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Background: The extent of the SARS-CoV-2 short-term evolution under Remdesivir (RDV) exposure and whether it varies across different upper respiratory compartments are not fully understood. Methods: Patients hospitalized for COVID-19, with or without RDV therapy, were enrolled and completed up to three visits, in which they provided specimens from four respiratory compartments. Near full-length genome SARS-CoV-2 sequences were obtained from viral RNA, standard lineage and variant assignments were performed, and viral mutations in the RNA-dependent RNA polymerase (RdRp) region—the RDV target gene—were detected and compared between participants with and without RDV, across the four compartments, within participants across visits, and versus a larger sequence dataset. The statistical analysis used a generalized linear mixed-effects model. Results: A total of 139 sequences were obtained from 37 out of the 44 (84%) enrolled participants. The genotyping success varied across respiratory compartments, which ranged from 42% with oropharyngeal specimens to 67% with nasopharyngeal specimens and showed improvement with higher viral loads. No RdRp mutations known to be associated with RDV resistance were identified, and for 34 detected mutations at 32 amino acid positions that are not known as RDV-associated, there was no evidence of any associations with the RDV exposure, respiratory compartment, or time. At least 1 of these 34 mutations were detected in all participants, and some differed from the larger sequence dataset. Conclusions: This study highlighted the SARS-CoV-2 short-term genomic stability within hosts and across upper respiratory compartments, which suggests a lack of evolution of RDV resistance over time. This contributes to our understanding of SARS-CoV-2 genomic dynamics.

The aim of this study was to investigate the effects of administrating Remdesivir at the acute COVID-19 phase on developing post-COVID symptoms in previously hospitalized COVID-19 survivors by controlling factors such as age, sex, body mass index, and vaccination status. A case-control study was performed. Hospitalized COVID-19 survivors who had received intravenous Remdesivir during the acute phase (n = 216) were matched by age, sex, body mass index, and vaccination status with survivors who did not receive antiviral treatment (n = 216). Participants were asked to self-report the presence of any post-COVID symptom (defined as a symptom that started no later than three months after infection) and whether the symptom persisted at the time of study (mean: 18.4, SD: 0.8 months). Anxiety levels (HADS-A), depressive symptoms (HADS-D), sleep quality (PSQI), and severity/disability (FIC) were also compared. The multivariate analysis revealed that administration of Remdesivir at the acute COVID-19 phase was a protective factor for long-term COVID development (OR0.401, 95%CI 0.256–0.628) and specifically for the following post-COVID symptoms: fatigue (OR0.399, 95%CI 0.270–0.590), pain (OR0.368, 95% CI 0.248–0.548), dyspnea at rest (OR0.580, 95%CI 0.361–0.933), concentration loss (OR0.368, 95%CI 0.151–0.901), memory loss (OR0.399, 95%CI 0.270–0.590), hair loss (OR0.103, 95%CI 0.052–0.207), and skin rashes (OR0.037, 95%CI 0.005–0.278). This study supports the potential protective role of intravenous administration of Remdesivir during the COVID-19 acute phase for long-lasting post-COVID symptoms in previously hospitalized COVID-19 survivors.

(1) Background: Geriatric patients are at high risk of complications of Coronavirus disease-2019 (COVID-19) and are good candidates for antiviral drugs. (2) Methods: A retrospective study of electronic health records (EHRs) aiming to describe antiviral (nirmatrelvir and ritonavir (nirmatrelvir/r) or remdesivir) use, drug–drug interactions (DDIs) and adverse drug reactions (ADRs) in elderly patients (75 and over), hospitalized with mild-to-moderate COVID-19 between July 2022 and June 2023. (3) Results: Out of 491 patients (mean age: 86.9 years), 180 (36.7%) received nirmatrelvir/r, 78 (15.9%) received remdesivir, and 233 (47.4%) received no antiviral therapy. No association was found between the choice of antiviral and the demographic or medical data. No serious ADR was observed. Nirmatrelvir/r dosage adjustment was inadequate in 65% of patients with renal impairment. In total, 128 patients (71%) on nirmatrelvir/r had potential pharmacokinetic DDIs, with 43 resulting in a possibly related ADR. In the remdesivir group, pharmacodynamic DDIs were more frequent, with QTc prolongation risk in 56 patients (72%). Only 20 patients underwent follow-up ECG, revealing QTc prolongation in 4. (4) Conclusions: There is an underutilization of antivirals despite their justified indications. Nirmatrelvir/r dosage was rarely adjusted to renal function. Dose adjustments and closer monitoring are needed due to the high risk of drug interactions.

Due to immunosuppression, transplant recipients are at higher risk of infections with SARS-CoV-2 and worse clinical outcomes than immunocompetent hosts. Furthermore, lung transplant patients represent a special group among solid organ recipients, since pneumonia is the main manifestation of COVID-19. However, data on the course of disease and the changes in morbidity and mortality during the course of the pandemic are limited. In our pulmonary rehabilitation clinic, we treat patients shortly after lung transplant as well as long-term transplant patients. Over the last almost 4 years of pandemic, we witnessed several COVID-19 infections in lung transplant patients in our clinic as well as patients who acquired an infection beforehand. In this paper, we aim at retrospectively describing a series of recent COVID-19 cases in our clinic, looking at the clinical course of disease and outcomes in lung transplant patients.

Remdesivir (RDV) is a broad-spectrum nucleotide analog prodrug approved for the treatment of COVID-19 in hospitalized and non-hospitalized patients with clinical benefit demonstrated in multiple Phase 3 trials. Here we present SARS-CoV-2 resistance analyses from the Phase 3 SIMPLE clinical studies evaluating RDV in hospitalized participants with severe or moderate COVID-19 disease. The severe and moderate studies enrolled participants with radiologic evidence of pneumonia and a room-air oxygen saturation of ≤94% or >94%, respectively. Virology sample collection was optional in the study protocols. Sequencing and related viral load data were obtained retrospectively from participants at a subset of study sites with local sequencing capabilities (10 of 183 sites) at timepoints with detectable viral load. Among participants with both baseline and post-baseline sequencing data treated with RDV, emergent Nsp12 substitutions were observed in 4 of 19 (21%) participants in the severe study and none of the 2 participants in the moderate study. The following 5 substitutions emerged: T76I, A526V, A554V, E665K, and C697F. The substitutions T76I, A526V, A554V, and C697F had an EC50 fold change of ≤1.5 relative to the wildtype reference using a SARS-CoV-2 subgenomic replicon system, indicating no significant change in the susceptibility to RDV. The phenotyping of E665K could not be determined due to a lack of replication. These data reveal no evidence of relevant resistance emergence and further confirm the established efficacy profile of RDV with a high resistance barrier in COVID-19 patients.

Coronaviruses represent a significant threat to both human and animal health, encompassing a range of pathogenic strains responsible for illnesses, from the common cold to more severe diseases. VV116 is a deuterated derivative of Remdesivir with oral bioavailability that was found to potently inhibit SARS-CoV-2. In this work, we investigated the broad-spectrum antiviral activity of VV116 against a variety of human and animal coronaviruses. We examined the inhibitory effects of VV116 on the replication of the human coronaviruses HCoV-NL63, HCoV-229E, and HCoV-OC43, as well as the animal coronaviruses MHV, FIPV, FECV, and CCoV. The findings reveal that VV116 effectively inhibits viral replication across these strains without exhibiting cytotoxicity, indicating its potential for safe therapeutic use. Based on the results of a time-of-addition assay and an rNTP competitive inhibition assay, it is speculated that the inhibitory mechanism of VV116 against HCoV-NL63 is consistent with its inhibition of SARS-CoV-2. Our work presents VV116 as a promising candidate for broad-spectrum anti-coronavirus therapy, with implications for both human and animal health, and supports the expansion of its therapeutic applications as backed by detailed experimental data.

