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Background: The formation of extracellular vesicles (EVs) occurs during cold storage of RBCs. Transfusion of EVs may contribute to adverse responses in recipients receiving RBCs. However, EVs are poorly characterized with limited data on whether distinct vesicles are formed, their composition, and potential biological effects. Study Design and Methods: Stored RBC‐derived EVs were purified using protocols that separate larger microvesicle‐like EVs (LEVs) from smaller exosome‐like vesicles (SEVs). Vesicles were analyzed by electron microscopy, content of hemoglobin, heme, and proteins (by mass spectrometry), and the potential to mediate lipid peroxidation and endothelial cell permeability in vitro. Results: SEVs were characterized by having an electron‐dense double membrane whereas LEVs had more uniform electron density across the particles. No differences in hemoglobin nor heme levels per particle were observed, however, due to smaller volumes, SEVs had higher concentrations of oxyHb and heme. Both particles contained antioxidant proteins peroxiredoxin‐2 and copper/zinc superoxide dismutase, these were present in higher molecular weight fractions in SEVs suggesting either oxidized proteins are preferentially packaged into smaller vesicles and/or that the environment associated with SEVs is more pro‐oxidative. Furthermore, total glutathione (GSH + GSSG) levels were lower in SEVs. Both EVs mediated oxidation of liposomes that were prevented by hemopexin, identifying heme as the pro‐oxidant effector. Addition of SEVs, but not LEVs, induced endothelial permeability in a process also prevented by hemopexin. Conclusion: These data show that distinct EVs are formed during cold storage of RBCs with smaller particles being more likely to mediate pro‐oxidant and inflammatory effects associated with heme. [ABSTRACT FROM AUTHOR]

Summary: Backgrounds and Aims: We investigated associations between hepatitis B virus (HBV) genome‐length haplotype number (HN) at baseline in subjects with HBeAg‐positive chronic hepatitis B (CHB), and the likelihood of achieving functional cure during direct‐acting antiviral therapy Method: We analysed 86 HBeAg‐positive baseline samples from patients with HBV genotypes A and D who were enrolled in a Phase II trial of tenofovir disoproxil fumarate (TDF) to determine if HN was a biomarker of HBsAg loss during therapy. Findings were validated using baseline samples from 181 patients with HBV genotypes A and D from an independent clinical trial utilising TDF or tenofovir alafenamide therapy in HBeAg‐positive CHB. Results: In the HBeAg‐positive test cohort, patients with genotypes A or D and ≤2 haplotypes had a minimum of 21‐fold higher likelihood of achieving HBsAg loss on TDF. Baseline HN (p < 0.0001) was a stronger predictor of HBsAg loss on therapy than HBsAg titre (p = 0.03), HBeAg titre (p = 0.0002), or the presence of HBV basal core promoter (A1762T, p = 0.0379 and G1764A, p = 0.0176) or G1896A precore mutations (p = 0.0218). This finding was validated in the independent validation cohort. HN was statistically higher in patients with HBV genotypes B or C infection compared to genotypes A and D. Conclusion: Baseline HN ≤2 predicts which patients with HBV genotypes A or D will more likely progress to functional cure on current direct‐acting antiviral therapy, with greater accuracy than current biomarkers including baseline HBsAg and HBeAg titre. [ABSTRACT FROM AUTHOR]

Chronic hepatitis B (CHB) is characterized by progression through different phases of hepatitis B virus (HBV) infection and disease. Although not necessary for HBV replication, there is increasing evidence that HBV splice variants are associated with liver disease progression and pathogenesis. However, there have been no studies till date on the frequency or diversity of splice variants for different HBV genotypes across the phases of CHB. Next generation sequencing data from 404 patient samples of HBV genotype A, B, C or D in Phase I, Phase II or Phase IV of CHB was analysed for HBV splice variants using an in house bioinformatics pipeline. HBV splice variants differed in frequency and type by genotype and phase of natural history. Splice variant Sp1 was the most frequently detected (206/404, 51% of patients), followed by Sp13 (151/404 37% of patients). The frequency of variants was generally highest in Phase II (123/165, 75% of patients), a phase typically associated with enhanced immune activation, followed by Phase I (69/99, 70% of patients). Splice variants were associated with reduced hepatitis B e antigen (HBeAg) levels and statistically reduced likelihood of achieving HBsAg loss (functional cure) in Phase II patients for Sp1 and Sp13 (p =.0014 and.0156, respectively). The frequency of HBV splice variants in patient serum differed markedly by HBV genotype and phase of CHB natural history. The increased levels of HBV splice variants detected in CHB phase II patients compared with the higher replicative Phase I in particular warrants further investigation. [ABSTRACT FROM AUTHOR]

