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1.
J Formos Med Assoc ; 123(7): 788-795, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38310071

ABSTRACT

BACKGROUND: Locoregional therapy and multi-kinase inhibitor agent have been the backbone of treatment for hepatocellular carcinoma (HCC) patients. However, the effect of combination or sequential use of locoregional therapy on HCC patients receiving multi-kinase inhibitor remain uncertain. Therefore, we aim to explore whether the subsequent locoregional therapy provides better survival in HCC patients under lenvatinib treatment. METHODS: From March 2018 to April 2020, a total of 78 unresectable HCC patients receiving lenvatinib were recruited. Image response was evaluated by dynamic image using the modified RECIST criteria. Among patients with tumor progression under lenvatinib treatment, whether receiving subsequent locoregional therapy or not were documented. Overall survival between two groups and the predictors for tumor progression were also analyzed. RESULTS: Among the 78 patients receiving lenvatinib, the median age was 67.8 years old, and 69.2 % were male. Forty-four patients (56.4 %) experienced tumor progression with time to progression 5.1 months (95 % confidence interval (CI): 4.7-6.8) months. In multivariable Cox regression analysis, albumin-bilirubin (ALBI) grade II (adjusted HR: 2.883, P = 0.0104), and treatment duration less than three months (adjusted HR: 3.801, P = 0.0014) were the independent predictive factors for tumor progression, while patients achieving objective response under lenvatinib treatment within 12 weeks was the independent protective factor for tumor progression (adjusted HR: 0.144, P = 0.0020). Among the 44 patients with tumor progression, twenty-six (59.1 %) patients received subsequent locoregional therapy after tumor progression. Comparing to those with tumor progression without locoregional treatment, patients who received subsequent locoregional therapy had significantly better survival (1st year cumulative survival rate 70 % vs 27 %, log-rank P = 0.003). CONCLUSION: ALBI grade, treatment duration of lenvatinib, and achieving objective image response within twelve weeks were the independent predictive factors for tumor progression. Furthermore, longer overall survival was observed in tumor progression patients with subsequent locoregional therapy and with better liver preserved function.


Subject(s)
Carcinoma, Hepatocellular , Disease Progression , Liver Neoplasms , Phenylurea Compounds , Quinolines , Humans , Carcinoma, Hepatocellular/drug therapy , Carcinoma, Hepatocellular/mortality , Carcinoma, Hepatocellular/therapy , Liver Neoplasms/drug therapy , Liver Neoplasms/mortality , Liver Neoplasms/therapy , Phenylurea Compounds/therapeutic use , Male , Quinolines/therapeutic use , Female , Aged , Middle Aged , Antineoplastic Agents/therapeutic use , Protein Kinase Inhibitors/therapeutic use , Retrospective Studies , Taiwan , Aged, 80 and over , Chemoembolization, Therapeutic/methods
2.
Hepatology ; 76(3): 803-818, 2022 09.
Article in English | MEDLINE | ID: mdl-35060158

ABSTRACT

BACKGROUND AND AIMS: HCV-specific T cells are few and exhausted in patients with chronic hepatitis C (CHC). Whether these T cells are responsible for the liver damage and fibrosis is still debated. However, cluster of differentiation 38-positive (CD38+ ) human leukocyte antigen DR-positive (HLA-DR+ ) CD8+ T cells are regarded as bystander CD8+ T cells that cause liver injury in acute hepatitis. We propose that these innate CD8+ T cells play a pathogenic role in CHC. METHODS: Lymphocytes from peripheral blood were obtained from 108 patients with CHC and 43 healthy subjects. Immunophenotyping, functional assays, T-cell receptor (TCR) repertoire, and cytotoxic assay of CD38+ HLA-DR+ CD8+ T cells were studied. RESULTS: The percentage of CD38+ HLA-DR+ CD8+ T cells increased significantly in patients with CHC. These cells expressed higher levels of effector memory and proinflammatory chemokine molecules and showed higher interferon-γ production than CD38- HLA-DR- CD8 T cells. They were largely composed of non-HCV-specific CD8+ T cells as assessed by HLA-A2-restricted pentamers and next-generation sequencing analysis of the TCR repertoire. In addition, these CD38+ HLA-DR+ CD8+ T cells had strong cytotoxicity, which could be inhibited by anti-DNAX accessory molecule 1, anti-NKG2 family member D, and anti-natural killer NKp30 antibodies. Lastly, the percentage of CD38+ HLA-DR+ CD8+ T cells was significantly associated with liver injury and fibrosis and decreased significantly along with serum alanine aminotransferase normalization after successful direct-acting antiviral treatment. CONCLUSIONS: The TCR-independent, cytokine-responsive bystander CD38+ HLA-DR+ CD8+ T cells are strongly cytotoxic and play a pathogenic role in patients with CHC.


Subject(s)
CD8-Positive T-Lymphocytes , Hepatitis C, Chronic , ADP-ribosyl Cyclase 1/immunology , Antiviral Agents , HLA-DR Antigens , Humans , Membrane Glycoproteins/immunology , Receptors, Antigen, T-Cell
3.
Dig Dis Sci ; 68(1): 323-332, 2023 01.
Article in English | MEDLINE | ID: mdl-35895234

