scholarly journals Clinical effect and antiviral mechanism of T-705 in treating severe fever with thrombocytopenia syndrome

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Hao Li ◽  
Xia-Ming Jiang ◽  
Ning Cui ◽  
Chun Yuan ◽  
Shao-Fei Zhang ◽  
...  

AbstractSevere fever with thrombocytopenia syndrome (SFTS) virus (SFTSV) is an emerging tick-borne virus with high fatality and an expanding endemic. Currently, effective anti-SFTSV intervention remains unavailable. Favipiravir (T-705) was recently reported to show in vitro and in animal model antiviral efficacy against SFTSV. Here, we conducted a single-blind, randomized controlled trial to assess the efficacy and safety of T-705 in treating SFTS (Chinese Clinical Trial Registry website, number ChiCTR1900023350). From May to August 2018, laboratory-confirmed SFTS patients were recruited from a designated hospital and randomly assigned to receive oral T-705 in combination with supportive care or supportive care only. Fatal outcome occurred in 9.5% (7/74) of T-705 treated patients and 18.3% (13/71) of controls (odds ratio, 0.466, 95% CI, 0.174–1.247). Cox regression showed a significant reduction in case fatality rate (CFR) with an adjusted hazard ratio of 0.366 (95% CI, 0.142–0.944). Among the low-viral load subgroup (RT-PCR cycle threshold ≥26), T-705 treatment significantly reduced CFR from 11.5 to 1.6% (P = 0.029), while no between-arm difference was observed in the high-viral load subgroup (RT-PCR cycle threshold <26). The T-705-treated group showed shorter viral clearance, lower incidence of hemorrhagic signs, and faster recovery of laboratory abnormities compared with the controls. The in vitro and animal experiments demonstrated that the antiviral efficacies of T-705 were proportionally induced by SFTSV mutation rates, particularly from two transition mutation types. The mutation analyses on T-705-treated serum samples disclosed a partially consistent mutagenesis pattern as those of the in vitro or animal experiments in reducing the SFTSV viral loads, further supporting the anti-SFTSV effect of T-705, especially for the low-viral loads.

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S314-S314
Author(s):  
Lillian B Brown ◽  
Lisa Gail Winston ◽  
Barbara Haller ◽  
Phong Pham ◽  
Beatrice Marcelo ◽  
...  

Abstract Background Most diagnostic tests for SARS-CoV-2, the causative agent of COVID-19, are RT-PCR based. This method is sensitive but cannot distinguish replicating from non-replicating virus. RT-PCR cycle threshold (Ct) values are inversely correlated with viral load, and higher Ct values have been correlated with lower in vitro viral infectivity. However, relatively few data exist on the association between Ct values and patients’ duration of symptoms remains unclear. We thus evaluated Ct values and symptom duration in a cohort of patients hospitalized with COVID-19. Methods We assessed all patients admitted to San Francisco General Hospital between April 1 and May 18, 2020 with confirmed COVID-19 infection based on RT-PCR testing (Abbott m2000 platform). We included patients having diagnostic testing for suspected COVID-19 and patients having asymptomatic testing per hospital policy. For symptomatic patients, date of symptom onset was abstracted from hospital records, and time from symptom onset to test date was calculated. RT-PCR Ct values were manually extracted. Median Ct and IQR were calculated for patients with &lt; 10 days of symptoms, ≥10 days of symptoms, and asymptomatic disease. Between-group comparisons were performed using the Kruskal-Wallis test. Results Among 61 patients with positive RT-PCR tests, 40 patients reported &lt; 10 days of symptoms at the time of testing, 15 reported ≥10 days of symptoms, and 6 were asymptomatic. The median Ct value was 14.2 cycles (IQR, 10.2, 18.3) among patients reporting &lt; 10 days of symptoms, 19.7 cycles (IQR, 15.3, 23.9) among patients reporting ≥10 days of symptoms, and 26.3 (IQR, 25.0, 29.1) among asymptomatic patients. Ct values were significantly lower among patients with &lt; 10 days of symptoms compared to patients with &gt;=10 days of symptoms (p=0.01) and when compared to asymptomatic patients (p=0.0002) [Figure]. Cycle threshold (Ct) by days of symptoms at time of testing Conclusion SARS-CoV-2 RT-PCR cycle threshold values were higher (indicating lower viral load) in patients with longer symptom duration and were highest in asymptomatic patients. These results add to emerging data suggesting that strategies for optimal isolation of patients in both community and hospital settings could be informed by a combination of symptom duration and RT-PCR Ct values. Disclosures All Authors: No reported disclosures


2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Vanessa De Pace ◽  
Patrizia Caligiuri ◽  
Valentina Ricucci ◽  
Nicola Nigro ◽  
Barbara Galano ◽  
...  