Summary: Background: Sofosbuvir, a prodrug nucleoside inhibitor of hepatitis C virus, has a predominant circulating metabolite that is renally eliminated. Whether sofosbuvir is associated with chronic kidney disease (CKD) progression is not well understood. Methods: We performed a retrospective analysis of patients with estimated glomerular filtration rate (eGFR) 30–89 mL/min/1.73 m2 treated with sofosbuvir in 76 Phase 2/3 registrational trials. We evaluated eGFR at each study visit. Separately, we performed a retrospective analysis of an administrative claims database (IQVIA PharMetrics Plus™) to compare the risk of incident end‐stage renal disease (ESRD) associated with the use of sofosbuvir or non‐sofosbuvir regimens among patients with CKD using propensity score methods. Exposure, CKD status and outcomes were determined using diagnosis and medication claim codes. Cox proportional hazards methods were used to estimate ESRD risk. Results: Among 4642 trial participants with baseline stage 2 CKD (eGFR 60–89 ml/min/1.73 m2) and 682 trial participants with stage 3 CKD (eGFR 30–59 ml/min/1.73 m2) mean (SD) eGFR improved from baseline to 4 weeks post‐treatment (+0.7 [9.3] and +2.6 [8.8] ml/min/1.73 m2, respectively; p < 0.001 each). In the second analysis, among 2042 patients with CKD receiving sofosbuvir‐based regimens compared to 431 receiving non‐sofosbuvir‐based regimens, after adjusting for baseline covariates and weighting based on treatment propensity scores, there was no significant difference in risk of ESRD (adjusted HR = 0.85, 95% CI: 0.51–1.42). Conclusions: Clinical trial participants with CKD did not experience worsening eGFR during sofosbuvir‐based treatment, and sofosbuvir was not associated with an increased risk of ESRD in patients with CKD in a nationally‐representative administrative claims database. [ABSTRACT FROM AUTHOR]

Summary: Background: Entecavir (ETV) and tenofovir disoproxil fumarate (TDF) are the first‐line treatment agents for chronic hepatitis B virus (HBV). Recently, whether the degree to which the risk of hepatocellular carcinoma (HCC) may be reduced by ETV vs TDF has been debated. We compared the incidence of HCC among treatment‐naïve patients receiving TDF vs ETV in the United States. Methods: From a large administrative medical claims database of commercially insured patients, we identified 166,933 adults with a diagnosis of chronic hepatitis B and a minimum of 12 months of prior enrolment, of whom 3934 and 6127 initiated ETV and TDF respectively. Fine‐Gray hazard regression models incorporating treatment propensity scores (PS) were used to estimate the risk of HCC incidence associated with TDF vs ETV; variables considered for adjustment included demographic characteristics, concomitant medication use and baseline comorbidities, as well as competing events including liver transplantation and medication changes. Results: After PS weighting, the TDF and ETV groups were well‐matched. During the follow‐up, 90 patients developed HCC, including 50 receiving ETV and 40 receiving TDF, giving rise to crude incidence rates of 0.62 per 100 person‐years (PY) and 0.30 per 100 PY respectively. In PS‐weighted, multivariable analysis, TDF was associated with a subdistribution hazard ratio for HCC of 0.58 (95% confidence interval [CI]: 0.38–0.89) compared to ETV. Results were similar when patients ≥40 years and men and women were analysed separately. Conclusion: Among commercially insured, treatment‐naïve patients with chronic hepatitis B in the United States, treatment with TDF was associated with significantly lower risk of HCC than ETV. [ABSTRACT FROM AUTHOR]

