What is the latest data and news regarding hydroxychloroquine for COVID-19?

Can you summarize the latest data and news regarding hydroxychloroquine?

Comment by InpharmD Researcher

Studies published in June/July 2020 (so far) suggest hydroxychloroquine likely has little to no benefit in treating or preventing (post-exposure prophylaxis) COVID-19. Interim analyses of two large randomized, controlled trials showed no benefit, so these studies were discontinued prematurely. The FDA also revoked their previous Emergency Use Authorization allowing hydroxychloroquine to treat COVID-19. Some retrospective studies have shown a mortality benefit, but these studies are limited by their retrospective design and selection bias.

Background

On June 15, 2020, the Food and Drug Administration (FDA) determined that chloroquine and hydroxychloroquine are unlikely to be effective in treating COVID-19, and thus revoked the previous Emergency Use Authorization (EUA). Based on emerging scientific data, concerns due to serious cardiac adverse events, and other potential serious side effects, the agency decided the benefits of both agents no longer outweigh the potential risks for the authorized use. These agents could still be used by physicians as off label treatment if deemed appropriate. [1]

On June 20, 2020, the National Institutes of Health (NIH) stopped a clinical trial (the Outcomes Related to COIVD-19 treated with hydroxychloroquine among inpatients with symptomatic disease study [ORCHID] study) to assess the efficacy and safety of hydroxychloroquine to treat COVID-19 patients. This decision comes after a fourth interim analysis showing the drug was very likely to not be beneficial to hospitalized COVID-19 patients while also showing no harms. More than 470 patients were enrolled at the time of the study’s closure. [2]

On July 4, 2020, the World Health Organization (WHO) accepted the recommendation from the Solidarity Trial’s International Steering Committee to discontinue the trial’s hydroxychloroquine and lopinavir/ritonavir arms. The recommendation was made based on the evidence for hydroxychloroquine vs standard-of-care and for lopinavir/ritonavir vs standard-of-care from the Solidarity trial interim results and from a review of the evidence from all trials presented at the July 1-2 WHO Summit on COVID-19 research and innovation. The interim results for both treatments show little to no reduction in mortality in hospitalized COVID-19 patients compared to standard of care. Although there was no solid evidence of increased mortality, there was also a safety concern with these agents. [3]

Literature Review

A search of the published medical literature revealed 5 studies investigating the researchable question:

Can you summarize the latest data and news regarding hydroxychloroquine?

Please see Tables 1-5 for your response.

