By Jake Scott, MD
Clinical Assistant Professor, Infectious Diseases and Geographic Medicine, Stanford University School of Medicine; Antimicrobial Stewardship Program Medical Director, Stanford Health Care Tri-Valley
SYNOPSIS: In a Phase II randomized clinical trial involving 118 participants in Brazil with human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS)-related disseminated histoplasmosis, induction therapy with single high-dose (10 mg/kg) liposomal amphotericin B was safe and non-inferior as compared with standard dose (3 mg/kg) liposomal amphotericin B given once daily for 14 days.
SOURCE: Pasqualotto AC, Dalla Lana D, Godoy CSM, et al. Single high-dose of liposomal amphotericin B in HIV/AIDS-related disseminated histoplasmosis: A randomized trial. Clin Infect Dis 2023; May 26:ciad313. doi: 10.1093/cid/ciad313. [Online ahead of print].
Pasqualotto and colleagues conducted a prospective, randomized, open-label Phase II trial in six Brazilian tertiary care medical centers that assessed the safety and clinical effectiveness of three different dosing strategies of liposomal amphotericin B (L-AMB) given intravenously as induction therapy for human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS)-related disseminated histoplasmosis (DH).1 Participants were randomized in a 1:1:1 ratio to receive either a single dose of 10 mg/kg, 10 mg/kg on day 1 followed by 5 mg/kg on day 3, or 3 mg/kg daily for 14 days (control), which is the dose currently recommended by guidelines.2,3 All participants were transitioned to long-term oral itraconazole therapy within 24 hours of completing induction therapy with L-AMB.
The study was conducted between February 2020 and April 2022 and included 118 participants in the intention-to-treat analysis. The primary endpoint of the trial was clinical resolution on day 14, which was defined as resolution of fever and acute signs and symptoms associated with DH. Secondary endpoints included survival on day 14 as well as kidney and liver function abnormalities and anemia. Follow-up of participants was conducted for one year and survival was evaluated at 12, 24, and 48 weeks.
Baseline characteristics of participants were similar among the three groups. The majority (82%) of participants were male and the median age was 38 years. At baseline, 32% of participants in the single-dose L-AMB group were on antiretroviral therapy, as compared with 38% in the two-dose L-AMB arm and 26% in the control arm. Median CD4 cell counts were 27, 27, and 22 cells per microliter, and median HIV viral loads were 5.3, 5.2, and 5.6 log10 copies per milliliter, respectively. The majority of participants presented with common clinical manifestations of DH, such as fever (66%), weight loss (70%), respiratory symptoms (67%), and lymphadenopathy (38%). Skin lesions, which are significantly more common in those infected with South American strains, were reported in 38% of participants. Fifty-three percent of participants had baseline pancytopenia. Participants were excluded from the study if their baseline serum creatinine was greater than 1.5 times the upper limit. Histoplasmosis was diagnosed primarily by detection of Histoplasma antigen in the urine (97%); diagnosis also was made using fungal culture in 41% of participants and by multiple other methods.
Clinical resolution of acute illness on day 14 was 84.0% (32 out of 38) in the single-dose L-AMB group, 69.0% (25 out of 36) in the two-dose L-AMB group, and 74.0% (28 out of 38) in the control group. Overall survival on day 14 was 89.0% (34/38), 78.0% (29/37), and 89.7% (35/38), respectively (P = 0.82), and survival rates did not differ at one year (P = 0.440). Nephrotoxicity was noted in 12% of participants in the single-dose L-AMB group and no statistically significant differences were observed between groups. Mild to moderate hypokalemia (serum potassium 2.5 mg/dL to 3.5 mg/dL) on day 14 occurred in 9% (3/34) of those in the single-dose L-AMB group compared with 33% in the control group (12/36) (P = 0.040); none of the participants in the single-dose L-AMB group were noted to have severe hypokalemia (serum potassium < 2.5 mg/dL) compared with two out of 36 (6%) participants in the control group. No hepatotoxicity was observed. Non-severe infusion-related reactions occurred in more participants in the single-dose L-AMB group (18.9%) than in the control group (10.3%), but the difference was not statistically significant (P = 0.561). There were no severe infusion-related reactions observed in the study, and none of the participants in any group discontinued therapy due to infusion-related reactions.
COMMENTARY
Histoplasmosis is acquired from inhalation of soil-based Histoplasma capsulatum microconidia and mycelial fragments. Cases have been reported from every continent except Antarctica, and disseminated disease can occur in patients with impairment in cellular immunity due to advanced HIV/AIDS or pharmaceutic agents. Without therapy, progressive disseminated histoplasmosis in severely immunocompromised individuals is nearly always fatal, yet with therapy, survival is approximately 80% to 90%, as this study demonstrates.
