Ms Heather Bresch
Chief Executive Officer, Mylan
cc: Mr Anil Soni
Head of Global Infectious Diseases, Mylan
Dear Ms Bresch,
Evidence supporting the use of flucytosine (5-FC) for the treatment of cryptococcal meningitis (CM), a leading cause of AIDS-related death, is overwhelming. The results of the ACTA trial, published in March 2018, demonstrated firstly that a one-week course of amphotericin B deoxycholate (AmB) in combination with 5-FC could reduce mortality to 24%, just over one-third of the current 70% mortality rate in many low- and middle-income countries (LMICs). Secondly, an all oral, easy to provide treatment of two weeks’ 5-FC plus fluconazole (FLU) also performed very well and cut mortality down to 35%. Lastly, the ACTA trial clearly showed that 5-FC is preferred over fluconazole for use in combination with AmB.
These optimised strategies (one week of AmB + 5-FC or two weeks of 5-FC + FLU) are included in the 2018 WHO guidelines on cryptococcal disease and will become the new gold standard treatments for resource-limited settings. The 2017 WHO guidelines on managing advanced HIV disease puts a focus on reducing the high mortality rate of people living with HIV, approximately one-third of which have advanced disease when presenting to care1. Momentum from WHO, international public health organisations, international donors, leading program implementers and local Ministries of Health (MOH) will only increase around tackling advanced HIV disease in 2018 and beyond.
To date, 5-FC remains unregistered and unavailable in African and Asian LMICs, which have the highest rates of CM. According to the latest data, approximately 181,000 people living with HIV die of cryptococcal disease globally, without access to the most basic essential treatments including 5-FC. The majority of these people live in sub-Saharan African countries. Furthermore, the current dosing schedule for 5-FC (100 mg/kg/day in 4 divided doses) is problematic for resource-limited settings. The development of a once or twice daily slow-release formulation of 5-FC is a priority; however, this should not detract from registration and improving access to the current formulations of 5-FC.
On March 14, 2018, the approval of Mylan’s 5-FC by the WHO Prequalified Medicines List opened the avenue for accelerated registration in many LMICs. In light of this, and the urgent need for 5-FC in these contexts to reduce mortality due to advanced HIV disease, members of the cryptoMAG group, together with leading researchers/clinicians and local Ministries of Health call upon Mylan to:
- Initiate registration of Pre-Qualified (PQ) or stringent regulatory agency (SRA)-approved 5-FC formulations in high burden LMICs, including South Africa, through the WHO Collaborative Procedure for Accelerated Registration for prequalified or SRA-approved products;
- Prioritize the development of a slow-release formulation of 5-FC;
- Ensure capacity for sustainable supply to meet country demands with implementation and scale up.
The cryptoMAG group looks forward to continuing the discussion on access and development of flucytosine for LMICs,
Yours sincerely,
Dr Angela Loyse
Senior Academic Clinical Lecturer
Honorary Infectious Disease Consultant
CryptoMAG chair
Jessica Burry
MSF Access Campaign
MSF Access Campaign
Mosepele Mosepele MD, MSc
Chair, Department of Internal Medicine, University of Botswana
Chair, Africa Meningitis Trials Network
University Teaching Hospital
Gaborone, Botswana
Dr Suzaan Marais
Consultant Neurologist
Inkosi Albert Luthuli Central Hospital
Durban, South Africa
Mina C. Hosseinipour, MD, MPH
Professor of Medicine
University of North Carolina at Chapel Hill
Scientific Director
UNC Project-Malawi
Timothée Boyer Chammard, MD
Infectious Diseases Physician and Clinical Researcher
AMBITION-cm clinical advisor
Molecular Mycology Unit, Institut Pasteur
Service des Maladies Infectieuses et Tropicales, Hôpital Necker-Enfants malades
Centre d’Infectiologie Necker-Pasteur
Paris, France
Olivier Lortholary, MD, PhD
Professor, Paris Descartes University
IHU Imagine
Service des Maladies Infectieuses et Tropicales, Hôpital Necker-Enfants malades, Paris
Centre d’Infectiologie Necker-Pasteur
Deputy Director of the National Reference Center for Mycoses and Antifungals
Molecular Mycology Unit, Institut Pasteur
Paris, France
Dr Douglas Wilson
Head of Internal Medicine at Edendale Hospital
Pietermaritzburg, South Africa
Nabila Youssouf, PhD
Ambiton-cm Trial Manager
London School of Hygiene and Tropical Medicine/ Botswana Harvard HIV Partnership
Princess Marina Hospital
Gaborone, Botswana
Dr Elisabeth Szumilin
HIV advisor, medical department.
