Adjunctive Single-Dose Liposomal Amphotericin to Prevent Cryptococcal Meningitis in People With Human Immunodeficiency Virus (HIV)-Associated Cryptococcal Antigenemia and Low Plasma Cryptococcal Antigen (CrAg) Titers.

BACKGROUND: Cryptococcal meningitis is a leading cause of AIDS-related mortality. Cryptococcal antigen (CrAg) predicts the development of meningitis. Historically, despite standard- of-care fluconazole, 25%-30% of asymptomatic CrAg-positive persons develop breakthrough meningitis or death. We evaluated whether adding single high-dose liposomal amphotericin B to standard pre-emptive fluconazole therapy could improve meningitis-free survival. METHODS: Participants with human immunodeficiency virus (HIV) and asymptomatic cryptococcal antigenemia in Uganda were randomized to liposomal amphotericin B (10 mg/kg once) with fluconazole or fluconazole alone through 24 weeks. We compared 24-week, meningitis-free survival time between treatment groups. After the second interim review, the Data Safety and Monitoring Board recommended no further enrollment of participants with low plasma CrAg lateral flow assay titers (≤1:80) due to futility. Herein, we present the results of participants with low plasma CrAg titers. RESULTS: 168 participants enrolled into the ACACIA trial had low plasma CrAg titers (≤1:80). During 24 weeks of follow-up, meningitis or death occurred in 14.5% (12/83) of participants randomized to liposomal amphotericin B with fluconazole versus 10.6% (9/85) assigned to fluconazole alone (hazard ratio, 1.42; 95% CI, .60-3.36; P = .431). Adverse events were more frequent in participants assigned to the intervention versus standard-of-care (28% vs 12%; P = .011). CONCLUSIONS: Among CrAg-positive persons with low titers (≤1:80), the addition of single-dose liposomal amphotericin B to fluconazole as pre-emptive therapy provided no additional clinical benefit. This trial provides supportive evidence that, in asymptomatic populations with low plasma CrAg titers, lumbar punctures are likely unnecessary as administration of meningitis treatment did not improve outcomes. CLINICAL TRIALS REGISTRATION: Clinicaltrials.gov (NCT03945448).

Effect of Coronavirus Disease 2019 Lockdowns on Identification of Advanced Human Immunodeficiency Virus Disease in Outpatient Clinics in Uganda.

Using data from 67 Ugandan human immunodeficiency virus (HIV) clinics (July 2019-January 2022), we report a 40% (1005/1662) reduction in the number of people with HIV presenting to care after August 2021 compared to prepandemic levels, with a greater proportion presenting with advanced HIV disease (20% vs 16% in the pre-coronavirus disease 2019 period).

Outpatient Cryptococcal Antigen Screening Is Associated With Favorable Baseline Characteristics and Improved Survival in Persons With Cryptococcal Meningitis in Uganda.

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.

Barriers to HIV care in Uganda and implications for universal test-and-treat: a qualitative study.

Achieving universal HIV test-and-treat will require targeted interventions for those with worse outcomes, including advanced HIV. We conducted qualitative, semi-structured interviews with healthcare workers (HCWs) and people living with HIV (PLWH) at 5 HIV clinics in Kampala, Uganda, to understand barriers to care. PLWH enrolled started/restarted on HIV treatment ≤3 months prior. PLWH were grouped as 1) "ART-experienced" or those restarted therapy after ≥12 months off, 2) ART naïve CD4 count <100 cells/uL "late presenters" or 3) ART naïve CD4 count >350 cells/uL "early presenters". In-depth interviews were conducted in Luganda, translated, and transcribed verbatim. Between May and August 2017, 58 PLWH and 20 HCWs were interviewed. High stigma and low social support emerged as themes among all as barriers to care. Alcohol abuse was a barrier for men. Fear of domestic violence and abandonment were barriers for women, limiting disclosure of their HIV status to their male partners. Clinic factors such as rapport with staff, distance, efficiency, and privacy impacted care. Future interventions to decrease delayed ART initiation should target stigma and social support. Assisted disclosure, contact tracing, and alcohol abuse treatment should be implemented. Strengthening client support, reducing wait times, and increasing privacy assurances would improve care-seeking behaviors.

Adjunctive sertraline for asymptomatic cryptococcal antigenemia: A randomized clinical trial.

