Antiviral Combination Research Articles

METHOD DEVELOPMENT AND VALIDATION FOR SIMULTANEOUS ESTIMATION OF LAMIVUDINE, DOLUTEGRAVIR AND TENOFOVIR DISOPROXIL FUMARATE IN BULK AND PHARMACEUTICAL DOSAGE FORM USING RP-HPLC AND ITS APPLICATION TO IN-VITRO DISSOLUTION STUDY

A simple, rapid, and economical method has been developed for the simultaneous estimation of the latest FDA approved antiviral drug combination, Dolutegravir, Lamivudine, and tenofovir disoproxil fumarate in tablet dosage form using Shimadzu LC-20 AT HPLC with a Phenomenex Luna column compartment., the method was developed using HPLC graded methanol with o-phosphoric acid as a mobile phase and successfully validated the developed method as per the ICH guidelines. The method was found to be linear, accurate, precise, robust, and rugged. The limit of detection and the limit of quantification was found to be 2.6μg/ml and 8.18μg/ml for Dolutegravir, 14.63 μg/ml and 44.35 μg/ml for Lamivudine and 16.43 μg/ml and 49.81 μg/ml for tenofovir disoproxil fumarate respectively. The retention time was found to be 3.0, 2.3 and 2.7 min for Dolutegravir, Lamivudine and tenofovir disoproxil fumarate respectively. All of assessed parameters complied with the acceptance criteria hence indicated the usefulness of the RP-HPLC method for the determination of assay and in-vitro dissolution study for tablet dosage form which contains lamivudine, tenofovir disoproxil fumarate, and dolutegravir active substances. Hence the method can be applied for routine quality control of the drugs.

Antiviral Combination Clinically Better Than Standard Therapy in Severe but Not in Non-Severe COVID-19.

PurposeDefinitive antiviral treatment is not available for COVID-19 infection, with the exception of remdesivir, which still evokes many doubts. Various monotherapy or combination therapies with antivirals or other agents have been tried. The present study aims to evaluate the therapeutic potential of hydroxychloroquine and lopinavir–ritonavir in combination with ribavirin in mild–severe COVID-19.Patients and MethodsA single-center, open-label, parallel-arm, stratified randomized controlled trial evaluated the therapeutic potential of combination antiviral therapies. Enrolled patients in the severe category were randomized into three groups: (A) standard treatment, (B) hydroxychloroquine+ribavirin+standard treatment, or (C) lopinavir+ritonavir+ribavirin+standard treatment; while the non-severe category comprised two groups: (A) standard treatment or (B) hydroxychloroquine+ribavirin. Combination antivirals were given for 10 days and followed for 28 days. The primary endpoints were safety, symptomatic and laboratory recovery of organ dysfunctions, and time to SARS-CoV-2 RT-PCR negative report.ResultsIn total, 111 patients were randomized: 24, 23, and 24 in severe categories A, B, and C, respectively, and 20 in each of the non-severe groups. Two patients receiving ribavirin experienced drug induced liver injury, and another developed QT prolongation after hydroxychloroquine. In the severe category, 47.6%, 55%, and 30.09% in A, B, and C groups, respectively, showed symptomatic recovery, compared to 93.3% and 86.7% in A and B groups, respectively, in the non-severe category at 72 hours (P>0.05).ConclusionThough the results failed to show statistical superiority of the antiviral combination therapies to that of the standard therapy in both the severe and non-severe categories in symptomatic adult patients of COVID-19 due to very small sized trial, clinically hydroxychloroquine+ribavirin therapy is showing better recovery by 7.4% than standard therapy in the former category. However, results do indicate the benefit of standard therapy in the non-severe category by 6.6%. Furthermore, the dose of ribavirin needs to be reconsidered in the Indian population.

