Hepatitis: de Knegt RJ

de Bruijne J, Buster EH, Gelderblom HC, Brouwer JT, de Knegt RJ, van Erpecum KJ, Schalm SW, Bakker CM, Zaaijer HL, Janssen HL, Reesink HW, Anonymous00041. · Department of Gastroenterology and Hepatology, Academic Medical Centre Amsterdam, the Netherlands. · Neth J Med. · Pubmed #18663263 links to  free full text

Abstract: The development of this guideline was initiated and coordinated by the Netherlands Association of Gastroenterologists and Hepatologists (Nederlandse Vereniging van Maag-Darm-Leverartsen). The aim is the establishment of practical guidelines in the evaluation and antiviral treatment of patients with chronic hepatitis C virus (HCV) infection. This includes recommendations for the initial evaluation of patients, the choice and duration of antiviral therapy and the follow-up after antiviral therapy. Hepatitis C is a slowly progressive disease. The initial evaluation of chronically HCV-infected patients should include liver biochemistry testing, virological testing and abdominal ultrasound imaging. Liver biopsy is no longer a routine procedure. Antiviral treatment should be considered for all HCV-infected patients. Current antiviral treatment is a long-term process and is associated with substantial side effects. When deciding whether to start treatment or not, the chance of successful treatment (80% with hepatitis C genotype 2 and 3 and 50% with hepatitis C genotype 1 and 4), the fibrosis stage, the expected side effects and the compliance of the patient should be taken into consideration. In the absence of significant fibrosis and necroinflammation in liver biopsy, postponing treatment is an option. Current antiviral treatment is contraindicated in patients with Child-Pugh-class B or C cirrhosis. The possibility of a liver transplantation should be investigated in these patients. Significant comorbidity with a limited life expectancy is an absolute contraindication for antiviral treatment Treatment of chronic hepatitis C consists of administration of peginterferon and ribavirin for 24 or 48 weeks. Patients with hepatitis C genotype 1 or 4 are treated for 48 weeks. Patients with hepatitis C genotype 2 or 3 are treated for 24 weeks. In patients with undetectable HCV RNA after four weeks (28 days) of treatment, a shorter treatment is equally effective (12 to 16 weeks for hepatitis C genotype 2 or 3; 24 weeks for hepatitis C genotype 1 or 4). Outpatient clinic visits are recommended at the start and after 2, 4, 8, and 12 weeks of treatment, and thereafter every four to six weeks until the end of treatment. It is recommended to stop treatment if the HCV RNA level has not decreased by at least 2 log10 IU/ml (c/ml) after 12 weeks of treatment or when HCV RNA is still detectable after 24 weeks of treatment. The recommended frequency of outpatient clinic visits for patients who are not being treated is once every six months in patients with cirrhosis, otherwise every 12 months. It is expected that new anti-HCV-medication (STAT-C, specifically targeted antiviral therapy for HCV) will become available in the near future. Therefore treatment of chronic HCV infection will probably be more effective in the future.

Buster EH, van Erpecum KJ, Schalm SW, Zaaijer HL, Brouwer JT, Gelderblom HC, de Knegt RJ, Minke Bakker C, Reesink HW, Janssen HL, Anonymous00062. · Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Centre Rotterdam, the Netherlands. · Neth J Med. · Pubmed #18663260 links to  free full text

