Browsing by Author "Yu, Ming-Lung"

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A real world cost effectiveness analysis of interferon-based therapy for HCV naive super-responders
(2018-08-01)
Tsai, Pei-Chien
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Liu, Ta-Wei
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Huang, Chung-Feng
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Yeh, Ming-Lun
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Dai, Chia-Yen
Background: A direct-acting antiviral (DAA) era in hepatitis C virus (HCV) treatment is fast approaching; unfortunately, the availability and affordability of DAAs in Asia Pacific areas vary, making it difficult to develop universal HCV practice guidelines appropriate for the all Asian populations. This study aimed to evaluate the real-world cost-effectiveness of IFN-based therapy according to the current strategies with PegIFN/RBV for "easy-to-treat" to provide a reference for application of future DAA development for IFN-eligible, treatment nave HCV patients. Methods: A total of 1032 chronic hepatitis C treatment-naive patients who corresponded to response-guided therapy (RGT) guidelines of PegIFN/RBV regimens were linked to the entire population of expenditures and order in the National Health Insurance Research Database of Taiwan. The average total cost per SVR achieved was calculated as the summation of the total cost for all treated patients/number of SVR cases. Results: Current RGT suggested 24 weeks of PegIFN/RBV for GI naive patients with baseline LVL and RVR at treatment week 4 achieved an average treatment cost per SVR of $5090 +/- 2400. This was of superior cost-effectiveness compared with those other subgroups of GI patients. In terms of G2 patients, according to current RGT of 16 weeks of treatment duration, PegIFN/RBV treatment with RVR achieved was of a very competitive cost per SVR ($3237 +/- 488). Conclusion: For a nave patient in the new DAA era, the PegIFN/RBV treatment might be conserved for those with all favorable risk parameters, considering the treatment duration and cost per SVR, in the resource-constrained countries. Copyright (C) 2018, the Chinese Medical Association. Published by Elsevier Taiwan LLC.
An Open-Label, Randomized, Active-Controlled Trial of 8 Versus 12 Weeks of Elbasvir/Grazoprevir for Treatment-Naive Patients With Chronic Hepatitis C Genotype 1b Infection and Mild Fibrosis (EGALITE Study): Impact of Baseline Viral Loads and NS5A Resistance-Associated Substitutions
(2019-08-15)
Huang, Chung-Feng
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Hung, Chao-Hung
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Cheng, Pin-Nan
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Bair, Ming-Jong
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Huang, Yi-Hsiang
Background. A 12-week grazoprevir/elbasvir regimen is highly effective against hepatitis C virus genotype 1 (HCV-1) infection. The efficacy of an 8-week regimen for treatment-naive HCV-1-infected patients with mild fibrosis has not been determined. Methods. Treatment-naive HCV-1b-infected patients with mild fibrosis were randomly assigned to receive 8 (n = 41) or 12 (n = 41) weeks of grazoprevir/elbasvir therapy. The primary end point was a sustained virologic response, defined as an HCV RNA level of < 12 IU/mL, at posttreatment week 12 (SVR12). Results. SVR12 was achieved by 87.8% of patients (36 of 41) in the 8-week arm and 100% (41 of 41) in the 8-week arm of the full-analysis population and by 90.0% (36 of 40) and 100% (41 of 41), respectively, in the per-protocol population (all P = .055). In the 8-week arm, a significantly lower SVR12 rate was observed among patients with a high HCV-1b load, defined as >= 1 500 000 IU/mL (79% vs 100%; P =.042), and among those with a baseline Y93H resistance-associated substitution (RAS) frequency of >15% in HCV nonstructural protein 5A (NS5A; 40.0% vs 97.1%; P = .004). Between-group analysis demonstrated that, among patient with a high HCV-1b load and a baseline Y93H RAS frequency of >15%, those in the 8-week arm had a substantially lower SVR12 rate than those in the 12-week arm (40.0% vs 100.0%). All 4 HCV-1b relapses had a Y93H RAS frequency of >99% at posttreatment week 12. Conclusions. Twelve weeks of grazoprevir/elbasvir therapy is highly effective for treatment-naive patients with mild fibrosis. A truncated, 8-week grazoprevir/elbasvir regimen might be applied for those with low viral loads or without a significant NS5A RAS frequency.
