Chloroquine & Hydroxychloroquine
NIH recommends against the use of chloroquine, hydroxychloroquine or hydroxychloroquine plus azithromycin for the treatment of COVID-19, except as part of a clinical trial
The FDA granted an Emergency Use Authorization (EUA) for the use of chloroquine and hydroxychloroquine for the treatment of COVID-19 from the National Stockpile in February 2020. In April the FDA issued a safety reminder regarding the risk of QT prolongation with chloroquine and hydroxychloroquine, especially when used in combination with azithromycin and other QT prolonging medicines. The FDA also reminded health care professionals the EUA covered use in hospitalized patients, where the patients could be monitored more closely. After a review of new evidence, the FDA rescinded the EUA for chloroquine and hydroxychloroquine on June 15, 2020. The FDA determined that chloroquine and hydroxychloroquine were unlikely to be effective in treating COVID-19 and the potential for serious cardiac adverse events and other serious side effects no longer justified the EUA. On the same day the EUA was rescinded, the FDA issued a warning that co-administration of remdesivir with chloroquine or hydroxychloroquine is not recommended because it may reduce the antiviral activity of remdesivir.
Chloroquine and hydroxychloroquine became potential treatments for COVID-19 based on some early in-vitro testing. The 4-aminoquinolines inhibit endosomal acidification, so chloroquine and hydroxychloroquine have been tested as potential treatments. In vitro data suggested that chloroquine has activity against COVID-19 in achievable levels.
The early studies for chloroquine and hydroxychloroquine were small and had design flaws, inaccurate or incomplete descriptions of results or missing information. The trials did not adequately control for confounders, so the true effect of the intervention was not clear. Most often the problem involved the addition of several drugs that may have antiviral properties included in the supportive care of the patient. Therefore, it is unclear which treatment(s) produced an effect. Another problem is when the drug was not given until 1-2 weeks after the patient developed symptoms, which may be too late to have a full effect.
The report that first increased interest in hydroxychloroquine was a small French observational study. French researchers compared 26 COVID-19 patients treated with hydroxychloroquine 200 mg three times per day for ten-days to ten patients from the same hospital and other hospitals that did not receive hydroxychloroquine. Six of the hydroxychloroquine patients also received a standard 5-day azithromycin regimen. After six days, nasopharyngeal samples were negative in eight of the fourteen (57%) hydroxychloroquine patients, all six (100%) hydroxychloroquine/azithromycin patients and two of sixteen in the control group. In a separate report, French researchers released data from 80 patients showing that 83% of patients at day 7 had negative nasopharyngeal tests and 93% at day 8. Virus cultures from respiratory samples at Day 5 were negative in 97.5% patients. In an unreviewed, unedited abstract, the same French researchers provided data on 1,061 patients not previously included in their reports. There was no randomization or comparative group. Patients were treated with hydroxychloroquine and azithromycin for at least 3-days and followed for at least 9-days. The clinicians reported a good clinical outcome and virologic cure in 91.7% of patients. A 30 patient Chinese trial (NCT04261517) and a 62 patient, Chinese trial provided some support for the French results.
Based on the early reports chloroquine and hydroxychloroquine began to be used as treatments for COVID-19. So, researchers began retrospective analyses of patient records.
The WHO removed hydoxychloroquine and chloroquine as treatments in the multi-national SOLIDARITY COVID-19 trial in June 2020. NIH discontinued the ORCHID study in June 2020. that was evaluating hydroxychloroquine as a treatment of hospitalized patients with COVID-19. The discontinuation was recommended by the data and safety monitoring board after an interim analysis of data from 470 patients indicated that while hydroxychloroquine as safe, it was unlikely to unlikely to demonstrate efficacy.
Oxford University is evaluating hydroxychloroquine and chloroquine as prophylaxis of COVID-19 in health care professionals at risk for infection in the 40,000 patient, COPCOV trial (NCT04303507). The UK Medicines Healthcare Regulatory Agency (MHRA) halted enrollment in the COPCOV study on 5/26/2020. After review, MHRA allowed the study to continue on 6/26/2020.
