Cryptococcal meningitis: Validation of new therapeutic regimens

The results of the ACTA trial were presented at the 9th IAS Conference on HIV Science held in Paris from 23 to 26 July 2017 . Professor Thomas Harrison and his colleagues at St George's University of London, the Institut Pasteur in Paris, Paris Descartes University (Hôpital Necker-Enfants Malades), the ANRS site in Cameroon, and the MRC sites in Malawi, Tanzania, and Zambia show in this trial that new therapeutic regimens are of benefit in HIV-infected patients with cryptococcal meningitis.

Cryptococcal meningitis is a serious fungal infection frequent in immunosuppressed people, in particular AIDS patients. Despite increased use globally of antiretroviral treatment of people living with HIV, cryptococcal disease has not declined in incidence and accounts for over 180 000 deaths worldwide every year.

The ACTA trial in 721 HIV-infected patients with cryptococcal meningitis compared three 1- or 2-week induction treatments of this fungal infection, followed by 8- to 9-week consolidation therapy. The most effective was 1-week induction treatment comprising daily infusion of amphotericin B and oral flucytosine followed by two weeks of fluconazole and flucytosine. Ten weeks after treatment initiation, mortality had dropped significantly compared with the therapeutic regimen recommended hitherto in several countries. These results are reported in the 15 March 2018 issue of the New England Journal of Medicine.

The new therapeutic regimens highlighted by the ACTA trial could potentially save over 80 000 lives a year. In the light of these findings, the WHO has just changed its guidelines for the management of cryptococcal disease and recommends 1-week induction treatment based on amphotericin B and flucytosine. If amphotericin is unavailable, high-dose fluconazole combined with oral flucytosine should be proposed. Olivier Lortholary and Charles Kouanfack, the investigators for the ANRS Cameroon site concluded that "These results will have a major impact on AIDS-related mortality in Africa. They show that flucytosine should rapidly be made available in resource-limited countries."

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Antifungal Combinations for Treatment of Cryptococcal Meningitis in Africa S. Molloy1, C. Kanyama2, R. Heyderman3,4,5, A. Loyse1, C. Kouanfack6, D. Chanda7, S. Mfinanga8, E. Temfack9,10, S. Lakhi11, S. Lesikari8, A. Chan12, N. Stone1,7, N. Kalata4,5, N. Karunaharan1,7, K. Gaskell4,5, M. Peirse4,5, J. Ellis4,5, C. Chawinga2, S. Lontsi6, J.-G. Ndong6, P. Bright7,12, D. Lupiya12, T. Chen13, J. Bradley14, J. Adams1, C. van der Horst2,15, J. van Oosterhout12, V. Sini6, Y.N. Mapoure9, P. Mwaba7, T. Bicanic1, D. Lalloo13, D. Wang13, M. Hosseinipour2,15, O. Lortholary10,16, S. Jaffar13, T. Harrison1, ACTA Trial Study Team. 1) St George's University of London, Centre for Global Health, Institute for Infection and Immunity, London, United Kingdom, 2) UNC Project, Kamuzu Central Hospital, Lilongwe, Malawi, 3) University College London, London, United Kingdom, 4) Malawi-Liverpool-Wellcome Trust Clinical Research Programme, Blantyre, Malawi, 5) College of Medicine, Queen Elizabeth Hospital, Blantyre, Malawi, 6) Hopital Central Yaounde/Site ANRS Cameroun, Yaounde, Cameroon, 7) Institute for Medical Research and Training, University Teaching Hospital, Lusaka, Zambia, 8) National Institute Medical Research, Muhimbili Medical Research Centre, Dar Es Salaam, Tanzania, United Republic of, 9) Douala General Hospital, Douala, Cameroon,10) Institut Pasteur, Molecular Mycology Unit (E.T., O.L.), and Paris Descartes University, Necker Pasteur Center for Infectious Diseases and Tropical Medicine, IHU Imagine, Assistance Publique-Hopitaux de Paris, 11) University Teaching Hospital, Lusaka, Zambia, 12) Dignitas International, Zomba Hospital, Zomba, Malawi, 13) Liverpool School of Tropical Medicine, Liverpool, United Kingdom, 14) London School of Hygiene and Tropical Medicine, London, United Kingdom, 15) University of North Carolina, Chapel Hill, United States, 16) Necker Pasteur Center for Infectious Diseases and Tropical Medicine, Paris, France.