The coronavirus disease COVID-19, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a pandemic on a massive scale, with more than 3.66 million cases and over 257,000 deaths.
Chloroquine (CQ) has shown itself to be effective in vitro with inhibiting the replication of SARS-CoV-2.
After a pilot study (Huang et al.Journal of Molecular Cell Biology, in press), having proved the safety and effectiveness of the drug to reduce the viral RNA to undetectable levels in 10 COVID-19 patients, the researchers began this current study, published on the preprint server medRxiv.
The mechanism of CQ against the SARS-CoV-2 is not entirely clear. Still, it may involve the inhibition of viral entry into the cell via suppression of endosomal acidification, thus stopping clathrin-mediated endocytosis. It also suppresses autophagy by increasing the pH of the lysosome, inhibiting the fusion of the autophagosome with this cell organelle. CQ also has a favorable effect on lipid and sugar metabolism.
How was the study done?
The study was a multicenter prospective in 197 adult COVID-19 patients, with 176 patients as historical controls. The median age was 43 years and 47.5 years, respectively. Most patients had moderate illness.
Due to the later addition of the drug into the Diagnosis and Treatment Guidelines for COVID-19 in China, it was generally begun much later after the onset of symptoms than other therapies – an absolute difference of 4 days. In Wuhan, the interval was even longer, at a median of 17 days, compared to a median of 5 days for Guangdong province.
What were the results?
The study found that patients given CQ cleared viral RNA faster than the controls (absolute difference in median time, -5.4 days). At the time points day 10 and day 14, viral RNA had become undetectable in 91% and 96% of CQ patients, respectively, compared to 57% and 80% in the non-CQ group.
Concerning the clinical features, fever lasted for a shorter time in the CQ group, though this may have been because of the known antipyretic activity of CQ as well.
There were no deaths among the CQ patients or controls, but 1 and 9 patients in the CQ and non-CQ groups developed symptoms of severe illness.
The chloroquine effect was further classified by dosage, clinical features, province of origin, and the related period from symptom onset to treatment. The study found beneficial features of CQ in all categories. Statistically, a significant benefit was not perceived in severe illness patients in Guangdong province with a symptom onset-treatment initiation duration of over 14 days, and patients from the Fifth Affiliated Hospital of Sun-Yat Sen University (SYSU5).
Reinfection or relapse?
The investigators also examined detailed clinical data on the improvement of chest CT scanning, serum CQ levels, and reappearance of viral RNA on testing after discharge, in one subgroup of patients from the Fifth Affiliated 142 Hospital of Sun Yat-sen University (SYSU5). There were few significant differences between the CQ and non-CQ groups. However, there were three patients with positive viral RNA tests in fecal samples (though not in respiratory samples) after discharge. These patients are being evaluated to rule out reinfection and identify other causes.
A head-to-head comparison between CQ and non-CQ patients in Guangdong province was performed with a subgroup of 29 patients in which 500 mg CQ was used once a day – half of the standard dosage. Here too, the median time to undetectable viral RNA was reduced by five days, and 33% more of patients had undetectable viral RNA by day 10 in the CQ group.
Safety analysis showed that gastrointestinal and neurological adverse effects were higher in the CQ group but were fewer in the subgroup, which was treated with a lower dose.
Serious adverse effects were rare, an encouraging sign. Cardiovascular complications were not seen in this small trial. The small dose had a lower rate of adverse events compared to the full dosing protocol.
The long half-life of CQ, at 20-60 days, could mean it has the potential to accumulate in the body. To assess the cumulative effect of short-term CQ accumulation, the serum concentration was measured in one subgroup, both during and after treatment. The mean serum concentration rose slowly until it reached a high of 1.80 (±0.49) μmol/L during the period of treatment, and then declined to 0.13 (±0.08) μmol/L within 28 days of stopping the drug.
What does the study show?
The researchers comment on the findings: “These findings indicate that chloroquine could be effective in treating patients with COVID-19.” However, the limitations of the present study include the emergency situation under which treatment was initiated, which made a randomized controlled study design impossible; the difference in the clinical experience with treating the virus infection at the two periods (CQ being significantly later than non-CQ); and the more extended period of illness before CQ was initiated which means the patients might already have been on the mend. Attenuation of the virus could also be a factor.
Compared to the results of other studies evaluating the safety and clinical efficacy of CQ or hydroxychloroquine (HCQ), the current study included younger and generally more healthy patients. This mandates prospective randomized trials to validate the present results.
The investigators recommend further investigation of the prophylactic and therapeutic potential of CQ in randomized controlled trials, to determine the right dose, the benefit of the drug in severe illness, and in other situations than in advanced medical facilities. This will tell if CQ has something to offer in managing this pandemic illness.
medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.