HCQ controversies in COVID era

1. Revisiting Hydroxychloroquine (HCQ) toxicity in COVID era -
truth versus fallacies
Dr Ritasman Baisya
Assistant Professor , Clinical Immunology and Rheumatology
Nizam’s Institute of Medical Sciences ,Hyderabad

2. Introduction
• Hydroxychloroquine (HCQ) – Anti malarial drug of aminoquinoline group
• Backbone of SLE treatment since 1894 , FDA approved in USA since
1955.
• Generally safe – visual toxicity is a concern for prolonged use
• COVID 19 pandemic creates controversy with its safety .

3. How HCQ acts ?
Padiyar S, Danda D. Revisiting cardiac safety of hydroxychloroquine in rheumatological diseases during COVID-19 era: Facts and
myths. Eur J Rheumatol 2021; 8(2): 100-4.

4. HCQ toxicities
• GI: Most common, Nausea, vomiting, diarrhea (800-1200
mg/day)
• Cardiotoxicity: Conduction-abnormalities, ventricular
hypertrophy, heart failure, valvular disorders. ( case series
based )
• Dermatologic - Drug eruptions , hyperpigmentation, pruritis,
SJS-TEN , AGEP ( SLE (72%) , RA (14%)
• Neuropsychiatric - Headache(2.8%), dizziness (2.1%),
paraesthesia (0.6%) , psychosis , neuropathy
Short term
• Retinopathy – Prevalence 8% ,
rapid onset rarely reported .
• Cardiac – Cardiomyopathy ,
heart failure
• Neuro-myotoxicity – myositis
and muscle weakness , with
/without elevated CK , extremity
weakness, pseudo-
parkinsonism
Long term
Cassandra Doyno, Diana M. Sobieraj & William L. Baker (2021) Toxicity of
chloroquine and hydroxychloroquine following therapeutic use or
overdose, Clinical Toxicology, 59:1, 12-23

5. Revisiting toxicity in COVID era
• GI – most common , more with macrolide ,
hepatotoxicity
• Glucose abnormality – Not significant
• Cardiac – QT prolongation , cardiac arrest ,
ventricular arrhythmia
• Dermatologic – Less reported
• Neuropsychiatric – Dizziness , vertigo , headache ,
irritability , EPS symptoms ( Heath care workers )
Cardiotoxicity
– main concern

6. Pendulum of HCQ use in COVID
Period Time Evidence
Early adopter Early In vitro study
Miracle cure Mar- Mid
Apr
You tube , Political influence ,
pre-print study – approved for
EUA
Rise of skepticism Late Apr Increased cardiomyopathy ,
high mortality
Pendulum swings
back
May-June Increased concern of efficacy ,
suspension of solidarity trial
Returning to the
center
Beyond
June
RECOVERY trial- no efficacy
Sattui SE, Liew JW, Graef ER et al .Swinging the pendulum: lessons learned from public discourse concerning hydroxychloroquine and
COVID-19. Expert Rev Clin Immunol. 2020 Jul;16(7):659-666.

7. Gastrointestinal toxicity

8. A
Active RA (212 ) , 6 week –
600/800/1200 mg/day followed by 18
week 400 mg/d
Higher HCQ dose – more GI events ,
mainly in early weeks
Munster T, Gibbs JP et al. Arthritis Rheum.
2002
GI effects common , but not
significant
More with chloroquine

9. Revisiting GI complaints…
• 150 mild- moderate COVID patients
• 10 % of HCQ group - vomiting , diarrhea
• Blurred vision in 1 , No cardio toxicity
• Post exposure prophylaxis ( within 4 days)
in 821 persons , high dose HCQ used for 5
days .
• HCQ arm – vomiting /diarrhea 23% , visual
blurring 0.9 , no cardiac event
• 2.4 % had adverse event , MC – Diarrhea, others –
vomiting , pain abdomen , rash

