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1. Integrated management of cryptococcal meningitis and concurrent opportunistic infections to improve outcomes in advanced HIV disease: a randomised strategy trial

Author

Ellis, Jayne, primary, Nsangi, Laura, additional, Bangdiwala, Ananta, additional, Hale, Gila, additional, Gakuru, Jane, additional, Kagimu, Enock, additional, Mugabi, Timothy, additional, Kigozi, Enos, additional, Tukundane, Asmus, additional, Okirwoth, Michael, additional, Kandole, Tadeo Kiiza, additional, Cresswel, Fiona, additional, Harrison, Thomas S., additional, Moore, David, additional, Fielding, Katherine, additional, Meya, David, additional, Boulware, David, additional, and Jarvis, Joseph N., additional

Published
2024
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2. Estimating Survival in Melanoma Patients With Brain Metastases: An Update of the Graded Prognostic Assessment for Melanoma Using Molecular Markers (Melanoma-molGPA).

Author

Sperduto, Paul W, Jiang, Wen, Brown, Paul D, Braunstein, Steve, Sneed, Penny, Wattson, Daniel A, Shih, Helen A, Bangdiwala, Ananta, Shanley, Ryan, Lockney, Natalie A, Beal, Kathryn, Lou, Emil, Amatruda, Thomas, Sperduto, William A, Kirkpatrick, John P, Yeh, Norman, Gaspar, Laurie E, Molitoris, Jason K, Masucci, Laura, Roberge, David, Yu, James, Chiang, Veronica, and Mehta, Minesh

Subjects
Humans, Melanoma, Brain Neoplasms, Proto-Oncogene Proteins B-raf, Genetic Markers, Prognosis, Karnofsky Performance Status, Regression Analysis, Age Factors, Aged, Aged, 80 and over, Middle Aged, Clinical Decision-Making, Brain Cancer, Neurosciences, Clinical Research, Rare Diseases, Patient Safety, Cancer, Brain Disorders, Detection, screening and diagnosis, 4.2 Evaluation of markers and technologies, Other Physical Sciences, Clinical Sciences, Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract

PurposeTo update the Diagnosis-Specific Graded Prognostic Assessment (DS-GPA) for a markedly heterogeneous patient population, patients with melanoma and brain metastases, using a larger, more current cohort, including molecular markers.MethodsThe original Melanoma-GPA is based on data from 483 patients whose conditions were diagnosed between 1985 and 2005. This is a multi-institutional retrospective database analysis of 823 melanoma patients with newly diagnosed brain metastases from January 1, 2006, to December 31, 2015. Multivariable analyses identified significant prognostic factors, which were weighted and included in the updated index (Melanoma-molGPA). Multiple Cox regression was used to select and weight prognostic factors in proportion to their hazard ratios to design the updated Melanoma-molGPA in which scores of 4.0 and 0.0 are associated with the best and worst prognoses, as with all of the diagnosis-specific GPA indices. Log-rank tests were used to compare adjacent classes.ResultsThere were 5 significant prognostic factors for survival (age, Karnofsky performance status [KPS], extracranial metastases [ECM], number of brain metastases, and BRAF status), whereas only KPS and the number of brain metastases were significant in the original Melanoma-GPA. Median survival improved from 6.7 to 9.8 months between the 2 treatment eras, and the median survival times for patients with Melanoma-molGPA of 0 to 1.0, 1.5 to 2.0, 2.5 to 3.0, and 3.5 to 4.0 were 4.9, 8.3, 15.8, and 34.1 months (P

Published
2017

3. The Prognostic Value of BRAF, C-KIT, and NRAS Mutations in Melanoma Patients With Brain Metastases.

Author

Sperduto, Paul W, Jiang, Wen, Brown, Paul D, Braunstein, Steve, Sneed, Penny, Wattson, Daniel A, Shih, Helen A, Bangdiwala, Ananta, Shanley, Ryan, Lockney, Natalie A, Beal, Kathryn, Lou, Emil, Amatruda, Thomas, Sperduto, William A, Kirkpatrick, John P, Yeh, Norman, Gaspar, Laurie E, Molitoris, Jason K, Masucci, Laura, Roberge, David, Yu, James, Chiang, Veronica, and Mehta, Minesh

Subjects
Humans, Melanoma, Brain Neoplasms, Proto-Oncogene Proteins B-raf, Antineoplastic Agents, Prognosis, Immunotherapy, Linear Models, Proportional Hazards Models, Statistics, Nonparametric, Retrospective Studies, Mutation, Genes, ras, Time Factors, Adult, Aged, Aged, 80 and over, Middle Aged, Female, Male, Proto-Oncogene Proteins c-kit, Molecular Targeted Therapy, Brain Cancer, Cancer, Brain Disorders, Clinical Research, Neurosciences, Rare Diseases, Other Physical Sciences, Clinical Sciences, Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract

PurposeBrain metastases are a common problem in patients with melanoma, but little is known about the effect of gene mutations on survival in these patients.Methods and materialsWe created a retrospective multi-institutional database of 823 patients with melanoma and brain metastases diagnosed between 2006 and 2015. Clinical parameters, gene mutation status (BRAF, C-KIT, NRAS), and treatment were correlated with survival. Treatment patterns and outcomes were compared with a prior era (1985-2005).ResultsBRAF status was known in 584 of 823 patients (71%). BRAF, NRAS, and C-KIT mutations were present in 51%, 22%, and 11% of tested patients, respectively. The median time from primary diagnosis to brain metastasis was 32 months, and overall median survival (MS) from the time of initial treatment of brain metastases was 10 months. MS for BRAF-positive and BRAF-negative patients was 13 months and 9 months, respectively (P=.02). There was no significant difference in MS in patients with or without NRAS or C-KIT mutations. The time from primary diagnosis to brain metastasis did not vary by mutation and was not associated with survival after the diagnosis of brain metastases. MS for the 1985 to 2005 and 2006 to 2015 cohorts was 6.7 months and 10.0 months, respectively (P

