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Hepatitis B-related outcomes following direct-acting antiviral therapy in Taiwanese patients with chronic HBV/HCV co-infection
(2020-07-01)
Yeh, Ming-Lun
;
Huang, Chung-Feng
;
Huang, Ching-, I
;
Holmes, Jacinta A.
;
Hsieh, Meng-Hsuan
dynamics of HBsAg and HBV virological reactivation, among patients coinfected with HCV receiving direct-acting antivirals (DAAs) remains unclear. Thus, we aimed to analyze HBV-related outcomes in these patients. Methods: Serial HBsAg and HBV DNA levels were measured in 79 HBV/HCV-coinfected patients receiving DAAs (13 receiving anti-HBV nucleot(s)ide analog [NUC] therapy simultaneously). The endpoints included HBsAg dynamics and seroclearance, HBV reactivation (HBV DNA >1 log increase or >100 IU/ml if undetectable at baseline) and HBV-related clinical reactivation. Results: HBsAg levels declined from a median of 73.3 IU/ml at baseline to 16.2 IU/ml at the end-of-DAA treatment and increased to 94.1 IU/ml at 12 months post-treatment. During a mean 11.1-months of follow-up, 8 (10.1%) patients experienced HBsAg seroclearance and 30 (38.0%) HBV reactivation (12-month cumulative incidence, 10.3% and 40.4%, respectively). Patients with pre-treatment HBsAg <= 10 IU/ml had a significantly higher rate of HBsAg seroclearance (hazard ratio [HR] 8.52; 95% CI 1.048-69.312) and lower risk of HBV reactivation than those with pre-treatment HBsAg >10 IU/ml (HR 2.88; 95% CI 1.057-7.844) in multivariate analyses. Six patients (4 cirrhotics) not receiving NUC therapy experienced HBV-related clinical reactivation; 3 of the 4 cirrhotics developed liver failure and 2 died despite immediate NUC therapy. Compared to untreated HBV-monoinfected patients, HBV/HCV-coinfected patients without NUC prophylaxis had a similar rate of HBsAg seroclearance, but a significantly higher risk of HBV reactivation following DAA therapy (HR 6.59; 95% CI 2.488-17.432). Conclusions: DAA-treated HBV/HCV-coinfected patients had significantly higher rates of HBV seroclearance, particularly among those with low pre-treatment HBsAg titer, but were at higher risk of HBV reactivation, particularly among those with higher pretreatment HBsAg titer. Prophylactic anti-HBV therapy is essential for cirrhotic patients, irrespective of baseline HBV DNA levels. Lay summary: We studied outcomes relating to hepatitis B virus (HBV) in patients coinfected with both hepatitis B and C. Patients receiving direct-acting antiviral treatment for hepatitis C were more likely to experience seroclearance (or functional cure of HBV), but were also more likely to experience HBV reactivation, which can lead to hepatitis, liver failure and death. In coinfected cirrhotic patients being treated for HCV, prophylactic treatment for HBV is mandatory. (C) 2020 European Association for the Study of the Liver. Published by Elsevier B.V.
