Hepatitis: de Man RA

de Man RA, van der Eijck A, Veldhuijzen I. · Erasmus MC, University Medical Center Rotterdam, Department of Gastroenterology & Hepatology, The Netherlands. · Adv Exp Med Biol. · Pubmed #18193658 No free full text.

This publication has no abstract.

Leemans WF, Ter Borg MJ, de Man RA. · Department of Gastroenterology & Hepatology, Erasmus Medical Center, University Medical Center, Rotterdam, The Netherlands. · Aliment Pharmacol Ther. · Pubmed #18081660 No free full text.

Abstract: BACKGROUND: Strong suppression of viral replication and normalization of alanine aminotransferase is feasible with nucleos(t)ide analogues. It is estimated viral replication and liver inflammation can be controlled in 90% of patients with chronic hepatitis B with the current available treatments. AIM: To review the studies currently available on the management of chronic hepatitis B with nucleos(t)ide analogues. RESULTS: Although very potent, nucleos(t)ide analogues are not effective in every patient. Some factors are known to influence treatment outcome, but many host and viral factors are still unknown. Stopping rules have to be defined to assess treatment efficacy in an early stage and change the regimen. Discontinuation of nucleos(t)ide analogues is often followed by reactivation of HBV. Data on the risk factors for relapse are necessary in order to decide if treatment can be safely discontinued. Another major drawback of nucleos(t)ide analogues is the emergence of resistance. The efficacy of compounds for the treatment of mutant virus and the impact of cross-resistance is largely unknown. The use of combination therapy to prevent resistance looks promising, but has to be proven. CONCLUSIONS: HBV has become a treatable disease, however much research is needed to optimize treatment for individual patients and treatment failures.

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.

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.

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.

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.

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.

Orlent H, Vrolijk JM, de Man RA, Schalm SW. · Erasmus Medisch Centrum, afd. Maag-, Darm- en Leverziekten, Postbus 2040, 3000 CA Rotterdam. · Ned Tijdschr Geneeskd. · Pubmed #12848055 No free full text.

Abstract: The recent advances in the antiviral therapy of hepatitis C have significantly lowered the threshold for offering such therapy to patients. Sustained virological response rates of 42-46% are achieved after 48 weeks of combination therapy with peginterferon alpha and ribavirin in patients with genotype 1 infection. In patients with a genotype 2 or 3 infection, 24 weeks of combination therapy leads to a sustained response rate of almost 80%. The U.S. National Institutes of Health consensus states that every patient with hepatitis C should be considered for antiviral therapy. Identification of the patients, selection for therapy, the provision of good information, guidance of the patient during therapy and a successful management of side effects lead to better treatment compliance and are of paramount importance in obtaining maximal therapeutic efficacy. Supportive guidance during substance abuse withdrawal programmes and the adequate use of selective serotonin reuptake inhibitors should be part of these measures.

Willems M, Metselaar HJ, Tilanus HW, Schalm SW, de Man RA. · Department of Gastroenterology, University Hospital Dijkzigt, P.O. Box 2040, 3000 Rotterdam, The Netherlands. · Transpl Int. · Pubmed #11935162 No free full text.

Abstract: End-stage liver disease caused by chronic hepatitis C viral infection is one of the major indications for liver transplantation. However, evidence for ongoing viral replication can already be found days after surgery and may lead sequentially to lobular hepatitis, chronic active hepatitis, fibrosis and liver cirrhosis. In some patients, this evolution is remarkably fast, most probably enhanced by the immunosuppressive therapy. A minority of patients develop a clinical picture of progressive cholestatic liver disease with histological signs of chronic rejection, which may necessitate retransplantation. While the 1- and 5-year survival rates for all patients transplanted because of hepatitis C virus (HCV)-induced liver cirrhosis are satisfactory, severe complications of disease recurrence are nonetheless expected during the first and second decade after liver transplantation. Larger and preferably randomized studies are needed to investigate whether combination therapy with interferon and ribavirin, preferably initiated as soon as possible after liver transplantation, prevents the fast evolution to cirrhosis without the appearance of chronic rejection and the expected complications of recurrent end-stage HCV-induced liver disease. The final goal should be the inhibition of viral replication even before liver transplantation, but other antiviral strategies should probably be used to attain this goal in patients with decompensated cirrhosis. Although the recurrence of a hepatitis C infection and concomitant disease in the liver graft may cause substantial morbidity, end-stage liver disease and liver failure caused by a chronic hepatitis C infection remain good indications for liver transplantation.

