Background Cryptococcal meningitis is a leading cause of HIV-related mortality in sub-Saharan Africa. Based on phase-II data, we performed a phase-III randomized controlled non-inferiority trial to determine the efficacy of a single high-dose liposomal amphotericin B based treatment regimen. Methods HIV-positive adults with cryptococcal meningitis in Botswana, Malawi, South Africa, Uganda and Zimbabwe were randomized 1:1 to induction therapy of either (i) single, high-dose liposomal amphotericin B 10mg/kg given with 14 days of flucytosine 100mg/kg/day and fluconazole 1200mg/day (AmBisome group), or (ii) the current WHO recommended treatment of 7 daily doses of amphotericin B deoxycholate (1mg/kg/day) plus flucytosine (100mg/kg/day), followed by 7 days of fluconazole 1200mg/day (control group). The primary endpoint was all-cause mortality at 10 weeks with the trial powered to show non-inferiority at a 10% margin. Results We randomized 844 participants. None were lost-to-follow-up. In intention-to-treat analysis, 10-week mortality was 24.8% (101 of 407; 95% confidence interval [CI] 20.7-29.3%) in the AmBisome group and 28.7% (117 of 407; 95% CI 24.4-33.4%) in controls. The absolute difference in mortality was -3.9%, with an upper 1-sided 95% confidence interval of 1.2%. Fungal clearance from cerebrospinal fluid was -0.40 log 10 CFU/ml/day in the AmBisome group and -0.42 log 10 CFU/ml/day in the control group. Fewer participants experienced grade 3 or 4 adverse events in the AmBisome group than the control group (50.0% vs. 62.3%). Conclusions Single dose liposomal amphotericin B (10mg/kg) on a backbone of flucytosine and fluconazole was non-inferior to the current WHO recommended standard of care for HIV-associated cryptococcal meningitis and associated with fewer adverse events. (Trial registration number: ISRCTN72509687.)

BackgroundCryptococcal meningitis (CM) is a major cause of mortality in HIV programmes in Africa despite increasing access to antiretroviral therapy (ART). Mortality is driven in part by limited availability of amphotericin-based treatment, drug-induced toxicities of amphotericin B deoxycholate and prolonged hospital admissions. A single, high-dose of liposomal amphotericin (L-AmB, Ambisome) on a fluconazole backbone has been reported as non-inferior to 14 days of standard dose L-AmB in reducing fungal burden. This trial examines whether single, high-dose L-AmB given with high-dose fluconazole and flucytosine is non-inferior to a seven-day course of amphotericin B deoxycholate plus flucytosine (the current World Health Organization [WHO] recommended treatment regimen).MethodsAn open-label phase III randomised controlled non-inferiority trial conducted in five countries in sub-Saharan Africa: Botswana, Malawi, South Africa, Uganda and Zimbabwe. The trial will compare CM induction therapy with (1) a single dose (10 mg/kg) of L-AmB given with 14 days of fluconazole (1200 mg/day) and flucytosine (100 mg/kg/day) to (2) seven days amphotericin B deoxycholate (1 mg/kg/day) given alongside seven days of flucytosine (100 mg/kg/day) followed by seven days of fluconazole (1200 mg/day). The primary endpoint is all-cause mortality at ten weeks with a non-inferiority margin of 10% and 90% power. Secondary endpoints are early fungicidal activity, proportion of grade III/IV adverse events, pharmacokinetic parameters and pharmacokinetic/pharmacodynamic associations, health service costs, all-cause mortality within the first two and four weeks, all-cause mortality within the first ten weeks (superiority analysis) and rates of CM relapse, immune reconstitution inflammatory syndrome and disability at ten weeks. A total of 850 patients aged ≥ 18 years with a first episode of HIV-associated CM will be enrolled (425 randomised to each arm). All patients will be followed for 16 weeks. All patients will receive consolidation therapy with fluconazole 800 mg/day to complete ten weeks of treatment, followed by fluconazole maintenance and ART as per local guidance.DiscussionA safe, sustainable and easy to administer regimen of L-AmB that is non-inferior to seven days of daily amphotericin B deoxycholate therapy may reduce the number of adverse events seen in patients treated with amphotericin B deoxycholate and shorten hospital admissions, providing a highly favourable and implementable alternative to the current WHO recommended first-line treatment.Trial registrationISRCTN, ISRCTN72509687. Registered on 13 July 2017.Electronic supplementary materialThe online version of this article (10.1186/s13063-018-3026-4) contains supplementary material, which is available to authorized users.

BackgroundThere 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.MethodsWe 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.ResultsGXM-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.ConclusionsStatistical 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.

