Correspondence Address:
Aditya Prasad Dash
Central University of Tamil Nadu, Tiruvarur, Tamil Nadu
India

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In India, as of April 30, 2020, >33,000 coronavirus disease-2019 (COVID-19) cases have been reported, and the death toll has exceeded 1000. Clinical data indicate that one out of six COVID-19 patients will develop respiratory distress and will need adequate medical care.[1] Acute respiratory failure is a common secondary outcome in severe cases of COVID-19, and despite mechanical ventilation, mortality rates of 40%–65% have been reported.[2] As of now, there is no clinically approved drug or vaccine, and the treatment is mostly supportive. Clinical trials are ongoing worldwide to test the efficacy of antiviral drugs and also hydroxychloroquine (HCQ), an antimalarial drug.[3]

Chloroquine (CQ) is a cheap and relatively safe antimalarial that has been used for decades in India and other malaria-endemic countries. Earlier studies have shown CQ to be highly effectivein vivo to treat avian influenza A (H5N1)[4] andin vitro against severe acute respiratory syndrome coronavirus (SARS-CoV).[5],[6] CQ raises the intracellular pH by sequestering the protons into lysosomes, which affects the fusion and uncoating of the virion, and viral replication.[4],[5],[6] In addition, it has been suggested that CQ can interfere with the terminal glycosylation process of the angiotensin-converting enzyme-2, the cellular receptor for entry of SARS-CoV.[6] CQ and HCQ share a similar chemical structure and action, but HCQ has lower toxicity.[7] HCQ has been shown to augment the early virological response against hepatitis C and also reduce the HIV-1 load.[8],[9] HCQ also has immunosuppressive properties that may help reduce the cytokine storm in severe COVID-19.[10],[11] Even though HCQ is relatively safe, in adverse conditions, it can lead to cardiac disorders such as QT segment prolongation, which could lead to arrhythmia and myocardial arrest.[12]

Recentin vitro studies have shown that both CQ and HCQ can inhibit the replication of SARS-CoV-2.[13],[14],[15] Based on these encouragingin vitro data, CQ was used in multicentric clinical trials involving 100 COVID-19 patients in China to test itsin vivo efficacy. The study concluded that CQ reduced the lung pathology and shortened the disease course without any serious adverse reactions.[16] Another Chinese study with 62 patients showed that HCQ reduced the time to clinical recovery[17] Furthermore, two studies conducted in France have suggested that HCQ, especially in combination with azithromycin (AZM), can reduce the viral load in COVID-19 patients.[18],[19] These encouraging preliminary studies should have guided the Indian Council of Medical Research (ICMR) to recommend HCQ for chemoprophylaxis of asymptomatic health workers treating suspected or confirmed COVID-19 cases and asymptomatic household contacts of confirmed patients.[20] For asymptomatic health workers, the recommended dose is 400 mg twice on day 1, followed by 400 mg once every week for 7 weeks, while for asymptomatic household contacts, the duration is 3 weeks and has to be prescribed by a registered medical practitioner.[20] However, there is no previous research to support the use of CQ and HCQ as prophylaxis to COVID-19. Recently, the US Food and Drug Administration has authorized HCQ for emergency use to treat COVID-19 pneumonia.[21]

It is pertinent to note that in the clinical studies conducted in China[16],[17] and France,[18],[19] critically ill COVID-19 patients were not included. The safety of HCQ is yet to be proven (metabolism and clearance) in severe COVID-19 patients with hepatic and renal dysfunction and are administered other medications.[22] The early clinical studies in France that supported the use of HCQ have been criticized by many researchers for its serious shortcomings.[22],[23] A small observational study (11 patients) treated with HCQ and AZM has shown the persistence of viral load and no clinical benefit.[24] A multinational, network cohort, and self-controlled case series study has found an increased risk of 30-day cardiovascular mortality when HCQ was used in combination with AZM but not alone.[25]

Overall, we do not have compelling evidence for and against HCQ's use to treat COVID-19, however, it is unsafe to use HCQ in combination with AZM.[25] We do not know if HCQ can prevent the progression from mild to severe COVID-19 or its role in severely ill patients. We need data from international multicenter, randomized, and open clinical trials such as discovery[26] and solidarity[27] to assess the efficacy of HCQ in the treatment of COVID-19. Given the gravity of the pandemic, and ICMR's experience of using HCQ for treating malaria, the rationale behind the recommendation of HCQ as chemoprophylaxis is understandable. Furthermore, ICMR guidelines prohibit HCQ's use in children <15 years and individuals with retinopathy and known hypersensitivity to HCQ and 4-aminoquinolines.[20] Importantly, by limiting HCQ's use to health workers and household contacts of confirmed patients, information on adverse events, if any, of HCQ can be collected efficiently to guide its future use. If not initiated already, the recommending authorities should conduct a clinical trial on the efficacy of HCQ for chemoprophylaxis of COVID-19 in India. HCQ chemoprophylaxis trials have already commenced in the US (NCT04318444) and Mexico (NCT04318015). The earliest estimated primary completion dates for the Mexico and US trials are December 2020 and March 2021, respectively. These trials may reveal negligible to no effect of HCQ in chemoprophylaxis of COVID-19. However, if the trials prove otherwise, waiting 9–12 months for initial evidence is not desirable, especially with HCQ's low cost and India's ability to manufacture. As of now, in India, self-medication of CQ and HCQ by the public without medical advice is a greater concern. To prevent unauthorized use, the availability of CQ and HCQ has to be tightly regulated.

Evidence from drug discovery efforts in the past strongly indicates that vast majority of the molecules cannot replicate theirin vitro efficacy in biological systems. Unlike antiviral drugs, HCQ has no direct effect on SARS-CoV-2. Its use against COVID-19, even as a prophylaxis, has to be continuously monitored, especially in individuals with preexisting heart conditions.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

References