London School of Hygiene & Tropical Medicine

The London School of Hygiene & Tropical Medicine is to lead a major new clinical trial in Southern and East Africa which aims to tackle the high number of deaths caused by HIV-associated cryptococcal meningitis (CM), a severe fungal infection of the brain that occurs in patients with advanced HIV infection.

AMBITION hopes to identify a new very clinically-effective and cost-effective treatment for CM using very high single doses of the drug Liposomal Amphotericin B (Ambisome). The project will recruit 850 patients across six African sites, making it the largest ever CM trial. Recruitment will commence in late 2017.

Joe Jarvis, Associate Professor from the London School of Hygiene & Tropical Medicine and Research Associate at the Botswana Harvard AIDS Institute Partnership is AMBITION’s Chief Investigator. He said: “Cryptococcal meningitis is a leading cause of death in HIV-infected individuals in Africa. Current drugs used to treat it are either ineffective or cost too much to administer. There is an urgent need to find novel treatments that can be safely given in low resource settings where the majority of cryptococcal meningitis cases occur. Being able to effectively treat this severe infection with a single high dose of liposomal amphotericin would revolutionise the management of late stage HIV-infection in Africa, and has the potential to save many thousands of lives every year.”

The €10m (£9m) AMBITION-cm Phase III project is funded by the European & Developing Countries Clinical Trials Partnership (EDCTP), the UK Joint Global Health Trials Scheme - a partnership of the Medical Research Council, the Department for International Development, the National Institute of Health Research, the Wellcome Trust and the Swedish International Development Agency. The EDCTP acts as the principal funder for the project. Sponsored by the School, it will be conducted with partners across Europe and Africa.

The study consortium is comprised of Institut Pasteur, University of Liverpool, Liverpool School of Tropical Medicine, and St. George’s University of London in Europe, and the University of Cape Town, the Botswana-Harvard Partnership, the University of Zimbabwe,  UNC Project Malawi (Lilongwe), Malawi-Liverpool-Wellcome Trust Unit in Malawi (affiliated to the Liverpool School of Tropical Medicine), and the Infectious Diseases Institute, Uganda. The AMBITION-cm project is part of the EDCTP2 Programme which is supported by the European Union.

Dr Michael Makanga, EDCTP Executive Director: “It is heartening and timely to support a project such as AMBITION-cm which stands for much of what we aim for: impact on the lives of populations suffering from poverty-related infectious diseases with no or limited treatment options, excellent collaborative international clinical research, and research partnerships with institutions in sub-Saharan Africa.”

Treatment of HIV-associated cryptococcal meningitis

Early mortality in HIV programmes in Africa is considerably greater than in high-income countries and almost 20% of deaths are directly attributable to CM. It is estimated that roughly 180,000 people die from CM each year around the globe, with approximately 75% of these deaths occurring in sub-Saharan Africa.

The two treatments currently available to treat CM are not fit for purpose. Fluconazole is linked with death rates of approximately 60%, and treatment with the drug amphotericin-B-deoxycholate, while more effective, involves 14 days of intravenous infusions given in hospital, making it difficult and costly to administer. It also can cause side effects such as kidney failure and low blood count. This means close laboratory monitoring is essential, which is either not available or prohibitively expensive in most of Africa.

Liposomal amphotericin (Ambisome) is a modified form of amphotericin and is considerably less toxic. It is effective in treating CM and widely available. Nonetheless, its use has been curtailed by the high cost of therapy which lasts two weeks. However, evidence suggests that much shorter courses of Ambisome may be effective in the treatment of cryptococcal meningitis. A recent Phase II study completed by the AMBITION team has confirmed that a single, high dose of Ambisome is comparable to two weeks of a standard dose in terms of the rate of clearance of cryptococcal infection. The AMBITION Phase III trial will take this research forward to identify the most effective and cost-effective treatment for CM using clinical outcomes.