Pibrentasvir (PIB) has been demonstrated to block exonuclease activity of the SARS-CoV-2 polymerase, protecting favipiravir (FVP) and remdesivir (RDV) from post-incorporation excision and eliciting antiviral synergy in vitro. The present study investigated the chemoprophylactic efficacy of PIB, FVP, RDV, FVP with PIB, or RDV with PIB dosed intranasally twice a day, using a Syrian golden hamster contact transmission model. Compared to the saline control, viral RNA levels were significantly lower in throat swabs in FVP (day 7), RDV (day 3, 5, 7), and RDV+PIB (day 3, 5) treatment groups. Similarly, findings were evident for nasal turbinate after PIB and RDV treatment, and lungs after PIB, FVP, and FVP+PIB treatment at day 7. Lung viral RNA levels after RDV and RDV+PIB treatment were only detectable in two animals per group, but the overall difference was not statistically significant. In situ examination of the lungs confirmed SARS-CoV-2 infection in all animals, except for one in each of the RDV and RDV+PIB treatment groups, which tested negative in all virus detection approaches. Overall, prevention of transmission was observed in most animals treated with RDV, while other agents reduced the viral load following contact transmission. No benefit of combining FVP or RDV with PIB was observed.

Background: Scarce data exist that analyze the outcomes of hematological patients with SARS-CoV-2 infection during the Omicron variant period who received treatment with remdesivir or nirmatrelvir/ritonavir. Methods: This study aims to address this issue by using a retrospective observational registry, created by the Spanish Hematopoietic Stem Cell Transplantation and Cell Therapy Group, spanning from 27 December 2021 to 30 April 2023. Results: This study included 466 patients, 243 (52%) who were treated with remdesivir and 223 (48%) with nirmatrelvir/ritonavir. Nirmatrelvir/ritonavir was primarily used for mild cases, resulting in a lower COVID-19-related mortality rate (1.3%), while remdesivir was preferred for moderate to severe cases (40%), exhibiting a higher mortality rate (9%). A multivariate analysis in the remdesivir cohort showed that male gender (odds ratio (OR) 0.35, p = 0.042) correlated with a lower mortality risk, while corticosteroid use (OR 9.4, p < 0.001) and co-infection (OR 2.8, p = 0.047) were linked to a higher mortality risk. Prolonged virus shedding was common, with 52% of patients shedding the virus for more than 25 days. In patients treated with remdesivir, factors associated with prolonged shedding included B-cell malignancy as well as underlying disease, severe disease, a later onset of and shorter duration of remdesivir treatment and a higher baseline viral load. Nirmatrelvir/ritonavir demonstrated a comparable safety profile to remdesivir, despite a higher risk of drug interactions. Conclusions: Nirmatrelvir/ritonavir proved to be a safe and effective option for treating mild cases in the outpatient setting, while remdesivir was preferred for severe cases, where corticosteroids and co-infection significantly predicted worse outcomes. Despite antiviral therapy, prolonged shedding remains a matter of concern.

Remdesivir is one of the most attractive options for patients with hypoxemic respiratory failure due to coronavirus disease 2019 (COVID-19). The aim of our study was to evaluate the effect of remdesivir on the hypoxic and inflammatory state in patients with moderate to severe COVID-19. We retrospectively enrolled 112 patients admitted for COVID-19 pneumonia, requiring low-flow oxygen, 57 treated with remdesivir plus standard of care (SoC) and 55 treated only with SoC that were similar for demographic and clinical data. We evaluated changes in hypoxemia and inflammatory markers at admission (Day 0) and after 5 days of treatment (Day 5) and the clinical course of the disease. From Day 0 to Day 5, the ratio of arterial oxygen partial pressure to fractional inspired oxygen (P/F) increased from 222 ± 62 to 274 ± 97 (p < 0.0001) in the remdesivir group and decreased from 223 ± 62 to 183 ± 76 (p < 0.05) in the SoC group. Interleukine-6 levels decreased in the remdesivir (45.9 to 17.5 pg/mL, p < 0.05) but not in the SoC group. Remdesivir reduced the need for ventilatory support and the length of hospitalization. In conclusion, compared to standard care, remdesivir rapidly improves hypoxia and inflammation, causing a better course of the disease in moderate to severe COVID-19.

The coronavirus disease (COVID-19) pandemic continues to threaten global public health. Remdesivir and monoclonal antibodies have shown promise for COVID-19 treatment of patients who are immunocompromised, including those with cancer, transplant recipients, and those with autoimmune disorder. However, the effectiveness and safety of this combination therapy for patients who are immunosuppressed remain unclear. We compared the efficacy and safety of combination therapy and remdesivir monotherapy for patients with mild-to-moderate COVID-19 who were immunosuppressed. Eighty-six patients treated in July 2021–March 2023 were analyzed. The combination therapy group (CTG) showed a statistically significant reduction in viral load compared with the monotherapy group (MTG) (p < 0.01). Patients in the CTG also experienced earlier resolution of fever than those in the MTG (p = 0.02), although this difference was not significant in the multivariate analysis (p = 0.21). Additionally, the CTG had significantly higher discharge rates on days 7, 14, and 28 than the MTG (p < 0.01, p < 0.01, and p = 0.04, respectively). No serious adverse events were observed with combination therapy. These findings suggest that combination therapy may improve the clinical outcomes of immunosuppressed COVID-19 patients by reducing the viral load and hastening recovery. Further studies are required to fully understand the benefits of this combination therapy for immunocompromised COVID-19 patients.

Background: The extent of the SARS-CoV-2 short-term evolution under Remdesivir (RDV) exposure and whether it varies across different upper respiratory compartments are not fully understood., Methods: Patients hospitalized for COVID-19, with or without RDV therapy, were enrolled and completed up to three visits, in which they provided specimens from four respiratory compartments. Near full-length genome SARS-CoV-2 sequences were obtained from viral RNA, standard lineage and variant assignments were performed, and viral mutations in the RNA-dependent RNA polymerase (RdRp) region-the RDV target gene-were detected and compared between participants with and without RDV, across the four compartments, within participants across visits, and versus a larger sequence dataset. The statistical analysis used a generalized linear mixed-effects model., Results: A total of 139 sequences were obtained from 37 out of the 44 (84%) enrolled participants. The genotyping success varied across respiratory compartments, which ranged from 42% with oropharyngeal specimens to 67% with nasopharyngeal specimens and showed improvement with higher viral loads. No RdRp mutations known to be associated with RDV resistance were identified, and for 34 detected mutations at 32 amino acid positions that are not known as RDV-associated, there was no evidence of any associations with the RDV exposure, respiratory compartment, or time. At least 1 of these 34 mutations were detected in all participants, and some differed from the larger sequence dataset., Conclusions: This study highlighted the SARS-CoV-2 short-term genomic stability within hosts and across upper respiratory compartments, which suggests a lack of evolution of RDV resistance over time. This contributes to our understanding of SARS-CoV-2 genomic dynamics.

Background: Nirmatrelvir/ritonavir (NMV/r) and three-day course remdesivir (3RDV) have been approved as early treatments for COVID-19 outpatients not requiring supplemental oxygen. Real-life data on the efficacy of antivirals among immunocompromised patients or directly comparing their effectiveness in preventing hospitalization and/or death are scarce. Methods: Prospective, observational study conducted in a tertiary care hospital, from 1 January 2022 until 15 March 2023, during the prevalence of the Omicron variant. Inverse probability of treatment weighting (IPTW) was used to account for differences between treatment groups. Results: We included 521, mainly immunocompromised (56%), patients in our analysis; 356 (68.3%) received 3RDV and 165 (31.7%) NMV/r. Overall, 15/521 (2.9%) patients met the primary end-point of hospitalization at 30 days (3RDV arm: 10/356, 2.8% vs. NMV/r arm: 5/165, 3%, p = 1). On IPTW-adjusted univariable analysis, the choice of treatment did not affect outcomes. In multivariable logistic regression analysis, we found that one (OR 0.26, 95%CI 0.07–0.99, p = 0.049) or two (OR 0.06, 95%CI 0.01–0.55, p = 0.014) vaccine booster shots reduced the risk for adverse outcomes. Conclusion: In our patient population of high-risk, mainly immunocompromised, vaccinated patients during the prevalence of the Omicron variant, NMV/r and 3RDV were equally effective early treatments for the prevention of hospitalization and/or death.

