Also a literaure review on Hydroxychloroquine. Detail of different research articles on the subject + news articles

1. H Y D R O X Y C H L O R O Q U I N E
Rami Bechara, PhD
1
Potential Drugs for Covid-19
treatment

2. Hydroxychloroquine
Rami Bechara, PhD
2
 Prescription medicine
 Variant of chloroquine with proven greater worth
 Approved decades ago to treat malaria.
 Also used to treat autoimmune diseases like
rheumatoid arthritis and lupus.
 It is sometimes referred to by its brand name,
Plaquenil, and is closely related to chloroquine,
which is also used to treat malaria.
 It is seen as one of the main hopes in fighting
CoronaVirus

3. Advantage of Chloroquine
Rami Bechara, PhD
3
 Most important, the maximum tolerable dose for
HCQ is 1200 mg, which has an antiviral effect
equivalent to 750 mg CQ (for which the maximum
tolerable dose is 500 mg).
 Thus HCQ can be administered at a higher dosage
and may therefore achieve a more powerful antiviral
effect.

4. Mechanism
Rami Bechara, PhD
4
 Weak base with characteristic ‘deep’ volume of
distribution and a half-life of around 50 days.
 Increases the intracellular pH
 Interferes with lysosomal activity and autophagy,
 Interacts with membrane stability
 Alters signaling pathways and transcriptional activity
  Results in inhibition of cytokine production and
modulation of certain co-stimulatory molecules.

5. Illustration of mechanism
Rami Bechara, PhD
5

6. Reasons for hope
Rami Bechara, PhD
6
 Drug can rein in an overactive immune system
 Reason it is used to treat lupus and rheumatoid
arthritis.
 In some severe cases of Covid-19, the immune
system becomes overactive and causes inflammation
that can damage the lungs and other organs.
 Doctors hope hydroxychloroquine might calm the
condition, sometimes called a cytokine storm

7. Motivation for clinical trial
Rami Bechara, PhD
7
 Early demonstration of anti-SARS-CoV activity in
vitro
 Hydroxychloroquine clinical safety profile
 Better than that of chloroquine (during long-term use)
 Allows higher daily dose
 Has fewer concerns about drug-drug interactions
 Clinical Trial undertaken by D. Raoult

8. Inclusion / Exclusion criteria
Rami Bechara, PhD
8
 2 primary criteria for patient inclusion
 : i) age >12 years;
 ii) PCR documented SARS-CoV-2 carriage in nasopharyngeal
sample at admission
 Excluded patients
 Allergy to hydroxychloroquine or chloroquine
 A known contraindication to treatment with the study drug,
including retinopathy, G6PD deficiency and QT prolongation.
 Breastfeeding and pregnant patients were excluded based on
their declaration and pregnancy test results when required

9. Procedure
Rami Bechara, PhD
9
 Day 0: Patients seen for enrolment, initial data collection and
treatment
 Each day for 14 days: patients received a standardized clinical
examination and when possible, a nasopharyngeal sample was
collected. Data collection done using standardized questionnaires.
 Patients proposed oral hydroxychloroquine sulfate 200 mg, three
times per day during ten days
 Patients who refused the treatment or had an exclusion criteria,
served as controls
 Patients who did not receive hydroxychloroquine served as controls.
 Symptomatic treatment and antibiotics as a measure to prevent
bacterial super-infection was provided by investigators based on
clinical judgment.
 Hydroxychloroquine was provided by the National Pharmacy of
France on nominative demand.

10. Patient Categories
Rami Bechara, PhD
10
 Asymptomatic
 With upper respiratory tract infection (URTI) when
presenting with rhinitis, pharyngitis, or isolated low-
grade fever and myalgia
 With lower respiratory tract infections (LRTI) when
presenting with symptoms of pneumonia or
bronchitis.

11. Outcomes
Rami Bechara, PhD
11
 The primary endpoint was virological clearance at
day-6 post-inclusion.
 Secondary outcomes were
 virological clearance overtime during the study period,
 clinical follow-up (body temperature, respiratory rate, long of
stay at hospital and mortality)
 occurrence of side-effects.

12. Patient treatment
Rami Bechara, PhD
12
 36 out of 42 patients met inclusion criteria
 26 patients received hydroxychloroquine and 16 were control patients.
 Six hydroxychloroquine-treated patients were lost in follow-up during
the survey because of early cessation of treatment.
 Reasons are as follows:
 three patients were transferred to intensive care units
 one transferred on day2 post-inclusion who was PCR-positive on day1,
 one transferred on day3 post-inclusion who was PCR-positive on days1-2
 one transferred on day4 post-inclusion who was PCR-positive on day1 and day3
 one patient died on day3 post inclusion and was PCR-negative on day2;
 one patient decided to leave the hospital on day3 post-inclusion and was
PCR-negative on days1-2.
 finally, one patient stopped the treatment on day3 post-inclusion because of
nausea and was PCR-positive on days1-2-3.
 Results are for 36: 20 treated 16 control

13. Effect of hydroxychloroquine
Rami Bechara, PhD
13
 Proportion of patients with negative PCR at day6
post-inclusion,
 70% of hydroxychloroquine-treated patients were virologicaly
cured
 Vs. 12.5% in the control group (p= 0.001).

