Buster, E.H.C.J.

The importance of HBV genotype in HBeAg-positive chronic hepatitis B patients in whom sustained response is pursued (Article)

2011-01-01T00:00:00Z

Prediction of the response to peg-interferon-alfa in patients with HBeAG positive chronic hepatitis B using decline of HBV DNA during treatment (Article)

2010-07-01T00:00:00Z

Peginterferon (PEG-IFN) results in HBeAg loss combined with virologic response in only a minority of patients with HBeAg positive chronic hepatitis B. Baseline predictors of response to PEG-IFN include HBV-genotype, pre-treatment HBV DNA levels, and ALT. The aims of this study were to develop a model, which improves the baseline prediction of response to PEG-IFN for individual patients by including early HBV DNA measurements during treatment and to establish an early indication for cessation of treatment. One hundred thirty-six patients treated with PEG-IFN were included in the study. Response was defined as loss of HBeAg and HBV DNA <10,000 copies/ml at 26 weeks post-treatment. Logistic regression analysis techniques were used to develop a dynamic prediction model with HBV DNA during the first 32 weeks of therapy. An early clinically useful rule for dis(continuation) of treatment was identified with a grid of cut-off values of HBV DNA decline during treatment. Adding HBV DNA decline to baseline prediction increased c-statistics from 0.846 to 0.857, 0.855 to 0.866 at weeks 4, 12, and 24. A HBV DNA decline of at least 2 log10 within 24 weeks was strongly associated with response when added to the baseline prediction model: OR 5.7 (95% CI: 1.70-20.0; P=0.004). A dynamic model including HBV DNA decline during treatment provides more accurate predictions of response to PEG-IFN. The model strongly supports individual decision making on treatment (dis)continuation in patients with HBeAg positive chronic hepatitis B. It is recommended that PEG-IFN treatment is stopped by 24 weeks if HBV DNA declined <2 log10.

The importance of HBV genotype in HBeAg-positive chronic hepatitis B patients in whom sustained response is pursued (Article)

2010-01-01T00:00:00Z

Factors That Predict Response of Patients With Hepatitis B e Antigen-Positive Chronic Hepatitis B to Peginterferon-Alfa (Article)

2009-12-01T00:00:00Z

Background & Aims: Therapy with pegylated interferon (PEG-IFN)-alfa results in sustained response in a minority of patients with chronic hepatitis B virus (HBV) infection and has considerable side effects. We analyzed data from the 2 largest global trials of hepatitis B e antigen (HBeAg)-positive patients with chronic hepatitis B to determine which are most likely to respond to PEG-IFN-alfa therapy. Methods: The study included 542 patients treated with PEG-IFN-alfa-2a (180 μg/wk, 48 wk) and 266 patients treated with PEG-IFN-alfa-2b (100 μg/wk, 52 wk). Eighty-seven patients were excluded, leaving 721 patients for analysis. A sustained response was defined as HBeAg loss and HBV-DNA level less than 2.0 × 103IU/mL 6 months after treatment. Logistic regression analysis was used to identify predictors of sustained response and a multivariable model was constructed. Results: HBV genotype, high levels of alanine aminotransferase (ALT; ≥2 × upper limit of normal), low levels of HBV DNA (<2.0 × 108IU/mL), female sex, older age, and absence of previous IFN therapy predicted a sustained response. Genotype A patients with high ALT and/or low HBV-DNA levels had a high predicted probability (>30%) of a sustained response. The strongest predictors of response were a high level of ALT in genotype B patients and a low level of HBV DNA in genotype C patients. Genotype D patients had a low chance of sustained response, irrespective of ALT or HBV-DNA levels. Conclusions: The best candidates for a sustained response to PEG-IFN-alfa are genotype A patients with high levels of ALT or low levels of HBV DNA, and genotypes B and C patients who have both high levels of ALT and low HBV DNA. Genotype D patients have a low chance of sustained response.

