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: A randomized, controlled trial by Boulware and colleagues demonstrated that a new oral lipid nanocrystal formulation of amphotericin had similar antifungal activity and survival rates but significantly less toxicity compared to intravenous amphotericin when used as induction therapy for human immunodeficiency virus-associated cryptococcal meningitis.
SOURCE: Boulware DR, Atukunda M, Kagimu E, et al. Oral lipid nanocrystal amphotericin B for cryptococcal meningitis: A randomized clinical trial. Clin Infect Dis 2023; Aug 22. doi: 10.1093/cid/ciad440. [Online ahead of print].
Boulware and colleagues conducted a randomized clinical trial to evaluate a novel oral lipid nanocrystal (LNC) formulation of amphotericin B plus flucytosine (5FC) as compared with intravenous (IV) amphotericin B plus 5FC when given as induction therapy for human immunodeficiency virus (HIV)-associated cryptococcal meningitis.1 Since IV amphotericin B is well known to potentially cause serious adverse effects (AEs), such as acute kidney injury, electrolyte abnormalities (particularly hypokalemia), anemia, and thrombophlebitis, and since it requires IV administration and close monitoring, this study was conducted to assess whether a less toxic and more convenient alternative could be used safely and effectively.
The LNC formulation is comprised of amphotericin B, which is hydrophobic and embedded within phosphatidylserine bilayers, along with calcium ions. Its structure protects it from degradation by stomach acids after oral ingestion. Once absorbed, LNC becomes phagocytosed by macrophages, where the drug is triggered by a calcium ion concentration gradient to be released intracellularly, killing fungi that may be present within, thereby minimizing plasma concentrations and reducing the risk of systemic amphotericin toxicity. In a murine model of cryptococcal meningitis, Lu and colleagues demonstrated successful oral absorption of LNC amphotericin that reached therapeutic levels in the central nervous system (cerebrospinal fluid [CSF]) and showed that LNC amphotericin was as efficacious as parenterally administered amphotericin B when both were combined with 5FC.2 In a Phase I trial, LNC amphotericin was shown to have a more favorable toxicity profile compared to that of IV amphotericin B, with much less kidney and electrolyte toxicity, and that it was well tolerated.3
This study by Boulware and colleagues was an open-label, Phase II trial that included four cohorts of participants randomized in a 2.5 to 1 ratio to an oral LNC amphotericin arm or IV amphotericin control. Participants living in Uganda with HIV and cryptococcal meningitis, as diagnosed by a positive CSF cryptococcal antigen test, were enrolled in the study if they had a Glasgow Coma Scale score of 15 and were able to receive enteral medications. Additional exclusion criteria included pregnancy, breastfeeding, use of chemotherapy or corticosteroids, initiation of HIV therapy within two weeks of enrollment, and paradoxical immune reconstitution inflammatory syndrome.
Cohorts 1 and 3 were pilot safety cohorts, whereas cohorts 2 and 4 were designed to evaluate efficacy. Participants in cohort 1 received 2 g per day (d) of oral LNC amphotericin B and 5FC as induction therapy through two weeks, followed by 1.5 g/d through six weeks. After gastrointestinal intolerance was reported among 80% of participants in the experimental arm of this pilot cohort, the induction daily dose was reduced for the other cohorts to 1.8 g/d, followed by 1.2 g/d for the consolidation phase, which was significantly better tolerated. Participants in the control groups received IV liposomal amphotericin at a standard dose of 3 mg/kg/d or IV amphotericin B deoxycholate 1.0 mg/kg/d plus 5FC for seven days and then oral fluconazole 1,200 mg/d through 14 days as induction therapy, followed by fluconazole 800 mg/d to 10 weeks, and then 200 mg/d thereafter. Participants were screened from July 2020 through October 2022, and liposomal amphotericin was not available until 2021, which is why some participants were given the similarly effective yet more toxic IV amphotericin B deoxycholate.4 Routine blood tests were performed during the first two weeks and then repeated at weeks 4 and 6. Serial lumbar punctures and quantitative CSF cultures were performed at diagnosis and on days 3, 7, and 14.
