Antiviral Combination Research Articles

Antiviral combination treatment strategies for SARS-CoV-2 infection in immunocompromised patients.

The purpose of this review is to report the available evidence regarding the use of combination regimens of antivirals and/or antibody-based therapy in the treatment of SARS-CoV-2 in immunocompromised patients. Literature search identified 24 articles, excluding single case reports, which included mainly patients with hematological malignancies and/or B-cell depletion. Data were divided based on the timing and reason for administration of combination treatment, that is, early treatment to prevent progression to severe COVID-19 and treatment of prolonged or relapsed infection. We described the treated populations, treatment duration and composition of combination treatment. We briefly addressed new treatment options and we proposed an algorithm for the management of COVID-19 infection in patients affected by hematological malignancies. Combination treatment seems an effective (73-100%) and well tolerated (<5% reported bradycardia, hepatotoxicity, neutropenia) strategy for treating prolonged/relapsed SARS-CoV-2 infections in the immunocompromised host, although its optimal composition and duration cannot be defined based on the currently available evidence. The role of combination treatment as an early treatment strategy for immunocompromised patients at a high risk of progression to severe disease/persistent shedding requires further evidence from comparison with monotherapy, even though high efficacy was reported for combinations of antivirals plus mAbs in case of previous viral variants.

Update on Cytomegalovirus Infection Management in Allogeneic Hematopoietic Stem Cell Transplant Recipients. A Consensus Document of the Spanish Group for Hematopoietic Transplantation and Cell Therapy (GETH-TC).

Cytomegalovirus (CMV) infection is a common complication following allogeneic hematopoietic stem cell transplantation (allo-HSCT) and in patients receiving novel hematological therapies. Its impact on morbidity and mortality necessitates effective management strategies. Despite recent advances in diagnostics and treatment, unresolved questions persist regarding monitoring and treatment, prompting the need for updated recommendations. A consensus was reached among a panel of experts selected for their expertise in CMV research and clinical practice. Key clinical areas and questions were identified based on previous surveys and literature reviews. Recommendations were formulated through consensus and graded using established guidelines. Recommendations were provided for virological monitoring, including the timing and frequency of CMV DNAemia surveillance, especially during letermovir (LMV) prophylaxis. We evaluated the role of CMV DNA load quantification in diagnosing CMV disease, particularly pneumonia and gastrointestinal involvement, along with the utility of specific CMV immune monitoring in identifying at-risk patients. Strategies for tailoring LMV prophylaxis, managing breakthrough DNAemia, and implementing secondary prophylaxis in refractory cases were outlined. Additionally, criteria for initiating early antiviral treatment based on viral load dynamics were discussed. The consensus provides updated recommendations for managing CMV infection in hematological patients, focusing on unresolved issues in monitoring, prophylaxis, treatment, and resistance. These recommendations aim to guide clinical practice and improve outcomes in this high-risk population. Further research is warranted to validate these recommendations and address ongoing challenges in CMV management with emerging antiviral combinations, particularly in pediatric populations.

The effectiveness of risperidone on PANSS score and IL-6 in confirmed COVID-19 schizophrenic patients

The study aimed to determine the efficacy of risperidone on PANSS scores and Interleukin 6 (IL-6) levels in schizophrenia patients with confirmed COVID-19. The study type was analytical observational, with a prospective cohort design. The subjects included inpatient Schizophrenia patients with and without COVID-19, mild-moderate and asymptomatic COVID-19, and schizophrenic patients without COVID-19 who were hospitalized and met the inclusion and exclusion criteria, for a total of 22 subjects in each group. The Positive and Negative Syndrome Scale (PANSS) and Elisa Interleukin 6 (IL-6) serum were sampled consecutively for this study. In the positive covid-19 group, the Mean IL-6 Post was significantly lower than Pre (23.0 vs. 26.1, p&lt;0.001), while in the control group, the Mean IL-6 Post (four weeks) was significantly lower than Pre (baseline), with 19.3 vs. 21.0 (p&lt;0.001). Serum IL-6 levels appeared to be an effective prognostic biomarker in COVID-19 patients. The 35 pg/mL cut-off point could distinguish mild-moderate patients from more severe ones. We discovered that schizophrenia patients with verified positive COVID-19 received COVID-19 therapy in the form of a combination of antipsychotic and antivirals had IL-6 levels lower than 35 pg/mL, indicating the role of antipsychotic (risperidone) and antiviral in reducing IL-6 levels.

