Adams, J

Bicanic, T

Bradley, J

Bright, P

Chan, A

Chanda, D

Chawinga, C

Chen, T

Ellis, J

Gaskell, K

Harrison, T

Heyderman, R

Hosseinipour, M

Jaffar, S

Kalata, N

Kanyama, C

Karunaharan, N

Kouanfack, C

Lakhi, S

Lalloo, D

Lesikari, S

Lontsi, S

Lortholary, O

Loyse, A

Lupiya, D

Mapoure, YN

Mfinanga, S

Molloy, S

Mwaba, P

Ndong, J-G

Peirse, M

Sini, V

Stone, N

Team, ACTATS

Temfack, E

van der Horst, C

van Oosterhout, JJ

Wang, D

St George's Online Research Archive

MOAX0201LBA randomized controlled trial for the treatment of HIV-associated cryptococcal meningitis in Africa: oralfluconazole plus flucytosine or one week amphotericin-based therapy versus two weeks amphotericin-basedtherapy. The ACTA TrialS 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; PBright7,12; D Lupiya12; T Chen13; J Bradley14; J Adams1; C van derHorst2,15; JJ van Oosterhout12; V Sini6; YN Mapoure9; P Mwaba7; TBicanic1; D Lalloo13; D Wang13; M Hosseinipour2,15; OLortholary10,16; S Jaffar13; T Harrison1; ACTA Trial Study Team1St George’s University of London, Centre for Global Health,Institute for Infection and Immunity, London, UK. 2UNC Project,Kamuzu Central Hospital, Lilongwe, Malawi. 3University CollegeLondon, London, UK. 4Malawi-Liverpool-Wellcome Trust ClinicalResearch Programme, Blantyre, Malawi. 5College of Medicine,Queen Elizabeth Hospital, Blantyre, Malawi. 6Hopital CentralYaounde/Site ANRS Cameroun, Yaounde, Cameroon. 7Institute forMedical Research and Training, University Teaching Hospital, Lusaka,Zambia. 8National Institute Medical Research, Muhimbili MedicalResearch Centre, Dar Es Salaam, Tanzania, United Republic of.9Douala General Hospital, Douala, Cameroon. 10Paris DescartesUniversity/Institut Pasteur, Paris, France. 11University TeachingHospital, Lusaka, Zambia. 12Dignitas International, Zomba Hospital,Zomba, Malawi. 13Liverpool School of Tropical Medicine, Liverpool,UK. 14London School of Hygiene and Tropical Medicine, London, UK.15University of North Carolina, Chapel Hill, USA. 16Necker PasteurCenter for Infectious Diseases and Tropical Medicine, Paris, FrancePresenting author email: smolloy@sgul.ac.ukBackground: Cryptococcal meningitis (CM) accounts for 10–20% ofHIV-related deaths and >100,000 deaths/year. Amphotericin (AmB)plus flucytosine for 2 weeks is considered the gold standard but isunavailable in resource-limited settings where fluconazole treat-ment predominates.Methods: Based on Phase II studies, we tested, against 2 weeksAmB-based treatment, 2 new strategies, which could be sustain-able in Africa, and more effective than fluconazole: optimized oraltherapy of high dose fluconazole plus flucytosine, and short(1 week) induction with AmB-based treatment. In the AmB arms,we compared fluconazole and flucytosine as adjunctive treatments.Between 2013 and 2016, 721 participants from 9 centres inMalawi, Zambia, Cameroon and Tanzania with first-episode CMwere randomized to:Oral (238): fluconazole (1200mg/day) plus flucytosine (100mg/kg/day) for 2 weeks.1-week (240): AmB (1mg/kg/d), plus fluconazole (1200mg/day), orflucytosine (100mg/kg/day) (ratio 1:1), for 7 days. Days 8–14,fluconazole 1200mg/day.2-weeks (243): AmB (1mg/kg/d) plus fluconazole (1200mg/day), orflucytosine (100mg/kg/day) (ratio 1:1), for 14 days.After 2 weeks, all received standard fluconazole consolidation. ARTwas started, or restarted, at 4 weeks, and patients followed-up to10 weeks.Results: Only 4 participants were lost-to-follow-up. Mortality at 2and 10 weeks for oral, 1-week and 2-weeks was 18%, 22%, 21%,and 35%, 36%, 40%, respectively. The upper 1-sided 95% CI limitsfor the difference in mortality comparing oral and 1-week against2 weeks AmB-based treatment (primary endpoint) were 3.0% and6.8%, below the pre-specified 10% non-inferiority margin. Hazardratios (95% CI) were 0.82 (0.54–1.25) and 1.01 (0.68–1.51) at 2,and 0.83 (0.61–1.13) and 0.89 (0.66–1.21) at 10 weeks, for oral and1-week versus 2-weeks, respectively. As adjunctive treatment withAmB, flucytosine was superior to fluconazole (HR(95% CI): 1.62(1.19–2.20) p = 0.002). One week AmB plus flucytosine had thelowest 10-week mortality (24%), significantly lower than all otherAmB arms (HR(95%CI): 0.56(0.35–0.91) comparing 1-week with 2-weeks AmB plus flucytosine). Side effects were more frequent with2 weeks AmB than with 1 week AmB, or oral therapy.Conclusions: One week AmB plus flucytosine and the oral combi-nation provide safe, effective and sustainable induction therapy inresource-limited settings. Flucytosine should be made widely avail-able for treatment of cryptococcosis.105Abstracts of the 9th IAS Conference on HIV Science (IAS 2017)Journal of the International AIDS Society 2017, 20 (Suppl 5) Late Breaker Oral AbstractsJournal InformationAbout the journalThe Journal of the International AIDS Society, an