Short-course High-dose Liposomal Amphotericin B for Human Immunodeficiency Virus-associated Cryptococcal Meningitis: A Phase 2 Randomized Controlled Trial.

Abstract

Background:

We performed a phase 2 noninferiority trial examining the early fungicidal activity (EFA) of 3 short-course, high-dose liposomal amphotericin B (L-AmB) regimens for cryptococcal meningitis (CM) in Tanzania and Botswana.

Methods:

Human immunodeficiency virus (HIV)-infected adults with CM were randomized to (i) L-AmB 10 mg/kg on day 1 (single dose); (ii) L-AmB 10 mg/kg on day 1 and 5 mg/kg on day 3 (2 doses); (iii) L-AmB 10 mg/kg on day 1 and 5 mg/kg on days 3 and 7 (3 doses); or (iv) L-AmB 3 mg/kg/day for 14 days (control). All patients also received oral fluconazole 1200 mg/day for 14 days. Primary endpoint was mean rate of clearance of cerebrospinal fluid cryptococcal infection (EFA). Noninferiority was defined as an upper limit of the 2-sided 95% confidence interval (CI) of difference in EFA between intervention and control <0.2 log10 colony-forming units (CFU)/mL/day.

Results:

Eighty participants were enrolled. EFA for daily L-AmB was -0.41 log10 CFU/mL/day (standard deviation, 0.11; n = 17). Difference in mean EFA from control was -0.11 (95% CI, -.29 to .07) log10 CFU/mL/day faster with single dose (n = 16); -0.05 (95% CI, -.20 to .10) log10 CFU/mL/day faster with 2 doses (n = 18); and -0.13 (95% CI, -.35 to .09) log10 CFU/mL/day faster with 3 doses (n = 18). EFA in all short-course arms was noninferior to control. Ten-week mortality was 29% (n = 23) with no statistical difference between arms. All arms were well tolerated.

Conclusions:

Single-dose 10 mg/kg L-AmB was well tolerated and led to noninferior EFA compared to 14 days of 3 mg/kg/day L-AmB in HIV-associated CM. Induction based on a single 10 mg/kg L-AmB dose is being taken forward to a phase 3 clinical endpoint trial.

Clinical Trials Registration:

ISRCTN 10248064.

• Authors: Joseph N Jarvis, Tshepo B Leeme, Mooketsi Molefi, Awilly A Chofle, Gabriella Bidwell, Katlego Tsholo, Nametso Tlhako, Norah Mawoko, Raju K K Patel, Mark W Tenforde, Charles Muthoga, Gregory P Bisson, Jeremiah Kidola, John Changalucha, David Lawrence, Shabbar Jaffar, William Hope, Si le F Molloy, Thomas S Harrison
• Journal: Clinical infectious diseases : an official publication of the Infectious Diseases Society of America (Clin Infect Dis) Vol. 68 Issue 3 Pg. 393-401 (01 18 2019) ISSN: 1537-6591 [Electronic] United States
• PMID: 29945252 (Publication Type: Clinical Trial, Phase II, Journal Article, Randomized Controlled Trial, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antifungal Agents
• liposomal amphotericin B
• Amphotericin B

Topics

• Adult
• Amphotericin B (administration & dosage)
• Antifungal Agents (administration & dosage)
• Botswana
• Cerebrospinal Fluid (microbiology)
• Cryptococcus neoformans (isolation & purification)
• Female
• HIV Infections (complications)
• Humans
• Male
• Meningitis, Cryptococcal (drug therapy)
• Tanzania
• Treatment Outcome