The evaluation of risk factors for prolonged viral shedding during anti-SARS-CoV-2 monoclonal antibodies and long-term administration of antivirals in COVID-19 patients with B-cell lymphoma treated by anti-CD20 antibody

BackgroundThe global impact of the coronavirus disease 2019 (COVID-19) pandemic has resulted in significant morbidity and mortality. Immunocompromised patients, particularly those treated for B-cell lymphoma, have shown an increased risk of persistent infection with SARS-CoV-2 and severe outcomes and mortality. Multi-mutational SARS-CoV-2 variants can arise during the course of such persistent cases of COVID-19. No optimal, decisive strategy is currently available for patients with persistent infection that allows clinicians to sustain viral clearance, determine optimal timing to stop treatment, and prevent virus reactivation. We introduced a novel treatment combining antivirals, neutralizing antibodies, and genomic analysis with frequent monitoring of spike-specific antibody and viral load for immunocompromised patients with persistent COVID-19 infection. The aim of this retrospective study was to report and evaluate the efficacy of our novel treatment for immunocompromised B-cell lymphoma patients with persistent COVID-19 infection.MethodsThis retrospective descriptive analysis had no controls. Patients with B-cell lymphoma previously receiving immunotherapy including anti-CD20 antibodies, diagnosed as having COVID-19 infection, and treated in our hospital after January 2022 were included. We selected anti-SARS-CoV-2 monoclonal antibodies according to subvariants. Every 5 days, viral load was tested by RT-PCR, with antivirals continued until viral shedding was confirmed. Primary outcome was virus elimination. Independent predictors of prolonged viral shedding time were determined by multivariate Cox regression.ResultsForty-four patients were included in this study. Thirty-five patients received rituximab, 19 obinutuzumab, and 26 bendamustine. Median treatment duration was 10 (IQR, 10–20) days; 22 patients received combination antiviral therapy. COVID-19 was severe in 16 patients, and critical in 2. All patients survived, with viral shedding confirmed at median 28 (IQR, 19–38) days. Bendamustine use or within 1 year of last treatment for B-cell lymphoma, and multiple treatment lines for B-cell lymphoma significantly prolonged time to viral shedding.ConclusionsAmong 44 consecutive patients treated, anti-SARS-CoV-2 monoclonal antibodies and long-term administration of antiviral drugs, switching, and combination therapy resulted in virus elimination and 100% survival. Bendamustine use, within 1 year of last treatment for B-cell lymphoma, and multiple treatment lines for B-cell lymphoma were the significant independent predictors of prolonged viral shedding time.

Innovative eco-friendly stability-indicating HPLC-PDA method for simultaneous determination of the emerging antiviral drugs against COVID-19 infection molnupiravir and favipiravir; degradation kinetic studies along with LC-MS based structure elucidation

