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1.
PLoS One ; 16(6): e0252388, 2021.
Article in English | MEDLINE | ID: covidwho-1262547

ABSTRACT

BACKGROUND: Hydroxychloroquine combined with azithromycin (HCQ/AZI) has initially been used against coronavirus disease-2019 (COVID-19). In this retrospective study, we assessed the clinical effects of HCQ/AZI, with a 28-days follow-up. METHODS: In a registry-study which included patients hospitalized for COVID-19 between March 15 and April 2, 2020, we compared patients who received HCQ/AZI to those who did not, regarding a composite outcome of mortality and mechanical ventilation with a 28-days follow-up. QT was monitored for patients treated with HCQ/AZI. Were excluded patients in intensive care units, palliative care and ventilated within 24 hours of admission. Three analyses were performed to adjust for selection bias: propensity score matching, multivariable survival, and inverse probability score weighting (IPSW) analyses. RESULTS: Overall, 203 patients were included: 60 patients treated by HCQ/AZI and 143 control patients. During the 28-days follow-up, 32 (16.3%) patients presented the primary outcome and 23 (12.3%) patients died. Propensity-score matching identified 52 unique pairs of patients with similar characteristics. In the matched cohort (n = 104), HCQ/AZI was not associated with the primary composite outcome (log-rank p-value = 0.16). In the overall cohort (n = 203), survival and IPSW analyses also found no benefit from HCQ/AZI. In the HCQ/AZI group, 11 (18.3%) patients prolonged QT interval duration, requiring treatment cessation. CONCLUSIONS: HCQ/AZI combination therapy was not associated with lower in-hospital mortality and mechanical ventilation rate, with a 28-days follow-up. In the HCQ/AZI group, 18.3% of patients presented a prolonged QT interval requiring treatment cessation, however, control group was not monitored for this adverse event, making comparison impossible.


Subject(s)
Azithromycin/therapeutic use , COVID-19/drug therapy , Hydroxychloroquine/therapeutic use , SARS-CoV-2/drug effects , Anti-Bacterial Agents/therapeutic use , Antimalarials/therapeutic use , COVID-19/mortality , COVID-19/pathology , COVID-19/virology , Female , Follow-Up Studies , Humans , Intensive Care Units , Male , Middle Aged , Respiration, Artificial , Retrospective Studies , SARS-CoV-2/isolation & purification , Survival Rate , Treatment Outcome
2.
J Am Heart Assoc ; 9(12): e017144, 2020 06 16.
Article in English | MEDLINE | ID: covidwho-1255736

ABSTRACT

Background Despite a lack of clinical evidence, hydroxychloroquine and azithromycin are being administered widely to patients with verified or suspected coronavirus disease 2019 (COVID-19). Both drugs may increase risk of lethal arrhythmias associated with QT interval prolongation. Methods and Results We analyzed a case series of COVID-19-positive/suspected patients admitted between February 1, 2020, and April 4, 2020, who were treated with azithromycin, hydroxychloroquine, or a combination of both drugs. We evaluated baseline and postmedication QT interval (corrected QT interval [QTc]; Bazett) using 12-lead ECGs. Critical QTc prolongation was defined as follows: (1) maximum QTc ≥500 ms (if QRS <120 ms) or QTc ≥550 ms (if QRS ≥120 ms) and (2) QTc increase of ≥60 ms. Tisdale score and Elixhauser comorbidity index were calculated. Of 490 COVID-19-positive/suspected patients, 314 (64%) received either/both drugs and 98 (73 COVID-19 positive and 25 suspected) met study criteria (age, 62±17 years; 61% men). Azithromycin was prescribed in 28%, hydroxychloroquine in 10%, and both in 62%. Baseline mean QTc was 448±29 ms and increased to 459±36 ms (P=0.005) with medications. Significant prolongation was observed only in men (18±43 ms versus -0.2±28 ms in women; P=0.02). A total of 12% of patients reached critical QTc prolongation. Changes in QTc were highest with the combination compared with either drug, with much greater prolongation with combination versus azithromycin (17±39 ms versus 0.5±40 ms; P=0.07). No patients manifested torsades de pointes. Conclusions Overall, 12% of patients manifested critical QTc prolongation, and the combination caused greater prolongation than either drug alone. The balance between uncertain benefit and potential risk when treating COVID-19 patients should be carefully assessed.


Subject(s)
Azithromycin/therapeutic use , Betacoronavirus , Coronavirus Infections/drug therapy , Electrocardiography/drug effects , Hydroxychloroquine/therapeutic use , Long QT Syndrome/chemically induced , Pandemics , Pneumonia, Viral/drug therapy , Anti-Bacterial Agents/therapeutic use , Antimalarials/therapeutic use , COVID-19 , Coronavirus Infections/complications , Drug Therapy, Combination , Female , Humans , Long QT Syndrome/physiopathology , Male , Middle Aged , Pneumonia, Viral/complications , Prognosis , Risk Factors , SARS-CoV-2
3.
Bull Natl Res Cent ; 45(1): 94, 2021.
Article in English | MEDLINE | ID: covidwho-1243824

ABSTRACT

BACKGROUND: As of April 23, 2021, more than 145 million cases and almost 3.07 million related deaths were noted because of the coronavirus (Covid-19) Pandemic. Considering the low rate vaccination, the alternative that divided opinions for a long time is an old medicine called hydroxychloroquine. MAIN BODY: The aim of this review was to synthesize the different highlights of the most important studies published since the beginning of the epidemic crisis. After a precise study of the available bibliography dealing with this subject and the addition of an adapted example, which is the current situation of Algeria, the results showed the effectiveness of the Algerian method as well as the impact that this treatment had. CONCLUSION: We concluded that in brief, given the inexistence of a better solution, we ultimately recommend that patients with severe COVID-19 to be treated for the moment with Hydroxychloroquine combined with Azithromycin in view of its effectiveness, while waiting for another solution.

