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Zinc and vitamin C intake increases spike and neutralising antibody production following SARS-CoV-2 infection.
Quek, AML, Ooi, DSQ, Teng, O, Chan, CY, Ng, GJL, Ng, MY, Yee, S, Cheong, EW, Weng, R, Cook, AR, et al
Clinical and translational medicine. 2022;(2):e731
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Remdesivir plus standard of care versus standard of care alone for the treatment of patients admitted to hospital with COVID-19 (DisCoVeRy): a phase 3, randomised, controlled, open-label trial.
Ader, F, Bouscambert-Duchamp, M, Hites, M, Peiffer-Smadja, N, Poissy, J, Belhadi, D, Diallo, A, Lê, MP, Peytavin, G, Staub, T, et al
The Lancet. Infectious diseases. 2022;(2):209-221
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Abstract
BACKGROUND The antiviral efficacy of remdesivir against SARS-CoV-2 is still controversial. We aimed to evaluate the clinical efficacy of remdesivir plus standard of care compared with standard of care alone in patients admitted to hospital with COVID-19, with indication of oxygen or ventilator support. METHODS DisCoVeRy was a phase 3, open-label, adaptive, multicentre, randomised, controlled trial conducted in 48 sites in Europe (France, Belgium, Austria, Portugal, Luxembourg). Adult patients (aged ≥18 years) admitted to hospital with laboratory-confirmed SARS-CoV-2 infection and illness of any duration were eligible if they had clinical evidence of hypoxaemic pneumonia, or required oxygen supplementation. Exclusion criteria included elevated liver enzymes, severe chronic kidney disease, any contraindication to one of the studied treatments or their use in the 29 days before random assignment, or use of ribavirin, as well as pregnancy or breastfeeding. Participants were randomly assigned (1:1:1:1:1) to receive standard of care alone or in combination with remdesivir, lopinavir-ritonavir, lopinavir-ritonavir and interferon beta-1a, or hydroxychloroquine. Randomisation used computer-generated blocks of various sizes; it was stratified on severity of disease at inclusion and on European administrative region. Remdesivir was administered as 200 mg intravenous infusion on day 1, followed by once daily, 1-h infusions of 100 mg up to 9 days, for a total duration of 10 days. It could be stopped after 5 days if the participant was discharged. The primary outcome was the clinical status at day 15 measured by the WHO seven-point ordinal scale, assessed in the intention-to-treat population. Safety was assessed in the modified intention-to-treat population and was one of the secondary outcomes. This trial is registered with the European Clinical Trials Database, EudraCT2020-000936-23, and ClinicalTrials.gov, NCT04315948. FINDINGS Between March 22, 2020, and Jan 21, 2021, 857 participants were enrolled and randomly assigned to remdesivir plus standard of care (n=429) or standard of care only (n=428). 15 participants were excluded from analysis in the remdesivir group, and ten in the control group. At day 15, the distribution of the WHO ordinal scale was: (1) not hospitalised, no limitations on activities (61 [15%] of 414 in the remdesivir group vs 73 [17%] of 418 in the control group); (2) not hospitalised, limitation on activities (129 [31%] vs 132 [32%]); (3) hospitalised, not requiring supplemental oxygen (50 [12%] vs 29 [7%]); (4) hospitalised, requiring supplemental oxygen (76 [18%] vs 67 [16%]); (5) hospitalised, on non-invasive ventilation or high flow oxygen devices (15 [4%] vs 14 [3%]); (6) hospitalised, on invasive mechanical ventilation or extracorporeal membrane oxygenation (62 [15%] vs 79 [19%]); (7) death (21 [5%] vs 24 [6%]). The difference between treatment groups was not significant (odds ratio 0·98 [95% CI 0·77-1·25]; p=0·85). There was no significant difference in the occurrence of serious adverse events between treatment groups (remdesivir, 135 [33%] of 406 vs control, 130 [31%] of 418; p=0·48). Three deaths (acute respiratory distress syndrome, bacterial infection, and hepatorenal syndrome) were considered related to remdesivir by the investigators, but only one by the sponsor's safety team (hepatorenal syndrome). INTERPRETATION No clinical benefit was observed from the use of remdesivir in patients who were admitted to hospital for COVID-19, were symptomatic for more than 7 days, and required oxygen support. FUNDING European Union Commission, French Ministry of Health, Domaine d'intérêt majeur One Health Île-de-France, REACTing, Fonds Erasme-COVID-Université Libre de Bruxelles, Belgian Health Care Knowledge Centre, Austrian Group Medical Tumor, European Regional Development Fund, Portugal Ministry of Health, Portugal Agency for Clinical Research and Biomedical Innovation. TRANSLATION For the French translation of the abstract see Supplementary Materials section.