offi cial journal of the Society, provides a peer-reviewed, open access forum for essential and innovative HIV research, across all disciplines.All articles published by the Journal of the International AIDS Society are freely accessible online. The editorial decisions are made independently by the journal’s editors-in-chief.Email: editorial@jiasociety.orgWebsite: http://www.jiasociety.orgeISSN: 1758-2652PublisherInternational AIDS SocietyAvenue de France 231202 Geneva, SwitzerlandTel: +41 (0) 22 710 0800Email: info@iasociety.orgWebsite: http://www.iasociety.orgIndexing/abstractingThe Journal of the International AIDS Society is indexed in a variety of databases including PubMed, PubMed Central, MEDLINE, Science Citation Index Expanded and Google Scholar. The journal’s impact factor is 6.296 (*2016 Journal Citation Report® Science Edition - a Clarivate Analytics product).Advertising, sponsorship and donationsPlease contact the editorial offi ce if you are interested in advertising on our journal’s website. We also gladly receive inquiries on sponsorship and donations to support open access publications from authors in low- and middle-income countries.SupplementsThe Journal of the International AIDS Society publishes supplements, special issues and thematic series on own initiative or based on proposals by external organizations or authors. Inquiries can be sent to the editorial offi ce at editorial@jiasociety.org.  All articles submitted for publication in supplements are subject to peer review. Published supplements are fully searchable and freely accessible online and can also be produced in print.DisclaimerThe authors of the articles in this supplement carry the responsibility for the content and opinions expressed therein. The editors have made every effort to ensure that no inaccurate or misleading content or statements appear in this supplement. However, in all cases, the publisher, the editors and editorial board, and employees involved accept no liability for the consequences of any inaccurate or misleading content or statement.CopyrightThe content in this supplement is published under the Creative Commons Attribution 3.0 Unported (http:// http://creativecommons.org/licenses/by/3.0/) license. The license allows third parties to share the published work (copy, distribute, transmit) and to adapt it  under the condition that the authors are given credit, and that in the event of reuse or distribution, the terms of this license are made clear. Authors retain the copyright of their articles, with fi rst publication rights granted to the Journal of the International AIDS Society.EditorsEditors-in-Chief: Susan Kippax (Australia), Kenneth Mayer (United States), Papa Salif Sow (Senegal)Deputy Editors: Morna Cornell (South Africa)Anna Grimsrud (South Africa)Martin Holt (Australia)Luis Soto-Ramirez (Mexico)Iryna Zablotska (Australia)Executive Editor: Marlène Bras (Switzerland)Support Editor: Elisa de Castro Alvarez (Switzerland)Editorial Assistant: Mikko Lahdensuo (Switzerland)Editorial BoardLaith J Abu-Raddad (Qatar)Joseph Amon (United States)Jintanat Ananworanich (Thailand)Judith Auerbach (United States)Françoise Barré-Sinoussi (France)Linda-Gail Bekker (South Africa)Chris Beyrer (United States)Andrew Boulle (South Africa)Carlos Cáceres (Peru)Pedro Cahn (Argentina)Elizabeth Connick (United States)Mark Cotton (South Africa)Jocelyn DeJong (Lebanon)Diana Dickinson (Botswana)Sergii Dvoriak (Ukraine)Paul Flowers (United Kingdom)Nathan Ford (South Africa)Omar Galárraga (Mexico)Beatriz Grinsztejn (Brazil)Huldrych Günthard (Switzerland)Diane Havlir (United States)Adeeba Kamarulzaman (Malaysia)Rami Kantor (United States)Sukhontha Kongsin (Thailand)Kathleen MacQueen (United States)Navid Madani (United States)Nelly Mugo (Kenya)Paula Munderi (Uganda)Christy Newman (Australia)Richard Parker (United States)Linda Richter (South Africa)Jürgen Rockstroh (Germany)Sean Rourke (Canada)Naomi Rutenberg (United States)Gabriella Scarlatti (Italy)Mauro Schechter (Brazil)Lorraine Sherr (United Kingdom)Colette Smith (United Kingdom)Tim Spelman (Australia)Ndèye Coumba Touré-Kane (Senegal)Sten Vermund (United States)Ian Weller (United Kingdom)Alan Whiteside (South Africa)David Wilson (Australia)Iryna Zablotska (Australia)ZIAS_COVER_20-S5.indd   2 7/26/2017   6:21:53 PM

A randomized controlled trial for the treatment of HIV-associated cryptococcal meningitis in Africa: oral fluconazole plus flucytosine or one week amphotericin-based therapy versus two weeks amphotericin-based therapy. The ACTA Trial

A randomized controlled trial for the treatment of HIV-associated cryptococcal meningitis in Africa: oral fluconazole plus flucytosine or one week amphotericin-based therapy versus two weeks amphotericin-based therapy. The ACTA Trial

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