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1.
J Antimicrob Chemother ; 77(10): 2706-2712, 2022 09 30.
Article in English | MEDLINE | ID: covidwho-1992221

ABSTRACT

BACKGROUND: The COVER trial evaluated whether nitazoxanide or sofosbuvir/daclatasvir could lower the risk of SARS-CoV-2 infection. Nitazoxanide was selected given its favourable pharmacokinetics and in vitro antiviral effects against SARS-CoV-2. Sofosbuvir/daclatasvir had shown favourable results in early clinical trials. METHODS: In this clinical trial in Johannesburg, South Africa, healthcare workers and others at high risk of infection were randomized to 24 weeks of either nitazoxanide or sofosbuvir/daclatasvir as prevention, or standard prevention advice only. Participants were evaluated every 4 weeks for COVID-19 symptoms and had antibody and PCR testing. The primary endpoint was positive SARS-CoV-2 PCR and/or serology ≥7 days after randomization, regardless of symptoms. A Poisson regression model was used to estimate the incidence rate ratios of confirmed SARS-CoV-2 between each experimental arm and control. RESULTS: Between December 2020 and January 2022, 828 participants were enrolled. COVID-19 infections were confirmed in 100 participants on nitazoxanide (2234 per 1000 person-years; 95% CI 1837-2718), 87 on sofosbuvir/daclatasvir (2125 per 1000 person-years; 95% CI 1722-2622) and 111 in the control arm (1849 per 1000 person-years; 95% CI 1535-2227). There were no significant differences in the primary endpoint between the treatment arms, and the results met the criteria for futility. In the safety analysis, the frequency of grade 3 or 4 adverse events was low and similar across arms. CONCLUSIONS: In this randomized trial, nitazoxanide and sofosbuvir/daclatasvir had no significant preventative effect on infection with SARS-CoV-2 among healthcare workers and others at high risk of infection.


Subject(s)
COVID-19 , Antiviral Agents/therapeutic use , COVID-19/prevention & control , Carbamates , Humans , Imidazoles , Nitro Compounds , Pyrrolidines , SARS-CoV-2 , Sofosbuvir/therapeutic use , South Africa , Thiazoles , Treatment Outcome , Valine/analogs & derivatives
2.
Rev Bras Ter Intensiva ; 34(1): 44-55, 2022.
Article in Portuguese, English | MEDLINE | ID: covidwho-1988374

ABSTRACT

Repurposed drugs are important in resource-limited settings because the interventions are more rapidly available, have already been tested safely in other populations and are inexpensive. Repurposed drugs are an effective solution, especially for emerging diseases such as COVID-19. The REVOLUTIOn trial has the objective of evaluating three repurposed antiviral drugs, atazanavir, daclatasvir and sofosbuvir, already used for HIV- and hepatitis C virus-infected patients in a randomized, placebo-controlled, adaptive, multiarm, multistage study. The drugs will be tested simultaneously in a Phase II trial to first identify whether any of these drugs alone or in combination reduce the viral load. If they do, a Phase III trial will be initiated to investigate if these medications are capable of increasing the number of days free respiratory support. Participants must be hospitalized adults aged ≥ 18 years with initiation of symptoms ≤ 9 days and SpO2 ≤ 94% in room air or a need for supplemental oxygen to maintain an SpO2 > 94%. The expected total sample size ranges from 252 to 1,005 participants, depending on the number of stages that will be completed in the study. Hence, the protocol is described here in detail together with the statistical analysis plan. In conclusion, the REVOLUTIOn trial is designed to provide evidence on whether atazanavir, daclatasvir or sofosbuvir decrease the SARS-CoV-2 load in patients with COVID-19 and increase the number of days patients are free of respiratory support. In this protocol paper, we describe the rationale, design, and status of the trial. ClinicalTrials.gov identifier: NCT04468087.


Os medicamentos reaproveitados são importantes em contextos de recursos limitados porque as intervenções estão mais rapidamente disponíveis, já foram testadas com segurança em outras populações e são, em geral, mais baratas. Os medicamentos reaproveitados são uma solução eficaz, especialmente para doenças emergentes, como a COVID-19. O estudo REVOLUTIOn visa avaliar três medicamentos antivirais reaproveitados: atazanavir, daclatasvir e sofosbuvir, já utilizados em pacientes infectados pelo HIV ou pelo vírus da hepatite C, em um estudo randomizado, controlado por placebo, adaptativo, multibraço e em múltiplos estágios. Os medicamentos serão testados simultaneamente em um ensaio de Fase II para primeiro identificar se algum deles, isoladamente ou em combinação, reduz a carga viral. Se reduzirem, será iniciado um estudo de Fase III para investigar se tais medicamentos são capazes de aumentar o número de dias sem suporte respiratório. Os participantes devem ser adultos hospitalizados com idade ≥ 18 anos com início dos sintomas ≤ 9 dias e saturação de oxigênio ≤ 94% em ar ambiente ou necessidade de oxigênio suplementar para manter saturação de oxigênio > 94%. O tamanho total esperado da amostra varia entre 252 e 1.005 participantes, dependendo do número de estágios que serão concluídos no estudo. Assim, o protocolo é aqui descrito em detalhes, juntamente do plano de análise estatística. Em conclusão, o estudo REVOLUTIOn foi concebido para fornecer evidências se o atazanavir, o daclatasvir ou o sofosbuvir reduzem a carga viral de SARS-CoV-2 em pacientes com COVID-19 e aumentam o número de dias em que os pacientes ficam sem suporte respiratório. Neste artigo de protocolo, descrevem-se a fundamentação, o desenho e a situação do ensaio. Identificador do ClinicalTrials.gov: NCT04468087.


