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Explaining the Research on Covid-19

Hydroxychloroquine

A List of Hydroxychloroquine Studies

Overview: Some studies show that hydroxychloroquine (HCQ) works and other studies that it does not work. Meta-analyses and studies using HCQ with other medications, esp. Zinc or Ivermectin, show, overall, that HCQ has a degree of effectiveness against Covid-19, including for treatment and for prophylaxis. However, it is not the ideal medication. It does not reduce the mortality rate to near zero; it does not keep patients out of the hospital or ICU and off of ventilation. So it does work, but it is not the solution that we all seek. On the other hand, ivermectin may be closer to the ideal treatment.

Note that the Indian Council of Medical Research in New Delhi, India, has recommended hydroxychloroquine for prophylaxis against Covid-19. PDF file is here.

Summary of Hydroxychloroquine studies and their outcomes. The review shows that early treatment with HCQ works much better than later treatment.

The Studies

* Prodromos August 20, 2020

Conclusion: “HCQ/azithromycin were uniformly found to substantially reduce cardiac mortality and also to decrease thrombosis, arrhythmia and cholesterol in treated patients in recent peer reviewed studies and meeting presentations.”

Prodromos, Chadwick C. “Hydroxychloroquine Is Protective To The Heart, Not Harmful: A Systematic Review.” Study Link

* Hong et al. July 16, 2020

Peer-reviewed study in Infection and Chemotherapy

“We observed and analyzed the clinical efficacy of the most used hydroxychloroquine (HCQ) for 30 days. In this study, administration of HCQ <5 days from diagnosis (odds ratio: 0.111, 95% confidence interval: 0.034 – 0.367, P = 0.001) was the only protective factor for prolonging of viral shedding in COVID-19 patients. Early administration of HCQ significantly ameliorates inflammatory cytokine secretion by eradicating COVID-19, at discharge. Our findings suggest that patients confirmed of COVID-19 infection should be administrated HCQ as soon as possible."

Hong, Kyung Soo, et al. “Early Hydroxychloroquine Administration for Rapid Severe Acute Respiratory Syndrome Coronavirus 2 Eradication.” Infection & Chemotherapy 52 (2020).

* Monforte, July 29, 2020
Assessment of hydroxychloroquine: positive
Assessment of hydroxychloroquine and azithromycin: positive

A: hydroxychloroquine alone
B: with azithromycin
C: antiviral medications as controls

“The percent of death in the 3 groups was 27%, 23% and 51%. Mechanical ventilation was used in 4.3% of hydoxychloroquine, 14.2% of hydroxycholoroquine + azithromycin and 26.1% of controls.”

Reduction in rate of death for “the use of hydroxycholoroquine + azithromycin was” 66%.

Monforte, Antonella d’Arminio, et al. “Effectiveness of Hydroxychloroquine in COVID-19 disease: A done and dusted situation?.” International Journal of Infectious Diseases (2020).
PDF file of Study

* Sirijatuphat, July 29, 2020

100% of patients treated with hydroxychloroquine or chloroquine, as part of a multi-drug therapy were discharged alive.

25.2% of patients in this study had pneumonia, the rest did not; all survived
“Combination antiviral therapies for COVID-19 patients were well-tolerated and produced a favorable outcome.”

Therapies used:
2-drug antiviral therapy: lopinavir/ritonavir or darunavir/ritonavir plus chloroquine or
hydroxychloroquine
3-drug antiviral therapy: lopinavir/ritonavir or darunavir/ritonavir plus chloroquine or
hydroxychloroquine plus favipiravir

Note: ritonavir affects the liver, allowing lopinavir to remain in the patient’s system longer; that’s why lopinavir/ritonavir is considered one drug.

The researchers state: “Even though the risk of QT prolongation from hydroxychloroquine was increased in previous study (particularly when being used concurrently with azithromycin), we did not find any serious cardiac events in our patients, which may be due to younger age, milder disease, and less comorbidity compared with previous study”

Sirijatuphat, Rujipas, et al. “Epidemiology, Clinical Characteristics, And Treatment Outcomes Of Patients With COVID-19 At Siriraj Hospital–Thailand’s Largest University-Based Super-Tertiary Referral Center.” (2020).
PDF file of study

* Arshad, July 01, 2020
Assessment of hydroxychloroquine: positive (lowest mortality rate)
Assessment of hydroxychloroquine with azithromycin: negative (higher mortality rate)

Multi-center retrospective observational study.
Hospitalized Covid-19 patients
March 10, 2020 to May 2, 2020
4 Arms: HCQ alone; HCQ with AZT, AZT alone, or neither.
The primary outcome was in-hospital mortality.

