Hepatitis B relapse after entecavir or tenofovir alafenamide cessation under anti-viral prophylaxis for cancer chemotherapy.

BACKGROUND: No study has comparing hepatitis B virus (HBV) relapse rates among patients with both cancer and hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB) who completed anti-viral prophylaxis for chemotherapy and then stopped taking entecavir or tenofovir alafenamide (TAF). METHODS: A total of 227 HBeAg-negative cancer patients without cirrhosis who previously took entecavir (n = 144) or TAF (n = 83) for antiviral prophylaxis were enrolled. RESULTS: The cumulative incidence of virological and clinical relapse at 2 years was 37% and 10.4%, respectively, in the entecavir group, and 46.7% and 19.5%, respectively, in the TAF group. The multivariate analysis revealed that the use of hematologic malignancy, TAF use, and high-viremia group at baseline were independent risk factors for virological relapse, and use of rituximab, TAF use, higher FIB-4 index and high-viremia group at baseline were independent risk factors for clinical relapse. After propensity score-matching, the patients who discontinued TAF therapy still exhibited higher virological (P = 0.031) and clinical relapse rates (P = 0.012) than did those who discontinued entecavir therapy. The patients were allocated to high- (> 2000 IU/mL), moderate- (between 20 and 2000 IU/mL) and low- (< 20 IU/mL) viremia groups. In the high-viremia group, those who had taken TAF for antiviral prophylaxis had higher rates of virological and clinical relapse than did those who had taken entecavir; in the moderate- and low-viremia groups, no significant difference in virological and clinical relapse rates was detected between the entecavir and TAF groups. Three patients experienced hepatic decompensation upon clinical relapse. All three patients were lymphoma and underwent rituximab therapy. One patient developed acute on chronic liver failure and died even though timely retreatment. CONCLUSIONS: In patients with both cancer and CHB who underwent antiviral prophylaxis, TAF use was associated with a higher chance of HBV relapse than entecavir use after nucleos(t)ide analogue cessation, particularly in the high-viremia group. Patients who are hematologic malignancy and undergo a rituximab-containing cytotoxic therapy should be monitored closely after withdrawal from prophylactic NA treatment.

The association between steatosis and diabetes with hepatocellular carcinoma in non-genotype 3 chronic hepatitis C patients.

BACKGROUND & AIMS: Diabetes mellitus (DM) has been found to be strongly associated with an increased risk of hepatocellular carcinoma (HCC) among chronic hepatitis C (CHC) patients. Several studies have also found an association between metabolic steatosis and the risk of HCC in CHC patients, whether this latter association has been accounted for by the known relationship between DM and HCC is still unknown. METHODS: A cohort consisting of 976 non-genotype 3 patients histologically proven to have CHC and treated with interferon and ribavirin was studied. Cumulative incidence and HCC risk were analysed using the Kaplan-Meier method and Cox proportional hazard analysis. RESULTS: Hepatocellular carcinoma developed in 140 subjects over a median follow-up period of 97.3 months, while 699 patients achieved sustained virological response (SVR). According to multivariate analyses, age ≥ 60 years, advanced fibrosis and genotype 1 were identified as independent factors significantly associated with HCC development in SVR patients. Furthermore, using the absence of steatosis and absence of DM as references, the presence of steatosis without DM (HR = 2.09, 95% CI = 1.12-3.9, P = .021), the presence of DM without steatosis (HR = 2.78, 95% CI = 1.3-5.92, P = .008) and the combined presence of steatosis and DM (HR = 3.25, 95% CI = 1.44-7.33, P = .004) were identified as independent factors significantly associated with HCC development in the SVR patients. In contrast, steatosis alone, DM alone and the combined presence of steatosis and DM were not associated with HCC development in non-SVR patients. CONCLUSIONS: Steatosis and DM may be associated with HCC development in non-genotype 3 CHC patients with SVR.

Role of hepatitis B surface antigen in hepatitis B virus relapse after entecavir or tenofovir prophylaxis in patients undergoing cancer chemotherapy.

