Efficacy and resistance of entecavir following 3 years of treatment of Japanese patients with lamivudine-refractory chronic hepatitis B

Purpose

Lamivudine treatment of chronic hepatitis B (CHB) is associated with frequent resistance and loss of clinical benefit. We present outcomes of lamivudine-refractory Japanese patients treated with entecavir for 3 years.

Methods

Eighty-two patients refractory to lamivudine therapy received entecavir 0.5 or 1 mg daily for 52 weeks in phase II study ETV-052, directly entered rollover study ETV-060, and received entecavir 1 mg daily. Responses were evaluated among patients with available samples.

Results

After 96 weeks in ETV-060 (148 weeks total entecavir treatment time), 55% (36/65) of patients had hepatitis B virus (HBV) DNA of >400 copies/mL, 85% (52/61) had alanine aminotransferase (ALT) of ≥1 × upper limit of normal (ULN), and 14.6% (7/48) achieved HBe seroconversion. A subset of 42 patients received entecavir 1 mg from phase II baseline through 148 weeks: 54% (19/35) had HBV DNA of >400 copies/mL, 84% (27/32) had ALT of ≥1 × ULN, and 15% (4/27) achieved HBe seroconversion. Sixteen patients in the 1-mg subset had baseline and week 148 evaluable biopsy pairs: 81% (13/16) showed histologic improvement and 38% (6/16) showed improvement in fibrosis. Genotypic resistance to entecavir emerged in 31 patients for a 3-year cumulative resistance probability of 35.9%. Entecavir was generally well tolerated during ETV-060, with no on-treatment ALT flares.

Conclusions

Long-term entecavir treatment of lamivudine-refractory CHB resulted in virologic suppression, ALT normalization, and improvements in liver histology. Resistance was consistent with that observed in worldwide studies.     

Development of ulcerative colitis in a patient with multiple sclerosis following treatment with interferonβ la

To alert clinicians to a potential novel adverse drug effect of interferonβ la, we herein report a patient with relapsing-remitting multiple sclerosis who developed ulcerative colitis following treatment with interferonβ la. Ulcerative colitis persisted despite discontinuation of interferonβ la treatment and switching the patient to glatiramer acetate. Tacrolimus （FK506）, 6-mercaptopurine, and prednisolone were required to induce remission. Both ulcerative colitis and multiple sclerosis were eventually well controlled using this regimen. Our report underscores that caution should be exercised when prescribing immunostimulatory agents in patients with inflammatory bowel disease （IBD） and challenges current efforts to stimulate innate immunity as a novel therapeutic concept for IBD.     

Resolution of Crohn’s disease and complex regional pain syndrome following treatment of paratuberculosis

A cohort of family members with various chronic diseases including Crohn’s disease, asthma, complex regional pain syndrome, hypothyroidism, type 1 diabetes mellitus, and lymphangiomatosis and/or evidence of infection by Mycobacterium avium subsp. paratuberculosis(MAP) are described in this series of case reports. MAP was cultured from the blood of three members affected by the first five diseases and there was accompanying elevated anti-MAP Ig G in two members. The patient affected by the sixth disease has a markedly elevated anti-MAP titer. The two patients affected by the first four diseases have been treated with a combination of anti-MAP antibiotics and ultraviolet blood irradiation therapy with resolution of the disease symptomatology and inability to culture MAP in post treatment blood samples. These case reports of patients with MAP infections provide supportive evidence of a pathogenic role of MAP in humans.     

