CROI 2024 Abstract eBook

Abstract eBook

Poster Abstracts

888

Quantitative Antifungal Activity of Daily Liposomal Amphotericin With 5FC in Cryptococcal Meningitis David R Boulware 1 , Biyue Dai 1 , Laura Nsangi 2 , Jane Gakuru 2 , Enock Kagimu 2 , Enos Kigozi 3 , Timothy Mugabi 2 , Derrick Kasozi 2 , Suzan Namombwe 2 , Sara Kimuda 2 , Jayne P. Ellis 2 , Caleb P. Skipper 1 , Ann Fieberg 1 , Conrad Muzoora 3 , David B. Meya 2 1 University of Minnesota, Minneapolis, MN, USA, 2 Infectious Diseases Institute, Kampala, Uganda, 3 Mbarara University of Science and Technology, Mbarara, Uganda Background: Daily liposomal amphotericin B (AMB) with flucytosine (5FC) is recommended as first line therapy in US cryptoococcal meningitis treatment guidelines. Liposomal AMB monotherapy at 3mg/kg/d in its FDA registrational trial did not meet the prespecified non-inferiority criteria of <10% difference in 10-week survival or 10-week culture conversion rate compared to AMB dexoxycholate. Daily liposomal AMB combination therapy with 5FC, although recommended, has not been studied in a clincial trial. We sought to assess the quantitative antifungal activity of this first-line recommended regimen. Methods: We enrolled Ugandans with HIV-related cryptococcal meningitis into prospective cohorts and clinical trials from 2018-2023. We assessed the early fungicidal activity (EFA) of the cerebrospinal fluid (CSF) Cryptococcus clearance rate between those receiving AMB deoxycholate 1mg/kg + 5FC 100 mg/kg/d versus those receiving daily liposomal AMB 3 mg/kg/d + 5FC 100 mg/kg/d. Induction AMB + 5FC was given for 7 days, followed by fluconazole 1200 mg/d. We calculated EFA by linear regression from longitudinal quantitative CSF fungal cultures collected over 2 weeks of therapy. Results: Among 199 participants with longitudinal quantitative CSF culture data, 156 received AMB deoxycholate, and 43 received liposomal AMB. For AMB deoxycholate, the mean EFA was 0.403 (95%CI, 0.36-0.44) log 10 CFU/mL/day. For daily liposomal AMB, the mean EFA was 0.493 (95%CI, 0.35-0.64) log 10 CFU/ mL/day. The absolute EFA difference was 0.09 (95%CI, -0.02 to 0.20) log 10 CFU/ mL/day favoring liposomal AMB. Grade ≥3 adverse events were less frequent among those receiving liposomal AMB. Conclusion: Despite never being quantified in a randomized clinical trial, the combination of liposomal AMB with 5FC had good antifungal activity in humans with cryptococcosis which did not statistically differ from that of AMB deoxycholate. IgG Responses Are Associated With Severe Disease and Mortality in AIDS-Associated Talaromycosis Shanti Narayanasamy 1 , Matthew T. Burke 2 , Ngo Thi Hoa 3 , Thuy Le 2 , Thu T. Nguyen 2 , Vo Trieu Ly 4 1 Duke Global Health Institute, Durham, NC, USA, 2 Duke University School of Medicine, Durham, NC, USA, 3 Oxford University Clinical Research Unit in Vietnam, Ho Chi Minh City, Vietnam, 4 Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam Background: There is dearth of data on antibody responses to AIDS-associated talaromycosis and how they impact disease phenotype and patient outcomes. Data from our talaromycosis Itraconazole versus Amphotericin B for Penicilliosis (IVAP) trial (N=440) showed that patients presenting with an acute pulmonary syndrome had higher mortality. Here, we tested the hypothesis that acute pulmonary syndrome is associated with a serological pattern of acute infection, and an acute serological pattern is associated with severe disease and mortality. Methods: Longitudinal IgG antibody responses to talaromycosis were measured in available plasma samples of IVAP patients using a direct anti-Mp1p IgG enzyme immunoassay. Patients were classified into three IgG response types: Negative IgG, Increasing IgG, and Positive Unchanged IgG through analysis of the IgG trend over 24-weeks. Univariate and multivariate logistic regression were used to assess association of IgG type and disease severity (defined as a respiratory rate >22, dyspnea requiring oxygen, and/or respiratory failure diagnosis at presentation) and 24-week mortality. Results: Plasma samples and complete data were available for 409 of 440 IVAP patients. Mean age was 34.7 years (SD:7.4). Mean CD4 count was 23.3cell/mm 3 (SD:49.1). Serial samples for classification of IgG response into 3 types were available for 312 patients: 88 (28.2%) Negative IgG, 114 (36.5%) Increasing IgG, 110 (35.3%) Positive Unchanged IgG. In the multivariate models of the 312 sub population (N=312) adjusting for age, history of injection drug use, CD4 count, and antifungal treatment arm, Negative IgG was associated with higher risk of death (OR=3.20,95% CI:1.18-8.96,P=0.023) while Increasing IgG was protective of death (OR=0.14,95% CI:0.02-0.56,P=0.013). In the multivariate models of the full population (N=409) where IgG type could only be classified as Negative or Positive at baseline, Negative IgG was associated with disease severity

