A major clinical trial finds no benefit of hydroxychloroquine in treating covid-19

A newly published study out of the United Kingdom has found that hydroxychloroquine is not effective in the fight against covid-19. The study was performed by the RECOVERY research team, the same collaboration that published the ground-breaking randomized clinical trial on the use of dexamethasone in covid-19, the first treatment shown in a clinical trial to improve mortality among patients who required oxygen or mechanical ventilation (though no benefit was found in patients without those needs, with a suggestion of potential harm among those patients). This new randomized clinical trial was conducted across 176 hospitals in the U.K. Patients included in the study were diagnosed with SARS-CoV-2 infection and the primary outcome of interest was mortality after 28 days. A total of 1,561 and 3,155 patients were randomized either to hydroxychloroquine (HCQ) plus standard-of-care treatments (such as oxygen as needed, and other non-specific supportive treatments) or standard-of-care treatment only, respectively. The results of the study were sobering. The mortality rate from covid-19 was 26.8% in the HCQ group and 25% in the standard-of-care group—which was not a statistically significant difference. Not only did a quarter of subjects die, but HCQ provided no mortality benefit. Interestingly, those who received HCQ had longer lengths of stay in the hospital and were also more likely to reach what researchers call a "composite endpoint," of two outcomes (in this case the need for mechanical ventilation or death) when compared to patients who did not receive HCQ (29.8% vs. 26.5%; with a risk ratio 1.12. (Risk ratios refer to the probability of a certain outcome in one group compared to the probability of the same outcome in another group, in this case, receiving HCQ or not) The statistical analysis suggests that the researchers can be 95% confident that the true number is somewhere between 1.01 and 1.25.  The one silver-lining of the study is that high-doses of HCQ did not confer an excess risk of side effects (i.e., new major cardiac arrhythmia, which is a known risk associated with the medication). 

There are a few major takeaways from this study. First, this study represents the largest and most important randomized clinical trial on the use of HCQ in hospitalized covid-19 patients to date. Patients receiving HCQ were randomized to the drug or not, whereas in previous observational studies (in which researchers looked back at charts of previous cases) sicker patients were often exposed to HCQ, thereby introducing selection bias (in other words, it is possible that patients who received HCQ in those studies fared worse because they were more seriously ill at the outset). In the final analysis, these new results from the RECOVERY study highlight a lack of mortality reduction among patients who received HCQ, and an apparent association with (if not a direct cause of) increased hospital lengths of stay and the need for mechanical ventilation. The argument for HCQ use in covid-19 is quickly dying. 17 July 2020.

Research Section Editor

Coronavirus vaccine based on genetic material reports Phase 1 results

The authors of a new study appearing in The New England Journal of Medicine published evidence that an mRNA vaccine made by Moderna Therapeutics did not show signs of being toxic, was well-tolerated, and induced the production of antibodies against the Spike protein, a component of the virus thought to be responsible for the virus' increased virulence. In this Phase 1 trial, 45 volunteers with no detectable coronavirus received two shots 28 days apart. The 45 participants were divided into three groups depending on whether they received 25, 100, or 250 micrograms of the vaccine. Three out of 15 participants in the highest dose group had severe adverse effects, including a large red rash and one episode of passing out.

An mRNA vaccine is a novel approach. Moderna's vaccines would be the first approved for human use based on this recent technology. Instead of the usual approach of baiting the immune system with a weakened form of a virus, mRNA vaccines act like a software update for the genome of immune cells. One upside of mRNA vaccines is that they do not integrate into the DNA of the host's cells. This means they are less likely to have the side effects associated with similar vaccines that are made from DNA. A downside is that mRNA vaccines are less likely to give a provide long-lasting immune responses precisely because they don't fully integrate into the host's DNA.

One major gap in the data: the vaccine was not was not studied in older individuals with pre-existing medical conditions, the part of the population most at risk for death or disability from covid-19. Older individuals may not respond as briskly to these doses of the vaccine, which could force a choice between higher doses which would be accompanied by more adverse effects and lower doses that are less likely to confer immunity, though would have fewer side effects.

The results of this study are encouraging, though successful Phase I trials only indicate that a vaccine is not immediately toxic among a small group of healthy volunteers. Even if the phase II and phase III trials are less promising, the development of preliminarily safe mRNA vaccine is a substantial achievement. Abbreviated from Brief19 for 15 July 2020.

Has covid-19 affected the prison population?

One of the foundational mitigation principles in the covid-19 pandemic is social distancing. Unfortunately, the prison system makes social distancing uniquely difficult. Given this context, an interesting paper was recently published in JAMA that examined covid-19 case rates and deaths among federal and state prisoners. The researchers used data from the UCLA School of Law "COVID-19 Behind Bars Data Project," an extensive and nationally comprehensive database of the prison system in the United States, covering March 31, 2020, to June 6, 2020.

Astonishingly, by June 6 there were 42,107 cases of covid-19 among U.S. prisoners with a SARS-CoV-2 case rate of 3,251 per 100,000 prisoners. This case rate was approximately 5.5 times higher than that measured among the general U.S. population, a case rate of 587 per 100,000 persons during the same time period. The crude death rate was also higher in the prison population compared to the U.S. population at 39 deaths versus 29 deaths per 100,000 persons, respectively. When accounting for age and sex differences between the prison population and the general population, the adjusted death rate from covid-19 was three times greater for prisoners than the general U.S. population. Finally, the mean daily case growth rate was 8.3% per day in prisons versus 3.4% per day in the U.S. population.

