Qualitative synthesis
A total of 1385 studies were identified after electronic database searching. After 399 duplicates were removed, we screened the title and abstracts of 986 studies. 808 studies were excluded and 178 articles were seen for full-text eligibility. A total of 164 studies were excluded with definite reasons mentioned in the PRISMA flow diagram in figure 2. We included a total of 13 studies in our study. The summary of the 13 studies is discussed in table 2.00
Table 1:- NHLBI quality assessment tool for observational cohort and cross-sectional studies
Study, Year
|
Bias risk (out of 14, 2 points not applicable)
|
Percentage
|
Rosenberg [18], 2020
|
10/12
|
83.3%
|
Magagnoli [19], 2020
|
9/12
|
75%
|
Geleris [20], 2020
|
9/12
|
75%
|
Mahevas [21], 2020
|
9/12
|
75%
|
Mallat [22], 2020
|
8/12
|
66.6%
|
Membrillo [23], 2020
|
8/12
|
66.6%
|
Yu [24], 2020
|
8/12
|
66.6%
|
Lee [25], 2020
|
7/12
|
58%
|
Good if they fulfilled 60-100% of the tool items, Fair if 50-59% or Poor if 0-49%.
Table 2: Summary of included studies
Study, Year
|
Study Type
|
Study Population
|
Intervention
|
Outcome
|
Barbosa [26], 2020, USA
|
Quasi-randomized trial
|
63
T:- 32
C:-31
Subgroup analysis
T:- 17
C:- 21
|
HCQ 400 mg BD for 1-2 days followed by 200mg OD for 4 days in the treatment group
Standard care in control
|
· Mortality rate 4/32 T and 1/ 31 C
· Escalation of respiratory support level compared to 5 days
Among match cases (n=38)
· Mortality Rate 2/17 (11.76%) T and 1/21 C
· Rate of Intubation (MV) =7/17 (41.18%) T and 2/21 (9.52%) C
|
Chen Jun [27], 2020, China
|
RCT
|
30
T:- 15
C:- 15
|
HCQ 400 mg BD for 5 days in the treatment group
|
· Negative viral load in 13 T and 14 C
· Median time for the negative viral load was 4 (1, 9) days T and 2 (1, 4) days in C
· Median time for body temperature normalization in HCQ group was 1 (0, 2) T and 1 (0, 3) day] in C
· Radiological progression in 5 cases (33.3%) of the HCQ group and 7
cases (46.7%) of the control group
· All patients showed improvement in follow-up examinations.
· 4 cases in T and 3 in C had transient diarrhea and liver abnormalities
|
Chen [28], 2020, China
|
RCT
|
62
T:- 31
C:- 31
|
HCQ 400 mg BD for 5 days in treatment group
|
· Improvement of fever in treatment group [2.2 (0.4) days].
· Improvement of cough in the treatment group.