Background: This study aims to investigate the activity of the remdesivir–nirmatrelvir combination against Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) and to report a case of Coronavirus Disease 2019 (COVID-19) cured with this combination. Methods: A Vero E6 cell-based infection assay was used to investigate the in vitro activity of the remdesivir–nirmatrelvir combination. The SARS-CoV-2 strains tested were 20A.EU1, BA.1 and BA.5. After incubation, a viability assay was performed. The supernatants were collected and used for viral titration. The Highest Single Agent (HSA) reference model was calculated. An HSA score >10 is considered synergic. Results: Remdesivir and nirmatrelvir showed synergistic activity at 48 and 72 h, with an HSA score of 52.8 and 28.6, respectively (p < 0.0001). These data were confirmed by performing supernatant titration and against the omicron variants: the combination reduced the viral titer better than the more active compound alone. An immunocompromised patient with prolonged and critical COVID-19 was successfully treated with remdesivir, nirmatrelvir/ritonavir, tixagevimab/cilgavimab and dexamethasone, with an excellent clinical–radiological response. However, she required further off-label prolonged therapy with nirmatrelvir/ritonavir until she tested negative. Conclusions: Remdesivir–nirmatrelvir combination has synergic activity in vitro. This combination may have a role in immunosuppressed patients with severe COVID-19 and prolonged viral shedding.

Base pairing based on hydrogen bonding has, since its inception, been crucial in the antiviral activity of arabinosyladenine, 2′-deoxyuridines (i.e., IDU, TFT, BVDU), acyclic nucleoside analogues (i.e., acyclovir) and nucleoside reverse transcriptase inhibitors (NRTIs). Base pairing based on hydrogen bonding also plays a key role in the mechanism of action of various acyclic nucleoside phosphonates (ANPs) such as adefovir, tenofovir, cidofovir and O-DAPYs, thus explaining their activity against a wide array of DNA viruses (human hepatitis B virus (HBV), human immunodeficiency (HIV) and human herpes viruses (i.e., human cytomegalovirus)). Hydrogen bonding (base pairing) also seems to be involved in the inhibitory activity of Cf1743 (and its prodrug FV-100) against varicella-zoster virus (VZV) and in the activity of sofosbuvir against hepatitis C virus and that of remdesivir against SARS-CoV-2 (COVID-19). Hydrogen bonding (base pairing) may also explain the broad-spectrum antiviral effects of ribavirin and favipiravir. This may lead to lethal mutagenesis (error catastrophe), as has been demonstrated with molnutegravir in its activity against SARS-CoV-2.

In the years of Coronavirus Disease 2019 (COVID-19), various treatment options have been utilized. COVID-19 continues to circulate in the global population, and the evolution of the Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus has posed significant challenges to the treatment and prevention of infection. Remdesivir (RDV), an anti-viral agent with in vitro efficacy against coronaviruses, is a potent and safe treatment as suggested by a plethora of in vitro and in vivo studies and clinical trials. Emerging real-world data have confirmed its effectiveness, and there are currently datasets evaluating its efficacy and safety against SARS-CoV-2 infections in various clinical scenarios, including some that are not in the SmPC recommendations according for COVID-19 pharmacotherapy. Remdesivir increases the chance of recovery, reduces progression to severe disease, lowers mortality rates, and exhibits beneficial post-hospitalization outcomes, especially when used early in the course of the disease. Strong evidence suggests the expansion of remdesivir use in special populations (e.g., pregnancy, immunosuppression, renal impairment, transplantation, elderly and co-medicated patients) where the benefits of treatment outweigh the risk of adverse effects. In this article, we attempt to overview the available real-world data of remdesivir pharmacotherapy. With the unpredictable course of COVID-19, we need to utilize all available knowledge to bridge the gap between clinical research and clinical practice and be sufficiently prepared for the future.

Introduction: Remdesivir (REM) and monoclonal antibodies (mAbs) could alleviate severe COVID-19 in at-risk outpatients. However, data on their use in hospitalized patients, particularly in elderly or immunocompromised hosts, are lacking. Methods: All consecutive patients hospitalized with COVID-19 at our unit from 1 July 2021 to 15 March 2022 were retrospectively enrolled. The primary outcome was the progression to severe COVID-19 (P/F < 200). Descriptive statistics, a Cox univariate–multivariate model, and an inverse probability treatment-weighted (IPTW) analysis were performed. Results: Overall, 331 subjects were included; their median (q1–q3) age was 71 (51–80) years, and they were males in 52% of the cases. Of them, 78 (23%) developed severe COVID-19. All-cause in-hospital mortality was 14%; it was higher in those with disease progression (36% vs. 7%, p < 0.001). REM and mAbs resulted in a 7% (95%CI = 3–11%) and 14% (95%CI = 3–25%) reduction in the risk of severe COVID-19, respectively, after adjusting the analysis with the IPTW. In addition, by evaluating only immunocompromised hosts, the combination of REM and mAbs was associated with a significantly lower incidence of severe COVID-19 (aHR = 0.06, 95%CI = 0.02–0.77) when compared with monotherapy. Conclusions: REM and mAbs may reduce the risk of COVID-19 progression in hospitalized patients. Importantly, in immunocompromised hosts, the combination of mAbs and REM may be beneficial.

In this retrospective comparative study, we evaluated the effectiveness of remdesivir (RDSV) in patients with SARS-CoV-2 pneumonia. Individuals hospitalized between March 2020 and August 2022 at S.M. Goretti Hospital, Latina, with a positive test for SARS-CoV-2 and, concomitantly, pneumonia, were included. The overall survival was the primary endpoint. The composite secondary endpoint included death or progression in severe ARDS at 40 days. The study population was stratified according to treatment into two groups: the RDSV group (patients treated with RDSV-based regimens) and the no-RDSV group (patients treated with any other, not RDSV-based, regimens). Factors associated with death and progression to severe ARDS or death were assessed by multivariable analysis. A total of 1153 patients (632 belonging to the RDSV group and 521 to the no-RDSV group) were studied. The groups were comparable in terms of sex, PaO2/FiO2 at admission, and duration of symptoms before hospitalization. Further, 54 patients (8.5%) in the RDSV group and 113 (21.7%) in the no-RDSV group (p < 0.001) died. RDSV was associated with a significantly reduced hazard ratio (HR) of death (HR, 0.69 [95% CI, 0.49–0.97]; p = 0.03), compared to the no-RDSV group, as well as a significantly reduced OR of progression in severe ARDS or death (OR, 0.70 [95% CI 0.49–0.98]; p = 0.04). An overall significantly higher survival rate was observed in the RDSV group (p < 0.001, by log-rank test). These findings reinforce the survival benefit of RDSV and support its routine clinical use for the treatment of COVID-19 patients.

In 2022, three antiviral drugs—molnupiravir, remdesivir and nirmatrelvir/ritonavir—were introduced for treatment of mild-to-moderate COVID-19 in high-risk patients. The aim of this study is the evaluation of their effectiveness and tolerability in a real-life setting. A single-center observational study was set up, with the involvement of 1118 patients, with complete follow-up data, treated between the 5th of January and the 3rd of October 2022 at Santa Maria Goretti’s hospital in Latina, Central Italy. A univariable and a multivariable analysis were performed on clinical and demographic data and composite outcome, the persistence of symptoms at 30 days and time to negativization, respectively. The three antivirals showed a similar effectiveness in containing the progression of the infection to severe COVID-19 and a good tolerability in the absence of serious adverse effects. Persistence of symptoms after 30 days was more common in females than males and less common in patients treated with molnupiravir and nirmatrelvir/r. The availability of different antiviral molecules is a strong tool and, if correctly prescribed, they can have a significant role in changing the natural history of infection for frail persons, in which vaccination could be not sufficient for the prevention of severe COVID-19.