APASL HCV guidelines of virus-eradicated patients by DAA on how to monitor HCC occurrence and HBV reactivation
(2019-11-01)
Kanda, Tatsuo
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Lau, George K. K.
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Wei, Lai
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Moriyama, Mitsuhiko
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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.
Association of hyperuricemia with disease severity in chronic hepatitis C patients
(2018-11-05)
Jang, Tyng-Yuan
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Yeh, Ming-Lun
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Huang, Ching-, I
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Lin, Zu-Yau
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Chen, Shinn-Cherng
Background/aims Hepatitis C virus (HCV) infection is associated with extrahepatic manifestations such as metabolic abnormalities. The association between chronic hepatitis C (CHC) and uric acid levels has rarely been investigated. We aimed to evaluate the levels of serum uric acid in CHC patients. Methods Three hundred and seventy-three histologically confirmed CHC patients who were scheduled to receive antiviral therapy were consecutively enrolled, and 746 age- and sex-matched uninfected controls were included for comparison. Hyperuricemia was defined as a uric acid level > 7 mg/dL in men and > 6.0 mg/dL in women. Results Hyperuricemia was identified in 15.8% of the CHC patients. The uric acid levels did not differ between the CHC patients and the controls (5.54 +/- 1.20 mg/dL vs. 5.45 +/- 1.45 mg/dL, P = 0.3). Among the 373 CHC patients, the factors associated with hyperuricemia included body mass index (BMI) (OR/CI: 1.13/1.04-1.21, P = 0.003) and estimated glomerular filtration rate (eGFR) (OR/CI: 0.98/0.97-1.00, P = 0.02). Logistic regression analysis revealed that the factors associated with hyperuricemia in male patients included BMI (OR/CI: 1.12/1.05-1.30, P = 0.006) and advanced fibrosis (F3-4) (OR/CI: 0.27/0.09-0.83, P = 0.02), whereas the factors associated with hyperuricemia in female patients included eGFR (OR/CI: 0.97/0.95-0.99, P = 0.02) and diabetes (OR/CI: 3.03/1.11-8.25, P = 0.03). There was a significant decreasing trend of serum uric acid levels with the progression of fibrotic stages among male patients (6.21 +/- 1.03 mg/dL 5.82 +/- 1.16 mg/dL and 5.44 +/- 1.28 mg/dL in stages F0-2, F3, and F4, respectively, trend P = 0.01). Conclusions Hyperuricemia was inversely associated with liver disease severity in CHC male 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
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Wang, Shu-Chi
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Yeh, Ming-Lun
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Huang, Ching-I
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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.
