Background: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in December ... more Background: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in December 2019 causing the coronavirus disease 2019 (COVID-19) pandemic. Currently, there are a lack of evidence-based therapies to prevent COVID-19 following exposure, or to prevent worsening of symptoms following confirmed infection. We describe the design of a clinical trial of hydroxychloroquine for post-exposure prophylaxis and pre-emptive therapy for COVID-19. Methods: We will conduct two nested multicenter international double-blind randomized placebo-controlled clinical trials of hydroxychloroquine for: 1) post-exposure prophylaxis (PEP) of asymptomatic household contacts or healthcare workers exposed to COVID-19 within the past four days, and 2) pre-emptive therapy (PET) for symptomatic outpatients with COVID-19 with a total symptom duration of less than 4 days. We will recruit 1500 patients for each the PEP and PET trials. Participants will be randomized 1:1 to receive 5 days of hydroxyc...
Tuberculosis (TB) and cryptococcal meningitis are leading causes of morbidity and mortality in ad... more Tuberculosis (TB) and cryptococcal meningitis are leading causes of morbidity and mortality in advanced HIV disease. Data are limited on TB co-infection among individuals with cryptococcal meningitis. We performed a retrospective analysis of HIV-infected participants with cryptococcal meningitis from 2010–2017. Baseline demographics were compared between three groups: ‘prevalent TB’ if TB treated >14 days prior to cryptococcal meningitis diagnosis, ‘concurrent TB’ if TB treated ± 14 days from diagnosis, or ‘No TB at baseline’. We used time-updated proportional-hazards regression models to assess TB diagnosis as a risk for death. Of 870 participants with cryptococcal meningitis, 50 (6%) had prevalent TB, 67 (8%) had concurrent TB, and 753 (86%) had no baseline TB. Among participants without baseline TB, 67 (9%) were diagnosed with incident TB (after >14 days), with a median time to TB incidence of 41 days (IQR, 22–69). The 18-week mortality was 50% (25/50) in prevalent TB, 46% ...
ObjectivesAnaemia represents a common toxicity with amphotericin B‐based induction therapy in HIV... more ObjectivesAnaemia represents a common toxicity with amphotericin B‐based induction therapy in HIV‐infected persons with cryptococcal meningitis. We sought to examine the impact of amphotericin‐related anaemia on survival.MethodsWe used data from Ugandan and South African trial participants to characterize the variation of haemoglobin concentrations from diagnosis to 12 weeks post‐diagnosis. Anaemia severity was classified based on the haemoglobin concentration at cryptococcal meningitis diagnosis, and nadir haemoglobin values during amphotericin induction. Cox proportional hazard models were used to estimate 2‐ and 10‐week mortality risk. We also estimated 10‐week mortality risk among participants with nadir haemoglobin < 8.5 g/dL during amphotericin induction and who survived ≥ 2 weeks post‐enrolment.ResultsThe median haemoglobin concentration at meningitis diagnosis was 11.5 g/dL [interquartile range (IQR) 9.7–13 g/dL; n = 311] with a mean decline of 4.2 g/dL [95% confidence in...
Cryptococcus is the most common cause of adult meningitis in Africa. We assessed the safety and m... more Cryptococcus is the most common cause of adult meningitis in Africa. We assessed the safety and microbiological efficacy of adjunctive sertraline, previously shown to have in-vitro and in-vivo activity against cryptococcus. In this open-label dose-finding study, we recruited HIV-infected individuals with cryptococcal meningitis who presented to Mulago Hospital in Kampala, Uganda between Aug 14, 2013, and Aug 30, 2014. To assess safety and tolerability, the first 60 participants were given sertraline at escalating doses of 100 mg/day, 200 mg/day, 300 mg/day, or 400 mg/day as induction therapy for 2 weeks, followed by consolidation therapy with 200 mg/day for an additional 8 weeks. From Nov 29, 2013, participants were randomly assigned (1:1) to receive open-label sertraline at predetermined doses of 200 mg/day, 300 mg/day, or 400 mg/day as induction therapy for 2 weeks, followed by consolidation therapy with 200 mg/day for 8 weeks. Dose assignment was made via computer-generated, perm...