Wolters LM, Niesters HG, de Man RA. · Department of Gastroenterology & Hepatology, University Hospital Rotterdam, The Netherlands. · Eur J Gastroenterol Hepatol. · Pubmed #11742201 No free full text.

Abstract: Hepatitis B virus replicates inside the hepatocyte through an intermediate step of reverse transcription mediated by the viral polymerase. We describe five nucleoside/nucleotide analogues that interfere with the replication mechanisms of the hepatitis B virus. The resemblance of nucleoside analogues to natural nucleosides may lead to direct cytotoxicity. Therefore, antiviral activity should always be interpreted in the light of cellular toxicity. In addition, prolonged therapy with a nucleoside analogue may induce mutations in the viral polymerase, causing structural and configurational changes of the polymerase resulting in a decreased affinity for the nucleoside analogue. Subsequently, the mutated virus is capable of renewed replication during continued antiviral pressure of the nucleoside analogue. The best antiviral strategy in the future is probably combination therapy, either with several nucleoside analogues or with a nucleoside analogue and interferon.

van Nunen AB, Janssen HL, Wolters LM, Niesters HG, de Man RA, Schalm SW. · Department of Hepatogastroenterology, Erasmus University Hospital Rotterdam, PO Box 2040, 3000 CA Rotterdam, The Netherlands. · Antiviral Res. · Pubmed #11672823 No free full text.

Abstract: For the treatment of chronic hepatitis B (CHB) two drugs have been licensed world-wide: interferon-alpha (IFN) and lamivudine. Both drugs significantly increase the hepatitis B e-antigen (HBeAg) seroconversion rate, but a sustained treatment response occurs in less than 40% of patients. To explore whether there is an additional benefit of combining these two drugs, we reviewed the literature on lamivudine-IFN combination therapy in comparison to the two monotherapies in compensated, HBeAg-positive, CHB patients. We focussed on two clinically relevant outcome measures: HBeAg seroconversion, and change in liver histology. Candidates for lamivudine-IFN combination therapy were, previously untreated, patients with moderately elevated alanine aminotransferase (ALT). Such regimen should still be considered experimental. Viral kinetics may provide insight into how long therapy should be continued; prolongation of therapy to 52 weeks currently appears a reasonable approach. According to principles of anti-viral therapy today, simultaneously dosing of both drugs is to be preferred, since rapid maximal virus suppression is thought to be essential to prevent drug resistance and enhance seroconversion. From an immunological point of view, pre-treatment with lamivudine or IFN may alter the virus-host balance and set the stage for the other drug to enhance the effect of treatment. Further clinical research on lamivudine-IFN combination therapy appears warranted.

Schalm SW, Wolters LM, van Nunen AB, Niesters HG, de Man RA. · Dept. of Hepatogastroenterology & Virology, University Hospital Rotterdam, The Netherlands. · Acta Gastroenterol Belg. · Pubmed #10925461 No free full text.

This publication has no abstract.

de Man RA, Bosman A, Stevens-Schretzmeijer M, Niesters HG. · Academisch Ziekenhuis Rotterdam-Dijkzigt, Rotterdam. · Ned Tijdschr Geneeskd. · Pubmed #10568322 No free full text.

Abstract: Hepatitis B was diagnosed in two homosexual men aged 41 and 31 years. Both had undergone piercing on the same day in the same saloon. The word piercing means application of decorations in the skin which is pierced for the purpose. The breeching of the skin combined with the conditions under which this is performed leads to a risk of transmission of especially viral infections. An assumed connection between the patients was supported by the results of molecular-biological examination of the hepatitis B virus isolates. The piercings were applied with the same pair of pincers, which was not sterilized in between. In view of these findings hygienic measures were taken in the piercing saloon in question to prevent future transmission of infections. Piercing entails health risks that are not always recognized either by those who do it or by those who have it done.

de Man RA, Honkoop P, Janssen HL, Schalm SW. · Academisch Ziekenhuis Rotterdam-Dijkzigt, afd. Maag-, Darm- en Leverziekten. · Ned Tijdschr Geneeskd. · Pubmed #10526598 No free full text.

