Clinical impact of five large-scale screening projects for chronic hepatitis B in Chinese migrants in the Netherlands.

BACKGROUND & AIMS: In low-endemic countries it is debated whether first-generation migrants should be screened for chronic hepatitis B infection. We describe the clinical impact of five large-scale Dutch screening projects for hepatitis B in first-generation Chinese migrants. METHODS: Between 2009 and 2013 five independent outreach screening projects for hepatitis B targeting first-generation Chinese migrants were conducted in five main Dutch regions. To explore the relevance of our screening we defined clinical impact as the presence of an indication for: (i) antiviral therapy, (ii) strict follow-up because of high hepatitis B DNA levels and/or (iii) surveillance for hepatocellular carcinoma. RESULTS: In total, 4423 persons participated in the projects of whom 6.0% (n = 264) were HBsAg positive. One hundred and twenty-nine newly diagnosed HBsAg-positive patients were analysed in specialist care. Among these patients prevalence of cirrhosis was 6.9% and antiviral therapy for hepatitis B was started in 32 patients (25%). In patients without a treatment indication, strict follow-up because of high hepatitis B DNA levels and/or surveillance for hepatocellular carcinoma was considered indicated in 64 patients (50%). CONCLUSIONS: In our screening project in first-generation Chinese migrants, antiviral treatment, strict follow-up because of high hepatitis B DNA levels and/or surveillance for hepatocellular carcinoma were considered indicated in three of four analysed HBsAg-positive patients. These data show that detection of hepatitis B in Chinese migrants can have considerable impact on patient care.

Effects of preventive versus "on-demand" nutritional support on paid labour productivity, physical exercise and performance status during PEG-interferon-containing treatment for hepatitis C.

BACKGROUND AND OBJECTIVE: Deterioration of nutritional status during PEG-interferon containing therapy for chronic hepatitis C can be ameliorated by preventive nutritional support. We aimed to explore whether such support also affects paid labour productivity, physical exercise and performance status. METHODS: In this prospective randomized controlled trial (J Hepatol 2012;57:1069-75), 53 patients with chronic hepatitis C had been allocated to "on demand" support (n=26: nutritional intervention if weight loss>5%) or preventive support (n=27: regular dietary advice plus energy- and protein-rich evening snack) during PEG-interferon-containing therapy. Paid labour productivity, physical exercise and performance status were evaluated at baseline, after 24 and (if applicable) after 48 weeks of treatment. RESULTS: At baseline, 46% of patients performed paid labour and 62% performed some kind of physical exercise. Furthermore, most patients were able to carry out normal activity with only minor symptoms of disease (mean Karnofsky performance score: 94). Decreases of paid labour productivity (-21% vs. -70%, P=0.003), physical exercise activity (-43% vs. -87%, P=0.005) and Karnofsky performance scores (-12% vs. -24%, P<0.001) were less in the preventive than in "on demand" group after 24 weeks of treatment. Effects of preventive nutritional support were even more pronounced after 48 weeks. CONCLUSIONS: Preventive nutritional support markedly ameliorates decreases of paid labour productivity, physical exercise and performance status during PEG-interferon-containing treatment for chronic hepatitis C.

Measuring ribavirin concentrations during the earliest stages of antiviral therapy for hepatitis C: potential relevance for treatment outcome.

BACKGROUND: Correlations between ribavirin (RBV) concentrations and sustained virological response (SVR) to hepatitis C virus treatment have been demonstrated previously. As steady state is reached after several weeks of RBV treatment, dose modifications based on steady-state levels can only be applied relatively late in treatment, possibly too late to influence SVR rates. The authors aimed to determine whether measurement of early concentrations is useful to predict optimal steady-state RBV concentrations. METHODS: In 61 treatment-naive genotype 1/4 patients RBV concentrations were determined in samples collected after 1, 2, 4, 8, 12, and 24 weeks of therapy. RBV concentrations were compared between responders and nonresponders; Receiver Operating Characteristic analyses were conducted to find optimal cut-off values to predict week 8 concentrations from earlier measurements. RESULTS: Median week 8 RBV concentrations were significantly higher in patients with SVR compared with those without: 3.4 (interquartile range 2.4-3.9) versus 2.6 (interquartile range 2.0-3.5) mg/L (P < 0.05). RBV concentration at week 8 was an independent predictor of SVR [adjusted odds ratio 2.3 (95% confidence interval: 1.1-4.9; P = 0.03)]. The optimal cut-off value of week 8 RBV concentration to predict SVR was 2.20 mg/L [sensitivity 87%, specificity 40%, positive predictive value 64%, negative predictive value 71%]. Optimal cut-off values at weeks 1, 2, or 4 to predict an RBV concentration ≥2.20 mg/L at week 8 were 0.92, 1.29, and 1.67 mg/L, respectively, with positive predictive values and negative predictive values ranging from 88% to 91% and 71% to 86%, respectively. CONCLUSIONS: RBV concentrations in the earliest stages of antiviral therapy predict therapeutic steady-state concentrations, allowing timely dose adjustments with potential implications for treatment outcome.

