Azvudine for COVID-19

Current guidelines prioritize the use of the Azvudine in coronavirus disease 2019 (COVID-19) patients. However, the clinical effectiveness of Azvudine in real-world studies was lacking, despite the clinical trials showed shorter time of nucleic acid negative conversion. To evaluate the clinical effectiveness following Azvudine treatment in hospitalized COVID-19 patients, we identified 1505 hospitalized COVID-19 patients during the study period, with a follow-up of up to 29 days. After exclusions and propensity score matching, we included 226 Azvudine recipients and 226 matched controls. The lower crude incidence rate of composite disease progression outcome (4.21 vs. 10.39 per 1000 person-days, P=0.041) and all-cause mortality (1.57 vs. 6.00 per 1000 person-days, P=0.027) were observed among Azvudine recipients compared with matched controls. The incidence rates of initiation of invasive mechanical ventilation were also statistically different between the groups according to the log-rank tests (P=0.020). Azvudine treatment was associated with significantly lower risks of composite disease progression outcome (hazard ratio [HR]: 0.43; 95% confidence interval [CI]: 0.18 to 0.99) and all-cause death (HR: 0.26; 95% CI: 0.07 to 0.94) compared with matched controls. Subgroup analyses indicated robustness of the point estimates of HRs (ranged from 0.14 to 0.84). Notably, male Azvudine recipients had a stronger effectiveness than female recipients with respect to both composite outcome and all-cause death. These findings suggest that Azvudine treatment showed substantial clinical benefits in hospitalized COVID-19 patients, and should be considered for use in this population of patients.

IntroductionThe SARS-CoV-2 outbreak has threatened the human population globally as the numbers of reinfection cases even after large-scale vaccination. Trials have been carried out to find drugs effective in fighting the disease, as COVID-19 is being considered a treatable disease only after we have antivirals. A clinical candidate originally developed for HIV treatment, AZVUDINE (FNC), is a promising drug in the treatment of COVID-19.MethodsTo predict the clinical outcome of COVID-19, we examined the course of viral load, every 48 h, by RT-PCR, and disease severity using an antiviral drug, FNC, with 281 participants. A randomized clinical trial was performed to evaluate the efficacy of FNC added to standard treatment, compared with placebo group added to standard treatment, for patients with mild COVID-19. RT-qPCR and ddPCR were applied to estimate the viral load in samples from patients. Also, the clinical improvement was evaluated as well as the liver and kidney function.Results and discussionNotably, the FNC treatment in the mild COVID-19 patients may shorten the time of the nucleic acid negative conversion (NANC) versus placebo group. In addition, the FNC was effective in reducing the viral load of these participants. The present clinical trial results showed that the FNC accelerate the elimination of the virus in and could reduce treatment time of mild patients and save a lot of medical resources, making it a strong candidate for the outpatient and home treatment of COVID-19.Clinical trial registrationhttps://clinicaltrials.gov/ct2/show/NCT05033145, identifier NCT05033145.

The rapid spread of the new coronavirus disease (COVID-19) caused by SARS-CoV-2 has become a global pandemic. Although specific vaccines are available and natural drugs are being researched, supportive care and specific treatments to alleviate symptoms and improve patient quality of life remain critical. Chinese medicine (CM) has been employed in China due to the similarities between the epidemiology, genomics, and pathogenesis of SARS-CoV-2 and SARS-CoV. Moreover, the integration of other traditional oriental medical systems into the broader framework of integrative medicine can offer a powerful approach to managing the disease. Additionally, it has been reported that integrated medicine has better effects and does not increase adverse drug reactions in the context of COVID-19. This article examines preventive measures, potential infection mechanisms, and immune responses in Western medicine (WM), as well as the pathophysiology based on principles of complementary medicine (CM). The convergence between WM and CM approaches, such as the importance of maintaining a strong immune system and promoting preventive care measures, is also addressed. Current treatment options, traditional therapies, and classical prescriptions based on empirical knowledge are also explored, with individual patient circumstances taken into account. An analysis of the potential benefits and challenges associated with the integration of complementary and Western medicine (WM) in the treatment of COVID-19 can provide valuable guidance, enrichment, and empowerment for future research endeavors.

