The Norwegian Nucleoside Analogue Stop Study
- Conditions
- Hepatitis B, Chronic
- Interventions
- Other: Stop of therapy
- Registration Number
- NCT03681132
- Lead Sponsor
- Oslo University Hospital
- Brief Summary
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
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 127
- 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.
- 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)
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Low-threshold re-start Stop of therapy Re-start antiviral therapy if HBV DNA viral load \>2000 IU/ml and ALT \>80 U/L. High-threshold re-start Stop of therapy 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.
- Primary Outcome Measures
Name Time Method HBsAg loss Within 3 years after stopping therapy Undetectable HBsAg measured by a standard assay
- Secondary Outcome Measures
Name Time Method Time to re-start of antiviral therapy Within 3 years after stopping therapy Time from randomization to re-start of therapy according to the specified criteria
Changes in health-related quality of life Within 3 years after stopping therapy 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.
Time to HBsAg loss Within 3 years after stopping therapy Time from randomization to undetectable HBsAg
Severe unintended medical events Within 3 years after stopping therapy Liver failure or other liver-related grade 4/5 SAEs
Immune control Within 3 years after stopping therapy Sustained off-therapy response viz HBV DNA \<2000 IU/ml and ALT \<40 U/L
Liver fibrosis evolution Within 3 years after stopping therapy Changes in transient elastography from baseline
Trial Locations
- Locations (11)
Bodø Hospital
🇳🇴Bodø, Norway
Akershus University Hospital
🇳🇴Lørenskog, Norway
St Paul Hospital Millennium Medical College
🇪🇹Addis Abeba, Ethiopia
Oslo University Hospital
🇳🇴Oslo, Norway
Hvidovre Hospital
🇩🇰København, Denmark
Stavanger University Hospital
🇳🇴Stavanger, Norway
Karonlinska University Hospital
🇸🇪Stockholm, Sweden
Drammen Hospital
🇳🇴Drammen, Norway
Tønsberg Hospital
🇳🇴Tønsberg, Norway
Ålesund Hospital
🇳🇴Ålesund, Norway
Bærum Hospital
🇳🇴Sandvika, Norway