Comprehensive outcomes of on- and off-antiviral prophylaxis in hepatitis B patients undergoing cancer chemotherapy: A competing risks analysis.

Although antiviral prophylaxis is essential in hepatitis B patients in the context of cancer chemotherapy, there is little evidence-based consensus regarding the appropriate prevention strategy depending on the underlying type of cancer and viral status. This retrospective study included a comprehensive cohort of 302 hepatitis B surface antigen-positive patients with various cancers undergoing chemotherapy and antiviral prophylaxis. The rates of hepatitis B virus (HBV) reactivation during antiviral therapy (>1 log10 IU/mL increase or positive conversion of serum HBV DNA) and relapse when off antivirals ([re]appearance of HBV DNA >2,000 IU/ml with related alanine aminotransferase elevation) were evaluated, together with the associated risk factors, in a competing risks analysis where cancer death was considered as the competing event. During antiviral prophylaxis, HBV was reactivated in six patients (1.9%), who had leukemia (n = 4) or lymphoma (n = 2) and were treated with lamivudine (n = 4) or entecavir (n = 2). The incidence rate of HBV relapse in 127 off-prophylaxis patients was 21.3% during a median post-antiviral period of 11.7 months. Lymphoma, pre-prophylactic HBV DNA ≥2,000 IU/ml, and age ≥50 years were independent predictors of off-treatment HBV relapse (adjusted hazard ratios 5.25, 3.07, and 0.34, respectively; Ps < 0.05). Antiviral and anticancer drugs, duration of consolidation on antiviral prophylaxis, and HBeAg positivity were not independent predictors. In conclusion, hepatitis B flare-ups are not rare in patients receiving cancer chemotherapy during and after anti-HBV prophylaxis, even when potent antivirals are used. Patients with hematopoietic or lymphoid neoplasms or high viral burdens should receive prolonged and powerful HBV prophylaxis. J. Med. Virol. 88:1576-1586, 2016. © 2016 Wiley Periodicals, Inc.

Catalytic Reforming of Lignin-Derived Bio-Oil Over a Nanoporous Molecular Sieve Silicoaluminophosphate-11.

Catalytic pyrolysis of lignin, a major constituent of biomass, was performed. A nanoporous molecular sieve silicoaluminophosphate-11 (SAPO-11) was selected as catalyst. Thermogravimetric analysis showed that 500 degrees C was the optimal pyrolysis temperature. Pyrolyzer-gas chromatography/mass spectroscopy was used to investigate the pyrolysis product distribution. Production of phenolics, the dominant product from the pyrolysis of lignin, was promoted by the increase in the catalyst dose. In particular, low-molecular-mass phenolics were produced more over SAPO-11, while high-molecular-mass phenolics and double-bond-containing phenolics were produced less. The fraction of aromatic compounds, including benzene, toluene, xylene, and ethylbenzene, was also increased by catalytic reforming. The catalytic effects were more pronounced when the catalyst/biomass ratio was increased. The enhanced production of aromatic compounds by an acidic catalyst obtained in this study is in good agreement with the results of previous studies.

Highly Dispersed Pt Nanoparticles for the Production of Aromatic Hydrocarbons by the Catalytic Degrading of Alkali Lignin.

Aromatic hydrocarbons were produced from lignin, a complex natural amorphous polymer commonly regarded as by-product of the pulping process and from biofuel production. The catalytic decomposition of lignin using supported Pt catalysts was performed to produce small molecule hydrocarbons. Aromatic small-molecule hydrocarbon products were identified and quantified using GC/MS and GC-FID, which demonstrated that 27.6% of aromatic hydrocarbons were obtained from the activated carbon-supported Pt (Pt/AC) catalyst which had the highest Pt surface area.

Catalytic Depolymerization of Alkali Lignin Using Supported Pt Nanoparticle Catalysts.

Alkali lignin, a byproduct of the pulping process, was depolymerized using Pt nanoparticle catalysts. A depolymerized lignin with a lower molecular weight was obtained and characterized with GPC and NMR. 31P-NMR using OH-sensitive probing molecules showed the formation of guaiacyl OHs during the reaction, indicating the cleavage of guaiacyl ether bonds.

Mortality, liver transplantation, and hepatocellular carcinoma among patients with chronic hepatitis B treated with entecavir vs lamivudine.