Cure or curd: Modification of lipid profiles and cardio-cerebrovascular events after hepatitis C virus eradication
(1970-01-01)
Huang, Chung-Feng
;
Dai, Chia-Yen
;
Yeh, Ming-Lun
;
Huang, Ching-, I
;
Lee, Hsiang-Chun
Hepatitis C virus (HCV) eradication deteriorates lipid profiles. Although HCV eradication may reduce the risk of vascular events as a whole, whether deteriorated lipid profiles increases the risk of cardio-cerebral disease in certain patients is elusive. Serial lipid profiles were measured before, during, at and 3 months after the end of direct-acting antivirals (DAAs) therapy, and annually thereafter in chronic hepatitis C patients who achieved a sustained virological response (SVR, undetectable HCV RNA at posttreatment week 12). The primary end-point was the occurrence of the events. A total of 617 patients were included, with a mean follow-up period of 26.8 months (range: 1-65 months). The total cholesterol and low-density lipoprotein cholesterol (LDL-C) levels increased significantly from treatment week 4 to 2 years after treatment. Logistic regression analysis revealed that the factors independently associated with a significant cholesterol increase included age (odds ratio [OR]/95% confidence intervals [CIs]:1.02/1.006-1.039,P= .007) and smoking (OR/CI:3.21/1.14-9.02,P= .027). Five patients developed cardio-cerebral diseases during 1376 person-years follow-up period. Compared to patients without vascular events, a significantly higher proportion of those with vascular events experienced an LDL-C surge >40% (80% vs 19.9%,P= .001). Cox-regression analysis revealed that an LDL-C surge >40% was the only factor predictive of vascular events (HR/CI: 15.44/1.73-138.20,P= .014). Dyslipidemia occurred after HCV eradication, and it was associated with the risk of cardio-cerebrovascular diseases. Attention should also be paid to the extrahepatic consequence beyond liver-related complications in the post-SVR era.
APASL HCV guidelines of virus-eradicated patients by DAA on how to monitor HCC occurrence and HBV reactivation
(2019-11-01)
Kanda, Tatsuo
;
Lau, George K. K.
;
Wei, Lai
;
Moriyama, Mitsuhiko
;
Yu, Ming-Lung
In the direct-acting antiviral (DAA) era for hepatitis C virus (HCV) infection, sustained virological response (SVR) is very high, but close attention must be paid to the possible occurrence of hepatocellular carcinoma (HCC) and reactivation of hepatitis B virus (HBV) in patients with co-infection who achieved SVR in short term. HCC occurrence was more often observed in patients with previous HCC history. We found occurrence of HCC in 178 (29.6%) of 602 patients with previous HCC history (15.4 months mean follow-up post-DAA initiation) but, in contrast, in only 604 (1.3%) of 45,870 patients without previous HCC history (18.2 months mean follow-up). Thus, in these guidelines, we recommend the following: in patients with previous HCC history, surveillance at 4-month intervals for HCC by ultrasonography (US) and tumor markers should be performed. In patients without previous HCC history, surveillance at 6- to 12-month intervals for HCC including US is recommended until the long-term DAA treatment effects, especially for the resolution of liver fibrosis, are confirmed. This guideline also includes recommendations on how to follow-up patients who have been infected with both HCV and HBV. When HCV was eradicated in these HBsAg-positive patients or patients with previous HBV infection ( anti-HBc and/ or anti-HBs-positive), it was shown that HBV reactivation or HBV DNA reappearance was observed in 67 (41.4%) of 162 or 12 (0.9%) of 1317, respectively. For these co-infected patients, careful attention should be paid to HBV reactivation for 24 weeks post-treatment.
Elevated interleukin-4 levels predicted advanced fibrosis in chronic hepatitis C
(2019-04-01)
Batsaikhan, Batbold
;
Lu, Ming-Ying
;
Yeh, Ming-Lun
;
Huang, Ching-, I
;
Huang, Chung-Feng
Background: Cytokine imbalance has been associated with chronic hepatitis C virus (HCV) infection. We hypothesized that cytokines have an important role in fibrosis development in HCV infection. Methods: Data of 92 patients were analyzed retrospectively. Fluorescent Bead immunoassay was used to measure the following serum cytokine levels: Interferon , tumor necrosis factor , interleukin (IL)-1, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, and IL-12. Various statistical analyses were used as appropriate. Results: Of the 92 HCV-infected patients, 49 (53.3%) were male, 23 (25%) patients had advanced (fibrosis grades 3-4) fibrosis, and the mean age of the study population was 51.9 9.4 years. Elevation of baseline IL-4 level (>490 pg/mL) was associated with liver fibrosis grade by (2) test (odds ratio [OR] = 2.99; 95%, CI = 1.02-8.78; p = 0.042) and multivariate logistic regression (OR = 4.26; 95% CI = 1.13-16.02; p = 0.032). Also, IL-4 had strong diagnostic value in advanced liver fibrosis by using area under receiver operating characteristics curve analysis. Assessment of fibrosis score was consequently developed from our findings and compared with other noninvasive serum markers to assess liver fibrosis. Conclusion: This study provides evidence that increased IL-4 expression predicted advanced liver fibrosis in treatment of naive HCV-infected patients. The newly developed FIL4 score had good predictive value for advanced fibrosis before treatment and this value was even strong in HCV-genotype 1b patients.