Autophagy-related gene LC3 expression in tumor and liver microenvironments significantly predicts recurrence of hepatocellular carcinoma after surgical resection
(2018-07-02)
Lin, Chih-Wen
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Chen, Yaw-Sen
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Lin, Chih-Che
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Lee, Po-Huang
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Lo, Gin-Ho
Background: The role of autophagy-related markers as the prognostic factor of post-operative hepatocellular carcinoma (HCC) recurrence remained controversial. Methods: Overall, 535 consecutive HCC patients undergoing curative resection from 2010 to 2014 were followed and classified with early (ER, < 2 years) or late recurrence (LR). Autophagy-related markers, LC3, Beclin-1, and p62 expression was immunohistochemically assessed in HCC and adjacent non-tumor (ANT) tissues. Results: HCC recurred in 245 patients: 116 with ER and 129 with LR. The cumulative incidence of recurrence at 1, 3, 5, and 7 years was 9.7%, 33.9%, 53.3%, and 66.3%, respectively. In multivariate analysis, HCC recurrence was significantly associated with low LC3 expression in tumor and ANT tissues, HCC tissues only and ANT tissues only (hazard ratio/95% confidence interval: 6.12/2.473-17.53, 4.18/1.285-13.61, and 1.89/1.299-2.757) and macrovascular invasion (1.63/1.043-2.492) and cirrhosis (1.59/1.088-2.326). ER was significantly associated with low LC3 expression in tumor and ANT tissues, HCC tissues only and ANT tissues only (6.54/2.934-15.81, 3.26/1.034-10.27, and 2.09/1.313-3.321) and macrovascular and microvascular invasion (2.65/1.306-5.343 and 2.55/1.177-5.504). LR was significantly associated with low LC3 expression in tumor and ANT tissues, HCC tissues only and ANT tissues only (5.02/1.372-18.83, 3.19/1.13-12.09, and 1.66/1.051-2.620) and cirrhosis (1.66/1.049-2.631). Patients with low and high LC3 expression in tumor and ANT tissues showed a 5-year cumulative recurrence of 94.3% and 41.7%, respectively (p < 0.001). Conclusions: The high LC3 expression in the tumor and liver microenvironments is significantly associated with lower HCC recurrence. Furthermore, tumor characteristics and liver microenvironment were also significantly associated with ER and LR, respectively. Translational impact: The analysis for LC3 expression in both the HCC and ANT tissues could identify patients at risk of HCC recurrence.
Axl and autophagy LC3 expression in tumors is strongly associated with clinical prognosis of hepatocellular carcinoma patients after curative resection
(2019-07-01)
Hsu, Chia-Chang
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Hsieh, Pei-Min
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Chen, Yaw-Sen
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Lo, Gin-Ho
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Lin, Hung-Yu
Background The role of Axl and LC3 as predictors of tumor recurrence and overall survival (OS) after hepatocellular carcinoma (HCC) resection remains unclear. Methods We retrospectively included 535 HCC patients who underwent hepatectomy from 2010 to 2014 in this study. Axl and the autophagy-related marker LC3 were immunohistochemically assessed in tumors. Results Axl expression was significantly associated with advanced clinicopathological features, including cirrhosis, microvascular invasion, macrovascular invasion, tumor size, BCLC stage, recurrence, and mortality. HCC recurrence occurred in 245 patients, and 219 patients died. The 5-year cumulative incidences of HCC recurrence and OS rate after HCC resection were 53.3% and 58.8%, respectively. In the Cox proportional analyses, high Axl expression and high LC3 expression were significantly associated with HCC recurrence (hazard ratio [HR]: 3.85, 95% confidence interval [CI]: 2.95-5.02, P < 0.001; and HR: 0.38, 95% CI: 0.26-0.55, P < 0.001, respectively). In addition, HCC recurrence (HR: 2.87, 95% CI: 2.01-4.01, P < 0.0001), microvascular invasion (HR: 1.85, 95% CI: 1.08-3.19, P = 0.026), hepatitis B virus-related HCC (HR: 1.77, 95% CI: 1. 21-2.56, P = 0.003), high Axl expression (HR: 1.66, 95% CI: 1.41-1.97, P < 0.0001), antiviral therapy (HR: 0.54, CI: 0.38-0.76, P < 0.001) and LC3 expression (HR: 0.41, 95% CI: 0.28-0.58, P < 0.001) were significantly associated with mortality. Furthermore, patients with a combination of high Axl and low LC3 expression had the highest risk of HCC recurrence (HR: 6.53, 95% CI: 4.11-10.4, P < 0.001) and mortality (HR: 6.66, 95% CI: 4.07-10.9, P < 0.001). In patients with high Axl, low LC3, and combined high Axl and low LC3 expression, the 5-year cumulative incidences of HCC recurrence and OS rate were 77.9%, 73.3%, and 90.0% and 28.8%, 26.7%, and 16.8%, respectively. Conclusion High Axl expression in tumors is associated with aggressive tumor behavior and worse clinical outcomes. Furthermore, the combination of high Axl and low LC3 expression significantly predicts poorer prognosis for HCC patients who underwent hepatectomy.
