A pilot study of 0.4% povidone-iodine nasal spray to eradicate SARS-CoV-2 in the nasopharynx (preprint)

We studied the virucidal efficacy of 0.4% povidone-iodine (PVP-I) nasal spray against SARS-CoV-2 in the patients nasopharynx at 3 minutes and 4 hours after PVP-I exposure. We used an open-label single-arm pilot study of adult patients with RT-PCR-confirmed COVID-19. All patients received three puffs of 0.4% PVP-I spray in each nostril. Nasopharyngeal (NP) swabs were collected before the PVP-I spray (baseline, left NP samples), and at 3 minutes (left and right NP samples) and 4 hours post-PVP-I spray (right NP samples). All swabs were tested by RT-PCR and cultured to measure the viable SARS-CoV-2 within 24 hours after collection. Fourteen patients were enrolled but viable SARS-CoV-2 was cultured from 12 patients (85.7%). The median viral titer at baseline was 3.5 log TCID 50 /mL (IQR 2.8-4.0 log TCID 50 /mL). At 3 minutes post-PVP-I spray via the left nostril, viral titers were reduced in 8 patients (66.7%). At 3 minutes post-PVP-I, the median viral titer was 3.4 log TCID 50 /mL (IQR 1.8-4.4 log TCID 50 /mL) ( P =0.162). At 4 hours post-PVP-I spray via the right nostril, 6 of 11 patients (54.5%) had either the same or minimal change in viral titers. The median viral titer 3 minutes post-PVP-I spray was 2.7 log TCID 50 /mL (IQR 2.0-3.9 log TCID 50 /mL). Four hours post-PVP-I spray the median titer was 2.8 log TCID 50 /mL (IQR 2.2-3.9 log TCID 50 /mL) ( P =0.704). No adverse effects of PVP-I nasal spray were detected. We concluded that 0.4% PVP-I nasal spray demonstrated minimal virucidal efficacy at 3 minutes post-exposure. At 4 hours post-exposure, the viral titer was unchanged from baseline. The poor virucidal activity of 0.4% PVP-I nasal spray is unlikely to reduce transmission of SARS-CoV-2 if used for prophylaxis.

Early Treatment of Favipiravir in COVID-19 Patients Without Pneumonia: A Multicentre, Open-Labelled, Randomized Control Study (preprint)

We investigated Favipiravir (FPV) efficacy in mild cases of COVID-19 without pneumonia and its effects towards viral clearance, clinical condition, and risk of COVID-19 pneumonia development. PCR-confirmed SARS-CoV-2-infected patients without pneumonia were enrolled (2:1) within 10 days of symptomatic onset into FPV and control arms. The former received 1800 mg FPV twice-daily (BID) on Day 1 and 800 mg BID 5-14 days thereafter until negative viral detection, while the latter received supportive care only. The primary endpoint was time to clinical improvement, which was defined by a reduced National Early Warning Score (NEWS) or score of <1. 62 patients (41 female) comprised the FPV arm (median age: 32 years, median BMI: 22 kg/m2) and 31 patients (19 female) comprised the control arm (median age: 28 years, median BMI: 22 kg/m2). The median time to sustained clinical improvement by NEWS was 2 vs 14 days for FPV and control arms respectively (adjusted hazard ratio (aHR) of 2.77, 95% CI 1.57-4.88, P <0.001). The FPV arm also had significantly higher likelihoods of clinical improvement within 14 days after enrolment by NEWS (79% vs 32% respectively, P <0.001), particularly female patients (aOR 6.35, 95% CI 1.49-27.07, P <0.001). 8 (12.9%) and 7 (22.6%) patients in FPV and control arms developed mild pneumonia at a median (range) 6.5 (1-13) and 7 (1-13) days after treatment, respectively (P = 0.316); all recovered well without complications. We can conclude that early treatment of FPV in symptomatic COVID-19 patients without pneumonia was associated with faster clinical improvement.

Benefits of Early Combination Antiviral Treatment Containing Favipiravir for COVID-19 in Thailand (preprint)

We report the clinical outcomes following implementation of initial COVID-19 treatment guidelines in Thailand. A composite poor outcome was defined as death, ICU admission, requiring intubation, or high-flow oxygen. 744 COVID-19 patients (48.8% male) were included, median (IQR) age was 37 (27-48) years [8.4% >60 years] and 21.4% had pneumonia at admission. Admission <4 days from symptom onset had a reduced risk of poor outcome. In a subgroup analysis, favipiravir use reduced the risk of a poor outcome for patients admitted <4 days from symptom onset (OR 0.320 (0.152-0.662), P=0.003). Thai guidelines now include favipiravir to treat all symptomatic COVID-19 patients.

