AIM: To identify hepatitis B virus polymerase gene mutations during antiviral therapy using lamivudine-adefovir sequential monotherapy followed by lamivudine-adefovir combination therapy.
METHODS: The patient cohort included four adult chronic hepatitis B patients who had undergone sequential monotherapy, first with lamivudine (LMV) and then, after developing viral breakthrough, with adefovir (ADV) therapy. All of the patients had non-response or viral breakthrough after LMV-ADV sequential monotherapy, which resulted in the switching of their antiviral regimen to LMV-ADV combination therapy. Eleven serum samples from the four patients who showed non-response to rescue LMV-ADV combination therapy were collected sequentially at a time before the antiviral treatment and then during the LMV monotherapy, ADV monotherapy, and LMV-ADV combination therapy. For the genotypic analysis, the whole 1310-bp polymerase gene region was amplified, cloned and sequenced.
RESULTS: All patients had been previously treated with 100 mg of LMV once daily for a 15- to 26-mo period. The emergence of resistance mutations to LMV, such as rtM204V/I and/or rtL180M, were found in all patients. Their antiviral regimens were switched to ADV monotherapy as the second line treatment. All patients had viral breakthrough or non-response after the LMV-ADV sequential monotherapy. ADV-resistant mutations were detected after 13 to 19 mo of LMV-ADV sequential monotherapy. The rtA181V/T mutations were predominantly identified during the ADV treatment in the LMV-resistant patients. Twenty-seven of 38 clones were combined with an amino acid change at rt181; three clones had mutations in rt236 and one clone had a combined mutation. The rtA181V/T mutations were not suppressed by the LMV-ADV combination therapy. Thirty-nine of 64 clones showed an rtA181V/T mutation and six clones showed combined mutations in rt181 and rt236. Mutations in rt204 re-emerged during the combination treatment. The rt181 and rt204 mutations did not co-exist in one clone.
CONCLUSION: Add-on lamivudine therapy with adefovir for adefovir resistance may not suppress the pre-existing adefovir-resistant mutation that develops during lamivudine-adefovir sequential monotherapy.
Hepatitis B virus; Lamivudine; Adefovir; Mutation; Drug resistance
This study evaluated the clinical outcomes of balloon-occluded retrograde transvenous obliteration (BRTO) for the treatment of hemorrhage from gastric varices (GV) in Korean patients with liver cirrhosis (LC).
We retrospectively analyzed data from 183 LC patients who underwent BRTO for GV bleeding in 6 university-based hospitals between January 2001 and December 2010.
Of the 183 enrolled patients, 49 patients had Child-Pugh (CP) class A LC, 105 had CP class B, and 30 had CP class C at the time of BRTO. BRTO was successfully performed in 177 patients (96.7%). Procedure-related complications (e.g., pulmonary thromboembolism and renal infarction) occurred in eight patients (4.4%). Among 151 patients who underwent follow-up examinations of GV, 79 patients (52.3%) achieved eradication of GV, and 110 patients (72.8%) exhibited marked shrinkage of the treated GV to grade 0 or I. Meanwhile, new-appearance or aggravation of esophageal varices (EV) occurred in 54 out of 136 patients who underwent follow-up endoscopy (41.2%). During the 36.0±29.2 months (mean±SD) of follow-up, 39 patients rebled (hemorrhage from GV in 7, EV in 18, nonvariceal origin in 4, and unknown in 10 patients). The estimated 3-year rebleeding-free rate was 74.8%, and multivariate analysis showed that CP class C was associated with rebleeding (odds ratio, 2.404; 95% confidence-interval, 1.013-5.704; P=0.047).
BRTO can be performed safely and effectively for the treatment of GV bleeding. However, aggravation of EV or bleeding from EV is not uncommon after BRTO; thus, periodic endoscopy to follow-up of EV with or without prophylactic treatment might be necessary in LC patients undergoing BRTO.
Balloon-occluded retrograde transvenous obliteration; Esophageal varices; Gastric varices; Liver cirrhosis; Variceal hemorrhage
AIM: To evaluate seroprevalence of hepatitis A virus (HAV) antibody and investigate demographic, clinical, and laboratory features of recent cases in Korea.
METHODS: For the evaluation of hepatitis A seroprevalence, we analyzed the data from 3127 subjects including, healthcare workers and patients who visited Konkuk University Hospital, a secondary referral center, from January to October 2009. The sera with positive IgM were excluded from seroprevalence data for total HAV antibody. We retrospectively reviewed the electronic medical records of 419 patients with HAV, who were diagnosed by the presence of serum IgM antibodies against HAV. All patients presented at Konkuk University Hospital between August 2005 and September 2008.
