A preliminary study from Gautret from France showed that the combination of hydroxychloroquine and azithromycin lead to a significant reduction of SARS-CoV-2 viral load in a small number of COVID-19 patients.
A study from Tongji Hospital, Shanghai Institute of Materia Medica, and Shanghai Institute of Advanced Histochemical Studies in China published a new study showing that hydroxychloroquine is associated with decreased mortality in critically ill patients with COVID-19.[1]
The retrospective, non-randomized study was published in medRxiv and is not yet peer-reviewed.
In the study, 48 patients who received hydroxychloroquine (HCQ) 200 mg twice a day for 7 to 10 days were compared with 520 patients who did not receive the (NHCQ).
Both HCQ and NHCQ groups received comparable antivirals. They were Lopinavir and Ritonavir, Entecavir hydrate, or Ribavirin.
The HCQ group is comprised of 48 patients who received HCQ in addition to the antivirals.
Three Significant Result
A. Lower Mortality Rates in HCQ group
Nine (18.8%) out of 48 HCQ patients died compared to 238/520 (45.8%) in the NHCQ group showing a statistically significant difference.
B. Longer Admission to Death Stay in HCQ group
There was no statistical difference in the total length of hospital stays among the two groups. HCQ at 32 and NHCQ at 30 days.
The hospital length of stay from admission until death is significantly longer in the HCQ group at 15 days compared to the NHCQ at 8.
The authors interpreted the more prolonged admission until the death stay of the HCQ group as a result of milder disease progression even though the patients eventually died.
Below are the Mortality and Hospital stay time before death results.
From: Hydroxychloroquine decreases COVID-19 mortality p 17
C. Lower Levels of IL- 6 Among the HCQ group
Interleukin-6 or IL-6 is an inflammatory cytokine. In severe COVID-19 infections, elevated IL-6 is associated with poor prognosis.
Before HCQ administration in the HCQ group, the IL-6 levels were 22.2. During the HCQ, the IL-6 was 5.2.
In the NHCQ group, the IL-6 levels remained elevated from 21.3 to 20.2.
Interestingly, while the IL-6 in the HCQ group remained low during the therapy, it went up again to the pre-therapy level after the HCQ was stopped. See the figure below.
The authors conclude:
Hydroxychloroquine treatment is significantly associated with a decreased mortality in critically ill patients with COVID-19 through attenuation of inflammatory cytokine storm.
Therefore, hydroxychloroquine should be prescribed for treatment of critically ill
COVID-19 patients to save lives.
This study mentioned above is a retrospective study wherein they reviewed what already happened. The ideal investigation for a new drug application is a randomized, prospective study. Prospective studies look forward.
HCQ works by interfering with the SARS-CoV-2 entry and replication into the host cells. It also accumulates in the lymphocytes and the macrophages and results in anti-inflammatory properties. HCQ reduces the secretion of proinflammatory cytokines like the tumor necrosis factor – α (TNFα).[2]
SARS-CoV-2 could infect and kill the lymphocytes.[3] The destruction of lymphocytes can explain the lymphopenia or low levels of lymphocytes, usually seen in COVID-19. The different types of lymphocytes, like the T cells, B cells, and natural killer cells, are all essential in the innate and adaptive immunity to eradicate infections.
The accumulation of HCQ inside the lymphocytes may give it protection against the SARS-CoV-2 and thus preserve their immune fighting abilities.[3]. Unfortunately, the HCQ study did not show the levels of lymphocytes between the two groups.
Proinflammatory cytokines like the TNFα and IL6 are essential in an immune response. But if excessive, a cytokine storm can happen, and ARDS and multi-organ damage can occur. Acute Respiratory Distress Syndrome (ARDS) is the number one cause of death in COVID-19.
HCQ decreases the production of TNFα and IL-6. Decreasing both attenuates the immune response in several autoimmune diseases like Rheumatoid Arthritis and SLE.
The National Institute of Health in its Therapeutic Options for COVID-19 Currently Under Investigation website list HCQ as a recommendation AIII. Here is what they say.
There are insufficient clinical data to recommend either for or against using chloroquine or hydroxychloroquine for the treatment of COVID-19 (AIII).
- If chloroquine or hydroxychloroquine is used, clinicians should monitor the patient for adverse effects, especially prolonged QTc interval (AIII).
Except in the context of a clinical trial, the COVID-19 Treatment Guidelines Panel (the Panel) recommends against the use of the following drugs for the treatment of COVID-19:
- The combination of hydroxychloroquine plus azithromycin (AIII) because of the potential for toxicities.
AIII means A: Strong recommendation for the statement, III: Expert opinion. The highest recommendation is AI.
The main reasons why HCQ is not AI are lack of prospective trials (many are ongoing) and the danger of prolonged QT interval.
What is Prolonged QT Interval?
The prolonged QT interval is a lengthening of the distance from the Q wave to the T wave on an EKG.
QT interval can get longer with drugs like HCQ. QT prolongation could cause a dangerous if not fatal arrhythmia called Torsade de Pointes (TdP). It was discovered in France and translates as ‘twisting of peaks” because of the different patterns of each beat.
What’s the Risk of Getting a Prolonged QT interval with HCQ?
A retrospective study from New York University Langone and San Paolo Hospital in Italy was released on May 1, 2020. It is another non-peer reviewed article. The study is about QT prolongation and TdP in COVID-19 patients treated with HCQ and Azithromycin (AZ).
In 251 patients, HCQ was given at a dose of 400 mg twice daily on the first day, followed by 200 mg twice daily. AZ was given at a dose of 500 mg per day. Both were given for five days.
Extreme prolongation of the QTc to >500 ms developed in 15.9% of the patients.
