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AMBITION-cm: AMBIsome Therapy Induction OptimizatioN - Intermittent high dose AmBisome® on a high dose fluconazole backbone for cryptococcal meningitis induction therapy in sub-Saharan Africa.

The Ambition trial is a phase II trial currently being conducted in Mwanza, Tanzania and Gabarone, Botswana. The aim of the trial is to identify an effective and sustainable treatment for cryptococcal meningitis in resource limited settings.

Cryptococcal meningitis is a leading cause of death in HIV-infected individuals in Africa. The current standard for initial treatment in developed countries is 2 weeks of amphotericin B-based therapy. The combination of the costs associated with prolonged hospital admissions, the difficulties in administration and the need for laboratory monitoring make amphotericin B deoxycholate treatment difficult in much of Africa.


A modified form of amphotericin B is available called liposomal amphotericin B (AmBisome®). This is considerably less toxic than standard amphotericin B, and is known to be effective in the treatment of cryptococcal meningitis. Its use has been limited by the high cost of therapy, but recent data suggest that due to its lower toxicity, higher doses of AmBisome® can be given safely and much shorter courses may be effective in the treatment of cryptococcal meningitis.


A large reduction in the number of doses and duration of hospitalisation, together with reduced pricing of AmBisome®, may result in cryptococcal meningitis treatment costs that are not more than the costs of 2 weeks of conventional amphotericin B, and provide a convenient, safe and effective alternative to conventional amphotericin B therapy. This study aims to define the most effective and most cost-effective schedules for AmBisome® use in the treatment of cryptococcal meningitis.

TRIP: Implementation of cryptococcal antigen screening and enhanced ART in advanced HIV patients accessing routine care in Dar es Salaam, Tanzania.


This is an EDCTP-funded follow-on study to the Lancet published REMSTART study which was the first study to show a mortality benefit of cryptococcal antigen (CrAg) screening in combination with enhanced antiretroviral therapy (ART).  TRIP is led by Dr Sayoki Mfinanga who is rolling out CrAg screening and enhanced ART adherence in 18 rural and urban clinics within routine care.  Dr Mfinanga is assisted by our team at SGUL (Loyse, Harrison, Robb, Molloy) and close collaborators at Liverpool School of Tropical Medicine (LSTM) (Jaffar).

ACTA: Advancing Cryptococcal meningitis Treatment for Africa

 


A phase III, randomised, controlled trial for the treatment of HIV-associated cryptococcal meningitis: oral fluconazole plus flucytosine or one week amphotericin B-based therapy vs two weeks amphotericin B-based therapy
The ACTA trial is currently being conducted at 9 hospitals in 4 countries across Africa; Zambia, Malawi, Tanzania and Cameroon. The aim of the trial is to identify an effective and sustainable treatment for cryptococcal meningitis in resource limited settings.
Cryptococcal meningitis is a leading cause of death in HIV-infected individuals in Africa. In developed countries, the current standard for initial treatment of HIV-associated cryptococcal meningitis is 2 weeks of amphotericin B-based therapy. However, in many settings in Africa, amphotericin B is not available or not used due to its requirements for in-hospital care and close monitoring. The combination of fluconazole with a second oral drug, flucytosine, has been shown to lead to much more rapid control of infection, and to be associated with fewer deaths than fluconazole alone in a small study.
In addition, shorter 5-7 day courses of amphotericin B have been shown to be much better tolerated than 2 weeks amphotericin B, reducing the length of hospital stay and the need for intensive monitoring of treatment. Such short-course amphotericin B would be much more easily implemented in the many centres in Africa and Asia currently using fluconazole, and may not be associated with any loss in effectiveness compared with 2-week courses.
Therefore, this study will compare the best oral treatment, a combination of fluconazole and flucytosine, with a one-week amphotericin B-based strategy, and with the standard of 2 weeks amphotericin B, in resource-limited settings where implementation of 2 weeks of amphotericin B would be difficult to sustain, and therefore would not be used unless shown to be superior to more readily implementable alternatives. Additionally, fluconazole and flucytosine will be compared as additional drugs to be given with amphotericin B, in the two amphotericin B treatment strategies.

DREAMM (Driving REduced AIDS-associated Meningo-encephalitis Mortality) project: This is an EDCTP-funded (1.88 million euros) implementation project that aims to drive down HIV-associated meningo-encephalitis mortality in Tanzania, Cameroon and Malawi. 

 

The chief investigator is Dr Angela Loyse who is working in partnership with the respective African Principal Investigator leads: Dr Sayoki Mfinanga, Dr Charles Kouanfack and Dr Cecilia Kanyama as well as their hospital counterparts.  Muirgen Stack is the project manager and Dr Sile Molloy the epidemiologist/senior project manager.  DREAMM has backing from Institut Pasteur and Centers for Disease Prevention and Control (CDC).  

The project is in three phases: 1) Audit, 2) Training (laboratory and clinical) and 3) Implementation.  The audit phase will determine current HIV-associated meningo-encephalitis mortality rates and availability of diagnostic tests and essential medicines in routine care.  75 patients in total will be recruited into the audit phase of DREAMM-25 patients from each study site.  Key clinical and laboratory personnel will be trained on the latest point of care diagnostic tests and safe administration of essential medicines for HIV-associated meningo-encephalitis such as amphotericin B deoxycholate.  They will disseminate this knowledge to their hospital counterparts.  Institut Pasteur (in particular Ms Aude Sturny-Leclerc) is playing a leading role in the design and delivery of the laboratory part of the training program.  In the third and final part of the project optimised laboratory and patient pathways will be implemented in order to reduce the time from patient presentation to diagnostic testing and administration of effective, microbiologically-driven treatment.  The two and ten week all-cause mortality of the implementation phase of the project will be compared to that documented in the audit phase.  A total of 450 patients will be recruited into the implementation phase of the study across the three sites.

Important sub-studies include a health economics evaluation study to determine the cost of the intervention and routine care costs.  A new semi-quantitative cryptococcal antigen lateral flow assay (CrAg LFA) (CryptoPS, Biosynex, Strasburg, France) will be evaluated uniquely for the diagnosis of patients with meningo-encephalitis.  New, point of care (POC) polyvalent tests (CrAg/HIV) and (CrAg/Streptococcus pneumoniae) will also be evaluated. Lastly, nanopore technology (MinION, Oxford Nanopore Technology, Oxford, UK) will be optimised for the diagnosis of HIV-associated meningo-encephalitis in African low and middle income countries (LMICs).