Total plasma clearance versus urinary plasma clearance of (51)Cr-EDTA in patients with cirrhosis with and without fluid retention.

BACKGROUND AND AIM: In patients with fluid retention, the total plasma clearance of (51)Cr-EDTA (ClP) may overestimate the glomerular filtration rate (GFR). The present study was therefore undertaken in order to compare ClP with the urinary plasma clearance of (51)Cr-EDTA (ClU) in patients with cirrhosis with and without fluid retention. MATERIAL AND METHODS: A total of 136 patients with cirrhosis (24 without fluid retention, 112 with ascites) received a quantitative intravenous injection of (51)Cr-EDTA followed by plasma and quantitative urinary samples for 5 hours. ClP was determined from the injected dose relative to the plasma concentration-time area, extrapolated to infinity. ClU was determined as urinary excretion relative to the plasma concentration-time area up to voiding. RESULTS: In patients without fluid retention, the difference between ClP and ClU (ClP - ClU = ClΔ) was mean 4.5 mL/min/1.73 m(2). In patients with ascites, ClΔ was significantly higher (17.6 mL/min/1.73 m(2), p < 0.0001). ClΔ increased with lower values of GFR (r = - 0.458, p < 0.001). Repeated measurements of ClU in a subgroup of patients with fluid retention (n = 25) gave almost identical values. Different types of corrections of one-pool clearance were almost identical with ClP, except for higher clearance values, which were somewhat underestimated by the former. CONCLUSION: In patients with fluid retention and ascites ClP and corrected one-pool clearance overestimates GFR substantially. Although ClU may underestimate GFR slightly, patients with ascites should collect urine quantitatively in order to obtain a reliable measurement of GFR.

IL28B genetic variation and treatment response in patients with hepatitis C virus genotype 3 infection.

UNLABELLED: Polymorphisms near the IL28B gene, which code for interferon (IFN)-λ3, predict response to pegylated interferon-α (PEG-IFN) and ribavirin treatment in hepatitis C virus (HCV) genotype 1 infected patients. Follow-up studies of the effect of IL28B gene in HCV non-genotype 1 infected patients have almost always used predominantly HCV genotype 2-infected or mixed genotype 2/3-infected cohorts with results partly conflicting with HCV genotype 1. We performed a retrospective analysis of 281 patients infected with HCV genotype 3 for association of response to therapy with IL28B polymorphisms. We found that the HCV genotype 1 responder genotypes at rs12979860 and rs8099917 did not associate with sustained virological response to PEG-IFN/ribavirin therapy. However, the responder genotypes of both SNPs showed association with rapid viral response measured at 4 weeks (rs12979860, P = 3 × 10(-5) ; rs8099917, P = 3 × 10(-4) ). In multivariate analysis, age (<40 years), baseline viral load (<4 × 10(5) IU/mL) and the responder genotypes of SNPs rs12979860 or rs8099917 remained significant independent predictors of rapid viral response to therapy. Furthermore, we show that IL28B polymorphisms are associated with relapse in patients who achieve rapid viral response to PEG-IFN/ribavirin therapy. The responder genotypes also showed association with markers of stage and activity of liver disease, namely high aspartate aminotransferase platelet ratio index (APRI, rs12979860, P = 0.018; rs8099917, not significant) and high alanine aminotransferase (ALT, rs12979860, P = 0.002; rs8099917, P = 0.001), in addition to a high baseline viral load (rs12979860, P = 1.4 × 10(-5) ; rs8099917, P = 7.3 × 10(-6) ). CONCLUSION: Polymorphisms near the IL28B gene show association with rapid viral response but not sustained viral response to PEG-IFN/ribavirin therapy in HCV genotype 3-infected patients.

Negative HCV-RNA 2 weeks after initiation of treatment predicts sustained virological response to pegylated interferon alfa-2a and ribavirin in patients with chronic hepatitis C.

