Antibody Responses in HIV-Infected Patients With Advanced Immunosuppression and Asymptomatic Cryptococcal Antigenemia.

BACKGROUND: There are no host biomarkers of risk for HIV-associated cryptococcal meningitis (CM) except CD4+ T-cell deficiency. At present, serum cryptococcal antigen (CrAg) screening of those with CD4 <100 cells/µL is used to identify persons at risk for HIV-associated CM. We determined if plasma antibody profiles could discriminate CrAg+ from CrAg- patients. METHODS: We performed serological analyses of 237 HIV-infected asymptomatic Zimbabwean patients with CD4 <100 cells/µL; 125 CrAg- and CrAg+ but cerebrospinal fluid CrAg- by CrAg lateral flow assay. We measured plasma immunoglobulin M (IgM), immunoglobulin G (IgG) 1, and IgG2 concentrations by Luminex, and titers of Cryptococcus neoformans (Cn) glucuronoxylomannan (GXM) polysaccharide and naturally occurring Laminarin (natural Lam, a β-(1-3)-glucan linked polysaccharide)-binding IgM and IgG by enzyme-linked immunosorbent assay. RESULTS: GXM-IgG, -IgM, and -IgG2 levels were significantly higher in CrAg+ patients, whereas natural Lam-IgM and Lam-IgG were higher in CrAg- patients before and after adjustment for age, sex, and CD4 T-cell count, despite overlap of values. To address this variability and better discriminate the groups, we used Akaike Information Criteria to select variables that independently predicted CrAg+ status and included them in a receiver operating characteristic curve to predict CrAg status. By inclusion of CD4, GXM-IgG, GXM-IgM, and Lam-IgG, -IgG2, and -IgM, this model had an 80.4% probability (95% confidence interval, 0.75-0.86) of predicting CrAg+ status. CONCLUSIONS: Statistical models that include multiple serological variables may improve the identification of patients at risk for CM and inform new directions in research on the complex role that antibodies may play in resistance and susceptibility to CM

Adverse outcomes after partner bereavement in people with reduced kidney function: Parallel cohort studies in England and Denmark.

OBJECTIVES: To investigate whether partner bereavement is associated with adverse cardiovascular and kidney-related events in people with reduced kidney function. DESIGN: Two parallel matched cohort studies using linked routinely collected health data. SETTING: England (general practices and hospitals using linked Clinical Practice Research Datalink, Hospital Episode Statistics, and Office of National Statistics) and Denmark (hospitals and community pharmacies using the Danish National Patient, Prescription and Education Registries and the Civil Registration System). PARTICIPANTS: Bereaved people with reduced kidney function (estimated glomerular filtration rate (eGFR) <60mL/min/1.73m2 (England) or hospital-coded chronic kidney disease (Denmark)) and non-bereaved people with reduced kidney function similarly defined, matched on age, sex, general practice (England), and county of residence (Denmark) and followed-up from the bereavement date of the exposed person. MAIN OUTCOME MEASURES: Cardiovascular disease (CVD) or acute kidney injury (AKI) hospitalization, or death. RESULTS: In people with reduced kidney function, we identified 19,820 (England) and 5,408 (Denmark) bereaved individuals and matched them with 134,828 (England) and 35,741 (Denmark) non-bereaved individuals. Among the bereaved, the rates of hospitalizations (per 1000 person-years) with CVD were 31.7 (95%-CI: 30.5-32.9) in England and 78.8 (95%-CI: 74.9-82.9) in Denmark; the rates of hospitalizations with AKI were 13.2 (95%-CI: 12.5-14.0) in England and 11.2 (95%-CI: 9.9-12.7) in Denmark; and the rates of death were 70.2 (95%-CI: 68.5-72.0) in England and 126.4 (95%-CI: 121.8-131.1) in Denmark. After adjusting for confounders, we found increased rates of CVD (England, HR 1.06 [95%-CI: 1.01-1.12]; Denmark, HR 1.10 [95%-CI: 1.04-1.17]), of AKI (England, HR 1.20 [95%-CI: 1.10-1.31]; Denmark HR 1.36 [95%-CI: 1.17-1.58]), and of death (England, HR 1.10 [95%-CI: 1.05-1.14]; Denmark HR 1.20 [95%-CI: 1.15-1.25]) in bereaved compared with non-bereaved people. CONCLUSIONS: Partner bereavement is associated with an increased rate of CVD and AKI hospitalization, and death in people with reduced kidney function. Additional supportive care for this at-risk population may help prevent serious adverse events

Survival following screening and preemptive antifungal therapy for subclinical cryptococcal disease in advanced HIV infection

OBJECTIVES: Our study’s primary objective was to compare 1-year survival rates between serum cryptococcal antigen (sCrAg)-positive and sCrAg-negative HIV-positive individuals with CD4 counts <100 cells/μl without symptoms of meningitis in Zimbabwe. DESIGN: This was a prospective cohort study. METHODS: Participants were enrolled as either sCrAg-positive or sCrAg-negative and followed up for ≤52 weeks, with death as the outcome. Lumbar punctures (LPs) were recommended to all sCrAg-positives and inpatient management with intravenous amphotericin B and high-dose fluconazole was recommended to those with disseminated Cryptococcus. Antiretroviral therapy was initiated immediately in sCrAg-negatives and after ≥4 weeks following initiation of antifungals in sCrAg-positives. Multivariable logistic regression models were used to determine risk factors for mortality. RESULTS: We enrolled 1320 participants and 130 (9.8%) were sCrAg positive, with a median sCrAg titre of 1:20. Sixty-six (50.8%) sCrAg-positives had LPs and 16.7% (11/66) had central nervous system (CNS) dissemination. Cryptococcal blood cultures were performed in 129 sCrAg-positives, with 10 (7.8%) being positive. One-year (48–52 weeks) survival rates were 83.9% and 76.1 % in sCrAg-negatives and sCrAg-positives, respectively, p=0.011. Factors associated with increased mortality were a positive sCrAg, CD4 count <50 cells/μl and having presumptive tuberculosis (TB) symptoms. CONCLUSION: Our study reports a high prevalence of subclinical cryptococcal antigenemia and reiterates the importance of TB and a positive sCrAg as risk factors for mortality in advanced HIV disease (AHD). Therefore, TB and sCrAg screening remains a crucial component of AHD package, hence it should always be part of the comprehensive clinical evaluation in AHD patients