A multiplexed Cas13-based assay with point-of-care attributes for simultaneous COVID-19 diagnosis and variant surveillance (preprint)

Point-of-care (POC) nucleic acid detection technologies are poised to aid gold-standard technologies in controlling the COVID-19 pandemic, yet shortcomings in the capability to perform critically needed complex detection, such as multiplexed detection for viral variant surveillance, may limit their widespread adoption. Herein, we developed a robust multiplexed CRISPR-based detection using LwaCas13a and PsmCas13b to simultaneously diagnose SARS-CoV-2 infection and pinpoint the causative SARS-CoV-2 variant of concern (VOC)-including globally dominant VOCs Delta (B.1.617.2) and Omicron (B.1.1.529)-all while maintaining high levels of accuracy upon the detection of multiple SARS-CoV-2 gene targets. The platform has several attributes suitable for POC use: premixed, freeze-dried reagents for easy use and storage; convenient direct-to-eye or smartphone-based readouts; and a one-pot variant of the multiplexed detection. To reduce reliance on proprietary reagents and enable sustainable use of such a technology in low- and middle-income countries, we locally produced and formulated our own recombinase polymerase amplification reaction and demonstrated its equivalent efficiency to commercial counterparts. Our tool, CRISPR-based detection for simultaneous COVID-19 diagnosis and variant surveillance which can be locally manufactured, may enable sustainable use of CRISPR diagnostics technologies for COVID-19 and other diseases in POC settings.

Pharmacokinetics of favipiravir in adults with mild COVID-19 in Thailand (preprint)

We assessed the pharmacokinetics of favipiravir (FPV) in adults with symptomatic SARS-CoV-2 infection without pneumonia in Thailand. FPV dosing was 1800 mg twice-daily on day 1, then 800 mg twice-daily for 14 days. Eight subjects (7 female), median (range) age 39 (19-53) years and BMI 27.9 (18.0-33.6) were included. Inter-subject variability was high but all achieved minimum plasma concentrations (Cmin) above EC50 (9.7 mg/L). FPV was well tolerated; 1 subject stopped prematurely due to rash.

Safety and Immunogenicity of CoronaVac and ChAdOx1 Against the SARS-CoV-2 Circulating Variants of Concern (Alpha, Delta, Beta) in Thai Healthcare Workers (preprint)

Importance: Inactivated vaccine (CoronaVac) and chimpanzee adenovirus-vector vaccine (ChAdOx1) have been more available in resource-limited settings. However, the data comparing between these two vaccines in the same setting are limited. Objectives: To determine adverse events (AEs) and immunogenicity of CoronaVac and ChAdOx1 in health care workers (HCWs). Design: This prospective study was conducted from February to July 2021. Setting: A single center, university-based tertiary care center in Bangkok. Participants: Healthy HCWs. Exposure: Two doses of CoronaVac (4 weeks apart) or ChAdOx1 (8 weeks apart) intramuscularly. Main Outcomes and Measures: Self-reported AEs were collected for 7 days following each vaccination using electronic diary. The immunogenicity was determined by the level of IgG antibodies against receptor binding domain (RBD) of the SARS-CoV-2 spike protein (S1 subunit). The 50% plaque reduction neutralization tests against original Wuhan strain and circulating VOCs were performed in subset of samples at 2 weeks after the second dose. Results: Of the 360 HCWs, 180 received each vaccine. The median (interquartile range: IQR) age was 35 (29-44) years old and 84.2% were female. Participants who received ChAdOx1 reported higher frequency of AEs than those received CoronaVac after both the first dose (84.4% vs. 66.1%, P < 0.001) and second dose (75.6% vs. 60.6%, P = 0.002), with more AEs in those younger than 30 years of age for both vaccines. The seroconversion rate was 75.6% and 100% following the first dose of CoronaVac and ChAdOx1, respectively. All participants seroconverted at 2 weeks after the second dose. The anti-SARS-CoV-2 RBD IgG levels induced by CoronaVac was lower than ChAdOX1 with geometric means of 164.4 and 278.5 BAU/mL, respectively (P = 0.0066). Both vaccines induced similar levels of neutralizing antibodies against the Wuhan strain, geometric mean titer (GMT) of 337.4 vs 331.2; however, CoronaVac induced significantly lower GMT against Alpha (23.1 vs. 92.5), Delta (21.2 vs. 69.7), and Beta (10.2 vs. 43.6) variants, respectively. Conclusions and Relevance: CoronaVac induces lower measurable antibodies but with lower frequency of AEs than ChAdOx1. The low neutralizing antibodies against the circulating VOCs induced by CoronaVac supports the need for earlier boosting to prevent breakthrough infections. Trial Registration: TCTR20210720002 https://www.thaiclinicaltrials.org/

Understanding the Potential Impact of Different Drug Properties On SARS-CoV-2 Transmission and Disease Burden: A Modelling Analysis (preprint)