Subject(s)
COVID-19 , Adult , Antiviral Agents/therapeutic use , Atazanavir Sulfate , Brazil , COVID-19/drug therapy , Clinical Trials, Phase II as Topic , Clinical Trials, Phase III as Topic , Humans , Multicenter Studies as Topic , Randomized Controlled Trials as Topic , SARS-CoV-2 , Sofosbuvir , Treatment Outcome
3.
Expert Rev Clin Pharmacol ; 15(8): 997-1002, 2022 Aug.
Article in English | MEDLINE | ID: covidwho-1937599

ABSTRACT

BACKGROUND: This study investigated the clinical efficacy sofosbuvir/daclatasvir (SOF-DCV) in patients with COVID-19. RESEARCH DESIGN AND METHODS: PubMed, Ovid MEDLINE, Embase, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov databases were searched for relevant articles written before January 6, 2022. Only randomized controlled trials (RCTs) comparing the clinical efficacy of SOF-DCV (study group) with alternative treatments (control group) in patients with COVID-19 were included. RESULTS: A total of 9 RCTs were included. The all-cause mortality rate in the study group was 10.7% (96/898), which was lower than that in the control group (12.3%, 108/871). However, this difference was not statistically significant (odds ratio [OR] = 0.83; 95% CI, 0.62-1.12; I2 = 49%). The overall clinical recovery rate was significantly higher in the study group than in the control group (OR = 2.34; 95% CI, 1.47-3.72; I2 = 20%). Furthermore, the average length of hospital stay was shorter in the study group than in the control group (mean deviation = -1.84; 95% CI, -3.42 to -0.26, I2 = 68%). CONCLUSIONS: Although SOF-DCV did not confer a survival benefit in patients with COVID-19, it may increase a patient's odds of clinical recovery, and shorten the length of their hospital stay.


Subject(s)
COVID-19 , Sofosbuvir , Antiviral Agents/therapeutic use , COVID-19/drug therapy , Carbamates , Drug Therapy, Combination , Genotype , Hepacivirus , Humans , Imidazoles , Pyrrolidines , Randomized Controlled Trials as Topic , Treatment Outcome , Valine/analogs & derivatives
4.
Arab J Gastroenterol ; 23(3): 165-171, 2022 Aug.
Article in English | MEDLINE | ID: covidwho-1821101

ABSTRACT

BACKGROUND AND STUDY AIMS: Currently, there is no therapy approved for COVID-19. We evaluated the efficacy and safety of sofosbuvir/ledipasvir and nitazoxanide for the treatment of patients with COVID-19 infection. PATIENTS AND METHODS: A multicenter, open-label randomized controlled trial included one hundred and ninety patients with non-severe COVID-19 infection. Patients were randomized into three groups. All groups received standard care treatment (SCT). In addition, group 1 received sofosbuvir/ledipasvir, and group 2 received nitazoxanide. Follow-up by reverse-transcriptase polymerase chain reaction (RT-PCR) was done at intervals of 5, 8, 11, and 14 days. The primary endpoint was viral clearance. RESULTS: Viral clearance was significantly higher in the sofosbuvir/ledipasvir and nitazoxanide groups compared to the SCT group in all follow-up intervals (p < 0.001). In the sofosbuvir/ledipasvir arm, 36.9% showed early viral clearance by day 5. By day 14, 83.1% of the sofosbuvir/ledipasvir group, 39.7% of the nitazoxanide group, and 19.4% of the SCT group tested negative for SARS-CoV-2. Sofosbuvir/ledipasvir and nitazoxanide treatment were the only significant factors in Cox regression of negative RT-PCR with the highest OR (17.88, 95% CI: 6.66-47.98 and 2.59, 95% CI: 1.11-6.07, respectively). No mortality or serious adverse events were recorded. CONCLUSION: The addition of sofosbuvir/ledipasvir or nitazoxanide to the SCT results in an early and high viral clearance rate in mild and moderate patients with COVID-19. These drugs represent a safe and affordable treatment for COVID-19.


Subject(s)
COVID-19 , Sofosbuvir , Antiviral Agents/therapeutic use , Benzimidazoles , COVID-19/drug therapy , Drug Repositioning , Drug Therapy, Combination , Fluorenes , Genotype , Hepacivirus , Humans , Nitro Compounds , SARS-CoV-2 , Sofosbuvir/therapeutic use , Thiazoles , Treatment Outcome , Viral Load
5.
J Med Life ; 15(3): 350-358, 2022 Mar.
Article in English | MEDLINE | ID: covidwho-1811951

