The Antiviral Effect of Nirmatrelvir/Ritonavir during COVID-19 Pandemic Real-World Data.

INTRODUCTION: Vaccination against SARS-CoV-2 and the prevalence of Omicron variants have reduced the risk of the severe clinical progress of COVID-19. However, the risk of breakthrough infections has increased, and early administration of an effective antiviral treatment is significant in order to prevent the severe progression of COVID-19 in vulnerable patients with comorbidities. PATIENTS AND METHODS: Adults with confirmed SARS-CoV-2 infection were included in a matched-pair retrospective study based on age, gender, comorbidities and vaccination status. They were divided into two groups: group A (n = 200) consisted of outpatients at increased risk of severe clinical progress who were treated with nirmatrelvir/ritonavir and group B (n = 200) consisted of non-hospitalized patients who did not receive antiviral treatment. Demographic data, clinical outcome (death, intubation), days of hospitalization, time for recovery, adverse events and treatment compliance were reported. RESULTS: The median age (75.24 ± 13.12 years in the study group and 76.91 ± 14.02 years in the comparison group) and the proportion of males (59% vs. 60.5%, respectively) were similar between the two groups. A total of 6.5% of patients in group A and 10.5% in group B were unvaccinated against SARS-CoV-2. Three patients from group A (1.5%) and one hundred eleven (55.5%) from group B required hospitalization. The duration of hospitalization (3 days vs. 10 days in group B, p < 0.001) and the total time needed for recovery (5 days vs. 9 days, p < 0.001) was shorter in the study group. A rebound of SARS-CoV-2 infection within 8-12 days after diagnosis was documented in 6.5% of patients in group A and 8% of patients in group B. CONCLUSION: Oral treatment with nirmatrelvir/ritonavir in high-risk non-hospitalized patients was safe and effective in preventing the severe clinical progress of COVID-19 pneumonia. Early administration of antiviral agents in vulnerable outpatients combined with a full vaccination scheme is significant in order to avoid hospitalization and severe clinical outcomes.

Nirmatrelvir treatment of SARS-CoV-2-infected mice blunts antiviral adaptive immune responses.

Alongside vaccines, antiviral drugs are becoming an integral part of our response to the SARS-CoV-2 pandemic. Nirmatrelvir-an orally available inhibitor of the 3-chymotrypsin-like cysteine protease-has been shown to reduce the risk of progression to severe COVID-19. However, the impact of nirmatrelvir treatment on the development of SARS-CoV-2-specific adaptive immune responses is unknown. Here, by using mouse models of SARS-CoV-2 infection, we show that nirmatrelvir administration blunts the development of SARS-CoV-2-specific antibody and T cell responses. Accordingly, upon secondary challenge, nirmatrelvir-treated mice recruited significantly fewer memory T and B cells to the infected lungs and mediastinal lymph nodes, respectively. Together, the data highlight a potential negative impact of nirmatrelvir treatment with important implications for clinical management and might help explain the virological and/or symptomatic relapse after treatment completion reported in some individuals.

Oral Antiviral Therapy Utilization Among Adults with Recent COVID-19 in the United States.

BACKGROUND: This is the first study, to our knowledge, to assess uptake of oral antiviral treatment (OAV) for COVID-19 in the US and assess whether it is reaching recommended groups. OBJECTIVE: The study evaluated uptake among persons of all ages, with emphasis on utilization among individuals ages 65 + who comprise 75% of all COVID-19 deaths. To maximize public health outreach and benefit, we sought to understand reasons for use and non-use of OAV among individuals 65 + with at least mild COVID-19 symptoms. DESIGN: Data were collected from phase 3.5 of the US Census Household Pulse Survey, during three 2022 time periods: June 1-13, June 29-July 11, and July 27-August 8. PARTICIPANTS: Respondents (n = 12,299) were ages 18 + with active or resolved COVID-19 within the last 4 weeks of their survey participation. MAIN MEASURE(S): Comparisons of demographic variables were made for OAV uptake using the chi-square test of independence. A logistic regression was conducted to identify characteristics of participants independently associated with receipt of an OAV. Comparisons were made with chi-square testing, between those ages 65 + with at least mild symptoms who endorsed one of a number of specific reasons for not using OAV. KEY RESULTS: Utilization was low-17.9% of all respondents, 20.5% of respondents ages 50-64, and 33.9% of respondents 65 years and older received guideline-concordant treatment for their infection. Receipt did not differ by income or sex. The average response across the three phases was 5.4%. Most common reasons for not receiving treatment included having minimal symptoms, not thinking that they needed treatment, and not receiving a recommendation from their healthcare provider. CONCLUSIONS: A minority of increased-risk US residents have accessed early therapy for COVID-19 despite being made available without cost. Responses suggest that efforts to improve patient and provider knowledge could improve utilization to mitigate future COVID-19 hospitalizations.

