Are displaced distal clavicle fractures associated with inferior clinical outcomes following nonoperative management? A systematic review.

BACKGROUND: Management of displaced distal clavicle fractures remains a topic of discussion because of notoriously high nonunion rates, but there is little documented in the literature as to what effect this may have on patient-reported function. The aim of this systematic review was to look at nonoperative management following displaced distal clavicle fractures to determine union rates, complications, and patient-reported outcome measures. METHODS: A review of the online databases MEDLINE and Embase was conducted according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. Clinical studies that included a cohort of nonoperatively managed displaced distal clavicle fractures and reported on union rate, complications, and patient-reported functional scores were included. RESULTS: Eleven studies were eligible for inclusion (2 randomized controlled trials, 1 prospective noncomparative cohort study, 5 retrospective comparative cohort studies, and 3 case series) with a total of 779 patients included in this review. Average union rate was 63.2% (22.2%-94.4%) in nonoperatively managed patients, compared with 96.3% (87.9%-100%) in operatively managed patients. The Constant-Murley score and Disabilities of the Arm, Shoulder, and Hand questionnaire were the most frequently used outcome measure tools. No study demonstrated any significant difference in any outcome measure when comparing nonoperative with operative treatment. Complication rate (including nonunion) in nonoperatively managed patients was 45.1%, with 11.1% requiring delayed surgery. Average complication rate in the operatively managed groups was 41.2%, with 40.1% requiring a second operation. CONCLUSION: Nonoperative management of displaced distal clavicle fractures results in higher nonunion rates, but shoulder function remains excellent, and risk of complications and delayed surgery are low. Decision making must take into account patient factors and expectations to provide high-quality, individualized care.

Report of the Assay Guidance Workshop on 3-Dimensional Tissue Models for Antiviral Drug Development.

The National Center for Advancing Translational Sciences (NCATS) Assay Guidance Manual (AGM) Workshop on 3D Tissue Models for Antiviral Drug Development, held virtually on 7-8 June 2022, provided comprehensive coverage of critical concepts intended to help scientists establish robust, reproducible, and scalable 3D tissue models to study viruses with pandemic potential. This workshop was organized by NCATS, the National Institute of Allergy and Infectious Diseases, and the Bill and Melinda Gates Foundation. During the workshop, scientific experts from academia, industry, and government provided an overview of 3D tissue models' utility and limitations, use of existing 3D tissue models for antiviral drug development, practical advice, best practices, and case studies about the application of available 3D tissue models to infectious disease modeling. This report includes a summary of each workshop session as well as a discussion of perspectives and challenges related to the use of 3D tissues in antiviral drug discovery.

Deformation Rate-Adaptive Conducting Polymers and Composites.

Materials are more easily damaged during accidents that involve rapid deformation. Here, a design strategy is described for electronic materials comprised of conducting polymers that defies this orthodox property, making their extensibility and toughness dynamically adaptive to deformation rates. This counterintuitive property is achieved through a morphology of interconnected nanoscopic core-shell micelles, where the chemical interactions are stronger within the shells than the cores. As a result, the interlinked shells retain material integrity under strain, while the rate of dissociation of the cores controls the extent of micelle elongation, which is a process that adapts to deformation rates. A prototype based on polyaniline shows a 7.5-fold increase in ultimate elongation and a 163-fold increase in toughness when deformed at increasing rates from 2.5 to 10 000% min-1 . This concept can be generalized to other conducting polymers and highly conductive composites to create "self-protective" soft electronic materials with enhanced durability under dynamic movement or deformation.

Lanthanide Contraction: What is Normal?

Renewed interest in lanthanide contraction results from its possible effect on the properties and applications of Ln(III) compounds and the theory related to these issues. To understand this effect, it is important to know what is a normal dependence of the contraction on the number of 4f electrons, n. The normal trend is based on recent values of ionic radii that have a linear dependence on n for coordination numbers (CNs) of 6, 8, and 9. If the normal trend is not followed, then some other interactions in the system are affecting the extent of contraction. However, the suggestion that the variation is curved and fitted by a quadratic function has become popular in recent years. This report examines the Ln(III)-to-ligand atom distances for coordination compounds with CNs of 6-9 and the nitrides and phosphides. Least-squares fits to the linear and quadratic models are applied to all of the bond distances to determine when a quadratic model is justified. The result is that complex systems show a mixture of linear and quadratic dependencies when individual bond distances are considered and that the linear model is most common and representative of the true lanthanide contraction.

