Reijnders, J.G.P.

Virological response to entecavir is associated with a better clinical outcome in chronic hepatitis B patients with cirrhosis (Article)

2013-05-01T00:00:00Z

Objective Entecavir (ETV) is a potent inhibitor of viral replication in chronic hepatitis B and prolonged treatment may result in regression of fibrosis. The aim of this study was to investigate the effect of ETV on disease progression. Design In a multicentre cohort study, 372 ETV-treated patients were investigated. Clinical events were defined as development of hepatocellular carcinoma (HCC), hepatic decompensation or death. Virological response (VR) was defined as HBV DNA <80 IU/ml. Results Patients were classified as having chronic hepatitis B without cirrhosis (n=274), compensated cirrhosis (n=89) and decompensated cirrhosis (n=9). The probability of VR was not influenced by severity of liver disease (p=0.62). During a median follow-up of 20 months (IQR 11e32), the probability of developing clinical events was higher for patients with cirrhosis (HR 15.41 (95% CI 3.42 to 69.54), p<0.001). VR was associated with a lower probability of disease progression (HR 0.29 (95% CI 0.08 to 1.00), p=0.05) which remained after correction for established risk factors such as age. The benefit of VR was only significant in patients with cirrhosis (HR 0.22 (95% CI 0.05 to 0.99), p=0.04) and remained after excluding decompensated patients (HR 0.15 (95% CI 0.03 to 0.81), p=0.03). A higher HBV DNA threshold of 2000 IU/ml was not associated with the probability of disease progression (HR 0.20 (95% CI 0.03 to 1.10), p=0.10). Conclusion VR to ETV is associated with a lower probability of disease progression in patients with cirrhosis, even after correction for possible baseline confounders. When using a threshold of 2000 IU/ml, the association between viral replication and disease progression was reduced, suggesting that complete viral suppression is essential for nucleoside/nucleotide analogue treatment, especially in patients with cirrhosis.

Precore and core promoter mutants are associated with higher HBeAg seroconversion but low disease remission rates in HBV patients treated with nucleos(t)ide analogues (Article)

2013-05-01T00:00:00Z

HBeAg seroconversion in HBV patients is considered an important event. We determined precore (PC) and base core promoter (BCP) mutations in 137 HBeAg-positive nucleos(t)ide analogues (NA) treated patients by INNO-LiPA HBV PreCore assay (Innogenetics). The majority of patients with nongenotype A had PC/BCP mutants present at baseline (P = 0.02). During 29 months of therapy, 45 patients achieved HBeAg seroconversion. Probability of HBeAg seroconversion was higher in patients with PC and/or BCP mutants (P = 0.01). After HBeAg seroconversion, patients with BCP mutants had more HBeAg relapse (P = 0.07), and PC mutants less often achieved HBV DNA < 2000 IU/mL (P = 0.07).

Identification and treatment of chronic hepatitis B in Chinese migrants: Results of a project offering on-site testing in Rotterdam, the Netherlands (Article)

2012-12-01T00:00:00Z

Background & Aims: Migrants born in countries where hepatitis B is endemic are a risk group for chronic hepatitis B virus (HBV) infection. Treatment options have improved, but due to the asymptomatic nature of chronic HBV infection, the majority of patients remain unidentified. Methods: In 2009, a campaign targeting the Chinese community was held in the city of Rotterdam, The Netherlands. The campaign combined disease awareness activities with free HBV testing at outreach locations. Chronically HBV infected patients were referred to specialist care based on a referral guideline. Before and after the campaign, knowledge of chronic hepatitis B was measured through questionnaires in a convenience sample of the target population (n = 285 and n = 277). Results: In a period of 3 months, 13 outreach activities took place and 1090 Chinese migrants were tested for HBV. Forty-nine percent had serological signs of a past or recent HBV infection and 8.5% (n = 92) were chronically infected. Thirty-eight percent (n = 35) of chronically infected patients were referred for evaluation by a specialist and of these, 15 started antiviral treatment within 1 year of follow-up. Before the campaign, 55% answered correctly to 6 or more out of 10 knowledge items. Knowledge was positively associated with educational level. After the campaign, an increase in knowledge was observed in participants with low levels of education. Conclusions: Chinese migrants could be reached with an outreach campaign, and on-site testing was well accepted. A high prevalence of chronic HBV infection was found and referral to specialist care and initiation of treatment was successful.

