The Norwegian Nucleoside Analogue Stop Study (Nuc-Stop)

University of Oslo (UIO)

Status and phase: Completed; Phase 4

Conditions: Hepatitis B, Chronic

Treatments: Other: Stop of therapy

Study type: Interventional

Funder types: Other

Identifiers

NCT03681132

2018/988

Details and patient eligibility

About

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

Enrollment: 127 patients

Sex: All

Ages: 18 to 70 years old

Volunteers: No Healthy Volunteers

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)

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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127 participants in 2 patient groups

Low-threshold re-start

Other group

Description:

Re-start antiviral therapy if HBV DNA viral load \>2000 IU/ml and ALT \>80 U/L.

Treatment:

Other: Stop of therapy

High-threshold re-start

Other group

Description:

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.

Treatment:

Other: Stop of therapy