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Background: CNS infections cause approximately a third of HIV-related deaths. The Driving Reduced AIDS-Associated Meningo-encephalitis Mortality DREAMM study aimed to prospectively diagnose the aetiology of HIV-related CNS infection in five public hospitals in Cameroon, Malawi, and Tanzania., Methods: DREAMM was a multicentre, hybrid type-2 implementation science project. Adults (aged ≥18 years) presenting with a first episode of suspected CNS infection, who were HIV seropositive or willing to have an HIV test, were eligible for recruitment. Following implementation of the DREAMM model of care, we measured the prevalence of cryptococcal meningitis, tuberculous meningitis, bacterial meningitis, and cerebral toxoplasmosis and did a χ 2 test to assess whether prevalence differed between countries. We also reported disease-specific mortality and Toxoplasma gondii seroprevalence., Findings: Of 356 participants with suspected CNS infection analysed at baseline, 269 (76%) were diagnosed as having a CNS infection. Of these, 202 (75%) had a confirmed diagnosis. Between Cameroon, Malawi, and Tanzania, the prevalence of the four main types of CNS infection differed (cryptococcal meningitis p=0·0014, bacterial meningitis p=0·0043, CNS tuberculosis p<0·0001, and toxoplasmosis p<0·0001). Cryptococcal meningitis (148 [55%] of 269) was the leading cause overall. The next most common causes were CNS tuberculosis in Tanzania (29 [29%] of 99) and bacterial meningitis in Malawi (15 [19%] of 80). In Cameroon, cerebral toxoplasmosis (39 [43%] of 90) was the leading cause followed by cryptococcal meningitis (36 [40%] of 90). For cryptococcal meningitis, all-cause 2-week mortality was 23% (34 of 147) and all-cause 10-week mortality was 45% (66 of 146)., Interpretation: Within the study population, the aetiology of HIV-related CNS infection varied substantially between Malawi, Cameroon, and Tanzania. Additional prospective epidemiological data are needed to inform HIV programmes. 2-week cryptococcal meningitis mortality outcomes were similar to those of clinical trials. However, new interventions are urgently needed to sustain mortality reductions following hospital discharge., Funding: European and Developing Countries Clinical Trials Partnership and French Agency for Research on AIDS and Viral Hepatitis., Translations: For the French and Portuguese translations of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2025 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: HIV-associated cryptococcal meningitis is the second leading cause of AIDS-related deaths, with a 10-week mortality rate of 25-30%. Fungal load assessed by colony-forming unit (CFU) counts is used as a prognostic marker and to monitor response to treatment in research studies. PCR-based assessment of fungal load could be quicker and less labour-intensive. We sought to design, optimise, and validate quantitative PCR (qPCR) assays for the detection, identification, and quantification of Cryptococcus infections in patients with cryptococcal meningitis in sub-Saharan Africa., Methods: We developed and validated species-specific qPCR assays based on DNA amplification of QSP1 (QSP1A specific to Cryptococcus neoformans, QSP1B/C specific to Cryptococcus deneoformans, and QSP1D specific to Cryptococcus gattii species) and a pan-Cryptococcus assay based on a multicopy 28S rRNA gene. This was a longitudinal study that validated the designed assays on cerebrospinal fluid (CSF) of 209 patients with cryptococcal meningitis at baseline (day 0) and during anti-fungal therapy (day 7 and day 14), from the AMBITION-cm trial in Botswana and Malawi (2018-21). Eligible patients were aged 18 years or older and presenting with a first case of cryptococcal meningitis., Findings: When compared with quantitative cryptococcal culture as the reference, the sensitivity of the 28S rRNA was 98·2% (95% CI 95·1-99·5) and of the QSP1 assay was 90·4% (85·2-94·0) in CSF at day 0. Quantification of the fungal load with QSP1 and 28S rRNA qPCR correlated with quantitative cryptococcal culture (R 2 =0·73 and R 2 =0·78, respectively). Both Botswana and Malawi had a predominant C neoformans prevalence of 67% (95% CI 55-75) and 68% (57-73), respectively, and lower C gattii rates of 21% (14-31) and 8% (4-14), respectively. We identified ten patients that, after 14 days of treatment, harboured viable but non-culturable yeasts based on QSP1 RNA detection (without any positive CFU in CSF culture)., Interpretation: QSP1 and 28S rRNA assays are useful in identifying Cryptococcus species. qPCR results correlate well with baseline quantitative cryptococcal culture and show a similar decline in fungal load during induction therapy. These assays could be a