RESULTS: Among 3127 sera tested, 1428 (45.7%) were positive for anti-HAV antibody. The seroprevalence was very low in teenagers or those in their twenties, increased in those in their thirties, and was > 90% in older patients. In children younger than 10 years, seroprevalence was increased again. Most patients with HAV hepatitis were in their twenties and thirties. The γ-glutamyl transpeptidase increased with age and was significantly higher in patients older than 30 years. Indicators of severity, such as decreased albumin and increased bilirubin, were also more prominent in the older age group; however, the leukocyte count was higher and the frequency of leukopenia was lower in younger patients than in older adults.
CONCLUSION: There has been an apparent epidemiological shift in HAV seroprevalence and a change in the peak age of HAV hepatitis. This study could provide baseline data of recent hepatitis A in Asia.
Hepatitis A virus; Seroprevalence; Epidemiology; Korea
Many surgical patients are admitted to the intensive care unit (ICU), resulting in an increased demand, and possible waste, of resources. Patients who undergo liver resection are also transferred postoperatively to the ICU. However, this may not be necessary in all cases. This study was designed to assess the necessity of ICU admission.
The medical records of 313 patients who underwent liver resections, as performed by a single surgeon from March 2000 to December 2010 were retrospectively reviewed.
Among 313 patients, 168 patients (53.7%) were treated in the ICU. 148 patients (88.1%) received only observation during the ICU care. The ICU re-admission and intensive medical treatment significantly correlated with major liver resection (odds ratio [OR], 6.481; P = 0.011), and intraoperative transfusions (OR, 7.108; P = 0.016). Patients who underwent major liver resection and intraoperative transfusion were significantly associated with need for mechanical ventilator care, longer postoperative stays in the ICU and the hospital, and hospital mortality.
Most patients admitted to the ICU after major liver resection just received close monitoring. Even though patients underwent major liver resection, patients without receipt of intraoperative transfusion could be sent to the general ward. Duration of ICU/hospital stay, ventilator care and mortality significantly correlated with major liver resection and intraoperative transfusion. Major liver resection and receipt of intraoperative transfusions should be considered indicators for ICU admission.
Hepatectomy; Major resection; Intensive care units; Intraoperative transfusion
This retrospective study was done to characterize the levels of vascular endothelial growth factor (VEGF) and hypoxia inducible factor 1 (HIF-1α) in dog brains with neo-vascularization in the cerebral cortex of frontal, temporal, and parietal lobe by using immunohistochemistry (IHC) and Western blot. In neo-vascularized (NV) brains, we analyzed the number and area of blood vessels and the expression of VEGF and HIF-1α. The IHC results showed that the number and area of blood vessels, as assessed by immunolabeling for von Willebrand factor, was higher in the NV brain than in the control brain. The Western blot results showed that the level of VEGF was increased, predominantly in NV brain of the cerebral cortex relative to the clinically normal cerebral cortex, whereas the expression of HIF-1α in NV brains was not different from the control brains. Our study showed that dilatation of vessels and development of new vessels in the cerebral cortex were observed in cases of canine CNS disease and found increased expression of VEGF in canine brains with neo-vascularization.
Lamivudine has a high rate of antiviral resistance. Sequential treatment of anti-hepatitis B virus (HBV) is commonly used for lamivudine resistance. We report 4 cases of patients with rapid redetection of HBV mutants during the lamivudine retreatment. The four patients received lamivudine as an initial treatment of HBV and adefovir and lamivudine as a rescue therapy consecutively. HBV-DNA level, YMDD mutations and adefovir -resistant mutations (RFMP) were tested every 3 mo during the sequential treatment. All the patients showed YMDD mutations during the initial lamivudine therapy. After adefovir therapy for lamivudine resistance, they showed viral breakthrough. Adefovir was switched to lamivudine, however, it did not induce viral suppression at all, rather increased HBV-DNA with rapid reemergence of the YMDD mutations. All the patients had ALT flares, and hepatic decompensation occurred in two patients. After switching to adefovir combined with entecavir or lamivudine for a rescue therapy, the patients had reduction in HBV-DNA and ALT improvement. These cases demonstrated that lamivudine retreatment of patients with preexposed lamivudine resistance leads to rapid reemergence of YMDD mutation with significant viral rebounds and subsequent hepatic decompensation. Sequential administration of lamivudine in patients with a prior history of YMDD mutation should be abandoned.
