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<meta name="author" content="David Mai" />
<meta name="author" content="COVID-19 Review Consortium" />
<meta name="author" content="Rishi Raj Goel" />
<meta name="dcterms.date" content="2021-02-11" />
<meta name="dcterms.date" content="2021-02-12" />
<meta name="keywords" content="covid-19, coronavirus, pandemic, viral infection" />
<title>SARS-CoV-2 and COVID-19: An Evolving Review of Diagnostics and Therapeutics</title>
<style>
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<meta name="citation_title" content="SARS-CoV-2 and COVID-19: An Evolving Review of Diagnostics and Therapeutics" />
<meta property="og:title" content="SARS-CoV-2 and COVID-19: An Evolving Review of Diagnostics and Therapeutics" />
<meta property="twitter:title" content="SARS-CoV-2 and COVID-19: An Evolving Review of Diagnostics and Therapeutics" />
<meta name="dc.date" content="2021-02-11" />
<meta name="citation_publication_date" content="2021-02-11" />
<meta name="dc.date" content="2021-02-12" />
<meta name="citation_publication_date" content="2021-02-12" />
<meta name="dc.language" content="en-US" />
<meta name="citation_language" content="en-US" />
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<meta name="citation_fulltext_html_url" content="https://greenelab.github.io/covid19-review/" />
<meta name="citation_pdf_url" content="https://greenelab.github.io/covid19-review/manuscript.pdf" />
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Expand All @@ -276,10 +276,10 @@ <h1 class="title">SARS-CoV-2 and COVID-19: An Evolving Review of Diagnostics and
</header>
<p><small><em>
This manuscript
(<a href="https://greenelab.github.io/covid19-review/v/5822da1e097d49fb38a7d428fce08296475aaa07/">permalink</a>)
(<a href="https://greenelab.github.io/covid19-review/v/c416bb3246187a6aea9a94f8695807123994fd34/">permalink</a>)
was automatically generated
from <a href="https://github.com/greenelab/covid19-review/tree/5822da1e097d49fb38a7d428fce08296475aaa07">greenelab/covid19-review@5822da1</a>
on February 11, 2021.
from <a href="https://github.com/greenelab/covid19-review/tree/c416bb3246187a6aea9a94f8695807123994fd34">greenelab/covid19-review@c416bb3</a>
on February 12, 2021.
</em></small></p>
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One week later, 4,593 confirmed cases had been identified, spanning not only Asia, but also Australia, North America, and Europe <span class="citation" data-cites="fLTiwToY">[<a href="#ref-fLTiwToY" role="doc-biblioref">2</a>]</span>.
On March 11, 2020, the WHO formally classified the situation as a pandemic <span class="citation" data-cites="x9975iBK">[<a href="#ref-x9975iBK" role="doc-biblioref">3</a>]</span>.
On April 4, 2020, the WHO reported that the global number of confirmed cases had surpassed one million <span class="citation" data-cites="1GACP7OZY">[<a href="#ref-1GACP7OZY" role="doc-biblioref">4</a>]</span>.
<!--2,341,104 COVID-19 deaths had been reported worldwide as of February 9, 2021 (Figure @fig:csse-deaths).
<!--2,354,561 COVID-19 deaths had been reported worldwide as of February 10, 2021 (Figure @fig:csse-deaths).

![
**Cumulative global COVID-19 deaths since January 22, 2020.**
Data are from the COVID-19 Data Repository by the Center for Systems Science and Engineering at Johns Hopkins University [@https://github.com/CSSEGISandData/COVID-19/tree/master/csse_covid_19_data/csse_covid_19_time_series].
](https://github.com/greenelab/covid19-review/raw/d6a1b50233412eb17be0cdd498936cdd35ba58a5/csse/csse-deaths.png "Global COVID-19 deaths"){#fig:csse-deaths secno=1} --></p>
](https://github.com/greenelab/covid19-review/raw/63d77f6dd1352bbaeaa48f27ed1200032e9058c6/csse/csse-deaths.png "Global COVID-19 deaths"){#fig:csse-deaths secno=1} --></p>
<p>As international attention remains focused on the ongoing public health crisis, the scientific community has responded by mobilizing resources and turning much of its attention to the virus and disease.
