Young Suk Lim

The oral toll-like receptor-7 agonist GS-9620 in patients with chronic hepatitis B virus infection

BACKGROUND & AIMSnGS-9620 is an oral agonist of toll-like receptor 7, a pattern-recognition receptor whose activation results in innate and adaptive immune stimulation. We evaluated the safety, pharmacokinetics, and pharmacodynamics of GS-9620 in patients with chronic hepatitis B.nnnMETHODSnIn two double-blind, phase 1b trials of identical design, 49 treatment-naïve and 51 virologically suppressed patients were randomized 5:1 to receive GS-9620 (at doses of 0.3mg, 1mg, 2mg, 4mg) or placebo as a single dose or as two doses seven days apart. Pharmacodynamic assessment included evaluation of peripheral mRNA expression of interferon-stimulated gene 15 (ISG15), serum interferon gamma-induced protein 10 and serum interferon (IFN)-alpha.nnnRESULTSnOverall, 74% of patients were male and 75% were HBeAg negative at baseline. No subject discontinued treatment due to adverse events. Fifty-eight percent experienced ⩾1 adverse event, all of which were mild to moderate in severity. The most common adverse event was headache. No clinically significant changes in HBsAg or HBV DNA levels were observed. Overall, a transient dose-dependent induction of peripheral ISG15 gene expression was observed peaking within 48 hours of dosing followed by return to baseline levels within seven days. Higher GS-9620 dose, HBeAg positive status, and low HBsAg level at baseline were independently associated with greater probability of ISG15 response. Most patients (88%) did not show detectable levels of serum IFN-alpha at any time point.nnnCONCLUSIONSnOral GS-9620 was safe, well tolerated, and associated with induction of peripheral ISG15 production in the absence of significant systemic IFN-alpha levels or related symptoms.

Adjuvant immunotherapy with autologous cytokine-induced killer cells for hepatocellular carcinoma.

BACKGROUND & AIMSnNo adjuvant therapy has been shown to extend the survival of patients with hepatocellular carcinoma (HCC) receiving curative treatment. We investigated whether injections of activated cytokine-induced killer (CIK) cells (CD3+/CD56+ and CD3+/CD56- T cells and CD3-/CD56+ natural killer cells) prolongs recurrence-free survival of patients after curative therapy for HCC.nnnMETHODSnWe performed a multicenter, randomized, open-label, phase 3 trial of the efficacy and safety of adjuvant immunotherapy with activated CIK cells (created by incubation of patients peripheral blood mononuclear cells with interleukin 2 and an antibody against CD3). The study included 230 patients with HCC treated by surgical resection, radiofrequency ablation, or percutaneous ethanol injection at university-affiliated hospitals in Korea. Patients were assigned randomly to receive immunotherapy (injection of 6.4 × 10(9) autologous CIK cells, 16 times during 60 weeks) or no adjuvant therapy (controls). The primary end point was recurrence-free survival; secondary end points included overall survival, cancer-specific survival, and safety.nnnRESULTSnThe median time of recurrence-free survival was 44.0 months in the immunotherapy group and 30.0 months in the control group (hazard ratio with immunotherapy, 0.63; 95% confidence interval [CI], 0.43-0.94; P = .010 by 1-sided log-rank test). Hazard ratios also were lower in the immunotherapy than in the control group for all-cause death (0.21; 95% CI, 0.06-0.75; P = .008) and cancer-related death (0.19; 95% CI, 0.04-0.87; P = .02). A significantly higher proportion of patients in the immunotherapy group than in the control group had an adverse event (62% vs 41%; P = .002), but the proportion of patients with serious adverse events did not differ significantly between groups (7.8% vs 3.5%; P = .15).nnnCONCLUSIONSnIn patients who underwent curative treatment for HCC, adjuvant immunotherapy with activated CIK cells increased recurrence-free and overall survival. ClinicalTrials.gov number: NCT00699816.

Mortality, Liver Transplantation, and Hepatocellular Carcinoma among Patients with Chronic Hepatitis B Treated with Entecavir vs Lamivudine

BACKGROUND & AIMSnLittle 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.nnnMETHODSnWe performed a retrospective analysis of data from 5374 consecutive adult patients with chronic hepatitis B, treated with entecavir (nxa0= 2000) or lamivudine (nxa0= 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.nnnRESULTSnDuring 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 andxa0lamivudine did not have significantly different effects on clinical outcome in 878 pairs of patients without cirrhosis.nnnCONCLUSIONSnIn 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.