Treatment with Hydroxychloroquine, Azithromycin, and Combination in Patients Hospitalized with COVID-19
Design	Multi-center, retrospective, observational study N= 2541
Objective	To evaluate the role of hydroxychloroquine therapy alone and in combination with azithromycin in hospitalized patients positive for COVID-19
Study Groups	Hydroxychloroquine (n= 1,202) Azithromycin (n= 147) Hydroxychloroquine + Azithromycin (n=783) Neither Hydroxychloroquine nor Azithromycin (n= 409)
Methods	Inclusion criteria: patients with a COVID-related admission in the health system from March 10 to May 2, 2020; 18 years of age or older, inpatients for at least 48 hours unless they expired within the time period Exclusion criteria: readmission, left against medical advice, transferred to another healthcare facility, not been discharged. Hydroxychloroquine was dosed as 400 mg twice daily for 2 doses on day 1, followed by 200 mg twice daily on days 2-5. Azithromycin was dosed as 500 mg once daily on day 1 followed by 250 mg once daily for the next 4 days. The combination of hydroxychloroquine + azithromycin was reserved for selected patients with severe COVID-19 and with minimal cardiac risk factors.
Duration	4-10 days of hospitalization with a median follow up of 28.5 days
Outcome Measures	Primary outcome: In-hospital mortality.
Baseline Characteristics		HQC (n= 1,202)	AZM (n= 147)	HCQ + AZM (n=783)	Neither HCQ nor AZM (n= 409)	P-value
	Age, years	63.3 ± 17.3	63.2 ± 15.6	62.3 ± 15.9	68.1 ± 18.9	<0.001
	Women	568 (47.2%)	85 (57.8%)	380 (48.5%)	210 (51.3%)	0.072
	Black	724 (60.2%)	76 (51.7%)	424 (54.2%%)	187 (45.7%)	<0.001
	BMI, kg/m²	31.9 ± 8.6	31.4 ± 8.7	32.9 ± 8.4	28.8 ± 7.6	<0.001
	COPD	144 (12.0%)	24 (16.3%)	99 (12.6%)	58 (14.2%)	0.380
	Ever in ICU	243 (20.2%)	19 (12.9%)	290 (37.0%)	62 (15.2%)	<0.001
Results		HQC (n= 1,202)	AZM (n= 147)	HCQ + AZM (n=783)	Neither HCQ nor AZM (n= 409)	P-value
	Mortality	162 (13.5%)	33 (22.4%)	157 (20.1%)	108 (26.4%)	<0.001
	The overall main cause of mortality was respiratory failure (88%). No patient had documented torsades de pointes. In the multivariate Cox regression model of mortality using the group receiving neither hydroxychloroquine or azithromycin as the reference, treatment with hydroxychloroquine alone decreased the mortality hazard ratio by 66% (P<0.001), and hydroxychloroquine+azithromycin decreased the mortality hazard ratio by 71% (P<0.001).
Adverse Events	Not reported
Study Author Conclusions	This retrospective study found out that treatment with hydroxychloroquine alone and in combination with azithromycin was associated with a reduction in COVID-19 associated mortality.
InpharmD Researcher Critique	Limitations of this study include the retrospective, non-randomized, non-blinded study design, which may be subject to selection bias. There did not appear to be a standardized protocol of which patients received these agents, except for severe patients who received both study drugs. The no-treatment group is also significantly older than the treatment groups, meaning they may be more at risk for adverse outcomes.

References:

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;S1201-9712(20)30534-8. doi:10.1016/j.ijid.2020.06.099