This rapid influx of information is disseminated by traditional publishing mechanisms, preprint servers, and press releases, which provide a venue for scientists to release findings without undergoing the formal publication process.
While having information available is valuable to efforts to understand and combat COVID-19, many contributions come from researchers across a wide range of fields who have varying degrees of experience working on coronaviruses and related topics.
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Prophylactics bolster immunity to prevent an individual from contracting a disease, whereas therapeutics treat a disease in individuals who have already been infected.
While vaccine development programs have attracted significant attention and produced a number of promising candidates, there is also an immediate need for treatments that palliate symptoms and prevent the most severe outcomes from infection.
Fortunately, prior developments during other recent pandemics, especially those caused by human coronaviruses (HCoV), has provided a number of hypotheses guiding a biomedical approach to the novel coronavirus infection.</p>
<p>2,341,104 COVID-19 deaths had been reported worldwide as of February 9, 2021 (Figure <a href="#fig:csse-deaths">2</a>).</p>
<p>2,354,561 COVID-19 deaths had been reported worldwide as of February 10, 2021 (Figure <a href="#fig:csse-deaths">2</a>).</p>
<div id="fig:csse-deaths" class="fignos">
<figure>
<img src="https://github.com/greenelab/covid19-review/raw/d6a1b50233412eb17be0cdd498936cdd35ba58a5/csse/csse-deaths.png" alt="" /><figcaption><span>Figure 2:</span> <strong>Cumulative global COVID-19 deaths since January 22, 2020.</strong>
<img src="https://github.com/greenelab/covid19-review/raw/63d77f6dd1352bbaeaa48f27ed1200032e9058c6/csse/csse-deaths.png" alt="" /><figcaption><span>Figure 2:</span> <strong>Cumulative global COVID-19 deaths since January 22, 2020.</strong>
Data are from the COVID-19 Data Repository by the Center for Systems Science and Engineering at Johns Hopkins University <span class="citation" data-cites="MrwDDw9R">[<a href="#ref-MrwDDw9R" role="doc-biblioref">368</a>]</span>.</figcaption>
</figure>
</div>
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As results become available from additional clinical trials, we will continue to update this manuscript to keep pace with the current understanding of which therapeutics may be effective against SARS-CoV-2 or for COVID-19.</p>
<div id="fig:ebm-trials" class="fignos">
<figure>
<img src="https://github.com/greenelab/covid19-review/raw/d6a1b50233412eb17be0cdd498936cdd35ba58a5/ebmdatalab/ebmdatalab-trials.png" alt="" /><figcaption><span>Figure 3:</span> <strong>COVID-19 clinical trials.</strong>
<img src="https://github.com/greenelab/covid19-review/raw/63d77f6dd1352bbaeaa48f27ed1200032e9058c6/ebmdatalab/ebmdatalab-trials.png" alt="" /><figcaption><span>Figure 3:</span> <strong>COVID-19 clinical trials.</strong>
There are 6,417 COVID-19 clinical trials and 168 trials with results as of November 9, 2020.
The recruitment statuses and trial phases are shown only for trials in which the status or phase is recorded.
The study types include only types used in at least five trials.
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<h5 data-number="5.4.2.2.1" id="trials-assessing-therapeutic-administration-of-hcqcq"><span class="header-section-number">5.4.2.2.1</span> Trials Assessing Therapeutic Administration of HCQ/CQ</h5>
<p>The initial study evaluating HCQ as a treatment for COVID-19 patients was published on March 20, 2020 by Gautret et al. <span class="citation" data-cites="ovHLMvCi">[<a href="#ref-ovHLMvCi" role="doc-biblioref">463</a>]</span>.
This non-randomized, non-blinded, non-placebo clinical trial compared HCQ to standard of care (SOC) in 42 hospitalized patients in southern France.
It reported that patients who received HCQ showed higher rates of virological clearance by nasopharyngeal swab on Days 3-6 when compared to SOC.