Prophylactic and therapeutic remdesivir (GS-5734) treatment in the rhesus macaque model of MERS-CoV infection.

The continued emergence of Middle East Respiratory Syndrome (MERS) cases with a high case fatality rate stresses the need for the availability of effective antiviral treatments. Remdesivir (GS-5734) effectively inhibited MERS coronavirus (MERS-CoV) replication in vitro, and showed efficacy against Severe Acute Respiratory Syndrome (SARS)-CoV in a mouse model. Here, we tested the efficacy of prophylactic and therapeutic remdesivir treatment in a nonhuman primate model of MERS-CoV infection, the rhesus macaque. Prophylactic remdesivir treatment initiated 24 h prior to inoculation completely prevented MERS-CoV-induced clinical disease, strongly inhibited MERS-CoV replication in respiratory tissues, and prevented the formation of lung lesions. Therapeutic remdesivir treatment initiated 12 h postinoculation also provided a clear clinical benefit, with a reduction in clinical signs, reduced virus replication in the lungs, and decreased presence and severity of lung lesions. The data presented here support testing of the efficacy of remdesivir treatment in the context of a MERS clinical trial. It may also be considered for a wider range of coronaviruses, including the currently emerging novel coronavirus 2019-nCoV.

Remdesivir targets a structurally analogous region of the Ebola virus and SARS-CoV-2 polymerases.

Remdesivir is a broad-spectrum antiviral nucleotide prodrug that has been clinically evaluated in Ebola virus patients and recently received emergency use authorization (EUA) for treatment of COVID-19. With approvals from the Federal Select Agent Program and the Centers for Disease Control and Prevention's Institutional Biosecurity Board, we characterized the resistance profile of remdesivir by serially passaging Ebola virus under remdesivir selection; we generated lineages with low-level reduced susceptibility to remdesivir after 35 passages. We found that a single amino acid substitution, F548S, in the Ebola virus polymerase conferred low-level reduced susceptibility to remdesivir. The F548 residue is highly conserved in filoviruses but should be subject to specific surveillance among novel filoviruses, in newly emerging variants in ongoing outbreaks, and also in Ebola virus patients undergoing remdesivir therapy. Homology modeling suggests that the Ebola virus polymerase F548 residue lies in the F-motif of the polymerase active site, a region that was previously identified as susceptible to resistance mutations in coronaviruses. Our data suggest that molecular surveillance of this region of the polymerase in remdesivir-treated COVID-19 patients is also warranted.

Suture Button Fixation in Latarjet Has Similar Load to Failure and Clinical Outcomes but Lower Bone Resorption Compared With Screw Fixation: A Systematic Review.

