A phase III randomised controlled trial of oral fluconazole plus flucytosine versus amphotericin B-based therapy for o

Lead Research Organisation: St George's University of London
Department Name: Cellular and Molecular Medicine


Cryptococcal meningitis is one of the commonest causes of death in patients with AIDS and
is associated with up to 500,000 deaths each year in Africa alone. A large proportion of
patients die from the infection, in part because the current recommended treatment,
amphotericin B for 2 weeks, is difficult to give in hospitals in the developing world, because
it is relatively expensive and needs to be given intravenously and has side effects, often
starting in the second week, meaning monitoring is needed with frequent blood tests. The
alternative oral tablet treatment, fluconazole, that is available and cheap and currently
commonly used, is much less effective.
Therefore, based on a number of earlier small trials by the study team, we wish to test 2
new treatments, (1) Short, 1-week amphotericin B, and (2) Combination tablet treatment
with high dose fluconazole plus another drug called flucytosine, that are as fast and effective
in killing the infection as 2 weeks of amphotericin B. We will compare these new treatments
with 2 weeks amphotericin B, in a larger, randomised trial that will enable us to see whether
they are as good in preventing deaths from the infection. After 2 weeks of the study
treatments, all patients will receive the usual follow on therapy with fluconazole, and will be
started on drugs for the underlying HIV infection, as currently recommended, and followed
up for 10 weeks. 570 patients (190 given each alternative treatment) will be studied. This is
the minimum number needed to reliably compare the results of the treatments.
The project has been developed with doctors in 3 centres in Malawi and Zambia where there
are many cases and where alternative, affordable and practical treatments are urgently
needed. Each centre has the laboratories needed, and experience in doing such trials. Both
test treatments have been shown to be much more rapidly effective than fluconazole alone,
and would have less side effects and be much more easily given in developing countries than
2 weeks amphotericin B. However, if 2 weeks amphotericin B was found to be the best
treatment, then the costs required for its use could be justified. The costs as well as the
effectiveness of the treatments will be compared to help decide which treatment to
recommend in the future.

Technical Summary

Cryptococcal meningitis is one of the commonest causes of death in cohorts of HIV-infected
patients, and of early mortality in antiretroviral (ART) programmes in Africa, being
associated with up to 500,000 deaths per year in Africa alone. The high case fatality rate of
cryptococcal meningitis is driven in substantial part by the lack of effective antifungal
regimens for resource-constrained settings. In many centres the standard initial treatment of
2 weeks intravenous amphotericin B (AmB) is not available or not safely sustainable due to
the drug and administration costs, the close monitoring required, and common dose-related
side effects. Fluconazole, the commonly used but slowly-acting alternative, widely available
through a donation programme, when used alone, is associated with a 10-week mortality of
Therefore, based on a series of phase II studies by the study team, 2 novel regimens, (1)
Short, 1-week AmB-based induction, and (2) Combination oral therapy with high dose
fluconazole plus flucytosine, that are associated with a rate of clearance of infection similar
to that seen with 2 weeks AmB, will be compared with the internationally-accepted standard
of 2 weeks AmB, in a randomised non-inferiority trial with 2-week mortality as primary
endpoint. After 2 weeks, all patients will receive fluconazole consolidation and maintenance
therapy, will be commenced on ART at 3-4 weeks, in line with current guidelines, and
followed to 10 weeks. 570 patients (190 per arm) will be studied in order to achieve 85%
power, using a non-inferiority design with 10% non-inferiority margin, and assuming 85% 2-
week survival in the 2-week AmB arm.
The project has been developed with collaborators from 3 African sites (Blantyre and
Lilongwe, Malawi, and Lusaka, Zambia) with a high, ongoing burden of cryptococcal disease
where alternative, sustainable regimens are urgently needed. Each site has laboratory
infrastructure in place and experience of conducting trials to GCP standard. Both test
regimens have been shown to be much more rapidly active than fluconazole monotherapy,
and would be better tolerated and much more easily implemented in resource-limited
settings than 2 weeks AmB. Alternatively, if 2 weeks AmB proved superior, then the
resources required for its wider implementation could be justified. A cost effectiveness substudy
will be developed to inform policy-making decisions.


