What is the status of hydroxychloroquine and chloroquine in the treatment of coronavirus disease 2019 (COVID-19)?

Updated: Jul 01, 2020
  • Author: Medscape Drugs & Diseases; more...
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On June 15, 2020, the FDA revoked the emergency use authorization (EUA) for hydroxychloroquine and chloroquine donated to the Strategic National Stockpile to be used for treating certain hospitalized patients with COVID-19 when a clinical trial was unavailable or participation in a clinical trial was not feasible. [45]

Based on its ongoing analysis of the EUA and emerging scientific data, the FDA determined that hydroxychloroquine is unlikely to be effective in treating COVID-19 for the authorized uses in the EUA. Additionally, in light of ongoing serious cardiac adverse events and other potential serious adverse effects, the known and potential benefits of hydroxychloroquine no longer outweigh the known and potential risks for the EUA.

While additional clinical trials may continue to evaluate potential benefit, the FDA determined the EUA was no longer appropriate.

Hydroxychloroquine and chloroquine are widely used antimalarial drugs that elicit immunomodulatory effects and are therefore also used to treat autoimmune conditions (eg, systemic lupus erythematosus, rheumatoid arthritis). As inhibitors of heme polymerase, they are also believed to have additional antiviral activity via alkalinization of the phagolysosome, which inhibits the pH-dependent steps of viral replication. Wang et al reported that chloroquine effectively inhibits SARS-CoV-2 in vitro. [46] The pharmacological activity of chloroquine and hydroxychloroquine was tested using SARS-CoV-2–infected Vero cells. Physiologically based pharmacokinetic models (PBPK) were conducted for each drug. Hydroxychloroquine was found to be more potent than chloroquine in vitro. Based on PBPK models, the authors recommend a loading dose of hydroxychloroquine 400 mg PO BID, followed by 200 mg BID for 4 days. [47]

Published reports stemming from the worldwide outbreak of COVID-19 have evaluated the potential usefulness of these drugs in controlling cytokine release syndrome in critically ill patients. Owing to widely varying dosage regimens, disease severity, measured outcomes, and lack of control groups, efficacy data have been largely inconclusive.

The UK RECOVERY Trial randomized 1542 patients to hydroxychloroquine and 3132 patients to usual care alone. Preliminary results found no significant difference in the primary endpoint of 28-day mortality (25.7% hydroxychloroquine vs 23.5% usual care; hazard ratio 1.11 [95% CI, 0.98-1.26]; P = 0.10). There was also no evidence of beneficial effects on hospital stay duration or other outcomes. [48]

An observational study of 2512 hospitalized patients in New Jersey with confirmed COVID-19 was conducted between March 1, 2020 and April 22, 2020, with follow-up through May 5, 2020. Outcomes included 547 deaths (22%) and 1539 (61%) discharges; 426 (17%) remained hospitalized. Patients who received at least one dose of hydroxychloroquine totaled 1914 (76%), and those who received hydroxychloroquine plus azithromycin totaled 1473 (59%). No significant differences were observed in associated mortality among patients receiving any hydroxychloroquine during the hospitalization (HR, 0.99 [95% CI, 0.80-1.22]), hydroxychloroquine alone (HR, 1.02 [95% CI, 0.83-1.27]), or hydroxychloroquine with azithromycin (HR, 0.98 [95% CI, 0.75-1.28]). The 30-day unadjusted mortality rate in patients receiving hydroxychloroquine alone, azithromycin alone, the combination, or neither drug was 25%, 20%, 18%, and 20%, respectively. [39]

Because of these findings, the WHO paused the hydroxychloroquine arm of the Solidarity Trial. The FDA issued a safety alert for hydroxychloroquine or chloroquine use in COVID-19 on April 24, 2020. [49]

A phase 3 trial is planned to include approximately 440 hospitalized patients at multiple US sites. All patients enrolled in the trial will receive standard of care for COVID-19 and will be randomized into 3 groups—hydroxychloroquine, hydroxychloroquine plus azithromycin, or placebo. [50]

An observational study of consecutively hospitalized patients (n = 1446) at a large medical center in the New York City area showed hydroxychloroquine was not associated with either a greatly lowered or an increased risk of the composite endpoint of intubation or death. [51]

A retrospective analysis of data from patients hospitalized with confirmed COVID-19 infection in all US Veterans Health Administration medical centers between March 9, 2020, and April 11, 2020, has been published. Patients who had received hydroxychloroquine (HC) alone or with azithromycin (HC + AZ) as treatment in addition to standard supportive care were identified. A total of 368 patients were evaluated (HC n=97; HC + AZ n=113; no HC n=158). Death rates in the HC, HC + AZ, and no-HC groups were 27.8%, 22.1%, 11.4%, respectively. Rates of ventilation in the HC, HC + AZ, and no-HC groups were 13.3%, 6.9%, 14.1%, respectively. The authors concluded that they found no evidence that hydroxychloroquine, with or without azithromycin, reduced the risk of mechanical ventilation and that the overall mortality rate was increased with hydroxychloroquine treatment. Furthermore, they stressed the importance of waiting for results of ongoing, prospective, randomized controlled trials before wide adoption of these drugs. [52]

According to a consensus statement from a multicenter collaboration group in China, chloroquine phosphate 500 mg (300 mg base) twice daily in tablet form for 10 days may be considered in patients with COVID-19 pneumonia. [53] While no peer-reviewed treatment outcomes are available, Gao and colleagues profess that 100 patients have demonstrated significant improvement with this regimen without documented toxicity. [54] It should be noted this is 14 times the typical dose of chloroquine used per week for malaria prophylaxis and 4 times that used for treatment. Cardiac toxicity should temper enthusiasm for this as a widespread cure for COVID-19. It should also be noted that chloroquine was previously found to be active in vitro against multiple other viruses but has not proven fruitful in clinical trials, even resulting in worse clinical outcomes in human studies of Chikungunya virus infection (a virus unrelated to SARS-CoV-2).

A randomized controlled trial in Wuhan, China, enrolled 62 hospitalized patients (average age, 44.7 years) with confirmed COVID-19. Additional inclusion criteria included age 18 years or older, chest CT scans showing pneumonia, and SaO2/SPOs ratio of more than 93% (or PaOs/FIOs ratio >300 mm Hg). Patients with severe or critical illness were excluded. All patients enrolled in the study received standard treatment (oxygen therapy, antiviral agents, antibacterial agents, and immunoglobulin, with or without corticosteroids). Thirty-one patients were randomized to receive hydroxychloroquine sulfate (200 mg PO BID for 5 days) in addition to standardized treatment. Changes in time to clinical recovery (TTCR) was evaluated and defined as return of normal body temperature and cough relief, maintained for more than 72 hours. Compared with the control group, TTCR for body temperature and cough were significantly shortened in the hydroxychloroquine group. Four of the 62 patients progressed to severe illness, all of whom were in the control group. [55]

The French have embraced hydroxychloroquine as a potentially more potent therapy with an improved safety profile to treat and prevent the spread of COVID-19. [56] If it is effective, the optimal regimen of hydroxychloroquine is not yet known, although some experts have recommended higher doses, such as 600-800 mg per day. A study of hydroxychloroquine for postexposure prophylaxis in healthcare workers or household contacts is underway. [57]

An open-label multicenter study using high-dose hydroxychloroquine or standard of care did not show a difference at 28 days for seronegative conversion or the rate of symptom alleviation between the two treatment arms. The trial was conducted in 150 patients in China with mild-to-moderate disease. [58]

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