Treatment cessation of entecavir in Asian patients with hepatitis B e antigen negative chronic hepatitis B: A multicentre prospective study

Gut (Impact Factor: 14.66). 05/2014; 64(4). DOI: 10.1136/gutjnl-2014-307237
Source: PubMed


The off-treatment durability of nucleos(t)ide analogue therapy in Asian hepatitis B e antigen (HBeAg) negative chronic hepatitis B (CHB) and the role of hepatitis B surface antigen (HBsAg) levels in predicting off-treatment durability has not been well investigated.
Following Asia-Pacific Association for the Study of the Liver guidelines, entecavir was stopped in Asian HBeAg negative patients treated for ≥2 years with undetectable HBV DNA levels on ≥3 separate occasions 6 months apart before treatment cessation. HBsAg and HBV DNA levels were prospectively monitored every 6-12 weeks for 48 weeks. Entecavir was restarted if there was virologic relapse (defined as HBV DNA >2000 IU/mL).
184 patients (mean age 53.9 years, 67.9% male) were recruited. The cumulative rate of virologic relapse at 24 and 48 weeks was 74.2% and 91.4%, respectively. The median HBV DNA level at virologic relapse was 11 000 (range 2115 to >1.98×10(8)) IU/mL. 42 (25.8%) patients had elevated alanine aminotransferase (median level 97 U/L, range 37-1058 U/L) during virologic relapse. Mean rate of off-treatment HBsAg decline was 0.018 (±0.456) log IU/mL/year. No patients cleared HBsAg. There was no correlation between off-treatment serial HBsAg and HBV DNA levels (r=-0.026, p=0.541). HBsAg levels at the time of entecavir commencement, entecavir cessation and the subsequent rate of HBsAg reduction were not associated with virologic relapse (all p>0.05).
Entecavir cessation in Asian HBeAg negative CHB resulted in high rates of virologic relapse, suggesting nucleos(t)ide analogue therapy should be continued indefinitely until the recognised treatment endpoint of HBsAg seroclearance.