PURPOSE: To compare the 2 Latarjet fixation techniques-screw fixation (SF) versus suture button (SB) -for clinical, biomechanical, and radiologic outcomes. METHODS: A systematic review was conducted in accordance with Preferred Reporting Items for Systematic and Meta-Analyses guidelines using MEDLINE and Embase databases and was prospectively registered on PROSPERO. Only comparative clinical and biomechanical studies of Latarjet with SF and SB were included. Studies were appraised using the Methodical Index for Non-Randomised Studies (MINORS) tool. RESULTS: Eleven studies met eligible criteria: 7 clinical studies (SB, n = 279; SF, n = 845) and 4 biomechanical. In total, 80.9% (SB) and 84.2% (SF) of patients were male. Follow-up ranged from 6 to 63.6 months. The overall recurrent instability rate for SB ranged from 0 to 8.3% and for SF ranged from 0 to 2.75%. Only one study demonstrated a greater recurrent instability rate with SB (P = .02). Overall SB complication rates ranged from 0 to 12.5% and SF ranged from 0 to 27%. Two studies reported greater complications and reoperations with SF related to hardware. Summary forest plots from 4 studies showed no significant difference in Walch Duplay score (mean difference, range -5.00 to 1.20 [95% confidence interval {CI} -12.13 to 8.56], I2 inconsistency = 0%), Rowe score (mean difference, range -2.00 to 4.00 [95% CI -7.37 to 7.66], I2 inconsistency = 45%), and VAS for pain (mean difference, range -0.10 to 0.60 [95% CI -0.72 to 1.33], I2 inconsistency = 0%). There was no statistically significant difference between SB and SF in the postoperative range of motion. Radiologically, there was no significant difference in graft positioning and union at final follow-up, but graft resorption was greater in SF (range 25.2%-47.6%) compared with SB (range 10.1%-18.5%). Biomechanical studies showed no significant difference in maximum load to failure (SB, range 184-266 N vs SF, range 148-288 N). CONCLUSIONS: Clinically, SB fixation demonstrated similar functional outcome and range of motion when compared with SF, with the potential benefit of lower rates of graft resorption and hardware-related complications. Biomechanically there was no difference in maximum load to failure. LEVEL OF EVIDENCE: Level III, cohort studies (all clinical studies were Level III cohort studies).

Preoperative topical benzoyl peroxide treatment is effective in reducing Cutibacterium acnes in shoulder surgery: a systematic review.

BACKGROUND: Cutibacterium acnes (C acnes) colonization can have a significant impact on patients undergoing both arthroscopic and open shoulder surgery with regard to postoperative infection. Its resistance to standard preoperative skin preparations and prophylactic antibiotics has led to a need for a more targeted therapy. Topical benzoyl peroxide (BPO) has been used by dermatologists in the treatment for acnes due to its bactericidal and penetrative effects through the dermal layer. The aim of this systematic review is to review the effectiveness of topical BPO preoperatively in shoulder surgery in reducing C acnes colonization and postoperative infection. METHODS: A review of the online databases Medline and Embase was conducted on December 15, 2021, according to Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. The review was registered prospectively in the PROSPERO database. Clinical studies reporting superficial and deep sample microbiology and postoperative complications were included. The studies were appraised using the revised Cochrane Risk of Bias 2 (ROB 2) tool for randomized studies and the Methodological Index for Non-Randomized Studies (MINORS) tool. RESULTS: The search strategy identified 10 studies for inclusion (6 randomized control trials, 2 prospective cohort studies, and 2 case series), including a total of 482 patients. Seven studies were comparable, testing BPO against alternative standard skin preparations. Of the 10 studies, 7 showed a decrease in the load of C acnes on the skin and/or deep tissues, of which 6 demonstrated statistical significance. Men were shown to have a statistically significant increase in the colonization rate of C acnes. Scheer et al (2021) demonstrated 4500 colony-forming units/mL in males and 900 colony-forming units/mL in females. In studies where the number of BPO applications was higher, BPO appeared more effective. Dizay et al demonstrated C acnes elimination in 78.9% with more than 1 application compared with 66.7% if only applied once. Three studies looked at the effectiveness of BPO during the operative timeline with 1 demonstrating its statistically significant effectiveness at reducing colonization 2 hours into the operation (P = .048). CONCLUSION: BPO is effective as a topical treatment at reducing C acnes colonization before shoulder surgery. However, the relationship between duration of treatment, frequency of application, and gender requires further research.

A systematic review and meta-analysis comparing the use of hook plates and superior plates in the treatment of displaced distal clavicle fractures.