Results by mortality rate:
13.5% for HCQ alone
20.1% for HCQ with AZT
22.4% for AZT alone
26.4% for neither

“Hydroxychloroquine was dosed as 400 mg twice daily for 2 doses on day 1, followed by 200 mg twice daily on days 2–5.”

Arshad, Samia, et al. “Treatment with hydroxychloroquine, azithromycin, and combination in patients hospitalized with COVID-19.” International Journal of Infectious Diseases (2020).
A Link to the Full Study

* Lopez, August 8, 2020

Assessment: HCQ was not effective in critically ill patients in a hospital intensive care unit.

Studies were more likely to be effective in use of HCQ when administered as prophylactic or early in course of disease; use with zinc and/or ivermectin also incraease likelihood that a study will find a positive result.

Lopez, Alexandre, et al. “Effects of Hydroxychloroquine on Covid-19 in Intensive Care Unit Patients: Preliminary Results.” International Journal of Antimicrobial Agents (2020): 106136.
Study Link

* Kadnur, July 22, 2020
Assessment of hydroxychloroquine as prophylactic: positive
Assessment of hydroxychloroquine for safety: positive
Use of HCQ for prophylaxis reduced risk of Covid-19 infection by 87%. Results were statistically significant.

The Lancet, manuscript draft
Non-randomized, prospective study
Two arms, taking HCQ and not taking HCQ
Study participants did not have Covid-19 at recruitment
Study is testing HCQ for Pre-exposure Prophylaxis

Location: New Delhi, India
Participants: 334 Healthcare Workers at risk for contracting Covid-19.
Primary outcome was incidence of adverse effects.
Secondary outcome was efficacy in preventing COVID-19.

Dosage: 800 mg loading dose, followed by 400 mg weekly.

Results: 4.4% of participants discontinued use of HCQ due to side effects. No heart abnormalities found.
“In the group taking HCQ, 2(0·8%) tested positive compared to 5(5·8%) in the group not taking HCQ (p=0·013). Odds ratio with HCQ intake was 0·13(95% CI 0·02-0·85, p=0·03) and the number needed to treat was 26.”

Conclusion: “HCQ is safe at the recommended dose for pre-exposure prophylaxis of COVID-19. HCQ chemo-prophylaxis may decrease COVID-19 incidence.”

Kadnur, Harshith B., et al. “Hydroxychloroquine Pre-Exposure Prophylaxis for COVID-19 Among Healthcare Workers: Initial Experience from India.” (2020).
Link to the Full Study

* Bernaola, July 21, 2020
Assessment of hydroxychloroquine as treatment: positive
Assessment of prednisone as treatment: positive
Patients treated with hydroxychloroquine were 17% more likely to have a better outcome, and patients treated with prednisone were 15% more likely to have a better outcome, than patients treated with antivirals or antibiotics.

medRxiv, not peer reviewed
Observational study, comparative, no control
Sixteen treatments in four groups (steroids, antivirals, antibiotics and immunomodulators)

Location: Madrid, Spain
1,645 patients at hospitals in Madrid, admitted for Covid-19.
Outcomes: 16% of patients died; 18.9% of patients either died or required intubation.

Conclusion: “After propensity matching we found an association between treatment with hydroxychloroquine and prednisone and better outcomes (hazard ratios with 95% CI of 0.83 ± 0.06 and 0.85 ± 0.03). Results were similar in multiple sensitivity analyses”

Bernaola, Nikolas, et al. “Observational Study of the Efficiency of Treatments in Patients Hospitalized with Covid-19 in Madrid.” medRxiv (2020).
PDF file of the Full Study

* Carlucci, May 08, 2020
Assessment of hydroxychloroquine and azithromycin with zinc as treatment: positive
Patients given triple therapy were 55.1% less likely to die or be sent to a hospice, and 53% more likely to be discharged home. Overall mortality rate was 13.2%, which is better than the typical hospital mortality rate of 22%.

Retrospective Observational Study
Location: 4 hospitals in New York City
932 patients treated for Covid-19, divided into two groups.
March 2, 2020 through April 5, 2020
Hydroxychloroquine and Azithromycin with Zinc versus Hydroxychloroquine and Azithromycin without Zinc.