Tenofovir alafenamide versus tenofovir disoproxil fumarate for the treatment of patients with HBeAg-negative chronic hepatitis B virus infection: a randomised, double-blind, phase 3, non-inferiority trial

BACKGROUNDnThe novel prodrug tenofovir alafenamide delivers the nucleotide reverse transcriptase inhibitor tenofovir to target cells more efficiently at a lower dose than tenofovir disoproxil fumarate, thereby reducing systemic exposure. We compared the efficacy and safety of the two drugs in patients with HBeAg-negative chronic hepatitis B virus (HBV) infection in a non-inferiority study.nnnMETHODSnIn this ongoing randomised, double-blind, phase 3, non-inferiority study in 105 centres in 17 countries, patients with HBeAg-negative chronic HBV were randomly assigned (2:1) by a computer-generated allocation sequence (block size six), stratified by plasma HBV DNA concentration and previous treatment status, to receive once-daily oral doses of tenofovir alafenamide 25 mg or tenofovir disoproxil fumarate 300 mg, each with matching placebo. Participants, investigators, and those assessing outcomes were masked to group assignment. Eligible patients were aged at least 18 years with HBeAg-negative chronic HBV infection (with plasma HBV DNA concentrations of >20u2008000 IU/mL), serum alanine aminotransferase concentrations of greater than 60 U/L in men or greater than 38 U/L in women and at no more than ten times the upper limit of normal, and estimated creatinine clearance of at least 50 mL/min (by the Cockcroft-Gault method). The primary efficacy endpoint was the proportion of patients who had HBV DNA less than 29 IU/mL at week 48 in those who received at least one dose of study drug; the study was powered to show non-inferiority with a 10% efficacy margin of tenofovir alafenamide compared with tenofovir disoproxil fumarate. Bone and renal safety, and key secondary safety endpoints were assessed sequentially. The study will be conducted for a total of 3 years as a double-blind comparison to assess the longer term response to treatment. This study is registered with ClinicalTrials.gov, number NCT01940341.nnnFINDINGSnBetween Sept 12, 2013, and Oct 31, 2014, 426 patients were randomly assigned (285 assigned to tenofovir alafenamide and 141 assigned to tenofovir disoproxil fumarate; one patient assigned to tenofovir disoproxil fumarate did not receive the treatment. 268 (94%) of 285 patients receiving tenofovir alafenamide had HBV DNA less than 29 IU/mL at week 48 versus 130 (93%) of 140 patients receiving tenofovir disoproxil fumarate (difference 1·8% [95% CI -3·6 to 7·2]; p=0·47), which demonstrates non-inferiority. Patients receiving tenofovir alafenamide had significantly smaller mean percentage declines in bone mineral density than those receiving tenofovir disoproxil fumarate (hip -0·29% [95% CI -0·55 to -0·03] vs -2·16% [-2·53 to -1·79], adjusted percentage difference 1·87% [95% CI 1·42 to 2·32; p<0·0001]; spine -0·88% [-1·22 to -0·54] vs -2·51% [-3·09 to -1·94], adjusted percentage difference 1·64% [95% CI 1·01 to 2·27]; p<0·0001). At week 48, mean change in serum creatinine was small in both groups (tenofovir alafenamide 0·01 mg/dL [95% CI 0·00 to 0·02] vs tenofovir disoproxil fumarate 0·02 mg/dL [0·00 to 0·04], adjusted percentage difference -0·01 mg/dL [95% CI -0·03 to 0·01]; p=0·32), but patients receiving tenofovir alafenamide had a smaller reduction in creatinine clearance (median change in estimated glomerular filtration rate -1·8 mL/min [IQR -7·8 to 6·0] vs -4·8 mL/min [-12·0 to 3·0]; p=0·004). Most adverse events were mild to moderate in severity in the two treatment groups. The most common adverse events overall were headache (tenofovir alafenamide 40 [14%] patients vs tenofovir disoproxil fumarate 14 [10%] patients), nasopharyngitis (30 [11%] vs 15 [11%]), and upper respiratory tract infection (35 [12%] vs ten [7%]). 14 (5%) patients receiving tenofovir alafenamide and nine (6%) patients receiving tenofovir disoproxil fumarate had serious adverse events, none of which was deemed by investigators to be related to study treatment; one patient in the tenofovir disoproxil fumarate group died, but this was not deemed to be related to study treatment.nnnINTERPRETATIONnIn patients with HBeAg-negative chronic HBV, the efficacy of tenofovir alafenamide was non-inferior to that of tenofovir disoproxil fumarate, and had improved bone and renal effects. Longer term follow-up is needed to better understand the clinical impact of these changes.nnnFUNDINGnGilead Sciences.