Abstract: The development of this guideline was initiated and coordinated by the Netherlands Association of Gastroenterologists and Hepatologists (Nederlandse Vereniging van Maag-Darm-Leverartsen). The aim is the establishment of national standards in the evaluation and antiviral treatment of patients with chronic hepatitis B virus (HBV) infection. This includes recommendations on the initial evaluation of patients, choice and duration of antiviral therapy, follow-up after antiviral therapy and monitoring of patients not currently requiring antiviral therapy. The initial evaluation of chronic HBV-infected patients should include testing of liver biochemistry, virus serology and abdominal imaging. In patients without cirrhosis, antiviral treatment is recommended for those with a serum HBV DNA of at least 1.0 x 105 c/ml (>or=2.0 x 10(4) IU/ml) in combination with: a) elevation of serum alanine aminotransferase (ALAT) level above twice the upper limit of normal during at least three months, and/or b) histological evidence of porto-portal septa or interface hepatitis on liver histology. In patients with cirrhosis, antiviral treatment is recommended if serum HBV DNA is 1.0 x 10(4)c/ml (>or=2.0 x 10(3) IU/ml) or higher, independent of ALAT levels or histological findings. If the patient has decompensated cirrhosis, antiviral treatment is recommended if serum HBV DNA is 1000 c/ml (>or=200 IU/ml) or higher. Patients who do not have an indication for antiviral treatment should be monitored because there is a risk of (re)activation of disease activity. Monitoring every three to six months is recommended for HBeAg-positive and HBeAg-negative patients with high viraemia (HBV DNA >or=1.0 x 10(5) c/ml or >or=2.0 x 10(4) IU/ml) and normal ALAT levels. For patients with serum HBV DNA below 1.0 x 10(5) c/ml (<2.0 x 10(4) IU/ml) the recommended frequency of monitoring is every three to six months for HBeAg-positive patients and every six to 12 months for HBeAg-negative patients. Peginterferon (PEG-IF N) therapy should be considered as initial therapy in both HBeAg-positive and HBeAg-negative patients without contraindications for treatment with this drug because of the higher chance of achieving sustained response compared with nucleos(t)ide analogue therapy. In patients starting nucleos(t)ide analogue therapy, the use of lamivudine is not preferred if long-term antiviral treatment is expected due to the high risk of antiviral resistance against this drug. Of the currently licensed nucleos(t)ide analogues, entecavir has the lowest risk of antiviral resistance (compared with lamivudine, adefovir and telbivudine), while suppression of viral replication seems most profound with either entecavir or telbivudine. The recommended duration of treatment with PEG-IF N is one year for both HBeAg-positive and HBeAg-negative patients. In HBeAg-positive patents, nucleos(t)ide analogue therapy should at least be continued until HBeAg seroconversion and a decline in HBV DNA to below 400 c/ml (80 IU/ml) has been achieved and maintained for six months during therapy. Whether nucleos(t)ide analogue therapy can be safely discontinued in HBeAg-negative patients is unknown; usually prolonged or indefinite antiviral treatment is necessary. Patients receiving PEG-IF N should be monitored once a month, while three monthly monitoring suffices for those receiving nucleos(t)ide analogues. Genotypic analysis of the HBV polymerase is indicated if an increase in serum HBV DNA of at least 1 log(10) c/ml (IU/ml) compared with the nadir value is observed during nucleos(t)ide analogue therapy. Antiviral therapy should be changed as soon as possible in case of confirmed genotypic resistance. Adding a second antiviral agent seems beneficial over switching to another agent. With the availability of multiple new antiviral drugs for the treatment of chronic hepatitis B, effective treatment is now possible for more patients and for longer periods. However, the complexity of HBV therapy has also increased. Nowadays, virtually all chronic HBV-infected patients can be effectively managed, either by inducing sustained off-treatment response or by maintaining an on-treatment response.

Bezemer G, Schalm SW, van Gool AR, de Knegt RJ. · Erasmus MC-Centrum, Postbus 2040, 3000 CA Rotterdam. · Ned Tijdschr Geneeskd. · Pubmed #17373393 No free full text.

Abstract: Since hepatitis C can be treated more and more successfully, treatment should be considered in every patient. In some of the patients infected by viral genotype I, the duration of treatment can be shortened: 24 weeks instead of 48 weeks. Maintaining the optimal dosage of ribavirin and peginterferon alpha is of great importance for successful treatment. For this purpose, new guidelines are proposed with reference to the haematological side effects, recommending more restraint with the reduction of the dosage and treatment in case of complaints. Treatment with peginterferon alpha frequently causes psychiatric problems, particularly depressive symptoms that are sometimes severe. Adequate treatment and support, including the use of antidepressants, are necessary in such cases and are often effective.

Verveer C, de Knegt RJ. · Department Gastroenterology and Hepatology, Erasmus Medical Center, Rotterdam, The Netherlands. · Scand J Gastroenterol Suppl. · Pubmed #16782627 No free full text.

Abstract: The liver biopsy is still regarded as the gold standard for the assessment of liver disease. However, there is a growing demand for non-invasive assessment of liver fibrosis, which is the most important prognostic factor in chronic liver disease, in particular in viral hepatitis. Transient elastography is a novel, non-invasive and rapid bedside method for assessing liver fibrosis by measuring liver stiffness. Some recent extensive studies, mainly from France, have demonstrated that measurement with the FibroScan is a good alternative for the liver biopsy. The amount of fibrosis can be quantified very easily and reliably. In this review, we describe the technique and discuss the available studies in order to establish applicability and to provide points for discussion.

de Knegt RJ. · Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands. · Scand J Gastroenterol Suppl. · Pubmed #16782624 No free full text.