Dosages: hydroxychloroquine (400 mg load followed by 200 mg twice daily for five days) and azithromycin (500 mg once daily) alone or with zinc sulfate (220 mg capsule containing 50 mg elemental zinc twice daily for five days).

The triple therapy (hydroxychloroquine, azithromycin, zinc) was very effective for a certain subset of patients, those hospitalized with Covid-19 but not requiring ICU admission. This group of patients was 53% more likely to be discharged home and 55.1% less likely to either die or be sent to a hospice (to die). The results for the reduction in mortality were highly statistically significant (p-value=0.002).

In the group of patients not needing ICU care, patients given the triple therapy had a mortality rate of 6.9%, compared to 13.2% for the double therapy (no zinc). This improvement in the mortality rate was called “striking” by the researchers.

When we compare the overall mortality rate for triple therapy patients, 13.1% (including ICU and non-ICU patients), this is considerably better than the typical mortality rate in many hospitals of about 22 to 24%. So this study does not depend solely on a comparison between hydroxychloroquine and hydroxychloroquine.

A mortality rate of 22% for hospitalized Covid-19 patients was found in a German study of 10,021 patients. And a rate of 24% was cited by Dr. Paul Mark in this interview with Dr. Mobeen Syed.

Carlucci, Philip, et al. “Hydroxychloroquine and azithromycin plus zinc vs hydroxychloroquine and azithromycin alone: outcomes in hospitalized COVID-19 patients.” medRxiv (2020).
Link to the Study at medRxiv

* Cavalcanti, July 23, 2020
Assessment of hydroxychloroquine: negative
Assessment of hydroxychloroquine with azithromycin: negative

Study Summary:
NEJM, peer-reviewed
Multicenter, randomized, open-label, three-group, controlled trial
Mild to Moderate Covid-19 in 504 patients
Location: 55 hospitals in Brazil
a) Standard Care (discretion of physician)
b) Hydroxychloroquine 400 mg BID
c) Hydroxychloroquine 400 mg BID and Azithromycin 500 mg OD

Deaths: less than 1% of total population; HCQ+AZ 0 deaths; HCQ 1 death 0.6%; Control 1 death, 0.6%.

Conclusion: “Among patients hospitalized with mild-to-moderate Covid-19, the use of hydroxychloroquine, alone or with azithromycin, did not improve clinical status at 15 days as compared with standard care.”

Notes: No zinc. Dosage of hydroxychloroquine was high at 800 mg/day.

Cavalcanti, Alexandre B., et al. “Hydroxychloroquine with or without Azithromycin in Mild-to-Moderate Covid-19.” New England Journal of Medicine (2020).
Link to the Study at NEJM

* Satlin, July 23, 2020
Assessment of hydroxychloroquine: negative
Assessment of hydroxychloroquine with azithromycin: negative

PLOS ONE, peer-reviewed
Retrospective cohort study of hospitalized patients; no control.
Mild to moderate Covid-19 in 141 patients.
Location: 2 NYC hospitals
a) Hydroxychloroquine loading dose, then 400 mg/day.
b) 18% also received Azithromycin; 16% also Doxycycline; 31% Ceftriaxone.

“We found that HCQ was reasonably safe and well-tolerated. Nearly 90% of patients were able to complete their HCQ course and the majority of discontinuations were not related to an adverse event.”

“However, nearly one-half of patients did not improve with this treatment….”
“Co-administration of azithromycin was not associated with improved outcomes.”

No control group.
Half improved; one quarter worsened or died; so even if HCQ works, it does not work well enough.
Death Rate: 31% for those on MV; 18% on supplemental O2; 8% on neither died.
No zinc.

Notes: Groups receiving different antibiotics not separated in the results.

Satlin, Michael J., et al. “Safety, tolerability, and clinical outcomes of hydroxychloroquine for hospitalized patients with coronavirus 2019 disease.” PloS one 15.7 (2020): e0236778.
Link to the Full Study

* Scholz, Derwand, Zelenko, July 3, 2020
Assessment of hydroxychloroquine: positive

A lower rate of hospitalization and a lower rate of death was found with use of HCQ plus zinc.

Retrospective Case Series Study
141 COVID-19 patients, most not hospitalized
Control group is not randomized; no detailed information on controls
Triple 5-day therapy: zinc, low dose HCQ, and azithromycin
Location: New York State

Treatment: zinc sulfate (220 mg capsule once daily, containing 50 mg elemental zinc), HCQ (200 mg twice daily), and azithromycin (500 mg once daily). No loading dose was used.

