Use of hydroxychloroquine for pre-exposure prophylaxis in COVID 19: debate and suggested future course

Agarwal, Mudit; Ranjan, Piyush; Mittal, Ankit; Baitha, Upendra

doi:10.1080/14787210.2021.1828062

Cited by 11 publications

(12 citation statements)

References 18 publications

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“…Interestingly, hydroxychloroquine was reported to increase expression of CXCL10 and IFIT3 in human lung carcinoma cells and mouse macrophages (Wang et al, 2015), the opposite of the desired effect proposed from our computational findings. This finding is surprising since other compound affect expression of some of our gene candidates in a manner consistent with our computational findings, and the efficacy of hydroxychloroquine in treating COVID-19 is debated (Agarwal et al, 2020; Badgujar et al, 2020; Meo et al, 2020; Rosenke et al, 2020). Further work is needed to assess the viability of these therapeutic options and interpret findings presented here for the advancement therapeutic options for SARS and other β-coronavirus infections.…”

Section: Discussionsupporting

confidence: 73%

Gene Expression Meta-Analysis Reveals Interferon-induced Genes

Park

Harris

2020

Preprint

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BackgroundSevere Acute Respiratory Syndrome (SARS) corona virus (SARS-CoV) infections are a serious public health threat because of their pandemic-causing potential. This work uses mRNA expression data to predict genes associated with SARS-CoV infection through an innovative meta-analysis examining gene signatures (i.e., gene lists ranked by differential gene expression between SARS and mock infection).MethodsThis work defines 29 gene signatures representing SARS infection across seven strains with established mutations that vary virulence (infectious clone SARS (icSARS), Urbani, MA15, ΔORF6, BAT-SRBD, ΔNSP16, and ExoNI) and host (human lung cultures and/or mouse lung samples) and examines them through Gene Set Enrichment Analysis (GSEA). To do this, first positive and negative icSARS gene panels were defined from GSEA-identified leading-edge genes between 500 genes from positive or negative tails of the GSE47960-derived icSARSvsmock signature and the GSE47961-derived icSARSvsmock signature, both from human cultures. GSEA then was used to assess enrichment and identify leading-edge icSARS panel genes in the other 27 signatures. Genes associated with SARS-CoV infection are predicted by examining membership in GSEA-identified leading-edges across signatures.ResultsSignificant enrichment (GSEA p<0.001) was observed between GSE47960-derived and GSE47961-derived signatures, and those leading-edges defined the positive (233 genes) and negative (114 genes) icSARS panels. Non-random (null distribution p<0.001) significant enrichment (p<0.001) was observed between icSARS panels and all verification icSARSvsmock signatures derived from human cultures, from which 51 over- and 22 under-expressed genes were shared across leading-edges with 10 over-expressed genes already being associated with icSARS infection. For the icSARSvsmock mouse signature, significant, non-random enrichment (both p<0.001) held for only the positive icSARS panel, from which nine genes were shared with icSARS infection in human cultures. Considering other SARS strains, significant (p<0.01), non-random (p<0.002) enrichment was observed across signatures derived from other SARS strains for the positive icSARS panel. Five positive icSARS panel genes, CXCL10, OAS3, OASL, IFIT3, and XAF1, were found in mice and human signatures.ConclusionThe GSEA-based meta-analysis approach used here identified genes with and without reported associations with SARS-CoV infections, highlighting this approach’s predictability and usefulness in identifying genes that have potential as therapeutic targets to preclude or overcome SARS infections.

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Section: Discussionsupporting

confidence: 73%

Gene Expression Meta-Analysis Reveals Interferon-induced Genes

Park

Harris

2020

Preprint

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“…The prophylactic use of hydroxychloroquine was associated with some protection level (p=0.059), which was not statistically significant. With its in-vitro effectivity against SARS-CoV-2 and good lung concentration, hydroxychloroquine is a drug candidate selected to be used as prophylaxis against COVID-19 [ 13 - 15 ]. But the actual protection level is still unknown, and it is to be established by larger studies.…”

Section: Discussionmentioning

confidence: 99%

Association Between Self-Reported Adherence to Preventive Practices and Probability of Turning COVID-19 Positive: A Cross-Sectional Analytical Study

