Hepatitis: Netherlands

Pan QW, Henry SD, Scholte BJ, Tilanus HW, Janssen HL, van der Laan LJ. · Erasmus MC-University Medical Centre, Department of Gastroenterology, Room L458, sGravendijkwal 230, 3015 CE, Rotterdam, The Netherlands. · World J Gastroenterol. · Pubmed #17724797 links to  free full text

Abstract: Hepatitis C virus (HCV) infection is one of the major causes of chronic liver disease, including cirrhosis and liver cancer and is therefore, the most common indication for liver transplantation. Conventional antiviral drugs such as pegylated interferon-alpha, taken in combination with ribavirin, represent a milestone in the therapy of this disease. However, due to different viral and host factors, clinical success can be achieved only in approximately half of patients, making urgent the requirement of exploiting alternative approaches for HCV therapy. Fortunately, recent advances in the understanding of HCV viral replication and host cell interactions have opened new possibilities for therapeutic intervention. The most recent technologies, such as small interference RNA mediated gene-silencing, anti-sense oligonucleotides (ASO), or viral vector based gene delivery systems, have paved the way to develop novel therapeutic modalities for HCV. In this review, we outline the application of these technologies in the context of HCV therapy. In particular, we will focus on the newly defined role of cellular microRNA (miR-122) in viral replication and discuss its potential for HCV molecular therapy.

Gutteling JJ, de Man RA, Busschbach JJ, Darlington AS. · Department of Gastroenterology and Hepatology, Erasmus Medical Centre, Rotterdam, the Netherlands. · Neth J Med. · Pubmed #17656809 links to  free full text

Abstract: Health-related quality of life (HRQoL) has become an important outcome measure in patients with chronic liver disease (CLD). In this article, an overview is given of the most common measurement instruments of HRQoL, determinants of HRQoL in patients with CLD, and current developments in the implementation of routine measurement of HRQoL in daily clinical practice. Well-developed generic instruments of HRQoL are the Short Form-36 (SF-36), the Nottingham Health Profile (NHP) and the Sickness Impact Profile (SIP). Well-developed liver disease-specific HRQoL instruments are the Hepatitis Quality of Life Questionnaire (HQLQ), the Chronic Liver Disease Questionnaire (CLDQ), the Liver Disease Quality Of Life Questionnaire (LDQOL ), and the Liver Disease Symptom Index 2.0 (LDSI 2.0). Commonly used HRQoL measures in cost-effectiveness studies are the Health Utilities Index (HUI), Short Form-6D (SF-6D) and the EuroQol-5D (EQ-5D). HRQoL of patients with chronic liver disease has been shown to be impaired, with patients with hepatitis C showing the worst HRQoL. Disease severity, pruritus, joint pain, abdominal pain, muscle cramps, fatigue, depression and anxiety have been associated with HRQoL in patients with CLD. Recently, studies assessing the feasibility and effectiveness of measuring HRQoL in daily clinical practice have been performed, generally showing positive results regarding the discussion of HRQoL-related topics, but mixed results regarding the added value of actual improvement in HRQoL. Furthermore, logistic and attitudinal barriers seem to impede successful implementation. Nevertheless, given the importance of HRQoL in liver patients, we should persist in measuring and subsequently improving HRQoL in clinical practice.

Scholing M, Schneeberger PM, van den Dries P, Drenth JP. · Department of Medical Microbiology and Infection Control, VU University Medical Center, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands. · Infection. · Pubmed #17646920 No free full text.

Abstract: Clinical features of liver involvement due to Listeria monocytogenes infection in adults are rarely reported in literature. This is surprising, regarding the current opinion that the portal system is extensively involved in the first stages of pathogenesis in invasive L. monocytogenes disease. A literature search in the PubMed and Embase database revealed 34 cases with clinical features of hepatic involvement due to listeriosis. We systematically analyzed all case reports with respect to clinical manifestations, treatment and outcome. In addition, we added clinical information on a patient diagnosed with a solitary liver abscess due to L. monocytogenes, who was seen at our institution. This review describes the different presentations of liver-involvement reported in listeriosis; solitary liver abscess, multiple liver abscesses and diffuse or granulomatous hepatitis. Distinction between these different forms of liver involvement is clinically relevant as they have a different outcome. We delve into the different pathogenic events leading to different forms of liver involvement. In addition, diagnostic modalities and possible treatments are reviewed.

