Table 1.
All published studies that reported the effectiveness or safety of hydroxychloroquine, chloroquine, or azithromycin.
| Study | Country | Case definition | No. patients (intervention/standard care) | aAge (intervention-standard care) | Sex (total male percentage) | Treatment | Duration (days) | Primary outcomes | Findings |
|---|---|---|---|---|---|---|---|---|---|
| Type of study | Intervention | ||||||||
| Study setting | Control | ||||||||
| Borba25 | Brazil | Clincally suspected adults with severe COVID, | 81 (41:40) | 47.4 ± 13.3 | 75.3% males | HCQ 600 mg bid | 23 March–5 April 2020 | Lethality until day 13 | 39% (high dose) and 15% (low dose) |
| RCT | HCQ 450 mg bid for one day then 450 mg/d for 4 days | ||||||||
| Chang26 | USA | COVID-19 positive | 117 (HCQ: 66 HCQ + AZM: 51) | 60.2 ± 14.9 | 59.5% males | HCQ 400 mg bid for 1 d then 200 mg bid for 4 d | – | Assess QTc | 32.1 ± 25.1 ms (HCQ) 35.7 ± 28.9 ms (HCQ + AZM), P = 0.66 |
| Prospective cohort | HCQ as before + AZM | ||||||||
| Chen27 | China | PCR-confirmed COVID-19 | 30 (15:15) | HCQ: 50.5 ± 3.8; SC: 46.7 ± 3.6 | HCQ: 60% males; SC: 80% males | HCQ 400 mg/d for 5 d | 6 Feb–25 Feb 2020 | PCR conversion One week after hospitalization | 86.7% (HCQ) and 93.3%(SC) |
| RCT | SC | ||||||||
| Chen28 | China | Covid-19 | 62 (31:31) | HCQ: 44.1 ± 16.1 | Intervention 45.2% males | HCQ 400 mg/d | 4 Feb–28 Feb 2020 | Absorption of pneumonia in CT | 80.6% (HCQ) and 54.8% (SC) Shorter duration of cough and fever in HCQ group |
| RCT | SC: 45.2 ± 14.7 | Standard care 48.3% males | SC | Clinical improvement | Two patients experienced side effect (HCQ) | ||||
| Four paients deterirated in the (SC) | |||||||||
| Chong29 | China | Covid-19 | 11 | 51.55 ± 12.54 | 63.6% males | LPV/r 400/100 mg bid for 14 days + HCQ 400 mg bid day‐1 then 200 mg bid for 2‐5) | N/A | Developed QT prolongation | 27.3% developed prolonged QTc |
| Case-series | |||||||||
| Gautret30 | France | PCR positive mildly infected Covid-19 patients | 80 | 52.5 (42–62) | 53.8% males | HCQ 200 mg tid for 10 d + AZM 500 mg for 1 d then 250 mg/d for 4 d | 3–21 March 2020 | Clinical course, viral clearance and hospital stay | Clinical course: 81.3% with favorable outcome |
| Retrospective observational | Viral clearance: 93% had viral clearance at Day8 | ||||||||
| Hospital stay: mean length of stay of 4.6 days | |||||||||
| Gautret30 | France | PCR confirmed COVID-19 patients | 36 (HCQ: 14 HCQ + AZM: 6; SC: 16) | Total HCQ 51.2 ± 18.7 SC: 37.3 ± 24.0 | Total HCQ: 45% males; SC: 37.5% males | HCQ 200 mg tid for 10 d | Early March-16 March | Virological cure | 57.1% (HCQ), 100% (HCQ + AZM) and 12.5% (SC) |
| Clinical trial | HCQ as before + AZM: loading 500 mg then 250 mg/d for 4 d | ||||||||
| SC | |||||||||
| Geleris6 | USA | All Hospitalized adult patients with positive COVID-19 infection | 1376 (811:565) | – | HCQ: 58.4% male; SC: 54.3% males | HCQ 600 mg bid one day then 400 mg/d for 4 days | 7 March–8 April 2020 | Composite of time to intubation or death (time-to-event analysis) | No significant association between HCQ and intubation or death (hazard ratio, 1.04; 95% CI 0.82–1.32) |
