Early antiretroviral therapy (ART) initiation after cryptococcal meningitis increases mortality, ... more Early antiretroviral therapy (ART) initiation after cryptococcal meningitis increases mortality, and those unmasking cryptococcosis after <2 weeks of ART have higher mortality. However, it is unknown if those presenting as ART experienced are actually adherent to their ART. Unknowingly, restarting ART in persons, who have discontinued ART, may be a fatal iatrogenic error. To evaluate ART adherence in an exploratory analysis, we collected dried blood spots on 44 HIV-infected persons presenting with cryptococcal meningitis. We quantified tenofovir diphosphate (TFV-DP) and lamivudine (3TC) from dried blood spots. We quantified cumulative ART adherence over the preceding 6-8 weeks based on TFV-DP concentrations and adherence over the last few days based on 3TC concentrations. Of 22 ART experienced, 20 (91%) had quantifiable concentrations. Of 18 receiving tenofovir, 15 (83%) had TFV-DP consistent with drug intake of ‡4 doses/week or moderate adherence. With 3TC, 72% (18/22) had detectable levels consistent with adherence over the last 3 days before measurement. Only three ART-experienced subjects were alive and virally suppressed at 4 months (n = 2 on ART for <30 days; n = 1 with undetectable antiretrovirals). Surprisingly, of 22 who reported not receiving ART, 4 (18%) had quantifiable tenofovir. Most ART-experienced subjects were taking their ART with moderate to good adherence with the majority likely having viral resistance given generally at good ART levels, receipt of intensive adherence counseling, and lack of subsequent viral suppression. The World Health Organization (WHO) guidelines recommend adherence counseling with ART continuation and repeat viral loads in 1-3 months before switching to second-line ART. These recommendations are likely inappropriate in those with central nervous system infections given the additional possible harm of central nervous system immune reconstitution syndrome. Further study to evaluate continuation of ART regimens when presenting with cryptococcosis has benefit, with checking blood levels at presentation potentially being a helpful option. ClinicalTrials.gov Identifier: NCT01802385.
The role of biological sex on clinical outcomes and the pathogenesis of AIDS-related opportunisti... more The role of biological sex on clinical outcomes and the pathogenesis of AIDS-related opportunistic infections is unknown. We assessed baseline biomarkers and outcomes between 577 men and 400 women in HIV-related cryptococcal meningitis cohorts in Uganda and South Africa from 2010 to 2017. We compared 10-week mortality by sex via Cox proportional hazards models. The 10-week mortality for women was 50% (198/400) and 43% (247/577) for men. Women had higher risk of death in an unadjusted model (Hazard Ratio (HR) = 1.20; 95%CI, 1.00–1.45; P = .05). Women maintained a higher risk when adjusting for quantitative CSF culture, altered mental status, CSF pleocytosis, age, and antiretroviral status (HR = 1.31; 95%CI, 1.07–1.59; P < .01). However, after adjusting for hemoglobin, the risk of death did not differ between women and men (HR = 1.17; 95%CI, 0.94–1.45; P = .17). Moderate to severe anemia (hemoglobin < 8.5 g/dL) was present among 16% (55/355) of women and 10% (55/532) of men (P =...
Background: Despite the high infectivity of SARS-CoV-2, the incidence of COVID-19 in Africa has b... more Background: Despite the high infectivity of SARS-CoV-2, the incidence of COVID-19 in Africa has been slower than predicted. We aimed to investigate a possible association between parasitic infections and COVID-19. Methods: An ecological study in which we analysed WHO data on COVID-19 cases in comparison to WHO data on helminths and malaria cases using correlation, regression, and Geographical Information Services analyses. Results: Of the global 3.34 million COVID-19 cases and 238,628 deaths as at May 4th 2020, Africa reported 0.029/3.3 million (0.88%) cases and 1,064/238,628 (0.45%) deaths. In 2018, Africa reported 213/229 million (93%) of all malaria cases, 204/229 million (89%) of schistosomiasis cases, and 271/1068 million (25%) of soil-transmitted helminth cases globally. In contrast, Europe reported 1.5/3.3 million (45%) of global COVID-19 cases and 142,667/238,628 (59%) deaths. Europe had 5.8/1068 million (0.55%) soil-transmitted helminths cases and no malaria/schistosomiasis...
