Outcomes of flucytosine-containing combination treatment for cryptococcal meningitis in a South African national access programme: a cross-sectional observational study. Mashau, R. C, Meiring, S. T, Quan, V. C, Nel, J., Greene, G. S, Garcia, A., Menezes, C., Reddy, D. L, Venter, M., Stacey, S., Madua, M., Boretti, L., Harrison, T. S, Meintjes, G., Shroufi, A., Trivino-Duran, L., Black, J., Govender, N. P, Abrahams, S., Pearce, V., Moncho, M., Ntlemo, M. G., Wadula, J., Richards, L., Nchabeleng, M., Tsitsi, M., Moshe, M., Said, M., Kolojane, M., Mothibi, L., Plessis, N. D., Chomba, R., Thomas, T., Avenant, T., Nana, T., Chibabhai, V., Maharj, A., Wilson, D., Naby, F., Dawood, H., Han, K. S. S., Sookan, L., Dlamini, N., Ramajathan, P., Mahabeer, P., Bhola, P., Naidoo, R., Haffejee, S., Sirkar, S., Ramkillawan, Y., Hamese, K., Sibiya, N., Mangena, P., Lekalakala, R., Hoyland, G., Ntuli, S., Variava, E., Khantsi, I., Mekgoe, O., Brink, A., Prentice, E., Reddy, K., Whitelaw, A., Hoosien, E., Zietsman, I., Marshall, T., Poswa, X., Govind, C., Smit, J., Pillay, K., Seetharam, S., Howell, V., Samuel, C., Senekal, M., Bamford, C., Dreyer, A., Marcus, L., Lowman, W., von Gottberg, A., Smith, A., Mathunjwa, A., D'Abreu, C., Miller, C., Cohen, C., Ismail, F., Moultrie, H., Ismail, H., Weyer, J., Kleynhans, J., Rossouw, J., Frean, J., Ebonwu, J., Mwansa-Kambafwile, J., Thomas, J., Bishop, K., McCarthy, K., Shuping, L., de Gouveia, L., Erasmus, L., Puren, A., Blumberg, L., Smith, M., Makgoba, M., Groome, M., du Plessis, M., Ngomane, M., Manaka, M., Moremi, M., Ismail, N., Legare, N., Page, N., Hoho, N., Perovic, O., Sekwadi, P., Magobo, R., Mpembe, R., Walaza, S., Dlamini, S., Njikho, S., Lebaka, T., & Ngubane, W. The Lancet Infectious Diseases, Elsevier, jun, 2022.
Outcomes of flucytosine-containing combination treatment for cryptococcal meningitis in a South African national access programme: a cross-sectional observational study [link]Paper  doi  abstract   bibtex   
Summary Background 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 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.
@article{Mashau2022,
abstract = {Summary Background 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{\textperiodcentered}7{\%}) individuals received a flucytosine-containing regimen and 943 (61{\textperiodcentered}3{\%}) received another regimen. The median age was 36 years (IQR 32–43) and 906 (58{\textperiodcentered}9{\%}) participants were male and 633 (41{\textperiodcentered}1{\%}) were female. The crude in-hospital case-fatality ratio was 23{\textperiodcentered}9{\%} (95{\%} CI 20{\textperiodcentered}0–27{\textperiodcentered}0; 143 of 596) in those treated with flucytosine-containing regimens and 37{\textperiodcentered}2{\%} (95{\%} CI 34{\textperiodcentered}0–40{\textperiodcentered}0; 351 of 943) in those treated with other regimens. Patients admitted to non-academic hospitals (adjusted odds ratio [aOR] 1{\textperiodcentered}95 [95{\%} CI 1{\textperiodcentered}53–2{\textperiodcentered}48]; p 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.},