· Rash in one and headache in one patient
· Improvement of pneumonia in 67.7% (42/62) of patients with 29.0%(T=6, C=12) ,moderately absorbed and 38.7% (T=19, C=5) significantly improved
|
Gautret [29], 2020,
France
|
RCT
|
36 (enrolled 42)
T:20
C:16
Six HCQ treated patients were lost in follow-up during the survey (1 cured, 1 death, 1 AE)
|
HCQ 200 mg, TID for 10 days
|
· Viral clearance at day-6 post-inclusion
T :- 70%(14/20)
C :-12.5%(2/16)
· Number of patients attaining viral clearance
HCQ + AZT : 100% (6/6)
HCQ: 57.1% (8/14)
CG: 12.5% (2/16)
|
Geleris [20], 2020,
USA
|
Observational study
|
1376
T: 811
C: 565
|
HCQ 600 mg BD on day 1, then 400 mg daily for a median of 5 days And
AZT 500 mg on day 1 and then 250
mg daily for 4
|
· Mortality Rate
T 157/811
C 75/565
· Rate of Intubation (MV)
T 154/811
C 26/565
|
Lee [25], 2020,
South Korea
|
Retrospective sohort Study
|
72
T: 27
C: 45
|
C=LPV/r (400/100 mg orally every 6-12 hours) T=HCQ (400 mg orally every 24 hours)
|
· Progression of clinical disease:-
(T 12/27; C 8/45)
· Adverse effects:
(T 7/27; C22/45)
Severe Effect:
(T 1/27; C 2/45)
· Ventilation:
(T 0/27: C 3/45)
· Death
(T 0/27; C 2/45)
|
Magagnoli [19], 2020, USA
|
Retrospective analysis
|
368
HCQ :- 97
HCQ + AZT:- 113
C :- 158
|
HCQ or HCQ + AZT in combination
|
· Mortality
(C:- 18; HCQ : - 27; HCQ + AZT :- 25)
· Risk of ventilation
(CG :- 25; HCQ :- 12; HCQ + AZT:- 7)
|
Mahevas [21], 2020, France
|
Comparative observational study
|
173
T:- 84
C:- 89
|
HCQ 600 mg within 48 hr of hospital visit
|
· Survival without transfer to intensive care unit at day 21
(T:- 17; C:- 22)
· Survival without ARDS
(T:- 25; C:- 23)
· Oxygen weaning
(T:- 66; C:- 66)
· Discharge from hospital to home or rehabilitation
(T:- 67; C:- 71)
· Death:
(T:- 9; C:- 8)
· Adverse outcome:
8 patients had abnormal ECG ( 7 QT prolongation, 1 1st degree AV Block and 1 LBBB)
|
Mallat [22], 2020, UAE
|
Retrospective observational study
|
34
T:- 21
C:- 13
|
HCQ 400 mg BD for 1 day followed by 400 mg ID for 10 days
|
· Time for negative viral load
( T:- 17 [13-21] days; C:- 10 [4-13] days)
· Percentage of patients with negative viral load
(T:- 14/23; C:- 10/11)
|
Membrillo [23], 2020, Spain
|
Observational cohort study
|
166
T:- 123
C:- 43
|
A loading dose of 1200 mg HCQ followed by a maintenance dose of 400 mg OD
|
· Mean hospital stay
6 (5) days in T; 5(7) days in the C
· Mortality Rate
T 27/123; C 21/43
|
Rosenberg [18], 2020, USA
|
Retrospective cohort study
|
1438
HCQ + AZT :- 735
HCQ:- 271
AZT:- 211
Standard therapy:- 221
|
HCQ + AZT, HCQ alone, AZT alone
|
· Death probability
HCQ+ AZT 189/735 (25.7%); HCQ Alone 54/271 (19.9%); AZT alone 21/211(10.0%); No drug 28/221(12.7%)
· Abnormal ECG
HCQ+ AZT 199/735; HCQ Alone 74/271; AZT alone 34/211; No drug 31/221
· Cardiac arrest
HCQ+ AZT 114/735; HCQ Alone 37/271; AZT alone 13/211; No drug 15/221
· QT prolongation
HCQ+ AZT 81/735; HCQ Alone 3/271; AZT alone 15/211; No drug 13/221
|
Tang [30], 2020, China
|
RCT
|
150
T:- 75
C:- 75
6 patients in T group refused HCQ and one control patient took HCQ
|
HCQ 1200 mg OD * 3days followed by 800 mg OD for 2-3 weeks in the treatment group
|
· Viral clearance in 56 in C and 53 in T before 28 days
· Median time for viral clearance 8d (95% CI :- 5 – 10 days) in T vs 7 (95% CI :- 5 – 8 days) in C
· Adverse effects in 21/70 (30%) in T and 7/80(8.8%) in C. Serious adverse event in 2 patients. Non-serious in 19/70 in T and 7/80 in C
· Median time to clinical improvement was 19 in T vs 21 in C
|
Yu [24], 2020, China
|
Retrospective study
|
550
T:- 48
C:- 502
|
HCQ 200 mg BD for 7-10 days in the treatment group
|
· Ventilator no. = 28/48 in T and 321/502 in C
· Death: 8.8% (9/48) in T and 47.4% (238/502) in C
|
Quantitative synthesis of treatment outcome
In the present meta-analysis, we have compared randomized and non-randomized studies to extract outcome on virological clearance, radiological progression, overall death, development of adverse effects (severe, minor), cardiac complications (QT-prolongation, de-novo arrhythmias), the requirement of intubation, and mechanical ventilation. Among the included studies in the meta-analysis, we found there is mild-substantial heterogeneity; which may be due to clinical and variability in study design and the risk of bias among studies which could not be omitted fully may be due to acute surge to COVID–19 cases having diversity in presenting and getting treatment due to pandemic.