14. Addition of azithromyc
Rami Bechara, PhD
14
 Patients with negative PCR results at day6 post-
inclusion
 100% of patients treated with hydroxychloroquine and
azithromycin combination were virologicaly cured
 Vs. 57.1% in patients treated with hydroxychloroquine only
 and 12.5% in the control group (p<0.001).
 Drug effect was significantly higher in patients with
symptoms of URTI and LRTI, as compared to
asymptomatic patients with p<0.05 (data not show).

15. Significant figures
Rami Bechara, PhD
15

16. Chinese Clinical Trial
Rami Bechara, PhD
16
 February 4 28, 2020, 142 patients with confirmed COVID-19
admitted.
 Selection criteria:
 1. Age ≥ 18 years;
 2. Laboratory (RT-PCR) positive of SARS-CoV-2;
 3. Chest CT with pneumonia;
 4. SaO2/SPO2 ratio > 93% or PaO2/FIO2 ratio > 300 mmHg under the condition
in the hospital room (mild illness);
 5. Willing to receive a random assignment to any designated treatment group and
not participating in another study at the same time.
 Exclusion criteria among others:
 1. Severe and critical illness patients 2. Retinopathy and other retinal diseases;
 3. Conduction block and other arrhythmias;
 4. Severe liver disease (e.g., Child-Pugh score ≥ C or AST> twice the upper limit);
 5. Pregnant or breastfeeding;

17. Patient selection
Rami Bechara, PhD
17
 62 admitted patients randomly assigned in two groups
 All received the standard treatment (oxygen therapy, antiviral
agents, antibacterial agents, and immunoglobulin, with or without
corticosteroids)
 Patients in the HCQ treatment group received additional oral HCQ
(hydroxychloroquine sulfate tablets, Shanghai Pharma) 400 mg/d
(200 mg/bid) between days 1 and 5 (Figure 1),
 Patients in the control group with the standard treatment only.
 Randomization was performed through a computer-generated list
stratified by site.
 Treatments were assigned after confirming the correctness of the
admission criteria.
 Neither the research performers nor the patients were aware of the
treatment assignments.

18. EndPoint
Rami Bechara, PhD
18
 Observation Endpoint : 5 days after enrollment or severe adverse
reactions appeared
 Changes in time to clinical recovery (TTCR) and clinical
characteristics of patients were evaluated after administration.
TTCR is defined as the return of body temperature and cough relief,
maintained for more than 72 h.
 Normalization and mitigation criteria included the following:
 a. Body temperature ≤ 36.6 °C on the surface, ≤ 37.2 °C under the armpit and
mouth or ≤ 37.8 °C in the rectum and tympanic membrane. Body temperature,
cough check three times daily to calculate the average level.
 b. Cough from patients’ reports, slight or no cough was in the asymptomatic
range. B For radiological changes, the chest CT results in one day before (Day 0)
and one day after (Day 6) the study for evaluation. Pulmonary recovery is defined
as three levels: exacerbated, unchanged, and improved, moderately improved
when less than 50 % of pneumonia were absorbed, and more than 50 % means
significantly improved

19. Results
Rami Bechara, PhD
19
 Body temperature recovery time significantly shortened
in the HCQ treatment group [2.2 (0.4) days] vs. control
group [3.2 (1.3) days].
 The cough remission time was significantly reduced in
the HCQ treatment group. Notably, a total of 4 of the 62
patients progressed to severe illness, all of which
occurred in the control group not receiving HCQ
treatment.
 For adverse effects, 2 patients with mild adverse
reactions in the HCQ treatment group, one patient
developed a rash, and one patient experienced a
headache, none severe side effects appeared among
them.

20. Effect on Pneumonia
Rami Bechara, PhD
20
 Compared and analyzed the chest CT of patients on
day 0 and day 6.
 Pneumonia was improved in 67.7% (42/62) of
patients, with 29.0% moderately absorbed and
38.7% significantly improved.
 A larger proportion of patients with improved
pneumonia in the HCQ treatment group (80.6%, 25
of 31) compared with the control group (54.8%, 17 of
31).
 Besides, 61.3% of patients in the HCQ treatment
group had a significant pneumonia absorption.

