A study from China found that hydroxychloroquine was ineffective in the treatment of mild to moderate COVID-19. Despite a high dose and long administration.

Last update and review: September 1st, 2020.

A short summary.

In this study by Tang et al., 2020 (1), the dose of hydroxychloroquine was high and the duration of administration long enough. And yet, the hydroxychloroquine group did not do better than the control group. Moreover, of the 75 patients on the hydroxychloroquine plus the standard of care protocol, 10 remained positive for SARS-CoV-2 on a PCR-test by day 21 from the start of hydroxychloroquine administration.

We could not find other facts or flaws in the study by Tang et al., 2020 (1), that could explain why hydroxychloroquine was not effective.

We take not of the results of this study. Hydroxychloroquine is not a panacea and, apparently, not always effective. We, therefore, stress again that the best strategy is to avoid getting infected with SARS-CoV-2.

Deconstruction of the study by Tang et al., 2020 (1).

The patients.

Tang et al., 2020 (1):

Of 150 patients, 148 had mild to moderate disease and two had severe disease.

Standard of care versus standard of care plus hydroxychloroquine.

No placebo was used, and drugs were not masked. 

Tang et al., 2020 (1):

1200 mg daily for three days followed by a maintenance dose of 800 mg daily (total treatment duration: two or three weeks for patients with mild to moderate or severe disease, respectively).

“The mean duration from symptom onset to randomization was 16.6 (SD 10.5; range 3-41) days.”

Tang et al., 2020 (1):

Participants in our trial had mainly mild to moderate disease, with a median 16 day delay between symptom onset and hydroxychloroquine treatment, so the negative results of our trial are applicable only to patients with persistently mild to moderate covid-19.

PCR-tests: Specimens form upper, lower respiratory tract or both, with cycle threshold value less than 37 defined as a positive test result.

Tang et al., 2020 (1):

Specimens from the upper respiratory tract, lower respiratory tract, or both were obtained from each patient on screening (day –3 to day 1) and during treatment and post-treatment follow-up at scheduled visits on days 4, 7, 10, 14, 21, and 28.

Methods for extraction and amplification of total RNA through RT-PCR were similar to those described elsewhere.13 Rather than quantitative data (cycle threshold value) reported from the RT-PCR assay, we collected only qualitative data reported from our trial sites. On the basis of a national recommendation, we defined a cycle threshold value less than 37 as a positive test result and a cycle threshold value of 40 or more as a negative test. Cycle threshold values between 37 and 40.

We defined negative conversion of SARS-CoV-2 as two consecutive reports of a negative result for SARS-CoV-2 at least 24 hours apart without a subsequent report of a positive result by the end of the study.

Of the 75 patients on hydroxychloroquine plus the standard of care protocol, 10 remained positive for SARS-CoV-2 on a PCR-test by day 21 from the start of hydroxychloroquine administration.

Tang et al., 2020 (1):

A total of 109 (73%) patients (56 standard of care; 53 standard of care plus hydroxychloroquine) had negative conversion well before 28 days, and the remaining 41 (27%) patients (19 standard of care; 22 standard of care plus hydroxychloroquine) were censored as they did not reach negative conversion of virus.

In the paragraph cited above, Tang et al., 2020 (1), are contradicting the data in their table. Indeed, we can see the table below that by day 21, the probability of conversion in the SOC plus HCQ group is 85.4%. 85.4% of 75 is approximately 65. So, 65 patients out of 76 became PCR-negative and 10 didn’t.

The most common adverse event in the hydroxychloroquine recipients was diarrhoea (in 10% of the patients).

Tang et al., 2020 (1):

Adverse events were recorded in 7/80 (9%) hydroxychloroquine non-recipients and in 21/70 (30%) hydroxychloroquine recipients. The most common adverse event in the hydroxychloroquine recipients was diarrhoea, reported in 7/70 (10%) patients. Two hydroxychloroquine recipients reported serious adverse events.

So, what was the standard of care?

Tang et al., 2020 (1):

All patients were managed with standard of care aligned with the indications from the updated national clinical practice guidelines for covid-19 in China.

Chinese Clinical Guidance for COVID-19 Diagnosis and Treatment (7th edition), updated March 16, 2020.

Another hint that China does not lie about the low number of COVID-19 cases.

Tang et al., 2020 (1):

Patients were enrolled by the site investigators in 16 government designated covid-19 treatment centres in three provinces in China (Hubei, Henan, and Anhui).

China may be telling the truth about the low number of COVID-19 cases: scientists there struggled to recruit patients for their studies.

However, the study was conducted in February 2020. There may have been enough cases of COVID-19 at the time.

Tang et al., 2020 (1):

16 government designated covid-19 treatment centres in China, 11 to 29 February 2020.

