#EMConf: Journal club
Our monthly journal club featured a topic that it on many of the headlines right now claiming Hydroxychloroquine is a miracle drug that could possibly cure coronavirus.
What are the facts? Hydroxychloroquine has shown to limit the ability of SARs-COV2 virus to enter cells in a laboratory study, however, this is not the same as testing the use of this drug in people COVID-19+. Although the researchers suggest that this drug has a potential to combat the disease, confirmation is still needed with clinical trials, and, as the CDC states, “There are no currently available data from Randomized Clinical Trials (RCTs) to inform clinical guidance on the use, dosing, or duration of hydroxychloroquine for prophylaxis or treatment of SARS-CoV-2 infection.”
A compelling study from a group in February reporting drugs Remdesivir and Chloroquine (CQ) were shown to inhibit viral yield of this novel SARs-COV2 virus in vitro.1 They suggested that since CQ was found to be effective in controlling COVID in vitro and has a more well studied track record for use then it should be assessed in human patients with novel coronavirus. CQ is known treatment for malaria and Hydroxychloroquine (HCQ), CQ analog, is a treatment for anti-inflammatory conditions such as lupus and rheumatoid arthritis. These drugs also show antiviral potential by increasing endosomal pH required for virus/cell fusion, as well as interfering with the glycosylation of cellular receptors of SARS-CoV (aka they stop the virus from getting into the cell). This group published a second study in Nature that showed that HCQ is more potent and less toxic than CQ.2
There is inconsistent data on the use of these drugs in COVID-19 patients. A recent multicenter clinical trial conducted in China showed CQ phosphate had a significant effect on clinical outcome and viral clearance compared to controls in “more than 100” patients with COVID-19 pneumonia.3 It was based on this small trial that Chinese public health expert started making recommendations on use of HCQ in COVID-19+ patients. The first RCT from Shanghai Public Health Clinical Center in China looking at HCQ in 30 treatment-naive and COVID-19 + patients showed no differences in seroconversion rate of the virus and in either group. Additionally, CT scans showed little difference in progression of disease for those taking HCQ vs standard of care.
Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial by Gautret P, Lagier JC, Parola P, et al.
This was a small non-blinded, non-randomized study performed in France to determine if Hydroxychloroquine (600mg daily) with Azithromycin (added only if clinically indicated) decreased viral load in patients diagnosed with COVID-19 compared to controls who did not get either of these medications.
There were no clinical outcomes reported, only viral load.
In order to obtain an 85% power (85% probability of detecting a true effect), a Type 1 error rate of 5% (5% probability of detecting an effect that occurred by chance alone), the study predicted they would need 24 patients in both the treatment arm and control arm (48 patients total).
Unfortunately, the study did not obtain these numbers.
Hospitalized patients who were COVID-19 positive by nasopharyngeal swab were enrolled in the study if they did not meet exclusion criteria (<12 years old, allergy to study drug, retinopathy, G6PD deficiency, QT prolongation, pregnant, or breastfeeding).
Those who refused enrollment or met exclusion criteria were placed in the control arm.
Of note, using patients who meet exclusion criteria as controls is frowned upon, if they are excluded from the treatment arm, they should be excluded from the study altogether. This method of choosing controls likely caused selection bias.
26 patients were initially enrolled in the treatment arm, however 6 were ultimately excluded from analysis, leaving only 20 patients in the treatment arm who were analyzed, and only 16 were enrolled in the control arm. (Both groups had fewer patients than deemed necessary to reach appropriate power and Type 1 error rate noted above.)
Baseline demographics were notable for a significant age difference in the two groups: the control group being 13 years younger than the treatment group on average.
Of the 6 excluded patients in the treatment arm, 3 went to the ICU and one died. Excluding these 4 patients who became sicker likely significantly biased their results. No patients in the control group were excluded (presumably because none went to the ICU or died).
Of the 20 patients in the Hydroxychloroquine arm included in the final analysis, 6 of them also received Azithromycin (500mg day 1 followed by 250mg per day for 4 days), who were suspected of having a bacterial superinfection (this was not random).
The study swabbed patients in both arms daily for COVID-19 viral load for 14 days, however curiously only reported results of the first 6 days.
Within these first 6 days, it appears that Hydroxychloroquine treatment was associated with a higher proportion of patients who had a negative PCR compared to placebo by day 6, and even higher proportion of negative PCR among patients who were treated with both Hydroxychloroquine and Azithromycin. See breakdown below.
Percentage of patients with negative nasopharyngeal PCR on Day 6:
12.5% of control group (16 patients)
57.1% of Hydroxychloroquine only group (14 patients)
100% of Hydroxychloroquine + Azithromycin group (6 patients)
Keep in mind:
These are extremely small numbers, almost anecdotal.
The researchers excluded 6 patients from the treatment group (6 out of 26, or 23% excluded. This is a large percentage.) 3 of these excluded patients went to the ICU and one died! Had they kept these 6 patients in the analysis, results would have likely been changed significantly.
Results were only reported for the first 6 days despite the fact that the study protocol was to swab patients for 14 days. There is likely missing information.
The study notes that one of the patients in the Hydroxychloroquine + Azithromycin group who tested negative on day 6 then tested positive again on day 8.
No clinical outcomes were reported - nearly 17% of the patients were asymptomatic during enrollment.
A low viral load does not imply the patient was less sick and a high viral load does not mean that the patient had severe symptoms. Again, no clinical results were reported, so it is impossible to draw clinical conclusions from viral loads, although most readers do assume a low viral load is preferable.
This very small, underpowered study with numerous flaws as highlighted above is now the basis for which many hospitals across the country and the world are now adding Hydroxychloroquine and Azithromycin to their COVID-19 patients' treatment regimens, including Cooper.
Unfortunately, many hospitals are using these treatments in ICU patients, which were altogether excluded from this study, thus we have no data on how these medications alter course of illness in critically ill patients.
The author mentioned that he plans to publish clinical outcomes in a separate paper, and we are anxiously awaiting these results!
There is a rush to find a cure or treatment for this disease that is continuing to cause thousands of deaths per day and disrupt daily life. Because of this, it appears that this has become a desperate situation and may lead to use of non-objective non-clinically driven data. Our journal club panel (and it was a general consensus amongst faculty present) recommend waiting for higher quality evidence from RCTs is warranted before making treatment protocols with these therapies.
Gautret P, Lagier JC, Parola P, et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. Int J Antimicrob Agents. 2020 Mar 20:105949. doi: 10.1016/j.ijantimicag.2020.105949.
- Wang M, Cao R, Zhang L, et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res 2020;10-0282.
- Yao X, Ye F, Zhang M, 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). Clin Infect Dis. 2020 Mar 9. pii: ciaa237. doi: 10.1093/cid/ciaa237.
- Zhonghua Jie He He Hu Xi Za Zhi. Multicenter collaboration group of Department of Science and Technology of Guangdong Province and Health Commission of Guangdong Province for chloroquine in the treatment of novel coronavirus pneumonia. Expert consensus on chloroquine phosphate for treatment of novel coronavirus pneumonia. 2020 Mar 12;43(3):185-188.
- A pilot study of hydroxychloroquine in treatment of patients with common coronavirus disease-19 (COVID-19). Journal of Zhejiang University (Medical Sciences). 2020;49.