BACKGROUND:TB meningitis (TBM) has up to 50% mortality in people living with HIV. We investigated differences in cerebrospinal fluid (CSF) host immune responses associated with short-term mortality. METHODS:We enrolled a prospective cohort of adults with definite, probable and possible HIV-related TBM in Kampala, Uganda. Metagenomic next-generation sequencing (mNGS) of bulk CSF RNA was used to detect co-infecting or alternate CNS pathogens and refine cohort diagnosis. Host transcriptomic profiles from the refined cohort were then compared between 14-day survivors and non-survivors. RESULTS:CSF mNGS reclassified or excluded 14% of participants based on pathogen detection, yielding 110 participants for transcriptomic analysis, of whom 23% (n=25) died within 14 days. More than 2000 genes were differentially expressed in the CSF based on 14-day mortality (adjusted p-value <0.05). Survivors upregulated T-cell receptor signaling (LCK, FYN, LAT), T-cell survival and differentiation (IL7, CD27, IL12RB1), B-cell receptor signaling (CD81, PLCG2, TNFRSF13C), cytotoxic lymphocyte and NK cell genes (KLRD1, ULBP1), TNF signaling, and class I MHC antigen processing pathways, while downregulating neutrophil chemoattractant CXCL1 and classical complement genes C4A and C4B. Unsupervised clustering identified a hypoinflammatory subgroup with significantly elevated mortality. CONCLUSIONS:Short-term TBM survival was associated with upregulation of adaptive immunity - including T-cell, B-cell, NK cell, and cytotoxic lymphocyte signaling - alongside TNF signaling and IFN-γ-driven class I MHC antigen processing pathways, with concurrent restraint of complement and neutrophil pathways. This supports investigation of targeted immunomodulatory agents that preserve protective responses while selectively dampening injurious innate pathways, rather than broad immunosuppression with corticosteroids.

Background:In cryptococcal meningitis, increased intracranial pressure (ICP) is associated with worse outcomes and increased mortality. We sought to understand how changes in ICP and mean arterial pressure (MAP) affect cerebral perfusion pressure (CPP) and influence clinical outcomes. Methods:We performed a secondary data analysis of a prospective cohort of Ugandan adults with HIV-associated cryptococcal meningitis. We summarize demographic variables, clinical presentation, and 2-week survival by CPP and MAP groups. Results:Among 593 participants, 41% had low CPP <70 mm Hg, 54% had normal CPP 70-100 mm Hg, and 5% had high CPP >100 mm Hg. There was no association between baseline CPP and 2-week mortality. As a time-varying covariate, we observed a 39% increased risk of 2-week mortality with CPP levels <70 or >100 mm Hg (hazard ratio [HR] 1.39; 95% confidence interval [CI] 1.02-1.88, P = .04). Among 686 participants with baseline MAP measurements, there was an increased risk of 2-week mortality among people with low MAP <70 mm Hg (HR 1.80; 95% CI 1.01-3.20; P = .047) or high MAP >100 mm Hg (HR 1.47; 95% CI 1.08-1.99; P = .014) compared with normal MAP 70-100 mm Hg. We identified 4 clinical profiles based on MAP, CPP, and ICP measurements: (1) uncompensated intracranial hypertension (low CPP, elevated ICP, and low MAP), (2) compensated intracranial hypertension (normal CPP, elevated ICP, and MAP), (3) cerebral hypoperfusion (low CPP and low MAP), and (4) cerebral hyperperfusion (high CPP and high MAP). Conclusions:In cryptococcal meningitis, there is an intricate relationship between ICP, MAP, and CPP. We provide a concept framework using data from a clinical cohort and recommendations for clinical management.