Abstract Background The ongoing SARS-CoV-2 pandemic requires the availability of accurate and rapid diagnostic tests, especially in such clinical settings as emergency and intensive care units. The objective of this study was to evaluate the diagnostic performance of the Vivalytic SARS-CoV-2 rapid PCR kit in lower respiratory tract (LRT) specimens. Methods Consecutive LRT specimens (bronchoalveolar lavage and bronchoaspirates) were collected from Intensive Care Units of San Martino Hospital (Genoa, Italy) between November 2020 and January 2021. All samples underwent RT-PCR testing by means of the Allplex™ SARS-CoV-2 assay (Seegene Inc., South Korea). On the basis of RT-PCR results, specimens were categorized as negative, positive with high viral load [cycle threshold (Ct) ≤ 30] and positive with low viral load (Ct of 31–35). A 1:1:1 ratio was used to achieve a sample size of 75. All specimens were subsequently tested by means of the Vivalytic SARS-CoV-2 rapid PCR assay (Bosch Healthcare Solutions GmbH, Germany). The diagnostic performance of this assay was assessed against RT-PCR through the calculation of accuracy, Cohen’s κ, sensitivity, specificity and expected positive (PPV) and negative (NPV) predictive values. Results The overall diagnostic accuracy of the Vivalytic SARS-CoV-2 was 97.3% (95% CI: 90.9–99.3%), with an excellent Cohen’s κ of 0.94 (95% CI: 0.72–1). Sensitivity and specificity were 96% (95% CI: 86.5–98.9%) and 100% (95% CI: 86.7–100%), respectively. In samples with high viral loads, sensitivity was 100% (Table 1). The distributions of E gene Ct values were similar (Wilcoxon’s test: p = 0.070), with medians of 35 (IQR: 25–36) and 35 (IQR: 25–35) on Vivalytic and RT-PCR, respectively (Fig. 1). NPV and PPV was 92.6% and 100%, respectively.Table 1 Demographic characteristics and data sample type of the study cases (N = 75) Male, N (%) 56 (74.6%) Age (yr), Median (IQR) 65 (31–81) BAS, N (%) 43 (57.3%)  Negative 30.2%  Positive—High viral load [Ct ≤ 30] 27.9%  Positive—Low viral load [Ct 31–35] 41.9% BAL, N (%) 32 (42.7%)  Negative 37.5%  Positive—High viral load [Ct ≤ 30] 40.6%  Positive—Low viral load [Ct 31–35] 21.9% Data were expressed as proportions for categorical variables. Specimens were categorized into negative, positive with high viral load [cycle threshold (Ct) ≤ 30] and positive with low viral load (Ct of 31–35). BAS bronchoaspirates, BAL bronchoalveolar lavage, Ct cycle threshold Conclusions Vivalytic SARS-CoV-2 can be used effectively on LRT specimens following sample liquefaction. It is a feasible and highly accurate molecular procedure, especially in samples with high viral loads. This assay yields results in about 40 min, and may therefore accelerate clinical decision-making in urgent/emergency situations.


Author(s):  
Teppei Sakano ◽  
Mitsuyoshi Urashima ◽  
Hiroyuki Takao ◽  
Kohei Takeshita ◽  
Hiroe Kobashi ◽  
...  

