An Update: Is hydroxychloroquine effective for COVID-19?
Medically reviewed by Leigh Ann Anderson, PharmD. Last updated on Dec 14, 2020.
In June 2020, the FDA revoked the emergency use authorization (EUA) of oral hydroxychloroquine and chloroquine phosphate for the treatment of COVID-19. An EUA can allow quicker access to critical medical products when there are no approved alternative options.
- Based on an evaluation of the scientific data to date, the FDA concluded that chloroquine and hydroxychloroquine are not likely to be effective in the treatment of COVID-19 for the authorized uses in the EUA.
- In addition, the risk for serious side effects with hydroxychloroquine and chloroquine phosphate are a concern. This includes the possibility of adverse cardiovascular (heart) events such as an abnormal heart rhythm which could be fatal.
- Additional worldwide studies are still ongoing to assess the use of these agents for the treatment or prevention or COVID-19. However, the FDA states these drugs should not be used outside of clinical trials in the U.S.
The World Health Organization (WHO) and the U.S. National Institutes of Health (NIH) have also stopped studies evaluating hydroxychloroquine for the treatment of COVID-19 due to a lack of benefit. Current NIH and US treatment guidelines do not recommend use of hydroxychloroquine and chloroquine phosphate for COVID-19 treatment outside of clinical studies.
Although earlier studies suggested that hydroxychloroquine could inhibit the SARs-CoV-2 virus and was more potent than chloroquine, recent studies do not support the use of hydroxychloroquine or chloroquine phosphate. The FDA stated on June 15, 2020 that the suggested dosing regimens for chloroquine and hydroxychloroquine are unlikely to kill or inhibit the virus that causes COVID-19.
Do studies show hydroxychloroquine is not effective for COVID-19?
Yes, multiple studies provide data that hydroxychloroquine is ineffective in the treatment of SARS-CoV-2, the virus that causes COVID-19 disease.
The RECOVERY Trial from the University of Oxford is a large, randomized, controlled, open-label study evaluating a number of potential treatments for patients hospitalized with COVID-19. The study is being conducted by researchers at the University of Oxford in the UK (the hydroxychloroquine arm is now halted).
- In the RECOVERY Trial, investigators reported that there was no beneficial effect or reduction of death in hospitalized patients with COVID-19 receiving hydroxychloroquine.
- In this study, 1561 patients received hydroxychloroquine and were compared to 3155 patients receiving standard care only. No difference was found in the primary endpoint, which was the incidence of death at 28 days (26.8% hydroxychloroquine vs. 25% usual care, 95% CI 0.96-1.23; p=0.18).
- In addition, hydroxychloroquine treatment was associated with an increased length of stay in the hospital and increased need for invasive mechanical ventilation.
- Based on this data, investigators stopped enrollment in the RECOVERY hydroxychloroquine arm on June 5th, 2020.
In a multicenter, randomized, open-label, controlled trial published in July 2020 by Cavalcanti and colleagues in the New England Journal of Medicine (NEJM), hydroxychloroquine use was studied in patients who were hospitalized with mild-to-moderate COVID-19.
- Patients received hydroxychloroquine (400 mg twice daily for 7 days), hydroxychloroquine with azithromycin (hydroxychloroquine 400 mg twice daily + azithromycin 500 mg once daily for 7 days), or standard care only.
- The clinical status of these patients at day 15 was not improved as compared with the patients receiving only standard care.
- In addition, researchers noted that prolonged QT intervals (which may lead to abnormal heart rates and death) and elevated liver enzymes were higher in patients receiving hydroxychloroquine, either with or without azithromycin.
A randomized, double-blind, placebo-controlled trial from Skipper and colleagues was conducted in 423 outpatients (not in the hospital) with early COVID-19. It was published in the Annals of Internal Medicine in July 2020.
- Patients received oral hydroxychloroquine (800 mg once, followed by 600 mg in 6 to 8 hours, then 600 mg daily for 4 more days) or a placebo (inactive treatment).