Published
2017

5. The Effect of Gene Alterations and Tyrosine Kinase Inhibition on Survival and Cause of Death in Patients With Adenocarcinoma of the Lung and Brain Metastases

Author

Sperduto, Paul W, Yang, T Jonathan, Beal, Kathryn, Pan, Hubert, Brown, Paul D, Bangdiwala, Ananta, Shanley, Ryan, Yeh, Norman, Gaspar, Laurie E, Braunstein, Steve, Sneed, Penny, Boyle, John, Kirkpatrick, John P, Mak, Kimberley S, Shih, Helen A, Engelman, Alex, Roberge, David, Arvold, Nils D, Alexander, Brian, Awad, Mark M, Contessa, Joseph, Chiang, Veronica, Hardie, John, Ma, Daniel, Lou, Emil, Sperduto, William, and Mehta, Minesh P

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Oncology and Carcinogenesis, Cancer, Lung Cancer, Rare Diseases, Lung, Clinical Research, Adenocarcinoma, Aged, Aged, 80 and over, Anaplastic Lymphoma Kinase, Antineoplastic Agents, Brain Neoplasms, ErbB Receptors, Female, Genetic Markers, Genetic Predisposition to Disease, Humans, Incidence, Lung Neoplasms, Male, Middle Aged, Mutation, Polymorphism, Single Nucleotide, Prevalence, Protein-Tyrosine Kinases, Receptor Protein-Tyrosine Kinases, Retrospective Studies, Risk Factors, Survival Rate, United States, Other Physical Sciences, Oncology & Carcinogenesis, Oncology and carcinogenesis, Theoretical and computational chemistry, Medical and biological physics
Abstract

PurposeLung cancer remains the most common cause of both cancer mortality and brain metastases (BM). The purpose of this study was to assess the effect of gene alterations and tyrosine kinase inhibition (TKI) on median survival (MS) and cause of death (CoD) in patients with BM from lung adenocarcinoma (L-adeno).MethodsA multi-institutional retrospective database of patients with L-adeno and newly diagnosed BM between 2006 and 2014 was created. Demographics, gene alterations, treatment, MS, and CoD were analyzed. The treatment patterns and outcomes were compared with those in prior trials.ResultsOf 1521 L-adeno patients, 816 (54%) had known alteration status. The gene alteration rates were 29%, 10%, and 26% for EGFR, ALK, and KRAS, respectively. The time from primary diagnosis to BM for EGFR-/+ was 10/15 months (P=.02) and for ALK-/+ was 10/20 months (P

Published
2016

6. 1490. Predictors of Early Mortality in HIV-associated Tuberculous Meningitis

Author

Kagimu, Enock, primary, Bangdiwala, Ananta, additional, Kasibante, John, additional, Kabahubya, Mable, additional, Gakuru, Jane, additional, Timothy, Mugabi, additional, Namombwe, Suzan, additional, Kimuda, Sarah, additional, Kasozi, Derrick, additional, Rutakingirwa, Morris K, additional, Ssebambulidde, Kenneth, additional, Tugume, Lillian, additional, Nuwagira, Edwin, additional, Okurut, Samuel, additional, Nsangi, Laura, additional, Atukunda, Mucunguzi, additional, Ellis, Jayne P, additional, Williams, Darlisha A, additional, Musubire, Abdu Kisekka, additional, Boulware, David R, additional, Meya, David, additional, Bahr, Nathan C, additional, and Cresswell, Fiona V, additional

Published
2023
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7. Post-exposure prophylaxis or pre-emptive therapy for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2): study protocol for a pragmatic randomized-controlled trial

Author

Lother, Sylvain A., Abassi, Mahsa, Agostinis, Alyssa, Bangdiwala, Ananta S., Cheng, Matthew P., Drobot, Glen, Engen, Nicole, Hullsiek, Kathy H., Kelly, Lauren E., Lee, Todd C., Lofgren, Sarah M., MacKenzie, Lauren J., Marten, Nicole, McDonald, Emily G., Okafor, Elizabeth C., Pastick, Katelyn A., Pullen, Matthew F., Rajasingham, Radha, Schwartz, Ilan, Skipper, Caleb P., Turgeon, Alexis F., Zarychanski, Ryan, and Boulware, David R.

Published
2020
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8. Adjunctive sertraline for HIV-associated cryptococcal meningitis: a randomised, placebo-controlled, double-blind phase 3 trial

Author

Rhein, Joshua, Huppler Hullsiek, Kathy, Tugume, Lillian, Nuwagira, Edwin, Mpoza, Edward, Evans, Emily E, Kiggundu, Reuben, Pastick, Katelyn A, Ssebambulidde, Kenneth, Akampurira, Andrew, Williams, Darlisha A, Bangdiwala, Ananta S, Abassi, Mahsa, Musubire, Abdu K, Nicol, Melanie R, Muzoora, Conrad, Meya, David B, Boulware, David R, Ndyetukira, Jane Francis, Ahimbisibwe, Cynthia, Kugonza, Florence, Namuju, Carolyne, Sadiq, Alisat, Namudde, Alice, Mwesigye, James, Tadeo, Kiiza K, Kirumira, Paul, Okirwoth, Michael, Luggya, Tonny, Kaboggoza, Julian, Laker, Eva, Atwine, Leo, Muganzi, Davis, Walukaga, Stewart, Jawed, Bilal, Merry, Matthew, Stadelman, Anna, Stephens, Nicole, Flynn, Andrew G, Fujita, Ayako W, Kwizera, Richard, Mukaremera, Liliane, Lofgren, Sarah M, Cresswell, Fiona V, Morawski, Bozena M, Bahr, Nathan C, and Nielsen, Kirsten

