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Gut Instinct Should Not Play a Part in Drug Repurposing

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For decades, hydroxychloroquine (HCQ) has been used for the treatment of many diseases, and when the pandemic began, early tests were conducted to establish whether it could also be used in the treatment of COVID-19. With a lack of compelling evidence, HCQ was advertised as an effective treatment for COVID-19.

Technology Networks spoke to Ahmad Besaratinia, PhD, professor of Research Population and Public Health Sciences, Keck School of Medicine of USC to find out more about drug repurposing and the dangers that come with using a drug without fully assessing its potential for harm.

Anna MacDonald (AM): You recently investigated the DNA damaging- and mutagenic effects of HCQ in mammalian cells. Why did you decide to conduct this study? Why is it important to consider the genotoxicity of a drug?

Ahmad Besaratinia
(AB): This study was launched during the early months of the pandemic when national and international efforts were mobilized to find a cure for COVID-19 as well as develop a vaccine against this disease. As part of these global efforts, many scientists began to conduct “drug re-purposing” research for COVID-19 – in which a drug with a good safety record and clinical efficacy is tested for treatment of other disease(s). One such drug was HCQ, which has been widely used for the treatment of a great variety of diseases, including malaria, rheumatoid arthritis, systemic lupus and other inflammatory disorders. The initial positive results from cell-culture studies with HCQ, which should have been considered preliminary and hypothesis-generating, not clinically actionable, led to premature and irresponsible promotion of this drug for COVID-19 treatment. Most disconcerting was the advocacy for HCQ by prominent political leaders and their allies who were touting the drug as a “magic cure” for COVID-19. Speaking on “gut instinct” instead of relying on compelling scientific evidence, politicians passionately advocated for HCQ use for COVID-19 treatment. Of note, in the world of science, the efficaciousness of a drug in the treatment of a disease is ultimately determined through randomized clinical trials (RCT) – at the time, there was no RCT data “for” or “against” HCQ efficacy for COVID-19 treatment.

As scientists, we felt obliged to raise concern about such inappropriate and potentially dangerous infusion of politics into the world of scientific evidence and discourse. Towards this goal, we set out to examine the biological consequences of HCQ use, specifically the adverse effects of this drug on the genome (i.e., genotoxicity) as we quickly realized that despite the decades-long use of HCQ, its exact mechanisms of action are only beginning to be understood. Most surprisingly, our extensive literature search showed that very little is known about the interaction of HCQ with DNA, including its DNA damaging- and mutagenic potentials (many therapeutic agents/drugs exert genotoxic effects, such as induction of DNA damage and mutation, that may lead to dysregulation of key genes involved in disease development).

AM: Can you give us an overview of your main findings and how they were obtained?

As a widely used drug for the treatment of a variety of diseases, HCQ has come to the forefront of research on drug repurposing for COVID-19 treatment/prevention. Despite the decades-long use of HCQ in the treatment of diseases, the exact mechanisms of action of this drug are only beginning to be elucidated. To date, no data are available on the genotoxic potential of HCQ in vitro or in vivo. The present study is the first investigation of the DNA damaging and mutagenic effects of HCQ in mammalian cells in vitro, at concentrations that are comparable to clinically achievable doses in patient populations. We demonstrate significant genotoxicity of HCQ, including its ability to induce oxidative DNA damage and mutation in mammalian cells in vitro. Remarkably, the observed genotoxic effects of HCQ are manifest at clinically achievable doses.

The widespread use of HCQ in the treatment of a great variety of diseases, and the renewed interest in the use of this drug for COVID-19 treatment/prevention, underscore the importance of our findings and their implications for safety monitoring in patient populations.

AM: What implications do your findings have for patients using hydroxychloroquine therapeutically?

Given the substantial number of the world’s population receiving HCQ for the treatment of various chronic diseases or in the context of clinical trials for COVID-19, our findings may have significant implications for safety monitoring in patient populations.

The use of HCQ is associated with cardiotoxicity (e.g., rhythm disorders), ophthalmologic complications (retinopathy) and gastrointestinal complications (e.g., nausea, vomiting, diarrhea and abdominal discomfort). The herein observed genotoxicity of HCQ in vitro suggests the possibility of additional side-effects, other than cardiac, ocular and gastrointestinal toxicities, which might impact patient populations. Being cognizant of this possibility, we emphasize, however, the importance of not over-interpreting or generalizing our in vitro findings before they are validated in follow up ex vivo/in vivo studies. If validated, these findings may add a new layer of complexity to the risk-benefit analysis of HCQ, especially in the context of clinical trials (involving healthy volunteers). We note that as of May 10, 2021, there were 247 clinical trials on HCQ, entered into ClinicalTrials.gov, which is a database of privately and publicly funded clinical studies conducted around the world. These include 22 “Active” trials (not recruiting), 64 “Recruiting” trials, 7 “Enrolling by invitation” trials, 36 “Not yet recruiting” trials, as well as 55 “Completed” trials, 8 “Suspended” trials, 25 “Terminated” trials, and 30 “Withdrawn” trials, involving thousands of human subjects.

AM: What are your next research steps in this space? How do you plan to validate your findings?

We plan to validate our findings in follow up studies, including in vitro studies in normal human cells as well as in vivo studies in experimental mice.

AM: Your study highlighted the possible risks of using a drug without fully assessing its potential for harm. Do you think this has become more of a concern during the COVID-19 pandemic? What can be done to address the issue?

The tale of HCQ is a learning lesson of the risks when medical decisions are not driven by science. It underscores why science-based decisions should be made using unbiased data generated through rigorous scientific research, not because of politicians’ “gut instinct” or “hunch”.

As research scientists, we should ensure the highest standards of scientific rigor in all areas of study design, approach, data collection, analysis and interpretation and transparency.

Ahmad Besaratinia was speaking to Anna MacDonald, Science writer for Technology Networks.