- Researchers found that over a 14 day period a change in symptom severity and the percent of patients with ongoing symptoms did not differ significantly between groups, signaling no effect from the hydroxychloroquine treatment.
- However, side effects were significantly greater in the group receiving hydroxychloroquine compared to placebo (43% hydroxychloroquine versus 22% placebo (P < 0.001). Rates of hospitalizations and deaths did not differ significantly.
In contrast, a retrospective, observational study conducted from March to early May of 2020 did report a positive effect with hydroxychloroquine on hospitalized patient mortality, used alone and with azithromycin when compared to no treatment. The study was published in the International Journal of Infectious Diseases in August 2020. Authors note a limitation to their analysis was the retrospective, non-randomized, non-blinded study design.
- Researchers looked at 2,541 patients, with a median total hospitalization time of 6 days.
- Mortality, by treatment, was 20.1% for hydroxychloroquine + azithromycin, 13.5% for hydroxychloroquine alone, 22.4% for azithromycin alone, and 26.4% for neither drug (p < 0.001). The primary cause of death was respiratory failure in 88% of patients.
- Adjunct therapy with corticosteroids (methylprednisolone and/or prednisone) and anti-IL-6 tocilizumab was provided in 68% and 4.5% of patients, respectively.
- Factors such as greater glucocorticoid use in the hydroxychloroquine groups and the nonrandomized study design suggested this data may be flawed and that prospective, randomized controlled studies were needed to validate these results.
Use of hydroxychloroquine is controversial, and has been politicized in the U.S. by some groups. Various studies have reported both a positive and negative effect, and data may not be robust: it may be nonrandomized, retrospective, observational or from a small sample size of patients.
Research for COVID is often quick to be published in non-peer reviewed, preprint online services due to the urgency of the pandemic. However, in general, preprint data should not be used to guide clinical practice. In addition, some hydroxychloroquine studies have been retracted due to lack of confidence in the data, including a Lancet study and one from the NEJM.
What is hydroxychloroquine used to treat?
Chloroquine and hydroxychloroquine are FDA-approved drugs in the U.S. The EUA revocation for COVID-19 does not change their approved uses.
Hydroxychloroquine sulfate is approved to treat and prevent malaria, as well as for treatment of lupus erythematosus and rheumatoid arthritis. Chloroquine phosphate is approved for the treatment and prevention of malaria only. The FDA has determined that these drugs are safe and effective when used as labeled for these conditions.
Hydroxychloroquine study for prevention after exposure to COVID-19
A randomized, double-blind, placebo-controlled study published online in the NEJM in June 2020 (Boulware, et al) looked at prevention of COVID-19 after exposure to the virus (post-exposure prophylaxis, or PEP).
- Researchers evaluated over 800 people in the U.S. and Canada who had been exposed to COVID-19. The primary outcome was the incidence of either laboratory-confirmed COVID-19 or illness compatible with the virus within 14 days.
- Hydroxychloroquine was given as 800 mg once, followed by 600 mg in 6 to 8 hours, then 600 mg daily for 4 additional days. Patients started treatment within 4 days after exposure, defined as being in close contact with a COVID-19 patient for more than 10 minutes without protection.
- Results showed that hydroxychloroquine did not prevent COVID-19 when compared to a placebo (used as post-exposure prophylaxis). The incidence of COVID-19 did not differ significantly between those who took hydroxychloroquine (11.8%) and those who took placebo (14.3%).
- Side effects were more common in the hydroxychloroquine group (40.1% compared to 16.8% with placebo), but were not reported as serious. Common adverse events included nausea, loose stools, and stomach pain.
- Limitations in this study were many, and included inability to confirm self-reported COVID-19 exposure, adherence to study drug, starting drug up to 4 days after reported exposure to the virus, and enrollment of a lower-risk population.
I took hydroxychloroquine for COVID-19. Is it dangerous?