ABSTRACT

COVID-19 is a pandemic disease caused by SARS-CoV-2, which is an RNA virus similar to the hepatitis C virus (HCV) in the replication process. Sofosbuvir/ledipasvir is an approved drug to treat HCV infection. This study investigates the efficacy of Sofosbuvir/ledipasvir as a treatment for patients with moderate COVID-19 infection. This is a single-blinded parallel-randomized controlled trial. The participants were randomized equally into the intervention group that received Sofosbuvir/ledipasvir (S.L. group), and the control group received Oseltamivir, Hydroxychloroquine, and Azithromycin (OCH group). The primary outcomes were the cure rate over time and the incidence of serious adverse events. The secondary outcomes included the laboratory findings. 250 patients were divided equally into each group. Both groups were similar regarding gender, but age was higher in the S.L. group (p=0.001). In the S.L. group, 89 (71.2%) patients were cured, while only 51 (40.8%) patients were cured in the OCH group. The cure rate was significantly higher in the S.L. group (RR=1.75, p<0.001). Kaplan-Meir plot showed a considerably higher cure over time in the S.L. group (Log-rank test, p=0.032). There were no deaths in the S.L. group, but there were six deaths (4.8%) in the OCH group (RR=0.08, p=0.013). Seven patients (5.6%) in the S.L. group and six patients (4.8%) in the OCH group were admitted to the intensive care unit (ICU) (RR=1.17, P=0.776). There were no significant differences between treatment groups regarding total leukocyte and neutrophils count, lymph, and urea. Sofosbuvir/ledipasvir is suggestive of being effective in treating patients with moderate COVID-19 infection. Further studies are needed to compare Sofosbuvir/ledipasvir with new treatment protocols.


Subject(s)
COVID-19 , Hepatitis C, Chronic , Hepatitis C , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Benzimidazoles , COVID-19/drug therapy , Drug Therapy, Combination , Egypt , Fluorenes , Genotype , Hepacivirus , Hepatitis C, Chronic/drug therapy , Humans , Ribavirin/adverse effects , SARS-CoV-2 , Sofosbuvir/pharmacology , Sofosbuvir/therapeutic use , Treatment Outcome , Uridine Monophosphate/adverse effects
6.
Sci Rep ; 12(1): 5771, 2022 04 06.
Article in English | MEDLINE | ID: covidwho-1778635

ABSTRACT

SARS-CoV-2 is still a health problem worldwide despite the availability of vaccines. Therefore, there is a need for effective and safe antiviral. SARS-CoV-2 and HCV necessitate RNA-dependent RNA polymerase (RdRp) for replication; therefore, it has been hypothesized that RdRp inhibitors used to treat HCV may be effective treating SARS-CoV-2. Accordingly, we evaluated the effect of the sofosbuvir/velpatasvir (SOF/VEL) combination in early SARS-CoV-2 infection. A multicenter case-control study was conducted, enrolling 120 patients with mild or moderate COVID-19, of whom 30, HCV coinfected or not, received SOF/VEL tablets (400/100 mg) once daily for 9 days within a median of 6 days from the beginning of infection and 90 controls were treated with standard care. The primary endpoint was the effect on viral clearance, and the secondary endpoint was the improvement of clinical outcomes. Nasal swabs for SARS-CoV-2 by PCR were performed every 5-7 days. Between 5-14 days after starting SOF/VEL treatment, SAS-CoV-2 clearance was observed in 83% of patients, while spontaneous clearance in the control was 13% (p < 0.001). An earlier SARS-CoV-2 clearance was observed in the SOF/VEL group than in the control group (median 14 vs 22 days, respectively, p < 0.001) also when the first positivity was considered. None of the patients in the SOF/VEL group showed disease progression, while in the control group, 24% required more intensive treatment (high flow oxygen or noninvasive/invasive ventilation), and one patient died (p < 0.01). No significant side effects were observed in the SOF/VEL group. Early SOF/VEL treatment in mild/moderate COVID-19 seems to be safe and effective for faster elimination of SARS-CoV-2 and to prevent disease progression.


Subject(s)
COVID-19 , Hepatitis C , Antiviral Agents/adverse effects , COVID-19/drug therapy , Carbamates , Case-Control Studies , Disease Progression , Genotype , Hepacivirus/genetics , Hepatitis C/drug therapy , Heterocyclic Compounds, 4 or More Rings/adverse effects , Humans , RNA-Dependent RNA Polymerase , SARS-CoV-2 , Sofosbuvir , Treatment Outcome
7.
Viruses ; 14(3)2022 02 25.
Article in English | MEDLINE | ID: covidwho-1765943

ABSTRACT

: Background:There are limited data available on the influence of direct-acting antivirals used to treat chronic hepatitis C (CHC) on growth in children. In this study, we aimed to analyze the growth parameters in children treated with ledipasvir/sofosbuvir (LDV/SOF). METHODS: We included38 patients (16 girls and 22 boys) aged 10-17 years treated with LDV/SOF for CHC (33 infected with genotype 1 and 5 with genotype 4; 36 were treated for 12 weeks, and 2 for 24 weeks according to the current guidelines). Patient weight and height were measured at baseline, after 4 weeks of treatment, at the end of the treatment (EOT), and 12 weeks and one year after the EOT. Body mass index (BMI), BMI z and height-for-age (HA) z scores were calculated according to the WHO Child Growth Standards and Growth reference data using the WHO anthropometric calculator AnthroPlus v. 1.0.4. In addition, correlations between BMI z scores and liver fibrosis (liver stiffness measurement, LSM), the aspartate transaminase (AST)-to-platelet ratio index (APRI), fibrosis-4 index (FIB-4) and liver steatosis (controlled attenuation parameter, CAP) were analyzed. RESULTS: At baseline, 5/38 (13%) patients were obese (BMI z score >2 SD), 4/38 (11%) were overweight, and 29 (76%) were normal. A significant increase was observed in mean weight, height and BMI both 12 weeks and one year after the treatment compared to the baseline, whereas no differences were observed for BMI z scores and HA z scores. Baseline BMI z scores correlated with alanine aminotransferase levels (r = 0.33, 95% CI 0.01-0.58, p =0.04), LSM (r = 0.40, 95% CI 0.09-0.65, p =0.01), the APRI (r = 0.33, 95% CI 0.02-0.59, p =0.03), and the CAP (r = 0.40, 95% CI 0.08-0.64, p =0.01). No similar correlations were reported at 12 weeks posttreatment. CONCLUSIONS: Treatment with LDV/SOF in children with CHC (genotypes 1 and 4) did not negatively influence the patients' growth. However, higher baseline BMI z scores correlated with more advanced liver fibrosis and steatosis in children with CHC.