Sofosbuvir/velpatasvir for the treatment of hepatitis C in pediatric patients

ABSTRACT Introduction: Sofosbuvir/velpatasvir is a combination of direct-acting antivirals with pangenotypic activity for treatment of chronic hepatitis C virus infection. It was approved in 2020 for use in children aged 6–17 years and in June 2021 by the United States Food and Drug Administration for the age group 3–5 years. Areas covered: A literature search of PUBMED and EMBASE was conducted on April 30th and updated on June 10th. Other citations were identified in references of available literature and from ClinicalTrials.gov. The aim of the present research was to outline and discuss the pharmacokinetics, clinical efficacy, tolerability and safety of sofosbuvir/velpatasvir, exploring its actual and potential use in children and adolescents with chronic hepatitis C virus infection. Expert opinion: Five combinations of direct-acting antivirals, of whom three with pangenotypic activity, are now approved for children. No major differences in efficacy and safety profile have been described. Limited access to treatment still is a major issue, especially in low and middle-income countries.

Combination of natural antivirals and potent immune invigorators: A natural remedy to combat COVID-19.

The flare‐up in severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) that emerged in December 2019 in Wuhan, China, and spread expeditiously worldwide has become a health challenge globally. The rapid transmission, absence of anti‐SARS‐CoV‐2 drugs, and inexistence of vaccine are further exacerbating the situation. Several drugs, including chloroquine, remdesivir, and favipiravir, are presently undergoing clinical investigation to further scrutinize their effectiveness and validity in the management of COVID‐19. Natural products (NPs) in general, and plants constituents specifically, are unique sources for various effective and novel drugs. Immunostimulants, including vitamins, iron, zinc, chrysin, caffeic acid, and gallic acid, act as potent weapons against COVID‐19 by reinvigorating the defensive mechanisms of the immune system. Immunity boosters prevent COVID‐19 by stimulating the proliferation of T‐cells, B‐cells, and neutrophils, neutralizing the free radicals, inhibiting the immunosuppressive agents, and promoting cytokine production. Presently, antiviral therapy includes several lead compounds, such as baicalin, glycyrrhizin, theaflavin, and herbacetin, all of which seem to act against SARS‐CoV‐2 via particular targets, such as blocking virus entry, attachment to host cell receptor, inhibiting viral replication, and assembly and release.

Research Progress on the Antiviral Activity of Glycyrrhizin and its Derivatives in Liquorice.

Liquorice is a traditional medicine. Triterpenoids such as glycyrrhizin and glycyrrhetinic acid are the main active constituents of liquorice. Studies have revealed that these compounds exert inhibitory effects on several viruses, including SARS-CoV-2. The main mechanisms of action of these compounds include inhibition of virus replication, direct inactivation of viruses, inhibition of inflammation mediated by HMGB1/TLR4, inhibition of β-chemokines, reduction in the binding of HMGB1 to DNA to weaken the activity of viruses, and inhibition of reactive oxygen species formation. We herein review the research progress on the antiviral effects of glycyrrhizin and its derivatives. In addition, we emphasise the significance of exploring unknown antiviral mechanisms, structural modifications, and drug combinations in future studies.

Report of the National Institutes of Health SARS-CoV-2 Antiviral Therapeutics Summit.

The NIH Virtual SARS-CoV-2 Antiviral Summit, held on 6 November 2020, was organized to provide an overview on the status and challenges in developing antiviral therapeutics for coronavirus disease 2019 (COVID-19), including combinations of antivirals. Scientific experts from the public and private sectors convened virtually during a live videocast to discuss severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) targets for drug discovery as well as the preclinical tools needed to develop and evaluate effective small-molecule antivirals. The goals of the Summit were to review the current state of the science, identify unmet research needs, share insights and lessons learned from treating other infectious diseases, identify opportunities for public-private partnerships, and assist the research community in designing and developing antiviral therapeutics. This report includes an overview of therapeutic approaches, individual panel summaries, and a summary of the discussions and perspectives on the challenges ahead for antiviral development.

Pharmacokinetic modelling to estimate intracellular favipiravir ribofuranosyl-5'-triphosphate exposure to support posology for SARS-CoV-2.