Abstract: Hepatitis C is a mild disease, with most infected people unaware that they have it. Worldwide, 170 million people are infected, and therefore the burden of morbidity and mortality is significant (decompensated liver cirrhosis and hepatocellular carcinoma). The treatment of patients with hepatitis C has significantly improved over the past few years, such that high sustained virological responses can be obtained: >80% in genotypes 2 and 3 and >50% in genotype 1. Treatment in genotypes 2 and 3 should be considered in all patients, whereas in genotype 1 the decision has to be based on the presence of fibrosis in the liver biopsy and general patient characteristics. Guidelines for antiviral therapy are given in this overview.

Vrolijk JM, de Knegt RJ, Veldt BJ, Orlent H, Schalm SW. · Department of Gastroenterology and Hepatology (Ca326), Erasmus Medical Centre, Rotterdam, the Netherlands. · Neth J Med. · Pubmed #15209471 links to  free full text

Abstract: The treatment of chronic hepatitis C has made remarkable progress over the past two decades. For interferon-alpha monotherapy, sustained virological response rates were between 2 and 9% in genotype 1 and between 16 and 23% in genotypes 2 and 3. By adjusting treatment duration up to 48 weeks for genotype 1 and combining regular interferon-alpha with ribavirin, sustained response rates could be improved to 28 to 31% in genotype 1 and around 65% in genotypes 2 and 3. Attempts to further increase efficacy included the addition of amantadine without conclusive evidence up till now. With the recent introduction of long-acting pegylated interferon-alpha in combination with ribavirin, sustained virological response rates of 8o% can be obtained in genotypes 2 and 3. However, sustained virological response rates for patients with either genotype 1, nonresponse to prior treatment, cirrhosis or a combination of these characteristics are still less than 50%. In view of results with daily high-dose interferon-alpha induction in combination with prolongation of treatment duration up to 18 months, such patients might benefit from induction and prolonged PEG-IFN-alpha treatment and should be treated in an experimental setting.

de Knegt RJ. · Dept. of Gastroenterology and Hepatology, Groningen University Hospital, The Netherlands. · Scand J Gastroenterol Suppl. · Pubmed #11768567 No free full text.

Abstract: Non-alcoholic steatohepatitis (NASH) is a form of liver disease resembling alcoholic liver disease in a patient who does not consume significant amounts of alcohol. Since its first description in 1980 it has been recognized with increasing frequency. The natural course is relatively benign, but liver cirrhosis. together with all its sequelae, may develop; sometimes liver transplantation is indicated. NASH should probably be regarded as a two-stage acquired metabolic disorder consisting of the development of the insulin resistance syndrome in a patient with pre-existing metabolic abnormalities. The insulin resistance syndrome may well be the most important metabolic abnormality giving rise to hepatic steatosis. The preexisting metabolic abnormalities can be diverse, and may well be multifactorial and/or polymorphogenetic. A steatotic liver may be more susceptible to the deleterious effects of the pre-existing metabolic abnormalities. Pre-existing metabolic abnormalities of particular interest are increased hepatic iron storage and derangements of lipoprotein metabolism. While awaiting the complete resolution of the pathogenesis, current treatment is largely conservative. Every patient should be encouraged to lose weight and to avoid alcohol and other hepatotoxins. In addition, diabetes, lipid abnormalities and increased iron stores should be looked for.

Veldt BJ, van der Vliet HJ, von Blomberg BM, van Vlierberghe H, Gerken G, Nishi N, Hayashi K, Scheper RJ, de Knegt RJ, van den Eertwegh AJ, Janssen HL, van Nieuwkerk CM. · Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, Room Ca 326a, PO Box 2040, 3000 CA Rotterdam, The Netherlands. · J Hepatol. · Pubmed #17599630 No free full text.

