Low CD4 count plus coma predicts cryptococcal meningitis in Tanzania

<p>Abstract</p> <p>Background</p> <p>Largely due to the lack of diagnostic reagents, the prevalence and clinical presentation of cryptococcal meningitis in Tanzania is poorly understood. This in turn is limiting the impact of increased fluconazole availability.</p> <p>Methods</p> <p>We evaluated a cohort of 149 consecutive HIV-infected adult inpatients presenting with headache or altered mental status for clinical features, CD4 count, cryptococcal infection, and outcome. Cryptococcal meningitis was diagnosed via India ink and latex agglutination assay of CSF (<it>n </it>= 24 and 40 positive, respectively). Associations between cryptococcal meningitis and clinical features were evaluated by t-test. The sensitivity, specificity, and positive likelihood ratio of such features were determined.</p> <p>Results</p> <p>Cryptococcal meningitis was associated with confusion, social withdrawal, seizures, fever, tachycardia, meningismus, oral candidiasis, and low Glasgow coma scales and CD4 count. CD4 count < 100/μl provided the highest sensitivity for the diagnosis (93%), coma (Glasgow coma scale ≤ 8) provided the highest specificity (84%), and the combination provided the highest positive likelihood ratio (3.8). All cryptococcal meningitis patients were initiated on 800 milligrams of fluconazole daily and 50% survived to discharge, however no clinical or laboratory findings correlated with prognosis.</p> <p>Conclusion</p> <p>Cryptococcal meningitis is common among Tanzanian HIV inpatients presenting with headache or altered mental status. Purely clinical features are insensitive for establishing the diagnosis or prognosis. We advocate expanding laboratory capacity for cryptococcal antigen testing to maximize survival.</p

Development and Validation of a Risk Score for Chronic Kidney Disease in HIV Infection Using Prospective Cohort Data from the D:A:D Study

Ristola M. on työryhmien DAD Study Grp ; Royal Free Hosp Clin Cohort ; INSIGHT Study Grp ; SMART Study Grp ; ESPRIT Study Grp jäsen.Background Chronic kidney disease (CKD) is a major health issue for HIV-positive individuals, associated with increased morbidity and mortality. Development and implementation of a risk score model for CKD would allow comparison of the risks and benefits of adding potentially nephrotoxic antiretrovirals to a treatment regimen and would identify those at greatest risk of CKD. The aims of this study were to develop a simple, externally validated, and widely applicable long-term risk score model for CKD in HIV-positive individuals that can guide decision making in clinical practice. Methods and Findings A total of 17,954 HIV-positive individuals from the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) study with >= 3 estimated glomerular filtration rate (eGFR) values after 1 January 2004 were included. Baseline was defined as the first eGFR > 60 ml/min/1.73 m2 after 1 January 2004; individuals with exposure to tenofovir, atazanavir, atazanavir/ritonavir, lopinavir/ritonavir, other boosted protease inhibitors before baseline were excluded. CKD was defined as confirmed (>3 mo apart) eGFR In the D:A:D study, 641 individuals developed CKD during 103,185 person-years of follow-up (PYFU; incidence 6.2/1,000 PYFU, 95% CI 5.7-6.7; median follow-up 6.1 y, range 0.3-9.1 y). Older age, intravenous drug use, hepatitis C coinfection, lower baseline eGFR, female gender, lower CD4 count nadir, hypertension, diabetes, and cardiovascular disease (CVD) predicted CKD. The adjusted incidence rate ratios of these nine categorical variables were scaled and summed to create the risk score. The median risk score at baseline was -2 (interquartile range -4 to 2). There was a 1: 393 chance of developing CKD in the next 5 y in the low risk group (risk score = 5, 505 events), respectively. Number needed to harm (NNTH) at 5 y when starting unboosted atazanavir or lopinavir/ritonavir among those with a low risk score was 1,702 (95% CI 1,166-3,367); NNTH was 202 (95% CI 159-278) and 21 (95% CI 19-23), respectively, for those with a medium and high risk score. NNTH was 739 (95% CI 506-1462), 88 (95% CI 69-121), and 9 (95% CI 8-10) for those with a low, medium, and high risk score, respectively, starting tenofovir, atazanavir/ritonavir, or another boosted protease inhibitor. The Royal Free Hospital Clinic Cohort included 2,548 individuals, of whom 94 individuals developed CKD (3.7%) during 18,376 PYFU (median follow-up 7.4 y, range 0.3-12.7 y). Of 2,013 individuals included from the SMART/ESPRIT control arms, 32 individuals developed CKD (1.6%) during 8,452 PYFU (median follow-up 4.1 y, range 0.6-8.1 y). External validation showed that the risk score predicted well in these cohorts. Limitations of this study included limited data on race and no information on proteinuria. Conclusions Both traditional and HIV-related risk factors were predictive of CKD. These factors were used to develop a risk score for CKD in HIV infection, externally validated, that has direct clinical relevance for patients and clinicians to weigh the benefits of certain antiretrovirals against the risk of CKD and to identify those at greatest risk of CKD.Peer reviewe

