Virus expert Dave Wessner explores a new study that shows that hydroxychloroquine doesn’t appear to prevent people from being infected with the coronavirus that causes Covid-19.

In a study published in The New England Journal of Medicine, researchers concluded that hydroxychloroquine, or HCQ, does not prevent infection with SARS-CoV-2 when administered to people soon after exposure to the virus. This work adds to the growing, and controversial, body of research examining the efficacy of HCQ as a Covid-19 therapeutic.

Hydroxychloroquine and Covid-19: Mixed results and controversial publications

What do we know about HCQ and the Covid-19 virus? Initial laboratory studies provided some hope that HCQ could serve as an effective antiviral agent. Both hydroxychloroquine and chloroquine inhibited replication of SARS-CoV-2 in mammalian cells. Studies in humans, however, have been less clear. In late March, French researchers reported that HCQ improved the clinical outcome of Covid-19 patients. However, the study design and data analysis have been criticized by other researchers and, in early April, the society that published the research noted that it did not meet their expected standards.  

In late May, in an article published in The Lancet, another group of scientists claimed that HCQ did not improve the clinical outcome of patients with Covid-19. More significantly, they noted that HCQ administration was associated with an increased risk of cardiac events and death. Largely in response to this article, the World Health Organization announced it was suspending the use of HCQ in human trials. But less than two weeks after this work was published, The Lancet retracted the article, with the lead authors admitting that they, “can no longer vouch for the veracity of the primary data sources.”

Other studies have been less controversial, but still not conclusive. In an observational study, researchers looked at the outcomes of patients with moderate or severe Covid-19 who either were or were not given HCQ. Based on their analysis, the scientists determined that HCQ had no discernible effect on patient outcomes. Although this study seems quite strong, it was not randomized. Some individuals received HCQ and some did not, but the members of both groups were not necessarily equivalent. Moreover, the authors only analyzed patients who had been hospitalized. The effects of HCQ on individuals with less severe disease was not investigated.

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What this study tells us

Rather than examining if HCQ improved the clinical outcome of people infected with SARS-CoV-2, these researchers examined the use of HCQ as post-exposure prophylaxis (PEP). In other words, they wanted to understand if HCQ, when given shortly after exposure to the virus, could reduce the likelihood of infection. There is precedent for this approach. Numerous studies have shown that PEP can reduce the risk of HIV infection. For example, a 1997 study showed that the risk of HIV infection in healthcare workers following a needlestick injury dropped over 80% if an antiretroviral drug was administered immediately after the accident.

If the rate of infection in people exposed to the virus can be reduced, the number of new cases will drop, but this study does not provide evidence that hydroxychloroquine can fulfill this goal.

To explore the ability of HCQ to prevent SARS-CoV-2 infections, the authors of this study enrolled over 800 people who had a moderate- or high-risk exposure to the virus. These individuals were randomly divided into two groups. Within four days of exposure, members of one group received HCQ, whereas members of the other group received a placebo. All individuals then were monitored. The conclusion: there was no discernible difference in the rate of infection in either group. Under these conditions, hydroxychloroquine did not function as an effective post-exposure prophylactic.

However, the study does have some limitations. Most notably, infections were defined primarily by the appearance of disease signs and symptoms. Because of the limited availability of PCR-based tests, the detection of asymptomatic infections was not possible. This means that it’s possible the post-exposure administration of HCQ reduced the number of these subclinical events. Additionally, one could argue that the timing of HCQ administration matters, because participants who began HCQ treatment one or two days after exposure became infected less frequently than participants who began treatment three or four days after exposure.

Why this study matters

The authors of this study note that development of drugs to treat people infected with SARS-CoV-2 is only part of the solution. We also must stop new infections. Harm reduction strategies, like social distancing and wearing masks, can reduce the infection rate. Certainly, an effective vaccine would decrease the number of new cases. Effective post-exposure prophylaxis also could help. If the rate of infection in people exposed to the virus can be reduced, then the number of new cases will drop. Unfortunately, this randomized, placebo-controlled study does not provide evidence that hydroxychloroquine can fulfill this goal.

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