Subject(s)
Hepatitis C, Chronic , Sofosbuvir , Adolescent , Antiviral Agents/therapeutic use , Benzimidazoles , Child , Drug Therapy, Combination , Female , Fluorenes , Genotype , Hepacivirus/genetics , Hepatitis C, Chronic/drug therapy , Hepatitis C, Chronic/genetics , Humans , Liver Cirrhosis/drug therapy , Male , Sofosbuvir/therapeutic use , Treatment Outcome
8.
Int J Antimicrob Agents ; 59(3): 106545, 2022 Mar.
Article in English | MEDLINE | ID: covidwho-1705649

ABSTRACT

This systematic review and meta-analysis examined the efficacy of sofosbuvir-based antiviral treatment against COVID-19 (coronavirus disease 2019). PubMed, Embase, Cochrane Central Register of Controlled Trials and ClinicalTrials.gov were searched from inception to 15 August 2021. Studies comparing the clinical efficacy and safety of sofosbuvir-based antiviral regimens (study group) with other antivirals or standard of care (control group) in patients with COVID-19 were included. Overall, 687 patients with COVID-19 were included, of which 377 patients received sofosbuvir-based treatment. Mortality was lower in the study group than in the control group [odds ratio (OR) = 0.49, 95% confidence interval (CI) 0.30-0.79; I2 = 0%]. The overall clinical recovery rate was higher in the study group than in the control group (OR = 1.82, 95% CI 1.20-2.76; I2 = 28%). The study group presented a lower requirement for mechanical ventilation (OR = 0.33, 95% CI 0.13-0.89; I2 = 0%) and intensive care unit admission (OR = 0.42, 95% CI 0.25-0.70; I2 = 0%) than the control group. Furthermore, the study group exhibited a shorter hospital length of stay [mean deviation (MD), -1.49, 95% CI -2.62 to -0.37; I2 = 56%] and recovery time (MD, -1.34, 95% CI -2.29 to -0.38; I2 = 46%) than the control group. Sofosbuvir-based treatment may help reduce mortality in patients with COVID-19 and improve associated clinical outcomes. Furthermore, sofosbuvir-based treatment was as safe as the comparator in patients with COVID-19. However, further large-scale studies are warranted to validate these findings.


Subject(s)
COVID-19 , COVID-19/drug therapy , Humans , Intensive Care Units , Randomized Controlled Trials as Topic , Respiration, Artificial , SARS-CoV-2 , Sofosbuvir/therapeutic use , Treatment Outcome
9.
Spectrochim Acta A Mol Biomol Spectrosc ; 272: 121012, 2022 May 05.
Article in English | MEDLINE | ID: covidwho-1671114

ABSTRACT

Simeprevir and sofosbuvir are direct-acting antiviral drugs approved for the treatment of chronic HCV infection. Reports demonstrate the similarities between HCV and SARS-CoV-2 in terms of structure and replication mechanism. Therefore, it is suggested that a combination of simeprevir and sofosbuvir may be considered for COVID-19 patients. To date, no spectrophotometric methods have been published for quantitative analysis of simeprevir and sofosbuvir in combination. In this work, two simple spectrophotometric methods allowed quantitative analysis of the studied drugs in the mixed form. The zero-order direct method allowed quantitative analysis of simeprevir at 333 nm, with sofosbuvir showing zero absorbance values. The dual wavelength method allowed quantitative analysis of sofosbuvir by measuring the difference in absorbance values at 259.40 and 276 nm, where the difference in absorbance values of simeprevir was zero. With the applied methods, the investigated drugs in the mixtures and tablets prepared in the laboratory were successfully analyzed quantitatively with acceptable results.


Subject(s)
COVID-19 , Hepatitis C, Chronic , Antiviral Agents/therapeutic use , Drug Therapy, Combination , Genotype , Hepacivirus , Hepatitis C, Chronic/drug therapy , Humans , SARS-CoV-2 , Simeprevir , Sofosbuvir
10.
J Antimicrob Chemother ; 77(3): 758-766, 2022 02 23.
Article in English | MEDLINE | ID: covidwho-1545994

