Monday, June 1, 2020

Clues to hydroxychloroquine effectiveness in cross-country comparisons. 2nd UPDATE: 7/8/2020.

Copyright 2020 Robert Clark

 Perhaps the evidence for HCQ effectiveness is there if we are willing to put together the clues:

Researchers ponder why covid-19 appears deadlier in the U.S. and Europe than in Asia.

 Graphic showing radically reduced death rates in Asian countries:


National Consumption of Antimalarial Drugs and COVID-19 Deaths Dynamics : an Ecological Study.
“COVID-19 (Coronavirus Disease-2019) is an international public health problem with a high rate of severe clinical cases. Several treatments are currently being tested worldwide. This paper focuses on anti-malarial drugs such as chloroquine or hydroxychloroquine, which have been currently reviewed by a systematic study as a good potential candidate and that has been reported as the most used treatment by a recent survey of physicians. We compare the dynamics of COVID-19 death rates in countries using anti-malaria drugs as a treatment from the start of the epidemic versus countries that do not, the day of the 3rd death and the following 10 days. We show that the first group have a much slower dynamic in death rates that the second group.”

 Here’s the key graphic showing radically reduced death rates in those countries using the antimalarials:


WORLD NEWS MARCH 12, 2020 / 9:51 AM
South Korea experts recommend anti-HIV, anti-malaria drugs for COVID-19
“The groups advised discretion among medical professionals, while recommending the administration of Kaletra, an anti-HIV medication that includes the drugs lopinavir and ritonavir.
Kaletra blocks the ability of HIV to replicate itself, and also inhibits the growth of cancer cells.
South Korean experts are also recommending the use of hydroxychloroquine in combination with the anti-HIV medication. HCQ is sold under the brand name Plaquenil, among others, and is used for the prevention and treatment of malaria.”

Treatment Response to Hydroxychloroquine, Lopinavir/Ritonavir, and Antibiotics for Moderate COVID 19: A First Report on the Pharmacological Outcomes from South Korea.   
“Conclusion: This first report on pharmacological management of COVID 19 from South Korea revealed that HQ with antibiotics was associated with better clinical outcomes in terms of viral clearance, hospital stay, and cough symptom resolution compared to Lop/R with antibiotics or conservative treatment. The effect of Lop/R with antibiotics was not superior to conservative management. The adjunct use of the antibiotics may provide additional benefit in COVID 19 management but warrants further evaluation.”


Indonesia to keep prescribing two malaria drugs for COVID-19 despite bans in Europe.  
“The world’s fourth-most populous nation has since late March recommended that chloroquine and its derivative, hydroxychloroquine, be widely administered, including to coronavirus patients with moderate to severe symptoms, according to Food and Drug Monitoring Agency guidelines.”


India Promotes Hydroxychloroquine, as WHO Stops Trials Over Safety Issues


Commentary on “Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open label non-randomized clinical trial” by Gautret et al.
Mondher Toumi & Samuel Aballea
Journal of Market Access & Health Policy, 8:1, 1758390, DOI:10.1080/20016689.2020.1758390
“Hydroxychloroquine treatment with massive testing and limited confinement has successfully worked in South Korea to control the outbreak with an impress- ively low rate of fatalities[44].”
“So far, European decision-makers have shown very little ability to learn from China [45] and South Korea [44], the only two countries that have been able to control the outbreak. Cultural differences, language barriers, and arrogance from the old Europe may cer- tainly explain why best practice knowledge sharing failed in this situation.”


The Battle Over the Numbers: Turkey’s Low Case Fatality Rate.
BLOG - 4 MAY 2020
“Despite the prevalence of the virus among the population and rapidly increasing infection rates, what is striking is Turkey’s lower death rate. Turkey’s death rate per 1 million population is 37, making it even more successful than most comparable European countries for COVID-19. On the basis of official figures, Turkey ranked better than Germany, which has received a great deal of attention and admiration for its low fatality rates.”
COVID-19 Rates (as of 30 April 2020)
Total cases
Total Deaths
Deaths/1 M population
Tests/1 Million population

Coronavirus: How Turkey took control of Covid-19 emergency.