The clinical management of COVID-19 in pregnant women, who are considered a vulnerable population, remains uncertain even as the pandemic subsides. SARS-CoV-2 affects pregnant individuals in multiple ways and has been associated with severe maternal morbidity and mortality, as well as neonatal complications. The unique anatomy and physiology of gestation make managing COVID-19 in this population a complex and challenging task, emphasizing the importance of spreading knowledge and expertise in this area. Therapeutic interventions require distinct clinical consideration, taking into account differences in pharmacokinetics, vertical transmission, drug toxicities, and postnatal care. Currently, there is limited data on antiviral and immunomodulating COVID-19 pharmacotherapy in pregnancy. Some medication has been shown to be safe and well tolerated among pregnant women with COVID-19; however, the lack of randomized clinical trials and studies in this patient population is evident. Available vaccines are considered safe and effective, with no evidence of harm to the fetus, embryo development, or short-term postnatal development. Pregnant women should be counseled about the risks of SARS-CoV-2 infection and informed of available ways to protect themselves and their families. Effective treatments for COVID-19 should not be withheld from pregnant individuals, and more research is needed to ensure the best outcomes.

Early COVID-19 treatments can prevent progression to severe disease. However, real-life data are still limited, and studies are warranted to monitor the efficacy and tolerability of these drugs. We retrospectively enrolled outpatients receiving early treatment for COVID-19 in 11 infectious diseases units in the Tuscany region of Italy between 1 January and 31 March 2022, when Omicron sublineages BA.1 and BA.2 were circulating. Eligible COVID-19 patients were treated with sotrovimab (SOT), remdesivir (RMD), nirmatrelvir/ritonavir (NRM/r), or molnupiravir (MOL). We gathered demographic and clinical features, 28-day outcomes (hospitalization or death), and drugs tolerability. A total of 781 patients (median age 69.9, 66% boosted for SARS-CoV-2) met the inclusion criteria, of whom 314 were treated with SOT (40.2%), 205 with MOL (26.3%), 142 with RMD (18.2%), and 120 with NRM/r (15.4%). Overall, 28-day hospitalization and death occurred in 18/781 (2.3%) and 3/781 (0.3%), respectively. Multivariable Cox regression showed that patients receiving SOT had a reduced risk of meeting the composite outcome (28-day hospitalization and/or death) in comparison to the RMD cohort, while no significant differences were evidenced for the MOL and NRM/r groups in comparison to the RMD group. Other predictors of negative outcomes included cancer, chronic kidney disease, and a time between symptoms onset and treatment administration > 3 days. All treatments showed good safety and tolerability, with only eight patients (1%) whose treatment was interrupted due to intolerance. In the first Italian multicenter study presenting real-life data on COVID-19 early treatments, all regimens demonstrated good safety and efficacy. SOT showed a reduced risk of progression versus RMD. No significant differences of outcome were observed in preventing 28-day hospitalization and death among patients treated with RMD, MOL, and NRM/r.

The aim of this study was to investigate the effects of administrating Remdesivir at the acute COVID-19 phase on developing post-COVID symptoms in previously hospitalized COVID-19 survivors by controlling factors such as age, sex, body mass index, and vaccination status. A case-control study was performed. Hospitalized COVID-19 survivors who had received intravenous Remdesivir during the acute phase (n = 216) were matched by age, sex, body mass index, and vaccination status with survivors who did not receive antiviral treatment (n = 216). Participants were asked to self-report the presence of any post-COVID symptom (defined as a symptom that started no later than three months after infection) and whether the symptom persisted at the time of study (mean: 18.4, SD: 0.8 months). Anxiety levels (HADS-A), depressive symptoms (HADS-D), sleep quality (PSQI), and severity/disability (FIC) were also compared. The multivariate analysis revealed that administration of Remdesivir at the acute COVID-19 phase was a protective factor for long-term COVID development (OR0.401, 95%CI 0.256-0.628) and specifically for the following post-COVID symptoms: fatigue (OR0.399, 95%CI 0.270-0.590), pain (OR0.368, 95% CI 0.248-0.548), dyspnea at rest (OR0.580, 95%CI 0.361-0.933), concentration loss (OR0.368, 95%CI 0.151-0.901), memory loss (OR0.399, 95%CI 0.270-0.590), hair loss (OR0.103, 95%CI 0.052-0.207), and skin rashes (OR0.037, 95%CI 0.005-0.278). This study supports the potential protective role of intravenous administration of Remdesivir during the COVID-19 acute phase for long-lasting post-COVID symptoms in previously hospitalized COVID-19 survivors.

This network meta-analysis compared the clinical efficacy and safety of anti-viral agents for the prevention of disease progression among non-hospitalized patients with COVID-19. PubMed, Embase, Web of Science, Cochrane Library, ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform were searched from their inception to 28 May 2022. Only randomized controlled trials (RCTs) that investigated the clinical efficacy of anti-viral agents for non-hospitalized patients with COVID-19 were included. Three RCTs involving 4241 patients were included. Overall, anti-viral agents were associated with a significantly lower risk of COVID-19 related hospitalization or death compared with the placebo (OR, 0.23; 95% CI: 0.06–0.96; p = 0.04). Compared with the placebo, patients receiving nirmatrelvir plus ritonavir had the lowest risk of hospitalization or death (OR, 0.12; 95% CI: 0.06–0.24), followed by remdesivir (OR, 0.13; 95% CI: 0.03–0.57) and then molnupiravir (OR, 0.67; 95% CI: 0.46–0.99). The rank probability for each treatment calculated using the P-score revealed that nirmatrelvir plus ritonavir was the best anti-viral treatment, followed by remdesivir and then molnupiravir. Finally, anti-viral agents were not associated with an increased risk of adverse events compared with the placebo. For non-hospitalized patients with COVID-19 who are at risk of disease progression, the currently recommended three anti-viral agents, nirmatrelvir plus ritonavir, molnupiravir and remdesivir, should continue to be recommended for the prevention of disease progression. Among them, oral nirmatrelvir plus ritonavir and intravenous remdesivir seem to be the better choice, followed by molnupiravir, as determined by this network meta-analysis. Additionally, these three anti-viral agents were shown to be as tolerable as the placebo in this clinical setting.

Newly emerging SARS-CoV-2 variants may escape monoclonal antibodies (mAbs) and antiviral drugs. By using live virus assays, we assessed the ex vivo inhibition of the B.1 wild-type (WT), delta and omicron BA.1 and BA.2 lineages by post-infusion sera from 40 individuals treated with bamlanivimab/etesevimab (BAM/ETE), casirivimab/imdevimab (CAS/IMD), and sotrovimab (SOT) as well as the activity of remdesivir, nirmatrelvir and molnupiravir. mAbs and drug activity were defined as the serum dilution (ID50) and drug concentration (IC50), respectively, showing 50% protection of virus-induced cytopathic effect. All pre-infusion sera were negative for SARS-CoV-2 neutralizing activity. BAM/ETE, CAS/IMD, and SOT showed activity against the WT (ID50 6295 (4355–8075) for BAM/ETE; 18,214 (16,248–21,365) for CAS/IMD; and 456 (265–592) for SOT) and the delta (14,780 (ID50 10,905–21,020) for BAM/ETE; 63,937 (47,211–79,971) for CAS/IMD; and 1103 (843–1334) for SOT). Notably, only SOT was active against BA.1 (ID50 200 (37–233)), whereas BA.2 was neutralized by CAS/IMD (ID50 174 (134–209) ID50) and SOT (ID50 20 (9–31) ID50), but not by BAM/ETE. No significant inter-variant IC50 differences were observed for molnupiravir (1.5 ± 0.1/1.5 ± 0.7/1.0 ± 0.5/0.8 ± 0.01 μM for WT/delta/BA.1/BA.2, respectively), nirmatrelvir (0.05 ± 0.02/0.06 ± 0.01/0.04 ± 0.02/0.04 ± 0.01 μM) or remdesivir (0.08 ± 0.04/0.11 ± 0.08/0.05 ± 0.04/0.08 ± 0.01 μM). Continued evolution of SARS-CoV-2 requires updating the mAbs arsenal, although antivirals have so far remained unaffected.

