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.

Figure 1.

Consolidated Standards of Reporting Trials (CONSORT) diagram. *All patients received their allocated intervention. No patients were lost to follow-up during the initial 2-week follow-up. †The single patient lost to follow-up had full follow-up data until hospital discharge at 2 weeks that were used in toxicity and mortality analyses. Abbreviations: CM, cryptococcal meningitis; EFA, early fungicidal activity; LP, lumbar puncture.

Figure 2.

Early fungicidal activity (EFA) by treatment group. A, Difference in mean EFA between intervention arms and control. All 3 short-course treatment arms were noninferior to control. B, Individual patient slopes over the initial 14 days of treatment. The mean slope (standard deviation) is given below each plot. Sterile cultures in the second week that lessened the slope and were excluded from EFA calculation (as sterility would have been achieved before that day’s lumbar punctures) are shown in the dotted gray line. C, Adjusted difference in mean EFA between intervention arms and control. All 3 short-course treatment arms remained noninferior to control when adjusted for (i) baseline fungal burden (quantitative cryptococcal culture [QCC]); (ii) baseline CD4 cell count; (iii) baseline mental status; (iv) QCC and CD4 cell count; (v) QCC, CD4 cell count, and mental status; and (vi) QCC, CD4 cell count, mental status, sex, age, and antiretroviral therapy status. Abbreviations: CFU, colony-forming units; CI, confidence interval; SD, standard deviation.