Elsevier

The Lancet

Volume 381, Issue 9865, 9–15 February 2013, Pages 468-475
The Lancet

Articles
Regression of cirrhosis during treatment with tenofovir disoproxil fumarate for chronic hepatitis B: a 5-year open-label follow-up study

https://doi.org/10.1016/S0140-6736(12)61425-1Get rights and content

Summary

Background

Whether long-term suppression of replication of hepatitis B virus (HBV) has any beneficial effect on regression of advanced liver fibrosis associated with chronic HBV infection remains unclear. We aimed to assess the effects on fibrosis and cirrhosis of at least 5 years' treatment with tenofovir disoproxil fumarate (DF) in chronic HBV infection.

Methods

After 48 weeks of randomised double-blind comparison (trials NCT00117676 and NCT00116805) of tenofovir DF with adefovir dipivoxil, participants (positive or negative for HBeAg) were eligible to enter a 7-year study of open-label tenofovir DF treatment, with a pre-specified repeat liver biopsy at week 240. We assessed histological improvement (≥2 point reduction in Knodell necroinflammatory score with no worsening of fibrosis) and regression of fibrosis (≥1 unit decrease by Ishak scoring system).

Findings

Of 641 patients who received randomised treatment, 585 (91%) entered the open-label phase, and 489 (76%) completed 240 weeks. 348 patients (54%) had biopsy results at both baseline and week 240. 304 (87%) of the 348 had histological improvement, and 176 (51%) had regression of fibrosis at week 240 (p<0·0001). Of the 96 (28%) patients with cirrhosis (Ishak score 5 or 6) at baseline, 71 (74%) no longer had cirrhosis (≥1 unit decrease in score), whereas three of 252 patients without cirrhosis at baseline progressed to cirrhosis at year 5 (p<0·0001). Virological breakthrough occurred infrequently and was not due to resistance to tenofovir DF. The safety profile was favourable: 91 (16%) patients had adverse events but only nine patients had serious events related to the study drug.

Interpretation

In patients with chronic HBV infection, up to 5 years of treatment with tenofovir DF was safe and effective. Long-term suppression of HBV can lead to regression of fibrosis and cirrhosis.

Funding

Gilead Sciences.

Introduction

Progression to cirrhosis, development of hepatocellular carcinoma, and liver-related mortality are associated with persistent replication of hepatitis B virus (HBV) and high plasma HBV DNA concentrations in patients chronically infected with the virus.1, 2, 3 In an estimated 15–40% of patients with chronic HBV infection, progression to cirrhosis, liver failure, or hepatocellular carcinoma will occur.4 Worldwide, HBV infection accounts for about 50% of all cases of hepatocellular carcinoma, most of which (up to 80%) are in patients with cirrhosis.5 Viral suppression by means of inhibitors of HBV polymerase/reverse transcriptase has achieved clinical benefits with a reduction in hepatic decompensation and lower rates of hepatocellular carcinoma in cirrhotic patients.6, 7, 8 However, little is known about progressive changes in liver histology with long-term antiviral therapy. Advanced liver fibrosis was previously thought to be irreversible, but evidence is accruing that cirrhosis can be reversed if the underlying cause of liver injury is addressed.6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 The evidence of an association between suppression of HBV replication and regression of liver fibrosis has, however, come from small studies that were not controlled adequately for antiviral use or treatment duration.6, 8, 17, 18, 19, 20, 21, 22, 23

Tenofovir disoproxil fumarate (DF), a nucleotide analogue and potent inhibitor of HBV polymerase/reverse transcriptase, is approved for the treatment of HIV-1 and chronic HBV infections.24 Two international, multicentre, randomised, double-blind phase 3 studies (NCT00117676 and NCT00116805) compared the efficacy and safety of once-daily tenofovir DF versus once-daily adefovir dipivoxil for 48 weeks.25 Tenofovir DF was more effective than adefovir in terms of viral suppression and relief of histological inflammation.25 After week 48, patients continued on open-label tenofovir DF or were switched from adefovir to open-label tenofovir DF for a planned 7 further years.26 Participants in the open-label phase were eligible for a prespecified third liver biopsy at week 240. We report here the effects of 5 years of viral suppression on histology in liver fibrosis and cirrhosis in 348 patients who had evaluable histology at baseline and week 240.

Section snippets

Study setting and patients

Patients were recruited from May, 2005, to June, 2006.25 After the initial 48-week randomised, masked comparison of tenofovir DF with adefovir, patients with chronic HBV infection (positive or negative for HBeAg) were switched to open-label tenofovir DF. Patients gave written consent for the open-label phase at the time of initial consent for study participation. Detailed descriptions of the study populations, design, and methods have been reported previously.25, 26

Procedures

Clinical, laboratory, and

Results

Of 641 patients enrolled and treated in the randomised trial, 585 (91%) entered the open label phase. 489 (76%) remained in the study at year 5. 634 patients (99%) had evaluable liver biopsy samples at baseline, and 348 (54%) had both baseline and year 5 liver biopsy results (figure 1). Ishak scores were available at all three timepoints (baseline, year 1, and year 5) for 344 patients. At 5 years of treatment, 141 (22%) patients had no biopsy data available (figure 1), mainly because patients

Discussion

Treatment for chronic HBV infection aims to maximise viral suppression with the objectives of controlling liver fibrosis and preventing progression to clinical complications associated with hepatic decompensation and hepatocellular carcinoma. Little evidence has been available on the effect of long-term HBV suppression on liver histology. Our study, of a large cohort of patients with baseline, year 1, and year 5 liver biopsy samples, has shown that up to 5 years of treatment with tenofovir DF

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