4.
J Biomol Struct Dyn ; : 1-14, 2021 May 25.
Article in English | MEDLINE | ID: covidwho-1242070

ABSTRACT

Remdesivir and hydroxychloroquine derivatives form two important classes of heterocyclic compounds. They are known for their anti-malarial biological activity. This research aims to analyze the physicochemical properties of remdesivir and hydroxychloroquine compounds by the computational approach. DFT, docking, and POM analyses also identify antiviral pharmacophore sites of both compounds. The antiviral activity of hydroxychloroquine compound's in the presence of zinc sulfate and azithromycin is evaluated through its capacity to coordinate transition metals (M = Cu, Ni, Zn, Co, Ru, Pt). The obtained bioinformatic results showed the potent antiviral/antibacterial activity of the prepared mixture (Hydroxychloroquine/Azithromycin/Zinc sulfate) for all the opportunistic Gram-positive, Gram-negative in the presence of coronavirus compared with the complexes Polypyridine-Ruthenium-di-aquo. The postulated zinc(II) complex of hydroxychloroquine derivatives are indeed an effective antibacterial and antiviral agent against coronavirus and should be extended to other pathogens. The combination of a pharmacophore site with a redox [Metal(OH2)2] moiety is of crucial role to fight against viruses and bacteria strains. [Formula: see text]Communicated by Ramaswamy H. Sarma.

5.
BMJ Open ; 11(5): e042943, 2021 05 06.
Article in English | MEDLINE | ID: covidwho-1219163

ABSTRACT

OBJECTIVE: To understand the outcome of hospitalised patients from Mumbai City, which had the highest number of COVID-19 cases in India. DESIGN: Observational study with follow-up. SETTING: Data extraction from medical records of patients with COVID-19 admitted to Nair Hospital & TN Medical College, Mumbai, India. PARTICIPANTS: 689 patients with COVID-19 were admitted in the hospital from 26 March 2020 to 11 May 2020. PRIMARY AND SECONDARY OUTCOME MEASURES: In-hospital mortality; joint effect of comorbidity and age on the risk of dying. RESULTS: A total of 689 patients (median age 44 years) admitted with RT-PCR-confirmed COVID-19 were included in the study. Of these, 77.36% of patients were discharged alive while 22.64% died. 11.61% required some kind of oxygen support while 2.8% of patients required intensive care unit admissions. Older age (HR 2.88, 95% CI 2.09 to 3.98), presence of comorbidities (HR 2.56, 95% CI 1.84 to 3.55), history of hypertension (HR 3.19, 95% CI 1.67 to 6.08), and presence of symptoms at the time of admission (HR 3.21, 95% CI 1.41 to 7.26) were associated with increased risk of in-hospital mortality. Treatment with a combination of azithromycin with hydroxychloroquine, antiviral or steroid compared with no treatment did not alter the disease course and in-hospital mortality. The combined effect of old age and presence of comorbid conditions was more pronounced in women than men. CONCLUSIONS: In-hospital patients were younger, less symptomatic with lesser need of ventilators and oxygen support as compared with many western countries. TRIAL REGISTRATION: Not applicable (observational study, not a clinical trial).


Subject(s)
COVID-19 , Adult , Aged , Comorbidity , Female , Hospital Mortality , Hospitalization , Humans , Hydroxychloroquine , India/epidemiology , Male , SARS-CoV-2
6.
Clin Transl Sci ; 14(5): 1799-1809, 2021 09.
Article in English | MEDLINE | ID: covidwho-1160763

ABSTRACT

Drug safety is generally established from clinical trials, by pharmacovigilance programs and during observational phase IV safety studies according to drug intended or approved indications. The objective of this study was to estimate the risk of potential adverse drug events (ADEs) associated with drugs repurposed for coronavirus disease 2019 (COVID-19) treatment in a large-scale population. Drug claims were used to calculate a baseline medication risk score (MRS) indicative of ADE risk level. Fictitious claims of repurposed drugs were added, one at a time, to patients' drug regimens to calculate a new MRS and compute a level of risk. Drug claims data from enrollees with Regence health insurance were used and sub-payer analyses were performed with Medicare and commercial insured groups. Simulated interventions were conducted with hydroxychloroquine and chloroquine, alone or combined with azithromycin, and lopinavir/ritonavir, along with terfenadine and fexofenadine as positive and negative controls for drug-induced Long QT Syndrome (LQTS). There were 527,471 subjects (56.6% women; mean [SD] age, 47 years [21]) were studied. The simulated addition of each repurposed drug caused an increased risk of ADEs (median MRS increased by two-to-seven points, p < 0.001). The increase in ADE risk was mainly driven by an increase in CYP450 drug interaction risk score and by drug-induced LQTS risk score. The Medicare group presented a greater risk overall compared to the commercial group. All repurposed drugs were associated with an increased risk of ADEs. Our simulation strategy could be used as a blueprint to preemptively assess safety associated with future repurposed or new drugs.