ObjectivesFavipiravir has discrepant activity against SARS-CoV-2 in vitro, concerns about teratogenicity and pill burden, and an unknown optimal dose. This analysis used available data to simulate the intracellular pharmacokinetics of the favipiravir active metabolite [favipiravir ribofuranosyl-5′-triphosphate (FAVI-RTP)].MethodsPublished in vitro data for intracellular production and elimination of FAVI-RTP in Madin–Darby canine kidney cells were fitted with a mathematical model describing the time course of intracellular FAVI-RTP as a function of favipiravir concentration. Parameter estimates were then combined with a published population pharmacokinetic model in Chinese patients to predict human intracellular FAVI-RTP. In vitro FAVI-RTP data were adequately described as a function of concentrations with an empirical model, noting simplification and consolidation of various processes and several assumptions.ResultsParameter estimates from fittings to in vitro data predict a flatter dynamic range of peak to trough for intracellular FAVI-RTP (peak to trough ratio of ∼1 to 1) when driven by a predicted free plasma concentration profile, compared with the plasma profile of parent favipiravir (ratio of ∼2 to 1). This approach has important assumptions, but indicates that, despite rapid clearance of the parent from plasma, sufficient intracellular FAVI-RTP may be maintained across the dosing interval because of its long intracellular half-life.ConclusionsPopulation mean intracellular FAVI-RTP concentrations are estimated to be maintained above the Km for the SARS-CoV-2 polymerase for 9 days with a 1200 mg twice-daily regimen (following a 1600 mg twice-daily loading dose on day 1). Further evaluation of favipiravir as part of antiviral combinations for SARS-CoV-2 is warranted.

Glecaprevir/pibrentasvir for 8weeks in patients with compensated cirrhosis: Safety and effectiveness data from the German Hepatitis C-Registry.

Glecaprevir/pibrentasvir, a pangenotypic, direct-acting antiviral combination approved for chronic hepatitis C virus treatment, has limited real-world evidence supporting 8-week therapy in compensated cirrhosis. We investigated effectiveness and safety of 187 hepatitis C virus-infected, treatment-naïve, patients with compensated cirrhosis receiving 8-week glecaprevir/pibrentasvir therapy in the German Hepatitis C-Registry between 2 August 2017 and 1 January 2020. Sustained virologic response was 98.4% (127/129) in the per-protocol analysis (excluding patients lost to follow-up or who discontinued treatment due to compliance) and was 85.8% (127/148) in patients with data available in an intention-to-treat analysis. Nineteen patients were lost to follow-up; nine genotype 3 patients, nine nongenotype 3 patients and one mixed genotype patient. One patient relapsed, and one died, unrelated to treatment. Adverse events (>5%) were fatigue and headache. Two serious adverse events occurred; no adverse events resulted in drug discontinuation. An 8-week glecaprevir/pibrentasvir therapy was effective and well-tolerated in this real-world analysis.

Potential Virus Involvement in Alzheimer's Disease: Results from a Phase IIa Trial Evaluating Apovir, an Antiviral Drug Combination.

Background:Accumulating data suggest infectious agents are involved in Alzheimer’s disease (AD). The two primary aims of this trial were to assess safety and efficacy of an antiviral drug combination on AD progression.Objective:The trial evaluated whether Apovir, a combination of two antiviral agents, pleconaril (active on enteroviruses) and ribavirin (active on several viruses), could slow AD progression.Methods:Sixty-nine patients 60–85 years were treated with Apovir or placebo for 9 months and followed until 12 months after end of treatment. Cognitive tests, safety, biomarkers, drug plasma, and cerebrospinal fluid concentrations were assessed.Results:The tolerability of Apovir was compromised as demonstrated by the large drop-out rate and increased frequency and severity of adverse events. The primary endpoint, demonstrating a difference in change from baseline to 9 months between groups in ADAS-cog total score, was not met (p = 0.1809). However, there were observations indicating potential effects on both ADAS-cog and CDR-SB but these effects need to be verified. Also, there was a decrease in cerebrospinal fluid amyloid-β in Apovir at 9 months (p = 0.0330) but no change in placebo.Conclusion:This was the first randomized, placebo controlled clinical trial exploring antiviral treatment on AD progression. The trial is considered inconclusive due to the large drop-out rate. New trials are needed to verify if the indications of effect observed can be confirmed and which component(s) in Apovir contributed to such effects. Pleconaril alone may be studied to improve the tolerability and to verify if enterovirus is involved in the disease process.

