No abstract

In a cross-sectional study among hospitalized human immunodeficiency virus (HIV)-infected patients in Ethiopia, we sought to determine the rates and predictors of cryptococcal disease and evaluate the test performance of a recently introduced point-of-care test for Cryptococcus neoformans detection in various biological samples. We tested serum, urine, and fingerstick blood samples from each patient with a cryptococcal antigen lateral flow assay (CRAG LFA; Immuno Mycologic Inc., Norman, OK). Cerebrospinal fluid was collected at the discretion of the treating physician. Logistic regression was used to identify risk factors for a positive test result. Agreement between different sample types was also assessed. Among 198 hospitalized HIV-infected patients with a median CD4 count of 93 cells/mm 3 , 18 patients (9.1%) had a positive serum CRAG LFA. Of these, 16 (8.1%) had confirmed cryptococcal meningitis (CM), all of whom had a positive fingerstick blood LFA result. There was a very high agreement between CRAG LFA tests in serum and fingerstick blood samples (κ = 0.97, 95% confidence interval [CI] = 0.91-1.00); this was higher than that between serum and urine samples (κ = 0.76, 95% CI = 0.58-0.93). A CD4 count < 100 cells/mm 3 was significantly associated with a positive CRAG LFA. The absence of fever, headache, meningismus, and neck stiffness had a negative predictive value of 100% for CM. In addition to finding high rates of cryptococcal disease, our study demonstrated that the use of the LFA on fingerstick whole blood is less invasive, and an effective method for CM case finding among hospitalized patients with HIV.

IntroductionIsoniazid preventive therapy (IPT) is a proven means to prevent tuberculosis (TB) disease among people living with HIV (PLHIV). However, there is a concern that patients often develop tuberculosis disease while receiving IPT, defined here as breakthrough tuberculosis, which may affect treatment outcome. In this study, we assessed the magnitude and determinants of breakthrough tuberculosis.MethodsA multisite retrospective longitudinal study from the year 2005 to 2014 involving 11 randomly selected hospitals from the Addis Ababa, SNNPR (Southern Nations Nationalities and Peoples Region), and Gambela regions of Ethiopia was carried out to assess the occurrence of breakthrough tuberculosis. Cox regression analysis was used to study factors associated with breakthrough TB.Results4,484 patients in chronic HIV care received IPT. Eighty percent of the same number received antiretroviral therapy (ART). Tuberculosis developed in 88 of 4,484 (2%) patients of which 24 (0.5%) were diagnosed while receiving IPT. Breakthrough TB incidence was 1106 per 100,000 person-years (PY) (95% CI: 742–1651) while TB incidence after completing IPT was 624 per 100,000 PY (95% CI: 488–797). Seven of the 24 (29%) breakthrough TB cases were diagnosed within the first month of IPT initiation. Of 15 patients who developed breakthrough TB while on ART, nine (60%) were diagnosed within the first six months of ART initiation. Having high CD4 cell count and being on ART were associated with having lower risk of developing TB and breakthrough TB.ConclusionBreakthrough TB was uncommon in the study setting. Even then, taking ART reduced the risk of its occurrence. Slightly more than a quarter of the cases of breakthrough TB occurred in the first month of treatment and may be existing undiagnosed TB cases which were missed during diagnostic work-up.

Epstein-Barr virus (EBV) is a human herpes virus that infects over 90% of the world’s population and is linked to development of cancer. In immune-competent individuals, EBV infection is mitigated by a highly efficient virus-specific memory T-cell response. Risk of EBV-driven cancers increases with immune suppression (IS). EBV-seronegative recipients of solid organ transplants are at high risk of developing post-transplant lymphoproliferative disease (PTLD) due to iatrogenic IS. While reducing the level of IS may improve EBV-specific immunity and regression of PTLD, patients are at high risk for allograft rejection and need for immune-chemotherapy. Strategies to prevent PTLD in this vulnerable patient population represents an unmet need. We have previously shown that BZLF1-specific cytotoxic T-cell (CTL) expansion following reduced IS correlated with immune-mediated PTLD regression and improved patient survival. We have developed a vaccine to bolster EBV-specific immunity to the BZLF1 protein and show that co-culture of dendritic cells (DCs) loaded with a αDEC205-BZLF1 fusion protein with peripheral blood mononuclear cells (PMBCs) leads to expansion and increased cytotoxic activity of central-effector memory CTLs against EBV-transformed B-cells. Human–murine chimeric Hu-PBL-SCID mice were vaccinated with DCs loaded with αDEC205-BZLF1 or control to assess prevention of fatal human EBV lymphoproliferative disease. Despite a profoundly immunosuppressive environment, vaccination with αDEC205-BZLF1 stimulated clonal expansion of antigen-specific T-cells that produced abundant IFNγ and significantly prolonged survival. These results support preclinical and clinical development of vaccine approaches using BZLF1 as an immunogen to harness adaptive cellular responses and prevent PTLD in vulnerable patient populations.