Remdesivir is the first drug approved for treatment of COVID-19 but current evidence for recommending its use for the treatment of moderate-to-severe disease is still controversial among clinical guidelines. We performed a nationwide, registry-based study including all Italian hospitalized patients with COVID-19 treated with remdesivir to assess the impact of major confounders on crude 15-day and 29-day mortality. Mortality was calculated using the Kaplan–Meier estimator and the Cox proportional-hazards model was applied to analyze the risks by patient’s baseline features. In total, 16,462 patients treated with remdesivir from 29 October 2020 to 17 December 2020 were entered in the study. Crude 15-day and 29-day mortality were 7.1% (95% CI, 6.7–7.5%) and 11.7% (95% CI, 11.2–12.2%), respectively. Being treated within two days of admission reduced the risk of death by about 40% (HR 1.4, 95% CI, 1.2–1.6). Results from the largest cohort of remdesivir-treated patients suggests that mortality in SARS-CoV-2 hospitalized patients is substantially influenced by the days between SARS-CoV-2 diagnosis and drug prescription. Current recommendations and future clinical trials for remdesivir alone or in combination should carefully consider the target population and timing for best efficacy of treatment.

Measles virus (MV) is a highly contagious respiratory virus responsible for outbreaks associated with significant morbidity and mortality among children and young adults. Although safe and effective measles vaccines are available, the COVID-19 pandemic has resulted in vaccination coverage gaps that may lead to the resurgence of measles when restrictions are lifted. This puts individuals who cannot be vaccinated, such as young infants and immunocompromised individuals, at risk. Therapeutic interventions are complicated by the long incubation time of measles, resulting in a narrow treatment window. At present, the only available WHO-advised option is treatment with intravenous immunoglobulins, although this is not approved as standard of care. Antivirals against measles may contribute to intervention strategies to limit the impact of future outbreaks. Here, we review previously described antivirals and antiviral assays, evaluate the antiviral efficacy of a number of compounds to inhibit MV dissemination in vitro, and discuss potential application in specific target populations. We conclude that broadly reactive antivirals could strengthen existing intervention strategies to limit the impact of measles outbreaks.

We extend our established agent-based multiscale computational model of infection of lung tissue by SARS-CoV-2 to include pharmacokinetic and pharmacodynamic models of remdesivir. We model remdesivir treatment for COVID-19; however, our methods are general to other viral infections and antiviral therapies. We investigate the effects of drug potency, drug dosing frequency, treatment initiation delay, antiviral half-life, and variability in cellular uptake and metabolism of remdesivir and its active metabolite on treatment outcomes in a simulated patch of infected epithelial tissue. Non-spatial deterministic population models which treat all cells of a given class as identical can clarify how treatment dosage and timing influence treatment efficacy. However, they do not reveal how cell-to-cell variability affects treatment outcomes. Our simulations suggest that for a given treatment regime, including cell-to-cell variation in drug uptake, permeability and metabolism increase the likelihood of uncontrolled infection as the cells with the lowest internal levels of antiviral act as super-spreaders within the tissue. The model predicts substantial variability in infection outcomes between similar tissue patches for different treatment options. In models with cellular metabolic variability, antiviral doses have to be increased significantly (>50% depending on simulation parameters) to achieve the same treatment results as with the homogeneous cellular metabolism.

(1) Background: Geriatric patients are at high risk of complications of Coronavirus disease-2019 (COVID-19) and are good candidates for antiviral drugs. (2) Methods: A retrospective study of electronic health records (EHRs) aiming to describe antiviral (nirmatrelvir and ritonavir (nirmatrelvir/r) or remdesivir) use, drug-drug interactions (DDIs) and adverse drug reactions (ADRs) in elderly patients (75 and over), hospitalized with mild-to-moderate COVID-19 between July 2022 and June 2023. (3) Results: Out of 491 patients (mean age: 86.9 years), 180 (36.7%) received nirmatrelvir/r, 78 (15.9%) received remdesivir, and 233 (47.4%) received no antiviral therapy. No association was found between the choice of antiviral and the demographic or medical data. No serious ADR was observed. Nirmatrelvir/r dosage adjustment was inadequate in 65% of patients with renal impairment. In total, 128 patients (71%) on nirmatrelvir/r had potential pharmacokinetic DDIs, with 43 resulting in a possibly related ADR. In the remdesivir group, pharmacodynamic DDIs were more frequent, with QTc prolongation risk in 56 patients (72%). Only 20 patients underwent follow-up ECG, revealing QTc prolongation in 4. (4) Conclusions: There is an underutilization of antivirals despite their justified indications. Nirmatrelvir/r dosage was rarely adjusted to renal function. Dose adjustments and closer monitoring are needed due to the high risk of drug interactions.

Due to immunosuppression, transplant recipients are at higher risk of infections with SARS-CoV-2 and worse clinical outcomes than immunocompetent hosts. Furthermore, lung transplant patients represent a special group among solid organ recipients, since pneumonia is the main manifestation of COVID-19. However, data on the course of disease and the changes in morbidity and mortality during the course of the pandemic are limited. In our pulmonary rehabilitation clinic, we treat patients shortly after lung transplant as well as long-term transplant patients. Over the last almost 4 years of pandemic, we witnessed several COVID-19 infections in lung transplant patients in our clinic as well as patients who acquired an infection beforehand. In this paper, we aim at retrospectively describing a series of recent COVID-19 cases in our clinic, looking at the clinical course of disease and outcomes in lung transplant patients.

Remdesivir (RDV) is a broad-spectrum nucleotide analog prodrug approved for the treatment of COVID-19 in hospitalized and non-hospitalized patients with clinical benefit demonstrated in multiple Phase 3 trials. Here we present SARS-CoV-2 resistance analyses from the Phase 3 SIMPLE clinical studies evaluating RDV in hospitalized participants with severe or moderate COVID-19 disease. The severe and moderate studies enrolled participants with radiologic evidence of pneumonia and a room-air oxygen saturation of ≤94% or >94%, respectively. Virology sample collection was optional in the study protocols. Sequencing and related viral load data were obtained retrospectively from participants at a subset of study sites with local sequencing capabilities (10 of 183 sites) at timepoints with detectable viral load. Among participants with both baseline and post-baseline sequencing data treated with RDV, emergent Nsp12 substitutions were observed in 4 of 19 (21%) participants in the severe study and none of the 2 participants in the moderate study. The following 5 substitutions emerged: T76I, A526V, A554V, E665K, and C697F. The substitutions T76I, A526V, A554V, and C697F had an EC 50 fold change of ≤1.5 relative to the wildtype reference using a SARS-CoV-2 subgenomic replicon system, indicating no significant change in the susceptibility to RDV. The phenotyping of E665K could not be determined due to a lack of replication. These data reveal no evidence of relevant resistance emergence and further confirm the established efficacy profile of RDV with a high resistance barrier in COVID-19 patients.