INTRODUCTION:HIV-associated cryptococcal meningitis is the second leading cause of AIDS-related mortality. Cryptococcal meningitis is a poverty-related disease and the majority of cases occur in settings where resources are limited and access to quality care is often linked to an individual's ability to pay for services. We have previously demonstrated the efficacy, safety and cost-effectiveness of a single, high-dose liposomal amphotericin-based treatment regimen within the AMBITION-cm trial. Here, we present a five-country, within-trial analysis exploring the household economic impact of cryptococcal meningitis. METHODS:Eight hundred and ten participants were recruited into this sub-study in Botswana, Malawi, South Africa, Uganda and Zimbabwe between January 2018 and February 2021. We collected data on annual household expenditure, direct costs and indirect costs incurred prior to enrolment and during the 10-week trial period. Costs were inflated and converted to 2022 USD. We calculated out-of-pocket expenditure, lost income and catastrophic healthcare expenditure, defined as costs exceeding 20% of annual household expenditure. RESULTS:The average total out-of-pocket expenditure plus lost income prior to enrolment was $132 and 17.9% (145/810, 95% CI 15.3-20.5) of participant households had already experienced catastrophic healthcare expenditure. Among the 592 surviving participants, when combining out-of-pocket expenditure and lost income, the average cost was $516 and 29.1% of annual household expenditure across all countries, ranging from $230 (7.6%) in South Africa to $592 (64.2%) in Zimbabwe. More than half (296/581, 51.0%, 95% CI 46.9-55.0) of households experienced catastrophic healthcare expenditure by the end of the trial, ranging from 16.0% (13/81, 95% CI 7.9-24.2) in South Africa to 68.1% (156/229, 95% CI 62.0-74.2) in Uganda. CONCLUSIONS:This is the first study exploring the household economic impact experienced by those diagnosed with cryptococcal meningitis. The household economic impact of cryptococcal meningitis is high and more than half of households of individuals who survive experience catastrophic healthcare expenditure. It is likely these figures are higher outside of the research setting. This highlights the profound financial impact of this devastating infection and provides a rationale to offer financial and social protection to those affected. TRIAL REGISTRATION NUMBER:ISRCTN72509687.

Background Neurocognitive impairment in HIV-associated cryptococcal meningitis survivors remains poorly characterized. We sought to identify risk factors associated with sustained neurocognitive impairment. Methods Cryptococcal meningitis survivors from the ASTRO-CM trial underwent neurocognitive assessment at 12 weeks. A composite quantitative neurocognitive performance score (QNPZ-8) was calculated as a mean of 8 independent z-scores. Participants were classified by QNPZ-8 score as having mild (QNPZ-8 >=-1), moderate (-2 < QNPZ-8 < -1), or severe (QNPZ-8 <=-2) impairment compared with the reference cohort of HIV-negative Ugandan adults. We compared differences in baseline demographics and clinical and laboratory variables by impairment categories. Results One hundred fifty-two participants completed >= 5 of the 8 neuropsychological tests and were included in the analysis. Overall, 37% (57/152) exhibited mild (QNPZ-8 >=-1), 37% (56/152) moderate (-2 < QNPZ-8 < -1), and 26% (39/152) severe impairment (QNPZ-8 <=-2). The overall mean QNPZ-8 score (SD) of -1.4 (0.82) denoted moderate neurocognitive impairment at 12 weeks. At baseline, lower weight (P = .03), Glasgow Coma Scale score <15 (P = .03), and education <= 7 years (P < .001) were more frequently observed among those with severe neurocognitive impairment at 12 weeks. Education <= 7 years (odds ratio, 6.13; 95% CI, 2.96-12.68; P < .001) and Glasgow Coma Scale score <15 (odds ratio, 2.61; 95% CI, 1.23-5.57; P = .013) were associated with moderate or severe neurocognitive impairment. Conclusions Neurocognitive impairment is prevalent at 12 weeks post-treatment in HIV-associated cryptococcal meningitis. Education level and Glasgow Coma Scale score <15 are associated with worse neurocognitive performance. Our findings underscore the need to further evaluate the impact of cryptococcal meningitis on neurocognitive outcomes.