The adoption of the principles of green chemistry in analytical procedures lowers the negative influence on both people and the environment, which presently has become the key goal. Additionally, the need for advanced analytical techniques for the simultaneous determination of antiviral combinations is highly recommended, one of those novel combinations that recently proved effective emerging antiviral drugs in the treatment of SARS-COV-2 is molnupiravir (MOL) and favipiravir (FAV). Therefore, the establishment of simple and precise stability-indicating HPLC-PDA method for their simultaneous determination is crucial for the probable co-formulation. The stability of MOL was studied along with FAV after forced degradation of both under different stress conditions Separation of MOL, FAV, and their corresponding degradation products was achieved by simple isocratic HPLC-PDA method using a mobile phase comprised of 25.0 mM phosphate buffer (pH 3.0 ± 0.05) − methanol (70:30, v/v) at flow rate 1.0 mL/min. A Zorbax C18 (250 × 4.6 mm, 5 μm; Agilent Technologies, USA) column was used for the separation of the components and the column oven was maintained at 30 °C, the selected wavelength for detection of both analytes and their degradation products was 230.0 nm. The method was linear over the range of 1.0 – 200.0 µg/mL for both MOL and FAV. MOL was found to be susceptible to all forced degradation conditions, namely, acid, alkali, oxidative, thermal, and photodegradation while FAV was susceptible only to acid, alkali, and oxidative degradation. The probable degradation mechanisms were assumed through the evaluation of the MS1 fragmentation pattern of the degradation products, also studying the kinetic behavior of the degradation reactions. Furthermore, the greenness profile for the proposed method was evaluated utilizing the new Complementary Green Analytical Procedure Index method (ComplexGAPI), and analytical greenness (AGREE) metrics with a score of the later one equals to 0.61 that indicated the greenness evaluation of the method. In addition, the new blue applicability grade index (BAGI) which is complementary to the green metrics showed a score of 85.0 that presents a good applicability potential of the method. The proposed method is the first sustainable, stability-indicating method developed for the simultaneous determination of this potential combination that would help in manufacturing both drugs in a fixed-dose drug combination.

Hepatitis C virus-induced differential transcriptional traits in host cells after persistent infection elimination by direct-acting antivirals in cell culture.

Chronic hepatitis C virus infection (HCV) causes liver inflammation and fibrosis, leading to the development of severe liver disease, such as cirrhosis or hepatocellular carcinoma (HCC). Approval of direct-acting antiviral drug combinations has revolutionized chronic HCV therapy, with virus eradication in >98% of the treated patients. The efficacy of these treatments is such that it is formally possible for cured patients to carry formerly infected cells that display irreversible transcriptional alterations directly caused by chronic HCV Infection. Combining differential transcriptomes from two different persistent infection models, we observed a major reversion of infection-related transcripts after complete infection elimination. However, a small number of transcripts were abnormally expressed in formerly infected cells. Comparison of the results obtained in proliferating and growth-arrested cell culture models suggest that permanent transcriptional alterations may be established by several mechanisms. Interestingly, some of these alterations were also observed in the liver biopsies of virologically cured patients. Overall, our data suggest a direct and permanent impact of persistent HCV infection on the host cell transcriptome even after virus elimination, possibly contributing to the development of HCC.

Safety and acceptance of nirmatrelvir/ritonavir in early SARS-CoV-2 treatment in Greek patients with solid cancer.

e23139 Background: Oncologic patients are at risk of developing severe SARS-CoV-2 infection. Nirmatrelvir/ ritonavir (N/R) is an oral antiviral combination effective in minimizing risk of hospital/ ICU admission/ death, if administered early. Adverse events are rare, but significant drug-drug interactions may necessitate modification of other therapies. We aimed to evaluate implementation, safety, and outcomes in Greek patients with solid tumors and SARS-CoV-2 infection, treated with N/R. Methods: The study was designed by the Hellenic Society of Medical Oncology; 11 Greek oncology centers participated. We retrospectively, prior to February 2023, or prospectively thereafter, recorded the use or not of N/R in oncologic patients, patient characteristics and infection course/ outcomes, post patient consent. No ethical issues exist, since this is the official early therapy recommended by the Greek Ministry of Health. Results: Data from182 patients were collected (55.5% women), aged 24-89 years (median 63). Most (64.8%) had stage IV or metastatic disease. 87.4% were on treatment (66% chemotherapy, 32% immunotherapy, 7.5% hormone therapy). Co-morbidities were present in 45%. This was the primary infection for 89.6%. Most (61.1%) were vaccinated ≥ 3 doses, with 85.2% receiving ≥ 1 dose. N/R was administered to 92.3%; for the non-recipients, patient refusal was the major cause. Symptomatic/ positivity relapse were rarely noted. Adverse reactions were reported by 5.9%, all mild/ moderate, mainly dysgeusia. Temporary adjustment or postponement of oncologic treatment course was needed in 33.9%. Hospitalization was needed in 1.1%, and ICU admission in 0.55%. No deaths were recorded in a 30-day period post diagnosis, but 2 deaths with possible SARS-CoV-2 contribution on them were reported in the 1-3 month follow-up period. The small number of patients not administered N/R precludes extraction of statistically significant comparisons. Conclusions: There is limited experience on efficacy/ safety of early N/R therapy for SARS-CoV-2 infection in oncologic patients; our series is the largest at present. The study demonstrates wide oncologic patient use of N/R with minimal side effects. Although 1/3 of the patients had to adjust their oncologic therapeutic course, this may have been due to the infection per se rather than drug-drug interactions. Most patients exhibited full recovery, with 1.1% in need of hospitalization and no deaths recorded during the first post-infection month. N/R is a convenient, effective early treatment for SARS-CoV-2 infection in solid cancer patients.