The path to find an HIV vaccine.

The path to find an HIV vaccine.

Epigallocatechin-3-Gallate (EGCG) Inhibits SARS-CoV-2 Infection in Primate Epithelial Cells: (A Short Communication).

SARS-CoV-2, the novel coronavirus responsible for the COVID-19 pandemic, caused >26 million cases in the United States and >437,000 deaths as of Jan 30, 2020. Worldwide by that date, there had been 102 million cases of infections, and deaths had climbed to 2.21 million. Mutated variants of SARS-CoV-2 that have emerged from the United Kingdom, Brazil, and South Africa are associated with higher transmission rates and associated deaths. Therefore, novel therapeutic and prophylactic methods against SARS-CoV-2 are in urgent need. While some antiviral drugs, such as Remdesivir, provide relief to certain patient populations, other existing antiviral drugs or combinations of FDA approved pharmaceuticals have yet to show clinical efficacy against COVID-19. Compounds that possess strong and broad antiviral properties with different mechanisms of action against respiratory viruses may provide novel approaches to combat SARS-CoV-2 and its variants, especially if the compounds are classified as generally recognized as safe (GRAS). A large body of evidence indicates a promising potential for the use of epigallocatechin-3-gallate (EGCG) and its derivatives as effective agents against infections from a wide range of pathogenic viruses. However, EGCG or its derivatives have not been tested directly against SARS-CoV-2. The current study was designed to evaluate the potential antiviral activity of EGCG against SARS-CoV-2 infection in primate epithelial cells. Methods applied in the study include cytopathic effect (CPE) assay and virus yield reduction (VYR) assays using Vero 76 (green monkey epithelial cells) and Caco-2 (human epithelial cells) cell lines, respectively. The results demonstrated that EGCG at 0.27 μg/ml (0.59 μM) inhibited SARS-CoV-2 infection in Vero 76 cells by 50% (i.e., EC50=0.27 μg/ml). EGCG also inhibited SARS-CoV-2 infection in Caco-2 cells with EC90=28 μg/ml (61 μM). These results, to the best of our knowledge, are the first observations on the antiviral activities of EGCG against SARS-CoV-2, and suggest that EGCG and its derivatives could be used to combat COVID-19 and other respiratory viral infection-induced illness, pending in vivo and clinical studies.

No Efficacy of the Combination of Lopinavir/Ritonavir Plus Hydroxychloroquine Versus Standard of Care in Patients Hospitalized With COVID-19: A Non-Randomized Comparison.

Objectives: No specific treatment has been approved for COVID-19. Lopinavir/ritonavir (LPV/r) and hydroxychloroquine (HCQ) have been used with poor results, and a trial showed advantages of combined antiviral therapy vs. single antivirals. The aim of the study was to assess the effectiveness of the combination of antivirals (LPV/r and HCQ) or their single use in COVID-19 hospitalized patients vs. standard of care (SoC). Methods: Patients ≥18 years with SARS-CoV-2 infection, defined as positive RT-PCR from nasal/oropharyngeal (NP/OP) swab or positive serology, admitted at L. Spallanzani Institute (Italy) were included. Primary endpoint: time to invasive ventilation/death. Secondary endpoint: time to two consecutive negative SARS-CoV-2 PCRs in NP/OP swabs. In order to control for measured confounders, a marginal Cox regression model with inverse probability weights was used. Results: A total of 590 patients were included in the analysis: 36.3% female, 64 years (IQR 51–76), and 91% with pneumonia. Cumulative probability of invasive ventilation/death at 14 days was 21.2% (95% CI 17.6, 24.7), without difference between SOC, LPV/r, hydroxychloroquine, HCQ + LPV/r, and SoC. The risk of invasive ventilation/death in the groups appeared to vary by baseline ratio of arterial oxygen partial pressure to fractional inspired oxygen (PaO2/FiO2). Overall cumulative probability of confirmed negative nasopharyngeal swabs at 14 days was 44.4% (95% CI 38.9, 49.9), without difference between groups. Conclusion: In this retrospective analysis, we found no difference in the rate of invasive ventilation/death or viral shedding by different strategies, as in randomized trials performed to date. Moreover, even the combination HCQ + LPV/r did not show advantages vs. SoC.

