**2. Review of pharmacotherapy**

## **2.1 Chloroquine/hydroxychloroquine**

The first studied drugs for COVID-19 were chloroquine and hydroxychloroquine (HCQ ). Chloroquine was found to be effective against Avian influenza A H5N1 virus in animal models [3, 4] and also had demonstrable activity resulting in in-vitro inhibition of SARS-CoV [5]. COVID-19 infection showed high pandemicity in countries where malaria is the least prevalent and least pandemicity where malaria is highly prevalent. This observation led to the concept that chloroquine may be beneficial in COVID-19 since it is used as an anti-malarial. The mechanism of chloroquine action depends on the pathogen involved. Chloroquine increases the endosomal pH and interferes with the glycosylation of cellular receptor [Angiotensin Converting Enzyme (ACE) II] of SARS-CoV [6]. It also inhibits quinone reductase-2, which is involved in sialic acid biosynthesis. There is inhibition of MAO-kinase, virion assembly, and processing of M protein [7]. Besides its antiviral activity, it also has immunomodulatory effects that may be synergistic. HCQ was found to be equally

effective as chloroquine, although a study concluded that HCQ was more effective and less toxic than chloroquine [8]. Chloroquine inhibitory actions against SARS-CoV were equal whether the primate cells were treated before or after exposure. This suggested that chloroquine could have both prophylactic and therapeutic applications [9]. One of the first studies performed to study the effect of chloroquine was done in the Chinese population. In this trial, patients in the study group who received chloroquine had reduced symptom duration, radiological improvement, and earlier seroconversion to the virus-negative state compared to controls [10]. Following this study, the National Health Commission of the People's Republic of China included chloroquine in its guideline for the management of pneumonia due to Covid-19. In a study conducted by Gautret et al. in France, chloroquine treatment group had significant clearing of the nasopharyngeal swab viral load compared to the control [11]. The virological clearance day-6 post inclusion (primary outcome) with HCQ vs. controls was 70% vs. 12.5% (p < 0.001). The virological clearance at day 6 in HCQ plus azithromycin, HCQ and control arms were 100%, 57.1%, and 12.5% respectively (p = 0.001) thus suggesting synergistic action of azithromycin to HCQ. Gradually the side effect profile of HCQ, that is QTc prolongation with concomitant use of Azithromycin, lead the American Heart Association (AHA) to recommend withdrawal/withholding these drugs in patients with QTc ≥ 500 millisecond (either baseline or developing during treatment). On 28 March 2020, Food and Drug Administration (FDA) had issued Emergency Use Authorization (EUA) for Chloroquine/HCQ. However, the Centers for Disease Control and Prevention (CDC) on April 7 issued a statement stating no drugs or other therapeutic measures were approved by the US FDA to prevent or treat COVID-19. In April, the FDA issued a Drug Safety Communication cautioning against the use of HCQ or chloroquine for COVID-19 outside the hospital setting or a clinical trial due to the risk of heart rhythm problems. In June 2020, it was announced by World Health Organization (WHO) that the HCQ arm of the Solidarity Trial (Multi-national trial including remdesivir, HCQ, lopinavir/ritonavir, and lopinavir/ritonavir with interferon beta-1a) would be stopped [12]. This was keeping in view the lack of any mortality benefit of HCQ. Hence in June itself, FDA revoked the EUA of HCQ and chloroquine [13]. The pre-exposure prophylaxis benefit of HCQ needs further research.