Background Acceptability of Pre-exposure Prophylaxis (PrEP) could be hampered by low self-perceiv... more Background Acceptability of Pre-exposure Prophylaxis (PrEP) could be hampered by low self-perceived risk for HIV acquisition. Moreover, discordance between risk perception and actual risk of HIV acquisition is likely to occur. We assessed congruence between the level of self- perceived and that of objectively scored risk of HIV acquisition among HIV-negative individuals in discordant relationships. Methods This was a cross-sectional study among a representative sample of HIV-negative adult males and females whose partners were receiving antiretroviral therapy for at least 3 months from the Infectious Diseases Institute Clinic in Kampala, Uganda. Perceived risk was measured based on self-report using a numerical rating scale whereas objective risk was measured using a validated risk score tool. Congruence between perceived risk and objectively scored risk was evaluated using descriptive statistics and validity measures. Incongruence between the two phenomena was further evaluated usi...
Journal of Pharmacokinetics and Pharmacodynamics, 2019
The ASTRO-CM dose-finding pilot study investigated the role of adjunctive sertraline for the trea... more The ASTRO-CM dose-finding pilot study investigated the role of adjunctive sertraline for the treatment of HIV-associated cryptococcal meningitis in HIV-infected Ugandan patients. The present study is a post-hoc pharmacokinetic-pharmacodynamic analysis of the ASTRO-CM pilot study to provide insight into sertraline exposure-response-outcome relationships. We performed a population pharmacokinetic analysis using sertraline plasma concentration data and correlated various predicted PK-PD indices with the percentage change in log 10 CFU/mL from baseline. Sertraline clearance was 1.95-fold higher in patients receiving antiretroviral (ART), resulting in 49 % lower drug exposure To quantify the clinical benefit of sertraline, we estimated rates of fungal clearance from cerebrospinal fluid (CSF) of ASTRO-CM patients using Poisson model and compared the clearance rates to a historical control study (COAT) in which patients received standard Cryptococcus therapy of amphotericin B (0•7-1•0 mg/kg per day) and fluconazole (800 *
W e read with great interest the recent article by Cox et al. regarding the use of the lipoarabin... more W e read with great interest the recent article by Cox et al. regarding the use of the lipoarabinomannan (LAM) lateral flow assay (Determine TB LAM; Alere, Waltham, MA, USA) on cerebrospinal fluid (CSF) for postmortem diagnosis of tuberculous meningitis (TBM) (1). Certainly, TBM is difficult to diagnose, and a delay in diagnosis often leads to poor outcomes for patients with TBM, including death (2, 3). Despite the recent interest in the use of Xpert MTB/Rif for TBM diagnosis (4-6), its sensitivity and negative predictive value remain insufficient for the use of Xpert as a "rule-out" test. The lack of sufficiently accurate and rapid diagnostics for TBM makes LAM an attractive candidate for TBM diagnosis. Cox and colleagues obtained CSF from the fourth ventricle of 91 subjects at autopsy (1). Samples were stored at Ϫ20°C initially, later thawed, and then heated to 95 to 100°C. After cooling, the samples were further processed by spinning (1 ml) at 10,000 rpm for 15 min. LAM testing was performed with 60 l of the supernatant, as well as unprepared CSF (aside from having been frozen) (1). When examining LAM with unprepared CSF against histopathologically definite or probable TBM, the authors found 50% sensitivity and 70% specificity. Against definite TBM cases, 75% sensitivity and 70% specificity were observed (1). When treated CSF supernatant was used, the authors found 88% sensitivity and 70% specificity of LAM against definite TBM cases and 71% sensitivity and 70% specificity against definite or probable cases. These results, if clinically applicable, would rival any currently available technology (4-6). Importantly, this study used autopsy specimens rather than diagnosing living persons via CSF obtained by lumbar puncture. Obtaining CSF from the fourth ventricle, while possible, is much more invasive and is not frequently performed in most settings. As part of our recent evaluation of the role of centrifugation of CSF specimens prior to testing for TBM using Xpert MTB/Rif, we evaluated the TB LAM lateral flow assay used in the study by Cox Citation Bahr NC, Tugume L, Boulware DR. 2016. A word of caution in considering the use of the lipoarabinomannan lateral flow assay on cerebrospinal fluid for detection of tuberculous meningitis.
