A Randomised, Open-Label, Comparative Study of Itraconazole vs. Amphotericin B for the Induction Therapy of Penicilliosi

Lead Research Organisation: University of Oxford
Department Name: Clinical Medicine

Abstract

Penicilliosis is one of the most common and life-threatening infections in people infected with Human Immunodeficiency Virus (HIV) in Asia. Despite the fast growing numbers of people infected with HIV in Asia where over one half of the world?s population lives, there has not been any clinical trials to evaluate the treatment of penicilliosis. The current international guideline recommends treatment with amphotericin B for 2 weeks followed by itraconazole for 10 weeks. This guideline is based on one observational study without a comparator group and is generally considered weak evidence in medicine. Further, amphotericin B is either unavailable or available in only selected major tertiary care centres in Asia, can only be given through a vein daily over 6 hours of infusion, has many side effects, and a 2 week treatment in Viet Nam for example would cost an average patient approximately 5 times his monthly salary . Itraconazole, on the other hand, appears to be a good alternative drug that is widely available in local pharmacies in the provinces and district clinics, can be given by mouth, is generally well tolerated, and costs a fraction of the price of amphotericin B. Available data from Viet Nam, Thailand, Hong Kong and India suggest that itraconazole may have similar treatment efficacy compared to amphotericin B. Therefore we will conduct a clinical trial comparing the relative effectiveness of itraconazole versus amphotericin in the treatment of penicilliosis. A total of 440 adults who are diagnosed with penicilliosis will be invited to participate in the study and will be randomly assigned to either itraconazole or amphotericin B during the first 2 week of therapy. Survival rates will be compared in the 2 treatment arms at the end of 2 weeks and in 6 months. This will be the landmark study for treatment of penicilliosis. The results will either change or support the current national and international guidelines for treatment of penicilliosis. If the investigators are correct, that itraconazole is proven to be at least as effective as amphotericin B, but is much cheaper, better tolerated, and easier to administer, then itraconazole represents a better treatment choice for the patients with penicilliosis while saving significant costs for the patients and the health care system. If the investigators are correct, then itraconazole can be given immediately for patients in the local provincial and district clinics, ensuring earlier treatment and better outcomes for patients.

Technical Summary

Penicilliosis is emerging as one of the three most common HIV-associated opportunistic infections in Asia. Despite the rapid growing HIV epidemics in a region that houses one half of the worlds population, there has not been a single randomised controlled trial to evaluate the treatment of penicilliosis. The current recommendation of amphotericin B for 2 weeks followed by itraconazole for 10 weeks is based on one non-comparative study [1]. Amphotericin B has extremely limited availability, has significant side effects, needs to adminstered through a vein daily over 6 hours of infusion, and is prohibitively expensive in most areas of Asia. Itraconazole, on the other hand, is widely available in local pharmacies throughout Asia, can be given orally at a fraction of the price. Further, data from available case series suggest that itraconazole and amphotericin B have similar efficacies. We therefore propose to conduct a randomised, open-label, non-inferiority trial of the efficacy of itraconazole versus amphotericin B for penicilliosis. 440 adults from in and outpatient settings with culture-confirmed penicilliosis will be recruited, randomly allocated to either itraconazole or amphotericin B treatment, monitored daily in-hospital for 2 weeks, and at monthly intervals for a total of 6 months. Primary outcome is mortality at 2 weeks. Secondary outcomes include 6-month survival, clinical response, relapse, drug tolerability, and economic costs. Correlates of interests include admission prognostic factors, time-to-culture-sterilization, fungicidal activities, pharmacokinetic parameters, and serologic titres. These results will be available within five years and will either change or support current treatment guidelines for penicilliosis.

Publications

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Beardsley J (2016) Adjunctive Dexamethasone in HIV-Associated Cryptococcal Meningitis. in The New England journal of medicine

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Bulterys PL (2013) Environmental predictors and incubation period of AIDS-associated penicillium marneffei infection in Ho Chi Minh City, Vietnam. in Clinical infectious diseases : an official publication of the Infectious Diseases Society of America

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Justin Beardley, Thuy Le (2014) CPE debate still unresolved

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Le T (2017) Itraconazole or Amphotericin B for Talaromycosis. in The New England journal of medicine

 
Description Member of the Infectious Disease Society of America for the diagnosis, treatment, and prevention of Talaromyces (Penicillium) marneffei infection
Geographic Reach Asia 
Policy Influence Type Membership of a guideline committee
 