ABSTRACT

BACKGROUND: Non-invasive tools including liver stiffness measurement (LSM) or FIB-4, assessed before or after direct acting antivirals (DAA), have been suggested to predict hepatocellular carcinoma (HCC). AIMS: This study aims to compare predictability of HCC by these methods at different time points, to validate the HCC surveillance suggestion by guidelines, and to propose personalized strategy. METHODS: Chronic hepatitis C whose LSM and FIB-4 were available at pretherapy and after sustained virological response (SVR) were enrolled. Advanced chronic liver disease (ACLD) was defined as pretherapy LSM ≥ 10 kPa or FIB-4 index ≥ 3.25 or ultrasound signs of cirrhosis plus platelet count < 150,000/µL. The predictabilities were compared by area under ROC. The cumulative HCC incidences were calculated by Kaplan-Meier analysis. RESULTS: Among 466 ACLD patients, 40 patients developed HCC during a follow-up duration of 26.8 months. Comparable predictive performances for HCC between LSM and FIB-4 at pretherapy and SVR were noted. By guidelines suggestion using pretherapy LSM = 10 kPa (advanced fibrosis) and 13 kPa (cirrhosis) for risk stratification, the annual HCC incidences of those with LSM of < 10, 10-12.9 and ≥ 13 kPa were 1.1, 3.6, and 5.0%, respectively. Combination of baseline LSM < 12 kPa and SVR FIB-4 < 3.7 could further stratify relatively low risk of HCC in ACLD patients of annal incidence of 1.2%. CONCLUSIONS: ACLD patients who met advanced fibrosis but not cirrhosis by guidelines' cut-offs still posed high risk of HCC. Baseline LSM with SVR FIB-4 can be applied to stratify low, intermediate, and high risk of HCC for personalizing surveillance strategies after SVR.


Subject(s)
Carcinoma, Hepatocellular , Hepatitis C, Chronic , Liver Neoplasms , Humans , Carcinoma, Hepatocellular/diagnosis , Carcinoma, Hepatocellular/epidemiology , Carcinoma, Hepatocellular/etiology , Hepatitis C, Chronic/complications , Hepatitis C, Chronic/drug therapy , Hepatitis C, Chronic/diagnosis , Antiviral Agents/therapeutic use , Liver Neoplasms/diagnosis , Liver Neoplasms/epidemiology , Liver Neoplasms/etiology , Liver Cirrhosis/diagnosis , Liver Cirrhosis/epidemiology , Liver Cirrhosis/complications , Sustained Virologic Response
4.
Clin Infect Dis ; 75(3): 453-459, 2022 08 31.
Article in English | MEDLINE | ID: mdl-34864948

ABSTRACT

BACKGROUND: For patients coinfected with hepatitis C virus (HCV) and hepatitis B virus (HBV), HCV treatment with direct-acting antivirals can lead to HBV reactivation. We evaluated HBV reactivation during ledipasvir/sofosbuvir treatment and 108-week follow-up. METHODS: In Taiwan, 111 patients with HCV genotype 1 or 2 and HBV received ledipasvir/sofosbuvir (90mg/400mg) once daily for 12 weeks. HBV virologic reactivation was defined as postbaseline increase in HBV DNA from either less than the lower limit of quantification (LLOQ, 20 IU/mL) to equal to or more than LLOQ or equal to or more than LLOQ to >1 log10 IU/mL. HBV clinical reactivation was HBV virologic reactivation with alanine aminotransferase (ALT) >2× upper limit of normal. Factors associated with development of HBV virologic or clinical reactivation were evaluated with logistic regression analysis. RESULTS: All patients (100%, 111/111) maintained HCV suppression through 108 weeks after treatment. HBV virologic reactivation occurred in 73% of patients (81/111). Clinical reactivation occurred in 9% (10/111). The majority of HBV virologic reactivations (86%, 70/81) occurred by follow-up week 12, whereas clinical reactivation was generally more delayed. Eight (7%, 8/111) initiated HBV therapy. In regression analyses, baseline HBV DNA and hepatitis B surface antigen (HBsAg) levels were associated with HBV virologic reactivation and baseline ALT and HBV DNA, and HBsAg levels were associated with HBV clinical reactivation. CONCLUSION: Among HCV/HBV coinfected patients treated with direct-acting antivirals for HCV, HBV virologic reactivation occurred in a majority of patients during treatment and follow-up. In most patients, HBV virologic reactivation was asymptomatic; only a small proportion initiated HBV treatment. Notably, clinical reactivation may still occur >3 months after end of therapy. CLINICAL TRIALS REGISTRATION: NCT02613871.


Subject(s)
Coinfection , Hepatitis B , Hepatitis C, Chronic , Hepatitis C , Antiviral Agents , Benzimidazoles , DNA, Viral , Fluorenes , Follow-Up Studies , Hepacivirus/genetics , Hepatitis B Surface Antigens , Hepatitis B virus/genetics , Hepatitis C/complications , Hepatitis C, Chronic/complications , Hepatitis C, Chronic/drug therapy , Humans , Sofosbuvir/therapeutic use , Taiwan
5.
Int J Mol Sci ; 22(6)2021 Mar 22.
Article in English | MEDLINE | ID: mdl-33809908

ABSTRACT

Endoglin (CD105) is a type-1 integral transmembrane glycoprotein and coreceptor for transforming growth factor-ß (TGF-ß) ligands. The endoglin/TGF-ß signaling pathway regulates hemostasis, cell proliferation/migration, extracellular matrix (ECM) synthesis and angiogenesis. Angiogenesis contributes to early progression, invasion, postoperative recurrence, and metastasis in hepatocellular carcinoma (HCC), one of the most widespread malignancies globally. Endoglin is overexpressed in newly formed HCC microvessels. It increases microvessel density in cirrhotic and regenerative HCC nodules. In addition, circulating endoglin is present in HCC patients, suggesting potential for use as a diagnostic or prognostic factor. HCC angiogenesis is dynamic and endoglin expression varies by stage. TRC105 (carotuximab) is an antibody against endoglin, and three of its clinical trials were related to liver diseases. A partial response was achieved when combining TRC105 with sorafenib. Although antiangiogenic therapy still carries some risks, combination therapy with endoglin inhibitors or other targeted therapies holds promise.


