David R Boulware

David R Boulware
University of Minnesota | UMN · Division of Infectious Diseases and International Medicine (IDIM)

MD, MPH

About

513
Publications
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Introduction
Dr. Boulware is an infectious disease physician-scientist with formal training in public health, clinical trials, and tropical medicine. As a translational researcher, Dr. Boulware combines his clinical research training with basic science investigations into disease pathogenesis. His primary research interests are in meningitis including diagnosis, prevention, treatment, and quality improvement initiatives incorporating cost-effectiveness analyses to translate knowledge into improved care.

Publications

Publications (513)
Preprint
Importance: The effect of metformin on reducing symptom duration among outpatient adults with coronavirus disease 2019 (COVID-19) has not been studied. Objective: Assess metformin compared with placebo for symptom resolution during acute infection with SARS-CoV-2. Design, Setting, and Participants: The ACTIV-6 platform evaluated repurposed medicati...
Article
Given extensive improvements in access to antiretroviral therapy (ART) over the past 12 years, the HIV and cryptococcal meningitis landscapes have dramatically changed since 2010. We sought to evaluate changes in clinical presentation and clinical outcomes of people presenting with HIV-associated cryptococcal meningitis between 2010 and 2022 in Uga...
Article
Importance The effect of montelukast in reducing symptom duration among outpatients with mild to moderate COVID-19 is uncertain. Objective To assess the effectiveness of montelukast compared with placebo in treating outpatients with mild to moderate COVID-19. Design, Setting, and Participants This randomized clinical trial (Accelerating COVID-19...
Article
Cerebrospinal fluid (CSF) protein levels exhibit high variability in HIV-associated cryptococcal meningitis; however, its clinical implications remain unclear. We analyzed data from 890 adults with HIV-associated cryptococcal meningitis randomized into two clinical trials in Uganda between 2015 and 2021. CSF protein was grouped into <100 mg/dL (72%...
Article
Background The role of the immune response in acute mortality of cryptococcal meningitis remains unclear. Methods Cerebrospinal fluid (CSF) from 337 Ugandans with first-episode cryptococcal meningitis was collected. CSF cytokines and chemokines were quantified and compared by 14-day survival, stratification by quartiles, and logistical regression...
Article
Background In 2022, the World Health Organization (WHO) recommended a single 10mg/kg dose of liposomal amphotericin B in combination with 14 days of flucytosine and fluconazole (AMBITION-cm regimen) for induction therapy of HIV-associated cryptococcal meningitis, based on the results of the multisite AMBITION-cm trial. We evaluated outcomes after r...
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Background The Visitect CD4 Advanced Disease test (AccuBio, Alva, United Kingdom) is a rapid, semi-quantitative assay that estimates CD4 results above or below 200 cells/μL. We evaluated the performance of the Visitect CD4 assay in semi-urban laboratories in Uganda. Methods We performed a pragmatic laboratory validation of the Visitect CD4 platfor...
Article
Histoplasmosis is a fungal disease associated with substantial mortality rates among persons with advanced HIV disease. Our systematic review synthesized data on the global prevalence of Histoplasma­-caused antigenuria in persons with HIV. We searched PubMed/Medline, Embase, and Scopus databases on January 3, 2023, to identify cross-sectional and c...
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Background Cryptococcal meningitis is a leading cause of AIDS-related mortality. Cryptococcal antigen (CrAg) predicts the development of meningitis. Historically, despite standard- of-care fluconazole, 25%–30% of asymptomatic CrAg-positive persons develop breakthrough meningitis or death. We evaluated whether adding single high-dose liposomal ampho...
Article
No accurate and rapid diagnostic test exists for tuberculous meningitis (TBM), leading to delayed diagnosis. We leveraged data from multiple studies to improve the predictive performance of diagnostic models across different populations, settings, and subgroups to develop a new predictive tool for TBM diagnosis. We conducted a systematic review to...