Cryptococcal antigen (CrAg) screening in HIV-infected persons with CD4 < 100 cells/µl can reduce meningitis and death, yet preemptive fluconazole therapy fails in ∼25%. Sertraline has in vitro and in vivo activity against Cryptococcus and is synergistic with fluconazole in mice. We evaluated the efficacy and safety of sertraline in asymptomatic cryptococcal antigenemia. We conducted a randomized trial of asymptomatic CrAg-positive Ugandans from November 2017 to February 2018. All subjects received WHO standard therapy of fluconazole 800 mg for 2 weeks, then 400 mg for 10 weeks, then 200 mg through 24 weeks. Participants were randomized to receive adjunctive sertraline or placebo, given in once-weekly escalating 100 mg/day doses up to 400 mg/day, which was then given for 8 weeks, then tapered. The primary endpoint was meningitis-free 6-month survival. The data and safety monitoring board halted the trial after 21 subjects were enrolled due to safety concerns. Meningitis-free 6-month survival occurred in 9 of 11 of placebo participants and 10 of 10 of sertraline participants. However, seven serious adverse events (SAEs) occurred (n = 4 sertraline group; n = 3 placebo group). Three SAEs in the sertraline group presented with psychosis and aggressive behavioral changes with one meeting Hunter's criteria for serotonin syndrome while receiving 200 mg/day sertraline. Two transient psychoses were associated with antecedent fluconazole and sertraline interruption. The serotonin syndrome resolved within 1 day, but psychosis persisted for 4 months after sertraline discontinuation. Sertraline was associated with excess SAEs of psychosis. Due to early stopping, we were unable to determine any efficacy for cryptococcal antigenemia.

Baseline C-reactive Protein as a Risk Factor for Cryptococcal Meningitis and Death in HIV-associated Cryptococcal Antigenemia With CrAg Titer as an Effect Modifier.

Background: Persons with HIV and cryptococcal antigenemia are at high risk of progression to cryptococcal meningitis or death. Baseline cryptococcal antigen (CrAg) plasma titer ≥1:160 is a known risk factor for poor outcomes, but other risk factors are unknown. In HIV-associated cryptococcal meningitis, baseline serum C-reactive protein (CRP) concentrations are positively associated with increased mortality. We hypothesized that CRP might also be associated with meningitis or death in persons with cryptococcal antigenemia. Methods: We measured plasma CrAg titers and CRP concentrations on cryopreserved serum from prospectively enrolled persons with HIV and cryptococcal antigenemia. Using time-to-event analyses, we compared 24-week meningitis-free survival in persons with normal CRP (<8 mg/L) and elevated CRP (≥8 mg/L). Logistic regression was used to assess how CRP concentration and CrAg titer might interact as covariates. Results: Of the 94 persons with elevated CRP, 19 (20.2%) developed meningitis or death, whereas of the 88 persons with normal CRP, 8 (9.1%) developed meningitis or death (P = .035). Persons with CrAg titer <1:160 and normal CRP had an ∼5% (3/61) event rate, whereas those with CrAg titer <1:160 but elevated CRP had an ∼20% (12/59) event rate. Importantly, we identified a statistically significant interaction effect between CrAg titer and CRP groups, in which elevated CRP increased risk in the low CrAg titer group (odds ratio, 1.54; 95% confidence interval, 1.16-2.04), but this effect was not present in high CrAg titer group (odds ratio, 0.78; 95% confidence interval, .53-1.15). Conclusions: Our findings demonstrate that CrAg titer may modify the direction of effect of CRP with meningitis-free survival; future studies should account for this interaction.

Hyponatremia as a Predictor of Cryptococcal Meningitis and Death Among Asymptomatic Persons With HIV and Cryptococcal Antigenemia.

Among persons with human immunodeficiency virus-associated cryptococcal meningitis serum hyponatremia is a risk factor for mortality; however, the role of hyponatremia in persons with asymptomatic cryptococcal antigenemia is unknown. We found that serum hyponatremia ≤130 mmol/L is an independent risk factor for progression to meningitis and death in asymptomatic persons with cryptococcal antigenemia.

Adherence of health workers to guidelines for screening and management of cryptococcal meningitis in Uganda.

INTRODUCTION: Health workers' failure to adhere to guidelines for screening, diagnosis and management of HIV-associated cryptococcal meningitis (CM) remains a significant public health concern. We aimed to assess adherence to the standards of care and management of HIV patients at risk of CM per the MoH guidelines and assess stock management of CM supplies in the period of January to June 2021 at selected public health facilities (HFs) in Uganda. METHODS: The study employed an observational cross-sectional design to assess the level of adherence of health workers to standards of clinical care and management of HIV positive patients at risk of CM as per the clinical guidelines for Uganda, and stock management of CM supplies in the period of January to June 2021in selected public health facilities. The study team used a survey guide designed by MoH to assess and score the screening, diagnosis and management practices of Health Facilities towards CM. Scoring was categorized as red (< 80%), light green (80%-95%), and dark green (˃95%) in the order from worst to best adherence. The data was transcribed into a spread sheet and analysed using STATA-v15. RESULTS: The study team visited a total of 15 public health facilities including 5 general hospitals, 9 regional referral hospitals (RRHs) and 1 National Referral hospital (NRH). The mean score for adherence to screening and management of CM for all the combined facilities was 15 (64.7%) classified as red. 10 (66.7%) HFs had not performed a baseline CD4 test for eligible patients within 2 weeks of ART initiation. With regards to treatment, 9 (60%) of the HFs were scored as light green on knowledge of the procedure for reconstituting intravenous Liposomal Amphotericin B. None of the HFs visited had potassium chloride tablets in stock. CONCLUSION: Major MoH guidelines are generally not being adhered to by health workers while managing cryptococcal meningitis. It is vital that government and implementing partners regularly support HFs with training, mentorship, and support supervision on CM management to improve adherence to CM screening and treatment guidelines.