The COVID-19 pandemic continues to threaten healthcare systems worldwide due to the limited access to vaccines, suboptimal treatment options, and the continuous emergence of new and more transmissible SARS-CoV-2 variants. Reverse-genetics studies of viral genes and mutations have proven highly valuable in advancing basic virus research, leading to the development of therapeutics. We developed a functional and highly versatile full-length SARS-CoV-2 infectious system by cloning the sequence of a COVID-19 associated virus isolate (DK-AHH1) into a bacterial artificial chromosome (BAC). Viruses recovered after RNA-transfection of in vitro transcripts into Vero E6 cells showed growth kinetics and remdesivir susceptibility similar to the DK-AHH1 virus isolate. Insertion of reporter genes, green fluorescent protein, and nanoluciferase into the ORF7 genomic region led to high levels of reporter activity, which facilitated high throughput treatment experiments. We found that putative coronavirus remdesivir resistance-associated substitutions F480L and V570L—and naturally found polymorphisms A97V, P323L, and N491S, all in nsp12—did not decrease SARS-CoV-2 susceptibility to remdesivir. A nanoluciferase reporter clone with deletion of spike (S), envelope (E), and membrane (M) proteins exhibited high levels of transient replication, was inhibited by remdesivir, and therefore could function as an efficient non-infectious subgenomic replicon system. The developed SARS-CoV-2 reverse-genetics systems, including recombinants to modify infectious viruses and non-infectious subgenomic replicons with autonomous genomic RNA replication, will permit high-throughput cell culture studies—providing fundamental understanding of basic biology of this coronavirus. We have proven the utility of the systems in rapidly introducing mutations in nsp12 and studying their effect on the efficacy of remdesivir, which is used worldwide for the treatment of COVID-19. Our system provides a platform to effectively test the antiviral activity of drugs and the phenotype of SARS-CoV-2 mutants.

The goal of this study was to develop a mathematical model to simulate the actions of drugs that target SARS-CoV-2 virus infection. To accomplish that goal, we have developed a mathematical model that describes the control of a SARS-CoV-2 infection by the innate and adaptive immune components. Invasion of the virus triggers the innate immunity, whereby interferon renders some of the target cells resistant to infection, and infected cells are removed by effector cells. The adaptive immune response is represented by plasma cells and virus-specific antibodies. The model is parameterized and then validated against viral load measurements collected in COVID-19 patients. We apply the model to simulate three potential anti-SARS-CoV-2 therapies: (1) Remdesivir, a repurposed drug that has been shown to inhibit the transcription of SARS-CoV-2, (2) an alternative (hypothetical) therapy that inhibits the virus’ entry into host cells, and (3) convalescent plasma transfusion therapy. Simulation results point to the importance of early intervention, i.e., for any of the three therapies to be effective, it must be administered sufficiently early, not more than a day or two after the onset of symptoms. The model can serve as a key component in integrative platforms for rapid in silico testing of potential COVID-19 therapies and vaccines.

After more than one year of the COVID-19 pandemic, antiviral treatment options against SARS-CoV-2 are still severely limited. High hopes that had initially been placed on antiviral drugs like remdesivir have so far not been fulfilled. While individual case reports provide striking evidence for the clinical efficacy of remdesivir in the right clinical settings, major trials failed to demonstrate this. Here, we highlight and discuss the key findings of these studies and underlying reasons for their failure. We elaborate on how such shortcomings should be prevented in future clinical trials and pandemics. We suggest in conclusion that any novel antiviral agent that enters human trials should first be tested in a post-exposure setting to provide rapid and solid evidence for its clinical efficacy before initiating further time-consuming and costly clinical trials for more advanced disease. In the COVID-19 pandemic this might have established remdesivir early on as an efficient antiviral agent at a more suitable disease stage which would have saved many lives, in particular in large outbreaks within residential care homes.

Coronaviruses represent a significant threat to both human and animal health, encompassing a range of pathogenic strains responsible for illnesses, from the common cold to more severe diseases. VV116 is a deuterated derivative of Remdesivir with oral bioavailability that was found to potently inhibit SARS-CoV-2. In this work, we investigated the broad-spectrum antiviral activity of VV116 against a variety of human and animal coronaviruses. We examined the inhibitory effects of VV116 on the replication of the human coronaviruses HCoV-NL63, HCoV-229E, and HCoV-OC43, as well as the animal coronaviruses MHV, FIPV, FECV, and CCoV. The findings reveal that VV116 effectively inhibits viral replication across these strains without exhibiting cytotoxicity, indicating its potential for safe therapeutic use. Based on the results of a time-of-addition assay and an rNTP competitive inhibition assay, it is speculated that the inhibitory mechanism of VV116 against HCoV-NL63 is consistent with its inhibition of SARS-CoV-2. Our work presents VV116 as a promising candidate for broad-spectrum anti-coronavirus therapy, with implications for both human and animal health, and supports the expansion of its therapeutic applications as backed by detailed experimental data.

Clinical trials demonstrated the role of vaccines and antiviral treatments against SARS-CoV-2 in reducing the likelihood of disease progression and death. However, there are limited data available regarding the time to negativity of people who received these treatments. Further, several comorbidities and risk factors might affect the impact of vaccines and antiviral treatments. To this end, we aimed to evaluate and disentangle the impact of anti-SARS-CoV-2 treatments and that of underlying clinical factors associated with a shortened length of SARS-CoV-2 infection. Hence, we recorded the timeframe of positive nasopharyngeal swab in people infected while being hospitalized for reasons other than SARS-CoV-2 infection. All patients who died or were discharged with a positive swab were excluded from the study. A total of 175 patients were included in this study. Clinical conditions encompass malignancies, immunological disorders, cardiovascular, metabolic, neurodegenerative, and chronic kidney disease. Most of the participants (91.4%) were vaccinated before admission to the hospital, and 65.1% received antiviral treatment within three days after the symptom's onset. Unvaccinated patients had a longer median time to negativity than people who received at least two doses of vaccine (18 vs. 10 days). Concerning the clinical conditions of all patients, multivariate analysis highlighted a lower probability of 14-day conversion of antigenic test positivity in patients with hematological malignancy, including those vaccinated and those exposed to antiviral therapies. In conclusion, our data showed that prompt administration of antiviral treatments accelerates the clearance of SARS-CoV-2. Further, in the elderly patients under study, previous vaccination and antiviral treatment synergize to reduce time to negativity. This translates into a shorter hospitalization time and a lower risk of transmission through patients and connected healthcare workers in a hospital ward setting, with considerable improvement in cost-effective care management.

Pibrentasvir (PIB) has been demonstrated to block exonuclease activity of the SARS-CoV-2 polymerase, protecting favipiravir (FVP) and remdesivir (RDV) from post-incorporation excision and eliciting antiviral synergy in vitro. The present study investigated the chemoprophylactic efficacy of PIB, FVP, RDV, FVP with PIB, or RDV with PIB dosed intranasally twice a day, using a Syrian golden hamster contact transmission model. Compared to the saline control, viral RNA levels were significantly lower in throat swabs in FVP (day 7), RDV (day 3, 5, 7), and RDV+PIB (day 3, 5) treatment groups. Similarly, findings were evident for nasal turbinate after PIB and RDV treatment, and lungs after PIB, FVP, and FVP+PIB treatment at day 7. Lung viral RNA levels after RDV and RDV+PIB treatment were only detectable in two animals per group, but the overall difference was not statistically significant. In situ examination of the lungs confirmed SARS-CoV-2 infection in all animals, except for one in each of the RDV and RDV+PIB treatment groups, which tested negative in all virus detection approaches. Overall, prevention of transmission was observed in most animals treated with RDV, while other agents reduced the viral load following contact transmission. No benefit of combining FVP or RDV with PIB was observed.

Remdesivir is one of the most attractive options for patients with hypoxemic respiratory failure due to coronavirus disease 2019 (COVID-19). The aim of our study was to evaluate the effect of remdesivir on the hypoxic and inflammatory state in patients with moderate to severe COVID-19. We retrospectively enrolled 112 patients admitted for COVID-19 pneumonia, requiring low-flow oxygen, 57 treated with remdesivir plus standard of care (SoC) and 55 treated only with SoC that were similar for demographic and clinical data. We evaluated changes in hypoxemia and inflammatory markers at admission (Day 0) and after 5 days of treatment (Day 5) and the clinical course of the disease. From Day 0 to Day 5, the ratio of arterial oxygen partial pressure to fractional inspired oxygen (P/F) increased from 222 ± 62 to 274 ± 97 ( p < 0.0001) in the remdesivir group and decreased from 223 ± 62 to 183 ± 76 ( p < 0.05) in the SoC group. Interleukine-6 levels decreased in the remdesivir (45.9 to 17.5 pg/mL, p < 0.05) but not in the SoC group. Remdesivir reduced the need for ventilatory support and the length of hospitalization. In conclusion, compared to standard care, remdesivir rapidly improves hypoxia and inflammation, causing a better course of the disease in moderate to severe COVID-19.