Hepatitis B surface antigen declines and clearance during long-term tenofovir therapy in patients coinfected with HBV and HIV (Article)

2012-09-15T00:00:00Z

Background.The kinetics of hepatitis B surface antigen (HBsAg) are predictive in HBV-infected patients treated with pegylated interferon. Knowledge about the value of HBsAg levels in patients coinfected with HBV and human immunodeficiency virus (HIV) is lacking.Methods.We quantified serum HBsAg in a Dutch multicenter cohort of 104 patients coinfected with HIV and HBV who were treated with tenofovir disoproxil fumarate (TDF) as part of highly active antiretroviral therapy. The median duration of therapy was 57 months (interquartile range, 34-72 months).Results.Hepatitis B e antigen (HBeAg)-positive patients achieved a decline of 2.2 log IU/mL in HBsAg, whereas HBeAg-negative patients only achieved a decline of 0.6 log IU/mL during 6 years of TDF therapy. Declines in HBsAg at months 6 and 12 correlated with CD4 cell count for HBeAg-positive patients. Five HBeAg-positive patients (8) and 3 HBeAg-negative patients (8) cleared HBsAg. HBeAg-negative patients who cleared HBsAg had lower baseline HBsAg as compared to patients who remained HBsAg positive. The majority of patients who cleared HBsAg achieved this end point within the first year. In HBeAg-positive patients, decline in HBsAg at month 6 was predictive of achieving HBsAg seroclearance.Conclusions.Receipt of TDF therapy by HIV/HBV-coinfected patients for up to 6 years led to a significant decrease in HBsAg in the HBeAg-positive population. HBsAg kinetics early during treatment were predictive of HBsAg seroclearance and correlated with an increased CD4 cell count, underlining the importance of immune restoration in HBV clearance. © 2012 The Author.

Entecavir treatment for chronic hepatitis B: Adaptation is not needed for the majority of naïve patients with a partial virological response (Article)

2011-08-01T00:00:00Z

Entecavir (ETV) is a potent inhibitor of viral replication in nucleos(t)ide analogue (NA)-naïve chronic hepatitis B (CHB) patients. The aim of this study was to investigate the long term efficacy and safety of ETV in NA-naïve CHB patients, particularly in those with detectable hepatitis B virus (HBV) DNA after 48 weeks, in whom treatment adaptation is suggested by current guidelines. In a multicenter cohort study, we investigated 333 CHB patients treated with entecavir monotherapy. The NA-naïve population consisted of 243 patients, whereas 90 were NA-experienced. Virological response (VR) (HBV DNA <80 IU/mL) was achieved in 48%, 76%, and 90% of hepatitis B e antigen (HBeAg)-positive and in 89%, 98%, and 99% of HBeAg-negative NA-naïve patients at weeks 48, 96, and 144, respectively. Thirty-six of 175 (21%) NA-naïve patients with at least 48 weeks of follow-up had a detectable load at week 48 (partial virological response [PVR]). Twenty-nine (81%) patients with PVR reached VR during prolonged ETV monotherapy, and none of them developed ETV-resistance. Among 22 patients with HBV DNA <1,000 IU/mL at week 48, VR was achieved in 21 (95%) patients, compared with eight of 14 (57%) patients with HBV DNA ≥1,000 IU/mL. Continuous HBV DNA decline was observed in most patients without VR during follow-up, and in three patients adherence was suboptimal according to the treating physician. ETV was safe and did not affect renal function or cause lactic acidosis. Conclusion: ETV monotherapy can be continued in NA-naïve patients with detectable HBV DNA at week 48, particularly in those with a low viral load because long-term ETV leads to a virological response in the vast majority of patients.