BACKGROUND AND AIM: This study investigated whether hepatitis B surface antigen (HBsAg) could predict hepatitis B virus (HBV) relapse after cessation of entecavir or tenofovir disoproxil fumarate (TDF) prophylaxis for chronic hepatitis B cancer patients who are undergoing chemotherapy. METHODS: The study enrolled 122 hepatitis B e-antigen-negative cancer patients who underwent chemotherapy with entecavir or TDF for antiviral prophylaxis and posttreatment follow-up for at least 6 months. RESULTS: Of the 122 patients, 52 and 18 experienced virological and clinical relapse, which had 3-year cumulative incidences of 46.6% and 18.6%, respectively. Multivariate analysis showed that end-of-treatment HBsAg levels and baseline HBV-DNA ≥ 2000 IU/mL were independent predictors of virological relapse. The best HBsAg cutoff value was 500 IU/mL. An end-of-treatment HBsAg of 500 IU/mL was useful for predicting virological relapse in patients with baseline HBV-DNA < 2000 IU/mL (3-year rate: 21.3% vs 46.4%, P = 0.038, in patients with HBsAg < 500 and ≥ 500 IU/mL, respectively), but not in patients with baseline HBV-DNA ≥ 2000 IU/mL. Of the 52 patients who experienced virological relapse, 13 experienced transient virological relapse. Patients with baseline HBV-DNA level < 2000 IU/mL experienced a higher rate of transient virological relapse (42.1% vs 15.2%, P = 0.031). Three patients experienced hepatic decompensation upon alanine aminotransferase flares, and no patient died after timely retreatment. Ten patients experienced posttreatment HBsAg loss, and the 3-year HBsAg loss rate was 30.7% in patients with end-of-treatment HBsAg < 100 IU/mL. CONCLUSIONS: The baseline HBV-DNA and end-of-treatment HBsAg levels could predict virological relapse after withdrawal of entecavir and TDF prophylaxis for chemotherapy.

Risk factors for development of hepatocellular carcinoma in patients with chronic hepatitis C without sustained response to combination therapy.

BACKGROUND/PURPOSE: Although antiviral therapy reduces development of hepatocellular carcinoma (HCC) in patients with chronic hepatitis C (CHC), HCC often develops in patients with non-sustained virologic response (non-SVR). We aimed to evaluate risk factors for HCC in HCV patients with non-SVR. METHODS: From March 2002 to December 2013, 800 patients with CHC who had received combined pegylated interferon (peg-IFN)/ribavirin (RBV) therapy without achieving SVR were enrolled. Main outcome measure was HCC development. Variables were cirrhosis, platelet count, α-fetoprotein (AFP) levels, aspartate aminotransferase (AST) to platelet ratio index (APRI), and IL28B polymorphism (CT + TT). RESULTS: One-hundred of 800 non-SVR patients developed HCC within a median 53.5-months follow-up. Cumulative incidence of HCC for all patients was 1.4%, 5.6% and 12.3%, respectively, at 1st, 3rd and 5th years of follow-up. In univariate analysis, patients who developed HCC tended to have LC (p< 0.001), lower platelet counts (<150 × 109/l, p < 0.001), higher AFP levels (≥20 ng/ml, p < 0.001), higher Fib-4 levels (p < 0.001), higher APRI levels (p < 0.001), IL 28B polymorphism (CT + TT) (p < 0.001) and higher incidence of diabetes mellitus (DM) (p = 0.019). Multivariate analysis in overall patients revealed that cirrhosis (HR: 2.94, 95% CI: 1.81-4.77, p < 0.001), IL28B rs12979860 (CT + TT) polymorphisms (HR: 3.22, 95% CI: 2.17-4.78, p < 0.001), and high APRI levels (≥2.57) (HR: 2.32, 95% CI: 1.47-3.67, p < 0.001) were independent risk factors for HCC. CONCLUSION: Liver cirrhosis, high APRI levels, and IL28B rs12979860 at baseline are independent risk factors for HCC development in patients without SVR after peg-IFN combination therapy.

Elevated body mass index is a risk factor associated with possible liver cirrhosis across different etiologies of chronic liver disease.

BACKGROUND/PURPOSE: Metabolic risk factors are associated with liver fibrosis. Whether or not metabolic risk factors affect the severity of liver fibrosis in patients with chronic hepatitis B (CHB), chronic hepatitis C (CHC), or risk factors associated with non-alcoholic fatty liver disease (NAFLD) remains unclear. We aimed to investigate this by transient elastography. METHODS: In this cross-sectional study, we enrolled 1513 patients who presented with chronic liver disease (CLD) at a tertiary hospital. Liver stiffness measurement (LSM) >13 kPa was used as a cutoff suggesting possible liver cirrhosis (LC). RESULTS: Possible LC was noted in 7.8% of the CHB patients, 19.9% of the CHC patients, and 11.9% of the patients with risk factors associated with NAFLD. After adjustments for biochemical and virological factors were made, BMI (per 1 kg/m2 increase) (OR: 1.17, 95% CI: 1.06-1.29, P = 0.002) was found to be an independent factor associated with possible LC in CHB patients; BMI (per 1 kg/m2 increase) (OR: 1.15, 95% CI: 1.07-1.24, P < 0.001) and diabetes mellitus (DM) (OR: 2.32, 95% CI: 1.25-4.30, P = 0.008) were found to be independent factors associated with possible LC in CHC patients; and BMI (per 1 kg/m2 increase) (OR: 1.19, 95% CI: 1.07-1.32, P = 0.002) and DM (OR: 10.35, 95% CI: 2.95-36.32, P < 0.001) were found to be independent factors associated with possible LC in patients with risk factors associated with NAFLD. CONCLUSION: Elevated BMI was an independent risk factor associated with possible LC across the three different etiologies of CLD. As such, weight loss may be beneficial in these patients.