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publication icon
Kanyama C (2020) One-year Mortality Outcomes From the Advancing Cryptococcal Meningitis Treatment for Africa Trial of Cryptococcal Meningitis Treatment in Malawi. in Clinical infectious diseases : an official publication of the Infectious Diseases Society of America

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Molloy SF (2018) Antifungal Combinations for Treatment of Cryptococcal Meningitis in Africa. in The New England journal of medicine

Description ACTA trial results have driven $20 million Unitaid programme to improve care of patients with advanced HIV disease in 7 African countries
Geographic Reach Africa 
Policy Influence Type Influenced training of practitioners or researchers
Impact The Unitaid programme includes provision of drugs, in particular flucytosine, and diagnostic cryptococcal antigen tests
URL https://unitaid.org/advanced-hiv-disease/?utm_source=English+list&utm_campaign=ca4e6db72a-News%2FRec...
Description Following ACTA results and guidelnes changes, Western Cape Province in South Africa provides flucytosine for routine use in treatment of cryptococcal meningitis
Geographic Reach Africa 
Policy Influence Type Implementation circular/rapid advice/letter to e.g. Ministry of Health
Impact initial surveilllance shows step change reduction in in-hospital mortality of cryptococcal meningitis patients from 36% to 24% with flucytosine combination treatment
Description Report of reduction in patient mortality using ACTA trial regimen, as now recommended by WHO, in routine care in South Africa
Geographic Reach Africa 
Policy Influence Type Implementation circular/rapid advice/letter to e.g. Ministry of Health
Impact The mortality reductions seen in the ACTA trial have been realised in routine care in South Africa. In the first 335 patients treated, 1 week AmB plus flucytosine has been associated with >30% reduction in in-hospital mortality, from 36% to 24% Govender NP, Mathebula R, Shandu M, et al, for GERMS-SA. Flucytosine-based combination treatment for cryptococcal meningitis in routine care, South Africa. Abstract number: 4441, International Conference on AIDS and STIs in Africa (ICASA) 2019 conference, Kigali, 3 Dec 2019. Also presented at IAS 2022 by Govender et al. Manuscript submitted
Guideline Title WHO Guidelines for Diagnosis, prevention and management of cryptococcal disease in HIV-infected adults, adolescents and children
Description Updated WHO guidelines for cryptococcal treatment - based very largely on ACTA trial results
Geographic Reach Multiple continents/international 
Policy Influence Type Citation in clinical guidelines
Impact Given current estimates of HIV-associated cryptococcal meningitis global burden (180,000 deaths per year), implementation of ACTA trial regimens now recommended as first and second choices in WHO guidance, through reduction in the case fatality rate for cryptococcal meningitis from around 70% in centres currently using fluconazole monotherapy, to the 25-35%, seen with the regimens in the trial, could save tens of thousands of lives each year.
Description led discussion of treatment guidance, based on the ACTA Trial results, for an update of Southern African HIV Clinicians Society Guidelines for Cryptococcal Infection
Geographic Reach Africa 
Policy Influence Type Membership of a guideline committee
Impact Redution in Mortality - predicted reduction will be from 60-70% where previous standard of care was fluconazole monotherapy, to 25-35% with ACTA regimens Reduction in the costs of care for cryptococcal meningitis patients in South Africa Zambia and Botswana, previously treated with 2 week courses of amphotericin B
Description Clinical Trials: High Dose AMBISOME on a Fluconazole Backbone for Cryptococcal Meningitis Induction Therapy in sub-Saharan Africa: A Randomized Controlled Trial.
Amount € 9,999,912 (EUR)
Organisation Sixth Framework Programme (FP6) 
Department European and Developing Countries Clinical Trials Partnership
Sector Public
Country Netherlands
Start 01/2017 
End 12/2020
Description Fluconazole plus flucytosine vs fluconazole alone for cryptococcal antigen-positive patients identified through screening: A randomised trial
Amount £4,482,310 (GBP)
Funding ID V005731 
Organisation St George's University of London 
Sector Academic/University
Country United Kingdom
Start 03/2021 
End 03/2025
Description ANRS 
Organisation French National Agency for Research on AIDS and Viral Hepatitis (ANRS)
Country France 
Sector Public 
PI Contribution Collaborators on phase III study
Collaborator Contribution Collaborators on phase III study
Impact studies underway
Start Year 2011
