Bulevirtide Combined with Pegylated Interferon for Chronic Hepatitis D.

BACKGROUND: In a phase 3 trial, bulevirtide monotherapy led to a virologic response in patients with chronic hepatitis D. Pegylated interferon (peginterferon) alfa-2a is recommended by guidelines as an off-label treatment for this disease. The role of combination therapy with bulevirtide and peginterferon alfa-2a, particularly with regard to finite treatment, is unclear. METHODS: In this phase 2b, open-label trial, we randomly assigned patients to receive peginterferon alfa-2a alone (180 µg per week) for 48 weeks; bulevirtide at a daily dose of 2 mg or 10 mg plus peginterferon alfa-2a (180 µg per week) for 48 weeks, followed by the same daily dose of bulevirtide for 48 weeks; or bulevirtide at a daily dose of 10 mg alone for 96 weeks. All the patients were followed for 48 weeks after the end of treatment. The primary end point was an undetectable level of hepatitis D virus (HDV) RNA at 24 weeks after the end of treatment. The primary comparison was between the 10-mg bulevirtide plus peginterferon alfa-2a group and the 10-mg bulevirtide monotherapy group. RESULTS: A total of 24 patients received peginterferon alfa-2a alone, 50 received 2 mg and 50 received 10 mg of bulevirtide plus peginterferon alfa-2a, and 50 received 10 mg of bulevirtide monotherapy. At 24 weeks after the end of treatment, HDV RNA was undetectable in 17% of the patients in the peginterferon alfa-2a group, in 32% of those in the 2-mg bulevirtide plus peginterferon alfa-2a group, in 46% of those in the 10-mg bulevirtide plus peginterferon alfa-2a group, and in 12% of those in the 10-mg bulevirtide group. For the primary comparison, the between-group difference was 34 percentage points (95% confidence interval, 15 to 50; P<0.001). At 48 weeks after the end of treatment, HDV RNA was undetectable in 25% of the patients in the peginterferon alfa-2a group, in 26% of those in the 2-mg bulevirtide plus peginterferon alfa-2a group, in 46% of those in the 10-mg bulevirtide plus peginterferon alfa-2a group, and in 12% of those in the 10-mg bulevirtide group. The most frequent adverse events were leukopenia, neutropenia, and thrombocytopenia. The majority of adverse events were of grade 1 or 2 in severity. CONCLUSIONS: The combination of 10-mg bulevirtide plus peginterferon alfa-2a was superior to bulevirtide monotherapy with regard to an undetectable HDV RNA level at 24 weeks after the end of treatment. (Funded by Gilead Sciences; MYR 204 ClinicalTrials.gov number, NCT03852433.).

A Phase 3, Randomized Trial of Bulevirtide in Chronic Hepatitis D.

BACKGROUND: Coinfection with hepatitis D virus (HDV) accelerates the progression of liver disease associated with chronic hepatitis B. Bulevirtide inhibits the entry of HDV into hepatocytes. METHODS: In this ongoing phase 3 trial, patients with chronic hepatitis D, with or without compensated cirrhosis, were randomly assigned, in a 1:1:1 ratio, to receive bulevirtide subcutaneously at 2 mg per day (2-mg group) or 10 mg per day (10-mg group) for 144 weeks or to receive no treatment for 48 weeks followed by bulevirtide subcutaneously at 10 mg per day for 96 weeks (control group). Patients will complete 96 weeks of additional follow-up after the end of treatment. The primary end point was a combined response at week 48 of an undetectable HDV RNA level, or a level that decreased by at least 2 log10 IU per milliliter from baseline, and normalization of the alanine aminotransferase (ALT) level. The key secondary end point was an undetectable HDV RNA level at week 48, in a comparison between the 2-mg group and the 10-mg group. RESULTS: A total of 49 patients were assigned to the 2-mg group, 50 to the 10-mg group, and 51 to the control group. A primary end-point response occurred in 45% of patients in the 2-mg group, 48% in the 10-mg group, and 2% in the control group (P<0.001 for the comparison of each dose group with the control group). The HDV RNA level at week 48 was undetectable in 12% of patients in the 2-mg group and in 20% in the 10-mg group (P = 0.41). The ALT level normalized in 12% of patients in the control group, 51% in the 2-mg group (difference from control, 39 percentage points [95% confidence interval {CI}, 20 to 56]), and 56% in the 10-mg group (difference from control, 44 percentage points [95% CI, 26 to 60]). Loss of hepatitis B virus surface antigen (HBsAg) or an HBsAg level that decreased by at least 1 log10 IU per milliliter did not occur in the bulevirtide groups by week 48. Headache, pruritus, fatigue, eosinophilia, injection-site reactions, upper abdominal pain, arthralgia, and asthenia were more common in the 2-mg and 10-mg groups combined than in the control group. No treatment-related serious adverse events occurred. Dose-dependent increases in bile acid levels were noted in the 2-mg and 10-mg groups. CONCLUSIONS: After 48 weeks of bulevirtide treatment, HDV RNA and ALT levels were reduced in patients with chronic hepatitis D. (Funded by Gilead Sciences; MYR 301 ClinicalTrials.gov number, NCT03852719.).