Association between PNPLA3 (rs738409 C>G) variant and hepatocellular carcinoma in Asian chronic hepatitis C patients: A longitudinal study.

BACKGROUND/PURPOSE: Prdevious meta-analyses assess whether or not patatin-like phospholipase domain containing 3 (PNPLA3) (rs738409 C > G) was associated with increased risk of hepatocellular carcinoma (HCC) in Caucasians patients with hepatitis C virus (HCV)-related cirrhosis, these meta-analyses did not provide firm conclusions. Only one cross-sectional study involving Asian patients has previously been conducted to explore this issue. We aim to investigate this in a longitudinal cohort of Asian chronic hepatitis C (CHC) patients. METHODS: We consecutively enrolled 1011 CHC patients who underwent liver biopsy before initiating interferon-based therapy. These patients were followed-up and screened for HCC up to a median of 6.9 years. The influence of rs738409 (GG) genotype on the occurrence of HCC was assessed using the Kaplan-Meier method, then according to the multivariate Cox model. RESULTS: During follow-up, 143 (14.1%) patients developed HCC. rs738409 (GG) genotype was not associated with time-to-HCC development on multivariate Cox regression (P = 0.634). When considering the occurrence of these events over time, rs738409 (GG) genotype did not influence the risk of HCC development (log-rank = 0.12). Among 261 patients with liver cirrhosis, rs738409 (GG) genotype was not associated with time-to-HCC development on multivariate Cox regression (P = 0.737). When considering the occurrence of these events over time, rs738409 (GG) genotype did not influence the risk of HCC development (log-rank = 0.72). CONCLUSION: In this longitudinal study with liver biopsy to stage liver fibrosis, we affirm there is no influence of the rs738409 (GG) genotype on the occurrence of HCC in Asian CHC patients, including cirrhotic patients.

The correlation of controlled attenuation parameter results with ultrasound-identified steatosis in real-world clinical practice.

BACKGROUND/PURPOSE: Controlled attenuation parameter (CAP) is a method for measuring steatosis based on FibroScan. Despite observer dependency, ultrasound (US) robustly diagnoses moderate and severe steatosis. Here, we aimed to evaluate the correlation of CAP with US-identified steatosis in real-world clinical practice. METHODS: CAP and US were performed for 1554 chronic liver disease (CLD) patients. CAP was performed by two technicians, and US was performed by 30 hepatologists. The performance of the CAP as compared with the US results was assessed using the area under the receiver operating characteristic curve (AUROC). RESULTS: 532 (34.2%) of the patients had hepatitis C virus (HCV) infection, 723 (46.5%) of the patients had hepatitis B virus (HBV) infection, and the rest were patients with metabolic risk factors. CAP values were significantly correlated with the steatosis grades identified by US for all the patients (ρ = 0.497, P < 0.001), for the HBV-infected patients (ρ = 0.495, P < 0.001), for the HCV-infected patients (ρ = 0.343, P < 0.001), and for the patients with metabolic risk factors (ρ = 0.515, P < 0.001). Using CAP, the AUROC values were 0.759, 0.795, 0.715, and 0.716 for ≥moderate steatosis identified by US in, respectively, all the patients, the HBV-infected patients, the HCV-infected patients, and the patients with metabolic risk factors. The AUROC values were 0.791, 0.868, 0.807 and 0.701 for severe steatosis identified by US in, respectively, all the patients, the HBV-infected patients, the HCV-infected patients, and the patients with metabolic risk factors. CONCLUSION: CAP values were well correlated with the steatosis grades assessed by US in real-world clinical practice.

Dynamic α-fetoprotein, platelets and AST-to-platelet ratio index predict hepatocellular carcinoma in chronic hepatitis C patients with sustained virological response after antiviral therapy.