Subject(s)
Carcinoma, Hepatocellular/etiology , Carcinoma, Hepatocellular/metabolism , Disease Susceptibility , Endoglin/genetics , Endoglin/metabolism , Liver Neoplasms/etiology , Liver Neoplasms/metabolism , Animals , Biomarkers, Tumor , Carcinoma, Hepatocellular/diagnosis , Carcinoma, Hepatocellular/therapy , Endoglin/blood , Endoglin/chemistry , Endothelial Cells/metabolism , Gene Expression Regulation, Neoplastic , Hepacivirus/physiology , Hepatitis C/metabolism , Hepatitis C/virology , Humans , Liver Neoplasms/pathology , Molecular Diagnostic Techniques , Molecular Targeted Therapy , Neovascularization, Pathologic/genetics , Neovascularization, Pathologic/metabolism , Signal Transduction , Structure-Activity Relationship , Viral Core Proteins/metabolism
6.
J Viral Hepat ; 27(5): 505-513, 2020 05.
Article in English | MEDLINE | ID: mdl-32039536

ABSTRACT

Elbasvir/grazoprevir with or without ribavirin has excellent efficacy and safety for the treatment of hepatitis C virus (HCV) genotype 1 and 4 patients. The real-world experience has been reported but the detailed analysis of liver and renal adverse effects is lacking. This study evaluated the real-world experience relating to the effectiveness and liver/renal safety of elbasvir/grazoprevir in HCV genotype 1 patients with compensated liver disease. In the four medical centres of Chang Gung Medical System, 350 HCV genotype 1 patients with compensated liver disease who were treated with elbasvir/grazoprevir were enrolled. Clinical characteristics and laboratory data were collected. The effectiveness (sustained virologic response 12 weeks after end of treatment, SVR12) and safety were assessed. A consecutive series of 350 patients with a mean age of 68.8 ± 10.0 years old were enrolled. The majority were treatment-naïve (72.3%), genotype 1b (97.7%) and advanced fibrosis/cirrhosis (94.3%). Seventy-nine (22.6%) had hepatocellular carcinoma and 23 (6.6%) had coinfection with hepatitis B. The effectiveness of SVR12 was 94.6% (95% CI: 92.2%-97.0%) in the full analysis set and 99.1% (95% CI: 98.1%-100.1%) in the per-protocol set. There were two relapses and one nonresponder. Seven (2.0%) patients had adverse events resulting in premature discontinuation of treatment. Five of them were considered drug-related. One was due to autoimmune hepatitis. Contrary to previous reports, around 49% of ALT elevation was observed after 8 weeks, and in two patients was due to hepatitis B flares. As to the renal function during the course of therapy, a minor deterioration of eGFR was observed in patients with baseline eGFR ≥60 mL/min/1.73 m2 , but not in those with baseline eGFR <60, <60-30 or <30 mL/min/1.73 m2 . In this real-world data, elbasvir/grazoprevir was effective with few liver/renal adverse effects. One patient developed autoimmune hepatitis.


Subject(s)
Amides/therapeutic use , Antiviral Agents/therapeutic use , Benzofurans/therapeutic use , Carbamates/therapeutic use , Cyclopropanes/therapeutic use , Hepatitis C, Chronic , Imidazoles/therapeutic use , Quinoxalines/therapeutic use , Sulfonamides/therapeutic use , Aged , Amides/adverse effects , Antiviral Agents/adverse effects , Benzofurans/adverse effects , Carbamates/adverse effects , Cyclopropanes/adverse effects , Drug Combinations , Drug Therapy, Combination , Genotype , Hepacivirus , Hepatitis C, Chronic/drug therapy , Humans , Imidazoles/adverse effects , Kidney/drug effects , Liver/drug effects , Middle Aged , Neoplasm Recurrence, Local , Quinoxalines/adverse effects , Sulfonamides/adverse effects , Taiwan
7.
Int J Hyperthermia ; 37(1): 1008-1015, 2020.
Article in English | MEDLINE | ID: mdl-32814458

ABSTRACT

BACKGROUND: The impact of prolonged post-ablation fever (PAF) defined as persistent fever > 24 h after radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC) had not been described before. This study aims to investigate the impact of prolonged PAF on early tumor recurrence in HCC patients after RFA. METHODS: From 2013 to 2015, a total of 135 patients with HCC meeting Milan criteria and all the tumors having confirmed complete ablation after RFA were enrolled. Study endpoint was any HCC recurrence within 1 year after ablation. Cox regression analysis was applied for multivariate analysis to determine the independent predictors of 1-year tumor recurrence. RESULTS: Post-ablation fever occurred in 42 (31.1%) patients after RFA, while prolonged PAF was found in 22 (16.3%) patients. Fifty-eight (42.8%) patients occurred any tumor recurrence within 1 year after complete ablation. Patients with prolonged PAF had a significantly higher rate of HCC recurrence within 1 year (72.7% vs. 37.1%, p = 0.002) and had a significantly shorter time-to-recurrence interval (19.6 vs. 40.5 months, Log rank test, p = 0.002) than those who had no prolonged PAF. Multivariate analysis by Cox regression showed the previous HCC recurrence history (aHR: 1.792, p = 0.0284), baseline AFP > 20 ng/ml (aHR: 1.868, p = 0.0211) and prolonged PAF (aHR: 2.092, p = 0.0138) were associated with early recurrence. CONCLUSIONS: Prolonged PAF may associate with early HCC recurrence after complete ablation by RFA. Patients with prolonged PAF need to be more clinical attentions.


Subject(s)
Carcinoma, Hepatocellular , Catheter Ablation , Liver Neoplasms , Radiofrequency Ablation , Carcinoma, Hepatocellular/surgery , Humans , Liver Neoplasms/surgery , Neoplasm Recurrence, Local/surgery , Retrospective Studies , Treatment Outcome
8.
J Formos Med Assoc ; 119(2): 635-643, 2020 Feb.
Article in English | MEDLINE | ID: mdl-31495543

