Optimizing antifungal therapy for HIV-associated cryptococcal meningitis in Africa

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

Abstract

We will test the activity of alternative doses and combinations of antifungal drugs in the treatment of cryptococcal meningitis in Africa. Cryptococcal meningitis is a very common infection and cause of death in patients with HIV and AIDS in Africa.
Current drug treatment takes a long time to control the infection. In addition, improvements in treatment have been slow because traditional trials of treatment need many patients and are therefore slow and expensive to undertake. However, we have now developed a new way to test the activity of new drug combinations and dosages in small numbers of patients, by measuring the rate of killing of the organism causing the infection.
Using this method, we will test alternative drug combinations and dosages in patients that laboratory testing and animal experiments have suggested will be more active and also safe. Parallel studies will be done: to optimize doses and combinations with the intravenous drug, amphotericin B, and with the oral drug, fluconazole.
The results of the studies will be used to determine how best to use the drugs that are currently available, and to select the best combinations for further trials to find out if the new combinations can reduce the number of deaths caused by this infection.

Technical Summary

Cryptococcal meningitis remains a very common infection, and the cause of death in 13-44% of HIV-infected patients in Africa. Current antifungal drug regimens still frequently take more than two weeks to sterilise the cerebrospinal fluid (CSF), and improvements in treatment have been slow due to the large number of patients needed for clinical endpoint trials. However, we have now developed and validated a new and more powerful marker of treatment response, the rate of decrease in cryptococcal colony-forming units (CFU) in cerebrospinal fluid (CSF) over the first 2 weeks, or early fungicidal activity, based on serial quantitative cultures of CSF (Brouwer et al. Lancet 2004; 363:1764). Pre-clinical and limited clinical data suggest novel drug combinations and higher than standard doses of some antifungal drugs may be more effective in treatment of cryptococcosis, without a significant increase in toxicity. Therefore, using this new endpoint, the objective of the proposal is to optimise initial antifungal treatment for HIV-associated cryptococcal meningitis in Africa. In a centre where facilities make amphotericin B-based therapy possible, randomized studies will determine the optimal amphotericin B (AmB) dose(0.7 mg/kg/d versus 1 mg/kg/d), and the optimal second drug and dose (flucytosine 100 mg/kg/d versus fluconazole 800 mg/d versus fluconazole 1200 mg/d). A second, parallel, dose-ranging, cohort study, in a centre, like many in Africa, where safe amphotericin B-based therapy is currently not possible and fluconazole is the only option for treatment, will define the dose-activity relationship for fluconazole monotherapy as initial therapy. The power of the fungicidal activity endpoint means the aims can be achieved with relatively few patients, facilitating close hands-on supervision. Enrolment is underway in pilot phase studies at both sites, confirming the feasibility of the work at these sites and the estimates for recruitment. The results of the studies will be used to (a) determine best use of currently available drugs for treatment of cryptococcal meningitis in Africa (b) taking account of fungicidal activity results, safety, and accessability issues, select the best regimens for testing in a phase 3, clinical endpoint trial.

Publications

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Bicanic T (2009) Immune reconstitution inflammatory syndrome in HIV-associated cryptococcal meningitis: a prospective study. in Journal of acquired immune deficiency syndromes (1999)

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Bicanic T (2008) High-dose amphotericin B with flucytosine for the treatment of cryptococcal meningitis in HIV-infected patients: a randomized trial. in Clinical infectious diseases : an official publication of the Infectious Diseases Society of America

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Bicanic T (2006) Symptomatic relapse of HIV-associated cryptococcal meningitis after initial fluconazole monotherapy: the role of fluconazole resistance and immune reconstitution. in Clinical infectious diseases : an official publication of the Infectious Diseases Society of America

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Bicanic T (2009) Independent association between rate of clearance of infection and clinical outcome of HIV-associated cryptococcal meningitis: analysis of a combined cohort of 262 patients. in Clinical infectious diseases : an official publication of the Infectious Diseases Society of America

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Conveners McCarthy K And Meintjes G; Bicanic T And Harrison TS Members Of The Writing Committee (2007) Guidelines for the prevention, diagnosis and management of cryptococcal meningitis and disseminated cryptococcosis in HIV-infected patients in Southern African J HIV Med

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Jackson A And Harrison TS (2009) Management of cryptococcal meningitis: What is important to know? in J Invasive Fungal Infections

 
Description 2013 - Updated Southern African HIV Clinicians Cryptococcal guidelines
Geographic Reach Africa 
Policy Influence Type Membership of a guidance committee
Impact widened use of best practice across the region
 
Description IDSA (Infectious Diseases Society of America) Cryptococcosis guidelines update 2010
Geographic Reach Multiple continents/international 
Policy Influence Type Membership of a guidance committee
Impact World-wide influence on management cryptococcal infection. Results of studies under the MRC funding were incorporated - especially into section on optimal management in resource limited settings which was written by TH
 
Description Southern African HIV Clinicians guidelines for management cryptococcal infection
Geographic Reach Africa 
Policy Influence Type Membership of a guidance committee
Impact Wide impact on management cryptococcal infection
 
Description WHO Rapid Advice: Diagnosis prevention and management of cryptococcal disease in HIV-infected adults, adolescents and children
Geographic Reach Multiple continents/international 
Policy Influence Type Membership of a guidance committee
Impact Widespread adoption best practice in management Results from MRC funding played major role in shaping the guidelines TH was on writing committee, TB and JJ was on peer-review committee
 
Description DFID Malawi Project Grant
Amount £102,000 (GBP)
Organisation Government of the UK 
Department Department for International Development (DfID)
Sector Public
Country United Kingdom
Start  
 
