Objective To assess the efficacy and safety of hydroxychloroquine plus standard of care compared with standard of care alone in adults with coronavirus disease 2019 (covid-19). Design Multicentre, open label, randomised controlled trial. Setting 16 government designated covid-19 treatment centres in China, 11 to 29 February 2020. Participants 150 patients admitted to hospital with laboratory confirmed covid-19 were included in the intention to treat analysis (75 patients assigned to hydroxychloroquine plus standard of care, 75 to standard of care alone). Interventions Hydroxychloroquine administrated at a loading dose of 1200 mg daily for three days followed by a maintenance dose of 800 mg daily (total treatment duration: two or three weeks for patients with mild to moderate or severe disease, respectively). Main outcome measure Negative conversion of severe acute respiratory syndrome coronavirus 2 by 28 days, analysed according to the intention to treat principle. Adverse events were analysed in the safety population in which hydroxychloroquine recipients were participants who received at least one dose of hydroxychloroquine and hydroxychloroquine non-recipients were those managed with standard of care alone. Results Of 150 patients, 148 had mild to moderate disease and two had severe disease. The mean duration from symptom onset to randomisation was 16.6 (SD 10.5; range 3-41) days. A total of 109 (73%) patients (56 standard of care; 53 standard of care plus hydroxychloroquine) had negative conversion well before 28 days, and the remaining 41 (27%) patients (19 standard of care; 22 standard of care plus hydroxychloroquine) were censored as they did not reach negative conversion of virus. The probability of negative conversion by 28 days in the standard of care plus hydroxychloroquine group was 85.4% (95% confidence interval 73.8% to 93.8%), similar to that in the standard of care group (81.3%, 71.2% to 89.6%). The difference between groups was 4.1% (95% confidence interval –10.3% to 18.5%). In the safety population, adverse events were recorded in 7/80 (9%) hydroxychloroquine non-recipients and in 21/70 (30%) hydroxychloroquine recipients. The most common adverse event in the hydroxychloroquine recipients was diarrhoea, reported in 7/70 (10%) patients. Two hydroxychloroquine recipients reported serious adverse events. Conclusions Administration of hydroxychloroquine did not result in a significantly higher probability of negative conversion than standard of care alone in patients admitted to hospital with mainly persistent mild to moderate covid-19. Adverse events were higher in hydroxychloroquine recipients than in non-recipients. Trial registration ChiCTR2000029868.

There is no satisfactory way to identify patients who will maintain a response after discontinuation of nuleos(t)ide analogue therapy for chronic hepatitis B virus (HBV) infection. We investigated whether patients with negative results from tests for HBV DNA and HBV RNA (double negative) at the end of treatment maintain a long-term response to treatment. We performed a post-hoc analysis of data from a 2-year multi-center randomized controlled trial, and its long-term extension trials, on 130 patients with chronic HBV infection who were positive for the HB e antigen (HBeAg-positive; mean age, 30.8 ± 6.9 years; 72.3% male) and received telbivudine with or without adefovir and stopped therapy after they had HBeAg seroconversion and levels of HBV DNA 2000 IU/mL and level of alanine aminotransferase more than 2-fold the upper limit of normal) or until 4 years off treatment. We validated our findings in a cohort of 40 HBeAg-positive patients (36.5 ± 9.4 years old; 72.5% male) treated with entecavir or tenofovir, and followed after discontinuation for up to 5.5 years. Patients were considered to be negative for HBV DNA if it was not detected in the COBAS Taqman assay. Patients were considered to be negative for HBV RNA if it was not detected by quantitative real-time PCR with 2 different pairs of primers. After 4 years off treatment, in the evaluation cohort, 30.8% of patients had a clinical relapse, 54.7% had virologic relapse (HBV DNA >2000 IU/mL in 2 tests), and 16.8% had reappearance of HBeAg in 2 tests (reversion). A significantly lower proportion of double negative patients had a clinical relapse 4 years later (2/35; 8.0%) than of patients who tested positive for either HBV DNA or RNA (32/102; 31.4%; P = .018). In the validation cohort, after 5.5 years of follow up, a lower proportion of double negative patients had clinical relapse (2/13; 15.4%) than of patients who tested positive for either HBV DNA or RNA at the end of treatment (9/27; 33.3%; P = .286) CONCLUSIONS: In an analysis of data from 2 independent cohorts, we associated negative results from tests for HBV DNA and RNA (double negative) at the end of treatment with continued response 4 or more years after discontinuation of therapy in HBeAg-positive patients. These results might be used to identify the best candidates for discontinuation of nuleos(t)ide analogue therapy.