Efficacy of Direct-Acting Antiviral Combination Therapy in the Treatment of Hepatitis C Virus Among Kidney Transplant Patients

Background: To date, there is no consensus on the best combination of direct-acting antivirals to treat hepatitis C virus in kidney transplant recipients. Objective: This study aims to analyze the efficacy of a combination of sofosbuvir and ledipasvir regimen for the treatment of hepatitis C virus infected kidney transplant patients. Methods: A cross-sectional study was conducted in a nephrology clinic and the Nephrology Center in Basrah Teaching Hospital from June 2015 to June 2018. Ledifos (90 mg Ledipasvir and 400 mg Sofosbuvir fixed-dose) was given as a single daily dose to all the participants for 12 weeks. Response for therapy was tested by a follow up hepatitis C virus load at the end of 12 weeks and after 24 weeks. The sustained virological response was defined as a negative viral load of hepatitis C virus (aviremia) at the end of therapy. This study was done according to the Helsinki Congress. Results: A total of 60 (16 females) patients with renal transplantation and hepatitis C virus infection were included. The mean age was 40±6.2 years. A sustained virological response was observed in all of the patients who received Ledifos after 12 and 24 weeks of therapy for all genotypes (1a, 1b and 4); p= 0.0001. Genotype 1a was more prevalent among males, in about 34 (56.6%) of the patients; p= 0.0001, and it was the most common genotype that tested negative serologically, 11 (18.3%). Conclusion: Ledifos therapy is an effective and safe option for the treatment of hepatitis C virus infection in the post-renal transplant setting.

Predictors of disease severity and outcome of hospitalized renal transplant recipients with COVID-19 infection: a systematic review of a globally representative sample.

Introduction. COVID-19 presents a special challenge to the kidney transplant population.Methods. A systematic review of articles that examined COVID-19 in kidney transplant recipients was performed. Patients' demographics, clinical, laboratory and radiological presentations, immunosuppression modification, and COVID-19 specific management were abstracted and analyzed. COVID-19 severity was classified into mild, moderate, and severe. Disease outcome was classified by whether the patient was discharged, still hospitalized, or died.Results. 44 articles reporting individual data and 13 articles reporting aggregated data on 149 and 561 kidney transplant recipients respectively with COVID-19 from Asia, Europe and America fulfilled all inclusion and exclusion criteria. Among studies reporting case specific data, 76% of cases had severe disease. Compared to patients with mild/moderate disease, patients with severe disease had higher CRP, LDH, Ferritin, D-dimer and were more likely to have bilateral lung involvement at presentation and longer time since transplantation (P < 0.05 for all). Recipients' age, gender and comorbidities did not impact disease severity. Patients with severe disease had a more aggressive CNI reduction and more antiviral medications utilization. Outcome was reported on 145 cases, of those 34 (23%) died all with severe disease. Longer duration from transplant to disease diagnosis, hypoxia and higher LDH were associated with mortality (P < 0.05). Different immunosuppression reduction strategies, high dose parenteral corticosteroids use and various antiviral combinations did not demonstrate survival advantage. Similar finding was observed for studies reporting aggregated data.Conclusion. COVID-19 in kidney transplant patients is associated with high rate of disease severity and fatality. Higher LDH and longer time since transplantation predicted both disease severity and mortality. None of the COVID-19 specific treatment correlated with, or improved disease outcome in kidney transplant recipients.