10. • Data on cardiotoxic effect of HCQ on rheumatic diseases
CARDIOTOXICITY

11. P – 28 SLE patients
I- seven-month chloroquine treatment with a 250 mg/day
Result-
1. No episodes of paroxysmal arrhythmias / conduction disturbances
2. Tendency to tachycardia, but no significant differences in mean heart rate.
3. No changes in heart rate variability / repolarization parameters
Lupus , 2006

12. • CQ used in 69.7% SLE patients , mean use of 8.5 ± 6.7 years.
• Negatively associated with AVB (P = 0.01) as was its longer use (6.1 ± 6.9 vs. 1.0 ± 2.5 years, P = 0.018).
• Time of CQ use was related with the absence of AVB
Protective

13. 85 SLE patients treated with HCQ , for a minimum of 1 year, without established cardiac
diseases.
Result -
• PR interval, QTc interval ,heart rate were not different from normal values.
• Evidence on the safety of HCQ compared with CQ.
Equivocal
Costedoat-Chalumeau N, et al .Heart conduction disorders related to antimalarials toxicity: an analysis of electrocardiograms in 85 patients
treated with hydroxychloroquine for connective tissue diseases. Rheumatology (Oxford). 2007 May;46(5):808-10.

14. • P= 133 consecutive pregnancies in 90 SLE patients
• I- HCQ ( 200 mg BD / OD)
• C- Not on HCQ , 70 consecutive pregnancies in 54 SLE
• R - PR interval , QTc not statistically different in children of both group
Equivocal
Costedoat-Chalumeau N, Amoura Z, Duhaut P, Huong DL, Sebbough D, Wechsler B, Vauthier D, Denjoy I, Lupoglazoff JM, Piette JC. Safety of hydroxychloroquine
in pregnant patients with connective tissue diseases: a study of one hundred thirty-three cases compared with a control group. Arthritis Rheum. 2003
Nov;48(11):3207-11

15. • 9 RCTs ( 8 = double-blind) with a total of 916 patients.
• Skin hyperpigmentation was more in HCQ group
• No Cardiotoxicity reported in the studies
• Other toxicities were also not statistically significant
No cardiac effect
Eljaaly K, Alireza KH, Alshehri S, Al-Tawfiq JA. Hydroxychloroquine safety: A meta-analysis of randomized controlled trials.
Travel Med Infect Dis. 2020 Jul-Aug;36:101812

16. • 86 articles - cases /short series - 127 patients
• Long time (median 7 y, 3 d-35 y) , a high cumulative dose (median 1235 g for
HCQ
• Conduction disorders - main side effect in 85%
• Treatment withdrawal leads to complete recovery in 45%
Cardiotoxic - Read with
caution
Chatre C, Roubille F, Vernhet H, Jorgensen C, Pers YM. Cardiac Complications attributed to Chloroquine and Hydroxychloroquine: A Systematic Review of the
Literature. Drug Saf. 2018 Oct;41(10):919-931.

17. Read with caution!
• Preselected , skewed , biased case reports
• Both rheumatic and non-rheumatic diseases , which can be linked to
inherent cardiac effects
• Median time to follow up 7 years

18. • 16/151 (10.6%) had elevated BNP , 9 had elevated cTropI
• Increased AM duration – high chance of elevated biomarker
• 6 patients as AM induced cardiomyopathy ( 2 biopsy proven )
Cardiotoxic
– read with
caution
Tselios K, Gladman DD, Harvey P, Akhtari S, Su J, Urowitz MB. Abnormal Cardiac Biomarkers in Patients with Systemic Lupus Erythematosus
and No Prior Heart Disease: A Consequence of Antimalarials? J Rheumatol. 2019 Jan;46(1):64-69

19. Caution !
• Older population ( mean age 54.7 yrs)
• Longer disease duration (22.54 ±10.44 yrs )
• High cumulative dose of HCQ (1251 ± 883 g )
• Not RCT , small sample size .

