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Background Cryptococcal meningitis (CM) causes substantial mortality in African countries with a high prevalence of human immunodeficiency virus (HIV), despite advances in disease management and increasing antiretroviral therapy (ART) coverage. Reliable diagnosis of CM is cheap and more accessible than other indicators of advanced HIV disease burden such as CD4 testing or investigation for disseminated tuberculosis; therefore, monitoring CM incidence has the potential to serve as a valuable metric of HIV programmatic success. Methods Botswana national meningitis surveillance data from 2015 to 2022 were obtained from electronic health records. All electronic laboratory records from cerebrospinal fluid samples analyzed within government healthcare facilities in Botswana were extracted from a central online repository. Adjustments for missing data were made through triangulation with prospective cohort study datasets. CM case frequency was enumerated using a case definition and incidence calculated using national census data. Results A total of 1744 episodes of CM were identified; incidence declined from 15.0 (95% confidence interval [CI], 13.4–16.7) cases/100 000 person-years in 2015 to 7.4 (95% CI, 6.4–8.6) cases/100 000 person-years in 2022. However, the rate of decline slowed following the introduction of universal treatment in 2016. The highest incidence was observed in men and individuals aged 40–44 years. The proportion of cases diagnosed through cryptococcal antigen testing increased from 35.5% to 86.3%. Conclusions CM incidence has decreased in Botswana following expansion of ART coverage but persists at a stubbornly high incidence. Most cases are now diagnosed through the cheap and easy-to-use cryptococcal antigen test, highlighting the potential of using CM as key metric of program success in the Treat All era. [ABSTRACT FROM AUTHOR]

Objectives: We compared the patterns of HIV-1 drug resistance mutations between the CSF and plasma of individuals with HIV-associated cryptococcal meningitis.Methods: This is a cross-sectional study of archived CSF and plasma samples collected from ART-exposed participants recruited in the Phase 3 AmBisome Therapy Induction Optimisation randomized controlled trial (ISRCTN72509687) conducted in Botswana between 2018 and 2021. HIV-1 RT and protease genes were genotyped using next-generation sequencing and HIV-1 drug resistance mutations were compared between the CSF and plasma compartments stratified by thresholds of ≥20% and <20%.Results: Overall, 66.7% (16/24) of participants had at least one HIV-1 drug resistance mutation in the CSF and/or plasma. A total of 15/22 (68.2%) participants had HIV-1 drug resistance mutations at ≥20% threshold in the plasma and of those, 11 (73.3%) had been on ART longer than 6 months. HIV-1 drug resistance mutations were highly concordant between the CSF and plasma at ≥20% threshold despite a substantial number of individuals experiencing CSF viral escape and with only 54.5% with CSF WBC count ≥20 cells/mm3. Minority HIV-1 drug resistance mutations were detected in 20.8% (5/24) of participants. There were no mutations in the CSF that were not detected in the plasma.Conclusions: There was high concordance in HIV-1 drug resistance mutations in the CSF and plasma, suggesting intercompartmental mixing and possibly a lack of compartmentalization. Some individuals harboured minority HIV-1 drug resistance mutations, demonstrating the need to employ more sensitive genotyping methods such as next-generation sequencing for the detection of low-abundance mutations. [ABSTRACT FROM AUTHOR]

Background: The AMBITION-cm trial for HIV-associated cryptococcal meningitis demonstrated that a single, high-dose of liposomal amphotericin (AmBisome) plus 14-days of oral flucytosine and fluconazole was non-inferior in terms of all-cause mortality to 7-days of amphotericin B deoxycholate and flucytosine followed by 7-days of fluconazole (Control). The AmBisome regimen was associated with fewer adverse events. We explored the acceptability of the AmBisome regimen from the perspective of participants and providers. Methods: We embedded a qualitative methods study within the AMBITION-cm sites in Botswana and Uganda. We conducted in-depth interviews with trial participants, surrogate decision makers, and researchers and combined these with direct observations. Interviews were transcribed, translated, and analysed thematically. Results: We interviewed 38 trial participants, 20 surrogate decision makers, and 31 researchers. Participant understanding of the trial was limited; however, there was a preference for the AmBisome regimen due to the single intravenous dose and fewer side effects. More time was required to prepare the single AmBisome dose but this was felt to be acceptable given subsequent reductions in workload. The AmBisome regimen was reported to be associated with fewer episodes of rigors and thrombophlebitis and a reduction in the number of intravenous cannulae required. Less intensive monitoring and management was required for participants in the AmBisome arm. Conclusions: The AmBisome regimen was highly acceptable, being simpler to administer despite the initial time investment required. The regimen was well tolerated and associated with less toxicity and resultant management. Widespread implementation would reduce the clinical workload of healthcare workers caring for patients with HIV-associated cryptococcal meningitis. Author summary: The AMBIsome Therapy Induction OptimisatioN (AMBITION-cm) clinical trial found that a single, high-dose, intravenous liposomal amphotericin B (AmBisome) based regimen for HIV-associated cryptococcal meningitis was non-inferior to the WHO recommended first-line treatment which includes seven daily doses of intravenous amphotericin B deoxycholate. The AmBisome regimen was also associated with fewer adverse events. In addition to the clinical efficacy data it is important to consider how acceptable the AmBisome regimen was from the perspectives of those who received the regimen as well as the healthcare workers administering it. To do this we conducted a qualitative methods study of in-depth interviews with AMBITION-cm trial participants, surrogate decision makers, and researchers working on the trial. These interviews were combined with direct observations of the research process and analysed thematically. The trial participants were often severely unwell and therefore the understanding of the trial was limited; however, the AmBisome regimen was generally preferred due to the single intravenous dose and fewer side effects. Researchers strongly preferred the AmBisome regimen which took less time to administer overall and was also associated with fewer side effects. We conclude that these findings complement the efficacy data from the clinical trial to support widespread implementation of the regimen. [ABSTRACT FROM AUTHOR]