In the coronavirus disease 2019 (COVID-19) pandemic, more than half of the cases of transmission may occur via asymptomatic individuals, which makes it difficult to contain. However, whether viral load in the throat during admission is different between asymptomatic and symptomatic patients is not well known. By conducting a prospective cohort study of patients with asymptomatic or mild COVID-19, cycle threshold (Ct) values of the polymerase chain reaction test for COVID-19 were examined every other day during admission. The Ct values during admission increased more steadily in symptomatic patients and febrile patients than in asymptomatic patients, with significance (p = 0.01 and p = 0.004, respectively), although the Ct values as a whole were not significantly different between the two groups. Moreover, the Ct values as a whole were higher in patients with dysosmia/dysgeusia than in those without it (p = 0.02), whereas they were lower in patients with a headache than those without (p = 0.01). Patients who were IgG-positive at discharge maintained higher Ct values, e.g., more than 35, during admission than those with IgG-negative (p = 0.03). Assuming that viral load and Ct values are negatively associated, the viral loads as a whole and their changes by time may be different by symptoms and immune reaction, i.e., IgG-positive at discharge.


2020 ◽  
Vol 94 (20) ◽  
Author(s):  
Zhen Wu ◽  
Yuanyuan Wu ◽  
Wei Zhang ◽  
Andres Merits ◽  
Peter Simmonds ◽  
...  

ABSTRACT Members of the Pegivirus genus, family Flaviviridae, widely infect humans and other mammals, including nonhuman primates, bats, horses, pigs, and rodents, but are not associated with disease. Here, we report a new, genetically distinct pegivirus in goose (Anser cygnoides), the first identified in a nonmammalian host species. Goose pegivirus (GPgV) can be propagated in goslings, embryonated goose eggs, and primary goose embryo fibroblasts, and is thus the first pegivirus that can be efficiently cultured in vitro. Experimental infection of GPgV in goslings via intravenous injection revealed robust replication and high lymphotropism. Analysis of the tissue tropism of GPgV revealed that the spleen and thymus were the organs bearing the highest viral loads. Importantly, GPgV could promote clinical manifestations of goose parvovirus infection, including reduced weight gain and 7% mortality. This finding contrasts with the lack of pathogenicity that is characteristic of previously reported pegiviruses. IMPORTANCE Members of the Pegivirus genus, family Flaviviridae, widely infect humans and other mammals, but are described as causing persistent infection and lacking pathogenicity. The efficiency of in vitro replication systems for pegivirus is poor, thus limiting investigation into viral replication steps. Because of that, the pathogenesis, cellular tropism, route of transmission, biology, and epidemiology of pegiviruses remain largely uncovered. Here, we report a phylogenetically distinct goose pegivirus (GPgV) that should be classified as a new species. GPgV proliferated in cell culture in a species- and cell-type-specific manner. Animal experiments show GPgV lymphotropism and promote goose parvovirus clinical manifestations. This study provides the first cell culture model for pegivirus, opening new possibilities for studies of pegivirus molecular biology. More importantly, our findings stand in contrast to the lack of identified pathogenicity of previously reported pegiviruses, which sheds lights on the pathobiology of pegivirus.


2020 ◽  
Vol 154 (4) ◽  
pp. 479-485 ◽  
Author(s):  
Blake W Buchan ◽  
Jessica S Hoff ◽  
Cameron G Gmehlin ◽  
Adriana Perez ◽  
Matthew L Faron ◽  
...  

Abstract Objectives We examined the distribution of reverse transcription polymerase chain reaction (RT-PCR) cycle threshold (CT) values obtained from symptomatic patients being evaluated for coronavirus disease 2019 (COVID-19) to determine the proportion of specimens containing a viral load near the assay limit of detection (LoD) to gain practical insight to the risk of false-negative results. We also examined the relationship between CT value and patient age to determine any age-dependent difference in viral load or test sensitivity. Methods We collected CT values obtained from the cobas severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) assay corresponding to 1,213 combined nasopharyngeal-oropharyngeal specimens obtained from symptomatic individuals that were reported as positive or presumptive positive for SARS-CoV-2. CT values were stratified by SARS-CoV target and patient age group. Results In total, 93.3% to 98.4% of specimens demonstrated CT values greater than 3× the assay LoD, at which point false-negative results would not be expected. The mean of CT values between age groups was statistically equivalent with the exception of patients in age group 80 to 89 years, which demonstrated slightly lower CTs. Conclusions Based on the distribution of observed CT values, including the small proportion of specimens with values near the assay LoD, there is a low risk of false-negative RT-PCR results in combined nasopharyngeal-oropharyngeal specimens obtained from symptomatic individuals.