Unraveling the dynamics of the Omicron and Delta variants of the 2019 coronavirus in the presence of vaccination, mask usage, and antiviral treatment.

The effectiveness of control interventions against COVID-19 is threatened by the emergence of SARS-CoV-2 variants of concern. We present a mathematical model for studying the transmission dynamics of two of these variants (Delta and Omicron) in the United States, in the presence of vaccination, treatment of individuals with clinical symptoms of the disease and the use of face masks. The model is parameterized and cross-validated using observed daily case data for COVID-19 in the United States for the period from November 2021 (when Omicron first emerged) to March 2022. Rigorous qualitative analysis of the model shows that the disease-free equilibrium of the model is locally-asymptotically stable when the control reproduction number of the model (denoted by R c ) is less than one. This equilibrium is shown to be globally-asymptotically stable for a special case of the model, where disease-induced mortality is negligible and both vaccine-derived immunity in fully-vaccinated individuals and natural immunity do not wane, when the associated reproduction number is less than one. The epidemiological implication of the latter result is that the combined vaccination-boosting strategy can lead to the elimination of the pandemic if its implementation can bring (and maintain) the associated reproduction number to a value less than one. An analytical expression for the vaccine-derived herd immunity threshold is derived. Using this expression, together with the baseline values of the parameters of the parameterized model, we showed that the vaccine-derived herd immunity can be achieved in the United States (so that the pandemic will be eliminated) if at least 68 % of the population is fully-vaccinated with two of the three vaccines approved for use in the United States (Pfizer or Moderna vaccine). Furthermore, this study showed (as of the time of writing in March 2022) that the control reproduction number of the Omicron variant was approximately 3.5 times that of the Delta variant (the reproduction of the latter is computed to be ≈ 0.2782 ), indicating that Delta had practically died out and that Omicron has competitively-excluded Delta (to become the predominant variant in the United States). Based on our analysis and parameterization at the time of writing of this paper (March 2022), our study suggests that SARS-CoV-2 elimination is feasible by June 2022 if the current baseline level of the coverage of fully-vaccinated individuals is increased by about 20 % . The prospect of pandemic elimination is significantly improved if vaccination is combined with a face mask strategy that prioritizes moderately effective and high-quality masks. Having a high percentage of the populace wearing the moderately-effective surgical mask is more beneficial to the community than having low percentage of the populace wearing the highly-effective N95 masks. We showed that waning natural and vaccine-derived immunity (if considered individually) offer marginal impact on disease burden, except for the case when they wane at a much faster rate (e.g., within three months), in comparison to the baseline (estimated to be within 9 months to a year). Treatment of symptomatic individuals has marginal effect in reducing daily cases of SARS-CoV-2, in comparison to the baseline, but it has significant impact in reducing daily hospitalizations. Furthermore, while treatment significantly reduces daily hospitalizations (and, consequently, deaths), the prospects of COVID-19 elimination in the United States are significantly enhanced if investments in control resources are focused on mask usage and vaccination rather than on treatment.

Impact of Early SARS-CoV-2 Antiviral Therapy on Disease Progression.