Abstract: The possibilities for antiviral treatment of patients with chronic hepatitis B virus (HBV) infections have been in flux for the last few years. Apart from interferon alpha, oral nucleoside analogues are given a place. The treatment focuses on the group of patients with active virus multiplication (hepatitis B e antigen (HBeAg) and HBV DNA are demonstrable), abnormal liver enzyme values and histologically demonstrated inflammatory activity in the liver. For the individual patient the pros and cons of protracted virus inhibition should be weighted by means of an orally administered nucleoside analogue such as lamivudine, immunostimulation with injections of interferon alpha or a combination of these two.

Marcellin P, Heathcote EJ, Buti M, Gane E, de Man RA, Krastev Z, Germanidis G, Lee SS, Flisiak R, Kaita K, Manns M, Kotzev I, Tchernev K, Buggisch P, Weilert F, Kurdas OO, Shiffman ML, Trinh H, Washington MK, Sorbel J, Anderson J, Snow-Lampart A, Mondou E, Quinn J, Rousseau F. · Hôpital Beaujon, Assistance Publique Hôpitaux de Paris, University of Paris 7 and INSERM Unité 773, Centre de Recherches Claude Bernard sur les Hepatites Virales, Clichy, France. · N Engl J Med. · Pubmed #19052126 links to  free full text

Abstract: BACKGROUND: Tenofovir disoproxil fumarate (DF) is a nucleotide analogue and a potent inhibitor of human immunodeficiency virus type 1 reverse transcriptase and hepatitis B virus (HBV) polymerase. METHODS: In two double-blind, phase 3 studies, we randomly assigned patients with hepatitis B e antigen (HBeAg)-negative or HBeAg-positive chronic HBV infection to receive tenofovir DF or adefovir dipivoxil (ratio, 2:1) once daily for 48 weeks. The primary efficacy end point was a plasma HBV DNA level of less than 400 copies per milliliter (69 IU per milliliter) and histologic improvement (i.e., a reduction in the Knodell necroinflammation score of 2 or more points without worsening fibrosis) at week 48. Secondary end points included viral suppression (i.e., an HBV DNA level of <400 copies per milliliter), histologic improvement, serologic response, normalization of alanine aminotransferase levels, and development of resistance mutations. RESULTS: At week 48, in both studies, a significantly higher proportion of patients receiving tenofovir DF than of those receiving adefovir dipivoxil had reached the primary end point (P<0.001). Viral suppression occurred in more HBeAg-negative patients receiving tenofovir DF than patients receiving adefovir dipivoxil (93% vs. 63%, P<0.001) and in more HBeAg-positive patients receiving tenofovir DF than patients receiving adefovir dipivoxil (76% vs. 13%, P<0.001). Significantly more HBeAg-positive patients treated with tenofovir DF than those treated with adefovir dipivoxil had normalized alanine aminotransferase levels (68% vs. 54%, P=0.03) and loss of hepatitis B surface antigen (3% vs. 0%, P=0.02). At week 48, amino acid substitutions within HBV DNA polymerase associated with phenotypic resistance to tenofovir DF or other drugs to treat HBV infection had not developed in any of the patients. Tenofovir DF produced a similar HBV DNA response in patients who had previously received lamivudine and in those who had not. The safety profile was similar for the two treatments in both studies. CONCLUSIONS: Among patients with chronic HBV infection, tenofovir DF at a daily dose of 300 mg had superior antiviral efficacy with a similar safety profile as compared with adefovir dipivoxil at a daily dose of 10 mg through week 48. (ClinicalTrials.gov numbers, NCT00116805 and NCT00117676.)

de Vries-Sluijs TE, Hansen BE, van Doornum GJ, Springeling T, Evertsz NM, de Man RA, van der Ende ME. · Departments of Internal Medicine, Infectious Diseases Section, Erasmus Medical Center, Rotterdam, The Netherlands. · J Infect Dis. · Pubmed #18177248 No free full text.

