COMMENTARY ON: Regression of cirrhosis during treatment with tenofovir disoproxil fumarate for chronic hepatitis B: a 5-year open-label follow-up study. Marcellin P, Gane E, Buti M, Afdhal N, Sievert W, Jacobson IM, Washington MK, Germanidis G, Flaherty JF, Schall RA, Bornstein JD, Kitrinos KM, Subramanian GM, McHutchison JG, Heathcote EJ. Lancet. 2013 Feb 9;381(9865):468–7. Copyright (2013). Abstract reprinted from The Lancet, with permission from Elsevier.http://www.ncbi.nlm.nih.gov/pubmed/23234725 Abstract: 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 5years’ treatment with tenofovir disoproxil fumarate (DF) in chronic HBV infection. Methods: After 48weeks 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 240weeks. 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 (⩾1unit 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 5years of treatment with tenofovir DF was safe and effective. Long-term suppression of HBV can lead to regression of fibrosis and cirrhosis. Chronic hepatitis B virus (HBV) infection is a dynamic state of interactions among HBV, hepatocytes, and host immune system. The resultant hepatic necroinflammatory response to injury, reflected by alanine aminotransferase (ALT) elevation or hepatitis activity, during the immune clearance phase may stimulate new fibrogenesis that may even progress to advanced fibrosis or cirrhosis [[1]Brown A. Goodman Z. Hepatitis B-associated fibrosis and fibrosis/cirrhosis regression with nucleoside and nucleotide analogs.Expert Rev Gastroenterol Hepatol. 2012; 6: 187-198Crossref PubMed Scopus (31) Google Scholar]. It has been demonstrated, in a literature review of 26 prospective studies in 1996–2002, that there are significant and consistent correlations between HBV DNA level and necroinflammatory activity in both untreated patients and treated patients, especially those with nucleos(t)ide analog (Nuc) therapy [[2]Mommeja-Marin H. Mondou E. Blum M.R. Rousseau F. Serum HBV DNA as a marker of efficacy during therapy for chronic HBV infection: analysis and review of the literature.Hepatology. 2003; 37: 1309-1319Crossref PubMed Scopus (253) Google Scholar]. Since hepatic necroinflammatory activity is the main stimulator of hepatic fibrosis [[1]Brown A. Goodman Z. Hepatitis B-associated fibrosis and fibrosis/cirrhosis regression with nucleoside and nucleotide analogs.Expert Rev Gastroenterol Hepatol. 2012; 6: 187-198Crossref PubMed Scopus (31) Google Scholar], it is conceivable that the fibrogenetic process will be arrested or even degraded along with the subsidence of hepatitis activity subsequent to HBV suppression. Studies do show that fibrosis regressed >1 unit in a variable proportion of patients after 1-year Nuc therapy [[1]Brown A. Goodman Z. Hepatitis B-associated fibrosis and fibrosis/cirrhosis regression with nucleoside and nucleotide analogs.Expert Rev Gastroenterol Hepatol. 2012; 6: 187-198Crossref PubMed Scopus (31) Google Scholar]. Several studies have shown that continued antiviral therapy is associated with continued improvement in liver histology. More importantly, these studies suggest that maintained HBV suppression is associated with regression of advanced fibrosis and even reversal of liver cirrhosis [3Dienstag J.L. Goldin R.D. Heathcote E.J. Hann H.W. Woessner M. Stephenson S.L. et al.Histological outcome during long-term lamivudine therapy.Gastroenterology. 2003; 124: 105-117Abstract Full Text Full Text PDF PubMed Scopus (680) Google Scholar, 4Rizzetto M. Tassopoulos N.C. Goldin R.D. Esteban R. Santantonio T. Heathcote E.J. et al.Extended lamivudine treatment in patients with HBeAg-negative chronic hepatitis B.J Hepatol. 2005; 42: 173-179Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar, 5Hadziyannis S.J. Tassopoulos N.C. Heathcote E.J. Chang T.T. Kitis G. Rizzetto M. et al.Long-term therapy with adefovir dipivoxil for HBeAg-negative chronic hepatitis B for up to 5 years.Gastroenterology. 