In hepatitis B “e” antigen–positive patients with chronic hepatitis B, peginterferon alfa-2a (peg-IFN) plus entecavir, either prior to or during 48 weeks of peg-IFN therapy, did not show superiority for off-treatment response compared with peg-IFN monotherapy. Background. Treatment with pegylated interferon (peg-IFN) alfa-2a (40KD) results in hepatitis B “e” antigen (HBeAg) seroconversion 6 months after treatment in up to 36% of HBeAg-positive chronic hepatitis B patients. This study explored the efficacy of a novel combination of peg-IFN alfa-2a and entecavir (ETV), a potent nucleoside analogue. Methods. In total, 218 treatment-naive Chinese HBeAg-positive patients were randomized to peg-IFN alfa-2a (180 µg/week) for 48 weeks, either as monotherapy (n = 72), or with 24 weeks of ETV (0.5 mg/daily) added at week 13 (ETV add-on, n = 73), or pretreatment with a 24-week course of ETV, starting peg-IFN alfa-2a at week 21 (ETV pretreatment, n = 73). The primary endpoint was reduction in quantitative HBeAg from baseline to 24 weeks posttreatment. Results. Significant reductions in HBeAg from baseline were achieved in all treatment groups 24 weeks posttreatment; reductions were comparable across treatment arms (shown as log₁₀ Paul Ehrlich international units [PEIU]/mL): monotherapy: −1.4 (SD, 1.8); ETV add-on: –1.6 (SD, 1.8); ETV pretreatment: –1.3 (SD, 1.7). Rates of HBeAg seroconversion were similar across treatment groups posttreatment (monotherapy: 22 [31%]; ETV add-on: 18 [25%]; ETV pretreatment: 19 [26%]). Significantly greater reductions of hepatitis B virus DNA were achieved with ETV add-on while on treatment, but were not sustained posttreatment. Safety profiles were comparable between treatment groups; adverse events were experienced by 62 (86%) monotherapy, 65 (89%) ETV add-on, and 58 (81%) ETV pretreatment patients. Conclusions. Neither ETV add-on nor ETV pretreatment demonstrated superiority compared with 48 weeks of peg-IFN alfa-2a monotherapy. The optimal treatment strategy using nucleos(t)ide analogues and peg-IFN alfa-2a remains to be determined. Clinical Trials Registration. NCT00614471.

To investigate whether respiratory muscle training is capable of reducing the occurrence of respiratory complications and improving dysphagia (swallowing or cough function) after stroke. Cochrane Library, Excerpta Medical Database (EMBASE), PUBMED, and Web of Science were searched for studies published in English; the China Biology Medicine (CBM), China Science and Technology Journal Database (VIP), China National Knowledge Infrastructure (CNKI), and Wanfang Database were searched for studies published in Chinese up to August 10, 2021. Eleven randomized control trials (RCTs) (N=523) met the inclusion criteria were included in this systematic review. Data and information were extracted by two reviewers independently and disagreements was resolved by consensus with a third coauthor. Primary outcome was the occurrence of respiratory complications, secondary outcomes would be represented by swallowing and cough function. The quality of each included RCT were assessed by Cochrane risk-of-bias criteria and the GRADE evidence profile was provided to present information about the body of evidence and judgments about the certainty of underlying evidence for each outcome. Respiratory muscle training reduced the risk of respiratory complications (relative risk, 0.51; 95% confidence interval [CI], 0.28-0.93; I²=0%; P=.03; absolute risk difference, 0.068; number need to treat, 14.71) compared with no or sham respiratory intervention. It also decreased the liquid-type Penetration-Aspiration Scale scores by 0.81 (95% CI, -1.19 to -0.43; I²=39%; P<.0001). There was no significant association between respiratory muscle training and Functional Oral Intake Scale (FOIS) scores, cough function: increased FOIS scores by 0.47 (95% CI, -0.45 to 1.39; I²=55%; P=.32), decreased peak expiratory cough flow of voluntary cough by 18.70 L per minute (95% CI, -59.74 to 22.33; I²=19%; P=.37) and increased peak expiratory cough flow of reflex cough by 0.05 L per minute (95% CI, -40.78 to 40.87; I²=0%; P>.99). This meta-analysis provided evidence that respiratory muscle training is effective in reducing the risk of respiratory complications and improving dysphagia by reducing penetration or aspiration during swallowing liquid bolus after stroke. However, there was no sufficient evidence to determine that respiratory muscle training improves cough function. Additional multicenter studies using larger patient cohorts are required to validate and support these findings. Furthermore, long-term follow-up studies should be performed to measure outcomes, while avoiding bias due to confounding factors such as heterogeneity of the etiologies of dysphagia.

Objectives: To assess the efficacy and safety of hydroxychloroquine (HCQ) plus standard–of–care (SOC) compared with SOC alone in adult patients with COVID–19. Design: Multicenter, open–label, randomized controlled trial. Setting: 16 government–designated COVID–19 treatment centers in China through 11 to 29 in February 2020. Participants: 150 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. Interventions: 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). Main outcome measures: 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. Results: Among 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. Conclusions: The 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 registration: ChiCTR2000029868 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 Study question: To assess the efficacy and safety of hydroxychloroquine (HCQ) plus standard–of–care (SOC) compared with SOC alone in adult patients with COVID–19. Methods: This 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 limitations: Among 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 adds: Our 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 sharing: This 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...