Outcomes of 3,737 COVID-19 patients treated with hydroxychloroquine/azithromycin and other regimens in Marseille, France: A retrospective analysis
Design	Retrospective analysis N = 3,737
Objective	To give a comprehensive analysis of early treatment with hydroxychloroquine (HCQ) in combination with azithromycin (AZ) in SARS-CoV-2 patients
Study Groups	HCQ-AZ ≥ 3 days (n=3,119) HCQ-AZ < 3 days (n=218) HCQ (n=101) AZ (n=137) No HCQ nor AZ (n=162)
Methods	Inclusion criteria: SARS-CoV-2 PCR positive test positive Exclusion criteria: age < 18 years Treatment consisted of the combination of HCQ 200 mg three times daily for 10 days and AZ 500 mg on day one followed by 250 mg daily for the next four days.
Duration	March 3^rd to April 27^th 2020
Outcome Measures	Primary outcomes: death, transfer to intensive care unit (ICU), hospitalization stay ≥ 10 days, viral shedding persistence
Baseline Characteristics		HCQ-AZ ≥ 3 days (n=3,119)	HCQ-AZ < 3 days (n=101)		HCQ (n=101)		AZ (n=137)		No HCQ nor AZ (n=162)
	Age, years 18 to 44 45 to 54 55 to 64 65 to 74 > 74	1649 (52.8%) 671 (21.5%) 503 (16.1%) 183 (5.9%) 113 (3.6%	76 (34.9%) 50 (22.9%) 38 (17.4%) 21 (9.6%) 33 (15.1%)		46 (45.5%) 29 (28.7%) 17 (16.8%) 4 (4%) 5 (4.9%)		24 (17.5%) 22 (16.1%) 25 (18.2%) 20 (14.6%) 46 (33.6%)		79 (48.8%) 32 (19.7%) 23 (14.2%) 13 (8%) 15 (9.3%)
	Men	1416 (45.4%)	105 (48.2%)		47 (46.5%)		64 (46.7%)		72 (44.4%)
	Chronic conditions
	Chronic heart diseases	125 (4%)	23 (10.5%)		7 (6.9%)		46 (33.6%)		18 (11.1%)
	Chronic respiratory diseases	267 (8.6%)	21 (9.6%)		9 (8.9%)		25 (18.2%)		16 (9.9%)
	Obesity	345 (11.1%)	25 (11.5%)		5 (4.9%)		28 (20.4%)		15 (9.3%)
	NEWS score 0 to 4	2925 (93.8%)	165 (75.7%)		94 (93.1%)		91 (66.4%)		145 (89.5%)
	NEWS=national early warning score; HCQ=hydroxychloroquine; AZ=azithromycin;
Results		HCQ-AZ ≥ 3 days (n=3,119)	HCQ-AZ < 3 days (n=101)	P-value	HCQ (n=101)	P-value	AZ (n=137)	P-value	No HCQ nor AZ (n=162)	P-value
	Death	16 (0.5%)	8 (3.7%)	<0.001	2 (2%)	0.1077	5 (3.6%)	0.0014	4 (2.5%)	0.0149
	ICU	25 (0.8%)	31 (14.2%)	<0.001	2 (2%)	0.2069	8 (5.8%)	<0.001	1 (0.6%)	1
	Death and/or ICU	35 (1.1%)	37 (17%)	<0.001	3 (3%)	0.1149	13 (9.5%)	<0.001	5 (3.1%)	0.0449
	Hospitalization ≥ 10 days	109 (3.5%)	41 (18.8%)	<0.001	6 (5.9%)	0.1741	30 (21.9%)	<0.001	11 (6.8%)	0.0481
	Duration of hospitalization, days	7.3 ± 7.0	11.8 ± 9.8	<0.001	5.7 ± 4.0	0.5963	8.8 ± 7.1	0.0135	7.5 ± 6.9	0.9885
	Poor clinical outcomes (Death, ICU and/or hospitalization ≥ 10 days)	121 (3.9%)	51 (23.4%)	<0.001	8 (7.9%)	0.0625	37 (27%)	<0.001	13 (8%)	0.0218
	HCQ=hydroxychloroquine;AZ=azithromycin;IQR=inter-quartile range;ICU=intensive care unit
Adverse Events	Common Adverse Events: diarrhea (54), nausea and vomiting (26), abdominal pain (24), prolonged QTc > 60 milliseconds (20)
Adverse Events	Percentage that Discontinued due to Adverse Events: 35 (mostly due to gastrointestinal symptoms)
Study Author Conclusions	Patients under HCQ-AZ treatment for at least three days had a better clinical outcome, based on mortality rates among patients > 60 years, less transfer to ICU and shorter length of stay at the hospital, and these patients also had a shorter duration of viral shedding than patients who did not receive this drug combination.
InpharmD Researcher Critique	Most patients with a good clinical outcome are grouped with young age and centered on HCQ-AZ treatment. The patients with a poor clinical outcome are all grouped with older age, which means the study may have a high level of selection bias.

References:

Lagier JC, Million M, Gautret P, et al. Outcomes of 3,737 COVID-19 patients treated with hydroxychloroquine/azithromycin and other regimens in Marseille, France: A retrospective analysis. Travel Med Infect Dis. 2020;:101791

