Browsing by Author "Musubire, Abdu K."

Now showing 1 - 7 of 7
  • 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
    Gastrointestinal cryptococcoma – Immune reconstitution inflammatory syndrome or cryptococcal relapse in a patient with AIDS?
    (Medical mycology case reports, 2015) Musubire, Abdu K.; Meya, David B.; Lukande, Robert; Kambugu, Andrew; Bohjanen, Paul R.; Boulware, David R.
    The introduction of antiretroviral therapy (ART) may lead to unusual paradoxical and unmasking pre- sentations of opportunistic infections. Intra-abdominal cryptococcosis is a rare manifestation of Cryp- tococcus. We present the case of an HIV-infected patient on ART, with a history of cryptococcal meningitis who presented with subacute, worsening abdominal pain during immune recovery. This evolved into chronic abdominal pain, with thickened bowel, and abdominal lymphadenopathy, while receiving em- piric tuberculosis treatment. At 6-months, he developed intestinal perforation due to a histologically confirmed cryptococcoma.
  • Thumbnail Image
    Item
    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
    (Clinical Infectious Diseases, 2021) Cresswell, Fiona V.; Meya, David B.; Kagimu, Enock; Grint, Daniel; Brake, Lindsey te; 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 M.; Aarnoutse, Rob; Boulware, David R.; Elliott, Alison M.
    High-dose rifampicin may improve outcomes of tuberculous meningitis (TBM). Little safety or pharmacokinetic (PK) data exist on high-dose rifampicin in human immunodeficiency virus (HIV) coinfection, and no cerebrospinal fluid (CSF) PK data exist from Africa. We hypothesized that high-dose rifampicin would increase serum and CSF concentrations without excess toxicity. Methods. In this phase II open-label trial, Ugandan adults with suspected TBM were randomized to standard-of-care control (PO-10, rifampicin 10 mg/kg/day), intravenous rifampicin (IV-20, 20 mg/kg/day), or high-dose oral rifampicin (PO-35, 35 mg/kg/ day). We performed PK sampling on days 2 and 14. The primary outcomes were total exposure (AUC0–24), maximum concentration (Cmax), CSF concentration, and grade 3–5 adverse events. Results. We enrolled 61 adults, 92% were living with HIV, median CD4 count was 50 cells/μL (interquartile range [IQR] 46–56). On day 2, geometric mean plasma AUC0–24hr was 42.9·h mg/L with 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 AUC0–24hr 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 ~6- and ~8-fold higher than standard of care, and CSF levels above the MIC.
  • Thumbnail Image
    Item
    Patients with Nodding Syndrome in Uganda Improve with Symptomatic Treatment: A Cross-Sectional Study
    (BMJ open, 2014) Idro, Richard; Namusoke, Hanifa; Abbo, Catherine; Mutamba, Byamah B.; Mwesige, Angelina Kakooza; Opoka, Robert O.; Musubire, Abdu K.; Mwaka, Amos D.; Opar, Bernard T.
    Nodding syndrome (NS) is a poorly understood neurological disorder affecting thousands of children in Africa. In March 2012, we introduced a treatment intervention that aimed to provide symptomatic relief. This intervention included sodium valproate for seizures, management of behaviour and emotional difficulties, nutritional therapy and physical rehabilitation. We assessed the clinical and functional outcomes of this intervention after 12 months of implementation.This was a cross-sectional study of a cohort of patients with NS receiving the specified intervention. We abstracted preintervention features from records and compared these with the current clinical status. We performed similar assessments on a cohort of patients with other convulsive epilepsies (OCE) and compared the outcomes of the two groups.Participants were patients with WHO-defined NS and patients with OCE attending the same centres.The primary outcome was the proportion of patients with seizure freedom (≥1 month without seizures). Secondary outcome measures included a reduction in seizure frequency, resolution of behaviour and emotional difficulties, and independence in basic self-care.Patients with NS had had a longer duration of symptoms (median 5 (IQR 3, 6) years) compared with those with OCE (4 (IQR 2, 6) years), p<0.001. The intervention resulted in marked improvements in both groups; compared to the preintervention state, 121/484 (25%) patients with NS achieved seizure freedom and there was a >70% reduction in seizure frequency; behaviour and emotional difficulties resolved in 194/327 (59%) patients; 193/484 (40%) patients had enrolled in school including 17.7% who had earlier withdrawn due to severe seizures, and over 80% had achieved independence in basic self-care. These improvements were, however, less than that in patients with OCE of whom 243/476 (51.1%) patients were seizure free and in whom the seizure frequency had reduced by 86%.Ugandan children with NS show substantial clinical and functional improvements with symptomatic treatments suggesting that NS is probably a reversible encephalopathy.
  • 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
    Xpert MTB/RIF Ultra for the Diagnosis of HIV-associated Tuberculous Meningitis: A Prospective Validation Study
    (The Lancet infectious diseases, 2020) Cresswell, Fiona V.; Tugume, Lillian; Kwizera, Richard; Bangdiwala, Ananta S.; Musubire, Abdu K.; Rutakingirwa, Morris; Kagimu, Enock; Nuwagira, Edwin; Mpoza, Edward; Rhein, Joshua; Williams, Darlisha A.; Muzoora, Conrad; Grint, Daniel; Elliott, Alison M.; Meya, David B.; Boulware, David R.; on behalf of the ASTRO-CM team
    Tuberculous meningitis accounts for 1–5% of tuberculosis cases. Diagnostic delay contributes to poor outcomes. We evaluated the performance of the new Xpert MTB/RIF Ultra (Xpert Ultra) for tuberculous meningitis diagnosis. In this prospective validation study, we tested the cerebrospinal fluid (CSF) of adults presenting with suspected meningitis (ie, headache or altered mental status with clinical signs of meningism) to the Mulago National Referral Hospital and Mbarara Regional Referral Hospital in Uganda. We centrifuged the CSF, resuspended the cell pellet in 2 mL CSF, and tested 0·5 mL aliquots with Xpert Ultra, Xpert MTB/RIF (Xpert), and mycobacterial growth indicator tube (MGIT) culture. We quantified diagnostic performance against the uniform case definition of probable or definite tuberculous meningitis and a composite microbiological reference standard. From Nov 25, 2016, to Jan 24, 2019, we screened 466 adults with suspected meningitis and tested 204 for tuberculous meningitis. Uniform clinical case definition classified 51 participants as having probable or definite tuberculous meningitis. Against this uniform case definition, Xpert Ultra had 76·5% sensitivity (95% CI 62·5–87·2; 39 of 51 patients) and a negative predictive value of 92·7% (87·6–96·2; 153 of 165), compared with 55·6% sensitivity (44·0–70·4; 25 of 45; p=0·0010) and a negative predictive value of 85·8% (78·9–91·1; 121 of 141) for Xpert and 61·4% sensitivity (45·5–75·6; 27 of 44; p=0·020) and negative predictive value of 85·2% (77·4–91·1; 98 of 115) for MGIT culture. Against the composite microbiological reference standard, Xpert Ultra had sensitivity of 92·9% (80·5–98·5; 39 of 42), higher than Xpert at 65·8% (48·6–80·4; 25 of 38; p=0·0063) and MGIT culture at 72·2% (55·9–86·2; 27 of 37; p=0·092). Xpert Ultra detected nine tuberculous meningitis cases missed by Xpert and MGIT culture. Xpert Ultra detected tuberculous meningitis with higher sensitivity than Xpert and MGIT culture in this HIV-positive population. However, with a negative predictive value of 93%, Xpert Ultra cannot be used as a rule-out test. Clinical judgment and novel highly sensitive point-of-care tests are still required.