ABSTRACT

BACKGROUND: The combination of sofosbuvir and daclatasvir has shown preliminary efficacy for hospitalized patients with COVID-19 in four open-label studies with small sample sizes. This larger trial aimed to assess if the addition of sofosbuvir/daclatasvir to standard care improved clinical outcomes in hospitalized patients with COVID-19. METHODS: This was a placebo-controlled, double-blind, randomized clinical trial in adults hospitalized with COVID-19 at 19 hospitals in Iran. Patients were randomized to oral sofosbuvir/daclatasvir 400/60 mg once-daily or placebo in addition to standard of care. Patients were included if they had positive PCR or diagnostic chest CT, O2 saturation <95% and compatible symptoms. The primary outcome was hospital discharge within 10 days of randomization. Secondary outcomes included mortality and time to clinical events. The trial is registered on the Iran Registry of Clinical Trials under IRCT20200624047908N1. RESULTS: Between July and October 2020, 1083 patients were randomized to either the sofosbuvir/daclatasvir arm (n = 541) or the placebo arm (n = 542). No significant difference was observed in the primary outcome of hospital discharge within 10 days, which was achieved by 415/541 (77%) in the sofosbuvir/daclatasvir arm and 411/542 (76%) in the placebo arm [risk ratio (RR) 1.01, 95% CI 0.95-1.08, P = 0.734]. In-hospital mortality was 60/541 (11%) in the sofosbuvir/daclatasvir arm versus 55/542 (10%) in the placebo arm (RR 1.09, 95% CI 0.77-1.54, P = 0.615). No differences were observed in time to hospital discharge or time to in-hospital mortality. CONCLUSIONS: We observed no significant effect of sofosbuvir/daclatasvir versus placebo on hospital discharge or survival in hospitalized COVID-19 patients.


Subject(s)
COVID-19 , Sofosbuvir , Adult , Antiviral Agents/therapeutic use , Carbamates , Humans , Imidazoles , Pyrrolidines , SARS-CoV-2 , Sofosbuvir/therapeutic use , Treatment Outcome , Valine/analogs & derivatives
11.
J Med Virol ; 93(12): 6750-6759, 2021 12.
Article in English | MEDLINE | ID: covidwho-1544329

ABSTRACT

Only a few treatments are approved for coronavirus disease-2019 (COVID-19) infections, with continuous debate about their clinical impact. Repurposing antiviral treatments might prove the fastest way to identify effective therapy. This trial aimed to evaluate the efficacy and safety of sofosbuvir (SOF) plus daclatasvir (DCV) or ravidasvir (RDV) added to standard care (SOC) for patients with moderate and severe COVID-19 infection. Multicentre parallel randomized controlled open-label trial. One hundred and twenty eligible patients with moderate and severe COVID-19 infection were randomized to one of the study arms. Ten days of treatment with SOF plus DCV or RDV in addition to the standard of care compared to SOC. Follow up in 7 days. Sum of the counted symptoms at 7 and 10 days, mean change in oxygen saturation level, viral negativity, and rate of intensive care unit (ICU) admission. Compared to SOC, the SOF-DCV group experienced a significantly lower sum of the counted symptoms (fever, headache, generalized aches, or respiratory distress) combined with no evidence of deterioration (ICU admission and mechanical ventilation) on Days 7 and 10 of treatment. Oxygen saturation also significantly improved among the SOF-DCV group compared to SOC starting from Day 4. The study also showed positive trends regarding the efficacy of SOF-DCV with a lower incidence of mortality. On the other hand, adding SOF-RDV to SOC did not show significant improvements in endpoints. The results support the efficacy and safety of SOF-DCV as an add-on to SOC for the treatment of moderate to severe COVID-19 infections.


Subject(s)
Antiviral Agents/therapeutic use , Benzimidazoles/therapeutic use , COVID-19/drug therapy , Carbamates/therapeutic use , Imidazoles/therapeutic use , Pyrrolidines/therapeutic use , Sofosbuvir/therapeutic use , Valine/analogs & derivatives , Adult , Drug Therapy, Combination/methods , Female , Genotype , Humans , Intensive Care Units , Male , Middle Aged , Prospective Studies , Treatment Outcome , Valine/therapeutic use
12.
Spectrochim Acta A Mol Biomol Spectrosc ; 267(Pt 2): 120623, 2022 Feb 15.
Article in English | MEDLINE | ID: covidwho-1510278

ABSTRACT

An innovative simple, rapid and sensitive spectrophotometric method was developed for the simultaneous analysis of sofosbuvir (SOF) and ledipasvir (LED) in their combined dosage forms. Sofosbuvir with ledipasvir (SOF/LED) as a combined dosage form was tried at the pandemic COVID 19 crisis. This technique has the advantages of both zero order and first order spectrophotometry. The zero and first derivative amplitudes were measured at 274.2 nm for SOF (zero crossing point of LED in first derivative spectrum) and 314 nm for LED (zero crossing point of SOF in first derivative spectrum) over the concentration range of 2.0-50.0 µg mL-1 with coefficients of determination (R2) > 0.9999 for both drugs and mean percentage recoveries of 100.25 ± 1.61 and 99.85 ± 0.99 for SOF and LED; respectively. This original method was validated according to ICH requirements and statistically compared to published comparison methods. This method was applied to estimate the average content and the uniformity of dosage units of SOF/LED combined dosage form according to British Pharmacopeia requirements.


Subject(s)
COVID-19 , Sofosbuvir , Benzimidazoles , Fluorenes , Humans , Reproducibility of Results , SARS-CoV-2 , Spectrophotometry
13.
Expert Rev Anti Infect Ther ; 20(4): 567-575, 2022 Apr.
Article in English | MEDLINE | ID: covidwho-1488110