Leemans WF, Janssen HL, de Man RA. · Department of Gastroenterology and Hepatology, Room H 437, Erasmus MC, University Medical Center Rotterdam's-Gravendijkwal 230, Rotterdam, The Netherlands. · World J Gastroenterol. · Pubmed #17552002 links to  free full text

Abstract: Chronic hepatitis B virus infection affects about 400 million people around the globe and causes approximately a million deaths a year. Since the discovery of interferon-alpha as a therapeutic option the treatment of hepatitis B has evolved fast and management has become increasingly complicated. The amount of viral replication reflected in the viral load (HBV-DNA) plays an important role in the development of cirrhosis and hepatocellular carcinoma. The current treatment modalities for chronic hepatitis B are immunomodulatory (interferons) and antiviral suppressants (nucleoside and nucleotide analogues) all with their own advantages and limitations. An overview of the treatment efficacy for both immunomodulatory as antiviral compounds is provided in order to provide the clinician insight into the factors influencing treatment outcome. With nucleoside or nucleotide analogues suppression of viral replication by 5-7 log(10) is feasible, but not all patients respond to therapy. Known factors influencing treatment outcome are viral load, ALT levels and compliance. Many other factors which might influence treatment are scarcely investigated. Identifying the factors associated with response might result in stopping rules, so treatment could be adapted in an early stage to provide adequate treatment and avoid the development of resistance. The efficacy of compounds for the treatment of mutant virus and the cross-resistance is largely unknown. However, genotypic and phenotypic testing as well as small clinical trials provided some data on efficacy in this population. Discontinuation of nucleoside or nucleotide analogues frequently results in viral relapse; however, some patients have a sustained response. Data on the risk factors for relapse are necessary in order to determine when treatment can be discontinued safely. In conclusion: chronic hepatitis B has become a treatable disease; however, much research is needed to tailor therapy to an individual patient, to predict the sustainability of response and determine the best treatment for those failing treatment.

Kok KF, Wahab PJ, Houwen RH, Drenth JP, de Man RA, van Hoek B, Meijer JW, Willekens FL, de Vries RA. · Department of Hepato-Gastroenterology, Rijnstate Hospital, Arnhem, the Netherlands. · Neth J Med. · Pubmed #17519511 links to  free full text

Abstract: Alpha-I antitrypsin (AIAT) is an acute-phase protein that is produced in liver cells. AIAT deficiency is a hereditary disease which is defined by the hepatic production of an abnormal protein that can not be released into the plasma. This leads to deficiency of plasma AIAT and subsequently to an impaired protection against proteases, resulting in pulmonary disease. Accumulation of the abnormal protein in hepatocytes can lead to liver damage. Serum level measurement, phenotyping and liver biopsy can be used for establishing the diagnosis. Homozygous AIAT deficiency can cause neonatal hepatitis; in adults end-stage liver disease, cirrhosis and hepatocellular carcinoma can develop. There are strong arguments to consider heterozygous AIAT deficiency as an important co-factor in the aetiology of chronic liver disease. Studies have shown that AIAT heterozygosity can be considered a modifier for hepatitis C virus, end-stage liver disease, cirrhosis and hepatocellular carcinoma. The accumulation of AIAT in the hepatocytes occurs more profoundly in a diseased liver, and as a consequence it affects the natural course of the liver disease. Therapeutic options include augmentation therapy (infusion of purified human plasma AIAT) in pulmonary disease; in end-stage liver disease liver transplantation is an option. For the future, other interventions such as gene therapy or strategies to inhibit polymerisation are promising.

Boot HJ, Schouls L, Hahné S, Berbers GA, van de Laar M, Kimman TG. · Rijksinstituut voor Volksgezondheid en Milieu (RIVM), Centrum Infectieziektebestrijding (CIb), Postbus i, 3720 BA Bilthoven. · Ned Tijdschr Geneeskd. · Pubmed #17288341 No free full text.