INTRODUCTION: Non-operative treatment of displaced distal clavicle fractures results in high non-union and yet there is no consensus on superior treatment modality. While there are a number of different techniques available for fixation, hook plate (HP) has been used most commonly. A number of modern techniques, including superior plate (SP), have shown less complications but equivocal union rate and shoulder function. The aim of this systematic review and meta-analysis is to compare the outcome of HP fixation with superior plate in surgical fixation of displaced distal clavicle fractures. PATIENTS AND METHODS: A review of the online databases MEDLINE and Embase was conducted on 15 January 2021 according to PRISMA guidelines. The review was registered prospectively in the PROSPERO database. Clinical studies reporting union rate, complications and shoulder function were included. The studies were appraised using the Methodological Index for Non-Randomized Studies (MINORS) tool. RESULTS: The search strategy identified 42 studies eligible for inclusion with a total of 1,261 patients. These included 17 hook-plate case series (n = 573), 18 superior plate case series, of which 6 used SP alone (n = 223) and 12 SP and simultaneous CCLR case series (n = 189), and 7 studies comparing HP and SP (n = 276). The overall complication rate was significantly higher with HP when compared to SP [(32.7% vs 12.7%; OR 6.31 (95% CI: 2.67-14.91)]. The overall union rates in the case series appeared comparable in the current SR; HP 96.4%, SP 96.9% and SP with simultaneous CCLR 97.9%. Shoulder function was most commonly assessed using CM score and the mean ranged from 83.8 to 97.2 in HP, 89 to 98 in SP group and 90.6 to 97.6 in SP with CCLR. Meta-analysis of CM score failed to show a significant difference for HP versus SP (pooled weighted mean difference was 2.67 (95% CI: - 0.09 to 5.43) with a trend to favour SP fixation. CONCLUSION: The current review has demonstrated that HP, SP alone or with CCLR all offer excellent union rate and appear to provide comparative functional outcomes. However, HP is associated with significantly higher complication rates.

Open coraco-clavicular ligament reconstruction (CCLR) in treatment of displaced distal clavicle fractures has low complication rate and excellent union rate: a systematic review.

BACKGROUND: It is well established that non-operative treatment of displaced distal clavicle fractures (DDCF) leads to a high non-union rate. A number of open surgical treatments in the past have shown good to excellent outcomes including shoulder function and union rate. Despite this there is no consensus on the outcome of open coraco-clavicular ligament reconstruction (CCLR). The aim of this systematic review was to assess the union rate, complications and shoulder function of open CCLR techniques in the treatment of DDCF. PATIENTS AND METHODS: A review of the online databases MEDLINE and Embase was conducted on 1 January 2021 according to PRISMA guidelines. The review was registered prospectively in the PROSPERO database. Clinical studies reporting union rate, complications and shoulder function were included. The studies were appraised using the Methodological Index for Non-Randomized Studies (MINORS) tool. RESULTS: The search strategy identified 18 studies eligible for inclusion with a total of 330 patients. These included 12 retrospective case series and 5 nonrandomized retrospective comparative studies and one RCT. All but one study reported on shoulder function, while all the studies reported on union rate and complications. The overall shoulder function was good to excellent using Constant-Murley score. The overall union rate was 97.6% and complication rate was 7.6%. CONCLUSION: Open CCLR for displaced distal clavicle fractures that have a disruption of CC ligament, is a reliable treatment with excellent union rate and good to excellent shoulder functional scores. LEVEL OF EVIDENCE: IV; Systematic review.

The use of intramedullary devices for adult radial head and neck fractures. A systematic review.

The management of isolated radial neck and head fractures is controversial. Plate fixation and tripod fixation are two commonly employed techniques but risk damage to soft tissues and implant-related complications. Intramedullary fixation is commonly used in pediatric cases and reduces the potential drawbacks of open fixation. This systematic review aimed to analyze outcomes of intramedullary fixation in adults in terms of function, union, and complication rates. A systematic review of the literature was conducted following the PRISMA guidelines using Medline and EMBASE's online databases. The review was registered on the PROSPERO database. Studies were appraised using the Methodological Index for non-randomized studies (MINORS) tool. Seven studies were deemed eligible for inclusion (n=55). Mean ages of patients ranged from 31.3 to 44.2 years, and mean follow-up ranged from 9 to 86 months. The Mayo Elbow Performance score (MEPs) was reported in five case series (mean scores 81.8 -97.9) and the prevalence of excellent results ranged from 71% and 83%. Although 100% of fractures united, the pooled complication rate was 24% (range 0-50%). The most common complications were elbow stiffness (7%), superficial radial nerve neuropraxia (7%), malunion (5%), and AVN (1.8%). No study reported any patients requiring revision surgery. Intramedullary fixation for radial head and neck fractures appears to provide a reliable alternative treatment option in terms of union, range of motion, and functional outcomes. Further robust trials direct comparing against open fixation techniques are required.