The FDA granted an Emergency Use Authorization (EUA) for the use of chloroquine and hydroxychloroquine for the treatment of COVID-19 from the National Stockpile in February 2020. In April the FDA issued a safety reminder regarding the risk of QT prolongation with chloroquine and hydroxychloroquine, especially when used in combination with azithromycin and other QT prolonging medicines. The FDA also reminded health care professionals the EUA covered use in hospitalized patients, where the patients could be monitored more closely. After a review of new evidence, the FDA rescinded the EUA for chloroquine and hydroxychloroquine on June 15, 2020. The FDA determined that chloroquine and hydroxychloroquine were unlikely to be effective in treating COVID-19 and the potential for serious cardiac adverse events and other serious side effects no longer justified the EUA. On the same day the EUA was rescinded, the FDA issued a warning that co-administration of remdesivir with chloroquine or hydroxychloroquine is not recommended because it may reduce the antiviral activity of remdesivir.
Chloroquine and hydroxychloroquine became potential treatments for COVID-19 based on some early in-vitro testing. The 4-aminoquinolines inhibit endosomal acidification, so chloroquine and hydroxychloroquine have been tested as potential treatments. In vitro data suggested that chloroquine has activity against COVID-19 in achievable levels.
The early studies for chloroquine and hydroxychloroquine were small and had design flaws, inaccurate or incomplete descriptions of results or missing information. The trials did not adequately control for confounders, so the true effect of the intervention was not clear. Most often the problem involved the addition of several drugs that may have antiviral properties included in the supportive care of the patient. Therefore, it is unclear which treatment(s) produced an effect. Another problem is when the drug was not given until 1-2 weeks after the patient developed symptoms, which may be too late to have a full effect.
The report that first increased interest in hydroxychloroquine was a small French observational study. French researchers compared 26 COVID-19 patients treated with hydroxychloroquine 200 mg three times per day for ten-days to ten patients from the same hospital and other hospitals that did not receive hydroxychloroquine. Six of the hydroxychloroquine patients also received a standard 5-day azithromycin regimen. After six days, nasopharyngeal samples were negative in eight of the fourteen (57%) hydroxychloroquine patients, all six (100%) hydroxychloroquine/azithromycin patients and two of sixteen in the control group. In a separate report, French researchers released data from 80 patients showing that 83% of patients at day 7 had negative nasopharyngeal tests and 93% at day 8. Virus cultures from respiratory samples at Day 5 were negative in 97.5% patients. In an unreviewed, unedited abstract, the same French researchers provided data on 1,061 patients not previously included in their reports. There was no randomization or comparative group. Patients were treated with hydroxychloroquine and azithromycin for at least 3-days and followed for at least 9-days. The clinicians reported a good clinical outcome and virologic cure in 91.7% of patients. A 30 patient Chinese trial (NCT04261517) and a 62 patient, Chinese trial provided some support for the French results.
Based on the early reports chloroquine and hydroxychloroquine began to be used as treatments for COVID-19. So, researchers began retrospective analyses of patient records.
- A retrospective review of 1,438 patients in New York hospitalized for COVID-19 infection found no difference for in-hospital mortality with hydroxychloroquine, azithromycin, or both compared to not receiving either drug.
- Researchers performed an observational study of 1,376 consecutive COVID-19 patients. An adjusted analysis of data found no evidence to support a reduction in death or intubation with hydroxychloroquine, but there was a higher incidence of cardiac arrest in patients receiving both hydroxychloroquine with azithromycin.
- A retrospective analysis of 96,032 patients from the proprietary Surgisphere multinational database of information from electronic health records, supply chain databases, and financial records compared patients that received chloroquine alone, chloroquine with a macrolide, hydroxychloroquine alone, or hydroxychloroquine with a macrolide to patients who received none of these treatments. The analysis found no benefit for chloroquine or hydroxychloroquine with or without a macrolide and the data suggested an increase in morbidity due to a higher incidence of arrhythmias. Due to the analysis of this trial, the WHO put a hold on the hydroxychloroquine arm of the trial for a safety review. The analysis was published in the journal Lancet. The Lancet editors issued an open letter to the authors of the analysis questioning the data integrity, highlighting flaws in the data aggregation and inadequate adjustment of confounders. They also pointed out the consequences of using a widely reported article on treatment decisions, clinical trials and public health policy. Information from the same database was used in an analysis of the safety of antihypertensive use in COVID-19 patients and published in the New England Journal of Medicine. The editors of NEJM published a similar letter of concern. After examining the concerns about the Lancet study, the WHO restarted the hydroxychloroquine arm of the study. Both NEJM and Lancet have asked to review the Surgisphere database and methods used to extract, store and retrieve data. In a response, Surgisphere has agreed to an independent academic audit to validate where the data comes from, the database, and the statistical analysis required for the two studies. Both the study published in Lancet and in NEJM have been retracted, because all authors of each article were not granted access to the full data set for either study.