BackgroundThe rapid development of vaccines in response to the COVID-19 pandemic has provided an effective tool for the management of COVID-19. However, in Africa there has been a poor uptake of COVID-19 vaccines with only 15% vaccine coverage compared to the WHO global target of 70%. One of the important drivers has been vaccine hesitancy, understanding late adopters of vaccination can provide insights into the attitudes, motivations and influences that can enhance vaccine uptake.MethodsBetween January 4 – February 11, 2022, we conducted a survey among adults presenting for their first dose of a COVID-19 vaccine almost 12-months after the vaccination program began. Vaccines were free and provided at clinics and outreach centers in Harare, Zimbabwe. The questionnaire assessed environmental and individual factors (attitudes, barriers, motivations, key influencers, and information sources) that influenced the decision to present for vaccination. Baseline socio-demographic data and responses to survey questions were summarized using descriptive statistics. Binary logistic regression models were developed to understand factors associated with vaccine confidence.Results1016 adults were enrolled into the study, 508 (50%) were female, 126 (12.4%) had HIV co-infection. The median age was 30 years (IQR 22 – 39). Women were more likely to have negative views about the COVID-19 vaccine compared to men (OR 1.51 (95%CI 1.16, 1.97, p=0.002). Women compared to men and older adults (≥ 40 years) compared with youth (18-25 years) were more likely to have ‘major concerns’ about vaccines. Most concerns were about safety with 602 (59.3%) concerned about immediate and 520 (51.2%) about long-term health effects of vaccines. People living with HIV (PLWH) were more likely to perceive vaccines as safe (OR 1.71 (95%CI: 1.07, 2.74, p=0.025), effective (1.68 (95%CI: 1.07, 2.64, p=0.026) and to trust regulatory systems for approving vaccines (OR 1.79 (95% CI: 1.11, 2.89, p=0.017) compared to those without HIV. Internet users were less likely to perceive vaccines as safe (OR 0.72 (95% CI: 0.55, 0.95, p=0.021), effective (OR 0.61 (95% CI: 0.47, 0.80, p<0.001) or trust regulatory processes for approving vaccines (OR 0.64 (95% CI: 0.48, 0.85, p=0.002) compared to non-internet users. Social influence was a key factor in the decision to be vaccinated with family members being the primary key influencers for 560 (55.2%) participants. The most important reason for receiving the COVID-19 vaccine today for 715 (70.4%) participants was the protection of individual health. The most trusted source of information regarding the vaccine was the Ministry of Health (79.7%) and the radio, television and social media were the preferred sources for obtaining this information. Social media was a more likely source for youth and those with higher levels of education.ConclusionImproving vaccine coverage will need targeted communication strategies that address negative perceptions of vaccines and associated safety and effectiveness concerns. Leveraging normative behavior as a social motivator for vaccination will be important as close social networks are key influences of vaccination. Traditional media remains important for health communication in Africa and should be strengthened to counter social media-based misinformation that drives concerns about safety and effectiveness particularly among internet users.

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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 þ cell counts less than 100 cells/ml 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 or less, with death as the outcome. Lumbar punctures 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 at least 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 lumbar punctures 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 ¼ 0.011. Factors associated with increased mortality were a positive sCrAg, CD4 þ cell count less than 50 cells/ml 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.

IntroductionCryptococcal meningitis is responsible for around 15% of all HIV-related deaths globally. Conventional treatment courses with amphotericin B require prolonged hospitalisation and are associated with multiple toxicities and poor outcomes. A phase II study has shown that a single high dose of liposomal amphotericin may be comparable to standard treatment. We propose a phase III clinical endpoint trial comparing single, high-dose liposomal amphotericin with the WHO recommended first-line treatment at six sites across five counties. An economic analysis is essential to support wide-scale implementation.Methods and analysisCountry-specific economic evaluation tools will be developed across the five country settings. Details of patient and household out-of-pocket expenses and any catastrophic healthcare expenditure incurred will be collected via interviews from trial patients. Health service patient costs and related household expenditure in both arms will be compared over the trial period in a probabilistic approach, using Monte Carlo bootstrapping methods. Costing information and number of life-years survived will be used as the input to a decision-analytic model to assess the cost-effectiveness of a single, high-dose liposomal amphotericin to the standard treatment. In addition, these results will be compared with a historical cohort from another clinical trial.Ethics and disseminationThe AMBIsome Therapy Induction OptimisatioN (AMBITION) trial has been evaluated and approved by the London School of Hygiene and Tropical Medicine, University of Botswana, Malawi National Health Sciences, University of Cape Town, Mulago Hospital and Zimbabwe Medical Research Council research ethics committees. All participants will provide written informed consent or if lacking capacity will have consent provided by a proxy. The findings of this economic analysis, part of the AMBITION trial, will be disseminated through peer-reviewed publications and at international and country-level policy meetings.Trial registrationISRCTN72509687; Pre-results.

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.