Médecins Sans Frontières
Paris, France
Dr Nelesh Govender
National Institute for Communicable Diseases
South Africa
Dr Síle F Molloy
Centre for Global Health
Institute for Infection and Immunity
St George's University of London)
Jeremy Day MA PhD FRCP
Head, CNS-HIV Infections Research Group
Ho Chi Minh CityVietnam
Professor of Infectious Diseases
Centre for Tropical Medicine
Nuffield Department of Medicine
University of Oxford
United Kingdom
In partnership with
The Hospital for Tropical Diseases
Ho Chi Minh City
Dr David W. Denning
Chief Executive
Global Action Fund for Fungal Infections
Professor of Infectious Diseases in Global Health, University of Manchester
Rue Le Corbusier 12, 1208 Geneva, Switzerland
Bridge House, Ashley Road, Hale, Altrincham WA14 2UT, UK
Professor Thomas S Harrison
Centre for Global Health
St Georges University of London
Jennifer Cohn, MD MPH
Assistant Professor, Division of Infectious Diseases
University of Pennsylvania
Juan Luis Rodriguez Tudela, MD, PhD
Senior advisor, GAFFI
Genève, Switzerland
Marcio L. Rodrigues, PhD
Oswaldo Cruz Foundation (Fiocruz)
Brazil
Ms Philippa Griffin
Financial & Administrative Project Manager, EDCTP-funded AMBITION
London School of Hygiene and Tropical Medicine
David Lee Chin, MD
Director Technical Strategy & Quality
Pharmaceuticals and Health Technologies Group
Management Sciences for Health
Arlington, VA
Henry C Mwandumba, MBChB (Hons), DTM & H, FRCP (UK), FCP (ECSA), PhD
Deputy Director, MLW
Reader & MRC/DfID African Research Leader
Consultant Physician in General (Internal) Medicine & Infectious Diseases
Malawi-Liverpool-Wellcome Trust Clinical Research Programme (MLW)
Malawi
Joseph Jarvis
Professor of Tropical Medicine and International Health
London School of Hygiene and Tropical Medicine
Dr Cecilia Kanyama
Physician Investigator
UNC Project
Lilongwe. Malawi
Prof Dr Sayoki G Mfinanga,
Chief Research Scientist and Director
Muhimbili Medical Research Centre National Institute for Medical Research (NIMR)
Professor of Global Health: Liverpool School Tropical Medicine,
Lecturer: Muhimbili University of Health and Allied Sciences
Graeme Meintjes
Professor of Medicine
University of Cape Town
Thuy Le, MD, DPhil
Associate Professor of Medicine (pending)
Division of Infectious Diseases and International Health
Duke University School of Medicine
Oxford University Clinical Research Unit in Vietnam
In partnership with the Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam
David Meya
Associate Professor
Infectious Diseases Institute
Dr Duncan M Chanda
Physician/Infectious Diseases Registrar
University Teaching Hospital
University of Zambia School of Medicine
Lusaka, Zambia
1Calmy A et al. The Persistent Challenge of Advanced HIV Disease and AIDS in the Era of Antiretroviral Therapy. CID 2018:66 (Suppl 2). Online: The Persistent Challenge of Advanced HIV Disease and AIDS in the Era of Antiretroviral Therapy
