A recent multicenter retrospective study conducted across 12 hospitals in Hubei Province, China, provides new insights into the relationship between hydroxychloroquine (HCQ) dosage and COVID-19 mortality among hospitalized patients. The study aimed to address previous inconsistencies in the literature by evaluating whether low-dose HCQ (≤600 mg/day) could offer mortality benefits with an acceptable safety profile, compared to the potential risks associated with high-dose HCQ (>600 mg/day). The study included 2,387 patients hospitalized between January and June 2020, categorized into three groups: non-HCQ users (n=1,124), low-dose HCQ users (n=893), and high-dose HCQ users (n=370). After adjusting for age, sex, comorbidities, disease severity, and concomitant treatments, the primary outcome assessed was all-cause mortality, with adverse events as secondary outcomes.
HCQ acts by raising lysosomal pH in antigen-presenting cells and blocking Toll-like receptor 9 (TLR9), which reduces innate immune responses. It also interferes with hemoglobin metabolism in susceptible parasites, inhibits lysosomal enzymes, and may modulate glucose metabolism through effects on insulin clearance and sensitivity. In this cohort, descriptive analysis revealed that high-dose HCQ users were generally older, predominantly male, and had more comorbidities, consistent with treatment escalation in more severe cases. Mortality rates differed significantly across groups: 15.2% in the low-dose HCQ group, 22.8% in non-HCQ users, and 28.9% in high-dose users (P <0.001). After propensity score matching, low-dose HCQ remained significantly associated with reduced mortality (adjusted HR=0.68, 95% CI: 0.51–0.90, P=0.008), while high-dose HCQ was associated with increased mortality (HR=1.32, 95% CI: 1.05–1.67, P=0.018). Subgroup analysis showed that low-dose HCQ conferred a protective effect in severe (HR=0.72, P=0.023) and critical (HR=0.65, P=0.011) patients, but not in those with mild disease.
Adverse event rates followed a dose-dependent pattern. Low-dose HCQ (12.7%) had an event rate comparable to non-HCQ users (10.9%, P=0.21), whereas high-dose HCQ led to significantly more adverse events (22.4%, P<0.001), including gastrointestinal symptoms, electrolyte disturbances, and ventricular arrhythmias (2.1% vs. 0.8%, P=0.03). Multivariate Cox regression analysis identified high-dose HCQ (HR=1.45, 95% CI: 1.12–1.87, P=0.005) and older age (HR=1.08 per year, P<0.001) as independent predictors of increased mortality. In contrast, low-dose HCQ (HR=0.79, 95% CI: 0.63–0.99, P=0.04) and early treatment initiation within five days of symptom onset (HR=0.64, P=0.002) were independently associated with improved survival. The authors propose that low-dose HCQ may help reduce cytokine storm activity and enhance autophagic antiviral responses without contributing to drug-related toxicity, unlike high-dose regimens, which offer no added therapeutic gain but significantly increase risk. These results may explain discrepancies with large trials like RECOVERY, which involved higher dosing and later treatment initiation, underscoring the importance of dose and timing in HCQ-based COVID-19 therapy.
Similarly, Castelnuovo et al found that hydroxychloroquine use showed no significant impact on COVID-19 mortality when limited to data from four randomized controlled trials. However, when observational studies were included in the analysis, a 7% to 33% reduction in mortality was observed—particularly in studies employing lower HCQ doses. These findings suggest that dosage and study design may be key factors in interpreting HCQ’s effectiveness and contribute valuable perspective to the ongoing debate over its role in COVID-19 treatment.
This study thus provides real-world observational evidence that low-dose HCQ, when initiated early in severe COVID-19 cases, may reduce mortality and carry an acceptable safety profile. The results underscore the importance of optimizing drug dosage and timing in antiviral therapy and may inform treatment decisions in resource-limited settings where access to newer antivirals remains constrained.
References
- He W, Xu K, Yan Y, Li G, Yu B, Wu J, Zhong K, Zhou D, Wang DW. Low dose of hydroxychloroquine is associated with reduced COVID-19 mortality: a multicenter study in China. Front Med. 2025 Apr;19(2):386-390. doi: 10.1007/s11684-025-1123-9. Epub 2025 Mar 4. PMID: 40035964.
- Hydroxychloroquine: Uses, Interactions, Mechanism of Action | DrugBank Online [Internet]. [cited 2025 Jul 7]. Available from: https://go.drugbank.com/drugs/DB01611
- Castelnuovo AD, Costanzo S, Cassone A, Cauda R, Gaetano G de, Iacoviello L. Low dose hydroxychloroquine is associated with lower mortality in COVID-19: a meta-analysis of 26 studies and 44,521 patients [Internet]. medRxiv; 2020 [cited 2025 Jul 7]. p. 2020.11.01.20223958. Available from: https://www.medrxiv.org/content/10.1101/2020.11.01.20223958v1