ABSTRACT

BACKGROUND & AIMS: Transarterial chemoembolization (TACE) is the standard of care for intermediate stage hepatocellular carcinoma (HCC) patients. Variceal bleeding is a life-threatening complication and may alter the initial treatment plan. This study was aimed to elucidate the risk factors for variceal bleeding in HCC patients receiving TACE treatment. METHODS: From 2005 to 2016, a total of 1233 treatment-naive HCC patients receiving first time TACE treatment in Chang Gung Memorial Hospital, Linkou medical center were recruited. Pre-TACE status including baseline characteristics, prior history of ascites, and parameters for liver function evaluation were analyzed. All the variables were compared between patients with and without variceal bleeding. RESULTS: Among the 1233 patients, the median age was 63.7 (range 25.8-91.5) years old, and 73.5% were male. Variceal bleeding events were documented in 19 patients (1.5%) within 3 months post TACE treatment. Patients with younger age, cirrhosis, pre-treatment ascites and advanced fibrosis status (higher MELD score, CTP score, ALBI grade, FIB-4 and APRI score) were more likely to encounter post-treatment variceal bleeding. Multivariate Cox regression analysis revealed existence of ascites (adjusted HR: 4.859 (1.947-12.124), p = 0.001), and higher FIB-4 score (adjusted HR: 4.481 (1.796-11.179), p = 0.001) were the independent predictive factors for variceal bleeding. Patients with post-TACE variceal bleeding are more likely to encounter tumor progression (42.1% vs. 20.3%, p = 0.039) and mortality owing to GI bleeding (15.8% vs. 3%, p = 0.032). CONCLUSION: The incidence of post-TACE variceal bleeding was 1.5%. Patients with post-TACE variceal bleeding have poorer TACE treatment response. The pre-treatment ascites and FIB-4 score are the independent predictors for post-TACE variceal bleeding.


Subject(s)
Carcinoma, Hepatocellular/therapy , Chemoembolization, Therapeutic/adverse effects , Esophageal and Gastric Varices/etiology , Gastrointestinal Hemorrhage/etiology , Liver Neoplasms/therapy , Adult , Aged , Aged, 80 and over , Carcinoma, Hepatocellular/mortality , Female , Gastrointestinal Hemorrhage/mortality , Humans , Incidence , Liver Cirrhosis/complications , Liver Neoplasms/mortality , Male , Middle Aged , Multivariate Analysis , Risk Factors , Survival Analysis , Taiwan/epidemiology , Treatment Outcome
9.
Int J Mol Sci ; 21(18)2020 Sep 18.
Article in English | MEDLINE | ID: mdl-32962123

ABSTRACT

Smoothened (SMO) belongs to the Hedgehog (HH) signaling pathway, which regulates cell growth, migration, invasion and stem cells in cancer. The HH signaling pathway includes both canonical and noncanonical pathways. The canonical HH pathway functions through major HH molecules such as HH ligands, PTCH, SMO and GLI, whereas the noncanonical HH pathway involves the activation of SMO or GLI through other pathways. The role of SMO has been discussed in different types of cancer, including breast, liver, pancreatic and colon cancers. SMO expression correlates with tumor size, invasiveness, metastasis and recurrence. In addition, SMO inhibitors can suppress cancer formation, reduce the proliferation of cancer cells, trigger apoptosis and suppress cancer stem cell activity. A better understanding of the role of SMO in cancer could contribute to the development of novel therapeutic approaches.


Subject(s)
Antineoplastic Agents/pharmacology , Breast Neoplasms/metabolism , Colonic Neoplasms/metabolism , Liver Neoplasms/metabolism , Neoplastic Stem Cells/drug effects , Pancreatic Neoplasms/metabolism , Smoothened Receptor/antagonists & inhibitors , Animals , Breast Neoplasms/drug therapy , Colonic Neoplasms/drug therapy , Female , Hedgehog Proteins/metabolism , Humans , Liver Neoplasms/drug therapy , Neoplastic Stem Cells/metabolism , Pancreatic Neoplasms/drug therapy , Signal Transduction/drug effects , Signal Transduction/genetics , Smoothened Receptor/metabolism
10.
Gastroenterology ; 154(4): 989-997, 2018 03.
Article in English | MEDLINE | ID: mdl-29174546

ABSTRACT

BACKGROUND & AIMS: There have been reports of reactivation of hepatitis B virus (HBV) infection during treatment of hepatitis C virus (HCV) infection with direct-acting antiviral agents. We performed a prospective study of risks and outcomes of HCV infection treatment with ledipasvir and sofosbuvir in patients with HBV infection. METHODS: We performed a phase 3b, multicenter, open-label study in Taiwan of 111 patients with HCV infection (61% HCV genotype 1, 39% HCV genotype 2 infection; 62% women, 16% with compensated cirrhosis) along with HBV infection. All but 1 were positive for the hepatitis B surface antigen (HBsAg); 1 patient who was HBsAg-positive at screening was found to be HBsAg-negative at baseline. Overall, 33% of participants had received prior treatment for HCV and 5% had previously been treated for HBV; no patient was on HBV therapy at the start of the study. All patients received a fixed-dose combination of 90 mg of the HCV NS5A inhibitor ledipasvir with 400 mg of the NS5B nucleotide analogue inhibitor sofosbuvir, once daily for 12 weeks. The primary endpoint was sustained virologic response 12 weeks after the end of therapy. RESULTS: All 111 patients (100%) achieved a sustained virologic response. Of the 37 patients with baseline HBV DNA below 20 IU/mL, 31 (84%) had at least 1 episode of quantifiable HBV DNA through posttreatment week 12. Of the 74 patients with baseline HBV DNA levels of 20 IU/mL or more, 39 (53%) had increases of HBV DNA greater than 1 log10 IU/mL through posttreatment week 12. Overall, 5 patients had increased levels of HBV DNA concomitant with a level of alanine aminotransferase >2 times the upper limit of normal through posttreatment week 12. Of these, 3 patients started HBV treatment. In addition, 1 patient with HBV reactivation since week 8 and concomitant alanine aminotransferase elevation >2 times upper limit of normal at posttreatment week 48 started treatment at posttreatment week 53. This patient had clinical signs and symptoms associated with HBV reactivation. The most common adverse events were headache, upper respiratory infection, and fatigue. CONCLUSIONS: In a prospective study, the combination of ledipasvir and sofosbuvir for 12 weeks produced a sustained virologic response in 100% of patients with HCV infection who were coinfected with HBV. Most patients had an increase in level of HBV DNA not associated with signs or symptoms. ClinicalTrials.gov no: NCT02613871.