Effect of bremelanotide on body weight of obese women: Data from two phase 1 randomized controlled trials.

AIMS: The melanocortin 4 receptor (MC4R) plays a central role in appetite regulation, and agonistic activity at this receptor promotes satiety. Results from two randomized controlled clinical trials examine the effects of bremelanotide's agonism at MC4R on caloric intake and body weight. METHODS: Premenopausal women with a body mass index >30 kg/m2 were studied in two phase 1, single-centre, randomized, double-blind, placebo-controlled trials. Study A matched subjects 1:1 to receive subcutaneous placebo or bremelanotide three times daily for days 1-15. Study B was a crossover trial with six distinct treatment sequences consisting of three 4-day treatment periods, investigating once-a-day and twice-a-day exposure to bremelanotide versus placebo. Subjects received one of the three treatments twice-daily during each period: 0 mg/0 mg, 2.5 mg/0 mg or 2.5 mg/2.0 mg bremelanotide. Body weight and food intake were recorded in detail daily. Adverse events were recorded throughout both studies. RESULTS: In Study A, 27 of 30 bremelanotide subjects (90.0%) completed the trial and exhibited a significantly greater reduction in body weight after 16 days versus placebo [least squares mean difference (95% CI), -1.3 (-1.9 to -0.8) kg; p < .0001]. Mean caloric intake in bremelanotide subjects was decreased versus placebo, with a magnitude of reduction of approximately 400 kcal/day throughout Study A (p < .01). In Study B, 15 of 27 subjects (55.6%) completed all three phases. Significantly greater reduction of mean body weight occurred in twice-daily bremelanotide subjects versus placebo (1.7 vs. 0.9 kg, respectively, p < .001). Total caloric intake reduction was significantly greater in the bremelanotide groups versus placebo (mean difference range: 398-469 kcal; p < .0001). CONCLUSIONS: Agonist activity at the MC4R may aid in reducing caloric intake and weight loss in obese women.

Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys.

The most recent Ebola virus outbreak in West Africa, which was unprecedented in the number of cases and fatalities, geographic distribution, and number of nations affected, highlights the need for safe, effective, and readily available antiviral agents for treatment and prevention of acute Ebola virus (EBOV) disease (EVD) or sequelae. No antiviral therapeutics have yet received regulatory approval or demonstrated clinical efficacy. Here we report the discovery of a novel small molecule GS-5734, a monophosphoramidate prodrug of an adenosine analogue, with antiviral activity against EBOV. GS-5734 exhibits antiviral activity against multiple variants of EBOV and other filoviruses in cell-based assays. The pharmacologically active nucleoside triphosphate (NTP) is efficiently formed in multiple human cell types incubated with GS-5734 in vitro, and the NTP acts as an alternative substrate and RNA-chain terminator in primer-extension assays using a surrogate respiratory syncytial virus RNA polymerase. Intravenous administration of GS-5734 to nonhuman primates resulted in persistent NTP levels in peripheral blood mononuclear cells (half-life, 14 h) and distribution to sanctuary sites for viral replication including testes, eyes, and brain. In a rhesus monkey model of EVD, once-daily intravenous administration of 10 mg kg(-1) GS-5734 for 12 days resulted in profound suppression of EBOV replication and protected 100% of EBOV-infected animals against lethal disease, ameliorating clinical disease signs and pathophysiological markers, even when treatments were initiated three days after virus exposure when systemic viral RNA was detected in two out of six treated animals. These results show the first substantive post-exposure protection by a small-molecule antiviral compound against EBOV in nonhuman primates. The broad-spectrum antiviral activity of GS-5734 in vitro against other pathogenic RNA viruses, including filoviruses, arenaviruses, and coronaviruses, suggests the potential for wider medical use. GS-5734 is amenable to large-scale manufacturing, and clinical studies investigating the drug safety and pharmacokinetics are ongoing.

