Dynamic tailoring of treatment durations improves efficiency of hepatitis C treatment with pegylated interferon and ribavirin.

The treatment durations for hepatitis C are guided by the analysis of hepatitis C virus (HCV) RNA in blood at certain time points. This multicentre, randomized open label trial evaluated the utility and performance of individualized treatment durations guided by viral decline rates in 103 patients with HCV genotype 1 infection. Pegylated interferon 2a and ribavirin were given as standard of care (SOC) for 24, 48 or 72 weeks or as dynamic treatment (DT) for 24-72 weeks. The DT duration was based on the time point when log HCV RNA would reach 0 log copies/mL, as estimated by the second-phase decline. The rate of sustained virologic response was 63% for SOC and 54% for DT, but this difference was not significant in multiple regression analysis taking predictive factors such as interleukin-28B genotypes, age and baseline viremia into account (P = 0.45). The mean required treatment time per cured patient was 51 weeks for DT as compared with 58 weeks for SOC (P = 0.22) when given per protocol (n = 95) and was significantly shorter (42 vs 51 weeks) among patients who achieved undetectable HCV RNA (P = 0.01). We conclude that DT was feasible and increased efficiency. The estimated time point for 0 log viral copies/mL is a new and quantitative response variable, which may be used as a complement to the qualitative variable rapid virologic response. The outcome parameter treatment weeks per cured patient could become a useful tool for comparing treatment efficiency also in the era of directly acting antivirals.

IL28B polymorphisms determine early viral kinetics and treatment outcome in patients receiving peginterferon/ribavirin for chronic hepatitis C genotype 1.

Single nucleotide polymorphisms (SNPs) upstream of IL28B predict the outcome of treatment in chronic hepatitis C virus (HCV) infection, but their impact on viral kinetics and relation to other predictors are not well known. Here, two SNPs, rs12979860 and rs8099917, were analysed and related to early viral kinetics during treatment in 110 patients with HCV genotype 1 infection. The reduction of HCV RNA after 7 days of therapy was more pronounced (P < 0.0001) in patients with CC(rs12979860) or TT(rs8099917) than in patients carrying TT(rs12979860) or GG(rs8099917), respectively. The two SNPs were in linkage disequilibrium (d' = 1, r2 = 0.44), but CC(rs12979860) was less common (43% vs. 71%) than TT(rs8099917). Patients carrying both CC(rs12979860) and TT(rs8099917) genotypes achieved lower levels of HCV RNA at week 4 than those with CT or TT at rs12979860 and TT(rs8099917) (P = 0.0004). The viral elimination was significantly influenced by rs12979860 independently of baseline viral load, age or fibrosis. This translated into high rates of sustained viral response (SVR) among patients carrying CC(rs12979860) despite the presence of high viral load at baseline (SVR 74%), high age (SVR 79%) or severe liver fibrosis (SVR 83%). We conclude that the IL28B variability influences the antiviral efficiency of interferon/ribavirin therapy and has a strong impact on SVR, independently of traditional response predictors. A combined assessment of these SNPs in conjunction with other response predictors may better predict outcome in difficult-to-treat patients.

Hepatitis C treatment response kinetics and impact of baseline predictors.

The optimal duration of treatment for hepatitis C virus (HCV) infections is highly variable but critical for achieving cure (sustained virological response, SVR). We prospectively investigated the impact of age, fibrosis, baseline viraemia and genotype on the early viral kinetics and treatment outcome. Patients treated with peginterferon alfa-2a and ribavirin in standard dosing were included: 49 with genotype 1 treated for 48weeks and 139 with genotype 2 or 3 treated for 24weeks. The reduced SVR rates in patients older than 45years, with severe liver fibrosis or pretreatment viraemia above 400,000IU/mL were strongly associated with slower second phase declines of HCV RNA. Genotype 2/3 infections responded more rapidly than genotype 1, reaching week 4 negativity (RVR) in 59%vs 22%. We conclude that baseline response predictors such as age, fibrosis and viral load were well reflected by the early viral kinetics as assessed by repeated HCV RNA quantifications. The kinetic patterns and the high relapse rate in genotype 2/3 patients without RVR suggest that this group might benefit from treatment durations longer than 24weeks.

Differences between heterozygous dominant and recessive von Willebrand's disease type I expressed by bleeding symptoms and combinations of factor VIII variables.

Three families with von Willebrand's disease (vWd) type I were investigated. A reliable identification of healthy and diseased individuals was achieved by number of bleeding symptoms, assays of bleeding time, FVIII:C (one stage and two stage), VIIIR:Ag (EIA) and ristocetin cofactor. The diagnoses-vWd or non-vWd were confirmed by laboratory indices based on predictive values of positive and negative tests, also including VIIIR:Ag (IRMA and RIA). The last mentioned two variables did not contribute to significantly better identification of vWd versus health. The best single test variable for this purpose was ristocetin cofactor. One vWd family had significantly higher levels of ristocetin cofactor and shorter bleeding time than the other two vWd families and is probably the typical example of a family transmitting classical severe vWd.

