The Role of Donor Bone Marrow Infusions in Withdrawal of Immunosuppression in Adult Liver Allotransplantation

We investigated the role of donor bone marrow cell (DBMC) infusions in immunosuppression withdrawal in adult liver transplantation. Patients enrolled were at least 3 years post-transplantation, with stable graft function. Forty-five (study group: G1) received DBMC, and 59 (control group: G2) did not. Immunosuppression was reduced by one third upon enrollment, by another third the second year of the study and was completely withdrawn the third year. Patient and graft survival were similar between the two groups. Although rejection episodes were significantly less in G1 the first 2 years of the study (35% vs. 57%, p = 0.016), there was no significant difference overall (74% vs. 81%, p = 0.14). Until February 2004, 20 patients, 10 in each group, were immunosuppression free for 1-3 years. Approximately 20% of long-term survivors of liver transplantation can successfully discontinue their immunosuppression. DBMC infusions, do not increase this likelihood.     

Long-term treatment of secondary hyperparathyroidism with the calcimimetic cinacalcet HCl.

BACKGROUND: Patients with secondary hyperparathyroidism often require therapy that provides long-term control of parathyroid hormone concentrations without increasing calcium and phosphorus concentrations. Cinacalcet modulates the calcium-sensing receptor on the parathyroid gland to reduce secretion of parathyroid hormone and lower serum calcium, phosphorus and calcium-phosphorus product in haemodialysis patients. METHODS: Dialysis patients with secondary hyperparathyroidism [parathyroid hormone (PTH) level > or =300 pg/ml] who were enrolled in one of four phase 2 placebo-controlled studies were eligible to enroll in an open-label extension study in which all patients received cinacalcet. For this extension study, cinacalcet was initiated at 30 mg in all patients and the dose was escalated to a maximum of 180 mg once daily if PTH concentrations were >250 pg/ml. Use of concomitant vitamin D sterols and phosphate binders was not restricted. RESULTS: The analysis of all patients (n = 59) completing 100 weeks of cinacalcet treatment showed long-term control of PTH and calcium-phosphorus product. Approximately 55% achieved a PTH concentration < or =300 pg/ml at the week-100 study visit, and approximately 60% had at least a 30% reduction in PTH from baseline. Serum calcium, phosphorus and the calcium-phosphorus product did not increase during the study. Concomitant vitamin D sterol and phosphate binder therapy remained stable. Cinacalcet was safe and generally well tolerated at doses up to 180 mg/day. CONCLUSIONS: In this long-term study, cinacalcet effectively sustained reductions in PTH for up to 3 years without increasing concentrations of serum calcium, phosphorus or calcium-phosphorus product.     

Inter-observer agreement in interpreting chest X-rays on children with acute lower respiratory tract infections and concurrent wheezing.

CONTEXT AND OBJECTIVE: Many children with acute lower respiratory tract infections (ALRI) present to the emergency ward with concurrent wheezing. A chest x-ray is often requested to rule out pneumonia. We assessed inter-observer agreement in interpreting x-rays on such children. DESIGNS AND SETTING: Prospective consecutive case study at Instituto de Salud del Ni?o, Lima, Peru. METHODS: Chest x-rays were obtained from eligible children younger than two years old with ALRI and concurrent wheezing who were seen in the emergency ward of a nationwide pediatric referral hospital. The x-rays were read independently by three different pediatric residents who were aware only that the children had a respiratory infection. All the children had received inhaled beta-adrenergic agonists before undergoing chest x-rays. Lobar and complicated pneumonia cases were excluded from the study. RESULTS: Two hundred x-rays were read. The overall kappa index was 0.2. The highest individual kappa values for specific x-ray findings ranged from 0.26 to 0.34 for rib horizontalization and from 0.14 to 0.31 for alveolar infiltrate. Inter-observer variation was intermediate for alveolar infiltrate (kappa 0.14 to 0.21) and for air bronchogram (kappa 0.13 to 0.23). Reinforcement of the bronchovascular network (kappa 0.10 to 0.16) and air trapping (kappa 0.05 to 0.20) had the lowest agreement. CONCLUSIONS: There was poor inter-observer agreement for chest x-ray interpretation on children with ALRI and concurrent wheezing seen at the emergency ward. This may preclude reliable diagnosing of pneumonia in settings where residents make management decisions regarding sick children. The effects of training on inter-observer variation need further studies.     

