Browsing by Author "Ssebambulidde, Kenneth"

Now showing 1 - 6 of 6
  • Thumbnail Image
    Item
    Adjunctive Sertraline in HIV-associated Cryptococcal Meningitis: A Randomized, Placebo-controlled, Double-blind Phase 3 Trial
    (The Lancet infectious diseases, 2019) Rhein, Joshua; Hullsiek, Kathy Huppler; Tugume, Lillian; Nuwagira, Edwin; Mpoza, Edward; Evans, Emily E.; Kiggundu, Reuben; Ssebambulidde, Kenneth; Akampurira, Andrew; Bangdiwala, Ananta S.; Abassi, Mahsa; Musubire, Abdu K.; Muzoora, Conrad; Meya, David B.; Boulware, David R.
    Identifying new antifungals for cryptococcal meningitis is a priority given the inadequacy of current therapy. Sertraline has previously shown in vitro and in vivo activity against cryptococcus. We aimed to assess the efficacy and cost-effectiveness of adjunctive sertraline in adults with HIV-associated cryptococcal meningitis compared with placebo.In this double-blind, randomised, placebo-controlled trial, we recruited HIV-positive adults with cryptococcal meningitis from two hospitals in Uganda. Participants were randomly assigned (1:1) to receive standard therapy with 7–14 days of intravenous amphotericin B (0·7–1·0 mg/kg per day) and oral fluconazole (starting at 800 mg/day) with either adjunctive sertraline or placebo. Sertraline was administered orally or via nasogastric tube at a dose of 400 mg/day for 2 weeks, followed by 200 mg/day for 12 weeks, then tapered off over 3 weeks. The primary endpoint was 18-week survival, analysed by intention-to-treat. This study is registered with ClinicalTrials.gov, number NCT01802385.Between March 9, 2015, and May 29, 2017, we screened 842 patients with suspected meningitis and enrolled 460 of a planned 550 participants, at which point the trial was stopped for futility. Three patients in the sertraline group and three patients in the placebo group were lost to follow-up and therefore discontinued before study end. At 18 weeks, 120 (52%) of 229 patients in the sertraline group and 106 (46%) of 231 patients in the placebo group had died (hazard ratio 1·21, 95% CI 0·93–1·57; p=0·15). The fungal clearance rate from cerebrospinal fluid was similar between groups (0·43 –log10 CFU/mL per day [95% CI 0·37–0·50] in the sertraline group vs 0·47 –log10 CFU/mL per day [0·40–0·54] in the placebo group; p=0·59), as was occurrence of grade 4 or 5 adverse events (72 [31%] of 229 vs 75 [32%] of 231; p=0·98), most of which were associated with amphotericin B toxicity. Sertraline did not reduce mortality and should not be used to treat patients with HIV-associated cryptococcal meningitis. The reasons for sertraline inactivity appear to be multifactorial and might be associated with insufficient duration of therapeutic sertraline concentrations.
  • Thumbnail Image
    Item
    Evaluation of the Dynamiker Cryptococcal Antigen Lateral Flow Assay for the Diagnosis of HIV-Associated Cryptococcosis
    (Journal of clinical microbiology, 2021) Kwizera, Richard; Omali, Denis; Tade, Kiiza; Kasibante, John; Rutakingirwa, Morris K.; Kagimu, Enock; Ssebambulidde, Kenneth; Williams, Darlisha A.; Rhein, Joshua; Boulware, David; Meya, David B.