Subject(s)
Antiviral Agents/adverse effects , COVID-19/drug therapy , Drug Repositioning , Long QT Syndrome/epidemiology , Administrative Claims, Healthcare/statistics & numerical data , Adolescent , Adult , Aged , Aged, 80 and over , Antiviral Agents/administration & dosage , Antiviral Agents/pharmacokinetics , COVID-19/complications , COVID-19/virology , Child , Child, Preschool , Computer Simulation , Cytochrome P-450 Enzyme System/metabolism , Drug Interactions , Female , Humans , Infant , Infant, Newborn , Long QT Syndrome/chemically induced , Male , Medicare/statistics & numerical data , Middle Aged , Pharmacovigilance , Retrospective Studies , Risk Assessment/methods , Risk Assessment/statistics & numerical data , United States/epidemiology , Young Adult
7.
J Pharm Bioallied Sci ; 13(1): 4-10, 2021.
Article in English | MEDLINE | ID: covidwho-1134328

ABSTRACT

The corona virus disease-19 (COVID-19) pandemic has affected the entire world causing huge economic losses and considerable morbidity and mortality. Considering the explosive growth of the pandemic repurposing existing medicines may be cost-effective and may be approved for use in COVID-19 faster. Researchers and medical practitioners worldwide have explored the use of chloroquine and hydroxychloroquine, in few occasions combined with the macrolide antibiotic azithromycin, for COVID-19 treatment. These two drugs are economic and easily available, and hence gained attention as a potential option for COVID-19 management. As per the available evidence, the outcomes of treatments with these medications are conflicting from both the efficacy and safety (predominantly cardiac related) perspectives. Currently, multiple studies are underway to test the safety and efficacy of these medications and more results are expected in the near future. The retina, the endocrine system (with risk of hypoglycemia), the musculoskeletal system, the hematological system, and the neurological system may also be affected. The use of these drugs is contraindicated in patients with arrhythmias, known hypersensitivity, and in patients on amiodarone. In addition to the published literature, personal communication with doctors treating COVID-19 patients seems to suggest the drugs may be effective in reducing symptoms and hastening clinical recovery. The literature evidence is still equivocal and further results are awaited. There has been recent controversy including retraction of articles published in prestigious journals about these medicines. Their low cost, long history of use, and easy availability are positive factors with regard to use of these drugs in COVID-19.

8.
Turk J Med Sci ; 51(1)2021 02 26.
Article in English | MEDLINE | ID: covidwho-1112807

ABSTRACT

Background/aim: New treatment regimens for COVID-19, which has threatened the world recently, continue to be investigated. Although some of the treatments are promising, it is thought to be early to state that there is definitive treatment. Experiences and treatment protocol studies from treatment centers are still important. The aim of this study is to evaluate factors affecting the treatment process of the first cases followed in our clinic. Materials and methods: The consecutive hospitalized patients with COVID-19 pneumonia were analyzed in this retrospective and cross-sectional study. Data were recorded from the electronic and written files of patients. Results: Eighty-three patients were evaluated. The median age was 50 ± 15 years. Forty-eight (57.8%) patients had one or more comorbidities. The most common comorbidity was hypertension. The most common symptom was cough in 58 patients (70%). The overall mortality was 15%, and 85% of the patients were discharged. The time between the onset of symptoms and hospitalization was statistically significantly longer in deceased patients (P = 0.039). Age, D-Dimer, troponin, CK, CK-MB, ferritin, procalcitonin, and neutrophil to lymphocyte ratio were statistically significantly higher in deceased patients than survivor patients. In subgroup analysis, in the patients receiving azithromycin plus hydroxychloroquine and other antibiotics plus hydroxychloroquine, the duration of hospitalization was shorter in the azithromycin group (P = 0.027). Conclusion: Early treatment and early admission to the hospital can be crucial for the better treatment process. Combination therapy with azithromycin may be preferred in the first treatment choice because it can shorten the length of hospital stay.


Subject(s)
Antiviral Agents/therapeutic use , Azithromycin/therapeutic use , COVID-19/drug therapy , Hospitalization , Hydroxychloroquine/therapeutic use , Age Factors , Aged , Antiviral Agents/administration & dosage , Azithromycin/administration & dosage , COVID-19/mortality , COVID-19/therapy , Cross-Sectional Studies , Drug Therapy, Combination , Female , Humans , Hydroxychloroquine/administration & dosage , Length of Stay , Male , Middle Aged , Retrospective Studies , Severity of Illness Index , Turkey
9.
EClinicalMedicine ; 33: 100773, 2021 Mar.
Article in English | MEDLINE | ID: covidwho-1103840