Subject(s)
Antiviral Agents/therapeutic use , Benzimidazoles/therapeutic use , Fluorenes/therapeutic use , Hepacivirus/drug effects , Hepatitis B/complications , Hepatitis C/drug therapy , Uridine Monophosphate/analogs & derivatives , Adult , Aged , Antiviral Agents/adverse effects , Benzimidazoles/adverse effects , Coinfection , DNA, Viral/genetics , Female , Fluorenes/adverse effects , Hepacivirus/genetics , Hepatitis B/diagnosis , Hepatitis B Antibodies/blood , Hepatitis B Surface Antigens/blood , Hepatitis B e Antigens/blood , Hepatitis B virus/genetics , Hepatitis B virus/immunology , Hepatitis C/complications , Hepatitis C/diagnosis , Humans , Male , Middle Aged , Prospective Studies , RNA, Viral , Sofosbuvir , Sustained Virologic Response , Taiwan , Time Factors , Treatment Outcome , Uridine Monophosphate/adverse effects , Uridine Monophosphate/therapeutic use , Viral Load
11.
J Viral Hepat ; 26(12): 1404-1412, 2019 12.
Article in English | MEDLINE | ID: mdl-31433885

ABSTRACT

Renal toxicity of direct-acting antivirals (DAAs) in chronic hepatitis C (CHC) patients has not been well-characterized. The aim of this study was to assess renal safety of DAAs in an Asian CHC patient cohort. Data from CHC patients (n = 1536) treated with DAAs were used in this retrospective study. Serial estimated glomerular filtration rate (eGFR) at pretreatment (1-year prior to treatment), baseline, end of treatment (EOT), and 12 weeks after treatment (SVR12 ) was evaluated. While a significant decrease in eGFR from baseline to EOT (84.8 â†’ 81.8 mL/min/1.73 m2 , P < .001) was observed; subsequently, a slight rise at SVR12 (84.3 mL/min/1.73 m2 ) was also evident. Changes in eGFR after DAA treatment were similar to those seen in PrOD, DCV/ASV and GZP/EBV regimens, except in the SOF-based regimen wherein eGFR remained unchanged from EOT to SVR12 , especially in liver transplant recipients. Multivariate analysis revealed that age >65 years (OR = 1.862, P = .011), baseline eGFR ≥ 60 mL/min/1.73 m2 (OR = 2.684, P = .023), and liver transplant (OR = 3.894, P = .001) were independent risk factors for deteriorating renal function. In conclusion, DAA treatment led to a significant decline in eGFR at EOT but was followed by a slight rise at 12 weeks after treatment. A similar trend was observed with PrOD, DCV/ASV and GZP/EBV, but not in SOF-based regimens. As age >65 years, baseline eGFR ≥ 60 mL/min/1.73 m2 and liver transplantation are significant risk factors for deterioration in renal function, we strongly advice close monitoring of renal function in these populations.


Subject(s)
Antiviral Agents/adverse effects , Antiviral Agents/therapeutic use , Hepatitis C, Chronic/complications , Hepatitis C, Chronic/drug therapy , Renal Insufficiency/diagnosis , Renal Insufficiency/etiology , Drug Therapy, Combination/adverse effects , Drug Therapy, Combination/methods , Female , Genotype , Glomerular Filtration Rate/drug effects , Hepacivirus/genetics , Hepatitis C, Chronic/epidemiology , Hepatitis C, Chronic/virology , Humans , Kidney Function Tests , Male , Odds Ratio , Prognosis , Renal Insufficiency/epidemiology , Retrospective Studies , Sustained Virologic Response , Viral Load
12.
Hepatology ; 68(2): 425-434, 2018 08.
Article in English | MEDLINE | ID: mdl-29108132

ABSTRACT

Hepatitis B surface antigen (HBsAg) loss is a rare event during nucleos(t)ide analogue (Nuc) therapy. Limited data suggest that stopping Nuc therapy may increase HBsAg loss rate in hepatitis B e antigen-negative patients. A large study was conducted to investigate this issue in more detail. Of the 1,075 hepatitis B e antigen-negative patients treated with Nuc for a median of 156 (61-430) weeks, 5 showed HBsAg seroclearance during treatment at an estimated annual incidence of 0.15%. Of the patients who remained HBsAg-seropositive, 691 (52.3 years old, 86% male, 44.6% cirrhosis) had stopped Nuc therapy by the Asian-Pacific Association for the Study of the Liver stopping rule and then were prospectively followed up. Baseline and on-treatment clinical and viral features, treatment duration, consolidation duration, time to undetectable hepatitis B virus DNA, time to normal alanine aminotransferase, end-of-treatment HBsAg, and HBsAg log reduction were compared between patients with and without HBsAg seroclearance after end of treatment. During a median off-therapy follow-up period of 155 (2-614) weeks, HBsAg seroclearance was confirmed in 42 patients. The 6-year cumulative incidence was 13% with an estimated annual incidence of 1.78%. Cox regression analysis showed that shorter time to undetectable hepatitis B virus DNA (<12 weeks), greater HBsAg reduction during therapy (>1 log10 ), lower end-of-treatment HBsAg level (<100 IU/mL), patients with sustained response, and relapsers not retreated were factors for off-therapy HBsAg seroclearance. CONCLUSION: The incidence of HBsAg seroclearance after stopping Nuc was much higher than that during therapy and highest in patients without virologic and clinical relapse; patients with clinical relapse who remained untreated had a 7.34 times higher incidence of HBsAg clearance than those who received retreatment, suggesting that transient untreated clinical relapse may drive sufficient immune control to functional cure. (Hepatology 2017).