HCQ with or without AZT regimen and SOC versus SOC only; effectiveness
Among the treatment group HCQ with or without AZT in addition to SOC versus SOC, we have compared the duration of virological clearance (negative RT-PCR) and radiological progression.
Virological clearance
The meta-analysis of RR for HCQ with or without AZT in addition to SOC effectiveness compared with SOC alone using a random effect model among randomized and non-randomized studies showed that there were no significant differences between the two arms (RR 0.95, 95% CI 0.67 to 1.34; participants = 250; studies = 4; I2 = 76%). Moreover, there is no significant risk difference (RD) between the two groups for the virological cure of HCQ with or without AZT in COVID–19 patients (RD 0.04, 95% CI –0.27 to 0.34) (Figure 3a).
Sensitivity analysis for HCQ with or without AZT in addition to SOC effectiveness compared with SOC alone
To evaluate the impact of inverse RRs as well as studies’ weight on the meta-analysis results, we conducted sensitivity analyses as according to the substantial relative weight of Tang et al. on the meta-analysis, by excluding that studies, as follows no significant change, was observed (RR 1.15, 95% CI 0.53 to 2.48). (Supplementary file 2/ figures 1, 2).
Radiological progression (pneumonia resolution)
Among the two studies reported radiological improvement, overall RR for HCQ with or without AZT in addition to SOC compared with SOC alone using a fixed-effect model showed that there was significant improvements among treatment arm (RR 1.40, 95% CI 1.03 to 1.91; participants = 92; studies = 2; I2 = 0%). Additionally, there is significant RD between the two groups for radiological progression for pneumonia resolution among HCQ with or without AZT in COVID–19 patients (RD 0.22, 95% CI 0.03 to 0.41) (Figure 3b).
HCQ with or without AZT regimen and SOC versus SOC only; mortality
The meta-analysis of death outcome in comparative randomized and non-randomized studies showed no significant differences for mortality rate between HCQ with or without AZT regimen and standard treatment group compared with SOC alone (RR 1.08, 95% CI 0.65 to 1.79; participants = 4012; studies = 9; I2 = 83%; RD –0.01, 95% CI –0.08 to 0.07) (Figure 3c).
Sensitivity analysis for HCQ with or without AZT in addition to SOC on mortality compared with SOC alone
To evaluate the impact of inverse RRs as well as studies’ weight on the meta-analysis results, we conducted sensitivity analyses as according to the substantial low relative weight excluding four studies <50 participants in treatment groups; Barbosa 2020 [26], Gautret 2020 [29], Lee 2020 [25], and Yu 2020 [24]; with total 702 participants from all 4 studies on the meta-analysis. By excluding those studies, no significant changes were observed(RR 1.28, 95% CI 0.75 to 2.17) (Supplementary file 2/ figures 3, 4). While swapping events between the treatment group with the control group also did not show significance in preventing from dying [(RR (Non-event) 0.93, 95% CI 0.86 to 1.01] (Supplementary file 2/ figure 5).