ABSTRACT

BACKGROUND: Treatment options for outpatients with COVID-19 could reduce morbidity and prevent SARS-CoV-2 transmission. METHODS: In this randomized, double-blind, three-arm (1:1:1) placebo-equivalent controlled trial conducted remotely throughout the United States, adult outpatients with laboratory-confirmed SARS-CoV-2 infection were recruited. Participants were randomly assigned to receive hydroxychloroquine (HCQ) (400 mg BID x1day, followed by 200 mg BID x9days) with or without azithromycin (AZ) (500 mg, then 250 mg daily x4days) or placebo-equivalent (ascorbic acid (HCQ) and folic acid (AZ)), stratified by risk for progression to severe COVID-19 (high-risk vs. low-risk). Self-collected nasal swabs for SARS-CoV-2 PCR, FLUPro symptom surveys, EKGs and vital signs were collected daily. Primary endpoints were: (a) 14-day progression to lower respiratory tract infection (LRTI), 28-day COVID-19 related hospitalization, or death; (b) 14-day time to viral clearance; secondary endpoints included time to symptom resolution (ClinicalTrials.gov: NCT04354428). Due to the low rate of clinical outcomes, the study was terminated for operational futility. FINDINGS: Between 15th April and 27th July 2020, 231 participants were enrolled and 219 initiated medication a median of 5.9 days after symptom onset. Among 129 high-risk participants, incident LRTI occurred in six (4.7%) participants (two control, four HCQ/AZ) and COVID-19 related hospitalization in seven (5.4%) (four control, one HCQ, two HCQ/AZ); no LRTI and two (2%) hospitalizations occurred in the 102 low-risk participants (one HCQ, one HCQ/AZ). There were no deaths. Among 152 participants with viral shedding at enrollment, median time to clearance was 5 days (95% CI=4-6) in HCQ, 6 days (95% CI=4-8) in HCQ/AZ, and 8 days (95% CI=6-10) in control. Viral clearance was faster in HCQ (HR=1.62, 95% CI=1.01-2.60, p = 0.047) but not HCQ/AZ (HR=1.25, p = 0.39) compared to control. Among 197 participants who met the COVID-19 definition at enrollment, time to symptom resolution did not differ by group (HCQ: HR=1.02, 95% CI-0.63-1.64, p = 0.95, HCQ/AZ: HR=0.91, 95% CI=0.57-1.45, p = 0.70). INTERPRETATION: Neither HCQ nor HCQ/AZ shortened the clinical course of outpatients with COVID-19, and HCQ, but not HCQ/AZ, had only a modest effect on SARS-CoV-2 viral shedding. HCQ and HCQ/AZ are not effective therapies for outpatient treatment of SARV-CoV-2 infection. FUNDING: The COVID-19 Early Treatment Study was funded by the Bill & Melinda Gates Foundation (INV-017062) through the COVID-19 Therapeutics Accelerator. University of Washington Institute of Translational Health Science (ITHS) grant support (UL1 TR002319), KL2 TR002317, and TL1 TR002318 from NCATS/NIH funded REDCap. The content is solely the responsibility of the authors and does not necessarily represent the views, decisions, or policies of the institutions with which they are affiliated. PAN and MJA were supported by the Mayo Clinic Windland Smith Rice Comprehensive Sudden Cardiac Death Program.Trial registration ClinicalTrials.gov number NCT04354428.

10.
Braz J Infect Dis ; 25(2): 101549, 2021.
Article in English | MEDLINE | ID: covidwho-1091924

ABSTRACT

OBJECTIVES: To assess the efficacy of hydroxychloroquine in combination with azithromycin in terms of clinical and biochemical outcomes in adult patients with COVID-19 hospitalized for acute respiratory distress syndrome (ARDS), and to describe the occurrence of adverse events. METHOD: Retrospective comparative study, based in a quaternary private hospital in Rio de Janeiro, Brazil, involving 193 adult patients hospitalized for mild and moderate COVID-19 related ARSD, analyzing treatment efficacy based on clinical and biochemical outcomes. RESULTS: The active group comprised 101 (52.3%) patients using hydroxychloroquine associated with azithromycin and the control group 92 (47.7%) patients who did not take these medications. Median age was 59 (47-70) in the active group and 65 (47-77) in the control group (p < 0.05). Patients in the control group had greater extent of pulmonary involvement on baseline chest CT scans (p < 0.05). All other baseline variables (BMI, comorbidities, previous use of medications and biochemical assessments) were similar between groups. In the medication group, 25% (25 out of 101) were admitted to the ICU, compared to 21% (19 out of 92) in the control group (p > 0.05). No difference in mortality, duration of non-invasive oxygen use or duration of hospitalization was seen between groups. The therapeutic regimen was well tolerated, with only eight (7.9%) patients presenting gastrointestinal symptoms and eight (7.9%) patients withdrawn treatment due to QTc prolongation. CONCLUSIONS: Patients treated with hydroxychloroquine combined with azithromycin and the control group had similar clinical outcomes. This therapeutic regimen was considered ineffective in hospitalized patients with mild to moderate COVID-19 related ARDS and was associated with few non-severe adverse events.


Subject(s)
COVID-19 , Hydroxychloroquine , Adult , Azithromycin/adverse effects , Brazil , COVID-19/drug therapy , Drug Therapy, Combination , Humans , Hydroxychloroquine/adverse effects , Middle Aged , Retrospective Studies , SARS-CoV-2
11.
BJGP Open ; 4(2)2020.
Article in English | MEDLINE | ID: covidwho-1067786