BACKGROUND & AIMS: Little is known about whether the antiviral agent entecavir is more effective than a less potent drug, lamivudine, in reducing the risk of death and hepatocellular carcinoma (HCC) in patients with chronic hepatitis B. METHODS: We performed a retrospective analysis of data from 5374 consecutive adult patients with chronic hepatitis B, treated with entecavir (n = 2000) or lamivudine (n = 3374), at a tertiary referral hospital in Seoul, Korea, from November 1, 1999, through December 31, 2011. Data were collected from patients for up to 6 years and analyzed by a multivariable Cox proportional hazards model for the entire cohort and for propensity score-matched cohorts. RESULTS: During the study period, 302 patients (5.6%) died, 169 (3.1%) received a liver transplant, and 525 (9.8%) developed HCC. Multivariable analyses showed that compared with lamivudine, entecavir therapy was associated with a significantly lower risk of death or transplantation (hazard ratio [HR], 0.49; 95% confidence interval [CI], 0.38-0.64), but a similar risk of HCC (HR, 1.08; 95% CI, 0.87-1.34). In the 1792 overall propensity-matched pairs, entecavir again was associated with a significantly lower risk of death or transplantation (HR, 0.49; 95% CI, 0.37-0.64) and a similar risk of HCC (HR, 1.01; 95% CI, 0.80-1.27). Entecavir also reduced the risk of death or transplantation, compared with lamivudine, in 860 pairs of patients with cirrhosis (HR, 0.42; 95% CI, 0.31-0.57) but there were no differences in risk for HCC (HR, 1.00; 95% CI, 0.78-1.28). However, entecavir and lamivudine did not have significantly different effects on clinical outcome in 878 pairs of patients without cirrhosis. CONCLUSIONS: In a retrospective study of 5374 patients with chronic hepatitis B virus infection, entecavir therapy was associated with a significantly lower risk of death or transplantation than lamivudine. However, the drugs did not have different effects on HCC risk.

HBsAg seroclearance after nucleoside analogue therapy in patients with chronic hepatitis B: clinical outcomes and durability.

OBJECTIVE: Little is known about the long-term clinical outcome and durability of HBsAg seroclearance following nucleos(t)ide analogue (NUC) therapy in patients with chronic hepatitis B (CHB). DESIGN: During a median follow-up period of 6 years (33 567 patient-years) of 5409 CHB patients who were initially treated with lamivudine or entecavir, a total of 110 achieved HBsAg seroclearance (0.33% annual seroclearance rate) and were included in this study. RESULTS: Baseline alanine aminotransferase (ALT) level >5 times of upper limit of normal was associated with higher probability of HBsAg seroclearance (HR 1.80, p<0.01), while HBeAg positivity (HR 0.46, p<0.01), high HBV DNA level (log(10) IU/mL; HR 0.61, p<0.01), and cirrhosis (HR 0.48, p<0.01) were inversely associated with the probability of HBsAg seroclearance by multivariable analysis. During follow-up for 287 patient-years after HBsAg seroclearance, only two patients with baseline cirrhosis developed hepatocellular carcinoma (HCC) or died (0.7% annual risk), which was of a significantly lower rate compared with propensity score-matched patients without HBsAg seroclearance (HR 0.09, p<0.01). HBsAg reversion and/or HBV DNA reversion occurred in 18 patients, most of which were transient with extremely low serum levels of HBsAg (0.05-1.00 IU/mL) and HBV DNA (17-1818 IU/mL). None required retreatment. The cumulative probability of anti-HBs seroconversion (detection of anti-HBs) at 4 years was 67.4% by Kaplan-Meier analysis. Selection for lamivudine-resistance HBV mutants during treatment was not associated with composite reversion (p=0.66). CONCLUSIONS: HBsAg seroclearance achieved after NUC treatment was associated with favourable clinical outcomes and was durable in most cases during long-term follow-up.

In situ catalytic pyrolysis of miscanthus over modified SBA-15 catalysts using Py-GC/MS.