Abstract: Double-dose hepatitis B virus revaccination of human immunodeficiency virus (HIV)-infected patients proved to be effective in 50.7% of 144 patients who had previously failed to respond to standard doses. In the multivariate analysis, female patients were found to have a significantly better response (P= .03). The effect of age on the response depended on the viral load at the time of revaccination. For patients with a detectable HIV RNA load, the effect of age was stronger (odds ratio [OR], 0.34 per 10 years older [95% confidence interval {CI}, 0.16-0.72]; P= .005) than for patients with an undetectable HIV RNA load (OR, 0.74 per 10 years older [95% CI, 0.50-1.09]; P= .12).

Sprengers D, van der Molen RG, Binda R, Kusters JG, de Man RA, Niesters HG, Schalm SW, Janssen HL. · Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands. · J Viral Hepat. · Pubmed #17875010 No free full text.

Abstract: Only in a minority of patients with chronic hepatitis B (CHB) will treatment with interferon (IFN)-alpha or nucleoside analogues lead to sustained virological response. In vivo immunization (IVI) following virus suppression aims to optimize conditions for an effective immune response: following rapid and profound virus suppression by interferon-lamivudine combination therapy, lamivudine is withdrawn intermittently during continued interferon therapy. It is thought that withdrawal of lamivudine will lead to increased viral replication and increased antigen expression with subsequent immune stimulation. The aim of this prospective pilot study was to evaluate IVI as a therapeutic approach for CHB. Fourteen HBeAg-positive CHB patients were treated for 42 weeks with a combination of pegylated interferon-alpha 2b and lamivudine. After 12 weeks of combination therapy lamivudine was withdrawn intermittently for three consecutive periods of 4 weeks until it was permanently stopped on week 36. At the end of follow-up (week 52) all patients had remained HBeAg positive and the median viral load was similar to baseline. During the initial 12 weeks of treatment, there was a reduction of both the hepatitis B virus (HBV)-specific proliferation capacity of Th-cells and the frequencies of IFNgamma-producing cells. During the lamivudine interruption-cycle there was an inverse relation between the increase of HBV-DNA, and the decrease in proliferation capacity and frequency of IFN-gamma-producing cells. The intrahepatic fraction of CD8(+) T-cells increased during lamivudine withdrawal. In conclusion, IVI was able to transiently stimulate the HBV-specific immune responsiveness of T-cells, but the magnitude of the response was insufficient to cause a beneficial virological effect.

van der Eijk AA, Niesters HG, Hansen BE, Heijtink RA, Janssen HL, Schalm SW, de Man RA. · Department of Gastroenterology & Hepatology, Erasmus MC, Rotterdam, The Netherlands. · J Viral Hepat. · Pubmed #16436127 No free full text.

Abstract: To reduce unnecessary exposure to treatment, physicians must decide at an early stage whether continuation of treatment has a reasonable chance of success for the individual patient. The objectives of our study were to evaluate the previously described quantitative hepatitis B e antigen (HBeAg) measurements vs quantitative hepatitis B virus (HBV) DNA measurements for prediction of nonresponse and response in interferon (IFN)-alpha treated HBeAg positive chronic HBV patients. Serum HBV DNA and HBeAg levels were assessed at baseline and weeks 8 and 12. For each test (HBV DNA level at baseline, HBV DNA decrease between baseline and weeks 8 and 12, or the combination of these two, as well as HBeAg level at baseline, HBeAg decrease between baseline and weeks 8 and 12, and the combination of these two), we calculated the positive predictive value, negative predictive value, sensitivity and specificity. Monitoring with quantitative HBV DNA levels (area under ROC 0.87) was superior to monitoring with quantitative HBeAg levels (0.76, P < 0.05). Step-wise logistic regression identified HBV DNA at baseline and decrease in HBV DNA from baseline to week 12, as independent predictors of response. The overall test performance of predicting nonresponse (predictive value 100%) was best for log HBV DNA testing at week 12 compared with testing at week 8 due to a better prediction of sustained response (46%vs 38%) and lower misidentification of nonresponse (39%vs 54%). This study showed that quantitative HBV DNA testing at baseline in combination with a decrease between baseline and week 12 has a high predictive value for identifying patients who have virtually no chance of reaching a sustained response with IFN therapy.

van der Eijk AA, Hansen BE, Niesters HG, Janssen HL, van de Ende M, Schalm SW, de Man RA. · Department of Gastroenterology and Hepatology, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands. · J Viral Hepat. · Pubmed #15985006 No free full text.

