Summary. The use of ReFacto Laboratory Standard (RLS) in the one‐stage clotting assay was proposed to reduce the underestimation of factor VIII (FVIII) plasma concentration after the infusion of ‘ReFacto®’ (B‐domain deleted recombinant FVIII) in haemophilia A patients. Both ReFacto® and RLS were recently recalibrated, with the resulting materials containing approximately 20% more protein than the previous products. The aim of this study was to evaluate the performance of recalibrated RLS in the measurement of FVIII plasma concentration after the infusion of recalibrated ReFacto®. In 13 severe haemophilia A patients, 25 IU kg−1 of ReFacto® were injected intravenously. Venous blood samples were collected at 0.25, 0.5, 1, 3, 6, 9, 24, 28 and 32 h after the end of the infusion. Pharmacokinetic parameters were measured for the chromogenic and one‐stage assays using International Plasma Standard (IPS) and RLS for both assays and assuming a non‐compartmental drug disposition. Comparisons among assays and standards were performed using anova. Pharmacokinetic estimates obtained with the chromogenic method were in agreement with those published in the literature. The one‐stage method was confirmed to be more sensitive to lower plasma concentrations of FVIII. The measured maximum plasma concentration (Cmax) was slightly higher than theoretical values and independent of the assay used. Cmax, area under the curve (AUC) and volume of distribution at steady state (Vss) presented non‐significant differences among the methods and standards used. The clinical utility of RLS in the evaluation of FVIII concentration after the infusion of ReFacto® seems to be reduced since recalibration of the product.

BACKGROUND:The in vivo recovery of recombinant factor IX (rFIX) is reported to be lower than that of plasma-derived products, with potential clinical implications for dosing. In clinical practice, a conversion (augmentation) factor is suggested to calculate the necessary doses of rFIX. The aim of this study was to assess the range of values for the conversion factor in usual clinical practice in Italy.MATERIALS AND METHODS:The study was questionnaire-based and proposed to all Italian Haemophilia centres treating patients with haemophilia B. Age, weight, dosage used in the last effective infusion, treatment regimen (prophylaxis versus on-demand), human immunodeficiency virus (HIV) and hepatitis C virus (HCV) status, and years of previous therapy with rFIX were recorded for patients with severe haemophilia B treated with rFIX. Mean, standard deviation, median and range were calculated for demographic and treatment data for the overall population and for subgroups. The conversion factor for the theoretical dosage of 40 IU/Kg was calculated.RESULTS:Among 207 patients with severe haemophilia B being followed in 24 centres, 138 (66.7%) were being treated with rFIX. The sample of 207 patients represents 83.1% of the population of Italian patients with severe haemophilia B. The age range of the studied patients was 0-72 years (mean, 24 years) and the weight range was 3-108 kg (mean, 60 kg). Nineteen patients (14.4%) were positive for HIV and 51 (42.9%) were positive for HCV. The mean dosage of rFIX was 44 IU/Kg, with no significant difference between those receiving the product as prophylaxis or on-demand. A reduction in dosage was observed with increasing age (0.23 IU/kg/year). The mean value for the conversion factor was 1.10 ± 0.36 (median 1.00, range 0.51-2.08), when estimated for the whole population. No effect of HIV and HCV status was found on the dose prescribed. No evident correlation was found with the underlying genetic mutation.DISCUSSION:We found that dosing of rFIX in clinical practice is very close to that of plasma-derived FIX concentrates. As a consequence, dosing in the non-surgical setting should be started using the same criteria as those for plasma-derived FIX and treatment effectiveness verified on a clinical basis rather than relying on in vivo recovery assessments.