Hepatitis B; Lamivudine; Adefovir dipivoxil; Mutations
AIM: To examine the characteristics of colonic polyps, where it is difficult to distinguish adenomatous polyps from hyperplastic polyps, with the aid of acetic acid chromoendoscopy.
METHODS: Acetic acid spray was applied to colonic polyps smaller than 10 mm before complete excision. Endoscopic images were taken before and 15-30 s after the acetic acid spray. Both pre- and post-sprayed images were shown to 16 examiners, who were asked to interpret the lesions as either hyperplastic or adenomatous polyps. Regression analysis was performed to determine which factors were most likely related to diagnostic accuracy.
RESULTS: In 50 cases tested by the 16 examiners, the overall accuracy was 62.4% (499/800). Regression analysis demonstrated that surrounding colonic mucosa was the only factor that was significantly related to accuracy in discriminating adenomatous from hyperplastic polyps (P < 0.001). Accuracy was higher for polyps with linear surrounding colonic mucosa than for those with nodular surrounding colonic mucosa (P < 0.001), but was not related to the shape, location, or size of the polyp.
CONCLUSION: The accuracy of predicting histology is significantly related to the pattern of colonic mucosa surrounding the polyp. Making a histological diagnosis of colon polyps merely by acetic acid spray is helpful for colon polyps with linear, regularly patterned surrounding colonic mucosa, and less so for those with nodular, irregularly patterned surrounding colonic mucosa.
Colon polyp; Chromoendoscopy; Acetic acid
The incidence of Hepatitis B has significantly declined since the introduction of an HBV vaccination program. The aim of this study was to investigate recent clinical features of acute viral hepatitis B (AVH-B) in Korea.
A total of 2241 patients with acute viral hepatitis were enrolled and their data were collected from nine medical-centers between January 2006 and December 2009.
One hundred nineteen (5.3%) of the 2241 were diagnosed as AVH-B. Among 78 patients with AVH-B whose data were analyzed, 50 were male, and the mean age was 38.6 years. In an initial test, mean AST, ALT and total-bilirubin levels were 1296.2 IU/L, 2109.6 IU/L and 9.3 mg/dl, respectively. Positivity frequencies for HBeAg and anti-HBe were 55.1% and 67.9%, respectively, and the mean HBV DNA level was 5.2 log10 copies/ml. The mean length of hospitalization was 11.6 days. During follow-up, AST, ALT and total bilirubin levels were normalized or near-normalized in all patients without serious complications. Sixty-three of 66 (95.4%) patients showed HBsAg loss and 37 (56.1%) patients showed HBsAg seroconversion. Only 3 patients (4.5%) showed persistent hepatitis B viremia. There was no case of death or liver transplantation. Nine patients (11.3%) had received anti-viral agents and their clinical outcomes were not significantly different from those of patients treated without antiviral agents.
The prevalence of AVH-B among acute hepatitis patients is relatively low in Korea. AVH-B infection can be cured without complications in almost all patients, regardless of antiviral treatment.
Acute hepatitis B; Prevalence; Prognosis
Hepatitis B virus (HBV) infection has been a major global cause of morbidity and mortality. The recognition of the problem led to a worldwide effort to reduce transmission of HBV through routine infant vaccination. HBV infection is the most common cause of chronic liver diseases and hepatocellular carcinoma in Korea. After hepatitis B vaccine era, seroprevalence of hepatits B surface antigen is decreasing, particularly in children. Hepatitis B vaccine is remarkably safe and shows high immunogenicity. Universal childhood immunization with three doses of hepatitis B vaccine in the first year of life is a highly effective method for prevention and control of hepatitis B.