Since the start of the SARS-CoV-2 pandemic, several treatments have been proposed to prevent the progression of the disease. Currently, three antiviral (molnupiravir, nirmaltrevir/r, remdesivir) and two monoclonal antibodies (casirivimab/imdevimab and sotrovimab) are available in Italy. Therefore, we aimed to evaluate the presence of risk factors associated with disease progression. We conducted a retrospective cohort study, including all patients with a confirmed diagnosis of SARS-CoV-2 evaluated between 01/01/2022 ad 10/05/2022 by our Unit of Infectious Diseases in Sassari. We defined disease progression as the necessity of starting O2 therapy. According to AIFA (Italian Medicines Agency) indications, preventive treatment was prescribed in patients with recent symptoms onset (≤five days), no need for oxygen supplementation, and risk factors for disease progression. Subgroup differences in quantitative variables were evaluated using Student's t-test. Pearson chi-square or Fisher's exact tests were used to assess differences for qualitative variables. Multivariate logistic regression modelling was performed to determine factors associated with progression. A two-tailed p-value less than 0.05 was considered statistically significant. All statistical analyses were performed with STATA version 17 (StataCorp, College Station, TX, USA). We included 1145 people with SARS-CoV-2 diagnosis, of which 336 (29.3%) developed severe disease with oxygen supplementation. In multivariate logistic regression analysis, age, dementia, haematologic tumors, heart failure, dyspnoea or fever at first evaluation, having ground glass opacities or consolidation at the first CT scan, and bacteria coinfection were associated with an increased risk of disease progression. Vaccination (at least two doses) and early treatment with antiviral or monoclonal antibodies were associated with a lower risk of disease progression. In conclusion, our study showed that vaccination and early treatment with antiviral and/or monoclonal antibodies significantly reduce the risk of disease progression.

COVID-19 symptom-onset to diagnosis and diagnosis to treatment intervals are significant predictors of disease progression and hospitalization in high-risk patients: A real world analysis.

BACKGROUND: Coronavirus disease (COVID-19) is overwhelming healthcare systems worldwide. This study aimed to elucidate factors that influence disease progression to pneumonia and hospitalization before and after antiviral treatment for COVID-19 in an outpatient setting. METHODS: A total of 206 high-risk patients with COVID-19 were treated with sotrovimab, remdesivir, and molnupiravir at the Toshiwakai clinic between January 4 and April 30, 2022. Of these, 49 patients visited the Toshiwakai clinic directly and were treated immediately after diagnosis (Toshiwakai-clinic study group). The remaining patients were diagnosed elsewhere, and of these, 102 patients were quarantined at home (health-center study group) and 55 at designated facilities (quarantine-facility study group) before being referred to Toshiwakai clinic. Patients were categorized into those with mild and moderate COVID-19, based on the presence of pneumonia at the initial visit to Toshiwakai clinic. RESULTS: The symptom-onset-to-diagnosis and diagnosis-to-treatment intervals were significant predictors of moderate disease. Age, dyspnea, and diagnosis-to-treatment interval at the first visit to Toshiwakai clinic were significant predictors for hospitalization even after antiviral treatment. Although the symptom-onset-to-diagnosis interval did not differ among the three study groups, the diagnosis-to-treatment and symptom-onset-to-treatment intervals were significantly longer in the health-center and quarantine-facility study groups than in the Toshiwakai-clinic study group. CONCLUSION: The symptom-onset-to-diagnosis and diagnosis-to-treatment intervals reflect diagnostic and interventional delays, respectively, which are closely related to the current COVID-19 clinical management protocol. Easy access to the clinics and immediate antiviral treatment after diagnosis may be the best methods to prevent disease progression and hospitalization in high-risk patients.

Paxlovid: A promising drug for the challenging treatment of SARS-COV-2 in the pandemic era.

Coronavirus infection is a pandemic threat and the most dangerous disease of the 21st century. Despite the rigorous exertion of world-class researchers, there is no perfect cure for it. It has been seen in presently available studies that Paxlovid prevents the progression of diseases and reduces severity in patients tremendously who are at high risk of hospitalization and death. It is a safe oral antiviral drug and has the potential to treat infections from multiple corona variants including omicron which affects humans. Paxlovid is comparatively less expensive than other available effective medicines. Consequently, it reduces hospitalization and death and helps to plummet the economic burden on patients and the health-care system globally. This medicine is still under investigation, and numerous clinical trials are still underway. Its potential side effects are minor and well tolerated by research study participants. Studies show its benefits outweigh the risk, and it is an effective and good alternative for the treatment of coronavirus disease.

Results from a test-and-treat study for influenza among residents of homeless shelters in King County, WA: A stepped-wedge cluster-randomized trial.