2006; 131: 1743-1751Abstract Full Text Full Text PDF PubMed Scopus (790) Google Scholar, 6Schiff E. Simsek H. Lee W.M. Chao Y.C. Sette Jr., H. Janssen H.L. et al.Efficacy and safety of entecavir in patients with chronic hepatitis B and advanced hepatic fibrosis or cirrhosis.Am J Gastroenterol. 2008; 103: 2776-2783Crossref PubMed Scopus (111) Google Scholar, 7Yokosuka O. Takaguchi K. Fujioka S. Shindo M. Chayama K. Kobashi H. et al.Long-term use of entecavir in nucleoside-naïve Japanese patients with chronic hepatitis B infection.J Hepatol. 2010; 52: 791-799Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar, 8Chang T.T. Liaw Y.F. Wu S.S. Schiff E. Han K.H. Lai C.L. et al.Long-term entecavir therapy results in the reversal of fibrosis/cirrhosis and continued histological improvement in patients with chronic hepatitis B.Hepatology. 2010; 52: 886-893Crossref PubMed Scopus (785) Google Scholar]. However, these studies involved a small proportion of patients enrolled in the original trials, and consisted of a small number of patients and even a smaller number of patients with advanced fibrosis or cirrhosis (Table 1). In addition, there were concerns about drug resistance and bias due to self-selection of patients to undergo repeat biopsy [[3]Dienstag J.L. Goldin R.D. Heathcote E.J. Hann H.W. Woessner M. Stephenson S.L. et al.Histological outcome during long-term lamivudine therapy.Gastroenterology. 2003; 124: 105-117Abstract Full Text Full Text PDF PubMed Scopus (680) Google Scholar]. Obviously, the evidence from these earlier studies was not strong enough to convincingly support a paradigm shift from the deep rooted traditional concept to a new concept that cirrhosis is reversible.Table 1Regression of fibrosis in patients with advanced fibrosis or cirrhosis under nucleos(t)ide analog therapy.ADV, adefovir; ETV, entecavir; HBeAg, hepatitis B e antigen; K, Knodell; LAM, lamivudine; Ref, reference; TDF, tenofovir; yr, year.aPatients with advanced fibrosis or cirrhosis.bPatients with cirrhosis.cIshak fibrosis score (I) decreased >2 points.dIshak fibrosis improved by 4 points. Open table in a new tab ADV, adefovir; ETV, entecavir; HBeAg, hepatitis B e antigen; K, Knodell; LAM, lamivudine; Ref, reference; TDF, tenofovir; yr, year. aPatients with advanced fibrosis or cirrhosis. bPatients with cirrhosis. cIshak fibrosis score (I) decreased >2 points. dIshak fibrosis improved by 4 points. The study of Marcellin et al. [[9]Marcellin P. Gane E. Buti M. Afdhal N. Sievert W. Jacobson I.M. et al.Regression of cirrhosis during treatment with tenofovir disoproxil fumarate for chronic hepatitis B: a 5-year open-label follow-up study.Lancet. 2013; 381: 468-475Abstract Full Text Full Text PDF PubMed Scopus (1284) Google Scholar] on the long-term tenofovir (TDF) therapy in a large number of patients, including patients with advanced fibrosis or cirrhosis, with prescheduled serial follow-up biopsies comes timely to address these concerns. Among the 641 patients enrolled in the original phase III trials, this study included 344 patients with liver biopsy at baseline, year 1 and 5 of therapy. At baseline, 133 (38.7% of the 344 patients) had Ishak fibrosis scores ⩾4, including 96 (28% of 344) with cirrhosis (Ishak fibrosis score ⩾5). Along with maintained HBV suppression in 99% of the patients and no or mild necroinflammation (Knodell score 0–3) in 80% of the patients, Ishak fibrosis scores improved to <4 in 36 (27%) and 91 (68%) of the 133 patients at year 1 and 5, respectively. More importantly, 71 (74%) of the 96 patients with liver cirrhosis at baseline had a reduction in fibrosis >2 units (except 1 patient) and were no longer cirrhotic at year 5. Excluding patients with body-mass index (BMI) ⩾25 kg/m2, which was found to be a significant negative predictor of cirrhosis regression, 29 (90%) of 32 patients with