Chronic Hepatitis B: Individualized Antiviral Therapy (Doctoral Thesis)

2009-10-23T00:00:00Z

The hepatitis B virus (HBV) was discovered in 1966 with the identification of the Australia antigen in Aboriginals by Dr. Baruch Blumberg, who received the 1976 Nobel Prize in Medicine for his work. We now know the Australia antigen as hepatitis B surface antigen (HBsAg). HBV belongs to a family of closely related DNA viruses called the hepadnaviruses. The viral genome of HBV is a partially double- stranded circular DNA of approximately 3200 base pairs that encodes four overlapping open reading frames: the surface or envelope gene, the core gene, the polymerase gene and the X gene. The core gene can also produce a soluble small molecular weight protein called hepatitis B e antigen (HBeAg) by an alternate start codon and post-translational modification. After entry in the hepatocyte, the HBV DNA is transported to the nucleus and converted to covalently closed circular DNA (cccDNA), which serves as the stable template for transcription of both messenger RNA (for translation of viral proteins) and pre-genomic RNA (for reverse transcription into genomic DNA). Because the cccDNA is highly resistant to antiviral therapy and the host's immunological response, complete eradication of HBV from the liver is probably not feasible.1 HBV is non-cytopathic, cellular injury in HBV infected persons appears immune-mediated.

Early hbeag loss during peginterferon α-2b therapy predicts HBsAg loss: Results of a long-term follow-up study in chronic hepatitis B patients (Article)

2009-10-01T00:00:00Z

OBJECTIVES:Treatment with pegylated interferon (PEG-IFN) α-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.METHODS:A total of 91 patients treated with PEG-IFN α-2b alone (100 g per week) and 81 patients treated with PEG-IFN α-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: 3.030.77 years 26 weeks post treatment).RESULTS: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 loss32 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; P0.009). Hepatitis B surface antigen (HBsAg) negativity was also observed significantly more often in patients with early HBeAg loss (36 vs. 4%, respectively, P0.001). 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%; P0.10), as did HBsAg loss (15 vs. 8%; P0.14).CONCLUSIONS: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.

Comments on the EASL practice guidelines for the management of chronic hepatitis B: Controversies in interferon-based therapy (Article)

2009-07-01T00:00:00Z

Peginterferon for the treatment of chronic hepatitis B in the era of nucleos(t)ide analogues (Article)

2008-12-01T00:00:00Z

The practising clinician is currently faced with a number of effective treatment options for chronic hepatitis B, including two formulations of interferon (standard IFN and pegylated IFN) and five nucleos(t)ide analogues (lamivudine, adefovir, entecavir, telbivudine and tenofovir). Treatment strategies can be divided into those aiming for sustained response after discontinuation of therapy and those that need to be maintained by prolonged antiviral therapy. Sustained response is particularly achieved with interferon-based therapy, while treatment-maintained response can be achieved with long-term nucleos(t)ide analogue therapy in the majority of patients. Of currently available drugs for the treatment of chronic hepatitis B, PEG-IFN seems to result in the highest rate of off-treatment sustained response after a 1-year course of therapy. Sustained transition to the immune-control phase (inactive HBsAg carrier state) can be achieved in 30-35% of HBeAg-positive patients and 20-25% of HBeAg-negative patients. Loss of HBsAg has been observed in 11% of both HBeAg-positive and HBeAg-negative patients after 3-4 years. Since hepatitis B virus (HBV) genotype is an important predictor of response to PEG-IFN, determination of HBV genotype is essential in patients in whom sustained off-treatment response is pursued. Aiming for sustained response is of particular interest because many HBV-infected patients are in need of antiviral therapy at a young age and may otherwise require indefinite antiviral therapy.

Sustained HBeAg and HBsAg Loss After Long-term Follow-up of HBeAg-Positive Patients Treated With Peginterferon α-2b (Article)

2008-08-01T00:00:00Z

Background & Aims: 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) α-2b alone or in combination with lamivudine. Methods: 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 α-2b (100 μg/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). Results: 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). Conclusions: HBeAg loss after treatment with PEG-IFN α-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 α-2b remains an important treatment option in this era of nucleos(t)ide analogue therapy.

Thiopurine-methyltransferase and inosine triphosphate pyrophosphatase polymorphism in a liver transplant recipient developing nodular regenerative hyperplasia on low-dose azathioprine (Article)

2008-01-01T00:00:00Z

The enzymes thiopurine-methyltransferase (TPMT) and inosine triphosphate pyrophosphatase (ITPA) are involved in thiopurine metabolism. We describe a liver transplant recipient who presented with liver enzyme abnormalities after 78 months of low-dose azathioprine (AZA) therapy (less than 1 mg/kg). No underlying etiology of these abnormalities was identified after extensive analysis including repeated liver biopsy. Fifteen years after transplantation, the patient presented with variceal bleeding, liver biopsy showed nodular regenerative hyperplasia (NRH). TPMT*3C genotype was found in the patient's lymphocytes and heterozygous ITPA (94C>A) genotype was found in both patient and donor liver. These findings further emphasize the importance of pharmacogenetics in predicting NRH and other adverse events during AZA therapy. Furthermore, a high index of suspicion with early detection of NRH is crucial, as improvement seems only to occur in patients with compensated liver disease. Liver biopsy and discontinuation of AZA are recommended in case of liver enzyme abnormalities or signs of portal hypertension.

