Baseline HBV DNA level is the most important factor associated with virologic breakthrough in chronic hepatitis B treated with lamivudine

AIM: To identify the factors associated with virologic breakthrough and to select a subgroup of patients who respond well to lamivudine without developing virologic breakthrough (VBT). METHODS: Of 79 patients who had received lamivudine therapy for 9-57 mo, 34 were HBeAg-positive and 45 were HBeAg-negative, 24 developed virologic breakthrough and 55 did not. Clinical and virologic factors were compared between the two groups. RESULTS: The median duration of therapy was 25 (9-57) mo. Virologic breakthrough was defined as a > 1 log HBV DNA increase following initial suppression. When several factors, including gender, duration of infection, baseline HBV DNA, and baseline ALT in HBeAg-positive chronic hepatitis patients were analyzed by logistic regression, the most important predictor of virologic breakthrough was the baseline HBV DNA (r2 = 0.12, P < 0.05). When HBeAg-postitive chronic hepatitis patients were divided into two groups by a point of 6.6 log HBV DNA, the incidence of virologic breakthough between two groups was significantly different. CONCLUSION: Lamivudine may remain an effective first line therapy for those HBeAg-positive patients with a baseline HBV DNA < 6.6 log10 copies/mL.

Safety and efficacy of tenofovir in chronic hepatitis B-related decompensated cirrhosis

AIM To evaluate the safety and efficacy of tenofovir disoproxil fumarate(TDF) as a first-line therapy in decompensated liver disease. METHODS We enrolled 174 chronic hepatitis B-related liver cirrhosis patients treated with 300 mg/d TDF at six Korean centers. Of the 174 cirrhosis patients, 57 were assigned to the decompensated cirrhosis group and 117 were assigned to the compensated cirrhosis group. We followed the patients for 12 mo and evaluated clinical outcomes, including biochemical, virological, and serological responses. We also evaluated changes in hepatic and renal function and compared the decompensated and compensated cirrhosis groups. RESULTS The 1-year complete virological response(CVR) and Hepatitis B e antigen(HBe Ag) seroconversion were seen in 70.2% and 14.2% in the decompensated cirrhosis group, respectively. The rates of HBe Ag seroconversion/loss and ALT normalization at month 12 were similar in both groups. TDF treatment was also effective for decreasing the level of hepatitis B virus(HBV) DNA in both groups, but CVR was higher in the compensated group(88.9% vs 70.2%, P = 0.005). Tenofovir treatment for 12 mo resulted in improved Child-Turcotte-Pugh(CTP) and model for end-stage liver disease(MELD) scores in decompensated group(P < 0.001). Of the 57 decompensated patients, 39(68.4%) achieved CTP class A and 27(49.1%) showed improvement in the CTP score of 2 points after 12 mo of TDF. The observed rate of confirmed 0.5 mg/d L increases in serum levels of creatinine in the decompensated and compensated cirrhosis group were 7.0% and 2.5%, respectively(P < 1.000).CONCLUSION TDF therapy in decompensated cirrhosis patients was effective for decreasing HBV DNA levels and improving hepatic function with relatively lower CVR than in compensated cirrhosis. Thus, physicians should carefully monitor not only renal function but also treatment responses when using TDF in decompensated cirrhosis patients.

Delayed hypersensitivity reaction resulting in maculopapular-type eruption due to entecavir in the treatment of chronic hepatitis B

Several clinical trials have demonstrated the potent antiviral efficacy of entecavir (ETV), and this relatively new nucleoside analogue drug has rapidly become a frequently prescribed therapy for chronic hepatitis B (CHB) worldwide. While the studies have also shown a good overall safety profile for ETV, adverse drug reactions (ADRs) in patients with advanced cirrhosis have been reported and represent a broad spectrum of drug-induced injuries, including lactic acidosis, myalgia, neuropathy, azotemia, hypophosphatemia, muscular weakness, and pancreatitis, as well as immune-mediated responses (i.e., allergic reactions). Cutaneous ADRs associated with ETV are very rare, with only two case reports in the publicly available literature; both of these cases were classified as unspecified hypersensitivity allergic (type I) ADR, but neither were reported as pathologically proven or as evaluated by cytokine release analysis. Here, we report the case of a 45-year-old woman who presented with a generalized maculopapular rash after one week of ETV treatment for lamivudine-resistant CHB. The patient reported having experienced a similar skin eruption during a previous three-month regimen of ETV, for which she had self-discontinued the medication. Histopathological analysis of a skin biopsy showed acanthotic epidermis with focal parakeratosis and a perivascular lymphocytic infiltrate admixed with interstitial eosinophils in the papillary and reticular dermis, consistent with a diagnosis of drug sensitivity. A lymphocyte stimulation test showed significantly enhanced IL-4, indicating a classification of type IVb delayed hypersensitivity. The patient was switched to an adefovir-lamivudine combination regimen and the skin eruption resolved two weeks after the ETV withdrawal. This case represents the first pathologically and immunologically evidenced ETV-induced delayed type hypersensitivity skin reaction reported to date. Physicians should be aware of the potential, although rare, for cutaneous ADRs associated with ETV treatment.

