Hydroxychloroquine in Nonhospitalized Adults With Early COVID-19
Authors: Caleb P. Skipper, David R. Boulware
Journal: Annals of Internal Medicine (2021)

LettersMarch 2021Hydroxychloroquine in Nonhospitalized Adults With Early COVID-19FREECaleb P. Skipper, MD, David R. Boulware, MD, MPHCaleb P. Skipper, MDUniversity of Minnesota, Minneapolis, MinnesotaSearch for more papers by this author, David R. Boulware, MD, MPHUniversity of Minnesota, Minneapolis, MinnesotaSearch for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/L20-1426 SectionsAboutVisual AbstractPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail IN RESPONSE: To address Drs. Paiva and Tausk, the protocol and statistical analysis plan called for an intention-to-treat analysis whereby everyone randomly assigned was analyzed. A modified intention-to-treat analysis had similar results when we excluded those who did not start therapy with the study medicine and those who received open-label HCQ (n = 1), as well as with carryforward of symptom status for patients who were hospitalized, died, or had resolved symptoms at day 10. Ongoing symptoms were present at study day 5 in 54.9% (100 of 182) of patients who received HCQ and 57.5% (104 of 181) of patients who received placebo. At study day 14, ongoing symptoms were present in 24.9% (46 of 185) of patients who received HCQ and 31.1% (56 of 180) of patients who received placebo. The number needed to treat to have 1 additional person be without symptoms at 14 days is 16 persons (95% CI, −34 [harm] to 6.5 [benefit] persons). The original intention-to-treat analysis reported that 24.4% of patients who received HCQ versus 30.4% of patients who received placebo had symptoms at day 14.A per protocol analysis is generally recognized as being biased, because it ignores those who stop medication because of adverse effects. In this randomized, double-blind trial, less than 100% adherence (range, 5% to 89%) was achieved more frequently with HCQ (11.8% [24 of 203] of patients) than with placebo (7.8% [15 of 194] of patients), often because of medication adverse effects or spontaneous improvement. As Supplement Table 2 presents, those with less than 75% adherence—which includes those who never started the medicine—had greater resolution of symptom severity. Yet, when restricting the analysis to those with 100% adherence as a per protocol analysis, ongoing symptoms existed at day 5 in 54.1% (85 of 157) of patients who received HCQ versus 56.6% (94 of 166) of patients who received placebo. At day 14, a total of 25.2% (39 of 155) of the HCQ group had ongoing symptoms. Thus, neither a modified intention-to-treat nor a per protocol analysis substantially differs from the original intention-to-treat analysis.In response to Dr. Araujo, we did not find a statistical difference in COVID-related hospitalizations or death with HCQ (2.2% [5 of 231] of patients) versus placebo (3.4% [8 of 234] of patients). Two non-COVID events took place in the placebo group that required hospital observations of less than 24 hours. Adjudication occurred while investigators were blinded. In a similar early outpatient treatment randomized trial (n = 293), Mitjà and colleagues found 0 virologic effect of HCQ (0.07 log10 copies/mL higher at 7 days with HCQ) compared with no therapy (1). Their incidence of all-cause hospitalization was 5.9% (8 of 136 patients) with HCQ versus 7.0% (11 of 157 patients) with standard of care in Catalonia (1). A second large randomized trial by Omrani and associates (n = 456) (2) similarly reported no virologic effect of either HCQ alone or HCQ with azithromycin, nor did they find any reduction in hospitalization with HCQ (2.0% [3 of 152 patients]), HCQ and azithromycin (2.6% [4 of 152 patients]), or placebo (2.6% [4 of 152 patients]). A third large randomized trial in Brazil was halted because of futility, with no effect on hospitalization or death (risk ratio, 1.00 [95% CI, 0.45 to 2.21]) (3). An ongoing effort is pursuing this by pooling data across 8 outpatient randomized trials.We note to Dr. Bhattacharyya and coworkers that the data on whether folic acid has activity against severe acute respiratory syndrome coronavirus 2 in humans to prevent or mitigate COVID-19 are underwhelming. Although interesting, in silica studies are low-quality evidence. In pregnant women, Acosta-Elias