Preprint
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Background Cryptococcal meningitis is a leading cause of adult community-acquired meningitis in sub-Saharan Africa with high mortality rates in the first 10 weeks post diagnosis. Practical tools to stratify mortality risk may help to tailor effective treatment strategies. Methods We pooled individual-level data from two randomised-controlled trial...
Article
Background Persons with HIV and cryptococcal antigenemia are at high risk of progression to cryptococcal meningitis or death. Baseline cryptococcal antigen (CrAg) plasma titer ≥1:160 is a known risk factor for poor outcomes, but other risk factors are unknown. In HIV-associated cryptococcal meningitis, baseline serum C-reactive protein (CRP) concen...
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Background Mortality amongst adults diagnosed with HIV-associated cryptococcal meningitis remains high (24-40%). We hypothesized that nutritional state, as measured by mid-upper arm circumference (MUAC), is a potentially modifiable risk factor for mortality. Methods Ugandan adults hospitalized with HIV-associated cryptococcal meningitis had MUAC m...
Article
Background Limited data exist on the antifungal activity of daily liposomal amphotericin B with flucytosine induction regimens for cryptococcal meningitis, which are recommended in high-income countries. Liposomal amphotericin B monotherapy at 3 mg/kg previously failed to meet non-inferiority criteria compared to amphotericin B deoxycholate in its...
Article
Background Central nervous system (CNS) compartmentalization provides opportunity for HIV persistence and resistance development. Differences between cerebrospinal fluid (CSF) and cerebral matter regarding HIV persistence are well described. However, CSF is often used as surrogate for CNS drug exposure, and knowledge from solid brain tissue is rare...
Article
Background: Mortality associated with HIV-associated cryptococcal meningitis remains high even in the context of clinical trials (24-45% at 10 weeks); mortality at 12-months is up to 78% in resource limited settings. Co-prevalent tuberculosis (TB) is common and preventable, and likely contributes to poor patient outcomes. Innovative strategies to...
Preprint
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Introduction Cryptococcal meningitis remains a prominent cause of death in persons with advanced HIV disease. CSF leukocyte infiltration predicts survival at 18 weeks; however, how CSF immune response relates to CSF leukocyte infiltration is unknown. Methods We enrolled 401 adults with HIV-associated cryptococcal meningitis in Uganda who received...
Preprint
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Importance: The effect of montelukast in reducing symptom duration among outpatients with mild to moderate coronavirus disease 2019 (COVID-19) is uncertain. Objective: To assess the effectiveness of montelukast compared with placebo, in treating outpatients with mild to moderate COVID-19. Design, Setting, and Participants: The ACTIV-6 platform rand...
Article
Background Metformin has antiviral activity against RNA viruses including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The mechanism appears to be suppression of protein translation via targeting the host mechanistic target of rapamycin pathway. In the COVID-OUT randomized trial for outpatient coronavirus disease 2019 (COVID-19), m...
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This study describes decentralized recruitment and enrollment for a COVID-19 treatment trial, while comparing 5 primary recruitment methods: search engine ads, paid advertising within a national testing company, paid advertising within a regional testing company, electronic health record messages, and word of mouth. These are compared across patien...
Article
Background Several recent randomized trials have been conducted in resource-limited settings for cryptococcal meningitis which have rapidly innovated international guidelines. The 2010 IDSA cryptococcal meningitis guideline has not been updated with recent trials. The 2022 AMBITION-cm trial found that single 10mg/kg dose of liposomal amphotericin B...
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Purpose of Review This review highlights the difficulties in diagnosing and treating persons with a prior history of cryptococcal meningitis who improve but suffer from a recurrence of symptoms. This scenario is well known to those who frequently care for patients with cryptococcal meningitis but is not well understood. We highlight major gaps in k...
Article
Cryptococcosis is a major worldwide disseminated invasive fungal infection. Cryptococcosis, particularly in its most lethal manifestation of cryptococcal meningitis, accounts for substantial mortality and morbidity. The breadth of the clinical cryptococcosis syndromes, the different patient types at-risk and affected, and the vastly disparate resou...