Various SBA-15-based catalysts, Si-SBA-15, Pt/Si-SBA-15, Al-SBA-15, and Pt/Al-SBA-15, were applied to the catalytic pyrolysis of miscanthus. Pt nanoparticles with three different sizes, 1.7 nm, 2.9 nm, and 7.1 nm, were used to synthesize Pt/Si-SBA-15 and Pt/Al-SBA-15. Pyrolysis-gas chromatography/mass spectrometry was used for the pyrolysis experiments. The catalysts were characterized by X-ray diffraction patterns, transmittance electron microscopy, N2 adsorption-desorption, and Brunaure-Emmett-Teller surface area. The product species distribution of pyrolysis of miscanthus was significantly affected by the acid property of the catalyst and the presence of Pt. In particular, Pt/Al-SBA-15, which has both acid sites and Pt, changed the product species distribution to the largest extent; the main products were phenolics and furans. The effect of Pt particle size on the species distribution of pyrolysis product was negligible.

Catalytic upgrading of xylan over mesoporous Y catalyst.

In-situ catalytic cracking of xylan, a model compound of hemicellulose, was carried out using pyrolysis-gas chromatography/mass spectrometry over mesoporous Y for the first time. Experiments were conducted at three different temperatures, 400 degrees C, 450 degrees C, and 500 degrees C, to investigate the effect of reaction temperature. Three different biomass-to-catalyst ratios, 1:1, 1:2, and 1:3, were tested at 500 degrees C to examine the effect of catalyst dose. In addition, the catalytic activity of mesoporous Y was compared with that of Al-MCM-41. The catalysts used were characterized by N2 adsorption-desorption, temperature programmed desorption of NH3, and X-ray diffraction. The main pyrolysis products of xylan were acids, hydrocarbons, phenolics, oxygenates, aromatics, and polycyclic aromatic hydrocarbons. Mesoporous Y, which has acid sites with larger quantity and stronger acidity than those of Al-MCM-41, was shown to enhance the quality of bio-oil to a larger extent, producing a larger quantity of high-value-added products, such as aromatics and furans.

Application of mesoporous Al-MCM-48 material to the conversion of lignin.

Al-MCM-48 was applied to the catalytic pyrolysis of lignin for the first time. The pyrolysis reaction and in-situ product were analyzed by pyrolysis gas chromatography/mass spectrometry. The main products of the non-catalytic pyrolysis of lignin were phenols. The use of Al-MCM-48 increased the production of light phenols considerably. The yields of high-value-added compounds, such as hydrocarbons and aromatics, were also increased by catalytic upgrading. Al-MCM-48 is believed to promote cracking, aromatization and deoxygenation, such as decarbonylation. On the other hand, Si-MCM-48, which has no acid sites, showed lower deoxygenation efficiency than Al-MCM-48. Al-MCM-48 could be regenerated by calcining in air.

Chemical upcycling of PVC-containing plastic wastes by thermal degradation and catalysis in a chlorine-rich environment.

Chlorine (Cl)-containing chemicals, including hydrogen chloride, generated during thermal degradation of polyvinyl chloride (PVC) and corresponding mixture impede the chemical recycling of PVC-containing plastic wastes. While upgrading plastic-derived vapors, the presence of Cl-containing chemicals may deactivate the catalysts. Accordingly, herein, catalytic upgrading of pyrolysis vapor prepared from a mixture of PVC and polyolefins is performed using a fixed-bed reactor comprising zeolites. Among the H-forms of zeolites (namely, ZSM-5, Y, ß, and chabazite) used in this study, a higher yield of gas products composed of hydrocarbons with lower carbon numbers is obtained using H-ZSM-5, thus indicating further decomposition of the pyrolysis vapor to C1-C4 hydrocarbons on it. Although the formation of aromatic compounds is better on H-ZSM-5, product distributions can be adjusted by further modifying the acidic properties via the alteration of the Si/Al molar ratio, and maximum yields of C1-C4 compounds (60.8%) and olefins (64.7%) are achieved using a Si/Al molar ratio of 50. Additionally, metal ion exchange on H-ZSM-5 is conducted, and upgrading of PVC-containing waste-derived vapor to aromatic chemicals and small hydrocarbon molecules was successfully performed using Co-substituted H-ZSM-5. It reveals that the highest yield of gas products on 1.74 wt% cobalt (Co)-substituted H-ZSM-5 is acquired via the selection of an appropriate metal and metal ion concentration adjustment. Nevertheless, introduction of excess Co into the H-ZSM-5 surface decreases the cracking activity, thereby implying that highly distributed Co is required to achieve excellent cracking activity. The addition of Co also adjusted the acid types of H-ZSM-5, and more Lewis acid sites compared to Brønsted acid sites selectively produced olefins and naphthenes over paraffins and aromatics. The proposed approach can be a feasible process to produce valuable petroleum-replacing chemicals from Cl-containing mixed plastic wastes, contributing to the closed loops for upcycling plastic wastes.

