FAQs on HCQ use in rheumatoid arthritis and other conditions

Dr Shashank Akerkar, consultant, rheumatology clarifies several doubts and misconceptions pertaining to hydroxychloroquine (HCQ) and highlights the safety and efficacy profile of HCQ. He mentions that in general, practicing rheumatologists prescribe HCQ without ordering a baseline ECG unless the patient has a history of cardiac disease. If the right dosage of HCQ is used for the right patient with no prior cardiac complication, it is not likely to cause cardiac adverse effects.

 What is the role of HCQ in the management of COVID-19? Can it in any way cure the disease?

COVID-19 has multiple pathological features and therefore its management requires multiple drug therapies. Hydroxychloroquine (HCQ) alone cannot cure COVID-19 but it has been used in combination with other drugs for this purpose.

However, HCQ is not approved by the Drugs Controller General of India (DCGI) for the management of COVID-19. The Indian Council of Medical Research (ICMR), has recommended it as a prophylaxis (prevention) for COVID-19 (March 23, 2020) and for the treatment of mild and moderate cases of COVID-19 (June 13, 2020 ICMR management protocol).

In many studies, it has been found to decrease morbidity and mortality in COVID-19 patients. For example, in one retrospective observational study that included 3,451 patients from 33 hospitals in Italy, use of HCQ was associated with a 30 per cent lower risk of death in COVID-19 hospitalised patients.

In India, HCQ has shown promising outcomes as a prophylaxis for COVID-19 amongst healthcare workers.  In a nation-wide case-control ICMR study with 751 health care workers, the intake of six or more doses of HCQ was linked to a >80 per cent reduction in the risk of COVID-19 infection.

For the last five decades, HCQ has been widely used for the management of rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). In in-vitro studies, HCQ has been found to possess antiviral activity against many viruses such as the rabies virus, poliovirus, HIV, hepatitis A virus, chikungunya virus, dengue virus, Zika virus and even SARS-CoV-2.

What are some of the common misconceptions about HCQ that have emerged since the COVID-19 pandemic?

During the pandemic, the use of HCQ has been linked to excessive cardiovascular adverse effects like QTc prolongation, arrhythmia and cardiovascular (CV) mortality. None of this has been conclusively proven through research.

In fact, for decades HCQ has been prescribed for those with RA and SLE, and CV adverse effects have been rare in these patients. A study with 1,537 RA patients on HCQ therapy, found no significant correlation between HCQ use and QT interval prolongation.

QTc prolongation is rarely seen with HCQ use and it is often a self-limiting event. QTc prolongation mostly occurs in the presence of several risk factors, such as high drug concentration and simultaneous exposure to QTc-prolonging drugs like azithromycin. It is possible that the QTc prolongation and arrhythmia observed in COVID-19 patients are cardiac manifestations of COVID-19 disease. Clinical evidence shows that patients with a severe case of COVID-19 are in an arrhythmogenic state with myocardial injury, hypoxia, renal insufficiency, and electrolyte disturbance. Use of antiviral drugs and azithromycin in COVID-19 patients has also been also linked to QTc prolongation.

In general, practicing rheumatologists prescribe HCQ without ordering a baseline ECG unless the patient has a history of cardiac disease. If the right dosage of HCQ is used for the right patient with no prior cardiac complication, it is not likely to cause cardiac adverse effects. However, an ECG (with estimation of QT interval) may be done before prescribing HCQ. The Indian Heart Rhythm Society recommends a baseline ECG to estimate the QTc interval in individuals receiving HCQ treatment. Thus, the rare CV risk linked to HCQ can be assessed proactively, which is why I believe the overall fear about serious CV adverse effects is unfounded and often exaggerated.

Of late, have you encountered any constraints when prescribing HCQ to patients?

There are no constraints in prescribing HCQ for patients with RA, SLE and type-2 diabetes. It has been approved by regulatory authorities such as the DCGI and US FDA for RA and SLE, and in addition to these indications, DCGI has approved it for the management of type 2 diabetes. HCQ has been used in these patients for a long period of time and it has a favourable safety profile.

Why do you believe that the controversy over HCQ is a myth?

Early in March, the WHO initiated a multinational trial of four untested drugs for COVID-19. HCQ was also a part of the trial. Then in May, Mehra et al published one multinational real-world analysis in The Lancet, in which they reported that HCQ treatment (alone or in combination with a macrolide) had no benefit on the in-hospital outcomes in patients with COVID-19. Instead, they concluded that HCQS increases mortality in patients with COVID-19, which led to the stopping of the WHO trial mentioned earlier.

Later on, Australian researchers found discrepancies in the mortality data for HCQ users. In response to this, The Lancet t published an expression of concern and retracted the article that had halted the HCQ trial. The members of the WHO trial committee recommend that there was no reason to modify the trial based on available mortality data. And on June 3, the WHO resumed the trial including the HCQs arm in patients with COVID-19. Most of the HCQS trials which were stopped earlier were also restarted.

What will be the consequences if HCQ is banned for use in COVID-19?

The COVID-19 pandemic is unprecedented and such a health crisis arises once in a century. The morbidity and mortality of COVID-19 is comparatively high. To control a viral pandemic of this kind, the following measures are generally required.

1) preventive healthcare measures e.g. social distancing, hand hygiene and wearing masks etc.

2) vaccination of the general population, when a vaccine is available

3) use of antiviral drugs

4) use of immunomodulatory drugs

5) repurposing of existing drugs when specific treatment is not available.

A vaccine that prevents COVID-19 would ideally have been the best measure. But it takes a long time to develop and test effective vaccines against RNA viruses with rapidly mutating strains. Similarly, it is extremely difficult to develop a specific antiviral drug in a short period of time.

Considering the high morbidity and mortality of COVID-19, newer antiviral drugs such as remdesivir, lopinavir/ritonavir have been repurposed to manage COVID-19 and existing drugs such as HCQ, azithromycin, other antiviral drugs, and dexamethasone have also been repurposed for the treatment of COVID-19. HCQ has been found effective for the treatment and prevention of COVID-19 disease.

No serious untoward effects have been observed with HCQ use for the last five decades that can cause the regulatory authorities to think about banning HCQ.  Such a possibility is extremely remote as millions of RA and SLE patients are being successfully treated with HCQ without serious safety concerns.

(Note: These are not recommendations, to be considered as an opinion.)