- In a 14-day, 821 patient trial, prophylactic use of hydroxychloroquine did not reduce the incidence of infection compared to placebo (11.8% vs 14.3%) in healthy patients exposed to a known or suspected COVID-19 patient. An NEJM editorial points out inconsistent proof of exposure and confirmation of the development of infection. The prophylaxis regimen was initialed three days or later after exposure, which could have also decreased efficacy.
- In 28-day, 150 patient, Chinese trial, the addition of hydroxychloroquine to standard of care treatment did not result in negative conversion of PCR viral tests compared to standard of care in patients hospitalized with mild to moderate COVID-19. Initiation of hydroxychloroquine was delayed with an average 16-days between symptom onset and drug administration. Standard of care included antivirals in half of patients. So, given the delayed initiation of the drug and high use of antivirals, it is difficult to use the information provided in this study.
- In a 21-day, 173 patient French retrospective analysis, hydroxychloroquine given within 48 hours of hospital admission did not reduce ICU admission or death compared to standard of care (76% vs 75%). The analysts used propensity scores to control for potential confounding variables. The study was performed in hospitalized French patients with a moderate COVID-19 requiring oxygen. No patients in the study received antivirals or anti-inflammatory treatments, including NSAIDs, steroids or biologics such as tocilizumab. This study controlled for many variables and excluded many confounders.
- In a 2,541 patient, retrospective study, hydroxychloroquine reduced the hazard ratio for death by 66% and the combination of hydroxychloroquine plus azithromycin reduced the hazard ratio by 71% compared to neither treatment in hospitalized patients with COVID-19. A high number of patients received corticosteroids and a small number received tocilizumab. More patients that received hydroxychloroquine also received a corticosteroid compared to not receiving the drug (78.9% vs 35.7%). The same was true with tocilizumab but use of the drug was small (2.7% vs 1.2%). When controlling for confounders using Cox regression modeling and propensity scores, hydroxychloroquine monotherapy and hydroxychloroquine combined with azithromycin were associated with higher survival among patients with COVID-19.
- In a 14-day, 423 patient, Phase III trial conducted by the University of Minnesota, hydroxychloroquine did not substantially reduce symptom severity (scale no symptoms to severe symptoms) in outpatients with early to mild COVID-19.
- In a 15-day, 667 patient, Phase III, Brazilian trial, hydroxychloroquine alone or with azithromycin did not improve clinical status (7-point scale from hospitalized and no symptoms to death) compared to placebo in hospitalized patients with COVID-19. Hydroxychloroquine alone or with azithromycin was associated with a prolongation of the QT interval and an increase in liver-enzymes.
- The 200 patient, Phase III, PATCH trial (NCT04329923) was terminated after 132 patients, when prophylactic hydroxychloroquine did not reduce the infection rate compared to placebo in hospital-based health care workers.
- In the 14-day, 479 patient, Phase III, ORCHARD trial (NCT04332991), treatment with hydroxychloroquine did not improve clinical status compared to placebo in hospitalized patients with COVID-19.
- In a 14-day, 2,314 patient, Phase III trial (NCT04304053), hydroxychloroquine did not prevent COVID-19 compared to placebo in patients exposed to COVID-19 patients.
The WHO removed hydoxychloroquine and chloroquine as treatments in the multi-national SOLIDARITY COVID-19 trial in June 2020. NIH discontinued the ORCHID study in June 2020. that was evaluating hydroxychloroquine as a treatment of hospitalized patients with COVID-19. The discontinuation was recommended by the data and safety monitoring board after an interim analysis of data from 470 patients indicated that while hydroxychloroquine as safe, it was unlikely to unlikely to demonstrate efficacy.
Oxford University is evaluating hydroxychloroquine and chloroquine as prophylaxis of COVID-19 in health care professionals at risk for infection in the 40,000 patient, COPCOV trial (NCT04303507). The UK Medicines Healthcare Regulatory Agency (MHRA) halted enrollment in the COPCOV study on 5/26/2020. After review, MHRA allowed the study to continue on 6/26/2020.
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