faster alternative to quantitative cryptococcal culture to determine fungal load clearance. The clinical implications of the possible detection of viable but non-culturable cells in CSF during induction therapy remain unclear., Funding: European and Developing Countries Clinical Trials Partnership; Swedish International Development Cooperation Agency; Wellcome Trust/UK Medical Research Council/UKAID Joint Global Health Trials; and UK National Institute for Health Research., Competing Interests: Declaration of interests AA received honoraria for educational activities and webinars from Gilead Sciences and Pfizer and travel grants from Astellas and Gilead Sciences, outside the submitted work. All other authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Four decades into the HIV epidemic, CNS infection remains a leading cause of preventable HIV-related deaths in routine care. The Driving Reduced AIDS-associated Meningo-encephalitis Mortality (DREAMM) project aimed to develop, implement, and evaluate pragmatic implementation interventions and strategies to reduce mortality from HIV-related CNS infection., Methods: DREAMM took place in five public hospitals in Cameroon, Malawi, and Tanzania. The main intervention was a stepwise algorithm for HIV-related CNS infections including bedside rapid diagnostic testing and implementation of WHO cryptococcal meningitis guidelines. A health system strengthening approach for hospitals was adopted to deliver quality care through a co-designed education programme, optimised clinical and laboratory pathways, and communities of practice. DREAMM was led and driven by local leadership and divided into three phases: observation (including situational analyses of routine care), training, and implementation. Consecutive adults (aged ≥18 years) living with HIV presenting with a first episode of suspected CNS infection were eligible for recruitment. The primary endpoint was the comparison of 2-week all-cause mortality between observation and implementation phases. This study completed follow-up in September, 2021. The project was registered on ClinicalTrials.gov, NCT03226379., Findings: From November, 2016 to April, 2019, 139 eligible participants were enrolled in the observation phase. From Jan 9, 2018, to March 25, 2021, 362 participants were enrolled into the implementation phase. 216 (76%) of 286 participants had advanced HIV disease (209 participants had missing CD4 cell count), and 340 (69%) of 494 participants had exposure to antiretroviral therapy (ART; one participant had missing ART data). In the implementation phase 269 (76%) of 356 participants had a probable CNS infection, 203 (76%) of whom received a confirmed microbiological or radiological diagnosis of CNS infection using existing diagnostic tests and medicines. 63 (49%) of 129 participants died at 2 weeks in the observation phase compared with 63 (24%) of 266 in the implementation phase; and all-cause mortality was lower in the implementation phase when adjusted for site, sex, age, ART exposure (adjusted risk difference -23%, 95% CI -33 to -13; p<0·001). At 10 weeks, 71 (55%) died in the observation phase compared with 103 (39%) in the implementation phase (-13%, -24 to -3; p=0·01)., Interpretation: DREAMM substantially reduced mortality from HIV-associated CNS infection in resource-limited settings in Africa. DREAMM scale-up is urgently required to reduce deaths in public hospitals and help meet Sustainable Development Goals., Funding: European and Developing Countries Clinical Trials Partnership, French Agency for Research on AIDS and Viral Hepatitis., Translations: For the French and Portuguese translations of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests AL, DSL, and JB all received support for this project from European and Developing Countries Clinical Trials Partnership (EDCTP), paid to their institutions. AL has received grants from EDCTP, the National Institute for Health and Care Research, and the National Institutes of Health, and consultancy fees from Unitaid to advise on the Unitaid-CHAI Advanced HIV Disease programme, all paid to St George's University of London; AL is also the Chair and Lead of the End AIDS Action Group, which encompasses the work of the Cryptococcal Meningitis Action gorup, an unfunded role. RR received a grant from The National Institute of Allergy and Infectious Diseases, paid to their institution. OL receives consulting fees and payments or honoraria of less than US$1000 per year from Gilead Sciences; and is part of the advisory board for Mundipharma. THa received an investigator award from Gilead Sciences and has received payments or honoraria from Gilead Sciences and Pfizer for speaking fees. All other authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)