Carriers and noncarriers of haemophilia A. Evaluation of bleeding symptoms registered by a self-administered questionnaire with binary (no/yes) questions.

Carriers of haemophilia A were recently described to have significantly more bleeding symptoms than healthy females. Eighteen obligate carriers and 20 females classified as carriers with approximately 95% confidence, as described in an accompanying paper, were compared with 56 noncarriers with respect to ten bleeding symptoms, registered by a questionnaire. A rank-order of negative findings indicating noncarrier state is presented, as well as a rank order of positive findings indicating carrier state. A summation index of the total diagnostic capacity of the ten questions shows that carriers have more bleeding symptoms than healthy females.

Carriers and noncarriers of haemophilia A: I. Multivariate analysis of pedigree data, screening blood coagulation tests and factor VIII variables.

From a material of 18 obligate carriers of haemophilia A and 40 healthy females, a discriminant function was created, based on ratio of factor VIII related antigen (electroimmunoassay = EIA) to factor VIII activity (one-stage assay), factor VIII related antigen (radioimmunoassay = RIA) and number of bleeding symptoms. The standard deviation of p-values for carrier- and non-carrier state (less than 0.05) was estimated by a procedure built on the 'jack-knife' method. By combined information of pedigree- and discriminant analysis data, 43 possible carriers were classified as carriers/noncarriers with about 95% confidence. Carriers were significantly older, had more bleeding symptoms, longer APTT, lower factor VIII activity, factor VIII procoagulant antigen, and higher ratio of factor VIII related antigen (EIA) to factor VIII activity (one-stage) and to factor VIII related antigen (RIA) respectively, than classified noncarriers. Individuals with blood group A, B, AB had significantly higher levels of factor VIII related antigen (EIA) and (RIA), and ristocetin cofactor, compared with blood group O. Obligate carriers with severe haemophilia A in their families had more bleeding symptoms than corresponding group with moderate haemophilia.

Fragmin (LMWH) vs heparin for anticoagulation during in vitro recycling of human blood in cardiopulmonary bypass circuits: dose-dependence and mechanisms of clotting.

Low-molecular-weight heparin (LMWH) (Fragmin) vs heparin was studied in vitro in order to investigate its antithrombotic efficacy in the isolated thrombogenic link of cardiopulmonary bypass (CPB). Fresh human blood (400 ml) with various dosages of the anticoagulant was recycled in a CPB circuit for 120 min. The standard dosage of heparin (1,500 IU, n = 6) was compared with a lower dosage (1,000 IU, n = 3) and several dosages of Fragmin (IU anti-FXa): 750 (n = 1), 1,500 (n = 3), 2,100 (n = 4) and 2,500 (n = 3). Clotting occurred in three Fragmin experiments at dosages of 750, 1,500 and 2,100 IU. This was associated with short activated clotting time (ACT) and activated partial thromboplastin time (aPTT) but was independent of the levels of anti-FXa, FVIII, von Willebrand factor and prothrombin complex. It was concluded that at least twice the dose of Fragmin (anti-FXa), compared with heparin, was required, suggesting that thrombin inhibition is crucial for the antithrombotic efficacy of heparin in CPB circuits. Absence of fibrinolytic markers suggests that the well known enhancement of fibrinolysis often seen during CPB, is not due to heparin interaction with normally circulating blood components, but rather to interaction with the vessel walls or to the surgical trauma itself.

Low-molecular-weight heparin (Fragmin) versus heparin for anticoagulation during cardiopulmonary bypass in open heart surgery, using a pig model.

Fragmin and heparin were studied in pigs during 120 min of cardiopulmonary bypass (CPB) and up to 240 min postoperatively, with respect to clotting, bleeding and the effects of protamine. Thirty-three pigs received bolus injections of 300 IU/kg with or without additional dosage during CPB and with or without subsequent protamine sulphate. Doses of Fragmin 60% higher were necessary to prevent clotting. These had 100% higher anti-FXa levels but about 50% shorter activated coagulation time (ACT) compared with heparin. Anti-FXa increased with cumulative doses of heparin and Fragmin but ACT and activated partial thromboplastin time (aPTT) did not, indicating a larger loss of thrombin inhibition compared with anti-FXa in both drugs during CPB. Thrombin inhibition was crucial for prevention of clotting. Protamine efficiently normalized ACT in the Fragmin group but left a residual 20% anti-FXa, which did not increase the bleeding tendency. Fragmin could adequately be monitored with ACT and would be a safe alternative to heparin in CPB.