There are no known residual side effects for patients who received chloroquine phosphate or hydroxychloroquine for COVID-19 treatment under the emergency use authorization, as stated by the FDA.
However, you should never self-treat for COVID-19 disease with hydroxychloroquine or any other drug. Hydroxychloroquine has not been proven helpful for COVID-19 and may lead to stomach or heart side effects, as well as serious drug interactions.
- On June 15, 2020 the FDA warned health care providers that the combined use of remdesivir (Veklury) and chloroquine phosphate or hydroxychloroquine sulfate is not recommended as it may result in reduced antiviral activity of remdesivir.
- Veklury, an antiviral used to treat SARS-CoV-2, the virus that causes COVID-19, is now approved by the FDA. This drug interaction is outlined in product labeling for Veklury.
If you have concerns about any side effect or drug interaction with your medications, always contact your doctor or other health care provider for advice.
What treatments or vaccines are available to treat COVID-19?
Remdesivir (brand name: Veklury) from Gilead Sciences was approved by the FDA on October 22, 2020 as the first treatment for SARS-CoV-2, the virus that causes COVID-19 and has led to a worldwide pandemic. Veklury is a SARS-CoV-2 nucleotide analog RNA polymerase inhibitor, an antiviral agent that stops replication of the virus. Previously remdesivir was available only via an emergency use authorization (EUA) to treat COVID-19.
- Veklury is approved for use in patients 12 years of age and older and weighing at least 40 kg (88 lb) for the treatment of COVID-19 who require hospitalization. It is given via intravenous infusion once daily for 5 to 10 days.
- Veklury should only be administered in a hospital or in a healthcare setting capable of providing acute care comparable to inpatient hospital care.
- Approval is based in part on results from the randomized, double-blind, placebo-controlled Phase 3 ACTT-1 trial with 1,062 hospitalized patients. This study demonstrated that patients receiving Veklury achieved clinical recovery 5 days faster than those receiving placebo (10 days versus 15 days). In patients who required oxygen support, clinical recovery was 7 days faster than those receiving placebo (11 days versus 18 days).
- Overall, the odds of clinical improvement at Day 15 were also statistically significantly higher in the Veklury group when compared to the placebo group.
The incidence of adverse events associated with Veklury was similar to placebo in the ACTT-1 trial. The most common adverse reactions (≥5%) were nausea and increases in liver function tests (ALT and AST).
The FDA has also revised the pediatric Emergency Use Authorization (EUA) for Veklury. Under the EUA, it can be used to treat suspected or laboratory confirmed COVID-19 in hospitalized pediatric patients weighing 3.5 kg (7.7 lb) to less than 40 kg (88 lb) OR hospitalized pediatric patients less than 12 years of age weighing at least 3.5 kg.
Dexamethasone, a corticosteroid drug that has been approved for over six decades, has been shown to statistically lower mortality from COVID-19, especially among patients receiving mechanical ventilation. In studies from the RECOVERY group, death occurred in 25.7% of patients in the usual care group and 22.9% in the dexamethasone group (P<0.001).
On Dec. 111, 2020 the FDA issued an Emergency Use Authorization (EUA) for Pfizer's COVID-19 vaccine. On Dec 14th, vaccine administration began in a rolling fashion for the most high-risk groups. Other vaccines candidates are expected to be available for 2021.
In August 2020, Russia announced it had approved a vaccine for COVID-19 prevention based on an adenovirus, similar to a vaccine being studied by AstraZeneca. However, the vaccine from Russia has not completed Phase 3 studies, prompting concern that the agent may not have been reviewed in enough people for safety or effectiveness. Phase 1 and 2 results were published in Lancet in Sept. 2020.
Learn more here: COVID-19: Prevention & Investigational Treatments
- The use of hydroxychloroquine in randomized trials for the treatment of hospitalized patients with COVID-19 has not been shown to have a benefit in reducing death.
- In addition, concerns exist over the benefit of the drug compared to its safety risk, especially with regard to abnormal heart rhythms.