author = {Mashau, Rudzani C and Meiring, Susan T and Quan, Vanessa C and Nel, Jeremy and Greene, Greg S and Garcia, Andrea and Menezes, Colin and Reddy, Denasha L and Venter, Michelle and Stacey, Sarah and Madua, Matamela and Boretti, Lia and Harrison, Thomas S and Meintjes, Graeme and Shroufi, Amir and Trivino-Duran, Laura and Black, John and Govender, Nelesh P and Abrahams, Shareef and Pearce, Vanessa and Moncho, Masego and Ntlemo, Motlatji Grace and Wadula, Jeanette and Richards, Lauren and Nchabeleng, Maphoshane and Tsitsi, Merika and Moshe, Moamokgethi and Said, Mohammed and Kolojane, Molebogeng and Mothibi, Lesego and Plessis, Nicolette Du and Chomba, Rispah and Thomas, Teena and Avenant, Theunis and Nana, Trusha and Chibabhai, Vindana and Maharj, Adhil and Wilson, Douglas and Naby, Fathima and Dawood, Halima and Han, Khine Swe Swe and Sookan, Lisha and Dlamini, Nomonde and Ramajathan, Praksha and Mahabeer, Prasha and Bhola, Prathna and Naidoo, Romola and Haffejee, Sumayya and Sirkar, Surendra and Ramkillawan, Yeishna and Hamese, Ken and Sibiya, Ngoaka and Mangena, Phetho and Lekalakala, Ruth and Hoyland, Greta and Ntuli, Sindi and Variava, Ebrahim and Khantsi, Ignatius and Mekgoe, Omphile and Brink, Adrian and Prentice, Elizabeth and Reddy, Kessendri and Whitelaw, Andrew and Hoosien, Ebrahim and Zietsman, Inge and Marshall, Terry and Poswa, Xoliswa and Govind, Chetna and Smit, Juanita and Pillay, Keshree and Seetharam, Sharona and Howell, Victoria and Samuel, Catherine and Senekal, Marthinus and Bamford, Colleen and Dreyer, Andries and Marcus, Louis and Lowman, Warren and von Gottberg, Anne and Smith, Anthony and Mathunjwa, Azwifarwi and D'Abreu, Cecilia and Miller, Cecilia and Cohen, Cheryl and Ismail, Farzana and Moultrie, Harry and Ismail, Husna and Weyer, Jacqueline and Kleynhans, Jackie and Rossouw, Jenny and Frean, John and Ebonwu, Joy and Mwansa-Kambafwile, Judith and Thomas, Juno and Bishop, Kate and McCarthy, Kerrigan and Shuping, Liliwe and de Gouveia, Linda and Erasmus, Linda and Puren, Adrian and Blumberg, Lucille and Smith, Marshagne and Makgoba, Martha and Groome, Michelle and du Plessis, Mignon and Ngomane, Mimmy and Manaka, Mokupi and Moremi, Myra and Ismail, Nazir and Legare, Neo and Page, Nicola and Hoho, Nombulelo and Perovic, Olga and Sekwadi, Phuti and Magobo, Rindidzani and Mpembe, Ruth and Walaza, Sibongile and Dlamini, Siyanda and Njikho, Sunnieboy and Lebaka, Tiisetso and Ngubane, Wendy},
doi = {10.1016/S1473-3099(22)00234-1},
file = {:C$\backslash$:/Users/Claire/Desktop/CIDRI-Africa backup/Documents/CIDRI-Africa papers and outputs/Mashau et al  - 2022 - Outcomes of flucytosine-containing combination treatment for cryptococcal meningitis in SA national access programme.pdf:pdf},
issn = {1473-3099},
journal = {The Lancet Infectious Diseases},
keywords = {fund{\_}not{\_}ack,original},
mendeley-tags = {fund{\_}not{\_}ack,original},
month = {jun},
pages = {S1473--3099(22)00234--1},
pmid = {35750065},
publisher = {Elsevier},
title = {{Outcomes of flucytosine-containing combination treatment for cryptococcal meningitis in a South African national access programme: a cross-sectional observational study}},
url = {http://www.thelancet.com/article/S1473309922002341/fulltext http://www.thelancet.com/article/S1473309922002341/abstract https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(22)00234-1/abstract},
year = {2022}
}

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