Symptomatic cytomegalovirus infection in renal transplant recipients given either Minnesota antilymphoblast globulin (MALG) or OKT3 for rejection prophylaxis.

Abstract To compare the impact of using Minnesota antilymphoblast globulin (MALG) versus the monoclonal antibody, OKT3, on the development of symptomatic cytomegalovirus (CMV) infection, we reviewed a cohort of 130 cadaveric renal transplant recipients enrolled in a prospective comparison of MALG versus OKT3 for rejection prophylaxis. Among the 112 patients at risk for CMV, prophylactic MALG was associated with an increased risk of symptomatic infection (relative hazard [rh] = 3.31; 95% confidence interval [CI], 1.50 to 7.30; P = 0.003). Transplantation of kidneys from CMV-seropositive donors into CMV-seronegative recipients (rh = 5.22; 95% CI, 2.34 to 11.63; P = 0.00004), first transplantation (rh = 4.76; 95% CI, 1.06 to 21.3; P = 0.039), and acute rejection therapy (rh = 2.03; 95% CI, 0.98 to 4.21; P = 0.055) were also associated with an increased risk. Prophylactic MALG followed by treatment with any agent for acute rejection was strongly correlated with symptomatic CMV infection (rh = 4.46; 95% CI, 3.71 to 5.21; P = 0.00006). Symptomatic CMV infection was not only more frequent, but more severe in recipients of prophylactic MALG, and more MALG recipients were treated with ganciclovir. There was no difference in rejection rate for the two rejection prophylaxis regimens (P = 0.625). Prophylactic OKT3 results in less risk of symptomatic CMV infection than prophylactic MALG in cadaveric renal transplant recipients who are seropositive for CMV or whose donors are seropositive for CMV. CMV prophylaxis studies or immunosuppression protocols with symptomatic CMV infection as an end point should be stratified according to the type of antilymphocyte therapy used for rejection prophylaxis, as well as donor and recipient CMV serologic status

Exploring the safety, effect on the tumor microenvironment, and efficacy of itacitinib in combination with epacadostat or parsaclisib in advanced solid tumors: a phase I study