Randomized trial of the virologic response during up to two years of entecavir-adefovir combination therapy in multiple-drug-refractory chronic hepatitis B virus patients.

A 1-year trial with entecavir plus adefovir resulted in a rate of virological response (VR) higher than that seen with lamivudine plus adefovir in multiple-drug-refractory chronic hepatitis B (CHB) patients. This extension study enrolled 89 of 90 patients who completed a 52-week randomized trial comparing treatment with entecavir plus adefovir (EA) to treatment with lamivudine plus adefovir (LA). At the baseline of the original study, all patients had lamivudine-resistant hepatitis B virus (HBV) and serum HBV DNA > 2,000 IU/ml despite prior lamivudine plus adefovir therapy. Of the 89 enrolled patients, 45 initially randomized to receive entecavir plus adefovir and the other 44 randomized to receive lamivudine plus adefovir received entecavir plus adefovir for an additional 52 weeks (EA-EA and LA-EA, respectively). The proportions of patients with a VR (serum HBV DNA < 60 IU/ml) gradually increased in both groups and were comparable at week 104 (42.2% in the EA-EA group and 34.1% in the LA-EA group; P = 0.51). The mean reductions in serum HBV DNA from baseline in the two groups were similar (-2.8 log10 IU/ml and -2.8 log10 IU/ml, respectively; P = 0.87). At week 104, the number of patients who retained the preexisting HBV mutants resistant to adefovir or entecavir had decreased from 8 to 2 in the EA-EA group and from 15 to 6 in the LA-EA group (P = 0.27). Both study groups had favorable safety profiles. In conclusion, up to 104 weeks of entecavir plus adefovir treatment was associated with a progressive VR, a decrease of levels of preexisting drug-resistant mutants, and no selection for additional resistance mutants of HBV in multiple-drug-refractory CHB patients. (This study has been registered at ClinicalTrials.gov under registration no. NCT01023217.).

A nationwide seroepidemiology of hepatitis C virus infection in South Korea.

BACKGROUND & AIMS: The aim of this study was to reveal nationwide seroprevalence of HCV infection in South Korea by a large-scale survey. METHODS: From January to December 2009, a total of 291 314 adults underwent health check-up in 29 centres nationwide. The data concerning anti-HCV antibody and biochemical tests were obtained from all participants. Among subjects with positive anti-HCV, such data as HCV RNA, genotypes and treatment detail were additionally analysed. RESULTS: Using an estimated 2009 population of Korea, the age, sex and area-adjusted anti-HCV positive rate was 0.78%. Anti-HCV prevalence in female patients (0.83%) was higher than that in male patients (0.75%). Gradual increase in anti-HCV positivity was observed, from 0.34% in those aged 20-29 years to 2.31% in those >70 years. The age- and sex-adjusted anti-HCV prevalence varied in different areas, being higher in Busan and Jeonnam (1.53-2.07%), mid-level in Seoul and surrounding districts (0.50-0.61%) and lower in Jeju (0.23%). The comparative analysis of laboratory variables between anti-HCV (+) and anti-HCV (-) group revealed significantly higher levels of alanine aminotransferase and lower levels of serum lipids in anti-HCV (+) group. Among 1 718 anti-HCV positive subjects, serum HCV RNA was measured only in 478 people, of whom 268 (56.1%) patients had detectable HCV RNA in serum. Among 50 patients for whom assessment of response to antiviral therapy was feasible, overall sustained virological response was achieved in 84% of patients. CONCLUSION: The prevalence of HCV infection is low in South Korea. Studies to analyse risk factors are warranted to reduce HCV infection.

Clinical usefulness of endoscopic palliation in patients with biliary obstruction caused by hepatocellular carcinoma.