More systematic analysis of hepatitis B virus (HBV) genome diversity, linked with tenofovir disoproxil fumarate (TDF) treatment and HBeAg seroconversion, are needed. GS‐US‐174–0115 was a double‐blind, placebo‐controlled, Phase 3, 192‐week clinical trial that evaluated TDF in adolescents with chronic hepatitis B (CHB). HBV full‐genome deep sequencing was performed using Illumina MiSeq at baseline (BL; n = 85), Week 8 (W8; n = 80), Week 72 (W72; PBO only, n = 42), and treatment‐free follow‐up (TDF only, n = 25). The viral diversity was calculated using Shannon entropy and population nucleotide diversity with a 2% variant cutoff. Our data showed (i) a higher viral diversity in the X region at baseline than the core/polymerase/surface regions, (ii) higher core/surface viral diversity at baseline for patients with seroconversion, (iii) an expected reduction in viral diversity after 8 weeks of TDF treatment, and (iv) a drop in viral diversity at W72 for patients receiving placebo with a seroconversion (n = 7). The higher viral diversity in X was associated with higher baseline alanine aminotransferase (ALT) levels (p <.001). Patients with greater reduction of diversity at W8 of TDF treatment had higher baseline ALT levels. For placebo patients who seroconverted, the drop in viral diversity at W72 (p =.04) coincided with reduction of serum HBV DNA (average change from baseline = −4.10 log10 copies/ml) and unique combinations of variants were enriched in a patient's viral population post seroconversion. The basal core promoter (BCP) variants, A1762T and G1764A, and the pC variant, G1896A, were most often enriched at or after seroconversion. [ABSTRACT FROM AUTHOR]

Hepatitis B virus (HBV) genotypes impact treatment outcomes and disease progression. The current genotyping methods have limitations in patients with low HBV viral load. In this study, a more sensitive assay has been developed for determining the HBV genotype in HBV DNA suppressed patients. Fifty‐five serum samples from 55 chronic hepatitis B patients (HBeAg−, n = 20; HBeAg+, n = 35) across genotypes A to H with long‐term nucleos(t)ide analogs (NAs) treatment were collected. All samples had HBV DNA less than 29 IU/mL. Total nucleic acid (viral DNA and RNA) was extracted and a 341 bp amplicon located at HBV S gene overlapping with reverse transcriptase domain of polymerase (pol/RT) was amplified via real time (RT)‐nested polymerase chain reaction (PCR) followed by population sequencing. HBV genotype was determined by phylogenetic analysis. The assay successfully amplified HBV S/RT gene from 53 of 55 (96.4%) patient serum samples. Phylogenetic analysis demonstrated that the genotypes of all the 53 PCR positive samples matched the historical genotypes as determined by INNO‐LiPA or RT sequence from the corresponding baseline samples. This assay was able to accurately determine HBV genotype irrespective of baseline genotype, HBeAg status, or duration of viral suppression. The ability to determine genotype in virally suppressed patients may facilitate the evaluation of novel treatment agents for HBV in this patient population. Highlights: A sensitive HBV genotyping assay using DNA and RNA sequencing followed by phylogenetic analysis was developed. Fifty three out of 55 patient serum samples with HBV DNA undetectable across genotypes A to H were successfully amplified and genotyped. This assay was able to accurately determine HBV genotype for HBV DNA suppressed patients. [ABSTRACT FROM AUTHOR]