Antiviral therapies for the management of persistent coronavirus disease 2019 in immunocompromised hosts: A narrative review.

Antiviral agents with activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have played a critical role in disease management; however, little is known regarding the efficacy of these medications in the treatment of SARS-CoV-2 infection in immunocompromised patients, particularly in the management of persistent SARS-CoV-2 positivity. This narrative review discusses the management of persistent coronavirus disease 2019 in immunocompromised hosts, with a focus on antiviral therapies. We identified 84 cases from the literature describing a variety of approaches, including prolonged antiviral therapy (n = 11), combination antivirals (n = 13), and mixed therapy with antiviral and antibody treatments (n = 60). A high proportion had an underlying haematologic malignancy (n = 67, 80%), and were in receipt of anti-CD20 agents (n = 51, 60%). Success was reported in 70 cases (83%) which varied according to the therapy type. Combination therapies with antivirals may be an effective approach for individuals with persistent SARS-CoV-2 positivity, particularly those that incorporate treatments aimed at increasing neutralizing antibody levels. Any novel approaches taken to this difficult management dilemma should be mindful of the emergence of antiviral resistance.

The high-throughput solid-phase extraction of cis-cyclo(L-Leu-L-Pro) and cis-cyclo(L-Phe-L-Pro) from Lactobacillus plantarum demonstrates efficacy against multidrug-resistant bacteria and influenza A (H3N2) virus.

Introduction: 2,5-diketopiperazines are the simplest forms of cyclic dipeptides (CDPs) and have diverse frameworks with chiral side chains that are useful for drug development. Previous research has investigated the antimicrobial properties of proline-linked CDPs and their combinations in the culture filtrate (CF) of Lactobacillus plantarum LBP-K10 using anion exchange chromatography (AEC). However, the quantity of CDPs showcasing notable anti-influenza virus activity derived from AECs was generally lower than those originating from Lactobacillus CF. Methods: To address this issue, the study aims to propose a more efficient method for isolating CDPs and to introduce the antiviral combinations of CDPs obtained using a new method. The study employed a novel technique entailing high-throughput C18-based solid-phase extraction with a methanol gradient (MeSPE). The MeSPE method involved increasing the methanol concentration from 5% to 50% in 5% increments. Results: The methanol SPE fractions (MeSPEfs) eluted with methanol concentrations between 35% and 45% evinced substantial efficacy in inhibiting the influenza A/H3N2 virus via plaque-forming assay. MeSPEf-45, the 45% MeSPEf, exhibited exceptional efficacy in preventing viral infections in Madin-Darby kidney cells, surpassing both individual CDPs and the entire set of MeSPEfs. To identify the specific antiviral components of MeSPEf-45, all MeSPEfs were further fractionated through preparative high-performance liquid chromatography (prep-HPLC). MeSPEf-45 fractions S8 and S11 presented the highest activity against multidrug-resistant bacteria and influenza A/H3N2 virus among all MeSPEfs, with 11 common fractions. Antiviral fractions S8 and S11 were identified as proline-based CDPs, specifically cis-cyclo(L-Leu-L-Pro) and cis-cyclo(L-Phe-L-Pro), using gas chromatography-mass spectrometry. The combination of MeSPEf-45 fractions S8 and S11 displayed superior antibacterial and anti-influenza virus effects compared to the individual fractions S8 and S11. Discussion: High-throughput MeSPE-derived MeSPEfs and subsequent HPLC-fractionated fractions presents an innovative approach to selectively purify large amounts of potent antimicrobial CDPs from bacterial CF. The findings also show the effectiveness of physiologically bioactive combinations that utilize fractions not containing CDP. This study provides the initial evidence demonstrating the antimicrobial properties of CDPs acquired through high-throughput SPE techniques.

