Small-molecule anti-COVID-19 drugs and a focus on China's homegrown mindeudesivir (VV116) / 医学前沿

The coronavirus disease 2019 (COVID-19) pandemic has stimulated tremendous efforts to develop therapeutic agents that target severe acute respiratory syndrome coronavirus 2 to control viral infection. So far, a few small-molecule antiviral drugs, including nirmatrelvir-ritonavir (Paxlovid), remdesivir, and molnupiravir have been marketed for the treatment of COVID-19. Nirmatrelvir-ritonavir has been recommended by the World Health Organization as an early treatment for outpatients with mild-to-moderate COVID-19. However, the existing treatment options have limitations, and effective treatment strategies that are cost-effective and convenient for tackling COVID-19 are still needed. To date, four domestically developed oral anti-COVID-19 drugs have been granted conditional market approval in China. These drugs include azvudine, simnotrelvir-ritonavir (Xiannuoxin), leritrelvir, and mindeudesivir (VV116). Preclinical and clinical studies have explored the efficacy and tolerability of mindeudesivir and supported its early use in mild-to-moderate COVID-19 cases at high risk for progression. In this review, we discuss the most recent findings regarding the pharmacological mechanism and therapeutic effects focusing on mindeudesivir and other small-molecule antiviral agents for COVID-19. These findings will expand our understanding and highlight the potential widespread application of China's homegrown anti-COVID-19 drugs.

Paving the way to improve clinical management of acute-on-chronic liver failure using international criteria / 临床肝胆病杂志

Acute-on-chronic liver failure (ACLF) is a clinical disease significantly different from acute liver failure and acute decompensation of simple liver cirrhosis, and it may have acute progression to liver failure and failure of other organs. ACLF has a high short-term mortality rate and has become a disease burden worldwide. In recent years, several international associations for the study of the liver have proposed different diagnostic criteria for ACLF and published their respective consensus or review on the diagnosis and treatment of ACLF, and there are still great differences in the comprehension of chronic liver diseases, acute injury, and organ failure. At present, there are still limited data for the key links of ACLF management in China, such as liver transplantation, intensive care unit, and palliative care, and in the context of no consensus on the diagnosis of ACLF around the world, it is necessary to further strengthen the application of existing international criteria and evidence and the accumulation of evidence-based data in China.

Hydroxychloroquine in patients with COVID-19: an open-label, randomized, controlled trial

