TY - JOUR
T1 - Oral Lipid Nanocrystal Amphotericin B for Cryptococcal Meningitis
T2 - A Randomized Clinical Trial
AU - Boulware, David R.
AU - Atukunda, Mucunguzi
AU - Kagimu, Enock
AU - Musubire, Abdu K.
AU - Akampurira, Andrew
AU - Tugume, Lillian
AU - Ssebambulidde, Kenneth
AU - Kasibante, John
AU - Nsangi, Laura
AU - Mugabi, Timothy
AU - Gakuru, Jane
AU - Kimuda, Sarah
AU - Kasozi, Derrick
AU - Namombwe, Suzan
AU - Turyasingura, Isaac
AU - Rutakingirwa, Morris K.
AU - Mpoza, Edward
AU - Kigozi, Enos
AU - Muzoora, Conrad
AU - Ellis, Jayne
AU - Skipper, Caleb P.
AU - Matkovits, Theresa
AU - Williamson, Peter R.
AU - Williams, Darlisha A.
AU - Fieberg, Ann
AU - Hullsiek, Kathy H.
AU - Abassi, Mahsa
AU - Dai, Biyue
AU - Meya, David B.
N1 - Publisher Copyright:
© 2023 Oxford University Press. All rights reserved.
PY - 2023/12/15
Y1 - 2023/12/15
N2 - Background. Amphotericin B is the gold standard treatment for severe mycoses. A new orally delivered, less-toxic formulation of amphotericin has been developed. Methods. In our randomized clinical trial, we tested oral lipid nanocrystal (LNC) amphotericin B (MAT2203, Matinas Biopharma) vs intravenous (IV) amphotericin for human immunodeficiency virus–associated cryptococcal meningitis in 4 sequential cohorts. Two pilot cohorts assessed safety and tolerability (n = 10 each), and 2 cohorts assessed efficacy with/ without 2 IV loading doses (n = 40 each). The experimental arm received 1.8 g/d oral LNC amphotericin through 2 weeks with 100 mg/kg/d flucytosine, then 1.2 g/d LNC amphotericin through 6 weeks. The randomized control arm (n = 41) received 7 days of IV amphotericin with flucytosine, then 7 days of fluconazole 1200 mg/d. The primary end point was cerebrospinal fluid (CSF) early fungicidal activity (EFA). Results. We randomized 80 participants to oral LNC amphotericin + flucytosine with (n = 40) and without (n = 40) 2 IV loading doses and 41 control participants to IV amphotericin + flucytosine. Mean EFA was 0.40 log10 colony-forming units (CFU)/mL/d for all-oral LNC amphotericin, 0.42 log10 Cryptococcus CFU/mL/d for oral LNC amphotericin with IV loading doses, and 0.46 log10 CFU/mL/d for IV amphotericin controls. LNC amphotericin groups achieved 2-week CSF sterility in 63% (44 of 70) vs 68% (23 of 34) of controls. The 18-week survival was 85% (34 of 40) with all-oral LNC amphotericin, 90% (36 of 40) with oral LNC amphotericin given IV loading doses, and 85% (35 of 41) with IV amphotericin. Grade 3–4 laboratory adverse events occurred less frequently in LNC amphotericin groups (41%) than the IV amphotericin group (61%, P = .05), particularly for anemia (21% vs 44%; P = .01) and potassium (5% vs 17%; P = .04). Conclusions. This new oral amphotericin B LNC formulation appears promising for cryptococcal meningitis with antifungal activity, similar survival, and less toxicity than IV amphotericin. Clinical Trials Registration. NCT04031833.
AB - Background. Amphotericin B is the gold standard treatment for severe mycoses. A new orally delivered, less-toxic formulation of amphotericin has been developed. Methods. In our randomized clinical trial, we tested oral lipid nanocrystal (LNC) amphotericin B (MAT2203, Matinas Biopharma) vs intravenous (IV) amphotericin for human immunodeficiency virus–associated cryptococcal meningitis in 4 sequential cohorts. Two pilot cohorts assessed safety and tolerability (n = 10 each), and 2 cohorts assessed efficacy with/ without 2 IV loading doses (n = 40 each). The experimental arm received 1.8 g/d oral LNC amphotericin through 2 weeks with 100 mg/kg/d flucytosine, then 1.2 g/d LNC amphotericin through 6 weeks. The randomized control arm (n = 41) received 7 days of IV amphotericin with flucytosine, then 7 days of fluconazole 1200 mg/d. The primary end point was cerebrospinal fluid (CSF) early fungicidal activity (EFA). Results. We randomized 80 participants to oral LNC amphotericin + flucytosine with (n = 40) and without (n = 40) 2 IV loading doses and 41 control participants to IV amphotericin + flucytosine. Mean EFA was 0.40 log10 colony-forming units (CFU)/mL/d for all-oral LNC amphotericin, 0.42 log10 Cryptococcus CFU/mL/d for oral LNC amphotericin with IV loading doses, and 0.46 log10 CFU/mL/d for IV amphotericin controls. LNC amphotericin groups achieved 2-week CSF sterility in 63% (44 of 70) vs 68% (23 of 34) of controls. The 18-week survival was 85% (34 of 40) with all-oral LNC amphotericin, 90% (36 of 40) with oral LNC amphotericin given IV loading doses, and 85% (35 of 41) with IV amphotericin. Grade 3–4 laboratory adverse events occurred less frequently in LNC amphotericin groups (41%) than the IV amphotericin group (61%, P = .05), particularly for anemia (21% vs 44%; P = .01) and potassium (5% vs 17%; P = .04). Conclusions. This new oral amphotericin B LNC formulation appears promising for cryptococcal meningitis with antifungal activity, similar survival, and less toxicity than IV amphotericin. Clinical Trials Registration. NCT04031833.
KW - AIDS-related opportunistic infection
KW - HIV
KW - amphotericin B
KW - cryptococcal meningitis
KW - randomized controlled trial
UR - http://www.scopus.com/inward/record.url?scp=85176273935&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85176273935&partnerID=8YFLogxK
U2 - 10.1093/cid/ciad440
DO - 10.1093/cid/ciad440
M3 - Article
C2 - 37606364
AN - SCOPUS:85176273935
SN - 1058-4838
VL - 77
SP - 1659
EP - 1667
JO - Clinical Infectious Diseases
JF - Clinical Infectious Diseases
IS - 12
ER -
