Lack of efficacy of hydroxychloroquine and azithromycin in patients hospitalized for COVID-19

Lack of efficacy of hydroxychloroquine and azithromycin in patients hospitalized for COVID-19 pneumonia: A retrospective study


Background

Hydroxychloroquine combined with azithromycin (HCQ/AZI) has initially been used against coronavirus disease-2019 (COVID-19). In this retrospective study, we assessed the clinical effects of HCQ/AZI, with a 28-days follow-up.


Methods

In a registry study that included patients hospitalized for COVID-19 between March 15 and April 2, 2020, we compared patients who received HCQ/AZI to those who did not, regarding a composite outcome of mortality and mechanical ventilation with a 28-days follow-up. QT was monitored for patients treated with HCQ/AZI. Were excluded patients in intensive care units, palliative care, and ventilated within 24 hours of admission. Three analyses were performed to adjust for selection bias: propensity score matching, multivariable survival, and inverse probability score weighting (IPSW) analyses.

Results

Overall, 203 patients were included: 60 patients treated by HCQ/AZI and 143 control patients. During the 28-days follow-up, 32 (16.3%) patients presented the primary outcome and 23 (12.3%) patients died. Propensity-score matching identified 52 unique pairs of patients with similar characteristics. In the matched cohort (n = 104), HCQ/AZI was not associated with the primary composite outcome (log-rank p-value = 0.16). In the overall cohort (n = 203), survival and IPSW analyses also found no benefit from HCQ/AZI. In the HCQ/AZI group, 11 (18.3%) patients prolonged QT interval duration, requiring treatment cessation.

Conclusions

HCQ/AZI combination therapy was not associated with lower in-hospital mortality and mechanical ventilation rate, with a 28-days follow-up. In the HCQ/AZI group, 18.3% of patients presented a prolonged QT interval requiring treatment cessation, however, the control group was not monitored for this adverse event, making comparison impossible.


Introduction

During the first few months after the coronavirus disease-2019 (COVID-19) outbreak, chloroquine and its derivative hydroxychloroquine (HCQ) have been suggested as treatment [1]. These molecules showed antiviral activity against the coronavirus in-vitro [2], although molecular mechanisms were not been fully explained, pH change on cell surface membrane has been suggested as a mechanism that may inhibit their fusion with COVID-19 [3]. A small non-randomized single-center study yielded moderate biological benefit in patients treated by HCQ combined with azithromycin (HCQ/AZI) compared to the control group, with a 6-days follow-up [4]. Its mains limitations were numerous: small sample (36 patients), no clinical endpoint, and a fourth of HCQ/AZI patients lost to follow-up. Even though numerous randomized and non-randomized controlled trials have yielded negative results since then [5–7]; during the first semester of 2020, many healthcare centers started to use HCQ/AZI for COVID-19 hospitalized patients by a decree of the French government, despite the lack of clear data demonstrating the effectiveness of the HCQ/AZI combination [8]. Using data extracted from a single-center regional hospital, we hereafter describe the effects of such treatment on mortality and the need for mechanical ventilation in patients hospitalized for COVID-19 pneumonia, during the first wave pandemic in France. We also assessed the incidence of QT prolongation, a known side effect of HCQ/AZI treatment combination [9].




Methods

Study design
This study is an observational retrospective cohort study based on a registry that included all patients hospitalized for COVID-19 at Montfermeil community hospital, a secondary care center, located in the Paris area with 670 beds and an ICU.
Patients were screened for eligibility if they satisfied the following criteria: adult patients with ward admission for COVID-19 pneumonia confirmed by real-time reverse transcription-PCR (RT-PCR) on a nasopharyngeal swab and/or typical imaging characteristics on chest computed tomography (CT) scan. The study period was March 15th, 2020 to April 2nd, 2020. They were then excluded if they required invasive mechanical ventilation (i.e. requiring orotracheal intubation) or were transferred to the intensive care medicine department within the first 24 hours, were recused for intensive care due to futility, or died within the first 24 hours.
The study was approved by the Research Ethics Committees (Comité de Protection des Personnes “SUD-EST IV” number 20.04.21.83855) and by our local ethics committee by French legislation on non-interventional studies. The study protocol conforms to the ethical guidelines of the 1975 Declaration of Helsinki as reflected in a priori approval by the institution’s human research committee. Written informed consent was waived by the Ethics Committee given the observational nature of the study. This study is ancillary to the Adverse Events Related to Treatments Used Against Coronavirus Disease 2019 (COVIDTox) study (registered on clinicaltrials.gov with NCT04314817).

Exposure
Patients were compared in two groups: those who received HCQ/AZI (HCQ/AZI group) and those who did not (control group). In the HCQ/AZI group, treatment was started within the first 24 hours as part of the local protocol. They received 200 mg three times per day of hydroxychloroquine for 10 days, and 500 mg once for azithromycin, on the first day. Azithromycin was then administered with 250 mg once per day for 4 days. The decision to administrate HCQ/AZI combination was taken for each patient individually by the medical team at the bedside. Pregnant women were systematically excluded from this treatment combination.

Study outcomes

The main outcome was a composite of mortality and need for invasive mechanical ventilation (i.e. which required orotracheal intubation), during the first 28 days after hospital admission. Tolerance was assessed by monitoring QT interval prolongation in the HCQ/AZI group. This safety protocol involved 12 lead electrocardiogram monitoring on days 1, 2, 3, 6, 9, and 12. Treatment was stopped in patients with corrected QT duration by Bazett’s or Framingham formulae more than 450 ms for men and 460 ms for women after first intake [10, 11].


Conclusion

In this retrospective study including patients hospitalized for COVID-19 pneumonia, HCQ/AZI combination therapy was not associated with lower 28 days mortality and mechanical ventilation rate. In the HCQ/AZI group, 18.1% presented a prolonged QT interval that required treatment cessation.

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