Abstract: Tenofovir, an antihuman immunodeficiency virus (HIV) drug, has activity against lamivudine-resistant hepatitis B virus (HBV) mutants. To describe the efficacy of tenofovir in patients with lamivudine-resistant hepatitis B we applied two investigative approaches based on mathematical models of viral dynamics: the individual nonlinear fitting and the mixed-effect group fitting approaches. Eleven chronic HBV patients on lamivudine for a median of 176 weeks (range: 72-382) with YMDD mutation-related HBV-DNA breakthrough received 'add-on' tenofovir 300 mg once-daily, while maintaining their existing therapy. Sequential sera were taken at day 1 (t = 0 and t = 8 h), days 2, 4, 7, 10, 14, 21, 28 and every 4 weeks thereafter, and HBV-DNA levels were assessed using a validated quantitative polymerase chain reaction (PCR) assay. Median baseline log HBV-DNA was 8.62 (range: 6.48-9.76 log HBV-DNA). Tenofovir treatment resulted in a mean (+/-SD) log HBV-DNA decline of 1.37 +/- 0.51 in the first phase, 2.54 +/- 0.91 after 4 weeks, and 4.95 +/- 0.90 log HBV-DNA after 24 weeks. The median effectiveness of blocking viral replication in the individual fit model was 93% (range: 73-99) for eta = 0 and 93% (range: 59-99) for eta = 1. There was only a small difference between the efficacy parameter 'epsilon' of the individual nonlinear fitting and mixed-effect group fitting on the biphasic exponential model. These data show that tenofovir has good efficacy in blocking viral replication in HBV patients with lamivudine-induced drug-resistant HBV mutants, but effectiveness varies greatly among individuals. Both models can be used to describe viral decay during tenofovir therapy.

Flink HJ, Sprengers D, Hansen BE, van Zonneveld M, de Man RA, Schalm SW, Janssen HL, Anonymous00075. · Department of Gastroenterology and Hepatology, Erasmus Medical Centre, Dr. Molewaterplein 40, Room Ca 326, 3015 GD Rotterdam, the Netherlands. · Gut. · Pubmed #15923670 links to  free full text

Abstract: BACKGROUND AND AIMS: Flares are a well known phenomenon during antiviral treatment for chronic hepatitis B. Little is known about the effect of flares on response. We investigated the timing and characteristics of flares, in relation to treatment response (hepatitis B e antigen loss). PATIENTS: A total of 266 patients, participating in a global randomised controlled study, were assigned to 52 weeks of 100 mug pegylated (Peg)-interferon alpha-2b weekly, combined with either daily lamivudine 100 mg or placebo. RESULTS: Sixty seven patients (25%) exhibited 75 flares, with 38 (51%) flares in the combination therapy and 37 (49%) in the monotherapy groups. Overall, 30% of patients with and 38% of patients without a flare responded to therapy (p = 0.25). In 24 patients (36%) the flare was followed by a decrease in hepatitis B virus (HBV) DNA (host induced flare). In 25 (38%) patients the flare was preceded by an increase in HBV DNA (virus induced flare). In 17 (26%) patients the flare did not meet one of these criteria (indeterminate flare). Of patients with host induced flare, 58% responded whereas only 20% of patients with virus induced flares responded (p = 0.008). Hepatitis B surface antigen loss (n = 8) was exclusively seen in patients experiencing a host induced flare. Multivariate logistic analysis showed that host induced flares was an independent predictor of response (p = 0.043). CONCLUSION: Flares are not more common in responders than in non-responders to Peg-interferon alpha-2b therapy. Virus induced flares, which occur after an increase in HBV DNA level, and most probably are indicative for increased expression of viral antigens, did not lead to treatment response. In contrast, host induced flares which were followed by a HBV DNA decrease were highly associated with treatment response.