20. • 52 year RA patient used 400 mg /day for 15
years
• Presented with rapidly progressive
decompensated- biventricular cardiomyopathy
• She improved transiently after discontinuing
drug and then died
Caution –
• RA itself risk factor
• Patient had CKD ,VTE , HTN
• 400 mg/day dose for 15 years
cytoplasmic inclusion bodies:some of which contain curvilinear and lamellar cha
(so-called ‘myelin bodies’)

21. Sumpter MD, Tatro LS, Stoecker WV, Rader RK. Evidence for risk of cardiomyopathy with hydroxychloroquine. Lupus. 2012
Dec;21(14):1594-6.
• 17 cases of HCQ cardiomyopathy
• 13- SLE , 4 – RA ,age 31-88 years
• CD – 290- 4380 g ( Median 1285 g)
• 12.5 yr exposure , 2 cases before 3 years
• Survived patients had improvement after drug discontinuation

22. Revisiting cardiotoxicity in COVID era

23. Hor CP, Hussin N, Nalliah S, Ooi WT, Tang XY, Zachariah S, et al. Experience of short-term hydroxychloroquine and azithromycin in COVID-
19 patients and effect on QTc trend. J Infect 2020; 81: e117-9
• Observational study , on 19 COVID patients
• QTc prolongation occurred even with short-term (5 days) course of low dose HCQ
and azithromycin in combination.
• Limitation - More than one-third of the patients in that study had pre-existing
comorbidities

24. P- 19 studies with a total of 5652 patients
R-
1. Pooled incidence of torsade de pointes, ventricular tachycardia, or cardiac arrest
was 3 /1000 (95% CI, 0-21; I 2 =96%)
2. Pooled incidence of change in QTc from baseline of ≥ 60 msec - 7% (95% CI, 3-14;
I 2 94% )

25. The pooled incidence of
discontinuation of CQ / HCQ due
to prolonged QTc or arrhythmias
was 5% (95% CI, 1-11) among
4334 patients from 13 studies

26. Limitation of the study
• Age
• CAD, hypertension
• Concomitant QT-prolonging medications
• ICU care
• Severity of illness

27. • Torsade-de-Pointes(TDP/VT ), LQT in both drugs
• For HCQ , no of TDP/VT – 83 , LQT - 53
• HCQ - conduction disorders ( AV block /BBB - 75 ) and
heart failure (203)
• Limitation – No data on number of exposed population
Nguyen LS, Dolladille C, Drici MD, Fenioux C, Alexandre J, Mira JP, et al. Cardiovascular toxicities associated with hydroxychloroquine and
azithromycin: An analysis of the World Health Organization pharmacovigilance database. Circulation 2020; 142: 303-5.

28. • P- 1438 patients hospitalized in New York
Result
1 . Combination therapy significantly causes more cardiac arrest than no drug therapy ( OR- 2.13
[1.12-4.05]), but not with individual drugs .
2. No significant differences in the mortality / relative likelihood of abnormal ECG findings.

29. No clinical benefit from use of HCQ in hospitalised patients with COVID-19
P- 1542 patients were randomized to HCQ , 3132 patients to usual care alone
R -
1. No significant difference in 28-day mortality (25.7%HCQ vs. 23.5% usual care; HR 1.11 [95% CI 0.98-
1.26]; p=0.10).
2. No evidence of beneficial effects on hospital stay duration or other outcomes.

30. Skin toxicity

31. Sharma AN, Mesinkovska NA, Paravar T. J Am Acad Dermatol. 2020;83(2):563–78
• Common diseases – SLE ,RA , DM
• 21 unique dermatologic reactions – drug eruption or
rash , cutaneous hyperpigmentation , pruritus , AGEP ,
SJS-TEN , hair loss , and stomatitis .( table )
• The range of mean cumulative dosages was wide, - 3 g
to 2500 g