Antiviral and Monoclonal Antibody Combination Therapy in Haematological Patients in the Omicron Era.

Abstract: Im We describe here a single-center case series of 27 IC COVID-19 inpatients (mostly with haematological disorders) treated with a combined therapy based on tixagevimab/cilgavimab (T/C) plus small-molecule antivirals (AV), between April 1 2022 and November 30 2022. Keywords: immunocompromised; SARS-CoV-2 infection; monoclonal antibodies; antivirals; persistent infection; viral evolution

Synergism between remdesivir and ribavirin leads to SARS-CoV-2 extinction in cell culture.

There is a need for effective anti-COVID-19 treatments, mainly for individuals at risk of severe disease such as the elderly and the immunosuppressed. Drug repositioning has proved effective in identifying drugs that can find a new application for the control of coronavirus disease, in particular COVID-19. The purpose of the present study was to find synergistic antiviral combinations for COVID-19 based on lethal mutagenesis. The effect of combinations of remdesivir and ribavirin on the infectivity of SARS-CoV-2 in cell culture has been tested. Viral populations were monitored by ultra-deep sequencing, and the decrease of infectivity as a result of the treatment was measured. Remdesivir and ribavirin exerted a synergistic inhibitory activity against SARS-CoV-2, quantified both by CompuSyn (Chou-Talalay method) and Synergy Finder (ZIP-score model). In serial passage experiments, virus extinction was readily achieved with remdesivir-ribavirin combinations at concentrations well below their cytotoxic 50 value, but not with the drugs used individually. Deep sequencing of treated viral populations showed that remdesivir, ribavirin, and their combinations evoked significant increases of the number of viral mutations and haplotypes, as well as modification of diversity indices that characterize viral quasi-species. SARS-CoV-2 extinction can be achieved by synergistic combination treatments based on lethal mutagenesis. In addition, the results offer prospects of triple drug treatments for effective SARS-CoV-2 suppression.

Toward a Functional Cure for Hepatitis B.

Current treatment of chronic hepatitis B virus (HBV) infection, pegylated interferon-α (pegIFN-α) and nucleos(t)ide analogue (NA), can suppress HBV replication, reverse liver inflammation and fibrosis, and decrease risks of cirrhosis and hepatocellular carcinoma, but hepatitis B surface antigen (HBsAg) loss is rare. Functional HBV cure is defined as undetectable HBsAg and unquantifiable serum HBV DNA for at least 24 weeks after a finite course of therapy. This requires suppression of HBV replication and viral protein production as well as restoration of immune response to HBV. Direct-acting antivirals targeting virus entry, capsid assembly, viral protein production and secretion are in clinical trials. In parallel, immune modulatory therapies to stimulate HBV-specific immune response and to remove immune blockade are being tested. Clinical trials of direct-acting antivirals alone or immune modulatory therapies alone have not been successful in achieving HBV cure. Recent combinations of direct-acting antivirals and immune modulatory therapies have shown promising results particularly with combinations that included pegIFN-α. These results need to be confirmed in larger studies with longer follow-up, and further work is needed to develop simpler regimens with fewer drugs that can be administered orally and safely. While there is a strong desire to develop finite therapies that can achieve HBV cure, safety is paramount and new therapies must provide incremental value compared to standard of care, which is predominantly long-term NA therapy.

