Reduction of covalently closed circular DNA with long-term nucleos(t)ide analogue treatment in chronic hepatitis B

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Early-life gut dysbiosis linked to juvenile mortality in ostriches

Imbalances in the gut microbial community (dysbiosis) of vertebrates have been associated with several gastrointestinal and autoimmune diseases. However, it is unclear which taxa are associated with gut dysbiosis, and if particular gut regions or specific time periods during ontogeny are more susceptible. We also know very little of this process in non-model organisms, despite an increasing realization of the general importance of gut microbiota for health

The detector system of the Daya Bay reactor neutrino experiment

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One-year treatment of entecavir results in reduction in intrahepatic covalently closed circular DNA level

BACKGROUND: Two phase 3, multicenter, double-blind trials on HBeAg-positive and HBeAg-negative patients demonstrate that, compared with lamivudine, entecavir is superior in inducing histologic improvement, serum HBV DNA suppression and transaminase normalization. Since intrahepatic HBV DNA and covalently closed circular (ccc) DNA are important for control of viral replication, the efficacy of entecavir vs. lamivudine in achieving suppression of these entities should be studied. METHODS AND PATIENTS: The patients involved in this study were recruited from patients participating in the two phase 3 entecavir trials at our center in Hong Kong. Forty chronic hepatitis B patients (14 HBeAg-positive and 26 anti-HBe-positive) were randomized to receive either entecavir (0.5 mg once daily) or lamivudine (100 mg once daily). Paired liver biopsy and serum samples were collected both at baseline and week 48 of treatment. Total intrahepatic HBV DNA and cccDNA were measured by the Invader® assay.1 Serum HBV DNA was measured by the COBAS Amplicor HBV Monitor Test. RESULTS: This is an interim report for the 14 HBeAg-positive patients. (The findings of the 26 anti-HBe-positive patients will be analyzed later.) For the 14 HBeAg-positive patients, 7 were randomized to receive entecavir, while the rest received lamivudine. CONCLUSION: The preliminary results of this study showed that 1 year of entecavir was superior to lamivudine in suppression of total intrahepatic and ccc DNA in liver biopsies. The addition of the data from the 26 anti-HBe patients may confirm these results.link_to_OA_fulltex

Interim report on a phase I/IIa, double-blind, randomized, placebo-controlled trial of a novel antiviral agent, LB80380 in Chinese patients with chronic hepatitis B infection

To investigate the safety and antiviral activity of LB80380, a novel guanosine analogue, in HBeAg-positive HBV patients, 28 patients in 4 cohorts (7 per group with 6:1 ratio of LB80380: placebo) were given escalating doses with 30mg, 60mg, 120mg and 240mg daily for 4 weeks. Patients were monitored till week 16. The median age and male:female ratio were 27.5 years and 20:8 respectively. The median follow-up was 8.9 weeks. HBV DNA reductions are depicted in the figure. HBV DNA reduction was greater with 60mg dose and above. HBV DNA returned to the pretreatment levels at a slower rate with higher doses. No serious adverse events were observed. In conclusion, four-week treatment of LB80380 was safe and associated with a reduction of HBV DNA levels greater than those observed with lamivudine and adefovir.link_to_subscribed_fulltex

Measurement of tumor necrosis factor-α, leukotriene B4, and interleukin 8 in the exhaled breath condensate in patients with acute exacerbations of chronic obstructive pulmonary disease