Arthroscopically Assisted Coraco-Clavicular Ligament Reconstruction in Treatment of Acute Displaced Distal Clavicle Fractures Provides Good to Excellent Shoulder Function Despite Low Union Rates and High Complication Rates: A Systematic Review.

PURPOSE: The aim of this systematic review was to assess the clinical outcome of arthroscopically assisted coraco-clavicular ligament (AACCL) reconstruction for treatment of displaced distal clavicle fractures in terms of union rate, complications, and shoulder function. METHODS: A review of the online databases Medline and Embase was conducted on January 1, 2021, according to PRISMA guidelines. The review was registered prospectively in the PROSPERO database. Clinical studies reporting union rate, complications, and shoulder function were included. The studies were appraised using the Methodological Index for Non-Randomized Studies (MINORS) tool. RESULTS: The search strategy identified 14 studies eligible for inclusion, 12 retrospective case series and 2 nonrandomized retrospective comparative studies. All studies reported on shoulder function, union rate, and complications. The overall shoulder function was good to excellent according to Constant-Murley score, with mean scores ranging from 81.8 to 96.2 [I2 (inconsistency) = 0% (95% confidence interval [CI] = 0% to 61%)]. The mean union rate ranged from 70% to 100% [I2 = 32.6% (95% CI = 0% to 63.4%)], and the mean complication rate ranged from 0 to 28.6% [I2 = 43.4% (95% CI = 0% to 68.4%)]. The most common complications were hardware related (3.1%), wound related (2.7%), and postoperative shoulder stiffness (2.2%). CONCLUSION: This systematic review analyzed clinical studies that evaluated the outcome of AACCL reconstruction in displaced distal clavicle fractures. The overall findings of this systematic review are that the union rate can be as low as 70% with this technique and the complication rate as high as 28.6%. Overall shoulder function was good to excellent according to Constant-Murley score. As the literature surrounding this topic is heterogeneous, further comparative clinical studies are required to assess superiority compared with other traditional techniques. LEVEL OF EVIDENCE: V: systematic review of level III and IV studies.

The use of the internal joint stabiliser for elbow instability Report of two cases and systematic review.

The management of elbow fracture-dislocations is challenging. The internal joint stabiliser (IJS) (Skeletal Dynamics, Miami, FL) has been advocated as an alternative to traditional techniques. This article shares our initial clinical experience and provide a systematic review analysing the ability of the IJS to maintain radiographic joint reduction and the associated complication profile. Two cases of elbow fracture-dislocations treated at our centre using the IJS are presented. A systematic review of the literature was conducted using the online databases Medline, Scopus and EMBASE. Clinical studies reporting the maintenance of joint reduction after the use of IJS in patients with acute or chronic elbow instability were included. The two cases reported remained radiographically concentric at 6 months follow up without complications. 5 studies met the inclusion criteria and were included in the systematic review (total n=65). Only two patients across the studies had ongoing radiological instability (3%) and both were associated with coronoid insufficiency. The mean flexion-extension arc ranged from 106° to 135° and pronation- supination arc ranged from 138° to 151°. The mean DASH scores ranged from 16 to 37.3 and the mean Broberg and Morrey Functional score from 68.2 to 93. Complication rates in the case series ranged from 21% to 40%, the commonest complications were heterotopic ossification, neuropathy and infections. Initial reports into the use of the Internal Joint Stabiliser for elbow instability have shown a low incidence of residual radiological joint incongruency.

Drug Resistance Assessment Following Administration of Respiratory Syncytial Virus (RSV) Fusion Inhibitor Presatovir to Participants Experimentally Infected With RSV.

