What medication options are available for COVID-19?

Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis

Background Hydroxychloroquine or chloroquine, often in combination with a second-generation macrolide, are being widely used for treatment of COVID-19, despite no conclusive evidence of their benefit. Although generally safe when used for approved indications such as autoimmune disease or malaria, the safety and benefit of these treatment regimens are poorly evaluated in COVID-19.

Methods We did a multinational registry analysis of the use of hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19. The registry comprised data from 671 hospitals in six continents.

Findings 96 032 patients (mean age 53·8 years, 46·3% women) with COVID-19 were hospitalised during the study period and met the inclusion criteria. Of these, 14 888 patients were in the treatment groups (1868 received chloroquine, 3783 received chloroquine with a macrolide, 3016 received hydroxychloroquine, and 6221 received hydroxychloroquine with a macrolide) and 81 144 patients were in the control group. 10 698 (11·1%) patients died in hospital.

Interpretation We were unable to confirm a benefit of hydroxychloroquine or chloroquine, when used alone or with a macrolide, on in-hospital outcomes for COVID-19. Each of these drug regimens was associated with decreased in-hospital survival and an increased frequency of ventricular arrhythmias when used for treatment of COVID-19.

PIIS0140673620311806 (1)

Where did you go my (CORONA) lovely?

This is a discussion in an email list-server between EBM experts.

“I was recently made aware that since April 16 or so, no new cases with COVID19 were reported in China [https://www.worldometers.info/coronavirus/country/china/]. Assuming that data are accurate, this is puzzling and I would be interested in learning possible explanations where did SARS-CoV2 go in China? 

Typically, pandemic is supposed to be under control when herd immunity develops, which in case of COVID19 requires that at least 60% of population develops effective antibody response. This is unlikely to be the case. Which leaves us with the question could social distancing measures followed by the contact tracing accomplish the feat?  In other words, after the curve is “crushed” using severe social distancing measures followed by testing, tracing and isolation as one reopens society, can this theoretically lead to elimination of the virus (as presumably every isolated case will recover or die without spreading the virus to uninfected people)? 
We have heard all along that social distancing only buys us time until effective vaccine is developed. But, if China has already effectively controlled the virus, then vaccine may not be necessary.  [A related question is what are possible mechanisms that lead to the end of pandemics]?
 
From New Zealand “That’s exactly what we have done in New Zealand. We had 1 month of severe restrictions, starting 25th March, then 2 weeks of moderate restrictions and now minimal restrictions other than a closed border. During that period we rapidly increased testing and contact tracing. 
We have only had 2 cases in the last 7 days, both linked to known clusters and who were already self-isolated.
Elimination is possible without a vaccine. All you have to do is keep infected people away from everyone else. It’s not rocket science, just a ton of work, and I would advise you to wear a mask.

Another member chipped in saying that this article  will shed some light- Seasonal and pandemic influenza: 100 years of progress, still much to learn https://www.nature.com/articles/s41385-020-0287-5 

In this list we really have an open conversation as another from the US stated: “Sorry to be non-evidenced (or is that non-scientific).  But, I’ve been told (“lots of people tell me”) that if something looks too good to be true, it is probably not true.  This has buzzed my ‘fake meter’.  I’d be interested to hear any other information about this.  
 
I certainly think that an ultra-authoritarian government could create an ‘ultra-lockdown’ that could prevent almost all interpersonal contact for over 2 weeks, enough to kill the spread of the virus.  That would probably need closed borders too.”
 
Came the reply from NZ, “A very non-ultra-authoritarian government (New Zealand) created an ultra-lockdown with closed borders for 4 weeks plus rapidly scaled up testing and contact tracing and voila! Elimination. Just took a bit of leadership.”
 
A UK expert suggested. 
It is helpful to have a fake o meter. 
However in this case it is simple: countries with good leaders who followed pre-existing pandemic plans have sorted Covid out with relatively minimal disruption. 
Others (esp UK and US) have been, according to Richard Horton (Editor Lancet), criminally incompetent. 
 