Article
Background: Mortality associated with HIV-associated cryptococcal meningitis remains high even in the context of clinical trials (24–45% at 10 weeks); mortality at 12-months is up to 78% in resource limited settings. Co-prevalent tuberculosis (TB) is common and preventable, and likely contributes to poor patient outcomes. Innovative strategies to i...
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After Mycobacterium tuberculosis (Mtb) infection, many effector T cells traffic to the lungs, but few become activated. Here we use an antigen receptor reporter mouse (Nur77-GFP) to identify recently activated CD4 T cells in the lungs. These Nur77-GFPHI cells contain expanded TCR clonotypes, have elevated expression of co-stimulatory genes such as...
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Introduction Survival among people with HIV-associated cryptococcal meningitis (CM) remains low, particularly among women, despite the currently optimal use of antifungal drugs. Cryptococcus dissemination into the central nervous system [brain, spinal cord, and cerebrospinal fluid (CSF)] elicits the local production of cytokines, chemokines, and ot...
Preprint
Full-text available
Background Cerebrospinal fluid (CSF) protein levels exhibit high variability in HIV-associated cryptococcal meningitis from being normal to markedly elevated. However, the clinical implications of CSF protein levels in cryptococcal meningitis remain unclear. Methods We analysed data from 890 adults with HIV-associated cryptococcal meningitis random...
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Background The EnACT trial was a phase 2 randomized clinical trial conducted in Uganda, which evaluated a novel orally delivered lipid nanocrystal (LNC) amphotericin B in combination with flucytosine for treatment of cryptococcal meningitis. When flucytosine (5FC) is used as monotherapy in cryptococcosis, 5FC can induce resistant Cryptococcus mutan...
Article
Cryptococcal meningitis is a leading cause of morbidity and mortality globally, especially in people with advanced HIV disease. Cryptococcal meningitis is responsible for nearly 20% of all deaths related to advanced HIV disease, with the burden of disease predominantly experienced by people in resource-limited countries. Major advancements in diagn...
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Full-text available
Background The EnACT trial was a phase 2 randomized clinical trial conducted in Uganda, which evaluated a novel orally delivered lipid nanocrystal (LNC) amphotericin B for treatment of cryptococcal meningitis. Oral LNC amphotericin B applies nanotechnology, which hopes to improve intracellular drug delivery to affected tissues while reducing extrac...
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Full-text available
Background Histoplasmosis is a major cause of mortality in persons with advanced HIV disease (CD4< 200 cells/mcL) and areas of endemicity are evolving. Presenting symptoms of histoplasmosis may overlap with that of tuberculosis (TB). The true burden of histoplasmosis remains unknown in persons with advanced HIV disease, in part due to poor diagnost...
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Background Tuberculous meningitis (TBM) mortality averages at 27% but may reach 70% in HIV co-infection. High MRC severity grade, lower cerebrospinal fluid (CSF) white blood cell count (WBC) count, low weight, low CD4 and low plasma sodium were linked to mortality in Vietnam. Prognostic factors in African adults with HIV-associated TBM are unknown....
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Cryptococcosis in HIV-negative patients can be an opportunistic or endemic disease. There are no published studies on the use of the finger-prick whole blood (point-of-care) cryptococcal antigen lateral flow assay (CrAg LFA) for diagnosing cryptococcosis in HIV-negative patients. We conducted a case series study of HIV-negative patients with crypto...
Article
Importance The effect of higher-dose fluvoxamine in reducing symptom duration among outpatients with mild to moderate COVID-19 remains uncertain. Objective To assess the effectiveness of fluvoxamine, 100 mg twice daily, compared with placebo, for treating mild to moderate COVID-19. Design, Setting, and Participants The ACTIV-6 platform randomized...
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Full-text available
Purpose of review Tuberculous meningitis (TBM) is the most severe form of tuberculosis. Inadequate diagnostic testing and treatment regimens adapted from pulmonary tuberculosis without consideration of the unique nature of TBM are among the potential drivers. This review focuses on the progress being made in relation to both diagnosis and treatment...