Background The role of the immune response in acute mortality of cryptococcal meningitis remains unclear. Methods Cerebrospinal fluid (CSF) from 337 Ugandans with first-episode cryptococcal meningitis was collected. CSF cytokines and chemokines were quantified and compared by 14-day survival, stratification by quartiles, and logistical regression to determine association with acute mortality. Results Eighty-four (24.9%) participants died by day 14. Persons who survived to day 14 had higher levels of proinflammatory macrophage inflammatory protein (MIP)-3 beta and interferon (IFN)-beta and cytotoxicity-associated granzyme B and inteferon gamma-induced protein (IP)-10 compared to those who died (P < .05 for each). Logistic regression analysis revealed that per 2-fold increase in proinflammatory interleukin (IL)-6, IL-1 alpha, MIP-1 beta, MIP-3 beta, and IFN-beta and cytotoxicity-associated IL-12, tumor necrosis factor-alpha, granzyme-B, and IP-10 CSF concentrations, the risk of acute 14-day mortality decreased. Similar biomarkers were implicated when stratified by quartiles and further identified that lower concentrations of anti-inflammatory IL-10 and IL-13 were associated with 14-day mortality (P < .05 for each). Conclusions Proinflammatory and cytotoxicity-associated cytokine and chemokine responses in the CSF decrease the risk of acute 14-day mortality. These data suggest that a cytotoxic immune environment in the CSF could potentially improve acute survival. Further research on cytotoxic cells is crucial to improve understanding of innate and adaptive immune responses in cryptococcal meningitis.

We investigated cerebrospinal fluid (CSF) host transcriptomic differences in TBM survivors compared to non-survivors as a means of understanding the role that the host response plays in surviving TBM

BACKGROUND:Incarcerated people have been disproportionately affected by the COVID-19 pandemic and face significant challenges to COVID-19 vaccine confidence. OBJECTIVES:(1) Describe our partnerships with community members directly impacted by incarceration, (2) discuss the partnership's process for co-developing and implementing project interventions to increase COVID-19 vaccine confidence, and (3) share lessons learned from this unique community-engaged partnership. METHODS:An advisory board of 14 formerly incarcerated community members participated in this project. Their wisdom and experience led to the development and implementation of interventions to increase confidence in COVID-19 vaccines among incarcerated people. LESSONS LEARNED:Valuable lessons learned were centering community, leaning into trusted sources of information, acknowledging historical and present harms, and investing in community-engaged work. CONCLUSIONS:Centering lived experiences of those directly impacted by incarceration has been crucial to increasing vaccine confidence among this population. Doing so reinforced the importance of long-term investments in community-based collaborations with communities impacted by incarceration.

Given extensive improvements in access to antiretroviral therapy (ART) over the past 12 years, the HIV and cryptococcal meningitis landscapes have dramatically changed since 2010. We sought to evaluate changes in clinical presentation and clinical outcomes of people presenting with HIV-associated cryptococcal meningitis between 2010 and 2022 in Uganda. We analyzed three prospective cohorts of HIV-infected Ugandans with cryptococcal meningitis during 2010-2012, 2013-2017, and 2018-2022. We summarized baseline demographics, clinical characteristics at presentation, and 2-week and 16-week mortality. Overall, 2022 persons had confirmed cryptococcal meningitis between 2010 and 2022. In the most recent 2018-2022 cohort, 48% presented as ART-naïve, and the median CD4 cell count was 26 cells/µl. Participants in the 2018-2022 cohort had the lowest cerebrospinal fluid (CSF) opening pressure (median 22 cmH2O) and the highest percentage with sterile CSF quantitative cultures (21%) compared with earlier cohorts (P < .001 for both), signifying a less severely ill population presenting with cryptococcal meningitis. Two-week mortality was lowest among participants with cryptococcal meningitis enrolled in a clinical trial in the 2018-2022 cohort at 13% compared to 26% in both 2010-2012 and 2013-2017 (P < .001). While AIDS-related deaths have dramatically declined over the past 12 years, cryptococcosis persists, presenting challenges to HIV program implementation. Two-week mortality has improved in the most recent cohort, likely due to the establishment of cryptococcal screening programs, better supportive care including scheduled lumbar punctures, and the availability of flucytosine-an essential component of antifungal therapy.