It reported that patients who received HCQ showed higher rates of virological clearance by nasopharyngeal swab on days 3-6 when compared to SOC.
This study also treated six patients with both HCQ + AZ and found this combination therapy to be more effective than HCQ alone.
However, the design and analyses used showed weaknesses that severely limit interpretability of results, including the lack of randomization, lack of blinding, lack of placebo, lack of Intention-To-Treat analysis, lack of correction for sequential multiple comparisons, trial arms entirely confounded by hospital, false negatives in outcome measurements, lack of trial pre-registration, and small sample size.
Two of these weaknesses are due to inappropriate data analysis and can therefore be corrected <em>post hoc</em> by recalculating the p-values (lack of Intention-To-Treat analysis and multiple comparisons).
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<p>Because of the preliminary data presented in this study, HCQ treatment was subsequently explored by other researchers.
About one week later, a follow-up case study reported that 11 consecutive patients were treated with HCQ + AZ using the same dosing regimen <span class="citation" data-cites="18KmvBOFr">[<a href="#ref-18KmvBOFr" role="doc-biblioref">465</a>]</span>.
One patient died, two were transferred to the intensive care unit (ICU), and one developed a prolonged QT interval, leading to discontinuation of HCQ + AZ administration.
As in the Gautret et al. study, the outcome assessed was virological clearance at Day 6 post-treatment, as measured from nasopharyngeal swabs.
Of the ten living patients on Day 6, eight remained positive for SARS-CoV-2 RNA.
As in the Gautret et al. study, the outcome assessed was virological clearance at day 6 post-treatment, as measured from nasopharyngeal swabs.
Of the ten living patients on day 6, eight remained positive for SARS-CoV-2 RNA.
Like in the original study, interpretability was severely limited by the lack of a comparison group and the small sample size.
However, these results stand in contrast to the claims by Gautret et al. that all six patients treated with HCQ + AZ tested negative for SARS-CoV-2 RNA by Day 6 post-treatment.
However, these results stand in contrast to the claims by Gautret et al. that all six patients treated with HCQ + AZ tested negative for SARS-CoV-2 RNA by day 6 post-treatment.
This case study illustrated the need for further investigation using robust study design to evaluate the efficacy of HCQ and/or CQ.</p>
<p>On April 10, 2020, a randomized, non-placebo trial of 62 COVID-19 patients at the Renmin Hospital of Wuhan University was released <span class="citation" data-cites="wzHb7Mj5">[<a href="#ref-wzHb7Mj5" role="doc-biblioref">466</a>]</span>.
This study investigated whether HCQ decreased time to fever break or time to cough relief when compared to SOC <span class="citation" data-cites="wzHb7Mj5">[<a href="#ref-wzHb7Mj5" role="doc-biblioref">466</a>]</span>.
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Trials that recruit across multiple countries do appear to broaden geographic representation, but these trials seem to be heavily dominated by the United States and European Union.</p>
<div id="fig:ebm-map" class="fignos">
<figure>
<img src="https://github.com/greenelab/covid19-review/raw/d6a1b50233412eb17be0cdd498936cdd35ba58a5/ebmdatalab/ebmdatalab-map.png" alt="" /><figcaption><span>Figure 6:</span> <strong>Geographic distribution of COVID-19 clinical trials.</strong>
<img src="https://github.com/greenelab/covid19-review/raw/63d77f6dd1352bbaeaa48f27ed1200032e9058c6/ebmdatalab/ebmdatalab-map.png" alt="" /><figcaption><span>Figure 6:</span> <strong>Geographic distribution of COVID-19 clinical trials.</strong>
The density of clinical trials is reported at the country level.
As of November 9, 2020, there are 6,417 trials in the University of Oxford Evidence-Based Medicine Data Lab’s COVID-19 TrialsTracker <span class="citation" data-cites="SSbnPnzT">[<a href="#ref-SSbnPnzT" role="doc-biblioref">371</a>]</span>.
The top figure demonstrates the density of trials recruiting only from a singular country, while the bottom shows the distribution of recruitment for trials that involve more than one country.</figcaption>
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