OBJECTIVE: The aim of this study was to examine the early viral kinetics as predictor for sustained virological response (SVR) during hepatitis C treatment. MATERIALS AND METHODS: We included patients with biopsy-proven chronic hepatitis C and ALT above the upper limit of normal, who received a standard treatment of pegylated interferon alfa-2a and ribavirin. The HCV-RNA concentration (limit of detection 20 IU/mL) was determined at days 0, 1, 2, 3, 4, 7, 14, 21 and monthly thereafter. RESULTS: Among 46 patients who completed the trial, 30 (65%) had SVR. Low baseline viral load, IL28B genotype CC and absence of cirrhosis were statistically associated with SVR. In multivariate analysis only absence of cirrhosis and HCV-RNA negativity at day 14 were independent predictors for SVR. Eight patients who became HCV-RNA negative on day 14 as well as 13 of 14 patients (93%) with HCV-RNA levels of <1000 IU/mL at day 7 obtained a SVR. Among 8 of 18 (44%) genotype 1 and 4 patients with more than a one log drop in HCV-RNA titer at day 7, 75% achieved SVR. CONCLUSIONS: We observed a correlation between low HCV-RNA titers in week 2 and SVR during pegylated interferon/ribavirin-based treatment. This may help identify a group of patients for whom SVR may be obtained without the addition of directly acting antivirals, and thereby save the patients for unnecessary side effects and the health care system for additional costs.

Pegylated interferon alfa and ribavirin for 14 versus 24 weeks in patients with hepatitis C virus genotype 2 or 3 and rapid virological response.

UNLABELLED: A recent nonrandomized pilot trial showed that hepatitis C virus (HCV) patients with genotype 2/3 and rapid virological response (RVR) had a 90% sustained virological response (SVR) rate after 14 weeks of treatment. We aimed to assess this concept in a randomized controlled trial. In the trial, 428 treatment-naïve HCV RNA-positive patients with genotype 2 or 3 were enrolled. Patients with RVR were randomized to 14 (group A) or 24 (group B) weeks of treatment. Patients were treated with pegylated interferon alpha-2b (1.5 microg/kg) subcutaneously weekly and ribavirin (800-1400 mg) orally daily. The noninferiority margin was set to be 10% between the two groups with a one-sided 2.5% significance level. RVR was obtained in 302 of 428 (71%), and 298 of these were randomized to group A (n = 148) or group B (n = 150). In the intention-to-treat analysis, SVR rates were 120 of 148 (81.1%) in group A and 136 of 150 (90.7%) in group B (difference, 9.6%; 95% confidence interval, 1.7-17.7). Among patients with an HCV RNA test 24 weeks after the end of treatment, 120 of 139 (86.3%) patients in group A achieved SVR compared with 136 of 146 (93.2%) in group B (difference, 6.9%; 95% confidence interval, -0.1 to +13.9). CONCLUSION: We cannot formally claim that 14 weeks of treatment is noninferior to 24 weeks of treatment. However, the SVR rate after 14 weeks of treatment is high, and although longer treatment may give slightly better SVR, we believe economical savings and fewer side effects make it rational to treat patients with genotype 2 or 3 and RVR for only 14 weeks.

The effect of antioxidant supplementation on hepatitis C viral load, transaminases and oxidative status: a randomized trial among chronic hepatitis C virus-infected patients.

OBJECTIVE: To assess the effect of antioxidant supplementation on hepatitis C viral load, transaminases and oxidative status. METHODS: We performed a randomized, placebo-controlled, double-blind trial to assess the effect of antioxidant supplementation on serum alanine aminotransferase, plasma hepatitis C viral load as well as oxidative and antioxidant markers in patients with hepatitis C virus infection. The participants received a daily dose of ascorbic acid (500 mg), D-alpha-tocopherol (945 IU) and selenium (200 microg) or placebo tablets for 6 months. RESULTS: Twenty-three patients were included. During supplementation, the antioxidant group had significantly higher levels of plasma ascorbic acid and alpha-tocopherol than the placebo group and the activity of erythrocyte glutathione peroxidase had significantly increased from baseline to month 6. No differences were observed in serum alanine aminotransferase and log10-transformed plasma hepatitis C virus-RNA between the groups or changes from the baseline at any time. No consistent differences between groups or changes from the baseline with respect to erythrocyte activities of antioxidative enzymes (glutathione reductase, superoxide dismutase and catalase) or plasma levels of oxidative markers (malondialdehyde and 2-amino-adipic semialdehyde) were found. CONCLUSION: Supplementation with vitamin C, E and selenium increased the antioxidant status, but had no effects on alanine aminotransferase, viral load or oxidative markers.