Urgent ERCP for acute cholangitis reduces mortality and hospital stay in elderly and very elderly patients

BACKGROUND： Acute cholangitis in old people is a cause of mortality and prolonged hospital stay. We evaluated the effects of methods and timing of biliary drainage on the outcomes of acute cholangitis in elderly and very elderly patients. METHODS： We analyzed 331 patients who were older than 75 years and were diagnosed with acute calculous cholangitis. They were admitted to our hospital from 2009 to 2014. Patients＇ demographics, severity grading, methods and timing of biliary drainage, mortality, and hospital stay were retrospectively obtained from medical records. Clinical parameters and outcomes were compared between elderly （75-80 years, n= 156） and very elderly （≥81 years, n=175） patients. We analyzed the effects of methods [none, endoscopic retrograde cholangio- pancreatography （ERCP）, percutaneous transhepatic biliary drainage, or failure] and timing （urgent or early） of biliary drainage on mortality and hospital stay in these patients. RESULTS： Acute cholangitis in older patients manifested as atypical symptoms characterized as infrequent Charcot＇s triad （4.2%） and comorbidity in one-third of the patients. Patients were graded as mild, moderate, and severe cholangitis in 104 （31.4%）, 175 （52.9%）, and 52 （15.7%）, respectively. Urgent bili-ary drainage （≤24 hours） was performed for 80.5% （247/307） of patients. Very elderly patients tended to have more severe grades and were treated with sequential procedures of transient hiliary drainage and stone removal at different sessions. Hospital stay was related to methods and timing of biliary drainage. Mortality was very low （1.5%） and not related to patient age but rather to the success or failure of biliary drainage and severity grading of the acute cholangitis. CONCLUSIONS： The methods and timing used for biliary drainage and severity of cholangitis are the major determinants of mortality and hospital stay in elderly and very elderly patients with acute cholangitis. Urgent successful ERCP is mandatory for favorable prognosis in these patients.

Long-term treatment outcomes of clevudine in antiviral-naive patients with chronic hepatitis B

AIM:To evaluate the treatment outcomes of clevudine compared with entecavir in antiviral-naive patients with chronic hepatitis B(CHB).METHODS:We retrospectively analyzed the clinical data of CHB patients treated with clevudine 30 mg/d and compared their clinical outcomes with patients treated with entecavir 0.5 mg/d.The biochemical response,as assessed by serum alanine aminotransferase(ALT) activity,virologic response,as assessed by serum hepatitis B virus DNA(HBV DNA) titer,serologic response,as assessed by hepatitis B e antigen(HBeAg) status,and virologic breakthrough with genotypic mutations were assessed.RESULTS:Two-hundred and fifty-four patients [clevudine(n = 118) vs entecavir(n = 136)] were enrolled.In clevudine-treated patients,the cumulative rates of serum ALT normalization were 83.9% at week 48 and 91.5% at week 96(80.9% and 91.2% in the entecavir group,respectively),the mean titer changes in serum HBV DNA were-6.03 and-6.55 log 10 copies/mL(-6.35 and-6.86 log 10 copies/mL,respectively,in the entecavir group),and the cumulative non-detection rates of serum HBV DNA were 72.6% and 83.1%(74.4% and 83.8%,respectively,in the entecavir group).These results were similar to those of entecavir-treated patients.The cumulative rates of HBeAg seroconversion were 21.8% at week 48 and 25.0% at week 96 in patients treated with clevudine,which was similar to patients treated with entecavir(22.8% and 27.7%,respectively).The virologic breakthrough in the clevudine group occurred in 9(7.6%) patients at weeks 48 and 15(12.7%) patients at week 96,which primarily corresponded to genotypic mutations of rtM204I and/or rtL180M.There was no virologic breakthrough in the entecavir group.CONCLUSION:In antiviral-naive CHB patients,longterm treatment outcomes of clevudine were not inferior to those of entecavir,except for virologic breakthrough.