21. Model based results
Rami Bechara, PhD
21
 Pharmacological activity tested using SARS-CoV-2
infected Vero cells.
 Physiologically-based pharmacokinetic models
implemented for both drugs separately by
integrating their in vitro data.
 Using the PBPK models, hydroxychloroquine
concentrations in lung fluid were simulated under 5
different dosing regimens to explore the most
effective regimen whilst considering the drug’s safety
profile.

22. Result of model based testing
Rami Bechara, PhD
22
 Hydroxychloroquine (EC50=0.72 μM) was found to
be more potent than chloroquine (EC50=5.47 μM) in
vitro.
 Based on PBPK models results, a loading dose of 400
mg twice daily of hydroxychloroquine sulfate given
orally, followed by a maintenance dose of 200 mg
given twice daily for 4 days is recommended for
SARS-CoV-2 infection, as it reached three times the
potency of chloroquine phosphate when given 500
mg twice daily 5 days in advance

23. Certain Figures
Rami Bechara, PhD
23
 Show prediction efficacy of used models

24. Actions of HCQ
Rami Bechara, PhD
24
 Regulation in pro-inflammatory cytokines [e.g.
Tumor necrosis factor-α (TNF-α), interleukin-1 (IL-
1), interleukin-1 (IL-6)], antioxidant activities.
 Antiviral and autoimmune regulation effects, HCQ
should be a protector in SARS-CoV-2 infection.
 In the present study, the reduced risk of progression
to severe illness in patients with HCQ treatment also
explained the intervention effect of HCQ on the
pathological process of the COVID-19.

25. Side effects
Rami Bechara, PhD
25
 Retinopathy is one of the major adverse reactions of
long-term therapy with HCQ.
 Besides, patients with rheumatoid diseases treated with
HCQ occasionally experience arrhythmias.
 Other rare adverse reactions caused by HCQ include
gastrointestinal reactions, cramps, liver dysfunction,
itching, headache, dizziness, insomnia, peripheral
neuropathy.
 Fortunately, deciding on individual treatment plans
scientifically, monitoring adverse reactions timely, to
avoid overdose, short-term application of HCQ is
relatively safe

26. Critique
Rami Bechara, PhD
26
 Despite the results, it is too early to say if
hydroxychloroquine has the potential or not to treat
COVID-19.
 Today, there is insufficient clinical evidence
to draw any conclusion.
 Large clinical studies are being conducted to assess
the safety and efficacy of hydroxychloroquine in
COVID-19 patients.

27. Challenges
Rami Bechara, PhD
27
 Unknown dose–response relationships
 Lack of definitions of the minimum dose needed for
clinical efficacy
 Lack of definition of what doses are toxic
 Patient non-adherence and possible context-
dependent variations in blood drug levels.
 Available mechanistic data give insights into the
immunomodulatory potency of hydroxychloroquine
and provide the rationale to search for more potent
and/or selective inhibitors.

28. Trump announcement
Rami Bechara, PhD
28
 Early on, before extensive clinical trials, US
President Donald Trump indicated that
hydroxychloroquine was a potential drug to fight
CoronaVirus
 This has prompted global drainage of this drug as
well as its misuse
 Moreover, it may have given non-scientific hope in
this drug
 But it has nonetheless prompted a global search for
drug validation

29. Production of HCQ
Rami Bechara, PhD
29
 70% of the world's supply of hydroxychloroquine
manufactured in India
 Main producers ramped up production to meet the
sudden surge in demand from 3 metric tons per
month to 20 and even 30 metric tons per month and
even 40-50 t/month
 Producing companies: backward integrated for
production, which means that they have the
necessary raw materials and key starting ingredients.
 Problem: production tightly controlled by small
group of manufacturers

30. Lebanese in action for HCQ
Rami Bechara, PhD
30
 It is interesting to note that the HCQ team in
Marseille contains a great number of Lebanese
people highlighting the country’s fight against this
disease

31. Conclusion
Rami Bechara, PhD
31
 HCQ is a potential drug to fight coronavirus
 Successful first trials waiting for more detailed ones
 Best to take with additional drugs
 One not studied route is combining the medicine
with remdesivir, another potential drug

32. References
Rami Bechara, PhD
32
 https://www.sciencedirect.com/science/article/pii/S
0924857920300996?casa_token=yRXQb_01TxIAA
AAA:5iR2DnbLvtdyk3YBW451nyhorlzAvU-
mEQSdv83qhaFeyazhGYClahbzSv3mYzSX7rG6TF1
OTbg#tbl0002
 https://www.medrxiv.org/content/10.1101/2020.03.
22.20040758v2.full.pdf
 https://www.nature.com/articles/s41584-020-0372-
x
 https://academic.oup.com/jac/advance-
article/doi/10.1093/jac/dkaa114/5810487