According to the World Health Organization (WHO), in the second half of 2022, there are about 606 million confirmed cases of COVID-19 and almost 6,500,000 deaths around the world. A pandemic was declared by the WHO in March 2020 when the new coronavirus spread around the world. The short time between the first cases in Wuhan and the declaration of a pandemic initiated the search for ways to stop the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or to attempt to cure the disease COVID-19. More than ever, research groups are developing vaccines, drugs, and immunobiological compounds, and they are even trying to repurpose drugs in an increasing number of clinical trials. There are great expectations regarding the vaccine’s effectiveness for the prevention of COVID-19. However, producing sufficient doses of vaccines for the entire population and SARS-CoV-2 variants are challenges for pharmaceutical industries. On the contrary, efforts have been made to create different vaccines with different approaches so that they can be used by the entire population. Here, we summarize about 8162 clinical trials, showing a greater number of drug clinical trials in Europe and the United States and less clinical trials in low-income countries. Promising results about the use of new drugs and drug repositioning, monoclonal antibodies, convalescent plasma, and mesenchymal stem cells to control viral infection/replication or the hyper-inflammatory response to the new coronavirus bring hope to treat the disease.

This article systematically presents the current clinically significant therapeutic developments for the treatment of COVID-19 by providing an in-depth review of molecular mechanisms of action for SARS-CoV-2 antivirals and critically analyzing the potential targets that may allow the selection of resistant viral variants. Two main categories of agents can display antiviral activity: direct-acting antivirals, which act by inhibiting viral enzymes, and host-directed antivirals, which target host cell factors that are involved in steps of the viral life cycle. We discuss both these types of antivirals, highlighting the agents that have already been approved for treatment of COVID-19, and providing an overview of the main molecules that are currently in drug development. Direct-acting antivirals target viral enzymes that are essential in the viral life cycle. Three direct-acting antivirals are currently in use: two are nucleoside analogs that inhibit the RNA-dependent RNA polymerase of SARS-CoV-2, i.e., remdesivir and molnupiravir, and the third one, nirmatrelvir/ritonavir, is an inhibitor of SARS-CoV-2 main protease. The potential for induction of viral resistance is discussed for each of these antivirals, along with their clinical activity on each of the SARS-CoV-2 variants and sublineages that have been dominant over the course of the pandemic, i.e., Alpha, Delta, as well as Omicron and its sublineages BA.1, BA.2, BA.5, BQ.1 and XBB. Host-directed antivirals are currently in preclinical or clinical development; these agents target host cell enzymes that are involved in facilitating viral entry, replication, or virion release. By blocking these enzymes, viral replication can theoretically be effectively stopped. As no SARS-CoV-2 host-directed antiviral has been approved so far, further research is still needed and we present the host-directed antivirals that are currently in the pipeline. Another specific type of agents that have been used in the treatment of COVID-19 are neutralizing antibodies (NAbs). Their main binding site is the spike protein, and therefore their neutralization activity is influenced by mutations occurring in this region. We discuss the main changes in neutralization activity of NAbs for the most important dominant SARS-CoV-2 variants. Close monitoring of emerging variants and sublineages is still warranted, to better understand the impact of viral mutations on the clinical efficiency of antivirals and neutralizing antibodies developed for the treatment of COVID-19.

Abstract The COVID-19 pandemic poses a fundamental challenge to global health. Since the outbreak of SARS-CoV-2, great efforts have been made to identify antiviral strategies and develop therapeutic drugs to combat the disease. There are different strategies for developing small molecular anti-SARS-CoV-2 drugs, including targeting coronavirus structural proteins (e.g. spike protein), non-structural proteins (nsp) (e.g. RdRp, Mpro, PLpro, helicase, nsp14, and nsp16), host proteases (e.g. TMPRSS2, cathepsin, and furin) and the pivotal proteins mediating endocytosis (e.g. PIKfyve), as well as developing endosome acidification agents and immune response modulators. Favipiravir and chloroquine are the anti-SARS-CoV-2 agents that were identified earlier in this epidemic and repurposed for COVID-19 clinical therapy based on these strategies. However, their efficacies are controversial. Currently, three small molecular anti-SARS-CoV-2 agents, remdesivir, molnupiravir, and Paxlovid (PF-07321332 plus ritonavir), have been granted emergency use authorization or approved for COVID-19 therapy in many countries due to their significant curative effects in phase III trials. Meanwhile, a large number of promising anti-SARS-CoV-2 drug candidates have entered clinical evaluation. The development of these drugs brings hope for us to finally conquer COVID-19. In this account, we conducted a comprehensive review of the recent advances in small molecule anti-SARS-CoV-2 agents according to the target classification. Here we present all the approved drugs and most of the important drug candidates for each target, and discuss the challenges and perspectives for the future research and development of anti-SARS-CoV-2 drugs.