(OR=1.62,95% CI:1.02-2.55,P=0.039) and had a non-statistically significant association with mortality. Disease severity was an independent predictor of death (OR=2.44,95% CI:1.38 – 4.34,P=0.002). Conclusion: Although these results were unexpected, the findings that 28% of talaromycosis patients do not mount an IgG response, and these patients have more severe disease and higher mortality suggest a central role of humoral immune response in talaromycosis pathogenicity, which has so far been overlooked. These findings have important clinical implications.

Poster Abstracts

890

Triple Screening for Invasive Mycoses in Patients With Advanced HIV Disease in Vietnam Vu Quoc Dat 1 , Dieu Q. Nguyen 2 , Hao T. Nguyen 2 , Vo Trieu Ly 3 , Thach N. Pham 4 , Do Duy Cuong 5 , Nam X. Ha 6 , Tran Thi Hong Chau 2 , Phuong L. Trinh 2 , Khanh H. Dang 2 , Phan Thi Hong Dao 2 , Trinh Thi Men 2 , Nguyen Thi Hoai Dung 4 , H. Rogier van Doorn 2 , Thuy Le 7 , for the Talaromcyosis Study Group 1 Hanoi Medical University, Hanoi, Vietnam, 2 Oxford University Clinical Research Unit in Vietnam, Ho Chi Minh City, Vietnam, 3 Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam, 4 National Hospital for Tropical Diseases, Hanoi, Vietnam, 5 Bach Mai Hospital, Hanoi, Vietnam, 6 Oxford University Clinical Research Unit in Vietnam, Ho Chi Minh, Vietnam, 7 Duke University School of Medicine, Durham, NC, USA Background: Invasive mycoses are second to TB as a leading cause of death in advanced HIV diseases (AHD). The WHO recommends screening for TB and cryptococcosis in a package of care for AHD; however, invasive mycoses endemic in Asia Pacific - talaromycosis and histoplasmosis - are not included due to the lack of diagnostics and data on burden of diseases to inform policy. We present the results of a triple fungal screening program for in patients with AHD in Vietnam. Methods: This is an ongoing multi-center prospective fungal screening cohort study of patients with AHD who presented for hospitalisation (cohort 1, n=900) or for ART initiation in outpatient clinics (cohort 2, n=600) in three hospitals in Hanoi and Ho Chi Minh city, Vietnam. We enrolled patients aged ≥18 years, with CD4 count ≤100 cells/mm 3 or WHO stage 3 or 4, not on ART OR recent ART ≤3 months OR suspected or confirmed treatment failure on ART ≥12 months. We excluded patients currently on effective systemic antifungal treatment. All patients received antigen screening for cryptococcosis using the IMMY Cryptococcal antigen lateral flow assay (CrAg LFA) in blood, histoplasmosis using the IMMY Clarus Histoplasma GM enzyme immunoassay (HAg EIA) in urine, and talaromycosis using a novel in-house Mp1p EIA (TmAg EIA) in blood and urine, alongside conventional diagnostics including BACTEC and MycoF/Lytic blood cultures. Patients were followed up monthly over 6 months (cohort 1) and 12 months (cohort 2) to assess outcomes. Results: 1366 patients were enrolled, including 900 hospitalised patients (100% target for cohort 1) and 466 outpatients (77.7% target for cohort 2) between February 2021 and August 2023. In cohort 1, the median age was 36 years (IQR: 30–44). 746 (82.9%) were men. The positivity for fungal antigens was 18.6% (95% CI: 16.1-21.2%) for TmAg, 4.3% (95% CI: 3.1-5.8%) for CrAg, and 4.1% (95% CI: 3.0-5.6%) for HcAg. Among TmAg-positive patients, 6.6% (95%CI 3.5-11.1%) were HAg-positive and 1.8% (95%CI 0.5-4.7%) were CrAg-positive. In cohort 2, the positivity for fungal antigens was 8.4% (95% CI: 6.1-11.1%) for TmAg, 3.9% (95% CI: 2.4-5.9%) for CrAg, and 2.1% (95% CI: 1.1-3.8%) for HcAg. The analysis of clinical outcome is ongoing.

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