Investigation of Four Cases of Stevens-Johnson Syndrome among Participants in a Mass Drug Administration Campaign with Sulfadoxine-Pyrimethamine and Primaquine in Haiti, 2020.

In 2018, a mass drug administration (MDA) campaign for malaria elimination was piloted in Haiti. The pilot treated 36,338 people with sulfadoxine-pyrimethamine (SP) and primaquine; no severe adverse events were detected. In 2020, another MDA campaign using the same medications was implemented to mitigate an upsurge in malaria cases during the COVID-19 pandemic. Four cases of Stevens-Johnson syndrome (SJS) were identified among the 42,249 people who took the medications. Three of these individuals required hospitalization; all survived. In addition to SP ingestion, an investigation of potential causes for increased SJS cases identified that all four cases had human leukocyte antigens A*29 and/or B*44:03, another known risk factor for SJS. Additionally, three of the four case individuals had antibodies to SARS-CoV-2, and the fourth may have been exposed around the same time. These findings raise the possibility that recent SARS-CoV-2 infection may have contributed to the increased risk for SJS associated with SP exposure during the 2020 campaign.

Safety, pharmacokinetics, and antimalarial activity of the novel triaminopyrimidine ZY-19489: a first-in-human, randomised, placebo-controlled, double-blind, single ascending dose study, pilot food-effect study, and volunteer infection study.

BACKGROUND: New antimalarials with novel mechanisms of action are needed to combat the emergence of drug resistance. Triaminopyrimidines comprise a novel antimalarial class identified in a high-throughput screen against asexual blood-stage Plasmodium falciparum. This first-in-human study aimed to characterise the safety, pharmacokinetics, and antimalarial activity of the triaminopyrimidine ZY-19489 in healthy volunteers. METHODS: A three-part clinical trial was conducted in healthy adults (aged 18-55 years) in Brisbane, QLD, Australia. Part one was a double-blind, randomised, placebo-controlled, single ascending dose study in which participants enrolled into one of six dose groups (25, 75, 150, 450, 900, or 1500 mg) were randomly assigned (3:1) to ZY-19489 or placebo. Part two was an open-label, randomised, two-period cross-over, pilot food-effect study in which participants were randomly assigned (1:1) to a fasted-fed or a fed-fasted sequence. Part three was an open-label, randomised, volunteer infection study using the P falciparum induced blood-stage malaria model in which participants were enrolled into one of two cohorts, with participants in cohort one all receiving the same dose of ZY-19489 and participants in cohort two randomly assigned to receive one of two doses. The primary outcome for all three parts was the incidence, severity, and relationship to ZY-19489 of adverse events. Secondary outcomes were estimation of ZY-19489 pharmacokinetic parameters for all parts; how these parameters were affected by the fed state for part two only; and the parasite reduction ratio, parasite clearance half-life, recrudescent parasitaemia, and pharmacokinetic-pharmacodynamic modelling parameters for part three only. This trial is registered with the Australian New Zealand Clinical Trials Registry (ACTRN12619000127101, ACTRN12619001466134, and ACTRN12619001215112). FINDINGS: 48 participants were enrolled in part one (eight per cohort for 25-1500 mg cohorts), eight in part two (four in each group, all dosed with 300 mg), and 15 in part three (five dosed with 200 mg, eight with 300 mg, and two with 900 mg). In part one, the incidence of drug-related adverse events was higher in the 1500 mg dose group (occurring in all six participants) than in lower-dose groups and the placebo group (occurring in one of six in the 25 mg group, two of six in the 75 mg group, three of six in the 150 mg group, two of six in the 450 mg group, four of six in the 900 mg group, and four of 12 in the placebo group), due to the occurrence of mild gastrointestinal symptoms. Maximum plasma concentrations occurred 5-9 h post-dosing, and the elimination half-life was 50-97 h across the dose range. In part two, three of seven participants had a treatment-related adverse event in the fed state and four of eight in the fasted state. Dosing in the fed state delayed absorption (maximum plasma concentration occurred a median of 12·0 h [range 7·5-16·0] after dosing in the fed state vs 6·0 h [4·5-9·1] in the fasted state) but had no effect on overall exposure (difference in area under the concentration-time curve from time 0 [dosing] extrapolated to infinity between fed and fasted states was -0·013 [90% CI -0·11 to 0·08]). In part three, drug-related adverse events occurred in four of five participants in the 200 mg group, seven of eight in the 300 mg group, and both participants in the 900 mg group. Rapid initial parasite clearance occurred in all participants following dosing (clearance half-life 6·6 h [95% CI 6·2-6·9] for 200 mg, 6·8 h [95% CI 6·5-7·1] for 300 mg, and 7·1 h [95% CI 6·6-7·6] for 900 mg). Recrudescence occurred in four of five participants in the 200 mg group, five of eight in the 300 mg group, and neither of the two participants in the 900 mg group. Simulations done using a pharmacokinetic-pharmacodynamic model predicted that a single dose of 1100 mg would clear baseline parasitaemia by a factor of 109. INTERPRETATION: The safety, pharmacokinetic profile, and antimalarial activity of ZY-19489 in humans support the further development of the compound as a novel antimalarial therapy. FUNDING: Cadila Healthcare and Medicines for Malaria Venture.