BACKGROUND: Hepatitis C virus (HCV)-infected patients who achieve viral eradication may still develop hepatocellular carcinoma (HCC). Little is known about the impact of dynamic change of serum markers on HCC development. METHODS: We enrolled 1351 HCV-infected patients who achieved sustained virological response (SVR). Laboratory data were collected at least 1 year after IFN-based therapy and to the latest follow-up. Data on α-fetoprotein (AFP) were obtained >6 months prior to HCC development to exclude HCC-related AFP elevation. RESULTS: HCC developed in 49 patients. Risk factors for HCC in SVR patients were old age, liver cirrhosis, higher pre- and post-treatment AFP and high post-treatment AST-to-platelet ratio index (APRI). Patients with pre-AFP ≥15 ng/mL → post-AFP ≥15 ng/mL (at 1 year, 23.1%; 5 years, 42.3%) and pre-AFP <15 ng/mL → post-AFP ≥15 ng/mL (at 1 year, 25%; 5 years, 50%) had the highest risk of HCC development, followed by pre-AFP ≥15 ng/mL → post-AFP <15 ng/mL (at 1 year, 5.2%; 5 years, 7.6%) and pre-AFP <15 ng/mL → post-AFP ng/mL <15 ng/mL (at 1 year, 0.5%; 5 years, 0.9%) (P < 0.001). The pattern was similar for platelets and APRI (P < 0.001). SVR patients with pre-APRI ≥0.7 → post-APRI ≥0.7 had the highest risk of HCC development, followed by comparable risks among the other three groups. CONCLUSIONS: SVR patients with a persistently high AFP level (≥15 ng/mL) and a high APRI (≥0.7) before and after treatment had the highest incidence of HCC development. Patients with a reduction of AFP and APRI to the normal range after treatment had a markedly decreased risk of HCC. The risk was lowest for patients who kept persistently normal AFP and APRI before and after treatment.

Three-year efficacy and safety of tenofovir in nucleos(t)ide analog-naïve and nucleos(t)ide analog-experienced chronic hepatitis B patients.

BACKGROUND AND AIMS: This study compared the efficacy and safety of tenofovir disoproxil fumarate (TDF) up to 3 years of innucleos(t)ide analog (NA)-naïve and NA-experienced chronic hepatitis B (CHB) patients. METHODS: Tenofovir disoproxil fumarate-treated NA-naïve and NA-experienced CHB patients were retrospectively analyzed. RESULTS: After 3 years of TDF therapy, 97.7%, 71%, and 45.5% NA-naïve patients achieved a virological response, alanine aminotransferase normalization, and hepatitis B e antigen seroconversion, respectively. Compared with NA-naïve patients, NA-experienced patients without drug resistance and infected with lamivudine/telbivudine-resistant mutants showed similar results. In contrast, patients previously infected with adefovir-resistant mutants and with a suboptimal entecavir response showed significantly lower rates of virological response and hepatitis B e antigen loss/seroconverion than NA-naïve patients. Mean estimated glomerular filtration rate markedly reduced within 12 months of TDF therapy; however, it did not decrease significantly during 12-36 months of treatment. Diabetes mellitus was an independent predictor of a ≥ 0.5 mg/dL increase above baseline in serum creatinine level, and age, hypertension, diabetes mellitus, and baseline creatinine level were independent factors for > 20% decline in estimated glomerular filtration rate from baseline. Liver stiffness measurements improved significantly, but bone mineral density did not change significantly during treatment. Hepatocellular carcinoma incidence was low at 36 months. Age of > 60 years, cirrhosis, a low baseline platelet count and a high α-fetoprotein level at 12 months were significant predictors of hepatocellular carcinoma development. CONCLUSIONS: Tenofovir disoproxil fumarate is effective and safe for NA-naïve and NA-experienced CHB patients and should be used cautiously in patients with comorbidities because of a renal dysfunction risk.

A polymorphism in interferon L3 is an independent risk factor for development of hepatocellular carcinoma after treatment of hepatitis C virus infection.

BACKGROUND & AIMS: Polymorphisms in interferon (IFN)L3 (encodes IFNλ3 or interleukin 28B) are associated with outcomes of treatment for hepatitis C virus (HCV) infection. However, there is controversy regarding how polymorphisms in IFNL3 affect the risk for development of hepatocellular carcinoma (HCC) in patients treated with pegylated interferon and ribavirin. METHODS: In a retrospective study, we analyzed data from 1118 patients with HCV infection (589 men; median age, 60 y; 49.9% infected with genotype 1; 51.3% with advanced fibrosis) treated with pegylated interferon and ribavirin from March 2000 through October 2009 at the Chang Gung Memorial Hospital in Kaohsiung, Taiwan (71.64% achieved sustained virologic response [SVR]). Baseline samples were collected before therapy. Starting 24 weeks after treatment, clinical and biochemical features were assessed every 3 to 6 months and patients underwent ultrasound examinations. Lesions detected were examined by computed tomography, angiography, or fine-needle aspiration biopsy analyses. Patients were followed up from the initiation of HCV therapy until a diagnosis of HCC (based on published guidelines), death, or March 31, 2013 (median, 60 mo). DNA samples from each patient were analyzed for rs12979860 in IFNL3. Kaplan-Meier analysis was used to determine the risk for development of HCC. RESULTS: The percentages of patients with the IFNL3 rs12979860 CC, CT, and TT genotypes were 86.4%, 13.2%, and 0.3%, respectively. A total of 108 patients (9.66%) developed HCC. The IFNL3 rs12979860 CT and TT genotypes correlated with high baseline levels of α-fetoprotein (AFP; ≥20 ng/mL), advanced stage of fibrosis, diabetes, or lack of an SVR (all P < .05). Based on multivariate Cox regression analysis, age 60 years and older, low platelet count (<15 × 10(9) cells/L), AFP level of 20 ng/mL or greater, advanced stage fibrosis, diabetes, lack of an SVR, and the IFNL3 rs12979860 CT and TT genotypes were significant risk factors for HCC (P < .05). Age 60 years and older, low numbers of platelets or high AFP level, and advanced fibrosis were risk factors for HCC among patients with a SVR. The IFNL3 rs12979860 genotype did not have a significant effect on risk for HCC among patients with SVRs, although some of these patients (with the CT or TT genotype) did develop HCC. Among patients without SVRs, only fibrosis stage and the IFNL3 rs12979860 CT and TT genotypes (hazard ratio, 1.80; 95% confidence interval, 1.06-3.07; P = .030) were independent risk factors for HCC. CONCLUSIONS: Based on a retrospective study of patients treated for HCV infection, the IFNL3 rs12979860 CT and TT polymorphisms are associated with a risk for HCC, especially in patients without a SVR.