Cerebrospinal fluid (CSF) viral escape has been poorly described among people with HIV-associated cryptococcal meningitis. We determined the prevalence of CSF viral escape and HIV-1 viral load (VL) trajectories in individuals treated for HIV-associated cryptococcal meningitis. A retrospective longitudinal study was performed using paired CSF and plasma collected prior to and during the antifungal treatment of 83 participants recruited at the Botswana site of the phase-3 AMBITION-cm trial (2018–2021). HIV-1 RNA levels were quantified then CSF viral escape (CSF HIV-1 RNA ≥ 0.5 log10 higher than plasma) and HIV-1 VL trajectories were assessed. CSF viral escape occurred in 20/62 (32.3%; 95% confidence interval [CI]: 21.9–44.6%), 13/52 (25.0%; 95% CI: 15.2–38.2%) and 1/33 (3.0%; 95% CI: 0.16–15.3%) participants at days 1, 7 and 14 respectively. CSF viral escape was significantly lower on day 14 compared to days 1 and 7, p = 0.003 and p = 0.02, respectively. HIV-1 VL decreased significantly from day 1 to day 14 post antifungal therapy in the CSF but not in the plasma (β = −0.47; 95% CI: −0.69 to −0.25; p < 0.001). CSF viral escape is high among individuals presenting with HIV-associated cryptococcal meningitis; however, antifungal therapy may reverse this, highlighting the importance of rapid initiation of antifungal therapy in these patients. [ABSTRACT FROM AUTHOR]

Syphilis data from low- and middle-income countries are lacking due to limited testing. Point-of-care tests (POCTs) have been promoted to expand testing but previously only included treponemal tests, which cannot distinguish active from past infection. We aimed to assess the feasibility of using a combined treponemal and non-treponemal POCT in HIV clinic patients in Gaborone, Botswana, and estimate syphilis prevalence in our clinic sample using this approach. We recruited 390 non-pregnant patients. Participants underwent a combined treponemal and non-treponemal POCT (Dual Path Platform (DPP®) Syphilis Screen and Confirm Assay (Chembio Diagnostic Systems)) on finger-prick blood sample and a questionnaire. Median age 45 years, 30% men, median CD4 count 565 cells/μL, and 91% had an HIV viral load <400 copies/mL. Five participants had active syphilis (1.3%, 95% CI 0.5–3.0%) and 64 had previous syphilis (16.4%, 95% CI 13.0–20.4%) using the DPP POCT. There was a reasonable level of agreement between digital and visual reading of the POCT (kappa statistic of 0.81); however, visual reading missed three active infections (60%). The level of active syphilis was similar to local antenatal data. The DPP POCT led to five participants with active syphilis being diagnosed and starting same-day treatment. The digital reader should be used. [ABSTRACT FROM AUTHOR]

Potential participants for clinical trials which aim to define treatments for life-threatening conditions are often extremely unwell. When exploring why individuals participate in clinical trials one common observation is a misplaced expectation of personal benefit - a therapeutic misconception. The care offered in some clinical trials is of a higher standard than is routinely available and this has led to criticism around the freedom of choice to enrol - structural coercion. We embedded an ethnographic study within a randomised controlled trial for HIV-associated cryptococcal meningitis in Gaborone, Botswana and Kampala, Uganda. We aimed to gain an understanding of decision-making around the trial and how this was impacted by the study design and broader social context. We conducted in-depth interviews with trial participants, surrogate decision makers and researchers, combined these with direct observations and analysed data using thematic analysis. Between January 2020 and June 2021 we interviewed 89 individuals. We found previous exposure to and awareness of clinical research was limited, as was understanding of the trial objectives and design. Through observations and engagement with healthcare facilities decision-makers were able to identify the trial as providing the best possible chance of survival. Hesitation and reluctance were mostly due to fear of lumbar punctures which was sometimes based on rumours but often based on tragic personal experience. Despite fear, and sometimes conviction that they would die, individuals agreed to consent, often against the wishes of family members. Reassurance and confidence came from trust in routine care staff and the research team but also from fellow participants and their surrogates. We argue that participants made informed decisions based on a therapeutic expectation from the trial and that rather than being the result of structural coercion this was an informed and voluntary choice. • Ethnographic study of a clinical trial for HIV-associated cryptococcal meningitis. • The trial was identified as providing the best possible chance of survival. • Decisions to enrol were made despite fears that trial procedures could be fatal. • Researchers, routine care staff, and other participants provided reassurance. • Decisions were made based on a therapeutic expectation. [ABSTRACT FROM AUTHOR]