Persistent pulmonary pathology after COVID-19 is associated with high viral load, weak antibody response, and high levels of matrix metalloproteinase-9.

The association between pulmonary sequelae and markers of disease severity, as well as pro-fibrotic mediators, were studied in 108 patients 3 months after hospital admission for COVID-19. The COPD assessment test (CAT-score), spirometry, diffusion capacity of the lungs (DLCO), and chest-CT were performed at 23 Norwegian hospitals included in the NOR-SOLIDARITY trial, an open-labelled, randomised clinical trial, investigating the efficacy of remdesivir and hydroxychloroquine (HCQ). Thirty-eight percent had a CAT-score ≥ 10. DLCO was below the lower limit of normal in 29.6%. Ground-glass opacities were present in 39.8% on chest-CT, parenchymal bands were found in 41.7%. At admission, low pO2/FiO2 ratio, ICU treatment, high viral load, and low antibody levels, were predictors of a poorer pulmonary outcome after 3 months. High levels of matrix metalloproteinase (MMP)-9 during hospitalisation and at 3 months were associated with persistent CT-findings. Except for a negative effect of remdesivir on CAT-score, we found no effect of remdesivir or HCQ on long-term pulmonary outcomes. Three months after hospital admission for COVID-19, a high prevalence of respiratory symptoms, reduced DLCO, and persistent CT-findings was observed. Low pO2/FiO2 ratio, ICU-admission, high viral load, low antibody levels, and high levels of MMP-9 were associated with a worse pulmonary outcome.

Effects of hydroxychloroquine and its metabolites in patients with connective tissue diseases.

Hydroxychloroquine has attracted attention in the treatment of COVID-19. Many conflicting findings have been reported regarding the efficacy and safety of this drug, which has been used safely in the rheumatological diseases for years. However, these studies lacked measurement methods that allow accurate assessment of hydroxychloroquine and its metabolite levels. The aim of this study was to measure hydroxychloroquine and its metabolite levels in whole blood samples of patients with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Sjogren's syndrome (SS) and scleroderma (Scl) by a robust, simple and accurate validated tandem mass spectrometric method, and to investigate the relationship between these levels with drug-related adverse effects and disease activity scores. The validated LC-MS/MS method was applied to measure blood hydroxychloroquine and its metabolite levels of patients with RA, SLE, SS, Scl. Various haematological and biochemical parameters were measured with Beckman-Coulter AU 5800 and Beckman Coulter LH 780 analyzers, respectively. QTc intervals were calculated with Bazett's formula, and the patients were followed up by clinicians in terms of clinical findings and adverse effects. Hydroxychloroquine levels of patients were similar to previous studies. There was a negative correlation between disease activity scores and hydroxychloroquine levels, while the highest correlation was between QTc interval, creatinine and GFR levels with desethylchloroquine. Bidetylchloroquine had the highest correlation with RBC count and liver function tests. Our findings showed that hydroxychloroquine and its metabolite levels were associated with disease activity scores, renal, hepatic function, QTc prolongation, and hematological parameters.

American College of Rheumatology White Paper on Antimalarial Cardiac Toxicity.