Background The unprecedented public health impact of the COVID-19 pandemic has motivated a rapid search for potential therapeutics, with some key successes. However, the potential impact of different treatments, and consequently research and procurement priorities, have not been clear. Methods and Findings We develop a mathematical model of SARS-CoV-2 transmission, COVID-19 disease and clinical care to explore the potential public-health impact of a range of different potential therapeutics, under a range of different scenarios varying: i) healthcare capacity, ii) epidemic trajectories; and iii) drug efficacy in the absence of supportive care. In each case, the outcome of interest was the number of COVID-19 deaths averted in scenarios with the therapeutic compared to scenarios without. We find the impact of drugs like dexamethasone (which are delivered to the most critically-ill in hospital and whose therapeutic benefit is expected to depend on the availability of supportive care such as oxygen and mechanical ventilation) is likely to be limited in settings where healthcare capacity is lowest or where uncontrolled epidemics result in hospitals being overwhelmed. As such, it may avert 22% of deaths in high-income countries but only 8% in low-income countries (assuming R=1.35). Therapeutics for different patient populations (those not in hospital, early in the course of infection) and types of benefit (reducing disease severity or infectiousness, preventing hospitalisation) could have much greater benefits, particularly in resource-poor settings facing large epidemics. Conclusions There is a global asymmetry in who is likely to benefit from advances in the treatment of COVID-19 to date, which have been focussed on hospitalised-patients and predicated on an assumption of adequate access to supportive care. Therapeutics that can feasibly be delivered to those earlier in the course of infection that reduce the need for healthcare or reduce infectiousness could have significant impact, and research into their efficacy and means of delivery should be a priority.

Understanding the Potential Role of Therapeutics in Preventing Deaths Due to COVID-19: A Modelling Analysis (preprint)

Background: The unprecedented public health impact of the COVID-19 pandemic has motivated a rapid search for potential therapeutics, with some key successes. However, the potential impact of current and proposed treatments, and consequently research and procurement priorities, have not been clear. Methods: First, we used a model of SARS-CoV-2 transmission, COVID-19 disease and clinical care pathways to explore the potential impact of dexamethasone - the main treatment currently for hospitalised COVID-19 patients - under scenarios varying: i) healthcare capacity, ii) epidemic trajectories; and iii) the efficacy of dexamethasone in the absence of supportive care. We then fit the model to the observed epidemic trajectory to-date in 165 countries and analysed the potential future impact of dexamethasone in different countries, regions, and country-income strata. Finally, we constructed hypothetical profiles of novel therapeutics based on current trials, and compared the potential impact of each under different circumstances. In each case, the outcome of interest was the number of COVID-19 deaths averted in scenarios with the therapeutic compared to scenarios without. Findings: We find the potential benefit dexamethasone is severely limited in settings where healthcare capacity is lowest or where uncontrolled epidemics result in hospitals being overwhelmed. As such, it may avert 22% of deaths in high-income countries but only 8% in low-income countries (assuming R=1.35). However, therapeutics for different patient populations (in particular, those not in hospital and early in the course of infection) and types of benefit (in particular, reducing disease severity or infectiousness) could have much greater benefits. Such therapeutics would have particular value in resource-poor settings facing large epidemics, even if the efficacy or achievable coverage of such therapeutics is lower in comparison to other types. Interpretation: People in low-income countries will benefit the least from advances in the treatment of COVID-19 to date, which have focussed on hospitalised-patients with adequate access to supportive care. Therapeutics that can feasibly be delivered to those earlier in the course of infection that reduce the need for healthcare or reduce infectiousness could have much greater impact. Such therapeutics may be feasible and research into their efficacy and means of delivery should be a priority. Funding: None to declare. Declaration of Interest: None to declare.

Epidemiology, Clinical Characteristics, And Treatment Outcomes Of Patients With COVID-19 At Siriraj Hospital – Thailand’s Largest University-Based Super-Tertiary Referral Center (preprint)

Background: The epidemiology and outcomes of COVID-19 patients in Thailand are scarce. Methods: This retrospective cohort study included adult hospitalized patients who were diagnosed with COVID-19 at Siriraj Hospital during February 2020 to April 2020. Results: Of 1,409 patients who underwent reverse transcription polymerase chain reaction (RT-PCR) testing for SARS-CoV-2, 1,029 patients (73%) had risk factors for COVID-19 acquisition of which 107 patients had laboratory-confirmed COVID-19. Among the 104 patients who were treated with antiviral medications, 78 (75%) received 2-drug regimen (lopinavir/ritonavir or darunavir/ritonavir plus chloroquine or hydroxychloroquine), and 26 (25%) received a 3-drug regimen with favipiravir added to the 2-drug regimen. Disease progression was observed in 18 patients (16.8%). All patients with COVID-19 were discharged alive. Conclusions: The prevalence of COVID-19 was 7.5% among patients who underwent RT-PCR testing, and 10% among those having risk factors for COVID-19 acquisition. Combination antiviral therapies for COVID-19 patients were well-tolerated and produced a favorable outcome.