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Available from: Vincent Wai-Sun Wong, Feb 25, 2015
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    • "This becomes more complete as a function of HBsAg decline and is maximal in those few patients achieving persistent HBsAg loss (Boni et al., 2012). Unfortunately, seroclearance of HBsAg rarely occurs and cessation of therapy results in virological and biochemical relapse in the majority of patients (Seto et al., 2015). As a result, lifelong NUC therapy is currently recommended. "
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    ABSTRACT: Current therapies for chronic hepatitis B virus infection (CHB) - nucleos(t)ide analogue reverse transcriptase inhibitors and interferons - result in low rates of functional cure defined as sustained off-therapy seroclearance of hepatitis B surface antigen (HBsAg). One likely reason is the inability of these therapies to consistently and substantially reduce the levels of viral antigen production. Accumulated evidence suggests that high serum levels of HBsAg result in exhaustion of the host immune system, rendering it unable to mount the effective antiviral response required for HBsAg clearance. New mechanistic approaches are required to produce high rates of HBsAg seroclearance in order to greatly reduce off-treatment disease progression. Already shown to be a clinically viable means of reducing gene expression in a number of other diseases, therapies based on RNA interference (RNAi) can directly target hepatitis B virus transcripts with high specificity, profoundly reducing the production of viral proteins. The fact that the viral RNA transcripts contain overlapping sequences means that a single RNAi trigger can result in the degradation of all viral transcripts, including all messenger RNAs and pregenomic RNA. Advances in the design of RNAi triggers have increased resistance to degradation and reduced nonspecific innate immune stimulation. Additionally, new methods to effectively deliver the trigger to liver hepatocytes, and specifically to the cytoplasmic compartment, have resulted in increased efficacy and tolerability. An RNAi-based drug currently in clinical trials is ARC-520, a dynamic polyconjugate in which the RNAi trigger is conjugated to cholesterol, which is coinjected with a hepatocyte-targeted, membrane-active peptide. Phase 2a clinical trial results indicate that ARC-520 was well tolerated and resulted in significant, dose-dependent reduction in HBsAg for up to 57days in CHB patients. RNAi-based therapies may play an important role in future therapeutic regimes aimed at improving HBsAg seroclearance and eliminating the need for lifelong therapy. This paper forms part of a symposium in Antiviral Research on "An unfinished story: from the discovery of the Australia antigen to the development of new curative therapies for hepatitis B." Copyright © 2015. Published by Elsevier B.V.
    Full-text · Article · Jun 2015 · Antiviral research
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    ABSTRACT: Background The treatment of HBeAg-negative chronic hepatitis B (CHB) is considered to be open-ended, with no guidelines for treatment cessation. Aim To evaluate biochemical and virological relapse requiring retreatment in noncirrhotic HBeAg-negative CHB in patients who stopped treatment following a period of prolonged viral suppression with nucleotides/nucleosides. Methods We performed a single-centre retrospective chart review of patients with HBeAg-negative CHB who maintained viral suppression for 4-5 years on antiviral treatment, and thus subsequently stopped treatment. The primary end point of composite relapse was defined by an increase in HBV DNA >2000 IU/mL, ALT elevation above 1.25x normal or doubling of ALT from cessation, and re-initiation of anti-viral therapy. Results We identified 33 patients with HBeAg-negative CHB who stopped treatment following viral suppression. Mean treatment duration was 5.28 +/- 2.73 years. Patients were treated with lamivudine (3), adefovir (14), entecavir (4), and tenofovir (12). Eleven (33%) patients met the primary end point of composite relapse. For individual end points, 21 (63%) patients had a viral relapse, 16 (48%) had a biochemical relapse, and 16 (48%) restarted treatment, leaving 17 (52%) patients who remained treatment-free over a median 36 months of follow-up. Lower pre-treatment ALT and detectable HBV DNA within the first month after treatment discontinuation were associated with increased rates of composite relapse (HR 1.01; P = 0.022 for ALT and HR 1.01; P = 0.038 for HBV DNA). Conclusion Patients with noncirrhotic HBeAg-negative CHB can stop treatment after greater than 4-5 years of suppressive therapy with nucleosides/nucleotides with more than 50% remaining treatment-free.
    No preview · Article · Aug 2014 · Alimentary Pharmacology & Therapeutics
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    ABSTRACT: Treatment cessation is one of the few challenges left to clinicians to deal with after the marketing and widespread use of third generation oral analogues (nucleos(t)ide analogue (NUC)), entecavir (ETV) and tenofovir (TDF) for the treatment of HBeAg negative chronic hepatitis B (CHB). Treatment efficacy is in fact unquestioned as more than 95% of patients, including NUC experienced and resistant ones, achieve complete suppression of viral replication and improvement of hepatic inflammation and fibrosis within the first 5 years of treatment.1-3 As a consequence, in a majority of patients, progression to cirrhosis is prevented, and clinical decompensation and portal hypertension either improved or prevented, with hepatocellular carcinoma (HCC) remaining the only complication in HBeAg negative patients long-term treated for with ETV or TDF.4 Indeed, the yearly attack rates of HCC range between 0.5% and 1% among non-cirrhotics and 2.5% and 4% among compensated cirrhotics, incidence rates not very different from what is expected in untreated patients.4 ,5 In these patients, the recommended stopping rule of NUC therapy is HBsAg seroconversion, defined as HBsAg loss and anti-HBs titres >100-200 IU/L,6-8 which has been proven to be safe in any clinical situation including patients with advanced liver disease, though a minority of patient clearing HBsAg following NUC therapy do not seroconvert to anti-HBs.9 ,10 One major caveat of this stopping rule is the small number of HBeAg negative patients who achieve HBsAg seroconversion, no more than 1% after 5 years and 5% after 10 years of continuous treatment, thereby questioning whether it is appropriate to stop NUC therapy before achieving HBsAg seronegativity. Asian Pacific Association for the Study of the Liver (APASL) guidelines indeed suggest this, but so far clinical evidence supporting these recommendations is more than scanty. In the study by Seto et al,11 treatment cessation … [Full text of this article]
    No preview · Article · Aug 2014 · Gut
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