Switch from ritonavir-boosted to unboosted atazanavir guided by therapeutic drug monitoring

Plasma concentration of atazanavir (ATV) may be reduced when coadministered with tenofovir (TDF) or proton pump inhibitors. Boosting ATV exposure with ritonavir (r) may make it possible to overcome these drug interactions. However, jaundice and loss of the metabolic advantages of ATV are more frequent using ATV/r than ATV alone. Herein, we assessed whether therapeutic drug monitoring (TDM) could make it possible to identify the subset of patients in whom removal of ritonavir could be attempted without risk of suboptimal plasma ATV exposure and subsequent virological failure. A total of 56 patients with undetectable plasma HIV-RNA under a stable triple regimen containing ATV 300/100 mg qd were switched to ATV 400 mg qd. Plasma ATV concentrations were measured using a reliable high-performance liquid chromatography method. Median plasma ATV C(min) fell from 880 to 283 ng/ml (p = 0.03) after removal of ritonavir. While all patients on ATV/r showed ATV plasma concentrations within therapeutic values (IC(min) above 150 ng/ml) before switching, four patients (7%) fell below this threshold after switching to ATV 400 mg qd. However, only one of this group experienced virological failure at week 24 of follow-up. TDF was part of the antiretroviral regimen in all four cases. From a total of 29 (52%) patients on ATV/r showing grade 3-4 hyperbilirubinemia, only 7 (12%) remained on it upon switching to ATV 400 mg qd (p < 0.001). Patients with complete viral suppression under ATV/r 300/100 mg qd may benefit from switching to ATV 400 mg qd guided by TDM, which may make it possible to minimize adverse events without compromising antiviral efficacy in most cases.     

Alcohol Modulation of Human Normal T-Cell Activation, Maturation, and Migration

We are interested in the characterization of the effects of alcohol on human T-cell activation, maturation, and migration, because this cell population is crucial in the initiation, regulation, and propagation of cellular immunity. We and others have described the effects of both acute and chronic exposure of human immune cells to ethanol (EtOH) in vitro. Herein, we briefly, review these reports and expand this body of literature with the inclusion of new data recently obtained in our laboratory. We confirm the blunting effects of EtOH on the production of interleukin-2 and mitogen proliferative response following T-cell mitogen stimulation, and on the expression of membrane markers of activation. We show that EtOH significantly alters the expression of the CD4 cell-associated marker of activation, CD26. We report the effect of EtOH on the expression of the homing receptor CD62L by CD4⁺ cells, and on their ability to adhere by a CD18-mediated process to a defined cellular substratum. Furthermore, we demonstrate the effects of EtOH and EtOH and 0-endor-phin pretreatment on the activation of CD4⁺ lymphocytes endowed with the homing receptor CD62L.     

Advances in treating drug-resistant hepatitis B virus in HIV-infected patients

Introduction: Treatment of HIV infection with nucleos(t)ide analogs active against hepatitis B virus (HBV) highly improves hepatic outcomes in HIV-HBV coinfected patients, especially when tenofovir (TDF) is part of the antiviral regimen. Drug resistance has been the major drawback and must remain as the most important caveat when planning to treat dually or HIV and HBV independently in coinfected patients.

Areas covered: The use of lamivudine (LAM) as the only active anti-HBV agent should strongly be discouraged in HIV-HBV coinfected patients, although it might be considered for individuals with low serum HBV-DNA and in the absence of liver cirrhosis as an exception. In any other case drug resistance may cause any clinical benefit of this antiviral HBV therapy to disappear, and lead to cross-resistance with other antivirals and even occasionally select for HBV vaccine escape mutants. In cirrhotics, liver enzyme flares may be accompanied by life-threatening decompensation. Entecavir is generally not recommended as an anti-HBV agent in HIV-HBV coinfected patients given its low residual antiretroviral activity and potential for selection of resistance mutations in HIV. Adefovir is not active against HIV using HBV dosing and is no longer recommended as HBV therapy given its limited antiviral effect. Finally, telbivudine is not active against HIV, it is less potent than TDF against HBV and depicts low barrier to resistance and cross-resistance to LAM or emtricitabine.

Expert Opinion: The introduction of TDF has drastically reduced the clinical relevance of hepatitis B drug resistance in HIV-HBV coinfected individuals. The use of LAM as the only active anti-HBV agent should strongly be discouraged in this population.