Association of serial serum major histocompatibility complex class I chain-related A measurements with hepatocellular carcinoma in chronic hepatitis C patients after viral eradication
(2019-01-01)
Huang, Chung-Feng
;
Wang, Shu-Chi
;
Yeh, Ming-Lun
;
Huang, Ching-I
;
Tsai, Pei-Chien
Background and Aim Major histocompatibility complex class I chain-related A (MICA) genetic variants and their serum levels (sMICA) were associated with the development of hepatitis C virus-related hepatocellular carcinoma (HCC) in untreated cohorts. The dynamic changes in serial sMICA levels and their association with HCC in the post-curative status are elusive. Methods Single nucleotide polymorphism rs2596542 of MICA and serial sMICA levels were analyzed in chronic hepatitis C patients with a sustained virologic response after antivirals. Forty-two patients who developed HCC and 84 age-matched, gender-matched, and cirrhosis propensity score-matched non-HCC controls were compared. Serial sMICA levels were measured within 6 months before treatment initiation (pre-sMICA), 6 months after the end of treatment (post-sMICA), and on the last visit before the development (or not) of HCC (last-sMICA). Results Cox regression analysis revealed that last-sMICA was the only predictive factor of HCC development (hazard ratio/95% confidence interval: 2.27 (per 1 log pg/mL increase)/1.672-3.082, P < 0.001). Patients without HCC development showed a significantly reduced trend of sMICA levels during follow-up (trend P = 0.001), which was observed only in GG genotype (trend P < 0.001) but not A allele carriers (P = 0.88). In contrast, patients with HCC showed an increased trend of sMICA levels (trend P = 0.024). However, only the GG genotype "high expressors" (trend P = 0.06) but not A allele carriers (P = 0.18) showed a correlation of substantially increased trend of sMICA levels and HCC development. Conclusions Serial sMICA levels were associated with HCC development in SVR patients. The clinical utility of this finding is restricted to MICA rs2596542 GG genotype carriers.
Post-treatment fibrotic modifications overwhelm pretreatment liver fibrosis in predicting HCC in CHC patients with curative antivirals
(2018-11-01)
Huang, Chung-Feng
;
Yeh, Ming-Lun
;
Huang, Ching-I
;
Liang, Po-Cheng
;
Lin, Yi-Hung
Background/aimsLiver fibrosis determined hepatocellular carcinoma (HCC) occurrence in chronic hepatitis C patients with sustained virological response (SVR). We aimed to determine whether post-treatment fibrotic modification overwhelmed pretreatment fibrotic status in terms of long-term HCC prediction.Methods265 SVR patients with paired biopsies before and after antiviral therapy were enrolled for analysis of the association of fibrotic changes with HCC.ResultsEighteen (6.8%) of the 265 patients developed HCC over 1931 person-years. Cox regression analysis without post-treatment fibrosis as a covariant revealed that factors predicted HCC included age (hazard ratio [HR]/confidence intervals [CI] 1.07/1.01-1.13, p=0.01), male gender (HR/CI 4.57/1.45-14.36, p=0.009), diabetes (HR/CI 3.60/1.32-9.85, p=0.01) and pretreatment advanced fibrosis (HR/CI 2.73/1.05-7.07, p=0.039). Advanced fibrosis in post-treatment status replaced pretreatment fibrosis as the most critical determinant of HCC when it was included for analysis (HR/CI 3.53/1.34-9.30, p=0.01). The incidences of HCC among patients with fibrotic modification from F0-2 to F0-2, F34 to F0-2, F0-2 to F34 and F34 to F34 were 0.41%, 0.84%, 1.68%, and 3.05%, respectively (p=0.004). Compared to patients whose fibrotic stage remained at F0-2 before and after treatment, the HCC risk decreased and did not differ among those whose fibrotic stage improved from F34 to F0-2. However, HCC risk increased significantly and gradually in patients whose fibrotic stages changed from F0-2 to F34 (HR/CI 4.13/1.11-15.36, p=0.035) and whose fibrotic stages remained at F34 before and after treatment (HR/CI 7.47/2.37-23.55, p=0.001) (trend p=0.003).ConclusionsPost-treatment fibrotic modifications overwhelmed pretreatment fibrotic statuses in predicting HCC.