BACKGROUND: Persons experiencing homelessness face increased risk of influenza as overcrowding in congregate shelters can facilitate influenza virus spread. Data regarding on-site influenza testing and antiviral treatment within homeless shelters remain limited. METHODS: We conducted a cluster-randomized stepped-wedge trial of point-of-care molecular influenza testing coupled with antiviral treatment with baloxavir or oseltamivir in residents of 14 homeless shelters in Seattle, WA, USA. Residents ≥3 months with cough or ≥2 acute respiratory illness (ARI) symptoms and onset <7 days were eligible. In control periods, mid-nasal swabs were tested for influenza by reverse transcription polymerase chain reaction (RT-PCR). The intervention period included on-site rapid molecular influenza testing and antiviral treatment for influenza-positives if symptom onset was <48 h. The primary endpoint was monthly influenza virus infections in the control versus intervention periods. Influenza whole genome sequencing was performed to assess transmission and antiviral resistance. RESULTS: During 11/15/2019-4/30/2020 and 11/2/2020-4/30/2021, 1283 ARI encounters from 668 participants were observed. Influenza virus was detected in 51 (4%) specimens using RT-PCR (A = 14; B = 37); 21 influenza virus infections were detected from 269 (8%) intervention-eligible encounters by rapid molecular testing and received antiviral treatment. Thirty-seven percent of ARI-participant encounters reported symptom onset < 48 h. The intervention had no effect on influenza virus transmission (adjusted relative risk 1.73, 95% confidence interval [CI] 0.50-6.00). Of 23 influenza genomes, 86% of A(H1N1)pdm09 and 81% of B/Victoria sequences were closely related. CONCLUSION: Our findings suggest feasibility of influenza test-and-treat strategies in shelters. Additional studies would help discern an intervention effect during periods of increased influenza activity.

Could widespread use of antiviral treatment curb the COVID-19 pandemic? A modeling study.

BACKGROUND: Despite the development of safe and effective vaccines, effective treatments for COVID-19 disease are still urgently needed. Several antiviral drugs have shown to be effective in reducing progression of COVID-19 disease. METHODS: In the present work, we use an agent-based mathematical model to assess the potential population impact of the use of antiviral treatments in four countries with different demographic structure and current levels of vaccination coverage: Kenya, Mexico, United States (US) and Belgium. We analyzed antiviral effects on reducing hospitalization and death, and potential antiviral effects on reducing transmission. For each country, we varied daily treatment initiation rate (DTIR) and antiviral effect in reducing transmission (AVT). RESULTS: Irrespective of location and AVT, widespread antiviral treatment of symptomatic adult infections (20% DTIR) prevented the majority of COVID-19 deaths, and recruiting 6% of all adult symptomatic infections daily reduced mortality by over 20% in all countries. Furthermore, our model projected that targeting antiviral treatment to the oldest age group (65 years old and older, DTIR of 20%) can prevent over 30% of deaths. Our results suggest that early antiviral treatment (as soon as possible after inception of infection) is needed to mitigate transmission, preventing 50% more infections compared to late treatment (started 3 to 5 days after symptoms onset). Our results highlight the synergistic effect of vaccination and antiviral treatment: as the vaccination rate increases, antivirals have a larger relative impact on population transmission. Finally, our model projects that even in highly vaccinated populations, adding antiviral treatment can be extremely helpful to mitigate COVID-19 deaths. CONCLUSIONS: These results suggest that antiviral treatments can become a strategic tool that, in combination with vaccination, can significantly reduce COVID-19 hospitalizations and deaths and can help control SARS-CoV-2 transmission.

Successful pediatric liver transplantation case with a positive SARS-CoV-2 test at the time of transplant.

AIM: We report a successful liver transplantation (LT) in a child with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. CASE PRESENTATION: A 3-year-old female patient with decompensated cirrhosis due to Alagille syndrome underwent a split LT with a left lateral segment graft. She had a history of SARS-CoV-2 infection 4 months before LT. She was exposed to SARS-CoV-2 after the decision for organ acceptance. We repeatedly confirmed the negative SARS-CoV-2 test by polymerase chain reaction (PCR) before LT. Liver transplantation was carried out in the negative pressure operational theater with full airborne, droplet, and contact precautions as the patient was considered to be within the incubation period of SARS-CoV-2. The SARS-CoV-2 PCR test became positive in the nasopharyngeal swab specimen at the operation. Remdesivir, the antiviral treatment, was held off due to potential hepatotoxicity and no exacerbation of COVID-19. She received tacrolimus and low-dose steroids per protocol. She remained SARS-CoV-2 positive on postoperative days (PODs) 1, 2, and 5. The presence of antibodies for SARS-CoV-2 at LT was confirmed later. On POD 53, she was discharged without any symptomatic infection. CONCLUSION: This case demonstrated that a positive SARS-CoV-2 result was not an absolute contraindication for a life-saving LT. Liver transplantation could be safely performed in a pediatric patient with asymptomatic COVID-19 and S-immunoglobulin G antibodies for SARS-CoV-2.