ABSTRACT

BACKGROUND: Several randomized trials have evaluated the effects of sofosbuvir-based direct-acting antivirals on the clinical outcomes in patients with COVID-19. METHODS: A systematic literature search with no language restrictions was performed on electronic databases and preprint repositories to identify eligible randomized trials published up to 8 July 2021. A random-effects model was used to estimate the pooled odds ratio (OR) for outcomes of interest with the use of sofosbuvir combined with direct-acting antiviral agents relative to the nonuse of sofosbuvir-based direct-acting antiviral agents at 95% confidence intervals (CI). RESULTS: The meta-analysis of 11 trials (n = 2,161) revealed statistically significant reduction in the odds of mortality (pooled odds ratio = 0.59; 95% confidence interval 0.36 to 0.99) but no statistically significant difference in the odds of development of composite endpoint of severe illness (pooled odds ratio = 0.79; 95% confidence interval 0.43 to 1.44) with the administration of sofosbuvir-based direct-acting antiviral agents among patients with COVID-19, relative to non-administration of sofosbuvir-based direct-acting antiviral agents.Subgroup analysis with seven trials involving sofosbuvir-daclatasvir revealed no significant mortality benefit (pooled odds ratio = 0.77; 95% confidence interval 0.48 to 1.22). CONCLUSION: Sofosbuvir-based direct-acting antiviral agents have no protective effects against the development of severe illness in patients with COVID-19 with the current dosing regimen. Whether sofosbuvir-based direct-acting antiviral agents could offer mortality benefits would require further investigations.


Subject(s)
COVID-19 , Hepatitis C, Chronic , Antiviral Agents , COVID-19/drug therapy , Drug Therapy, Combination , Hepatitis C, Chronic/drug therapy , Humans , Randomized Controlled Trials as Topic , SARS-CoV-2 , Sofosbuvir
14.
Enzymes ; 49: 63-82, 2021.
Article in English | MEDLINE | ID: covidwho-1432697

ABSTRACT

The therapeutic targeting of the nonstructural protein 5B (NS5B) RNA-dependent RNA polymerase (RdRp) of the Hepatitis C Virus (HCV) with nucleotide analogs led to a deep understanding of this enzymes structure, function and substrate specificity. Unlike previously studied DNA polymerases including the reverse transcriptase of Human Immunodeficiency Virus, development of biochemical assays for HCV RdRp proved challenging due to low solubility of the full-length protein and inefficient acceptance of exogenous primer/templates. Despite the poor apparent specific activity, HCV RdRp was found to support rapid and processive transcription once elongation is initiated in vitro consistent with its high level of viral replication in the livers of patients. Understanding of the substrate specificity of HCV RdRp led to the discovery of the active triphosphate of sofosbuvir as a nonobligate chain-terminator of viral RNA transcripts. The ternary crystal structure of HCV RdRp, primer/template, and incoming nucleotide showed the interaction between the nucleotide analog and the 2'-hydroxyl binding pocket and how an unfit mutation of serine 282 to threonine results in resistance by interacting with the uracil base and modified 2'-position of the analog. Host polymerases mediate off-target toxicity of nucleotide analogs and the active metabolite of sofosbuvir was found to not be efficiently incorporated by host polymerases including the mitochondrial RNA polymerase (POLRMT). Knowledge from studying inhibitors of HCV RdRp serves to advance antiviral drug discovery for other emerging RNA viruses including the discovery of remdesivir as an inhibitor of severe acute respiratory syndrome coronavirus 2 (SARS-CoV2), the virus that causes COVID-19.


Subject(s)
Hepacivirus , Sofosbuvir/pharmacology , Viral Nonstructural Proteins/antagonists & inhibitors , Hepacivirus/drug effects , Hepacivirus/enzymology , RNA, Viral , RNA-Dependent RNA Polymerase/genetics , SARS-CoV-2
15.
Biomed Chromatogr ; 36(1): e5238, 2022 Jan.
Article in English | MEDLINE | ID: covidwho-1380369

ABSTRACT

Sofosbuvir is a direct-acting antiviral drug that inhibits hepatitis C virus (HCV) NS5B polymerase, which in turn affects the virus replication inside biological systems. The clinical importance of sofosbuvir is based not only on its effect on HCV but also on other lethal viruses such as Zika and severe acute respiratory syndrome coronavirus disease 2019 (SARS-COVID-19). Accordingly, there is a continuous shedding of light on the development and validation of accurate and fast analytical methods for the determination of sofosbuvir in different environments. This work critically reviews the recent advances in chromatographic methods for the analysis of sofosbuvir and/or its metabolites in pure samples, pharmaceutical dosage forms, and in the presence of other co-administered drugs to highlight the current status and future perspectives to enhance its determination in different matrixes.


Subject(s)
Antiviral Agents/blood , Chromatography/methods , Hepatitis C, Chronic/drug therapy , Sofosbuvir/blood , Antiviral Agents/therapeutic use , Hepatitis C, Chronic/blood , Humans , Plasma/chemistry , Sofosbuvir/therapeutic use
16.
Expert Rev Anti Infect Ther ; 20(2): 291-295, 2022 02.
Article in English | MEDLINE | ID: covidwho-1294626

ABSTRACT

BACKGROUND: Limited experimental and clinical evidence suggests a potential role for sofosbuvir/daclatasvir in treating COVID19. We aim to evaluate the efficacy of generic sofosbuvir/daclatasvir in treating COVID-19 patients with pneumonia. RESEARCH DESIGN AND METHODS: This multicenter prospective study involved 174 patients with COVID-19. Patients were randomized into two groups. Group A (96 patients) received sofosbuvir (400 mg)/daclatasvir (60 mg) for 14 days in combination with conventional therapy. Group B (78 patients) received conventional therapy alone. Clinical, laboratory, and radiological data were collected at baseline, after 7, 14, and 28 days of therapy. Primary endpoint was rate of clinical/virological cure. RESULTS: A lower mortality rate was observed in group (A) (14% vs 21%, P = 0.07). After 1 month of therapy, no differences were found in rates of ICU admission, oxygen therapy, or ventilation. Additionally, a statistically significant shorter duration of hospital stay (9% vs 12%, P < 0.01) and a faster achievement of PCR negativity at day 14 (84% versus 47%, P < 0.01) were noticed in group (A). CONCLUSION: Adding sofosbuvir/daclatasvir to conventional therapy of COVID-19 is promising. Their use is associated with shorter hospital stay, faster PCR negativity and may be reduced mortality.