| Observational | SC | ||||||||
| Gerard31 | France | Reports of cardiotoxicity associated with HCQ, CQ, AZM, or LPV/r use in COVID-19 | 120 | 64.3 ± 13.4 | 76.7% males | HCQ/CQ/AZM/LPV/r | – | Cardiac adverse drug reactions | 86% (HCQ), 60% (AZM), 14%( LPV/r) and 2.5% (CQ) |
| Survey | |||||||||
| Hraiech32 | France | COVID-19 PCR positive ICU patients | 45 (HCQ + AZM: 17, LPV/r: 13, SC: 15) | HCQ + AZM: 60 ± 17 LPV/r: 62 ± 13; SC: 60 ± 16 | HCQ + AZM: 88% males; LPV/r: 69% males; SC: 73% males | HCQ 600 mg and AZM 500 mg then 250 mg/d | 2 March–31 March 2020 | Viral clearance at day 6 treatment | PCR was negative in 5/13 (38%) from the LPV/r group, 3/17 (1%) from the HCQ + AZM group and 2/15 (20%) from the control group |
| LPV/r: 800 mg/d | |||||||||
| Case control | SC | ||||||||
| Macías33 | Spain Retrospective cohort | patients with autoimmune rheumatic diseases with confirmed or suspected COVID 19 | 722 (290:432) | HCQ: 56 (45–65); No HCQ: 58 (48–68) | HCQ: 16%; No HCQ: 21% | HCQ vs. no HCQ (for autoimmune disease) | 27 Feb–16 April 2020 | Incidence of COVID 19 in patients with autoimmune rheumatic diseases receiving vs. not receiving HCQ | 5 cases (1.7%) in those on HCQ vs. 5 cases (1.2%) in those not on HCQ |
| Mahévas34 | France | severe acute respiratory syndrome | 173 (84/89) | HCQ: 59 (48–67); SC: 62 (54–69) | HCQ: 77% males; SC: 67% males | HCQ 600 mg/d | 12 March–31 March 2020 | the survival rate at day 21 without transfer to ICU | 76% (HCQ) and 75% (SC) |
| Comparative observational | SC | ||||||||
| Rosenberg35 | USA | Lab confirmed COVID-19 | 1438 (HCQ + AZM: 735; HCQ 27; AZM: 211SC: 221) | HCQ + AZM: 61.4; HCQ: 65.5; AZM: 62.5; SC: 64 | HCQ + AZ: 62; HCQ: 58.3; AZM: 63.5; SC: 49.8 | HCQ + AZ | 15 March–28 March 2020 | Mortality | 25.7% (HCQ + AZM), 19.9% (HCQ), 10% (AZM) and 12.7% (SC) |
| HCQ | |||||||||
| Retrospective cohort | AZ | ||||||||
| SC | |||||||||
| Stroppa36 | Italy | COVID-19, Cancer patients | 56 | 71.64 ± 10.08 | 80% males in cancer patients, 48% males in Non-cancer patients | 7 days or HCQ 400 mg/d alone or AV + HCQ | 21-Feb 21, 2020 to March 18, 2020 | Mortality | Of the 25 cancer patients, nine (36%) are dead and 16 (64%) are alive, with improvement from pneumonia, in the control group of patients hospitalized and treated with the same protocol in the same period, 16.13% are dead and 83.87% are alive P = 0.12 |
| Case–control | 25 Cancer patients,31 non-cancer patients | ||||||||
| Broek37 | Netherlands | Hospitalized and suspected with COVID-19 | 95 patients | 65 (min18-max 91) | 66.3% males | CQ 600 mg then 300 mg bid for 5 d | 8–27 March 2020 | Assess the degree of CQ induced QTc prolongation in hospitalized COVID-19 patients | 22 patients (23%) had a QTc interval exceeding 500 ms |
| Retrospective observational study | |||||||||
| Voisin38 | France | Hospitalized patients with COVID-19 pneumonia | 50 patients | 68 (53–81) | 55.2% males |
HCQ 600 mg/d for 6 d + AZM 500 mg/d for 1 d then 250 mg/d for 2–5 d N/A |