Various Combinations of Favipiravir, Lopinavir-Ritonavir, Darunavir-Ritonavir, High-Dose Oseltamivir, and Hydroxychloroquine for the Treatment of COVID-19: A Randomized Controlled Trial (FIGHT-COVID-19 Study)

Background: Monotherapy with Remdesivir, Favipiravir, Lopinavir-Ritonavir, or Hydroxychloroquine has been evaluated for the treatment of coronavirus disease 2019 (Covid-19). No antiviral agents have yet been shown to be efficacious in terms of viral clearance and reduction of death in moderate to severe Covid-19 in randomized controlled trials.Methods: We conducted an open-label, randomized, controlled trial of various oral combinations of Favipiravir, Lopinavir-Ritonavir, Darunavir-Ritonavir, high-dose Oseltamivir, and Hydroxychloroquine in adults who were hospitalized with Covid-19. Ninety patients were randomly assigned to receive either 1) high-dose Oseltamivir and Hydroxychloroquine, 2) Lopinavir-Ritonavir and high-dose Oseltamivir, or 3) Darunavir- Ritonavir, high-dose Oseltamivir, and Hydroxychloroquine, compared to thirty voluntary quarantine patients without antiviral agent for mild Covid-19. In addition, two hundred patients were randomly assigned to receive 1) high-dose Oseltamivir and Lopinavir- Ritonavir, 2) Favipiravir and Lopinavir-Ritonavir, 3) high-dose Oseltamivir and Darunavir-Ritonavir, or 4) Favipiravir and Darunavir-Ritonavir and Hydroxychloroquine for moderate to severe Covid-19.Results: A total of 320 patients were enrolled. Those mild Covid-19 patients who received high-dose Oseltamivir and Hydroxychloroquine had a better median time for negative Polymerase Chain Reaction test (PCR) for SARS-CoV-2 than who were voluntarily quarantined without antiviral agent (ITT: 7.5 days (IQR, 4 to 25) versus 11.5 days (IQR, 8 to 18) (P=0.02), LOCF: 7.5 days (IQR, 4.5 to 14) versus 10 days (IQR, 6.5 to18.5) (P=0.01), and PP 8 days (IQR, 4 to 15) versus 9 days (IQR, 6 to17) (P=0.01).For moderate to severe Covid-19 patients, Favipiravir plus Darunavir-Ritonavir plus Hydroxychloroquine had a better median time to negative PCR for SARS-CoV-2 than who received high-dose Oseltamivir plus Lopinavir-Ritonavir (ITT: 10 days (IQR, 5.5 to 13) versus 12 days (IQR, 7 to 15) (P=0.15), LOCF: 10 days (IQR, 5to 13) versus 11 days (IQR, 6 to 15) (P=0.005), and PP 10 days (IQR, 5 to 13) versus 9.5 days (IQR, 5 to15) (P=0.003). In moderate to severe Covid -19, The Kaplan–Meier estimates of mortality were 16.0% with high-dose Oseltamivir plus Lopinavir-Ritonavir compared to 4.0% with Favipiravir plus Darunavir-Ritonavir plus Hydroxychloroquine (P=0.04), and more patient deaths with high-dose Oseltamivir plus Lopinavir-Ritonavir, and Favipiravir plus Lopinavir-Ritonavir, compared to Favipiravir plus Darunavir-Ritonavir plus Hydroxychloroquine ( P=0.04).Conclusions: High-dose Oseltamivir and Hydroxychloroquine were superior to voluntary quarantine without antiviral agent in terms of viral clearance in mild Covid -19. Favipiravir plus Darunavir-Ritonavir plus Hydroxychloroquine were superior to other antiviral agent combinations in terms viral clearance and death in moderate to severe Covid -19. Clinical Trial Registration Details: ClinicalTrials.gov number NCT04303299.Funding Information: Department of Medical Services of Ministry of Public Health, Health System Research Institute of Ministry of Public Health, and The Office of the National Broadcasting and Telecommunications Commission Institute of Thailand. Declaration of Interests: All authors declare no conflicts of interest, no support from any organization for the submitted work, no financial relationships with any organizations that might have an interest in the submitted work in the previous three years, and no other relationships or activities that could appear to have influenced the submitted work. Ethics Approval Statement: The trial protocol was approved by the institutional review board at each site and the centralized institutional review board of the Ethics Committee of the Ministry of Public Health, Thailand. There were independent data and safety monitoring boards. Written informed consent was obtained from each patient or from the patient’s legally authorized representative if the patient was unable to provide consent.