Description MRC Global Health Trials
Amount £3,200,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start  
End 03/2018
 
Description Wellcome Trust Clinical Training Fellowship, NL
Amount £386,695 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 06/2011 
End 06/2014
 
Description Wellcome Trust Intermediate Clinical Fellowship, TB
Amount £446,692 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start  
 
Title Early Fungicidal Activity as outcome measure for phase II trials 
Description Rate of clearance of infection based serial quantitative cultures of CSF Technique further validated and association with clinical outcome demonstrated as result of this MRC funding 
Type Of Material Physiological assessment or outcome measure 
Year Produced 2006 
Provided To Others? Yes  
Impact Publications listed above Technique is now being taken up by other groups - has been included in 2 (one recently completed, one just started) phase III trials 
 
Title cryptococcal isolates 
Description cryptococcal isolates 
Type Of Material Database/Collection of Data/Biological Samples 
Year Produced 2007 
Provided To Others? Yes  
Impact not yet realised work is in progress on 1. Molecular epidemiology of African cryptococcal isolates 2. Studies on associations of pathogen genetic and phenotypic diversity with clinical parameters and outcomes (TB, Wellcome Fellowship) 
 
Description Jooste Hospital, Dept Medicine UCT, Desmond Tutu HIV Centre, Cape Town 
Organisation University of Cape Town
Department Desmond Tutu HIV Centre
Country South Africa 
Sector Public 
PI Contribution A Phase II study was designed, performed, analysed, and written up by our team in collaboration with the Cape Town site. See publications
Collaborator Contribution South African study site for phase II studies
Impact PMID: 16983622 PMID: 17554704 PMID: 18505387 PMID: 19279443 PMID: 19365271 PMID: 19451796 PMID: 19952714 PMID: 19613840
 
Description Mbarara University Hospital Uganda 
Organisation Mbarara Community Hospital
Country Uganda 
Sector Hospitals 
PI Contribution A Phase II study was designed, performed, analysed, and written up by our team in collaboration with the Mbarara site. See publications
Collaborator Contribution Mbarara University Hospital was study site for phase II study, now published: PMID: 18990067 This data also contributed importantly to PMID: 19613840
Impact PMID: 18990067 PMID: 19613840 Further manuscript submitted
 
Description Univeristy of North Carolina (UNC) Project Lilongwe Malawi 
Organisation University of North Carolina at Chapel Hill
Country United States 
Sector Academic/University 
PI Contribution A Phase II study was designed, performed, analysed, and written up by our team in collaboration with the UNC project site. See publication in press
Collaborator Contribution UNC project Lilongwe was study site for phase II study, now completed (20038244) and a further study with manuscript submitted
Impact Combination flucytosine and high-dose fluconazole compared with fluconazole monotherpay for the treatment of cryptococcal meningitis: A randomized trial in Malawi. Nussbaum et al Clin Infect Dis 2010 [20038244] Jackson A and Harrison TS. Management of cryptococcal meningitis: What is important to know? J Invasive Fungal Infection 2009 3:34-40. Further manuscript submitted.
Start Year 2007
 
Title More rapidly fungicidal amphotericin B-based antifungal regimen 
Description More rapidly fungicidal amphotericin B-based antifungal regimen. High dose amphotericin B (1 mg/kg/d) was shown to be more rapidly active than standard 0.7 mg/kg/d dosing 
Type Therapeutic Intervention - Drug
Current Stage Of Development Late clinical evaluation
Year Development Stage Completed 2008
Development Status Under active development/distribution
Clinical Trial? Yes
Impact A dose range of 0.7 to 1 mg/kg/d for amphotericin B has, as a result, been kept in current updated IDSA guidelines. A large phase trial in which the higher dose of amphotericin B was used will be reported shortly. 
 
Title Optimised oral antifungal regimen 
Description High dose Fluconazole plus flucytosine for initial therapy for HIV-related cryptococcal meningitis. Funding agreed from MRC for evaluation in phase III trial 
Type Therapeutic Intervention - Drug
Current Stage Of Development Late clinical evaluation
Year Development Stage Completed 2009
Development Status Under active development/distribution
Clinical Trial? Yes
Impact Adopted as preferred oral regimen if amphotericin B not available in updated IDSA cryptococcal guideline (world wide most influential guideline) Clin Infect Dis 2010 50:291-322 and by WHO guideline released Nov 2011. Higher dose fluconazole adopted by South Africa Clinicians guideline and DoH South Africa But impact not yet fully realised Will be used to advocate for wider access to flucytosine in resource limited settings And as rational basis for phase III trial Potential to reduce disease burden 
 
Title Phase III trial - ACTA 
Description phase III clinical trial Award G0501476 led directly to this trial and further funding from MRC - award G1100814 
Type Therapeutic Intervention - Drug
Current Stage Of Development Late clinical evaluation
Year Development Stage Completed 2011
Development Status Under active development/distribution
Clinical Trial? Yes
Impact under evaluation 
 
Title Short course amphotericin B for cryptococcal meningitis 
Description Short course (one week) amphotericin B induction for cryptococcal meningitis is much better tolerated than standard 2 week induction and not associated with any decline in the rate of clearance of infection during the second week of therapy. It may be much more effective than oral fluconazole - still widely used - and much more widely implementable than standard 2 week induction regimens. This early clinical evaluation was funded from MRC 
Type Therapeutic Intervention - Drug
Current Stage Of Development Late clinical evaluation
Year Development Stage Completed 2010
Development Status Under active development/distribution
Clinical Trial? Yes
Impact Publications are out. Improved survival vs fluconazole in phase II. Funding has been agreed from MRC to test in a phase III trial - against standard 2 week induction, and optimised oral therapy - in resource limited settings