Hydroxychloroquine (HCQ) and chloroquine (CQ) are well-established medications used in treating systemic lupus erythematosus and rheumatoid arthritis, as well as skin conditions such as cutaneous lupus erythematosus. In rare cases, arrhythmias and conduction system abnormalities, as well as cardiomyopathy, have been reported in association with HCQ/CQ use. Recently, however, the corrected QT interval (QTc)-prolonging potential of these medications, and risk of torsade de pointes (TdP) in particular, have been highlighted in the setting of their experimental use for COVID-19 infection. This report was undertaken to summarize the current understanding of HCQ/CQ cardiac toxicity, describe QTc prolongation and TdP risks, and discuss areas of priority for future research. A working group of experts across rheumatology, cardiology, and dermatology performed a nonsystematic literature review and offered a consensus-based expert opinion. Current data clearly indicate that HCQ and CQ are invaluable medications in the management of rheumatic and dermatologic diseases, but they are associated with QTc prolongation by directly affecting cardiac repolarization. Prescribing clinicians should be cognizant of this small effect, especially in patients taking additional medications that prolong the QTc interval. Long-term use of HCQ/CQ may lead to a cardiomyopathy associated with arrhythmias and heart failure. Risk and benefit assessment should be considered prior to initiation of any medication, and both initial and ongoing risk-benefit assessments are important with regard to prescription of HCQ/CQ. While cardiac toxicity related to HCQ/CQ treatment of rheumatic diseases is rarely reported, it can be fatal. Awareness of the potential adverse cardiac effects of HCQ and CQ can increase the safe use of these medications. There is a clear need for additional research to allow better understanding of the cardiovascular risk and safety profile of these therapies used in the management of rheumatic and cutaneous diseases.

The cardiovascular effects of amodiaquine and structurally related antimalarials: An individual patient data meta-analysis.

BACKGROUND: Amodiaquine is a 4-aminoquinoline antimalarial similar to chloroquine that is used extensively for the treatment and prevention of malaria. Data on the cardiovascular effects of amodiaquine are scarce, although transient effects on cardiac electrophysiology (electrocardiographic QT interval prolongation and sinus bradycardia) have been observed. We conducted an individual patient data meta-analysis to characterise the cardiovascular effects of amodiaquine and thereby support development of risk minimisation measures to improve the safety of this important antimalarial. METHODS AND FINDINGS: Studies of amodiaquine for the treatment or prevention of malaria were identified from a systematic review. Heart rates and QT intervals with study-specific heart rate correction (QTcS) were compared within studies and individual patient data pooled for multivariable linear mixed effects regression. The meta-analysis included 2,681 patients from 4 randomised controlled trials evaluating artemisinin-based combination therapies (ACTs) containing amodiaquine (n = 725), lumefantrine (n = 499), piperaquine (n = 716), and pyronaridine (n = 566), as well as monotherapy with chloroquine (n = 175) for uncomplicated malaria. Amodiaquine prolonged QTcS (mean = 16.9 ms, 95% CI: 15.0 to 18.8) less than chloroquine (21.9 ms, 18.3 to 25.6, p = 0.0069) and piperaquine (19.2 ms, 15.8 to 20.5, p = 0.0495), but more than lumefantrine (5.6 ms, 2.9 to 8.2, p < 0.001) and pyronaridine (-1.2 ms, -3.6 to +1.3, p < 0.001). In individuals aged ≥12 years, amodiaquine reduced heart rate (mean reduction = 15.2 beats per minute [bpm], 95% CI: 13.4 to 17.0) more than piperaquine (10.5 bpm, 7.7 to 13.3, p = 0.0013), lumefantrine (9.3 bpm, 6.4 to 12.2, p < 0.001), pyronaridine (6.6 bpm, 4.0 to 9.3, p < 0.001), and chloroquine (5.9 bpm, 3.2 to 8.5, p < 0.001) and was associated with a higher risk of potentially symptomatic sinus bradycardia (≤50 bpm) than lumefantrine (risk difference: 14.8%, 95% CI: 5.4 to 24.3, p = 0.0021) and chloroquine (risk difference: 8.0%, 95% CI: 4.0 to 12.0, p < 0.001). The effect of amodiaquine on the heart rate of children aged <12 years compared with other antimalarials was not clinically significant. Study limitations include the unavailability of individual patient-level adverse event data for most included participants, but no serious complications were documented. CONCLUSIONS: While caution is advised in the use of amodiaquine in patients aged ≥12 years with concomitant use of heart rate-reducing medications, serious cardiac conduction disorders, or risk factors for torsade de pointes, there have been no serious cardiovascular events reported after amodiaquine in widespread use over 7 decades. Amodiaquine and structurally related antimalarials in the World Health Organization (WHO)-recommended dose regimens alone or in ACTs are safe for the treatment and prevention of malaria.

