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Combination treatments with hydroxychloroquine and azithromycin are compatible with the therapeutic induction of anticancer immune responses.

ABSTRACT: Amid controversial reports that COVID-19 can be treated with a combination of the antimalarial drug hydroxychloroquine (HCQ) and the antibiotic azithromycin (AZI), a clinical trial (ONCOCOVID, NCT04341207) was launched at Gustave Roussy Cancer Campus to investigate the utility of this combination therapy in cancer patients. In this preclinical study, we investigated whether the combination of HCQ+AZI would be compatible with the therapeutic induction of anticancer immune responses. For this, we used doses of HCQ and AZI that affect whole-body physiology (as indicated by a partial blockade in cardiac and hepatic autophagic flux for HCQ and a reduction in body weight for AZI), showing that their combined administration did not interfere with tumor growth control induced by the immunogenic cell death inducer oxaliplatin. Moreover, the HCQ+AZI combination did not affect the capacity of a curative regimen (cisplatin + crizotinib + PD-1 blockade) to eradicate established orthotopic lung cancers in mice. In conclusion, it appears that HCQ+AZI does not interfere with the therapeutic induction of therapeutic anticancer immune responses.

SUBMITTER: Liu P

PROVIDER: S-EPMC7458592 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundHydroxychloroquine, a drug commonly used in the treatment of rheumatoid arthritis, has received much negative publicity for adverse events associated with its authorisation for emergency use to treat patients with COVID-19 pneumonia. We studied the safety of hydroxychloroquine, alone and in combination with azithromycin, to determine the risk associated with its use in routine care in patients with rheumatoid arthritis.MethodsIn this multinational, retrospective study, new user cohort studies in patients with rheumatoid arthritis aged 18 years or older and initiating hydroxychloroquine were compared with those initiating sulfasalazine and followed up over 30 days, with 16 severe adverse events studied. Self-controlled case series were done to further establish safety in wider populations, and included all users of hydroxychloroquine regardless of rheumatoid arthritis status or indication. Separately, severe adverse events associated with hydroxychloroquine plus azithromycin (compared with hydroxychloroquine plus amoxicillin) were studied. Data comprised 14 sources of claims data or electronic medical records from Germany, Japan, the Netherlands, Spain, the UK, and the USA. Propensity score stratification and calibration using negative control outcomes were used to address confounding. Cox models were fitted to estimate calibrated hazard ratios (HRs) according to drug use. Estimates were pooled where the I 2 value was less than 0·4.FindingsThe study included 956 374 users of hydroxychloroquine, 310 350 users of sulfasalazine, 323 122 users of hydroxychloroquine plus azithromycin, and 351 956 users of hydroxychloroquine plus amoxicillin. No excess risk of severe adverse events was identified when 30-day hydroxychloroquine and sulfasalazine use were compared. Self-controlled case series confirmed these findings. However, long-term use of hydroxychloroquine appeared to be associated with increased cardiovascular mortality (calibrated HR 1·65 [95% CI 1·12-2·44]). Addition of azithromycin appeared to be associated with an increased risk of 30-day cardiovascular mortality (calibrated HR 2·19 [95% CI 1·22-3·95]), chest pain or angina (1·15 [1·05-1·26]), and heart failure (1·22 [1·02-1·45]).InterpretationHydroxychloroquine treatment appears to have no increased risk in the short term among patients with rheumatoid arthritis, but in the long term it appears to be associated with excess cardiovascular mortality. The addition of azithromycin increases the risk of heart failure and cardiovascular mortality even in the short term. We call for careful consideration of the benefit-risk trade-off when counselling those on hydroxychloroquine treatment.FundingNational Institute for Health Research (NIHR) Oxford Biomedical Research Centre, NIHR Senior Research Fellowship programme, US National Institutes of Health, US Department of Veterans Affairs, Janssen Research and Development, IQVIA, Korea Health Industry Development Institute through the Ministry of Health and Welfare Republic of Korea, Versus Arthritis, UK Medical Research Council Doctoral Training Partnership, Foundation Alfonso Martin Escudero, Innovation Fund Denmark, Novo Nordisk Foundation, Singapore Ministry of Health's National Medical Research Council Open Fund Large Collaborative Grant, VINCI, Innovative Medicines Initiative 2 Joint Undertaking, EU's Horizon 2020 research and innovation programme, and European Federation of Pharmaceutical Industries and Associations.

Project description:IntroductionWe sought to determine the effectiveness and safety of hydroxychloroquine-azithromycin (HCQ-AZM) therapy in hospitalized patients with COVID-19.MethodsThis was a retrospective cohort study of 613 patients hospitalized (integrated health system involving three hospitals) for RT-PCR-confirmed COVID-19 infection between March 1, 2020 and April 25, 2020. Intervention was treatment with HCQ-AZM in hospitalized patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Outcomes of interest were in-hospital all-cause mortality, cardiovascular mortality, pulseless electrical activity (PEA) arrest, non-lethal arrhythmias, and length of hospital stay. Secondary measures included in-hospital corrected QT (QTc) interval parameters and serum biomarkers levels.ResultsPropensity-matched groups were composed of 173 patients given HCQ-AZM and 173 matched patients who did not receive treatment. There was no significant difference in in-hospital mortality (odds ratio [OR] 1.52; 95% confidence interval [CI] 0.80-2.89; p = 0.2), PEA arrest (OR 1.68, CI 0.68-4.15; p = 0.27), or incidence of non-lethal arrhythmias (10.4% vs. 6.8%; p = 0.28). Length of hospital stay (10.5 ± 7.4 vs. 5.8 ± 6.1; p < 0.001), peak CRP levels (252 ± 136 vs. 166 ± 124; p < 0.0001), and degree of QTc interval prolongation was higher for the HCQ-AZM group (28 ± 32 vs. 9 ± 32; p < 0.0001), but there was no significant difference in incidence of sustained ventricular arrhythmias (2.8% vs. 1.7%; p = 0.52). HCQ-AZM was stopped in 10 patients because of QT interval prolongation and 1 patient because of drug-related polymorphic ventricular tachycardia.ConclusionIn this propensity-matched study, there was no difference in in-hospital mortality, life-threatening arrhythmias, or incidence of PEA arrest between the HCQ-AZM and untreated control groups. QTc intervals were longer in patients receiving HCQ-AZM, but only one patient developed drug-related ventricular tachycardia.

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Combination treatments with hydroxychloroquine and azithromycin are compatible with the therapeutic induction of anticancer immune responses.

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