Subject(s)
Antiviral Agents , COVID-19 , Carbamates , Imidazoles , Pyrrolidines , Sofosbuvir , Valine/analogs & derivatives , Antiviral Agents/therapeutic use , COVID-19/drug therapy , COVID-19/mortality , Carbamates/therapeutic use , Drug Therapy, Combination , Egypt/epidemiology , Humans , Imidazoles/therapeutic use , Length of Stay , Prospective Studies , Pyrrolidines/therapeutic use , SARS-CoV-2 , Sofosbuvir/therapeutic use , Treatment Outcome , Valine/therapeutic use
17.
J Microbiol Immunol Infect ; 54(5): 767-775, 2021 Oct.
Article in English | MEDLINE | ID: covidwho-1284232

ABSTRACT

Despite aggressive efforts on containment measures for the coronavirus disease 2019 (COVID-19) pandemic around the world, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is continuously spreading. Therefore, there is an urgent need for an effective antiviral agent. To date, considerable research has been conducted to develop different approaches to COVID-19 therapy. In addition to early observational studies, which could be limited by study design, small sample size, non-randomized design, or different timings of treatment, an increasing number of randomized controlled trials (RCTs) investigating the clinical efficacy and safety of antiviral agents are being carried out. This study reviews the updated findings of RCTs regarding the clinical efficacy of eight antiviral agents against COVID-19, including remdesivir, lopinavir/ritonavir, favipiravir, sofosbuvir/daclatasvir, sofosbuvir/ledipasvir, baloxavir, umifenovir, darunavir/cobicistat, and their combinations. Treatment with remdesivir could accelerate clinical improvement; however, it lacked additional survival benefits. Moreover, 5-day regimen of remdesivir might show adequate effectiveness in patients with mild to moderate COVID-19. Favipiravir was only marginally effective regarding clinical improvement and virological assessment based on the results of small RCTs. The present evidence suggests that sofosbuvir/daclatasvir may improve survival and clinical outcomes in patients with COVID-19. However, the sample sizes for analysis were relatively small, and all studies were exclusively conducted in Iran. Further larger RCTs in other countries are warranted to support these findings. In contrast, the present findings of limited RCTs did not indicate the use of lopinavir/ritonavir, sofosbuvir/ledipasvir, baloxavir, umifenovir, and darunavir/cobicistat in the treatment of patients hospitalized for COVID-19.


Subject(s)
Antiviral Agents/therapeutic use , COVID-19/drug therapy , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/therapeutic use , Alanine/analogs & derivatives , Alanine/therapeutic use , Amides/therapeutic use , Carbamates/therapeutic use , Cobicistat/therapeutic use , Darunavir/therapeutic use , Dibenzothiepins/therapeutic use , Drug Combinations , Drug Therapy, Combination , Humans , Imidazoles/therapeutic use , Indoles/therapeutic use , Iran , Lopinavir/therapeutic use , Morpholines/therapeutic use , Pyrazines/therapeutic use , Pyridones/therapeutic use , Pyrrolidines/therapeutic use , Randomized Controlled Trials as Topic , Ritonavir/therapeutic use , SARS-CoV-2 , Sofosbuvir/therapeutic use , Treatment Outcome , Triazines/therapeutic use , Valine/analogs & derivatives , Valine/therapeutic use
18.
Postgrad Med J ; 98(1161): 509-514, 2022 Jul.
Article in English | MEDLINE | ID: covidwho-1262407

ABSTRACT

PURPOSE: This systematic review and meta-analysis aimed to evaluate the effect of sofosbuvir/daclatasvir (SOF/DCV) on mortality, the need for intensive care unit (ICU) admission or invasive mechanical ventilation (IMV) and clinical recovery in patients with COVID-19. METHODS: We performed a systematic literature search through the PubMed, Scopus and Embase from the inception of databases until 6 April 2021. The intervention group was SOF/DCV, and the control group was standard of care. The primary outcome was mortality, defined as clinically validated death. The secondary outcomes were (1) the need for ICU admission or IMV and (2) clinical recovery. The pooled effect estimates were reported as risk ratios (RRs). RESULTS: There were four studies with a total of 231 patients in this meta-analysis. Three studies were randomised controlled trial, and one study was non-randomised. SOF/DCV was associated with lower mortality (RR: 0.31 (0.12, 0.78); p=0.013; I2: 0%) and reduced need for ICU admission or IMV (RR: 0.35 (0.18, 0.69); p=0.002; I2: 0%). Clinical recovery was achieved more frequently in the SOF/DCV (RR: 1.20 (1.04, 1.37); p=0.011; I2: 21.1%). There was a moderate certainty of evidence for mortality and need for ICU/IMV outcome, and a low certainty of evidence for clinical recovery. The absolute risk reductions were 140 fewer per 1000 for mortality and 186 fewer per 1000 for the need for ICU/IMV. The increase in clinical recovery was 146 more per 1000. CONCLUSION: SOF/DCV may reduce mortality rate and need for ICU/IMV in patients with COVID-19 while increasing the chance for clinical recovery. PROTOCOL REGISTRATION: PROSPERO: CRD42021247510.