2014 Korean Liver Cancer Study Group-National Cancer Center Korea practice guideline for the management of hepatocellular carcinoma

The guideline for the management of hepatocellular carcinoma (HCC) was first developed in 2003 and revised in 2009 by the Korean Liver Cancer Study Group and the National Cancer Center, Korea. Since then, many studies on HCC have been carried out in Korea and other countries. In particular, a substantial body of knowledge has been accumulated on diagnosis, staging, and treatment specific to Asian characteristics, especially Koreans, prompting the proposal of new strategies. Accordingly, the new guideline presented herein was developed on the basis of recent evidence and expert opinions. The primary targets of this guideline are patients with suspicious or newly diagnosed HCC. This guideline provides recommendations for the initial treatment of patients with newly diagnosed HCC.

Surgical treatments and prognoses of patients with combined hepatocellular carcinoma and cholangiocarcinoma.

BackgroundCombined hepatocellular carcinoma and cholangiocarcinoma is a very rare form of primary liver cancer containing components of both tumor types. We evaluated the effectiveness of surgical treatment and factors related to survival and recurrence.Patients and MethodsOf the 2427 patients who underwent hepatectomy or liver transplantation because of a primary hepatic malignancy from January 1989 to July 2006 at the Asan Medical Center, Seoul, Korea, 29 had hepatocellular carcinoma and cholangiocarcinoma as a single mixed or transitional tumor. Their medical records were retrospectively reviewed.ResultsDisease-free survival rates at 6xa0months, 1xa0year, and 3xa0years were 51.1%, 38.3%, and 25.6%, respectively. Univariate analysis showed that CA 19–9 above 37xa0U/ml was predictive of low overall survival (Pxa0=xa0.03) and that TNM stage was significantly associated with disease-free survival (Pxa0=xa0.04).ConclusionsPatients with combined hepatocellular carcinoma and cholangiocarcinoma had poor postoperative survival rates. High CA 19–9 level was associated with poorer survival, suggesting that the cholangiocarcinoma portion may be a major determining factor for patient prognosis. Aggressive surgical treatment, including lymph node dissection, may improve survival in patients suspected of or diagnosed with these tumors.

Clinical features of adult patients with secondary hemophagocytic lymphohistiocytosis from causes other than lymphoma: an analysis of treatment outcome and prognostic factors

Although hemophagocytic syndrome (HS) featuring secondary hemophagocytic lymphohistiocytosis (HLH) has a grave prognosis, little is known about the natural course of the disease. Patients who showed the clinical features of HLH as well as tissue-proven hemophagocytosis when seen at Asan Medical Center between 1999 and 2010 were included in this analysis. Patients with proven lymphoma were excluded. The median age of our 23 study patients was 49xa0years. Epstein–Barr virus was suspected to have caused HS in 16 (70%) patients and hepatitis A virus in one patient. Twenty-two patients were treated, 13 according to the HLH protocol and nine using immunosuppressive agents such as corticosteroid and/or cyclosporine. Five patients undertook allogeneic hematopoietic cell transplantation (HCT) during their treatment-dependent relapse (nu2009=u20094) or responsive status (nu2009=u20091). After the median follow-up of 180xa0days, 17 (74%) died and six (26%) were alive. The median time from initial presentation until death was 41xa0days among those patients who died. The serum fibrinogen level ≥166xa0mg/dL determined at the initial visit was significantly associated with the survival time according to univariate analysis. The low histiocyte proportion in bone marrow and early initiation of treatment tended to correlate with a favorable outcome. On multivariate analysis, serum fibrinogen ≥166xa0mg/dL (hazard ratio, 0.175, Pu2009=u20090.018) was an independent clinical factor for determining the patient survival time. Despite appropriate patient management, the outcome of HS featuring HLH was grave. The serum fibrinogen level at the initial presentation was significant, and selected patients obtained some benefit from allogeneic HCT.

Tenofovir monotherapy versus tenofovir and entecavir combination therapy in adefovir-resistant chronic hepatitis B patients with multiple drug failure: results of a randomised trial