Amphotericin B is used for life-threatening systemic fungal infections. It exerts its antifungal effects by interacting with sterols in the fungal cytoplasmic membrane, leading to increased membrane permeability and subsequent cell death. The pharmacokinetics and pharmacodynamics make amphotericin B particularly well suited for short-duration, high-dose induction therapy for DH. The onset of action is rapid and its efficacy depends on peak concentrations.4 Additionally, amphotericin B has a long tissue half-life and penetrates well into the liver and other components of the reticuloendothelial system, which are affected by DH.5
Although it is generally less toxic than other formulations of amphotericin, L-AMB-infusion-related reactions frequently occur, causing dyspnea; chest pain; hypoxia; severe pain in the abdomen, back, flank, or legs; flushing; and urticaria.6 These reactions often require the administration of diphenhydramine and interruption of the infusion.
The management of DH is challenging and costly. The median cost for hospitalization for histoplasmosis in the United States in 2012 was $72,000 and total annual costs were $371 million.7 Access to the diagnosis and treatment of histoplasmosis is limited in many regions of South America, where it is needed because of prohibitive costs.8,9
L-AMB and other formulations of amphotericin B are costly for a number of reasons: the high purchase cost of the drugs themselves, the costs of hospitalization generally required for the infusions, and the costs associated with monitoring and managing the toxicities associated with them. In addition to the financial costs, toxicities related to amphotericin B — especially amphotericin B deoxycholate — can cause significant morbidity and mortality. For these reasons, a single-dose infusion of L-AMB for induction therapy, followed by an oral azole, is highly desirable if safe and effective.
In a recent study by Jarvis and colleagues, single-dose L-AMB was shown to be non-inferior to seven days of amphotericin B deoxycholate for the treatment of HIV-associated cryptococcal meningitis, when both regimens were combined with flucytosine and fluconazole, and was associated with fewer adverse events.10 An earlier study by Sundar and colleagues found single-dose L-AMB to be non-inferior to 15 infusions of amphotericin B deoxycholate given every other day for the treatment of visceral leishmaniasis.11 Further investigation into the safety and efficacy of single-dose L-AMB for DH with larger studies will be important. A Phase III randomized clinical trial comparing single 10 mg/kg dose L-AMB therapy to 14 days of 3 mg/kg L-AMB daily has been planned.12
REFERENCES
- Pasqualotto AC, Dalla Lana D, Godoy CSM, et al. Single high-dose of liposomal amphotericin B in HIV/AIDS-related disseminated histoplasmosis: A randomized trial. Clin Infect Dis 2023; May 26:ciad313. doi:10.1093/cid/ciad313. [Online ahead of print].
- National Institutes of Health. Guidelines for the Prevention and Treatment of Opportunistic Infections in Adults and Adolescents with HIV. Histoplasmosis. Published Sept. 13, 2019. https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-and-adolescent-opportunistic-infections/histoplasmosis
- Perez F, Caceres DH, Ford N, et al. Summary of guidelines for managing histoplasmosis among people living with HIV. J Fungi (Basel) 2021;7:134.
- Hope WW, Goodwin J, Felton TW, et al. Population pharmacokinetics of conventional and intermittent dosing of liposomal amphotericin B in adults: A first critical step for rational design of innovative regimens. Antimicrob Agents Chemother 2012;56:5303-5308.
- Groll AH, Rijnders BJA, Walsh TJ, et al. Clinical pharmacokinetics, pharmacodynamics, safety and efficacy of liposomal amphotericin B. Clin Infect Dis 2019;68(Suppl 4):S260-S274.
- Roden MM, Nelson LD, Knudsen TA, et al. Triad of acute infusion-related reactions associated with liposomal amphotericin B: Analysis of clinical and epidemiological characteristics. Clin Infect Dis 2003;36:1213-1220.
- Benedict K, Derado G, Mody RK. Histoplasmosis-associated hospitalizations in the United States, 2001-2012. Open Forum Infect Dis 2016;3:ofv219.
- Falci DR, Dalla Lana DF, Pasqualotto AC. The era of histoplasmosis in Brazilian endemic mycoses. Lancet Reg Health Am 2021;3:100037.
- Falci DR, Pasqualotto AC. Clinical mycology in Latin America and the Caribbean: A snapshot of diagnostic and therapeutic capabilities. Mycoses 2019;62:368-373.
- Jarvis JN, Lawrence DS, Meya DB, et al. Single-dose liposomal amphotericin B treatment for cryptococcal meningitis. N Engl J Med 2022;386:1109-1120.
- Sundar S, Chakravarty J, Agarwal D, et al. Single-dose liposomal amphotericin B for visceral leishmaniasis in India. N Engl J Med 2010;362:504-512.
- Pasqualotto A. Efficacy and safety of high-dose liposomal amphotericin B (10 mg/kg) for disseminated histoplasmosis in AIDS: A randomized Phase III trial. clinicaltrials.gov; 2023. https://clinicaltrials.gov/ct2/show/NCT05814432