The validation of the 2010 American Association for the Study of Liver Diseases guideline for the diagnosis of hepatocellular carcinoma in an endemic area.

BACKGROUND AND AIM: Hepatocellular carcinoma (HCC) diagnosis could be made with one typical imaging study in a cirrhotic liver by the guideline of the American Association for the Study of Liver Diseases (AASLD) in 2010. Patients with hepatitis B who may not have fully developed cirrhosis could be applied. We aim to retrospectively analyze and validate the diagnostic power of the 2010 guideline in an HCC endemic area (Taiwan). METHODS: From January 2006 to December 2010, a total of 648 patients with liver tumor post-surgical resection were reviewed. The fibrotic scores were verified by METAVIR score 4. Among the 648 patients, 569 (87.8%) were HCC patients. Hepatitis B accounts for 54.5%, hepatitis C 21.9%, hepatitis B + C 2.8%, and non-hepatitis B or C 20.7% of patients. Two hundred eighty-eight of 648 (44%) patients were with cirrhotic liver. RESULTS: The diagnostic sensitivity, specificity, positive predictive value (PPV), negative predictive value, and accuracy of the 2010 AASLD guideline f are 99.1%, 36.7%, 91.9%, 85.3%, and 91.5%, respectively. Cirrhotic liver exhibited a higher PPV (P < 0.001) but lower specificity (P = 0.0479) than non-cirrhotic liver. In both cirrhotic and non-cirrhotic condition, no difference existed in patients with hepatitis B or hepatitis C (P > 0.05). CONCLUSIONS: Similar sensitivity of HCC diagnosis existed between cirrhotic and non-cirrhotic liver, and across different fibrotic stages. But cirrhotic liver exhibited a higher PPV. Hepatitis B or C has no decisive effect in HCC diagnosis.

Entecavir vs. lamivudine in chronic hepatitis B patients with severe acute exacerbation and hepatic decompensation.

BACKGROUND & AIMS: We compared the mortality and treatment response between lamivudine (LAM) and entecavir (ETV) in chronic hepatitis B (CHB) patients with severe acute exacerbation and hepatic decompensation. METHODS: From 2003 to 2010 (the LAM group) and 2008 to 2010 (the ETV group), 215 and 107 consecutive CHB naïve patients with severe acute exacerbation and hepatic decompensation treated with LAM and ETV respectively, were recruited. RESULTS: At baseline, the LAM group had higher AST levels and end-stage liver disease (MELD) scores, and lower albumin levels than the ETV group. Univariate analysis showed that the LAM group had a higher rate of overall (p=0.02) and liver-related mortality (p=0.052) at week 24 than the ETV group, including in patients with acute-on-chronic liver failure. Multivariate analysis showed that MELD scores, ascites, and hepatic encephalopathy were independent factors for overall and liver-related mortality at week 24. ETV or LAM treatment was not an independent factor for mortality in all patients or patients with acute-on-chronic liver failure. The best cut-off value of MELD scores were 24 for 24-week liver-related mortality. The ETV group achieved better virological response (HBV DNA <300 copies/ml) than the LAM group at week 24 (p=0.043) and 48 (p=0.007). The T1753C/A mutation was also an independent predictor associated with overall and liver-related mortality at week 24. CONCLUSIONS: The choice between ETV and LAM was not an independent factor for mortality in CHB patients with acute exacerbation and hepatic decompensation. Patients with ascites, hepatic encephalopathy, and MELD scores ⩾24 were associated with poor outcome and should be considered for liver transplantation.

Telbivudine and adefovir combination therapy for patients with chronic lamivudine-resistant hepatitis B virus infections.