ObjectivesTo assess the efficacy and safety of hydroxychloroquine (HCQ) plus standard-of-care (SOC) compared with SOC alone in adult patients with COVID-19. DesignMulticenter, open-label, randomized controlled trial. Setting16 government-designated COVID-19 treatment centers in China through 11 to 29 in February 2020. Participants150 patients hospitalized with laboratory confirmed COVID-19 were included in the intention to treat analysis. 75 patients were assigned to HCQ plus SOC and 75 to SOC alone. InterventionsHCQ was administrated with a loading dose of 1, 200 mg daily for three days followed by a maintained dose of 800 mg daily for the remaining days (total treatment duration: 2 or 3 weeks for mild/moderate or severe patients, respectively). Main outcome measuresThe primary outcome was whether participants had a negative conversion of SARS-CoV-2 by 28 days, and was analyzed according to the intention-to-treat principle. Adverse events were analyzed in the safety population in which HCQ recipients were participants who actually received at least one dose of HCQ and HCQ non-recipients were those actually managed with SOC alone. ResultsAmong 150 patients, 148 were with mild to moderate disease and 2 were with severe disease. The mean days ({+/-} standard deviation, min to max) from symptoms onset to randomization was 16.6 ({+/-}10.5 days, 3 to 41 days). The negative conversion probability by 28 days in SOC plus HCQ group was 85.4% (95% confidence interval (CI) 73.8% to 93.8%), similar to that in the SOC group 81.3% (95%CI 71.2% to 89.6%). Between-group difference was 4.1% (95%CI -10.3% to 18.5%). In the safety population, adverse events were recorded in 7 (8.8%) HCQ non-recipients (N=80) and in 21 (30%) HCQ recipients (N=70). The most common adverse event in the HCQ recipients was diarrhea, reported in 7 (10%) patients. Two HCQ recipients reported serious adverse events. ConclusionsThe administration of HCQ did not result in a significantly higher negative conversion probability than SOC alone in patients mainly hospitalized with persistent mild to moderate COVID-19. Adverse events were higher in HCQ recipients than in HCQ non-recipients. Trial registrationChiCTR2000029868 What is already known on this topic-- The pandemic of coronavirus disease 2019 (COVID-19) imposes substantial burdens on individuals, communities, health-care facilities, markets, governments, etc. globally. -- There is no specific treatment approved for COVID-19 or vaccine to prevent infection with the novel coronavirus. -- During the urgent pandemic, media headlines the utility of drugs without solid evidence but buries the side-effects of these drugs. What this study adds-- In this randomized clinical trial of patients mainly with persistent mild to moderate COVID-19, exposure to hydroxychloroquine led to a similar probability of virus elimination comparing to the current standard-of-care. -- Adverse events, mostly gastrointestinal related, were significantly increased in patients who received hydroxychloroquine. -- Overall, the results from our trial do not support the use of hydroxychloroquine in patients with persistent mild to moderate COVID-19. Print abstractO_ST_ABSStudy questionC_ST_ABSTo assess the efficacy and safety of hydroxychloroquine (HCQ) plus standard-of-care (SOC) compared with SOC alone in adult patients with COVID-19. MethodsThis is a multicenter, open-label, randomized controlled trial conducted in 16 government-designated COVID-19 treatment centers in China through 11 to 29 in February 2020. A total of 150 patients hospitalized with laboratory confirmed COVID-19 were included in the intention to treat analysis. Among them, 75 patients were assigned to HCQ plus SOC and 75 to SOC alone. HCQ was administrated with a loading dose of 1, 200 mg daily for three days followed by a maintained dose of 800 mg daily for the remaining days (total treatment duration: 2 or 3 weeks for mild/moderate or severe patients, respectively). The primary outcome was whether participants had a negative conversion of SARS-CoV-2 by 28 days, and was analyzed according to the intention to treat principle. Adverse events were analyzed in the safety population in which HCQ recipients were participants who actually received at least one dose of HCQ and HCQ non-recipients were those actually managed with SOC alone. Study answer and limitationsAmong 150 patients, 148 were with mild to moderate disease and 2 were with severe disease. The mean days ({+/-} standard deviation, min to max) from symptoms onset to randomization was 16.6 ({+/-}10.5 days, 3 to 41 days). The negative conversion probability by 28 days in SOC plus HCQ group was 85.4% (95% confidence interval (CI) 73.8% to 93.8%), similar to that in the SOC group 81.3% (95%CI 71.2% to 89.6%). Between-group difference was 4.1% (95%CI -10.3% to 18.5%). In the safety population, adverse events were recorded in 7 (8.8%) HCQ non-recipients (N=80) and in 21 (30%) HCQ recipients (N=70) with two serious adverse events. The most common adverse event in the HCQ recipients was diarrhea, reported in 7 (10%) patients. Two HCQ recipients reported serious adverse events. What this study addsOur trial does not support the use of hydroxychloroquine in patients with persistent mild to moderate COVID-19 due to limited effects on virus eliminating and significantly increased adverse events. Funding, competing interests, data sharingThis work was supported by the Emergent Projects of National Science and Technology (2020YFC0844500), National Natural Science Foundation of China (81970020, 81770025), National Key Research and Development Program of China (2016YFC0901104), Shanghai Municipal Key Clinical Specialty (shslczdzk02202, shslczdzk01103), National Innovative Research Team of High-level Local Universities in Shanghai, Shanghai Key Discipline for Respiratory Diseases (2017ZZ02014), National Major Scientific and Technological Special Project for Significant New Drugs Development (2017ZX09304007), Key Projects in the National Science and Technology Pillar Program during the Thirteenth Five-year Plan Period (2018ZX09206005-004, 2017ZX10202202-005-004, 2017ZX10203201-008). All authors declared no competing interests. Anonymized datasets can be made available on reasonable request after approval from the trial management committee. Study registrationChiCTR2000029868

Development and features of infection in patients with acute-on-chronic liver failure and its influence on disease progression and prognosis / 中华肝脏病杂志

Acute-on-chronic liver failure (ACLF) is a clinical syndrome characterized by acute decompensation of chronic liver disease associating with multiple organ failures and high short- term mortality. Patients with ACLF are highly susceptible to infection due to the pathophysiology features including immune function disorder (overlap of excessive inflammatory reaction and immune dysfunction), gut bacterial overgrowth/dysbiosis and translocation of gut microbiota/products. Appropriate empirical antibiotics plays a pivotal role in the management of ACLF with infection.

Progress on serum levels of keratin-18 fragments in chronic hepatitis B and perspective of its application / 中华临床感染病杂志

The diagnostic value of keratin-18 and its fragments in liver diseases has drawn increasingly interests in recent years,but studies on its application in chronic hepatitis B is still few.This paper reviews the circulating levels of keratin-18 fragments M30 and M65 in chronic hepatitis B and its application in the future.