AMBIsome Therapy Induction OptimisatioN (AMBITION): High Dose AmBisome for Cryptococcal Meningitis Induction Therapy in sub-Saharan Africa: Study Protocol for a Phase 3 Randomised Controlled Non-Inferiority Trial.

BACKGROUND: Cryptococcal meningitis (CM) is a major cause of mortality in HIV programmes in Africa despite increasing access to antiretroviral therapy (ART). Mortality is driven in part by limited availability of amphotericin-based treatment, drug-induced toxicities of amphotericin B deoxycholate and prolonged hospital admissions. A single, high-dose of liposomal amphotericin (L-AmB, Ambisome) on a fluconazole backbone has been reported as non-inferior to 14 days of standard dose L-AmB in reducing fungal burden. This trial examines whether single, high-dose L-AmB given with high-dose fluconazole and flucytosine is non-inferior to a seven-day course of amphotericin B deoxycholate plus flucytosine (the current World Health Organization [WHO] recommended treatment regimen). METHODS: An open-label phase III randomised controlled non-inferiority trial conducted in five countries in sub-Saharan Africa: Botswana, Malawi, South Africa, Uganda and Zimbabwe. The trial will compare CM induction therapy with (1) a single dose (10 mg/kg) of L-AmB given with 14 days of fluconazole (1200 mg/day) and flucytosine (100 mg/kg/day) to (2) seven days amphotericin B deoxycholate (1 mg/kg/day) given alongside seven days of flucytosine (100 mg/kg/day) followed by seven days of fluconazole (1200 mg/day). The primary endpoint is all-cause mortality at ten weeks with a non-inferiority margin of 10% and 90% power. Secondary endpoints are early fungicidal activity, proportion of grade III/IV adverse events, pharmacokinetic parameters and pharmacokinetic/pharmacodynamic associations, health service costs, all-cause mortality within the first two and four weeks, all-cause mortality within the first ten weeks (superiority analysis) and rates of CM relapse, immune reconstitution inflammatory syndrome and disability at ten weeks. A total of 850 patients aged ≥ 18 years with a first episode of HIV-associated CM will be enrolled (425 randomised to each arm). All patients will be followed for 16 weeks. All patients will receive consolidation therapy with fluconazole 800 mg/day to complete ten weeks of treatment, followed by fluconazole maintenance and ART as per local guidance. DISCUSSION: A safe, sustainable and easy to administer regimen of L-AmB that is non-inferior to seven days of daily amphotericin B deoxycholate therapy may reduce the number of adverse events seen in patients treated with amphotericin B deoxycholate and shorten hospital admissions, providing a highly favourable and implementable alternative to the current WHO recommended first-line treatment. TRIAL REGISTRATION: ISRCTN, ISRCTN72509687 . Registered on 13 July 2017.

Cryptococcal meningitis treatment strategies in resource-limited settings: a cost-effectiveness analysis.

BACKGROUND: Cryptococcal meningitis (CM) is the most common form of meningitis in Africa. World Health Organization guidelines recommend 14-d amphotericin-based induction therapy; however, this is impractical for many resource-limited settings due to cost and intensive monitoring needs. A cost-effectiveness analysis was performed to guide stakeholders with respect to optimal CM treatment within resource limitations. METHODS AND FINDINGS: We conducted a decision analysis to estimate the incremental cost-effectiveness ratio (ICER) of six CM induction regimens: fluconazole (800-1,200 mg/d) monotherapy, fluconazole + flucytosine (5FC), short-course amphotericin (7-d) + fluconazole, 14-d of amphotericin alone, amphotericin + fluconazole, and amphotericin + 5FC. We computed actual 2012 healthcare costs in Uganda for medications, supplies, and personnel, and average laboratory costs for three African countries. A systematic review of cryptococcal treatment trials in resource-limited areas summarized 10-wk survival outcomes. We modeled one-year survival based on South African, Ugandan, and Thai CM outcome data, and survival beyond one-year on Ugandan and Thai data. Quality-adjusted life years (QALYs) were determined and used to calculate the cost-effectiveness ratio and ICER. The cost of hospital care ranged from $154 for fluconazole monotherapy to $467 for 14 d of amphotericin + 5FC. Based on 18 studies investigating outcomes for HIV-infected individuals with CM in resource-limited settings, the estimated mean one-year survival was lowest for fluconazole monotherapy, at 40%. The cost-effectiveness ratio ranged from $20 to $44 per QALY. Overall, amphotericin-based regimens had higher costs but better survival. Short-course amphotericin (1 mg/kg/d for 7 d) with fluconazole (1,200 mg/d for14 d) had the best one-year survival (66%) and the most favorable cost-effectiveness ratio, at $20.24/QALY, with an ICER of $15.11 per additional QALY over fluconazole monotherapy. The main limitation of this study is the pooled nature of a systematic review, with a paucity of outcome data with direct comparisons between regimens. CONCLUSIONS: Short-course (7-d) amphotericin induction therapy coupled with high-dose (1,200 mg/d) fluconazole is "very cost effective" per World Health Organization criteria and may be a worthy investment for policy-makers seeking cost-effective clinical outcomes. More head-to-head clinical trials are needed on treatments for this neglected tropical disease. Please see later in the article for the Editors' Summary.