18 March–25 March 2020 | Effect of HCQ + AZM combination on QTc in case of short term treatment of COVID 19 | 38 patients (76%) presented short term modifications of QTc (> 30 ms) |
| Cohort | |||||||||
| Yu39 | China | Confirmed COVID-19 in critically ill adult patients | 550 (48/502) | HCQ: 68 (60–75); SC: 68 (59–77) | HCQ: 66.7% males; SC: 62.2% males | HCQ 200 mg bid (7–10 days) | 1 Feb 2020 to 4 April, 2020 | Mortality and inflammatory cytokines level | Mortality: 18.8% (HCQ) and 47.7% (SC) |
| Retrospective cohort | SC | IL-6 reduced from 22.2 (8.3–118.9) pg/ml to 5.2 (3.0–23.4) pg/ml (HCQ) but no change in (SC) | |||||||
| Huang40 | China | Confirmed COVID-19 patients | 22 CQ: 10 LPV/r: 12 | CQ: 41.5 (33.8–50.0) LPV/r: 53.0 (41.8–63.5) | CQ: 30% LPV/r: 50% | CQ 500 mg bid for 10 d | 27 January 2020 to 15 Feb 2020 | Virological cure, CT scan improvement and hospital discharge at day 14 | Virological cure: 100% (HCQ) and 91.7% (LPV/r) |
| Case–control | LPV/r 400/100 mg bid for 10 d | CT scan improvement: 100% (HCQ) and 75% (LPV/r) | |||||||
| Hospital discharge: 100% (HCQ) and 50% (LPV/r) | |||||||||
| Magagnoli41 | USA | Lab confirmed COVID-19 hospitalized patients | 807 ( HCQ: 198 HCQ + AZ: 214 SC: 395) | HCQ: 71 (62–76.8), HCQ + AZ: 68 (59–74); SC: 70 (59–77) | HCQ: 97%; HCQ + AZ: 95.3%; SC: 95.2% | HCQ 400 mg/d for 5 d | 9 March 2020–29 April 2020 | Mortality and mechanical ventilation | Mortality: HCQ aHR, 1.83; 95% CI 1.16–2.89; P = 0.009, but HCQ + AZM aHR, 1.31; 95% CI 0.80–2.15; P = 0.28. compared to SC |
| Retrospective cohort | HCQ 422 mg/d + AZM for 5 d | Mechanical ventilation: HCQ aHR, 1.19; 95% CI 0.78–1.82; P = 0.42 but in the HC + AZ aHR, 1.09; 95% CI 0.72–1.66; P = 0.69, compared to SC | |||||||
| SC | |||||||||
| Ramireddy42 | USA | COVID-19 Confirmed/suspected patients | 98 (AZM: 27–HCQ: 10–AZM + HCQ: 61) | 62.3 ± 17 | 61% males | HCQ + AZM | 1 February 2020 to 4 April, 2020 | QT prolongation | Significant prolongation in men (12% of patients) reached critical QTc prolongation |
| Case-series | HCQ 400 mg bid on day1 then 200 bid on days 2 to 5 | Changes in QTc were highest with the combination group compared to either drug alone, with many-fold greater prolongation with the combination vs. AZM alone (17 ± 39 vs. 0.5 ± 40 ms, P = 0.07) | |||||||
| AZM either 500 mg daily or 500 mg on day1 followed by 250 mg daily on days 2–5 | |||||||||
| Barbosa43 | USA | PCR positive COVID-19 patients | 63 (32/31) | HCQ: 61.8 ± 15; SC: 63.7 ± 15.4 | HCQ: 46.9% males; SC: 71% males | HCQ 400 mg bid for 1–2 days then 200–400 mg/d for 3–4 days | 15 March 2020–31 March 2020 | Mortality rate | 12.9% (HCQ) and 3.13% (SC) |
| Retrospective cohort | SC | ||||||||
| Mallat44 | UAE | Hospitalized adult patients with confirmed SARS-CoV-2 infection | 34 (23/11) | HCQ: 33 (31–48); SC: 41 (30–55) | HCQ: 73.9% males; SC: 72.7% males |
HCQ 400 mg bid for 1 day, then 400 mg/d for 10 days SC |
1 March–25 March 2020 | The time to SARS-CoV-2 negativity | 17 (13–21) days HCQ and 10 (4–13) days SC |