The Usefulness of Defining Rapid Virological Response by a Very Sensitive Assay (TMA) during Treatment of HCV Genotype 2/3 Infection.

The aim of this study was to determine in patients with HCV genotype 2 or 3 the performance at week 4 of two assays with different sensitivities for HCV RNA detection, for the prediction of SVR and stratification for treatment duration (14 and 24 weeks). Recruitment was from two trials comparing 14 and 24 weeks treatment to patients with rapid virological response (RVR) (n = 550). RVR was originally defined as HCV RNA <50 IU/ml at week 4. Patients with an available frozen plasma sample drawn at week 4 and with follow-up data week 24 post-treatment were included (n = 429). HCV-RNA was prospectively measured with COBAS Amplicor V2, Roche (CA) (lower detection limit 50 IU/ml) and retrospectively assessed with VERSANT HCV-RNA Qualitative Assay, Siemens (TMA) (lower limit detection 10 IU/ml). Genotype 3 was present in 80% and genotype 2 in 20%. A SVR was achieved in 82%. At week 4 HCV-RNA was undetectable in 74.8% and 63% of serum samples tested with CA and TMA, respectively. CA undetectable/TMA positive was observed in 61/341 (18%) of the samples. In genotype 3 patients a relapse was seen in 9% of the patients with both CA and TMA undetectable and in 25% of the patients who were CA undetectable/TMA positive (p = 0.006). In patients allocated to 14 weeks treatment a relapse was observed in 11% of TMA undetectable patients and 26% of TMA positive (p = 0.031). In genotype 2 patients treated for 14 weeks relapse was observed in 6% of the patients with both CA and TMA undetectable week 4. Assays with high sensitivity for HCV RNA identifies patients at week 4 with high risk of virological relapse. We recommend that patients with genotype 3 and detectable HCV RNA at levels below 50 IU/ml do not receive truncated therapy with pegIFN and ribavirin.

The prognostic value of plasma soluble urokinase plasminogen activator receptor (suPAR) levels in stage III ovarian cancer patients.

The level of the urokinase plasminogen activator receptor (uPAR) is elevated in tumor tissue from several forms of cancer. uPAR is shed from the cell surface and the soluble form, soluble urokinase plasminogen activator receptor (suPAR), has been detected in several body fluids. High plasma levels of suPAR in patients with colorectal cancer and high serum levels of suPAR in patients with recurrent metastatic breast cancer have been associated with poor prognosis. In patients with ovarian cancer (OC) it has been shown that the level of suPAR is very high in ascites and cystic fluid and that high serum levels of suPAR were associated with shorter survival of the patients. We evaluated suPAR preoperatively in plasma from primary OC stage III patients and tested for association with prognosis. The prognostic significance of suPAR was also compared to two biochemical markers; cancer antigen 125 (CA125) and tetranectin (TN). No significant differences were found between patients who died of OC compared to patients still alive regarding median plasma suPAR levels (p=0.62) and median serum CA125 levels (p=0.26). In contrast, a significant difference was found between dead and alive OC patients for the median serum TN level (p<0.0001). Dividing the patients into two groups, corresponding to preoperative plasma suPAR levels below or equal to 2.0 ng/ml and higher than 2.0 ng/ml, no significant difference in survival was found between the two groups (p=0.49). When different cut-off levels of plasma suPAR were considered (2.74 ng/ml, 3.25 ng/ml and 4.18 ng/ml), no significant differences in survival could be detected (p=0.58, p=0.68 and p=0.05). Multivariate Cox regression analysis showed that the only independent prognostic factors were radicality after primary surgery (RH=5.34; 95% CI, 2.34-12.20; p<0.0001) and preoperative serum TN (RH=0.69, 95% CI, 0.57-0.82; p<0.0001), whereas plasma suPAR (4.18 ng/ml), age, histological type of tumour and serum CA 125 had no independent prognostic value. In conclusion, preoperative plasma suPAR level was of no prognostic value in this cohort of Danish stage III OC patients.