Background The EnACT trial was a phase 2 randomized clinical trial conducted in Uganda, which evaluated a novel orally delivered lipid nanocrystal (LNC) amphotericin B in combination with flucytosine for the treatment of cryptococcal meningitis. When flucytosine (5FC) is used as monotherapy in cryptococcosis, 5FC can induce resistant Cryptococcus mutants. Oral amphotericin B uses a novel drug delivery mechanism, and we assessed whether resistance to 5FC develops during oral LNC-amphotericin B therapy.Methods We enrolled Ugandans with HIV diagnosed with cryptococcal meningitis and who were randomized to receive 5FC and either standard intravenous (IV) amphotericin B or oral LNC-amphotericin B. We used broth microdilution to measure the minimum inhibitory concentration (MIC) of the first and last cryptococcal isolates in each participant. Breakpoints are inferred from 5FC in Candida albicans. We measured cerebral spinal fluid (CSF) 5FC concentrations by liquid chromatography and tandem mass spectrometry.Results Cryptococcus 5FC MIC50 was 4 mu g/mL, and MIC90 was 8 mu g/mL. After 2 weeks of therapy, there was no evidence of 5FC resistance developing, defined as a >4-fold change in susceptibility in any Cryptococcus isolate tested. The median CSF 5FC concentration to MIC ratio (interquartile range) was 3.0 (1.7-5.5) mu g/mL. There was no association between 5FC/MIC ratio and early fungicidal activity of the quantitative rate of CSF yeast clearance (R-2 = 0.004; P = .63).Conclusions There is no evidence of baseline resistance to 5FC or incident resistance during combination therapy with oral or IV amphotericin B in Uganda. Oral amphotericin B can safely be used in combination with 5FC.

Abstract Background Tuberculous meningitis (TBM) mortality averages at 27% but may reach 70% in HIV co-infection. High MRC severity grade, lower cerebrospinal fluid (CSF) white blood cell count (WBC) count, low weight, low CD4 and low plasma sodium were linked to mortality in Vietnam. Prognostic factors in African adults with HIV-associated TBM are unknown. We sought to determine the baseline factors predictive of death in HIV-positive Ugandan adults with TBM. Methods We prospectively enrolled patients who received TBM treatment and were classified as definite, probable or possible TBM by the uniform case definition from January 2019 to March 2023 in two National Referral Hospitals in Uganda. Participants received standard quadruple TB and corticosteroid therapy. We assessed association between baseline clinical and CSF characteristics (WBC< 5, 5-100, >100 cells/µl), antiretroviral therapy (ART) status and 14-day mortality. Results In 261 participants, median age was 36 years, 46% were women, median CD4 count was 74 cells/µl. 27% had definite, 39% probable, and 34% possible TBM. 142 (54%) had baseline CSF WBC < 5, 50 (19%) had 5-100, and 69 (27%) had >100 cells/µl. Overall, 14-day mortality was 25.9%. Mortality was 73.6% in participants with CSF WBC count < 5, 7.5% in 5-100, and 18.9% in >100 cells/µl, p=0.0012. Factors associated with 14-day mortality were MRC severity grade, CSF WBC, CSF opening pressure (OP), CSF protein and glucose, CD4 count. ART status did not influence survival. The hazard of 14-day mortality was 4 times as high for those with CSF WBC < 5 cells/µl as for those with >100 cells/ µl (95%CI 1.47-11.5, P=0.004). However, on adjustment for Glasgow Coma Scale (GCS), CSF OP, glucose, and CD4 count the association was less significant (aHR, 2.93, 0.82-10.4, P=0.13). Conclusion 14-day mortality varied significantly by baseline CSF WBC group, being extremely high (73.6%) in those with a paucity of CSF inflammation (WBC < 5 cells/µl). Those with intermediate inflammation (CSF WBC 5-100 cells/µl) had lowest mortality in-line with the damage response framework parabola. The association with acellular CSF and mortality was ameliorated by adjustment for CD4 count. CSF inflammation is at predictor of mortality in HIV-associated TBM and CSF WBC-directed corticosteroid therapy needs further exploration. Disclosures All Authors: No reported disclosures

