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.
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

Beale MA
(2015)
Genotypic Diversity Is Associated with Clinical Outcome and Phenotype in Cryptococcal Meningitis across Southern Africa.
in PLoS neglected tropical diseases

Bicanic T
(2007)
Fungal burden, early fungicidal activity, and outcome in cryptococcal meningitis in antiretroviral-naive or antiretroviral-experienced patients treated with amphotericin B or fluconazole.
in Clinical infectious diseases : an official publication of the Infectious Diseases Society of America

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

Bicanic T
(2015)
Toxicity of Amphotericin B Deoxycholate-Based Induction Therapy in Patients with HIV-Associated Cryptococcal Meningitis.
in Antimicrobial agents and chemotherapy

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

Bicanic T
(2009)
Relationship of cerebrospinal fluid pressure, fungal burden and outcome in patients with cryptococcal meningitis undergoing serial lumbar punctures.
in AIDS (London, England)

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

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

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
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 | Public |
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 | Academic/University |
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. |
URL | http://www.isrctn.com/ISRCTN68133435 |
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 |
URL | http://www.isrctn.com/ISRCTN02725351 |
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 |
URL | http://www.isrctn.com/ISRCTN45035509 |
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 |
URL | http://www.isrctn.com/ISRCTN02725351 |