and Espinosa-Tanguma reported a 0.95-fold risk for COVID-19–related hospitalization, which is decreased relative to influenza (4). However, the Centers for Disease Control and Prevention reported that pregnant women were 2- to 3-fold more likely to require an intensive care unit stay, invasive ventilation support, or extracorporeal membrane oxygenation (5) despite being a population that commonly receives prenatal folate supplementation. The referenced 50-person case–control study involved a different population of hospitalized patients with COVID-19 that used a substantially higher 150-mg total dose of folic acid versus the 7.6 mg given in our trial (6). When we compared symptom severity by placebo composition, the mean visual analogue scale score did not differ at day 5 (mean score of 2.1 [SD, 2.5] for folic acid vs. 2.5 [SD, 2.7] for lactose; P = 0.51) or at days 10 (P = 0.27) or 14 (P = 0.76). Further, Mitjà and colleagues, who used no placebo, reported similar overall results (1). As the available data currently stand, we believe placebo remains valid. Effective early outpatient therapy to prevent disease progression is important; among repurposed oral medicines, fluvoxamine seems more promising than HCQ or folic acid (7).References1. Mitjà O, Corbacho-Monné M, Ubals M, et al; BCN PEP-CoV-2 Research Group. Hydroxychloroquine for early treatment of adults with mild COVID-19: a randomized-controlled trial. Clin Infect Dis. 2020. [PMID: 32674126] doi:10.1093/cid/ciaa1009 MedlineGoogle Scholar2. Omrani AS, Pathan SA, Thomas SA, et al. Randomized double-blinded placebo-controlled trial of hydroxychloroquine with or without azithromycin for virologic cure of non-severe COVID-19. EClinicalMedicine. 2020;29:100645. [PMID: 33251500] doi:10.1016/j.eclinm.2020.100645 CrossrefMedlineGoogle Scholar3. Lee Z, Rayner CR, Forrest JI, et al. The rise and fall of hydroxychloroquine for the treatment and prevention of COVID-19. Am J Trop Med Hyg. 2021;104:35-8. [PMID: 33236703] doi:10.4269/ajtmh.20-1320 CrossrefMedlineGoogle Scholar4. Acosta-Elias J, Espinosa-Tanguma R. The folate concentration and/or folic acid metabolites in plasma as factor for COVID-19 infection. Front Pharmacol. 2020;11:1062. [PMID: 32765270] doi:10.3389/fphar.2020.01062 CrossrefMedlineGoogle Scholar5. Zambrano LD, Ellington S, Strid P, et al; CDC COVID-19 Response Pregnancy and Infant Linked Outcomes Team. Update: characteristics of symptomatic women of reproductive age with laboratory-confirmed SARS-CoV-2 infection by pregnancy status—United States, January 22-October 3, 2020. MMWR Morb Mortal Wkly Rep. 2020;69:1641-7. [PMID: 33151921] doi:10.15585/mmwr.mm6944e3 CrossrefMedlineGoogle Scholar6. Boyko AN, Shamalov NA, Boyko OV, et al. The first experience with Angiovit in the combination treatment of acute COVID-19 infection. Neurology, Neuropsychiatry, Psychosomatics. 2020;12:82-6. doi:10.14412/2074-2711-2020-3-82-86 CrossrefGoogle Scholar7. Lenze EJ, Mattar C, Zorumski CF, et al. Fluvoxamine vs placebo and clinical deterioration in outpatients with symptomatic COVID-19: a randomized clinical trial. JAMA. 2020;324:2292-300. [PMID: 33180097] doi:10.1001/jama.2020.22760 CrossrefMedlineGoogle Scholar Comments 0 Comments Sign In to Submit A Comment Author, Article, and Disclosure InformationAuthors: Caleb P. Skipper, MD; David R. Boulware, MD, MPHAffiliations: University of Minnesota, Minneapolis, MinnesotaDisclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M20-4207. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetailsSee AlsoHydroxychloroquine in Nonhospitalized Adults With Early COVID-19 Caleb P. Skipper , Katelyn A. Pastick , Nicole W. Engen , Ananta S. Bangdiwala , Mahsa Abassi , Sarah M. Lofgren , Darlisha A. Williams , Elizabeth C. Okafor , Matthew F. Pullen , Melanie R. Nicol , Alanna A. Nascene , Kathy H. Hullsiek , Matthew P. Cheng , Darlette Luke , Sylvain A. Lother , Lauren J. MacKenzie , Glen Drobot , Lauren E. Kelly , Ilan S. Schwartz , Ryan Zarychanski , Emily G. McDonald , Todd C. Lee , Radha Rajasingham , and David R. Boulware Hydroxychloroquine in Nonhospitalized Adults With Early COVID-19 Anusuya Bhattacharyya , Phulen Sarma , Hardeep Kaur , Bikash Medhi Hydroxychloroquine in Nonhospitalized Adults With Early COVID-19 Claudia N. Paiva , Daniel V. 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