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      Hydroxychloroquine prophylaxis for high-risk COVID-19 contacts in India: a prudent approach

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          Abstract

          We read with interest the Correspondence from Sahaj Rathi and colleagues 1 on hydroxychloroquine prophylaxis for COVID-19 contacts in India. The authors see the decision by the Indian Council of Medical Research, under the Ministry of Health and Family Welfare, to recommend chemoprophylaxis with hydroxychloroquine in select groups of contacts at high risk as an abandonment of scientific reasoning in desperate times. We present our counterview on this issue. The safety concerns raised by Rathi and colleagues include haemolysis in individuals with glucose-6-phosphate dehydrogenase deficiency and QTc prolongation. The prevalence of glucose-6-phosphate dehydrogenase deficiency in India ranges from 0% to 10%, with heterogenous distribution and incomplete penetrance. 2 Haemolysis is not clinically significant when hydroxychloroquine is administered in usual therapeutic doses to individuals with WHO class II and III glucose-6-phosphate dehydrogenase deficiency, and the safety of hydroxychloroquine is well established with prolonged use. Furthermore, a routine electrocardiogram for QTc interval is not essential before hydroxychloroquine initiation in clinical practice and is not recommended in any guidelines. Decades of experience with this drug in autoimmune disorders is enough to allay these fears. Concerns have been raised regarding lack of data on efficacy of hydroxychloroquine against severe acute respiratory syndrome coronavirus 2. A paucity of data is expected in the first wave of a pandemic caused by a novel virus. Hydroxychloroquine has been shown to have in-vitro activity against the virus. Recently published human trials, 4 along with other unpublished data, 5 suggest that it could decrease the duration of viral shedding and symptoms if given early. A study from South Korea shows the efficacy of hydroxychloroquine for post-exposure prophylaxis. 6 Historically, many drugs used in the treatment of an infectious disease have also been used for prophylaxis. The pharmacokinetics of hydroxychloroquine, such as its long half-life and high lung concentration (500-times the blood concentration), are ideally suited for use as an agent for prophylaxis. 7 The criticisms made by Rathi and colleagues overlook the fact that prophylactic hydroxychloroquine would be targeted to individuals at high risk rather than the general population. Projection of adverse events to the population level causes unjustified alarm. The advisory from the Indian Council of Medical Research includes a section of key considerations that address all such concerns, which have been ignored by Rathi and colleagues. In addition, the argument that there will be a shortage of the drug is not tenable. Production has been ramped up and the Government of India is supplying hydroxychloroquine to more than 50 countries, which has received widespread appreciation. We are in the midst of a once-in-a-generation pandemic, given the scale of morbidity and mortality. The frontline health-care workers are at great risk of infection; in Italy, 20% of the responding health-care workers have been infected. 8 A wide variety of therapeutic interventions are being tried in COVID-19 patients, without any evidence but following a prudent approach. We believe that the hydroxychloroquine prophylaxis in selected groups of high-risk contacts is a prudent approach considering the risk–benefit analysis. Implemented as envisaged in the recommendation document from the Indian Council of Medical Research, evidence will be generated for future recommendations.

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          Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial

          Background Chloroquine and hydroxychloroquine have been found to be efficient on SARS-CoV-2, and reported to be efficient in Chinese COV-19 patients. We evaluate the role of hydroxychloroquine on respiratory viral loads. Patients and methods French Confirmed COVID-19 patients were included in a single arm protocol from early March to March 16th, to receive 600mg of hydroxychloroquine daily and their viral load in nasopharyngeal swabs was tested daily in a hospital setting. Depending on their clinical presentation, azithromycin was added to the treatment. Untreated patients from another center and cases refusing the protocol were included as negative controls. Presence and absence of virus at Day6-post inclusion was considered the end point. Results Six patients were asymptomatic, 22 had upper respiratory tract infection symptoms and eight had lower respiratory tract infection symptoms. Twenty cases were treated in this study and showed a significant reduction of the viral carriage at D6-post inclusion compared to controls, and much lower average carrying duration than reported of untreated patients in the literature. Azithromycin added to hydroxychloroquine was significantly more efficient for virus elimination. Conclusion Despite its small sample size our survey shows that hydroxychloroquine treatment is significantly associated with viral load reduction/disappearance in COVID-19 patients and its effect is reinforced by azithromycin.
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            Is Open Access

            Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro

            Dear Editor, The outbreak of coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2/2019-nCoV) poses a serious threat to global public health and local economies. As of March 3, 2020, over 80,000 cases have been confirmed in China, including 2946 deaths as well as over 10,566 confirmed cases in 72 other countries. Such huge numbers of infected and dead people call for an urgent demand of effective, available, and affordable drugs to control and diminish the epidemic. We have recently reported that two drugs, remdesivir (GS-5734) and chloroquine (CQ) phosphate, efficiently inhibited SARS-CoV-2 infection in vitro 1 . Remdesivir is a nucleoside analog prodrug developed by Gilead Sciences (USA). A recent case report showed that treatment with remdesivir improved the clinical condition of the first patient infected by SARS-CoV-2 in the United States 2 , and a phase III clinical trial of remdesivir against SARS-CoV-2 was launched in Wuhan on February 4, 2020. However, as an experimental drug, remdesivir is not expected to be largely available for treating a very large number of patients in a timely manner. Therefore, of the two potential drugs, CQ appears to be the drug of choice for large-scale use due to its availability, proven safety record, and a relatively low cost. In light of the preliminary clinical data, CQ has been added to the list of trial drugs in the Guidelines for the Diagnosis and Treatment of COVID-19 (sixth edition) published by National Health Commission of the People’s Republic of China. CQ (N4-(7-Chloro-4-quinolinyl)-N1,N1-diethyl-1,4-pentanediamine) has long been used to treat malaria and amebiasis. However, Plasmodium falciparum developed widespread resistance to it, and with the development of new antimalarials, it has become a choice for the prophylaxis of malaria. In addition, an overdose of CQ can cause acute poisoning and death 3 . In the past years, due to infrequent utilization of CQ in clinical practice, its production and market supply was greatly reduced, at least in China. Hydroxychloroquine (HCQ) sulfate, a derivative of CQ, was first synthesized in 1946 by introducing a hydroxyl group into CQ and was demonstrated to be much less (~40%) toxic than CQ in animals 4 . More importantly, HCQ is still widely available to treat autoimmune diseases, such as systemic lupus erythematosus and rheumatoid arthritis. Since CQ and HCQ share similar chemical structures and mechanisms of acting as a weak base and immunomodulator, it is easy to conjure up the idea that HCQ may be a potent candidate to treat infection by SARS-CoV-2. Actually, as of February 23, 2020, seven clinical trial registries were found in Chinese Clinical Trial Registry (http://www.chictr.org.cn) for using HCQ to treat COVID-19. Whether HCQ is as efficacious as CQ in treating SARS-CoV-2 infection still lacks the experimental evidence. To this end, we evaluated the antiviral effect of HCQ against SARS-CoV-2 infection in comparison to CQ in vitro. First, the cytotoxicity of HCQ and CQ in African green monkey kidney VeroE6 cells (ATCC-1586) was measured by standard CCK8 assay, and the result showed that the 50% cytotoxic concentration (CC50) values of CQ and HCQ were 273.20 and 249.50 μM, respectively, which are not significantly different from each other (Fig. 1a). To better compare the antiviral activity of CQ versus HCQ, the dose–response curves of the two compounds against SARS-CoV-2 were determined at four different multiplicities of infection (MOIs) by quantification of viral RNA copy numbers in the cell supernatant at 48 h post infection (p.i.). The data summarized in Fig. 1a and Supplementary Table S1 show that, at all MOIs (0.01, 0.02, 0.2, and 0.8), the 50% maximal effective concentration (EC50) for CQ (2.71, 3.81, 7.14, and 7.36 μM) was lower than that of HCQ (4.51, 4.06, 17.31, and 12.96 μM). The differences in EC50 values were statistically significant at an MOI of 0.01 (P   30 cells) was quantified and is shown in b. Representative confocal microscopic images of viral particles (red), EEA1+ EEs (green), or LAMP1+ ELs (green) in each group are displayed in c. The enlarged images in the boxes indicate a single vesicle-containing virion. The arrows indicated the abnormally enlarged vesicles. Bars, 5 μm. Statistical analysis was performed using a one-way analysis of variance (ANOVA) with GraphPad Prism (F = 102.8, df = 5,182, ***P   30 cells for each group). By contrast, in the presence of CQ or HCQ, significantly more virions (35.3% for CQ and 29.2% for HCQ; P   30 cells) (Fig. 1b, c). This suggested that both CQ and HCQ blocked the transport of SARS-CoV-2 from EEs to ELs, which appears to be a requirement to release the viral genome as in the case of SARS-CoV 7 . Interestingly, we found that CQ and HCQ treatment caused noticeable changes in the number and size/morphology of EEs and ELs (Fig. 1c). In the untreated cells, most EEs were much smaller than ELs (Fig. 1c). In CQ- and HCQ-treated cells, abnormally enlarged EE vesicles were observed (Fig. 1c, arrows in the upper panels), many of which are even larger than ELs in the untreated cells. This is in agreement with previous report that treatment with CQ induced the formation of expanded cytoplasmic vesicles 8 . Within the EE vesicles, virions (red) were localized around the membrane (green) of the vesicle. CQ treatment did not cause obvious changes in the number and size of ELs; however, the regular vesicle structure seemed to be disrupted, at least partially. By contrast, in HCQ-treated cells, the size and number of ELs increased significantly (Fig. 1c, arrows in the lower panels). Since acidification is crucial for endosome maturation and function, we surmise that endosome maturation might be blocked at intermediate stages of endocytosis, resulting in failure of further transport of virions to the ultimate releasing site. CQ was reported to elevate the pH of lysosome from about 4.5 to 6.5 at 100 μM 9 . To our knowledge, there is a lack of studies on the impact of HCQ on the morphology and pH values of endosomes/lysosomes. Our observations suggested that the mode of actions of CQ and HCQ appear to be distinct in certain aspects. It has been reported that oral absorption of CQ and HCQ in humans is very efficient. In animals, both drugs share similar tissue distribution patterns, with high concentrations in the liver, spleen, kidney, and lung reaching levels of 200–700 times higher than those in the plasma 10 . It was reported that safe dosage (6–6.5 mg/kg per day) of HCQ sulfate could generate serum levels of 1.4–1.5 μM in humans 11 . Therefore, with a safe dosage, HCQ concentration in the above tissues is likely to be achieved to inhibit SARS-CoV-2 infection. Clinical investigation found that high concentration of cytokines were detected in the plasma of critically ill patients infected with SARS-CoV-2, suggesting that cytokine storm was associated with disease severity 12 . Other than its direct antiviral activity, HCQ is a safe and successful anti-inflammatory agent that has been used extensively in autoimmune diseases and can significantly decrease the production of cytokines and, in particular, pro-inflammatory factors. Therefore, in COVID-19 patients, HCQ may also contribute to attenuating the inflammatory response. In conclusion, our results show that HCQ can efficiently inhibit SARS-CoV-2 infection in vitro. In combination with its anti-inflammatory function, we predict that the drug has a good potential to combat the disease. This possibility awaits confirmation by clinical trials. We need to point out, although HCQ is less toxic than CQ, prolonged and overdose usage can still cause poisoning. And the relatively low SI of HCQ requires careful designing and conducting of clinical trials to achieve efficient and safe control of the SARS-CoV-2 infection. Supplementary information Supplemental Materials
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              COVID-19: protecting health-care workers