Using Community Feedback to Inform Strategies for Inclusive Participation in Research: Lessons Learned From the Louisiana Community Engagement Alliance (LA-CEAL) Leslie S. Craig PhD, Daniel F. Sarpong PhD, Erin M. Peacock PhD, MPH, Shearon Roberts PhD, Katherine P. Theall PhD, LaKeisha Williams PharmD, MSPH, Sara Al-Dahir PhD, PharmD, Terry C. Davis PhD, Connie L. Arnold PhD, Allie Williams , Tynesia Fields MPA, Michelle Wilson MPH, and Marie Krousel-Wood MD, MSPH Affiliation Leslie S. Craig, Erin M. Peacock, Michelle Wilson, and Marie Krousel-Wood are with Tulane University, School of Medicine, Department of Medicine, Center for Health Outcomes, Implementation and Community-Engaged Science, New Orleans, LA. Daniel F. Sarpong, LaKeisha Williams, Sara Al-Dahir, and Tynesia Fields are with Xavier University of Louisiana, College of Pharmacy, New Orleans. Shearon Roberts is with Xavier University of Louisiana, Department of Mass Communication, New Orleans. Katherine P. Theall and Allie Williams are with Tulane University, School of Public Health and Tropical Medicine, New Orleans. Terry C. Davis and Connie L. Arnold are with Louisiana State University Health Sciences Center‒Shreveport, Shreveport, LA. CopyRightCorrespondence should be sent to Marie Krousel-Wood, MD, MSPH, Tulane University, School of Medicine, Department of Medicine, Center for Health Outcomes, Implementation and Community-Engaged Science, Suite 2400, New Orleans, LA 70112 (e-mail: mawood@tulane.edu). Reprints can be ordered at https://ajph.org by clicking the “Reprints” link. CONTRIBUTORS L. S. Craig conceptualized and wrote the original draft of the article. M. Krousel-Wood, D. F. Sarpong, E. M. Peacock, and L. Williams acquired LA-CEAL funding. D. F. Sarpong, E. M. Peacock, L. S. Craig, S. Roberts, M. Krousel-Wood, and K. P. Theall led qualitative study and quantitative survey design. E. M. Peacock, L. S. Craig, D. F. Sarpong, S. Roberts, M. Wilson, and T. Fields coordinated data collection. All authors provided critical review of the article. https://doi.org/10.2105/AJPH.2023.307457 Accepted: September 15, 2023 Published Online: November 09, 2023

BACKGROUND:Diverse, equitable and inclusive participation in clinical research is needed to ensure evidence-based clinical practice and lessen disparities in health outcomes. Yet, clinical trial participation remains critically low in minoritized communities, particularly among Blacks. The Louisiana Community Engagement Alliance against COVID-19 Disparities (LA-CEAL) was launched in response to the disproportionate impact of COVID-19 on Black Louisianans to understand community barriers and preferences and increase inclusive participation in research. This study aims to understand perceptions regarding COVID-19 trial participation among underrepresented Louisianans.METHODS:A rapid assessment integrating cross-sectional, surveys among federally qualified health center (FQHC) patients and community residents, and focus group discussions (FGDs) from community representatives was conducted in 2020-2021. Factors and perceptions underlying trial participation were identified using logistic regression models and thematic analyses, respectively.RESULTS:Quantitative findings (FQHC: N=908, mean age=46.6 years, 66.4% Black; community: N=504, mean age=54.2 years, 93.7% Black) indicated that 0.9% and 3.6%, respectively, ever participated in a COVID-19 trial. Doctors/Healthcare providers were most trusted (FQHC=55.1%; community=59.3%) sources of information about trials. Advancing age was associated with increased odds of being very willing to participate (ORFQHC=1.03, 95% CI 1.02-1.05; ORCommunity=1.02, 95% CI 1.00-1.04). Qualitative data (6 FGDs, 29 attendees) revealed limited awareness, experimentation/exploitation-based fears, and minimal racial/ethnic representation among trialists as barriers to participation.CONCLUSION:COVID-19 trial participation rates were low in our sample. Altruism was a key facilitator to participation; fear, mistrust, and low awareness were predominant barriers. Community-centered approaches, engaging informed providers and trusted community members, may facilitate inclusive trial participation.