Clusters of Circulating let-7 Family Tumor Suppressors Are Associated with Clinical Characteristics of Chronic Hepatitis C
(2020-07-01)
Tsai, Yi-Shan
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Yeh, Ming-Lun
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Tsai, Pei-Chien
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Huang, Ching-, I
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Huang, Chung-Feng
Hepatitis C virus (HCV) infections can cause permanent liver-related diseases, including hepatocellular carcinoma (HCC). Low mortality and incidence of HCC have been observed in patients with chronic hepatitis C undergoing direct-acting antiviral therapy. Tumor suppressive let-7 family members are down-regulated in HCC. The present study, therefore, aimed to investigate whether expression levels for the full spectrum of let-7 family members (let-7a, 7b, 7c, 7d, 7e, 7f, 7g, 7i, and miR-98) in the circulatory system are useful as surveillance biomarkers for liver-related diseases to monitor treatment efficacy during HCV infection. To this end, we measured the levels of mature circulating let-7 family members using quantitative reverse transcription-PCR in 236 patients with HCV infection, and 147 age- and sex-matched controls. Using hierarchical cluster analysis and principal component analysis, three clusters were obtained after measuring expression levels of let-7 family members in the patients and controls. Cluster 1 included let-7a/d/e/g, Cluster 2 comprised let-7b and let-7i, and Cluster 3 comprised let-7c/f/miR-98. Let-7b/c/g represented the three clusters and showed the best survival response to liver cancer when analyzed with respect to patient data. Therefore, considering the circulating levels of let7 b/c/g as representatives of the let-7 family may facilitate effective monitoring of liver-related disease.
Cure or curd: Modification of lipid profiles and cardio-cerebrovascular events after hepatitis C virus eradication
(1970-01-01)
Huang, Chung-Feng
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Dai, Chia-Yen
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Yeh, Ming-Lun
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Huang, Ching-, I
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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.
Direct-acting antivirals response in hepatocellular carcinoma: Does the presence of hepatocellular carcinoma matter?
(2019-06-01)
Huang, Chung-Feng
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Yu, Ming-Lung
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生物科技學院
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生醫工程研究所
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College of Biological Science and Technology
During the clinical trial development of directly acting antivirals (DAAs), evidence regarding the treatment efficacy in chronic hepatitis C patients with hepatocellular carcinoma (HCC) was scarce because these patients have always been excluded. Apart from the clinical trials, more HCC patients are currently being treated in daily practice, given that these treatments are highly effective and involve well-tolerated regimens. Large scale, real-world studies have demonstrated potentially suboptimal antiviral treatment efficacy in HCC patients who received DAAs. It is postulated that the impairment of the bioavailability of DAAs may account for the inferior treatment response. However, the results could not be generalized across all studies. The differing results were attributed to diverse patient characteristics, suboptimal regimens or imprecise definitions of active cancer statuses at the time of treatment initiation. Additional large-scale studies that utilize the treatment of choice in clearly defined HCC patients with different disease severities are warranted to clarify the issue.
Elevated interleukin-4 levels predicted advanced fibrosis in chronic hepatitis C
(2019-04-01)
Batsaikhan, Batbold
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Lu, Ming-Ying
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Yeh, Ming-Lun
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Huang, Ching-, I
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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.
