. Moreover, anti-HCV seropositives with positive HCV RNA had elevated risks for both hepatic and extrahepatic diseases. Our results indicated that management of anti-HCV seropositives with HCV RNA viremia is important for HCV infection and HCV-related disease controls.