BACKGROUND:It is unknown whether persons with symptomatic cryptococcal meningitis detected during routine blood cryptococcal antigen (CrAg) screening have better survival than persons presenting with overt meningitis. METHODS:We prospectively enrolled Ugandans with HIV and cryptocococcal meningitis from December 2018 to December 2021. Participants were treated with amphotericin-based combination therapy. We compared outcomes between persons who were CrAg screened then referred to hospital with those presenting directly to the hospital with symptomatic meningitis. RESULTS:Among 489 participants with cryptococcal meningitis, 40% (194/489) received blood CrAg screening and were referred to hospital (median time to referral 2 days; interquartile range [IQR], 1-6). CrAg-screened persons referred to hospital had lower 14-day mortality than non-CrAg-screened persons who presented directly to hospital with symptomatic meningitis (12% vs 21%; hazard ratio, .51; 95% confidence interval, .32-.83; P = .006). Fewer CrAg-screened participants had altered mental status versus non-CrAg-screened participants (29% vs 41%; P = .03). CrAg-screened persons had lower quantitative cerebrospinal fluid (CSF) culture burden (median [IQR], 4570 [11-100 000] vs 26 900 [182-324 000] CFU/mL; P = .01) and lower CSF opening pressures (median [IQR], 190 [120-270] vs 225 [140-340] mmH2O; P = .004) compared with non-CrAg-screened persons. CONCLUSIONS:Survival from cryptococcal meningitis was higher in persons with prior CrAg screening than those without CrAg screening. Altered mental status was the most potent predictor for mortality in a multivariate model. We suggest that CrAg screening detects cryptococcal meningitis at an earlier stage, as evidenced by a favorable baseline risk profile and notably fewer persons with altered mental status.

Background Amphotericin B is the gold standard treatment for severe mycoses. A new orally delivered, less-toxic formulation of amphotericin has been developed. Methods In our randomized clinical trial, we tested oral lipid nanocrystal (LNC) amphotericin B (MAT2203, Matinas Biopharma) vs intravenous (IV) amphotericin for human immunodeficiency virus-associated cryptococcal meningitis in 4 sequential cohorts. Two pilot cohorts assessed safety and tolerability (n = 10 each), and 2 cohorts assessed efficacy with/without 2 IV loading doses (n = 40 each). The experimental arm received 1.8 g/d oral LNC amphotericin through 2 weeks with 100 mg/kg/d flucytosine, then 1.2 g/d LNC amphotericin through 6 weeks. The randomized control arm (n = 41) received 7 days of IV amphotericin with flucytosine, then 7 days of fluconazole 1200 mg/d. The primary end point was cerebrospinal fluid (CSF) early fungicidal activity (EFA). Results We randomized 80 participants to oral LNC amphotericin + flucytosine with (n = 40) and without (n = 40) 2 IV loading doses and 41 control participants to IV amphotericin + flucytosine. Mean EFA was 0.40 log(10) colony-forming units (CFU)/mL/d for all-oral LNC amphotericin, 0.42 log(10)Cryptococcus CFU/mL/d for oral LNC amphotericin with IV loading doses, and 0.46 log(10) CFU/mL/d for IV amphotericin controls. LNC amphotericin groups achieved 2-week CSF sterility in 63% (44 of 70) vs 68% (23 of 34) of controls. The 18-week survival was 85% (34 of 40) with all-oral LNC amphotericin, 90% (36 of 40) with oral LNC amphotericin given IV loading doses, and 85% (35 of 41) with IV amphotericin. Grade 3-4 laboratory adverse events occurred less frequently in LNC amphotericin groups (41%) than the IV amphotericin group (61%, P = .05), particularly for anemia (21% vs 44%; P = .01) and potassium (5% vs 17%; P = .04). Conclusions This new oral amphotericin B LNC formulation appears promising for cryptococcal meningitis with antifungal activity, similar survival, and less toxicity than IV amphotericin. A new oral amphotericin B lipid nanocrystal formulation appears promising for cryptococcal meningitis with similar quantitative antifungal activity in human CSF, similar 18-week survival, and less toxicity than intravenous amphotericin B in a randomized phase 2 trial.