Summary: Background: Guidelines recommend liver biopsy to rule out significant inflammatory activity in chronic hepatitis B (CHB) patients with elevated hepatitis B virus (HBV) DNA but without other indications for treatment. Aim: To study rates and determinants of clinically significant liver inflammation. Methods: We selected patients with HBV DNA > 2000 IU/mL from the SONIC‐B database. The presence of significant inflammation (METAVIR ≥ A2 or HAI ≥ 9) was assessed by liver biopsy and correlated with alanine aminotransferase (ALT) levels (according to AASLD upper limits of normal [ULN]) and stratified by the presence of significant liver fibrosis (Ishak ≥ 3 or METAVIR ≥ F2). Results: The cohort included 2991 patients; 1672 were HBeAg‐positive. ALT was < ULN in 270 (9%), 1‐2 times ULN in 852 (29%) and > 2 times ULN in 1869 (63%). Significant fibrosis was found in 1419 (47%) and significant inflammatory activity in 630 (21%). Significant inflammatory activity was found in 34% of patients with liver fibrosis, compared to 9.5% of those without (P < 0.001). Among patients without fibrosis, significant inflammatory activity was detected in 3.6% of those with normal ALT, 5.0% of those with ALT 1‐2 times ULN and in 13% of those with ALT > 2 times ULN (P < 0.001). ALT < 2 times ULN had a negative predictive value of 95% for ruling out significant inflammatory activity among patients without liver fibrosis. Conclusions: Among patients without significant fibrosis, an ALT level < 2 times ULN is associated with < 5% probability of significant inflammatory activity. If fibrosis can be ruled out using non‐invasive methods, liver biopsy solely to assess inflammatory activity should be discouraged. [ABSTRACT FROM AUTHOR]

Aim: The combination of ledipasvir and sofosbuvir (LDV/SOF) has been approved for the treatment of various hepatitis C virus (HCV) genotypes across many countries. This article presents an integrated analysis of three prospective phase II/III trials in the Asia‐Pacific region to evaluate the efficacy and safety of 12 weeks of LDV/SOF in HCV genotype 2 patients without cirrhosis or with compensated cirrhosis. Methods: A total of 200 patients were included in the integrated analysis. The primary end‐point was the rate of sustained virologic response for 12 weeks after the end of therapy (SVR12), analyzed by fibrosis stage, treatment history, HCV genotype subtype, and presence of baseline resistance‐associated substitutions (RAS). Safety was evaluated by adverse events and laboratory abnormalities. Results: Twelve weeks of treatment with LDV/SOF was associated with high SVR12 rates (overall 98%) in patients with genotype 2 HCV, irrespective of fibrosis stage, treatment history, genotype 2 subtype, and presence of baseline non‐structural protein 5A resistance‐associated substitution (NS5A RAS), and LDV/SOF was well tolerated. Conclusions: Twelve weeks of treatment with LDV/SOF provides a highly effective and safe treatment for patients with genotype 2 HCV, including those with advanced fibrosis. As a ribavirin‐free and protease inhibitor‐free regimen with minimal on‐treatment monitoring requirements, LDV/SOF can potentially play a crucial role in achieving the WHO's goal of HCV elimination. [ABSTRACT FROM AUTHOR]

Nucleos(t)ide analogues (NUC) treatment prevents progression of liver fibrosis in subjects with chronic hepatitis B (CHB). However, risk of hepatocellular carcinoma (HCC) persists despite viral suppression. Specific HBV variants have been associated with adverse outcomes, including HCC; however, the frequency of these variants during the seemingly benign immunotolerant (IT) phase is unknown. Next‐generation sequencing and detailed virological characterization on a cohort of treatment‐naïve IT subjects were performed to determine the frequency of clinically relevant viral variants. Samples from 97 subjects (genotype B/C 55%/45%, median HBV‐DNA 8.5 log10 IU/mL, median HBsAg 4.8 log10 IU/mL, median HBeAg 3.6 log10 PEIU/mL) were analysed. Despite subjects being in the IT phase, clinically relevant HBV variants were common at baseline, particularly in the basal core promoter (BCP, overlaps the hepatitis B X (HBx) gene), precore and PreS regions. BCP/HBx variants were independently associated with lower baseline HBeAg, HBsAg and HBV‐DNA titres. Precore variants were independently associated with higher baseline ALT. Increased viral diversity was associated with increased age and lower HBV‐DNA, HBsAg and HBeAg levels. Low‐level (<5%) drug resistance–associated amino acid substitutions in the HBV reverse transcriptase were detected in 9 (9%) subjects at pre‐treatment but were not associated with reduced antiviral activity. Future studies should evaluate whether the detection of HBV variant during IT CHB is predictive of progression to immune clearance and poor prognosis, and whether early initiation of antiviral therapy during IT CHB to prevent the selection of HBV variants is clinically beneficial. [ABSTRACT FROM AUTHOR]

