Histological outcome during long-term lamivudine therapy

doi:10.1053/gast.2003.50013

Gastroenterology

Volume 124, Issue 1, January 2003, Pages 105-117

https://doi.org/10.1053/gast.2003.50013 Get rights and content

Abstract

Background & Aims: One year of lamivudine for chronic hepatitis B results in histologic improvement. We aimed to assess the histological impact of longer-term treatment. Methods: Sets of 3 liver biopsies, from 63 patients before and after 1 year of randomized lamivudine treatment and after 2 years of further open-label treatment, were assigned Histologic Activity Index scores under code. Results: At the end of year 1, 36/63 (57%) showed ≥2 point improvement and 24/63 (38%) no change in necroinflammatory activity; after 2 additional years of lamivudine, 38/63 (60%) remained stable and 12/63 (19%) continued to improve. Worsening occurred in similar proportions of patients with and without YMDD (tyrosine, methionine, aspartate, aspartate) variants. After all 3 years of lamivudine treatment, 35/63 (56%) of patients showed improvement, 21/63 (33%) no change, and 7/63 (11%) worsening. Those without, compared with those with, YMDD variants were more likely to improve (17/22 [77%] vs. 18/41 [44%]) and less likely to deteriorate (1/22 [5%] vs. 6/41 [15%]). Patients with YMDD variants for >2 years were least likely to improve (8/22 [36%]). Bridging fibrosis improved by ≥1 level in 12/19 (63%), and cirrhosis improved (score of 4 to ≤3) in 8/11 (73%). Only 1/52 [2%]) showed progression to cirrhosis, and 3/34 (9%) showed progression to bridging fibrosis (all with YMDD variants). Conclusions: Three years of lamivudine therapy reduces necroinflammatory activity and reverses fibrosis (including cirrhosis) in most patients. The emergence of YMDD variants blunts histologic responses; therefore, extended-duration YMDD variants may require additional therapies to maintain the histological benefit of treatment.

GASTROENTEROLOGY 2003;124:105-117

Section snippets

Study design

In this open-label study, patients were enrolled who remained HBeAg-positive and lacked detectable antibody to HBeAg (anti-HBe) after participation in a qualifying phase III lamivudine trial, i.e., feeder study.13, 14, 20 The analysis reported here includes patients who received lamivudine 100 mg in the feeder studies and had liver biopsies available at 3 defined time points: before the start of the feeder study (pretreatment), at the end of randomized treatment in the feeder study (1 year),

Pretreatment characteristics

One hundred seventy-nine patients who received lamivudine 100 mg in the feeder studies and failed to undergo HBeAg seroconversion were enrolled in this follow-up study. Of these, 152 patients had 24 months of treatment in the follow-up study (1 patient was still being treated but had not reached month 24, and 26 patients had withdrawn). Liver biopsy in the follow-up study was encouraged strongly but, ultimately, as required by institutional review boards, was optional, and of the 152 patients,

Discussion

We have performed a detailed histological study of 63 sets of liver biopsies, a median of 3.5 years apart, from patients with chronic hepatitis B who had received at least an additional 2 years of lamivudine after 1 year of lamivudine in a feeder study. The patients included in this analysis consisted of a population who had failed to achieve HBeAg seroconversion during previous lamivudine trials,13, 14, 20 and almost two thirds of these patients had also failed to respond to a prior course of

Acknowledgements

The authors thank Lynn D. Condreay, Vincent A. Lopez, and Eric J. Bourne, Department of Clinical Virology, GlaxoSmithKline, Research Triangle Park, North Carolina, for evaluation of genotypic resistance and Nathaniel Brown, formerly of GSK, for his role in this study. The authors thank all the other participants who recruited patients in this trial: Dr. B. Bacon, Dr. A. Baker, Dr. V. Balan, Dr. H. Bodenheimer, Dr. S. Caldwell, Dr. J. Cooper, Dr. R. Gish, Dr. N. Gitlin, Dr. S. Gordon, Dr. I.

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^☆: Supported (protocol number NUCA/B3017) by GlaxoSmithKline Research and Development, Research Triangle Park, North Carolina. Additional support was provided by the Hepatitis Research Fund, the Muriel Gabron Research Fund, and the Betty and Newell Hale Research Fund of the Massachusetts General Hospital.

^☆☆: Address requests for reprints to: Jules L. Dienstag, M.D., Gastrointestinal Unit, Massachusetts General Hospital, Boston, Massachusetts 02114. e-mail: [email protected]; fax: (617) 726-3673.

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Clinical–Liver, Pancreas, and Biliary TractHistological outcome during long-term lamivudine therapy☆,☆☆

Abstract

Section snippets

Study design

Pretreatment characteristics

Discussion

Acknowledgements

Sem Virol

Gastroenterology

J Hepatol

Gastroenterology

Hepatology

State of the World's Vaccines and Immunization

Is liver fibrosis reversible?

Gut

Is liver fibrosis reversible?

N Engl J Med

Regression of hepatic fibrosis in hepatitis C with long-term interferon treatment

Dig Dis Sci

Sustained biochemical and histologic remission of primary biliary cirrhosis in response to medical treatment

Ann Intern Med

Reversal of “cirrhosis” in idiopathic hemochromatosis following long-term intensive venesection therapy

Australas Ann Med

Regression of liver fibrosis after biliary drainage in patients with chronic pancreatitis and stenosis of the common bile duct

N Engl J Med

Clinical–Liver, Pancreas, and Biliary Tract
Histological outcome during long-term lamivudine therapy☆,☆☆