Abstract Background The COVID-19 pandemic has disproportionately impacted individuals in carceral facilities – both incarcerated people and staff. Vaccination is an important tool in reducing the risk of COVID-19 infection, hospitalization, and death. While the importance of promoting vaccination is clear, there are considerable barriers to doing so. This study aims to better understand: (1) why individuals chose to receive the COVID-19 vaccine; (2) why individuals were hesitant to vaccinate; (3) what motivators might influence a person’s decision to get vaccinated; and (4) what sources of information about COVID-19 vaccination people trust. Methods We conducted a survey of incarcerated people and facility staff in three, large state prisons in Minnesota to identify barriers and facilitators to COVID-19 vaccination. Facilities were recruited to participate through purposive sampling, and surveys were administered between November and December 2021. Descriptive statistics were calculated using Stata. Results Findings demonstrate that, for incarcerated individuals (N = 1,392), the most common reason for getting vaccinated was to return to normal activities in prison (61%, n = 801); the most common reason for being hesitant to get vaccinated was “other” (41%, n = 342), with individuals citing a variety of concerns. For staff (N = 190), the most common reason for getting vaccinated was to protect the health of family and friends (79%, n = 114); the most common reasons for being hesitant were disbelief that vaccination is necessary (55%, n = 23) and distrust of healthcare and public health systems (55%, n = 23). Incarcerated individuals reported that monetary and programmatic incentives would help motivate them to get vaccinated, while staff members said speaking with healthcare professionals and monetary incentives would help motivate them. Lastly, trusted sources of information for incarcerated individuals were healthcare professionals outside of prisons and jails, along with friends and family members. Staff members reported that they trusted healthcare professionals and national health organizations for information about COVID-19 vaccination. Conclusions While considerable barriers to COVID-19 vaccination persist among both incarcerated individuals and staff members, these findings also highlight areas of intervention to increase COVID-19 vaccine confidence and promote health equity among those disproportionately impacted by the COVID-19 pandemic.

Abstract Background The EnACT trial was a phase 2 randomized clinical trial conducted in Uganda, which evaluated a novel orally delivered lipid nanocrystal (LNC) amphotericin B for treatment of cryptococcal meningitis. Oral LNC amphotericin B applies nanotechnology, which hopes to improve intracellular drug delivery to affected tissues while reducing extracellular concentrations and thereby adverse events. When flucytosine (5-FC) is used as monotherapy, it can induce stable, highly resistant mutants of Cryptococcus. Since LNC amphotericin is a novel drug delivery mechanism, we assessed whether resistance to 5-FC develops in this context. Results from the ACTA and AMBITION Clinical Trials 10-week mortality by antifungal regimen for cryptococcal meningitis from the clinical trial by Molloy et al. (ACTA) in top section and Jarvis et al. (AMBITION) in bottom section. Mean survival for each group is represented by diamonds and 95% confidence interval represented by error bars. Encapsulation of Amphotericin B in a Lipid nanocrystal Particle Lipid nanocrystal particle encapsulates amphotericin B molecule and delivers the drug to antigen presenting cells. Methods The trial enrolled subjects with HIV who were diagnosed with cryptococcal meningitis and randomized to receive 5-FC and either standard IV amphotericin or LNC amphotericin. Subjects had a lumbar puncture (LP) performed on screening and days 3, 7, and 14. We used broth microdilution methods, standardized by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) to assess the MIC of isolates in each arm of the trial. We tested cryptococcal isolates from the cerebrospinal fluid (CSF) on the day of screening and then on the last positive CSF to contain cryptococcal growth. Statistical analysis included chi-square to test for a difference in MIC between the control and LNC amphotericin groups; and linear regression to compare MIC with early fungicidal activity (EFA), which is a surrogate endpoint. Intervention and Control Gropus for EnACT Phase 2 The EnACT trial phase 2 was completed in 4 cohorts to determine the ideal combination of IV and LNC amphotericin. The MIC analysis was completed in the 4th cohort. In the 4th cohort, participants randomized to the intervention group started LNC amphotericin B from the day of enrollment. Broth Microdilution for 5-Flucytosine Susceptibility Testing A 96-well plate was prepared with serial dilutions of 5-FC ranging from 256 µg/mL to 0.5 µg/mL in columns 1-10. Columns 11 and 12 were drug-free controls. The first and last CSF isolate from each unique participant was inoculated into rows B-D and E-G, respectively. The first row is a negative control and the last row is a positive control. Results The MIC50 was 4 µg/mL and MIC90 was 8 µg/mL for both the control and LNC amphotericin B groups. There was no evidence of 5-FC resistance in any Cryptococcus isolate tested after 2 weeks of therapy. 73% (n=8) of participants in the control group and 73% (n=19) in the LNC amphotericin group had no change or a decrease in MIC from the first to last Cryptococcus isolate. 27% (n=3) in the control group and 19% (n=5) in the LNC amphotericin group had a 2-fold increase in MIC. 9% (n=2) in the LNC amphotericin group had a 4-fold increase in MIC. There was no association with MIC and EFA. 5-FC CSF levels were above the MIC50. Distribution of MIC for flucytosine The MIC for each CSF isolate in the control and oral amphotericin B arms of the trial with the percents of each MIC level in each trial arm. Chi-squared statistic testing for a difference in MIC between each trial arm. Early Fungicidal Activity Compared to MIC for Each Trial Arm The EFA is compared to MIC in the control and oral amphotericin groups. Linear regression comparing EFA and control group shows that there is no correlation between MIC and EFA. Change in MIC During Treatment with Flucytosine and Amphotericin B A) Percent of participants in each trial group who had an increase in MIC over the treatment course. B) Individual participants are represented by a line with the MIC represented by a dot on the end of each line. Conclusion There is no evidence of baseline resistance to 5-FC or incident resistance during therapy in individuals presenting with cryptococcal meningitis in Uganda. LNC amphotericin B can safely be used in combination with 5-FC. Disclosures All Authors: No reported disclosures