BACKGROUND/AIMS: To evaluate the clinical usefulness of endoscopic biliary drainage (EBD) in patients with hepatocellular carcinoma (HCC). METHODS: A total of 111 jaundiced patients underwent attempted EBD for relief of HCC-related biliary stricture at our hospital over a 5-year period and all were included in the intention-to-treat (ITT) analysis. RESULTS: After an endoscopic attempt at drainage, 46 (41.4%) of the 111 patients achieved a favorable response. Biliary cannulation failed in 5 patients. Child-Pugh class C, portal vein thrombosis and severe hyperbilirubinemia were negatively correlated with a favorable EBD response. In the ITT population, 40 (87.0%) of the favorable responders received further treatment for HCC, >2 (3.1%) of the unfavorable responders (p < 0.001). The median survival time for ITT patients with and without a favorable response to EBD was 8.7 and 1.3 months, respectively (p < 0.001). Cox's model showed that a favorable EBD response was an independent predictor of longer survival (hazard ratio 0.20, p < 0.001). CONCLUSIONS: For HCC patients with tumor-related biliary obstruction, predictors of effective endoscopic palliation of cholestasis were relatively mild hyperbilirubinemia and preserved liver function and intact portal vein flow. A favorable EBD response was associated with longer survival outcomes.

Catalytic fast pyrolysis of lignin over mesoporous Y zeolite using Py-GC/MS.

The catalytic pyrolysis of lignin was carried out at 500 degrees C using pyrolysis gas chromatography/mass spectrometry. In-situ vapor cracking method, in which the vapor-phase products from the noncatalytic pyrolysis step were catalytically upgraded in the second step, was used. Mesoporous Y zeolite, which was synthesized from commercial zeolite Y (CBV720) using the pseudomorphic synthesis method, was used for the catalytic pyrolysis of lignin for the first time. Further, a representative mesoporous material, Al-MCM-41, was applied for the catalytic pyrolysis of lignin. The main products of the non-catalytic pyrolysis of lignin were phenolic compounds because lignin mainly comprises phenylpropane units. Catalytic upgrading of the non-catalytic pyrolysis products resulted in increased yields of low-molecular-mass phenolics, mono aromatics, and poly aromatic hydrocarbons (PAHs). The production of mono aromatics and PAHs was enhanced remarkably when the more acidic mesoporous Y zeolite was used. Conversely, the yield-of alkoxy phenolics was higher when the less acidic Al-MCM-41 was used. With increasing mesoporous Y/lignin ratio, the yield of total phenolics decreased and that of light phenolics increased. The yields of mono aromatics and PAHs increased sharply with increasing mesoporous Y/lignin ratio.

Maximum number of target lesions required to measure responses to transarterial chemoembolization using the enhancement criteria in patients with intrahepatic hepatocellular carcinoma.

BACKGROUND & AIMS: The European Association for the Study of the Liver (EASL) criteria and, more recently, the modified Response Evaluation Criteria in Solid Tumors (mRECIST), have been widely adopted for evaluating responses to locoregional therapies for hepatocellular carcinoma (HCC). We wished to establish the optimum maximum number of target lesions that need to be measured in enhancement estimations. METHODS: From a prospective registry in our institution we identified 160 consecutive patients who had at least two measurable HCCs of nodular type exceeding 10mm in diameter, and who initially underwent transarterial chemoembolization (TACE). Intra-patient and inter-method agreement on confirmed response status were evaluated based on a maximum of one, two, or three target lesions selected among the measurable lesions according to size, versus all baseline lesions. RESULTS: Per patient analyses showed that the most consistent response distribution under both EASL and mRECIST was obtained using two or three targets versus all measurable lesions. These features were maintained even in analyses of subgroups stratified according to size, distribution, and number of tumors. The kappa values of comparisons between using a maximum of two or three targets versus using all the lesions were near 1.0, significantly higher than those obtained under both criteria using just the largest tumor. Similar conclusions were obtained when either two or three targets were measured. CONCLUSIONS: Our data indicate that evaluating the largest two lesions is generally the most useful procedure for measuring TACE responses under both EASL and mRECIST.

Randomized trial of entecavir plus adefovir in patients with lamivudine-resistant chronic hepatitis B who show suboptimal response to lamivudine plus adefovir.

