The Norwegian Nucleoside Analogue Stop Study

Study Overview
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Brief Summary
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Globally, an estimated 257 million individuals have chronic hepatitis B-virus infection (CHB). In the absence of treatment 15-40% of these will progress to liver cirrhosis and/or hepatocellular carcinoma. Oral antiviral treatment suppresses the virus and improves prognosis, but less than 0.5% per year achieve a functional cure (i.e. HBsAg loss). One remaining controversy, therefore, is whether antiviral treatment must continue life-long. Observational studies have assessed stopping antiviral treatment after years of viral suppression; however, HBsAg loss has rarely been seen. But interestingly, a few small trials that chose watchful waiting instead of re-initiation of treatment when reactivation occurred, achieved 40% HBsAg loss during 6 years follow-up. The present proposal is a randomized controlled trial that will assess the safety, efficacy, and cost-effectiveness of treatment discontinuation - and delayed restart - in HBeAg negative CHB. The study is sufficiently powered to address the hypotheses, and a pilot study that demonstrates feasibility has been performed. Patients will be enrolled at 12 Norwegian hospitals, in addition to our collaborating institution in Ethiopia - the largest CHB treatment center in sub-Saharan Africa. If the study shows that discontinuation is safe and effective, it will directly impact both national and international treatment guidelines. Main objective: -To study whether stopping nucleoside analogue (NA) therapy - and delaying re-start - can trigger an immune response and set off a functional cure (viz HBsAg loss) Secondary objectives: Assess whether stopping NA therapy - and delaying re-start - leads to a higher chance of HBsAg loss Assess the safety of stopping NA therapy - and delaying re-start - in terms of hepatic decompensation, fibrosis progression, and/or adverse events Study whether stopping NA therapy - and delaying re-start - leads to a higher chance of sustained off-therapy immune control (low viral load and normal ALT) Assess the quality of life and cost-effectiveness of stopping NA therapy - and delaying re-start Identify predictors of HBsAg loss

Official Title
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The Norwegian Nucleoside Analogue Stop Study: a Randomized Open-label Trial in HBeAg Negative Chronic Hepatitis B, Aiming at Achieving a Functional Cure.

Conditions
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Hepatitis B, Chronic

Intervention / Treatment
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* Other: Stop of therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adults (18-70 years) with HBeAg negative chronic hepatitis B HBeAg negative at start of antiviral therapy Treated minimum 2 years with either tenofovir or entecavir without interruption (i.e. no self-reported episodes of ≥2 weeks off therapy) Full viral suppression >2 years: at least 3 measurements at least 6 months apart with at least 24 months between the first and last measurement. Most recent liver fibrosis assessment, performed within the past 12 months, does not show advanced fibrosis (i.e. Metavir score <F3 or Fibroscan <9 kPa). For the (few) patients who lack pre-treatment fibrosis assessment, a more conservative Fibroscan threshold of <8 kPa will apply. Exclusion Criteria: A history of decompensated liver disease, either by clinical signs (ascites, encephalopathy, portal hypertension, jaundice) or suggestive laboratory results (total bilirubin >38 umol/L, INR >1.5, platelets <75,000/mm3, serum albumin <30 g/L). Any previous diagnosis of cirrhosis, either by liver biopsy (Metavir score F4) or elastography (Fibroscan >12 kPa). Elastography results with concomitant ALT >200 U/L are not considered. Previous hepatocellular carcinoma (HCC). Co-infections with HIV, hepatitis C or hepatitis D. Other disease or medication that can interfere with the study (e.g. ongoing alcohol or illicit drug abuse, immunosuppressive medication, other active liver disease, or any other condition which in the opinion of the physician is incompatible with participation)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Low-threshold re-start<br>Re-start antiviral therapy if HBV DNA viral load >2000 IU/ml and ALT >80 U/L. | Other: Stop of therapy<br>* The active intervention is to stop antiviral therapy, and delay re-start in the high-threshold group.<br>|
| Other: High-threshold re-start<br>Re-start antiviral therapy if: ALT >100 U/L persisting for more than 4 months without any spontaneous decline toward normal; OR ALT >400 U/L persisting for more than 2 months in consecutive assays. | Other: Stop of therapy<br>* The active intervention is to stop antiviral therapy, and delay re-start in the high-threshold group.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| HBsAg loss | Undetectable HBsAg measured by a standard assay | Within 3 years after stopping therapy | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to HBsAg loss | Time from randomization to undetectable HBsAg | Within 3 years after stopping therapy | 
| Time to re-start of antiviral therapy | Time from randomization to re-start of therapy according to the specified criteria | Within 3 years after stopping therapy | 
| Severe unintended medical events | Liver failure or other liver-related grade 4/5 SAEs | Within 3 years after stopping therapy | 
| Immune control | Sustained off-therapy response viz HBV DNA <2000 IU/ml and ALT <40 U/L | Within 3 years after stopping therapy | 
| Changes in health-related quality of life | Changes in the EuroQol standardized measure of health status (EQ-5D-5L) score. The summary index (from 0 to 1) as described by the manufacturer (euroqol.org) will be employed. | Within 3 years after stopping therapy | 
| Liver fibrosis evolution | Changes in transient elastography from baseline | Within 3 years after stopping therapy |