Abstract: All infants in the Netherlands, which are born after March 2006, receive additional vaccinations at the age of 2, 3, 4 and 11 months to protect them against pneumococcal infections. During the same visit to a consultation bureau, the children also receive a combination vaccine against diphtheria, pertussis, tetanus, poliomyelitis and Haemophilus influenzae (DTPa-IPV-Hib). Children of which at least one parent was born in a country where hepatitis B occurs relatively often are also vaccinated in the Netherlands against hepatitis B. This currently pertains to about 15% of all newborns. These children now receive a new combination vaccine in which a hepatitis B component has been added to the DTPa-IPV-Hib components. They will receive this combination vaccine 4 times. This combination vaccine is given during the same visit as the pneumococcal vaccination. Although pneumococcal vaccination may have a somewhat negative effect on the immune response to hepatitis B, it is expected that the new 4-fold vaccination schedule will induce good and long-lasting protection against hepatitis B in the vast majority of the children. About 700 children are born out of mothers infected with hepatitis B each year in the Netherlands. In the new vaccination schedule, they now receive 5 active vaccinations against hepatitis B and are examined serologically on an individual basis in order to detect breakthrough infections. This will also generate greater insight into the efficacy of the different vaccination schemes and intervention programmes to prevent vertical transmission of the virus.

Buis CI, Hoekstra H, Verdonk RC, Porte RJ. · Section of Hepatobiliary Surgery and Liver Transplantation, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. · J Hepatobiliary Pancreat Surg. · Pubmed #17139425 No free full text.

Abstract: Biliary complications are a major source of morbidity, graft loss, and even mortality after liver transplantation. The most troublesome are the so-called ischemic-type biliary lesions (ITBL), with an incidence varying between 5% and 15%. ITBL is a radiological diagnosis, characterized by intrahepatic strictures and dilatations on a cholangiogram, in the absence of hepatic artery thrombosis. Several risk factors for ITBL have been identified, strongly suggesting a multifactorial origin. The main categories of risk factors for ITBL include ischemia-related injury; immunologically induced injury; and cytotoxic injury, induced by bile salts. However, in many cases no specific risk factor can be identified. Ischemia-related injury comprises prolonged ischemic times and disturbance in blood flow through the peribiliary vascular plexus. Immunological injury is assumed to be a risk factor based on the relationship of ITBL with ABO incompatibility, polymorphism in genes coding for chemokines, and pre-existing immunologically mediated diseases such as primary sclerosing cholangitis and autoimmune hepatitis. The clinical presentation of patients with ITBL is often not specific; symptoms may include fever, abdominal complaints, and increased cholestasis on liver function tests. Diagnosis is made by imaging studies of the bile ducts. Treatment starts with relieving the symptoms of cholestasis and dilatation by endoscopic retrograde cholangiopancreaticography (ERCP) or percutaneous transhepatic cholangiodrainage (PTCD), followed by stenting if possible. Eventually up to 50% of the patients with ITBL will require a retransplantation or may die. In selected patients, a retransplantation can be avoided or delayed by resection of the extra-hepatic bile ducts and construction of a hepaticojejunostomy. More research on the pathogenesis of ITBL is needed before more specific preventive or therapeutic strategies can be developed.

Smink F, van Hoek B, Ringers J, van Altena R, Arend SM. · Department of Infectious Diseases, Leiden University Medical Centre, Leiden, the Netherlands. · Neth J Med. · Pubmed #17122456 links to  free full text

Abstract: Hepatotoxicity is a well-known side effect of antituberculosis treatment (ATT). If not recognised in time, drug-induced hepatitis can develop, which may rapidly progress to acute liver failure. We describe two patients with acute hepatic failure caused by ATT, whose pretreatment liver function had been normal. Both patients successfully underwent liver transplantation. Possible risk factors predisposing towards ATT-induced hepatic failure were evaluated, and at least four risk factors were present in these patients. Although available guidelines do not advocate routine monitoring of liver function during ATT unless baseline values are elevated or in the case of pre-existent liver disease, this is nevertheless common practice. Liver function should always be measured in patients who develop symptoms during ATT, and rising liver function parameters should prompt immediate action to prevent the occurrence of liver failure. This report underscores that regular monitoring of liver function parameters and adherence to guidelines is especially important in patients with risk factors for ATT-induced liver disease. An evaluation of chronic viral hepatitis in risk groups before starting ATT could be worthwhile.