The primary end point of the trial was the “early fungicidal activity” (EFA) rate of CSF Cryptococcus clearance, based on the change of log10 Cryptococcus colony-forming units (CFU) per milliliter (mL) per day that was measured over approximately two weeks. Secondary end points included laboratory and clinical AEs, tolerability, 18-week survival time, 18-week hospital-free survival time among two-week survivors, and additional IV amphotericin received. A total of 141 participants were enrolled in the study; 100 participants were randomized to LNC amphotericin and 41 were randomized to standard-of-care IV amphotericin across four cohorts. The median overall age was 36 years (interquartile range [IQR], 31 to 42), 50% were women, 67% were antiretroviral therapy (ART)-naïve, and the median CD4 count was 30 cells per microliter (IQR, 10 to 85). Eighty-five percent of participants had positive CSF cultures, with a median baseline CSF quantitative culture of 6,600 Cryptococcus CFU/mL (IQR, 65 to 75,860).
In cohort 2, the mean EFA for the experimental arm, which received two loading doses of IV amphotericin followed by oral LNC amphotericin, was 0.423 log10 Cryptococcus CFU/mL CSF/d (95% confidence interval [CI], 0.294 to 0.551), and the mean EFA for the IV amphotericin control group was 0.455 log10 CSF/d (95% CI, 0.359 to 0.551). The mean difference in EFA between the groups was -0.032 (95% CI, -0.196 to 1.31) log10 Cryptococcus CFU/mL CSF/d, which indicated no statistically significant difference. In cohort 4, the mean EFA for the experimental arm, which received an all-oral LNC amphotericin regimen without the IV loading doses, was 0.402 log10 Cryptococcus CFU/mL CSF/d (95% CI, 0.165 to 0.640), with a mean EFA difference between the all-oral regimen and IV amphotericin of -0.053 (95% CI, -0.317 to 0.211), which, again, was not a statistically significant difference. The incidence of CSF culture sterility by two weeks was similar between the groups; 62% of the LNC amphotericin arm of cohort 2 (23 of 37), 64% of the all-oral LNC amphotericin arm of cohort 4 (21 of 33), and 68% of participants who received IV amphotericin (23 of 34) achieved CSF sterility during the first two weeks.
The rates of 18-week survival were 85% for the IV amphotericin control group (35 of 41), 85% for the all-oral LNC amphotericin group (34 of 40), and 90% for the group that received oral LNC amphotericin after two IV loading doses of amphotericin (36 of 40). Rates of laboratory toxicities were significantly lower among participants who received six weeks of oral LNC amphotericin compared to those who received one week of IV amphotericin. Five percent of participants (4 of 80) in the oral LNC amphotericin group developed grade ≥ 3 potassium AEs compared to 17% (7 of 40) in the IV amphotericin group (P = 0.04). Among participants with a normal hemoglobin upon trial entry, anemia occurred among 38% of participants in the IV amphotericin group (11 of 29) compared to 4.2% in the oral LNC amphotericin group (2 of 48). Acute kidney injury also was significantly more common among those who received IV amphotericin (43%) compared with the group that received oral LNC amphotericin after two IV loading doses of amphotericin (23%) and the all-oral LN amphotericin group (13%). There were no statistically significant differences between groups regarding clinical toxicities, which were mostly attributed to HIV or cryptococcosis, and oral LNC amphotericin was very well tolerated.