This study had a few limitations that say more about the prison system in the U.S. than the research itself. First, officially reported data are the only available data on prison disease and deaths. Transparency could be an issue, though it is unknown if such issues had any effect on the data. Second, comprehensive data on testing rates were not made available. Finally, Departments of Corrections generally do not report demographic data on individuals who died. In this context, it is possible and even likely that the real covid-19 case rates and death rates are in reality substantially higher among the prison population than even these numbers suggest. National policies that improve prison conditions to prevent such outcomes are urgently needed. 13 July 2020.

Research Section Editor


Covid-19 and mental health

As the American public listens to extensive non-stop media coverage about covid-19, while sifting through piles of misinformation and battling an economic downturn, it is no surprise that anxiety and depression are on the rise. Mental health crises have become the underlying pandemic beneath the pandemic. In the United States, approximately 20 percent of the population will have some form of mental health problem per year; only half will receive treatment. A poll conducted by the Kaiser Family Foundation revealed that 56 percent of adults in the United States have experienced negative impacts on their mental health as a result of the covid-19 pandemic. Black and Latinx individuals reported a slightly higher rate of mental health concerns, likely as a result of the disproportionate effect covid-19 has had in those communities. Healthcare workers were also noted to be heavily affected. As a result, online therapy platforms, crisis hotlines and mental health centers are experiencing record surges.

In spite of these numbers, the Coronavirus Aid, Relief, and Economic Security Act (CARES Act) allocated only a fraction of its funding to mental health efforts; $425 million out of $2 trillion. This has major implications for a country that is still learning what to do with its fragmented and overburdened mental health care system. Various. 17 July 2020.

Why antibody tests that are "95 percent accurate" might actually be dangerous

Understanding statistics is never easy, but it is an essential skill in assessing covid-19 research and policy. We invited an expert in data sciences to write this essay on how and why antibody tests may mislead the public. —Brief19

Blood tests that detect antibodies against SARS-CoV-2 are being presented as a cure-all for letting people go back to work amid the covid-19 pandemic. The hope is that such tests might identify individuals who had unknowingly caught the virus and recovered, and are now immune. However, a statistical wrinkle means that even if an antibody test is correct 95 percent of the time that it gives a positive result (and never misses a real case) a positive test might still mean that there is well under a 50 percent chance that the person who took the test truly has antibodies. To understand why, let's first go through the four potential outcomes:

1) You are positive, and you test positive. Test did its job.

2) You are negative, and you test negative. Test did its job.

3) False negative. The test says you don't have antibodies, but you do.

4) False positive. The test says you do have the antibodies, but you don't.

In the case of coronavirus antibody testing, Option 4 (false positive) is dangerous. It might cause you to resume your normal life, mistakenly believing yourself to be immune to the virus and unable to spread it.

What is the chance of Option 4 occurring in an antibody test that has a known false positive rate of 5 percent (such as Cellex, the first FDA approved antibody test)? Let's imagine testing 1,000 people in a population in which 3 percent have been infected and have antibodies. Thirty people will have antibodies and test positive (3 percent of 1,000 people, as expected). But, 50 people will falsely test positives (5 percent of 1,000 people).

But all 80 of these individuals, whether they have antibodies or not, will have tested positive for them. This means that someone who tested positive for antibodies only has 37.5 percent chance of actually having them (30 actual cases out of 80 positive tests). So even a test that is 95 percent accurate leaves someone who tested positive with less than a 50/50 chance of having gained any information. It's worse than tossing a coin.

Some tests claim to be 98.8 percent effective, some 92 percent. Regardless, as the above math shows, many who take these tests will think they have antibodies and are therefore immune, but in reality, do not and are not.

Here's the catch. If a significant proportion of the population (i.e. far more than 3 percent) has already had coronavirus, then we are in a very different situation.

Imagine that instead of 3 percent, 90 percent of the population has actually been infected and now has antibodies. In this scenario, 900 out of 1000 people will test positive and be positive. Of course as before, 50 people (5 percent) will test positive while not actually having antibodies. But at least in this scenario, the chance of being positive, if you test positive is 95 percent (900/950).

What does this all mean? Unless a large percentage of the population has had coronavirus (and has antibodies), antibody tests are irrelevant.

We need to stop using the words "accurate" and confusing tests that sound useful with ones that are if we want the public to understand their risk with respect to testing. The development of sound policy over the coming months may depend upon it. 16 July 2020.

Professor of the Practice of Data Sciences, Washington University in St. Louis, and Feature Editor for the Harvard Data Science Review.

Reopening schools while infections are rising

Amidst the backdrop of multiple record-breaking days of new coronavirus cases, the Trump Administration is moving forward with plans to reopen schools in the fall, citing the return to academic normalcy as best for students. Contrasting with the United States Centers for Disease Control and Prevention (CDC)'s announcement that school guidelines will not be revised in an effort to hasten opening, and the National Institute of Allergy and Infectious Diseases director Dr. Anthony Fauci calling for a cautious, data-based approach, officials stated the risk to students' mental health and social development outweigh the risk posed by the coronavirus. As state and school officials have opposed what is seen as an unnecessary risk due to the unknown role of asymptomatic and airborne transmission, Department of Education Secretary Betsy DeVos raised the possibility of cutting federal funding to states that do not comply with the administration's stated wishes. Various. 13 July 2020.

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  • A major clinical trial finds no benefit of hydroxychloroquine in treating covid-19
  • HHS pledges $4 billion to healthcare providers
  • Covid-19 and mental health

  • Data from Italy suggests that covid-19 deaths are being undercounted there too
  • CDC in the news. Three major developments