Background In cryptococcal meningitis phase 2 clinical trials, early fungicidal activity (EFA) of... more Background In cryptococcal meningitis phase 2 clinical trials, early fungicidal activity (EFA) of Cryptococcus clearance from cerebrospinal fluid (CSF) is used as a surrogate endpoint for all-cause mortality. The Food and Drug Administration allows for using surrogate endpoints for accelerated regulatory approval, but EFA as a surrogate endpoint requires further validation. We examined the relationship between rate of CSF Cryptococcus clearance (EFA) and mortality through 18 weeks. Methods We pooled individual-level CSF data from 3 sequential cryptococcal meningitis clinical trials conducted during 2010–2017. All 738 subjects received amphotericin + fluconazole induction therapy and had serial quantitative CSF cultures. The log10-transformed colony-forming units (CFUs) per mL CSF were analyzed by general linear regression versus day of culture over the first 10 days. Results Mortality through 18 weeks was 37% for EFA > = 0.60 (n = 170), 36% for 0.40–0.59 (n = 182), 39% for 0.30–0...
Background Sodium abnormalities are frequent in central nervous system infections and may be caus... more 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 ini...
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.
The World Health Organization (WHO) has published a guideline for the management of individuals w... more The World Health Organization (WHO) has published a guideline for the management of individuals with advanced HIV disease (AHD) to reduce HIV-related deaths. The guideline consists of a package of recommendations including interventions to prevent, diagnose and treat common opportunistic infections, including tuberculosis (TB), cryptococcosis and severe bacterial infections, along with rapid initiation of antiretroviral treatment and enhanced adherence support. Currently no clear targets exist for these key interventions. Emerging programmatic data from Uganda, Tanzania and Nigeria suggest that an estimated 80% of eligible people continue to miss the recommended cryptococcal or TB testing, highlighting the remaining challenges to the effective implementation of WHO-recommended AHD packages of care in real-world resource-limited settings. The absence of mortality indicators for the leading causes of HIV-related deaths, because of the lack of mechanisms to ascertain cause of death, ha...
Objectives Tuberculous meningitis(TBM) is a common cause of meningitis in sub-Saharan Africa. CSF... more Objectives Tuberculous meningitis(TBM) is a common cause of meningitis in sub-Saharan Africa. CSF PCR with GeneXpert RIF/MTB Ultra is only 70% sensitive for detection of definite/probable TBM. Many infections can mimic TBM. Metagenomic next generation sequencing(mNGS) can detect the whole diversity of infectious microbes, but can be insensitive to TB in CSF. We assessed whether leveraging CSF mNGS to identify infections combined with a machine learning classifier(MLC), based on host transcriptomic data generated by mNGS, could enhance diagnostic accuracy for TBM. Methods Prospectively enrolled 347 HIV-infected Ugandan adults with subacute meningitis: RNA/DNA libraries were made from CSF and deep sequenced. Non-human sequences were interrogated to identify pathogens. A host transcriptomic MLC was developed from human RNA transcripts using 70 cases. The MLC and mNGS reporting thresholds were then tested on 108 blinded cases within the cohort. Results mNGS was 75% concordant(27/36) for...
Background High-dose rifampicin may improve outcomes of tuberculous meningitis (TBM). Little safe... more Background High-dose rifampicin may improve outcomes of tuberculous meningitis (TBM). Little safety or pharmacokinetic (PK) data exist on high-dose rifampicin in human immunodeficiency virus (HIV) coinfection, and no cerebrospinal fluid (CSF) PK data exist from Africa. We hypothesized that high-dose rifampicin would increase serum and CSF concentrations without excess toxicity. Methods In this phase II open-label trial, Ugandan adults with suspected TBM were randomized to standard-of-care control (PO-10, rifampicin 10 mg/kg/day), intravenous rifampicin (IV-20, 20 mg/kg/day), or high-dose oral rifampicin (PO-35, 35 mg/kg/day). We performed PK sampling on days 2 and 14. The primary outcomes were total exposure (AUC0–24), maximum concentration (Cmax), CSF concentration, and grade 3–5 adverse events. Results We enrolled 61 adults, 92% were living with HIV, median CD4 count was 50 cells/µL (interquartile range [IQR] 46–56). On day 2, geometric mean plasma AUC0–24hr was 42.9·h mg/L with s...