Adefovir serum levels do not differ between responders and nonresponders (Article)

2011-07-01T00:00:00Z

Primary or secondary failure of adefovir dipivoxil (ADV) therapy of chronic hepatitis B is not infrequent. The reasons for suboptimal responses are not well defined. In HIV and hepatitis C virus infection, failure of antiviral drug therapy has been linked with low blood drug levels. We have studied 20 well-defined patients with chronic hepatitis B who were treated with ADV for drug and virus kinetics. Importantly, neither Cmax levels (mean 26 ng/mL, range 14-59 ng/mL) nor the time to maximal drug levels (mean 4 h, range 2-8 h) differed between patients showing a complete virological response to adefovir (n = 10), patients with secondary treatment failure (n = 7) and patients with suboptimal primary response (hepatitis B virus-DNA >10 000 IU/mL after 6 months of treatment; n = 3). Thus, adefovir treatment failure is unlikely to be due to an inability to mount sufficient drug levels in the blood.

Frequency and clinical outcomes of flares related to nucleos(t)ide analogue therapy in patients with chronic hepatitis B (Article)

2011-07-01T00:00:00Z

Flares in chronic hepatitis B are often detrimental but sometimes lead to sustained immune control and disease remission. The aim of this study was to estimate the frequency of hepatitis flares which occur during and/or after cessation of nucleos(t)ide analogue (NA) therapy, and to assess their outcomes. In a single centre cohort study we investigated 227 patients who received a total of 351 NA treatment courses. NA therapy was discontinued after 149 treatment courses. In total, 27 flares were observed during 9779 on-treatment patient-months. The frequency was estimated as 3.2 per 100 person-years (95% CI 2.2-4.7). Lamivudine (LAM)-treated patients demonstrated the highest frequency (4.9/100 person-years, 95% CI 3.2-7.4). Twenty (74%) of 27 on-therapy flares were associated with development of genotypic resistance, which all occurred during LAM therapy. NA withdrawal flares occurred after a median post-treatment follow-up of 3.5 months in 17 (11%) of 149 treatment discontinuations. No flares were observed in patients who switched to another antiviral agent (n = 51). None of the on-therapy and withdrawal flares related to NA therapy were associated with sustained disease remission, and seven flares resulted in decompensated liver disease. In this study, flares related to NA therapy never led to immune control and sustained disease remission, and sometimes resulted in decompensated liver disease.

Long-term therapy with tenofovir is effective for patients co-infected with human immunodeficiency virus and hepatitis b virus (Article)

2010-12-01T00:00:00Z

Background & Aims We investigated the long-term efficacy and renal safety of tenofovir disoproxil fumarate (TDF), administered to patients co-infected with human immunodeficiency virus and hepatitis B virus (HBV) as part of an antiretroviral therapy. Methods We performed a multicenter, prospective cohort study of 102 patients co-infected with human immunodeficiency virus and HBV who were treated with TDF. Results At baseline, 80% of patients had a detectable viral load (HBV DNA >20 IU/mL). Among patients positive for hepatitis B e antigen (HBeAg) (n = 67), 92% had a virologic response (HBV DNA <20 IU/mL) after 5 years of treatment. There was no difference between patients with or without lamivudine resistance at baseline (P = .39). Loss rates of HBeAg and hepatitis B s antigen (HBsAg) were 46% and 12%, respectively. Among HBeAg-negative patients (n = 15), 100% had a virologic response after 4 years of treatment and 2 (13%) lost HBsAg. Twenty subjects (20%, all HBeAg-negative) had undetectable HBV DNA at baseline; during a median follow-up period of 52 months (interquartile range, 4163 mo), 19 (95%) maintained a virologic response and 2 (10%) lost HBsAg. Overall, one patient acquired a combination of resistance mutations for anti-HBV drugs and experienced a virologic breakthrough. Three (3%) patients discontinued TDF because of increased serum creatinine levels. The estimated decrease in renal function after 5 years of TDF therapy was 9.8 mL/min/1.73 m2, which was most pronounced shortly after TDF therapy was initiated. Conclusions TDF, administered as part of antiretroviral therapy, is a potent anti-HBV agent with a good resistance profile throughout 5 years of therapy. Only small nonprogressive decreases in renal function were observed.

