Evaluating the effectiveness of CQ and/or HCQ against SARS-CoV-2

by Puneetha Goli

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the virus that causes the coronavirus disease (COVID-19). Patients exhibit a spectrum of severity in their symptoms ranging from asymptomatic to breathing difficulties[1]. The purpose of this article is to evaluate the effectiveness of chloroquine (CQ) and its less toxic metabolite hydroxychloroquine (HCQ) as a viable treatment for SARS -CoV-2 through analyzing data from available research studies. In one of the early breakthrough studies published in February 2020, Gao et al. found that a low-micromolar concentration of CQ blocked COVID-19 infection in early in vitro studies and improved lung imaging, indicating a potential correlation between CQ administration and a decrease in the spread of COVID-19[2]. However, more recent studies, including Skipper et al., since then have indicated that there are no significant differences with the administration of the agents, and some even caution against the use of them because of potential long-term side effects [3,4]. The general consensus among the scientific community, however, remains that the use of agents must be rigorously considered on a case-by-case basis and with caution in research or clinical trial settings[4]. Determining the effectiveness of CQ/HCQ will aid in preventing the spread of misinformation. 

Introduction 

Responsible for taking the lives of 2,244,713 people worldwide (as of February 3, 2021), the World Health Organization (WHO) classified COVID-19 as a pandemic in March 2020 (5,6). SARS-CoV-2, the virus responsible for COVID-19, is only one of seven identified human coronaviruses and is primarily transmitted from person-to-person through direct contact, saliva, and airborne droplets. It is considered “novel” because it is newly identified and is different from the other coronaviruses that have been linked with causing mild illnesses, such as the common cold [7]. Because of its novel nature, there is much that is unknown about the virus and the disease, and unfortunately misinformation regarding treatments has been spread, specifically the effectiveness of chloroquine (CQ)/ hydroxychloroquine (HCQ) as a treatment [7]. 

CQ and HCQ are antimalarial treatments, and interest in these drugs as possible treatments for COVID-19 was spurred in part from the drugs’ history of in vitro activity against viruses such as influenza. HCQ’s role in modulating the immune system through treating other autoimmune diseases, including systemic lupus erythematosus and rheumatoid arthritis, could have also played a role [4,7].  

In April 2020, nearly 55 countries, including the US, Mauritius, and Seychelles, were in the process of receiving HCQ from India [8]. Country leaders, including Brazil’s President Jair Bolsonaro and United States’s President Donald Trump, showed support for the drug, some even claiming to have taken it [9,10]. 

In the months since, however, scientists and national agencies have discouraged the use of CQ and HCQ against treatment for COVID-19, claiming that its effectiveness hasn’t been proven yet. Evaluating the research surrounding CQ and HCQ’s effectiveness is critical in order to address misconceptions and misinformation that is being spread as well as to evaluate its role as a potential treatment.

This paper will be reviewing two studies presenting contradictory evidence regarding the effectiveness of CQ/HCQ. In the first study published on March 16, 2020, Gao et al. examines the effectiveness of CQ in the early stages of the COVID-19 pandemic. Later, a study published on October 20, 20202 by Skipper et al., provides a more comprehensive comparison documenting HCQ’s utility.

Materials and Methods 

Gao et al., one of the early breakthrough studies which found favorable results in treating pneumonia associated with COVID-19 with CQ/HCQ, first conducted in vitro studies in which CQ was tested against the COVID-19 infection [2]. After a determination of a half-maximal effective concentration (EC50) and a half-cytotoxic concentration (CC50), multiple clinical trials were then conducted in China.100 patients from more than 10 hospitals in Wuhan, Jingzhou, Guangzhou, Beijing, Shanghai, Chongqing, and Ningbo were treated with chloroquine phosphate and results, including lung imaging findings, were gathered. 

The following section examines the method used in Skipper et al, which found that HCQ did not significantly decrease the severity of symptoms among patients experiencing early, mild COVID-19[3]. The study is the first randomized clinical trial studying COVID-19 treatments among outpatients with early, mild COVID-19 through a randomized, placebo-controlled procedure.

Participants

Participants included non-hospitalized, symptomatic adults that either were lab-tested for COVID-19 or those who demonstrated COVID-19 compatible symptoms and had an epidemiologic link to a lab-confirmed COVID-19 contact. Due to the scarcity of COVID-19 tests during the time the study was conducted, not all of the participants were tested for COVID-19, and the second criterion had to be included to recruit subjects. Further, adults were only enrolled if they had experienced COVID-19 symptoms for 4 or fewer days.

A total of 491 subjects were enrolled in the study (244 assigned to HCQ and 247 assigned to placebo), however only 423 contributed toward data collection (231 assigned to HCQ and 234 assigned to placebo) because they had completed at least 1-follow up survey with symptom data. 

 14-Day Trial

Participants were given either 200-mg tablets of HCQ sulfate or masked placebos of either 400mcg folic acid or lactose by a research pharmacist. Both the HCQ and placebo shared similar physical characteristics and opaque dispensary bottles so that the two tablets were hard to distinguish between. 

On the first day, adults in the experimental group first took 800mg of oral HCQ (4 tablets) and an additional 600mg (3 tablets) after 6 to 8 hours. For 4 more days after, participants continued to take 600 mg daily (for a total of 5 days). Participants in the placebo group were prescribed to take the placebo tablets in a similar regiment. The dose was based on previously published pharmacokinetic measures that serve to maintain the HCQ concentration above the EC50 for SARS-Co-V-2. 