Corticotropin-releasing factor stimulates colonic motility via muscarinic receptors in the rat

AIM To measure exogenous corticotropin-releasing factor(CRF)-induced motility of the isolated rat colon and to demonstrate the effect of pharmacologic inhibition on CRF-induced motility. METHODS The isolated vascularly-perfused rat colon was used. Luminal pressure was monitored via microtip catheter pressure transducers in the proximal and distal colon. At first, exogenous CRF was administered in a stepwise manner and the concentration of CRF yielding maximal colonic motility was selected. After recording basal colonic motility, hexamethonium, phentolamine, propranolol, atropine and tetrodotoxin were infused into the isolated colon. Initially, only the test drug was infused; then, CRF was added. The motility index was expressed as percentage change over basal level. RESULTS Administration of 1.4, 14.4, 144 and 288 pmol/L CRF progressively increased colonic motility in the proximal and distal colon. Infusion of atropine or tetrodotoxin reduced CRF-induced motility of both the proximal and distal colon, whereas hexamethonium, phentolamine and propranolol had no effect.CONCLUSION CRF-induced colonic motility appears to be mediated by local cholinergic signaling via muscarinic receptors. Muscarinic receptors are potential targets for counteracting CRF-induced colonic hypermotility.

Efficacy of cap-assisted endoscopy for routine examining the ampulla of Vater

AIM: To determine the efficacy of a cap-assisted endoscopy (CAE) to completely visualize the ampulla of Vater (AV) in patients failed by conventional endoscopy. METHODS: A prospective study was conducted on 120 patients > 20 years of ages who visited the Health Promotion Center of Chungbuk National University Hospital for conscious sedation esophagogastroduodenoscopy (EGD) as a screening test from July to October, 2011. First, forward-viewing endoscopy was performed with reasonable effort using a push and pull method. We considered complete visualization of the AV when we could observe the entire AV including the orifice clearly, and reported the observation as complete or incomplete (partial or not found at all). Second, in cases of complete failure of the observation, an additional AV examination was conducted by attaching a short cap (D-201-10704, Olympus Medical Systems, Tokyo, Japan) to the tip of a forward-viewing endoscope. Third, if the second method failed, we replaced the short cap with a long cap (MH-593, Olympus Medical Systems) and performed a re-examination of the AV. RESULTS: Conventional endoscopy achieved complete visualization of the AV in 97 of the 120 patients (80.8%) but was not achieved in 23 patients (19.2%). Age (mean ± SD) and gender [male (%)] were not significantly different between the complete observation and the incomplete observation groups. Additional short CAE was performed in patients in whom we could not completely visualize the AV. This group included 13 patients (10.9%) with partial observation of the AV and 10 (8.3%) in which the AV was not found. Short CAE permitted a complete observation of the AV in 21 of the 23 patients (91.3%). Patients in whom visualization of the AV failed with short CAE had satisfactory outcomes by replacing the short cap with a long cap. The additional time for CAE took an average of 141 ± 88 s. There were no complications and no significant mucosal trauma. CONCLUSION: CAE is safe to use as a salvage method to achieve complete visualization of the AV when a regular EGD examination fails.

Metachronous bile duct cancer nine years after resection of gallbladder cancer

We report a rare case of a 74-year-old man with metachronous gallbladder cancer and bile duct cancer who underwent curative resection twice, with the operations nine years apart. At the age of 65 years, the patient underwent a cholecystectomy and resection of the liver bed for gallbladder cancer. This was a welldifferentiated adenocarcinoma, with negative resection margins （T2NOM0, stage Ⅰ B）. Nine years later, during a follow-up examination, abdominal computed tomography and MRCP showed an enhanced 1.7 cm mass in the hilum that extended to the second branch of the right intrahepatic bile duct. We diagnosed this lesion as a perihilar bile duct cancer, Bismuth type Ⅲ a, and performed bile duct excision, right hepatic Iobectomy and Roux-en-Y hepaticojejunostomy. The histological diagnosis was a well-differentiated adenocarcinoma with one regional lymph node metastasis （TINIM0, stage Ⅱ B）. Twelve months after the second operation, the patient is well, with no signs of recurrence. This case is compared with 11 other cases of metachronous biliary tract cancer published in the world medical literature.