Description Member of the World Health Organization Guideline Development Group for the diagnosis, treatment, and prevention of cryptococcal meningitis
Geographic Reach Multiple continents/international 
Policy Influence Type Membership of a guideline committee
Impact Member of the World Health Organization Guideline Development Group for the diagnosis, treatment, and prevention of cryptococcal meningitis. This updated guidelines provide the framework for reduction of morbidity and mortality associated with cryptococcal meningitis globally
URL http://www.who.int/hiv/pub/guidelines/advanced-HIV-disease/en/
 
Description Membership to the World Health Organization Working Group on Antiretroviral Treatment Options for Adults
Geographic Reach Multiple continents/international 
Policy Influence Type Participation in a advisory committee
 
Description This project led to membership to the World Health Organization Guideline Development Group on Management of Advanced HIV
Geographic Reach Asia 
Policy Influence Type Membership of a guideline committee
Impact The study provided the data on the mortality benefit of amphotericin B (compared to itraconazole) for treatment of talaromycosis. The study provided doctors in Vietnam with clinical trial evidence to use amphotericin B as initial treatment of talaromycosis in their clinical practice. The study team is meeting with Vietnam Ministry of Health later on this year to present the data and to advocate for improved procurement and access to amphotericin B therapy in Vietnam. The study will be cited in the 2017 updated WHO guidelines which will mention treatment options for talaromycosis.
 
Guideline Title Guidelines for managing advanced HIV disease and rapid initiation of antiretroviral therapy, July 2017. Geneva: World Health Organization
Description World Health Organization Guidelines for management of advanced HIV disease
Geographic Reach Asia 
Policy Influence Type Citation in clinical guidelines
Impact This guidelines provides evidence for a public health approach that enables HIV clinicians to provide a package of care that has the potential to reduce mortality in patients with advanced HIV in low and middle income countries
URL http://www.who.int/hiv/pub/guidelines/advanced-HIV-disease/en/
 
Description International Pilot Award
Amount $10,000 (USD)
Funding ID NIH P30 AI 027757 
Organisation University of Washington 
Sector Academic/University
Country United States
Start  
End 12/2012
 
Title Developement of a new real-time PCR assay for rapid diagnosis of penicilliosis 
Description This grant allows our group to develop a new real-time PCR assay that is able to detect pencilliosis within 5-6 hours in ~70% patients presenting without skin lesions, in whom conventional blood culture takes on average 5-7 days to diagnose the disease. 
Type Of Material Technology assay or reagent 
Provided To Others? No  
Impact Not yet. We are submitting the paper and hope to continue to develop the assay for clinical use. 
 
Title Development of a simple culture assay to quantify Penicillium marneffei in patient blood 
Description This funding has allowed us to develop a new simple assay to detect and quantify the fungal load in patient blood 
Type Of Material Technology assay or reagent 
Provided To Others? No  
Impact We are planning to publish this assay and hope that it can be used to monitor treatment response. 
 
Title Good Clinical Practice training and training in the conduct of clinical trials 
Description This project improves the capacity of the 5 hospitals in Vietnam to conduct clinical trials 
Type Of Material Improvements to research infrastructure 
Year Produced 2012 
Provided To Others? Yes  
Impact The five hospitals participated in this study has improved their capacity to conduct high standard clinical research 
 
Title Optimization of a serological assay for rapid diagnosis of talaromycosis 
Description The study enables the validation and optimization of a novel antigen detecting ELISA developed by our collaborators from Hong Kong for rapid and accurate diagnosis of talaromycosis 
Type Of Material Technology assay or reagent 
Provided To Others? No  
Impact This method has allowed reduction of time to diagnosis of talaromycosis to on average 4 days, enable early treatment and improves patient outcomes. 
 
Title This project has enabled 3 microbiology laboratories in the provinces of Vietnam to improve the capacity to diagnose talaromycosis by microscopy and culture 
Description This project has enabled 3 microbiology laboratories in the provinces of Vietnam to improve the capacity to diagnose talaromycosis by microscopy and culture 
Type Of Material Improvements to research infrastructure 
Year Produced 2015 
Provided To Others? Yes  
Impact The provincial hospitals participated in the study are now able to make microbiology-confirmed talarmycosis. They were only making clinical diagnosis before participating in the study. 
 
Title Talaromycosis patient database 
Description This study resulted in a largest prospectively collected data from more than 400 patients with culture-confirmed talaromycosis in the world to date. This rich dataset will allow multiple follow up evaluations of factors that impact patient outcomes as well as development of future models to predict outcomes in patients. 
Type Of Material Database/Collection of data 
Provided To Others? No  
Impact This dataset will be shared with the research communities once our policy on data sharing is finalized. 
 
