Hajo J Flink

Erasmus MC, Rotterdam, South Holland, Netherlands

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Publications (19)

  • Source
    Milan J Sonneveld · Roeland Zoutendijk · Hajo J Flink · [...] · Harry L A Janssen
    [Show abstract] [Hide abstract] ABSTRACT: Background: Alanine aminotransferase (ALT) flares occur frequently during peginterferon (PEG-IFN) therapy. We related occurrence of flares to presence of precore (PC) and/or basal core promoter (BCP) mutants and studied kinetics of hepatitis B e antigen (HBeAg) and hepatitis B surface antigen (HBsAg) levels during flares. Methods: Fifty of 214 (23%) patients treated with PEG-IFN ± lamivudine for 52 weeks experienced flares. Flares were host-induced (ALT elevation followed by HBV DNA decline, n = 19), virus-induced (HBV DNA increase with subsequent ALT elevation, n = 17) or indeterminate (n = 14). Presence of wild-type (WT) or non-WT (detectable PC/BCP mutants) was studied by lineprobe assay. Results: Fifty-eight percent of host-induced flares occurred in WT HBV patients, whereas 94% of virus-induced flares occurred in patients with PC and/or BCP mutants (P = .003). HBsAg loss was only achieved in patients with a host-induced flare, and WT patients with a host-induced flare cleared HBsAg in 64% of cases. Serum HBsAg levels declined after a host-induced flare, whereas virus-induced flares were accompanied by stable or increasing levels of HBsAg. Patients with a host-induced flare achieved a mean HBsAg reduction of 3.24 log IU/mL, compared with 0.25 log IU/mL in virus-induced flares (P < .001). Patients who achieved a decline in HBsAg of >0.5 log IU/mL within 4 weeks after the flare cleared HBsAg in 64% (7 of 11) of cases. Conclusions: Host-induced flares are associated with WT virus and may result in decline and clearance of HBV DNA, HBeAg, and HBsAg. Monitoring of HBsAg levels during and after flares may help predict a favorable treatment outcome.
    Full-text Article · Oct 2012 · Clinical Infectious Diseases
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    Erik H C J Buster · Hajo J Flink · Halis Simsek · [...] · Harry L A Janssen
    [Show abstract] [Hide abstract] ABSTRACT: Treatment with pegylated interferon (PEG-IFN) alpha-2b results in hepatitis B e antigen (HBeAg) loss in 36% of patients at 6 months post treatment. The aim of this study was to determine whether a long-term response to PEG-IFN is dependent on the timing of HBeAg loss. A total of 91 patients treated with PEG-IFN alpha-2b alone (100 microg per week) and 81 patients treated with PEG-IFN alpha-2b and lamivudine (100 mg/day) for 52 weeks were enrolled in this study. Patients were initially followed up at 4-week intervals and had one additional long-term follow-up (LTFU) visit (mean: 3.03+/-0.77 years 26 weeks post treatment). Of the 172 patients included, 78 patients (46%) did not have loss of HBeAg, 47 (27%) lost HBeAg within 32 weeks, and 47 patients (27%) had loss of HBeAg after week 32. At LTFU, patients with HBeAg loss< or =32 weeks had hepatitis B virus DNA of <400 copies/ml significantly more often than did those who lost HBeAg after week 32 (47 vs. 21%, respectively; P=0.009). Hepatitis B surface antigen (HBsAg) negativity was also observed significantly more often in patients with early HBeAg loss (36 vs. 4%, respectively, P<0.001). Early HBeAg loss tended to occur more often in patients treated with PEG-IFN and lamivudine combination therapy than in those treated with PEG-IFN alone (35 vs. 21%; P=0.10), as did HBsAg loss (15 vs. 8%; P=0.14). Early PEG-IFN-induced HBeAg loss results in a high likelihood of HBsAg loss and may be associated with more profound viral suppression during the first 32 weeks of therapy in patients treated with lamivudine combinations.