2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S213-S214
Author(s):  
Steven S Good ◽  
Adel Moussa ◽  
Xiao-Jian Zhou ◽  
Jean-Pierre Sommadossi ◽  
Keith Pietropaolo

Abstract Background The increasing global prevalence of human Dengue virus infection and the potential for life-threatening sequelae highlight the significance of this unmet medical need. Here we report the potent in vitro activity of AT-281, the free base form of AT-752, against Dengue virus and other flaviviruses and the in vivo efficacy of AT-752 in a mouse model of Dengue viral disease. Methods Antiviral activities of serial dilutions of AT-281 were evaluated in infected Huh-7 cells. Effective concentrations of AT-281 required to inhibit virus yield reduction by 90% (EC90) and to prevent cytopathic effect by 50% (EC50) were determined, respectively, by visual examination and by neutral red staining, as was cytotoxicity. AG129 (α-, β- and γ-interferon knock-out) mice received an oral dose of AT-752 (1000 mg/kg) 4 h before s.c. inoculation with Dengue virus type 2 (strain D2Y98P, 1x105 virus particles) followed by b.i.d. doses (500 mg/kg) for 7 days starting 1 h post-inoculation (p.i.). Six groups each (n=5) of treated and control mice were scheduled to be sacrificed on days 4, 6, 7, 8, 10 and 21 p.i. with serum and spleen viral RNA levels determined by plaque assay. AT-281 efficacy was evaluated based on overall health score, survival, weight loss and viral load in serum and spleen. Results In vitro EC90 values for AT-281 against Dengue, West Nile and Yellow Fever viruses ranged from 0.26 to 0.64 µM and EC50 values for Zika and Japanese encephalitis were 0.21 and 0.64 µM, respectively (Table 1). No toxicity was observed up to the highest concentrations tested (172 µM). Oral administration of AT-752 to Dengue-infected AG129 mice substantially improved survival, prevented weight loss and lowered viral loads by day 6, with virus being undetectable on day 8 and thereafter (Figure 1). Serum and spleen viral loads in control mice declined between days 4 and 8 but no control mice survived beyond day 8. In contrast, AT-752 treated mice survived up to day 19, eventually succumbing to model-induced CNS sequelae. Table 1. Antiviral Activity of AT-281 Against Various Flaviviruses in Huh-7 Cell Cultures Figure 1. Efficacy of AT-752 in the AG129 mouse model of Dengue infection. Panel a: health score: 1, healthy; 2, coat slightly ruffled; 3, coat ruffled/wet; 4, coat very ruffled, eyes slightly closed/inset; 5, coat very ruffled, eyes closed/inset; 6, coat very ruffled, eyes closed/inset, moribund requiring humane euthanasia; 7, found dead. Panel b: Kaplan-Meier survival plot. Panel c: percent weight loss. Panel d: serum viremia. Panel e: spleen viral load. Conclusion The potent activity of AT-281 against Dengue virus in vitro and the efficacy of its salt form, AT-752, in the terminal AG129 mouse model warrant further clinical development of the drug. Preclinical safety studies are in progress and clinical trials will be initiated thereafter. Disclosures Steven S. Good, MS, Atea Pharmaceuticals, Inc. (Employee) Adel Moussa, PhD, Atea Pharmaceuticals, Inc. (Employee) Xiao-Jian Zhou, PhD, Atea Pharmaceuticals, Inc. (Employee) Jean-Pierre Sommadossi, PhD, Atea Pharmaceuticals, Inc. (Board Member) Keith Pietropaolo, BA, Atea Pharmaceuticals, Inc. (Employee)


2020 ◽  
Author(s):  
Reem A. AlDossary ◽  
Amani Alnimr ◽  
Reem Aljindan ◽  
Khaled Alkharsah ◽  
Ahmed Al-Qurayn ◽  
...  