Optimizing Treatment Strategies Using Nucleos(t)ide Analogues for Patients with Chronic Hepatitis B (Doctoral Thesis)

2010-11-24T00:00:00Z

Hepatitis B infection has a complex natural history and causes a wide spectrum of disease. Although effective vaccines are available, universal vaccination has yet not been reached. Currently, an estimated 350 million people are chronically infected, and 0.5-1.2 million subjects die every year due to long-term sequalae of hepatitis B related chronic liver disease, such as liver cirrhosis and hepatocellular carcinoma Despite evidence-based treatment guidelines areas of disagreement on the management of chronic hepatitis B virus (HBV) infection still exist. With the currently approved treatment options the ultimate goal is to prevent the development of long-term sequelae of chronic liver disease. Current treatment strategies consist of either therapies with fi nite duration that aims to achieve sustained off-treatment remission (interferon-based therapy), or long-term therapy that aims to maintain on-treatment response (nucleos(t)ide analogues).

Nucleos(t)ide analogues only induce temporary hepatitis B e antigen seroconversion in most patients with chronic hepatitis B (Article)

2010-08-17T00:00:00Z

Background & Aims: Inconsistencies in results and guideline recommendations regarding the durability of nucleos(t)ide analogue-induced hepatitis B e antigen (HBeAg) seroconversion require clarification. We studied the long-term durability of nucleos(t)ide analogue-induced HBeAg seroconversion in patients with chronic hepatitis B virus (HBV) infection. Methods: We performed a single-center cohort study of 132 HBeAg-positive patients who had received nucleos(t)ide analogue therapy. Results: During a median treatment duration of 26 months (range, 16-43 mo), HBeAg seroconversion occurred in 46 of 132 subjects (35%). Forty-two subjects (91%) had follow-up evaluation after HBeAg seroconversion. During a median follow-up period of 59 months (range, 28-103 mo) after HBeAg seroconversion, 13 of 42 patients (31%) showed a durable remission (defined as HBeAg negative and HBV-DNA level <10,000 copies/mL). Overall, 33 of 42 subjects (79%) continued therapy after HBeAg seroconversion; of these, 22 (67%) showed serologic and/or virologic recurrence. Nine of 42 subjects (21%) discontinued therapy after HBeAg seroconversion and at least 6 months of consolidation therapy. Only 2 patients showed a durable response in the absence of therapy. Disease recurrence in patients who continued therapy after HBeAg seroconversion was preceded by the development of resistance (80% of these patients); resistance only occurred in subjects given lamivudine monotherapy. In contrast, recurrence after treatment discontinuation or noncompliance was observed in all patients given nucleos(t)ide analogues. Conclusions: Induction of HBeAg seroconversion by nucleos(t)ide analogues is temporary in most patients with chronic HBV infection. Long-term continuation of nucleos(t)ide analogue treatment, irrespective of the occurrence of HBeAg seroconversion, appears to be necessary.

Antiviral effect of entecavir in chronic hepatitis B: Influence of prior exposure to nucleos(t)ide analogues (Article)