Mathematical Modeling and Analysis of the Dynamics of RNA Viruses in Presence of Immunity and Treatment: A Case Study of SARS-CoV-2.

The emergence of novel RNA viruses like SARS-CoV-2 poses a greater threat to human health. Thus, the main objective of this article is to develop a new mathematical model with a view to better understand the evolutionary behavior of such viruses inside the human body and to determine control strategies to deal with this type of threat. The developed model takes into account two modes of transmission and both classes of infected cells that are latently infected cells and actively infected cells that produce virus particles. The cure of infected cells in latent period as well as the lytic and non-lytic immune response are considered into the model. We first show that the developed model is well-posed from the biological point of view by proving the non-negativity and boundedness of model's solutions. Our analytical results show that the dynamical behavior of the model is fully determined by two threshold parameters one for viral infection and the other for humoral immunity. The effect of antiviral treatment is also investigated. Furthermore, numerical simulations are presented in order to illustrate our analytical results.

Is the 4C Score Still a Valid Item to Predict In-Hospital Mortality in People with SARS-CoV-2 Infections in the Omicron Variant Era?

Since the start of the SARS-CoV-2 pandemic, several scores have been proposed to identify infected individuals at a higher risk of progression and death. The most famous is the 4C score. However, it was developed in early 2020. Our study aimed to evaluate the accuracy of the 4C score during the wave in which the Omicron variant was prevalent. An observational study was conducted at an Italian University Hospital between 1 January and 31 July 2022. A receiver operating characteristic (ROC) curve analysis was performed to evaluate the ability of the 4C score to predict mortality. Overall, 1186 people were recruited, of which 160 (13.5%) died. According to the 4C score, 177 (11.6%) were classified as having a low risk of mortality, 302 (25.5%) were intermediate, 596 (50.3%) were high, and 151 (12.7%) were very high. The ROC curve of the 4C score showed an AUC (95% CI) value of 0.78 (0.74−0.82). At the criterion value of > 10, the sensitivity was 76.2% and the specificity was 62.67%. Similar to previous studies, the 4C mortality score performed well in our sample, and it is still a useful tool for clinicians to identify patients with a high risk of progression. However, clinicians must be aware that the mortality rate reported in the original studies was higher than that observed in our study.

Antiviral Treatment against Monkeypox: A Scoping Review.

During the COVID-19 pandemic, the increase in reports of human monkeypox virus infection cases spreading in many countries outside Africa is a major cause for concern. Therefore, this study aimed to explore the evidence of antiviral pharmacotherapy available for the treatment of adult patients with monkeypox. A scoping review of the literature was conducted using PubMed, Scopus, Web of Science, Embase, and CENTRAL databases until 12 September 2022. The key search terms used were "monkeypox" and "treatment". A total of 1927 articles were retrieved using the search strategy. After removing duplicates (n = 1007) and examining by title, abstract, and full text, 11 studies reporting case reports of monkeypox with antiviral treatment were included, detailing the number of monkeypox cases, clinical manifestations, number of participants with antiviral treatment, history of sexually transmitted diseases, method of diagnosis, location of skin lesions, drugs used in antiviral treatment, route of administration, and outcome. A total of 1281 confirmed cases of monkeypox have been reported, of which 65 monkeypox cases had antiviral treatment distributed most frequently in the United States (n = 30), the United Kingdom (n = 6), and Spain (n = 6). Of the total cases, 1269 (99.1%) were male with an age range of 18 to 76 years, and 1226 (95.7%) had a sexual behavior of being men who have sex with men. All confirmed cases of monkeypox were diagnosed by reverse transcriptase polymerase chain reaction (RT-PCR). The most frequent clinical manifestations were skin lesions, fever, lymphadenopathy, headache, fatigue, and myalgia. The most frequent locations of the lesions were perianal, genital, facial, and upper and lower extremities. The most commonly used drugs for antiviral treatment of monkeypox were: tecovirimat, cidofovir, and brincidofovir. All patients had a complete recovery. According to current evidence, the efficacy and safety of antiviral drugs against monkeypox is of low quality and scarce.

[Recurrent SARS-CoV-2 infections in immunodeficiency]. / Rezidivierende SARS-CoV-2-Infektionen bei Immundefizienz.