Interference of hepatitis B virus dual infection in platelet count recovery in chronic hepatitis C patients with curative antiviral therapy
(2018-05-01)
Huang, Chung-Feng
;
Yeh, Ming-Lun
;
Huang, Ching-I
;
Lin, Zu-Yau
;
Chen, Shinn-Cherng
Background and AimHepatitis C virus infection is associated with thrombocytopenia. Thrombocytopenia recovers after viral eradication. The current study explored the rate and factors associated with platelet (PLT) recovery, which may represent the degree of liver fibrosis regression. MethodsA total of 466 patients who achieved a sustained virological response were enrolled to compare the PLT change after a mean follow-up period of 85.5months (range 12-163months). ResultsPlatelet counts increased significantly after achieving sustained virological response (from 16655x10(3) to 201 +/- 61x10(3)u/L, P<0.001). The median PLT count increment was 5.03x10(3)u/L per year. Logistic regression analysis revealed that factors associated with slow PLT count recovery were high pretreatment PLT counts (odds ratio [OR]/ 95% confidence intervals [CI]: 0.992/0.989-0.996, P<0.001) and hepatitis B virus (HBV) co-infection (OR/CI: 0.416/0.220-0.785, P=0.007). High PLT counts were the only factor associated with slow PLT recovery in patients with mild liver disease (F0-2) (OR/CI: 0.992/0.987-0.996, P<0.001). On the other hand, HBV co-infection was the only factor associated with slow PLT recovery in patients with advanced fibrosis (OR/CI: 0.207/0.054-0.789, P=0.02). Linear regression analysis of factors correlated to the delta PLT count change per year in patients with F0-2 included pretreatment white blood cell (: -0.001; CI: -0.002-0.000; P=0.01) and pretreatment PLT counts (: -0.037; CI: -0.061 to -0.013; P=0.003). HBsAg seropositivity was the only factor correlated to the delta PLT count change per year (: -10.193; CI: -16.752-3.635; P=0.003) among patients with F3-4. ConclusionsPlatelet counts recovered after hepatitis C virus eradication. HBV dual infection disrupted PLT count recovery, especially in CHC patients with advanced liver disease.
Treating hepatitis C in the elderly: pharmacotherapeutic considerations and developments
(2017-01-01)
Huang, Chung-Feng
;
Yu, Ming-Lung
;
生物科技學院
;
College of Biological Science and Technology
Introduction: The seroprevalence of hepatitis C virus (HCV) infection tends to be higher in the elderly than in younger populations. Meanwhile, age per sec is an unfavorable determinant that has an impact on liver-related outcomes. Geriatric chronic hepatitis C (CHC) patients would be viewed as a special population and have an urgent need for viral eradication. Areas covered: The antivirals for CHC have evolved from interferon (IFN)-based therapyto interferon-free DAAs. The treatment strategy, in terms of its clinical efficacy and drug safety, in the elderly is presented. Expert opinion: In the previous IFN era, the sustained virological response (SVR) rate of the elderly was lower. More unfavorable safety concerns attributing to the underlying liver disease severity and extrahepatic presentations further compromised the treatment efficacy. In the IFN-free DAA era, data showing similar SVR rates and safety profiles between the elderly and their counterparts have been demonstrated. Notably, aging is an unfavorable factor for fibrosis regression and HCC development even after HCV eradication. The extent of the improvement of extra-hepatic manifestations in the elderly with SVR is also unclear. The long-term benefits of viral eradication by DAAs in the elderly await further explorations.