Preventive versus "on-demand" nutritional support during antiviral treatment for hepatitis C: a randomized controlled trial.

BACKGROUND & AIMS: Although antiviral treatment for hepatitis C (HCV) is highly effective, side effects often occur, including weight loss, digestive symptoms, and impaired quality of life. We aimed at exploring the beneficial effects of preventive nutritional support. METHODS: In a randomized controlled trial, 53 HCV patients were allocated to "on demand" support (n=26: nutritional intervention if weight loss >5%) or preventive support (n=27: regular dietary advice plus energy- and protein-rich evening snack). Nutritional state (including validated Jamar Hand Grip Strength), digestive symptoms (visual analog score), and quality of life (SF-36 survey) were evaluated at baseline, and after 24 and 48 weeks of peginterferon α-2b and ribavirin treatment. RESULTS: The primary end point (weight loss at 24 weeks) was reached in 22 patients in both groups. Weight decreased markedly in the "on demand" group (decrease at 24 weeks: 5.4 kg or 6.9%, p<0.001), but not in the preventive group (decrease 0.3 kg or 0.3%, p=n.s.). Jamar Hand Grip Strength deteriorated in the "on demand" group (from 40.3 ± 15.5 kg to 32.0 ± 13.1 kg, p<0.001) but not in the preventive group (from 40.7 ± 10.4 kg to 39.7 ± 8.9 kg, p=n.s.). Intake of energy, proteins, and fat decreased markedly in the "on demand" group but increased in the preventive group. Although digestive symptoms and quality of life deteriorated, impairment was significantly less in the preventive group. CONCLUSIONS: Preventive nutritional advice plus supplementation prevents weight loss and catabolic state during HCV antiviral therapy, with improved digestive symptoms and quality of life.

Impact of Fibroscan on management of chronic viral hepatitis in clinical practice.

BACKGROUND: Liver stiffness measurement (LSM) using Fibroscan is an increasingly popular non-invasive method for quantifying liver fibrosis in patients with chronic viral hepatitis. We aimed to explore potential impact of Fibroscan on clinical management. MATERIAL AND METHODS: 133 patients with chronic hepatitis B (HBV, n = 75) or C (HCV, n = 58) underwent Fibroscan measurement. LSM results were compared with liver biopsy results, ultrasound, and APRI-scores, and the impact of LSM on clinical management was evaluated. RESULTS: LSM results indicated fibrosis stage F0-F1 in 84 patients (63%), F2 in 28 (21%), F3 in 8 (6%), and F4 in 13 patients (10%). Nineteen patients had liver biopsies within one year of LSM. In ten patients, LSM and biopsy showed the same fibrosis stage, in 8 there was one stage difference, and in 1 three stages difference. Ultrasound only showed cirrhosis in three patients, who all exhibited advanced cirrhosis at LSM. There was a statistically significant, but weak correlation between LSM results and APRI scores (r = 0.31, pvalue < 0.001). LSM results changed clinical management in 39% of patients (55 cases): in 15 patients antiviral treatment was indicated, in 21 patients surveillance for hepatocellular carcinoma was indicated, and 19 successfully treated hepatitis C patients could be discharged from clinical follow-up in absence of severe fibrosis or cirrhosis. CONCLUSION: LSM appears to be a valuable non-invasive tool to manage patients with chronic viral hepatitis in clinical practice.

Suboptimal endogenous erythropoietin response in chronic hepatitis C patients during ribavirin and PEG interferon treatment.