Background This phase I multicenter study was designed to evaluate the safety, tolerability, efficacy, and translational effects on the tumor microenvironment of itacitinib (Janus-associated kinase 1 (JAK1) inhibitor) in combination with epacadostat (indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor) or parsaclisib (phosphatidylinositol 3-kinase δ (PI3Kδ) inhibitor).Methods Patients with advanced or metastatic solid tumors were enrolled and received itacitinib (100–400 mg once a day) plus epacadostat (50–300 mg two times per day; group A), or itacitinib (100–400 mg once a day) plus parsaclisib or parsaclisib monotherapy (0.3–10 mg once a day; group B).Results A total of 142 patients were enrolled in the study. The maximum tolerated dose was not reached for either the combination of itacitinib plus epacadostat (n=47) or itacitinib plus parsaclisib (n=90). One dose-limiting toxicity of serious, grade 3 aseptic meningitis was reported in a patient receiving itacitinib 300 mg once a day plus parsaclisib 10 mg once a day, which resolved when the study drugs were withdrawn. The most common treatment-related adverse events among patients treated with itacitinib plus epacadostat included fatigue, nausea, pyrexia, and vomiting, and for patients treated with itacitinib plus parsaclisib were fatigue, pyrexia, and diarrhea. In the itacitinib plus epacadostat group, no patient had an objective response. Among patients receiving itacitinib 100 mg once a day plus parsaclisib 0.3 mg once a day, three achieved partial response for an objective response rate (95% CI) of 7.1% (1.50 to 19.48). Treatment with itacitinib plus epacadostat demonstrated some increase in tumor CD8+ T cell infiltration and minor changes in six plasma proteins, whereas treatment with itacitinib plus high-dose parsaclisib resulted in downregulation of 20 plasma proteins mostly involved in immune cell function, with no observed change in intratumoral CD8+ T cell infiltration.Conclusion Adverse events with JAK1 inhibition combined with either IDO1 or PI3Kδ inhibition were manageable, but the combinations demonstrated limited clinical activity or enhancement of immune activation in the tumor microenvironment.Trial registration number NCT02559492

Immunobiology, preliminary safety, and efficacy of CPI-006, an anti-CD73 antibody with immune modulating activity, in a phase 1 trial in advanced cancers

2505 Background: CPI-006 inhibits CD73, a nucelotidase that converts AMP to adenosine and functions as a lymphocyte adhesion molecule. CPI-006 is a humanized IgG1 FcγR binding-deficient antibody that binds to CD73+ T and B lymphocytes leading to activation of B cells and expression of CD69. This study investigates the immunobiology, safety, and efficacy of CPI-006 monotherapy and in combination with CPI-444, an adenosine A2A receptor (A2AR) antagonist (NCT03454451). Methods: Patients with relapsed solid tumors were treated in a 3 + 3 escalation study with 1, 3, 6 or 12 mg/kg CPI-006 (Q3w IV infusion) monotherapy or in combination with CPI-444 (100 mg, PO, BID). Flow cytometry was performed on blood samples for lymphocyte subset analysis and receptor occupancy. Results: 17 patients were enrolled; 11 monotherapy and 6 combination. CPI-006 was associated with Grade 1 infusion reactions occuring within 30 minutes of the first infusion and were eliminated by premedication with non-steroidals. No DLTs with monotherapy or combination therapy were seen. Receptor occupancy on peripheral lymphocytes was maintained for the full dosing interval at 12 mg/kg. Pharmacodynamic effects suggesting immune modulation were observed within 1 hr of infusion at all dose levels and included a decrease in peripheral blood CD73pos B cells (mean reduction 86%, p < 0.05), increased CD73neg CD4 T cells (mean increase 37%, p < 0.01), and decreased CD8 T cells (mean reduction 20%, p < 0.01) compared to baseline. Overall, CD4:CD8 ratios were increased. Tumor regression was observed in a prostate cancer patient after 5 cycles of monotherapy at 6 mg/kg; peripheral B cells partially returned by the second cycle and reached a new homeostatic level through subsequent cycles. No change in serum immunoglobulins were observed. Conclusions: CPI-006 induces a rapid lymphocyte redistribution, including a transient reduction of circulating CD73pos B cells suggesting redistribution to lymphoid tissues, and an increased CD4:CD8 ratio, consistent with increased TH effector/memory cells in the blood. The treatment has been well-tolerated, and there is early evidence of anti-tumor activity of CPI-006 monotherapy. Clinical trial information: NCT03454451