Down, but not out: hydroxychloroquine could still have a role against COVID-19

As the COVID-19 pandemic emerged, researchers across the world began thinking about how we can repurpose drugs we already use — such as the 4-aminoquinolines chloroquine and hydroxychloroquine (CQ/HCQ) — to treat or prevent the virus.

Back in February 2020, reports from China suggested CQ/HCQ could be effective in treating COVID-19^[1]
, and, by 20 July 2020, ClinicalTrials.gov (the US National Institutes of Health’s clinical trial database) had listed 184 studies of CQ/HCQ in the context of the virus.

Among these trials are a range of large-scale clinical trials focusing on interventions at different stages of disease: treating hospitalised patients; treating people who are ill but not (yet) hospitalised (for example, the PRINCIPLE trial); or preventing infection, either in people already exposed to COVID-19 (post-exposure prophylaxis), or in people who are at high risk of exposure (pre-exposure prophylaxis).

One such pre-exposure prophylaxis trial, the COPCOV (CQ/HCQ to prevent COVID-19) trial, recruits healthcare workers and evaluates whether a daily dose taken as a tablet of either CQ or HCQ reduces the chances of catching COVID-19. Its first participants were enrolled on 28 April 2020.

But soon CQ/HCQ’s safety was called into question. By 22 May 2020 — while several world leaders taking prophylactic HCQ were receiving substantial media attention — The Lancet published a paper by Mehra et al. purporting to show increased risk of death among patients treated with CQ/HCQ for COVID-19^[2]
. The UK’s Medicines and Healthcare products Regulatory Agency (MHRA) responded by suspending enrolment into all trials involving CQ/HCQ, including the COPCOV trial.

Subsequently, the RECOVERY trial team announced they found HCQ did not, in fact, lower the risk of death from COVID-19 in hospitalised patients. And a North American study of post-exposure prophylaxis using HCQ found that people randomised to HCQ had a lower risk of infection, but this was not “statistically significant”^[3]
. Importantly, neither trial reported any concerns over safety.

Soon after The Lancet retracted Mehra et al.’s paper over concerns about the data, and after reviewing all the available evidence relating to safety and potential efficacy, the MHRA gave the COPCOV trial the green light to re-start recruitment in the UK^[4]
.

There is evidence that these drugs could prevent COVID-19 safely, effectively and cheaply, so here is why we should not write them off just yet.

Why we are looking at this group

The 4-aminoquinolines CQ and HCQ have been used in humans since the Second World War, namely as antimalarials. Although these drugs are toxic in overdose, their established track record of safety and tolerability make them very well-suited for use as prophylactic agents. For many years, from laboratory and some animal experimental models, we have known that CQ/HCQ can exhibit antiviral activity^{[5]
,[6]
,[7]}
.

The antiviral effect against coronavirus appears to involve impaired interaction between the viral spike protein (on the surface of the coronavirus) and its ACE2 receptor, which it uses to attach to human cells; as well as reduced intracellular transport of virions (entire viral particles)^[8]
,[9]
.

It remains to be seen how these ideas translate into clinical effectiveness for COVID-19; so far, animal models and observational studies have produced conflicting results^[10]
. Although these drugs also have anti-inflammatory effects, the antiviral mechanisms take place at viral entry or early in replication, and indicate that the earlier CQ/HCQ are used in the course of COVID-19 infection, the more likely they could have a clinically useful effect.

This concept is in keeping with antiviral treatments in general, where even potent antiviral agents are most effective when they are given as early as possible in disease. Good examples include neuraminidase inhibitors (such as Tamiflu) for influenza; and combined tenofovir and emtricitabine, which can effectively prevent, but cannot cure, HIV infection.

HCQ is already widely used in the treatment of rheumatic diseases. Intriguingly, two recent observational studies of patients with rheumatological diseases have reported lower rates of COVID-19 among patients taking HCQ compared with those taking other medications
<sup>[11]

,
[12]</sup>
. It is possible that the people who took HCQ were at fundamentally lower risk of getting COVID-19 compared with those who did not take HCQ. This is why undertaking a randomised trial — where people who take and do not take HCQ are similar in every respect — is so important.

What the trials tell us

Hydroxychloroquine is no treatment for COVID-19

In the UK, the RECOVERY platform trial assesses treatments for COVID-19 in hospitalised patients. RECOVERY’s HCQ arm compared 1,561 patients treated with HCQ with 3,155 patients receiving usual care and found that HCQ did not reduce 28-day mortality
^[13]
. Notably, the RECOVERY dosing regimen involved a substantial loading and daily dose designed to ensure rapid attainment of high drug levels in lung tissue.

The trial identified no specific safety issues and no increased risk of cardiac arrhythmias, although patients given HCQ at these higher doses did have an increased length of hospital stay and increased risk of progressing to invasive mechanical ventilation, or death, compared with people randomised to standard care.

Cavalcanti et al. have reported a controlled trial of 667 patients hospitalised for mild to moderate COVID-19 infection in Brazil, who were randomised to either HCQ with or without azithromycin compared with standard care^[14]
. Again, no benefit of HCQ was found; and although HCQ was associated with prolongation of the QT interval and elevation of liver enzyme levels, there was no excess of serious adverse events in the HCQ-treated patients.

