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.

RMMJ Rambam Maimonides Medical Journal Rambam Health Care Campus 2020 July; 11(3): e0025. ISSN: 2076-9172
Published online 2020 July 31. doi: 10.5041/RMMJ.10416.