BACKGROUND: During the treatment of hepatitis C, anaemia may necessitate pegylated-interferon and ribavirin dose reductions with reduced sustained viral response rates. Although erythropoietic growth factors are frequently used to improve anaemia, it is controversial whether endogenous erythropoietic response is insufficient under these circumstances. We aimed to identify risk factors for more pronounced anaemia and to evaluate endogenous erythropoietic response during antiviral therapy. METHODS: One hundred and forty-five naive chronic hepatitis C patients on pegylated-interferon-ribavirin treatment were evaluated for haemoglobin, haematocrit, serum ribavirin and erythropoietin levels. RESULTS: About 99% of patients developed anaemia, with maximal decrease in haemoglobin of 2.5 ± 1.0 mmol/l (range 0.3-5.5 mmol/l). Older age, lower baseline creatinine clearance, higher baseline haemoglobin, more pronounced haemoglobin decrease after 2 weeks and higher week 24 serum ribavirin concentrations were independent risk factors for more pronounced anaemia. Serum erythropoietin levels increased from median 12 IU/l (range 4-63 IU/l) at baseline to 41 IU/l (range 12-683 IU/l) after 12 weeks of therapy and to 43 IU/l (range 7-3238 IU/l) at week 24 (P<0.001). Erythropoietin levels at baseline, week 12 and week 24 negatively correlated with haematocrit. The erythropoietic response to anaemia in our study population was significantly different from the normal human response to anaemia. CONCLUSION: Older age, lower baseline creatinine clearance, higher baseline haemoglobin, more pronounced haemoglobin decrease after 2 weeks and higher week 24 serum ribavirin concentrations were independent risk factors for more pronounced anaemia during antiviral therapy. Endogenous erythropoietin production is suboptimal during antiviral therapy, supporting use of erythropoietic growth factors.

Influence of alpha-1 antitrypsin heterozygosity on treatment efficacy of HCV combination therapy.

BACKGROUND: The role of heterozygosity for alpha-1 antitrypsin (A1AT) alleles in patients with chronic hepatitis C virus (HCV) is unclear. There is limited evidence to suggest that there is an increased prevalence of heterozygous A1AT carriers in HCV, but it is unclear how this affects treatment success. AIM: To investigate the (i) prevalence of A1AT heterozygosity among two HCV cohorts and (ii) its effect on treatment outcome. METHODS: We performed a retrospective cohort study using two different cohorts. Cohort 1 consisted of 678 German HCV patients, 507 of them were treated for HCV with standard therapy. Cohort 2 consisted of 370 Dutch HCV patients of which 252 were part of a clinical trial (treatment with amantadine or placebo, in combination with pegylated interferon alpha-2b and ribavirin) whereas 37 HCV patients received standard therapy. We analyzed A1AT status using direct sequencing of the A1AT gene (cohort 1) or isoelectric focusing of serum (cohort 2). In addition, we measured A1AT serum levels (cohort 2). RESULTS: In total, we included 1048 HCV patients; 986 (94%) were wildtype [protease inhibitor (Pi) MM], whereas 61 (6%) were heterozygous for a mutant A1AT allele (41 Pi MS, 20 Pi MZ). Mean A1AT serum levels (370 patients) were lower in A1AT heterozygous patients (1.68 vs. 1.36 g/l), (P<0.05) compared with wildtypes. Sustained viral response (SVR) after treatment was equal between the wildtypes and heterozygotes (54 vs. 56%). CONCLUSION: We found a heterozygosity rate of 0.06, in line with healthy controls in other studies. Serum A1AT levels from A1AT heterozygous HCV patients are significantly lower compared with wildtype patients, although they do not discriminate on an individual level. Finally, SVR in A1AT wildtypes was not different from SVR in A1AT heterozygotes.

No beneficial effects of amantadine in treatment of chronic hepatitis C patients.

BACKGROUND: Benefit of adding amantadine to antiviral therapy for hepatitis C is controversial. AIMS: We aimed to examine whether such policy enhances sustained viral response in treatment-naïve patients. METHODS: 297 naïve hepatitis C patients were randomized for treatment with amantadine 200mg or placebo, combined with weight-based ribavirin and 12-day high-dose interferon alpha-2b induction therapy, followed by PEG-interferon alpha-2b (1.5 microg/kg/week up to 26 weeks and thereafter, 1.0 microg/kg/week until week 52). Treatment was discontinued if hepatitis C virus (HCV) RNA was positive at week 24. RESULTS: 49% of patients were (former) drug users. Genotype 1 occurred in 45%, high viral load in 70% and severe fibrosis/cirrhosis in 32%, without differences between amantadine or placebo groups. 90 patients prematurely discontinued treatment, mainly because of grade 3 or 4 toxicity. Intention-to-treat analysis revealed sustained viral response in 47% and 51% of amantadine and placebo groups (p=0.49). Amantadine did not enhance sustained viral response in patients with genotype 1 or high viral load nor did it improve primary non-response, breakthrough or relapse rates. Genotype non-1 and lower pre-treatment gamma GT levels were independent predictors for sustained viral response. CONCLUSION: Adding amantadine to antiviral therapy of previously untreated chronic hepatitis C patients has no beneficial effects.

Clinical and basal aspects of anemia during antiviral therapy for hepatitis C.