[The use of albumin infusion in decompensated liver cirrhosis]. / Anvendelse af human albumin-infusion ved dekompenseret levercirrose.

For patients with refractory ascites, paracentesis is the standard therapy and for many it is the only treatment option. When more than five litres of ascitic fluid are removed, the use of a plasma expander effectively prevents "postparacentesis circulatory dysfunction", which is associated with a high mortality. Randomised controlled studies show that albumin is more effective than synthetic plasma expanders in the prevention of this complication. In selected patients with ascites, long-term administration of albumin may improve the diuretic response. A randomised controlled study in patients with spontaneous bacterial peritonitis has demonstrated that treatment with albumin infusion in addition to an antibiotic reduces the incidence of hepatorenal syndrome. Albumin infusion in combination with the administration of a vasopressin analogue may be able to reverse established hepatorenal syndrome; however, no controlled studies have been published. Whereas the use of albumin infusion with large-volume paracentesis is strongly supported by the available evidence, additional conclusive studies of the use of albumin for spontaneous bacterial peritonitis are awaited.

Genetic variants at the ITPA locus protect against ribavirin-induced hemolytic anemia and dose reduction in an HCV G2/G3 cohort.

OBJECTIVES: Two functional genetic variants in the inosine triphosphatase (ITPA) gene have been shown to be strongly associated with protection from ribavirin (RBV)-induced hemolysis. We aimed at evaluating this finding in a chronic hepatitis C genotype 2/3 cohort with a predominance of genotype 3 patients where available data are scarce. A second objective was to determine whether a protective association translated into the need for RBV reduction and hence a possible impact on treatment response. METHODS: Overall, 457 patients were recruited from two trials of genotype 2/3 patients treated with pegylated interferon α-2b and weight-based RBV. rs1127354 and rs7270101 were genotyped and a composite ITPAase deficiency variable was graded according to the two single nucleotide polymorphisms. The primary endpoints were hemoglobin (Hb) decline from baseline and Hb decline of more than 3 g/dl at week 4. RESULTS: Both single nucleotide polymorphisms and the composite ITPAase deficiency variable were strongly and independently associated with protection from a decline in Hb at week 4 in multivariate linear regression models (Prs1127354=7.0×10, Prs7270101=0.0036, PITPase deficiency variable =6.3×10). Patients with any degree of reduced ITPAase activity were less likely to have their RBV dose reduced (odds ratio 0.39, 95% confidence interval 0.16-0.96, P=0.040), although this did not translate into increased rapid viral response or sustained viral response (Prvr=0.93, Psvr=0.22). CONCLUSION: We have confirmed a strong association between functional ITPA variants and RBV-induced hemolysis and showed protection from RBV dose reduction, although this did not translate into increased rapid viral response or sustained viral response.

In patients with HCV genotype 2 or 3 infection and RVR 14 weeks treatment is noninferior to 24 weeks. Pooled analysis of two Scandinavian trials.