Posthouwer D, Mauser-Bunschoten EP, Fischer K, Makris M. · Van Creveldkliniek, University Medical Center, Utrecht, The Netherlands. · Haemophilia. · Pubmed #16919076 No free full text.

Abstract: Chronic hepatitis C is a major cause of morbidity and mortality in haemophilia patients. In contrast to studies in the general population, the studies of antiviral therapy in haemophilia patients are limited and often include small numbers of patients. A review of the literature was performed to assess the efficacy of interferon (IFN)-based therapy for patients with haemophilia chronically infected with hepatitis C virus (HCV). Studies were identified by electronic searches (Medline, Embase) and hand searches in references of key articles. Data of the included studies were pooled, and responses to therapy were stratified according to treatment regimen, HIV co-infection status, and treatment history. The main outcome was a sustained virological response (SVR) defined as absence of HCV RNA both at the end of treatment and 24-week post-treatment. Thirty-five studies were identified that included 1151 patients. After pooling the data of included patients, the SVR in HIV-negative treatment naïve patients was 22% for IFN monotherapy, 43% for IFN and ribavirin, and 57% for pegylated IFN and ribavirin, respectively. Re-treatment with IFN and ribavirin of those who failed to respond to previous IFN monotherapy was successful in 33%. In HCV/HIV-coinfected patients, response to IFN monotherapy was 8% and to IFN combined with ribavirin 39%. Responses to IFN-based therapy in patients with haemophilia have been improved over time and are nowadays approximately 50-60%. However, data on haemophilic HCV/HIV-coinfected patients and in patients who failed to respond to previous therapy are limited and future studies in these specific patient population are necessary.

Buster EH, Janssen HL. · Department of Gastroenterology and Hepatology (CA 326), Erasmus Medical Centre, University Medical Centre Rotterdam, Rotterdam, the Netherlands. · Neth J Med. · Pubmed #16788215 links to  free full text

Abstract: 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.

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.

van Erpecum KJ. · Department of Gastroenterology, University Hospital Utrecht, The Netherlands. · Scand J Gastroenterol Suppl. · Pubmed #16782626 No free full text.

Abstract: Liver cirrhosis is a frequent phenomenon in chronic liver diseases such as hepatitis B, hepatitis C, alcohol-related liver damage, autoimmune hepatitis and hemochromatosis. Ascites is the most frequent complication of cirrhosis. We discuss pathogenesis, diagnosis and state-of-the-art clinical management of ascites with emphasis on recent promising developments, such as covered transjugular intrahepatic portosystemic shunt (TIPS). Spontaneous bacterial peritonitis occurs in up to 10% of patients with ascites because of bacterial overgrowth with translocation through the increased permeable small intestinal wall and impaired defence mechanisms. The addition of albumin to standard antibiotic therapy may decrease mortality of spontaneous bacterial peritonitis by decreasing the incidence of renal insufficiency. Patients with coexistent marked hyperbilirubinaemia or pre-existent renal impairment could benefit from adjuvant albumin. Probiotics (bacterial food supplements) have been claimed to improve the state of underlying liver disease and may be useful in the primary and secondary prevention of spontaneous bacterial peritonitis.

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.

Haasnoot J, Berkhout B. · Department of Human Retrovirology, Academic Medical Centre, University of Amsterdam, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands. · Handb Exp Pharmacol. · Pubmed #16594614 No free full text.