Abstract: BACKGROUND/AIMS: The glycosphingolipid alpha-galactosylceramide has been shown to activate invariant natural killer T cells when presented in the context of CD1d and induces powerful antiviral immune responses via the production of inflammatory cytokines. The aim of this study was to investigate the safety and the antiviral activity of alpha-galactosylceramide as a novel class of treatment for chronic hepatitis C patients. METHODS: International multicenter dose-escalating randomized placebo-controlled phase I/II trial. RESULTS: Forty patients were allocated to a dose of 0.1 microg/kg (n=9), 1 microg/kg (n=9), 10 microg/kg (n=11) or to placebo (n=11). alpha-Galactosylceramide was well tolerated and no patients were withdrawn due to side effects. Although most patients showed a decrease in invariant natural killer T cells after administration, no clinically relevant suppression of viral replication was observed. Only one patient, a previous non-responder to peginterferon and ribavirin with high baseline invariant natural killer T cell levels, showed profound signs of immune activation, accompanied by a transient 1.3 log decrease in HCV-RNA and a concomitant increase in ALT after the first administration. CONCLUSIONS: alpha-Galactosylceramide used as monotherapy for interferon-refractory patients in doses of 0.1-10 microg/kg is safe and it exerts moderate immunomodulatory effects. However, in its current form it has no significant effect on HCV-RNA levels.

Slavenburg S, Lamers MH, Roomer R, de Knegt RJ, van Oijen MG, Drenth JP. · Departments of Gastroenterology and Hepatology, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands. · Neth J Med. · Pubmed #19581667 links to  free full text

Abstract: BACKGROUND: Recently, the Dutch Association of Gastroenterology and Hepatology issued new guidelines for the treatment of chronic hepatitis C virus (HCV). These guidelines reflect the current standard of care. Before these guidelines were published and implemented we (1) studied the current clinical care of HCV patients among Dutch physicians, and (2) identified areas for future refinement in the current treatment. METHODS: We conducted a non-targeted survey among Dutch medical specialists in Gastroenterology, Hepatology and Internal Medicine who actively treat HCV patients. The questionnaire contained items about facility, duration and dosing of treatment, and side effect management using clinical vignettes followed by short questions. RESULTS: We received 49 questionnaires from treating HCV specialists. The majority (65%) of respondents treat HCV patients during regular outpatient clinics, while 35% treat these patients in a separate setting dedicated to the care of HCV patients. The majority of physicians follow the stipulated dosage regimens of pegylated interferon (88%) and ribavirin (83%). A minority (13%) exceed the advised dosage of ribavirin. Side effects such as neutropenia are mostly managed by decreasing the interferon dosage (42%). Some 35% of physicians reduce ribavirin if haemoglobin levels drop below 5.4 mmol/l, and 41% initiate erythropoietin treatment. CONCLUSION: Dutch clinical practice reflects the recently issued HCV guidelines. An important area of refinement in treatment of HCV is the management of side effects.

Veldt BJ, Chen W, Heathcote EJ, Wedemeyer H, Reichen J, Hofmann WP, de Knegt RJ, Zeuzem S, Manns MP, Hansen BE, Schalm SW, Janssen HL. · Erasmus MC University Medical Center, Department of Gastroenterology and Hepatology, Rotterdam, the Netherlands. · Hepatology. · Pubmed #18506898 No free full text.

Abstract: Recent studies suggest that diabetes mellitus increases the risk of developing hepatocellular carcinoma (HCC). The aim of this study is to quantify the risk of HCC among patients with both diabetes mellitus and hepatitis C in a large cohort of patients with chronic hepatitis C and advanced fibrosis. We included 541 patients of whom 85 (16%) had diabetes mellitus. The median age at inclusion was 50 years. The prevalence of diabetes mellitus was 10.5% for patients with Ishak fibrosis score 4, 12.5% for Ishak score 5, and 19.1% for Ishak score 6. Multiple logistic regression analysis showed an increased risk of diabetes mellitus for patients with an elevated body mass index (BMI) (odds ratio [OR], 1.05; 95% confidence interval [CI], 1.00-1.11; P = 0.060) and a decreased risk of diabetes mellitus for patients with higher serum albumin levels (OR, 0.81; 95% CI, 0.63-1.04; P = 0.095). During a median follow-up of 4.0 years (interquartile range, 2.0-6.7), 11 patients (13%) with diabetes mellitus versus 27 patients (5.9%) without diabetes mellitus developed HCC, the 5-year occurrence of HCC being 11.4% (95% CI, 3.0-19.8) and 5.0% (95% CI, 2.2-7.8), respectively (P = 0.013). Multivariate Cox regression analysis of patients with Ishak 6 cirrhosis showed that diabetes mellitus was independently associated with the development of HCC (hazard ratio, 3.28; 95% CI, 1.35-7.97; P = 0.009). CONCLUSION: For patients with chronic hepatitis C and advanced cirrhosis, diabetes mellitus increases the risk of developing HCC.