Abstract Background Multiple studies worldwide reported the clinical and epidemiological features of coronavirus disease 2019 (COVID-19) with limited reports form the Middle East area. Methods This is an observational study to describe the clinical and epidemiological features of 341 COVID-19 cases in the Eastern Province of Saudi Arabia over the first three months from reporting the first case in the country and identify factors associated with severity of the illness. Results The median age was 45 years and males were twice as affected as females (p value < 0.0001). The duration of viral shedding ranged from 9 to 36 days. The most common clinical presentations include fever, shortness of breath, cough, myalgia, sore throat, vomiting, and headache. Severe and critical cases were significantly higher in males compared to females (23% vs 8.7%), senior adults (> 65 years), Bengali ethnicity, and in patient with com-morbidities including diabetes, hypertension, and dyslipidemia (p-value = 0.001). Furthermore, case fatality rate was found to be 10% and was significantly higher in male gender compared to female (13.8%vs 2.6%), and in Asian ethnicity (17.9%) compared to Arabs (6%) and African counterparts (0) (p-value = 0.002). No association was found between viral load represented by the RT-PCR cycle threshold (Ct) values and severity of illness. Conclusion Age, gender and ethnicity are important predictors of COVID-19 severity while Cycle threshold (Ct) of SARS-CoV-2 RT-PCR test cannot be used as a predictor of criticality of illness.


2020 ◽  
Author(s):  
Kai-qian Kam ◽  
Koh Cheng Thoon ◽  
Matthias Maiwald ◽  
Chia Yin Chong ◽  
Han Yang Soong ◽  
...  

It is important to understand the temporal trend of pediatric severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral load to estimate the transmission potential of children in schools and communities. We determined differences in SARS-CoV-2 viral load dynamics between nasopharyngeal samples of infected asymptomatic and symptomatic children. The daily cycle threshold values of SARS-CoV-2 in the nasopharynx of a cohort of infected children were collected for analysis. Among 17 infected children, 10 (58.8%) were symptomatic. Symptomatic children, when compared to asymptomatic children, had higher viral load (mean cycle threshold on day 7 of illness 28.6 versus 36.7, p = 0.02). Peak SARS-CoV-2 viral loads occured around days 2-3 of illness/days of diagnosis in infected children. After adjusting for the estimated date of infection, the higher SARS-CoV-2 viral loads in symptomatic children remained. We postulate that symptomatic SARS-CoV-2-infected children may have higher transmissibility than asymptomatic children. As peak viral load in infected children occurred in the early stage of illness, viral shedding and transmission in the pre-symptomatic phase probable. Our study highlights the importance of screening for SARS-CoV-2 in children with epidemiological risk factors, even when they are asymptomatic in order to improve containment of the virus in the community, including educational settings.


2021 ◽  
Author(s):  
Elisa Teyssou ◽  
Cathia Soulie ◽  
Benoit Visseaux ◽  
Sidonie Lambert-Niclot ◽  
Valentine Ferre ◽  
...  

The 501Y.V2 and the 501Y.V1 SARS-CoV-2 variants emerged and spread rapidly into the world. We analysed the RT-PCR cycle threshold values of 643 nasopharyngeal samples of COVID-19 patients at diagnosis and found that the 501Y.V2 variant presented an intermediate viral load between the 501Y.V1 and the historical variants.


2021 ◽  
Author(s):  
Abdulkarim Abdulrahman ◽  
Saad Mallah ◽  
Manaf AlQahtani

Abstract Background: Being able to use COVID-19 RT-PCR Ct values as simple markers of disease outcome or prognosis would allow for the easy and proactive identification and triaging of high-risk cases. This study’s objective was thus to assess whether a correlation exists between COVID-19 viral loads, as indicated by RT-PCR Ct values, and disease severity, as indicated by respiratory indices Results: A multi-centre cross-sectional retrospective study was conducted, using data obtained from Bahrain’s National COVID-19 Task force’s centralised database. The study period was from May 2, 2020 to July 31, 2020. A multivariable logistic regression was used to assess for a correlation. The covariates adjusted for included sex, age, presentation, and comorbidities. In our cohort, Ct value showed no statistical significance for an association with requirement for oxygenation on admission (Odds ratio 1.046; 95%CI 0.999 to 1.096, p=0.054). Conclusion: Viral load, as indicated by Ct values, did not seem to be associated with requirement for oxygenation on admission in our cohort. We postulate however that time since onset of symptom may have acted as an unaccounted-for confounder.


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