Hepatitis B virus; Epidemiology; Vaccine; Prevention
Clevudine (CLV) is a nucleoside analog with potent antiviral activity against chronic hepatitis B virus (HBV) infection. Viral resistance to CLV in patients receiving CLV therapy has not been reported. The aim of this study was to characterize CLV-resistant HBV in patients with viral breakthrough (BT) during long-term CLV therapy. The gene encoding HBV reverse transcriptase (RT) was analyzed from chronic hepatitis B patients with viral BT during CLV therapy. Sera collected from the patients at baseline and at the time of viral BT were studied. To characterize the mutations of HBV isolated from the patients, we subjected the HBV mutants to in vitro drug susceptibility assays. Several conserved mutations were identified in the RT domain during viral BT, with M204I being the most common. In vitro phenotypic analysis showed that the mutation M204I was predominantly associated with CLV resistance, whereas L229V was a compensatory mutation for the impaired replication of the M204I mutant. A quadruple mutant (L129M, V173L, M204I, and H337N) was identified that conferred greater replicative ability and strong resistance to both CLV and lamivudine. All of the CLV-resistant clones were lamivudine resistant. They were susceptible to adefovir, entecavir, and tenofovir, except for one mutant clone. In conclusion, the mutation M204I in HBV RT plays a major role in CLV resistance and leads to viral BT during long-term CLV treatment. Several conserved mutations may have a compensatory role in replication. Drug susceptibility assays reveal that adefovir and tenofovir are the most effective compounds against CLV-resistant mutants. These data may provide additional therapeutic options for CLV-resistant patients.
Distribution and characterization of interlukin-10 (IL-10)-secreting cells in lymphoid tissues of pigs naturally infected with porcine circovirus type 2 (PCV2) were evaluated in accordance with PCV2 antigen detection. After screening a total of 56 pigs showing the symptoms of postweaning multisystemic wasting syndrome (PMWS), 15 pigs were PCV2 positive and 5 pigs, which showed stronger positive signals over multiples tissues were further investigated. This study showed that in PCV2-infected lymphoid tissues, particularly mandibular lymph node, spleen and tonsil, IL-10 expression was mainly localized in T-cell rich areas but rarely in B cell rich areas. IL-10 was highly expressed in bystander cells but rarely in PCV2-infected cells. Elevated IL-10 expression was predominantly associated with T cells, but rarely with B cells or with macrophages. The results of this study provide evidence for the role of IL-10 in chronic PCV2 infection and its relation to PCV2 antigen in affected tissues. Constantly elevated levels of IL-10 lead to immunosuppression in persistent and chronic viral infections. The increased IL-10 expression observed in PCV2 infection in this study suggests that IL-10-mediated immunosuppression may play an important role in the pathogenesis and maintenance of naturally occurring PCV2 infection.
B-cells; immunohistochemistry; interlukin-10; porcine circovirus type 2; T-cells
The emergence of antiviral resistance can negate the benefits of antiviral therapy in patients with chronic hepatitis B (CHB). This study aimed to assess how physicians in Asia manage suspected antiviral resistance.
Randomly selected CHB-treating physicians in Mainland China, South Korea, Taiwan, and Thailand underwent a face-to-face interview. A standardized questionnaire was used to assess how physicians identify, monitor, and manage suspected resistance and its associated medical costs.
We interviewed 575 physicians from January to May 2008. Most physicians preferred a “prevention-of-antiviral resistance” strategy over a “rescue-once-resistance-develops” strategy. Physicians had encountered lamivudine resistance most frequently (96–100% of respondents), followed by the resistance to adefovir (18–58%) and entecavir (3–7%). While physicians in South Korea and Taiwan have access to resistance testing, physicians in Mainland China and Thailand have limited access to resistance testing but rely on HBV DNA and alanine aminotransferase (ALT) tests to identify resistance. Once resistance is suspected, 60% of the physicians in Mainland China, South Korea, and Thailand monitored these patients quarterly and the remaining 40% opted for monthly follow-up. In comparison, 70% of the Taiwanese physicians monitored these patients monthly. The average total direct medical costs, excluding antiviral costs, to manage a patient during the first year after suspected resistance is identified ranged from USD $319 to USD $709.
Limited access to HBV resistance tests causes physicians in Asia to manage suspected resistance by various HBV DNA assays and ALT tests. This raises concerns that resistance may not be detected early enough to be rescued efficiently.
Chronic hepatitis B; Nucleoside/nucleotide analogs; HBV DNA; ALT; Antiviral resistance; Asia
Functional gastrointestinal disorders are more common in women in relation to the fluctuations of female sex hormones. We tried to know the gender-related differences in the prevalence of irritable bowel syndrome and gastrointestinal symptoms according to the menstrual phase. A total of 253 women before menopause and 252 men below age 50 were examined by a gastroenterologist after completing the questionnaire. Blood tests, endoscopic procedures, and imaging studies were done, if needed. Women were subclassified into three groups according to their menst- ruation period; menstrual phase, proliferative phase, and secretory phase. Finally, 179 men and 193 women were analyzed. Irritable bowel syndrome was more frequently noticed in women than in men (p=0.01). The diarrhea-dominant type was more common in men, while constipation-dominant or alternating types were more common in women (p<0.001). Of 193 women, there was no significant difference in their gastrointestinal symptoms according to their menstrual phase. Regardless of the menstrual phase, gastrointestinal symptoms are more frequent in women. Physicians should consider different symptomatic manifestations between men and women should be considered when evaluating functional gastrointestinal disorders.