BackgroundAntiviral treatment for chronic hepatitis C may be less effective if patients are co-infected with human immunodeficiency virus (HIV).ObjectivesTo assess the benefits and harms of antiviral treatment for chronic hepatitis C in patients with HIV.Search strategyTrials were identified through manual and electronic searches in The Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, and Science Citation Index Expanded. The last search was May 2009.Selection criteriaRandomised trials comparing at least 12 weeks of any anti-HCV treatment versus another treatment regimen or no treatment. Included patients had chronic hepatitis C and stable HIV irrespective of previous antiviral therapy.Data collection and analysisData extraction and assessment of risk of bias were done in duplicate. Analysis was by intention-to-treat.Main resultsFourteen trials were included. None of the included 2269 patients were previously treated for chronic hepatitis C. Peginterferon (either 2a, 180 microgram, or 2b, 1.5 microgram/kg, once weekly) plus ribavirin was more effective in achieving end of treatment and sustained virological response compared with interferon plus ribavirin (5 trials, 1340 patients) or peginterferon (2 trials, 714 patients). The benefit of peginterferon plus ribavirin was seen irrespective of HCV genotype although patients with genotype 1 or 4 had lower response rates (27%) than patients with genotype 2 or 3 (56%). The remaining trials compared different treatment regimens in patients who were treatment naive or had no virological response after three months of treatment, but overall they had not enough power to show any effect of increasing the dose of interferon or adding both amantadine or ribavirin. The overall mortality was 23/2111 patients with no significant differences between treatment regimens. Treatment increased the risk of adverse events including anaemia and flu-like symptoms, and several serious adverse events occurred including fatal lactic acidosis, liver failure, and suicide due to depression.Authors' conclusionsPeginterferon plus ribavirin may be considered a treatment for patients with chronic hepatitis C and stable HIV who have not received treatment for hepatitis C as the intervention may clear the blood of HCV RNA. Supporting evidence comes mainly from the analysis of this non-validated surrogate outcome assessed in comparisons against other antiviral treatments. There is no evidence on treatment of patients who have relapsed or did not respond to previous therapy. Careful monitoring of adverse events is warranted.

The study evaluates the risk/benefit of influenza vaccination in patients on stable long-term oral anticoagulant therapy (OAT). One hundred and four consecutive patients with indication for influenza vaccination were randomized to receive one dose of 2004/2005 influenza vaccine followed by placebo after 6 weeks, or vice versa, in a cross-over blinded trial. All patients were tested for anticoagulation levels and for hemagglutination inhibiting antibody titres against the influenza vaccine antigens. The highly protective antibody titres induced by influenza vaccination and the absence of statistically relevant interactions between vaccination and OAT suggest that influenza vaccination can be used safely and successfully in elderly patients on OAT.

Several methods have been developed for measurement of plasma total homocysteine (tHcy), a proven graded risk factor for cardiovascular diseases. The aim of the study was to compare 3 commonly used clinical methods (enzyme immunoassay, Axis Biochemicals, Oslo, Norway; and fluorescence polarization immunoassay [FPIA], Axis, on the Abbott IMx System, Abbott Laboratories, Abbott Park, IL; and BioRad high-performance liquid chromatography [HPLC], Laboratories, Munich, Germany) for tHcy determination in samples from cardiovascular patients also undergoing methionine load measurement. Only HPLC reached the required coefficient of variation (<6%) for desirable performance for tHcy concentrations ranging between 0.68 and 5.41 mg/L (5 and 40 micromol/L). A higher variability was observed for postmethionine load vs fasting samples, which reached statistical significance for FPIA (P = .0013). The closest agreement between methods was observed between HPLC and FPIA for fasting tHcy concentrations (-0.23 mg/L [-1.69 micromol/L], -30% to 8%).Both immunoassays could be suitable alternatives for laboratories with high workloads when HPLC is not available. Differences among tHcy values must be taken into account when these methods will be used interchangeably for diagnosis and monitoring of treatment.

BACKGROUNDXimelagatran has been approved in Europe for VTE prophylaxis in orthopedic surgery at fixed doses and without laboratory monitoring. Aim of the study was to evaluate safety and efficacy of ximelagatran in a meta-analysis of prophylaxis and/or treatment randomized controlled trials.METHODSAbsolute risk of events for ximelagatran and OR for its comparison with LMWH and coumarins were calculated. Subgroup analysis was performed for ximelagatran regimen, comparator agent, type of surgery, starting time of prophylaxis.RESULTSTwelve studies and 16,992 patients were meta-analysed. Ximelagatran showed an absolute risk of major VTE of 4.04% and 1.69% and of major bleedings of 1.68% and 1.03% in prophylaxis and treatment trials, respectively. In prophylaxis trials, a significant excess mortality (OR: 2.5; 95% CI: 1.02 - 6.13) and an excess in major bleedings (OR: 1.41; 95% CI: 0.93 - 2.14) was found in the whole ximelagatran group. No evidence of treatment effect for major VTE was seen in the comparison with LMWH (OR: 1.01; 95% CI: 0.52 - 1.97). The cohort of patients treated with 24 mg b.i.d. showed similar results. An increase in the absolute risk of bleeding (from 1.04% to 3.03%) was found between post and preoperative administration of ximelagatran. Major VTE risk was increased when ximelagatran was compared to b.i.d. LMWH.CONCLUSIONSXimelagatran can be considered for its potential advantages for prevention and treatment of VTE. Future efforts are needed by researchers to prospectively investigate the best postoperatively starting time and by clinicians to monitor overall mortality in prophylactic use.