DDX3 RNA解螺旋脢及其交互作用蛋白於C型肝炎病毒複製所扮演之角色及作用機制之探討
(2010)
吳妍華
;
國立交通大學生物科技學系（所）
C 型肝炎病毒為輸血性非A 非B 型肝炎的主要肇因，其持續性潛伏感染可導致慢性肝炎,肝硬化甚至肝癌的發生。目前為止，C 型肝炎病毒之生活史尚未完全釐清，然透過部分基因組複製系統Con-1 及具感染力之全基因組複製病毒株JFH-1 之研究，已有了長足的看見。研究指出，多種細胞因子可與病毒蛋白或病毒RNA 基因組之5’或3’端結合而調節病毒之基因組複製，並為病毒複製所必須。而RNA 解螺旋酶DDX3 則為其中之一。多年來，本實驗室致力於闡明RNA 解螺旋酶DDX3 之生物功能，過去之研究成果指出DDX3 廣泛地參與轉錄、轉譯、RNA 剪輯等細胞生理活動之調控，並影響細胞之生長，為一新穎之抑癌基因。此外，該蛋白可與C 型肝炎病毒核心蛋白發生交互作用，其ATP 水解及RNA 解螺旋酵素活性並因此而增強。目前，利用試管內及活體內結合實驗，本實驗室亦發現C 型肝炎病毒非結構蛋白5B 可與DDX3 發生交互作用。由於研究報告指出，DDX3 可與病毒RNA 基因組之3’端結合，因此，我們推測DDX3 可藉由與病毒複製所必須之病毒蛋白發生交互作用並與病毒基因組結合而參與了病毒的基因組複製。因此，為驗證此一假說並釐清DDX3 參與病毒複製的作用機轉，本計畫將進行下述研究：由於DDX3 為病毒複製所必須且其酵素活性受病毒蛋白之調控，故本實驗室首先將釐清DDX3 之酵素活性對於C 型肝炎病毒複製之調控是否必須。我們將檢視DDX3 是否亦可與HCV RNA 基因組之5’端或反基因組之5’與3’非轉譯區域結合，並劃定這些 RNA 片段上之DDX3 結合區。我們亦將找出DDX3 之RNA 結合功能區，並利用定點突變的方式破壞DDX3 的ATP 水解，RNA 解螺旋及RNA 結合活性，並偵測這些酵素活性的喪失對病毒複製的影響，以瞭解DDX3 酵素活性對病毒複製的重要性。接著，我們將進一步闡明DDX3 與病毒蛋白之交互作用對於病毒複製的影響。本實驗室將檢視DDX3 與核心蛋白及非結構蛋白5B 之交互作用是否增強病毒之複製，並偵測病毒蛋白對DDX3 酵素活性的影響，及DDX3 對非結構蛋白5B 之RNA依賴性RNA 聚合酶活性之調節，以明瞭DDX3 與病毒蛋白交互作用對病毒複製影響的作用機轉。最後，我們將探討一個可與病毒RNA 基因組之3’端非轉譯區域結合之DDX3 交互作用蛋白YB-1 於C 型肝炎病毒複製中扮演的角色。我們將探討細胞中YB-1 表現與否對於病毒複製的影響。研究該蛋白與C 型肝炎病毒基因組與反基因組RNA 之結合，及其RNA 結合特性對於病毒複製之調控是否必須。我們亦將檢視該蛋白是否與病毒蛋白或病毒複製酵素複合物結合而參與了病毒的複製過程，並探討YB-1 與DDX3 之交互作用對於病毒複製的影響，以進一步釐清宿主細胞因子影響病毒複製之作用機轉。總而言之，透過本計畫，吾人將瞭解DDX3 影響C 型肝炎病毒複製之分子作用機轉，並提供宿主細胞因子透過蛋白交互作用而介入病毒複製之模式，將有利於未來C 型肝炎病毒治療方式之設計與開發。
DDX3 RNA解螺旋脢及其交互作用蛋白於C型肝炎病毒複製所扮演之角色及作用機制之探討
(2009)
吳妍華
;