Objective Little clinical data are available regarding the optimal treatment of patients who harbour adefovir-resistant HBV. Design In this multicentre trial, patients who had adefovir-resistant HBV with serum HBV DNA levels >60u2005IU/mL were randomised to receive tenofovir disoproxil fumarate (TDF, 300u2005mg/day) monotherapy (n=50) or TDF and entecavir (ETV, 1u2005mg/day) combination therapy (TDF/ETV, n=52) for 48u2005weeks. All who completed 48u2005weeks in either group received TDF monotherapy for 48 additional weeks. Results Baseline characteristics were comparable between groups, including HBV DNA levels (median, 3.38 log10 IU/mL). All patients had adefovir-resistant HBV mutations; rtA181V/T and/or rtN236T. The proportion of patients with HBV DNA <15u2005IU/mL was not significantly different between the TDF-TDF and TDF/ETV-TDF groups at weeks 48 (62% vs 63.5%; p=0.88) and 96 (64% vs 63.5%; p=0.96). The mean change in HBV DNA levels from baseline was not significantly different between groups at week 48 (−3.03 log10 IU/mL vs −3.31 log10 IU/mL; p=0.38). Virological breakthrough occurred in one patient on TDF-TDF and two patients on TDF/ETV-TDF over 96u2005weeks; all were attributed to poor drug adherence. At week 96, five and two patients in the TDF-TDF and TDF/ETV-TDF groups, respectively, retained some of their baseline resistance mutations (p=0.44). None developed additional resistance mutations. Safety profiles were comparable in the two groups. Conclusions In patients with adefovir-resistant HBV and multiple-drug failure, TDF monotherapy provided a virological response comparable to that of TDF and ETV combination therapy, and was safe up to 96u2005weeks. Trial registration number NCT01639066.

Tenofovir monotherapy versus tenofovir and entecavir combination therapy in patients with entecavir-resistant chronic hepatitis B with multiple drug failure: results of a randomised trial

Objective Little clinical data are available regarding the optimal treatment of patients who harbour entecavir (ETV)-resistant HBV. Design In this multicentre randomised trial, patients who had HBV with ETV resistance-associated mutations and serum HBV DNA concentrations >60u2005IU/mL were randomised to receive tenofovir disoproxil fumarate (TDF, 300u2005mg/day) monotherapy (n=45) or TDF and ETV (1u2005mg/day) combination therapy (n=45) for 48u2005weeks. Results Baseline characteristics were comparable between groups, including HBV DNA levels (median, 4.02u2005log10u2005IU/mL) and hepatitis B e antigen-positivity (89%). All patients had at least one ETV-resistance mutation: rtT184A/C/F/G/I/L/S (n=49), rtS202G (n=43) and rtM250L/V (n=7), in addition to rtM204V/I (n=90). All except one patient in the TDF group completed 48u2005weeks of treatment. At week 48, the proportion of patients with HBV DNA <15u2005IU/mL, the primary efficacy endpoint, was not significantly different between the TDF and TDF+ETV groups (71% vs 73%; p>0.99). The mean change in HBV DNA levels from baseline was not significantly different between groups (−3.66 vs −3.74u2005log10u2005IU/mL; p=0.81). Virological breakthrough occurred in one patient on TDF, which was attributed to poor drug adherence. At week 48, six and three patients in the TDF and TDF+ETV groups, respectively, retained their baseline resistance mutations (p>0.99). None developed additional resistance mutations. Safety profiles were comparable in the two groups. Conclusions TDF monotherapy for 48u2005weeks provided a virological response comparable to that of TDF and ETV combination therapy in patients infected with ETV-resistant HBV. Trial registration number ClinicalTrials.gov ID NCT01639092.

Combination of transarterial chemoembolization and three-dimensional conformal radiotherapy for hepatocellular carcinoma with inferior vena cava tumor thrombus.

PURPOSEnTo evaluate the effects of transarterial chemoembolization (TACE) and three-dimensional conformal radiotherapy (CRT) in patients with hepatocellular carcinoma (HCC) and inferior vena cava tumor thrombus (IVCTT).nnnMETHODS AND MATERIALSnA total of 42 consecutive patients who underwent TACE and CRT (TACE+CRT group) for the treatment of HCC with IVCTT were prospectively enrolled from July 2004 to October 2006. As historical controls, 29 HCC patients with IVCTT who received TACE alone (TACE group) between July 2003 and June 2004 were included. CRT was designed to target only the IVCTT and to deliver a median total dose of 45 Gy (range, 28-50 Gy).nnnRESULTSnMost baseline characteristics of the two groups were similar (p > 0.05). The response and progression-free rates of IVCTT were significantly higher in the TACE+CRT group than in the TACE group (42.9% and 71.4% vs. 13.8% and 37.9%, respectively; p < 0.01 for both rates). Overall, patient survival was significantly higher in the TACE+CRT group than in the TACE group (p < 0.01), with a median survival time of 11.7 months and 4.7 months, respectively. Treatment with TACE+CRT (hazard ratio [HR] = 0.38; 95% confidence interval [CI], 0.20-0.71), progression of IVCTT (HR = 4.05; 95% CI, 2.00-8.21), Child-Pugh class B (HR = 3.44; 95% CI, 1.79-6.61), and portal vein invasion (HR = 2.31; 95% CI, 1.19-4.50) were identified as independent predictors of mortality by multivariable analysis.nnnCONCLUSIONSnThe combination of TACE and CRT is more effective in the control of IVCTT associated with HCC and improves patient survival compared with TACE alone.