Outcomes of flucytosine-containing combination treatment for cryptococcal meningitis in a South African national access programme: a cross-sectional observational study
2022; Elsevier BV; Volume: 22; Issue: 9 Linguagem: Inglês
10.1016/s1473-3099(22)00234-1
ISSN1474-4457
AutoresRudzani Mashau, Susan Meiring, Vanessa Quan, Jeremy Nel, Greg Greene, Andrea Arnaiz García, Colin Menezes, Denasha L. Reddy, Michelle Venter, Sarah Stacey, Matamela Madua, Lia Boretti, Thomas S. Harrison, Graeme Meintjes, Amir Shroufi, Laura Triviño-Duran, John Black, Nelesh P. Govender, Shareef Abrahams, Vanessa Pearce, Masego Moncho, Jeanette Wadula, Motlatji Reratilwe Bonnie Maloba, A A Hoosen, Charl Verwey, Colin Menezes, David Moore, Dina Pombo, Gary Reubenson, Grace Ntlemo, Lauren Richards, Maphoshane Nchabeleng, Merika Tsitsi, Moamokgethi Moshe, Mohammed Y. Said, Molebogeng Kolojane, Lesego Mothibi, Nicolette du Plessis, Rispah Chomba, Teena Thomas, Theunis Avenant, Trusha Nana, Vindana Chibabhai, Adhil Maharj, Douglas Wilson, Fathima Naby, Halima Dawood, Khine Swe Swe-Han, Lisha Sookan, Nomonde Dlamini, Praksha Ramajathan, Prasha Mahabeer, Prathna Bhola, Romola Naidoo, Sumayya Haffejee, Surendra Sirkar, Yeishna Ramkillawan, Ken Hamese, Ngoaka Sibiya, Phetho Mangena, Ruth Lekalakala, Greta Hoyland, Sindi Ntuli, Ebrahim Variava, Ignatius Khantsi, Omphile Mekgoe, Adrian Brink, Elizabeth Prentice, Kessendri Reddy, Andrew Whitelaw, Ebrahim Hoosien, Inge Zietsman, Terry Marshall, Xoliswa Poswa, Chetna Govind, J.A.H. Smit, Keshree Pillay, Sharona Seetharam, Victoria Howell, Catherine Samuel, Marthinus Senekal, Colleen Bamford, Andries Dreyer, Louis Marcus, Warren Lowman, Anne von Gottberg, Anthony M. Smith, Azwifarwi Mathunjwa, Cecilia d'Abreu, Cecilia Miller, Cheryl Cohen, Farzana Ismail, Harry Moultrie, Husna Ismail, Jacqueline Weyer, Jackie Kleynhans, Jennifer Rossouw, John Frean, Joy Ebonwu, Judith Mwansa-Kambafwile, Juno Thomas, Kate Bishop, Kerrigan McCarthy, Liliwe Shuping, Linda de Gouveia, Linda Erasmus, Adrian Puren, Lucille Blumberg, Marshagne Smith, Martha Makgoba, Michelle J. Groome, Mignon du Plessis, Mimmy Ngomane, Mokupi Manaka, Myra Moremi, Nazir Ismail, Neo Legare, Nicola Page, Nombulelo Hoho, Olga Perovic, Phuti Sekwadi, Rindidzani E. Magobo, Ruth Mpembe, Sibongile Walaza, Siyanda Dlamini, Sunnieboy Njikho, Tiisetso Lebaka, Wendy Ngubane,
Tópico(s)Nail Diseases and Treatments
ResumoBackground Although flucytosine is a key component of WHO-recommended induction treatment for HIV-associated cryptococcal meningitis, this antifungal agent is not widely available in low-income and middle-income countries due to limited production and cost. In 2018, a national flucytosine access programme was initiated in South Africa. We aimed to determine the effectiveness of flucytosine-containing induction regimens in routine care to motivate for the urgent registration of flucytosine and its inclusion in treatment guidelines. Methods In this cross-sectional study, we compared outcomes of adults aged 18 years and older with incident laboratory-confirmed cryptococcal meningitis treated with or without flucytosine-containing regimens at 19 sentinel hospitals in South Africa. A case of cryptococcosis was defined as illness in an adult with: (1) positive cerebrospinal fluid (CSF) India ink microscopy; (2) a positive CSF cryptococcal antigen test; or (3) culture of Cryptococcus neoformans or Cryptococcus gattii from CSF or any other specimen. We excluded patients without a case report form, those with an unknown or negative HIV serology result, those with a recurrent episode, and those who did not receive antifungal treatment in hospital. We assessed cumulative in-hospital mortality at 14 days and 30 days and calculated the overall crude in-hospital case-fatality ratio. We used random-effects logistic regression to examine the association between treatment group and in-hospital mortality. Findings From July 1, 2018, to March 31, 2020, 10 668 individuals were diagnosed with laboratory-confirmed cryptococcal meningitis, 7787 cases diagnosed at non-enhanced surveillance sites and 567 cases from eight enhanced surveillance sites with no access to flucytosine were excluded. Of 2314 adults with a first episode of cryptococcosis diagnosed at 19 facilities with access to flucytosine, 1996 had a case report form and of these, 1539 received induction antifungal treatment and were confirmed HIV-seropositive first-episode cases. Of 1539 patients who received antifungal therapy, 596 (38·7%) individuals received a flucytosine-containing regimen and 943 (61·3%) received another regimen. The median age was 36 years (IQR 32–43) and 906 (58·9%) participants were male and 633 (41·1%) were female. The crude in-hospital case-fatality ratio was 23·9% (95% CI 20·0–27·0; 143 of 596) in those treated with flucytosine-containing regimens and 37·2% (95% CI 34·0–40·0; 351 of 943) in those treated with other regimens. Patients admitted to non-academic hospitals (adjusted odds ratio [aOR] 1·95 [95% CI 1·53–2·48]; p<0·0001) and those who were antiretroviral treatment-experienced (aOR 1·30 [1·02–1·67]; p=0·033) were more likely to receive flucytosine. After adjusting for relevant confounders, flucytosine treatment was associated with a 53% reduction in mortality (aOR 0·47 [95% CI 0·35–0·64]; p<0·0001). Among survivors, the median length of hospital admission in the flucytosine group was 11 days (IQR 8–15) versus 17 days (13–21) in the comparison group (p=0·0010). Interpretation In-hospital mortality among patients treated with a flucytosine-containing regimen was comparable to reduced mortality reported in patients receiving a flucytosine-containing regimen in a recent multicentre African clinical trial. Flucytosine-based treatment can be delivered in routine care in a middle-income country with a substantial survival benefit. Funding National Institute for Communicable Diseases, a Division of the National Health Laboratory Service. Translation For the Zulu translation of the abstract see Supplementary Materials section.
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