Morphological adaptation of muscle collagen and receptor of advanced glycation end product (RAGE) in osteoarthritis patients with 12 weeks of resistance training: influence of anti-inflammatory or glucosamine treatment

The aim of this study was to investigate the effect of 12-week resistance training on morphological presence of collagen and RAGE (receptor for advanced glycation end products) in skeletal muscle of patients with knee osteoarthritis (OA). Little is known about the influence of exercise on the skeletal muscle matrix that supports joints affected by OA mainly when it is associated with medication taken by OA patients (non-steroid anti-inflammatory drugs (NSAID) and glucosamine). A biopsy was collected from the vastus lateralis muscle in all patients before and after 12-week period of training. The patients (age 55–69 years) were divided into three groups, treated with NSAID, glucosamine or placebo. In addition, the muscle samples were analysed by immunohistochemistry for collagen types, RAGE and capillaries ratio. An increment in immunoreactivity for type IV collagen after the training period was observed in 72 % of all biopsies when compared with their respective baseline samples. Reduced immunoreactivity of collagen type I was observed in all patients treated with glucosamine. A significant increase with training in the amount of RAGE was detected in the placebo group only (p < 0.05). Comparison of post-treatment states indicated significant differences between the placebo and glucosamine group data, demonstrating increased levels in the placebo group (p < 0.05). These findings suggest a basement membrane remodelling in favour of a strengthened extracellular matrix surrounding individual muscle fibres after 12 weeks of resistance training. Glucosamine with training appeared to attenuate RAGE accumulation more than was seen with NSAID or placebo in skeletal muscle of OA patients.     

Long-term clinical outcomes in type 1 Gaucher disease following 10 years of imiglucerase treatment

Objective

We studied the effect of long-term alglucerase/imiglucerase (Ceredase®/Cerezyme®, Genzyme, a Sanofi company, Cambridge, MA, USA) treatment on hematological, visceral, and bone manifestations of Gaucher disease type 1 (GD1).

Methods

The International Collaborative Gaucher Group (ICGG) Gaucher Registry identified GD1 patients treated with alglucerase/imiglucerase who had dose and clinical data at first infusion and after 10 years of follow-up. Data for hemoglobin, platelet count, organ volumes, bone pain, and bone crisis were analyzed. Tests of the null hypothesis (no change from first infusion to 10 years) were performed using t tests for within-patient absolute change in continuous measurements and McNemar/chi-square tests for change in distributions using categorical values. An alpha level of 0.05 designated statistical significance.

Results

As of October 2011, 557 nonsplenectomized and 200 splenectomized patients met the inclusion criteria. The majority of GD1 patients had at least one N370S allele. Compared with nonsplenectomized patients at first infusion, splenectomized patients had lower percentages of anemia (26.0 % vs. 42.8 %) and thrombocytopenia (14.2 % vs. 76.3 %), similar percentages of moderate or severe hepatomegaly (81.2 % vs. 80.0 %), and higher percentages of bone pain (88.9 % vs. 52.4 %) and bone crises (38.3 % vs. 16.0 %). After 10 years, both groups showed significant (p?<?0.05) improvements in mean hemoglobin levels, platelet count, liver, and spleen (nonsplenectomized) volumes, and bone crises. Initial dosing in both groups ranged from <15 U/kg to ≤90 U/kg every 2 weeks. After 10 years, the majority was receiving 15 to ≤45 U/kg every 2 weeks.

Conclusion

Ten years of imiglucerase treatment results in sustainable improvements in all GD1 parameters.     

Thrombolytic treatment in a patient with antiphospholipid syndrome

Antiphospholipid syndrome (APS), a leading entity in acquired thrombophilia, is characterized by recurrent thrombosis, morbidity in pregnancy and presence of antiphospholipid antibodies (APA). Although the etiopathogenesis is unclear, APA against negatively charged phospholipids and phospholipid–protein complexes are held responsible for the clinical picture. In case of acute thrombosis due to APS, thrombolytic therapy is not a commonly administered treatment option. Here, we present a case with acute thrombosis in the left renal artery showing partial response to thrombolytic therapy.     