Outcomes and Data Collection

Researchers collected data regarding symptoms and severity through participant-reported surveys on day 1 (baseline), 3, 5 (end of medication), 10, and 14. A 10-point visual analogue scale was used to collect data regarding symptom severity. The study’s primary endpoint was a measure of overall change in symptoms throughout the study’s 14-day period.

Results 

Although both Gao et al. and Skipper et al. examine the effectiveness of CQ and/or HCQ against SARS -CoV-2, the studies report different experimental approaches and results

While Gao et al. didn’t publish the exact data and figures for their study, they concluded that the patients treated with CQ showed better results in inhibiting the exacerbation of pneumonia, facilitating an environment for virus-negative conversion, improving lung imaging, and reducing the disease course [2]. Researchers also noted that no severe adverse reactions as a result of the CQ were found among the 100 patients.

In the Skipper et al. study however, differences in data collected between the placebo and HCQ were not significant [3]. As depicted in Figure 1, data on day 5 of the study showed that 54% of participants in the HCQ group reported symptoms versus 56% in the placebo group. Further, at day 14, 24% in the HCQ group reported symptoms compared to 30% in the placebo group. The study concluded that the proportion of participants that reported symptoms was not significantly different between the HCQ and placebo group.

Figure 1. Percentage of participants reporting COVID-19 symptoms throughout the Skipper et al. study’s 14-day time period [3]. On day 5, the percentage of HCQ participants with symptoms was 2 points less than that of the placebo participants, and by day 14, the difference had increased to 6 points, but still not enough for statistical significance.

In addition to the proportion of COVID-19 symptoms observed in both groups, Skipper et al. recorded the severity of the symptoms based on a 10-point visual scale. As shown in Figure 2, the participants in the HCQ group reported an average reduction of symptom severity of 2.60 throughout the 14 day period, while placebo participants reported a 2.33-point reduction. Although the HCQ group saw an overall 12% more reduction in symptom severity compared to the placebo group, the difference was, once again, not statistically significant.

Figure 2. Overall scores of symptom severity throughout the Skipper et al. study’s 14-day time period [3]. Although the data showed a 12% relative reduced severity difference for the HCQ in comparison to the placebo, it was not statistically significant.

Discussion

Gao et al. is one of the earliest studies that showed favorable results for CQ. The researchers have hypothesized that evidence for the CQ’s anti-viral properties lies in previous studies which have found the drug to increase the endosomal pH needed for the fusion of the virus. In addition the drug is suspected to cause interference with the glycosylation of the SARS-CoV cellular receptors [11,12]. Based on these findings along with the timing of the study (before the WHO classified COVID-19 as a pandemic), the researchers recommended CQ be used to treat patients that experience pneumonia associated with COVID-19 in China.

Therefore, although Skipper et al. points out differences among the HCQ and placebo groups, they weren’t statistically significant, contradictory to the findings of Gao et al.

Conclusion

Differences in results across studies, as sampled through Gao et al. and Skipper et al., have led scientists to continue to question and rethink the effectiveness of HCQ/CQ against COVID-19. While a concrete conclusion regarding the drugs’ fates is yet to be determined, scientists continue to caution the use of HCQ/CQ for public use and rather recommend the drug to preferably only be administered under carefully designed clinical trials, as well as examined on a case-by-case basis [4]. 

With vaccinations becoming more widely available, discussion and debate centered around the administration of HCQ/CQ has largely reduced, and rather, the focus has shifted towards the effectiveness of the vaccines. Although a 2021 study has found the Moderna vaccine to be antibody persistent through 6 months, there isn’t exact data regarding the maximum efficiency of this particular vaccine as well as that for the Pfizer-BioNTech and Johnson & Johnson vaccines, the two others approved by the Food and Drug Administration [13]. Future directions of study can involve a close examination of these vaccines. Results and information collected from the close examination of these vaccines would be critical in planning the continued management of the COVID-19 pandemic in the United States. 

References 

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[2] Gao, J. et al. BioSci. Trends 2020, 14, 72-73

[3] Skipper, C. P. et al. Ann. Intern. Med 2020, 173, 623-631

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[7] Centers for Disease Control and Prevention. https://www.cdc.gov/ (accessed Feb. 3, 2021)

[8] India sending hydroxychloroquine to 55 coronavirus-hit countries. The Economic Times, April 16, 2020. https://economictimes.indiatimes.com/news/politics-and-nation/india-sending-hydroxychloroquine-to-55-coronavirus-hit-countries/articleshow/75186938.cms?utm_source=contentofinterest&utm_medium=text&utm_campaign=cppst (accessed Feb. 3, 2021)

[9]Stargardter, G.; Paraguassu, L. Special Report: Bolsonaro bets 'miraculous cure' for COVID-19 can save Brazil - and his life. Reuters, July 8, 2020. https://www.reuters.com/article/us-health-coronavirus-brazil-hydroxychlo/special-report-bolsonaro-bets-miraculous-cure-for-covid-19-can-save-brazil-and-his-life-idUSKBN249396 (accessed Feb. 3, 2021)

[10] Bruggeman, L. Hydroxychloroquine returns as wedge between President Trump, health advisers. ABC News, July 28, 2020. https://abcnews.go.com/Politics/hydroxychloroquine-returns-wedge-president-trump-health-advisers/story?id=72036996 (accessed Feb. 3, 2021)

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[13] Doria-Rose, N. et al. NEJM. 2021