ABSTRACT

BACKGROUND: There are no established effective treatments for COVID-19. While novel drugs are being developed, azithromycin has been identified as a candidate treatment in the interim. AIM: To review the evidence for the effectiveness and safety of azithromycin in treating COVID-19. DESIGN & SETTING: A rapid review of the literature was conducted. METHOD: Electronic searches were conducted on 16 April 2020 of PubMed, TRIP, EPPI COVID Living Map, MedRxiv, GoogleScholar, and Google. In vivo and in vitro studies were included assessing the safety and effectiveness of azithromycin for treatment of COVID-19, and/or the activity of azithromycin against SARS-CoV-2. In vivo studies needed to include a comparator group. RESULTS: Three studies were identified, two in vitro and one in vivo, which were suitable for inclusion. All three were published as pre-prints. The in vitro studies revealed conflicting results, with one finding anti-SARS-CoV-2 activity for azithromycin alone, while the other found activity against SARS-CoV-2 only when azithromycin was combined with hydroxychloroquine. A small trial of 36 patients, with high risk of bias, found superior viral clearance in patients with COVID-19 treated with azithromycin and hydroxychloroquine combined, compared with hydroxychloroquine alone. CONCLUSION: There is no evidence to support the use of azithromycin for the treatment of COVID-19 outside of the context of clinical trials, unless it is used to treat bacterial super-infection. There is extremely limited evidence of a possible synergy between azithromycin and hydroxychloroquine. The adverse events profile of azithromycin in the context of COVID-19 has not yet been established. Well-conducted clinical trials are urgently needed in this area.

12.
Int J Gen Med ; 14: 267-271, 2021.
Article in English | MEDLINE | ID: covidwho-1060965

ABSTRACT

We sought to examine the trend (April-July) in the treatment patterns among hospitalized COVID-19 patients using the Premier Healthcare Database (PHD). In the analysis, we identified 53,264 patients from 302 hospitalsthat continuously provided inpatient data from April 1, 2020 to July 31, 2020 to the PHD, a nationwide, population-based multihospital research database in the US. We used generalized estimating equations (GEE) models to assess changes in the proportion of therapies used during the study period. After adjusting for patient and provider factors, a decline in hydroxychloroquine and an increase in azithromycin and dexamethasone were observed among COVID-19 patients during the 4-month study period.

13.
Int J Cardiol ; 331: 333-339, 2021 05 15.
Article in English | MEDLINE | ID: covidwho-1056682

ABSTRACT

BACKGROUND: QTc interval monitoring, for the prevention of drug-induced arrhythmias is necessary, especially in the context of coronavirus disease 2019 (COVID-19). For the provision of widespread use, surrogates for 12­lead ECG QTc assessment may be useful. This prospective observational study compared QTc duration assessed by artificial intelligence (AI-QTc) (Cardiologs®, Paris, France) on smartwatch single­lead electrocardiograms (SW-ECGs) with those measured on 12­lead ECGs, in patients with early stage COVID-19 treated with a hydroxychloroquine-azithromycin regimen. METHODS: Consecutive patients with COVID-19 who needed hydroxychloroquine-azithromycin therapy, received a smartwatch (Withings Move ECG®, Withings, France). At baseline, day-6 and day-10, a 12­lead ECG was recorded, and a SW-ECG was transmitted thereafter. Throughout the drug regimen, a SW-ECG was transmitted every morning at rest. Agreement between manual QTc measurement on a 12­lead ECG and AI-QTc on the corresponding SW-ECG was assessed by the Bland-Altman method. RESULTS: 85 patients (30 men, mean age 38.3 ± 12.2 years) were included in the study. Fair agreement between manual and AI-QTc values was observed, particularly at day-10, where the delay between the 12­lead ECG and the SW-ECG was the shortest (-2.6 ± 64.7 min): 407 ± 26 ms on the 12­lead ECG vs 407 ± 22 ms on SW-ECG, bias -1 ms, limits of agreement -46 ms to +45 ms; the difference between the two measures was <50 ms in 98.2% of patients. CONCLUSION: In real-world epidemic conditions, AI-QTc duration measured by SW-ECG is in fair agreement with manual measurements on 12­lead ECGs. Following further validation, AI-assisted SW-ECGs may be suitable for QTc interval monitoring. REGISTRATION: ClinicalTrial.govNCT04371744.


Subject(s)
Arrhythmias, Cardiac/diagnosis , Artificial Intelligence , COVID-19/drug therapy , Electrocardiography , Long QT Syndrome , Adult , Arrhythmias, Cardiac/chemically induced , Azithromycin/adverse effects , Azithromycin/therapeutic use , Female , Humans , Hydroxychloroquine/adverse effects , Hydroxychloroquine/therapeutic use , Long QT Syndrome/epidemiology , Male , Middle Aged , Pandemics
14.
PLoS Med ; 17(12): e1003501, 2020 12.
Article in English | MEDLINE | ID: covidwho-999797