Efficacy and safety of artemisinin-based combination therapies for the treatment of uncomplicated malaria in pediatrics: a systematic review and meta-analysis.

BACKGROUND: Malaria is a major cause of morbidity and mortality in pediatrics in malaria endemic areas. Artemisinin-based combination therapies (ACTs) are the drugs of choice for malaria management particularly across malaria-endemic countries. This systematic review and meta-analysis was performed to assess efficacy and safety of ACTs for uncomplicated malaria in pediatric populations. METHODS: A body of evidence was searched for published ACT trials until March 06, 2020. The search was focused on efficacy and safety studies of ACTs for uncomplicated malaria in pediatrics. PubMed library was searched using best adapted search terms after multiple trials. References were exported to the endnote library and then to Covidence for screening. Data was extracted using the Covidence platform. The per-protocol analysis report for the efficacy and the intention-to-treat analysis for the safety were synthesized. Met-analysis was carried using Open Meta-Analyst software. Random effects model was applied and the heterogeneity of studies was evaluated using I2 statistic. RESULTS: Nineteen studies were included in the final analysis. Overall, crude, PCR-corrected P. falciparum malaria treatment success rate was 96.3 and 93.9% for day 28 and 42, respectively. In the subgroup analysis, PCR-corrected adequate clinical and parasitological response (ACPR) of dihydroartemisinin-piperaquine (DP) was 99.6% (95% CI: 99.1 to 100%, I2 = 0%; 4 studies) at day 28 and 99.6% (95% CI of 99 to 100%, I2 = 0%; 3 studies) at day 42. Nine studies reported ACT related adverse drug reactions (ADR) (8.3%, 356/4304). The reported drug related adverse reactions ranged from 1.8% in DP (two studies) to 23.3% in artesunate-pyronaridine (AP). Gastrointestinal symptoms were the most common ACT related adverse effects, and all ADRs were reported to resolve spontaneously. CONCLUSION: ACTs demonstrated a high crude efficacy and tolerability against P. falciparum. The high treatment success and tolerability with low heterogeneity conferred by DP has implication for policy makers who plan the use of ACTs for uncomplicated falciparum malaria treatment in pediatrics.

A Monoclonal Antibody for Malaria Prevention.

BACKGROUND: Additional interventions are needed to reduce the morbidity and mortality caused by malaria. METHODS: We conducted a two-part, phase 1 clinical trial to assess the safety and pharmacokinetics of CIS43LS, an antimalarial monoclonal antibody with an extended half-life, and its efficacy against infection with Plasmodium falciparum. Part A of the trial assessed the safety, initial side-effect profile, and pharmacokinetics of CIS43LS in healthy adults who had never had malaria. Participants received CIS43LS subcutaneously or intravenously at one of three escalating dose levels. A subgroup of participants from Part A continued to Part B, and some received a second CIS43LS infusion. Additional participants were enrolled in Part B and received CIS43LS intravenously. To assess the protective efficacy of CIS43LS, some participants underwent controlled human malaria infection in which they were exposed to mosquitoes carrying P. falciparum sporozoites 4 to 36 weeks after administration of CIS43LS. RESULTS: A total of 25 participants received CIS43LS at a dose of 5 mg per kilogram of body weight, 20 mg per kilogram, or 40 mg per kilogram, and 4 of the 25 participants received a second dose (20 mg per kilogram regardless of initial dose). No safety concerns were identified. We observed dose-dependent increases in CIS43LS serum concentrations, with a half-life of 56 days. None of the 9 participants who received CIS43LS, as compared with 5 of 6 control participants who did not receive CIS43LS, had parasitemia according to polymerase-chain-reaction testing through 21 days after controlled human malaria infection. Two participants who received 40 mg per kilogram of CIS43LS and underwent controlled human malaria infection approximately 36 weeks later had no parasitemia, with serum concentrations of CIS43LS of 46 and 57 µg per milliliter at the time of controlled human malaria infection. CONCLUSIONS: Among adults who had never had malaria infection or vaccination, administration of the long-acting monoclonal antibody CIS43LS prevented malaria after controlled infection. (Funded by the National Institute of Allergy and Infectious Diseases; VRC 612 ClinicalTrials.gov number, NCT04206332.).