    Cryptococcal meningitis is a leading cause of meningitis in sub-Saharan Africa. Given the need for rapid point-of-care testing, we evaluated the diagnostic performance of the Dynamiker cryptococcal antigen (CrAg) lateral flow assay (LFA). We assessed the diagnostic performance of the Dynamiker CrAg LFA compared to the IMMY CrAg LFA as the reference standard. We tested 150 serum, 115 plasma, and 100 cerebrospinal fluid (CSF) samples from HIV patients with symptomatic meningitis and 113 serum samples from patients with suspected asymptomatic cryptococcal antigenemia. Compared to the IMMY CrAg LFA, sensitivity of Dynamiker CrAg LFA was 98% in serum, 100% in plasma, 100% in CSF from symptomatic patients and 96% in serum from asymptomatic patients. Specificity was 66% in serum, 61% in plasma, and 91% in CSF from symptomatic patients, and 86% in serum from asymptomatic patients. The positive predictive value was 85% in serum, 82% in plasma, and 96% in CSF from symptomatic patients, and 69% in serum from asymptomatic patients. The negative predictive value was 94% in serum, 100% in plasma, and 100% in CSF from symptomatic patients, and 99% in serum from asymptomatic patients. The interassay reproducibility was 100% across the four sample types with no observed discordant results when Dynamiker CrAg LFA was tested in duplicate. However, a high number of false positives were observed on serum of symptomatic patients (11%), serum of asymptomatic patients (11%) and plasma of symptomatic patients (14%). The Dynamiker CrAg LFA had excellent sensitivity but poor specificity, particularly when tested on serum and plasma.
  • Thumbnail Image
    Item
    Factors associated with HIV self‑testing among female university students in Uganda: a cross‑sectional study
    (AIDS Research and Therapy, 2022) Segawa, Ivan; Bakeera‑Kitaka, Sabrina; Ssebambulidde, Kenneth; Muwonge, Timothy R.; Oriokot, Lorraine; Ouma Ojiambo, Kevin; Mujugira, Andrew
    Adolescent girls and young women (AGYW) at institutions of higher learning are at high risk of HIV, and conventional HIV testing services may not reach them sufficiently. HIV self-testing (HIVST) scalability can be informed by identifying AGYW who have used or are interested in using HIVST. We aimed to determine factors associated with use and willingness to use HIVST among female university students. Methods: An online cross-sectional survey was conducted among 483 female students at Makerere University, Uganda. Proportions of students who have used or are willing to use HIVST and their associated factors were determined. Modified Poisson regression models were used to estimate prevalence ratios (PR) and their 95% confidence intervals (CI). Results: The median age of the participants was 22 (Interquartile range [IQR] 21–23) years, and 21% had never tested for HIV. Over 93% were willing to utilize HIVST, and 19% had ever used HIV self-test kits. Increasing age (adjusted prevalence ratio [aPR] 1.23 per year, 95% CI 1.07–1.43) was significantly associated with HIVST use. Predictors of willingness to self-test for HIV were college type (arts vs. science-based, aPR 0.92, 95% CI 0.88–0.97), number of sexual partners (one, aPR 1.07, 95% CI 1.03–1.12 or ≥ 2, aPR 1.08, 95% CI 1.04–1.19, vs. none), alcohol (aPR 1.04, 95% CI: 1.00–1.09) or injection drug (aPR 1.04, 95% CI 1.00–1.09) use, a history of sexually transmitted infections in past 12 months (aPR 1.05, 95% CI 1.01–1.09), and HIV testing experience (tested in past 12 months, aPR 1.12, 95% CI 1.02–1.22 or over 12 months, aPR 1.13, 95% CI 1.03–1.24, vs. never tested). Conclusion: HIVST was highly acceptable despite its limited use. This study demonstrates female student characteristics that can be leveraged to scale up HIVST programs in higher institutions of learning.