We evaluated second-line salvage therapy with adefovir + telbivudine (group 1), adefovir followed by adefovir + telbivudine (group 2), or lamivudine + adefovir followed by adefovir + telbivudine (group 3) in hepatitis B patients with an inadequate virologic response to lamivudine treatment. Simple linear regression analysis showed that for each additional month of treatment, the most significant reduction in viral load occurred in group 1 (HBV DNA [Log10 IU/mL]: group 1, -0.149; group 2, -0.081; group 3, -0.123). Generalized estimating equation analysis revealed that compared to group 1, hepatitis B virus (HBV) DNA levels were 1.203 and 0.443 Log10 IU/mL higher in groups 2 and 3, respectively. Overall, a significant reduction in viral load (-0.060 Log10 IU/mL) was observed for each additional month of treatment. Adefovir + telbivudine treatment resulted in a significant reduction in HBV DNA levels. Moreover, telbivudine treatment resulted in a significant reduction in viral load (-0.050 Log10 IU/mL) compared to lamivudine treatment after the emergence of lamivudine resistance.

Comparing the efficacy and clinical outcome of telbivudine and entecavir naïve patients with hepatitis B virus-related compensated cirrhosis.

BACKGROUND AND AIM: There is limited data on the efficacy and outcome of telbivudine (LdT) therapy in patients with chronic hepatitis B and compensated cirrhosis. We evaluated LdT as first-line therapy in these patients and compared with those treated with entecavir (ETV). METHODS: We consecutively enrolled 88 chronic hepatitis B patients with compensated cirrhosis primarily treated with LdT at least for 2 years or less than 2 years but developed resistance, and evaluated the efficacy and clinical outcomes. Meanwhile, we matched a control group who treated with ETV for comparison. RESULTS: In LdT group, alanine aminotransferase normalization (65.8%), hepatitis B e antigen seroconversion (39.8%), hepatitis B virus (HBV) DNA undetectablility (71.6%), and virologic resistance (23.9%) were noted after 2 years treatment. Compared with ETV group, there were significant difference in HBV DNA undetectablility (P < 0.001) and virologic resistance (P < 0.001). In addition, the decline of serum hepatitis B surface antigen levels, hepatocellular carcinoma development, mortality, disease progression, and the change of renal function were similar. Cox regression analysis showed that pretreatment low albumin level and high model for end-stage liver disease scores were risk factors for disease progression. CONCLUSIONS: These results indicated that although LdT and ETV are similar in clinical outcomes for patients with HBV-related compensated cirrhosis, LdT still had lower HBV undetectablility and higher resistant rate after 2 years treatment, which was a challenge for being as first-line therapy in these patients who need lifelong therapy.

Hepatocellular carcinoma surveillance at 4- vs. 12-month intervals for patients with chronic viral hepatitis: a randomized study in community.

OBJECTIVES: To compare the efficacy of hepatocellular carcinoma (HCC) surveillance at 4- and 12-month intervals in a community for patients with chronic viral hepatitis and thrombocytopenia. METHODS: In 10 townships, adults (≥ 40 years) with platelet ≤ 150 (× 10(9))/l, positive hepatitis B surface antigen, or antibody to hepatitis C virus were invited to this study. These townships were randomized into 4- (group A) and 12-month (group B) interval surveillance groups. Seven hundred and eighty-five and 796 residents met the study criteria in groups A and B. Ultrasonography (US) was the surveillance method. RESULTS: A total of 744 residents (group A: 387; group B: 357) were enrolled. In the study period, HCC was diagnosed in 39 residents (group A: 24; group B: 15). There was no difference in cumulative 3-year HCC incidence between the two groups. The tumors were smaller in group A than in group B, though group A had more patients with tumor ≤ 2 cm (P = 0.003) who were in Barcelona Clinic Liver Cancer (BCLC) very-early stage (P = 0.017) and had undergone curative treatments (P = 0.049). Male gender, cirrhosis, and platelet ≤ 100 (× 10(9))/l were associated factors of HCC occurrence. There was no difference in 4-year overall survival between the two groups. Patients undergoing recommended treatments had better 4-year survival rates. CONCLUSIONS: Compared with 12-month interval, US surveillance at 4-month interval detected more patients with HCC ≤ 2 cm who were in BCLC very-early stage and were fit for curative treatments. Up to 4-year follow-up, however, the overall survival was not different.

Efficacy and safety of pegylated interferon alfa-2b and ribavirin combination therapy versus pegylated interferon monotherapy in hemodialysis patients: a comparison of 2 sequentially treated cohorts.