BACKGROUND AND RATIONALE: Anemia is a major side effect of combination therapy for chronic hepatitis C. In this study, severity, potential risk factors for and potential underlying mechanisms of anemia were evaluated. PATIENTS AND METHODS: 44 chronic hepatitis C patients on interferon-ribavirin treatment were included. Anemia-related parameters were measured before and during treatment. Potential changes in membrane phospholipids composition of erythrocytes of patients on anti-viral treatment and potentially increased erythrocyte susceptibility to osmotic or bile salt induced stress were explored. RESULTS: Anemia was almost universal during treatment, with evidence of hemolysis. Decrease of Hb after six months of therapy was 2.1 +/- 0.1 mmol/L (range -0.6-4.1). Higher pre-treatment Hb, highest ribavirin dose (15-17.5 mg/kg) and lower pre-treatment platelet level were independent risk factors for decrease of Hb. Serum erythropoietin levels increased during treatment with negative correlation to Hb levels at week 12 (r = -0.70, p = 0.002) and 24 (r = -0.72, p = 0.002). Erythrocyte membrane phospholipid composition did not differ between anemic patients and healthy controls. Also, resistance to osmotic or bile salt induced stress was normal in anemic patients. Phosphatidylserine exposure at the outer membrane leaflet did not change upon 24 hrs ex vivo incubation with pharmacological ribavirin concentration. CONCLUSIONS: Anemia is almost universal during anti-HCV treatment. The extent of anemia correlates with pre-treatment levels of thrombocytes and Hb and with high ribavirin dosing. Although we found hemolysis as contributing factor, our data do not indicate that altered membrane phospholipids composition is an important factor in pathogenesis of anemia.

Growth and final height after liver transplantation during childhood.

OBJECTIVE: To evaluate the effect of end-stage pediatric liver disease and liver transplantation on growth and final height. PATIENTS AND METHODS: We evaluated growth at 2 years (n = 101) and 5 years (n = 63) after pediatric liver transplantation (LTx). Twenty-three children reached final height. Height was expressed as a standard deviation score of the target height (zTH score) of each patient. RESULTS: At the first 2 years after LTx, the zTH score was significantly increased from -1.7 to -1.3 SD (P < 0.05). Growth at 2 or 5 years after LTx, expressed as DeltazTH score, was positively correlated with pretransplant growth retardation (P < 0.05). In comparison with patients with noncholestatic primary liver disease, patients with cholestatic primary liver disease were more severely growth retarded before LTx (zTH score -2.0 vs -1.2 SD, P < 0.05) and had better growth in the first 2 years after LTx (DeltazTH score +0.6 vs -0.1 SD, P < 0.05). Twelve of the 23 patients had a final height below -1.3 SD of their target height. CONCLUSIONS: Growth retardation is common in children before LTx, particularly in children with an underlying cholestatic disease. After LTx, catch-up growth was partial and was prominent only in cholestatic children who had been severely growth retarded before LTx. After LTx during childhood, approximately 50% of patients reach a final height lower than -1.3 SD of their genetic potential.

Cerebral oxygen extraction and autoregulation during extracorporeal whole body hyperthermia in humans.

BACKGROUND: The effects of hyperthermia on the human brain are incompletely understood. This study assessed the effects of whole body hyperthermia on cerebral oxygen extraction and autoregulation in humans. METHODS: Nineteen patients with chronic hepatitis C virus infection, not responding to interferon treatment, were subjected to experimental therapy with extracorporeal whole body hyperthermia at 41.8 degrees C for 120 min under propofol anesthesia (23 sessions total). During treatment series A (13 sessions), end-tidal carbon dioxide was allowed to increase during heating. During series B (10 sessions), end-tidal carbon dioxide was maintained approximately constant. Cerebral oxygen extraction (arterial to jugular venous difference of oxygen content) and middle cerebral artery blood flow velocity were continuously measured. Cerebral pressure-flow autoregulation was assessed by static tests using phenylephrine infusion and by assessing the transient hyperemic response to carotid compression and release. RESULTS: For treatment series A, cerebral oxygen extraction decreased 2.2-fold and cerebral blood flow velocity increased 2.0-fold during heating. For series B, oxygen extraction decreased 1.6-fold and flow velocity increased 1.5-fold. Jugular venous oxygen saturation and lactate measurements did not indicate cerebral ischemia at any temperature. Static autoregulation test results indicated loss of cerebrovascular reactivity during hyperthermia for both series A and series B. The transient hyperemic response ratio did not decrease until the temperature reached approximately 40 degrees C. Per degree Celsius temperature increase, the transient hyperemic response ratio decreased 0.07 (95% confidence interval, 0.05-0.09; P = 0.000). This association remained after adjustment for variations in arterial partial pressure of carbon dioxide, mean arterial pressure, and propofol blood concentration. CONCLUSION: Profound hyperthermia during propofol anesthesia is associated with decreased cerebral oxygen extraction, increased cerebral blood flow velocity, and impaired pressure-flow autoregulation, indicating transient partial vasoparalysis.