32. Revisiting skin toxicity
• In post-exposure prophylaxis of COVID-19 , the frequency of skin reaction was
1.1 vs 0.6% ( HCQ vs placebo ) (NEJM study) , 1.6% ( hair fall / itching , oral ulcer
) in HyPE study
• Rare , confounded by COVID itself
• Boulware DR, Pullen MF et al A Randomized Trial of Hydroxychloroquine as Postexposure Prophylaxis for Covid-19. N Engl J Med.
2020 Aug 6;383(6):517-525.
• Bada S Nagaraja et al . HyPE study: hydroxychloroquine prophylaxis-related adverse events’ analysis among
healthcare workers during COVID-19 pandemic: a rising public health concern, Journal of Public Health, 2020

33. Neuropsychiatric
• More data on CQ
• 10 reported cases of HCQ neuro-
myotoxicity - Muscle biopsy
consistently reveals curvilinear bodies
and muscle fiber atrophy with
vacuolar changes
Stein M, Bell MJ, Ang LC. Hydroxychloroquine neuromyotoxicity. J Rheumatol. 2000 Dec;27(12):2927-31
HCQ arm had slight higher neurological reactions
– irritability , dizziness or vertigo ( 5.4% vs 3.7%)
,tinnitus ( 2.3% vs 0.9% ) , headache (3.7 vs 2.3 %)
Past data
Data on COVID era
HyPE study – 6/166

34. Retinal toxicity

35. Jorge, A., Ung, C., Young, L.H. et al. Hydroxychloroquine retinopathy — implications of research advances for rheumatology care. Nat
SD-OCT/VFA
based study
No of
patients
Mean duration
(years)
Cumulative or daily dose Prevalence of retinopathy
with risk factors
Melles et al 2361
rheumatic
15.1 yrs with
retinopathy
Cumulative dose 1856 g
,daily dose 345 mg
7.5% ( long term , CKD ,
tamoxifen, daily dose >5
mg/kg ABW
Eo et al 310 9.1 CD - 952 g 5.2% treated for > 5 years
Browning et al 510
autoimmune
6.9 CD- 694 g 8% ( female , LBW , > 400 g
dose )
Lee et al 218 SLE /RA 9.7 CD- 991.9 g 4.1% ( age ,CD )
Johnston et al 126 Median 9. CD-14.4G/KG 1.6%

36. Recommendation
Jorge, A., Ung, C., Young, L.H. et al. Hydroxychloroquine retinopathy — implications of research advances for rheumatology
care. Nat Rev Rheumatol 14, 693–703 (2018
Criteria Daily dose Body weight Screening

37. TRUTHs regarding HCQ use
• HCQ , used for decades , has effective & safety profile in rheumatic diseases
• It prevents flare in lupus ,lower disease activity & shorten use of long term steroid
• Prolonged use ( > 5 years) can cause irreversible retinotoxicity
• GI & skin adverse effects comparatively common but mild in nature
• Cardiotoxicity - extremely rare , mostly with active disease / comorbidity , even
cardioprotective.
• Cardiotoxicity in COVID due to multifactorial causes ( COVID per se , comorbidity ,
hypercoagulable state , high dose use )
Dima A, Jurcut C, Chasset F, Felten R, Arnaud L. Hydroxychloroquine in systemic lupus erythematosus: overview of current knowledge. Ther Adv
Musculoskelet Dis. 2022 Feb 14;

38. Fallacies
• Potential benefit and harm effect of HCQ is not well
studied in COVID 19
• Lack of effective ,timely open peer & community
review studies in COVID
• Pressure by social media , pre-print publication ,
political interruption
• Multifactorial causes of cardiac toxicity in COVID were
ignored in criticism
Kumar D, Nikhil Vaidya G, Venkatesh A, et al. The Rise and Fall of Hydroxychloroquine (HCQ) in COVID Era: A Therapeutic Journey and Synthetic
Progress . ChemRxiv. Cambridge: Cambridge Open Engage; 2022;

39. A large study suggesting hydroxychloroquine does not benefit COVID-19 patients,
and may even increase deaths, has been retracted. But that doesn't mean
hydroxychloroquine does — or does not — work. - Buda Mendes / Getty Images
Thank you