Efficacy and Safety of Bepirovirsen in Chronic Hepatitis B Infection.

BACKGROUND: Bepirovirsen is an antisense oligonucleotide that targets all hepatitis B virus (HBV) messenger RNAs and acts to decrease levels of viral proteins. METHODS: We conducted a phase 2b, randomized, investigator-unblinded trial involving participants with chronic HBV infection who were receiving or not receiving nucleoside or nucleotide analogue (NA) therapy. Participants were randomly assigned (in a 3:3:3:1 ratio) to receive weekly subcutaneous injections of bepirovirsen at a dose of 300 mg for 24 weeks (group 1), bepirovirsen at a dose of 300 mg for 12 weeks then 150 mg for 12 weeks (group 2), bepirovirsen at a dose of 300 mg for 12 weeks then placebo for 12 weeks (group 3), or placebo for 12 weeks then bepirovirsen at a dose of 300 mg for 12 weeks (group 4). Groups 1, 2, and 3 received loading doses of bepirovirsen. The composite primary outcome was a hepatitis B surface antigen (HBsAg) level below the limit of detection and an HBV DNA level below the limit of quantification maintained for 24 weeks after the planned end of bepirovirsen treatment, without newly initiated antiviral medication. RESULTS: The intention-to-treat population comprised 457 participants (227 receiving NA therapy and 230 not receiving NA therapy). Among those receiving NA therapy, a primary-outcome event occurred in 6 participants (9%; 95% credible interval, 0 to 31) in group 1, in 6 (9%; 95% credible interval, 0 to 43) in group 2, in 2 (3%; 95% credible interval, 0 to 16) in group 3, and 0 (0%; post hoc credible interval, 0 to 8) in group 4. Among participants not receiving NA therapy, a primary-outcome event occurred in 7 participants (10%; 95% credible interval, 0 to 38), 4 (6%; 95% credible interval, 0 to 25), 1 (1%; post hoc credible interval, 0 to 6), and 0 (0%; post hoc credible interval, 0 to 8), respectively. During weeks 1 through 12, adverse events, including injection-site reactions, pyrexia, fatigue, and increased alanine aminotransferase levels, were more common with bepirovirsen (groups 1, 2, and 3) than with placebo (group 4). CONCLUSIONS: In this phase 2b trial, bepirovirsen at a dose of 300 mg per week for 24 weeks resulted in sustained HBsAg and HBV DNA loss in 9 to 10% of participants with chronic HBV infection. Larger and longer trials are required to assess the efficacy and safety of bepirovirsen. (Funded by GSK; B-Clear ClinicalTrials.gov number, NCT04449029.).

Patient-reported outcomes in chronic hepatitis delta: An exploratory analysis of the Phase III MYR301 trial of bulevirtide.