Subject(s)
Antiviral Agents/therapeutic use , Hepatitis B Surface Antigens/blood , Hepatitis B, Chronic/drug therapy , Adult , Aged , Aged, 80 and over , DNA, Viral/blood , Female , Follow-Up Studies , Hepatitis B e Antigens , Hepatitis B virus/genetics , Hepatitis B, Chronic/virology , Humans , Incidence , Male , Middle Aged , Prospective Studies , Withholding Treatment/statistics & numerical data
13.
J Formos Med Assoc ; 118(8): 1239-1246, 2019 Aug.
Article in English | MEDLINE | ID: mdl-30581103

ABSTRACT

BACKGROUND: Secondary prevention of hepatocellular carcinoma (HCC) among patients with chronic hepatitis C (CHC) who achieve sustained virologic response (SVR) with interferon-based therapy has been proved effective. However, tertiary prevention with PegIFN/RBV therapy of HCC recurrence seems limited effect in CHC-HCC patients post curative therapies. This study aims to investigate the timing and impact of PegIFN/RBV treatment on prevention of HCC recurrence in patients after RFA treatment. METHODS: From 2013 to 2016, a total of 137 CHC-HCC patients from a 508 patient based cohort receiving complete RFA treatment in Chang Gung Memorial Hospital, Linkou Medical Center were retrospectively recruited. Pre-RFA patient demographics were analyzed by cox regression analysis for prediction on tumor recurrence. Statistics analysis was performed with SPSS V.20 (IBM, USA). RESULTS: The mean age of the 137 patients were 69.6 year-old and 71.5% of patients were cirrhotic. After propensity score matching, one hundred and two patients were enrolled into the analysis. Fifty-one patients (50%) received PegIFN/RBV therapy and twenty-seven patients (52.9%) achieved SVR. Patients who could achieve SVR had lower tumor recurrence rate than non-SVR and untreated groups (29.6% vs. 66.7% vs. 49.0%, P = 0.030). The effect is more prominent in those achieve SVR prior to compared with after RFA despite not reach statistically significant (26.1% vs. 50.0%, P = 0.334). CONCLUSION: Timely treatment with SVR achievement has the lowest tumor recurrence rate in CHC-HCC patients. Secondary prevention might be even more important than tertiary prevention in CHC patients, especially regarding prevention of post RFA HCC recurrence.


Subject(s)
Antiviral Agents/therapeutic use , Carcinoma, Hepatocellular/virology , Hepatitis C, Chronic/drug therapy , Interferon-alpha/therapeutic use , Liver Neoplasms/virology , Ribavirin/therapeutic use , Aged , Carcinoma, Hepatocellular/etiology , Carcinoma, Hepatocellular/mortality , Drug Therapy, Combination , Female , Hepatitis C, Chronic/complications , Humans , Liver Neoplasms/etiology , Liver Neoplasms/mortality , Male , Middle Aged , Neoplasm Recurrence, Local , Polyethylene Glycols , Proportional Hazards Models , Retrospective Studies , Secondary Prevention , Sustained Virologic Response , Taiwan , Tertiary Prevention , Viral Load , Viremia/drug therapy
15.
Int J Mol Sci ; 19(5)2018 May 05.
Article in English | MEDLINE | ID: mdl-29734730

ABSTRACT

Overexpression of Sonic Hedgehog signaling (Shh) pathway molecules is associated with invasiveness and recurrence in breast carcinoma. Therefore, inhibition of the Shh pathway downstream molecule Glioma-associated Oncogene Homolog (Gli) was investigated for its ability to reduce progression and invasiveness of patient-derived breast cancer cells and cell lines. Human primary breast cancer T2 cells with high expression of Shh signaling pathway molecules were compared with breast cancer line MDA-MB-231 cells. The therapeutic effects of Gli inhibitors were examined in terms of the cell proliferation, apoptosis, cancer stem cells, cell migration and gene expression. Blockade of the Shh signaling pathway could reduce cell proliferation and migration only in MDA-MB-231 cells. Hh pathway inhibitor-1 (HPI-1) increased the percentages of late apoptotic cells in MDA-MB-231 cells and early apoptotic cells in T2 cells. It reduced Bcl2 expression for cell proliferation and increased Bim expression for apoptosis. In addition, Gli inhibitor HPI-1 decreased significantly the percentages of cancer stem cells in T2 cells. HPI-1 worked more effectively than GANT-58 against breast carcinoma cells. In conclusion, HPI-1 could inhibit cell proliferation, reduce cell invasion and decrease cancer stem cell population in breast cancer cells. To target Gli-1 could be a potential strategy to suppress breast cancer stem cells.


Subject(s)
Breast Neoplasms/drug therapy , Hedgehog Proteins/genetics , Neoplastic Stem Cells/drug effects , Zinc Finger Protein GLI1/genetics , Apoptosis/drug effects , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Cell Line, Tumor , Cell Movement/drug effects , Cell Proliferation/drug effects , Female , Gene Expression Regulation, Neoplastic/drug effects , Hedgehog Proteins/antagonists & inhibitors , Humans , Neoplasm Recurrence, Local/drug therapy , Neoplasm Recurrence, Local/genetics , Neoplasm Recurrence, Local/pathology , Pyridines/administration & dosage , Signal Transduction/drug effects , Thiophenes/administration & dosage , Zinc Finger Protein GLI1/antagonists & inhibitors
16.
BMC Gastroenterol ; 17(1): 169, 2017 Dec 29.
Article in English | MEDLINE | ID: mdl-29284412

ABSTRACT

BACKGROUND: Chemokines/cytokines play important roles in the pathogenesis of chronic hepatitis C (CHC). However, their clinical characteristics and implications in treatment responses to pegylated interferon plus ribavirin treatment (PegIFN/RBV) have not been fully illustrated yet. In this study, we intended to investigate the possible predictability of serum chemokines/cytokines on the treatment response in Taiwanese of CHC, genotype-1 (GT-1). METHODS: 60 Patients with GT-1 CHC infection who had been treated with PegIFN/RBV were enrolled, including 27 (45%) with sustained virological response (SVR), 11 (18%) with relapse after 48 weeks of treatment and 22 (37%) non-response (NR). Clinical parameters, seven chemokines/cytokines, CCL3, CCL4, CXCL9, CXCL10, CXCL11, IL-10 and IFN-γ, and genotypes of rs12979860, the single nucleotide polymorphisms (SNPs) of interleukin-28B (IL28B) were analyzed for their relationship to treatment response. RESULTS: Baseline serum levels of CXCL10, CXCL11, CCL3 and CCL4 were significantly higher in NR group while comparing with non-NR group. (CXCL10: p = 0.001; CXCL11: p < 0.001; CCL3: p = 0.006; CCL4: p = 0.005). However, only rs12979860 CC genotype was the independent factors for NR in GT-1 CHC infection (OR, 8.985; p = 0.008). In addition, baseline serum level of CCL4 was found to be the only independent factor for NR in GT-1 CHC patients with favorable IL28B genotype (OR, 1.134; p = 0.039). CONCLUSIONS: IL28B genotype is the predictor for NR in GT-1 CHC patients treated with PegIFN/RBV, while baseline serum level of CCL4 is the only predictor for NR in GT-1 CHC patients with favorable IL28B genotype.