BACKGROUND: Pegylated interferon (peginterferon; interferon with an attached polyethylene glycol molecule) monotherapy is the recommended treatment for chronic hepatitis C virus (HCV) infection in hemodialysis patients. Limited data concerning peginterferon alfa-2b and ribavirin treatment in this population are available. STUDY DESIGN: 2 prospective observational cohort studies. SETTING & PARTICIPANTS: From 2007-2009, a total of 26 patients received peginterferon alfa-2b monotherapy. From 2009-2012, an additional 26 patients were treated with peginterferon alfa-2b and ribavirin. PREDICTORS: Peginterferon alfa-2b monotherapy, 1.0 µg/kg/wk, versus peginterferon alfa-2b, 1.0 µg/kg/wk, and ribavirin, 200 mg, 3 times per week. Treatment durations were 24 and 48 weeks for HCV genotypes non-1 and 1, respectively. OUTCOMES & MEASUREMENTS: End-of-treatment virologic response and sustained virologic response (SVR) were undetectable HCV RNA at the end of treatment and 24 weeks after treatment ended, respectively. SVR and treatment-related withdrawal rate were evaluated by intention-to-treat (ITT) and per-protocol (PP) analyses. Severe anemia was defined as nadir hemoglobin level <8 g/dL. RESULTS: Patients who received combination therapy had a higher end-of-treatment virologic response than patients who received monotherapy (85% vs 62% in ITT [P = 0.03] and 100% vs 80% in PP [P = 0.03]). The SVR rate was higher in the combination-treatment cohort than in the monotherapy cohort (62% vs 27% in ITT [P = 0.01] and 73% vs 35% in PP [P = 0.01]). Patients who received combination therapy had a significantly higher rate of severe anemia than those who received monotherapy (58% vs 27%; P = 0.03). However, treatment withdrawal rates were similar between the combination (15%) and monotherapy (23%) groups. LIMITATIONS: Comparison of 2 sequential cohorts rather than a randomized control study. CONCLUSIONS: Peginterferon alfa-2b and ribavirin combination therapy provided a higher SVR rate than peginterferon alfa-2b monotherapy for treatment-naive dialysis patients with chronic HCV infection through careful monitoring of hematologic parameters and ribavirin dose modification. Severe anemia was significantly higher in patients receiving combination therapy than patients treated with monotherapy.

Long-term comparisons of the durability of 6 months versus 12 months antiviral therapy for hepatitis B after chemotherapy cessation.

BACKGROUND: Prophylaxis antiviral therapy is recommended for patients with hepatitis B receiving chemotherapy but the ideal treatment duration after chemotherapy cessation needs more evidence for clarification. AIMS: This study aimed to compare the relapse rate of short finite intervals of 6 months and 12 months of -nucleos(t)ide analogue (NA) therapy in patients stratified by low hepatitis B virus (HBV)-DNA of < 2000 IU/ml or high HBV DNA of ≥ 2000 IU/ml. METHODS: Patients started tenofovir or entecavir treatment 1 week before chemotherapy and were assigned to different treatment duration groups randomly after stratified by HBV DNA pretreatment: (1) HBV DNA of < 2000 IU/ml at 6-month or 12-month duration; (2)HBV DNA of ≥ 2000 IU/ml at 6-month or 12-month duration. Virological relapse (VR) was defined as HBV DNA of > 2000 IU/ml, and clinical relapse (CR) was defined as HBV DNA of > 2000 IU/ml and alanine aminotransferase of > 80 IU/L during the follow-up period. The primary endpoint was to compare the durability between groups 1 year after antiviral therapy cessation. The secondary endpoint was VR and CR rate at long-term follow-up after antiviral therapy cessation. RESULTS: This study enrolled 61 patients, and 5 patients were lost to follow-up or tumor recurrence. VR and CR rates were 46.4% and 14.3% at 1-year and 55.3% and 16.1%, at long-term follow-up, respectively. VR and CR rates demonstrated no difference between the groups. Pretreatment HBV DNA at ≥ 2000 IU/ml and end-of-treatment hepatitis B surface antigen (HBsAg) at ≥ 500 IU/ml were the predictor of VR (hazard ratio [HR]: 2.98; p = 0.010 and HR: 2.38; p = 0.037). CONCLUSIONS: Prolongation from 6 months to 12 months of NA consolidation after chemotherapy cessation did not affect the VR or CR of HBV. High pretreatment HBV DNA and end-of-treatment HBsAg levels could predict VR after antiviral therapy cessation for chemotherapy.

Inhibition of lncRNA RPPH1 activity decreases tumor proliferation and metastasis through down-regulation of inflammation-related oncogenes.

