No benefit from hydroxychloroquine, with or without macrolide antibiotics in analysis of 96,000 patients
Simon Collins, HIV i-Base
On 22 May 2020, a large retrospective international meta-analysis published in the Lancet failed to show a benefit of either hydroxychloroquine (HCQ) or chloroquine (CQ) for treating COVID-19, with or without a macrolide antibiotic (generally azithromycin or clarithromycin) but did report increased risk of side effects. 
The results are important given the extensive ongoing studies using HCQ (largely based on variable results from small uncontrolled studies), especially since positive results have now been reported for remdesivir in a large placebo controlled study. 
Off-label use of HCQ has also been reported, including as prophylaxis for COVID-19, and stockpiling drugs have led to shortages for people with approved indications.
This analysis included results from more than 96,000 people hospitalised with PCR-confirmed COVID-19 between 20 December 2019 and 14 April 2020, and involved 671 hospitals in six continents.
The analysis included 14,888 people in four treatments (started within 48 hours): chloroquine alone (n=1868), chloroquine with a macrolide (n=3783), hydroxychloroquine alone (n=3016), or hydroxychloroquine with a macrolide (n=62210. This left 81,144 in the control group. Main outcomes included time in hospital for efficacy against COVID-19 and new ventricular arrhythmias as a safety measure. Starting treatment when on mechanical ventilation and use of remdesivir were exclusion criteria.
Baseline characteristics include mean age 53·8 years and 53.7% were men. Mean BMI was 27·6 kg/m2 (SD +/–5·5) and 30·7% were obese (BMI ≥30). The mean length of stay in hospital was 9·1 days (SD 6·4), with an overall in-hospital mortality of 11·1%.
Geographically, participants were from North America (65·9%), Europe (17·3%), Asia (7·9%), Africa (4·6%), South America (3·7%), and Australia (0·6%).
Overall, 10698 (11·1%) people died in hospital. In multivariate analysis, controlling for age, sex, race or ethnicity, body-mass index, underlying cardiovascular disease and its risk factors, diabetes, underlying lung disease, smoking, immunosuppressed condition, and baseline disease severity) all four treatment groups had significantly higher rates of in-hospital mortality and new ventricular arrhythmias compared to the control group, see Table 1.
The commonly reported risk factors associated with poor outcomes to COVID-19 were significantly associated with higher risk of mortality, and with use of all four treatment groups, hence the importance of adjusted analysis.
Table 1: risk of in-hospital mortality with COVID-19
|Treatment arm||Mortality rate||HR
|New ventricular arrhythmias||HR
(1·223 to 1·457)
(1·935 to 2·900)
|HCQ _ macrolide||23·8%||1·447
(1·368 to 1·531)
(4·106 to 5·983)
(1·218 to 1·531)
(2·760 to 4·596)
|CQ + macrolide||22·2%||1·368
(1·273 to 1·469)
(3·344 to 4·812)
Other independent predictors of higher rates of in-hospital mortality included:
- Black race HR: 1·344 (95%CI: 1·276 to 1·415).
- Hispanic race HR: 1·495 (95%CI: 1·400 to 1·597).
- Congestive heart failure HR: 1·756 (95%CI: 1·609 to 1·915).
- Arrhythmia HR: 1·626 (95%CI: 1·504 to 1·758).
- Oxygen saturation (SPO2) <94% HR: 1·664 (95%CI: 1·587 to 1·746).
Protective factors associated with a reduced risk included:
- Asian race HR: 0·717 (95%CI: 0·668 to 0·769).
- Use of an ACE inhibitor HR: 0·566 (95%CI: 0·514 to 0·624).
- Use of a statin HR: 0·793 (95%CI: 0·736 to 0·855) and
- qSOFA* <1 HR: 0·758 (95%CI: 0·726 to 0·792.
* Quick sepsis-related organ failure assessment
Independent predictors of ventricular arrythmia included:
- Coronary artery disease HR: 1·830 (95%CI: 1·613 to 2·076).
- congestive heart failure HR: 3·914 (95%CI: 3·283 to 4·665).
- history of cardiac arrhythmia HR: 4·119 (95%CI: 3·525 to 4·812).
- COPD HR: 1·585 (95%CI: 1·256 to 2·001).
The discussion included a data review of other studies, largely reporting similar lack of benefit.
Although the investigators noted limitations from observational data they concluded that this large-scale, international, real-world analysis supports the absence of a clinical benefit of chloroquine and hydroxychloroquine and points to potential harm in hospitalised patients with COVID-19.
They suggested that these drug regimens should not be used outside of clinical trials and urgent that confirmation from randomised clinical trials is needed.
A growing number of studies are now questioning the use of HCQ or CQ for COVID-19. [3, 4]
This includes a recent article (ahead of peer review) looking at in-vitro and animal studies of HCQ as both treatment and PrEP. 
- Mehra MR et al. Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis. The Lancet. DOI: 10.1016/ S0140-6736(20)31180-6. (22 May 2020).
- Collins S. Remdesivir improves recovery time in early COVID-19 infection: first definitive results of benefit. HTB (22 May 2020).
- No benefit of hydroxychloroquine and azithromycin in people hospitalised with COVID-19. HTB (17 April 2020).
- Studies reporting lack of benefit from hydroxychloroquine to treat COVID-19. HTB (14 May 2020).
- Maisonnasse P et al. Hydroxychloroquine in the treatment and prophylaxis of SARS-CoV-2 infection in non-human primates. NatureReseach. Pre-peer-review article. 10.21203/rs.3.rs-27223/v1. (6 May 2020).