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INEXAS: A Phase 2 Randomized Trial of On-demand Inhaled Interferon Beta-1a in Severe Asthmatics.
McCrae, C, Olsson, M, Gustafson, P, Malmgren, A, Aurell, M, Fagerås, M, Da Silva, CA, Cavallin, A, Paraskos, J, Karlsson, K, et al
Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology. 2021;(2):273-283
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Abstract
BACKGROUND Upper respiratory tract infections (URTIs) are important triggers for asthma exacerbations. We hypothesized that inhalation of the anti-viral cytokine, interferon (IFN)-β, during URTI, could prevent these exacerbations. OBJECTIVE To evaluate the efficacy of on-demand inhaled IFN-β1a (AZD9412) to prevent severe asthma exacerbations following symptomatic URTI. METHODS This was a randomized, double-blind, placebo-controlled trial in which patients with severe asthma (GINA 4-5; n = 121) reporting URTI symptoms were randomized to 14 days of once-daily nebulized AZD9412 or placebo. The primary endpoint was severe exacerbations during treatment. Secondary endpoints included 6-item asthma control questionnaire (ACQ-6) and lung function. Exploratory biomarkers included IFN-response markers in serum and sputum, blood leucocyte counts and serum inflammatory cytokines. RESULTS Following a pre-planned interim analysis, the trial was terminated early due to an unexpectedly low exacerbation rate. Asthma worsenings were generally mild and tended to peak at randomization, possibly contributing to the lack of benefit of AZD9412 on other asthma endpoints. Numerically, AZD9412 did not reduce severe exacerbation rate, ACQ-6, asthma symptom scores or reliever medication use. AZD9412 improved lung function (morning peak expiratory flow; mPEF) by 19.7 L/min. Exploratory post hoc analyses indicated a greater mPEF improvement by AZD9412 in patients with high blood eosinophils (>0.3 × 109 /L) at screening and low serum interleukin-18 relative change at pre-treatment baseline. Pharmacodynamic effect of AZD9412 was confirmed using IFN-response markers. CONCLUSIONS & CLINICAL RELEVANCE Colds did not have the impact on asthma patients that was expected and, due to the low exacerbation rate, the trial was stopped early. On-demand AZD9412 treatment did not numerically reduce the number of exacerbations, but did attenuate URTI-induced worsening of mPEF. Severe asthma patients with high blood eosinophils or low serum interleukin-18 response are potential subgroups for further investigation of inhaled IFN-β1a.
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Short-term and long-term safety and efficacy of tenofovir alafenamide, tenofovir disoproxil fumarate and entecavir treatment of acute-on-chronic liver failure associated with hepatitis B.