HCQ with or without AZT regimen and SOC versus SOC only; mortality among RCTs
The meta-analysis of death outcome in randomized studies using fixed effect showed no significant differences for mortality rate between HCQ with or without AZT regimen and standard treatment group compared with SOC alone (RR 2.23, 95% CI 0.35 to 14.37; participants = 80; studies = 2; I2 = 0%; RD 0.05, 95% CI –0.05 to 0.16) (Figure 3d).
HCQ with or without AZT regimen and SOC versus SOC only; intubation and mechanical ventilation
The meta-analysis on intubation rate and mechanical ventilation among randomized and non-randomized studies showed no significant differences between HCQ with or without AZT regimen and SOC versus SOC only about the odds of intubation during treatment (OR 1.52, 95% CI 0.61 to 3.77; participants = 3506; studies = 6; I2 = 89%) (Figure 3e).
Excluding the three studies, Barbosa 2020 [26], Lee 2020 [25], and Yu 2020 [24] with substantial low relative weight (<50 participants in the treatment group) showed no significant odds of intubation during/after the beginning of treatment among HCQ with or without AZT regimen and SOC on the meta-analysis sensitivity (OR 1.72, 95% CI 0.51 to 5.83) (Supplementary file 2/ figure 7).
HCQ with or without AZT regimen and SOC versus SOC only: overall adverse effects
The meta-analysis of among randomized and non-randomized studies showed that the odds of having overall adverse effects among those under HCQ with or without AZT regimen addition to SOC regimen was approximately 2.2 times higher than SOC only taking individuals without HCQ regimen though it was not statistically significant (OR 2.21, 95% CI 0.95 to 5.17) (Figure 3f). Patients under HCQ with or without AZT regimen and SOC regimen were having 2 times higher odds of having severe adverse effects, though it is also not statistically significant (OR 2.08, 95% CI 0.40 to 10.74) (Figure 3f).
We conducted sensitivity analyses as according to the substantial relative weight of Rosenberg 2020 [18] (>500 participants in events) on the meta-analysis, by excluding that study also no statistically significant findings observed on odds of having Overall adverse effects among HCQ with or without AZT regimen and SOC on the meta-analysis (Overall: OR 2.22, 95% CI 0.61 to 8.04) (Supplementary file 2/ figure 8).
HCQ with or without AZT regimen and SOC versus SOC only: overall adverse effects among RCTs
The meta-analysis of among randomized controlled trials showed that the odds of having overall adverse effects among those under HCQ with or without AZT regimen addition to SOC regimen was approximately 3.5 times higher than SOC only taking individuals without HCQ regimen (OR 3.48, 95% CI 1.64 to 7.42; participants = 284; studies = 4; I2 = 0%; RD 0.14, 95% CI 0.06 to 0.22) (Figure 3g).
Arrhythmias and significant QT-prolongation
The meta-analysis of non-randomized studies showed that the odds of having Arrhythmias and significant QT-prolongation among those under HCQ with or without AZT addition to SOC regimen were approximately 2.5 times higher than SOC only taking individuals without HCQ regimen (OR 2.49, 95% CI 1.67 to 3.70; participants = 1400) (Figure 3h). While for sensitivity analysis done using random effect and inverse variance, it showed no significant odds of developing arrhythmias and QT prolongation (Supplementary file 2/ figure 9).
Clinical trials
There are 207 trials registered focusing on the safety and efficacy of hydroxychloroquine for COVID–19 treatment along with different parameters around the globe as of 30 May 2020 [31] (Supplementary table 2). Among these, 5 trials have recently been completed. A total of 103 trials are recruiting participants, 74 trials have not yet started recruiting, 9 trials are active but not recruiting participants, and 10 trials are enrolling by invitation. Out of these, 16 trials are observational and the rest are RCTs. Altogether, 6 trials are either suspended or terminated or withdrawn due to different reasons. According to the location provided, around 42 countries are regulating trials on such subjects, where the USA is at the highest position conducting most of the 52 trials followed by France which is managing 24 trials. The largest trial is RCT conducted in Thailand with 40,000 cases, while the smallest trial is an observational type conducted in Belgium with 12 participants [31].