{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,28]],"date-time":"2026-01-28T20:06:21Z","timestamp":1769630781212,"version":"3.49.0"},"reference-count":41,"publisher":"Public Library of Science (PLoS)","issue":"5","license":[{"start":{"date-parts":[[2024,5,21]],"date-time":"2024-05-21T00:00:00Z","timestamp":1716249600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000061","name":"Fogarty International Center","doi-asserted-by":"publisher","award":["R21TW012439"],"award-info":[{"award-number":["R21TW012439"]}],"id":[{"id":"10.13039\/100000061","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000061","name":"Fogarty International Center","doi-asserted-by":"publisher","award":["D43 TW009345"],"award-info":[{"award-number":["D43 TW009345"]}],"id":[{"id":"10.13039\/100000061","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100011125","name":"School of Medicine and Dentistry, University of Rochester","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100011125","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100011123","name":"Academic Health Center, University of Minnesota","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100011123","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100012375","name":"School of Nursing, University of Washington","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100012375","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100022627","name":"Fulbright U.S. Scholar Program","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100022627","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006492","name":"Division of Intramural Research, National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["T32AI055433"],"award-info":[{"award-number":["T32AI055433"]}],"id":[{"id":"10.13039\/100006492","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:sec id=\"sec001\">\n<jats:title>Background<\/jats:title>\n<jats:p>Cryptococcal meningitis (CM) remains a major cause of death among people living with HIV in rural sub-Saharan Africa. We previously reported that a CM diagnosis and treatment program (CM-DTP) improved hospital survival for CM patients in rural, northern Uganda. This study aimed to evaluate the impact on long-term survival.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec002\">\n<jats:title>Methods<\/jats:title>\n<jats:p>We conducted a retrospective study at Lira Regional Referral Hospital in Uganda evaluating long-term survival (\u22651 year) of CM patients diagnosed after CM-DTP initiation (February 2017-September 2021). We compared with a baseline historical group of CM patients before CM-DTP implementation (January 2015-February 2017). Using Cox proportional hazards models, we assessed time-to-death in these groups, adjusting for confounders.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec003\">\n<jats:title>Results<\/jats:title>\n<jats:p>We identified 318 CM patients, 105 in the Historical Group, and 213 in the CM-DTP Group. The Historical Group had a higher 30-day mortality of 78.5% compared to 42.2% in the CM-DTP Group. The overall survival rate for the CM-DTP group at three years was 25.6%. Attendance at follow-up visits (HR:0.13, 95% CI: [0.03\u20130.53], <jats:italic>p<\/jats:italic> &lt;0.001), ART adherence (HR:0.27, 95% CI: [0.10\u20130.71], <jats:italic>p<\/jats:italic> = 0.008), and fluconazole adherence: (HR:0.03, 95% CI: [0.01\u20130.13], <jats:italic>p<\/jats:italic> &lt;0.001), weight &gt;50kg (HR:0.54, 95% CI: [0.35\u20130.84], <jats:italic>p<\/jats:italic> = 0.006), and performance of therapeutic lumbar punctures (HR:0.42, 95% CI: [0.24\u20130.71], <jats:italic>p<\/jats:italic> = 0.001), were associated with lower risk of death. Altered mentation was associated with increased death risk (HR: 1.63, 95% CI: 1.10\u20132.42, <jats:italic>p<\/jats:italic> = 0.016).<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec004\">\n<jats:title>Conclusion<\/jats:title>\n<jats:p>Long-term survival of CM patients improved after the initiation of the CM-DTP. Despite this improved survival, long-term outcomes remained sub-optimal, suggesting that further work is needed to enhance long-term survival.<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pone.0303805","type":"journal-article","created":{"date-parts":[[2024,5,21]],"date-time":"2024-05-21T17:24:58Z","timestamp":1716312298000},"page":"e0303805","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":3,"title":["Poor long-term outcomes despite improved hospital survival for patients with cryptococcal meningitis in rural, Northern 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Consolidated Guidelines for Prevention and Treatment of HIV in Uganda | MOH Knowledge Management Portal. 20 Dec 2016 [cited 16 May 2023]. http:\/\/library.health.go.ug\/communicable-disease\/hivaids\/consolidated-guidelines-prevention-and-treatment-hiv-uganda"},{"key":"pone.0303805.ref019","doi-asserted-by":"crossref","first-page":"e0251749","DOI":"10.1371\/journal.pone.0251749","article-title":"Three-year mortality in cryptococcal meningitis: Hyperglycemia predict unfavorable outcome","volume":"16","author":"S-T Tsai","year":"2021","journal-title":"PLoS ONE"},{"key":"pone.0303805.ref020","doi-asserted-by":"crossref","first-page":"e1000384","DOI":"10.1371\/journal.pmed.1000384","article-title":"Clinical Features and Serum Biomarkers in HIV Immune Reconstitution Inflammatory Syndrome after Cryptococcal Meningitis: A Prospective Cohort Study","volume":"7","author":"DR Boulware","year":"2010","journal-title":"PLoS Med"},{"key":"pone.0303805.ref021","doi-asserted-by":"crossref","first-page":"2487","DOI":"10.1056\/NEJMoa1312884","article-title":"Timing of Antiretroviral Therapy after Diagnosis of Cryptococcal Meningitis","volume":"370","author":"DR Boulware","year":"2014","journal-title":"N Engl J Med"},{"key":"pone.0303805.ref022","doi-asserted-by":"crossref","first-page":"ofz478","DOI":"10.1093\/ofid\/ofz478","article-title":"Seizures in Human Immunodeficiency Virus-Associated Cryptococcal Meningitis: Predictors and Outcomes","volume":"6","author":"KA Pastick","year":"2019","journal-title":"Open Forum Infect Dis"},{"key":"pone.0303805.ref023","doi-asserted-by":"crossref","first-page":"105873","DOI":"10.1016\/j.nedt.2023.105873","article-title":"Lack of education, knowledge, and supplies are barriers to cryptococcal meningitis care among nurses and other healthcare providers in rural Uganda: A mixed methods study","volume":"128","author":"A Link","year":"2023","journal-title":"Nurse Educ Today"},{"key":"pone.0303805.ref024","article-title":"Long-Term Cryptococcal Meningitis Survival, Uganda (DATA)","year":"2024","journal-title":"figshare"},{"key":"pone.0303805.ref025","unstructured":"Lira Hospital.pdf. https:\/\/budget.finance.go.ug\/sites\/default\/files\/Sector%20Spending%20Agency%20Budgets%20and%20Performance\/Lira%20Hospital.pdf"},{"key":"pone.0303805.ref026","unstructured":"WHO 2022: World Health Organization 2022. 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