Subject(s)
COVID-19 , Sofosbuvir , COVID-19/drug therapy , Carbamates , Controlled Clinical Trials as Topic , GRADE Approach , Humans , Imidazoles , Pyrrolidines , Sofosbuvir/therapeutic use , Valine/analogs & derivatives
19.
J Antimicrob Chemother ; 76(8): 2158-2167, 2021 07 15.
Article in English | MEDLINE | ID: covidwho-1243491

ABSTRACT

OBJECTIVES: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the COVID-19 pandemic. The majority of patients experience asymptomatic to mild self-limited disease, but some cases progress to respiratory and multi-organ failure. However, so far, no approved antiviral therapy has been available for treatment of COVID-19. Sofosbuvir/velpatasvir (SOF/VEL) is an approved anti-HCV drug that is capable of suppressing other families of positive-sense RNA viruses with conserved polymerase and may be effective against SARS-CoV-2. This study was conducted to evaluate the efficacy of the SOF/VEL combination in addition to the national standard of care versus the national standard of care alone (hydroxychloroquine and lopinavir/ritonavir as well as supportive care) in patients with moderate to severe COVID-19 infection. METHODS: This single-centre, randomized, open-labelled, prospective clinical trial was done in patients with moderate to severe COVID-19 admitted to Farabi Hospital in Kermanshah Province, Iran. Eligible patients were randomly assigned in a 1:1 ratio to the SOF/VEL arm (SOF/VEL plus the national standard of care) or the control arm (the national standard of care alone). The main outcome of the study was the mortality on Day 28 after randomization. Secondary outcomes were time from the start of medication to clinical improvement, hospital length of stay, need for mechanical ventilation, duration of mechanical ventilation and conversion of RT-PCR results from positive to negative from the time of randomization to discharge. Adverse events were evaluated in all patients who started their assigned treatment. RESULTS: Between 11 April and 8 June 2020, 80 patients were recruited and randomly assigned into the SOF/VEL (n = 40) and control (n = 40) arms. The primary outcome was not significantly different between the two arms (P = 1.00). Secondary outcomes, including time to clinical improvement, hospital length of stay, need for mechanical ventilation, duration of mechanical ventilation and RT-PCR conversion, were not significantly different between arms either (P > 0.05). SOF/VEL treatment and the national standard of care were tolerated similarly. CONCLUSIONS: Although treatment with SOF/VEL was safe, adding SOF/VEL to the standard of care did not improve the clinical status or reduce mortality in patients with moderate to severe COVID-19. However, larger randomized clinical trials including more parameters are needed for accurate estimation of the efficacy of SOF/VEL.


Subject(s)
COVID-19 , Sofosbuvir , Adult , Antiviral Agents/adverse effects , Carbamates , Heterocyclic Compounds, 4 or More Rings , Humans , Iran , Pandemics , Prospective Studies , SARS-CoV-2 , Sofosbuvir/adverse effects , Standard of Care , Treatment Outcome
20.
J Antimicrob Chemother ; 76(7): 1874-1885, 2021 06 18.
Article in English | MEDLINE | ID: covidwho-1195719

ABSTRACT

BACKGROUND: Current approaches of drug repurposing against COVID-19 have not proven overwhelmingly successful and the SARS-CoV-2 pandemic continues to cause major global mortality. SARS-CoV-2 nsp12, its RNA polymerase, shares homology in the nucleotide uptake channel with the HCV orthologue enzyme NS5B. Besides, HCV enzyme NS5A has pleiotropic activities, such as RNA binding, that are shared with various SARS-CoV-2 proteins. Thus, anti-HCV NS5B and NS5A inhibitors, like sofosbuvir and daclatasvir, respectively, could be endowed with anti-SARS-CoV-2 activity. METHODS: SARS-CoV-2-infected Vero cells, HuH-7 cells, Calu-3 cells, neural stem cells and monocytes were used to investigate the effects of daclatasvir and sofosbuvir. In silico and cell-free based assays were performed with SARS-CoV-2 RNA and nsp12 to better comprehend the mechanism of inhibition of the investigated compounds. A physiologically based pharmacokinetic model was generated to estimate daclatasvir's dose and schedule to maximize the probability of success for COVID-19. RESULTS: Daclatasvir inhibited SARS-CoV-2 replication in Vero, HuH-7 and Calu-3 cells, with potencies of 0.8, 0.6 and 1.1 µM, respectively. Although less potent than daclatasvir, sofosbuvir alone and combined with daclatasvir inhibited replication in Calu-3 cells. Sofosbuvir and daclatasvir prevented virus-induced neuronal apoptosis and release of cytokine storm-related inflammatory mediators, respectively. Sofosbuvir inhibited RNA synthesis by chain termination and daclatasvir targeted the folding of secondary RNA structures in the SARS-CoV-2 genome. Concentrations required for partial daclatasvir in vitro activity are achieved in plasma at Cmax after administration of the approved dose to humans. CONCLUSIONS: Daclatasvir, alone or in combination with sofosbuvir, at higher doses than used against HCV, may be further fostered as an anti-COVID-19 therapy.


Subject(s)
COVID-19 , Pharmaceutical Preparations , Animals , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Carbamates , Chlorocebus aethiops , Humans , Imidazoles , Pyrrolidines , RNA, Viral , SARS-CoV-2 , Sofosbuvir/pharmacology , Valine/analogs & derivatives , Vero Cells
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