Background: Scarce data exist that analyze the outcomes of hematological patients with SARS-CoV-2 infection during the Omicron variant period who received treatment with remdesivir or nirmatrelvir/ritonavir., Methods: This study aims to address this issue by using a retrospective observational registry, created by the Spanish Hematopoietic Stem Cell Transplantation and Cell Therapy Group, spanning from 27 December 2021 to 30 April 2023., Results: This study included 466 patients, 243 (52%) who were treated with remdesivir and 223 (48%) with nirmatrelvir/ritonavir. Nirmatrelvir/ritonavir was primarily used for mild cases, resulting in a lower COVID-19-related mortality rate (1.3%), while remdesivir was preferred for moderate to severe cases (40%), exhibiting a higher mortality rate (9%). A multivariate analysis in the remdesivir cohort showed that male gender (odds ratio (OR) 0.35, p = 0.042) correlated with a lower mortality risk, while corticosteroid use (OR 9.4, p < 0.001) and co-infection (OR 2.8, p = 0.047) were linked to a higher mortality risk. Prolonged virus shedding was common, with 52% of patients shedding the virus for more than 25 days. In patients treated with remdesivir, factors associated with prolonged shedding included B-cell malignancy as well as underlying disease, severe disease, a later onset of and shorter duration of remdesivir treatment and a higher baseline viral load. Nirmatrelvir/ritonavir demonstrated a comparable safety profile to remdesivir, despite a higher risk of drug interactions., Conclusions: Nirmatrelvir/ritonavir proved to be a safe and effective option for treating mild cases in the outpatient setting, while remdesivir was preferred for severe cases, where corticosteroids and co-infection significantly predicted worse outcomes. Despite antiviral therapy, prolonged shedding remains a matter of concern.

The coronavirus disease (COVID-19) pandemic continues to threaten global public health. Remdesivir and monoclonal antibodies have shown promise for COVID-19 treatment of patients who are immunocompromised, including those with cancer, transplant recipients, and those with autoimmune disorder. However, the effectiveness and safety of this combination therapy for patients who are immunosuppressed remain unclear. We compared the efficacy and safety of combination therapy and remdesivir monotherapy for patients with mild-to-moderate COVID-19 who were immunosuppressed. Eighty-six patients treated in July 2021-March 2023 were analyzed. The combination therapy group (CTG) showed a statistically significant reduction in viral load compared with the monotherapy group (MTG) ( p < 0.01). Patients in the CTG also experienced earlier resolution of fever than those in the MTG ( p = 0.02), although this difference was not significant in the multivariate analysis ( p = 0.21). Additionally, the CTG had significantly higher discharge rates on days 7, 14, and 28 than the MTG ( p < 0.01, p < 0.01, and p = 0.04, respectively). No serious adverse events were observed with combination therapy. These findings suggest that combination therapy may improve the clinical outcomes of immunosuppressed COVID-19 patients by reducing the viral load and hastening recovery. Further studies are required to fully understand the benefits of this combination therapy for immunocompromised COVID-19 patients.

Remdesivir (GS-5734) is a 1′-cyano-substituted adenosine nucleotide analogue prodrug that shows broad-spectrum antiviral activity against several RNA viruses. This compound is currently under clinical development for the treatment of Ebola virus disease (EVD). While antiviral effects have been demonstrated in cell culture and in non-human primates, the mechanism of action of Ebola virus (EBOV) inhibition for remdesivir remains to be fully elucidated. The EBOV RNA-dependent RNA polymerase (RdRp) complex was recently expressed and purified, enabling biochemical studies with the relevant triphosphate (TP) form of remdesivir and its presumptive target. In this study, we confirmed that remdesivir-TP is able to compete for incorporation with adenosine triphosphate (ATP). Enzyme kinetics revealed that EBOV RdRp and respiratory syncytial virus (RSV) RdRp incorporate ATP and remdesivir-TP with similar efficiencies. The selectivity of ATP against remdesivir-TP is ~4 for EBOV RdRp and ~3 for RSV RdRp. In contrast, purified human mitochondrial RNA polymerase (h-mtRNAP) effectively discriminates against remdesivir-TP with a selectivity value of ~500-fold. For EBOV RdRp, the incorporated inhibitor at position i does not affect the ensuing nucleotide incorporation event at position i+1. For RSV RdRp, we measured a ~6-fold inhibition at position i+1 although RNA synthesis was not terminated. Chain termination was in both cases delayed and was seen predominantly at position i+5. This pattern is specific to remdesivir-TP and its 1′-cyano modification. Compounds with modifications at the 2′-position show different patterns of inhibition. While 2′-C-methyl-ATP is not incorporated, ara-ATP acts as a non-obligate chain terminator and prevents nucleotide incorporation at position i+1. Taken together, our biochemical data indicate that the major contribution to EBOV RNA synthesis inhibition by remdesivir can be ascribed to delayed chain termination. The long distance of five residues between the incorporated nucleotide analogue and its inhibitory effect warrant further investigation.

Background: This study aims to investigate the activity of the remdesivir-nirmatrelvir combination against Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) and to report a case of Coronavirus Disease 2019 (COVID-19) cured with this combination., Methods: A Vero E6 cell-based infection assay was used to investigate the in vitro activity of the remdesivir-nirmatrelvir combination. The SARS-CoV-2 strains tested were 20A.EU1, BA.1 and BA.5. After incubation, a viability assay was performed. The supernatants were collected and used for viral titration. The Highest Single Agent (HSA) reference model was calculated. An HSA score >10 is considered synergic., Results: Remdesivir and nirmatrelvir showed synergistic activity at 48 and 72 h, with an HSA score of 52.8 and 28.6, respectively ( p < 0.0001). These data were confirmed by performing supernatant titration and against the omicron variants: the combination reduced the viral titer better than the more active compound alone. An immunocompromised patient with prolonged and critical COVID-19 was successfully treated with remdesivir, nirmatrelvir/ritonavir, tixagevimab/cilgavimab and dexamethasone, with an excellent clinical-radiological response. However, she required further off-label prolonged therapy with nirmatrelvir/ritonavir until she tested negative., Conclusions: Remdesivir-nirmatrelvir combination has synergic activity in vitro. This combination may have a role in immunosuppressed patients with severe COVID-19 and prolonged viral shedding.

Background: Nirmatrelvir/ritonavir (NMV/r) and three-day course remdesivir (3RDV) have been approved as early treatments for COVID-19 outpatients not requiring supplemental oxygen. Real-life data on the efficacy of antivirals among immunocompromised patients or directly comparing their effectiveness in preventing hospitalization and/or death are scarce., Methods: Prospective, observational study conducted in a tertiary care hospital, from 1 January 2022 until 15 March 2023, during the prevalence of the Omicron variant. Inverse probability of treatment weighting (IPTW) was used to account for differences between treatment groups., Results: We included 521, mainly immunocompromised (56%), patients in our analysis; 356 (68.3%) received 3RDV and 165 (31.7%) NMV/r. Overall, 15/521 (2.9%) patients met the primary end-point of hospitalization at 30 days (3RDV arm: 10/356, 2.8% vs. NMV/r arm: 5/165, 3%, p = 1). On IPTW-adjusted univariable analysis, the choice of treatment did not affect outcomes. In multivariable logistic regression analysis, we found that one (OR 0.26, 95%CI 0.07-0.99, p = 0.049) or two (OR 0.06, 95%CI 0.01-0.55, p = 0.014) vaccine booster shots reduced the risk for adverse outcomes., Conclusion: In our patient population of high-risk, mainly immunocompromised, vaccinated patients during the prevalence of the Omicron variant, NMV/r and 3RDV were equally effective early treatments for the prevention of hospitalization and/or death.