Pharmacodynamics of Remdesivir: How to Improve for COVID-19 Treatment

Potential clinical benefit in SARS-CoV-2 with remdesivir have been noticed. Recently, FDA has granted the use of remdesivir for COVID-therapy. However, the efficacy of remdesivir alone or with combination of other antivirals, like chloroquine or hydroxychloroquine is still questionable, especially in terms of benefits vs. risk ratio. We here did a search for relevant pharmacological evidences with regards to the Pharmacokinetics (PK) and Pharmacodynamics (PD) of appropriate antiviral compounds against COVID-19 alone or in combination with other potential therapies. Drug–Drug Interactions (DDIs), if any in case of combo treatment have also been taken into consideration. We found promising in vitro evidence for using remdesivir, in combination with (hydroxy) chloroquine and/or favipiravir against SARS-CoV-2. However, clinical trial results are not that satisfactory as expected and limit the use in practice. Additionally, some other drug combination with remdesivir have been proposed in this article for future improvement in therapies.

Therapeutic Effectiveness of Interferon Alpha 2b Treatment for COVID-19 Patient Recovery.

A previous report on 814 patients who were coronavirus disease 2019 (COVID-19) positive provided preliminary therapeutic efficacy evidence with interferon-α2b (IFN-α2b) in Cuba, from March 11 to April 14, 2020. This study re-evaluates the effectiveness of IFN-α2b during the period from March 11 to June 17, 2020. Patients received a combination of oral antivirals (lopinavir/ritonavir and chloroquine) with intramuscular or subcutaneous administration of IFN-α2b. The primary endpoint was the proportion of patients discharged from the hospital; the secondary endpoint was the case fatality rate, and several outcomes related to time variables were also evaluated. From March 11 to June 17, 2,295 patients had been confirmed to be severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) positive in Cuba, 2,165 were treated with Heberon® Alpha R, and 130 received the approved protocol without IFN. The proportion of fully recovered patients was higher in the IFN-treated compared with the non-IFN-treated group. Prior IFN treatment decreases the likelihood of intensive care and increases the survival after severe or critical diseases. Benefits of IFN were significantly supported by time variables analyzed. This second report confirmed our preliminary evidence about the therapeutic effectiveness of IFN-α2b in SARS-CoV-2 infection and postulated Heberon Alpha R as the main component within antiviral drugs used in the Cuban protocol COVID-19.

Efficacy and Safety of Lopinavir/Ritonavir for Treatment of COVID-19: A Systematic Review and Meta-Analysis.

(Background) Lopinavir-ritonavir (LPV/RTV) is a human immunodeficiency virus (HIV) antiviral combination that has been considered for the treatment of COVID-19 disease. (Aim) This systematic review aimed to assess the efficacy and safety of LPV/RTV in COVID-19 patients in the published research. (Methods) A protocol was developed based on the Preferred Reporting Items for Systematic reviews and Meta-Analysis (PRISMA) statement. Articles were selected for review from 8 electronic databases. This review evaluated the effects of LPV/RTV alone or in combination with standard care ± interferons/antiviral treatments compared to other therapies, regarding duration of hospital stay, risk of progressing to invasive mechanical, time to virological cure and body temperature normalization, cough relief, radiological progression, mortality and safety. (Results) A consensus was reached to select 32 articles for full-text screening; only 14 articles comprising 9036 patients were included in this study; and eight of these were included for meta-analysis. Most of these studies did not report positive clinical outcomes with LPV/RTV treatment. In terms of virological cure, three studies reported less time in days to achieve a virological cure for LPV/RTV arm relative to no antiviral treatment (−0.81 day; 95% confidence interval (CI), −4.44 to 2.81; p = 0.007, I2 = 80%). However, the overall effect was not significant (p = 0.66). When comparing the LPV/RTV arm to umifenovir arm, a favorable affect was observed for umifenovir arm, but not statically significant (p = 0.09). In terms of time to body normalization and cough relief, no favorable effects of LPV/RTV versus umifenovir were observed. The largest trials (RECOVERY and SOLIDARITY) have shown that LPV/RTV failed to reduce mortality, initiation of invasive mechanical ventilation or hospitalization duration. Adverse events were reported most frequently for LPV/RTV (n = 84) relative to other antivirals and no antiviral treatments. (Conclusions) This review did not reveal any significant advantage in efficacy of LPV/RTV for the treatment of COVID-19 over standard care, no antivirals or other antiviral treatments. This result might not reflect the actual evidence.

