Shorter Survival of SDF1-3′A/3′A Homozygotes Linked to CD4+ T Cell Decrease in Advanced Human Immunodeficiency Virus Type 1 Infection

The SDF-1 3′A allelic polymorphism has been reported to influence either positively or negatively the progression of human immunodeficiency virus type 1 (HIV-1) disease. Therefore, the SDF-1 genotype of 729 HIV-1-infected individuals pooled from 3 distinct cohorts was determined. A statistically nonsignificant association between the SDF1-3′A/3′A genotype and accelerated disease progression was evident among seroconverters (n = 319), but a striking correlation of decreased survival after either diagnosis of AIDS according to the 1993 definition or loss of CD4+ T cell counts <200 was observed. The relative hazards for SDF1-3′A/3′A homozygotes, compared with heterozygotes and wild-type homozygotes were 2.16 (P = .0047), for time from diagnosis according to the 1993 Centers for Disease Control and Prevention AIDS case definition (AIDS-'93) to death, and 3.43 (P = .0001), for time from CD4+ T cells <200 to death. Because no difference in survival was observed after diagnosis according to AIDS-'87, the association of the SDF1-3′A/3′A genotype with the accelerated progression of late-stage HIV-1 disease appears to be explained for the most part by the loss of CD4+ T lymphocyte

Case report: Complete pathologic response with first-line immunotherapy combination in a young adult with massive liver dissemination of mismatch repair–deficient metastatic colorectal cancer: Immunological and molecular profiling

The current level of evidence for immunotherapy in previously untreated microsatellite unstable metastatic colorectal cancer is based on recent pieces of evidence of few studies that demonstrated durable response and clinical benefit, in terms of objective response rate, disease control rate, and progression-free survival in this subgroup of patients. On the basis of combinatorial immunotherapy with nivolumab plus ipilimumab, we report the exceptional case of a complete pathological response in a 21-year-old woman presenting a clinically aggressive stage IV colorectal cancer with massive nodal and liver involvement. Extensive molecular analyses based on whole genome next-generation DNA sequencing, RNA sequencing, fluorescent multiplex immunohistochemistry, and flow cytometry provided a detailed description of tumoral and immunological characteristics of this noteworthy clinical case

A genome-wide association study of resistance to HIV infection in highly exposed uninfected individuals with hemophilia A

Human genetic variation contributes to differences in susceptibility to HIV-1 infection. To search for novel host resistance factors, we performed a genome-wide association study (GWAS) in hemophilia patients highly exposed to potentially contaminated factor VIII infusions. Individuals with hemophilia A and a documented history of factor VIII infusions before the introduction of viral inactivation procedures (1979-1984) were recruited from 36 hemophilia treatment centers (HTCs), and their genome-wide genetic variants were compared with those from matched HIV-infected individuals. Homozygous carriers of known CCR5 resistance mutations were excluded. Single nucleotide polymorphisms (SNPs) and inferred copy number variants (CNVs) were tested using logistic regression. In addition, we performed a pathway enrichment analysis, a heritability analysis, and a search for epistatic interactions with CCR5 Δ32 heterozygosity. A total of 560 HIV-uninfected cases were recruited: 36 (6.4%) were homozygous for CCR5 Δ32 or m303. After quality control and SNP imputation, we tested 1 081 435 SNPs and 3686 CNVs for association with HIV-1 serostatus in 431 cases and 765 HIV-infected controls. No SNP or CNV reached genome-wide significance. The additional analyses did not reveal any strong genetic effect. Highly exposed, yet uninfected hemophiliacs form an ideal study group to investigate host resistance factors. Using a genome-wide approach, we did not detect any significant associations between SNPs and HIV-1 susceptibility, indicating that common genetic variants of major effect are unlikely to explain the observed resistance phenotype in this populatio

From theory to practice: Applying current clinical knowledge and treatment strategies to the care of hemophilia A patients with inhibitors

Two bypassing agents are currently available to circumvent the need for factor FVIII in hemophilia A patients with inhibitors: the activated prothrombin complex FEIBA VH and recombinant activated factor VII (NovoSeven (R)). Both products are highly effective in controlling bleeding in the presence of inhibitory alloantibodies, yet their hemostatic efficacy can be unpredictable. As the results of the FEIBA NovoSeven (R) Comparative (FENOC) study illustrate, patients may respond better to one bypassing agent than the other. Furthermore, guidelines from an expert panel reflect that responsiveness to bypassing therapy may change from one bleed to the next in the same patient and even from hour to hour during the course of a single bleeding event. These findings underscore the need to have both bypassing products available to treat bleeding episodes in inhibitor patients, to frequently evaluate the efficacy of hemostasis during the course of a bleeding event, and to switch products early if the response to treatment is unsatisfactory. (C) 2008 Elsevier Ltd. All rights reserved

New Approaches to Using FEIBA in the Treatment of Inhibitor Patients.

Managing hemophilia becomes particularly difficult in patients with inhibitory antibodies, especially in those requiring surgery or with refractory bleeding events. Equally challenging are those patients who develop autoantibodies against factor VIII (FVIII) in the absence of a prior history of FVIII deficiency (acquired hemophilia). Physicians seeking both short- and long-term treatment strategies for bleeding events must often rely on FVIII-bypassing agents such as activated prothrombin complex concentrate (e.g., factor eight bypassing activity [FEIBA VH, Baxter BioScience, Westlake Village, CA]) or recombinant factor VIIa (rFVIIa [NovoSeven, NovoNordisk, Bagsvaerd, Denmark]). Surgical procedures in patients with inhibitors present a considerable challenge, from both a risk-benefit and a cost-benefit aspect. Hemostasis is difficult to achieve in these patients and new treatment options are being explored. Similarly challenging are refractory bleeds, the management of which is likely to benefit from a systematic treatment approach

Identifying Nonresponsive Bleeding Episodes in Patients With Haemophilia and Inhibitors: A Consensus Definition

International audienceIntroduction: Assessing response to treatment with bypassing agents presents a substantial challenge in the treatment of patients with haemophilia and inhibitors. Rapid and accurate identification of bleeding episodes that are nonresponsive to bypassing therapy with either Factor Eight Inhibitor Bypassing Activity (FEIBA; Baxter AG, Vienna, Austria) or recombinant activated factor VII (rFVIIa; NovoSeven®, Novo Nordisk A/S, Bagsvaerd, Denmark) is essential to guide treatment decisions and optimise patient outcomes through early intervention. Although both bypassing agents are effective, differential responses to therapy necessitate multiple therapeutic options. Aim: This paper provides a consensus definition for non-life-threatening joint and muscle bleeds that are nonresponsive to bypassing agents. Methods: An international panel of 7 physicians met in December 2008 to develop the consensus definition using a modified National Institutes of Health Consensus Development Conference method. Results: The consequent definition of non-life-threatening bleeding episodes that are nonresponsive to bypassing treatment provides a global picture of the condition of the patient during such an event. Identification of nonresponsiveness is based on various criteria: pain, swelling/tension, mobility, patient perception, and laboratory parameters. Criteria can be assessed subjectively by the patient/parent, and/or objectively by the clinician. Although the precise timing of each determination should be at the discretion of the physician, bleeds should be considered nonresponsive if the clinical situation meets the specified criteria 24 hours from the start of treatment. Conclusion: Although it is not intended to replace clinical judgment, this definition can guide the optimal course of treatment for patients with haemophilia and inhibitors