Mary Wilson
Well-known member
March 24, 2022
N Engl J Med 2022; 386:1109-1120
DOI: 10.1056/NEJMoa2111904
Joseph N. Jarvis, M.R.C.P., Ph.D., David S. Lawrence, M.B., Ch.B., David B. Meya, Ph.D., Enock Kagimu, M.B., Ch.B., John Kasibante, M.B., Ch.B., Edward Mpoza, M.B., Ch.B., Morris K. Rutakingirwa, M.B., Ch.B., Kenneth Ssebambulidde, M.B., Ch.B., Lillian Tugume, M.B., Ch.B., Joshua Rhein, M.D., David R. Boulware, M.D., Henry C. Mwandumba, Ph.D., et al.,for the Ambition Study Group[SUP]*[/SUP]
Abstract
BACKGROUND
Cryptococcal meningitis is a leading cause of human immunodeficiency virus (HIV)–related death in sub-Saharan Africa. Whether a treatment regimen that includes a single high dose of liposomal amphotericin B would be efficacious is not known.
METHODS
In this phase 3 randomized, controlled, noninferiority trial conducted in five African countries, we assigned HIV-positive adults with cryptococcal meningitis in a 1:1 ratio to receive either a single high dose of liposomal amphotericin B (10 mg per kilogram of body weight) on day 1 plus 14 days of flucytosine (100 mg per kilogram per day) and fluconazole (1200 mg per day) or the current World Health Organization–recommended treatment, which includes amphotericin B deoxycholate (1 mg per kilogram per day) plus flucytosine (100 mg per kilogram per day) for 7 days, followed by fluconazole (1200 mg per day) for 7 days (control). The primary end point was death from any cause at 10 weeks; the trial was powered to show noninferiority at a 10-percentage-point margin.
RESULTS
A total of 844 participants underwent randomization; 814 were included in the intention-to-treat population. At 10 weeks, deaths were reported in 101 participants (24.8%; 95% confidence interval [CI], 20.7 to 29.3) in the liposomal amphotericin B group and 117 (28.7%; 95% CI, 24.4 to 33.4) in the control group (difference, −3.9 percentage points); the upper boundary of the one-sided 95% confidence interval was 1.2 percentage points (within the noninferiority margin; P<0.001 for noninferiority). Fungal clearance from cerebrospinal fluid was −0.40 log[SUB]10[/SUB] colony-forming units (CFU) per milliliter per day in the liposomal amphotericin B group and −0.42 log[SUB]10[/SUB] CFU per milliliter per day in the control group. Fewer participants had grade 3 or 4 adverse events in the liposomal amphotericin B group than in the control group (50.0% vs. 62.3%).
CONCLUSIONS
Single-dose liposomal amphotericin B combined with flucytosine and fluconazole was noninferior to the WHO-recommended treatment for HIV-associated cryptococcal meningitis and was associated with fewer adverse events.
https://www.nejm.org/doi/full/10.1056/NEJMoa2111904#.YjuUKJEq8Oc.twitter
N Engl J Med 2022; 386:1109-1120
DOI: 10.1056/NEJMoa2111904
Joseph N. Jarvis, M.R.C.P., Ph.D., David S. Lawrence, M.B., Ch.B., David B. Meya, Ph.D., Enock Kagimu, M.B., Ch.B., John Kasibante, M.B., Ch.B., Edward Mpoza, M.B., Ch.B., Morris K. Rutakingirwa, M.B., Ch.B., Kenneth Ssebambulidde, M.B., Ch.B., Lillian Tugume, M.B., Ch.B., Joshua Rhein, M.D., David R. Boulware, M.D., Henry C. Mwandumba, Ph.D., et al.,for the Ambition Study Group[SUP]*[/SUP]
Abstract
BACKGROUND
Cryptococcal meningitis is a leading cause of human immunodeficiency virus (HIV)–related death in sub-Saharan Africa. Whether a treatment regimen that includes a single high dose of liposomal amphotericin B would be efficacious is not known.
METHODS
In this phase 3 randomized, controlled, noninferiority trial conducted in five African countries, we assigned HIV-positive adults with cryptococcal meningitis in a 1:1 ratio to receive either a single high dose of liposomal amphotericin B (10 mg per kilogram of body weight) on day 1 plus 14 days of flucytosine (100 mg per kilogram per day) and fluconazole (1200 mg per day) or the current World Health Organization–recommended treatment, which includes amphotericin B deoxycholate (1 mg per kilogram per day) plus flucytosine (100 mg per kilogram per day) for 7 days, followed by fluconazole (1200 mg per day) for 7 days (control). The primary end point was death from any cause at 10 weeks; the trial was powered to show noninferiority at a 10-percentage-point margin.
RESULTS
A total of 844 participants underwent randomization; 814 were included in the intention-to-treat population. At 10 weeks, deaths were reported in 101 participants (24.8%; 95% confidence interval [CI], 20.7 to 29.3) in the liposomal amphotericin B group and 117 (28.7%; 95% CI, 24.4 to 33.4) in the control group (difference, −3.9 percentage points); the upper boundary of the one-sided 95% confidence interval was 1.2 percentage points (within the noninferiority margin; P<0.001 for noninferiority). Fungal clearance from cerebrospinal fluid was −0.40 log[SUB]10[/SUB] colony-forming units (CFU) per milliliter per day in the liposomal amphotericin B group and −0.42 log[SUB]10[/SUB] CFU per milliliter per day in the control group. Fewer participants had grade 3 or 4 adverse events in the liposomal amphotericin B group than in the control group (50.0% vs. 62.3%).
CONCLUSIONS
Single-dose liposomal amphotericin B combined with flucytosine and fluconazole was noninferior to the WHO-recommended treatment for HIV-associated cryptococcal meningitis and was associated with fewer adverse events.
https://www.nejm.org/doi/full/10.1056/NEJMoa2111904#.YjuUKJEq8Oc.twitter