BACKGROUND & AIMS: Once-daily treatment of chronic hepatitis delta (CHD) with bulevirtide is well tolerated and associated with significant reductions in HDV RNA in the blood and in biochemical liver disease activity. This study explored the effects of 48-week bulevirtide treatment on health-related quality of life (HRQoL) in patients with CHD. METHODS: In an open-label, randomised, Phase 3 trial, 150 patients with CHD and compensated liver disease were stratified by liver cirrhosis status and randomised 1:1:1 to no treatment (control), bulevirtide 2 mg/day, or bulevirtide 10 mg/day for 48 weeks. HRQoL was evaluated by the following patient-reported outcome (PRO) instruments at baseline, 24 weeks, and 48 weeks: EQ-5D-3L, Hepatitis Quality of Life Questionnaire (HQLQ), and Fatigue Severity Scale (FSS). RESULTS: Patient characteristics and HRQoL scores were balanced at baseline between the treatment (2 mg, n = 49; 10 mg, n = 50) and control (n = 51) groups. Patients receiving 2-mg bulevirtide reported significant improvements compared with controls on the HQLQ domains of role physical, hepatitis-specific limitations, and hepatitis-specific health distress. Numerically higher scores for general health, hepatitis-specific limitations, and hepatitis-specific health distress domains were reported by patients with cirrhosis who received bulevirtide vs control. FSS scores remained stable across treatment groups throughout. At week 48, patients in the 2-mg group showed greater mean improvement from baseline in health status compared with controls on the EQ-5D-3L visual analogue scale. CONCLUSION: PROs indicate that 48-week treatment with bulevirtide monotherapy may improve aspects of HRQoL in patients with CHD. IMPACT AND IMPLICATIONS: Bulevirtide 2 mg is the only approved treatment for patients with chronic hepatitis delta (CHD) in the EU. Patients with CHD have worse quality of life scores than those with chronic hepatitis B. Bulevirtide treatment for 48 weeks reduced HDV RNA and alanine aminotransferase levels and was well tolerated among patients with CHD. For the first time, this study shows that patients who received bulevirtide therapy for 48 weeks reported improvements in physical and hepatitis-related quality of life domains compared to those who did not receive therapy (control group). CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier, NCT03852719.

Bulevirtide monotherapy in patients with chronic HDV: Efficacy and safety results through week 96 from a phase III randomized trial.

BACKGROUND & AIMS: Bulevirtide (BLV), a first-in-class entry inhibitor, is approved in Europe for the treatment of chronic hepatitis delta (CHD). BLV monotherapy was superior to delayed treatment at week (W) 48, the primary efficacy endpoint, in the MYR301 study (NCT03852719). Here, we assessed if continued BLV therapy until W96 would improve virologic and biochemical response rates, particularly among patients who did not achieve virologic response at W24. METHODS: In this ongoing, open-label, randomized phase III study, patients with CHD (N = 150) were randomized (1:1:1) to treatment with BLV 2 mg/day (n = 49) or 10 mg/day (n = 50), each for 144 weeks, or to delayed treatment for 48 weeks followed by BLV 10 mg/day for 96 weeks (n = 51). Combined response was defined as undetectable hepatitis delta virus (HDV) RNA or a decrease in HDV RNA by ≥2 log10 IU/ml from baseline and alanine aminotransferase (ALT) normalization. Other endpoints included virologic response, ALT normalization, and change in HDV RNA. RESULTS: Of 150 patients, 143 (95%) completed 96 weeks of the study. Efficacy responses were maintained and/or improved between W48 and W96, with similar combined, virologic, and biochemical response rates between BLV 2 and 10 mg. Of the patients with a suboptimal early virologic response at W24, 43% of non-responders and 82% of partial responders achieved virologic response at W96. Biochemical improvement often occurred independently of virologic response. Adverse events were mostly mild, with no serious adverse events related to BLV. CONCLUSIONS: Virologic and biochemical responses were maintained and/or increased with longer term BLV therapy, including in those with suboptimal early virologic response. BLV monotherapy for CHD was safe and well tolerated through W96. IMPACT AND IMPLICATIONS: In July 2023, bulevirtide was fully approved for the treatment of chronic hepatitis delta (CHD) in Europe based on clinical study results from up to 48 weeks of treatment. Understanding the efficacy and safety of bulevirtide over the longer term is important for healthcare providers. In this analysis, we demonstrate that bulevirtide monotherapy for 96 weeks in patients with CHD was associated with continued improvements in combined, virologic, and biochemical responses as well as liver stiffness from week 48 at both the 2 mg and 10 mg doses. Patients with suboptimal virologic responses to bulevirtide at week 24 also benefited from continued therapy, with the majority achieving virologic response or biochemical improvement by week 96. GOV IDENTIFIER: NCT03852719.

On stomatocysts of Paraphysomonas caelifrica (Stramenopiles, Paraphysomonadida).