Equal treatment efficacy of direct-acting antivirals in patients with chronic hepatitis C and hepatocellular carcinoma? A prospective cohort study
(2019-05-01)
Huang, Chung-Feng
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Yeh, Ming-Lun
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Huang, Ching-I
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Liang, Po-Cheng
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Lin, Yi-Hung
Objective The treatment outcome of direct-acting antivirals (DAAs) in chronic hepatitis C patients with hepatocellular carcinoma (HCC) is controversial. The current study aimed to address the treatment efficacy and safety of DAAs in patients with curative or active HCC, compared with those of patients without HCC. Design A prospective cohort study Setting A medical centre and two regional hospitals in Taiwan Participants A total of 713 Taiwanese patients (601 non-HCC, 74 curative HCC and 38 active HCC patients) who received standard-of-care DAAs were consecutively enrolled in the study. Main outcome measurement The primary objective was to determine treatment efficacy, defined as undetectable hepatitis C virus RNA throughout 12 weeks of the post-treatment follow-up period (sustained virological response 12 [SVR12]). Results The overall SVR12 rate was 96.9%. The SVR12 rate was similar between the patients with HCC and those without HCC (95.5% vs 97.2%, p=0.37). The HCC patients were divided into two groups, those with curative HCC and those with viable HCC; a substantially but not significantly lower SVR rate, 92.1% (35/38), was observed in the patients with viable HCC compared with the SVR rate, 97.3% (72/74), in those with curative HCC (p=0.33). Compared with the patients with curative HCC, the patients with viable HCC had a significantly higher proportion of serious adverse events (10.5% vs 1.0%, p=0.002), early treatment discontinuation (10.5% vs 2.8%, p=0.03) and mortality (5.3% vs 0.1%, p=0.008). Conclusions An equivalently high SVR rate was observed in patients with either past or active HCC compared with those without HCC. The safety concerns in the HCC patients did not compromise treatment efficacy.
Hepatitis B-related outcomes following direct-acting antiviral therapy in Taiwanese patients with chronic HBV/HCV co-infection
(2020-07-01)
Yeh, Ming-Lun
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Huang, Chung-Feng
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Huang, Ching-, I
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Holmes, Jacinta A.
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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.
Hepatitis C virus leaves an epigenetic signature post cure of infection by direct-acting antivirals
(2019-06-01)
Perez, Shira
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Kaspi, Antony
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Domovitz, Tom
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Davidovich, Ateret
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Lavi-Itzkovitz, Anat
The increasing worldwide prevalence of Hepatocellular carcinoma (HCC), characterized by resistance to conventional chemotherapy, poor prognosis and eventually mortality, place it as a prime target for new modes of prevention and treatment. Hepatitis C Virus (HCV) is the predominant risk factor for HCC in the US and Europe. Multiple epidemiological studies showed that sustained virological responses (SVR) following treatment with the powerful direct acting antivirals (DAAs), which have replaced interferon-based regimes, do not eliminate tumor development. We aimed to identify an HCV-specific pathogenic mechanism that persists post SVR following DAAs treatment. We demonstrate that HCV infection induces genome-wide epigenetic changes by performing chromatin immunoprecipitation followed by next-generation sequencing (ChIP-seq) for histone post-translational modifications that are epigenetic markers for active and repressed chromatin. The changes in histone modifications correlate with reprogramed host gene expression and alter signaling pathways known to be associated with HCV life cycle and HCC. These epigenetic alterations require the presence of HCV RNA or/and expression of the viral proteins in the cells. Importantly, the epigenetic changes induced following infection persist as an "epigenetic signature" after virus eradication by DAAs treatment, as detected using in vitro HCV infection models. These observations led to the identification of an 8 gene signature that is associated with HCC development and demonstrate persistent epigenetic alterations in HCV infected and post SVR liver biopsy samples. The epigenetic signature was reverted in vitro by drugs that inhibit epigenetic modifying enzyme and by the EGFR inhibitor, Erlotinib. This epigenetic scarring of the genome, persisting following HCV eradication, suggest a novel mechanism for the persistent pathogenesis of HCV after its eradication by DAAs. Our study offers new avenues for prevention of the persistent oncogenic effects of chronic hepatitis infections using specific drugs to revert the epigenetic changes to the genome. Author summary Hepatitis C virus (HCV) is a leading cause of hepatocellular carcinoma (HCC) in western countries. While direct acting antivirals (DAAs) therapy for HCV efficiently eradicates the infection, sustained virological response (SVR) following anti-HCV treatment does not eliminate the risk for HCC development. With the 3-4 million newly infected cases each year, it is estimated that HCV-associated disease burden remains high in the next decade and the population of post-DAA-based SVR patients is expected to grow exponentially in the near future. Therefore, Post-SVR HCC is an emerging problem with an urgent unmet need for the elucidation of its molecular mechanisms for therapeutic target and biomarker discovery. We demonstrate that HCV-induce epigenetic missregulation. These HCV-induced epigenetic changes reprogram host gene expression and persist as an "epigenetic signature" following virus eradication. Treatment of HCV-cured cells with specific inhibitors reverted the epigenetic signature. These results suggest a "hit and run" scenario that may explain why some chronic HCV infected patients do proceed to develop HCC after HCV eradication. Our discoveries provide an insight into the outcomes of HCV infection and HCC development, also following SVR, and novel approaches for its prevention.