A combination of nirmatrelvir and ombitasvir boosts inhibition of SARS-CoV-2 replication

Antiviral therapeutics are highly effective countermeasures for the treatment of coronavirus disease 2019 (COVID-19). However, development of resistance to antivirals undermines their effectiveness. Combining multiple antivirals during patient treatment has the potential to overcome the evolutionary selective pressure towards antiviral resistance, as well as provide a more robust and efficacious treatment option. The current evidence for effective antiviral combinations to inhibit severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication is limited. Here, we demonstrate a combination of nirmatrelvir with ombitasvir, to jointly bring about potent inhibition of SARS-CoV-2 replication. We developed an in vitro 384- well plate cytopathic effect assay for the evaluation of antiviral combinations against Calu-3 cells infected with SARS-CoV-2 and found, that a combination of ombitasvir and nirmatrelvir was synergistic; thereby decreasing the nirmatrelvir IC50 by approx. 16-fold. The increased potency of the nirmatrelvir-ombitasvir combination, over nirmatrelvir alone afforded a greater than 3 log10 reduction in viral titre, which is sufficient to fully prevent the detection of progeny SARS-CoV-2 viral particles at 48 h post infection. The mechanism of this potentiated effect was shown to be, in-part, due to joint inhibition of the 3-chymotrypsin-like protease via a positive allosteric modulation mechanism.

The combination of pleconaril, rupintrivir, and remdesivir efficiently inhibits enterovirus infections in vitro, delaying the development of drug-resistant virus variants

Enteroviruses are a significant global health concern, causing a spectrum of diseases from the common cold to more severe conditions like hand-foot-and-mouth disease, meningitis, myocarditis, pancreatitis, and poliomyelitis. Current treatment options for these infections are limited, underscoring the urgent need for effective therapeutic strategies. To find better treatment option we analyzed toxicity and efficacy of 12 known broad-spectrum anti-enterovirals both individually and in combinations against different enteroviruses in vitro. We identified several novel, synergistic two-drug and three-drug combinations that demonstrated significant inhibition of enterovirus infections in vitro. Specifically, the triple-drug combination of pleconaril, rupintrivir, and remdesivir exhibited remarkable efficacy against echovirus (EV) 1, EV6, EV11, and coxsackievirus (CV) B5, in human lung epithelial A549 cells. This combination surpassed the effectiveness of single-agent or dual-drug treatments, as evidenced by its ability to protect A549 cells from EV1-induced cytotoxicity across seven passages. Additionally, this triple-drug cocktail showed potent antiviral activity against EV-A71 in human intestinal organoids. Thus, our findings highlight the therapeutic potential of the pleconaril-rupintrivir-remdesivir combination as a broad-spectrum treatment option against a range of enterovirus infections. The study also paves the way towards development of strategic antiviral drug combinations with virus family coverage and high-resistance barriers.

Efficacy and safety of antiviral plus anti-spike monoclonal antibody combination therapy vs. monotherapy for high-risk immunocompromised patients with mild-to-moderate SARS-CoV2 infection during the Omicron era: A prospective cohort study

Antivirals and monoclonal antibodies lower the risk of progression in immunocompromised patients. However, combination therapy with both types of agents has not been studied. This was a single-centre, prospective, cohort study. All immunocompromised patients who received treatment for mild-to-moderate COVID-19 from 1 January 2022 to 30 October 2022 were enrolled. The primary endpoint was COVID-19 progression at 90 days, defined as hospital admission or death due to COVID-19 and/or seronegative persistent COVID-19. A total of 304 patients were included: 43 patients (14.1%) received sotrovimab plus a direct-acting antiviral, and 261 (85.9%) received monotherapy. Primary outcome occurred more frequently after monotherapy (4.6% vs. 0%, P=0.154). Among patients with anti-spike immunoglobulin G (anti-S IgG) titre <750 BAU/mL, COVID-19 progression was more common after monotherapy (23.9% vs. 0%, P=0.001), including more frequent COVID-related admission (15.2% vs. 0%, P=0.014) and seronegative persistent COVID-19 (10.9% vs. 0%, P=0.044). Combination therapy was associated with lower risk of progression (odds ratio [OR] 0.08, 95% confidence interval [95% CI] 0.01-0.64). Anti-S IgG titre <750 BAU/mL and previous anti-CD20 were associated with higher risk of progression (OR 13.70, 95% CI 2.77-67.68; and OR 3.05, 95% CI 1.20-10.94, respectively). In immunocompromised patients, combination therapy with sotrovimab plus an antiviral may be more effective than monotherapy for SARS-CoV2.