2010-04-01T00:00:00Z

Background & Aims: Entecavir is a potent inhibitor of viral replication in nucleos(t)ide analogue (NA)-naïve chronic hepatitis B patients, but data on the efficacy in NA-experienced subjects are limited. Methods: In a multi-center cohort study we investigated 161 chronic hepatitis B patients (34% NA-experienced) treated with entecavir monotherapy. Results: During a median follow-up of 11 (3-23) months, 82 (79%) of 104 NA-naïve patients achieved virologic response (VR), defined as HBV DNA <80 IU/ml, and none of the patients (0%) developed genotypic entecavir-resistance. VR was demonstrated in 31 (54%) of 57 NA-experienced patients during a median follow-up of 12 (3-31) months. Patients with lamivudine-resistant mutations at the start of entecavir monotherapy had a reduced probability of achieving VR compared to lamivudine-naïve patients (HR 0.14; 95% CI 0.04-0.58; p = 0.007). Antiviral efficacy was not decreased by prior treatment with lamivudine when lamivudine-resistance had never developed (HR 0.81; 95% CI 0.43-1.52; p = 0.52). Prior adefovir therapy without development of adefovir-resistance (HR 0.84; 95% CI 0.43-1.64; p = 0.61) and presence of adefovir-resistance (HR 0.86; 95% CI 0.27-2.71; p = 0.80) did not influence antiviral response to entecavir. Switching to a tenofovir-containing treatment regimen resulted in viral load decline in patients with entecavir-resistance associated mutations. Conclusions: Entecavir proved to be efficacious in NA-naïve patients. The antiviral efficacy of entecavir was not influenced by prior treatment with adefovir or presence of adefovir-resistance. Entecavir should not be used in patients with previous lamivudine-resistance, yet it may still be an option in lamivudine-experienced patients in case lamivudine-resistance never developed.

Kinetics of hepatitis B surface antigen differ between treatment with peginterferon and entecavir (Article)

2010-01-01T00:00:00Z

Background & Aims: We aimed to investigate serum hepatitis B surface antigen (HBsAg) levels in patients with chronic hepatitis B virus (HBV) infection during peginterferon (PEG-IFN) and entecavir (ETV) monotherapy. Methods: HBsAg was quantified (Abbott ARCHITECT) at baseline and during antiviral therapy (weeks 12, 24, 36, 48) in hepatitis B e antigen (HBeAg-) positive patients treated with ETV (n = 33) or PEG-IFN (n = 61) and in HBeAg-negative patients treated with ETV (n = 37) or PEG-IFN (n = 69). Results: Within the HBeAg-positive population, patients treated with PEG-IFN tended to have a steeper HBsAg decline than ETV-treated patients (mean decline 0.94 versus 0.38 log IU/ml at week 48, p = 0.07 for comparison of the slope of HBsAg decline). The HBsAg decline was larger in those patients who became HBeAg negative, irrespective of the treatment regimen. A decline in HBsAg was confined to ETV-treated patients with elevated baseline alanine aminotransferase (ALT) levels, whereas HBsAg decline was not associated with baseline ALT in patients treated with PEG-IFN. Within the HBeAg-negative population, PEG-IFN induced a significant HBsAg decline, while HBsAg did not decrease in ETV-treated patients (0.56 versus -0.10 log IU/ml, p <0.001). Both in HBeAg-positive and HBeAg-negative patients, the decline in serum HBV DNA was larger in patients who received ETV as compared with patients treated with PEG-IFN. Conclusions: In HBeAg-positive patients, the decline in serum HBsAg is mainly confined to patients who clear HBeAg, by either PEG-IFN or ETV treatment. In HBeAg-negative patients, PEG-IFN therapy resulted in a significant reduction in HBsAg levels, whereas HBsAg did not decrease in ETV-treated patients.Association for the Study of the Liver.

Treatment with nucleos(t)ide analogues in chronic hepatitis B: Where does the road map lead us? (Article)

2009-07-01T00:00:00Z

Entecavir shows limited efficacy in HBeAg-positive hepatitis B patients with a partial virologic response to adefovir therapy (Article)