Background Cerebrospinal fluid (CSF) lactate levels can be used to differentiate between bacteria... more Background Cerebrospinal fluid (CSF) lactate levels can be used to differentiate between bacterial and viral meningitis. We measured CSF lactate in individuals with cryptococcal meningitis to determine its clinical significance. Methods We measured point-of-care CSF lactate at the bedside of 319 Ugandan adults living with human immunodeficiency virus at diagnosis of cryptococcal meningitis. We summarized demographic variables and clinical characteristics by CSF lactate tertiles. We evaluated the association of CSF lactate with clinical characteristics and survival. Results Individuals with high CSF lactate >5 mmol/L at cryptococcal diagnosis more likely presented with altered mental status (P < .0001), seizures (P = .0005), elevated intracranial opening pressure (P = .03), higher CSF white cells (P = .007), and lower CSF glucose (P = .0003) compared with those with mid-range (3.1 to 5 mmol/L) or low (≤3 mmol/L) CSF lactate levels. Two-week mortality was higher among individual...
Over the last decade excellent progress has been made globally in HIV management thanks to antire... more Over the last decade excellent progress has been made globally in HIV management thanks to antiretroviral therapy (ART) rollout and international guidelines now recommending immediate initiation of ART in people living with HIV. Despite this, advanced HIV disease (CD4 less than 200 cells/mL) and opportunistic infections remain a persistent challenge and contribute significantly to HIV-associated mortality, which equates to 23,000 deaths in Uganda in 2018 alone. Our Meningitis Research Team based in Uganda is committed to conducting clinical trials to answer important questions regarding diagnostics and management of HIV-associated opportunistic infections, including tuberculosis and cryptococcal meningitis. However, clinical research is impossible without research participants and results are meaningless unless they are translated into benefits for those affected by the disease. Therefore, we held a series of community engagement events with the aims of 1) giving research participan...
Cryptococcal meningitis accounts for 15% of all HIVrelated deaths [1]. The overall number of cryp... more Cryptococcal meningitis accounts for 15% of all HIVrelated deaths [1]. The overall number of cryptococcal meningitis cases has remained relatively stable in many low-to-middle income countries (LMICs) despite increasing roll-out of antiretroviral therapy (ART). Increasing numbers of patients are at risk of developing a Malawi-Liverpool-Wellcome Trust Clinical Research Programme,
Early antiretroviral therapy (ART) initiation after cryptococcal meningitis increases mortality, ... more Early antiretroviral therapy (ART) initiation after cryptococcal meningitis increases mortality, and those unmasking cryptococcosis after <2 weeks of ART have higher mortality. However, it is unknown if those presenting as ART experienced are actually adherent to their ART. Unknowingly, restarting ART in persons, who have discontinued ART, may be a fatal iatrogenic error. To evaluate ART adherence in an exploratory analysis, we collected dried blood spots on 44 HIV-infected persons presenting with cryptococcal meningitis. We quantified tenofovir diphosphate (TFV-DP) and lamivudine (3TC) from dried blood spots. We quantified cumulative ART adherence over the preceding 6-8 weeks based on TFV-DP concentrations and adherence over the last few days based on 3TC concentrations. Of 22 ART experienced, 20 (91%) had quantifiable concentrations. Of 18 receiving tenofovir, 15 (83%) had TFV-DP consistent with drug intake of ‡4 doses/week or moderate adherence. With 3TC, 72% (18/22) had detectable levels consistent with adherence over the last 3 days before measurement. Only three ART-experienced subjects were alive and virally suppressed at 4 months (n = 2 on ART for <30 days; n = 1 with undetectable antiretrovirals). Surprisingly, of 22 who reported not receiving ART, 4 (18%) had quantifiable tenofovir. Most ART-experienced subjects were taking their ART with moderate to good adherence with the majority likely having viral resistance given generally at good ART levels, receipt of intensive adherence counseling, and lack of subsequent viral suppression. The World Health Organization (WHO) guidelines recommend adherence counseling with ART continuation and repeat viral loads in 1-3 months before switching to second-line ART. These recommendations are likely inappropriate in those with central nervous system infections given the additional possible harm of central nervous system immune reconstitution syndrome. Further study to evaluate continuation of ART regimens when presenting with cryptococcosis has benefit, with checking blood levels at presentation potentially being a helpful option. ClinicalTrials.gov Identifier: NCT01802385.