Treatment Response to Hydroxychloroquine and Antibiotics for mild to moderate COVID-19: a retrospective cohort study from South Korea
Design	Retrospective, cohort study N=226
Objective	To assess the efficacy of hydroxychloroquine (HCQ) on mild-moderate COVID-19 patients in South Korea
Study Groups	Hydroxychloroquine and antibiotics (n=31) conservative treatment (n=195)
Methods	Inclusion criteria: patients who received at least three days of HQ treatment or any duration of standard therapy Exclusion criteria: patients who didn't adhere to treatment protocols, patients with severe symptoms, patients referred from another hospital, patients switched treatments from HQ to other treatments Patients were given HQ 200 mg twice daily with azithromycin 500 mg once daily for up to 5 days (most of them for 3 days) or with cefixime 100 mg twice daily. Participants were propensity score-matched 1:1 to balance baseline characteristics.
Duration	February 2020 to April 2020
Outcome Measures	Primary outcome: duration of viral clearance, length of hospital stay and symptom duration
Baseline Characteristics		Total			Propensity score matching
		Standard (n=195)	HQ (n=31)	P-value	Standard (n=20)	HQ (n=20)	P-value
	Age, years	35.26 ± 14.22	43.48 ± 15.50	0.003	38.65 ± 14.88	38.50 ± 16.45	0.976
	Female	117 (60.0%)	26 (83.9%)	0.01	19 (95.0%)	16 (80.0%)	0.342
	Fever ≥ 37.5 ºC	24 (12.3%)	9 (29.0%)	0.025	5 (25.0%)	4 (20.0%)	1.0
	Duration of treatment delay Diagnosis to HQ, days Diagnosis to admission, days	0 4.51 ± 4.35	6.19 ± 4.01 2.35 ± 1.52	<0.001 <0.001	0 4.10 ± 4.41	6.70 ± 3.92 2.60 ± 1.64	<0.001 0.162
	Labotory values WBCs, 10⁹/L Lymphocytes, K/mm³ Albumin, g/dL	6.05 ± 1.56 2.03 ± 0.52 4.36 ± 0.28	5.28 ± 1.52 1.73 ± 0.56 4.07 ± 0.32	0.012 0.003 <0.001	5.42 ± 1.0 1.85 ± 0.46 4.15 ± 0.19	5.73 ± 1.49 1.87 ± 0.59 4.14 ± 0.33	0.436 0.946 0.968
	HQ=hydroxychloroquine; WBCs=white blood cells
Results		Total			Propensity score matching
		Standard (n=195)	HQ (n=31)	P-value	Standard (n=20)	HQ (n=20)	P-value
	Mortality	0	0	1.00	0	0	1.00
	Viral clearance duration, days	18.82 ± 6.52	22.68 ± 5.42	0.002	21.35 ± 4.69	23.45 ± 5.68	0.211
	Hospital stay, days	15.43 ± 6.24	21.52 ± 5.34	<0.001	19.45 ± 4.43	22.10 ± 5.51	0.0102
	Symptom resolution, days	11.45 ± 9.67	18.00 ± 8.29	<0.001	18.95 ± 6.69	14.55 ± 8.08	0.07
	A multivariable Cox regression analysis showed that time to viral clearance (Hazard ratio [HR 0.97; 95% confidence interval [CI] 0.57-1.67]) and symptom duration (HR 1.05; 95% CI 0.62-1.78) were not different between groups.
Adverse Events	Common Adverse Events: aspartate aminotransferase(AST)/alanine transaminase(ALT) elevation (5% vs 15%), nausea/vomiting (0 vs 5%), diarrhea (0 vs 5%)
Adverse Events	No severe adverse event or death was observed in either group.
Study Author Conclusions	Hydroxychloroquine with antibiotics was not associated with better clinical outcomes in terms of time to viral clearance, length of hospital stay, and duration of symptoms compared to conservative treatment alone.
InpharmD Researcher Critique	Limitations of this study include the retrospective, observational nature. Some patients also received azithromycin and/or cefixime for management of pneumonia and/or bacterial co-infection. Propensity score matching was used so that the differences in baseline and confounding were minimized.