Description Collaboration with Prof. William Hope to study the clinical phamacology of itraconazole and amphotericin B in treatment of penicilliosis 
Organisation University of Liverpool
Department Department of Molecular and Clinical Pharmacology
Country United Kingdom 
Sector Academic/University 
PI Contribution We designed and collected samples for the PK/PD study to determine therapeutic drug level and dosing intervals for treatment of penicilliosis
Collaborator Contribution Prof. William Hope's lab provided measurement of drug levels (in kind) and provided expertise in PK/PD modeling
Impact This collaboration is leading to a program grant application we are writing.
Start Year 2013
 
Description Havard Medical School AIDS Inititive in Vietnam (HAIVN) 
Organisation Harvard University
Country United States 
Sector Academic/University 
PI Contribution Collaborate in a randomized controlled trial to evaluate viral load monitoring to improve HIV treatment outcome in Vietnam
Collaborator Contribution HAIVN runs the clinical trials and provides clinical samples and data for us to study HIV drug resistance development.
Impact Ongoing
Start Year 2011
 
Description Partnership with Duke Mycology Research Unit, Duke University School of Medicine 
Organisation Duke University
Department School of Medicine Duke
Country United States 
Sector Academic/University 
PI Contribution Partnership to develop translational research capacity to study pathogenesis and therapeutics for endemic mycoses. We bring in clinical expertise and access to clinical isolates and clinical data to link pathogen genetics and biochemical functions to clinical outcomes
Collaborator Contribution Genetic and in vivo modeling research capacity
Impact funding to bring a Vietnamese researcher to Duke to develop basic science research capacity for 3 years
Start Year 2018
 
Description Partnership with the University of Hong Kong to develop serological diagnostics for talaromycosis 
Organisation University of Hong Kong
Country Hong Kong 
Sector Academic/University 
PI Contribution We have developed a sera bank of samples from patients with culture-confirmed talaromycosis and control patients without the disease that enable external validation and optimization of the antigen detecting Mp1p ELISA developed by the research group in Hong Kong
Collaborator Contribution Researcher at the University of Hong Kong (Prof. KY Yuen's group) has developed a monoclonal antibody-based ELISA that enable rapid diagnosis of talaromycosis. They will be providing antibodies for the validation of the assay to be performed in Vietnam, and will continue to collaborate on future grant applications to improve talaromycosis diagnostics.
Impact This collaboration has resulted in 2 abstracts presented at the Vietnam National Infectious Disease Conference, 2016 and the 24th Conference on Retroviruses and Opportunistic Infection in Seattle, 2017, as follows: 1. Thu NTM, Hien HTA, Tung NLN, Day J, Vinh Chau NV, Thwaites G, Chan FWC, Yuen KY, and Le T. Rapid serodiagnosis of Talaromyces marneffei infection. 5th Vietnam National Conference in Infectious Diseases and HIV. Sep 17-18, 2016. Hanoi, Vietnam. 2. Thu NTM, Chan JFW, Hien HTA, Tung NLN, Thanh NT, Day JN, Vinh Chau NV, Thwaites G, Woo P, Yuen KY, Le T. Clinical Performance of the Mp1p Immunoassay for Rapid Diagnosis of Talaromyces marneffei Infection. Conference of Retroviruses and Opportunistic Infections. Feb 13-16, 2017. Seattle, WA, USA.
Start Year 2015
 
Description Partnership with the University of Oxford Health Economic Centre 
Organisation University of Oxford
Department The James Martin Stem Cell Facility
Country United Kingdom 
Sector Academic/University 
PI Contribution This project has brought together a collaborative partnership with Prof. Alaistar Gray at the University of Oxford Health Economic Research Centre to conduct the cost and cost effective analyses of talaromycosis treatment
Collaborator Contribution Data analysis is ongoing
Impact An abstract submitted to a conference on Revolutions in the Economics of Health Systems in Boston July 2017
Start Year 2012
 
Description Vietnam Hawaii AIDS Research Partnership 
Organisation University of Hawaii
Department Hawaii Center for AIDS
Country United States 
Sector Hospitals 
PI Contribution Collaborate with The Hawaii Center for AIDS in a clinical trial evaluating hepatoxicity of raltegravir versus efavirenz in combination with tenofovir and emtricitabine for treatment of HIV in patients coinfected with hepatitis C. I run the clinical trial in Vietnam.
Collaborator Contribution Obtaining the funding and providing research laboratory expertise
Impact ongoing
Start Year 2012
 
Description The epidemiology, diagnosis and treatment of penicilliosis 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Local
Primary Audience Health professionals
Results and Impact I gave a talk by video conference to HIV doctors in Vietnam about penicilliosis epidemiology, diagnosis and treatment

This is part of continue education for health care professionals in Vietnam
Year(s) Of Engagement Activity 2012,2013