Abstract: RNA interference (RNAi) is a sequence-specific gene-silencing mechanism that has been proposed to function as a defence mechanism of eukaryotic cells against viruses and transposons. RNAi was first observed in plants in the form of a mysterious immune response to viral pathogens. But RNAi is more than just a response to exogenous genetic material. Small RNAs termed microRNA (miRNA) regulate cellular gene expression programs to control diverse steps in cell development and physiology. The discovery that exogenously delivered short interfering RNA (siRNA) can trigger RNAi in mammalian cells has made it into a powerful technique for generating genetic knock-outs. It also raises the possibility to use RNAi technology as a therapeutic tool against pathogenic viruses. Indeed, inhibition of virus replication has been reported for several human pathogens including human immunodeficiency virus, the hepatitis B and C viruses and influenza virus. We reviewed the field of antiviral RNAi research in 2003 (Haasnoot et al. 2003), but many new studies have recently been published. In this review, we present a complete listing of all antiviral strategies published up to and including December 2004. The latest developments in the RNAi field and their antiviral application are described.

Niesters HG, Pas S, de Man RA. · Department of Virology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands. · J Clin Virol. · Pubmed #16461222 No free full text.

Abstract: Characterization results of the hepatitis B virus (HBV) genome before, during and after antiviral treatment have changed in the last year for a number of reasons. First of all, with the introduction of more nucleoside and nucleotide antiviral therapies, it has become clear that variants or mutants do emerge in time. Viral genomic changes in the HBV polymerase gene can result in a direct antiviral effect, but compensatory mutations can also be identified during prolonged treatment periods. Furthermore, there is an increasing number of reports suggesting that HBV genotypes can be related to, for example, disease progression or the effect of antiviral treatment itself (alpha-interferon or lamivudine). Combined with HBV DNA viral load monitoring, an increase in viral load or a limited reduction during treatment is indicative of genomic changes related to resistance. However, these genomic changes can also be present in the absence of an increase in HBV DNA. Methodologies for the detection of these variants, as well as the determination of genotypes, are rather straightforward. Sequence analysis is time-consuming and expensive, but provides the most information, particularly if not all information on mutations related to antiviral resistance is known. However, the sensitivity of direct sequencing for the presence of minor variant populations is poor, and no mixtures of variant populations are, in general, detected. The ability to detect minor populations and, if possible, even quantify them, gives more insightful information on the dynamic evolution of the virus itself. Antiviral treatment can result in the appearance of more than one population of variants, which can be present for a prolonged period of time, and even remain undetected with current technologies. However, screening specifically for these variant populations before starting treatment for so-called untreated patients (who have received no antiviral treatment for, e.g., 6 months) has already shown that the effects of treatment can be biased. Furthermore, the detection of more dynamic viral populations - including both wild-type and resistant variants - during, but also after therapy, does provide helpful information in the analysis of virological data. Technologies enabling the detection and quantification of these variant populations are presented and discussed.

Moorer WR. · Department of Cariology, Endodontology, Pedodontology, Academic Center for Dentistry, Amsterdam, the Netherlands. · Int J Dent Hyg. · Pubmed #16451513 No free full text.

Abstract: Bacteria and viruses from the patient's mouth travel with dental splatter and spills. A surface disinfectant should possess antiviral activity as well as antibacterial action. Because of frequent and 'open' application in the dental office, such a disinfectant should be non-toxic, non-allergenic and safe for the hygienist. It now appears that high-concentration alcohol mixtures (i.e. 80% ethanol + 5% isopropanol) are not only excellent antibacterials, but quickly inactivate HIV as well as hepatitis B and hepatitis C viruses. Compared to alternative surface disinfectants, use of high-concentration alcohol for the spray-wipe-spray method of surface disinfection in dentistry appears safe and efficient. However, dried matter should be wiped and hydrated first.

Rietmeijer CB, Boot CR, Rietmeijer CA, Vonk P, Meijman FJ. · Universiteit van Amsterdam, Bureau Studentenartsen, Oude Turfmarkt GC Amsterdam. · Ned Tijdschr Geneeskd. · Pubmed #16398172 No free full text.