Indeed, the graph below shows that in February 2020, there were around 3 thousand new COVID-19 cases reported in China. There was enough patients for clinical trials at that time.

As we read the article of of Tang et al., 2020 (1), further, we learn that indeed, the researchers had difficulties with recruiting more patients. First, there were multiple trial of different drugs, and later, when the epidemic was suppressed, there were not enough COVID-19 patients for any kind of trials. Tang et al., 2020 (1):

The results of our main prespecified outcomes are not entirely conclusive, being based on an underpowered sample size due to the lack of enough eligible patients to enrol. The recruitment of eligible patients was unexpectedly difficult, with many clinical trials launched in the same period in response to the urgent call by the national health authorities for the exploration of effective treatment against covid-19. The rapid decline in eligible new cases owing to the successful containment of covid-19 in the middle of March 2020 in China precluded further recruitment to reach our targeted sample size.

Alleviation of clinical symptoms: by day 22, 40% of hydroxychloroquine group are still symptomatic.

Tang et al., 2020 (1), on some of the clinical criteria that are particularly interesting to us:

50% decline of C-reactive protein, erythrocyte sedimentation rate, IL-6 and TNF-α level from baseline and normalization of absolute blood lymphocyte count.

Tang et al., 2020 (1):

Definition for radiology improvement: Resolved more than 50% from baseline on chest CT.

Unfortunately, the authors decided not to publish the data on clinical and biological changes due to the early termination of the study. Tang et al., 2020 (1):

Owing to the early termination of our study,we could not justify the results from these analyses with an underpowered sample size and therefore decided not to emphasise them in this paper to avoid misinterpretation.

Only a subset of clinical symptoms was included in the study. Tang et al., 2020 (1):

The definition of the alleviation of clinical symptoms was resolving from fever to an axilliary temperature of 36.6°C or below, normalisation of SpO 2 (>94% on room air), and disappearance of respiratory symptoms including nasal congestion, cough, sore throat, sputum production, and shortness of breath.

The median time to alleviation of clinical symptoms was not different (19 v 21 days; HR 1.01, 0.59–1.74).

Baseline demographic and clinical characteristics of patients.

There was no “cytokine storm” in these mild to moderate COVID-19 patients.

The levels of neutrophils and lymphocytes and their ratio remained did not reach extremities associated with severe COVDI-19 in the study participants (see the table above). IL-6 and TNF-alpha were also elevated only mildly.

For comparision, we insert a table showing IL-6 levels in younger and older adults in the general population.

Other treatments: a lot of antivirals and limited use of corticosteroids during the study.

Lung injury: no data.

It would be interesting to learn what happened to the lungs of the patients who did not become PCR-negative for SARS-CoV-2 by day 21 of the study period. However, Tang et al., 2020 (1), do not provide any information on this. The word “lungs” is used only one time in the text of the article, in the “Methods” section.

Tang et al., 2020 (1):

However, as the trial was stopped early and only two patients with severe disease were enrolled, results on clinical improvement are not presented

Totalitarian China did not ban its doctors and citizens from using hydroxychloroquine to treat COVID-19.

Tang et al., 2020 (1):

Despite their unclear benefits, chloroquine and hydroxychloroquine are both recommended for off label use in the treatment of covid-19 by the Chinese national guideline.

The presence of SARS-CoV-2 in respiratory samples of many patients is longer than 10 days.

Tang et al., 2020 (1):

With the increasing knowledge of covid-19 from our clinical practice, we realised that the duration of SARS-CoV-2 in respiratory samples of many patients was longer than 10 days.

Conclusions.

In this study by Tang et al., 2020 (1), the dose of hydroxychloroquine was high and the duration of administration long enough. And yet, the hydroxychloroquine group did not do better than the control group. Moreover, of the 75 patients on the hydroxychloroquine plus the standard of care protocol, 22 remained positive for SARS-CoV-2 on a PCR-test by day 23 from the start of hydroxychloroquine administration.

We could not find other facts or flaws in the study by Tang et al., 2020 (1), that could explain why hydroxychloroquine was not effective.

We take note of the results of this study. Hydroxychloroquine is not a panacea and, apparently, not always effective. We, therefore, stress again that the best strategy is to avoid getting infected with SARS-CoV-2.

If you need help with a review of your preventive measures or with other issues related to COVID-19, do not hesitate to get in contact with us.

Selected references:

1. Tang Wei, Cao Zhujun, Han Mingfeng, Wang Zhengyan, Chen Junwen, Sun Wenjin et al. Hydroxychloroquine in patients with mainly mild to moderate coronavirus disease 2019: open label, randomised controlled trial BMJ 2020; 369 :m1849

2. Valiathan et al. Scandinavian Journal of Immunology, 2016, 83, 255–266.