These results demonstrate that HCQ should not be used as treatment for COVID-19 in hospitalised patients, but they do not exclude the possibility that, given earlier in disease (in pre-hospitalised patients, for example), they could be beneficial.

But there is evidence it could prevent COVID-19

Boulware et al. have reported the findings of a post-exposure prophylaxis trial of 821 people who had had recent contact with COVID-19, and who then took either HCQ or placebo. Those given HCQ developed symptoms of COVID-19 less often, but the study did not have enough participants to determine if this was due to chance, or if it represents a real effect.

The absolute reduction in new incidences of COVID-19 was -2.4% (95% confidence interval [CI] 7.0−2.2; P =0.35), translating into a relative risk reduction of 17%^[3]
. Furthermore, most participants started taking HCQ 3−4 days after their exposure; it takes approximately 24 hours for HCQ loading to achieve therapeutic tissue levels.

Among participants in this trial who took HCQ earlier following exposure, there was a greater trend towards protection, such that among the few participants in this trial who took HCQ one day after exposure, the point estimate for relative risk reduction was -49%. Therefore, while the Boulware et al. paper indicates that HCQ given several days after exposure does not offer significant protection against COVID-19, it does indicate that pre-exposure prophylaxis could have quite a large protective effect. And it appears to be safe too: even at doses higher than those given in the COPCOV trial, there were, again, no cardiac arrhythmias or reported adverse events.

Despite the absence of high-quality evidence, CQ/HCQ is now widely used to prevent COVID-19 in countries accounting for up to 20% of the world’s healthcare workers. Indeed, in India, for example, the Health Ministry recommends its use for a wide range of frontline workers, citing observational studies showing its benefit^[15]
. At a global level, this divergence of opinion can only be addressed through a definitive trial. Without this, people will continue either to take these drugs unnecessarily or to be deprived of the protection they could offer.

Chloroquine/hydroxychloroquine seem safe and tolerable

Like any drug, CQ/HCQ can have adverse effects and interact with other drugs. But there is a wealth of experience and evidence attesting to their safety and tolerability in the doses used to prevent COVID-19.

The drugs have been used for more than 60 years as long-term treatments for rheumatological conditions at adult doses between 155 and 610mg base/day. The COPCOV trial provides a maintenance dose of 155mg base/day.

By far the most clinically significant potential harm associated with 4-aminoquinolones is cardiac dysrhythmia, particularly among patients who are on other drugs that prolong the QT interval or who have pre-existing cardiac disease; for example, older people^[16]
. While CQ/HCQ can prolong the QT interval, there is little evidence that this translates into an increased risk of ventricular dysrhythmia in the absence of specific co-morbid diseases and interacting drugs.

Toxicity is related to dose and duration, and a recent analysis of data from almost 1 million patients starting HCQ for treatment of rheumatoid arthritis identified no excess risks associated with HCQ compared with anti-inflammatory drug sulfasalazine, unless combined with azithromycin; instead, there was a decreased incidence of arrhythmias in the first month^[17]
.

In Boulware et al.’s study, in which participants received 1400mg in the first 24 hours, and 600mg daily for the 4 following days, no cardiac events were noted. COPCOV has a loading dose of 465−755mg HCQ base. CQ/HCQ are also associated with more common and mild dose-related side effects that could affect tolerability^[3]
.

Although 40% of participants given HCQ experienced side effects (most commonly gastrointestinal symptoms), 17% of participants taking placebo also experienced side effects; and less than half the participants taking HCQ correctly identified that they were taking an active drug rather than placebo. Skin reactions and visual changes occurred in only 1% of HCQ-treated participants^[3]
.

The COPCOV trial, while we wait for a vaccine

While rates of COVID-19 in the UK and Europe are currently low, globally the pandemic continues, and further waves of infection are anticipated over the coming months. Vaccines will offer the best hope for robust population-wide protection against COVID-19, but while we wait for a safe and effective vaccine, we must protect healthcare workers and other key workers in occupations that risk exposure to COVID-19.

COPCOV is a global trial and will evaluate whether CQ (in Asia) or HCQ (in the UK, Africa and elsewhere) can offer protection. The dosing schedule in COPCOV has been designed to safely achieve drug levels that could offer protection. The trial is open to anyone working in a care environment where people may have COVID-19, as long as participants are not taking certain drug treatments or could not be pregnant.

Our drug armoury throughout disease progression

Intriguingly, trial evidence supports a paradigm in which antiviral interventions (such as remdesivir) are effective early, and anti-inflammatory interventions are effective late, in COVID-19 progression^[18]
,[19]
.

If this is correct, there is potential for cheap, safe drugs with antiviral activity such as that exhibited by CQ/HCQ to be taken as early as possible, as pre-exposure prophylaxis. Promisingly, no evidence has come to light to question the long-established excellent safety record of these drugs, at these doses and for these durations.

If CQ/HCQ were able to safely protect us from COVID-19, it would become enormously important in our efforts to combat the pandemic. Randomised controlled trials such as COPCOV are vital to confirming or refuting this possibility.