    Full-text Article · Aug 2009 · The American Journal of Gastroenterology
  • Buster EH · Flink HJ · Simsek H · [...] · Hansen
    Article · Jan 2009 · The American Journal of Gastroenterology
  • Erik H.C.J. Buster · Hajo J Flink · Yilmaz Cakaloglu · [...] · Harry L.A. Janssen
    [Show abstract] [Hide abstract] ABSTRACT: The aim of this study was to evaluate the long-term sustainability of response in patients with hepatitis B e antigen (HBeAg)-positive chronic hepatitis B treated with pegylated interferon (PEG-IFN) alpha-2b alone or in combination with lamivudine. All 266 patients enrolled in the HBV99-01 study were offered participation in a long-term follow-up (LTFU) study. Patients were treated with PEG-IFN alpha-2b (100 mug/wk) alone or in combination with lamivudine (100 mg/day) for 52 weeks. Initial response was defined as HBeAg negativity at 26 weeks posttreatment. For the LTFU study, patients had one additional visit after the initial study (mean interval, 3.0 +/- 0.8 years). Of 266 patients enrolled in the initial study, 172 (65%) participated in the LTFU study. At LTFU, HBeAg and hepatitis B surface antigen (HBsAg) negativity were observed in 37% and 11% of 172 patients, respectively. Sixty-four patients were classified as initial responders and 108 as nonresponders. Among the initial responders, sustained HBeAg negativity and HBsAg loss were observed in 81% and 30%, respectively. Significantly higher rates of HBeAg negativity were observed in genotype A-infected initial responders compared with those with genotype non-A (96% vs 76%; P = .06) as well as HBsAg loss (58% vs 11%; P < .001). HBeAg loss after treatment with PEG-IFN alpha-2b alone or in combination with lamivudine is sustained in the majority of patients and is associated with a high likelihood of HBsAg loss, particularly in genotype A-infected patients. Therefore, PEG-IFN alpha-2b remains an important treatment option in this era of nucleos(t)ide analogue therapy.
    Article · May 2008 · Gastroenterology
  • Source
    H J Flink · E H C J Buster · I Merican · [...] · H L A Janssen
    Full-text Article · Nov 2007 · Gut
  • Article · Apr 2007 · Journal of Hepatology
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    Hajo J Flink · Bettina E Hansen · E Jenny Heathcote · [...] · Harry L A Janssen
    [Show abstract] [Hide abstract] ABSTRACT: Antiviral therapy leads to HBeAg seroconversion in 10-40% of the patients with HBeAg-positive chronic hepatitis B. Nonresponse may result in progression of liver disease and increased risk of hepatocellular carcinoma. As part of a global randomized controlled trial we investigated the efficacy (i.e., loss of HBeAg at the end of follow-up) of peginterferon alfa-2b (Peg-IFN alpha2b) in patients who failed to respond to previous courses of standard interferon (IFN) or lamivudine. We analyzed a total of 76 previous nonresponders: 37 were nonresponders to standard IFN, 17 were nonresponders to lamivudine, and 22 were nonresponders to both therapies. All patients received a 52-wks course of 100 microg Peg-IFN alpha2b weekly combined with either 100 mg lamivudine daily or a placebo. After therapy patients were followed for 26 wks. Thirteen (35%) nonresponders to previous IFN, five (29%) nonresponders to previous lamivudine, and four (22%) nonresponders to both IFN and lamivudine responded to treatment with Peg-IFN alpha2b. No difference in response was found for those treated with Peg-IFN alpha2b alone or in combination with lamivudine. Nonresponders to prior IFN therapy with baseline ALT (alanine aminotransferase) > 4 x ULN (upper limit of normal) responded better to Peg-IFN alpha2b than those with ALT levels <or= 4 x ULN (53%vs 20%, respectively, p= 0.036). Peg-IFN alpha2b is effective in approximately one-third of patients who failed to respond to previous treatment with standard IFN or lamivudine. High serum ALT level at baseline of Peg-IFN alpha2b therapy was the best predictor for response in these patients.