Conversations goes on,
‘I totally agree with you R and J.   However, in my infinite ignorance I think of New Zealand as a small and very congenial country while China is HUGE and much more diverse.  Also, whenever someone reports 0 (yes, ZERO) cases it just doesn’t seem correct.  There must have been a few slip ups.  Sorry, but this just doesn’t make sense.  If it were true it would blow the “so what test” out of the water.  And, we’d all want to know the details.  Sorry to keep jamming on this theme.’
 
This is truely Global list! comes a Canadian Chinese academic. ‘The data from the link you checked below weren’t updated very well. Please look at this one at the English version: https://sa.sogou.com/new-weball/page/sgs/epidemic?type_page=VR. The data on this website are updated everyday, at least the info for Canada is consistent with what I know from Canadian websites.

I asked my friends in China and confirmed that there are some asymptomatic patients and few symptomatic patients in China everyday. If everyone wears a mask and keep social distance, we probably really do not need vaccine for COVID-19 or any influenza. However, it’s impossible and also I don’t like this life style. So, I still look forward to the effective vaccine.’

Reply from the list: ‘Whether the cases are zero or few, the implications remain the same: it is possible to eliminate the virus by social measures only! I have never heard this before but R from NZ confirmed in one of his earlier responses that this is possible. 
(And, given huge differences in geography and the population size between China and NZ, this also implies that density is not an issue, which has been a key force causing a huge number of deaths in NYC and Northern Italy).
R and colleagues: are you aware of any historical precedents that a pandemic was controlled by social/public health  measures only (and in such a short period of time)? Any references to this effect would be welcome.
 
An Oxford university EBM expert has this to say….
‘You are correct that 0 is unlikely, thanks for making that important point. It assumes perfect testing etc.
I think we need to look at the claim about 0 tests more charitably (while pointing out that it is based on strong assumptions). 
This is because there is a range of countries who have got close enough to 0 for the virus to be manageable enough to open up the economy. These include Taiwan (beside PR China more densely populated than anyone who has not been there can imagine), NZ (sparsely populated, got it late) and others.
The countries where it is a s*+t show, and where they are making decisions between lives lost due to virus and lives lost due to economic disaster are those that did not Follow pre-existing pandemic plans (many were published a long time ago: https://www.who.int/influenza/preparedness/pandemic/en/). 
This is a key point because we need to follow the same plans now and for the next one. 
 
A very interesting email from UK…
This is a key point because we need to follow the same plans now and for the next one.
The key point is: Who is “we”.
In many parts of the world a lockdown that would effectively stop an epidemic is (a) impossible; (b) made more impossible by their country’s poor leadership, corrupt governance, limited public services; and (c) aggravates food insecurity and other humanitarian crisis.
Life is a lot more complicated than simply blaming poor leadership or ineffective lock downs.’
Another
‘Cannot agree more about the need to follow well-tested procedures, particularly when it comes to such serious public health threats as in case of COVID19. However, even when these rules are abolished, people still have to make their decisions. In such cases, they often resort to heuristics such as the one we described in this article [https://www.medrxiv.org/content/10.1101/2020.05.14.20093633v1] when in the wake of  reluctance of federal government in the US to assume leadership, the governors of individual states were left to make their own decisions how to deal with the corona-virus. The results show that the governors’ make predictable decisions according to the Weber-Fechner law of psychophysics.’
 
Then comes an Indian
Great point. The incompetent, corrupt governments and leaders may have created a new crises (hinge, malnourishment, death) while not dissolving the original crises. Die of Corona or die of malnutrition and hunger. Take your pick is the slogan for some of these countries. India’s youthful and old migrant laborer are literally walking hundred of miles, hungry and broken to reach their home destinations as they have no employment!. 
Hope we study both of these Public Health Crises along with COVID 19 when time is opportune in an evidence based fashion as what is the ‘cost of these interventions’ and the outcomes. And by the way, to me both are 2 legged animal made!’
In the current scenario, there are at least two main drugs that are being used – Hydroxychloroquine and Remdesevir. We need a head-to-head RCT of these two drugs ASAP.
 