Stomatocysts of the rare heterotrophic chrysophyte, Paraphysomonas caelifrica, were discovered from a shallow ephemeral pond Tavolgasai ("Orenburgskiy" State Nature Reserve, Orenburg Region, Russia). Morphology of stomatocysts was studied using scanning electron microscopy. Stomatocysts of P. caelifrica are spherical and smooth with a cylindrical collar surrounding the regular pore. So, they do not belong to the stomatocyst 1 Duff and Smol as previously thought. The description of a new stomatocyst morphotype is provided.

Effect of liraglutide on microcirculation in rat model with absolute insulin deficiency.

INTRODUCTION: The investigations of angiotropic effects of liraglutide are an issue of significant scientific and practical interest. The successful application of liraglutide has been shown in glycemic control in patients with the type 2 diabetes mellitus (DM), but the effect of liraglutide in patients with type 1 DM has not been completely studied yet in clinical practice. Therefore, the present study is aimed to investigate the effect of liraglutide which is agonist of glucagon-like peptide-1 receptors, on microcirculation in white outbred rats with the alloxan-induced diabetes. MATERIALS AND METHODS: The study was performed with 70 white outbred rats, divided into 4 groups: 1) control group (intact animals (Control)); 2) comparison group (diabetes mellitus (DM)) - animals with the alloxan-induced diabetes; 3) experimental group no. 1 (liraglutide low dose (LLD)) - animals with the alloxan-induced diabetes, which were injected by liraglutide at dosage of 0.2 mg/kg of animal weight per a day; 4) experimental group no. 2 (liraglutide high dose (LHD)) - animals with the alloxan-induced diabetes, which were injected by liraglutide at dosage of 0.4 mg/kg of animal weight per a day. The carbohydrate metabolism disorders, the microcirculation of posterior paw skin, as well as the concentration of catecholamines and markers of endothelial alteration in blood were estimated at the 42nd day of the experiment in the comparison and experimental groups. RESULTS: It was found that the correction of carbohydrate metabolism by liraglutide is succeeded by the normalization of skin perfusion of posterior paw skin of the experimental animals. Recovery of microcirculation is associated with a decrease in vascular tone and stimulation of endothelium-dependent vasodilation, caused by simultaneous decrease of catecholamines, endothelin-1 and asymmetric dimethylarginine (ADMA) concentrations in blood serum. At the same time, the administration of liraglutide on the background of insulin-deficiency results in decrease of endothelial cell alteration markers concentration in blood, such as sE-selectin, syndecan-1, and vascular endothelial growth factor (VEGF). CONCLUSION: Administration of liraglutide leads to the normalization of the carbohydrate metabolism simultaneously with the correction of microcirculation in rats with the absolute insulin deficiency. The demonstrated recovery of microcirculation by liraglutide, which represents an analogue of glucagon-like peptide-1, provides new prospects for its approval as a potential drug for pathogenetic correction of microcirculatory disorders in patients with the type 1 DM.

Diversity of Silica-Scaled Chrysophytes in the Steppe Zone of the Southern Urals with a Description of a New Species from the Genus Mallomonas.

This paper is devoted to the study of the flora of silica-scaled chrysophytes in water bodies of the steppe zone of the Southern Urals (Russia). Twenty-four taxa were identified via scanning and transmission electron microscopy, twenty of which are representatives of the genus Mallomonas Perty, while four are species of the genus Synura Ehrenberg. In the course of the study, a species new to science from the genus Mallomonas, M. baturinae sp. nov., was described. This species belongs to the section Papillosae. The stomatocyst of M. doignonii was described. For the first time in Russia and for the third time since description, M. phasma and M. solea-ferrea var. irregularis were reported in the studied area. Here, their extended description is provided with illustrations of their scales in detail. Some rare taxa for the flora of Russia have been identified: M. doignonii, M. pillula f. exannulata, and M. pillula f. valdiviana. One taxon of the genus Mallomonas has not been identified to a species level and is probably a taxon new to science.

Influence of the new formulation based on silver alginate microcapsules loaded with tannic acid on the microcirculation of the experimental periodontitis in rats.

