My Authors
Read all threads
1/
Should we use #hydroxychloroquine (HCQ) +/- azithromycin to treat #COVID19 #SARSCoV2? Let’s take a look at the data.

Here’s: #HowIReadThisPaper on the only trial published to date on HCQ for COVID19 in humans:

Gautret et al: mediterranee-infection.com/wp-content/upl…

(Thread)
2/
Background: HCQ has antiviral activity against SARS-CoV-1 in vitro, is already available in much of the world, and has a known side-effect profile. It was used for #COVID19 in China, but data on clinical outcomes are not yet available.
3/
Question: Does HCQ shorten the duration of viral shedding in patients with #COVID19?

Date Published: 17 March 2020 (In Press)

Funding: Agence Nationale de la Recherche (Government of France)
4/
Study Design: Open-label (unblinded) non-randomized clinical trial, also known as a prospective cohort study

Population: 42 patients with PCR-confirmed #COVID19 in France were included; 26 received HCQ, 16 received usual care

Study Period: The first half of March, 2020
5/
Intervention: HCQ 200 mg PO TID x10 days +/- azithromycin (to prevent bacterial superinfection) at the discretion of treating clinicians

Control: Usual care (without HCQ or azithromycin)
6/
Study Procedures: HCQ was offered to patients at one study site. Patients who consented = intervention group, patients who refused or were admitted at the other three study sites = control group.
7/
Inclusion Criteria: Hospitalized patients aged >12 years, NP swab + for #SARSCoV2 on admit, able to provide informed consent

Exclusion Criteria: Allergy or contraindication to HCQ (retinopathy, G6PD deficiency, or prolonged QT interval), pregnant or breastfeeding women
8/
Protocol available? Yes: clinicaltrialsregister.eu/ctr-search/sea…

Primary outcome: Percentage of patients with detectable viral shedding on day 6

Secondary outcomes: Time to normalization of T and RR, LOS, and mortality
9/
Duration of follow-up: 14 days

Loss to follow-up: 6/26 (23%) patients receiving HCQ +/- azithromycin; 0/20 (0%) patients receiving usual care
10/
Results:
Table 1: Mean age = 45 years, 40% male.

~60% had URI Sx, ~20% had lower respiratory tract infection Sx, ~20% had no Sx.

Mean time from Sx onset to enrollment = 4 days
11/
Figure 1:
14/16 (88%) controls had detectable viral shedding at day 6, compared with 6/20 (30%) patients receiving HCQ +/- azithromycin

Figure 2:
HCQ alone: 6/14 (43%) patients had detectable virus at day 6
HCQ + azithromycin: 0/6 (0%) patients had detectable virus at day 6
12/
Author’s conclusions: HCQ + azithromycin is associated with a reduction in viral shedding at day 6 in hospitalized patients with #COVID19 compared with usual care.
13/
My appraisal: This study was “positive,” meaning it showed that HCQ was associated with a ~58% reduction in the proportion of patients with any viral shedding at day 6. What are the limitations that threaten the validity of this conclusion?
14/
The primary outcome in the manuscript (shedding at day 6) was different from what was specified in the protocol (shedding at days 1,4,7,14), and the authors do not provide data on viral shedding after day 6. This raises the likelihood of a false-positive result due to chance.
15/
Lack of blinding and lack of randomization in this study are serious threats to internal validity because they influence allocation of patients and assessment of the outcome. In this study, they are both likely to bias towards a benefit of HCQ +/- azithromycin.
16/
There was differential loss to follow-up: all control patients were included, but 6/26 (23%) of HCQ patients were not. Among them, 3 patients were transferred to the ICU, 1 died, 1 left the hospital, and 1 stopped HCQ due to nausea. This problem is called attrition bias.
17/
Additionally, among the 6 HCQ patients who dropped out, the authors report that 4 of them were still PCR-positive at the time of dropout. This is likely to bias the results towards a benefit of HCQ.
18/
Further, 5/16 (31%) of control patients did not have PCR performed on day 6, compared with only 1/20 (5%) of HCQ patients. This means the primary outcome was assessed differently in the two groups. This problem is called ascertainment bias.
19/
Finally, the primary endpoint is a surrogate endpoint, and none of the clinical secondary endpoints specified are reported. This is called selective outcome reporting, or outcome reporting bias.
20/
One caveat: because of the small size, short duration, and limited clinical assessment, if there are other real benefits of HCQ +/- azithro in #COVID19, it does not seem likely that this study would have identified them.
21/
Bottom line:

This study is at high risk of bias. Due to small size, lack of randomization or blinding, and multiple sources of bias towards a benefit of HCQ, this evidence should be considered low quality. Better-designed RCTs are needed (and are in process).

(End)
Missing some Tweet in this thread? You can try to force a refresh.

Enjoying this thread?

Keep Current with Rahul Ganatra

Profile picture

Stay in touch and get notified when new unrolls are available from this author!

Read all threads

This Thread may be Removed Anytime!

Twitter may remove this content at anytime, convert it as a PDF, save and print for later use!

Try unrolling a thread yourself!

how to unroll video

1) Follow Thread Reader App on Twitter so you can easily mention us!

2) Go to a Twitter thread (series of Tweets by the same owner) and mention us with a keyword "unroll" @threadreaderapp unroll

You can practice here first or read more on our help page!

Follow Us on Twitter!

Did Thread Reader help you today?

Support us! We are indie developers!


This site is made by just three indie developers on a laptop doing marketing, support and development! Read more about the story.

Become a Premium Member ($3.00/month or $30.00/year) and get exclusive features!

Become Premium

Too expensive? Make a small donation by buying us coffee ($5) or help with server cost ($10)

Donate via Paypal Become our Patreon

Thank you for your support!