Disentangling the Association of Hydroxychloroquine Treatment with Mortality in Covid-19 Hospitalized Patients through Hierarchical Clustering.

The efficacy of hydroxychloroquine (HCQ) in treating SARS-CoV-2 infection is harshly debated, with observational and experimental studies reporting contrasting results. To clarify the role of HCQ in Covid-19 patients, we carried out a retrospective observational study of 4,396 unselected patients hospitalized for Covid-19 in Italy (February-May 2020). Patients' characteristics were collected at entry, including age, sex, obesity, smoking status, blood parameters, history of diabetes, cancer, cardiovascular and chronic pulmonary diseases, and medications in use. These were used to identify subtypes of patients with similar characteristics through hierarchical clustering based on Gower distance. Using multivariable Cox regressions, these clusters were then tested for association with mortality and modification of effect by treatment with HCQ. We identified two clusters, one of 3,913 younger patients with lower circulating inflammation levels and better renal function, and one of 483 generally older and more comorbid subjects, more prevalently men and smokers. The latter group was at increased death risk adjusted by HCQ (HR[CI95%] = 3.80[3.08-4.67]), while HCQ showed an independent inverse association (0.51[0.43-0.61]), as well as a significant influence of cluster∗HCQ interaction (p < 0.001). This was driven by a differential association of HCQ with mortality between the high (0.89[0.65-1.22]) and the low risk cluster (0.46[0.39-0.54]). These effects survived adjustments for additional medications in use and were concordant with associations with disease severity and outcome. These findings suggest a particularly beneficial effect of HCQ within low risk Covid-19 patients and may contribute to clarifying the current controversy on HCQ efficacy in Covid-19 treatment.

COVID-19 presenting as acute generalized exanthematous pustulosis associated with multiorgan dysfunction in a 44-year-old female patient.

Acute generalised exanthematous pustulosis (AGEP) is an unusual cutaneous reaction, most often related with a hypersensitivity reaction to commonly used drugs. It is characterized by an abrupt onset of a pustular rash within hours or days after drug exposure and usually resolves spontaneously within 1-2 weeks after drug discontinuation. Some cases associated with systemic involvement and shock have been reported. We present the case of a severe AGEP, manifesting in association with systemic involvement and haemodynamic instability resulting in shock and multiorgan dysfunction in an adult female patient diagnosed with COVID-19 infection. There were no identifiable associated drugs, and the patient was not initiated on antimalarial drugs. Our patient improved rapidly, both hemodynamically and dermatologically with no directed therapy.

Impact of Treatment Regimens on Antibody Response to the SARS-CoV-2 Coronavirus.

The coronavirus disease 2019 (COVID-19) is widely spread and remains a global pandemic. Limited evidence on the systematic evaluation of the impact of treatment regimens on antibody responses exists. Our study aimed to analyze the role of antibody response on prognosis and determine factors influencing the IgG antibodies' seroconversion. A total of 1,111 patients with mild to moderate COVID-19 symptoms admitted to Leishenshan Hospital in Wuhan were retrospectively analyzed. A serologic SARS-CoV-2 IgM/IgG antibody test was performed on all the patients 21 days after the onset of symptoms. Patient clinical characteristics were compared. In the study, 42 patients progressed to critical illness, with 6 mortalities reported while 1,069 patients reported mild to moderate disease. Advanced age (P = 0.028), gasping (P < 0.001), dyspnea (P = 0.024), and IgG negativity (P = 0.006) were associated with progression to critical illness. The mortality rate in critically ill patients with IgG antibody was 6.45% (95% CI 1.12-22.84%) and 36.36% (95% CI 12.36-68.38%) in patients with no IgG antibody (P = 0.003). Symptomatic patients were more likely to develop IgG antibody responses than asymptomatic patients. Using univariable analysis, fever (P < 0.001), gasping (P = 0.048), cancer (P < 0.001), cephalosporin (P = 0.015), and chloroquine/hydroxychloroquine (P = 0.021) were associated with IgG response. In the multivariable analysis, fever, cancer, cephalosporins, and chloroquine/hydroxychloroquine correlated independently with IgG response. We determined that the absence of SARS-CoV-2 antibody IgG in the convalescent stage had a specific predictive role in critical illness progression. Importantly, risk factors affecting seropositivity were identified, and the effect of antimalarial drugs on antibody response was determined.