              The Lancet (2020)
              Worldwide, as millions of people stay at home to minimise transmission of severe acute respiratory syndrome coronavirus 2, health-care workers prepare to do the exact opposite. They will go to clinics and hospitals, putting themselves at high risk from COVID-2019. Figures from China's National Health Commission show that more than 3300 health-care workers have been infected as of early March and, according to local media, by the end of February at least 22 had died. In Italy, 20% of responding health-care workers were infected, and some have died. Reports from medical staff describe physical and mental exhaustion, the torment of difficult triage decisions, and the pain of losing patients and colleagues, all in addition to the infection risk. As the pandemic accelerates, access to personal protective equipment (PPE) for health workers is a key concern. Medical staff are prioritised in many countries, but PPE shortages have been described in the most affected facilities. Some medical staff are waiting for equipment while already seeing patients who may be infected or are supplied with equipment that might not meet requirements. Alongside concerns for their personal safety, health-care workers are anxious about passing the infection to their families. Health-care workers who care for elderly parents or young children will be drastically affected by school closures, social distancing policies, and disruption in the availability of food and other essentials. Health-care systems globally could be operating at more than maximum capacity for many months. But health-care workers, unlike ventilators or wards, cannot be urgently manufactured or run at 100% occupancy for long periods. It is vital that governments see workers not simply as pawns to be deployed, but as human individuals. In the global response, the safety of health-care workers must be ensured. Adequate provision of PPE is just the first step; other practical measures must be considered, including cancelling non-essential events to prioritise resources; provision of food, rest, and family support; and psychological support. Presently, health-care workers are every country's most valuable resource. © 2020 Denis Lovrovic/AFP/Getty Images 2020 Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.
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                Author and article information

                Contributors
                Journal
                Lancet Infect Dis
                Lancet Infect Dis
                The Lancet. Infectious Diseases
                Elsevier Ltd.
                1473-3099
                1474-4457
                22 May 2020
                22 May 2020
                Affiliations
                [a ]Department of Medicine, All India Institute of Medical Sciences, New Delhi 110029, India
                Article
                S1473-3099(20)30430-8
                10.1016/S1473-3099(20)30430-8
                7255125
                32450054
                cb04ef01-4e25-4729-aadb-665e8e4343a2
                © 2020 Elsevier Ltd. All rights reserved.

                Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

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                Infectious disease & Microbiology
                Infectious disease & Microbiology

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