normal BMI were no longer cirrhotic. Furthermore, only 7 (7.3%) of the 96 patients with baseline cirrhosis developed hepatocellular carcinoma (HCC) between week 50 and 206 of therapy. Though there were no parallel untreated controls for comparison, the estimated annual incidence is far lower than the previously reported annual incidence of 2–6% in untreated cirrhotic patients. The results of this prescheduled large and long-term histologic study in TDF treated patients with advanced fibrosis or cirrhosis have confirmed the preliminary observations in earlier small studies that fibrosis regression increases with the duration of maintained HBV suppression. With similar potency and a low rate of drug resistance, it is not clear why TDF treated patients with advanced fibrosis or cirrhosis tend to have numerically lower rates of fibrosis regression than in entecavir treated counterparts [6Schiff E. Simsek H. Lee W.M. Chao Y.C. Sette Jr., H. Janssen H.L. et al.Efficacy and safety of entecavir in patients with chronic hepatitis B and advanced hepatic fibrosis or cirrhosis.Am J Gastroenterol. 2008; 103: 2776-2783Crossref PubMed Scopus (111) Google Scholar, 7Yokosuka O. Takaguchi K. Fujioka S. Shindo M. Chayama K. Kobashi H. et al.Long-term use of entecavir in nucleoside-naïve Japanese patients with chronic hepatitis B infection.J Hepatol. 2010; 52: 791-799Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar, 8Chang T.T. Liaw Y.F. Wu S.S. Schiff E. Han K.H. Lai C.L. et al.Long-term entecavir therapy results in the reversal of fibrosis/cirrhosis and continued histological improvement in patients with chronic hepatitis B.Hepatology. 2010; 52: 886-893Crossref PubMed Scopus (785) Google Scholar, 9Marcellin P. Gane E. Buti M. Afdhal N. Sievert W. Jacobson I.M. et al.Regression of cirrhosis during treatment with tenofovir disoproxil fumarate for chronic hepatitis B: a 5-year open-label follow-up study.Lancet. 2013; 381: 468-475Abstract Full Text Full Text PDF PubMed Scopus (1284) Google Scholar]. Given the big difference in the number of patients, perhaps the results of the largest study is more accurate (Table 1). The interobserber variation between different pathologists may also be a factor. While the evidence for fibrosis regression in this study is pretty convincing, one may remain skeptical as to whether the distorted liver parenchyma and altered blood flow in the cirrhotic liver are reversible. One study demonstrated that 12-month lamivudine therapy reduced hepatic venous pressure gradient (HVPG) in 18 of 19 patients with cirrhosis or decreased ⩾20% and <12 mmHg in 10 of 13 patients with baseline HVPG ⩾12 mmHg, suggesting that vascular changes of cirrhosis are reversible in patients with virological and biochemical response [[10]Manolakopoulos S. Triantos C. Theodoropoulos J. Vlachogiannakos J. Kougioumtzan A. Papatheodoridis G. et al.Antiviral therapy reduces portal pressure in patients with cirrhosis due to HBeAg-negative chronic hepatitis B and significant portal hypertension.J Hepatol. 2009; 51: 468-474Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar]. Together with the translated clinical benefit of a far lower incidence of HCC development in the study of Marcellin et al. [[9]Marcellin P. Gane E. Buti M. Afdhal N. Sievert W. Jacobson I.M. et al.Regression of cirrhosis during treatment with tenofovir disoproxil fumarate for chronic hepatitis B: a 5-year open-label follow-up study.Lancet. 2013; 381: 468-475Abstract Full Text Full Text PDF PubMed Scopus (1284) Google Scholar], there is little doubt that liver cirrhosis is reversible in Nuc treated hepatitis B patients with maintained or sustained HBV suppression and resolved hepatitis activity. Y.F. Liaw has been involved in clinical trials and served as a global advisory board member of Roche, BMS, Novartis, Gilead Sciences.
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