COVID-19 in hospitalised patients in Spain: a cohort study in Madrid

Few large series describe the clinical characteristics, outcomes and costs of COVID-19 in Western countries. This cohort reports the first 1255 adult cases receiving anti-COVID-19 treatment at a Spanish hospital (1-24 March 2020). Treatment costs were calculated. A logistic regression model was used to explore risk factors on admission associated with ARDS. A bivariate Cox proportional hazard ratio (HR) model was employed to determine the HR between individual factors and death. We included 1255 patients (median age 65 years; 57.8% male), of which 92.3% required hospitalisation. The prevalence of hypertension, cardiovascular disease and diabetes mellitus (DM) was 45.1%, 31.4% and 19.9%, respectively. Lymphocytopenia (54.8%), elevated alanine aminotransferase (33.0%) and elevated lactate dehydrogenase (58.5%) were frequent. Overall, 36.7% of patients developed ARDS, 10.0% were admitted to an ICU and 21.3% died. The most frequent antiviral combinations were lopinavir/ritonavir plus hydroxychloroquine (44.2%), followed by triple therapy with interferon beta-1b (32.7%). Corticosteroids and tocilizumab were used in 25.3% and 12.9% of patients, respectively. Total cost of anti-COVID-19 agents was €511 825 (€408/patient). By multivariate analysis, risk factors associated with ARDS included older age, obesity, DM, severe hypoxaemia, lymphocytopenia, increased creatine kinase and increased C-reactive protein. In multivariate Cox model, older age (HR 1.07, 95% CI 1.06-1.09), cardiovascular disease (HR 1.34, 95% CI 1.01-1.79), DM (HR 1.45, 95% CI 1.09-1.92), severe hypoxaemia (HR 2.01, 95% CI 1.49-2.72), lymphocytopenia (HR 1.62, 95% CI 1.20-2.20) and increased C-reactive protein (HR 1.04, 95% CI 1.02-1.06) were risk factors for mortality.

Hepatitis C Virus Treatment as Prevention: Challenges and Opportunities in Men Who Have Sex With Men.

Since 2002, a global epidemic of acute hepatitis C virus (HCV) infection has been noted in men who have sex with men (MSM). Transmission of HCV, particularly in the context of traumatic sex practices that increase the risk of blood-blood contacts (eg, anal sex and fisting), was initially found in human immunodeficiency virus (HIV)-coinfected and more recently in HIV-uninfected MSM, especially those receiving pre-exposure prophylaxis (PrEP). Early HCV treatment with all-oral direct-acting antiviral combination therapy has been associated with very high HCV cure rates of up to 100%. Indeed, immediate treatment of recently acquired HCV directly after new HCV diagnosis, or after 4 weeks if no 2-log10 drop in HCV RNA level occurs, promises rapid HCV elimination. Reports from the Netherlands, Switzerland, and the United Kingdom all show that with increased treatment uptake in this particular patient group, dramatic reductions in new HCV infections can be achieved. A general consensus on how to best screen for and manage acute HCV infections, along with broad access to rapid HCV therapy initiation, is crucial to attaining HCV elimination, a goal that is challenged by high HCV reinfection rates among MSM.