Antimicrobial agents and chemotherapy, Jan 31, 2015
Cryptococcal antigen screening is recommended among people living with AIDS when entering HIV car... more Cryptococcal antigen screening is recommended among people living with AIDS when entering HIV care with CD4 count <100 cells/μL, and preemptive fluconazole monotherapy treatment is recommended for those with subclinical cryptococcal antigenemia. Yet, knowledge is limited of current antimicrobial resistance in Africa. We examined antifungal drug susceptibility in 198 clinical isolates collected from Kampala, Uganda, between 2010-2014 using the CLSI broth microdilution assay. In comparison with two previous studies from 1998/99 reporting an MIC50 of 4 μg/mL and an MIC90 of 8 μg/mL prior to wide-spread human fluconazole and agricultural azole fungicide usage, we report an upward shift in fluconazole MIC50 to 8 μg/mL, and a MIC90 value of 32 μg/mL. We observed an amphotericin B MIC50 of 0.5 μg/mL and an MIC90 of 1 μg/mL, of which 99.5% (197/198) of isolates were still susceptible. No correlation between MIC and clinical outcome was observed in the context of amphotericin B and flucon...
Both HIV infection and antiretroviral therapy (ART) may increase cardiovascular disease (CVD) ris... more Both HIV infection and antiretroviral therapy (ART) may increase cardiovascular disease (CVD) risk. Assessments of vascular function and structure can be used to study the pathogenesis and progression of CVD, including the effects of ART and other interventions. The objective of this report is to understand methods to assess vascular (dys)function and report our experience in the Arterial Elasticity Substudy in the Strategic Timing of AntiRetroviral Treatment (START) trial. We review literature and analyze baseline data from the Arterial Elasticity Substudy, which estimated vascular (dys)function through analysis of the diastolic blood pressure (BP) waveform. Linear regression was used to study cross-sectional associations between baseline clinical factors and small or large arterial elasticity. Arterial elasticity measurement was chosen for its improved measurement reproducibility over other methodologies and the potential of small arterial elasticity to predict clinical risk. Anal...
As socioeconomic factors may impact the risk of chronic kidney disease (CKD), we evaluated the in... more As socioeconomic factors may impact the risk of chronic kidney disease (CKD), we evaluated the incidence and risk factors of incident CKD among an HIV-infected cohort with universal access to health care and minimal injecting drug use (IDU). Incident CKD was defined as an estimated glomerular filteration rate (eGFR) &amp;amp;lt;60 ml/min/1.73 m(2) for ≥ 90 days. eGFR was calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. Rates were calculated per 1000 person-years (PY). Associations with outcomes were assessed using two separate Cox proportional hazard models, adjusting for baseline and time-updated covariates. Among 3360 participants [median age 29 years; 92% male; 44% African American (AA)] contributing 23,091 PY of follow-up, 116 developed incident CKD [5.0/1000 PY; 95% confidence interval (CI) 4.2-6.0/1000 PY]. The median first eGFR value was 97.0 mL/min/1.73 m(2) [interquartile range (IQR) 85.3-110.1 mL/min/1.73 m(2)]. Baseline factors associated with CKD included older age, lower CD4 count at HIV diagnosis [compared with CD4 count ≥ 500 cells/μL, hazard ratio (HR) 2.1 (95% CI 1.2-3.8) for CD4 count 350-499 cells/μL; HR 3.6 (95% CI 2.0-6.3) for CD4 count 201-349 cells/μL; HR 4.3 (95% CI 2.0-9.4) for CD4 count ≤ 200 cells/μL], and HIV diagnosis in the pre-highly active antiretroviral therapy (HAART) era. In the time-updated model, low nadir CD4 counts, diabetes, hepatitis B, hypertension and less HAART use were also associated with CKD. AA ethnicity was not associated with incident CKD in either model. The low incidence of CKD and the lack of association with ethnicity observed in this study may in part be attributable to unique features of our cohort such as younger age, early HIV diagnosis, minimal IDU, and unrestricted access to care. Lower baseline CD4 counts were significantly associated with incident CKD, suggesting early HIV diagnosis and timely introduction of HAART may reduce the burden of CKD.
