HIV infection results in CD4

One hundred and 16 patients contributed to an analysis of the impact of the consequences of severe haemophilia A or B (factor levels < 2%) on orthopaedic status, resources consumed in relation to this status and resultant cost, and quality of life as perceived by the patient, using the MOS 36-Item-Short-Form Health Survey (SF-36). This French cross-sectional study involved outpatients regularly attending a haemophilia treatment centre. Data were collected retrospectively over a period of 1 year by the physician of the haemophilia treatment centre. Patients had a mean age of 23, and consisted of 50% students, 25% salaried workers, 17.2% with no professional activity and 7.8% physically impaired; 82.8% of them had type A haemophilia. Mean pain score was 2.5 per patient for the six main joints; 7.7 for the clinical score and 18.8 for the radiological score, with a mean number of bleeds of 16.3 per year per patient. During the year prior to inclusion, and because of their orthopaedic status, 22.4% of patients were hospitalized, 76.7% attended for an outpatient visit and 76.7% required at least one special investigation; 97.4% received replacement therapy, 41.4% required treatment for joint pain and 42.2% orthopaedic equipment. The less affected dimensions were the physical function (76.8 +/- 22. 2) and the social relations (76.1 +/- 23.1). Least good quality of life scores concerned the pain (60.2 +/- 25.2), perception of general health (59.3 +/- 23.1) and vitality (57.8 +/- 19.5) dimensions. The age was a discriminant criterion since quality of life was better in patients of the 18-23 age group for five dimensions. Mean annual treatment costs of a patient with severe haemophilia were determined as 425 762 French francs ($73 029). Loss of production was estimated at a mean of 4609 French francs ($791) per active patient over the course of the year. Results showed indirect evidence of the usefulness of early home treatment.

Interleukin 7 induces a well-tolerated, dose-dependent, and sustained increase of CD4 T cells in human immunodeficiency virus-infected individuals treated with antiretroviral therapy, through an expansion of peripheral T cells that do not express activation markers, and increases thymic output in some patients.

Delays in immune recovery after allogeneic hematopoietic stem cell transplantation (allo-HSCT) are associated with increased risks of infection and relapse. IL-7 has a central role in T-cell development and survival and enhances immune recovery in murine models of allo-HSCT. We performed a phase 1 trial of r-hIL-7 (CYT107) in recipients of T-cell depleted allo-HSCTs. Twelve patients were treated with escalating doses of r-hIL-7 administered weekly for 3 weeks. The study drug was well tolerated with only one patient developing acute skin GVHD. At baseline, patients were profoundly lymphopenic. CYT107 induced a doubling in CD4 ؉ and CD8 ؉ T cells. The main effect of IL-7 was an expansion of effector memory T cells, the predominant subset identified in our patients. There was no significant effect on CD4 ؉ CD25 ؉ FoxP3 ؉ T cells, NK, or B cells. Importantly, we not only saw quantitative increases in T cells after a short course of IL-7 but also demonstrated an increase in functional T cells, including viral-specific T cells that recognize CMV. Enhanced TCR diversity was also observed after treatment. Our results indicate that r-hIL-7 can enhance immune recovery after a T cell-depleted allo-HSCT without causing significant GVHD or other serious toxicity (www.clinicaltrials.gov; NCT00684008). (Blood. 2012;120(24): 4882-4891) IntroductionDelays in immune recovery after allogeneic hematopoietic stem cell transplantation (allo-HSCT) are associated with increased risks of infection, relapse, and secondary malignancies. [1][2][3][4][5][6] The risk of opportunistic infections is correlated with T-cell recovery, and in particular CD4 ϩ T cells. 1,7 Strategies to enhance T-cell reconstitution may therefore decrease posttransplantation morbidity and mortality. IL-7 has a central role in T-cell development and survival, and it enhances thymopoiesis and peripheral T-cell survival and expansion in murine models of allo-HSCT. [8][9][10][11][12][13][14][15][16][17][18][19] Initial trials with recombinant human IL-7 (r-hIL-7) demonstrated an expansion of CD4 ϩ and CD8 ϩ T cells in patients with solid tumors or HIV infection. [20][21][22][23][24][25] We conducted a phase 1 trial of r-hIL-7 (CYT107, Cytheris Inc) in recipients of T cell-depleted (TCD) allo-HSCTs and showed that r-hIL-7 was well tolerated and induced a rapid increase in peripheral CD4 ϩ and CD8 ϩ T cells. Methods Patient populationPatients more than 15 years of age were in remission without active or prior GVHD 60-210 days after TCD allo-HSCT from an 8 of 8 HLA-matched donor for treatment of nonlymphoid hematologic malignancy. The timing interval of study entry was selected to allow for adequate engraftment and the absence of significant transplant-related complications, as well as the inclusion of patients with poor immune recovery at 6 months after HSCT (CD4 Ͻ 100/mm 3 ). Additional requirements included documented engraftment (sustained absolute neutrophil count Ͼ 1000/mm 3 , platelet count Ͼ 20 000/mm 3 ), Karnofsky performance status Ͼ 60, normal left ventricular...

Despite antiretroviral therapy (ART), some HIV-infected persons maintain lower than normal CD4+ T-cell counts in peripheral blood and in the gut mucosa. This incomplete immune restoration is associated with higher levels of immune activation manifested by high systemic levels of biomarkers, including sCD14 and D-dimer, that are independent predictors of morbidity and mortality in HIV infection. In this 12-week, single-arm, open-label study, we tested the efficacy of IL-7 adjunctive therapy on T-cell reconstitution in peripheral blood and gut mucosa in 23 ART suppressed HIV-infected patients with incomplete CD4+ T-cell recovery, using one cycle (consisting of three subcutaneous injections) of recombinant human IL-7 (r-hIL-7) at 20 µg/kg. IL-7 administration led to increases of both CD4+ and CD8+ T-cells in peripheral blood, and importantly an expansion of T-cells expressing the gut homing integrin α4β7. Participants who underwent rectosigmoid biopsies at study baseline and after treatment had T-cell increases in the gut mucosa measured by both flow cytometry and immunohistochemistry. IL-7 therapy also resulted in apparent improvement in gut barrier integrity as measured by decreased neutrophil infiltration in the rectosigmoid lamina propria 12 weeks after IL-7 administration. This was also accompanied by decreased TNF and increased FOXP3 expression in the lamina propria. Plasma levels of sCD14 and D-dimer, indicative of systemic inflammation, decreased after r-hIL-7. Increases of colonic mucosal T-cells correlated strongly with the decreased systemic levels of sCD14, the LPS coreceptor - a marker of monocyte activation. Furthermore, the proportion of inflammatory monocytes expressing CCR2 was decreased, as was the basal IL-1β production of peripheral blood monocytes. These data suggest that administration of r-hIL-7 improves the gut mucosal abnormalities of chronic HIV infection and attenuates the systemic inflammatory and coagulation abnormalities that have been linked to it.