A substantial proportion of patients with lamivudine-resistant hepatitis B virus (HBV) show suboptimal virologic response during rescue combination treatment with lamivudine plus adefovir. In this randomized active-control trial, 90 patients with serum HBV DNA levels of >2,000 IU/ml after at least 24 weeks of treatment with lamivudine-plus-adefovir therapy for lamivudine-resistant HBV were randomized to combination treatment with entecavir plus adefovir (ETV+ADV, n = 45) or continuation of lamivudine plus adefovir (LAM+ADV, n = 45) for 52 weeks. At baseline, patients' mean serum HBV DNA level was 4.60 log(10) IU/ml (standard deviation [SD], 1.03). All 90 patients completed 52 weeks of treatment. At week 52, the proportion of patients with serum HBV DNA levels of <60 IU/ml, the primary endpoint, was significantly higher in the ETV+ADV group than in the LAM+ADV group (n = 13, 29%, versus n = 2, 4%, respectively; P = 0.004). The mean reduction in serum HBV DNA levels from baseline was significantly greater in the ETV+ADV group than in the LAM+ADV group (-2.2 log(10) IU/ml versus -0.6 log(10) IU/ml, respectively; P < 0.001). At week 52, additional mutations causing resistance to adefovir or entecavir were analyzed in all patients with detectable HBV DNA by restriction fragment mass polymorphism assays and detected in none of the ETV+ADV group but in 15% of patients in the LAM+ADV group (P = 0.018). Safety and adverse event profiles were similar in the two groups. In conclusion, entecavir-plus-adefovir combination therapy provides superior virologic response and favorable resistance profiles, compared with the continuing lamivudine-plus-adefovir combination, in patients with lamivudine-resistant HBV who fail to respond to lamivudine-plus-adefovir combination therapy.

Which response criteria best help predict survival of patients with hepatocellular carcinoma following chemoembolization? A validation study of old and new models.

PURPOSE: To identify differences in radiologic assessment methods and determine optimal imaging criteria for response evaluation in hepatocellular carcinoma (HCC) patients treated with chemoembolization. MATERIALS AND METHODS: Institutional review board approval was obtained, and patient informed consent was waived. The present study included 332 patients with intermediate stage HCC and Child-Pugh A cirrhosis who underwent serial chemoembolization. All measurable target lesions of 1 cm or larger in diameter were uni- and bidimensionally measured both at baseline and during follow-up. Intermodel agreement among the guidelines of the World Health Organization (WHO), Response Evaluation Criteria in Solid Tumors (RECIST), the European Association for the Study of the Liver (EASL), and modified RECIST (mRECIST) were examined. The most reliable model was selected on the basis of the correlation with survival prediction. RESULTS: The κ values of comparisons among WHO, RECIST, and mRECIST guidelines were less than 0.20, whereas the κ value for the comparison of EASL and mRECIST guidelines was 0.94. In patients with a partial response (PR), stable disease (SD), or progressive disease (PD), compared with patients with a complete response (CR), hazard ratios (HRs) for survival were 2.99 (95% confidence interval [CI]: 2.14, 4.17), 3.49 (95% CI: 1.71, 7.10), and 15.63 (95% CI: 9.51, 25.69), respectively, for EASL criteria. In patients with a PR, SD, or PD, compared with patients with a CR, the HRs were 2.75 (95% CI: 1.96, 3.87), 6.32 (95% CI: 3.67, 10.90), and 16.06 (95% CI: 9.76, 26.43), respectively, for mRECIST guidelines (P<.001). The C index for the multivariate model was 0.76 (95% CI: 0.72, 0.79) for both EASL and mRECIST guidelines, thus exhibiting satisfactory capability to help predict survival. The Cox regression model revealed that both mRECIST and EASL guidelines were independent predictors of overall survival (P<.001 for both). CONCLUSION: The enhancement models more accurately helped predict long-term survival in HCC patients treated with chemoembolization.

Sorafenib dose escalation in the treatment of advanced hepatocellular carcinoma.

OBJECTIVE: Although sorafenib has shown survival benefits in patients with hepatocellular carcinoma (HCC), many patients require discontinuation or dose reduction due to adverse events (AEs). We applied a dose escalation scheme to increase patient compliance and avoid AEs. METHODS: Of 267 HCC patients treated with first-line sorafenib, 25 at increased risk of AEs, including those with advanced liver cirrhosis, a history of liver transplantation, or cytopenia, received the dose escalation scheme. They started on a reduced dose of sorafenib which increased to the standard dosage according to tolerance in each patient. We analyzed the efficacy and safety of the dose escalation scheme. RESULTS: Patients with risk factors showed a lower disease control rate, shorter survival, and more frequently grade 3/4 AEs. Among patients presenting risk factors, the dose scheme did not affect the efficacy of sorafenib or survival, but reduced the incidence of grade 3/4 AEs. Rates of sorafenib discontinuation and dose reduction related to AEs were also lower in the dose escalation group. Dose escalation to the standard dose of sorafenib was achieved in 16 of the 25 patients in the dose escalation group (64.0%). After 2 weeks, the dose intensity of sorafenib did not differ between the two dose schemes. CONCLUSIONS: The sorafenib dose escalation scheme may increase patient compliance and tolerance to prolonged treatment, thus enhancing the efficacy of sorafenib in patients at high risk of AEs or with poor tolerance. Further prospective analyses are needed to determine the usefulness of the dose escalation scheme.