AIM: To compare 14 and 24 weeks treatment to patients with HCV genotype 2 or 3 infection and rapid virological response (RVR). MATERIALS AND METHODS: Patients included in two Scandinavian trials, one nonrandomized pilot trial (n=122) and one randomized controlled trial (RCT) (n=428) were entered into a pooled database. In both trials treatment naïve patients with genotype 2 or 3 were treated with pegylated interferon alpha 2b (1.5 microg/kg, subcutaneous) weekly and ribavirin (800-1400 mg, orally) daily. Primary endpoint was sustained virological response (SVR). RVR was defined as HCV RNA less than 50 IU/ml after 4 weeks of treatment. In the pilot trial all patients with RVR were treated for 14 weeks and in the RCT patients with RVR were randomised to either 14 or 24 weeks treatment. Patients treated per protocol were included in the primary analysis. The noninferiority margin was set to be 10% between the two groups with a one-sided 5% significance level. RESULTS: In patients with RVR and genotype 2 or 3 SVR was obtained in 181 of 199 (91.0%) and 93 of 98 (94.9%) after 14 and 24 weeks treatment, respectively. The observed difference in SVR rates was 3.9% (90% confidence interval: +1 to -8.8). The relapse rate was highest among those older than 40 years and those with genotype 3 and high viral load, but prolongation of treatment from 14 to 24 weeks did not reduce the relapse rate substantially in any of these groups. CONCLUSION: In patients with HCV genotype 2 or 3 infection and RVR 14 weeks treatment is noninferior to 24 weeks.

Hyperammonemia acts synergistically with lipopolysaccharide in inducing changes in cerebral hemodynamics in rats anaesthetised with pentobarbital.

BACKGROUND/AIMS: The aim was to determine the effect of ammonia (NH(3)) and lipopolysaccharide (LPS) alone or in combination, on cerebral blood flow (CBF) and intracranial pressure (ICP) in the rat. Since amiloride-sensitive-ion-pathways in the blood-brain barrier (BBB) modulate CBF, we also aimed to test if Na(+)/H(+)-inhibitors could prevent this possible synergism between NH(3) and LPS. METHODS: In experiment A, four groups of rats received ammonium acetate (140 micromol/kg/min) or saline, each of them associated with either vehicle or LPS (2 mg/kg). In experiments B and C, rats received similar treatments after having received amiloride (30 mg/kg) or 5-(N-methyl-N-isobutyl)-amiloride (MIA, 5 mg/kg). Plasma tumor-necrosis-factor-alpha (TNF-alpha), ICP (via a cisterna magna catheter) and CBF (by laser-Doppler flowmetry) were measured. RESULTS: An increase in ICP and CBF within 60 min was observed only in rats that received NH(3) together with LPS as compared to any other group (P<0.01), which could be prevented by amiloride (P<0.05), but not by MIA. Both amiloride and MIA decreased the plasma TNF-alpha concentration. CONCLUSIONS: In rats anaesthetised with pentobarbital NH(3) infusion aggravates a LPS induced rise in ICP and induces an increase in CBF less clearly seen with LPS alone. This effect is prevented by the non-specific Na(+)/H(+) inhibitor amiloride, but not by MIA, a specific inhibitor of Na(+)/H(+) exchanger. Thus, the synergistic effect of NH(3) and LPS seems mediated by other amiloride-sensitive-ion-pathways in the BBB than the Na(+)/H(+) exchanger.

Viral load is a negative predictor of antioxidant levels in hepatitis C patients.

The pathogenesis of chronic hepatitis C (HCV) infection is not fully known, but oxidative stress may play a role. The aim of this study was to assess the relationship between HCV load and antioxidant status among patients with chronic HCV infection. Among 23 patients, HCV load, as well as plasma beta-carotene, retinol, ascorbic acid and alpha-tocopherol were measured. Plasma retinol, ascorbic acid and alpha-tocopherol were low in 17%, 26% and 4% of the patients, respectively. Plasma ascorbic acid and alpha-tocopherol declined 9.7 micromol/l (95% CI 3.3-16.2) and 4.5 micromol/l (95% CI 2.1-7.0), respectively, and plasma beta-carotene declined by a factor of 0.60 (95% CI 0.37-0.98) per log increase in viral load. Smoking was independently associated with 8.9 micromol/l (95% CI 4.1-13.7), lower levels of plasma alpha-tocopherol and with 0.27 (95% CI 0.11-0.71) times lower plasma beta-carotene. The effect on plasma ascorbic acid was not significant (-9.2 micromol/l, 95% CI - 21.9-3.5). The association may reflect consumption of antioxidants due to HCV, although effects of low antioxidant status on viral replication cannot be excluded.