Abstract Background Increased intracranial pressure (ICP) frequently complicates cryptococcal meningitis. Therapeutic lumbar punctures (LPs) have acute survival benefits in the first week, and we sought to understand the longer-term survival impact of therapeutic LPs. Methods We prospectively enrolled human immunodeficiency virus (HIV)–seropositive adults with cryptococcal meningitis from 2013 to 2017 in Uganda. We assessed the association between clinical characteristics, CSF parameters, and 14- and 30-day mortality by baseline ICP. We also assessed 30-day mortality by number of follow-up therapeutic LPs performed within 7 days. Results Our analysis included 533 participants. Participants with baseline ICP >350 mm H2O were more likely to have Glasgow Coma Scale (GCS) score <15 (P < .001), seizures (P < .01), and higher quantitative cryptococcal cultures (P < .001), whereas participants with ICP <200 mm H2O were more likely to have baseline sterile CSF cultures (P < .001) and CSF white blood cell count ≥5 cells/µL (P = .02). Thirty-day mortality was higher in participants with baseline ICP >350 mm H2O and ICP <200 mm H2O as compared with baseline ICP 200–350 mm H2O (hazard ratio, 1.55 [95% confidence interval, 1.10–2.19]; P = .02). Among survivors at least 7 days, the 30-day relative mortality was 50% higher among participants who did not receive any additional therapeutic LPs compared to those with ≥1 additional follow-up LP (33% vs 22%; P = .04), irrespective of baseline ICP. Conclusions Management of increased ICP remains crucial in improving clinical outcomes in cryptococcal meningitis. Guidelines should consider an approach to therapeutic LPs that is not dictated by baseline ICP.

Abstract Background Sodium abnormalities are frequent in central nervous system infections and may be caused by cerebral salt wasting, syndrome of inappropriate antidiuretic hormone secretion, or medication adverse events. In cryptococcal meningitis (CM), the prevalence of baseline hyponatremia and whether hyponatremia adversely impacts survival is unknown. Methods We conducted a secondary analysis of data from 2 randomized trials of human immunodeficiency virus–infected adult Ugandans with CM. We grouped serum sodium into 3 categories: <125, 125–129, and 130–145 mmol/L. We assessed whether baseline sodium abnormalities were associated with clinical characteristics and survival. Results Of 816 participants with CM, 741 (91%) had a baseline sodium measurement available: 121 (16%) had grade 3–4 hyponatremia (<125 mmol/L), 194 (26%) had grade 2 hyponatremia (125–129 mmol/L), and 426 (57%) had a baseline sodium of 130–145 mmol/L. Hyponatremia (<125 mmol/L) was associated with higher initial cerebrospinal fluid (CSF) quantitative culture burden (P < .001), higher initial CSF opening pressure (P < .01), lower baseline Glasgow Coma Scale score (P < .01), and a higher percentage of baseline seizures (P = .03). Serum sodium <125 mmol/L was associated with increased 2-week mortality in unadjusted and adjusted survival analyses (adjusted hazard ratio, 1.87 [95% confidence interval, 1.26–2.79]; P < .01) compared to those with sodium 130–145 mmol/L. Conclusions Hyponatremia is common in CM and is associated with excess mortality. A standardized management approach to correctly diagnose and correct hyponatremia in CM needs to be developed and tested.