- Multiple worldwide public health organizations, including the FDA, NIH and WHO have halted emergency use and studies of hydroxychloroquine as a treatment for hospitalized patients with COVID-19 based on studies showing a lack of effect and possible serious side effects.
- Veklury (remsedivir) is now FDA-approved as an antiviral treatment for COVID-19, and dexamethasone, a corticosteroid agent, has shown a mortality benefit.
- NIH halts clinical trial of hydroxychloroquine. Study shows treatment does no harm, but provides no benefit. US National Institutes of Health. Accessed August 13, 2020 at https://www.nih.gov/news-events/news-releases/nih-halts-clinical-trial-hydroxychloroquine
- Solidarily Clinical Trials for COVID-19 Treatments. WHO. Accessed August 12, 2020 at https://www.who.int/emergencies/diseases/novel-coronavirus-2019/global-research-on-novel-coronavirus-2019-ncov/solidarity-clinical-trial-for-covid-19-treatments
- Coronavirus (COVID-19) Update: FDA Revokes Emergency Use Authorization for Chloroquine and Hydroxychloroquine. US Food and Drug Administration. Accessed August 12, 2020 at https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-revokes-emergency-use-authorization-chloroquine-and
- The RECOVERY Trial. No clinical benefit from use of hydroxychloroquine in hospitalised patients with COVID-19. Accessed August 12, 2020 at https://www.recoverytrial.net/files/hcq-recovery-statement-050620-final-002.pdf
- Hornby P, Mafham M, Linsel L, et al Effect of Hydroxychloroquine in Hospitalized Patients with COVID-19: Preliminary results from a multi-centre, randomized, controlled trial. medRxiv 2020.07.15.20151852; doi: https://doi.org/10.1101/2020.07.15.20151852
- Kim A, Gandhi R, Hirsh M, et al. Coronavirus disease 2019 (COVID-19): Management in hospitalized adults. Up to Date. Accessed August 12, 2020 at https://www.uptodate.com/contents/coronavirus-disease-2019-covid-19-management-in-hospitalized-adults
- Cavalcanti AB, Zampieri FG, Rosa RG, et al. Hydroxychloroquine with or without Azithromycin in Mild-to-Moderate Covid-19. N Engl J Med. 2020;10. doi:10.1056/NEJMoa2019014
- Skipper C, Pastick K, Engen N. Hydroxychloroquine in Nonhospitalized Adults With Early COVID-19. A Randomized Trial. Ann Intern Med. July 16, 2020. Accessed August 13, 2020 at doi.org/10.7326/M20-4207
- Arshad S, Kilgore P, Chaudhry ZS, et al. Treatment with hydroxychloroquine, azithromycin, and combination in patients hospitalized with COVID-19. Int J Infect Dis. 2020;97:396-403. doi:10.1016/j.ijid.2020.06.099
- Boulware D, Pullen M, Bangdiwala A, et al. A Randomized Trial of Hydroxychloroquine as Postexposure Prophylaxis for Covid-19 N Engl J Med 2020; 383:517-525 DOI: 10.1056/NEJMoa2016638
- Veklury (remdesivir) [product information]. Foster City, CA, Gilead Sciences. Accessed Oct. 23, 2020 at https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/214787Orig1s000lbl.pdf
- FDA Approves First Treatment for COVID-19. US Food and Drug Administration (FDA). Accessed Oct. 23, 2020 at https://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-covid-19
- The RECOVERY Collaborative Group. Dexamethasone in hospitalized patients with Covid-19 — preliminary report. July 17, 2020. N Engl J Med. Accessed Oct. 23, 2020 at DOI: 10.1056/NEJMoa2021436.
- Beigel J, Tomashek K, Dodd L, et al. Remdesivir for the Treatment of Covid-19 — Final Report. October 8, 2020. N Engl J Med. Accessed Oct. 23, 2020 at DOI: 10.1056/NEJMoa2007764
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