Higher NAFLD fibrosis score is associated with impaired eGFR
(2020-01-01)
Hsieh, Meng-Hsuan
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Wu, Kuan-Ta
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Chen, Yi-Yu
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Yang, Jeng-Fu
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Lin, Wen-Yi
Background/Purpose: Chronic kidney disease (CKD) has become a worldwide health problem, leading to high morbidity and mortality, and non-alcoholic fatty liver disease (NAFLD) is considered a risk factor for CKD. The aim of this study was to explore the relationship between NAFLD fibrosis score (NFS) and the estimated glomerular filtration rate (eGFR), and identify possible risk factors related to the NFS among Taiwanese subjects. Methods: Subjects were enrolled from the database of the Department of Preventive Medicine of Kaohsiung Municipal Hsiao-Kang Hospital. The eGFR was calculated according to the Taiwanese Modification of Diet in Renal Disease (TMDRD) equation, and the NFS was employed to evaluate the fibrotic level. Results: In total, 11,376 subjects were enrolled in this study, with a mean age of 52.0 +/- 6.81 years, including 4529 (39.8%) males. A fasting sugar level >= 100 mg/dL (OR = 1.70, 95% CI = 1.52-1.87) and an abnormal waist circumference (OR = 1.81, 95% CI = 1.65-1.99) were significant factors associated with NFS (p < 0.05). Trends of a decreasing TMDRD score and an increasing NFS with increasing age were noted (p < 0.05). The NFS was significantly negatively correlated with the TMDRD score (standard coefficients: -0.067, p < 0.001). Conclusion: A higher NFS is associated with an impaired eGFR in Taiwanese subjects. Controlling risk factors, especially fasting sugar level and waist circumference, may be useful in preventing NFS deterioration, which is negatively correlated with the eGFR. Copyright (C) 2019, Formosan Medical Association. Published by Elsevier Taiwan LLC.
Improvement of hyperuricemia in chronic hepatitis C patients receiving directly acting antiviral agents
(1970-01-01)
Jang, Tyng-Yuan
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Huang, Ching-, I
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Yeh, Ming-Lun
;
Liang, Po-Cheng
;
Tsai, Pei-Chien
Background and Aim Hepatitis C virus eradication via the use of antivirals ameliorates metabolic profiles. The changes in serum uric acid (SUA) levels in chronic hepatitis C patients who receive antivirals are not well understood. We aimed to address this issue by comparing the SUA changes before and after the achievement of a sustained virological response (which is defined as hepatitis C virus RNA seronegativity at 12 weeks after the end of treatment). Methods Two hundred and thirteen sustained virological response patients who were treated by directly acting antivirals were consecutively enrolled. Pretreatment and post-treatment SUA levels were compared. Hyperuricemia was defined as a uric acid level > 7.0 mg/dL in men and > 6.0 mg/dL in women. Results The SUA levels significantly decreased after treatment, as compared to the pretreatment levels (5.6 +/- 1.5 vs 6.0 +/- 1.7 mg/dL, respectively; P < 0.001). The proportion of hyperuricemia incidences significantly decreased after treatment (25.8% vs 35.7%, respectively; P = 0.001). The improvement was only observed in patients with a fibrosis-4 index (FIB-4) < 6.5 (25.7% vs 37.1%, P = 0.001) but not in those patients with a FIB-4 >= 6.5 (26.3% vs 28.9%, P = 1.00). A multivariate analysis revealed that the factor that was associated with significantly decreased SUA levels was FIB-4 < 6.5 (odds ratio [OR]/95% confidence interval [CI]: 3.22/1.04-9.95, P = 0.04) and estimated glomerular filtration rate < 60 mL/min/1.73 m(2) (OR/CI: 4.34/1.94-9.73, P < 0.001). There existed a trend of a higher proportion of patients with significant SUA improvement along with the decrement of FIB-4 (29.7%, 25%, and 10.5% in patients with FIB-4 < 3.25, 3.25-6.5, and > 6.5, respectively; trend P = 0.03). Conclusions SUA levels were significantly decreased in chronic hepatitis C patients after viral eradication. The improvement was particularly enhanced in patients with mild liver disease.
