HIV/meningitis: a treatment adapted for resource-limited countries

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The “Advancing Cryptococcal Meningitis Treatment for Africa” (ACTA) trial, supported by the Medical Research Council (MRC) and ANRS, and carried out in 4 African countries has demonstrated the non-inferiority of two antifungal combinations for the inductive treatment of HIV-associated cryptococcal meningitis. These two treatments would reduce the use as well as the duration of administration of amphotericin B, an antifungal which though effective, is not readily available in many African settings and sometimes results in serious side effects. These findings are crucial because cryptococcal meningitis is a serious disease responsible for over 100 000 deaths per year in HIV-infected adults in Africa. This trial was conducted by Professor Thomas Harrison and colleagues at St George's University of London, Institut Pasteur in Paris, the ANRS sites in Cameroon, and MRC sites of Malawi, Tanzania, and Zambia.  Initial results will be presented as an oral communication on July 24th 2017, during the 9th Conference on HIV Science (IAS 2017), organized by the International AIDS Society and the ANRS in Paris from July 23rd to 26th 2017.

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Cryptococcal meningitis (CM) is a serious fungal infection common in severely immune compromised people, particularly those with AIDS. Despite increased global antiretroviral therapy coverage the incidence of HIV-associated cryptococcal meningitis has not decreased and is responsible for over 100 000 deaths every year in Africa1. Present standard World Health Organization (WHO) inductive antifungal therapy for CM relies on daily infusions of amphotericin B (AmB) plus oral flucytosine (5-FC) for 2 weeks, followed by a consolidation and maintenance treatment with oral fluconazole (FLU).AmB is an effective antifungal, which is scarce in resource-limited countries and sometimes results in serious side effects.

The ACTA “Advancing Cryptococcal Meningitis Treatment for Africa” trial, sponsored by the Medical Research Council (UK) and the ANRS (France), was conducted on 721 HIV-infected patients with cryptococcal meningitis, by Professor Thomas Harrison and colleagues of St George's University of London (SGUL), the Institut Pasteur (Paris), the ANRS sites in Cameroon and the MRC sites in Malawi, Tanzania, and Zambia. It aimed at evaluating the non-inferiority of two induction treatment combinations to the one presently recommended by the WHO. These treatments include a two-week oral combination of FLU and 5-FC without AmB, and a one-week AmB containing regimen (combined to either 5FC or FLU). Following inductive treatment, all trial patients took 8 – 9 weeks consolidation fluconazole-based treatment for a follow up period of 10 weeks and maintenance treatment according to local national guidelines of each trial site. 

Evaluation at 10 weeks revealed that one-week combination of AmB + 5-FC was associated with the lowest mortality (24%). This and the 5FC + FLU arm were more effective and better tolerated than the WHO currently recommended inductive treatment (2 weeks AmB + 5-FC) for patients with HIV-associated cryptococcal meningitis. In addition, these treatments shorten or could even obviate the need for administration of AmB, and are quite promising to be cost-effective in resource-limited settings. The ACTA trial results will be presented for the first time as an oral communication by Dr Sile Molloy (St George's, University of London) on Monday July 24th 2017 during the 9th Conference on HIV Science (IAS 2017), organized by the International AIDS Society  and the ANRS in Paris from July 23rd to 26th 2017.

1 Radha Rajasingham et al The Lancet HIV, 5 may 2017
 

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A randomized controlled trial for the treatment of HIV-associated cryptococcal meningitis in Africa: oral fluconazole plus flucytosine or one week amphotericinbased therapy vs two weeks amphotericin-based therapy. The ACTA Trial.
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) Paris Descartes University/Institut Pasteur, Paris, France, 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.