References:

An MH, Kim MS, Park Y, et al. Treatment Response to Hydroxychloroquine and Antibiotics for mild to moderate COVID-19: a retrospective cohort study from South Korea. medRxiv 2020.07.04.20146548

Observational Study of Hydroxychloroquine in Hospitalized Patients with Covid-19
Design	Nonrandomized, prospective, observational trial N=1,376
Objective	To examine the association between hydroxychloroquine (HCQ) use and respiratory failure
Study Groups	HCQ (n=811) No HCQ (n=565)
Methods	Inclusion criteria: adults with positive SARS-CoV-2 test results from March 7 - April 8 Exclusion criteria: transfer to another facility, intubation, or death within 24 hours of admission to the ED Eligible patients who had a resting oxygen saturation of less than 94% while breathing ambient air were considered to have moderate-to-severe respiratory illness and recommended to received HCQ. Patients who received treatment were monitored and compared to those who did not receive HCQ. Propensity score matching was used to minimize confounding in a secondary analysis.
Duration	Median duration of treatment: 5 days Follow up continued through April 25, 2020
Outcome Measures	Primary outcome: intubation or death
Baseline Characteristics		HCQ (n=811)	No HCQ (n=565)
	Age, years < 40 40-59 60-79 ≥ 80	90 (9.9%) 217 (26.8%) 367 (45.3%) 147 (18.1%)	105 (18.6%) 142 (25.1%) 220 (28.9%) 98 (17.3%)
	Women	337 (41.6%)	258 (45.7%)
	Race White Black Hispanic Other Missing data	74 (9.1%) 89 (11%) 412 (50.8%) 48 (5.9%) 188 (23.2%)	57 (10.1%) 92 (16.3%) 286 (50.6%) 36 (6.4%) 94 (16.6%)
	Current smoking	89 (11%)	68 (12%)
	Past diagnosis Chronic lung disease Diabetes Hypertension Cancer Chronic kidney disease Transplant/HIV/immune-suppressive medications	146 (18 %) 301 (37.1 %) 398 (49.1%) 109 (13.4%) 133 (16.4%) 40 (4.9%)	105 (18.6%) 190 (33.6%) 38 (6.7%) 67 (11.9%) 105 (18.6%) 18 (3.2%)
	HIV = human immunodeficiency virus
Results		HCQ (n=811)	No HCQ (n=565)
	Intubation or Death	262 (32.3%)	84 (14.9%)
	Crude analysis - hazard ratio (95% CI): 2.37 (1.84-3.02) Multivariable analysis - hazard ratio (95% CI): 1.00 (0.76-1.32) Propensity-score analysis - hazard ratio (95% CI): With inverse probability weighting: 1.04 (0.73 - 1.31) With Matching: 0.98 (0.73-1.32) Adjusted for propensity score: 0.97 (0.74-1.28)
Adverse Events	Not disclosed
Study Author Conclusions	Hydroxychloroquine administration was not associated with either a greatly lowered or an increased risk of the composite endpoint of intubation or death.
InpharmD Researcher Critique	Strengths of this analysis include adjustments for confounding variables via propensity-score matching; however, none of the HCQ groups were excluded during matching. Limitations of this analysis include the nonrandomized, single-center design with a large Hispanic population.

References:

Geleris J, Sun Y, Platt J, et al. Observational Study of Hydroxychloroquine in Hospitalized Patients with Covid-19. N Engl J Med. 2020;[E-pub ahead of print].