Background and Aims: Most patients with cirrhosis induced by chronic HBV infection experience fibrosis regression after long‐term antiviral treatment, while some remain cirrhotic. Fibrosis regression is associated with lower odds of developing hepatic decompensation and hepatocellular carcinoma, but mechanisms impacting differential fibrosis regression between individuals are unclear. We asked whether soluble molecules, including serum microRNAs, could serve as biomarkers of fibrosis regression. Methods: We analysed cryopreserved sera from clinical trials in which cirrhotic HBV‐infected patients (baseline Ishak fibrosis score of 5‐6) received 240 weeks of nucleotide analogue treatment. Liver biopsies at week 240 in these trials showed 71/96 patients (74%) had fibrosis regression (Ishak ≤ 4) while 25/96 (26%) remained cirrhotic (Ishak 5‐6). We quantified inflammatory markers (CXCL10, soluble CD163) and miRNAs (n = 179) from serum at baseline, week 48 and week 240 of treatment in a sub‐cohort of patients with (n = 14) or without (n = 14) fibrosis regression. Results: CXCL10, sCD163 and miRNAs previously associated with HBV replication and inflammation decreased during treatment but did not differ based on fibrosis regression. Two miRNAs (miR‐421 and miR‐454‐3p) had lower baseline expression in patients with subsequent fibrosis regression. In all, 27 miRNAs differed at week 240 and had higher expression in patients with fibrosis regression (eg miR‐199a‐3p, miR‐423‐3p, miR‐142‐3p, miR‐let‐7d‐5p). Several miRNAs (miR‐141‐3p, let‐7d‐5p) that correlated with regression have previously been implicated in the pathophysiology of non‐alcoholic steatohepatitis. Conclusions: In cirrhotic patients with chronic HBV infection treated with antiviral therapy, serum miRNAs have differential expression based on fibrosis regression, suggesting potential utility as biomarkers. [ABSTRACT FROM AUTHOR]

Investigational agents that reduce or eliminate covalently closed circular DNA (cccDNA) or enhance host immunity against hepatitis B virus (HBV)‐infected hepatocytes are intended to induce a durable off‐treatment clearance of hepatitis B surface antigen (HBsAg) (referred to as functional cure). The aim of this paper was to highlight challenges in interpreting liver safety data in clinical trials of these agents when given alone or in combination regimens. The incidence, grading and management of spontaneous serum ALT flares in untreated chronic HBV patients are reviewed along with a summary of serum ALT flares observed during the registration trials for peginterferon and nucleos(t)ide reverse transcriptase inhibitors. Recommendations regarding the detection, management and interpretation of liver safety biomarker data in future clinical trials as well as suggested inclusion and exclusion criteria for phase 1/2 vs phase 3 studies are provided. Criteria to help classify liver safety signals as being due to the intended therapeutic response, emergence of drug‐resistant HBV virions, or idiosyncratic drug‐induced liver injury are provided along with a review of the role of an expert hepatic adjudication panel in assessing a compound's hepatotoxicity profile. Finally, an algorithmic approach to the differential diagnosis and recommended medical evaluation and management of individual clinical trial patients that develop a liver safety signal is provided along with the rationale to collect and test research blood samples for future mechanistic studies. [ABSTRACT FROM AUTHOR]

