BackgroundThe rapid development of vaccines in response to the COVID-19 pandemic has provided an ... more 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 res...
BACKGROUND Cryptococcal meningitis is a leading cause of human immunodeficiency virus (HIV)relate... more BACKGROUND Cryptococcal 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. METHODS In 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. RESULTS A 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; P<0.001 for noninferiority). Fungal clearance from cerebrospinal fluid was −0.40 log 10 colonyforming units (CFU) per milliliter per day in the liposomal amphotericin B group and −0.42 log 10 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%). CONCLUSIONS Single-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.
Background: Cryptococcal meningitis (CM) is a major cause of mortality in HIV programmes in Afric... more Background: Cryptococcal 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, highdose 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). (Continued on next page) * Correspondence: [email protected] Department of Clinical Research, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, UK Botswan...
Objectives To investigate whether partner bereavement is associated with adverse cardiovascular a... more 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...
Background There are no host biomarkers of risk for HIV-associated cryptococcal meningitis (CM) e... more 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 natu...
Background: Cryptococcal meningitis (CM) is a major cause of mortality in HIV programmes in Afric... more Background: Cryptococcal 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, highdose 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).
Cryptococcal disease (CD) remains a leading cause of morbidity and mortality among individuals wi... more Cryptococcal disease (CD) remains a leading cause of morbidity and mortality among individuals with advanced HIV disease (AHD). Identifying point of care (POC) approaches to screening for CD in asymptomatic individuals is important to guide therapeutic management.
OBJECTIVES Our study's primary objective was to compare 1-year survival rates between serum c... more 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...
BackgroundThe rapid development of vaccines in response to the COVID-19 pandemic has provided an ... more 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 res...
BACKGROUND Cryptococcal meningitis is a leading cause of human immunodeficiency virus (HIV)relate... more BACKGROUND Cryptococcal 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. METHODS In 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. RESULTS A 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; P<0.001 for noninferiority). Fungal clearance from cerebrospinal fluid was −0.40 log 10 colonyforming units (CFU) per milliliter per day in the liposomal amphotericin B group and −0.42 log 10 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%). CONCLUSIONS Single-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.
Background: Cryptococcal meningitis (CM) is a major cause of mortality in HIV programmes in Afric... more Background: Cryptococcal 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, highdose 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). (Continued on next page) * Correspondence: [email protected] Department of Clinical Research, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, UK Botswan...
Objectives To investigate whether partner bereavement is associated with adverse cardiovascular a... more 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...
Background There are no host biomarkers of risk for HIV-associated cryptococcal meningitis (CM) e... more 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 natu...
Background: Cryptococcal meningitis (CM) is a major cause of mortality in HIV programmes in Afric... more Background: Cryptococcal 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, highdose 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).
Cryptococcal disease (CD) remains a leading cause of morbidity and mortality among individuals wi... more Cryptococcal disease (CD) remains a leading cause of morbidity and mortality among individuals with advanced HIV disease (AHD). Identifying point of care (POC) approaches to screening for CD in asymptomatic individuals is important to guide therapeutic management.
OBJECTIVES Our study's primary objective was to compare 1-year survival rates between serum c... more 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...
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