Article
Cryptococcus neoformans and Cryptococcus gattii species complexes cause meningoencephalitis with high fatality rates and considerable morbidity, particularly in persons with deficient T cell-mediated immunity, most commonly affecting people living with HIV. Whereas the global incidence of HIV-associated cryptococcal meningitis (HIV-CM) has decrease...
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The COVID-19 pandemic accelerated the development of decentralized clinical trials (DCT). DCT’s are an important and pragmatic method for assessing health outcomes yet comprise only a minority of clinical trials, and few published methodologies exist. In this report, we detail the operational components of COVID-OUT, a decentralized, multicenter, q...
Article
Background: The effectiveness of inhaled glucocorticoids in shortening the time to symptom resolution or preventing hospitalization or death among outpatients with mild-to-moderate coronavirus disease 2019 (Covid-19) is unclear. Methods: We conducted a decentralized, double-blind, randomized, placebo-controlled platform trial in the United State...
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Background Adults with HIV-associated cryptococcal meningitis have overlapping burdens of cytomegalovirus (CMV) and tuberculosis (TB) coinfections. CMV infection/reactivation is strongly associated with CMV-specific memory T-cell activation and upregulation of type 1 interferons, which may lead to increased risk of TB disease and poor outcomes. Me...
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Background: Amphotericin B is the gold standard treatment for severe mycoses. A new orally delivered, less-toxic formulation of amphotericin has been developed. Methods: In our randomized clinical trial, we tested oral lipid nanocrystal (LNC) amphotericin B (MAT2203, Matinas Biopharma) vs intravenous (IV) amphotericin for human immunodeficiency...
Preprint
Full-text available
Survival among people with HIV-associated cryptococcal meningitis (CM) remains low, exceptionally among women with the increased threat of death on current optimal use of antifungal drugs. Cryptococcus dissemination into the central nervous system (CNS) prompts a neuroimmune reaction to activate pathogen concomitant factors. However, no consistent...
Article
Full-text available
Background Prior randomized clinical trials have reported benefit of fluvoxamine ≥200 mg/day vs placebo for patients infected with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Methods This randomized, double-blind, placebo-controlled, fully-remote multi-site clinical trial evaluated whether fluvoxamine prevents clinical deteriorat...
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Full-text available
In sub-Saharan Africa, an estimated 25% of people with HIV present with advanced HIV and are at high risk of opportunistic infections. Whereas histoplasmosis has occasionally been seen in Uganda, the understanding of the local risk of acute infection is limited. We sought to determine the prevalence of Histoplasma antigenuria using an enzyme immuno...
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Objective We studied the safety and efficacy of hydroxychloroquine (HCQ) as pre-exposure prophylaxis for COVID-19 in healthcare workers (HCWs), using a meta-analysis of randomised controlled trials (RCTs). Data sources PubMed and EMBASE databases were searched to identify randomised trials studying HCQ. Study selection Ten RCTs were identified (n...
Preprint
Full-text available
Current antiviral treatment options for SARS-CoV-2 infections are not available globally, cannot be used with many medications, and are limited to virus-specific targets.1-3 Biophysical modeling of SARS-CoV-2 replication predicted that protein translation is an especially attractive target for antiviral therapy.4 Literature review identified metfor...
Article
Background: Post-COVID-19 condition (also known as long COVID) is an emerging chronic illness potentially affecting millions of people. We aimed to evaluate whether outpatient COVID-19 treatment with metformin, ivermectin, or fluvoxamine soon after SARS-CoV-2 infection could reduce the risk of long COVID. Methods: We conducted a decentralised, r...
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Full-text available
Background: Histoplasmosis is a major AIDS-defining illness in Latin America. Liposomal amphotericin B (L-AmB) is the drug of choice for treatment, but access is restricted due to the high drug and hospitalization costs of the conventional long regimens. Methods: Prospective randomized multicenter open-label trial of one or two-dose induction th...
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OBJECTIVES/GOALS: Chronic or new symptoms after infection with severe-acute-respiratory-coronavirus-2 (SARS-CoV-2) has been termed post-acute sequelae of Covid-19 (PASC) or Long Covid. Our objective is to present results from COVID-OUT, a phase 3 double-blind, randomized controlled trial of early outpatient treatment of Covid-19 with repurposed med...