SARS-CoV 2 Infection (Covid-19) and Cardiovascular Disease in Africa: Health Care and Socio-Economic Implications.

The current pandemic of SARS-COV 2 infection (Covid-19) is challenging health systems and communities worldwide. At the individual level, the main biological system involved in Covid-19 is the respiratory system. Respiratory complications range from mild flu-like illness symptoms to a fatal respiratory distress syndrome or a severe and fulminant pneumonia. Critically, the presence of a pre-existing cardiovascular disease or its risk factors, such as hypertension or type II diabetes mellitus, increases the chance of having severe complications (including death) if infected by the virus. In addition, the infection can worsen an existing cardiovascular disease or precipitate new ones. This paper presents a contemporary review of cardiovascular complications of Covid-19. It also specifically examines the impact of the disease on those already vulnerable and on the poorly resourced health systems of Africa as well as the potential broader consequences on the socio-economic health of this region.

System for administering and monitoring hydroxychloroquine prophylaxis for COVID-19 in accordance with a national advisory: preliminary experience of a tertiary care institute in India.

BACKGROUND: Hydroxychloroquine (HCQ) was one of the earliest drugs to be recommended for tackling the COVID-19 threat leading to its widespread usage. We provide preliminary findings of the system, established in a tertiary care academic center for the administration of HCQ prophylaxis to healthcare workers (HCW) based on Indian Council of Medical Research (ICMR) advisory. METHODS: A dedicated clinical pharmacology and internal medicine team screened for contraindications, administered informed consent, maintained compliance and monitored for adverse events. RESULTS: Among the 194 HCWs screened for ruling out contraindications for prophylaxis, 9 were excluded and 185 were initiated on HCQ. A total of 55 adverse events were seen in 38 (20.5%) HCWs out of which 70.9%, 29.1% were mild and moderate & none were severe. Before the completion of therapy, a total of 23 participants discontinued. Change in QTc interval on day 2 was 5 (IQR: -3.75, 11) ms and the end of week 1 was 15 ms (IQR: 2, 18). Out of the 5 HCW who turned positive for COVID-19, 2 were on HCQ. CONCLUSION: HCQ prophylaxis was found to be safe and well tolerated in HCW when administered after appropriate screening and with monitoring for adverse events.

