Hydroxychloroquine (HCQ) has been the biggest buzzword across the world lately. Until December 2019, this was a meek drug, used mainly by rheumatologists, internists, and dermatologists for inflammatory diseases. Its cousin Chloroquine has been the most popular drug for malaria. We have known and used these drugs for decades.

The antiviral properties of these drugs are known since the 90s, when it was found to inhibit HIV, Dengue, Ebola and SARS — though all in lab studies. At each time in history, it was touted as “The” drug to cure these diseases. However, when used on humans as part of clinical trials, the drug failed to show any benefits, and these doors were all but closed.

Revival

The end of 2019 brought about the worst healthcare disaster seen in over a century, as a small outbreak of Wuhan mutated into a deadly pandemic over a course of months. This extent and rapidity of spread did not give scientists enough time to understand the virus or figure out a treatment strategy. Desperate times called for desperate measures, and scientists in China and France started using Hydroxychloroquine off label as well as in clinical trials.

Is HCQ effective as a treatment for those who already have COVID-19?

Early results of small trials from both countries suggested a faster clearance of the virus from the nose, and possibly faster recovery. However, these results were never affirmed in larger studies. In fact, there has been mounting evidence of higher deaths in patients hospitalized for Covid 19 and put on HCQ. This evidence is not proof of harm, but is strong enough to raise serious concerns. On 24 May even WHO suspended the use of HCQ in its large, multinational trial. The WHO is looking at published data, the interim analysis from the Solidarity trial by the committee that is monitoring drug safety and the findings from other ongoing trials that include hydroxychloroquine as one of their study arms. Possibly, WHO might restart the trial only after an interim analysis of ongoing trials confirms the safety of this drug.

ICMR actually took a pragmatic approach in using HCQ in those already suffering from COVID-19. Despite some evidence of efficacy in treatment, they decided to first conduct clinical trials in India. For now, they have allowed the use of HCQ for patients with severe disease on a case-by-case basis.

HCQ for prophylaxis in healthy, but at risk people

This is where the baffling absurdity of idiosyncrasies begin. It is scientifically, ethically, and morally wrong to prescribe a drug to anyone, let alone a healthy person, when we have no clear idea of its risk- benefit ratio. It violates the first principle of medicine – Primum non nocere: First, do not harm.

Every drug has side effects. Yet physicians prescribe the drugs when the expected benefits outweigh the potential harms. As an example, clot blusters used to treat heart attacks can cause fatal strokes, but overall their benefits far outweigh the small risk of a stroke and thus they have become the standard of care in the treatment of heart attacks. Therefore, any new intervention (drug, operation or a procedure) strategy needs to be ratified by large clinical trials; these trials must be monitored for drug safety, trial findings peer-reviewed by experts and should be published in medical journals. A drug arrives at the patient’s bedside only after it proves its mettle. This applies even to old drugs, whenever they are picked up for a new disease.

On 23 March 2020, ICMR recommended that people in close contact with COVID-19 patients should take weekly HCQ for 7 weeks. This was a blanket recommendation, not a trial. The advisory document assured there was both pre-clinical and clinical data to support this strategy. Interestingly, as on 25 May 2020, not a single published clinical trial backs this recommendation. No other country is following this strategy outside of clinical trial settings.

ICMR decided to give an untested drug to thousands of healthy people, who were at a high risk of developing COVID-19, without any clinical data to back its claims. Instead of a trial, they decided to offer the prophylaxis to people, and observe them. They failed to disclose the experimental nature or the unclear efficacy of this intervention. The “participants” were to report any side effects themselves, and there was no provision to screen for COVID before, during, or after the drug was taken.

Effectively, this has been a large, poorly designed, unmonitored, human trial without an informed consent.

The latest ICMR advisory now cites “Observational data” derived from this population, which they claim supports the use of HCQ as prophylaxis. What would be the veracity of such data when neither testing nor adverse effect reporting has been standardized? Moreover, the data is not available on public domain—either raw or as a research paper—for external review. The study parameters are unknown and the results unclear. ICMR released a snippet that among 1323 healthcare workers, 1.9% developed “cardio-vascular” effects, and 1.7% developed hypoglycemia. These sound concerning, but the nature or severity of these events was never reported. Moreover, the side effect numbers much lower than reported from across the world, raising doubts on the validity of this self-reported safety data.

Unless we have an accurate idea of the efficacy of HCQ in preventing COVID, and the adverse effect profile, how are we to calculate the risk-benefit ratio? HCQ is a relatively safe drug in autoimmune diseases, and we have used for a long time. Doctors are well aware that it can cause electrical conduction problems in the heart, which are usually mild and inconsequential. However, we do not fully understand COVID yet. The corona virus is known to cause cardiac problems. Is it safe to use HCQ in those who are at high risk of developing COVID? Can it contribute to chaotic heart rhythms?

The answer is, we do not know. If only there was a double-blind, randomized controlled trial, maybe we would have known better.

The way forward

Now that WHO has put on hold HCQ in its trial, does it mean we should dump it?

No, that is not how the science works. Hasty reactions to incomplete evidence create more problems than they solve. Moreover, ill-conceived, rapidly changing recommendations erode the faith of people in medicine. HCQ, Remdesivir, plasma therapy seem to be the frontrunners for treatment of COVID-19, but none of these have yet shown overwhelming promise. ICMR needs to ensure there are appropriate placebo controlled trials to make sure we find which one works. ICMR today argued that because we know that the drug may be beneficial, it does not need to be tested in trials—a statement that holds little water. This precisely is the perfect setting to launch a trial.

As for prophylaxis, regardless of the “observational evidence”, ICMR is yet to present, thousands cannot be subjected to this drug without proof of safety and efficacy. This needs to be restricted to clinical trials only.

Currently, we do not know how many people need to take the drug for how long to prevent one infection. We also have no idea how many develop adverse reactions. So, we have effectively no idea what the risk-benefit ratio is for taking this drug.

As per its March 23rd advisory, ICMR seems to have decided that HCQS is effective as prophylaxis. It has repeatedly brushed aside any need of a controlled trial, and has started an observational study. This is not acceptable. Nowhere else in the world has HCQ been recommended for prophylaxis outside of clinical trials. The observational study ICMR is busy with is in no way a substitute for randomized, placebo-controlled trials.

Now that the WHO has put HCQ arm of its trial on hold, and ICMR is no mood to start a clinical trial, the public is caught between Scylla of coronavirus and the Charybdis of Hydroxychloroquine. We need expert policy makers to steer the ship to safer shores.

CNBC TV18 carried this story on 28 May 2020.