No abstract

Key Points• High-dose intensive factor VIII treatment increases the risk for inhibitor development in patients with severe hemophilia A.• In patients with severe hemophilia A, factor VIII prophylaxis decreases inhibitor risk, especially in patients with low-risk F8 mutations.The objective of this study was to examine the association of the intensity of treatment, ranging from high-dose intensive factor VIII (FVIII) treatment to prophylactic treatment, with the inhibitor incidence among previously untreated patients with severe hemophilia A. This cohort study aimed to include consecutive patients with a FVIII activity < 0.01 IU/mL, born between 2000 and 2010, and observed during their first 75 FVIII exposure days. Intensive FVIII treatment of hemorrhages or surgery at the start of treatment was associated with an increased inhibitor risk (adjusted hazard ratio [aHR], 2.0; 95% confidence interval [CI], 1.3-3.0). High-dose FVIII treatment was associated with a higher inhibitor risk than low-dose FVIII treatment (aHR, 2.3; 95% CI, 1.0-4.8). Prophylaxis was only associated with a decreased overall inhibitor incidence after 20 exposure days of FVIII. The association with prophylaxis was more pronounced in patients with low-risk F8 genotypes than in patients with high-risk F8 genotypes (aHR, 0.61, 95% CI, 0.85, 95% CI, respectively). In conclusion, our findings suggest that in previously untreated patients with severe hemophilia A, high-dosed intensive FVIII treatment increases inhibitor risk and prophylactic FVIII treatment decreases inhibitor risk, especially in patients with low-risk F8 mutations. (Blood. 2013;121(20):4046-4055)

Impaired function of the brain vasculature might contribute to the development of HIV-associated dementia. For example, injury or dysfunction of brain microvascular endothelial cells (BMEC) can lead to the breakdown of the blood-brain barrier (BBB) and thus allow accelerated entry of the HIV-1 virus into the CNS. Mechanisms of injury to BMEC during HIV-1 infection are not fully understood, but the viral gene product Tat may be, at least in part, responsible for this effect. Tat can be released from infected perivascular macrophages in the CNS of patients with AIDS, and thus BMEC can be directly exposed to high concentrations of this protein. To study oxidative and inflammatory mechanisms associated with Tat-induced toxicity, BMEC were exposed to increasing doses of Tat 1)72 , and markers of oxidative stress, as well as redox-responsive transcription factors such as nuclear factor-jB (NF-jB) and activator protein-1 (AP-1), were measured. Tat 1)72 treatment markedly increased cellular oxidative stress, decreased levels of intracellular glutathione and activated DNA binding activity and transactivation of NF-jB and AP-1. To determine if Tat 1)72 can stimulate inflammatory responses in brain endothelium in vivo, expression of monocyte chemoattractant protein-1 (MCP-1), an NF-jB and AP-1-dependent chemokine, was studied in brain tissue in mice injected with Tat 1)72 into the right hippocampus. Tat 1)72 markedly elevated the MCP-1 mRNA levels in brain tissue. In addition, a double immunohistochemistry study revealed that MCP-1 protein was markedly overexpressed on brain vascular endothelium. These data indicate that Tat 1)72 can induce redox-related inflammatory responses both in in vitro and in vivo environments. These changes can directly lead to disruption of the BBB. Thus, Tat can play an important role in the development of detrimental vascular changes in the brains of HIV-infected patients.

The management of patients with inhibitors is an important challenge in haemophilia care. The lack of randomized controlled trials means that clinical decisions are generally based on subjective opinions, and purchasers' attention is likely to focus on the costs of treatment. In order to assess the current management of inhibitor patients and use of immune tolerance induction therapy (ITI) in Europe, we performed a survey within a European network of 21 comprehensive care centres from 14 countries (the European Haemophilia Therapy Standardisation Board). The survey identified a total of 381 patients with inhibitors attending the centres, 211 (55.4%) of whom had never been exposed to ITI. Between 1998 and 2003, the centres performed 233 procedures and 114 (48.9%) were successful. The survey demonstrated that dosing, which is the time to start and stop the ITI, the type of concentrate to use and the definition of success varied among the centres. Well-designed trials are warranted to guide decision-making, but in the absence of these studies we have developed consensus guidance for the management of inhibitor patients based on current clinical practice, as identified by the survey, and review of the literature.

A multicentre, international, cross-sectional study was carried out in the frame of field testing of the first haemophilia-specific quality-of-life (QoL) questionnaire (Haemo-QoL). The aim of this paper is to describe health status and health care and their impact on QoL in haemophilic children in Western Europe. Children aged 4-16 years with severe haemophilia without inhibitors were enrolled by 20 centres in France, Germany, Italy, the Netherlands, Spain and the United Kingdom. Clinical information was collected by the physicians with a medical documentation form. Health-related QoL (HRQoL) of children was assessed with Haemo-QoL, available for three age groups. Clinical data were available in 318 patients, 85.5% with haemophilia A. The mean age at first bleeding was 11 months, at first joint bleed 25 months. Functional joint impairments were found in 11.3%. Prophylaxis treatment was given to 66.7% of children in whom breakthrough bleeds occurred 0.4 times a month compared to 1.1 bleeds in children receiving on-demand treatment. A significantly higher factor consumption was found only in the two younger age groups of prophylaxis patients compared to on-demand patients. HRQoL was satisfactory in this cohort: young children were impaired mainly in the dimension 'family' and 'treatment', whereas older children had higher impairments in the so-called 'social' dimensions, such as 'perceived support' and 'friends'. Health care of children in Western Europe is progressively improving with a large diffusion of home treatment and prophylaxis. This provides a high level of health status and HRQoL, being better in haemophilic adolescents on prophylaxis.