Published
2019
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10. Baseline Cytomegalovirus Viremia at Cryptococcal Meningitis Diagnosis Is Associated With Long-term Increased Incident TB Disease and Mortality in a Prospective Cohort of Ugandan Adults With HIV

Author

Ellis, Jayne, primary, Bangdiwala, Ananta S, additional, Skipper, Caleb P, additional, Tugume, Lillian, additional, Nsangi, Laura, additional, Matovu, John, additional, Pastick, Katelyn A, additional, Ssebambulidde, Kenneth, additional, Morawski, Bozena M, additional, Musubire, Abdu K, additional, Schleiss, Mark R, additional, Moore, David A J, additional, Jarvis, Joseph N, additional, Boulware, David R, additional, Meya, David B, additional, and Castelnuovo, Barbara, additional

Published
2023
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11. Diagnostic accuracy of Xpert MTB/RIF Ultra for tuberculous meningitis in HIV-infected adults: a prospective cohort study

Author

Williams, Darlisha A, Taseera, Kabanda, Nyehangane, Dan, Ivan, Mugisha, Orikiriza, Patrick, Rhein, Joshua, Hullsiek, Kathy Huppler, Musubire, Abdu, Pastick, Katelyn, Nabeta, Pamela, Mwesigye, James, Rajasingham, Radha, Bahr, Nathan C, Nuwagira, Edwin, Evans, Emily E, Cresswell, Fiona V, Bystrom, Philip V, Byamukama, Adolf, Bridge, Sarah C, Bangdiwala, Ananta S, Meya, David B, Denkinger, Claudia M, Muzoora, Conrad, and Boulware, David R

Published
2018
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17. Diagnostic and Prognostic Value of Cerebrospinal Fluid Lactate and Glucose in HIV-Associated Tuberculosis Meningitis

Author

Nuwagira, Edwin, primary, Huppler Hullsiek, Kathy, additional, Jjunju, Samuel, additional, Rutakingirwa, Morris, additional, Kasibante, John, additional, Tadeo, Kiiza Kandole, additional, Kagimu, Enock, additional, Tugume, Lillian, additional, Ssebambulidde, Kenneth, additional, Musubire, Abdu K., additional, Bangdiwala, Ananta, additional, Muzoora, Conrad, additional, Meya, David B., additional, Boulware, David R., additional, Bahr, Nathan C., additional, and Creswell, Fiona V., additional

Published
2022
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18. Evaluation of the effectiveness of a South African laboratory cryptococcal antigen screening programme using a retrospective cohort and a cluster-randomised trial design

Author

DeSanto, Daniel J, primary, Bangdiwala, Ananta S, additional, Van Schalkwyk, Erika, additional, Skipper, Caleb P, additional, Greene, Greg, additional, Paxton, Juliet, additional, Huppler Hullsiek, Kathy, additional, Mashau, Rudzani, additional, Rajasingham, Radha, additional, Boulware, David R, additional, and Govender, Nelesh P, additional

Published
2022
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21. Outpatient Cryptococcal Antigen Screening Is Associated With Favorable Baseline Characteristics and Improved Survival in Persons With Cryptococcal Meningitis in Uganda

Author

Levin, Anna E, primary, Bangdiwala, Ananta S, additional, Nalintya, Elizabeth, additional, Kagimu, Enock, additional, Kasibante, John, additional, Rutakingirwa, Morris K, additional, Mpoza, Edward, additional, Jjunju, Samuel, additional, Nuwagira, Edwin, additional, Naluyima, Rose, additional, Kirumira, Paul, additional, Hou, Cody, additional, Ssebambulidde, Kenneth, additional, Musubire, Abdu K, additional, Williams, Darlisha A, additional, Abassi, Mahsa, additional, Muzoora, Conrad, additional, Hullsiek, Katherine H, additional, Rajasingham, Radha, additional, Meya, David B, additional, Boulware, David R, additional, and Skipper, Caleb P, additional

Published
2022
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24. Outpatient Cryptococcal Antigen Screening Is Associated With Favorable Baseline Characteristics and Improved Survival in Persons With Cryptococcal Meningitis in Uganda.

Author

Levin, Anna E, Bangdiwala, Ananta S, Nalintya, Elizabeth, Kagimu, Enock, Kasibante, John, Rutakingirwa, Morris K, Mpoza, Edward, Jjunju, Samuel, Nuwagira, Edwin, Naluyima, Rose, Kirumira, Paul, Hou, Cody, Ssebambulidde, Kenneth, Musubire, Abdu K, Williams, Darlisha A, Abassi, Mahsa, Muzoora, Conrad, Hullsiek, Katherine H, Rajasingham, Radha, and Meya, David B

Subjects
*MENINGITIS diagnosis, *AMPHOTERICIN B, *COMBINATION drug therapy, *CONFIDENCE intervals, *CRYPTOCOCCUS, *MEDICAL screening, *COMPARATIVE studies, *CRYPTOCOCCUS neoformans, *MEDICAL referrals, *DESCRIPTIVE statistics, *RESEARCH funding, *MENINGITIS, *OUTPATIENTS, *ANTIGENS
Abstract

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. [ABSTRACT FROM AUTHOR]

Published
2023
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27. Feasibility of SARS-CoV-2 Antibody Testing in Remote Outpatient Trials

Author

Lofgren, Sarah M, primary, Okafor, Elizabeth C, additional, Colette, Alanna A, additional, Pastick, Katelyn A, additional, Skipper, Caleb P, additional, Pullen, Matthew F, additional, Nicol, Melanie R, additional, Bold, Tyler D, additional, Bangdiwala, Ananta S, additional, Engen, Nicole W, additional, Collins, Lindsey, additional, Williams, Darlisha A, additional, Axelrod, Margaret L, additional, Thielen, Beth K, additional, Hullsiek, Kathy H, additional, Boulware, David R, additional, and Rajasingham, Radha, additional

