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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]

References:

[1] Food and Drug Administration. Coronavirus (COVID-19) Update: FDA Revokes Emergency Use Authorization for Chloroquine and Hydroxychloroquine. https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-revokes-emergency-use-authorization-chloroquine-and. Published June 15, 2020. Accessed July 7, 2020.
[2] National Institutes of Health. NIH halts clinical trial of hydroxychloroquine. https://www.nih.gov/news-events/news-releases/nih-halts-clinical-trial-hydroxychloroquine. Published June 20, 2020. Accessed on July 7, 2020.
[3] World Health Organization. “Solidarity” clinical trial for COVID-19 treatments. https://www.who.int/emergencies/diseases/novel-coronavirus-2019/global-research-on-novel-coronavirus-2019-ncov/solidarity-clinical-trial-for-covid-19-treatments. Published July 6, 2020. Accessed on July 7, 2020.

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 3rd to April 27th 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%) 

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)

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

 

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%)

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%)

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].