Fanny WS Ko1, Ting-Fan Leung2, Gary WK Wong2, Jenny Ngai1, Kin W To1, Susanna Ng1, David SC Hui11Department of Medicine and Therapeutics; 2Department of Pediatrics, The Chinese University of Hong Kong, Hong KongBackground: Assessment of airway inflammation in the clinical course of acute exacerbations of chronic obstructive pulmonary disease (AECOPD) may advance our understanding of the pathogenesis and treatment.Objectives: To assess airway inflammation in patients during the course of AECOPD by serial analyses of their exhaled breath condensates (EBC).Methods: Twenty-six patients with AECOPD (22 males, mean[SD] percentage predicted forced expiratory volume in one second (FEV1) 44.8 [14.3]), 11 with stable COPD, and 14 age and sex-matched healthy controls were studied. Patients with AECOPD were treated with systemic steroid and antibiotic for 7 days. EBC was collected from each patient with AECOPD on Day 5, 14, 30, and 60 post-hospitalization using EcoScreen (VIASYS Healthcare, USA) during tidal breathing over 10 minutes. Concentrations of tumor necrosis factor-α (TNF-α), leukotriene B4 (LTB4), and interleukin-8 (IL-8) were measured by enzyme-linked immunosorbent assay.Results: The median (IQR) of TNF-α level on Day 5 was 5.08 (3.80–6 .32) pg/ml, which was lower than on Day 14 (5.84 [4.91–9.14] pg/ml, p = 0.017), Day 30 (6.14 [3.82–7.67] pg/ml, p = 0.045), and Day 60 (5.60 [4.53–8.80] pg/ml, p = 0.009). On Day 60, subjects receiving inhaled corticosteroid (ICS) had a lower level of TNF-α than those who were not (4.82 [4.06–5.65] vs 7.66 [5.48–10.9] pg/ml, p = 0.02). EBC LTB4 level did not change significantly during recovery from AECOPD whereas IL-8 was mostly undetectable.Conclusions: EBC TNF-α level was low in patients receiving systemic steroid and antibiotic therapy for AECOPD. These findings suggest a potential role for serial EBC TNF-α for noninvasive monitoring of disease activity.Keywords: COPD, exacerbation, exhaled breath condensate, TNF-α, LTB

Phase I/II double-blind, randomized, placebo-controlled study of the novel anti-HBV agent LB80380/ANA380 in patients with chronic HBV infection

BACKGROUND: LB80380/ANA380 is an orally available drug that is converted after dosing to LB80331 and subsequently to LB80317, a novel guanosine phosphonate nucleotide analogue that exhibits activity against HBV in vitro, including HBV variants resistant to lamivudine. The compound has a favourable toxicity profile in vitro, including low potential for renal toxicity. Animal toxicology studies confirmed the favourable tolerability of LB80380/ANA380, and studies in woodchucks showed reductions in serum viral titre greater than six log after four weeks of dosing. Phase I studies in healthy volunteers demonstrated good safety, tolerability, and pharmacokinetics consistent with once daily dosing. We report the final study results of a Phase 1/11 study designed to assess the safety, pharmacokinetics, and antiviral activity of LB803801 ANA380 in HBeAg positive, HBV DNA positive patients. Study Design: This study was a double-blind, randomised, placebo-controlled, multiple ascending dose evaluation of LB80380/ ANA380 dosed once daily for 28 days at 30mg, 60mg, 120mg, and 240 mg. Cohorts of seven patients were randomised (6:l active: placebo) at each dose level, and safety was established at each dose prior to dose escalation. Patients were followed for 12 weeks after completing the dosing phase. RESULTS: The median age and male: female ratio was 27.5 years and 208 respectively. Serum HBV levels at screening ranged from lx107 to 5x109. LB80380 was well tolerated, with no serious or moderate adverse events attributed to treatment. Systemic exposure to LB80331 and LB80317 was proportional to LB803801 ANA380 dose. HBV DNA reductions were observed during treatment in all patients receiving LB80380/ANA380, and returned to pre-treatment levels during follow-up. Median log serum HBV reductions on day 28 of treatment were 3 to 4 log. CONCLUSIONS: Treatment with LB803801ANA380 for 28 days at doses up to 240mg was well tolerated and safe in this study population. Substantial anti-HBV effects were observed at all doses of LB803801ANA380. These results encourage additional investigation for longer duration and in other study populations.link_to_OA_fulltex