Prognosis And Safety Of Antifungal Therapy In HIV-infected Patients With Talaromycosis

Objective: The objective of our study was to assess the predictors,the efficacy and adverse events of voriconazole and amphotericin B deoxycholate as induction therapy for talaromycosis in people living with HIV,in order to provide these patients with appropriate,effective,and potentially life-saving interventions at an early stage of their illness.Methods: In this open-labelled,multicenter,prospective controlled trial,we enrolled patients at 15 hospitals in China from February 19,2019,through September30,2020.Participants received treatment with either intravenous amphotericin B deoxycholate(255 patients)or voriconazole(104 patients).The risk factors of clinical resolution,fungal clearance,drug-induced hepatitis and severe anemia were analyzed with logistics regression model.The end points were clinical resolution of talaromycosis and fungal clearance at week 2,and mortality during the first 2 weeks and during 48 weeks after baseline.In order to compare amphotericin B deoxycholate group and voriconazole group,we chose logistics regression model and Cox proportional-hazards modelling to control confounding factors and used subgroup analysis by age and sex to investigate the efficacy of voriconazole versus amphotericin B deoxycholate induction treatment.The clinical prognostic model of severe anemia was constructed according to the risk factors,and 1000 times repeated sampling were done to include the data to verify the model internally.The external validation is also completed.The levels of IFN-γ,IL-17 A,IL-2,IL-4,IL-6 and IL-10 in serum were determined before antifungal by ELISA.Results: Male,no skin lesions and amphotericin B deoxycholate use were independent predictors of clinical resolution.Age(per 10-year increase)and amphotericin B deoxycholate use were independent predictors of fungal clearance.Age(per 10-year increase)were independent risk factors for death during 2 weeks,and age(per 10-year increase),diarrhea,hemoglobin were independent risk factors for death during 48weeks.We observed no difference in the risk of death at weeks 2 or at week 48 after multivariable logistic regression and multivariable Cox proportional-hazards modelling.Logistic regression analysis revealed a significantly lower odds ratio of clinical resolution and fungal clearance over the course of 2 weeks in voriconazole users than in amphotericin B deoxycholate users.In the subgroup of patients aged≥50 years and the subgroup of males,logistic regression analysis revealed a significantly lower odds ratio of clinical resolution and fungal clearance over the course of 2 weeks in voriconazole users than in amphotericin B deoxycholate users,while there were not differences in the subgroup of patients aged <50 years and the subgroup of females.Baseline total bilirubin was an independent risk factor for grade 2 or higher drug-induced liver injury.The predicted value C-index of the prediction model for severe anemia in HIV patients with talaromycosis after amphotericin B treatment was0.809 in the derivative cohort and 0.803 in the validation cohort,indicating that the prediction model had a good predictive value.There were no significant differences in IL-2,IL-4,IL-6,IL-10,IL-17 A and IFN-γbefore treatment in the death group compared with the non-death group.The IL-17 A factor was higher in the fungal-clearance group within 2 weeks(P <0.05).IL-6 and IL-10 were higher in HIV patients with talaromycosis than in HIV patients without talaromycosis(P <0.05).HIV patients with talaromycosis had higher IL-6 than those with cryptococcal meningitis(P <0.05).Conclusion: Male,no skin lesions and amphotericin B deoxycholate use were independent predictors of clinical resolution.Age(per 10-year increase)and amphotericin B deoxycholate use were independent predictors of fungal clearance.Age(per 10-year increase)were independent risk factors for death during 2 weeks,and age(per 10-year increase),diarrhea,hemoglobin were independent risk factors for death during 48 weeks.Induction therapy using voriconazole had a similar efficacy in terms of all-cause mortality rate to induction therapy using amphotericin B deoxycholate in HIV-infected patients with talaromycosis over a 48-week observation period.Amphotericin B deoxycholate contributed to earlier fungal clearance and clinical resolution of symptoms,especially in older patients and males.The prognostic scoring system for severe anemia assessment developed in the present study is an easy-to-use clinical tool designed to accurately assist clinicians in identifying high-risk patients with talaromycosis using amphotericin B deoxycholate.