van Zonneveld M, Flink HJ, Verhey E, Senturk H, Zeuzem S, Akarca US, Cakaloglu Y, Simon C, So TM, Gerken G, de Man RA, Hansen BE, Schalm SW, Janssen HL, Anonymous00231. · Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands. · Aliment Pharmacol Ther. · Pubmed #15854180 links to  free full text

Abstract: BACKGROUND: Treatment with interferon-alpha has been shown to be effective in one-third of hepatitis B e antigen-positive chronic hepatitis B patients, but is clinically associated with relevant adverse events. AIM: To investigate the safety of pegylated interferon alpha-2b in 300 hepatitis B e antigen-positive patients with compensated liver disease. METHODS: Patients were treated with pegylated interferon alpha-2b for 52 weeks combined with either lamivudine 100 mg/day or placebo. Pegylated interferon alpha-2b was administered for 100 microg once a week for 32 weeks; thereafter, the dose was reduced to 50 microg once a week. Adverse events and their effect on study medication were reported at monthly visits in a standardized way. RESULTS: The most frequently reported side-effects were flu-like syndrome (68%), headache (40%), fatigue (39%), myalgia (29%) and local reaction at the injection site (29%). These symptoms typically occurred within the first month of therapy and subsided during the course of therapy. Neutropenia and thrombocytopenia induced by pegylated interferon alpha-2b increased the risk of infections and bleeding complications, but these complications were rare and mild. The frequency of all side-effects was not different between patients treated with pegylated interferon alpha-2b combined with lamivudine or placebo. In 69 (22%) patients the dose of pegylated interferon alpha-2b was reduced prematurely. Of these dose reductions, 36 (52%) were because of neutropenia. Therapy was discontinued in 28 (8%) patients. The most frequent reasons for early discontinuation were psychiatric side-effects (depression, psychosis) and flu-like symptoms. Multivariate Cox regression analysis showed that low neutrophil count at baseline and cirrhosis were independent predictors of dose reduction or therapy discontinuation. CONCLUSION: We conclude that in patients with chronic hepatitis B and compensated liver disease prolonged pegylated interferon alpha-2b therapy is safe, and that pre-existent cirrhosis and neutropenia are the most important predictors of dose reduction or early treatment discontinuation.

Janssen HL, van Zonneveld M, Senturk H, Zeuzem S, Akarca US, Cakaloglu Y, Simon C, So TM, Gerken G, de Man RA, Niesters HG, Zondervan P, Hansen B, Schalm SW, Anonymous00102, Anonymous00103. · Department of Gastroenterology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands. · Lancet. · Pubmed #15639293 No free full text.

Abstract: BACKGROUND: Treatment of HBeAg-positive patients with chronic hepatitis B is not effective in most. A combination of immunomodulatory pegylated interferon alfa-2b and antiviral lamivudine might improve the rate of sustained response. METHODS: 307 HBeAg-positive patients with chronic hepatitis B were assigned combination therapy (100 microg/week pegylated interferon alfa-2b and 100 mg/day lamivudine) or monotherapy (100 microg/week pegylated interferon alfa-2b and placebo) for 52 weeks. During weeks 32-52 the pegylated interferon dose was 50 microg/week in both treatment groups. The analyses were based on the modified intention-to-treat population after exclusion of 24 patients from one centre withdrawn for misconduct, ten who lost HBeAg before the study start, and seven who received no study medication. All included patients were followed up for 26 weeks after treatment. FINDINGS: 49 (36%) of 136 patients assigned monotherapy and 46 (35%) of 130 assigned combination therapy had lost HBeAg at the end of follow-up (p=0.91). More of the combination-therapy than of the monotherapy group had cleared HBeAg at the end of treatment (57 [44%] vs 40 [29%]; p=0.01) but relapsed during follow-up. Patterns were similar when response was assessed by suppression of serum hepatitis B virus (HBV) DNA or change in concentrations of alanine aminotransferase. Response rates (HBeAg loss) varied by HBV genotype (p=0.01): A, 42 (47%) patients; B, ten (44%); C, 11 (28%); and D, 26 (25%). INTERPRETATION: Treatment with pegylated interferon alfa-2b is effective for HBeAg-positive chronic hepatitis B. Combination with lamivudine in the regimen used is not superior to monotherapy. HBV genotype is an important predictor of response to treatment.