Published
2021
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28. Neurocognitive outcomes of HIV-associated tuberculous meningitis

Author

Quinn, Carson M, primary, Kasibante, John, additional, Namudde, Alice, additional, Bangdiwala, Ananta S, additional, Kabahubya, Mable, additional, Nakasujja, Noeline, additional, Lofgren, Sarah, additional, Elliott, Alison, additional, Boulware, David R, additional, Meya, David B, additional, and Cresswell, Fiona V, additional

Published
2021
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29. The effect of sertraline on depression and associations with persistent depression in survivors of HIV-related cryptococcal meningitis

Author

Lofgren, Sarah M, Velamakanni, Sruti S, Huppler Hullsiek, Katherine, Bangdiwala, Ananta S, Namudde, Alice, Musubire, Abdu K, Mpoza, Edward, Abassi, Mahsa, Pastick, Katelyn A, Nuwagira, Edwin, Evans, Emily E, Rajsasingham, Radha, Williams, Darlisha A, Muzoora, Conrad, Creswell, Fiona V, Rhein, Joshua, Bond, David J, Nakasujja, Noeline, Meya, David B, and Boulware, David R

Abstract

Background: Depression is a risk factor for worse outcomes in persons living with HIV/AIDS and has a prevalence more than three times as high as in the general population. Despite this, there are few randomized studies of antidepressants in HIV-infected Africans. Methods: We enrolled 460 HIV-infected Africans with cryptococcal meningitis into a randomized clinical trial of adjunctive sertraline vs placebo (2015-2017). We defined depression using depression using a Center for Epidemiologic Studies Depression Scale (CES-D) score of >15, and severe depression as >26 at one and three months after meningitis diagnosis and initiation of treatment.We evaluated the relationship between sertraline and depression, as well as associations with persistent depression, at three months. Results: At one- and three-months post meningitis diagnosis, 62% (108/174) and 44% (74/169) of all subjects had depression (CES>15), respectively. At three months, sertraline-treated subjects had consistent risk for depression as placebo-treated subjects but were significantly less likely to have severe depression (CES>26) (OR 0.335; 95%CI, 0.130-0.865). Of those with depression at one month, sertraline-treated subjects were less likely than placebo-treated subjects to be depressed at three months (p=0.05). Sertraline was the only factor we found significant in predicting persistent depression at three months among those who had depression at one month. Conclusions: Depression is highly prevalent in HIV-infected persons who have survived cryptococcal meningitis. We found that sertraline is associated with a modest reduction in depression in those with depression at baseline and a significant decrease in severe depression.

Published
2021

30. Fujifilm SILVAMP TB LAM Assay on Cerebrospinal Fluid for the Detection of Tuberculous Meningitis in Adults With Human Immunodeficiency Virus

Author

Quinn, Carson M, Kagimu, Enock, Okirworth, Michael, Bangdiwala, Ananta S, Mugumya, Gerald, Ramachandran, Prashanth S, Wilson, Michael R, Meya, David B, Cresswell, Fiona V, Bahr, Nathan C, and Boulware, David R

Subjects
urologic and male genital diseases
Abstract

BACKGROUND: Tuberculous meningitis (TBM) has a high fatality rate, with inadequate diagnostic tests being a major contributor. The rollout of Xpert MTB/Rif and Xpert MTB/RIF Ultra (Xpert Ultra) have improved time-to-diagnosis with sensitivities similar to culture, yet test availability and sensitivity are inadequate. The TB lipoarabinomannan lateral flow assay (AlereLAM) offers ease of use, but its low sensitivity in cerebrospinal fluid (CSF) limits clinical utility for TBM. The Fujifilm SILVAMP TB LAM (FujiLAM) assay has excellent sensitivity in urine, but performance on cerebrospinal fluid is uncertain. METHODS: We conducted a prospective cohort study at Kiruddu National Referral Hospital in Kampala, Uganda, enrolling patients suspected to have TBM. CSF was tested using AlereLAM, Xpert Ultra, culture, and FujiLAM. Results were compared with 2 reference standards: probable and definite TBM or definite TBM alone by the uniform TBM case definition. RESULTS: Of 101 patients enrolled (95/101 HIV-positive), 34 had definite TBM and 24 had probable TBM. FujiLAM sensitivity on CSF was 52% (30/58) for definite or probable TBM compared with 55% (32/58) for Xpert Ultra. AlereLAM had lower sensitivity than FujiLAM in the subgroup of patients tested with both assays (14% [4/28] vs 50% [14/28]; P < .01). FujiLAM specificity was 98% (42/43) for patients without probable or definite TBM. CONCLUSIONS: FujiLAM showed higher sensitivity than AlereLAM, with sensitivity potentially approaching that of Xpert Ultra. FujiLAM could improve time-to-treatment-initiation, especially in settings where the more technical Xpert Ultra system might not be feasible. Large confirmatory studies are needed.