Article
Background: Previous trials have demonstrated the effects of fluvoxamine alone and inhaled budesonide alone for prevention of disease progression among outpatients with COVID-19. Objective: To determine whether the combination of fluvoxamine and inhaled budesonide would increase treatment effects in a highly vaccinated population. Design: Rand...
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Introduction Health workers’ failure to adhere to guidelines for screening, diagnosis and management of HIV-associated cryptococcal meningitis (CM) remains a significant public health concern. We aimed to assess adherence to the standards of care and management of HIV patients at risk of CM per the MoH guidelines and assess stock management of CM s...
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Among persons with HIV-associated cryptococcal meningitis serum hyponatremia is a risk factor for mortality; however, the role of hyponatremia in persons with asymptomatic cryptococcal antigenemia is unknown. We found that serum hyponatremia <130 mmol/L is an independent risk factor for progression to meningitis and death in asymptomatic persons wi...
Article
(See the Major Article by Suzanne Ingle et al.) Human immunodeficiency virus (HIV)–associated cryptococcal meningitis continues to have acute mortality rates in excess of 15% even in well-resourced settings [1, 2]. Rapid restoration of immune function with early antiretroviral therapy (ART) in immunosuppressed patients could facilitate clearance of...
Article
Importance It is unknown whether ivermectin, with a maximum targeted dose of 600 μg/kg, shortens symptom duration or prevents hospitalization among outpatients with mild to moderate COVID-19. Objective To evaluate the effectiveness of ivermectin at a maximum targeted dose of 600 μg/kg daily for 6 days, compared with placebo, for the treatment of e...
Article
Using data from 67 Ugandan HIV clinics (July 2019-January 2022), we report a 40% (1,005/1,662) reduction in the number of people with HIV presenting to care after August 2021 compared to pre-pandemic levels, with a greater proportion presenting with advanced HIV disease (20% vs. 16% in the pre-Covid period).
Article
Importance: The effectiveness of fluvoxamine to shorten symptom duration or prevent hospitalization among outpatients with mild to moderate symptomatic COVID-19 is unclear. Objective: To evaluate the efficacy of low-dose fluvoxamine (50 mg twice daily) for 10 days compared with placebo for the treatment of mild to moderate COVID-19 in the US. D...
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Full-text available
Cryptococcus is the leading cause of AIDS-related meningitis in sub-Saharan Africa. The clinical implications of a sterile cerebrospinal fluid (CSF) culture among individuals diagnosed with cryptococcal meningitis using CSF cryptococcal antigen (CrAg) are unclear. We prospectively enrolled 765 HIV-positive Ugandans with first-episode cryptococcal m...
Preprint
Full-text available
Background Long Covid is an emerging chronic illness potentially affecting millions, sometimes preventing the ability to work or participate in normal daily activities. COVID-OUT was an investigator-initiated, multi-site, phase 3, randomized, quadruple-blinded placebo-controlled clinical trial (NCT04510194). The design simultaneously assessed three...
Article
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Background Cryptococcal meningitis (CM) is the most common cause of meningitis in adults in Sub-Saharan Africa (SSA), causing significant morbidity and mortality in people living with HIV. Early initiation of antiretroviral therapy (ART) after cryptococcal diagnosis is associated with increased mortality. With increasing access to ART in SSA, an in...
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Background Despite HIV test and treat initiatives, the World Health Organization (WHO) estimates that 25% to 40% of persons living with HIV (PLWH) have advanced HIV disease (CD4< 200 cells/mcL). The objective of this study is to understand how the Covid-19 pandemic affected identification of persons with advanced HIV disease in Ugandan HIV clinics....
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Full-text available
Background The effectiveness of inhaled corticosteroids to shorten time to symptom resolution or prevent hospitalization or death among outpatients with mild-to-moderate coronavirus 2019 (Covid-19) is unclear. Methods ACTIV-6 is an ongoing, decentralized, double-blind, randomized, placebo-controlled platform trial testing repurposed medications in...