  • 29 May 2020
Turkey embraces hydroxychloroquine
The country has public health lessons to offer, according to acting head of the World Health Organization (WHO) in Turkey, Dr Irshad Shaikh.
"Initially we were worried," he told the BBC. "They were having 3,500 positive cases per day. But what has worked is testing. And they did not have to wait five or six days for results." He also credits the quarantine, isolation and contract tracing measures but says it's too soon to judge Turkey's treatment protocol for patients.
Controversially that includes the anti-malarial drug, hydroxychloroquine, as standard. It's much touted by President Donald Trump - but has been roundly rejected by the latest international research.
The WHO has temporarily suspended it from their trial of possible treatments for the virus. That followed research published in the Lancet which suggested hydroxychloroquine can cause cardiac problems in Covid-19 patients, and could do more harm than good.
We were given access to a hospital where it has been part of the standard treatment for thousands of patients. The Dr Sehit Ilhan Varank hospital, a two-year old-state hospital, is also state of the art. It's a bright, spacious battlefront against the virus.
Turkey has been using the drug hydroxychloroquine to treat Covid-19 patients

Chief doctor Nurettin Yiyit - whose art work is on the hospital walls - says it's key to use hydroxychloroquine early. "Other countries are using this drug too late," he says, "especially the United States. We only use it at the beginning. We have no hesitation about this drug. We believe it's effective because we get the results."

  Bob Clark

UPDATED, 6/10/2020:

 It can be argued that because of confounding effects this is not a firm argument for the effectiveness of HCQ against COVID-19. For example many of the Asian countries have much reduced rates of obesity compared to Western countries, and obesity is a key risk factor for poor outcome for COVID-19.

 More persuasive would be rates of infection and death within the same country. In this post I discussed some doctors in Italy who found HCQ effective with early treatment: Success in Italy reported in early treatment of COVID-19 using hydroxychloroquine.

 Dr. Pietro Garavalli in Italy also found it effective for early treatment:

NEWS | april 28, 2020, 5:40 pm
Hydroxychloroquine VS Covid-19, a therapy considered effective but controversial. The opinion of the Infectivologist Pietro Garavelli.

 And this report noted greatly reduced recent COVID-19 death rates in two Italian provinces and suggests antivirals such as HCQ as a possible explanation:

SARS-CoV-2 lethality decreased over time in two Italian Provinces.

Maria Elena Flacco, Cecilia Acuti Martellucci, Francesca Bravi, Giustino Parruti, Alfonso Mascitelli, Lorenzo Mantovani,  View ORCID Profile Lamberto Manzoli

 "In the two provinces under investigation, the treatment is currently based upon antiviral agents (Chloroquine / Hydroxychloroquine or Lopinavir / Ritonavir), intensive respiratory support [18, 19], and, from the latest days of March, low molecular weight heparin and monoclonal antibodies against inflammatory cytokines (e.g. Tocilizumab), which showed some preliminary, promising results [18, 20-23]."

 In regard to this report however, I am dismayed that the authors decided to release a second version where they deleted all mention of HCQ:

SARS-CoV-2 lethality decreased over time in two Italian Provinces.

Maria Elena Flacco, Cecilia Acuti Martellucci, Francesca Bravi, Giustino Parruti, Alfonso Mascitelli, Lorenzo Mantovani,  View ORCID ProfileLamberto Manzoli
"In the two provinces under investigation, the treatment is currently based upon antiviral agents (lopinavir / ritonavir), intensive respiratory support [18, 19], and, from the latest days of March, low molecular weight heparin and monoclonal antibodies against inflammatory cytokines (e.g. tocilizumab), which showed some preliminary, promising results [18, 20-23]."

 In the first version, the authors report on the antivirals used in treatments which included HCQ. So that must have still been true in the second version released three days later.

  Another case where great differences in COVID-19 death rates occur within the same country is in France:

A Look at COVID Mortality in Paris, Marseille, New York and Montreal.

Posted on May 23, 2020
"COVID mortality is found to be 5 times higher in Paris than in Marseille: 751 deaths per million in Paris, versus 147 deaths per million in Marseille.

The table compiled by France Soir shows that, in Marseille, 3295 COVID patients were treated with the hydroxychloroquine – azithromycin bi-therapy, while 1564 were not.

In Marseille, the case fatality rate among those treated with the bi-therapy was 0.52%, while it was 8.63% for those who did not receive it.

The average case fatality rate was 3.13% for Marseille as whole. In Paris, the case fatality rate reached a staggering 19.12%."

 The 5 times lower mortality in Marseille compared to Paris is quite significant. But even beyond that focusing on Dr. Raoults hospital at IHU Marseille, it has nearly 40 times lower mortality than Paris(!)

 Dr. Raoult in noting this disparity has asserted that COVID-19 is disappearing in Marseille:

Covid-19 is disappearing in Marseille, says leading virologist Dr Raoult.