Abstract: OBJECTIVE: To gain insight into the rate of immunization for hepatitis B and the status of infectious-disease prevention among Dutch medical students working in areas where HIV is endemic. Additionally, to provide an overview of the preparedness of medical schools in the Netherlands to collaborate in the development of a collective occupational disability insurance for their students. DESIGN: Literature review and survey. METHOD: A questionnaire was sent to all 8 Dutch medical schools in 2003 and a follow-up telephone interview was conducted in July 2005. The results of this survey were compared with the international scientific literature, which was systematically searched using PubMed, Web of Science and Picarta up to and including March 2005. RESULTS: There was a great deal of international variation in the proven degree of immunization against hepatitis B. Infectious-disease prevention measures for students on rotation in HIV-endemic areas left much to be desired. Occupational-disability insurance for students who started their clinical rotations was described, particularly in the United States, but details on participation and costs were lacking. In 2003 there were considerable differences between medical schools in the Netherlands regarding hepatitis-B immunization. However, in 2005, all schools reported the implementation of a new national hepatitis-B immunization protocol. Compared to 2003, most schools reported higher safety standards for electives in HIV-endemic areas and post-exposure prophylaxis was more frequently made available at no cost. Individual preparation for these electives still occurred infrequently. None of the medical schools were pursuing a policy of providing occupational disability insurance for students from the beginning of their clinical rotations.

van der Eijk AA, de Man RA, Niesters HG, Schalm SW, Zaaijer HL. · Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, the Netherlands. · J Viral Hepat. · Pubmed #16364075 No free full text.

Abstract: Different guidelines exist for the management of hepatitis B virus (HBV)-infected health care workers (HCWs). Various HBV DNA levels are used as a cutoff level to determine whether an HBV-infected HCW is allowed to perform exposure-prone procedures (EPPs) or not. In this paper we discuss the factors that determine HBV DNA levels and the implications of different HBV DNA cutoff levels for EPP performing HCWs. If the level of HBV DNA in the serum of HCWs is used to determine acceptability for the conduct of EPPs, it is necessary to take into account the variability in time of HBV DNA levels in HBV carriers and the reliability and reproducibility of the molecular diagnostic test involved. The issue of standardization has to be addressed, before a universal, maximum level of viraemia for EPP performing HCWs can be introduced.

Arends JE, Boucher CA, Hoepelman AI. · Department of Internal Medicine and Infectious Diseases, Utrecht University Medical Centre, The Netherlands. · Neth J Med. · Pubmed #15952483 links to  free full text

Abstract: Both human immunodeficiency virus (HIV) and hepatitis C (HCV) are globally infecting millions of people. Since these viruses are both transmitted through blood-blood contact the rate of coinfection is as high as 30% and among i.v. drug users in the Western world 70%. In The Netherlands, 8% of HCV-infected patients are coinfected with HIV. After the successful introduction of antiretroviral therapy (HAART) the survival of patients with HIV has increased considerably. Coinfection leads to accelerated progression of liver cirrhosis and liver failure but conflicting evidence exists about the effect of HCV on the natural course of HIV. Four randomised controlled trials have shown that treatment with pegylated interferon plus ribavirin leads to an overall sustained viral response (SVR) rate between 27 and 44%. Divided by genotype the SVR is between 14 and 38% in genotype 1 (and 4) while between 53 and 73% for genotype 2 and 3. These percentages are calculated based on an intention-to-treat analysis. Although lower than in HCV-monoinfected patients this is much higher than achieved with conventional interferon. However, coinfected patients with genotypes 2 and 3 also need to be treated for 48 weeks in contrast to monoinfected patients. As the number and severity of side effects is low, coinfected patients now have a substantially better option for treatment.

Kappelhoff BS, Huitema AD, Beijnen JH. · Department of Pharmacy and Pharmacology, Slotervaart Hospital, Louwesweg 6, 1066 EC Amsterdam, The Netherlands. · Drugs R D. · Pubmed #15777100 No free full text.