ABSTRACT

BACKGROUND: Numerous clinical trials and observational studies have investigated various pharmacological agents as potential treatment for Coronavirus Disease 2019 (COVID-19), but the results are heterogeneous and sometimes even contradictory to one another, making it difficult for clinicians to determine which treatments are truly effective. METHODS AND FINDINGS: We carried out a systematic review and network meta-analysis (NMA) to systematically evaluate the comparative efficacy and safety of pharmacological interventions and the level of evidence behind each treatment regimen in different clinical settings. Both published and unpublished randomized controlled trials (RCTs) and confounding-adjusted observational studies which met our predefined eligibility criteria were collected. We included studies investigating the effect of pharmacological management of patients hospitalized for COVID-19 management. Mild patients who do not require hospitalization or have self-limiting disease courses were not eligible for our NMA. A total of 110 studies (40 RCTs and 70 observational studies) were included. PubMed, Google Scholar, MEDLINE, the Cochrane Library, medRxiv, SSRN, WHO International Clinical Trials Registry Platform, and ClinicalTrials.gov were searched from the beginning of 2020 to August 24, 2020. Studies from Asia (41 countries, 37.2%), Europe (28 countries, 25.4%), North America (24 countries, 21.8%), South America (5 countries, 4.5%), and Middle East (6 countries, 5.4%), and additional 6 multinational studies (5.4%) were included in our analyses. The outcomes of interest were mortality, progression to severe disease (severe pneumonia, admission to intensive care unit (ICU), and/or mechanical ventilation), viral clearance rate, QT prolongation, fatal cardiac complications, and noncardiac serious adverse events. Based on RCTs, the risk of progression to severe course and mortality was significantly reduced with corticosteroids (odds ratio (OR) 0.23, 95% confidence interval (CI) 0.06 to 0.86, p = 0.032, and OR 0.78, 95% CI 0.66 to 0.91, p = 0.002, respectively) and remdesivir (OR 0.29, 95% CI 0.17 to 0.50, p < 0.001, and OR 0.62, 95% CI 0.39 to 0.98, p = 0.041, respectively) compared to standard care for moderate to severe COVID-19 patients in non-ICU; corticosteroids were also shown to reduce mortality rate (OR 0.54, 95% CI 0.40 to 0.73, p < 0.001) for critically ill patients in ICU. In analyses including observational studies, interferon-alpha (OR 0.05, 95% CI 0.01 to 0.39, p = 0.004), itolizumab (OR 0.10, 95% CI 0.01 to 0.92, p = 0.042), sofosbuvir plus daclatasvir (OR 0.26, 95% CI 0.07 to 0.88, p = 0.030), anakinra (OR 0.30, 95% CI 0.11 to 0.82, p = 0.019), tocilizumab (OR 0.43, 95% CI 0.30 to 0.60, p < 0.001), and convalescent plasma (OR 0.48, 95% CI 0.24 to 0.96, p = 0.038) were associated with reduced mortality rate in non-ICU setting, while high-dose intravenous immunoglobulin (IVIG) (OR 0.13, 95% CI 0.03 to 0.49, p = 0.003), ivermectin (OR 0.15, 95% CI 0.04 to 0.57, p = 0.005), and tocilizumab (OR 0.62, 95% CI 0.42 to 0.90, p = 0.012) were associated with reduced mortality rate in critically ill patients. Convalescent plasma was the only treatment option that was associated with improved viral clearance rate at 2 weeks compared to standard care (OR 11.39, 95% CI 3.91 to 33.18, p < 0.001). The combination of hydroxychloroquine and azithromycin was shown to be associated with increased QT prolongation incidence (OR 2.01, 95% CI 1.26 to 3.20, p = 0.003) and fatal cardiac complications in cardiac-impaired populations (OR 2.23, 95% CI 1.24 to 4.00, p = 0.007). No drug was significantly associated with increased noncardiac serious adverse events compared to standard care. The quality of evidence of collective outcomes were estimated using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework. The major limitation of the present study is the overall low level of evidence that reduces the certainty of recommendations. Besides, the risk of bias (RoB) measured by RoB2 and ROBINS-I framework for individual studies was generally low to moderate. The outcomes deducted from observational studies could not infer causality and can only imply associations. The study protocol is publicly available on PROSPERO (CRD42020186527). CONCLUSIONS: In this NMA, we found that anti-inflammatory agents (corticosteroids, tocilizumab, anakinra, and IVIG), convalescent plasma, and remdesivir were associated with improved outcomes of hospitalized COVID-19 patients. Hydroxychloroquine did not provide clinical benefits while posing cardiac safety risks when combined with azithromycin, especially in the vulnerable population. Only 29% of current evidence on pharmacological management of COVID-19 is supported by moderate or high certainty and can be translated to practice and policy; the remaining 71% are of low or very low certainty and warrant further studies to establish firm conclusions.


Subject(s)
Anti-Inflammatory Agents/therapeutic use , COVID-19/drug therapy , Hydroxychloroquine/adverse effects , Adenosine Monophosphate/adverse effects , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/therapeutic use , Alanine/adverse effects , Alanine/analogs & derivatives , Alanine/therapeutic use , Anti-Inflammatory Agents/adverse effects , Azithromycin/adverse effects , Azithromycin/therapeutic use , COVID-19/mortality , COVID-19/therapy , Critical Illness , Hospitalization , Humans , Hydroxychloroquine/therapeutic use , Immunization, Passive , Network Meta-Analysis , Observational Studies as Topic , Randomized Controlled Trials as Topic
15.
Sci Rep ; 10(1): 22139, 2020 12 17.
Article in English | MEDLINE | ID: covidwho-989948