There are a number of registered RCTs in the ClinicalTrials.gov
This is just two of the more than 50 trials registered (only in one register).
 
‘Coronavirus: scientists promoting chloroquine and remdesivir are acting like sports rivals’ states a CEBM expert [Reference-2]. Please read this excellent piece in the ‘Conversation’ for an in-depth view of the situation regarding treatment for COVID-19.
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A more advanced summary statistics that I do not understand very much which I include for the sake of completion – a technique called Network Meta-Analysis [Reference-3]. What these techniques can say about the available articles. 
 
The key question is what is the best treatment for COVID-19? (if medications are available in the market and Sri Lanka can afford the cost)
 
Obviously, it will have to be decided by an RCT. 
RCT is a ‘fair test’ that is done to decide the best treatment when more than more options are available.

Why treatment comparisons must be fair

Untrustworthy treatment comparisons are those in which biases, or the play of chance, or both result in misleading estimates of the effects of treatments. Fair treatment comparisons avoid biases and reduce the effects of the play of chance.

Failure to test theories about treatments in practice is not the only preventable cause of treatment tragedies. Tragedies have also occurred because the tests used to assess the effects of treatments have been unreliable and misleading. The principles of fair tests have been evolving for at least a millennium (list records coded Principles of Testing) – and they continue to evolve today (Savovic et al. 2012Jefferson et al. 2014).

To Do No Harm

For example, in the 1950s, theory and poorly controlled tests yielding unreliable evidence suggested that giving a synthetic sex hormone, diethylstilboestrol (DES), to pregnant women who had previously had miscarriages and stillbirths would increase the likelihood of a successful outcome of later pregnancies. Although fair tests had suggested that DES was useless, theory and the unreliable evidence, together with aggressive marketing, led to DES being prescribed to millions of pregnant women over the next few decades. The consequences were disastrous: some of the daughters of women who had been prescribed DES developed cancers of the vagina, and other children had other health problems, including malformations of their reproductive organs and infertility (Apfel and Fisher 1984).

HRT

Problems resulting from inadequate tests of treatments continue to occur. Again, because of unreliable evidence and aggressive marketing, millions of women were persuaded to use hormone replacement therapy (HRT). It was claimed that, not only could it reduce unpleasant menopausal symptoms, but also the chances of having heart attacks and strokes. When these claims were assessed in fair tests, the results showed that in women over 60, far from reducing the risks of heart attacks and strokes, HRT increases the risks of these life-threatening conditions, as well as having other undesirable effects. (McPherson 2004).

These examples of the need for fair tests of treatments are a few of many that illustrate how treatments can do more harm than good. Improved general knowledge about fair tests of treatments is needed so that – laced with a healthy dose of scepticism – we can all assess claims about the effects of treatments more critically. That way, we will all become more able to judge which treatments are likely to do more good than harm.

Fair tests entail taking steps to reduce the likelihood that we will be misled by the effects of biases of various sorts.  Those addressed in the James Lind Library include design biasallocation biasco-intervention biasobserver biasanalysis biasbiases in assessing unanticipated effectsreporting biasbiases in systematic reviews, and researcher biases and fraud.

Essays on taking account of the play of chance address recording and interpreting numbers, quantifying uncertainty, and reducing the play of chance using meta-analysis.


 
The basics of clinical epidemiology / EBM about treatment states that the normal step first is a placebo control RCT for each medication followed by a head-to-head RCT
e.g.
1) Remdesivir vs placebo/standard of care
2) Hydroxychloroquine vs placebo/standard of care
3) Azithromycin vs placebo/standard of care
 
“The best reason to do a placebo trial is if the treatment is decently effective you can show this with a relatively small number of patients. A comparative trial requires a lot more.” 
 
 

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