Background: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in December ... more Background: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in December 2019 causing the coronavirus disease 2019 (COVID-19) pandemic. Currently, there are a lack of evidence-based therapies to prevent COVID-19 following exposure, or to prevent worsening of symptoms following confirmed infection. We describe the design of a clinical trial of hydroxychloroquine for post-exposure prophylaxis and pre-emptive therapy for COVID-19. Methods: We will conduct two nested multicenter international double-blind randomized placebo-controlled clinical trials of hydroxychloroquine for: 1) post-exposure prophylaxis (PEP) of asymptomatic household contacts or healthcare workers exposed to COVID-19 within the past four days, and 2) pre-emptive therapy (PET) for symptomatic outpatients with COVID-19 with a total symptom duration of less than 4 days. We will recruit 1500 patients for each the PEP and PET trials. Participants will be randomized 1:1 to receive 5 days of hydroxyc...
Tuberculosis (TB) and cryptococcal meningitis are leading causes of morbidity and mortality in ad... more Tuberculosis (TB) and cryptococcal meningitis are leading causes of morbidity and mortality in advanced HIV disease. Data are limited on TB co-infection among individuals with cryptococcal meningitis. We performed a retrospective analysis of HIV-infected participants with cryptococcal meningitis from 2010–2017. Baseline demographics were compared between three groups: ‘prevalent TB’ if TB treated >14 days prior to cryptococcal meningitis diagnosis, ‘concurrent TB’ if TB treated ± 14 days from diagnosis, or ‘No TB at baseline’. We used time-updated proportional-hazards regression models to assess TB diagnosis as a risk for death. Of 870 participants with cryptococcal meningitis, 50 (6%) had prevalent TB, 67 (8%) had concurrent TB, and 753 (86%) had no baseline TB. Among participants without baseline TB, 67 (9%) were diagnosed with incident TB (after >14 days), with a median time to TB incidence of 41 days (IQR, 22–69). The 18-week mortality was 50% (25/50) in prevalent TB, 46% ...
ObjectivesAnaemia represents a common toxicity with amphotericin B‐based induction therapy in HIV... more ObjectivesAnaemia represents a common toxicity with amphotericin B‐based induction therapy in HIV‐infected persons with cryptococcal meningitis. We sought to examine the impact of amphotericin‐related anaemia on survival.MethodsWe used data from Ugandan and South African trial participants to characterize the variation of haemoglobin concentrations from diagnosis to 12 weeks post‐diagnosis. Anaemia severity was classified based on the haemoglobin concentration at cryptococcal meningitis diagnosis, and nadir haemoglobin values during amphotericin induction. Cox proportional hazard models were used to estimate 2‐ and 10‐week mortality risk. We also estimated 10‐week mortality risk among participants with nadir haemoglobin < 8.5 g/dL during amphotericin induction and who survived ≥ 2 weeks post‐enrolment.ResultsThe median haemoglobin concentration at meningitis diagnosis was 11.5 g/dL [interquartile range (IQR) 9.7–13 g/dL; n = 311] with a mean decline of 4.2 g/dL [95% confidence in...
Cryptococcus is the most common cause of adult meningitis in Africa. We assessed the safety and m... more Cryptococcus is the most common cause of adult meningitis in Africa. We assessed the safety and microbiological efficacy of adjunctive sertraline, previously shown to have in-vitro and in-vivo activity against cryptococcus. In this open-label dose-finding study, we recruited HIV-infected individuals with cryptococcal meningitis who presented to Mulago Hospital in Kampala, Uganda between Aug 14, 2013, and Aug 30, 2014. To assess safety and tolerability, the first 60 participants were given sertraline at escalating doses of 100 mg/day, 200 mg/day, 300 mg/day, or 400 mg/day as induction therapy for 2 weeks, followed by consolidation therapy with 200 mg/day for an additional 8 weeks. From Nov 29, 2013, participants were randomly assigned (1:1) to receive open-label sertraline at predetermined doses of 200 mg/day, 300 mg/day, or 400 mg/day as induction therapy for 2 weeks, followed by consolidation therapy with 200 mg/day for 8 weeks. Dose assignment was made via computer-generated, perm...