Tang TJ, de Man RA, Kusters JG, Kwekkeboom J, Hop WC, van der Molen RG, Schalm SW, Janssen HL. · Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center Rotterdam, The Netherlands. · J Med Virol. · Pubmed #14695662 No free full text.

Abstract: Recognition of HBV-infected hepatocytes by CD8 T-lymphocytes is important for viral clearance. Expression of hepatitis B core antigen (HBcAg) in HBV-infected hepatocytes can trigger this antiviral T-cell response. The intrahepatic CD8 T-lymphocytes and HBcAg expression were investigated in relation to response to antiviral therapy. Forty chronic HBeAg-positive patients treated with either lamivudine (n = 20) or interferon-alpha (n = 20) were investigated. Ten patients from each treatment group exhibited a response. Liver biopsies were carried out before and after therapy. CD8 T-lymphocytes and HBcAg expression were detected by immunohistochemistry. The number of pretreatment intrahepatic CD8 T-lymphocytes was significantly higher in responders (P = 0.008). In responders baseline nuclear HBcAg expression tended to be lower (P = 0.09). Cytoplasmic expression was not significantly different between responders and non-responders (P = 0.46). The number of CD8 T-lymphocytes correlated with cytoplasmic HBcAg (r(s) = 0.31; P = 0.04); CD8 T-lymphocytes were situated in clusters of hepatocytes with cytoplasmic HBcAg. Longitudinal analysis showed a significant reduction of CD8 T-lymphocytes after treatment in responders (P < 0.001). Multivariate analysis revealed pretreatment CD8 T-lymphocytes and age as independent prognostic factors for response (n = 40). The number of pretreatment CD8 T-lymphocytes was the only independent prognostic indicator for response to interferon-alpha (P = 0.03); it was of borderline significance for lamivudine therapy (P = 0.06). It is concluded that the number of pretreatment intrahepatic CD8 T-lymphocytes is an important predictor of response to HBV therapy with either interferon-alpha or lamivudine. Response to therapy led to a significant reduction of intrahepatic CD8 T-lymphocytes. Co-localisation of CD8 T-lymphocytes and HBcAg-positive hepatocytes suggests antiviral activity predominantly at the site of maximum HBV replication.

Schiff ER, Dienstag JL, Karayalcin S, Grimm IS, Perrillo RP, Husa P, de Man RA, Goodman Z, Condreay LD, Crowther LM, Woessner MA, McPhillips PJ, Brown NA, Anonymous00314. · Division of Hepatology, University of Miami, Jackson Medical Towers, 1500 N.W. 12th Avenue, Suite 1101, Miami, FL 33136, USA. · J Hepatol. · Pubmed #12763376 No free full text.

Abstract: BACKGROUND/AIMS: Lamivudine is effective in treatment-naive patients with chronic hepatitis B, but its role in interferon nonresponders has not been described. We assessed lamivudine treatment, with or without added interferon, in patients with hepatitis B e antigen (HBeAg)-positive chronic hepatitis B who had failed interferon therapy previously. METHODS: Patients were randomized to lamivudine (100 mg) or placebo for 52 weeks or to a 24-week regimen of lamivudine plus interferon. Primary treatment comparisons were at week 52, with a 16-week posttreatment follow-up period. Measurements included histology (primary endpoint), HBeAg response, normalization of alanine aminotransferase, reduction of hepatitis B virus (HBV) DNA, and safety. RESULTS: Among 238 patients, histologic response was significantly more common in patients treated with lamivudine (52 versus placebo 25%, P=0.002) or the combination regimen (32%, P=0.01). HBeAg loss was also more common with lamivudine (33 versus 13 versus 21%), as were virologic and alanine aminotransferase responses. Among 28 subjects with HBeAg loss/seroconversion, 71% had durable responses 16 weeks posttreatment. CONCLUSIONS: Lamivudine for 52 weeks is as effective in interferon nonresponders as in previously reported treatment-naive patients; however, a combination of lamivudine for 24 weeks and interferon for 16 weeks was not effective in this population.