Background and Aim: Functional cure is the major goal of chronic hepatitis B (CHB) therapy though few biomarkers predict this outcome. HBsAg epitope occupancy can be influenced by therapeutic and immune pressure. The aim of this study was to map the HBsAg epitope profiles during long‐term nucleos(t)ide analogue therapy in patients with genotype A CHB, in the context of HBsAg loss (SL)/seroconversion. Methods: We evaluated 25 genotype A CHB patients in the GS‐US‐174‐0103 trial of HBeAg‐positive CHB patients treated with tenofovir or adefovir for 4 years, 14 who achieved SL whilst 11 had no change. We epitope mapped the major domains of HBsAg to identify those patients with HBsAg clearance profile (CP) (loss of binding at both loops 1 and 2 epitopes of the 'a' determinant) vs non‐clearance profile (no change in epitope recognition, or loss of epitope binding at one loop only), correlating this to on‐treatment HBsAg responses. Complexed anti‐HBs was also measured. Results: Analysis of the HBsAg epitope profiles of the 25 patients at baseline identified no predictive correlation with SL. In contrast, analysis at week 48 and end of study (week 192) or prior to SL identified significant predictive associations between development of HBsAg CPs and outcome of functional cure. The detection of a CP also correlated with the development of an alanine aminotransferase flare and detection of anti‐HBs complexed with HBsAg. Conclusion: The detection of HBsAg CPs by epitope mapping represents a novel viral biomarker, reflecting an emerging anti‐HBs selection pressure prior to functional cure. [ABSTRACT FROM AUTHOR]

Background & Aims: Tenofovir disoproxil fumarate (TDF) is a first‐line treatment for chronic hepatitis B (CHB). We aimed to describe the efficacy and safety profiles of TDF treatment for up to 10 years in a well‐described cohort of CHB patients. Methods: Hepatitis B e antigen (HBeAg)‐negative and HBeAg‐positive patients from two randomised, double‐blind trials (ClinicalTrials.gov: NCT00117676 and NCT00116805) completed 48 weeks of randomised treatment with TDF or adefovir dipivoxil. A subset of these patients was then eligible to receive open‐label TDF treatment for up to 10 years. At Year 10, patients were assessed for virological suppression, alanine aminotransferase (ALT) normalisation, serological response, safety and tolerability. Results: Of 641 randomised and treated patients, 585 (91%) entered the open‐label extension phase with 203 (32%) patients completing Year 10 of the study. At Year 10, 118/118 (100%) of HBeAg‐negative patients and 78/80 (98%) of HBeAg‐positive patients with available data achieved hepatitis B virus (HBV) DNA < 69 IU/mL, while 88/106 (83%) and 60/77 (78%) patients achieved ALT normalisation, respectively. Of the 23 patients with HBeAg status available at Year 10, 12 (52%) and six (27%) experienced HBeAg loss and seroconversion, respectively. No resistance to TDF was documented up to Year 10. In the period between Year 8 and Year 10, the safety profile of TDF was similar to previous reports, with few patients experiencing renal‐ or bone‐related adverse events. Conclusions: Over 10 years, TDF had a favourable safety profile, was well tolerated, and resulted in continued maintenance of virological suppression with no documented resistance. [ABSTRACT FROM AUTHOR]

Background: Interferon regulatory factor 6 (IRF6) plays a critical role in embryonic tissue development, including differentiation of epithelial cells. Besides orofacial clefting due to haploinsufficiency of IRF6, recent human genetic studies indicated that mutations in IRF6 are linked to small mandible and digit abnormalities. The function of IRF6 has been well studied in oral epithelium; however, its role in craniofacial skeletal formation remains unknown. In this study, we investigated the role of Irf6 in craniofacial bone development using comparative analyses between wild‐type (WT) and Irf6‐null littermate mice. Results: Immunostaining revealed the expression of IRF6 in hypertrophic chondrocytes, osteocytes, and bone matrix of craniofacial tissues. Histological analysis of Irf6‐null mice showed a remarkable reduction in the number of lacunae, embedded osteocytes in matrices, and a reduction in mineralization during bone formation. These abnormalities may explain the decreased craniofacial bone density detected by micro‐CT, loss of incisors, and mandibular bone abnormality of Irf6‐null mice. To validate the autonomous role of IRF6 in bone, extracted primary osteoblasts from calvarial bone of WT and Irf6‐null pups showed no effect on osteoblastic viability and proliferation. However, a reduction in mineralization was detected in Irf6‐null cells. Conclusions: Altogether, these findings suggest an autonomous role of Irf6 in regulating bone differentiation and mineralization. Developmental Dynamics 248:221‐232, 2019. © 2019 Wiley Periodicals, Inc. Key Findings: Irf6 is expressed in osteocytes and hypertrophic chondrocytes of craniofacial tissues.Loss of Irf6 leads to a reduction in the number embedded osteocytes and TRAP+ osteoclasts in bone matrices.Irf6‐null mice exhibit delay and reduction in bone mineralization, loss of incisors and mandibular hypoplasia. [ABSTRACT FROM AUTHOR]