Li, J, Hu, C, Chen, Y, Zhang, R, Fu, S, Zhou, M, Gao, Z, Fu, M, Yan, T, Yang, Y, et al
BMC infectious diseases. 2021;(1):567
Abstract
BACKGROUND & AIMS There is limited evidence on the efficacy and safety of nucleos(t) ide analogues (NAs) in the treatment of HBV-ACLF. Our objective was to evaluate the outcomes among TAF, TDF and ETV, three first-line antivirals against chronic hepatitis B, in patients with HBV-ACLF. METHODS Patients with HBV-related ACLF were recruited and received daily TAF (25 mg/d), TDF (300 mg/d) and ETV (0.5 mg/d). They were prospectively followed-up. The primary endpoint was overall survival at week 12 and week 48, the secondary endpoints were virological response and biochemical response. RESULTS Forty gender and age matched eligible subjects were recruited and divided into three groups: TAF group, TDF group and ETV group. By week 48, 8 (80%) patients in TAF group, 6 (60%) patients in TDF group and 17 (85%) patients in ETV group survived without liver transplantation (P = 0.251). After 4 weeks of NAs treatment, all three groups showed paralleling reduction of HBV DNA levels. All three groups presented similar biochemical responses at week 4, patients treated with TAF showed a priority in total bilirubin reduction, albumin and cholesterol maintenance. Additionally, although there was no significant difference in changes of serum urea, serum creatinine, serum cystatin C and estimated GFR among the three groups by treatment week 4, TDF showed unfavorable renal safety even in short -term treatment. The treatment using NAs was well-tolerated and there was no serious drug-related adverse event reported. CONCLUSIONS TAF, TDF and ETV are of similar efficacy and safety in short-term and long-term treatment of HBV-ACLF. TRIAL REGISTRATION This study is ongoing and is registered with ClinicalTrials.gov , NCT03640728 (05/02/2019).
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How Semiphysiological Population Pharmacokinetic Modeling Incorporating Active Hepatic Uptake Supports Phase II Dose Selection of RO7049389, A Novel Anti-Hepatitis B Virus Drug.
Cosson, V, Feng, S, Jaminion, F, Lemenuel-Diot, A, Parrott, N, Paehler, A, Bo, Q, Jin, Y
Clinical pharmacology and therapeutics. 2021;(4):1081-1091
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Abstract
The pharmacokinetics (PK) of RO7049389, a new hepatitis B virus (HBV) core protein allosteric modulator of class I, and of its active metabolite M5 were studied in fasted and fed conditions after single and multiple once-a-day and twice-a-day doses in healthy subjects and patients with HBV. The nonlinearity of the pharmacokinetics, the large variability, the small sample size per dose arms, the higher plasma exposure in Asians, and the heterogeneity in patient baseline characteristics seen in phase I studies made the ethnic sensitivity assessment and the selection of the recommended phase II dose difficult. A population PK model, simultaneously modeling RO7049389 and M5, was developed to characterize the complex PK, quantify ethnicity (i.e., Asian vs. non-Asian) and gender effects on the PK of RO7049389 and M5, and infer the quantity of RO7049389 in liver relative to plasma. Exposures in the liver are of particular importance for dose selection since the liver is the site of action of the compound. The model described and reproduced the population PK profiles as well as the between-subject variability of RO7049389 and its metabolite. It could show that the PK is similar between healthy subjects and in HBV patients, once the ethnicity and gender effects are accounted for. The model predicts that, despite a large difference in the plasma exposure of RO7049389 between Asians and non-Asians, the exposure in the liver is comparable, allowing the use of the same dose to treat Asian and non-Asian patients. This model provides a valuable basis to develop this new anti-HBV drug and to define optimal dosing.
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Efficacy of interferon beta-1a plus remdesivir compared with remdesivir alone in hospitalised adults with COVID-19: a double-bind, randomised, placebo-controlled, phase 3 trial.