OBJECTIVE: Ribonuclease P RNA component H1 (RPPH1) is a long non-coding RNA (lncRNA) associated with cancer progression. Higher RPPH1 expression in breast and cervical cancer samples than that in normal tissues were observed through the lncRNASNP2 database; therefore, silencing RPPH1 expression might be a potential strategy for cancer treatments, even though RPPH1 is also an RNA subunit of ribonuclease P involved in processing transfer RNA (tRNA) precursors and the effect of RPPH1 knockdown is not yet fully understood. METHODS: Differentially expressed genes (DEGs) were identified through RNA sequencing in each shRNA-transfected RPPH1 knockdown MDA-MB-231, RPPH1 knockdown HeLa cell, and respective control cells, then the gene ontology enrichment analysis was performed by IPA and MetaCore database according to these DEGs, with further in vitro experiments validating the effect of RPPH1 silencing in MDA-MB-231 and HeLa cells. RESULTS: Hundreds of down-regulated DEGs were identified in RPPH1 knockdown MDA-MB-231 and HeLa cells while bioinformatics analysis revealed that these genes were involved in pathways related to immune response and cancerogenesis. Compared to mock- and vector-transfected cells, the production of mature tRNAs, cell proliferation and migration capacity were inhibited in RPPH1-silenced HeLa and MDA-MB-231 cells. Additionally, RPPH1 knockdown promoted G1 cell cycle arrest mainly through the down-regulation of cyclin D1, although glycolytic pathways were only affected in RPPH1 knockdown HeLa cells but not MDA-MB-231 cells. CONCLUSION: This study demonstrated that knockdown RPPH1 affected tRNA production, cell proliferation and metabolism. Our findings might provide insight into the role of RPPH1 in tumor development.

A comparison of telbivudine and entecavir for chronic hepatitis B in real-world clinical practice.

OBJECTIVES: To evaluate the efficacy of telbivudine and entecavir in chronic hepatitis B (CHB) patients over a 1 year period. METHODS: Ninety-seven telbivudine-naive and 98 entecavir-naive CHB patients who had been treated for at least 1 year were enrolled. Serial serum hepatitis B virus (HBV) DNA levels were checked at baseline and at weeks 24 and 48 after treatment. RESULTS: Entecavir and telbivudine groups had similar baseline HBV DNA levels (5.9 ± 1.7 versus 6.0 ± 1.5 log copies/mL, P=0.529). The undetectable rate of HBV DNA after 1 year of treatment was significantly higher in the entecavir group than the telbivudine group (94.9% versus 82.0%, P=0.009). Resistance developed in 6.7% of the telbivudine-naive patients after 1 year compared with none of the entecavir-naive patients (P=0.009). However, there was a significant difference between the telbivudine and entecavir groups in hepatitis B e antigen (HBeAg) seroconversion 24 weeks after treatment (40% versus 12.5%, P=0.007). Multiple logistic regression analysis revealed that baseline alanine aminotransferase (ALT) >200 IU/L (P=0.008) was independently associated with HBeAg seroconversion. Applying the roadmap concept with ALT >2× upper limit of normal at baseline, telbivudine and entecavir had favourable outcomes in PCR negativity, ALT normalization, HBeAg seroconversion and resistance. CONCLUSIONS: In real-world clinical practice, telbivudine resulted in higher rates of HBeAg seroconversion and drug resistance at week 48 compared with entecavir. A combination with baseline ALT plus 24 week HBV DNA levels led to the lowest rates of resistance in HBeAg-positive telbivudine-naive patients and had the highest probability of HBeAg seroconversion in both entecavir- and telbivudine-naive patients.

A novel predictive score for hepatocellular carcinoma development in patients with chronic hepatitis C after sustained response to pegylated interferon and ribavirin combination therapy.

OBJECTIVES: Antiviral therapy can prevent the development of hepatocellular carcinoma (HCC) in chronic hepatitis C (CHC) patients. However, HCC still develops in patients achieving sustained virological response (SVR). We proposed to evaluate the risk factors and derive a novel risk score for HCC (score(HCC)) by summation of products of clinical weights based on the regression coefficients in the final proportional hazards model. METHODS: From March 2002 to October 2009, we enrolled 871 patients with biopsy-proven CHC, who received combined pegylated interferon and ribavirin therapy and achieved SVR. RESULTS: Cox regression analysis showed that old age [hazard ratio (HR) 3.82, 95% CI 1.74-8.37, P = 0.001], high α-fetoprotein levels (HR 3.15, 95% CI 1.60-6.19, P = 0.001), low platelet counts (HR 2.81, 95% CI 1.22-6.44, P = 0.015) and high fibrotic stage (HR 3.95, 95% CI 1.46-10.70, P = 0.007) were independent risk factors. The cut-off level of risk scores was a derived value of 10 and was able to predict the HCC risk with 89.2% sensitivity and 69.5% specificity. The AUC value for the prediction was 0.848. The score(HCC) values were further categorized into three risk groups: low risk (score(HCC) ≤10), intermediate risk (score(HCC) 11-15) and high risk (score(HCC) ≥16). The proportion of HCC development increased from 1.37% (9/657) in the low-risk group to 9.14% (16/175) in the intermediate-risk group and 30.77% (12/39) in the high-risk group (P < 0.001). CONCLUSIONS: With the novel risk scores, we can estimate the chance of HCC development more exactly and practically. This approach can be used for HCC screening in CHC patients achieving SVR.