國立交通大學生物科技學系（所）
C 型肝炎病毒為輸血性非A 非B 型肝炎的主要肇因，其持續性潛伏感染可導致慢性肝炎,肝硬化甚至肝癌的發生。目前為止，C 型肝炎病毒之生活史尚未完全釐清，然透過部分基因組複製系統Con-1 及具感染力之全基因組複製病毒株JFH-1 之研究，已有了長足的看見。研究指出，多種細胞因子可與病毒蛋白或病毒RNA 基因組之5’或3’端結合而調節病毒之基因組複製，並為病毒複製所必須。而RNA 解螺旋酶DDX3 則為其中之一。多年來，本實驗室致力於闡明RNA 解螺旋酶DDX3 之生物功能，過去之研究成果指出DDX3 廣泛地參與轉錄、轉譯、RNA 剪輯等細胞生理活動之調控，並影響細胞之生長，為一新穎之抑癌基因。此外，該蛋白可與C 型肝炎病毒核心蛋白發生交互作用，其ATP 水解及RNA 解螺旋酵素活性並因此而增強。目前，利用試管內及活體內結合實驗，本實驗室亦發現C 型肝炎病毒非結構蛋白5B 可與DDX3 發生交互作用。由於研究報告指出，DDX3 可與病毒RNA 基因組之3’端結合，因此，我們推測DDX3 可藉由與病毒複製所必須之病毒蛋白發生交互作用並與病毒基因組結合而參與了病毒的基因組複製。因此，為驗證此一假說並釐清DDX3 參與病毒複製的作用機轉，本計畫將進行下述研究：由於DDX3 為病毒複製所必須且其酵素活性受病毒蛋白之調控，故本實驗室首先將釐清DDX3 之酵素活性對於C 型肝炎病毒複製之調控是否必須。我們將檢視DDX3 是否亦可與HCV RNA 基因組之5’端或反基因組之5’與3’非轉譯區域結合，並劃定這些 RNA 片段上之DDX3 結合區。我們亦將找出DDX3 之RNA 結合功能區，並利用定點突變的方式破壞DDX3 的ATP 水解，RNA 解螺旋及RNA 結合活性，並偵測這些酵素活性的喪失對病毒複製的影響，以瞭解DDX3 酵素活性對病毒複製的重要性。接著，我們將進一步闡明DDX3 與病毒蛋白之交互作用對於病毒複製的影響。本實驗室將檢視DDX3 與核心蛋白及非結構蛋白5B 之交互作用是否增強病毒之複製，並偵測病毒蛋白對DDX3 酵素活性的影響，及DDX3 對非結構蛋白5B 之RNA依賴性RNA 聚合酶活性之調節，以明瞭DDX3 與病毒蛋白交互作用對病毒複製影響的作用機轉。最後，我們將探討一個可與病毒RNA 基因組之3’端非轉譯區域結合之DDX3 交互作用蛋白YB-1 於C 型肝炎病毒複製中扮演的角色。我們將探討細胞中YB-1 表現與否對於病毒複製的影響。研究該蛋白與C 型肝炎病毒基因組與反基因組RNA 之結合，及其RNA 結合特性對於病毒複製之調控是否必須。我們亦將檢視該蛋白是否與病毒蛋白或病毒複製酵素複合物結合而參與了病毒的複製過程，並探討YB-1 與DDX3 之交互作用對於病毒複製的影響，以進一步釐清宿主細胞因子影響病毒複製之作用機轉。總而言之，透過本計畫，吾人將瞭解DDX3 影響C 型肝炎病毒複製之分子作用機轉，並提供宿主細胞因子透過蛋白交互作用而介入病毒複製之模式，將有利於未來C 型肝炎病毒治療方式之設計與開發。

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🏛️國立陽明交通大學機構典藏

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