The role of biological sex on clinical outcomes and the pathogenesis of AIDS-related opportunisti... more The role of biological sex on clinical outcomes and the pathogenesis of AIDS-related opportunistic infections is unknown. We assessed baseline biomarkers and outcomes between 577 men and 400 women in HIV-related cryptococcal meningitis cohorts in Uganda and South Africa from 2010 to 2017. We compared 10-week mortality by sex via Cox proportional hazards models. The 10-week mortality for women was 50% (198/400) and 43% (247/577) for men. Women had higher risk of death in an unadjusted model (Hazard Ratio (HR) = 1.20; 95%CI, 1.00–1.45; P = .05). Women maintained a higher risk when adjusting for quantitative CSF culture, altered mental status, CSF pleocytosis, age, and antiretroviral status (HR = 1.31; 95%CI, 1.07–1.59; P < .01). However, after adjusting for hemoglobin, the risk of death did not differ between women and men (HR = 1.17; 95%CI, 0.94–1.45; P = .17). Moderate to severe anemia (hemoglobin < 8.5 g/dL) was present among 16% (55/355) of women and 10% (55/532) of men (P =...
Background: Despite the high infectivity of SARS-CoV-2, the incidence of COVID-19 in Africa has b... more Background: Despite the high infectivity of SARS-CoV-2, the incidence of COVID-19 in Africa has been slower than predicted. We aimed to investigate a possible association between parasitic infections and COVID-19. Methods: An ecological study in which we analysed WHO data on COVID-19 cases in comparison to WHO data on helminths and malaria cases using correlation, regression, and Geographical Information Services analyses. Results: Of the global 3.34 million COVID-19 cases and 238,628 deaths as at May 4th 2020, Africa reported 0.029/3.3 million (0.88%) cases and 1,064/238,628 (0.45%) deaths. In 2018, Africa reported 213/229 million (93%) of all malaria cases, 204/229 million (89%) of schistosomiasis cases, and 271/1068 million (25%) of soil-transmitted helminth cases globally. In contrast, Europe reported 1.5/3.3 million (45%) of global COVID-19 cases and 142,667/238,628 (59%) deaths. Europe had 5.8/1068 million (0.55%) soil-transmitted helminths cases and no malaria/schistosomiasis...
Background Acceptability of Pre-exposure Prophylaxis (PrEP) could be hampered by low self-perceiv... more Background Acceptability of Pre-exposure Prophylaxis (PrEP) could be hampered by low self-perceived risk for HIV acquisition. Moreover, discordance between risk perception and actual risk of HIV acquisition is likely to occur. We assessed congruence between the level of self- perceived and that of objectively scored risk of HIV acquisition among HIV-negative individuals in discordant relationships. Methods This was a cross-sectional study among a representative sample of HIV-negative adult males and females whose partners were receiving antiretroviral therapy for at least 3 months from the Infectious Diseases Institute Clinic in Kampala, Uganda. Perceived risk was measured based on self-report using a numerical rating scale whereas objective risk was measured using a validated risk score tool. Congruence between perceived risk and objectively scored risk was evaluated using descriptive statistics and validity measures. Incongruence between the two phenomena was further evaluated usi...
Journal of Pharmacokinetics and Pharmacodynamics, 2019
The ASTRO-CM dose-finding pilot study investigated the role of adjunctive sertraline for the trea... more The ASTRO-CM dose-finding pilot study investigated the role of adjunctive sertraline for the treatment of HIV-associated cryptococcal meningitis in HIV-infected Ugandan patients. The present study is a post-hoc pharmacokinetic-pharmacodynamic analysis of the ASTRO-CM pilot study to provide insight into sertraline exposure-response-outcome relationships. We performed a population pharmacokinetic analysis using sertraline plasma concentration data and correlated various predicted PK-PD indices with the percentage change in log 10 CFU/mL from baseline. Sertraline clearance was 1.95-fold higher in patients receiving antiretroviral (ART), resulting in 49 % lower drug exposure To quantify the clinical benefit of sertraline, we estimated rates of fungal clearance from cerebrospinal fluid (CSF) of ASTRO-CM patients using Poisson model and compared the clearance rates to a historical control study (COAT) in which patients received standard Cryptococcus therapy of amphotericin B (0•7-1•0 mg/kg per day) and fluconazole (800 *