Issued on: 16/04/2020 - 08:37
Modified: 16/04/2020 - 08:37

  Robert Clark

UPDATED, 7/8/2020:

During a discussion of treatments of COVID-19 the question of Indonesia and Singapore came up. A commonly given explanation for why the Asian countries have death rates at 50 to 100 times lower rates than Western countries is because of their greater testing. However, Indonesia belies that explanation as it counts among the worst in testing but among the best in lowering the death rate:

Indonesia ranks among world's worst in coronavirus testing rate.
Wahyudi Soeriaatmadja
The Straits Times/Asia News Network
Jakarta, Indonesia   /   Tue, April 7, 2020   /   11:11 am

 But as shown in the first image above it counts among the lowest in COVID-19 death rates. And like most of the Asian countries it advocates for extensive use of HCQ:

Indonesia, major advocate of hydroxychloroquine, told by WHO to stop using it.
Kate Lamb and Tom Allard
Indonesia, the world's fourth most populous nation, had told doctors to use the drugs to treat all COVID-19 patients with symptoms from mild to severe. The country has ramped up production since March, granting two dozen licenses to local manufacturers who have churned out millions of doses. 

 Singapore, again like most Asian countries has a remarkably low COVID-19 death rate. Singapore though does not promote HCQ as the primary treatment regimen for COVID-19. But actually it promotes a drug that might be even better, interferon. 

 In this blog post I wrote about an early report that claimed that HCQ was ineffective against COVID-19, "A new possible treatment for COVID-19: interferon alpha." I was really quite amazed in reading the various news articles about the report that the most important take away was missed: the report showed that for the patients in their study interferon alpha had a 100% cure rate against COVID-19! 

 It was really quite remarkable in reading the news articles about the report that the focus was so much on highlighting the (inaccurate) claim that it disproved HCQ, that science journalists and doctors reviewing the results of the report completely missed the surprising results on interferon it contained.

 Since that report numerous other reports have come out reporting on the effectiveness of interferon of various types on treating COVID-19. 

 The Singapore treatment protocol is discussed here:

Interim Treatment Guidelines for COVID-19.
(Version 1.0, dated 2 April 2020). 

 It's interesting also how the Singaporeans breakdown their treatment guidelines. The guidelines recommend Lopinavir-Ritonavir (Kaletra), an antiviral HIV medication, for early treatment, i.e., less than 12 days after symptoms appear, and interferon for later treatment, after 12 days after symptoms appear. 

 Lopinavir-Ritonavir has not been found effective for patients under severe disease, but as an antiviral it would be expected to be most effective for early treatment. And the Singapore guideline document does give a reference to a report, ref. #3, where it was effective for early treatment.

 The fact that antivirals are most effective when given early is a well known fact among infectious disease experts - for other infectious diseases. But, oddly, this doesn't seem to be appreciated for COVID-19. The Singaporean treatment guideline document is rather singular and recognizing this fact in their treatment guidelines on COVID-19.

 Based on the facts that they used an effective antiviral early and included the potent antiviral and anti cancer medication interferon as part of their treatment protocol, and that they have been very successful in keeping their death rates low, I think the Singaporeans treatment strategies should be investigated as possible models to follow for Western countries.

 I must say I have been dismayed that Western countries have been so loathe to consider the treatment strategies used in Asian countries as models for their own treatment strategies. The Western countries have been content to look just at things like the infection tracking policies used, which is certainly important. But with death rates from 50 to 100 times lower than in Western countries it is really unfortunate that the Asian countries treatment strategies are not also considered.

 Another recent study reported on some surprising results:

Evidence That Quinine Exhibits Antiviral Activity against SARS-CoV-2 Infection In Vitro. 

 Not only did quinine have antiviral capability in vitro against COVID-19 but at 10 times better effectiveness than HCQ or CQ! 

 Interesting! I’ve been puzzling about the low death rate in Germany compared to other European nations:

 I once read someone suggest on Facebook that it was because the amount of tonic water, which is quinine in water, that the Germans drink. This possibility was discounted by medical professionals because of the low amount of quinine in tonic water:

 For instance, it might take ten times the amount of quinine you would get in a liter of tonic water to have the beneficial effects of hydroxychloroquine or chloroquine. But if this report is true that quinine itself has ten times the antiviral activity that HCQ or CQ has that means the amount in a liter would be in the therapeutic range!

Note also here that in alcoholic spirits the amount allowed is much higher:

 A couple ways this could be tested would be to see if people who drink tonic water or mixed drinks with tonic water on a regular basis have reduced rates of COVID-19. Another test would be to see if regular users have higher levels of quinine or its metabolites in their blood, and if this is high enough to be protective according to this recent research. 