BACKGROUND: Presatovir is an oral respiratory syncytial virus (RSV) fusion inhibitor targeting RSV F protein. In a double-blind, placebo-controlled study in healthy adults experimentally infected with RSV (Memphis-37b), presatovir significantly reduced viral load and clinical disease severity in a dose-dependent manner. METHODS: Viral RNA from nasal wash samples was amplified and the F gene sequenced to monitor presatovir resistance. Effects of identified amino acid substitutions on in vitro susceptibility to presatovir, viral fitness, and clinical outcome were assessed. RESULTS: Twenty-eight treatment-emergent F substitutions were identified. Of these, 26 were tested in vitro; 2 were not due to lack of recombinant virus recovery. Ten substitutions did not affect presatovir susceptibility, and 16 substitutions reduced RSV susceptibility to presatovir (2.9- to 410-fold). No substitutions altered RSV susceptibility to palivizumab or ribavirin. Frequency of phenotypically resistant substitutions was higher with regimens containing lower presatovir dose and shorter treatment duration. Participants with phenotypic presatovir resistance had significantly higher nasal viral load area under the curve relative to those without, but substitutions did not significantly affect peak viral load or clinical manifestations of RSV disease. CONCLUSIONS: Emergence of presatovir-resistant RSV occurred during therapy but did not significantly affect clinical efficacy in participants with experimental RSV infection.

Remdesivir (GS-5734) Is Efficacious in Cynomolgus Macaques Infected With Marburg Virus.

Marburg virus (MARV) is a filovirus with documented human case-fatality rates of up to 90%. Here, we evaluated the therapeutic efficacy of remdesivir (GS-5734) in nonhuman primates experimentally infected with MARV. Beginning 4 or 5 days post inoculation, cynomolgus macaques were treated once daily for 12 days with vehicle, 5 mg/kg remdesivir, or a 10-mg/kg loading dose followed by 5 mg/kg remdesivir. All vehicle-control animals died, whereas 83% of animals receiving a 10-mg/kg loading dose of remdesivir survived, as did 50% of animals receiving a 5-mg/kg remdesivir regimen. Remdesivir-treated animals exhibited improved clinical scores, lower plasma viral RNA, and improved markers of kidney function, liver function, and coagulopathy versus vehicle-control animals. The small molecule remdesivir showed therapeutic efficacy in this Marburg virus disease model with treatment initiation 5 days post inoculation, supporting further assessment of remdesivir for the treatment of Marburg virus disease in humans.

A Phase 2b, Randomized, Double-blind, Placebo-Controlled Multicenter Study Evaluating Antiviral Effects, Pharmacokinetics, Safety, and Tolerability of Presatovir in Hematopoietic Cell Transplant Recipients with Respiratory Syncytial Virus Infection of the Lower Respiratory Tract.

BACKGROUND: Presatovir significantly reduced nasal viral load, signs, and symptoms of respiratory syncytial virus (RSV) infection in a human challenge study. We evaluated presatovir in hematopoietic-cell transplant (HCT) recipients with RSV lower respiratory tract infection (LRTI). METHODS: Patients with confirmed RSV in upper and lower respiratory tract and new chest X-ray abnormalities were randomized (1:1), stratified by supplemental oxygen and ribavirin use, to receive oral presatovir 200 mg or placebo every 4 days for 5 doses. The primary endpoint was time-weighted average change in nasal RSV viral load through day 9. Secondary endpoints included supplemental oxygen-free days, incident respiratory failure requiring mechanical ventilation, and all-cause mortality. RESULTS: From January 31, 2015, to March 20, 2017, 60 patients from 17 centers were randomized (31 presatovir, 29 placebo); 59 received study treatment (50 allogeneic, 9 autologous HCT). In the efficacy population (29 presatovir, 28 placebo), presatovir treatment did not significantly reduce time-weighted average change in viral load (-1.12 vs -1.09 log10 copies/mL; treatment difference -0.02 log10 copies/mL, 95% confidence interval: -.62, .57; P = .94), median supplemental oxygen-free days (26 vs 28 days, P = .84), incident respiratory failure (10.3 vs 10.7%, P = .98), or all-cause mortality (0 vs 7.1%, P = .19) versus placebo. Adverse events were similar between arms (presatovir 80%, placebo 79%). Resistance-associated substitutions in RSV fusion protein emerged in 6/29 presatovir-treated patients. CONCLUSIONS: Presatovir treatment was well tolerated in HCT patients with RSV LRTI but did not improve virologic or clinical outcomes versus placebo. CLINICAL TRIALS REGISTRATION: www.clinicaltrials.gov, NCT02254421; EudraCT, #2014-002475-29.