The microvascular changes caused by disorders of host immune response to oral microorganisms resulting in long-lasting inflammation of gums play a critical role in the periodontal lesion in the pathogenesis of chronic periodontitis. Current strategies of non-surgical periodontal therapy are aimed at the attainment of anti-inflammatory effects. We hypothesized that the usage of the microencapsulated form of anti-inflammatory substances with vasoactive effects could enhance the efficiency of the therapy by the prolonged release of active components. The prepared suspension of silver-alginate microcapsules loaded with tannic acid in the hydrogel was applied in vivo to the experimental model of periodontitis in rats induced by a ligature. The effect of this formulation was assessed by monitoring changes in local microcirculation performed by the Laser Doppler Flowmetry (1 and 24 h after application of hydrogel on intact gums and 21-days after the start of periodontitis' modeling). Application of the hydrogel containing multicomponent microcapsules to the affected area of gums allows correction of inflammatory microcirculatory disorders in model periodontitis. Immobilization of tannic acid into microcapsules allows increasing the correction of the following parameters: perfusion disorders, neurogenic tone of arterioles, myogenic tone of precapillary sphincters, as well as a venous outflow in the microvasculature of the gums. The hydrogel containing multicomponent microcapsules reduces the vascular inflammatory response in the model of periodontitis. Loading of silver-alginate microcapsules with tannic acid enhances the efficiency of microvascular disorders' correction in the model of periodontitis that suggests the prospects for application of this drug delivery system for non-surgical treatment of periodontitis.

SARS-CoV-2 Seroprevalence Structure of the Russian Population during the COVID-19 Pandemic.

The SARS-CoV-2 pandemic, which came to Russia in March 2020, is accompanied by morbidity level changes and can be tracked using serological monitoring of a representative population sample from Federal Districts (FDs) and individual regions. In a longitudinal cohort study conducted in 26 model regions of Russia, distributed across all FDs, we investigated the distribution and cumulative proportions of individuals with antibodies (Abs) to the SARS-CoV-2 nucleocapsid antigen (Ag), in the period from June to December 2020, using a three-phase monitoring process. In addition, during the formation of the cohort of volunteers, the number of seropositive convalescents, persons who had contact with patients or COVID-19 convalescents, and the prevalence of asymptomatic forms of infection among seropositive volunteers were determined. According to a uniform methodology, 3 mL of blood was taken from the examined individuals, and plasma was separated, from which the presence of Abs to nucleocapsid Ag was determined on a Thermo Scientific Multiascan FC device using the "ELISA anti-SARS-CoV-2 IgG" reagent set (prod. Scientific Center for Applied Microbiology and Biotechnology), in accordance with the developer's instructions. Volunteers (74,158) were surveyed and divided into seven age groups (1-17, 18-29, 30-39, 40-49, 59-59, 60-69, and 70+ years old), among whom 14,275 were identified as having antibodies to SARS-CoV-2. The average percent seropositive in Russia was 17.8% (IQR: 8.8-23.2). The largest proportion was found among children under 17 years old (21.6% (IQR: 13.1-31.7). In the remaining groups, seroprevalence ranged from 15.6% (IQR: 8-21.1) to 18.0% (IQR: 13.4-22.6). During monitoring, three (immune) response groups were found: (A) groups with a continuous increase in the proportion of seropositive; (B) those with a slow rate of increase in seroprevalence; and (C) those with a two-phase curve, wherein the initial increase was replaced by a decrease in the percentage of seropositive individuals. A significant correlation was revealed between the number of COVID-19 convalescents and contact persons, and between the number of contacts and healthy seropositive volunteers. Among the seropositive volunteers, more than 93.6% (IQR: 87.1-94.9) were asymptomatic. The results show that the COVID-19 pandemic is accompanied by an increase in seroprevalence, which may be important for the formation of herd immunity.

TNF-alpha and gamma-irradiation induced activation of the Salmonella typhimurium reproduction in the organs of infected animals.

The goal of the current work is to determine the role of the TNF-alpha on the activation of the bacterial growth in an in vivo system. In order to reach this goal we studied the dynamics of the reproduction of vegetative forms of Salmonella and the recultivation of non-cultivating forms of Salmonella in infected animals. Experiments have been conducted both on animals that had been injected with exogenous TNF together with bacterial suspension and on animals that had been exposed to gamma-radiation before infection, since it is known that irradiation increases the secretion of TNF. We demonstrate that in all cases the increase in the level of TNF-alpha in animals leads to the activation of the Salmonella growth. Moreover, in this paper we present the data obtained by the method of molecular display on the identification of genes that are highly expressed in the Salmonella cells cultivated in vitro in the presence of TNF.