Antimicrobial agents and chemotherapy, Jan 31, 2015
Cryptococcal antigen screening is recommended among people living with AIDS when entering HIV car... more Cryptococcal antigen screening is recommended among people living with AIDS when entering HIV care with CD4 count <100 cells/μL, and preemptive fluconazole monotherapy treatment is recommended for those with subclinical cryptococcal antigenemia. Yet, knowledge is limited of current antimicrobial resistance in Africa. We examined antifungal drug susceptibility in 198 clinical isolates collected from Kampala, Uganda, between 2010-2014 using the CLSI broth microdilution assay. In comparison with two previous studies from 1998/99 reporting an MIC50 of 4 μg/mL and an MIC90 of 8 μg/mL prior to wide-spread human fluconazole and agricultural azole fungicide usage, we report an upward shift in fluconazole MIC50 to 8 μg/mL, and a MIC90 value of 32 μg/mL. We observed an amphotericin B MIC50 of 0.5 μg/mL and an MIC90 of 1 μg/mL, of which 99.5% (197/198) of isolates were still susceptible. No correlation between MIC and clinical outcome was observed in the context of amphotericin B and flucon...
Both HIV infection and antiretroviral therapy (ART) may increase cardiovascular disease (CVD) ris... more Both HIV infection and antiretroviral therapy (ART) may increase cardiovascular disease (CVD) risk. Assessments of vascular function and structure can be used to study the pathogenesis and progression of CVD, including the effects of ART and other interventions. The objective of this report is to understand methods to assess vascular (dys)function and report our experience in the Arterial Elasticity Substudy in the Strategic Timing of AntiRetroviral Treatment (START) trial. We review literature and analyze baseline data from the Arterial Elasticity Substudy, which estimated vascular (dys)function through analysis of the diastolic blood pressure (BP) waveform. Linear regression was used to study cross-sectional associations between baseline clinical factors and small or large arterial elasticity. Arterial elasticity measurement was chosen for its improved measurement reproducibility over other methodologies and the potential of small arterial elasticity to predict clinical risk. Anal...
As socioeconomic factors may impact the risk of chronic kidney disease (CKD), we evaluated the in... more As socioeconomic factors may impact the risk of chronic kidney disease (CKD), we evaluated the incidence and risk factors of incident CKD among an HIV-infected cohort with universal access to health care and minimal injecting drug use (IDU). Incident CKD was defined as an estimated glomerular filteration rate (eGFR) &amp;amp;lt;60 ml/min/1.73 m(2) for ≥ 90 days. eGFR was calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. Rates were calculated per 1000 person-years (PY). Associations with outcomes were assessed using two separate Cox proportional hazard models, adjusting for baseline and time-updated covariates. Among 3360 participants [median age 29 years; 92% male; 44% African American (AA)] contributing 23,091 PY of follow-up, 116 developed incident CKD [5.0/1000 PY; 95% confidence interval (CI) 4.2-6.0/1000 PY]. The median first eGFR value was 97.0 mL/min/1.73 m(2) [interquartile range (IQR) 85.3-110.1 mL/min/1.73 m(2)]. Baseline factors associated with CKD included older age, lower CD4 count at HIV diagnosis [compared with CD4 count ≥ 500 cells/μL, hazard ratio (HR) 2.1 (95% CI 1.2-3.8) for CD4 count 350-499 cells/μL; HR 3.6 (95% CI 2.0-6.3) for CD4 count 201-349 cells/μL; HR 4.3 (95% CI 2.0-9.4) for CD4 count ≤ 200 cells/μL], and HIV diagnosis in the pre-highly active antiretroviral therapy (HAART) era. In the time-updated model, low nadir CD4 counts, diabetes, hepatitis B, hypertension and less HAART use were also associated with CKD. AA ethnicity was not associated with incident CKD in either model. The low incidence of CKD and the lack of association with ethnicity observed in this study may in part be attributable to unique features of our cohort such as younger age, early HIV diagnosis, minimal IDU, and unrestricted access to care. Lower baseline CD4 counts were significantly associated with incident CKD, suggesting early HIV diagnosis and timely introduction of HAART may reduce the burden of CKD.
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Papers by K. Hullsiek