Background Histoplasmosis is a major AIDS-defining illness in Latin America. Liposomal amphotericin B (L-AmB) is the drug of choice for treatment, but access is restricted due to the high drug and hospitalization costs of the conventional long regimens. Methods Prospective randomized multicenter open-label trial of one or two-dose induction therapy with L-AmB versus control for disseminated histoplasmosis in AIDS, followed by oral itraconazole therapy. We randomized subjects to: (i) Single dose 10 mg/kg of L-AmB; (ii) 10 mg/kg of L-AmB on D1, and 5 mg/kg of L-AmB on D3; (iii) 3 mg/kg of L-AmB daily for 2 weeks (control). The primary outcome was clinical response (resolution of fever and signs/symptoms attributable to histoplasmosis) at day 14. Results A total of 118 subjects were randomizedMedian CD4+ counts and clinical presentations were similar between arms. Infusion-related toxicity, kidney toxicity at multiple time-points and frequency of anemia, hypokalemia, hypomagnesemia, and liver toxicity were similar. Day 14 clinical response was 84% for Single-dose L-AmB, 69% Two-dose L-AmB, and 74% Control arm (p=0.69). Overall survival on D14 was 89.0% (34/38) for Single-dose L-AmB, 78.0% (29/37) for Two-dose L-AmB, and 92.1% (35/38) for Control arm (p=0.82). Conclusions One day induction therapy with 10 mg/kg of L-AmB in AIDS-related histoplasmosis was safe. Although clinical response may be non-inferior to standard L-AmB therapy, a confirmatory phase III clinical trial is needed. A single induction dose would markedly reduce drug-acquisition costs (>4-fold) and markedly shorten and simplify treatment, which are key points in terms of increased access.

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Background Histoplasmosis is a major AIDS-defining infection in Latin America. Liposomal amphotericin B (L-AmB) is the drug of choice for treatment, but access is limited. Methods Prospective randomized open-label trial of induction therapy with L-AmB for disseminated histoplasmosis in AIDS, followed by oral itraconazole therapy (started on the day after L-AmB was finished). We conducted this trial at 6 centers in Brazil (2019-2022). We randomized subjects to 3 arms of: Single dose 10 mg/kg of L-AmB;10 mg/kg of L-AmB on D1, and 5 mg/kg of L-AmB on D3;3 mg/kg of L-AmB for 2 weeks (control). As a non-inferiority trial, 80% power could detect > 20% non-inferiority margin for a one-sided alpha=0.05 with a sample size of 29 subjects per arm. Clinical response at day 14 was the primary outcome. Results Of 512 screened patients, 118 subjects were randomized (Arm 1, n=40; Arm 2, n=39; Arm 3, n=39). Median CD4 was 25 cells/µL. Subjects presented with weight loss (70%), pulmonary complaints (67%), fever (66%), abdominal findings (59%), skin lesions (38%), lymphadenopathy (38%), and oral lesions (36%). Clinical and lab findings did not differ among arms. Histoplasmosis diagnosis was predominantly via urine antigen (97%). Infusion-related toxicity on D1 was similar in each arm (p=0.56). Kidney toxicity was similar on D3 (p=0.83), D7 (p=0.10), and D14 (p=0.17) as was frequency of anemia, hypokalemia, hypomagnesemia, and liver toxicity (all p >0.05). No subject withdrew due to drug toxicities. D14 clinical response was 82% for Arm 1, 68% Arm 2, and 72% Arm 3 (p=0.69). Absolute risk difference for Arm 1 was 10.3% (95%CI, -8.3% to 28.8%) vs. Arm 3 controls; Arm 2 was -4.2% (95%CI, -24.9% to 16.4%) to controls. Overall survival on D14 was 89.5% (34/38) for Arm 1, 78.4% (29/37) for Arm 2, and 92.1% (35/38) for Arm 3 (p=0.82); 2 subjects were excluded from efficacy analysis due to meningitis and tuberculosis, and 3 were lost to follow up. Conclusion Induction therapy with 10 mg/kg of L-AmB in AIDS-related histoplasmosis was safe. Although efficacy is likely to be non-inferior to standard L-AmB therapy, a confirmatory phase III trial is needed. Such a strategy would markedly reduce drug-acquisition costs (> 4-fold), therefore improving access to L-AmB across the globe. Disclosures Alessandro C. Pasqualotto, FECMM, Gilead: Grant/Research Support|United Medical: Advisor/Consultant|United Medical: Honoraria Diego R. Falci, MD, United Medical: Advisor/Consultant|United Medical: Honoraria Andrej Spec, MD, MSCI, Astellas: Grant/Research Support Dennis Israelski, MD, Gilead Sciences: Empoyee.