    Robert Clark


  1. I see in today's (6-4-2020) newspaper a report concerning a study published in the New England Journal of Medicine. A blind study with controls found no effective difference between hydroxychloroquine and a placebo at preventing Covid-19. About 40% of those taking hydroxychloroquine experienced mild side effects, such as stomach distress. Nobody had a serious effect like heart arrythmia. The study team expressed disappointment; they were hoping it would work. But that is not what they found. -- GW

    1. I was looking forward to this study, and was following the lead doctors reporting on its progress via his twitter account:

      However, see this review article:

      Hydroxychloroquine for the Prevention of Covid-19 — Searching for Evidence.
      Myron S. Cohen, M.D.

      This review article was published in the same issue as the article by Boulware which reported on using HCQ for prophylaxis against COVID-19. Unfortunately as noted in this review, the study had a key flaw: most of the subjects weren’t actually tested. For most of the subjects, the question of whether or not they had COVID-19 was determined by the subjects self-reporting of symptoms. In fact, only 17% of the study subjects were actually tested.

      However, as much as 80% of COVID-19 cases can be asymptomatic and as much as 80% of cases with self-reported apparent “symptoms” can be wind up testing negative for COVID-19.

      So from the start the design of this study was such that as much as 80% of the study results were wrong.

      Bob Clark

    2. I think that just goes to prove (1) things get done wrong when you are rushed, and (2) it's hard to design proper studies when not much is yet known about the problem. Meanwhile there is essentially-anecdotal evidence as to whether or not (evidence both ways!) the anti-malarial drug helps with Covid-19, and whether it has bad side effects or not when used for that purpose. There is better evidence for bad side effects when used for other purposes. But for treating Covid-19, the jury is still out. -- GW

  2. I see in the 12 June issue of AAAS's "Science" that multiple studies on hydroxychloroquine and chloroquine as Covid-19 treatments, are coming to conclusions. That issue of the magazine had a science news article about those outcomes, and I would expect in coming weeks we will see the actual individual reports published or cited there. The net result consensus of several large studies seems to be "no different from a placebo". -- GW

  3. I'm looking forward to reading those new studies when they are finally published. But keep in mind there have been some severe problems with some other published studies. The Lancet study apparently used faked data. The University of Minnesota study didn't actually test the great majority of subjects, relying instead on self-reporting of "symptoms" for most subjects. And the recent RECOVERY trial in the UK used near toxic levels of hydroxychloroquine, due to mixing up HCQ with a completely different medication, hydroxyquinoline.
    In the study from Spain mentioned in the Science article I hope they didn't also just rely on self-reported "symptoms" to determine if someone had it or not.

    I'm writing in a blog post about another published study that concluded HCQ had no beneficial effect. But when I read the accompanying Supplementary data file, I was startled to find that in the actual data the survivability for intubated patients was twice as good for those on HCQ than those not. Because the intubated patients were a small proportion of the total patients this effect was swamped by the overall similar numbers of survivability.

    I'm mystified that the authors didn't find this significant enough to mention. The death rates for intubated patients are quite bad in general under COVID-19. If there is a medication that can double the survival rates of intubated patients that fact should be championed rather than hidden.

    And in another report I'll write about, the authors also concluded no beneficial effect on the measure of reducing viral load. But they included in the article that HCQ did have a beneficial clinical effect on reducing severity of symptoms and therefore also likely survivability. However, I was stunned to find in a second version of the article the authors removed that discussion of the beneficial clinical effects!

    Whether intentional or not some bizarre things are happening in regards to the studies on HCQ.

    Bob Clark

  4. If you could break out the Case Fatality Rate (CFR) for those 60 and above, that would be a better comparison. It's difficult (for me) to find that data.

    Here are some examples of 60 and above CFRs:
    California: 16%
    Australia: 4.5%
    South Dakota: 6.36% (Governor led HCQ studies and promote its use. They offered it to my nephew who refused because of fear of the drug. He later went to the hospital due to collapsed lung from Covid.)
    India: 4.7%
    US: 18% (Note: I could only find data for 65 and above)

    1. Do you have a reference for those numbers? One explanation for the low values of deaths in the Asian countries is the low numbers of the elderly. If that number were also lower for the elderly, that would cancel out that explanation.

      Robert Clark

    2. Numbers for figuring US CFR 65 and over:
      US 65 and over covid cases and deaths:
      31% of cases are 65 and over:

      Data for SD:

      Data for California:

  5. "I once read someone suggest on Facebook that it was because the amount of tonic water, which is quinine in water, that the Germans drink. This possibility was discounted by medical professionals because of the low amount of quinine in tonic water"

    Dr. Zelenko's prophylactic dosage of HCQ is 200mg a week. Tonic water usually has about 84mg of tonic water a week. The halflife of tonic water is something like 3 weeks. Therefore, drinking under 3 liters per week would give you the quinine that some doctors say you need as a prophylactic...

    Jim Young