  • Thumbnail Image
    Item
    Symptomatic Cryptococcal Antigenemia Presenting as Early Cryptococcal Meningitis With Negative Cerebral Spinal Fluid Analysis
    (Clinical infectious diseases, 2019) Ssebambulidde, Kenneth; Kwizera, Richard; Kandole, Tadeo Kiiza; Tugume, Lillian; Kiggundu, Reuben; Mpoza, Edward; Nuwagira, Edwin; Williams, Darlisha A.; Lofgren, Sarah M.; Abassi, Mahsa; Musubire, Abdu K.; Cresswell, Fiona V.; Muzoora, Conrad; Boulware, David R.; Meya, David B.; for the Adjunctive Sertraline for Treatment of HIV-associated Cryptococcal Meningitis Team
    Individuals with cryptococcal antigenemia are at high risk of developing cryptococcal meningitis if untreated. The progression and timing from asymptomatic infection to cryptococcal meningitis is unclear. We describe a subpopulation of individuals with neurologic symptomatic cryptococcal antigenemia but negative cerebral spinal fluid (CSF) studies.We evaluated 1201 human immunodeficiency virus–seropositive individuals hospitalized with suspected meningitis in Kampala and Mbarara, Uganda. Baseline characteristics and clinical outcomes of participants with neurologic–symptomatic cryptococcal antigenemia and negative CSF cryptococcal antigen (CrAg) were compared to participants with confirmed CSF CrAg+ cryptococcal meningitis. Additional CSF testing included microscopy, fungal culture, bacterial culture, tuberculosis culture, multiplex FilmArray polymerase chain reaction (PCR; Biofire), and Xpert MTB/Rif.We found 56% (671/1201) of participants had confirmed CSF CrAg+ cryptococcal meningitis and 4% (54/1201) had neurologic symptomatic cryptococcal antigenemia with negative CSF CrAg. Of those with negative CSF CrAg, 9% (5/54) had Cryptococcus isolated on CSF culture (n = 3) or PCR (n = 2) and 11% (6/54) had confirmed tuberculous meningitis. CSF CrAg-negative patients had lower proportions with CSF pleocytosis (16% vs 26% with ≥5 white cells/μL) and CSF opening pressure >200 mmH2O (16% vs 71%) compared with CSF CrAg-positive patients. No cases of bacterial or viral meningitis were detected by CSF PCR or culture. In-hospital mortality was similar between symptomatic cryptococcal antigenemia (32%) and cryptococcal meningitis (31%; P = .91).Cryptococcal antigenemia with meningitis symptoms was the third most common meningitis etiology. We postulate this is early cryptococcal meningoencephalitis. Fluconazole monotherapy was suboptimal despite Cryptococcus-negative CSF. Further studies are warranted to understand the clinical course and optimal management of this distinct entity.
  • Thumbnail Image
    Item
    Therapeutic Lumbar Punctures in HIV-associated Cryptococcal Meningitis: should opening pressure direct management?
    (In Open Forum Infectious Diseases., 2022) Kagimu, Enock; Engen, Nicole; Ssebambulidde, Kenneth; Kasibante, John; Kiiza, Tadeo K; Mpoza, Edward; L., Lillian Tugume; Nuwagira, Edwin; Nsangi, Laura; Meya, David B.; Rhein, Joshua; Abassi, Mahsa; Musubire, Abdu K.
    Increased intracranial pressure (ICP) frequently complicates cryptococcal meningitis. Therapeutic lumbar punctures (LPs) have acute survival benefits in the first week, and we sought to understand the longer-term survival impact of therapeutic LPs. We prospectively enrolled HIV-seropositive adults with cryptococcal meningitis from 2013 to 2017 in Uganda. CSF opening pressure was measured at diagnosis. Therapeutic LPs were scheduled on days 3, 7, 10, 14, and performed additionally as clinically indicated. We assessed the association between clinical characteristics, CSF parameters, and 14- and 30-day mortality by baseline ICP. We also assessed 30-day mortality by number of follow-up therapeutic LPs performed within 7 days.
  • Thumbnail Image
    Item
    Tuberculosis in HIV-Associated Cryptococcal Meningitis is Associated with an Increased Risk of Death
    (Journal of Clinical Medicine, 2020) Rutakingirwa, Morris K.; Cresswell, Fiona V.; Kwizera, Richard; Ssebambulidde, Kenneth; Kagimu, Enock; Nuwagira, Edwin; Tugume, Lillian; Mpoza, Edward; Dobbin, Joanna; Williams, Darlisha A.; Muzoora, Conrad; Meya, David B.; Boulware, David R.; Hullsiek, Kathy H.; Rhein, Joshua
    uberculosis (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% (31/67) in concurrent TB, and 45% (341/753) in the no TB group (p = 0.81). However, TB co-infection was associated with an increased hazard of death (HR = 1.75; 95% CI, 1.33–2.32; p < 0.001) in a time-updated model. TB is commonly diagnosed in cryptococcal meningitis, and the increased mortality associated with co-infection is a public health concern.