Prevalence and management of non-albicans vaginal candidiasis.

OBJECTIVES: It is thought that widespread use of 'over-the-counter' azoles may increase the incidence of resistant Candida species such as Candida glabrata. Infections with species other than Candida albicans frequently do not respond to standard azole treatments. Intravaginal nystatin is an option but is no longer available in the UK. In this paper, the authors review the prevalence of non-albicans candida over the past 5 years, and assess the efficacy of amphotericin and flucytosine vaginal cream in the treatment of non-albicans VVC. METHODS: Retrospective review of all vaginal yeast isolates collected from women attending a city centre sexual-health clinic between 2004 and 2008. The women prescribed amphotericin and flucytosine vaginal cream were identified through pharmacy records, and their clinical notes reviewed for treatment outcome. RESULTS: Between 2004 and 2008, the number of isolates of all Candida species increased with increasing clinic workload, but the prevalence of non-albicans yeasts remained stable at between 0.87 and 1.06%. Eighteen patients were prescribed amphotericin and flucytosine vaginal cream. At follow-up, all 18 were clear of their initial yeast isolate on culture, but two had persistent symptoms and had positive cultures for C albicans. CONCLUSIONS: There is no evidence of any increase in prevalence of non-albicans Candida species such as C glabrata. The authors have treated 18 women who had non-albicans VVC with amphotericin and flucytosine vaginal cream and achieved clearance of the non-albicans species in all of them.

Optimization of the dosage of flucytosine in combination with amphotericin B for disseminated candidiasis: a pharmacodynamic rationale for reduced dosing.

Amphotericin B and flucytosine (5FC) have an additive effect when used for disseminated candidiasis. Here, we bridge the results of an experimental pharmacodynamic study to humans and demonstrate that a 5FC dosage of 25 mg/kg of body weight/day in four divided doses in combination with amphotericin B produces near-maximal effect.

Antifungal therapy for keratomycoses.

Keratomycoses have recently emerged as an important cause of ocular morbidity, especially in third-world countries. Available antifungal agents are limited in their efficacy, due to limited penetration into the cornea, the fungistatic nature and the development of drug resistance. Effective usage of the available drugs is hampered by the inefficiency of currently available antibiotic sensitivity tests for fungal organisms. There is also limited knowledge regarding the ideal combination(s) of antifungal agents, including issues of synergism and antagonism. Despite these problems, recent publications indicate encouraging outcomes in the treatment of a large series of fungal keratitis. Advances include better drug formulations, new agents and novel methods of drug delivery into the eye. As our ability to deal with advanced fungal keratitis remains limited, the importance of early diagnosis has been stressed and molecular biological techniques may play an important role in the future. This article summarises the important new advances in these areas in the past 2 years and provides guidelines for the management of these serious corneal infections.

Cost implications of alternative treatments for AIDS patients with cryptococcal meningitis. Comparison of fluconazole and amphotericin B-based therapies.

The extra demands placed upon health care resources by management of AIDS patients have increased the focus on cost implications of therapeutic alternatives. Cryptococcal meningitis is a common life-threatening infection in AIDS patients, usually treated with amphotericin B, often in combination with flucytosine. Administered intravenously, this therapy is associated with frequent and often severe side effects. Fluconazole is a new alternative which can be given orally once daily and has fewer such side effects. The purpose of this study was to examine the cost implications of these different therapies for both primary and maintenance treatment of cryptococcal meningitis. Comparison of these two therapies in recent clinical trials has indicated that fluconazole is at least as effective as amphotericin B, and therefore cost-minimisation analysis is an appropriate method to study the economic consequences of the alternative treatments. Patient management and resource-use information for both treatments was obtained using a modified Delphi technique with a panel of European physicians experienced in the treatment of this disease, and three models were developed to reflect the variability of practice evident among the panel members. U.K. health care costs were used to value these resources. The results indicated that, despite the higher cost of the drug itself, the costs associated with fluconazole were likely to be markedly less than those for amphotericin B for primary treatment, and similar or slightly cheaper for maintenance treatment. Over 1 year of treatment, the saving from the use of fluconazole would be in the range of 4000-14,000 pounds.