Abstract: In the treatment of HIV-infected patients, an urgent need exists for more conveniently dosed and better tolerated regimens with improved virological and immunological efficacy. Based on preclinical studies, the combination of two non-nucleoside reverse transcriptase inhibitors (NNRTIs) was considered to fulfill this. Several clinical studies, however, have shown different results with regard to mechanism of action, pharmacokinetics, efficacy and toxicity of dual NNRTI regimens. Combinations of two NNRTIs have shown additive or synergistic inhibitory effects on the HIV-1 reverse transcriptase activity and the viral replication of HIV-1 in vitro, although antagonistic effects have also been described. When nevirapine and efavirenz were administered in combination, the exposure to efavirenz was decreased due to induction of metabolism by nevirapine. When compared with single NNRTI regimens, dual NNRTI regimens showed similar but not superior results with regard to virological and immunological success in treatment-naive and pretreated HIV-1-infected patients. However, NNRTI-associated adverse events, such as clinical hepatitis, elevated liver enzymes, rash, central nervous system toxicity and psychiatric disorders, occurred more frequently when two NNRTIs were administered concomitantly.In conclusion, regimens with both nevirapine and efavirenz seem to result in similar antiviral and immunological efficacy with an increased incidence of adverse events compared with single NNRTI regimens. The combination of two NNRTIs is therefore less desirable than other available and effective treatment options.

de Boer NK, van Nieuwkerk CM, Aparicio Pages MN, de Boer SY, Derijks LJ, Mulder CJ. · Dept of Gastroenterology and Hepatology, VU University Medical Center, Amsterdam, The Netherlands. · Eur J Gastroenterol Hepatol. · Pubmed #15756101 No free full text.

Abstract: The use of corticosteroids in autoimmune hepatitis is an established therapy. To avoid the possible serious side effects of corticosteroids, immunosuppression with azathioprine is often warranted. Azathioprine, a purine analogue, is frequently used to taper or replace corticosteroids. However, approximately 10% of the patients are intolerant to azathioprine. Alternative therapies using mycophenolate, tacrolimus, budesonide, cyclosporine and 6-mercaptopurine have been studied, with variable results. The use of 6-thioguanine, an agent more directly leading to the down-stream active metabolites of azathioprine (6-thioguanine nucleotides) in inflammatory bowel disease patients intolerant to azathioprine or 6-mercaptopurine showed conflicting results. We report three patients with autoimmune hepatitis who could not tolerate azathioprine but tolerated 6-thioguanine 0.3 milligram per kilogram daily well. All three patients improved clinically. Therapeutic drug monitoring was performed. The prospective evaluation of 6-thioguanine as a possible immunosuppressive drug in autoimmune hepatitis patients is warranted.

Jansen PL. · Academisch Medisch Centrum/Universiteit van Amsterdam, afd. Maag-, Darm- en Leverziekten, Levercentrum, Meibergdreefg, 1105 AZ Amsterdam. · Ned Tijdschr Geneeskd. · Pubmed #15730035 No free full text.

Abstract: Nonalcoholic steatohepatitis and chronic viral hepatitis C are the two dominant liver diseases in the Netherlands. Hepatic steatosis is usually innocuous but in twenty percent of patients it develops into steatohepatitis. One-fifth of these patients develop liver cirrhosis and hepatocellular carcinoma can also be a consequence of the disease. Nonalcoholic steatohepatitis is characterized by macrovesicular steatosis, necroinflammation, loss ofhepatocytes and fibrosis. Nonalcoholic steatohepatitis often is associated with type 2 diabetes mellitus, hypertension, dyslipoproteinemia and obesity. Insulin resistance plays a major role in the pathogenesis of this disease. Drugs against insulin resistance can ameliorate nonalcoholic steatohepatitis. Gradual weight loss, a diet including polyunsaturated fatty acids and exercise are other important treatment components of this condition.

van Hoek B. · Dept. of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands. · Scand J Gastroenterol Suppl. · Pubmed #15696851 No free full text.