Article
Full-text available
Background Histoplasmosis is a major AIDS-defining infection in Latin America. Liposomal amphotericin B (L-AmB) is the drug of choice for treatment, but access is limited. Methods Prospective randomized open-label trial of induction therapy with L-AmB for disseminated histoplasmosis in AIDS, followed by oral itraconazole therapy (started on the da...
Article
Full-text available
Background Intravenous (IV) amphotericin B is the gold standard treatment of severe mycoses. A new orally absorbed, less-toxic formulation of amphotericin has been developed (Matinas Biopharma). We evaluated the efficacy of this novel anti-fungal agent amongst adults with cryptococcal meningitis. Methods We conducted a phase II randomized clinical...
Article
Background : Depression is a risk factor for worse HIV outcomes in persons living with HIV/AIDS, including engagement-in-care, HIV medication adherence, and retention-in-care. Depression has a prevalence of more than three times as high as in the general population. Despite this, there are few randomized studies of antidepressants in HIV-infected A...
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Background HIV-associated cryptococcal meningitis is a leading cause of AIDS-related mortality. The AMBITION-cm trial showed that a regimen based on a single high dose of liposomal amphotericin B deoxycholate (AmBisome group) was non-inferior to the WHO-recommended treatment of seven daily doses of amphotericin B deoxycholate (control group) and wa...
Article
Background: Cryptococcal meningitis is a common cause of AIDS-related mortality. Although symptom recurrence after initial treatment is common, the etiology is often difficult to decipher. We sought to summarize characteristics, etiologies and outcomes among persons with second-episode symptomatic recurrence. Methods: We prospectively enrolled U...
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The AMBITION-cm phase III randomized controlled trial, conducted in east and southern Africa, showed that a single high dose (10 mg/kg) of liposomal amphotericin B, given with an optimized oral backbone of fluconazole and flucytosine, was non-inferior to the World Health Organization (WHO)-recommended regimen of seven days of amphotericin B deoxych...
Article
Background: SARS-CoV-2 vaccination has decreasing protection from acquiring any infection with emergence of new variants; however, vaccination continues to protect against progression to severe COVID-19. The impact of vaccination status on symptoms over time is less clear. Methods: Within a randomized trial on early outpatient COVID-19 therapy t...
Article
Background Optimal penetration of anti-infectives in the female genital tract (FGT) is paramount in the treatment and prevention of infectious diseases. While exposure of anti-infectives in lower FGT tissues (e.g. cervix, vagina) has been described, little data exist on upper genital tissues (e.g. ovary, uterus). Methods Autopsies were performed a...
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Late presentation to HIV care, i.e., presenting with < 200 CD4 cells/mL, is associated with higher mortality and worse outcomes. Despite that, a quarter of people living with HIV in Uganda still present late to care. We surveyed Ugandans living with HIV who enrolled in clinic ≤ 90 days prior. We compared groups who presented 'late' with CD4 < 200 a...
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Introduction Cryptococcal meningitis is a common fungal opportunistic infection and a leading cause of death among people with advanced HIV disease in sub-Saharan Africa. The WHO recommends cryptococcal antigen (CrAg) screening followed by pre-emptive therapy to prevent cryptococcal meningitis and death in this population. In 2016, South Africa was...
Article
Background Cryptococcal meningitis is the most common cause of meningitis in adults living with HIV in sub-Saharan Africa. The estimates of national, regional, and global burden of cryptococcal meningitis are essential to guide prevention strategies and determine needs for diagnostic tests and treatments. We present a 2020 estimate of the global bu...
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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 HIV-infected Ugandans with cryptococcal meningitis from December 2018 to December 2021. Participa...
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Objectives : Cytomegalovirus (CMV) viremia is associated with increased mortality in persons with HIV. We previously demonstrated that CMV viremia was a risk factor for 10-week mortality in antiretroviral therapy (ART)-naïve persons with cryptococcal meningitis. We investigated whether similar observations existed over a broader cohort of HIV-assoc...