Chloroquine or hydroxychloroquine for prevention and treatment of COVID-19.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has resulted in substantial mortality. Some specialists proposed chloroquine (CQ) and hydroxychloroquine (HCQ) for treating or preventing the disease. The efficacy and safety of these drugs have been assessed in randomized controlled trials. OBJECTIVES: To evaluate the effects of chloroquine (CQ) or hydroxychloroquine (HCQ) for 1) treating people with COVID-19 on death and time to clearance of the virus; 2) preventing infection in people at risk of SARS-CoV-2 exposure; 3) preventing infection in people exposed to SARS-CoV-2. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, Current Controlled Trials (www.controlled-trials.com), and the COVID-19-specific resources www.covid-nma.com and covid-19.cochrane.org, for studies of any publication status and in any language. We performed all searches up to 15 September 2020. We contacted researchers to identify unpublished and ongoing studies. SELECTION CRITERIA: We included randomized controlled trials (RCTs) testing chloroquine or hydroxychloroquine in people with COVID-19, people at risk of COVID-19 exposure, and people exposed to COVID-19. Adverse events (any, serious, and QT-interval prolongation on electrocardiogram) were also extracted. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed eligibility of search results, extracted data from the included studies, and assessed risk of bias using the Cochrane 'Risk of bias' tool. We contacted study authors for clarification and additional data for some studies. We used risk ratios (RR) for dichotomous outcomes and mean differences (MD) for continuous outcomes, with 95% confidence intervals (CIs). We performed meta-analysis using a random-effects model for outcomes where pooling of effect estimates was appropriate. MAIN RESULTS: 1. Treatment of COVID-19 disease We included 12 trials involving 8569 participants, all of whom were adults. Studies were from China (4); Brazil, Egypt, Iran, Spain, Taiwan, the UK, and North America (each 1 study); and a global study in 30 countries (1 study). Nine were in hospitalized patients, and three from ambulatory care. Disease severity, prevalence of comorbidities, and use of co-interventions varied substantially between trials. We found potential risks of bias across all domains for several trials. Nine trials compared HCQ with standard care (7779 participants), and one compared HCQ with placebo (491 participants); dosing schedules varied. HCQ makes little or no difference to death due to any cause (RR 1.09, 95% CI 0.99 to 1.19; 8208 participants; 9 trials; high-certainty evidence). A sensitivity analysis using modified intention-to-treat results from three trials did not influence the pooled effect estimate.  HCQ may make little or no difference to the proportion of people having negative PCR for SARS-CoV-2 on respiratory samples at day 14 from enrolment (RR 1.00, 95% CI 0.91 to 1.10; 213 participants; 3 trials; low-certainty evidence). HCQ probably results in little to no difference in progression to mechanical ventilation (RR 1.11, 95% CI 0.91 to 1.37; 4521 participants; 3 trials; moderate-certainty evidence). HCQ probably results in an almost three-fold increased risk of adverse events (RR 2.90, 95% CI 1.49 to 5.64; 1394 participants; 6 trials; moderate-certainty evidence), but may make little or no difference to the risk of serious adverse events (RR 0.82, 95% CI 0.37 to 1.79; 1004 participants; 6 trials; low-certainty evidence). We are very uncertain about the effect of HCQ on time to clinical improvement or risk of prolongation of QT-interval on electrocardiogram (very low-certainty evidence). One trial (22 participants) randomized patients to CQ versus lopinavir/ritonavir, a drug with unknown efficacy against SARS-CoV-2, and did not report any difference for clinical recovery or adverse events. One trial compared HCQ combined with azithromycin against standard care (444 participants). This trial did not detect a difference in death, requirement for mechanical ventilation, length of hospital admission, or serious adverse events. A higher risk of adverse events was reported in the HCQ-and-azithromycin arm; this included QT-interval prolongation, when measured. One trial compared HCQ with febuxostat, another drug with unknown efficacy against SARS-CoV-2 (60 participants). There was no difference detected in risk of hospitalization or change in computed tomography (CT) scan appearance of the lungs; no deaths were reported. 2. Preventing COVID-19 disease in people at risk of exposure to SARS-CoV-2 Ongoing trials are yet to report results for this objective. 3. Preventing COVID-19 disease in people who have been exposed to SARS-CoV-2 One trial (821 participants) compared HCQ with placebo as a prophylactic agent in the USA (around 90% of participants) and Canada. Asymptomatic adults (66% healthcare workers; mean age 40 years; 73% without comorbidity) with a history of exposure to people with confirmed COVID-19 were recruited. We are very uncertain about the effect of HCQ on the primary outcomes, for which few events were reported: 20/821 (2.4%) developed confirmed COVID-19 at 14 days from enrolment, and 2/821 (0.2%) were hospitalized due to COVID-19 (very low-certainty evidence). HCQ probably increases the risk of adverse events compared with placebo (RR 2.39, 95% CI 1.83 to 3.11; 700 participants; 1 trial; moderate-certainty evidence). HCQ may result in little or no difference in serious adverse events (no RR: no participants experienced serious adverse events; low-certainty evidence). One cluster-randomized trial (2525 participants) compared HCQ with standard care for the prevention of COVID-19 in people with a history of exposure to SARS-CoV-2 in Spain. Most participants were working or residing in nursing homes; mean age was 49 years. There was no difference in the risk of symptomatic confirmed COVID-19 or production of antibodies to SARS-CoV-2 between the two study arms. AUTHORS' CONCLUSIONS: HCQ for people infected with COVID-19 has little or no effect on the risk of death and probably no effect on progression to mechanical ventilation. Adverse events are tripled compared to placebo, but very few serious adverse events were found. No further trials of hydroxychloroquine or chloroquine for treatment should be carried out. These results make it less likely that the drug is effective in protecting people from infection, although this is not excluded entirely. It is probably sensible to complete trials examining prevention of infection, and ensure these are carried out to a high standard to provide unambiguous results.

Applying the CiPA approach to evaluate cardiac proarrhythmia risk of some antimalarials used off-label in the first wave of COVID-19.