A patient with immunodeficiency due to a B-cell lymphoma has repeatedly been tested positive for SARS-CoV­2 during the ongoing SARS-CoV­2 pandemic and has twice received in-hospital treatment. Chronic and recurrent SARS-CoV­2 infections are a threat to the individual health of immunodeficient patients. Only few therapeutic options are available especially due to emerging virus variants with immune escape mechanisms. The medical care of immunodeficient patients with SARS-CoV­2 infections is a great challenge to the treating physician in the ongoing pandemic.

What progress has been made in treatment of immunocompromised COVID-19 patients?

While immunocompromised patients are at very high risk of developing severe COVID 19, few of them have been enrolled in studies aimed at evaluating treatments. In the early stages of research on this disease, glucocorticoid therapy became the standard of care for patients requiring oxygen supplementation. It has been demonstrated that the neutralizing monoclonal antibody combination of Casirivimab and Imdevimab reduced (by 28 days) mortality in COVID-19 patients admitted to hospital who were seronegative at baseline, but not in those who were seropositive. There is still a need to determine the place of available various antivirals (Molnupiravir or Nirmatrelvir plus Ritonavir) and passive immunotherapies (Sotrovimab…) as well as convalescent plasma therapy in immunocompromised settings.

Safety and efficacy of molnupiravir in SARS-CoV-2-infected patients: A real-life experience.

Since the start of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic, several treatments have been proposed to cure coronavirus disease 2019 (COVID-19) and prevent it. Molnupiravir is a ribonucleoside prodrug of N-hydroxycytidine with an in vitro and in vivo activity against SARS-CoV-2. We conducted a retrospective cohort study that included all people treated with molnupiravir between January 10, 2022, and March 31, 2022, at the University Hospital of Sassari. Molnupiravir was prescribed, according to the Italian Agency of Drug indications, to patients with recent symptom onset (≤5 days), no need for oxygen supplementation, and with a high risk of disease progression for the presence of chronic diseases. We included 192 people with a mean age of 70.4 ± 15.4 years, with 144 (75%) patients over 60 years. During the follow-up, 20 (10.4%) patients showed a disease progression. At the multivariate analysis, older age, having neurological disease, having dyspnea at the onset of the symptoms, and acquiring SARS-CoV-2 infection during hospital admission were associated with an increased risk of progression. In contrast, an early start of treatment was associated with a reduced risk of disease progression. Molnupiravir was also extremely safe since 13 (6.8%) adverse events were reported, with only one interruption. Our study shows that monlupiravir confirmed its efficacy and safety in a real-life cohort that included a high percentage of elderly people with a high comorbidity burden.

The burden of SARS-CoV-2 in patients receiving chimeric antigen receptor T cell immunotherapy: everything to lose.

INTRODUCTION: Chimeric antigen receptor T (CAR-T) cell immunotherapy has revolutionized the prognosis of refractory or relapsed B-cell malignancies. CAR-T cell recipients have immunosuppression generated by B-cell aplasia, leading to a higher susceptibility to respiratory virus infections and poor response to vaccination. AREAS COVERED: This review focuses on the challenge posed by B-cell targeted immunotherapies: managing long-lasting B-cell impairment during the successive surges of a deadly viral pandemic. We restricted this report to data regarding vaccine efficacy in CAR-T cell recipients, outcomes after developing COVID-19 and specificities of treatment management. We searched in MEDLINE database to identify relevant studies until 31 March 2022. EXPERT OPINION: Among available observational studies, the pooled mortality rate reached 40% in CAR-T cell recipients infected by SARS-CoV-2. Additionally, vaccine responses seem to be widely impaired in recipients (seroconversion 20%, T-cell response 50%). In this setting of B-cell depletion, passive immunotherapy is the backbone of treatment. Convalescent plasma therapy has proven to be a highly effective curative treatment with rare adverse events. Neutralizing monoclonal antibodies could be used as pre-exposure prophylaxis or early treatment but their neutralizing activity is constantly challenged by new variants. In order to reduce viral replication, direct-acting antiviral drugs should be considered.

Manipulation of Spray-Drying Conditions to Develop an Inhalable Ivermectin Dry Powder.

