AMBIsome Therapy Induction OptimisatioN (AMBITION): High dose AmBisome for cryptococcal meningitis induction therapy in sub-Saharan Africa: economic evaluation protocol for a randomised controlled trial-based equivalence study

IntroductionCryptococcal meningitis is responsible for around 15% of all HIV-related deaths globally. Conventional treatment courses with amphotericin B require prolonged hospitalisation and are associated with multiple toxicities and poor outcomes. A phase II study has shown that a single high dose of liposomal amphotericin may be comparable to standard treatment. We propose a phase III clinical endpoint trial comparing single, high-dose liposomal amphotericin with the WHO recommended first-line treatment at six sites across five counties. An economic analysis is essential to support wide-scale implementation.Methods and analysisCountry-specific economic evaluation tools will be developed across the five country settings. Details of patient and household out-of-pocket expenses and any catastrophic healthcare expenditure incurred will be collected via interviews from trial patients. Health service patient costs and related household expenditure in both arms will be compared over the trial period in a probabilistic approach, using Monte Carlo bootstrapping methods. Costing information and number of life-years survived will be used as the input to a decision-analytic model to assess the cost-effectiveness of a single, high-dose liposomal amphotericin to the standard treatment. In addition, these results will be compared with a historical cohort from another clinical trial.Ethics and disseminationThe AMBIsome Therapy Induction OptimisatioN (AMBITION) trial has been evaluated and approved by the London School of Hygiene and Tropical Medicine, University of Botswana, Malawi National Health Sciences, University of Cape Town, Mulago Hospital and Zimbabwe Medical Research Council research ethics committees. All participants will provide written informed consent or if lacking capacity will have consent provided by a proxy. The findings of this economic analysis, part of the AMBITION trial, will be disseminated through peer-reviewed publications and at international and country-level policy meetings.Trial registrationISRCTN72509687; Pre-results.

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Combination Therapy for HIV-Associated Cryptococcal Meningitis—A Success Story

Journal of Fungi ◽

10.3390/jof7121098 ◽

2021 ◽

Vol 7 (12) ◽

pp. 1098

Author(s):

William J. Hurt ◽

Thomas S. Harrison ◽

Síle F. Molloy ◽

Tihana A. Bicanic

Keyword(s):

Clinical Trials ◽

Combination Therapy ◽

Cryptococcal Meningitis ◽

Treatment Strategies ◽

Antifungal Drugs ◽

Sub Saharan Africa ◽

Phase Iii ◽

High Dose ◽

Success Story ◽

Phase Ii Studies

Cryptococcal meningitis is the leading cause of adult meningitis in patients with HIV, and accounts for 15% of all HIV-related deaths in sub-Saharan Africa. The mainstay of management is effective antifungal therapy, despite a limited arsenal of antifungal drugs, significant progress has been made developing effective treatment strategies by using combination regimens. The introduction of fluconazole as a safe and effective step-down therapy allowed for shorter courses of more fungicidal agents to be given as induction therapy, with higher doses achieving more rapid CSF sterilisation and improved treatment outcomes. The development of early fungicidal activity (EFA), an easily measured surrogate of treatment efficacy, has enabled rapid identification of effective combinations through dose ranging phase II studies, allowing further evaluation of clinical benefit in targeted phase III studies. Recent clinical trials have shown that shorter course induction regimens using one week of amphotericin paired with flucytosine are non-inferior to traditional two-week induction regimens and that the combination of fluconazole and flucytosine offers a viable treatment alternative when amphotericin is unavailable. Access to drugs in many low and middle-income settings remains challenging but is improving, and novel strategies based on single high dose liposomal amphotericin B promise further reduction in treatment complications and toxicities. This review aims to summarise the key findings of the principal clinical trials that have led to the success story of combination therapy thus far.

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HIV-associated Cryptococcal Meningitis: a Review of Novel Short-Course and Oral Therapies

Current Treatment Options in Infectious Diseases ◽

10.1007/s40506-020-00239-0 ◽

2020 ◽

Vol 12 (4) ◽

pp. 422-437

Author(s):

Letumile R. Moeng ◽

James Milburn ◽

Joseph N. Jarvis ◽

David S. Lawrence

Keyword(s):

Amphotericin B ◽

Cryptococcal Meningitis ◽

Liposomal Amphotericin ◽

Phase Iii ◽

Induction Treatment ◽

High Dose ◽

Ongoing Research ◽

Short Course ◽

Incidence And Mortality ◽

The Impact

Abstract Purpose of review HIV-associated cryptococcal meningitis remains a significant public health problem in parts of Africa and Asia and a major cause of AIDS-related mortality, accounting for 15% of all AIDS-related deaths worldwide. Cryptococcal meningitis is uniformly fatal if untreated, and access to antifungal therapy in regions with the highest burden is often limited. Outcomes with fluconazole monotherapy are poor, and induction treatment with amphotericin B and high-dose fluconazole for 2 weeks is associated with significant drug-related toxicities and prolonged hospital admissions. This review focuses on the potential of novel short-course and oral combination therapies for cryptococcal meningitis. Recent findings Recent clinical trials have shown that shorter courses of amphotericin, if paired with oral flucytosine, rather than fluconazole, can achieve non-inferior mortality outcomes. In addition, an oral combination of fluconazole and flucytosine is a potential alternative. Liposomal amphotericin B may further simplify treatment; it is associated with fewer drug-related toxicities, and a recent phase II randomised controlled trial demonstrated that a single, high dose of liposomal amphotericin is non-inferior to 14 standard daily doses at clearing Cryptococcus from cerebrospinal fluid. This has been taken forward to an ongoing phase III, clinical endpoint study. Summary The incidence and mortality associated with cryptococcal meningitis is still unacceptably high. There is evidence supporting the use of short-course amphotericin B and oral combination antifungal treatment regimens for cryptococcal meningitis (CM). Ongoing research into short-course, high-dose treatment with liposomal amphotericin may also help reduce the impact of this devastating disease.

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