Hepatitis C: The Story of a Long Journey through First, Second, and Third Generation NS3/4A Peptidomimetic Inhibitors. What Did We Learn?

Hepatitis C viral (HCV) infection is the leading cause of liver failure and still represents a global health burden. Over the past decade, great advancements made HCV curable, and sustained viral remission significantly improved to more than 98%. Historical treatment with pegylated interferon alpha and ribavirin has been displaced by combinations of direct-acting antivirals. These regimens include drugs targeting different stages of the HCV life cycle. However, the emergence of viral resistance remains a big concern. The design of peptidomimetic inhibitors (PIs) able to fit and fill the conserved substrate envelope region within the active site helped avoid contact with the vulnerable sites of the most common resistance-associated substitutions Arg155, Ala156, and Asp168. Herein, we give an overview of HCV NS3 PIs discovered during the past decade, and we deeply discuss the rationale behind the structural optimization efforts essential to achieve pangenotypic activity.

Middle East Respiratory Syndrome Coronavirus Could be a Priority Pathogen to Cause Public Health Emergency: Noticeable Features and Counteractive Measures.

Middle East respiratory syndrome (MERS) is caused by a specific strain of the 6 types of human coronaviruses (HCoV). MERS-CoV has spread unchecked since it was first discovered in Saudi Arabia in 2012. The virus most likely spreads through nosocomial and zoonotic channels. Genetic analyses suggest that bats were the initial hosts and that the disease spread to camels. Person-to-person transmission occurs with varying frequency, being most prevalent in clinical settings and the least common among the general population and among close relatives. Due to the severity of the illness, high fatality rate, potential for epidemic spread, and lack of adequate medical countermeasures, the World Health Organization (WHO) continues to list MERS-CoV as a priority pathogen. While no specific antiviral medicines exist, a combination of antivirals has shown promise in recent clinical trials. Vaccines against MERS-CoV are critically needed and are currently being developed. Early diagnosis and implementing appropriate infection control measures are keys to preventing hospital-associated outbreaks. Preventive measures include avoiding raw or undercooked meats and other animal products, ensuring proper hand hygiene in healthcare settings and around dromedaries, educating the public and healthcare personnel about the disease, and adhering to other recommended practices. Countries with a high prevalence of MERS should adhere to regulations designed to limit the transmission of the virus. The recent spread of MERS-CoV highlights the importance of public awareness regarding the significance of reporting symptoms so that appropriate control measures can be adopted. The narrative review discusses the incidence of MERS, its clinical presentation, potential transmission routes, recent reports, preventative and control measures, and current therapeutic options.

Combination therapy of nitazoxanide with oseltamivir compared with oseltamivir in hospitalized patients with seasonal influenza.

Antiviral combinations have been proposed as treatment for influenza in order to increase the antiviral activity by action at different sites of action as well as obviate the emergence of drug resistance to the commonly used antiviral agents like oseltamivir. Nitazoxanide has been found to exhibit anti-influenza viral activity with clinical benefit in a previous study. We recruited 242 cases of SARI, among whon 67 were confirmed to have influenza viral infection. In a randomized blinded fashion, 34 patients received a combination of nitazoxanide and oseltamivir whereas 33 cases received oseltamivir alone. Clinical parameters were followed in both groups and the nasal swabs were re-tested on day 6 for influenza positivity and the cycle threshold (CT) values. No significant differences were observed in terms of time for resolution of fever, other symptoms, and SOFA scores. Nine patients succumbed during the course of the illness that included three in the oseltamivir group and six in the combination group. All but one of those who expired had an underlying co-morbid illness. Our preliminary data suggest that the addition of nitazoxanide does not improve outcomes in hospitalized patients with influenza. Larger studies are recommended for statistically robust conclusions.