A Randomized Trial of Hydroxychloroquine as Postexposure Prophylaxis for Covid-19
Design	Randomized, double-blind, placebo-controlled trial N = 821
Objective	To assess the hypothesis that hydroxychloroquine could potentially be used as postexposure prophylaxis, to prevent symptomatic infection after exposure to Covid-19
Study Groups	Hydroxychloroquine (n=414) Placebo (n=407)
Methods	Inclusion criteria: participants who had household or occupational exposure to a person with confirmed Covid-19 at a distance of less than 6 ft for more than 10 minutes while wearing neither a face mask nor an eye shield (high-risk exposure) or while wearing a face mask but no eye shield (moderate-risk exposure) Exclusion criteria: younger than 18 years of age, were hospitalized, with symptoms of Covid-19 or with PCR-proven SARS-CoV-2 infection Participants were randomly assigned in a 1:1 ratio to receive either hydroxychloroquine or placebo. Participants in the hydroxychloroquine group received hydroxychloroquine 800 mg (4 tablets) once, then 600 mg (3 tablets) 6 to 8 hours later, then 600 mg (3 tablets) daily for 4 more days for a total course of 5 days (19 tablets total). If participants had gastrointestinal upset, they were advised to divide the daily dose into two or three doses.
Duration	Treatment: 5 days Follow-up: 14 days
Outcome Measures	Primary outcome: symptomatic illness confirmed by a positive molecular assay or, if testing was unavailable, COVID-19-related symptoms Secondary outcome: incidence of hospitalization for Covid-19, Covid-19 symptoms, death, adverse events
Baseline Characteristics		Hydroxychloroquine (n=414)	Placebo (n=407)
	Age, years (IQR)	41 (33–51)	40 (32–50)
	Women	218 (52.7%)	206 (50.6%)
	Weight, kg (IQR)	75 (64–86)	76 (64–91)
	Current smoker	15 (3.6%)	12 (2.9%)
	Health care worker	275 (66.4%)	270 (66.3%)
	High-risk exposure	65 (88.2%)	354 (87.0%)
	No PPE worn	258 (62.3%)	237 (58.2%)
	Time from exposure to enrollment 1 day 2 days 3 days 4 days	77 (18.6%) 100 (24.2%) 98 (23.7%) 138 (33.4%)	63 (15.5%) 106 (26.0%) 117 (28.7%) 121 (29.7%)
	Coexisting conditions None Hypertension Asthma Diabetes	306 (73.9%) 51 (12.3%) 31 (7.5%) 12 (2.9%)	290 (71.3%) 48 (11.8%) 31 (7.6%) 16 (3.9%)
Results		Hydroxychloroquine (n=414)	Placebo (n=407)	P-value
	Confirmed or probable Covid-19 Laboratory-confirmed diagnosis Symptoms compatible with Covid-19	49 (11.8%) 11 (2.7%) 48 (11.6%)	58 (14.3%) 9 (2.2%) 55 (13.5%)	0.35 0.82 0.46
	All new symptoms	57 (13.8%)	59 (14.5%)	0.84
	Any hospitalization	1 (0.2%)	1 (0.2%)	0.99
	Death	0	0	---
	Any side effects	40/349 (40.1%)	59/351 (16.8%)	<0.001
Adverse Events	Common Adverse Events: nausea/upset stomach (22.9% vs 7.7%), diarrhea/abdominal discomfort/vomiting (23.2% vs 4.3%), irritability/dizziness/vertigo (5.4% vs 3.7%)
Adverse Events	Percentage that Discontinued due to Adverse Events: 17 participants in the hydroxychloroquine group and 8 in the placebo group
Study Author Conclusions	This randomized trial did not demonstrate a significant benefit of hydroxychloroquine as postexposure prophylaxis for Covid-19. After high-risk or moderate-risk exposure to Covid-19, hydroxychloroquine did not prevent illness compatible with Covid-19 or confirmed infection when used as postexposure prophylaxis within 4 days after exposure. In order to end the pandemic, a reduction in community transmission is needed.
InpharmD Researcher Critique	A limitation of this study is the lack of availability of diagnostic testing in the United States, so an a priori symptomatic case definition was used as well as confirmed testing. Patients were of relatively similar risk stratification, but the actual risk of transmission may have been different depending on their individual environments.

References:

Boulware DR, Pullen MF, Bangdiwala AS, et al. A Randomized Trial of Hydroxychloroquine as Postexposure Prophylaxis for Covid-19. N Engl J Med. 2020;[E-pub ahead of print].