W e read with great interest the recent article by Cox et al. regarding the use of the lipoarabin... more W e read with great interest the recent article by Cox et al. regarding the use of the lipoarabinomannan (LAM) lateral flow assay (Determine TB LAM; Alere, Waltham, MA, USA) on cerebrospinal fluid (CSF) for postmortem diagnosis of tuberculous meningitis (TBM) (1). Certainly, TBM is difficult to diagnose, and a delay in diagnosis often leads to poor outcomes for patients with TBM, including death (2, 3). Despite the recent interest in the use of Xpert MTB/Rif for TBM diagnosis (4-6), its sensitivity and negative predictive value remain insufficient for the use of Xpert as a "rule-out" test. The lack of sufficiently accurate and rapid diagnostics for TBM makes LAM an attractive candidate for TBM diagnosis. Cox and colleagues obtained CSF from the fourth ventricle of 91 subjects at autopsy (1). Samples were stored at Ϫ20°C initially, later thawed, and then heated to 95 to 100°C. After cooling, the samples were further processed by spinning (1 ml) at 10,000 rpm for 15 min. LAM testing was performed with 60 l of the supernatant, as well as unprepared CSF (aside from having been frozen) (1). When examining LAM with unprepared CSF against histopathologically definite or probable TBM, the authors found 50% sensitivity and 70% specificity. Against definite TBM cases, 75% sensitivity and 70% specificity were observed (1). When treated CSF supernatant was used, the authors found 88% sensitivity and 70% specificity of LAM against definite TBM cases and 71% sensitivity and 70% specificity against definite or probable cases. These results, if clinically applicable, would rival any currently available technology (4-6). Importantly, this study used autopsy specimens rather than diagnosing living persons via CSF obtained by lumbar puncture. Obtaining CSF from the fourth ventricle, while possible, is much more invasive and is not frequently performed in most settings. As part of our recent evaluation of the role of centrifugation of CSF specimens prior to testing for TBM using Xpert MTB/Rif, we evaluated the TB LAM lateral flow assay used in the study by Cox Citation Bahr NC, Tugume L, Boulware DR. 2016. A word of caution in considering the use of the lipoarabinomannan lateral flow assay on cerebrospinal fluid for detection of tuberculous meningitis.
Background In cryptococcal meningitis phase 2 clinical trials, early fungicidal activity (EFA) of... more Background In cryptococcal meningitis phase 2 clinical trials, early fungicidal activity (EFA) of Cryptococcus clearance from cerebrospinal fluid (CSF) is used as a surrogate endpoint for all-cause mortality. The Food and Drug Administration allows for using surrogate endpoints for accelerated regulatory approval, but EFA as a surrogate endpoint requires further validation. We examined the relationship between rate of CSF Cryptococcus clearance (EFA) and mortality through 18 weeks. Methods We pooled individual-level CSF data from 3 sequential cryptococcal meningitis clinical trials conducted during 2010–2017. All 738 subjects received amphotericin + fluconazole induction therapy and had serial quantitative CSF cultures. The log10-transformed colony-forming units (CFUs) per mL CSF were analyzed by general linear regression versus day of culture over the first 10 days. Results Mortality through 18 weeks was 37% for EFA > = 0.60 (n = 170), 36% for 0.40–0.59 (n = 182), 39% for 0.30–0...
Background Sodium abnormalities are frequent in central nervous system infections and may be caus... more 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 ini...
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.
The World Health Organization (WHO) has published a guideline for the management of individuals w... more The World Health Organization (WHO) has published a guideline for the management of individuals with advanced HIV disease (AHD) to reduce HIV-related deaths. The guideline consists of a package of recommendations including interventions to prevent, diagnose and treat common opportunistic infections, including tuberculosis (TB), cryptococcosis and severe bacterial infections, along with rapid initiation of antiretroviral treatment and enhanced adherence support. Currently no clear targets exist for these key interventions. Emerging programmatic data from Uganda, Tanzania and Nigeria suggest that an estimated 80% of eligible people continue to miss the recommended cryptococcal or TB testing, highlighting the remaining challenges to the effective implementation of WHO-recommended AHD packages of care in real-world resource-limited settings. The absence of mortality indicators for the leading causes of HIV-related deaths, because of the lack of mechanisms to ascertain cause of death, ha...