| Retrospective cohort | |||||||||
| Huang3 | China | Confirmed COVID-19 cases | 373 (197/176) | CQ: 43.8 ± 13.1; SC: 45.6 ± 13.5 | CQ: 49% males; SC: 45% males | CQ 500 mg/d | 7 Feb-8 March 2020 | Median Time to undetectable viral RNA | 3 (3–5) CQ and 9 (6–12) SC |
| Prospective Observational | SC | ||||||||
| Feng45 | China | Confirmed COVID-19 cases | 50 (25/25) | CQ: 51 (41–62); SC: 46 (38–67) | 50.4% of males | CQ 500 mg bid | Jan 17–Feb. 28, 2020 | 1ry outcome: development of severe pneumonia | None of patients treated with CQ developed severe pneumonia, though without significance (difference, 12.0%; 95% CI − 3.5 to 30.0%; P = 0.074) |
| Retrospective cohort | SC | ||||||||
| Mathian46 | France | SLE with COVID-19 | HCQ: 17 | 53.5 (26.6–69.2) | 23.5% males | HCQ | 29 March–6 April 2020 | Clinical course | Admitted to hospital (82%); needed O2 therapy (64.7), ICU admission (41%) Respiratory complications: ARDS (29%) Respiratory failiure (65%) Pneumonia (76%) Acute renal failure (17.6%), hemodialysis (11.8%) Discharge (36%), Death (14%), remained in hospital (50%) |
| Case series | N/A | ||||||||
| Tang47 | China | patients hospitalized with PCR confirmed mild to moderate COVID–19 | 150 (75/75) | HCQ 48.0 ± 14.1; SC 44.1 ± 15.0 | HCQ: 56% males; SC: 53% males | HCQ 1200 mg/d for 3d then 800 mg/d for 14–21 d | 11 to 29 February | Rate of viral negative conversion at 28 days | (56/75 (74.6%) in SC and 53/75 (70.6%) in HCQ) negatively converted before 28 days |
| RCT | SC | ||||||||
| Carlucci48 | USA | PCR positive COVID-19 patients | 931 Zinc + HCQ + AZM: 411; HCQ + AZM: 521 | Zinc + HCQ + AZ: 63.19 ± 15.18; HCQ + AZ: 61.83 ± 15.97 | Zinc + HCQ + AZM: 64.3% males; HCQ + AZ: 61.4% males | HCQ 400 mg/d for 1 d then 200 mg bid for 5d + AZ 500 mg/d for 5 d + zinc sulfate 220 mg bid for 5 d | 2 March 2020–5 April 2020 | Effect of adding zinc to HCQ and AZM | The addition of zinc sulfate did not impact the length of hospitalization, duration of ventilation, or ICU duration |
| Retrospective observational | The same dose as in the other group but without zinc | ||||||||
| Singh49 | USA | Confirmed COVID-19 patients | 1820 (910/910) | HCQ: 62.17 ± 16.81; SC: 62.55 ± 17.62) | HCQ: 53.96% males; SC: 54.94% males | HCQ (dose not mentioned) | 20 January, 2020–1 May, 2020 | Mortality 30-day and need for mechanical ventilation | Mortality: 11.34% (HCQ) and 11.98% (SC) |
| Retrospective cohort | SC | Mechanical ventilation: 5.05% (HCQ) and 6.26% (SC) | |||||||
| Singh49 | USA | Confirmed COVID-19 patients | 1402 (701/701) | – | – | HCQ + AZM (dose not mentioned) | 20 January, 2020, to 1 May, 2020 | Mortality 30-day and Need for mechanical ventilation | Mortality: 12.27% (HCQ + AZM) and 10.27% (SC) |
| Retrospective cohort | – | – | SC | Mechanical ventilation: 5.71% (HCQ + AZM) and 5.85% (SC) | |||||
| Regina50 | Switzerland | laboratory confirmed SARS-CoV-2 patients | 200 | 70.0 (55.0–81.0) | 60% males | From March 1 to March 25, 2020 | Need for mechanical ventilation (MV) at day 14 | HCQ: (31.2%); Remdisivir: (100%); Protease inbititors: (31%); Tocilizumab: (82%) | |