Kalil, AC, Mehta, AK, Patterson, TF, Erdmann, N, Gomez, CA, Jain, MK, Wolfe, CR, Ruiz-Palacios, GM, Kline, S, Regalado Pineda, J, et al
The Lancet. Respiratory medicine. 2021;(12):1365-1376
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BACKGROUND Functional impairment of interferon, a natural antiviral component of the immune system, is associated with the pathogenesis and severity of COVID-19. We aimed to compare the efficacy of interferon beta-1a in combination with remdesivir compared with remdesivir alone in hospitalised patients with COVID-19. METHODS We did a double-blind, randomised, placebo-controlled trial at 63 hospitals across five countries (Japan, Mexico, Singapore, South Korea, and the USA). Eligible patients were hospitalised adults (aged ≥18 years) with SARS-CoV-2 infection, as confirmed by a positive RT-PCR test, and who met one of the following criteria suggestive of lower respiratory tract infection: the presence of radiographic infiltrates on imaging, a peripheral oxygen saturation on room air of 94% or less, or requiring supplemental oxygen. Patients were excluded if they had either an alanine aminotransferase or an aspartate aminotransferase concentration more than five times the upper limit of normal; had impaired renal function; were allergic to the study product; were pregnant or breast feeding; were already on mechanical ventilation; or were anticipating discharge from the hospital or transfer to another hospital within 72 h of enrolment. Patients were randomly assigned (1:1) to receive intravenous remdesivir as a 200 mg loading dose on day 1 followed by a 100 mg maintenance dose administered daily for up to 9 days and up to four doses of either 44 μg interferon beta-1a (interferon beta-1a group plus remdesivir group) or placebo (placebo plus remdesivir group) administered subcutaneously every other day. Randomisation was stratified by study site and disease severity at enrolment. Patients, investigators, and site staff were masked to interferon beta-1a and placebo treatment; remdesivir treatment was given to all patients without masking. The primary outcome was time to recovery, defined as the first day that a patient attained a category 1, 2, or 3 score on the eight-category ordinal scale within 28 days, assessed in the modified intention-to-treat population, defined as all randomised patients who were classified according to actual clinical severity. Safety was assessed in the as-treated population, defined as all patients who received at least one dose of the assigned treatment. This trial is registered with ClinicalTrials.gov, NCT04492475. FINDINGS Between Aug 5, 2020, and Nov 11, 2020, 969 patients were enrolled and randomly assigned to the interferon beta-1a plus remdesivir group (n=487) or to the placebo plus remdesivir group (n=482). The mean duration of symptoms before enrolment was 8·7 days (SD 4·4) in the interferon beta-1a plus remdesivir group and 8·5 days (SD 4·3) days in the placebo plus remdesivir group. Patients in both groups had a time to recovery of 5 days (95% CI not estimable) (rate ratio of interferon beta-1a plus remdesivir group vs placebo plus remdesivir 0·99 [95% CI 0·87-1·13]; p=0·88). The Kaplan-Meier estimate of mortality at 28 days was 5% (95% CI 3-7%) in the interferon beta-1a plus remdesivir group and 3% (2-6%) in the placebo plus remdesivir group (hazard ratio 1·33 [95% CI 0·69-2·55]; p=0·39). Patients who did not require high-flow oxygen at baseline were more likely to have at least one related adverse event in the interferon beta-1a plus remdesivir group (33 [7%] of 442 patients) than in the placebo plus remdesivir group (15 [3%] of 435). In patients who required high-flow oxygen at baseline, 24 (69%) of 35 had an adverse event and 21 (60%) had a serious adverse event in the interferon beta-1a plus remdesivir group compared with 13 (39%) of 33 who had an adverse event and eight (24%) who had a serious adverse event in the placebo plus remdesivir group. INTERPRETATION Interferon beta-1a plus remdesivir was not superior to remdesivir alone in hospitalised patients with COVID-19 pneumonia. Patients who required high-flow oxygen at baseline had worse outcomes after treatment with interferon beta-1a compared with those given placebo. FUNDING The National Institute of Allergy and Infectious Diseases (USA).
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The effects of β1 and β1+2 adrenergic receptor blockade on the exercise-induced mobilization and ex vivo expansion of virus-specific T cells: implications for cellular therapy and the anti-viral immune effects of exercise.