Description Given ACTA results showing essential role of flucytosine in optimal treatment, collaboration with DNDi and other partners to develop sustained release formulation of flucytosine 
Organisation Drugs for Neglected Diseases initiative (DNDi)
Country Switzerland 
Sector Charity/Non Profit 
PI Contribution data for need for sustained release formulation phase 2 studies to demonstrate PK and pharmacodynamic equivalence
Collaborator Contribution product development
Impact EDCTP funding is being currently being negotiated
Start Year 2019
Description LSHTM 
Organisation London School of Hygiene and Tropical Medicine (LSHTM)
Department Faculty of Epidemiology and Population Health
Country United Kingdom 
Sector Academic/University 
PI Contribution Collaborators n a phase III trial
Collaborator Contribution Collaborators on a phase III trial
Impact The trial is underway
Start Year 2006
Description Liverpool School Tropical Medicine 
Organisation Liverpool School of Tropical Medicine
Country United Kingdom 
Sector Academic/University 
PI Contribution Partnership in ACTA, Ambition clinical trials and related outputs Partnership in DREAMM study - of diagnosis and management HIV-related meningitis
Collaborator Contribution Clinical trials, Epidemiological, Statistical, Cost effectiveness support
Impact Studies are underway Outputs expected from late 2016 onwards
Start Year 2015
Description MLW Blantyre 
Organisation Wellcome Trust
Department Malawi-Liverpool Wellcome Trust Clinical Research Programme
Country Malawi 
Sector Academic/University 
PI Contribution collaborators on Phase III trial
Collaborator Contribution collaborators on Phase III trial
Impact studies currently underway
Start Year 2011
Description NIMR Dar Es Salaam (Dr Mfinanga, partner in clinical trials) 
Organisation National Institute for Medical Research, Tanzania
Department NIMR Dar Es Salaam
Country Tanzania, United Republic of 
Sector Public 
PI Contribution Training and capacity building around implementation ACTA trial, and care of cryptococcal meningitis patents in general
Collaborator Contribution Site participation in ACTA trial
Impact No outputs yet Enrolment ongoing here and at other sites 539 patients enrolled in the trial to date - making this the largest cryptococcal trial to date
Start Year 2015
Description UTH Lusaka 
Organisation University Teaching Hospital
Department School of Medicine
Country Zambia 
Sector Academic/University 
PI Contribution Collaborators on phase III study
Collaborator Contribution Collaborators on phase III study
Impact studies underway
Start Year 2011
Title Generic flucytosine for world-wide access 
Description The ACTA trial results have driven international efforts to make affordable generic flucytosine widely available Unitaids have committed to buying a large quantity of drug in order to secure and kick start generic maunfacture; with the aim that the Global Fund will then take over the funding of flucytosine for treating HIV-associated cryptococcal meningitis 
Type Therapeutic Intervention - Drug
Current Stage Of Development Wide-scale adoption
Year Development Stage Completed 2019
Development Status Under active development/distribution
Clinical Trial? Yes
Impact reduction in mortality with flucytosine containg regimens reduction in costs with new first line therapy of one week amphotericin B plus flucytosine compared with the prior international standard of 2 weeks amphotericin B 
URL http://www.isrctn.com/ISRCTN45035509
Title improved modified release formulation of flucytosine 
Description standard formulation flucytosine needs to be given 4 times per day, resulting in missed doses and the potential for reduced efficacy (given time-dependent pharmacodynamics) The ACTA trial results have stimulated interest in the development of a slow release formulation that coudl be given less frequently Development of such a formulation is ongoing, and funding is being sought 
Type Therapeutic Intervention - Drug
Current Stage Of Development Initial development
Year Development Stage Completed 2019
Development Status Under active development/distribution
Impact not yet applicable 
Description ACTA Trial results presented at IAS conference 2017 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact ACTA results presented at International AIDS Society (IAS) conference Paris 2017
led to rapid cahnge in WHO and other international and national guidelines
Year(s) Of Engagement Activity 2017
URL http://programme.ias2017.org/People/PeopleDetailStandalone/4291
Description BBC World Service interview for World Update programme 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Interview concenring ongoing burden Cryptococcal meningitis
Need for sustainable treatments and improved antifungal drug access for Sub Saharan Africa
Year(s) Of Engagement Activity 2016