Changes in disease pattern and treatment outcome of colorectal cancer: a review of 5,474 cases in 20 years

Background and aims Colorectal cancer (CRC) is the third most common cause of cancer-related death in Taiwan. During the past 20 years, several advances have improved the treatment outcome and quality of life of CRC patients. The purpose of this study was to identify the changes in the clinicopathological features and outcome of CRC over this period. Materials and methods Based on the computerized database of the Taipei Veterans General Hospital, between January 1981 and December 2000, 5,474 CRC patients were identified and divided into 2 groups based on the date of treatment (1981–1990 and 1991–2000). The clinicopathological features, outcome, and prognostic factors were analyzed and compared. Results/findings The age at onset of cancer was 61 years in the 1980s group and 66 years in the 1990s group. The frequency of rectal tumors decreased from 50% in the 1980s group to 44% in the 1990s group. Tumor, nodes, metastasis (TNM) stage distribution, surgical mortality, and anastomosis leakage were similar in the two groups. However, the 5-year overall survival rate was better in the 1990s group (56%) than that in the 1980s group (50%, P = 0.001). For rectal cancer patients, the local recurrence rate was lower in the 1990s group (6%) than that in the 1980s group (10%, P < 0.01). In stage III CRC, the 5-year overall survival rate was significantly higher in the 1990s group (54%) than that in the 1980s group (48%, P = 0.011). TNM stage was the most important independent prognostic factor for overall and disease-free survivals, followed by differentiation grade, CEA level, and treatment period. Interpretation/conclusion Advances in surgical technique and more standard use of chemotherapy have improved CRC outcome.     

Meta-analysis of patients with hepatitis C virus genotype 6: 48 weeks with pegylated interferon and ribavirin is superior to 24 weeks

Background

Hepatitis C virus genotype 6 (HCV-6) is common in patients from Southeast Asia and the surrounding regions. Optimal treatment duration for HCV-6 is unknown given the inconclusive evidence from studies with varying methodologies and small sample sizes.

Methods

A literature search for ‘genotype 6’ in MEDLINE and EMBASE in October 2013 produced 161 and 251 articles, respectively. Additional abstracts were identified from four major international GI/liver conferences in 2012/2013. Inclusion criteria were original studies with ≥10 HCV-6 treatment-naïve patients treated with pegylated interferon + ribavirin (PEG IFN+RBV). Exclusion criteria were coinfections with HBV, HIV, other HCV genotypes, and/or other liver diseases. Primary outcome was pooled sustained virologic response (SVR). Heterogeneity was defined by Cochrane Q test (p value of 0.10) and I ² statistic (≥50 %).

Results

A total of 13 studies with 641 patients were included. The pooled SVR estimate was 77 % (CI 70–83 %) (Q value = 38.4, p value <0.001, I ² = 68.7 %) overall, 79 % (CI 73–84 %) for the 48-week group and 59 % (CI 46–70 %) for 24-week group, respectively. In studies with direct comparison of the two groups, SVR was superior in patients treated for 48 versus 24 weeks, OR 1.9 (CI 1.08–3.2, p = 0.026). In studies with direct comparison of patients with rapid virologic response (RVR), there was no difference in SVR between 48 versus 24 weeks, OR 1.74 (CI 0.65–4.64, p = 0.27).

Conclusion

Hepatitis C virus genotype 6 patients should be treated for 48 weeks, and those who achieve RVR may receive the shorter 24-week treatment duration. The high SVR (~80 %) with 48 weeks of PEG IFN+RBV therapy may be a cost-effective option for HCV-6 patients from resource-poor regions.     

Non-Hodgkin��s lymphoma following treatment with etanercept in ankylosing spondylitis

Anti-TNF drugs may increase lymphoma risk in autoimmune rheumatic diseases, such as rheumatoid arthritis, but there have been no reports stating increased risk of lymphoma in ankylosing spondylitis (AS). Before 2 years, we had presented a case with AS developing Hodgkin’s lymphoma following 6 months of etanercept treatment. Hereby, we present another case with AS developing non-Hodgkin’s lymphoma (NHL), subsequent to 11 months of etanercept treatment. Pathological analysis revealed diffuse large B cell NHL. Although this is a report of a single case, cautious use of anti-TNF drugs is strongly recommended as they might cause lymphoma development even in AS.     