Optimizing COVID-19 treatment in immunocompromised patients: early combination therapy with remdesivir, nirmatrelvir/ritonavir and sotrovimab

BackgroundMorbidity and mortality are higher in immunocompromised patients affected by COVID-19 than in the general population. Some authors have successfully used antiviral combination, but never in the early phase of the infection.MethodsWe conducted a retrospective cohort study to determine the efficacy and safety of the combination of two antivirals, with and without a monoclonal antibody (mAb), in both the early (within 10 days of symptoms) and in a later phase (after 10 days) of SARS-CoV-2 infection in immunocompromised patients admitted to our Facility.ResultsWe treated 11 patients (seven in an early phase and four in a late phase of COVID-19) with 10 days of intravenous remdesivir plus five days of oral nirmatelvir/ritonavir, also combined with sotrovimab in 10/11 cases. Notably, all the “early” patients reached virological clearance at day 30 from the end of the therapy and were alive and well at follow-up, whereas the corresponding numbers in the “late” patients were 50% and 75%. Patients in the “late” group more frequently needed oxygen supplementation (p = 0.015) and steroid therapy (p = 0.045) during admission and reached higher COVID-19 severity (p = 0.017).DiscussionThe combination of antiviral and sotrovimab in the early phase of COVID-19 is well tolerated by immunocompromised patients and is associated with 100% of virological clearance. Patients treated later have lower response rates and higher disease severity, but whether therapy plays a causative role in such findings has yet to be determined.

Abstract 13912: Insights From a Multi-Center Consortium for HCV-Viremic Donor Heart Transplant: Outcomes Are Excellent Across Regimens Often Without Major Changes to Statin or PPI

Introduction: With the availability of pangenotypic direct-acting antivirals (DAA) for facile, curative treatment of hepatitis C virus (HCV) infections, HCV-viremic donors are utilized regularly to partially address the shortage of suitable organs for heart transplant (HT). This multi-center, retrospective registry characterized HT outcomes from HCV-positive donors. Methods: Of 138 isolated HT recipients from 8 sites across the US, the most common DAAs were the pangenotypic antiviral combinations sofosbuvir-velpatasvir (SOF/VEL, n=39) and glecaprevir-pibrentasvir (GLE/PIB, n=76); these 115 cases were analyzed in terms of primary graft dysfunction (PGD), episodes of rejection ≥ pAMR1 and/or Grade 2R, post-transplant infection, sustained virologic response at 12 weeks post-treatment (SVR12), and survival up to 1 year. Results: Comparing these two most common pangenotypic regimens, HT recipients differed in their listing status (p&lt;0.001), hospital stay length (p=0.04), time until HCV+ (p=0.01), DAA payor (p=0.01), induction therapy (p=0.03) and statin therapy (p=0.01). A concurrent open-label trial accounted for up to 13/39 SOF/VEL patients, partially accounting for differences in DAA payor. Despite potential interactions, statin and proton pump inhibitor (PPI) therapy typically continued uninterrupted with minimal dose adjustment. Both treatment groups showed 100% cure (SVR12) of donor-derived HCV. Although not powered for comparative effectiveness of DAA agents, there were no significant differences in study outcomes. SOF/VEL and GLE/PIB-treated patients demonstrated 97% and 96% survival at 1 year, respectively. Conclusions: As utilized to achieve cure of HT donor-derived HCV, two pangenotypic DAA regimens are safe and feasible, with coverage accessed across a variety of DAA payors. SVR12 can be achieved often without major modifications to PPIs or statins with either pangenotypic DAA regimen (with pravastatin most commonly utilized).