Cost-effectiveness of single, high-dose, liposomal amphotericin regimen for HIV-associated cryptococcal meningitis in five countries in sub-Saharan Africa: an economic analysis of the AMBITION-cm trial

BackgroundHIV-associated cryptococcal meningitis is a leading cause of AIDS-related mortality. The AMBITION-cm trial showed that a regimen based on a single high dose of liposomal amphotericin B deoxycholate (AmBisome group) was non-inferior to the WHO-recommended treatment of seven daily doses of amphotericin B deoxycholate (control group) and was associated with fewer adverse events. We present a five-country cost-effectiveness analysis.MethodsThe AMBITION-cm trial enrolled patients with HIV-associated cryptococcal meningitis from eight hospitals in Botswana, Malawi, South Africa, Uganda, and Zimbabwe. Taking a health service perspective, we collected country-specific unit costs and individual resource-use data per participant over the 10-week trial period, calculating mean cost per participant by group, mean cost-difference between groups, and incremental cost-effectiveness ratio per life-year saved. Non-parametric bootstrapping and scenarios analyses were performed including hypothetical real-world resource use. The trial registration number is ISRCTN72509687, and the trial has been completed.FindingsThe AMBITION-cm trial enrolled 844 participants, and 814 were included in the intention-to-treat analysis (327 from Uganda, 225 from Malawi, 107 from South Africa, 84 from Botswana, and 71 from Zimbabwe) with 407 in each group, between Jan 31, 2018, and Feb 17, 2021. Using Malawi as a representative example, mean total costs per participant were US$1369 (95$1237 (1181-1293) in the control group. The incremental cost-effectiveness ratio was $128 (59-257) per life-year saved. Excluding study protocol-driven cost, using a real-world toxicity monitoring schedule, the cost per life-year saved reduced to$80 (15-275). Changes in the duration of the hospital stay and antifungal medication cost showed the greatest effect in sensitivity analyses. Results were similar across countries, with the cost per life-year saved in the real-world scenario ranging from $71 in Botswana to$121 in Uganda.InterpretationThe AmBisome regimen was cost-effective at a low incremental cost-effectiveness ratio. The regimen might be even less costly and potentially cost-saving in real-world implementation given the lower drug-related toxicity and the potential for shorter hospital stays.FundingEuropean Developing Countries Clinical Trials Partnership, Swedish International Development Cooperation Agency, Wellcome Trust and Medical Research Council, UKAID Joint Global Health Trials, and the National Institute for Health Research.TranslationsFor the Chichewa, Isixhosa, Luganda, Setswana and Shona translations of the abstract see Supplementary Materials section

Single-Dose Liposomal Amphotericin B Treatment for Cryptococcal Meningitis.

BackgroundCryptococcal meningitis is a leading cause of human immunodeficiency virus (HIV)-related death in sub-Saharan Africa. Whether a treatment regimen that includes a single high dose of liposomal amphotericin B would be efficacious is not known.MethodsIn this phase 3 randomized, controlled, noninferiority trial conducted in five African countries, we assigned HIV-positive adults with cryptococcal meningitis in a 1:1 ratio to receive either a single high dose of liposomal amphotericin B (10 mg per kilogram of body weight) on day 1 plus 14 days of flucytosine (100 mg per kilogram per day) and fluconazole (1200 mg per day) or the current World Health Organization-recommended treatment, which includes amphotericin B deoxycholate (1 mg per kilogram per day) plus flucytosine (100 mg per kilogram per day) for 7 days, followed by fluconazole (1200 mg per day) for 7 days (control). The primary end point was death from any cause at 10 weeks; the trial was powered to show noninferiority at a 10-percentage-point margin.ResultsA total of 844 participants underwent randomization; 814 were included in the intention-to-treat population. At 10 weeks, deaths were reported in 101 participants (24.8%; 95% confidence interval [CI], 20.7 to 29.3) in the liposomal amphotericin B group and 117 (28.7%; 95% CI, 24.4 to 33.4) in the control group (difference, -3.9 percentage points); the upper boundary of the one-sided 95% confidence interval was 1.2 percentage points (within the noninferiority margin; P10 colony-forming units (CFU) per milliliter per day in the liposomal amphotericin B group and -0.42 log10 CFU per milliliter per day in the control group. Fewer participants had grade 3 or 4 adverse events in the liposomal amphotericin B group than in the control group (50.0% vs. 62.3%).ConclusionsSingle-dose liposomal amphotericin B combined with flucytosine and fluconazole was noninferior to the WHO-recommended treatment for HIV-associated cryptococcal meningitis and was associated with fewer adverse events. (Funded by the European and Developing Countries Clinical Trials Partnership and others; Ambition ISRCTN number, ISRCTN72509687.)