Antiviral treatment for chronic hepatitis B virus infection--immune modulation or viral suppression?

The availability of nucleoside analogues has broadened treatment options for chronic hepatitis B virus (HBV ) infection. Registered treatment for chronic hepatitis B currently consists of (pegylated) interferon, lamivudine and adefovir, while entecavir is expected to be licensed in the short term. Treatment is generally recommended for patients with high serum HBV DNA and elevated ALAT, indicating the host's immune response against HBV. Induction of an HBV -specific immune response seems crucial for persistent control of HBV infection. Currently available treatment strategies can be differentiated into those that provide sustained off-treatment response and those that provide therapy maintained response. A finite treatment course with immunomodulatory agents (interferon-based therapy) results in sustained response in about one third of patients, while nucleoside analogue treatment generally requires indefinite therapy without a clear stopping point. Since nucleoside analogues are well tolerated, prolonged therapy is feasible, but a major drawback is the considerable risk of developing antiviral resistance, which occurs most frequently in lamivudine treated patients and to a lesser extent during adefovir or entecavir therapy. In our opinion, treatment with peginterferon should therefore be considered first-line therapy in eligible patients with a high likelihood of response based on serum HBV DNA, ALAT and HBV genotype. Patients not responding to PEG-IF N therapy or not eligible for peginterferon therapy should be treated with nucleos(t)ide analogues

New approaches in the management of chronic hepatitis B: role of tenofovir

In the field of HIV management, tenofovir disoproxil fumarate (TDF) plays a pivotal role and has been demonstrated to be a safe and well-tolerated antiviral agent. Recent data showed the efficacy of TDF in the treatment of chronically hepatitis B virus (HBV)-infected patients. TDF was superior to adefovir dipivoxil (ADV) in both nucleos(t)ide-naïve HBeAg-positive and HBeAg-negative HBV patients, and appeared to be one of the most potent antiviral agents so far. In addition, several reports showed that TDF was also effective in the nucleos(t)ide-experienced population, although conflicting results have been presented concerning patients with genotypic resistance to ADV. TDF seems to have a good resistance profile as well. The rtA194T mutation in association with lamivudine resistance may confer resistance to TDF, although both in vivo and in vitro studies regarding this mutation demonstrate conflicting results. As treatment with TDF may be associated with nephrotoxicity, all TDF-treated patients should be monitored for renal function at baseline and periodically thereafter. While the relative roles of interferon vs nucleos(t)ide analogues (NA) as initial anti-HBV therapy remains unclear, TDF will probably become one of the key factors in HBV management both as first-choice NA for nucleos(t)ide-naïve patients and as rescue therapy for nucleos(t)ide-experienced patients

Clinical and virological studies on α-interferon treatment of chronic hepatitis type B

The positive results of a-interferon (IFN) therapy have generated an important change in the therapeutic approach of chronic hepatitis B patients. The studies presented in this thesis are directed to the question how the efficacy of a-IFN therapy for chronic hepatitis B could be improved (chapter 1). In particular we investigated whether patient selection, modification of the treatment schedule and new virological assessments could contribute to answer this question. For optimal management of the HBV-infected patients it is important to defme indications for new treatment modalities as a-IFN and liver transplantation. We followed a cohort of 98 patients with HBsAg-positive cirrhosis and determined which variables influenced the survival (chapter 2). High age, the presence of ascites and a high serum bilirubin level were indepently associated with a short duration survival. For the group with a compensated cirrhosis HBeAg-negative patients exhibited a significantly better prognosis than HBeAg-positive patients. In contrast we could not fmd a difference in survival in decompensated patients with a different HBeAg status. These fmdings suggest that there is an indication for antiviral therapy for patients with a compensated hepatitis B cirrhosis and active viral replication (HBeAg positive) whereas liver transplantation appears the major therapeutic option for patients with a decompensated chronic hepatitis B infection. The standard course of a-IFN therapy for chronic hepatitis B lasts 16 weeks and leads in about one third of the patients to cessation of virus replication. Intermittent a-IFN therapy of 24 weeks duration and prolongation of treatment in patients who already exhibited a partial response (HBV-DNA negative) could enhance the HBeAg serocvonversion rate (chapter 3). Another modification of the standard a-IFN treatment is combination therapy with zidovudine. In a randomized controlled study (chapter 4) we found that this combination was not more effective than a-IFN monotherapy. In patients treated with the combination of a-IFN and zidovudine side effects, in particular anemia and leucopenia, were more prominent than in those treated with a-IFN and placebo. In chapter 5 the benefit of a-IFN retreatment in chronic hepatitis B patients who previously failed to respond was evaluated. A response (HBeAg seroconversion) to therapy occurred in 2 of the 18 (11 %) investigated patients. This response rate may be comparable to the spontaneous HBeAg seroconversion incidence and therefore the efficacy of a-IFN retreatment in chronic hepatitis B appears limited. Variables with a known predictive value towards response for initial a-IFN courses (e.g. the level of inflammatory acitvity) did not influence the result of the retreatment

