Table 1.

Summary of Observational Studies Evaluating HCQ for COVID-19 Treatment.

Study Design	Pts	Study Groups	Results: Primary/Secondary* Outcomes	Methodological Issues
Comparative observational study18	3737	1. HCQ+AZ 2. Others sub divided to: HCQ-AZ <3 days HCQ AZ SOC	HCQ+AZ treatment compared to control: ↓ Risk of death or transfer to ICU (HR 0.18; 95% CI 0.11–0.27)* ↓ Hospitalization ≥10 days (OR 0.38; 95% CI 0.27–0.54) Shorter viral shedding duration in HCQ+AZ compared with all other subdivided groups, compared with SOC (HR 1.29; 95% CI 1.17–1.42)	Unequal group sizes (Tx Pts n=3,119 vs “Other” Pts n=618; with many Txs and no pre-specified protocol
Comparative observational study15	2541	1. HCQ 2. HCQ+AZ 3. AZ 4. SOC	Overall in-hospital mortality lower in all treatment groups: HCQ+AZ: 20.1% (95% CI 17.3%–23.0%) HCQ: 13.5% (95% CI 11.6%–15.5%) AZ: 22.4% (95% CI 16.0%–30.1%) SOC: 26.4% (95% CI 22.2%–31.0%)	Tx group Pts mean age 5 y older than in controls ↑ steroid Tx rates in HCQ groups Missing data due to reliance only on electronic health records
Comparative observational study10	1438	1. HCQ 2. HCQ+AZ 3. AZ 4. SOC	No Sig.Dif. in mortality rates for HCQ+AZ (HR 1.35; 95% CI 0.76–2.40), HCQ alone (HR 1.08; 95% CI 0.63–1.85), or AZ alone (HR 0.56; 95% CI 0.26–1.21) compared with control*	No follow-up of discharged Pts Missing group characteristics data Major difference between size of SOC vs Tx groups
Comparative observational study12	1376	1. HCQ 2. SOC	No significant association between HCQ and intubation or death vs SOC (HR 1.04; 95% CI 0.82–1.32)	HCQ Pts more severely ill than SOC at baseline
Comparative observational study of critically ill ventilated patients with ARDS14	568	1. HCQ 2. SOC	Primary Outcome Significant mortality rate differences between HCQ (18.8%) and SOC (45.8%) groups; P<0.001 Secondary Outcomes Longer HCQ hospitalization time before death compared to SOC (P<0.05) IL-6 levels significantly lower during Tx period for HCQ group; SOC group unchanged	Such dramatic ↓ in mortality rate not described in any other study Different rates of antibiotics use and interferon imply inherent selection bias for HCQ vs SOC (HCQ 0% interferon vs 10.8% in SOC (P=0.01)
Comparative observational study16	72	1. HCQ-asymptomatic 2. SOC-asymptomatic	No Sig.Dif. in recovery rates (HCQ 97.5% vs SOC 96.85%) Earlier Tx group recovery (5.4 days) vs SOC (7.6 days)	HCQ efficiency only assessed in asymptomatic Pts Inclusion to SOC due to HCQ contraindications that probably imply underlying medical conditions
Comparative observational study of only electronic health records13	368	1. HCQ 2. HCQ+AZ 3. SOC	Primary Outcomes ↑ mortality rates for HCQ (AHR 2.61; 95% CI 1.10–6.17; P=0.03) vs SOC, but not in HCQ+AZ (AHR 1.14; 95% CI 0.56–2.32; P=0.72) No Sig.Dif. in ventilation rates among HCQ, HCQ+AZ, and SOC (13.3%, 6.9%, 14.1%, respectively) Secondary Outcomes No difference in risk of death after ventilation in HCQ (AHR 4.08; 95% CI 0.77–21.70; P=0.10), HCQ+AZ (AHR 1.20; 95% CI 0.25–5.77; P=0.82), compared with the no HCQ group	Missing data due to reliance on electronic health record codes ~95% males in all groups
Comparative observational study of pneumonia patients requiring O2 without ICU admission11	181	1. HCQ 2. SOC	Primary Outcome No Sig.Dif. in survival rates at day 21 for Pts not transferred to the ICU; HCQ 76% vs SOC 75% (WHR 0.9; 95% CI 0.4–2.1) Secondary Outcomes No Sig.Dif. in overall survival at day 21: HCQ (89%) vs SOC (91%) (WHR 1.2; 95% CI 0.4–3.3) No SC for O2 weaning at day 21: HCQ 82% vs SOC 76% (WRR 1.1; 95% CI 0.9–1.3)	HCQ Pts with fewer comorbidities No Tx allocation protocols
Comparative observational study17	84	1. HCQ 2. SOC	No Sig.Dif. for: Reducing unfavorable outcome risk (defined as death, ICU admission, or decision to withdraw or withhold life-sustaining treatments) (HR 0.90; 95% CI 0.38–2.1; P=0.81) Overall survival (HR 0.89; 95% CI 0.23–3.47; P=1)	Small-scale study
Comparative observational study19	65	1. HCQ 2. Lopinavir-ritonavir	Primary Outcome Significantly shorter time to virological cure in lopinavir-ritonavir group (median 21 days vs 28 days; P=0.029) Secondary Outcome No Sig.Dif. in time to clinical improvement between groups (median 18 days vs 21 days; P=0.216)	More pneumonia Pts in lopinavir-ritonavir group
Comparative observational study20	60	1. Azithromycin, prednisolone, naproxen, and lopinavir/ritonavir 2. Meropenem, levofloxacin, vancomycin, HCQ, and oseltamivir	Primary Outcome SpO2 saturation, body temperature, and CRP values more favorable in Group 1 Pts (P=0.013, P=0.012, P<0.001, respectively). Secondary Outcome Significantly ↓ length of hospitalization for Group 1 vs Group 2 (P=0.001)	Due to multiple drug regimens, unclear relative contribution of each drug to the results Adding broad-spectrum antibiotic to COVID-19 is probably unnecessary21
Uncontrolled observational study9	1061	1. HCQ+AZ	Poor clinical outcome for 46 Pts (4.3%), 8 died (0.75%), 6 transferred to ICU (0.56%); 30 hospital stays >10 days (2.8%) Prolonged viral carriage in 47 Pts (4.4%)	Uncontrolled study Relatively young Pts: mean age 43.6 y
Uncontrolled observational study8	80	1. HCQ+AZ	Clinical improvement: 97.5% Pts Mean length of hospital stay: 5 days Negative virus cultures in 97.5% Pts at day 5	Uncontrolled study Inadequate length of post-treatment follow-up Relatively young Pts: median age 52.5 y

^*Only primary outcomes are shown, unless the study also provided secondary outcomes.

↓, decreased/lower; ↑, increased/higher; AHR, adjusted hazard ratio; ARDS, acute respiratory distress syn-drome; AZ, azithromycin; CI, confidence interval; CRP, C-reactive protein; HCQ, hydroxychloroquine; HR, haz-ard ratio; ICU, intensive care unit; O₂, oxygen; Pts, patients; Sig.Dif., significant difference(s); SOC, standard of care; SpO₂, oxygen saturation; Tx, treatment group; WHR, weighted hazard ratio; WRR, weighted risk ratio.