Objectives Tuberculous meningitis(TBM) is a common cause of meningitis in sub-Saharan Africa. CSF... more Objectives Tuberculous meningitis(TBM) is a common cause of meningitis in sub-Saharan Africa. CSF PCR with GeneXpert RIF/MTB Ultra is only 70% sensitive for detection of definite/probable TBM. Many infections can mimic TBM. Metagenomic next generation sequencing(mNGS) can detect the whole diversity of infectious microbes, but can be insensitive to TB in CSF. We assessed whether leveraging CSF mNGS to identify infections combined with a machine learning classifier(MLC), based on host transcriptomic data generated by mNGS, could enhance diagnostic accuracy for TBM. Methods Prospectively enrolled 347 HIV-infected Ugandan adults with subacute meningitis: RNA/DNA libraries were made from CSF and deep sequenced. Non-human sequences were interrogated to identify pathogens. A host transcriptomic MLC was developed from human RNA transcripts using 70 cases. The MLC and mNGS reporting thresholds were then tested on 108 blinded cases within the cohort. Results mNGS was 75% concordant(27/36) for...
Background High-dose rifampicin may improve outcomes of tuberculous meningitis (TBM). Little safe... more Background High-dose rifampicin may improve outcomes of tuberculous meningitis (TBM). Little safety or pharmacokinetic (PK) data exist on high-dose rifampicin in human immunodeficiency virus (HIV) coinfection, and no cerebrospinal fluid (CSF) PK data exist from Africa. We hypothesized that high-dose rifampicin would increase serum and CSF concentrations without excess toxicity. Methods In this phase II open-label trial, Ugandan adults with suspected TBM were randomized to standard-of-care control (PO-10, rifampicin 10 mg/kg/day), intravenous rifampicin (IV-20, 20 mg/kg/day), or high-dose oral rifampicin (PO-35, 35 mg/kg/day). We performed PK sampling on days 2 and 14. The primary outcomes were total exposure (AUC0–24), maximum concentration (Cmax), CSF concentration, and grade 3–5 adverse events. Results We enrolled 61 adults, 92% were living with HIV, median CD4 count was 50 cells/µL (interquartile range [IQR] 46–56). On day 2, geometric mean plasma AUC0–24hr was 42.9·h mg/L with s...
Background Cerebrospinal fluid (CSF) lactate levels can be used to differentiate between bacteria... more Background Cerebrospinal fluid (CSF) lactate levels can be used to differentiate between bacterial and viral meningitis. We measured CSF lactate in individuals with cryptococcal meningitis to determine its clinical significance. Methods We measured point-of-care CSF lactate at the bedside of 319 Ugandan adults living with human immunodeficiency virus at diagnosis of cryptococcal meningitis. We summarized demographic variables and clinical characteristics by CSF lactate tertiles. We evaluated the association of CSF lactate with clinical characteristics and survival. Results Individuals with high CSF lactate >5 mmol/L at cryptococcal diagnosis more likely presented with altered mental status (P < .0001), seizures (P = .0005), elevated intracranial opening pressure (P = .03), higher CSF white cells (P = .007), and lower CSF glucose (P = .0003) compared with those with mid-range (3.1 to 5 mmol/L) or low (≤3 mmol/L) CSF lactate levels. Two-week mortality was higher among individual...
Over the last decade excellent progress has been made globally in HIV management thanks to antire... more Over the last decade excellent progress has been made globally in HIV management thanks to antiretroviral therapy (ART) rollout and international guidelines now recommending immediate initiation of ART in people living with HIV. Despite this, advanced HIV disease (CD4 less than 200 cells/mL) and opportunistic infections remain a persistent challenge and contribute significantly to HIV-associated mortality, which equates to 23,000 deaths in Uganda in 2018 alone. Our Meningitis Research Team based in Uganda is committed to conducting clinical trials to answer important questions regarding diagnostics and management of HIV-associated opportunistic infections, including tuberculosis and cryptococcal meningitis. However, clinical research is impossible without research participants and results are meaningless unless they are translated into benefits for those affected by the disease. Therefore, we held a series of community engagement events with the aims of 1) giving research participan...
Cryptococcal meningitis accounts for 15% of all HIVrelated deaths [1]. The overall number of cryp... more Cryptococcal meningitis accounts for 15% of all HIVrelated deaths [1]. The overall number of cryptococcal meningitis cases has remained relatively stable in many low-to-middle income countries (LMICs) despite increasing roll-out of antiretroviral therapy (ART). Increasing numbers of patients are at risk of developing a Malawi-Liverpool-Wellcome Trust Clinical Research Programme,
Uploads
Papers by Lillian Tugume