Summary: Vesatolimod is an oral agonist of toll‐like receptor 7 designed to minimize systemic exposure and side effects. We assessed the safety and efficacy of vesatolimod in viremic chronic hepatitis B (CHB) patients not currently on oral antiviral treatment (OAV) in a phase 2, multicentre, double‐blind, randomized, placebo‐controlled study. A total of 192 patients stratified by HBeAg status and alanine aminotransferase level were randomized 2:2:2:1 to receive oral vesatolimod (1‐, 2‐ or 4‐mg) or placebo once weekly for 12 weeks; tenofovir disoproxil fumarate (300‐mg daily) was administered daily for 48 weeks. Efficacy was assessed by quantitative serum HBsAg decline at Week 24 from baseline. In addition to safety assessments, changes in whole‐blood interferon‐stimulated gene (ISG) transcripts and serum cytokines were explored. Most patients were male (64.1%) and HBeAg‐negative (60.9%) at baseline. Among vesatolimod‐treated patients, most (60.4%‐69.1%) experienced ≥1 treatment‐emergent adverse event; the majority were mild or moderate in severity. No clinically meaningful differences in HBsAg changes from baseline were observed between treatment groups. No patients experienced HBsAg loss, while 3 patients experienced HBeAg loss and hepatitis B e‐antibody seroconversion at week 48. HBV DNA suppression rates were similar across all treatment arms at Week 24. ISG15 induction was dose‐dependent and did not correlate with HBsAg changes. A small proportion of patients exhibited dose‐dependent interferon‐α induction that correlated with grade of influenza‐like adverse events. Overall, vesatolimod is safe and well tolerated in CHB patients. Although consistent dose‐dependent pharmacodynamic induction of ISGs was demonstrated, it did not result in clinically significant HBsAg decline. [ABSTRACT FROM AUTHOR]

Abstract: Background: Alanine aminotransferase (ALT) flares during NA therapy are uncommon but occur. Evaluation of ALT flares during nucleos(t)ide analogue (NA) therapy is important as new immunomodulatory therapies for hepatitis B virus (HBV) are developed. We evaluated the association between ALT flares and HBsAg loss during long‐term therapy for genotype A CHB. Methods: This analysis included genotype A subjects from a phase III study of tenofovir vs adefovir in HBeAg‐positive HBV. ALT flare was defined as (i) a rise in ALT >2x ULN from normal ALT levels; or (ii) a rise in ALT >2x baseline ALT level. HBsAg response at week 384 was recorded as one of HBsAg loss vs HBsAg decline (≥1 log10 IU/mL decline) vs non‐response. The primary analysis evaluated the association between ALT flare and HBsAg response. Results: 54 subjects were included. 23/54 (43%) subjects experienced an on‐treatment ALT flare. 45% achieved an HBsAg reduction ≥1 log10 IU/mL, and of these 67% achieved HBsAg loss at a median of 102 weeks [IQR: 64‐156]. Flare was associated with HBsAg decline vs non‐response (67% vs 23%, P = .002), and were more common in subjects who achieved HBsAg loss vs non‐response (56% vs 23%), P = .049). There was a median delay of 56 weeks [IQR: 40‐80] between a flare and HBsAg loss. Conclusion: In genotype A subjects undergoing long‐term NA therapy, ALT flares predict for HBsAg response. The delay between ALT flare and HBsAg loss has implications for clinical trial design for early phase development of immunomodulatory strategies aiming for HBsAg loss. [ABSTRACT FROM AUTHOR]