    Full-text Article · Dec 2006 · The American Journal of Gastroenterology
  • [Show abstract] [Hide abstract] ABSTRACT: The effect of pegylated interferon or its combination with lamivudine on liver histology of patients with chronic hepatitis B (CHB) is unknown. In a double-blinded, randomized, multi-center study we assessed histological changes in 110 hepatitis B e-antigen (HBeAg)-positive CHB patients treated for 52 weeks with Pegylated interferon alpha-2b (PEG-IFN) in combination with either lamivudine or placebo. Liver biopsies were taken before and at the end of treatment. All biopsies were blinded and scored according to the Ishak system. Necroinflammatory score improved (defined as a decrease of at least two points) in 25 patients (48%) of the PEG-IFN/lamivudine combination therapy group and in 31 patients (53%) of the PEG-IFN monotherapy group. The fibrosis score improved (decrease of at least 1 point) in 17 patients (33%) of the combination therapy group vs. 13 patients (22%) of the PEG-IFN monotherapy group (P=0.23). Responders (n=42), defined as serum HBeAg negative at the end of therapy, showed a larger decline in necroinflammatory score than non-responders (mean decline 2.3 and 1.2 points, respectively, P=0.02). Among patients receiving PEG-IFN monotherapy necroinflammation improved more frequently in responders (78% of responders vs. 43% of non-responders, P=0.01) and in patients who showed normalization of ALT (76% of patients with normal ALT vs. 40% of patients with abnormal ALT, P=0.01). Fibrosis score in the PEG-IFN monotherapy group improved more often in responders (39%) than in non-responders (15%, P=0.04). In the PEG-IFN/lamivudine combination therapy group, we found no significant association between virological and biochemical endpoints and histological improvement. Treatment with PEG-IFN therapy improves liver necroinflammation in HBeAg-positive CHB patients, particularly in responders to therapy. PEG-IFN also improves fibrosis in responders. Addition of lamivudine to PEG-IFN did not further improve the histological outcome.
    Article · Jun 2006 · Liver international: official journal of the International Association for the Study of the Liver
  • Wilhelmus F Leemans · Hajo J Flink · Harry L.A. Janssen · [...] · Robert A de Man
    [Show abstract] [Hide abstract] ABSTRACT: To determine the response to pegylated interferon-alpha treatment of HBeAg-positive hepatitis B patients with proven lamivudine resistance. Sixteen HBeAg-positive HBV patients with YMDD mutations were treated with pegylated interferon. Median treatment duration was 52 weeks (range 20-53), with a 26-week follow-up. Two of 16 (12.5%) patients seroconverted to HBeAg negative and achieved sustained virological (HBV-DNA levels below 10log 5 copies/ml) together with biochemical (normalization of serum ALT levels) responses. Compared with the strong signal in all other patients, only these two patients had a faint signal in the lamivudine resistance assay. For all patients, the median viral load decreased from 10log 9.4 to 7.9 copies/ml (P = 0.001) during treatment but rebounded to a median of 10log 8.7 copies/ml after treatment cessation. Similarly, elevated median ALT levels at baseline decreased with treatment but rebounded after the end of treatment. In the largest cohort study to date, pegylated interferon-alpha therapy showed marginal efficacy in the presence of lamivudine resistance but such therapy may be beneficial in patients with only small amounts of mutant virus. In our opinion, an analysis of the patient subgroup harbouring an YMDD-mutation should be included in all future studies of pegylated interferon-alpha in chronic hepatitis B.
    Article · Apr 2006 · Journal of Hepatology
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    [Show abstract] [Hide abstract] ABSTRACT: Hepatitis B surface antigen (HBsAg) loss is the hallmark of a complete response to antiviral therapy for chronic hepatitis B. In this study, we investigated the frequency of HBsAg loss after treatment with pegylated (Peg)-interferon alpha-2b. In a multicenter randomized controlled trial, 266 HBeAg-positive patients were treated for 52 wks with Peg-interferon alpha-2b (100 microg/wk) in combination with either lamivudine (100 mg/day) or placebo. Posttreatment follow-up was 26 wks. At the end of follow-up, 95 (36%) of the 266 patients exhibited HBeAg loss, 18 (7%) HBsAg loss, and 16 (6%) HBsAg seroconversion. Addition of lamivudine did not enhance HBeAg loss, HBsAg loss, or development of anti-HBs. All 18 patients who showed HBsAg loss had normal ALT; 11 (61%) of these patients were also hepatitis B virus (HBV) DNA negative (<400 copies/mL) at the end of follow-up. Loss of HBsAg differed according to HBV genotype: 14% for genotype A, 9% for genotype B, 3% for genotype C, and 2% for genotype D (A vs D: p = 0.006). One year of Peg-interferon alpha-2b for HBeAg-positive patients led to HBsAg loss in 7%. Our study indicates that treatment with Peg-interferon alpha-2b is the best therapy to achieve HBsAg clearance in patients with genotype A.