Abstract: The term 'non-alcoholic fatty liver disease' (NAFLD) includes cases with steatosis alone and those with non-alcoholic steatohepatitis (NASH). Usually there are no signs or symptoms, sometimes fatigue or pain, and apart from hepatomegaly the condition is revealed by abnormal liver biochemistry or by abdominal ultrasound. Most cases are associated with overweight or diabetes. Liver enzymes are usually elevated, especially GGT, ASAT and ALAT. Other conditions, including alcohol abuse and autoimmune hepatitis, have to be excluded. The diagnosis of steatosis can be made with ultrasound or CT scan. A liver biopsy is often needed to exclude other disease and to assess inflammation and fibrosis. Cirrhosis can develop. NAFLD is usually caused by two 'hits': the 'first hit' is peripheral insulin resistance, causing steatosis. The 'second hit' is caused by reactive oxygen species, inducing vicious cycles leading to inflammation. Weight loss, metformin or thiazolidinediones can improve NAFLD by increasing insulin sensitivity. Radical scavengers such as vitamin E, betaine and perhaps also urodeoxycholic acid may improve the hepatitis component. Further studies on treatment are needed.

Buster EH, van der Eijk AA, de Man RA, Schalm SW. · Dept. of Gastroenterology & Hepatology, Erasmus MC, University Medical Center Rotterdam, The Netherlands. · Scand J Gastroenterol Suppl. · Pubmed #15696849 No free full text.

Abstract: Hepatitis B virus (HBV)-infected health-care workers (HCWs) have infected patients during medical procedures. In many countries HBV-infected HCWs are restricted in performing exposure prone procedures based on either HBeAg status or serum HBV DNA level. To prevent loss of skilled HCWs and to minimize transmission risk, highly viraemic HCWs can be offered antiviral therapy. Nucleoside analogues have proven to be effective in reducing transmission of HIV and HBV in the setting of vertical mother-to-infant transmission. Following the same rationale, suppression of viral load in HBV-infected HCWs could minimize the risk of doctor-to-patient transmission to such an extent that job modifications are no longer indicated. To limit the risk of drug resistance, the use of combination therapy is advocated. We describe two chronic HBV-infected HCWs treated with antiviral therapy, eventually leading to well-tolerated and highly effective combination therapy with lamivudine and tenofovir, with continuation of medical practice.

Schiepers OJ, Wichers MC, Maes M. · Department of Psychiatry and Neuropsychology, Maastricht University, P.O. BOX 616, 6200 MD Maastricht, The Netherlands. · Prog Neuropsychopharmacol Biol Psychiatry. · Pubmed #15694227 No free full text.

Abstract: In the research field of psychoneuroimmunology, accumulating evidence has indicated the existence of reciprocal communication pathways between nervous, endocrine and immune systems. In this respect, there has been increasing interest in the putative involvement of the immune system in psychiatric disorders. In the present review, the role of proinflammatory cytokines, such as interleukin (IL)-1, tumour necrosis factor (TNF)-alpha and interferon (IFN)-gamma, in the aetiology and pathophysiology of major depression, is discussed. The 'cytokine hypothesis of depression' implies that proinflammatory cytokines, acting as neuromodulators, represent the key factor in the (central) mediation of the behavioural, neuroendocrine and neurochemical features of depressive disorders. This view is supported by various findings. Several medical illnesses, which are characterised by chronic inflammatory responses, e.g. rheumatoid arthritis, have been reported to be accompanied by depression. In addition, administration of proinflammatory cytokines, e.g. in cancer or hepatitis C therapies, has been found to induce depressive symptomatology. Administration of proinflammatory cytokines in animals induces 'sickness behaviour', which is a pattern of behavioural alterations that is very similar to the behavioural symptoms of depression in humans. The central action of cytokines may also account for the hypothalamic-pituitary-adrenal (HPA) axis hyperactivity that is frequently observed in depressive disorders, as proinflammatory cytokines may cause HPA axis hyperactivity by disturbing the negative feedback inhibition of circulating corticosteroids (CSs) on the HPA axis. Concerning the deficiency in serotonergic (5-HT) neurotransmission that is concomitant with major depression, cytokines may reduce 5-HT levels by lowering the availability of its precursor tryptophan (TRP) through activation of the TRP-metabolising enzyme indoleamine-2,3-dioxygenase (IDO). Although the central effects of proinflammatory cytokines appear to be able to account for most of the symptoms occurring in depression, it remains to be established whether cytokines play a causal role in depressive illness or represent epiphenomena without major significance.