Published
2021

31. High-Dose Oral and Intravenous Rifampicin for the Treatment of Tuberculous Meningitis in Predominantly Human Immunodeficiency Virus (HIV)-Positive Ugandan Adults : A Phase II Open-Label Randomized Controlled Trial

Author

Cresswell, Fiona, V, Meya, David B., Kagimu, Enock, Grint, Daniel, Te Brake, Lindsey, Kasibante, John, Martyn, Emily, Rutakingirwa, Morris, Quinn, Carson M., Okirwoth, Micheal, Tugume, Lillian, Ssembambulidde, Kenneth, Musubire, Abdu K., Bangdiwala, Ananta S., Buzibye, Allan, Muzoora, Conrad, Svensson, Elin, Aarnoutse, Rob, Boulware, David R., Elliott, Alison M., Cresswell, Fiona, V, Meya, David B., Kagimu, Enock, Grint, Daniel, Te Brake, Lindsey, Kasibante, John, Martyn, Emily, Rutakingirwa, Morris, Quinn, Carson M., Okirwoth, Micheal, Tugume, Lillian, Ssembambulidde, Kenneth, Musubire, Abdu K., Bangdiwala, Ananta S., Buzibye, Allan, Muzoora, Conrad, Svensson, Elin, Aarnoutse, Rob, Boulware, David R., and Elliott, Alison M.

Abstract

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 (AUC(0-24)), maximum concentration (C-max), CSF concentration, and grade 3-5 adverse events. Results: We enrolled 61 adults, 92% were living with HIV, median CD4 count was 50 cells/mu L (interquartile range [IQR] 46-56). On day 2, geometric mean plasma AUC(0-24hr) was 42.9.h mg/L with standard-of-care 10 mg/kg dosing, 249.h mg/L for IV-20 and 327.h mg/L for PO-35 (P<.001). In CSF, standard of care achieved undetectable rifampicin concentration in 56% of participants and geometric mean AUC(0-24hr) 0.27 mg/L, compared with 1.74 mg/L (95% confidence interval [CI] 1.2-2.5) for IV-20 and 2.17 mg/L (1.6-2.9) for PO-35 regimens (P<.001). Achieving CSF concentrations above rifampicin minimal inhibitory concentration (MIC) occurred in 11% (2/18) of standard-of-care, 93% (14/15) of IV-20, and 95% (18/19) of PO-35 participants. Higher serum and CSF levels were sustained at day 14. Adverse events did not differ by dose (P=.34). Conclusions: Current international guidelines result in sub-therapeutic CSF rifampicin concentration for 89% of Ugandan TBM patients. High-dose intravenous and oral rifampicin were safe and respectively resulted in exposures similar to 6- and similar to 8-fold higher than standard of care, and CSF levels above the MIC.

Published
2021
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32. A Descriptive Analysis of Dried Blood Spot Adherence Testing Among Ugandans with HIV Presenting with Cryptococcal Meningitis

Author

Lofgren, Sarah M., primary, Nicol, Melanie R., additional, Kandole, Tadeo K., additional, Castillo-Mancilla, Jose, additional, Anderson, Peter L., additional, Mpoza, Edward, additional, Tugume, Lillian, additional, Bangdiwala, Ananta S., additional, Ssebambulidde, Kenneth, additional, Hullsiek, Katherine Huppler, additional, Rhein, Joshua, additional, Meya, David B., additional, and Boulware, David R., additional

Published
2021
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33. High-Dose Oral and Intravenous Rifampicin for the Treatment of Tuberculous Meningitis in Predominantly Human Immunodeficiency Virus (HIV)-Positive Ugandan Adults: A Phase II Open-Label Randomized Controlled Trial

Author

Cresswell, Fiona V, primary, Meya, David B, additional, Kagimu, Enock, additional, Grint, Daniel, additional, te Brake, Lindsey, additional, Kasibante, John, additional, Martyn, Emily, additional, Rutakingirwa, Morris, additional, Quinn, Carson M, additional, Okirwoth, Micheal, additional, Tugume, Lillian, additional, Ssembambulidde, Kenneth, additional, Musubire, Abdu K, additional, Bangdiwala, Ananta S, additional, Buzibye, Allan, additional, Muzoora, Conrad, additional, Svensson, Elin M, additional, Aarnoutse, Rob, additional, Boulware, David R, additional, and Elliott, Alison M, additional

Published
2021
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34. Hydroxychloroquine as Pre-exposure Prophylaxis for Coronavirus Disease 2019 (COVID-19) in Healthcare Workers: A Randomized Trial

Author

Rajasingham, Radha, Bangdiwala, Ananta S, Nicol, Melanie R, Skipper, Caleb P, Pastick, Katelyn A, Axelrod, Margaret L, Pullen, Matthew F, Nascene, Alanna A, Williams, Darlisha A, Engen, Nicole W, Okafor, Elizabeth C, Rini, Brian I, Mayer, Ingrid A, McDonald, Emily G, Lee, Todd C, Li, Peter, MacKenzie, Lauren J, Balko, Justin M, Dunlop, Stephen J, Hullsiek, Katherine H, Boulware, David R, Lofgren, Sarah M, Abassi, Mahsa, Balster, Andrew, Collins, Lindsey B, Drobot, Glen, Krakower, Douglas S, Lother, Sylvain A, MacKay, Dylan S, Meyer-Mueller, Cameron, Selinsky, Stephen, Solvason, Dayna, Zarychanski, Ryan, and Zash, Rebecca

Subjects
0301 basic medicine, Microbiology (medical), Canada, medicine.medical_specialty, Health Personnel, Placebo, Loading dose, law.invention, 03 medical and health sciences, Pre-exposure prophylaxis, 0302 clinical medicine, Randomized controlled trial, law, Internal medicine, Intensive care, medicine, Clinical endpoint, Humans, 030212 general & internal medicine, Online Only Articles, SARS-CoV-2, business.industry, Hydroxychloroquine, COVID-19 Drug Treatment, Clinical trial, 030104 developmental biology, Infectious Diseases, Pre-Exposure Prophylaxis, business, medicine.drug
Abstract

Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a rapidly emerging virus causing the ongoing coronavirus disease 2019 (COVID-19) pandemic with no known effective prophylaxis. We investigated whether hydroxychloroquine could prevent SARS-CoV-2 in healthcare workers at high risk of exposure. Methods We conducted a randomized, double-blind, placebo-controlled clinical trial of healthcare workers with ongoing exposure to persons with SARS-CoV-2, including those working in emergency departments, intensive care units, COVID-19 hospital wards, and first responders. Participants across the United States and in the Canadian province of Manitoba were randomized to hydroxychloroquine loading dose then 400 mg once or twice weekly for 12 weeks. The primary endpoint was confirmed or probable COVID-19–compatible illness. We measured hydroxychloroquine whole-blood concentrations. Results We enrolled 1483 healthcare workers, of whom 79% reported performing aerosol-generating procedures. The incidence of COVID-19 (laboratory-confirmed or symptomatic compatible illness) was 0.27 events/person-year with once-weekly and 0.28 events/person-year with twice-weekly hydroxychloroquine compared with 0.38 events/person-year with placebo. For once-weekly hydroxychloroquine prophylaxis, the hazard ratio was .72 (95% CI, .44–1.16; P = .18) and for twice-weekly was .74 (95% CI, .46–1.19; P = .22) compared with placebo. Median hydroxychloroquine concentrations in whole blood were 98 ng/mL (IQR, 82–120) with once-weekly and 200 ng/mL (IQR, 159–258) with twice-weekly dosing. Hydroxychloroquine concentrations did not differ between participants who developed COVID-19–compatible illness (154 ng/mL) versus participants without COVID-19 (133 ng/mL; P = .08). Conclusions Pre-exposure prophylaxis with hydroxychloroquine once or twice weekly did not significantly reduce laboratory-confirmed COVID-19 or COVID-19–compatible illness among healthcare workers. Clinical Trials Registration Clinicaltrials.gov NCT04328467.

Published
2020
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35. Hydroxychloroquine in Nonhospitalized Adults With Early COVID-19

Author

Skipper, Caleb P., Pastick, Katelyn A., Engen, Nicole W., Bangdiwala, Ananta S., Abassi, Mahsa, Lofgren, Sarah M., Williams, Darlisha A., Okafor, Elizabeth C., Pullen, Matthew F., Nicol, Melanie R., Nascene, Alanna A., Hullsiek, Kathy H., Cheng, Matthew P., Luke, Darlette, Lother, Sylvain A., MacKenzie, Lauren J., Drobot, Glen, Kelly, Lauren E., Schwartz, Ilan S., Zarychanski, Ryan, McDonald, Emily G., Lee, Todd C., Rajasingham, Radha, and Boulware, David R.

Subjects
stomatognathic diseases, Original Research
Abstract

There is no known effective oral therapy for early COVID-19. This randomized, double-blind, placebo-controlled trial evaluated effects of oral hydroxychloroquine on symptoms and disease severity in adult outpatients with early COVID-19., Background: No effective oral therapy exists for early coronavirus disease 2019 (COVID-19). Objective: To investigate whether hydroxychloroquine could reduce COVID-19 severity in adult outpatients. Design: Randomized, double-blind, placebo-controlled trial conducted from 22 March through 20 May 2020. (ClinicalTrials.gov: NCT04308668) Setting: Internet-based trial across the United States and Canada (40 states and 3 provinces). Participants: Symptomatic, nonhospitalized adults with laboratory-confirmed COVID-19 or probable COVID-19 and high-risk exposure within 4 days of symptom onset. Intervention: Oral hydroxychloroquine (800 mg once, followed by 600 mg in 6 to 8 hours, then 600 mg daily for 4 more days) or masked placebo. Measures: Symptoms and severity at baseline and then at days 3, 5, 10, and 14 using a 10-point visual analogue scale. The primary end point was change in overall symptom severity over 14 days. Results: Of 491 patients randomly assigned to a group, 423 contributed primary end point data. Of these, 341 (81%) had laboratory-confirmed infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or epidemiologically linked exposure to a person with laboratory-confirmed infection; 56% (236 of 423) were enrolled within 1 day of symptoms starting. Change in symptom severity over 14 days did not differ between the hydroxychloroquine and placebo groups (difference in symptom severity: relative, 12%; absolute, −0.27 points [95% CI, −0.61 to 0.07 points]; P = 0.117). At 14 days, 24% (49 of 201) of participants receiving hydroxychloroquine had ongoing symptoms compared with 30% (59 of 194) receiving placebo (P = 0.21). Medication adverse effects occurred in 43% (92 of 212) of participants receiving hydroxychloroquine versus 22% (46 of 211) receiving placebo (P < 0.001). With placebo, 10 hospitalizations occurred (2 non–COVID-19–related), including 1 hospitalized death. With hydroxychloroquine, 4 hospitalizations occurred plus 1 nonhospitalized death (P = 0.29). Limitations: Only 58% of participants received SARS-CoV-2 testing because of severe U.S. testing shortages. Conclusion: Hydroxychloroquine did not substantially reduce symptom severity in outpatients with early, mild COVID-19. Primary Funding Source: Private donors., Visual Abstract. Hydroxychloroquine in Nonhospitalized Adults With Early COVID-19 There is no known effective oral therapy for early COVID-19. This randomized, double-blind, placebo-controlled trial evaluated effects of oral hydroxychloroquine on symptoms and disease severity in adult outpatients with early COVID-19. Visual Abstract. Hydroxychloroquine in Nonhospitalized Adults With Early COVID-19 There is no known effective oral therapy for early COVID-19. This randomized, double-blind, placebo-controlled trial evaluated effects of oral hydroxychloroquine on symptoms and disease severity in adult outpatients with early COVID-19.