Bergmann JF, Vrolijk JM, van der Schaar P, Vroom B, van Hoek B, van der Sluys Veer A, de Vries RA, Verhey E, Hansen BE, Brouwer JT, Janssen HL, Schalm SW, de Knegt RJ. · Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, The Netherlands. · Liver Int. · Pubmed #17919233 No free full text.

Abstract: BACKGROUND: High-dose peginterferon-alpha (PegIFN-alpha) induction and prolongation of therapy may be an option to improve sustained virological response (SVR) rates among hepatitis C virus (HCV) non-responders, although a higher and a longer dosing of PegIFN-alpha may intensify side effects. METHODS: We randomized 53 patients, who previously failed with standard IFN-alpha+/-ribavirin, to a high-dose induction and an extended regimen with PegIFN-alpha-2b [3.0 microg/kg once weekly (q.w.) 12 weeks-->2.0 microg/kg q.w. 12 weeks-->1.5 microg/kg q.w. 48 weeks] or a standard regimen (1.5 microg/kg q.w. 48 weeks). All patients received daily weight-based ribavirin (800-1200 mg/day). The short-form 36 health survey was used to evaluate health-related quality of life (HRQL). RESULTS: Intention-to-treat analysis showed no significant difference in SVR rate (44% vs. 37%, P=0.62) and relapse rate (9% vs. 31%, P=0.17) between experimental and standard treatment. Overall, 80% of the [positive predictive value (PPV)] patients with rapid virological response (RVR, HCV-RNA negativity at week 4) achieved SVR. No significant dose-related differences in HRQL were seen between both groups. At baseline, genotype 2 or 3 [odds ratio (OR): 7.4, 95% confidence interval (CI): 1.4-33.3, P=0.01] and gamma-glutamyltransferase (GGT) levels <2 x ULN (upper limit of normal) (OR: 6.76, 95% CI: 1.5-31.3, P=0.009) were significantly associated with SVR. Multivariate logistic regression at week 4 showed that only baseline GGT <2 x ULN (OR: 7.3, 95% CI: 1.4-38.5, P=0.01) and RVR (OR: 15.6, 95% CI: 3.2-76.9, P<0.001) were independently predictive for SVR. CONCLUSION: Retreatment with PegIFN-alpha-2b and ribavirin for a minimum of 48 weeks should be considered in all patients unresponsive to previous IFN-based therapies. Baseline GGT values and RVR are highly predictive for retreatment outcome.

Veldt BJ, Hansen BE, Eijkemans MJ, de Knegt RJ, Stijnen T, Habbema JD, Schalm SW. · Department of Gastroenterology and Hepatology, Erasmus MC University Medical Centre Rotterdam, Rotterdam, The Netherlands. · Aliment Pharmacol Ther. · Pubmed #15740537 links to  free full text

Abstract: BACKGROUND: Current guidelines for stopping treatment of chronic hepatitis C are based on hepatitis C ribonucleic acid measurements at 12 and 24 weeks. AIM: To explore an alternative approach for making individualized recommendations about treatment duration, based on simple alanine aminotransferase tests and on cost-per-cure. METHODS: We analysed individual patient data from 13 randomized, controlled trials with interferon alone or combined with ribavirin. Using multiple logistic regression, we built a model that estimated the probability of sustained virological response for treatment durations of 24 and 48 weeks. Decisions to prolong treatment were based on an increase in probability of sustained virological response. If the increase was 10%, the cost-per-cure became decisive with a limit of 50,000. RESULTS: Noncirrhotics with genotype 2 or 3 did not benefit when treatment was continued beyond 24 weeks. Sustained virological response rates in cirrhotic patients increased by 14-47% if treatment was continued up to 48 weeks. In noncirrhotic genotype 1 or 4 patients who had elevated alanine aminotransferase levels at week 4, the probability of sustained virological response increased by <10% if treatment was continued up to 48 weeks; the cost-per-cure for these patients would exceed 50,000. CONCLUSION: The dynamics of alanine aminotransferase levels and cost-per-cure provides a useful alternative to determine the duration of therapy in chronic hepatitis C.

Bergmann JF, Slavenburg S, Roomer R, de Knegt RJ, Drenth JP. · No affiliation provided · Neth J Med. · Pubmed #18219071 links to  free full text

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de Knegt RJ, van den Berg AP. · No affiliation provided · N Engl J Med. · Pubmed #11794188 No free full text.

This publication has no abstract.