ABSTRACT

Many recent studies have investigated the role of either Chloroquine (CQ) or Hydroxychloroquine (HCQ) alone or in combination with azithromycin (AZM) in the management of the emerging coronavirus. This systematic review and meta-analysis of either published or preprint observational studies or randomized control trials (RCT) aimed to assess mortality rate, duration of hospital stay, need for mechanical ventilation (MV), virologic cure rate (VQR), time to a negative viral polymerase chain reaction (PCR), radiological progression, experiencing drug side effects, and clinical worsening. A search of the online database through June 2020 was performed and examined the reference lists of pertinent articles for in-vivo studies only. Pooled relative risks (RRs), standard mean differences of 95% confidence intervals (CIs) were calculated with the random-effects model. Mortality was not different between the standard care (SC) and HCQ groups (RR = 0.99, 95% CI 0.61-1.59, I2 = 82%), meta-regression analysis proved that mortality was significantly different across the studies from different countries. However, mortality among the HCQ + AZM was significantly higher than among the SC (RR = 1.8, 95% CI 1.19-2.27, I2 = 70%). The duration of hospital stay in days was shorter in the SC in comparison with the HCQ group (standard mean difference = 0.57, 95% CI 0.20-0.94, I2 = 92%), or the HCQ + AZM (standard mean difference = 0.77, 95% CI 0.46-1.08, I2 = 81). Overall VQR, and that at days 4, 10, and 14 among patients exposed to HCQ did not differ significantly from the SC [(RR = 0.92, 95% CI 0.69-1.23, I2 = 67%), (RR = 1.11, 95% CI 0.26-4.69, I2 = 85%), (RR = 1.21, 95% CI 0.70-2.01, I2 = 95%), and (RR = 0.98, 95% CI 0.76-1.27, I2 = 85% )] respectively. Exposure to HCQ + AZM did not improve the VQR as well (RR = 3.23, 95% CI 0.70-14.97, I2 = 58%). The need for MV was not significantly different between the SC and HCQ (RR = 1.5, 95% CI 0.78-2.89, I2 = 81%), or HCQ + AZM (RR = 1.27, 95% CI 0.7-2.13, I2 = 88%). Side effects were more reported in the HCQ group than in the SC (RR = 3.14, 95% CI 1.58-6.24, I2 = 0). Radiological improvement and clinical worsening were not statistically different between HCQ and SC [(RR = 1.11, 95% CI 0.74-1.65, I2 = 45%) and (RR = 1.28, 95% CI 0.33-4.99), I2 = 54%] respectively. Despite the scarcity of published data of good quality, the effectiveness and safety of either HCQ alone or in combination with AZM in treating COVID-19 cannot be assured. Future high-quality RCTs need to be carried out.PROSPERO registration: CRD42020192084.


Subject(s)
Antiviral Agents/therapeutic use , Azithromycin/therapeutic use , COVID-19/drug therapy , Chloroquine/therapeutic use , Hydroxychloroquine/therapeutic use , Humans , SARS-CoV-2/drug effects , Treatment Outcome
16.
Expert Rev Pharmacoecon Outcomes Res ; 21(1): 159-168, 2021 Feb.
Article in English | MEDLINE | ID: covidwho-926348

ABSTRACT

Background: Hydroxychloroquine, an antimalarial drug, combined with azithromycin has been considered a potential treatment for COVID-19. However, these drugs may cause electrocardiogram QT prolongation (QTp) and torsade de Pointes (TdP). We examined potential safety signals for these cardiac arrhythmias. Methods: Using the OpenVigil 2.1 MedDRA platform, we mined data from the U.S. Food and Drug Administration's Adverse Event Reporting System (FAERS) from December 2019 to June 2020. We extracted individual case safety reports based on exposures of seven antimalarial drugs, azithromycin, and combinations. All other drugs in FAERS served as controls. Events of interest included QTp and TdP, with associations between drug exposures and events expressed as adjusted Reporting-Odds-Ratios (aRORs) and confidence intervals. The lower end of aROR 95% confidence interval >1 was used as the statistically significant signal detection threshold. Results: QTp safety signals were found for hydroxychloroquine[aROR:11.70 (10.40-13.16)], chloroquine[aROR:18.97 (11.30-31.87)], quinine[aROR:16.66 (10.18-27.25)], atovaquone[aROR:6.91 (4.14-11.56)], azithromycin alone [aROR:28.02 (22.87-34.32)] and hydroxychloroquine + azithromycin [aROR:75.23 (51.15-110.66)]. TdP safety signals were found for hydroxychloroquine [aROR: 5.62 (4.94-6.38)], chloroquine[aROR:49.37 (30.63-79.58)], and hydroxychloroquine + azithromycin[aROR:33.09 (21.22-51.61)]. Conclusion: Hydroxychloroquine/chloroquine and/or azithromycin was associated with QTp/TdP safety signals and their use should be monitored carefully.


Subject(s)
Anti-Bacterial Agents/adverse effects , Anti-Bacterial Agents/therapeutic use , Antimalarials/adverse effects , Antimalarials/therapeutic use , Arrhythmias, Cardiac/chemically induced , Azithromycin/adverse effects , Azithromycin/therapeutic use , COVID-19/drug therapy , Pharmacovigilance , Adverse Drug Reaction Reporting Systems , Drug Therapy, Combination , Electrocardiography/drug effects , Humans , Long QT Syndrome/chemically induced , Long QT Syndrome/epidemiology , Torsades de Pointes/chemically induced , Torsades de Pointes/epidemiology , United States , United States Food and Drug Administration
17.
Eur Endocrinol ; 16(2): 109-112, 2020 Oct.
Article in English | MEDLINE | ID: covidwho-875013