2009-04-01T00:00:00Z

Background/Aims: We investigated the efficacy of entecavir in lamivudine-experienced and -naïve patients with persistently high HBV DNA during adefovir treatment. Methods: Fourteen chronic hepatitis B patients (57% lamivudine-experienced) with a viral load above 5 log10 copies/mL after 12 months of adefovir therapy and thereafter were treated with entecavir 1 mg daily. Results: During a median follow-up of 15 months (range: 8-23 months) one of six lamivudine-naïve and none of the eight lamivudine-experienced patients achieved undetectable HBV DNA (<373 copies/mL). HBeAg loss occurred in none of the subjects. Two lamivudine-experienced patients demonstrated the rtM204I mutation; no other entecavir-resistant substitutions were detected (rtI169, rtT184, rtS202, and rtM250). Two of three patients with genotypic adefovir resistance at baseline demonstrated a rapid virologic response to entecavir, but undetectable HBV DNA was not achieved. To attain a better antiviral response the dosage of entecavir was increased to 2 mg daily in two patients, resulting in further viral load decline for both of them. Conclusions: Entecavir monotherapy dosed at 1 mg resulted in a slow reduction of viral load in both lamivudine-experienced and -naïve patients with persistently high HBV DNA during adefovir therapy. Increasing the dosage of entecavir led to further HBV DNA decline.

On-treatment monitoring of adefovir therapy in chronic hepatitis B: Virologic response can be assessed at 24 weeks (Article)

2009-02-01T00:00:00Z

Patients with chronic hepatitis B (CHB) who will and those who will not respond to adefovir (ADV) monotherapy need to be identified at an early stage in order to adjust treatment and prevent future development of antiviral resistance. In a single-centre cohort study, we investigated 76 CHB patients [50% hepatitis B e antigen (HBeAg)-positive] treated with long-term ADV monotherapy. During a median follow-up of 122 (24-185) weeks, 42 (55%) patients achieved virologic response (VR), defined as HBV-DNA levels <103copies/mL, and 10 patients (13%) developed genotypic ADV resistance. Independent baseline predictors of VR were HBeAg negativity [hazard ratio (HR) 2.98; 95% confidence interval (CI) 1.24-7.19; P = 0.02], high alanine aminotransferase (ALT) levels (HR 1.11; 95% CI 1.05-1.18; P = 0.001), and low HBV-DNA levels (HR 0.56; 95% CI 0.41-0.75; P < 0.001). HBV-DNA at week 24 demonstrated a higher predictive value for VR than HBV-DNA at week 48. Important predictors of genotypic resistance were presence of cirrhosis (HR 6.54; 95% CI 1.39-30.9; P = 0.018), and not achieving VR during treatment (HR 6.60; 95% CI 1.35-32.4; P = 0.008). Patients without VR at week 24 already demonstrated a trend towards the emergence of ADV resistance (P = 0.07). HBV-DNA at week 24 was a better on-treatment predictor of VR than HBV-DNA at week 48, and ADV-resistant mutations developed more frequently in patients without VR at week 24. Therefore, our study suggests that virologic response to ADV therapy can be assessed at 24 weeks, instead of the generally recommended 48 weeks.

How effective is adefovir dipivoxil plus lamivudine for the treatment of lamivudine-resistant chronic hepatitis B? (Article)

2008-10-15T00:00:00Z

Studies have demonstrated the superior efficacy of adding adefovir dipivoxil to existing lamivudine therapy compared with switching to adefovir dipivoxil monotherapy in patients with lamivudine-resistant chronic HBV infection. This Practice Point commentary discusses a study by Yatsuji et al., which investigated the long-term efficacy of adding adefovir dipivoxil to lamivudine as salvage therapy in a cohort of 132 patients with lamivudine-resistant chronic HBV infection. After 2 years of treatment, approximately 80% of patients achieved HBV DNA levels less than 400 copies/ml, and only 1.6% of patients developed adefovir-dipivoxil-resistant viral mutations during follow-up. Although these results are promising, the duration of follow-up in this study is too short to draw a definitive conclusion concerning the efficacy of this so-called adefovir dipivoxil 'add-on' strategy, as resistance rates could rapidly increase over time. In addition, tenofovir disoproxil seems to be superior to adefovir dipivoxil in this setting and treatment strategies focused on the prevention of drug resistance should be investigated.

Potency of tenofovir in chronic hepatitis B: Mono or combination therapy? (Article)

2008-03-01T00:00:00Z