Business Architectures in the Public Sector: Experiences from Practice

Government agencies need to transform the way in which they are organized in order to be able to provide better services to their constituents and adapt to changes in legislation. Whereas much e-government research has a technology focus, our goal is to investigate whether business architectures can help governments to recreate agencies to make them robust in dealing with political preferences, and further, whether their adoption can guide the realization of IT-oriented enterprise architectures. In this article the concept of business architecture and its implications are analyzed by investigating the case study of the Dutch Immigration and Naturalization Services. The case demonstrates the mediating role business architectures can play between policy and strategy on the one hand, and enterprise IT architecture on the other. Business architectures help: (1) to define business domains and the events connecting them, and (2) to use principles to integrate the domains and ensure synergies. Business domains can be designed and operated independently, which enable higher levels of adaptability. Our case analyses show that the pluriformity of the political visions, public values, and actors involved and the division of responsibilities complicate the creation of a business architecture

Baseline anti-NS4a antibodies in combination with on-treatment quantitative HCV-RNA reliably identifies nonresponders to pegylated interferon-ribavirin combination therapy after 4 weeks of treatment

Background Early detection of nonresponders to hepatitis C therapy limits unnecessary exposure to treatment and its side-effects. A recent algorithm combining baseline anti-NS4a antibodies and on-treatment quantitative PCR identified nonresponders to a combination of interferon and ribavirin after 1 week of treatment. Aim To validate a stopping rule based on baseline anti-NS4a antibody levels and early on-treatment virological response in treatment-naive genotype 1 chronic hepatitis C patients treated with the current standard pegylated interferon and ribavirin combination therapy. Methods Eighty-nine genotype 1 patients from the Dynamically Individualized Treatment of hepatitis C Infection and Correlates of Viral/Host dynamics Study treated for 48 weeks with standard 180 mu g pegylated interferon (PEG-IFN)-alpha-2a (weekly) and ribavirin 1000-1200mg (daily) were analysed. Baseline anti-NS4a antibody enzyme-linked immunosorbent assay (NS4a AA 1687-1718) was performed on pretreatment serum. Hepatitis C virus-RNA was assessed at days 0, 1, 4, 7, 8, 15, 22, 29, weeks 6, 7, 8, 10, 12 and 6 weekly thereafter until end of treatment. Multiple regression logistic analysis was performed. Results Overall 54 of 89 (61%) patients achieved sustained virological response. A baseline anti-NS4a antibody titre less than 1/1250 correlated with absence of favourable initial viral decline according to variable response types (P=0.015). The optimal algorithm was developed using the combination of the absence of anti-NS4a Ab (= 100.000 IU/ml at week 4. This algorithm has a specificity of 43% and negative predictive value of 100% to detect nonresponse to standard PEG-IFN-alpha-2a and ribavirin therapy at fourth week of therapy (intention-to-treat analysis). Conclusion The decision to stop the therapy in genotype 1 chronic hepatitis C patients treated with PEG-IFN-alpha-2a and ribavirin can be confidently made after 4 weeks of treatment based on the absence of baseline anti-NS4a Ab and a week-4 hepatitis C virus-RNA above 100.000 IU/ml. Eur J Gastroenterol Hepatol 22:1443-1448 (C) 2010 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins

A Nation-wide ePortfolio:Reflections on Ambitions and Experiences in the Netherlands

Janssen, J., Brouns, F., Vaessen, H., Weijnen, G., Huveneers, E., & Hodzelmans, R. (2011). A Nation-wide ePortfolio: Reflections on Ambitions and Experiences in the Netherlands. In Proceedings of the ePortfolio and Identity Conference (ePIC) 2011 (pp. 191-196). July, 10-12, 2011, London, UK. For the presentation, please see also: http://hdl.handle.net/1820/3436In the Netherlands 2008 stands out as a year of significant boosts for nation wide adoption of e-portfolios. In that year the Netherlands Institute for Normalisation (NEN) published the first version of a National Technical Agreement (NTA 2035) for the exchange of e-portfolios using an application profile based on (among others) the IMS ePortfolio specification. In that same year two important government advisory committees on employment and the labour market recommended nationwide adoption of e-portfolios as an instrument to assess and stimulate personal professional development and to increase mobility. In this paper we reflect on the current state of affairs from three different perspectives: a recent study investigating means to accelerate adoption of the NTA 2035, the Service Centre for Lifelong Learning Limburg project which aims to deploy the NTA, and current provision of software supporting the NTA.Service Center Leven Lang Leren Limbur

Temporal trends and spatial variation in stage distribution of non-small cell lung cancer in the Netherlands

Introduction To explore regional and temporal variation in clinical stage distribution of non-small cell lung cancer (NSCLC) and link the observations to the introduction of positron emission tomography (PET). Method All NSCLC patients diagnosed between 1989 and 2007 were selected from the Netherlands Cancer Registry (n=126,962). Maps of smoothed percentage distribution of clinical stage NSCLC were conducted by period of diagnosis. Join point regression analyses were performed to detect trends over time. Geographic variation in stage distribution was evaluated using spatial scan statistic. To evaluate the impact of PET in regions proportions of stage IV and Estimated Annual Percentage of Change (EAPC) were calculated for two regions in which PET was introduced between 1995 and 2000 and for two regions without a PET scanner during this period. Results The percentage of stage I and unknown decreased with 7.4% and 13.3% between 1989 and 2007, while the percentage of stage IV increased with 23.4%. The most rapid increase in stage I and IV were observed between 1997 and 2003. In two regions with a PET scan the proportion of stage IV increased annually with 10.3 and 8.5% compared to 5.4 and 6.4% in two regions without a PET scan. Conclusion The most rapid changes towards more stage IV NSCLC diagnoses correspond with the implementation of PET. However, trends were already visible before PET was introduced and regions without PET also showed considerable increases in stage IV diagnose, suggesting other factors or improvements in diagnostics also contributed substantially