Study group had a 2.8% hospitalization rate and a 0.7% mortality rate. (We don’t know what treatments were given after hospitalization.)

The comparison group had a 15.4% hospitalization rate and a 3.5% mortality rate.

Scholz, Martin, Roland Derwand, and Vladimir Zelenko. “COVID-19 outpatients–early risk-stratified treatment with zinc plus low dose hydroxychloroquine and azithromycin: a retrospective case series study.” (2020).
A link to the Study at Preprints.org

* Singh and Singh, June 14, 2020

This study found that zinc deficiency was negatively correlated with Covid-19 cases and deaths, meaning that have a zinc deficiency was somehow better. This finding contradicts the physiology of zinc, which should strengthen the immune system. However, it is known that iron deficiency can be beneficial in reducing risk of certain types of infection, such as malaria.

The study did not consider the effectiveness of zinc paired with a zinc ionophore. So the zinc may be helpful to the virus, in making the cells healthier, and therefore better able to spread the virus when the cell is infected.

Singh, Samer, and Rakesh K. Singh. “Assessing The Role Of Zinc In Covid-19 Infections And Mortality: Is Zinc Deficiency A Risk Factor For Covid-19?.” medRxiv (2020).
PDF file of the Full Study

* Ghazy, July 2020

Systematic Review and Meta-Analysis

Negative results:
The duration of hospital stay was 43% shorter in the standard care in comparison with HCQ group.
Side effects were more reported in the HCQ group than the standard care (RR=3.14, 95% CI 1.58- 6.24).
Mortality among the HCQ+AZM was more significantly higher than among the standard care (RR= 1.8, 95% CI 1.19-2.27).

Positive results:
Radiological improvement or clinical worsening was the same for standard care and HCQ.
Need for mechanical ventilation (MV) was not different between standard care and HCQ.
Mortality among HCQ was not affected by receiving HCQ.
The duration of hospital stay among the HCQ and AZM didn’t differ significantly from the standard care.

Giving Azithromycin with Hydroxychloroquine provided for a hospital stay length the same as standard care. The main negative for hydroxychloroquine with or without azithromycin was the increase in side effects. Otherwise, hydroxychloroquine with azithromycin did as well as standard care. So it cannot be said that hydroxychloroquine does not work; it works as well as standard care, especially on the most important outcomes, and the hospital stay length is also the same as standard care, if azithromycin is added. However, adding azithromycin increased risk of mortality.

Conclusion: Azithromycin should not be added to Hydroxychloroquine as a treatment, due to increased risk of mortality. Hydroxychloroquine is a useful medication, especially in nations where more expensive medications are in short supply. It is nearly as good as standard care in developed nations, with the same mortality and risk of MV.

Ghazy, Ramy Mohamed, et al. “Effectiveness and Safety of Chloroquine or Hydroxychloroquine as a mono-therapy or in combination with Azithromycin in the treatment of COVID-19 patients: Systematic Review and Meta-Analysis.”
A Link to the Full Study

* Yang, May 14, 2020

Conclusion: “The use of HCQ with or without AZI for treatment of COVID-19 patients, seems to be effective. The combination of HCQ and AZI has shown synergistic effects. However, mortality rate was increased when the treatment was conducted with HCQ.”

Systematic Review
Five trials involving 677 patients were included in the meta-analysis.

Yang, Tzu-Han, et al. “Systematic Review and Meta-analysis of the Effectiveness and Safety of Hydroxychloroquine in COVID-19.” medRxiv (2020).
A Link to the Study at medRxiv

* Axfors, June 23, 2020

Meta-analysis of mortality data from published and unpublished RCTs.
This study is on-going.

Axforsa, Cathrine, et al. “Hydroxychloroquine and chloroquine for survival in COVID-19: an international collaborative meta-analysis of randomized trials.”
Link to the Study

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More Studies on Hydroxychloroquine will be added soon.

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In Vitro Studies of Hydroxychloroquine:

Liu, Jia, et al. “Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro.” Cell discovery 6.1 (2020): 1-4.
Link to the Study at nature.com

Yao, Xueting, et al. “In vitro antiviral activity and projection of optimized dosing design of hydroxychloroquine for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).” Clinical Infectious Diseases (2020).
PDF file of the Study