Gastrointestinal Diseases; Women; Irritable Bowel Syndrome; Menstruation
Although numerous chemotherapeutic agents have been tested, the role of systemic chemotherapy for hepatocellular carcinoma (HCC) has not been clarified. New therapeutic strategies are thus needed to improve outcomes, and we designed this study with new effective drug combination.
Twenty-nine patients with histologically-confirmed, metastatic HCC received a combination chemotherapy with doxorubicin 60 mg/m2 and cisplatin 60 mg/m2 on day 1, plus capecitabine 2000 mg/m2/day as an intermittent regimen of 2 weeks of treatment followed by a 1-week rest.
The median age was 49 years (range, 32–64) and 19 patients were hepatitis B virus seropositive. Child-Pugh class was A in all patients and 4 had Zubrod performance status of 2. The objective response rate was 24% (95% CI 9–40) with 6 stable diseases. The chemotherapy was generally well tolerated despite one treatment-related death.
Combination chemotherapy with doxorubicin, cisplatin and capecitabine produced modest antitumor activity with tolerable adverse effects in patients with metastatic HCC.
Hepatitis B virus (HBV) infection is one of the major causes of hepatocellular carcinoma (HCC) development. Hepatitis B virus X protein (HBx) is known to play a key role in the development of hepatocellular carcinoma (HCC). Several cellular proteins have been reported to be over-expressed in HBV-associated HCC tissues, but their role in the HBV-mediated oncogenesis remains largely unknown. Here, we explored the effect of the over-expressed cellular protein, a ribosomal protein S3a (RPS3a), on the HBx-induced NF-κB signaling as a critical step for HCC development. The enhancement of HBx-induced NF-κB signaling by RPS3a was investigated by its ability to translocate NF-κB (p65) into the nucleus and the knock-down analysis of RPS3a. Notably, further study revealed that the enhancement of NF-κB by RPS3a is mediated by its novel chaperoning activity toward physiological HBx. The over-expression of RPS3a significantly increased the solubility of highly aggregation-prone HBx. This chaperoning function of RPS3a for HBx is closely correlated with the enhanced NF-κB activity by RPS3a. In addition, the mutational study of RPS3a showed that its N-terminal domain (1–50 amino acids) is important for the chaperoning function and interaction with HBx. The results suggest that RPS3a, via extra-ribosomal chaperoning function for HBx, contributes to virally induced oncogenesis by enhancing HBx-induced NF-κB signaling pathway.
The aim of our study was to define the potential role of virologic response at 12 months of treatment (VR12) in predicting subsequent virologic and clinical outcomes in adefovir (ADV)-treated lamivudine-resistant chronic hepatitis B.
Two hundred and four patients with lamivudine-resistant chronic hepatitis B virus (HBV) treated with ADV monotherapy were included. Serum HBV DNA was quantified by real-time polymerase chain reactions. VR12 was defined as a HBV DNA level of less than 4 log10 copies/mL after 12 months of ADV treatment.
VR12 was observed in 110 of the 204 patients (54%). The mean HBV DNA reductions from baseline after 12 months of ADV treatment were 3.8 and 1.9 log10 copies/mL in patients with and without VR12, respectively (p<0.001). The hepatitis B "e" antigen (HBeAg) seroconversion rates in patients with and without VR12 were 32% and 14% at 12 months treatment, respectively (p=0.018), and 40% and 27% at 24 months of treatment (p=0.032). The genotypic mutation rates to ADV in patients with and without VR12 were 0% and 6% at 12 months of treatment, respectively (p=0.033), and 21% and 42% at 24 months (p=0.012). The rates of viral breakthrough in patients with and without VR12 were 0% and 7% at 12 months of treatment, respectively (p=0.072), and 9% and 25% at 24 months (p=0.006).
Patients without VR12 may need to switch to or add on other potent antiviral drugs in their medical regimens.
Adefovir dipivoxil; Drug resistance; Virologic response