Subject(s)
Antiviral Agents/therapeutic use , Chemokines/blood , Cytokines/blood , Hepatitis C, Chronic/drug therapy , Hepatitis C, Chronic/immunology , Interferon-alpha/therapeutic use , Polyethylene Glycols/therapeutic use , Female , Genotype , Hepacivirus/genetics , Hepatitis C, Chronic/genetics , Humans , Interferon alpha-2 , Interferons , Interleukins/genetics , Male , Middle Aged , RNA, Viral/blood , Recombinant Proteins/therapeutic use , Retrospective Studies , Treatment Outcome
17.
Clin Gastroenterol Hepatol ; 14(12): 1813-1820.e1, 2016 12.
Article in English | MEDLINE | ID: mdl-27404969

ABSTRACT

BACKGROUND & AIMS: Of the hepatitis B e antigen-negative chronic hepatitis B patients with more than 1 year of sustained hepatitis B virus (HBV) suppression during therapy, the 1-year clinical relapse rate after cessation of entecavir therapy was 45%, of which 25.6% occurred within 6 months. The events after cessation of another preferred drug tenofovir were investigated. METHODS: A retrospective-prospective study was conducted in 85 hepatitis B e antigen-negative chronic hepatitis B patients with sustained HBV suppression who had stopped tenofovir therapy and were monitored every 1 to 3 months for a median duration of 39 weeks (range, 4-133 wk). RESULTS: Clinical relapse occurred in 38 patients, 57.9% and 86.8% within 3 and 6 months, respectively, with an estimated 1-year cumulative incidence of 52%. The optimal duration of therapy and consolidation therapy were calculated to be 3 and 2 years, respectively. Of the relapsers, 81.6% and 57.9% showed an alanine aminotransferase level greater than 5 and 10 times the upper limit of normal, respectively, 23.7% showed a bilirubin level of 2 mg/dL or greater, and 2 developed hepatic decompensation. Relapsers had significantly higher pretherapy baseline hepatitis B surface antigen level, more prior anti-HBV therapy experience, later alanine aminotransferase level normalization, and a shorter duration of treatment and consolidation therapy. Cox regression analyses showed that treatment for more than 3 years combined with consolidation therapy for more than 2 years was an independent significant manageable factor of clinical relapse (adjusted hazard ratio, 0.387; P = .008). With this combination, the clinical relapse rate was reduced to 30%. CONCLUSIONS: Clinical relapses occurred mostly within 6 months, with high alanine aminotransferase and serum bilirubin levels. Closer monitoring, monthly in the first 3 to 6 months, with timely re-treatment is mandatory for a safe cessation of tenofovir therapy.


Subject(s)
Antiviral Agents/administration & dosage , Hepatitis B, Chronic/drug therapy , Sustained Virologic Response , Tenofovir/administration & dosage , Withholding Treatment , Adult , Aged , Female , Hepatitis B e Antigens/blood , Humans , Incidence , Male , Middle Aged , Prospective Studies , Recurrence , Retrospective Studies
18.
Liver Int ; 36(8): 1101-7, 2016 08.
Article in English | MEDLINE | ID: mdl-26835876

ABSTRACT

BACKGROUND & AIMS: In Taiwan, patients with chronic hepatitis C virus (HCV) infection are currently treated with pegylated interferon-alpha plus ribavirin, but interferon-based regimens can be poorly tolerated, especially by those with advanced liver disease and the elderly. Sofosbuvir, an oral nucleotide analogue inhibitor of HCV NS5B polymerase, is approved in Europe, the USA and Japan for treating chronic HCV infection. This phase 3b study examined the efficacy and safety of sofosbuvir plus ribavirin in Taiwanese patients with chronic genotype 2 HCV infection ± compensated cirrhosis. METHODS: In this multicentre, open-label, phase 3b (NCT02021643) study, 87 patients (n = 43, treatment-naive; n = 44, treatment-experienced) received 12 weeks of treatment with sofosbuvir plus weight-based ribavirin. The primary efficacy endpoint was the proportion of patients with sustained virological response 12 weeks after treatment discontinuation (SVR12). Safety and pharmacokinetic data were also collected. RESULTS: All 87 patients (100%; 95% confidence interval, 92-100%) achieved SVR12, including the 13 patients with compensated cirrhosis. The most common treatment-emergent adverse events (AEs) were insomnia (16%, 14/87) and upper respiratory tract infection (16%, 14/87). No grade 3 or grade 4 AE was reported. There was one serious AE (biliary colic), which was deemed unrelated to study treatment. Laboratory abnormalities other than ribavirin-related reductions in haemoglobin were uncommon. CONCLUSIONS: The results from this phase 3b study demonstrate that 12 weeks of treatment with the interferon-free regimen sofosbuvir plus ribavirin is effective and well tolerated in both treatment-naive and treatment-experienced Taiwanese patients with chronic genotype 2 HCV infection.