Published
2020

36. Lessons Learned From Conducting Internet-Based Randomized Clinical Trials During a Global Pandemic

Author

Pullen, Matthew F, primary, Pastick, Katelyn A, additional, Williams, Darlisha A, additional, Nascene, Alanna A, additional, Bangdiwala, Ananta S, additional, Okafor, Elizabeth C, additional, Hullsiek, Katherine Huppler, additional, Skipper, Caleb P, additional, Lofgren, Sarah M, additional, Engen, Nicole, additional, Abassi, Mahsa, additional, McDonald, Emily G, additional, Lee, Todd C, additional, Rajasingham, Radha, additional, and Boulware, David R, additional

Published
2020
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37. Cerebrospinal Fluid Lactate as a Prognostic Marker of Disease Severity and Mortality in Cryptococcal Meningitis

Author

Abassi, Mahsa, primary, Bangdiwala, Ananta S, additional, Nuwagira, Edwin, additional, Kandole Tadeo, Kiiza, additional, Okirwoth, Michael, additional, Williams, Darlisha A, additional, Mpoza, Edward, additional, Tugume, Lillian, additional, Ssebambulidde, Kenneth, additional, Huppler Hullsiek, Kathy, additional, Musubire, Abdu K, additional, Muzoora, Conrad, additional, Rhein, Joshua, additional, Meya, David B, additional, and Boulware, David R, additional

Published
2020
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38. Safety of Hydroxychloroquine Among Outpatient Clinical Trial Participants for COVID-19

Author

Lofgren, Sarah M, primary, Nicol, Melanie R, additional, Bangdiwala, Ananta S, additional, Pastick, Katelyn A, additional, Okafor, Elizabeth C, additional, Skipper, Caleb P, additional, Pullen, Matthew F, additional, Engen, Nicole W, additional, Abassi, Mahsa, additional, Williams, Darlisha A, additional, Nascene, Alanna A, additional, Axelrod, Margaret L, additional, Lother, Sylvain A, additional, MacKenzie, Lauren J, additional, Drobot, Glen, additional, Marten, Nicole, additional, Cheng, Matthew P, additional, Zarychanski, Ryan, additional, Schwartz, Ilan S, additional, Silverman, Michael, additional, Chagla, Zain, additional, Kelly, Lauren E, additional, McDonald, Emily G, additional, Lee, Todd C, additional, Hullsiek, Kathy H, additional, Boulware, David R, additional, and Rajasingham, Radha, additional

Published
2020
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39. Cerebrospinal Fluid Bacillary Load by Xpert MTB/RIF Ultra Polymerase Chain Reaction Cycle Threshold Value Predicts 2-Week Mortality in Human Immunodeficiency Virus–Associated Tuberculous Meningitis

Author

Martyn, Emily M, primary, Bangdiwala, Ananta S, additional, Kagimu, Enock, additional, Rutakingirwa, Morris K, additional, Kasibante, John, additional, Okirwoth, Michael, additional, Stead, Gavin, additional, Wadda, Vincent, additional, Pullen, Matthew F, additional, Bold, Tyler D, additional, Meya, David B, additional, Boulware, David R, additional, Bahr, Nathan C, additional, and Cresswell, Fiona V, additional

Published
2020
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40. Phase I EnACT Trial of the Safety and Tolerability of a Novel Oral Formulation of Amphotericin B

Author

Skipper, Caleb P., primary, Atukunda, Mucunguzi, additional, Stadelman, Anna, additional, Engen, Nicole W., additional, Bangdiwala, Ananta S., additional, Hullsiek, Katherine H., additional, Abassi, Mahsa, additional, Rhein, Joshua, additional, Nicol, Melanie R., additional, Laker, Eva, additional, Williams, Darlisha A., additional, Mannino, Raphael, additional, Matkovits, Theresa, additional, Meya, David B., additional, and Boulware, David R., additional

Published
2020
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41. Hydroxychloroquine as pre-exposure prophylaxis for COVID-19 in healthcare workers: a randomized trial

Author

Rajasingham, Radha, primary, Bangdiwala, Ananta S, additional, Nicol, Melanie R, additional, Skipper, Caleb P, additional, Pastick, Katelyn A, additional, Axelrod, Margaret L, additional, Pullen, Matthew F, additional, Nascene, Alanna A, additional, Williams, Darlisha A, additional, Engen, Nicole W, additional, Okafor, Elizabeth C, additional, Rini, Brian I, additional, Mayer, Ingrid A, additional, McDonald, Emily G, additional, Lee, Todd C., additional, Li, Peter, additional, MacKenzie, Lauren J, additional, Balko, Justin M, additional, Dunlop, Stephen J, additional, Hullsiek, Katherine H, additional, Boulware, David R, additional, and Lofgren, Sarah M, additional

Published
2020
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42. High dose oral rifampicin to improve survival from adult tuberculous meningitis: A randomised placebo-controlled double-blinded phase III trial (the HARVEST study)

Author

Marais, Suzaan, primary, Cresswell, Fiona V, additional, Hamers, Raph L., additional, te Brake, Lindsey H.M., additional, Ganiem, Ahmad R., additional, Imran, Darma, additional, Bangdiwala, Ananta, additional, Martyn, Emily, additional, Kasibante, John, additional, Kagimu, Enock, additional, Musubire, Abdu, additional, Maharani, Kartika, additional, Estiasari, Riwanti, additional, Kusumaningrum, Ardiana, additional, Kusumadjayanti, Nadytia, additional, Yunivita, Vycke, additional, Naidoo, Kogieleum, additional, Lessells, Richard, additional, Moosa, Yunus, additional, Svensson, Elin M., additional, Huppler Hullsiek, Katherine, additional, Aarnoutse, Rob E., additional, Boulware, David R., additional, van Crevel, Reinout, additional, Ruslami, Rovina, additional, and Meya, David B., additional

Published
2020
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43. A Randomized Trial of Hydroxychloroquine as Postexposure Prophylaxis for Covid-19