Introduction: Remdesivir (REM) and monoclonal antibodies (mAbs) could alleviate severe COVID-19 in at-risk outpatients. However, data on their use in hospitalized patients, particularly in elderly or immunocompromised hosts, are lacking., Methods: All consecutive patients hospitalized with COVID-19 at our unit from 1 July 2021 to 15 March 2022 were retrospectively enrolled. The primary outcome was the progression to severe COVID-19 (P/F < 200). Descriptive statistics, a Cox univariate-multivariate model, and an inverse probability treatment-weighted (IPTW) analysis were performed., Results: Overall, 331 subjects were included; their median (q1-q3) age was 71 (51-80) years, and they were males in 52% of the cases. Of them, 78 (23%) developed severe COVID-19. All-cause in-hospital mortality was 14%; it was higher in those with disease progression (36% vs. 7%, p < 0.001). REM and mAbs resulted in a 7% (95%CI = 3-11%) and 14% (95%CI = 3-25%) reduction in the risk of severe COVID-19, respectively, after adjusting the analysis with the IPTW. In addition, by evaluating only immunocompromised hosts, the combination of REM and mAbs was associated with a significantly lower incidence of severe COVID-19 (aHR = 0.06, 95%CI = 0.02-0.77) when compared with monotherapy., Conclusions: REM and mAbs may reduce the risk of COVID-19 progression in hospitalized patients. Importantly, in immunocompromised hosts, the combination of mAbs and REM may be beneficial.

In the years of Coronavirus Disease 2019 (COVID-19), various treatment options have been utilized. COVID-19 continues to circulate in the global population, and the evolution of the Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus has posed significant challenges to the treatment and prevention of infection. Remdesivir (RDV), an anti-viral agent with in vitro efficacy against coronaviruses, is a potent and safe treatment as suggested by a plethora of in vitro and in vivo studies and clinical trials. Emerging real-world data have confirmed its effectiveness, and there are currently datasets evaluating its efficacy and safety against SARS-CoV-2 infections in various clinical scenarios, including some that are not in the SmPC recommendations according for COVID-19 pharmacotherapy. Remdesivir increases the chance of recovery, reduces progression to severe disease, lowers mortality rates, and exhibits beneficial post-hospitalization outcomes, especially when used early in the course of the disease. Strong evidence suggests the expansion of remdesivir use in special populations (e.g., pregnancy, immunosuppression, renal impairment, transplantation, elderly and co-medicated patients) where the benefits of treatment outweigh the risk of adverse effects. In this article, we attempt to overview the available real-world data of remdesivir pharmacotherapy. With the unpredictable course of COVID-19, we need to utilize all available knowledge to bridge the gap between clinical research and clinical practice and be sufficiently prepared for the future.

Base pairing based on hydrogen bonding has, since its inception, been crucial in the antiviral activity of arabinosyladenine, 2'-deoxyuridines (i.e., IDU, TFT, BVDU), acyclic nucleoside analogues (i.e., acyclovir) and nucleoside reverse transcriptase inhibitors (NRTIs). Base pairing based on hydrogen bonding also plays a key role in the mechanism of action of various acyclic nucleoside phosphonates (ANPs) such as adefovir, tenofovir, cidofovir and O-DAPYs, thus explaining their activity against a wide array of DNA viruses (human hepatitis B virus (HBV), human immunodeficiency (HIV) and human herpes viruses (i.e., human cytomegalovirus)). Hydrogen bonding (base pairing) also seems to be involved in the inhibitory activity of Cf1743 (and its prodrug FV-100) against varicella-zoster virus (VZV) and in the activity of sofosbuvir against hepatitis C virus and that of remdesivir against SARS-CoV-2 (COVID-19). Hydrogen bonding (base pairing) may also explain the broad-spectrum antiviral effects of ribavirin and favipiravir. This may lead to lethal mutagenesis (error catastrophe), as has been demonstrated with molnutegravir in its activity against SARS-CoV-2.

In 2022, three antiviral drugs-molnupiravir, remdesivir and nirmatrelvir/ritonavir-were introduced for treatment of mild-to-moderate COVID-19 in high-risk patients. The aim of this study is the evaluation of their effectiveness and tolerability in a real-life setting. A single-center observational study was set up, with the involvement of 1118 patients, with complete follow-up data, treated between the 5th of January and the 3rd of October 2022 at Santa Maria Goretti's hospital in Latina, Central Italy. A univariable and a multivariable analysis were performed on clinical and demographic data and composite outcome, the persistence of symptoms at 30 days and time to negativization, respectively. The three antivirals showed a similar effectiveness in containing the progression of the infection to severe COVID-19 and a good tolerability in the absence of serious adverse effects. Persistence of symptoms after 30 days was more common in females than males and less common in patients treated with molnupiravir and nirmatrelvir/r. The availability of different antiviral molecules is a strong tool and, if correctly prescribed, they can have a significant role in changing the natural history of infection for frail persons, in which vaccination could be not sufficient for the prevention of severe COVID-19.

In this retrospective comparative study, we evaluated the effectiveness of remdesivir (RDSV) in patients with SARS-CoV-2 pneumonia. Individuals hospitalized between March 2020 and August 2022 at S.M. Goretti Hospital, Latina, with a positive test for SARS-CoV-2 and, concomitantly, pneumonia, were included. The overall survival was the primary endpoint. The composite secondary endpoint included death or progression in severe ARDS at 40 days. The study population was stratified according to treatment into two groups: the RDSV group (patients treated with RDSV-based regimens) and the no-RDSV group (patients treated with any other, not RDSV-based, regimens). Factors associated with death and progression to severe ARDS or death were assessed by multivariable analysis. A total of 1153 patients (632 belonging to the RDSV group and 521 to the no-RDSV group) were studied. The groups were comparable in terms of sex, PaO2/FiO2 at admission, and duration of symptoms before hospitalization. Further, 54 patients (8.5%) in the RDSV group and 113 (21.7%) in the no-RDSV group ( p < 0.001) died. RDSV was associated with a significantly reduced hazard ratio (HR) of death (HR, 0.69 [95% CI, 0.49-0.97]; p = 0.03), compared to the no-RDSV group, as well as a significantly reduced OR of progression in severe ARDS or death (OR, 0.70 [95% CI 0.49-0.98]; p = 0.04). An overall significantly higher survival rate was observed in the RDSV group ( p < 0.001, by log-rank test). These findings reinforce the survival benefit of RDSV and support its routine clinical use for the treatment of COVID-19 patients.

The clinical management of COVID-19 in pregnant women, who are considered a vulnerable population, remains uncertain even as the pandemic subsides. SARS-CoV-2 affects pregnant individuals in multiple ways and has been associated with severe maternal morbidity and mortality, as well as neonatal complications. The unique anatomy and physiology of gestation make managing COVID-19 in this population a complex and challenging task, emphasizing the importance of spreading knowledge and expertise in this area. Therapeutic interventions require distinct clinical consideration, taking into account differences in pharmacokinetics, vertical transmission, drug toxicities, and postnatal care. Currently, there is limited data on antiviral and immunomodulating COVID-19 pharmacotherapy in pregnancy. Some medication has been shown to be safe and well tolerated among pregnant women with COVID-19; however, the lack of randomized clinical trials and studies in this patient population is evident. Available vaccines are considered safe and effective, with no evidence of harm to the fetus, embryo development, or short-term postnatal development. Pregnant women should be counseled about the risks of SARS-CoV-2 infection and informed of available ways to protect themselves and their families. Effective treatments for COVID-19 should not be withheld from pregnant individuals, and more research is needed to ensure the best outcomes.