    Full-text Article · Feb 2006 · The American Journal of Gastroenterology
  • MJ ter Borg · HJ Flink · BE Hansen · [...] · HLA Janssen
    Article · Jan 2006 · European Journal of Gastroenterology & Hepatology
  • WF Leemans · HJ Flink · HLA Janssen · [...] · RA de Man
    Article · Jan 2006 · European Journal of Gastroenterology & Hepatology
  • HJ Flink · BE Hansen · RA de Man · [...] · HLA Jansen
    [Show abstract] [Hide abstract] ABSTRACT: An abstract is unavailable. This article is available as HTML full text and PDF.
    Article · Jan 2006 · European Journal of Gastroenterology & Hepatology
  • Source
    H J Flink · D Sprengers · B E Hansen · [...] · H L A Janssen
    [Show abstract] [Hide abstract] ABSTRACT: 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). 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. 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). 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.
    Full-text Article · Dec 2005 · Gut
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    M van Zonneveld · H J Flink · E Verhey · [...] · H L A Janssen
    [Show abstract] [Hide abstract] ABSTRACT: 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. To investigate the safety of pegylated interferon alpha-2b in 300 hepatitis B e antigen-positive patients with compensated liver disease. 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. 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. 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.
    Full-text Article · Jun 2005 · Alimentary Pharmacology & Therapeutics
  • HJ Flink · M van Zonneveld · HGM Niesters · [...] · HLA Janssen
    Article · Jan 2005 · European Journal of Gastroenterology & Hepatology
  • HJ Flink · M van Zonneveld · HGM Niesters · [...] · HLA Janssen
    Article · Jan 2005 · European Journal of Gastroenterology & Hepatology
  • HJ Flink · BE Hansen · M van Zonneveld · [...] · HLA Janssen
    Article · Jan 2005 · European Journal of Gastroenterology & Hepatology
  • H. J. Flink
    [Show abstract] [Hide abstract] ABSTRACT: Word-wide, infection with the hepatitis B virus (HBV) is a major health problem. Over 2 billion people have been exposed to HBV, and approximately 400 million are chronic carriers of the virus. Chronic hepatitis B (CHB) infection may lead in term to liver cirrhosis, hepatic decompensation and hepatocellular carcinoma (HCC), and is responsible for an estimated 1 million deaths annually. The efficacy of the established treatment for CHB is limited.Treatment with conventional interferon (IFN) is only effective in 20-35%. Lamivudine needs to be given long-term to maintain response and leads to emergence of viral resistant strains. Several studies have investigated different treatment options such as peginterferon, adefovir and entecavir.The first randomized controlled trial in HBeAg-positive CHB with peginterferon - which had proven to be more effective than conventional IFN in chronic hepatitis C patients demonstrated that a 52-week course of peginterferon alfa-2b leads to HBeAg seroconversion in 36%, ALT normalization in 35% and HBV DNA < 2.0 x 105 copies/mL in 32% of patients at the end of post treatment follow-up.The addition of lamivudine did not enhance response rates compared to peginterferon alfa-2b alone.The use of conventional IFN is not suited for all patients due to the significant side effects and early treatment discontinuation that may occur.Although the safety profile of peginterferon has been studied in chronic hepatitis C, the side effects of peginterferon in CHB patients have not previously been investigated. We assessed the safety of peginterferon treatment in 266 HBeAg-positive patients who received peginterferon alfa-2b alone or in combination with lamivudine (chapter 2). The most common side effects were similar to those reported for conventional IFN. Flu-like symptoms, headache, fatigue, myalgia, local reaction at the injection, abdominal discomfort and psychiatric symptoms were most frequently reported, but in general subsided during the course of therapy. Hematologic abnormalities (leucopenia, neutropenia and thrombocytopenia) were frequent but did not lead to serious infections or bleeding complications. Neutropenia was the major cause for dose reductions of peginterferon, whereas psychiatric symptoms (depression, psychosis) were the most important reasons for early treatment discontinuation. Pre-existing cirrhosis at baseline was an important risk factor for thrombocytopenia and (minor) bleeding complications.
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