A Phase 2, Randomized, Double-blind, Placebo-Controlled Trial of Presatovir for the Treatment of Respiratory Syncytial Virus Upper Respiratory Tract Infection in Hematopoietic-Cell Transplant Recipients.

BACKGROUND: Hematopoietic-cell transplant (HCT) recipients are at risk for severe respiratory syncytial virus (RSV) infection. We evaluated the RSV fusion inhibitor presatovir in a randomized, double-blind, Phase II trial in HCT recipients with RSV upper respiratory tract infections. METHODS: Patients were stratified by lymphopenia (<200/µL) and ribavirin use; were randomized, stratified by lymphopenia (<200/µL) and ribavirin use, to receive oral presatovir at 200 mg or a placebo on Days 1, 5, 9, 13, and 17, and were followed through Day 28. The coprimary efficacy endpoints were the time-weighted average change in the nasal RSV viral load between Days 1 and 9 and the proportion of patients developing lower respiratory tract complications (LRTCs) through Day 28. RESULTS: From 23 January 2015 to 16 June 2017, 189 patients were randomly assigned to treatment (96 to presatovir and 93 to the placebo). Presatovir treatment, compared with the placebo treatment, did not significantly affect (prespecified α = 0.01) a time-weighted average decline in the RSV viral load from Day 1 to 9 (treatment difference, -0.33 log10 copies/mL; 95% confidence interval [CI] -.64 to -.02 log10 copies/mL; P = .040) or the progression to LRTC (11.2% vs 19.5%, respectively; odds ratio, 0.50; 95% CI, .22-1.18; P = .11). In a post hoc analysis among patients with lymphopenia, presatovir decreased LRTC development by Day 28 (2/15 [13.3%] vs 9/14 [64.3%], respectively; P = .008), compared with the placebo. Adverse events were similar for patients receiving presatovir and the placebo. CONCLUSIONS: Presatovir had a favorable safety profile in adult HCT recipients with RSV but did not achieve the coprimary endpoints. Exploratory analyses suggest an antiviral effect among patients with lymphopenia. CLINICAL TRIALS REGISTRATION: NCT02254408; EUDRA-CT#2014-002474-36.

Assessment of Drug Resistance during Phase 2b Clinical Trials of Presatovir in Adults Naturally Infected with Respiratory Syncytial Virus.

This study summarizes drug resistance analyses in 4 recent phase 2b trials of the respiratory syncytial virus (RSV) fusion inhibitor presatovir in naturally infected adults. Adult hematopoietic cell transplant (HCT) recipients, lung transplant recipients, or hospitalized patients with naturally acquired, laboratory-confirmed RSV infection were enrolled in 4 randomized, double-blind, placebo-controlled studies with study-specific presatovir dosing. Full-length RSV F sequences amplified from nasal swabs obtained at baseline and postbaseline were analyzed by population sequencing. Substitutions at RSV fusion inhibitor resistance-associated positions are reported. Genotypic analyses were performed on 233 presatovir-treated and 149 placebo-treated subjects. RSV F variant V127A was present in 8 subjects at baseline. Population sequencing detected treatment-emergent substitutions in 10/89 (11.2%) HCT recipients with upper and 6/29 (20.7%) with lower respiratory tract infection, 1/35 (2.9%) lung transplant recipients, and 1/80 (1.3%) hospitalized patients treated with presatovir; placebo-treated subjects had no emergent resistance-associated substitutions. Subjects with substitutions at resistance-associated positions had smaller decreases in viral load during treatment relative to those without, but they had similar clinical outcomes. Subject population type and dosing regimen may have influenced RSV resistance development during presatovir treatment. Subjects with genotypic resistance development had decreased virologic responses compared to those without genotypic resistance but had comparable clinical outcomes.