Kunz, HE, Agha, NH, Hussain, M, LaVoy, EC, Smith, KA, Mylabathula, P, Diak, D, Baker, FL, O'Connor, DP, Bond, RA, et al
Cell stress & chaperones. 2020;(6):993-1012
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Abstract
The adoptive transfer of donor-derived virus-specific T cells (VSTs) is an effective treatment for infections following allogeneic hematopoietic cell transplantation. Acute exercise mobilizes effector lymphocytes and VSTs to the circulation and augments the ex vivo manufacture of VSTs. This study determined if β2 adrenergic receptor (AR) signaling precipitated the VST response to acute exercise. Healthy participants (n = 12) completed 30 min of steady-state cycling exercise after ingesting a placebo, a β1 + 2 AR antagonist (nadolol) or a β1 AR antagonist (bisoprolol). Circulating VSTs to cytomegalovirus (CMV), Epstein-Barr virus (EBV), and adenovirus (AdV) antigens were enumerated before and after exercise, and peripheral blood mononuclear cells were cultured with viral peptides for 8 days to expand multi-VSTs. Compared with placebo, nadolol blunted the exercise-induced mobilization of CMV-VSTs (Δ VSTs/100,000 CD3+ T cells = 93 ± 104 vs. 22 ± 91 for placebo and nadolol, respectively; p = 0.036), while bisoprolol did not, despite both drugs evoking similar reductions in exercising heart rate and blood pressure. Circulating AdV and EBV VSTs (VSTs/mL blood) only increased after exercise with placebo. Although not significant, nadolol partially mitigated exercise-induced increases in multi-VST expansion, particularly in participants that demonstrated an exercise-induced increase in VST expansion. We conclude that exercise-induced enhancements in VST mobilization and expansion are at least partially β2 AR mediated, thus highlighting a role for the β2 AR in targeted therapy for the augmentation of VST immune cell therapeutics in the allogeneic adoptive transfer setting. Moreover, long-term regular exercise may provide additional viral protection in the host through frequent β2 AR-dependent mobilization and redistribution of VSTs cumulated with each bout of exercise.
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Treatment and re-treatment results of HCV patients in the DAA era.
Piecha, F, Gänßler, JM, Ozga, AK, Wehmeyer, MH, Dietz, J, Kluwe, J, Laschtowitz, A, von Felden, J, Sterneck, M, Jordan, S, et al
PloS one. 2020;(5):e0232773
Abstract
BACKGROUND Re-treatment in patients with a chronic hepatitis C virus (HCV) infection and a previous failure to direct-acting antiviral (DAA) treatment remains a challenge. Therefore, we investigated the success rate of treatment and re-treatment regimens used at our center from October 2011 to March 2018. METHODS A retrospective analysis of DAA-based HCV therapies of 1096 patients was conducted. Factors associated with a virological relapse were identified by univariable and multivariable logistic regression, treatment success of the re-treatment regimens was evaluated by an analysis of sustained virological response (SVR) rates in patients with a documented follow-up 12 weeks after the end of treatment. RESULTS Of 1096 patients treated with DAA-based regimens, 91 patients (8%) were lost to follow-up, 892 of the remaining 1005 patients (89%) achieved an SVR12. Most patients (65/113, 58%) who experienced a virological relapse received an interferon-based DAA regimen. SVR rates were comparable in special cohorts like liver transplant recipients (53/61, 87%) and people with a human immunodeficiency virus (HIV) coinfection (41/45, 91%). On multivariable analysis, interferon-based DAA therapy was associated with treatment failure (odds ratio 0.111, 95%-confidence interval 0.054-0.218) among others. One hundred seventeen patients with multiple DAA treatment courses were identified, of which 97 patients (83%) experienced a single relapse, but further relapses after two (18/117, 15%) or even three (2/117, 2%) treatment courses were also observed. Eighty-two of 96 (85%) re-treatment attempts with all-oral DAA regimens were successful after an initial treatment failure. CONCLUSION Overall, DAA re-treatments were highly effective in this real-world cohort and only a minority of patients failed more than two treatment courses. Switching to-or addition of-a new drug class seem to be valid options for the re-treatment of patients especially after failure of an interferon-based regimen.
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A platform in the use of medicines to treat chronic hepatitis C (PLATINUM C): protocol for a prospective treatment registry of real-world outcomes for hepatitis C.