Hodgkin’s lymphoma following treatment with etanercept in ankylosing spondylitis

It has been well known that anti-TNF drugs might increase lymphoma risk in rheumatoid arthritis (RA), where the rate of lymphoma has already been increased. However, unlike RA, an increased rate of lymphoma has not been reported in ankylosing spondylitis (AS). Hereby, we present a case with AS developing Hodgkin’s lymphoma (HL) following 6 months of etanercept treatment. Pathological analysis revealed mixed cellular type of HL. Although we report a single case, it should be kept in mind that anti-TNF drugs might cause lymphoma development not only in RA, but also in AS.     

Efficacy of esomeprazole and flupentixol and melitracen in treatment of non-erosive gastroesophageal reflux disease with depression and anxiety

Objective To investigate the efficacy of esomeprazole (Esomeprazole) and flupentixol and melitracen (Deanxit) in treatment of non-erosive gastroesophageal reflux disease (NERD) with depression and anxiety. Methods The diagnosis of NERD was based on the results of esomeprazole scale (reflux diagnostic questionnaires, RDQ) and endoscopy, the degree and frequency of symptoms were graded and scored. Hamilton depression scale was used to evaluate depression and anxiety status. Sixty-three patients were randomly divided into group A (esomeprazole 20 mg qd),B (Deanxit 1 tab     

Effects of 12 weeks’ treatment with a proton pump inhibitor on insulin secretion, glucose metabolism and markers of cardiovascular risk in patients with type 2 diabetes: a randomised double-blind prospective placebo-controlled study

Aims/hypothesis

Recent studies suggest that proton pump inhibitor treatment may increase insulin secretion and improve glucose metabolism in type 2 diabetes. In a randomised double-blind prospective placebo-controlled 2 × 2 factorial study, we examined the effect of esomeprazole on insulin secretion, HbA_1c and cardiovascular risk factors in type 2 diabetes.

Methods

Forty-one patients with type 2 diabetes using dietary control or oral glucose-lowering treatment were randomised to receive add-on esomeprazole 40 mg (n?=?20) or placebo (n?=?21) for 12 weeks. Randomisation was carried out prior to inclusion on the basis of a computer-generated random-number list. The allocation sequence was concealed in sealed envelopes from the researcher enrolling and assessing participants. The study was undertaken at Steno Diabetes Center, Gentofte, Denmark. The primary outcome was change in AUC for insulin levels during a meal test. Secondary outcomes were the levels of HbA_1c and biochemical markers of cardiovascular risk, including lipids, coagulation factors, inflammation markers, markers of endothelial function and 24 h ambulatory BP measurements.

Results

Forty-one participants were analysed. In the esomeprazole-treated group the AUC for insulin did not change (before vs after treatment: 28,049?±?17,659 vs 27,270?±?32,004 pmol/l × min (p?=?0.838). In the placebo group AUC for insulin decreased from 27,392?±?14,348 pmol/l × min to 22,938?±?11,936 pmol/l × min (p?=?0.002). Esomeprazole treatment (n?=?20) caused a ninefold increase in the AUC for gastrin. HbA_1c increased from 7.0?±?0.6% (53?±?5 mmol/mol) to 7.3?±?0.8% (56?±?6 mmol/mol) in the esomeprazole-treated group and from 7.0?±?0.6% (53?±?5 mmol/mol) to 7.4?±?0.8% (57?±?6 mmol/mol) in the placebo group (n?=?21) (p for difference in change >0.05). Except for BP, there were no differences between the groups in the markers of cardiovascular risk (p?>?0.05). Monitoring of 24 h ambulatory BP showed a significant decrease in daytime systolic BP, daytime diastolic BP and 24 h diastolic BP in the placebo group (p?<?0.05). No change in BP was seen in the patients treated with esomeprazole.

Conclusions/interpretation

Treatment with esomeprazole over 12 weeks did not improve insulin secretion, glycaemic control or cardiovascular disease biomarkers in patients with type 2 diabetes.

Trial registration

ClinicalTrials.gov NCT00699426

Funding

The study was funded by Novo Nordisk A/S and Christian Hansen A/S.