Hydroxychloroquine, pushed by US President Donald Trump and others as a possible treatment for people with COVID-19, displayed at a pharmacy in Utah, May 27, 2020. Photo: Reuters/George Frey.
As a possible cure for COVID-19, the anti-malarial drug hydroxychloroquine (HCQ) has garnered a lot of interest with several studies and public figures endorsing its use. But there is a concern that HCQ’s benefits have been exaggerated and that it may cause more harm than good to COVID-19 patients.
HCQ is a less-toxic end product of chloroquine’s metabolisation. Chloroquine itself is a derivative of quinine, a famous anti-malarial drug. Apart from malaria, HCQ has also been prescribed for autoimmune diseases like lupus and rheumatoid arthritis because of its ability to suppress the immune system. Its side effects include headache, dizziness, rash and gastric issues like nausea and diarrhoea, with a minor long-term risk of developing [retinopathy (1% after 5-7 years). HCQ may also reduce blood sugar, cause cardiac arrhythmia or arrest, especially in individuals with comorbidities or due to drug interactions. However, HCQ is regularly prescribed as the risks for these specific conditions are manageable for short-term use. Monitoring patients could be useful in avoiding long-term adverse effects.
Why use an anti-malarial drug for COVID-19?
HCQ treatment pre- or post-exposure to the novel coronavirus reduces viral replication in cultured primate cells. HCQ is thought to inhibit three major processes: cellular entry of the virus, intracellular release of viral RNA if already entered, and viral RNA replication if already released. Since these studies were performed in cultured cells, we do not know if the results will be the same in humans. Researchers also believe that HCQ’s immunomodulatory effect can prevent the cytokine storms in COVID-19 patients – an extreme immune reaction that can lead to organ failure and death.
Also read: Explained: What is a Cytokine Storm?
What do we know about use in COVID-19 patients?
The majority of human studies so far are observational and not randomised controlled trials (RCTs), the gold standard for testing safety and efficacy of drugs. While observational studies can be a quick way to ascertain large scale drug toxicity, confounding factors like selection bias, differential follow-up and treatment variations make them less useful for testing drug efficacy.
In early spring, studies emerged on HCQ as a potential treatment for COVID-19. Some suggested combining HCQ with azithromycin, an antibiotic, for improved outcomes while others dismissed any positive effect of HCQ or azithromycin on COVID-19 treatment. One such study suggested that HCQ treatment reduced hospital stay and improved outcomes in COVID-19 patients. Like most of these studies, this one was also plagued with several issues, especially low sample size and poor design.
The flurry of these studies generated a lot of buzz on HCQ as a potential COVID-19 treatment. Multiple clinical trials were announced – including a WHO-sponsored multinational study. However, the medical community also pointed out the associated risks of blood sugar reduction and cardiac arrhythmia, especially when combined with azithromycin. In late May, as the debate on HCQ was raging, two new retrospective studies using medical data provided by a little-known company called Surgisphere, emerged in renowned medical journals – The Lancet and the New England Journal of Medicine (NEJM). The Lancet study made astounding claims that HCQ treatment in COVID-19, instead of being beneficial, significantly increased cardiac arrhythmia and deaths. The dramatic results led the WHO to temporarily halt its HCQ clinical trials. The French and British government banned the prescription of HCQ for COVID-19 patients. Multiple other governments followed suit. However, India and Brazil continued to use HCQ prophylactically to prevent COVID-19 infection in healthcare workers.
Almost immediately, several scientists published an open letter to The Lancet identifying several issues with the study — nearly all related to Surgisphere’s data, claimed to have been collected from several hospitals across the world. The letter highlighted several data inconsistencies, including higher than official mortality data for Australia and higher than FDA-approved HCQ dosages in the US. The inconsistencies and the secrecy around Surgisphere ultimately led to the retraction of both studies and WHO resuming its COVID-19 HCQ trial.
Also read: Why That Observational Study of Hydroxychloroquine in The Lancet Seems Fishy
So what do we know?
In early June, NEJM published another study – a double-blinded RCT that showed manageable side effects from post-exposure prophylactic HCQ usage but no significant reduction in COVID-19 development. For the RCT, individuals with moderate to high-risk exposure to a COVID-19 patient randomly received HCQ or placebo within four days of exposure. The primary outcome was either a confirmed COVID-19 test or the development of COVID-19 compatible symptoms.
Better designed and performed than other studies hitherto, this study had its own confounding issues. These included possible problems with compliance, self-reporting of symptoms and enrolment of largely young and healthy participants. The risk and benefits of HCQ may vary in the elderly population, especially those with comorbidities.
All we can conclude from this study is that in relatively young and healthy individuals, a short HCQ course is safe. Since young individuals are less likely to develop severe symptoms of COVID-19, it is hard to conclude the prophylactic role of HCQ from this RCT.
What is going on in India?
The Indian Council of Medical Research (ICMR) recommends medically supervised prophylactic usage of HCQ for healthcare workers. In their latest retrospective, observational study, ICMR reported significant reduction in COVID-19 in healthcare workers using personal protective equipment and HCQ as a prophylactic. The study interviewed 751 workers – those positive for infection (~50%) were considered as ‘cases’, the negatives as ‘controls’. No significant HCQ adverse effects were observed.
The study had several drawbacks such as self-reporting, poor design, and nonrandomised subject selection. The controls had significantly higher PPE usage than the cases. Cumulatively, HCQ usage did not significantly reduce the incidence of a novel coronavirus infection. Only on dissection by HCQ dosage was significant reduction in infection seen.
Curiously, the data suggests low maintenance dosage of HCQ significantly raises the likelihood for developing COVID-19. With these and other confounding factors, this study is inconclusive and can at best be used as a rationale to conduct RCTs on HCQ use.
§
The tale of HCQ and COVID-19 mirrors our own anxiety about the disease: everyone is looking for a quick cure. And perhaps in attempting to hasten drug discovery, we are ignoring the utility of due process. At the end of the day, we need to wait for the results from several ongoing RCTs.
Salman Hasan is a business analyst for the US National Institutes of Health. Priyadarshi Ranjan is a nanochemist from the Indian Institute of Science Education and Research, Pune.