ABSTRACT

Hydroxychloroquine has been used in rheumatology for decades. This review highlights the mechanistic, clinical and safety data with regards to hydroxychloroquine use in novel coronavirus disease (COVID-19) in people with or without metabolic syndrome. PubMed and Medline were searched for articles published from January 1970 to March 2020 using the terms 'COVID-19', 'corona-virus 2019', 'hydroxychloroquine', 'hypertension', 'diabetes', 'cardiac disease', 'retina' and 'kidney disease'. Hypertension, diabetes and cardiovascular disease are the three most common comorbidities in people with COVID-19, meaning that such people have greater morbidity and mortality. Mechanistically, hydroxychloroquine inhibits SARS-CoV-2 virus uptake into cells by inhibiting angiotensin-converting enzyme 2 glycosylation. This inhibits lysosome activation and the associated cytokine storm, thus reducing the risk of acute respiratory distress syndrome and multiple organ dysfunction syndrome, which is the primary cause of death. Small, in-human studies have shown hydroxychloroquine to improve outcomes in COVID-19, either alone or in combination with azathioprine and other antiviral medications. Retina safety is not an issue with short term use of hydroxychloroquine in COVID-19. Dose reduction is warranted when glomerular filtration rate is <50 mL/min. Cardiac monitoring is warranted in people with established cardiac disease, and cardiac rhythm should be closely monitored when hydroxychloroquine is used with azithromycin, lopinavir, ritonavir or remdesivir. Anti-diabetes medication doses may need to be reduced during treatment with hydroxychloroquine. While we await data from large, in-human trials, short-term use of hydroxychloroquine in COVID-19 is justified, as this molecule has stood the test of time with regards to use in humans for other indications.

18.
J Clin Med ; 9(9)2020 Aug 30.
Article in English | MEDLINE | ID: covidwho-736700

ABSTRACT

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has led to widespread use of hydroxychloroquine and azithromycin despite the lack of conclusive evidence for their safety and efficacy. We evaluated the association between treatment with hydroxychloroquine and/or azithromycin and hospital mortality as the primary outcome. We compared the hospital mortality of patients treated with hydroxychloroquine alone, azithromycin alone, or their combination to the mortality of patients who received neither drug. A logistic multivariate model with overlap weight propensity score was used for estimation of odds ratios (ORs) with 95% confidence intervals (95% CIs). One thousand four hundred and three patients with SARS-CoV-2 infection were admitted to the hospital. At the time of the analysis, the outcome was available for 1376 (98%) of them. Five hundred and eighty-seven patients (42%) received azithromycin and 377 patients (27%) received hydroxychloroquine, alone or in combination. In-hospital mortality was 26%. After the adjusted analysis, azithromycin alone was associated with lower mortality (OR 0.60, 95% CI 0.42-0.85) compared to no treatment. Hydroxychloroquine alone (OR 0.76, 95% CI 0.53-1.08) and the combination of azithromycin and hydroxychloroquine (OR 1.13, 95% CI 0.77-1.69) were not associated with hospital mortality. In this cohort of patients, azithromycin alone was associated with lower hospital mortality but hydroxychloroquine was not associated with increased or reduced mortality. While we await randomized clinical trials, these data support the use of azithromycin in novel coronavirus disease 2019 (COVID-19) and can contribute to better understanding of its role in further meta-analyses.

19.
Int J Clin Pract ; 74(11): e13637, 2020 Nov.
Article in English | MEDLINE | ID: covidwho-693242

ABSTRACT

BACKGROUND: In late December 2019 and on 1st January 2020, the coronavirus (COVID-19) infecting humans was first identified in Wuhan, Hubei Province, China. Later cases have also been confirmed worldwide. Coronaviruses are RNA viruses that are phenotypically and genotypically diverse. Globally, as of 6th April 2020, laboratory confirmed cases of COVID-19 reported to the World Health Organisation (WHO) amounted to 1 211 214, including 67 666 deaths. AIM: In the current study, we performed a literature review on coronavirus outbreak to summarise details about the pathogenesis, epidemiology, diagnosis and the management strategies for the disease control. PATHOGENESIS: Coronaviruses are tremendously precise and mature only in differentiated respiratory epithelial cells, as seen in both organ cultures as well as human volunteers. This virus will cause the antiviral T-cell response to be erratic, owing to the T-cell apoptosis activation, triggering the immune system to collapse. TRANSMISSION: The understanding of the transmission of COVID-19 risk is incomplete. The transmission mainly occurs through the respiratory droplets once an infected person sneezes, like the spread of flu and other respiratory infectious agents. CLINICAL PRESENTATION: Presentations of COVID-19 includes fever, cough, shortness of breath, malaise and respiratory distress. TREATMENT: There have been no approved vaccines available for COVID-19 until today. The Ministry of Science and Technology in the People's Republic of China declared three potential antiviral medicines suitable for treating COVID-19. Those three medicines are, namely, favilavir, chloroquine phosphate and remdesivir. Hydroxychloroquine combined with azithromycin enhances the reduction of the viral load in COVID-19 patients. CONCLUSION: The corona virus transmits quicker than its two predecessors the MERS-CoV and SARS-CoV, but has reduced casualty. The global effects of this latest pandemic are still unclear. Nevertheless, considering that so far no vaccine has been available; preventive approaches are the best way to fight against the virus.


Subject(s)
Betacoronavirus , Coronavirus Infections/epidemiology , Disease Outbreaks , Pneumonia, Viral/epidemiology , Betacoronavirus/isolation & purification , COVID-19 , Coronavirus Infections/diagnosis , Coronavirus Infections/etiology , Coronavirus Infections/prevention & control , Global Health , Humans , Pandemics/prevention & control , Pneumonia, Viral/diagnosis , Pneumonia, Viral/etiology , Pneumonia, Viral/prevention & control , SARS-CoV-2
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