Relapse after treatment with peginterferon α-2b alone or in combination with lamivudine in HBeAg positive chronic hepatitis B (Article)

2007-10-01T00:00:00Z

Peginterferon alpha-2b is safe and effective in HBeAg-positive chronic hepatitis B patients with advanced fibrosis (Article)

2007-08-01T00:00:00Z

Chronic hepatitis B (CHB) patients with advanced fibrosis are often not considered for treatment with peginterferon (PEG-IFN) because IFN therapy may precipitate immunological flares, potentially inducing hepatic decompensation. We investigated the efficacy and safety of treating hepatitis B e antigen (HBeAg)-positive CHB patients with 52 weeks of PEG-IFN-α-2b (100 μg weekly) alone or in combination with lamivudine (100 mg daily). Seventy patients with advanced fibrosis (Ishak fibrosis score 4-6) and 169 patients without advanced fibrosis, all with compensated liver disease, participated in the study. Virologic response, defined as HBeAg seroconversion and hepatitis B virus (HBV) DNA < 10,000 copies/ml at week 78, occurred significantly more often in patients with advanced fibrosis than in those without (25% versus 12%, respectively; P = 0.02). Also patients with cirrhosis (n = 24) exhibited a virologic response more frequently than did patients without cirrhosis (30% versus 14%, respectively; P = 0.02). Improvement in liver fibrosis occurred more frequently in patients with advanced fibrosis (66% versus 26%, P < 0.001). HBV genotype A was more prevalent among patients with advanced fibrosis than among those without (57% versus 24%, P < 0.001). Most adverse events, including serious adverse events, were observed equally as frequently in patients with advanced fibrosis and those without. Fatigue, anorexia, and thrombocytopenia occurred more often in patients with advanced fibrosis than in those without (P < 0.01). Necessary dose reduction or discontinuation of therapy was comparable for both patient groups (P = 0.92 and P = 0.47, respectively). Conclusion: PEG-IFN is effective and safe for HBeAg-positive patients with advanced fibrosis. Because PEG-IFN therapy results in a high rate of sustained off-therapy response, patients with advanced fibrosis or cirrhosis but compensated liver disease should not be excluded from PEG-IFN treatment. Copyright

Prolonged antiviral therapy for hepatitis B virus-infected health care workers: A feasible option to prevent work restriction without jeopardizing patient safety (Article)

2007-05-01T00:00:00Z

To prevent transmission of hepatitis B virus (HBV) from health care workers (HCWs) to patients, highly viraemic HCWs are often advised to restrict performing exposure prone procedures (EPPs). To prevent loss of highly qualified medical personnel and simultaneously minimize transmission risk to patients, we offered highly viraemic HCWs antiviral therapy and evaluated the effects of this strategy. Eighteen chronic HBV-infected HCWs have been monitored every 3-6 months for a median period of 5.6 years (range 1.1-12.5 years). Antiviral therapy was offered if HBV DNA was above 105copies/mL and EPPs were performed or active liver disease was present. Median HBV DNA levels, the percentage of days with HBV DNA above 103, 104and 105copies/mL, and reduction of HBV DNA during antiviral treatment have been analysed for hepatitis B e antigen (HBeAg)-positive and HBeAg-negative HCWs separately. Prolonged viral suppression was achieved in both HBeAg-positive, as well as HBeAg-negative HCWs. In HBeAg-negative HCWs treatment with interferon or lamivudine maintained HBV DNA levels below 105copies/mL. For HBeAg-positive HCWs continuous treatment with tenofovir or entecavir was essential for reaching low viraemia persistently. In 2004, median HBV DNA levels in both HBeAg-negative and HBeAg-positive HCWs were below 103copies/mL and all HCWs executed their professional work full-range. For both HBeAg-positive and HBeAg-negative HCWs, antiviral treatment is effective in persistent suppression of virus levels below 105copies/mL. This observation supports antiviral therapy as a viable management option instead of work restriction, with the provision of regular expert monitoring including quantification of HBV DNA.

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

2006-01-01T00:00:00Z

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.