| Retrospective cohort | |||||||||
| Membrillo51 | Spain | laboratory-confirmed SARS-CoV-2 patients | 166 (123/43); 83 patients had a mild clinical picture at admission, 48 moderate, and 35 severe | HCQ: 61.5 ± 16.2; SC: 68.7 ± 18.8 | HCQ: 61.8% males; Non HCQ: 62.8% males | Loading dose of HCQ 800 mg + 400 mg, followed by maintenance dose of 400 mg/d | N/A | Mortality | 48.8% of patients not treated with HCQ died versus 22% in the group of HCQ (P = 0.002) |
| Observational Cohort | SC | HCQ increased the mean cumulative survival in the mild-moderate and severe group to 1.8, 1.4, 1.6 times respectively but the difference was statistically significant in the mild group | |||||||
| Lee52 | South Korea | Confirmed COVID-19 patients | 72 (LPV/r: 45 HCQ: 27 | Median (IQR); LPV/r: 39 (24–56); HCQ: 37 (24–53) | LPV/r: 44.4%; HCQ: 44.4% | LPV/r: 400/100 mg/d bid | 21 Feb 2020 to 21 March 2020 | Compare clinical outcomes of both treatments | Disease progression (HCQ) 44% and (LPV/r) 18% |
| Retrospective cohort | HCQ: 400 mg/d | ||||||||
| Million53 | France | PCR positive COVID-19 patients | 1061 | 43.6 ± 15.6 | 46.4% males | HCQ 200 mg tid for 10 d + AZM 500 mg on day 1 followed by 250 mg/d for 4 d | 3 March 2020 to 31 March 2020 | Death, clinical worsening, and viral shedding persistence (> 10 days) | 91.7% had good clinical outcome and virological cure, 4.4% had viral shedding persistence and 0.75% died |
| Retrospective cohort | |||||||||
| Okour54 | USA | Confirmed COVID-19 patients | 36 Patient | Not provided | Not provided | HCQ+/−AZM | March 2020 | Probability of negative-PCR in patients | Odds of positive-PCR decrease by 53% for each unit increase in HCQ log-concentration. Similarly, the odds decrease by 61%, and by 12% for each day increase, and azithromycin co-treatment, respectively |
| Non-RCT | |||||||||
| Saleh55 | USA | Confirmed COVID-19 patients | 201 CQ: 10; HCQ: 191 (119 patients received AZM in addition to HCQ) | 58.5 ± 9.1 | 57.2% males | CQ 500 mg bid for 1 d then 500 mg/d for 4 d or HCQ 400 mg bid for 1 d then 200 mg bid for 4 d | 1–23 March 2020 | Assess QT prolongation resulting in Torsade de pointes | 440.6 ± 24.9 ms (HCQ/CQ) and 439.9 ± 24.7 ms (HCQ/CQ + AZM) (P = 0.834) |
| Prospective cohort | The same doses as before + AZM 500 mg/d for 5 days | ||||||||
| Chorin56 | USA | COVID-19 patients | 251 patients | 64 ± 13 | 75% males | HCQ 400 mg bid for 1 d then; 200 mg bid for 4 days + AZM; 500 mg/d for 5 d | – | Assess the change in QTc | QTc > 500 ms, occurred in 23% of patients |
| Retrospective cohort |
aHR adjusted hazard ratio, ARDS acute respiratory distress syndrome; AZM azithromycin, CI confidence interval, CQ chloroquine, CT computed tomography, HCQ hydroxychloroquine, ICU intensive care unit, IQR interquartile range, LPV/r Lopinavir/ritonavir, ms milliseconds, N/A not applicable, PCR Polymerase chain reaction, QTc corrected QT interval, RCT randomized control trial, SC standard care.
aAge was presented either as mean ± Standard deviation or median (Interquartile range).