Subject(s)
Antiviral Agents/administration & dosage , Hepatitis C, Chronic/drug therapy , Ribavirin/administration & dosage , Sofosbuvir/administration & dosage , Adult , Aged , Antiviral Agents/adverse effects , Drug Therapy, Combination , Female , Hepacivirus/genetics , Hepatitis C, Chronic/complications , Humans , Liver Cirrhosis/virology , Male , Middle Aged , Ribavirin/adverse effects , Sofosbuvir/adverse effects , Taiwan , Treatment Outcome , Viral Load , Young Adult
19.
J Gastroenterol Hepatol ; 31(10): 1757-1765, 2016 Oct.
Article in English | MEDLINE | ID: mdl-26992248

ABSTRACT

BACKGROUND AND AIM: Chronic hepatitis C is an important public health problem in Asia. We evaluated the safety, efficacy, and pharmacokinetics of fixed-dose ritonavir-boosted danoprevir plus peginterferon alfa-2a/ribavirin in treatment-naive Asian patients with chronic hepatitis C virus (HCV) genotype (G)1 infection. METHODS: Treatment-naive G1 patients in Taiwan, Thailand, and Korea with serum HCV-RNA level ≥ 105 IU/mL received ritonavir-boosted danoprevir 125/100 mg twice daily plus peginterferon alfa-2a/ribavirin for either 12 (noncirrhotic patients: Arm A, n = 34) or 24 weeks (cirrhotic patients: Arm B, n = 27) in this phase II open-label study. Sustained virologic response was defined as HCV-RNA < 25 IU/mL 12 weeks after end of treatment (SVR12). RESULTS: Similar SVR12 rates were achieved in Arms A (88.2%; 95% confidence interval, 73.4-95.3%) and B (88.9%; 71.9-96.2%). Most patients had G1b infection, among whom SVR12 rates in Arms A and B were 96.7% and 91.7%, respectively. The overall SVR12 rate was 94.0% in noncirrhotic Taiwanese patients (100% in the subset of G1b patients). No patients withdrew for safety reasons. Three (11%) cirrhotic patients (Arm B) experienced serious adverse events, none of which was considered to be related to treatment. No Grade 3/4 alanine aminotransferase elevations were reported. The pharmacokinetic properties of danoprevir were broadly overlapping in noncirrhotic and cirrhotic patients both on Days 1 and 14. CONCLUSIONS: Ritonavir-boosted danoprevir plus peginterferon alfa-2a/ribavirin produced sustained virologic response rates > 90% after 12 weeks' treatment in noncirrhotic and 24 weeks' treatment in cirrhotic Asian patients with G1b infection and was well tolerated. These regimens are well suited to countries where G1b predominates.


Subject(s)
Antiviral Agents/therapeutic use , Hepatitis C, Chronic/drug therapy , Liver Cirrhosis/drug therapy , Adult , Aged , Antiviral Agents/adverse effects , Antiviral Agents/blood , Cyclopropanes , Drug Therapy, Combination , Female , Hepacivirus/genetics , Hepacivirus/isolation & purification , Hepatitis C, Chronic/complications , Humans , Interferon-alpha/adverse effects , Interferon-alpha/blood , Interferon-alpha/therapeutic use , Isoindoles , Lactams/adverse effects , Lactams/blood , Lactams/therapeutic use , Lactams, Macrocyclic , Liver Cirrhosis/virology , Male , Middle Aged , Polyethylene Glycols/adverse effects , Polyethylene Glycols/therapeutic use , Proline/analogs & derivatives , RNA, Viral/blood , Recombinant Proteins/adverse effects , Recombinant Proteins/blood , Recombinant Proteins/therapeutic use , Ribavirin/adverse effects , Ribavirin/blood , Ribavirin/therapeutic use , Ritonavir/adverse effects , Ritonavir/blood , Ritonavir/therapeutic use , Sulfonamides/adverse effects , Sulfonamides/blood , Sulfonamides/therapeutic use , Young Adult
20.
J Gastroenterol Hepatol ; 31(7): 1323-9, 2016 Jul.
Article in English | MEDLINE | ID: mdl-26841930

ABSTRACT

BACKGROUND AND AIM: Pegylated-interferon-alpha plus ribavirin is the current standard-of-care regimen for treating chronic hepatitis C virus (HCV) infection in Taiwan; however, interferon-based regimens can be poorly tolerated. The interferon-free, two-drug, fixed-dose combination tablet ledipasvir/sofosbuvir is approved in Europe, the USA, and Japan for treating chronic genotype 1 HCV infection. Little is known about its efficacy/safety in Taiwanese patients. METHODS: In this multicenter, open-label, phase 3b (NCT02021656) study, 85 Taiwanese patients (n = 42, treatment-naïve; n = 43, treatment-experienced) with chronic genotype 1 HCV infection (±compensated cirrhosis) received 12 weeks of ledipasvir/sofosbuvir fixed-dose combination tablet. The primary efficacy end point was the proportion of patients with sustained virologic response 12 weeks after treatment discontinuation (SVR12). Safety and pharmacokinetic data were collected. RESULTS: The overall SVR12 rate was 98% (83/85), with 100% (42/42) and 95% (41/43) of treatment-naïve and treatment-experienced patients, respectively, achieving SVR12. There were no on-treatment virologic failures. One patient relapsed after treatment discontinuation; one patient withdrew consent on day 2. The most common treatment-emergent adverse event (AE) was headache (14%, 12/85). There was one grade 3 AE (small cell lung cancer unrelated to ledipasvir/sofosbuvir), no grade 4 AEs, and four grade 3-4 laboratory abnormalities. Only the patient with small cell lung cancer prematurely discontinued treatment. Two patients reported three serious AEs; none was considered related to ledipasvir/sofosbuvir. CONCLUSIONS: Data from this phase 3b study suggest that 12 weeks of once-daily treatment with the interferon-free, ribavirin-free regimen ledipasvir/sofosbuvir is effective and well-tolerated in Taiwanese patients with chronic genotype 1 HCV infection, irrespective of treatment history.


Subject(s)
Benzimidazoles/administration & dosage , Carbamates/administration & dosage , Fluorenes/administration & dosage , Genotype , Hepacivirus/genetics , Hepatitis C, Chronic/drug therapy , Hepatitis C, Chronic/virology , Heterocyclic Compounds, 4 or More Rings/administration & dosage , Sofosbuvir/administration & dosage , Adult , Aged , Drug Combinations , Female , Humans , Male , Middle Aged , Tablets , Taiwan , Treatment Outcome
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