Author

Boulware, David R., primary, Pullen, Matthew F., additional, Bangdiwala, Ananta S., additional, Pastick, Katelyn A., additional, Lofgren, Sarah M., additional, Okafor, Elizabeth C., additional, Skipper, Caleb P., additional, Nascene, Alanna A., additional, Nicol, Melanie R., additional, Abassi, Mahsa, additional, Engen, Nicole W., additional, Cheng, Matthew P., additional, LaBar, Derek, additional, Lother, Sylvain A., additional, MacKenzie, Lauren J., additional, Drobot, Glen, additional, Marten, Nicole, additional, Zarychanski, Ryan, additional, Kelly, Lauren E., additional, Schwartz, Ilan S., additional, McDonald, Emily G., additional, Rajasingham, Radha, additional, Lee, Todd C., additional, and Hullsiek, Kathy H., additional

Published
2020
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44. Symptoms of COVID-19 Outpatients in the United States

Author

Pullen, Matthew F, primary, Skipper, Caleb P, additional, Hullsiek, Kathy H, additional, Bangdiwala, Ananta S, additional, Pastick, Katelyn A, additional, Okafor, Elizabeth C, additional, Lofgren, Sarah M, additional, Rajasingham, Radha, additional, Engen, Nicole W, additional, Galdys, Alison, additional, Williams, Darlisha A, additional, Abassi, Mahsa, additional, and Boulware, David R, additional

Published
2020
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45. Adjunctive sertraline for asymptomatic cryptococcal antigenemia: A randomized clinical trial

Author

Boulware, David R, primary, Nalintya, Elizabeth, additional, Rajasingham, Radha, additional, Kirumira, Paul, additional, Naluyima, Rose, additional, Turya, Fred, additional, Namanda, Sylvia, additional, Rutakingirwa, Morris K, additional, Skipper, Caleb P, additional, Nikweri, Yofesi, additional, Hullsiek, Kathy Huppler, additional, Bangdiwala, Ananta S, additional, and Meya, David B, additional

Published
2020
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46. Post-exposure Prophylaxis or Preemptive Therapy for SARS-Coronavirus-2: Study Protocol for a Pragmatic Randomized Controlled Trial

Author

Lother, Sylvain A, primary, Abassi, Mahsa, additional, Agostinis, Alyssa, additional, Bangdiwala, Ananta S, additional, Cheng, Matthew P, additional, Drobot, Glen, additional, Engen, Nicole, additional, Hullsiek, Kathy H, additional, Kelly, Lauren E, additional, Lee, Todd C, additional, Lofgren, Sarah M, additional, MacKenzie, Lauren J, additional, Marten, Nicole, additional, McDonald, Emily G, additional, Okafor, Elizabeth C, additional, Pastick, Katelyn A, additional, Pullen, Matthew F, additional, Rajasingham, Radha, additional, Schwartz, Ilan, additional, Skipper, Caleb P, additional, Turgeon, Alexis F, additional, Zarychanski, Ryan, additional, and Boulware, David R, additional

Published
2020
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47. Improving Tuberculous Meningitis Diagnostics - A Combined Host and Pathogen Classifier (5356)

Author

Ramachandran, Prashanth, primary, Ramesh, Akshaya, additional, Creswell, Fiona, additional, Quinn, Carson, additional, Rutakingirwa, Morris, additional, Bangdiwala, Ananta, additional, Kagimu, Enock, additional, Kandole, Kiiza Tadeo, additional, Tugume, Lillian, additional, Kasibante, John, additional, Ssebambulidde, Kenneth, additional, Okirwoth, Michael, additional, Musubire, Abdu, additional, Langelier, Charles, additional, Meya, David, additional, Crawford, Emily, additional, Boulware, David, additional, and Wilson, Michael, additional

Published
2020
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49. Standardized Urine-Based Tuberculosis (TB) Screening With TB-Lipoarabinomannan and Xpert MTB/RIF Ultra in Ugandan Adults With Advanced Human Immunodeficiency Virus Disease and Suspected Meningitis

Author

Cresswell, Fiona V, primary, Ellis, Jayne, primary, Kagimu, Enock, primary, Bangdiwala, Ananta S, primary, Okirwoth, Michael, primary, Mugumya, Gerald, primary, Rutakingirwa, Morris, primary, Kasibante, John, primary, Quinn, Carson M, primary, Ssebambulidde, Kenneth, primary, Rhein, Joshua, primary, Nuwagira, Edwin, primary, Tugume, Lillian, primary, Martyn, Emily, primary, Skipper, Caleb P, primary, Muzoora, Conrad, primary, Grint, Daniel, primary, Meya, David B, primary, Bahr, Nathan C, primary, Elliott, Alison M, primary, and Boulware, David R, primary

Published
2020
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50. Cerebrospinal Fluid Early Fungicidal Activity as a Surrogate Endpoint for Cryptococcal Meningitis Survival in Clinical Trials

Author

Pullen, Matthew F, primary, Hullsiek, Katherine Huppler, additional, Rhein, Joshua, additional, Musubire, Abdu K, additional, Tugume, Lillian, additional, Nuwagira, Edwin, additional, Abassi, Mahsa, additional, Ssebambulidde, Kenneth, additional, Mpoza, Edward, additional, Kiggundu, Ruben, additional, Akampurira, Andrew, additional, Nabeta, Henry W, additional, Schutz, Charlotte, additional, Evans, Emily E, additional, Rajasingham, Radha, additional, Skipper, Caleb P, additional, Pastick, Katelyn A, additional, Williams, Darlisha A, additional, Morawski, Bozena M, additional, Bangdiwala, Ananta S, additional, Meintjes, Graeme, additional, Muzoora, Conrad, additional, Meya, David B, additional, and Boulware, David R, additional

Published
2020
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