Clinical course of chronic hepatitis B patients who were off-treated after lamivudine treatment: analysis of 138 consecutive patients.

BACKGROUND/AIMS: Little is known about the long-term outcome of chronic hepatitis B (CHB) patients who discontinued antiviral therapy. We intended to analyze the long-term outcome of CHB patients who discontinued lamivudine therapy and to evaluate predictors for post-treatment outcome. MATERIAL/METHODS: From 2007 to 2008, 138 lamivudine off-treated CHB patients with alanine aminotransferase normalization were consecutively enrolled. Post-treatment virologic relapse, biochemical breakthrough, hepatitis flare, and retreatment results were retrospectively analyzed. RESULTS: Among 138 patients, 102 were initially HBeAg-positive at the start of lamivudine treatment. Virologic relapse, biochemical breakthrough, and hepatitis flare were observed in 45.2, 52.9, and 12.7% of HBeAg-positive and 29.4, 30.6, and 8.3% of HBeAg-negative patients during the median follow-up of 28 and 30 months, respectively. The cumulative virologic relapse and biochemical breakthrough rates were significantly lower in patients with HBV DNA <50 copies/mL than 50-104 copies/mL at lamivudine cessation. Hepatitis flare was observed in 4.8 and 11.8% of HBeAg-positive and HBeAg-negative patients with HBV DNA <50copies/mL, respectively. Thirty-eight among 138 patients received retreatment and most of them achieved biochemical (37/38) and virologic response (35/38) within 1 year of retreatment. Undetectable serum HBV DNA (<50 copies/mL) and young age at lamivudine cessation were inversely associated with virologic relapse. Undetectable HBV DNA at cessation, female, and initial HBeAg-negative were inversely associated with biochemical breakthrough. CONCLUSIONS: Post-treatment virologic relapse and biochemical breakthrough incidence were low in patients who achieved undetectable viral titer at lamivudine cessation. Retreatment after biochemical breakthrough or virologic relapse was safe and effective. Intermittent antiviral therapy might be cautiously considered in appropriately selected CHB patients.

rtL180M mutation of hepatitis B virus is closely associated with frequent virological resistance to adefovir dipivoxil therapy.

BACKGROUND AND AIM: We intended to investigate the effects of pre-existing mutations at reverse transcriptase region of hepatitis B virus (HBV) on the occurrence of virological breakthrough (VB) to adefovir dipivoxil (ADV) in patients with lamivudine (LAM)-resistant chronic hepatitis B (CHB). METHODS: Ninety-seven patients with LAM-resistant CHB were treated with ADV at a dose of 10 mg daily, and were followed for a median period of 13 months. Just before the initiation of ADV therapy, the whole length of reverse transcriptase region of serum HBV-DNA was sequenced using direct sequencing. RESULTS: All patients had genotype C HBV and mutations in the YMDD motif, specifically, YIDD (65%), YVDD (28%), or both (7%). The rtL180M and rtL80V/I mutations were identified in 68% and 69%, respectively. The cumulative probability of VB was 19% and 27% at 1 and 2 years, respectively. There was no difference in the occurrence of VB with regard to types of YMDD mutation or rtL80V/I. However, interestingly, patients carrying rtL180M experienced VB during ADV monotherapy more frequently than those not carrying rtL180M (2-year cumulative probability of VB: 37% vs 3% at 2 years, P < 0.01). On multivariate Cox proportional hazards analysis, rtL180M (hazard ratio [HR]: 8.62, 95% confidence interval: 1.08-69.09, P = 0.042) and decrease in HBV-DNA for 1 year of treatment (HR: 0.69, 95% CI: 0.51-0.95, P = 0.024) are independently associated with VB. CONCLUSIONS: The rtL180M mutation of HBV, as well as a small decrease in HBV-DNA after 1 year of treatment might be closely associated with frequent occurrence of virological resistance to ADV in patients with LAM-resistant CHB.