COMMENTARY
Cryptococcosis is primarily caused by the heterobasidiomycetous fungus Cryptococcus neoformans, which is found in soil around the world, especially that which is exposed to certain birds, such as pigeons, chickens, and turkeys. It is less commonly caused by Cryptococcus gattii, which is more geographically limited and primarily associated with particular trees in Australia and the Pacific Northwest.5-7 Cryptococcal meningitis has been a devastating opportunistic infection among people with advanced HIV. One study estimated that in 2006, there were nearly 1 million cases of cryptococcal meningitis worldwide and approximately 625,000 deaths, with the vast majority occurring in sub-Saharan Africa.8 While expanded access to ART has led to a significant reduction in the overall global burden of HIV-associated cryptococcal meningitis, a recent study estimated that it caused approximately 112,000 deaths in 2020, accounting for approximately 19% of advanced HIV-related deaths.9
Early diagnosis is important, and without treatment, cryptococcal meningitis is uniformly fatal. IV amphotericin has been the cornerstone of induction therapy for decades, and combination therapy with IV amphotericin and 5FC has long been the standard of care. World Health Organization guidelines recently have recommended single high-dose (10 mg/kg) liposomal IV amphotericin B, in combination with 5FC and oral fluconazole, as the preferred regimen for induction therapy, based on a recent Phase III trial conducted by Jarvis and colleagues.10,11 While this change represents a landmark improvement in the management of this challenging disease that is most prevalent in resource-restricted settings, IV amphotericin is nonetheless resource-intensive and often associated with infusion-related reactions and toxicities, albeit less so than non-lipid formulations.12 The use of oral amphotericin for other severe mycoses has been reported as far back as 1957, yet issues with achieving adequate absorption and delivery to sites of infection have been major limitations.13 The findings in this study by Boulware and colleagues show remarkable promise for this novel oral formulation, which could be a major breakthrough for the management of cryptococcal meningitis as well as other disseminated fungal infections. Further clinical investigations into this life-saving agent are imperative.
REFERENCES
- Boulware DR, Atukunda M, Kagimu E, et al. Oral lipid nanocrystal amphotericin B for cryptococcal meningitis: A randomized clinical trial. Clin Infect Dis 2023; Aug. 22:ciad440. doi:10.1093/cid/ciad440. [Online ahead of print].
- Lu R, Hollingsworth C, Qiu J, et al. Efficacy of oral encochleated amphotericin B in a mouse model of cryptococcal meningoencephalitis. mBio 2019;10:e00724-19.
- Skipper CP, Atukunda M, Stadelman A, et al. Phase I EnACT Trial of the safety and tolerability of a novel oral formulation of amphotericin B. Antimicrob Agents Chemother 2020;64:e00838-20.
- Hamill RJ, Sobel JD, El-Sadr W, et al. Comparison of 2 doses of liposomal amphotericin B and conventional amphotericin B deoxycholate for treatment of AIDS-associated acute cryptococcal meningitis: A randomized, double-blind clinical trial of efficacy and safety. Clin Infect Dis 2010;51:225-232.
- Emmons CW. Saprophytic sources of Cryptococcus neoformans associated with the pigeon (Columba livia). Am J Hyg 1955;62:227-232.
- Ellis DH, Pfeiffer TJ. Ecology, life cycle, and infectious propagule of Cryptococcus neoformans. Lancet 1990;336:923-925.
- Stephen C, Lester S, Black W, et al. Multispecies outbreak of cryptococcosis on southern Vancouver Island, British Columbia. Can Vet J 2002;43:792-794.
- Park BJ, Wannemuehler KA, Marston BJ, et al. Estimation of the current global burden of cryptococcal meningitis among persons living with HIV/AIDS. AIDS 2009;23:525-530.
- Rajasingham R, Govender NP, Jordan A, et al. The global burden of HIV-associated cryptococcal infection in adults in 2020: A modelling analysis. Lancet Infect Dis 2022;22:1748-1755.
- [No authors listed]. Guidelines for Diagnosing, Preventing and Managing Cryptococcal Disease among Adults, Adolescents and Children Living with HIV. [Internet]. World Health Organization; 2022.
- 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.
- Dupont B. Overview of the lipid formulations of amphotericin B. J Antimicrob Chemother 2002;49 Suppl 1:31-36.
- Fiese MJ. Treatment of disseminated coccidioidomycosis with amphotericin B; report of a case. Calif Med 1957;86:119-120.