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.
Lower protein expression levels of MHC class I chain-related gene A in hepatocellular carcinoma are at high risk of recurrence after surgical resection
(2018-10-25)
Huang, Chung-Feng
;
Wang, Shu-Chi
;
Chang, Wen-Tsan
;
Yeh, Ming-Lun
;
Huang, Ching-I
MHC class I chain-related gene A (MICA) variants have been associated with hepatocellular carcinoma (HCC). Their association with MICA expression in cancer cells and cancer recurrence is unknown. SNP rs2596542 of MICA was tested in 193 HCC patients with surgical resection. The corresponding MICA expression in the cancer tissue was measured by immunochemistry microarray. Patients with the SNP rs2596542 A allele had significantly lower MICA expression in tumor tissue than did those with the GG genotype (24.7 +/- 15.1% vs. 41.5 +/- 23.4%, P < 0.001). Patients who had HCC recurrence had significantly lower MICA expression in tumor tissue (34.2 +/- 21.8% vs. 24.0 +/- 19.8%, P = 0.03). Cox regression analysis revealed that the factors independently predictive of HCC recurrence included low MICA expression (hazard ratio [HR]/95% confidence intervals [CI]: 2.77/1.07-7.14, P = 0.035) and tumor size (HR/CI: 5.22/2.11-12.96, P < 0.001). Compared to patients with tumors <5 cm and MICA expression >30%, patients with either one and both two risk factors had HCC HRs of 9.76 (C.I. 1.27-75.03, P = 0.03) and 27.30 (C.I. 3.46-215.6, P = 0.002), respectively. We concluded that low cellular MICA expressions were at a greater risk of HCC recurrence after curative treatment.
Pharmacokinetics and pharmacodynamics of pegylated interferon for the treatment of hepatitis B
(2019-10-03)
Yeh, Ming-Lun
;
Huang, Jee-Fu
;
Dai, Chia-Yen
;
Yu, Ming-Lung
;
Chuang, Wan-Long
Introduction: Interferon (IFN) had both antiviral and immunomodulatory effects, and was one of the approved treatments for hepatitis B virus (HBV). Herein, we reviewed the pharmacokinetics and pharmacodynamics of pegylated IFN-? (PegIFN-?) for the treatment of HBV. Areas covered: The steady-state serum levels of PegIFN-? were reached within 5 to 8?weeks, and the week 48 mean trough concentrations were approximately 2-fold higher than week 1. There was also no difference of the pharmacokinetics in male or female, healthy volunteers or patients with hepatitis B or C infection. PegIFN-? did not affect the metabolism of the cytochrome P450 (CYP) isozymes, except inhibition of CYP1A2. There was also no pharmacokinetic interaction between PegIFN-? and HBV nucleot(s)ide analogues (NUCs). Forty-eight weeks of PegIFN-? achieved 32% of HBeAg seroconversion, 32-43% of HBV DNA suppression, 41-59% of ALT normalization, and 3% of HBsAg seroconversion rate with a post-treatment durable response up to 80% in the initial responders. Expert opinion: On-treatment HBsAg titer guided the treatment of HBV with PegIFN-?. The recommendation of PegIFN-? and NUC combination or switch remained controversial. New immunotherapeutic agents are now in development. Although, PegIFN-? should continue to play a role in the treatment of HBV.
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.