Disentangling the Association of Hydroxychloroquine Treatment with Mortality in Covid-19 Hospitalized Patients through Hierarchical Clustering
Authors: Di Castelnuovo Augusto , Gialluisi Alessandro , Antinori Andrea , Berselli Nausicaa , Blandi Lorenzo , Bonaccio Marialaura , Bruno Raffaele , Cauda Roberto , Costanzo Simona , Guaraldi Giovanni , Menicanti Lorenzo , Mennuni Marco , My Ilaria , Parruti Giustino , Patti Giuseppe , Perlini Stefano , Santilli Francesca , Signorelli Carlo , Stefanini Giulio , Vergori Alessandra , Ageno Walter , Agodi Antonella , Agostoni Piergiuseppe , Aiello Luca , Al Moghazi Samir , Arboretti Rosa , Aucella Filippo , Barbieri Greta , Barchitta Martina , Bonfanti Paolo , Cacciatore Francesco , Caiano Lucia , Cannata Francesco , Carrozzi Laura , Cascio Antonio , Castiglione Giacomo , Ciccullo Arturo , Cingolani Antonella , Cipollone Francesco , Colomba Claudia , Colombo Crizia , Crisetti Annalisa , Crosta Francesca , Danzi Gian Battista , D'Ardes Damiano , de Gaetano Donati Katleen , Di Gennaro Francesco , Di Tano Giuseppe , D'Offizi Gianpiero , Fusco Francesco Maria , Gaudiosi Carlo , Gentile Ivan , Gianfagna1 Francesco , Giuliano Gabriele , Graziani Emauele , Guarnieri Gabriella , Langella Valerio , Larizza Giovanni , Leone Armando , Maccagni Gloria , Magni Federica , Maitan Stefano , Mancarella Sandro , Manuele Rosa , Mapelli Massimo , Maragna Riccardo , Marcucci Rossella , Maresca Giulio , Marongiu Silvia , Marotta Claudia , Marra Lorenzo , Mastroianni Franco , Mengozzi Alessandro , Meschiari Marianna , Milic Jovana , Minutolo Filippo , Mussinelli Roberta , Mussini Cristina , Musso Maria , Odone Anna , Olivieri Marco , Palimodde Antonella , Pasi Emanuela , Pesavento Raffaele , Petri Francesco , Pivato Carlo A , Poletti Venerino , Ravaglia Claudia , Righetti Giulia , Rognoni Andrea , Rossato Marco , Rossi Ilaria , Rossi Marianna , Sabena Anna , Salinaro Francesco , Sangiovanni Vincenzo , Sanrocco Carlo , Schiano Moriello Nicola , Scorzolini Laura , Sgariglia Raffaella , Simeone Paola Giustina , Spinicci Michele , Tamburrini Enrica , Torti Carlo , Trecarichi Enrico Maria , Vettor Roberto , Vianello Andrea , Vinceti Marco , Virdis Agostino , De Caterina Raffaele , Iacoviello Licia 
Published: June 2021

The efficacy of hydroxychloroquine (HCQ) in treating SARS-CoV-2 infection is harshly debated, with observational and experimental studies reporting contrasting results. To clarify the role of HCQ in Covid-19 patients, we carried out a retrospective observational study of 4,396 unselected patients hospitalized for Covid-19 in Italy (February–May 2020). Patients’ characteristics were collected at entry, including age, sex, obesity, smoking status, blood parameters, history of diabetes, cancer, cardiovascular and chronic pulmonary diseases, and medications in use. These were used to identify subtypes of patients with similar characteristics through hierarchical clustering based on Gower distance. Using multivariable Cox regressions, these clusters were then tested for association with mortality and modification of effect by treatment with HCQ. We identified two clusters, one of 3,913 younger patients with lower circulating inflammation levels and better renal function, and one of 483 generally older and more comorbid subjects, more prevalently men and smokers. The latter group was at increased death risk adjusted by HCQ (HR[CI95%] = 3.80[3.08-4.67]), while HCQ showed an independent inverse association (0.51[0.43-0.61]), as well as a significant influence of cluster∗HCQ interaction (

p
<
0.001

). This was driven by a differential association of HCQ with mortality between the high (0.89[0.65-1.22]) and the low risk cluster (0.46[0.39-0.54]). These effects survived adjustments for additional medications in use and were concordant with associations with disease severity and outcome. These findings suggest a particularly beneficial effect of HCQ within low risk Covid-19 patients and may contribute to clarifying the current controversy on HCQ efficacy in Covid-19 treatment.