HIV-1 compartmentalization in reservoir sites remains a barrier to complete HIV eradication. It is unclear whether there is variation in HIV-1 env and gag between cerebrospinal fluid (CSF) and plasma of individuals with HIV-associated cryptococcal meningitis (CM). We compared HIV-1 env characteristics and the gag cytotoxic T-lymphocyte (CTL) escape mutations from CSF and plasma samples. Employing population-based Sanger sequencing, we sequenced HIV-1 env from CSF of 25 patients and plasma of 26 patients. For gag, 15 CSF and 21 plasma samples were successfully sequenced. Of these, 18 and 9 were paired env and gag CSF/plasma samples, respectively. There was no statistically significant difference in the proportion of CCR5-using strains in the CSF and plasma, (p = 0.50). Discordant CSF/plasma virus co-receptor use was found in 2/18 pairs (11.1%). The polymorphisms in the HIV-1 V3 loop were concordant between the two compartments. From the HIV-1 gag sequences, three pairs had discordant CTL escape mutations in three different epitopes of the nine analyzed. These findings suggest little variation in the HIV-1 env between plasma and CSF and that the CCR5-using strains predominate in both compartments. HIV-1 gag CTL escape mutations also displayed little variation in CSF and plasma suggesting similar CTL selective pressure. [ABSTRACT FROM AUTHOR]

Objectives: We compared the patterns of HIV-1 drug resistance mutations between the CSF and plasma of individuals with HIV-associated cryptococcal meningitis., Methods: This is a cross-sectional study of archived CSF and plasma samples collected from ART-exposed participants recruited in the Phase 3 AmBisome Therapy Induction Optimisation randomized controlled trial (ISRCTN72509687) conducted in Botswana between 2018 and 2021. HIV-1 RT and protease genes were genotyped using next-generation sequencing and HIV-1 drug resistance mutations were compared between the CSF and plasma compartments stratified by thresholds of ≥20% and <20%., Results: Overall, 66.7% (16/24) of participants had at least one HIV-1 drug resistance mutation in the CSF and/or plasma. A total of 15/22 (68.2%) participants had HIV-1 drug resistance mutations at ≥20% threshold in the plasma and of those, 11 (73.3%) had been on ART longer than 6 months. HIV-1 drug resistance mutations were highly concordant between the CSF and plasma at ≥20% threshold despite a substantial number of individuals experiencing CSF viral escape and with only 54.5% with CSF WBC count ≥20 cells/mm3. Minority HIV-1 drug resistance mutations were detected in 20.8% (5/24) of participants. There were no mutations in the CSF that were not detected in the plasma., Conclusions: There was high concordance in HIV-1 drug resistance mutations in the CSF and plasma, suggesting intercompartmental mixing and possibly a lack of compartmentalization. Some individuals harboured minority HIV-1 drug resistance mutations, demonstrating the need to employ more sensitive genotyping methods such as next-generation sequencing for the detection of low-abundance mutations., (© The Author(s) 2022. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: Individuals recruited into clinical trials for life-threatening illnesses are particularly vulnerable. This is especially true in low-income settings. The decision to enrol may be influenced by existing inequalities, poor healthcare infrastructure and fear of death. Where patients are confused or unconscious the responsibility for this decision falls to relatives. This qualitative study is nested in the ongoing AMBIsome Therapy Induction OptimisatioN (AMBITION) Trial. AMBITION is recruiting participants from five countries in sub-Saharan Africa and is trialling a novel treatment approach for HIV-associated cryptococcal meningitis, an infection known to affect brain function. We aim to learn from the experiences of participants, relatives and researchers involved in AMBITION., Methods and Analysis: We will collect data through in-depth interviews with trial participants and the next of kin of participants who were confused at enrolment and therefore provided surrogate consent. Data will be collected in Gaborone, Botswana; Kampala, Uganda and Harare, Zimbabwe. Interviews will follow a narrative approach including participatory drawing of participation timelines. This will be supplemented by direct observation of the research process at each of the three recruiting hospitals. Interviews will also take place with researchers from the African and European institutions that form the partnership through which the trial is administered. Interviews will be transcribed verbatim, translated (if necessary) and organised thematically for narrative analysis., Ethics and Dissemination: This study has been approved by the Health Research Development Committee, Gaborone (Reference: HPDME:13/18/1); Makerere School of Health Sciences Institutional Review Board, Kampala (Reference: 2019-061); University of Zimbabwe Joint Research Ethics Committee, Harare (Reference: 219/19), and the London School of Hygiene and Tropical Medicine (Reference: 17957). Study findings will be shared with research participants from the sites, key stakeholders at each research institution and ministries of health to help inform the development and implementation of future trials. The findings of this study will be published in journals and presented at academic meetings., Trial Registration: Registered at www.clinicaltrials.gov:NCT04296292., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)