Ramsay, J, Marsh, J, Pedrana, A, Andric, N, Norman, R, Cheng, W, Webb, S, Zeps, N, Bellgard, M, Graves, T, et al
BMC infectious diseases. 2020;(1):802
Abstract
BACKGROUND Safe, highly curative, short course, direct acting antiviral (DAA) therapies are now available to treat chronic hepatitis C. DAA therapy is freely available to all adults chronically infected with the hepatitis C virus (HCV) in Australia. If left untreated, hepatitis C may lead to progressive hepatic fibrosis, cirrhosis and hepatocellular carcinoma. Australia is committed to eliminating hepatitis as a public health threat by 2030 set by the World Health Organization. However, since the introduction of funded DAA treatment, uptake has been suboptimal. Australia needs improved strategies for testing, treatment uptake and treatment completion to address the persisting hepatitis C public health problem. PLATINUM C is a HCV treatment registry and research platform for assessing the comparative effectiveness of alternative interventions for achieving virological cure. METHODS PLATINUM C will prospectively enrol people with active HCV infection confirmed by recent detection of HCV ribonucleic acid (RNA) in blood. Those enrolled will agree to allow standardised collection of demographic, lifestyle, treatment, virological outcome and other relevant clinical data to better inform the future management of HCV infection. The primary outcome is virological cure evidenced by sustained virological response (SVR), which is defined as a negative HCV PCR result 6 to 18 months after initial prescription of DAA therapy and no less than 12 weeks after the completion of treatment. Study participants will be invited to opt-in to medication adherence monitoring and quality of life assessments using validated self-reported instruments (EQ-5D-5L). DISCUSSION PLATINUM C is a treatment registry and platform for nesting pragmatic trials. Data collected will inform the design, development and implementation of pragmatic trials. The digital infrastructure, study procedures and governing systems established by the registry will allow PLATINUM C to support a wider research platform in the management of hepatitis C in primary care. TRIAL REGISTRATION The trial is registered with the Australia and New Zealand Clinical Trials Register ( ACTRN12619000023156 ). Date of registration: 10/01/2019.
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The effect of twelve weeks of treatment with ezetimibe on HDV RNA level in patients with chronic hepatitis D.
Abbas, Z, Saad, M, Asim, M, Abbas, M, Samejo, SA
The Turkish journal of gastroenterology : the official journal of Turkish Society of Gastroenterology. 2020;(2):136-141
Abstract
BACKGROUND/AIMS: Sodium taurocholate co-transporting polypeptide (NTCP) is the receptor for the hepatitis B virus (HBV) and hepatitis D virus (HDV) entry into hepatocytes. Ezetimibe is a cholesterol-lowering drug that possesses the pharmacophore features to inhibit NTCP. This study evaluates the efficacy of ezetimibe in patients with chronic HDV infection in a nonrandomized trial. MATERIALS AND METHODS This proof of concept phase 2 trial evaluated the efficacy and safety of ezetimibe 10 mg daily in (interferon treatment-experienced or interferon ineligible) patients with chronic hepatitis D (CHD). Forty-four patients with CHD were recruited, 38 male and 6 female patients, mean age 35.2±8.7 (range 19-64). Fifteen (34%) patients were on concomitant nucleoside therapy, and cirrhosis was present in 14 subjects. The primary therapeutic endpoint was a decline in HDV RNA at one log or more from the baseline at week 12. RESULTS The mean HDV RNA level was 5.4±1.3 log10 IU/mL. HBeAg was non-reactive in 43 (98%). HBV DNA was undetectable in 28 (64%). One patient stopped treatment at week 4, and one patient did not follow-up. One log or more reduction in the HDV RNA levels was observed in 18/44 (41%) patients. No log reduction occurred in 16 patients, and 8 experienced a log increase. No adverse effects from the concomitant nucleoside analogue use or clinical cirrhosis were observed. The drug exhibited a positive safety profile. CONCLUSION Treatment of CHD patients with ezetimibe resulted in a one log reduction of viral load in 43% (18/42) of the patients who completed the 12 weeks of therapy.