7 (2.78%) patients had to stop the HCQ/AZ prematurely because of the development of prolonged QT. 1 (0.4%) patient developed TdP that needed cardioversion or an electrical shock to reverse.
The good thing is the QT prolongation shortened after stopping the HCQ/AZ combination. Hospitalized patients taking HCQ and AZI who develop TdP can be managed with cardioversion or intravenous magnesium.
To recap the study, the HCQ/AZ combination can lead to prolonged QT in 2.78% and life-threatening TdP in 0.4% of COVID-19 patients.
Going into the topic of risks, if we look at death rates, here is the tabulated case fatality rates (death rates) of COVID-19 among the different age group in the US.
The table shows that the death rate of COVID-19 patients 45 years and above are higher than the TdP risk of 0.4%
In a China CDC study of 72 thousand patients, the case fatality rates of COVID-19 patients with comorbidities are as follows —
- 10.5% for those with cardiovascular disease
- 7.3% for diabetes
- 6.3% for chronic respiratory disease
- 6.0% for hypertension and
- 5.6% for cancer.
Even though the risk of Torsade de Pointes is much lower than the risk of dying from COVID-19, the risk of TdP can still be lessened.
Can Prolonged QT and TdP Be Predicted?
In studies by Justo and Zeltser of non-cardiac drugs and antibiotics that can cause TdP, they concluded that the risk factors for the development of TdP could be identified.[7][8] These are:
- Female gender – have extended QT compared to men.
- Low serum potassium
- Advanced heart disease/heart failure – Advance heart disease downregulates potassium channels and upregulates calcium channels.
- Concomitant use of QT-interval prolonging agents or inhibitors of hepatic drug metabolism
- Amiodarone
- Digoxin
- Astemizole
- Quinidine
- Sotalol
- Disopyramide
- Cisapride
- Macrolides like azithromycin
- Quinolones
- Trimethoprim-sulfamethoxazole
- Metronidazole
- Terfenadine
- Fluconazole
- Amitriptyline
- Pentamidine
The study by Chorin et al. recommends daily EKG to monitor the QT of patients treated with HCQ/AZ.[5] It is standard practice in many hospitals to have a patient on a heart monitor if they are on medications that can cause an arrhythmia. Daily blood work can be done to monitor and correct any potassium or magnesium abnormalities.
Mayo Clinic Proceedings constructed a decision making tree when enrolling a patient for clinical trials using HCQ/AZ
The whole pdf of Urgent Guidance for Navigating and Circumventing the QTc-Prolonging and Torsadogenic Potential of Possible Pharmacotherapies for Coronavirus Disease
19 (COVID-19) by Mayo Clinic Proceedings is available for download.
Other links about drug interactions with HCQ and AZ to lower TdP risk are available at:
If the risk of TdP is absolutely unacceptable, is there an alternative to HCQ/AZ? Yes. Remdesivir has been approved. But is remdesivir better?
How Does HCQ compare with Remdesivir?
Remdesivir has obtained the US Food and Drug Administration Emergency Use Authorization for the treatment of COVID-19. In the news about the Remdesivir study, STAT NEWS reports, (highlights are mine)
The preliminary data showed that the time to recovery was 11 days on remdesivir compared to 15 days for placebo, a 31% decrease. The mortality rate for the remdesivir group was 8%, compared to 11.6% for the placebo group; that mortality difference was not statistically significant.
The benefit that Remdesivir provides is a 31% shorter duration of illness, but the mortality rate is not lower compared to the ones who did not take the remdesivir.
Looking back at the first study on this article about HCQ, there was a statistically significant difference in mortality compared to the NHCQ group.[1]
This article is for information only. Do not take hydroxychloroquine or azithromycin without a prescription or guidance from a physician. The HCQ study is non-peer reviewed and should not be used as a guide for treatment or policy decisions.
I have no conflicts of interest to declare.
Knowledge about Covid-19 is rapidly evolving. Information may update as new researches are done. Stay current by subscribing.
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References:
- Effects of chloroquine on viral infections: an old drug against today’s diseases. Savarino, A., Boelaert, J.R., Cassone, A., Majori, G., and Cauda, R., 2003. The Lancet infectious diseases, 3(11), pp.722-727.
- SARS-CoV-2 infects T lymphocytes through its spike protein-mediated membrane fusion. Wang, X., Xu, W., Hu, G. et al. Cell Mol Immunol (2020). https://doi.org/10.1038/s41423-020-0424-9
- Selective regulation of cytokine secretion by hydroxychloroquine: inhibition of interleukin 1 alpha (IL-1-alpha) and IL-6 in human monocytes and T cells. Sperber K, Quraishi H, Kalb TH, Panja A, Stecher V, Mayer L. J Rheumatol. 1993. May;20(5):803-8.
- QT Interval Prolongation and Torsade De Pointes in Patients with COVID-19 treated with Hydroxychloroquine/Azithromycin. Chorin et al. m
- Severe Outcomes Among Patients with Coronavirus Disease 2019 (COVID-19) — United States, February 12–March 16, 2020. MMWR Morb Mortal Wkly Rep. ePub: 18 March 2020. DOI: http://dx.doi.org/10.15585/mmwr.mm6912e2external icon.
- Torsade de pointes due to noncardiac drugs: most patients have easily identifiable risk factors. Zeltser D, Justo D, Halkin A, Prokhorov V, Heller K, and Viskin S.Medicine. 2003;82:282-90.
- Torsades de pointes induced by antibiotics. Justo D, Zeltser D. Eur J Intern
Med. 2006; 17: 254–259.
- QT interval By PeaBrainC – Own work, CC BY-SA 4.0, https://commons.wikimedia.org/w/index.php?curid=74185800
- Torsade de Pointes By Jer5150 – Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=19738256
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