SARS-CoV-2, the causative agent of COVID-19, predominantly affects the respiratory tract. As a consequence, it seems intuitive to develop antiviral agents capable of targeting the virus right on its main anatomical site of replication. Ivermectin, a U.S. FDA-approved anti-parasitic drug, was originally shown to inhibit SARS-CoV-2 replication in vitro, albeit at relatively high concentrations, which is difficult to achieve in the lung. In this study, we tested the spray-drying conditions to develop an inhalable dry powder formulation that could ensure sufficient antiviral drug concentrations, which are difficult to achieve in the lungs based on the oral dosage used in clinical trials. Here, by using ivermectin as a proof-of-concept, we evaluated spray-drying conditions that could lead to the development of antivirals in an inhalable dry powder formulation, which could then be used to ensure sufficient drug concentrations in the lung. Thus, we used ivermectin in proof-of-principle experiments to evaluate our system, including physical characterization and in vitro aerosolization of prepared dry powder. The ivermectin dry powder was prepared with a mini spray-dryer (Buchi B-290), using a 23 factorial design and manipulating spray-drying conditions such as feed concentration (0.2% w/v and 0.8% w/v), inlet temperature (80 °C and 100 °C) and presence/absence of L-leucine (0% and 10%). The prepared dry powder was in the size range of 1-5 µm and amorphous in nature with wrinkle morphology. We observed a higher fine particle fraction (82.5 ± 1.4%) in high feed concentration (0.8% w/v), high inlet temperature (100 °C) and the presence of L-leucine (10% w/w). The stability study conducted for 28 days confirmed that the spray-dried powder was stable at 25 ± 2 °C/<15% RH and 25 ± 2 °C/ 53% RH. Interestingly, the ivermectin dry powder formulation inhibited SARS-CoV-2 replication in vitro with a potency similar to ivermectin solution (EC50 values of 15.8 µM and 14.1 µM, respectively), with a comparable cell toxicity profile in Calu-3 cells. In summary, we were able to manipulate the spray-drying conditions to develop an effective ivermectin inhalable dry powder. Ongoing studies based on this system will allow the development of novel formulations based on single or combinations of drugs that could be used to inhibit SARS-CoV-2 replication in the respiratory tract.

A nonlinear optimal control method against the spreading of epidemics

To define a vaccination policy and antiviral treatment against the spreading of viral infections a nonlinear optimal (H-infinity) control approach is proposed. Actually, because of the scarcity of the resources for treating infectious diseases in terms of vaccines, antiviral drugs and other medical facilities, there is need to implement optimal control against the epidemics deployment. In this approach, the state-space model of the epidemics dynamics undergoes first approximate linearization around a temporary operating point which is recomputed at each time-step of the control method. The linearization is based on Taylor series expansion and on the computation of the associated Jacobian matrices. Next, an optimal (H-infinity) feedback controller is developed for the approximately linearized model of the epidemics. To compute the controller's feedback gains an algebraic Riccati equation is solved at each iteration of the control algorithm. Furthermore, the global asymptotic stability properties of the control scheme are proven through Lyapunov stability analysis. This paper's results confirm that optimal control of the infectious disease dynamics allows for eliminating its spreading while also keeping moderate the consumption of the related medication, that is vaccines and antiviral drugs.

SMYD2 Inhibition Downregulates TMPRSS2 and Decreases SARS-CoV-2 Infection in Human Intestinal and Airway Epithelial Cells.

The COVID-19 pandemic caused by SARS-CoV-2 has lasted for more than two years. Despite the presence of very effective vaccines, the number of virus variants that escape neutralizing antibodies is growing. Thus, there is still a need for effective antiviral treatments that target virus replication independently of the circulating variant. Here, we show for the first time that deficiency or pharmacological inhibition of the cellular lysine-methyltransferase SMYD2 decreases TMPRSS2 expression on both mRNA and protein levels. SARS-CoV-2 uses TMPRSS2 for priming its spike protein to infect target cells. Treatment of cultured cells with the SMYD2 inhibitors AZ505 or BAY598 significantly inhibited viral replication. In contrast, treatment of Vero E6 cells, which do not express detectable amounts of TMPRSS2, had no effect on SARS-CoV-2 infection. Moreover, by generating a recombinant reporter virus that expresses the spike protein of the Delta variant of SARS-CoV-2, we demonstrate that BAY598 exhibits similar antiviral activity against this variant of concern. In summary, SMYD2 inhibition downregulates TMPRSS2 and blocks viral replication. Targeting cellular SMYD2 represents a promising tool to curtail SARS-CoV-2 infection.