Using Chloroquine to Treat COVID-19: Q&A with Raghu Chivukula, MD, PhD

The drug chloroquine received international attention this month after a small French study in 36 patients found that patients taking the anti-malaria drug combined with azithromycin cleared the virus faster than controls. This news ignited excitement around the drug and increased demand, but many scientists question whether this enthusiasm is premature.

In this Q&A, Raghu Chivukula, MD, PhD, a physician-scientist in the Division of Pulmonary and Critical Care Medicine at Massachusetts General Hospital, who spends much of his time studying lung and lysosome biology (including using chloroquine in the lab), explains what is currently known about the drug and its use to treat COVID-19 patients.

Q: We’ve heard news recently that touted chloroquine as a “powerful drug” to treat COVID-19. What do we know about this drug and coronavirus today?

Chivukula: Coronaviruses like SARS-CoV-2 are enveloped, meaning they are coated in a piece of host cell membrane and utilize receptor-mediated endocytosis for viral entry. Through this process, the infecting virion ends up inside a membrane-bound compartment within the cell (known as an endosome) from which it must escape before making mischief elsewhere. This escape process depends on acidification of the endosome and fusion with lysosomes, which likewise require a low pH for function.

Chloroquine (CQ) belongs to a class of agents known as cationic amphiphilic drugs (CADs). CADs become trapped and highly concentrated in acidified subcellular compartments such as endosomes, lysosomes and the Golgi apparatus. By virtue of this trapping, CADs can increase pH and inhibit enzyme function within these organelles. CQ’s interference with endo-lysosomal processing of antigens likely accounts for its immunosuppressant activities, and a similar mechanism in virally-infected cells provides an opportunity to block viral endosome escape and replication. In line with this idea, it has been appreciated for decades that various CADs can interfere with the replication of a diverse array of enveloped viruses including influenza, Ebola virus, HIV, dengue, Zika and hepatitis C in vitro.

Q: Why is there a great deal of enthusiasm for this drug to treat COVID-19?

Chivukula: The majority of evidence supporting the use of CQ in COVID-19 comes from studies of the original SARS-CoV that emerged in 2002. In the ensuing years, basic virology studies established that SARS-CoV depends on endosomal escape and that its receptor (ACE2) requires processing in the Golgi—together making CQ a rational drug to test. Research in 2005 established the efficacy of CQ in inhibiting SARS-CoV replication in vitro and provided evidence that impaired endosomal acidification as well as impaired ACE2 glycosylation might be responsible. Similar data were reported by other groups. 

Building on these data, Wang and colleagues published two papers in February 2020 and March 2020 examining the effects of CQ and hydroxychloroquine (HCQ, more widely available and less toxic) on the novel SARS-CoV-2 in vitro. CQ dramatically inhibits SARS-CoV-2 replication at low micromolar concentrations, while HCQ inhibits replication at ~10µM. Importantly, and suggesting a reasonable therapeutic index, these concentrations are at least 10-fold lower than reported cytotoxic doses. 

If you have been following the news, you likely saw that President Trump voiced a great deal of enthusiasm for combination therapy with hydroxychloroquine and azithromycin (“H and A”, as he coined). This drug combination was studied in a very small group of French patients, where it appeared to increase rates of nasal viral clearance. There are several significant methodological issues with this study including its small size, lack of randomization, missing qRT-PCR data (particularly in controls), likely false negatives in the dataset, dropout of multiple HCQ-treated patients who clinically deteriorated, and ad hoc administration of azithromycin. Nevertheless, these data do suggest the possibility of therapeutic effect and need for further study. 

Q: What are the potential drawbacks or reservations associated with use of this drug? 

Chivukula: Reservations to the enthusiasm for CQ/HCQ use fall into two major categories: 

The first is passive: these drugs might simply be ineffective, sapping attention and resources from alternate treatments or trials and limiting supplies for patients who require HCQ for control of rheumatologic disease. There are legitimate reasons to be skeptical about possible benefits of these drugs in clinical settings given that clinical trials in other viral infections have been less than promising. Chloroquine failed to prevent influenza infection in a clinical trial and, if anything, increased viral load in an HIV trial. In COVID-19 specifically, a small trial recently randomized 30 patients to HCQ or placebo and found no significant difference in clinical endpoints, though these were generally mildly affected patients. 

The second is active: the possibility of harm associated with administering these agents, particularly to the critically ill. Concerningly, at least one group reported increased influenza replication in vitro in the presence of CQ and another found that CQ increased viremia in cynomolgus macaques infected with Chikungunya virus. 

Hydroxychloroquine also has significant toxicities, particularly in the heart where it can increase the QT interval (especially a concern if co-administered with macrolides) and in the eye where it can cause an irreversible retinopathy (caused by its lysosomal accumulation). Therefore, until larger randomized trial data is available, there remains equipoise about the role for these drugs in COVID-19 patients despite their preclinical promise. 

Q: Is Mass General involved in any studies or trials with this drug?

Chivukula: Unsurprisingly, there is intense interest at Mass General and elsewhere in studying CQ and HCQ in COVID-19 patients, with discussions underway to develop a multicenter trial in the United States. In addition, the World Health Organization is rapidly expanding the scope of its multinational SOLIDARITY trial, which includes HCQ among its tested agents. Finally, multiple trials in several countries (particularly China) have already enrolled patients and are likely to release data soon.

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