Ranjan¹,

Bhattacharya²,

Chakrawarty³

et al. 2020

Cureus

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Background Preventive practices are the mainstay to mitigate the spread of the COVID-19 pandemic. We tried to assess the self-reported adherence of our participants to the already known preventive practices. Furthermore, we tried to determine whether the non-compliance to specific preventive practices was associated with the acquisition of the infection or not. Methods We enrolled 379 healthcare workers, hospital staff, and their family members who were tested for COVID-19 by reverse transcription-polymerase chain reaction (RT-PCR) in an outpatient clinic. Socio-demography and the infection prevention practices of the individuals were recorded in a preformed questionnaire. Statistical analysis was performed to find out the statistical association between these factors and the RT-PCR results. Adjusted and unadjusted odds ratios were determined to find out the degree of protection provided by each of the preventive practices concerning the development of the disease. Results Social distancing (p<0.001), hand hygiene (p<0.001), ensuring N-95 mask fit check (p<0.001), and the use of alternative medications (p=0.002) were found to be protective. Resident doctors were at a lower risk of developing the disease as compared to the other healthcare workers (odds ratio: 0.39). Conclusion The failure to practice the already known preventive practices is probably one of the most important factors in the progression of the COVID-19 pandemic. Adherence to these practices is the intervention of choice to reduce disease transmission in the current scenario.

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“…None developed COVID-19, and acceptability was good, although this apparent protective benefit cannot be confirmed due to lack of a control group and use of facemask by the index case (Lee et al, 2020). Several randomized trials evaluating HCQ prophylaxis in HCW are currently ongoing (Agarwal et al, 2020), with the results of a few of them now available ( Table 1). The first trial, published in June, investigated HCQ as postexposure prophylaxis in adult HCW with high/moderate-risk exposure to a confirmed case of COVID-19.…”

Section: Critical Analysis Of the Clinical Evidencementioning

confidence: 99%

“…Many such patients are elderly and may have pre-existing cardiovascular disease. COVID-19 leads to viral myocardial injury in 7-23% patients (Pirzada et al, 2020); further patients are commonly treated with concomitant QT C -prolonging drugs like azithromycin; this increases the risk of cardiotoxic events (Agarwal et al, 2020;Padilla et al, 2020). Indeed, observational studies have reported that HCQ for treatment of COVID-19 leads to critical QT C prolongation (a marker for risk of Torsades de pointes) in 20-36% cases, frequently requiring drug discontinuation to avoid fatal arrhythmias (Bessière et al, 2020;Chorin et al, 2020;Mercuro et al, 2020).…”

Section: The Conundrum Of Dosing For Hydroxychloroquine Prophylaxismentioning

confidence: 99%

“…Reference ID: 4610984, 2020). It must be noted that most of these observations are from HCQ used as a therapy for COVID-19, but they may have implications for chemoprophylaxis as well owing to the doubtful efficacy and long half-life of HCQ (Agarwal et al, 2020). Therefore, it becomes important to balance risk with possible benefit.…”

Section: The Conundrum Of Dosing For Hydroxychloroquine Prophylaxismentioning

confidence: 99%

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Hydroxychloroquine as a Chemoprophylactic Agent for COVID-19: A Clinico-Pharmacological Review

et al. 2020

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Hydroxychloroquine has gained much attention as one of the candidate drugs that can be repurposed as a prophylactic agent against SARS-CoV-2, the agent responsible for the COVID-19 pandemic. Due to high transmissibility and presence of asymptomatic carriers and presymptomatic transmission, there is need for a chemoprophylactic agent to protect the high-risk population. In this review, we dissect the currently available evidence on hydroxychloroquine prophylaxis from a clinical and pharmacological point of view. In vitro studies on Vero cells show that hydroxychloroquine effectively inhibits SARS-CoV-2 by affecting viral entry and viral transport via endolysosomes. However, this efficacy has failed to replicate in in vivo animal models as well as in most clinical observational studies and clinical trials assessing pre-exposure prophylaxis and postexposure prophylaxis in healthcare workers. An analysis of the pharmacology of HCQ in COVID-19 reveals certain possible reasons for this failure—a pharmacokinetic failure due to failure to achieve adequate drug concentration at the target site and attenuation of its inhibitory effect due to the presence of TMPRSS2 in airway epithelial cells. Currently, many clinical trials on HCQ prophylaxis in HCW are ongoing; these factors should be taken into account. Using higher doses of HCQ for prophylaxis is likely to be associated with increased safety concerns; thus, it may be worthwhile to focus on other possible interventions.

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Use of hydroxychloroquine for pre-exposure prophylaxis in COVID 19: debate and suggested future course

Cited by 11 publications

References 18 publications

Gene Expression Meta-Analysis Reveals Interferon-induced Genes

Gene Expression Meta-Analysis Reveals Interferon-induced Genes

Association Between Self-Reported Adherence to Preventive Practices and Probability of Turning COVID-19 Positive: A Cross-Sectional Analytical Study

Hydroxychloroquine as a Chemoprophylactic Agent for COVID-19: A Clinico-Pharmacological Review

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