Background Hepatitis B e antigen ( HBeAg) seroconversion is a treatment endpoint for HBeAg-positive CHB, and a necessary precursor to HBsAg loss. Biomarkers that predict serological outcomes would be useful. Aim To evaluate the utility of measuring HBeAg levels for predicting HBeAg seroconversion and HBsAg loss under long-term tenofovir ( TDF) therapy. Methods A total of 266 patients were enrolled into a phase III study of TDF vs adefovir ( ADV) for 48 weeks in HBeAg-positive patients, followed by open-label TDF up to 384 weeks. Serum HBeAg levels were measured for subjects with samples available at both baseline and week 24 of treatment (n = 200). Analysis compared subjects who achieved HBeAg seroconversion by week 384 vs no HBeAg seroconversion. Results HBeAg seroconversion rate was 52% by week 384. Time to HBeAg seroconversion was 80 weeks ( IQR: 36-162). HBeAg decline at week 24 was associated with HBeAg seroconversion (1.63 vs 0.90 log10 PEIU/mL, P = .002). The optimal threshold for identifying HBeAg seroconversion was HBeAg decline ≥2.2 log10 PEIU/ mL at week 24, with HBeAg seroconversion achieved by 76% of patients, compared to 44% if HBeAg decline <2.2 log10 ( P < .0001). HBeAg decline ≥2.2 log10 PEIU/ mL at week 24 was associated with HBsAg loss in genotype A or D patients (38% vs 15%, P = .03). Precore/basal core promotor variants were associated with lower baseline HBeAg levels, but not HBeAg seroconversion. Conclusion Decline in HBeAg levels by week 24 was associated with HBeAg seroconversion and HBsAg loss in HBeAg-positive chronic hepatitis B patients treated with long-term TDF. [ABSTRACT FROM AUTHOR]

The Pulmonary Biospecimen Repository (PBR) at the University of Alabama at Birmingham (UAB) was launched in 2009. The purpose of the UAB PBR is to provide investigators within the pulmonary community at UAB and elsewhere with clinical samples derived from multiple lung diseases, including transplant recipients, idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, cystic fibrosis, and asthma. Cell and fluid samples isolated from bronchoalveolar lavage (BAL), plasma, and serum are collected and stored; samples are assessed routinely for viability. Each sample is linked directly with the respective patient information via the Pulmonary Translational Research and Clinical Database, a Health Insurance Portability and Accountability Act compliant database that includes detailed information allowing for the study of specific patient cohorts. To access samples, investigators must complete a request form, which is reviewed by the UAB PBR Steering Committee. To date, more than 800 patients have provided approximately 7,000 BAL, serum and plasma fluid, and cell samples. Over the past 4 years, nearly 800 of these samples have been distributed to investigators at UAB and elsewhere. Future plans for the UAB PBR include expanding sample collection to additional pulmonary diseases, such as mycobacterial infections, increasing the number of sample users and obtaining external funding to ensure its continued sustainability. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Although laboratory experiments suggest that negative affect inductions potentiate the relation between dieting and disinhibited eating, little research has tested whether this finding generalizes to binge eating in the natural environment. Thus, we assessed whether negative affect moderated the relation between dieting and binge eating in a passive-observational study. METHOD: This aim was addressed with longitudinal data from a community sample of adolescents (N = 631). RESULTS: For females, dieting and negative affect predicted binge eating in cross-sectional and prospective analyses, but negative affect potentiated the relation between dieting and binge eating only in the cross-sectional analyses. Similar, but attenuated results were found for males. DISCUSSION: Findings converge with those from laboratory studies in suggesting that negative affect moderates the relation between dieting and binge eating, but also imply that dieting and negative affect constitute independent risk factors for binge eating. The lack of prospective effects may suggest that the interactive relations have a short time lag or are difficult to detect prospectively. Copyright 2000 by John Wiley Sons, Inc. [ABSTRACT FROM AUTHOR]