We applied a set of in silico and in vitro assays, compliant with the Comprehensive In Vitro Proarrhythmia Assay (CiPA) paradigm, to assess the risk of chloroquine (CLQ) or hydroxychloroquine (OH-CLQ)-mediated QT prolongation and Torsades de Pointes (TdP), alone and combined with erythromycin (ERT) and azithromycin (AZI), drugs repurposed during the first wave of coronavirus disease 2019 (COVID-19). Each drug or drug combination was tested in patch clamp assays on seven cardiac ion channels, in in silico models of human ventricular electrophysiology (Virtual Assay) using control (healthy) or high-risk cell populations, and in human-induced pluripotent stem cell (hiPSC)-derived cardiomyocytes. In each assay, concentration-response curves encompassing and exceeding therapeutic free plasma levels were generated. Both CLQ and OH-CLQ showed blocking activity against some potassium, sodium, and calcium currents. CLQ and OH-CLQ inhibited IKr (half-maximal inhibitory concentration [IC50 ]: 1 µM and 3-7 µM, respectively) and IK1 currents (IC50 : 5 and 44 µM, respectively). When combining OH-CLQ with AZI, no synergistic effects were observed. The two macrolides had no or very weak effects on the ion currents (IC50  > 300-1000 µM). Using Virtual Assay, both antimalarials affected several TdP indicators, CLQ being more potent than OH-CLQ. Effects were more pronounced in the high-risk cell population. In hiPSC-derived cardiomyocytes, all drugs showed early after-depolarizations, except AZI. Combining CLQ or OH-CLQ with a macrolide did not aggravate their effects. In conclusion, our integrated nonclinical CiPA dataset confirmed that, at therapeutic plasma concentrations relevant for malaria or off-label use in COVID-19, CLQ and OH-CLQ use is associated with a proarrhythmia risk, which is higher in populations carrying predisposing factors but not worsened with macrolide combination.

Global Safety Database Summary of COVID-19-Related Drug Utilization-Safety Surveillance: A Sponsor's Perspective.

INTRODUCTION: Evidence-based clinical data on coronavirus disease 2019 (COVID-19) pharmacotherapies are scarce. OBJECTIVE: This study documented and characterized COVID-19 cases reported in individuals receiving treatment with Pfizer pharmaceutical products and cases that reported use of Pfizer pharmaceutical products for COVID-19 treatment. METHODS: This retrospective observational review leveraged the Pfizer safety database containing adverse event data collected in association with use of Pfizer products between 1 October, 2019, and 25 June, 2020; the database includes worldwide adverse event data from various sources. Selected Medical Dictionary for Drug Regulatory Activities (MedDRA®) Preferred Terms and subsequent clinical review were used to characterize COVID-19 cases. RESULTS: Over 1500 relevant cases were identified over an 8-month period. In cases that reported COVID-19, immunosuppressant/immunomodulating agents, followed by anticoagulant/antithrombic agents and corticosteroids, were the most frequently reported agents. The frequent reporting of immunosuppressant/immunomodulating agents among cases of COVID-19 suggests increased vulnerability to infection among treated patients, either because of immunosuppressive effects of certain agents or the nature of the underlying treated condition. In cases involving off-label pharmacotherapy use for the treatment of COVID-19-related conditions, the most frequently reported therapeutic classes included antibiotics, antimalarial agents, antivirals/antiretroviral agents, immunosuppressant/immunomodulating agents, corticosteroids, anticoagulants, and immunoglobulin/interferons. The most frequently reported pharmacotherapeutic agents were azithromycin and chloroquine/hydroxychloroquine, followed by lopinavir-ritonavir, ceftriaxone, and tofacitinib. The most frequently reported clinical adverse events associated with azithromycin (as sole therapy or combined with chloroquine/hydroxychloroquine) include electrocardiogram QT prolonged, drug interaction, hepatitis, diarrhea, and hepatitis acute. Regarding cardiac-related events, 19% (120/645) of azithromycin cases reported events associated with QT prolongation/torsade de pointes (which included seven fatal cardiac events). The most frequently reported clinical adverse events associated with other commonly used agents are also presented. CONCLUSIONS: This pharmacovigilance surveillance study provides a unique characterization of cases in which a broad range of pharmaceutical products was reported in relation to COVID-19.