Hydroxychloroquine (HCQ), an anti-inflammatory drug used for malaria and autoimmune diseases now for many years, has turned out to be a hare and not the tortoise (we hoped for) in the COVID-19 race. It has brought more chaos than clarity, thanks to the interplay of political, scientific, public and educational factors.The starting point was the publication of a controversial French study which showed reduction in viral load (dose of the virus detected) in nasopharyngeal swabs in Covid patients. This study underwent heavy criticism from the scientific community for its methodological flaws. Despite this, it created a wave of enthusiasm leading to an Emergency Use Authorization issued by the FDA.
Closer to home, the Indian Council of Medical Research (ICMR), recommended the use of HCQ (400 mg twice on day 1, then 400 mg once a week thereafter (for a period of time) as chemoprophylaxis for asymptomatic Health-Care Workers (HCWs) treating patients with suspected or confirmed COVID-19, and for asymptomatic household contacts of confirmed cases in an advisory released on 22 March 2020. This advisory came as a surprise especially given the lack of robust scientific evidence for the use of HCQ even as treatment, let alone chemoprophylaxis. The ICMR statement stated “its use in prophylaxis is derived from available evidence of benefit as treatment and supported by preclinical data” and did not provide any further detailed evidence base or review of evidence in its use for such purposes. Although some in-vitro evidence existed for the antiviral activity of HCQ, peer-reviewed evidence studies evaluating the drug for exposure prophylaxis of SARS-CoV-2 infection was definitely lacking at that time, and continues to be so now.
Foregoing the issue of proven efficacy, the issuance also proved problematic since it elicited a panic reaction from the lay public. Despite the explicit focus on HCWs and contacts of those tested positive, it led to a public perception that the drug is effective for prevention purposes.
This was demonstrated as there was a drug shortage within a few days. Furthermore, this made it difficult to test the hypothesis in carefully conducted clinical trials which may have provided justifiable evidence of this indication as it made the use of HCQ for prophylactic purposes a ‘de facto standard of care’ in certain high risk populations Back in the US, President Trump’s address was another turning point, when he touted the drug to be an effective coronavirus treatment despite the lack of scientific evidence and experts calling the evidence ‘anecdotal’. This highly publicized discussion saw a huge spike (1389%) in the internet searches for purchasing of the drug. His comment mentioning that he himself regularly consumes the drug might push this hype even further.
Over the past month as more evidence has emerged against the efficacy of HCQ (especially in combination with azithromycin), most US hospitals are refraining it for treatment purposes. In fact, the FDA has issued a warning against the use of HCQ outside of hospital settings. However, ICMR did not scale back its recommendation for chemo prophylactic use of HCQ despite the lack of evidence. This has led to its continued use, with concerns over indiscriminate use by health authorities. In Mumbai, the Brihanmumbai Municipal Corporation rolled out a seven-week course for slum dwellers, which is beyond even the purported scope laid out in the ICMR’s March advisory.
Although well intentioned, this erodes the public trust especially as evidence for a mass prophylaxis without rigorous monitoring is lacking and may be deleterious given that the drug can cause severe cardiac side effects and even death. It also could give a false sense of protection to these high risk populations and divert attention and resources from the need to focus on, or strengthen strategies, which could help reduce further spread of infection.
Furthermore, the issue is complicated by ethical and legal deficiencies given the lack of clarity on need for informed consent, screening for eligibility, lack of effective widespread pharmacovigilance, and monitoring of side effects, in those consuming the drug based on the advisory. Hence, one would think the ICMR will address these issues, ensure adequate oversight for those who are taking the drug and immediately withdraw its advisory as new data of a skewed risk-benefit equation has become available. However, the ICMR released a revised advisory on May 22, which revised the eligibility criteria for HCQ prophylaxis and broadened it to include asymptomatic frontline workers, such as surveillance workers deployed in containment zones and paramilitary/police personnel.
This puzzling revision is reportedly supported by data quoted in the advisory from in-vitro, safety and observational studies in India, none of which seem to be peer-reviewed or publicly available for independent review. This revision came on the same day when the results of a multinational registry analysis (from 671 hospitals in six continents) were published which did not demonstrate any benefit in in-hospital outcomes for COVID patients.
Given existing and emerging data, it should be clear that if the ICMR wants to explore the HCQ’s potential chemo-prophylactic use, it should only be done through properly designed and conducted randomized controlled trials. Apart from exposing some of the administrative, legislative and pharmaceutical deficiencies, this case study has unearthed another issue of the Indian healthcare system — failure of medical education to train doctors for modern practice.
Traditionally, much of the medical education has focused on learning well established diagnostics methods and treatment protocols. However, there is a dearth of training in understanding, evaluation and appraisal of scientific medical literature, and using this learning to drive clinical decision-making. With the ever-changing landscape of medicine, well demonstrated by the COVID-19 response, critical appraisal of medical literature is of paramount importance for a physician. With increasing trend of guideline driven medical care, it is important that physicians are able to make critical judgements on these recommendations by scientific bodies based on their evaluation of the existing scientific evidence. This is in their best interest, as well as for patients. Professional physician associations should take a lead in reinforcing the need for following evidence to drive health policy decisions, even at times of pandemics.
Thus, the HCQ fiasco excavated many of our familiar foes: inadequacy and short-sightedness of the governing scientific bodies, lack of accountability to the public, and inability to stay current and critically evaluate the growing body of scientific evidence. Despite the pandemic’s intensity, we must not abandon sound scientific reasoning in these desperate times, exemplified by the blanket recommendation on chemoprophylaxis in the absence of any credible evidence. As a nation, we must strive to learn a lesson from this crisis and view it as an opportunity to improve our healthcare infrastructure, and the way we practice medicine and public health.
Dr. Aakash Desai is an internal medicine resident in Dept of Medicine at the University of Connecticut Health Center, US. Dr. Anant Bhan is a researcher in global health, bioethics
and health policy. Follow them on Twitter @ADesaiMD @ AnantBhan