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Management of the Patient with HBV-Related Cirrhosis

Robert P. Perrillo
Section of Gastroenterology and Hepatology, Ochsner Clinic, New Orleans, USA

ABSTRACT

Cirrhosis due to chronic infection with hepatitis B virus (HBV) is associated with decreased survival. Treatment options for patients with this disorder have been limited until recently. Interferon is contraindicated in patients with Child Pugh B or C status cirrhosis and even carries risk in patients with milder decompensation. A number of studies have shown that lamivudine is well tolerated and often improves the liver function and clinical status of patients with decompensated cirrhosis. The major problem with lamivudine when used as monotherapy is the unacceptably high rate of drug resistance. There are, however, a number of alternative nucleosides with activity against wild type as well as lamivudine resistant HBV which will undoubtedly have a major therapeutic role in the future.

INTRODUCTION

If left untreated, cirrhosis due to chronic infection with hepatitis B virus (HBV) is associated with decreased survival (1-3, Figure 1). In one study, the survival of 130 patients with cirrhosis was found to be 40% at 15 years of follow up (3). Until recently, treatment options for patients with this disorder have been limited. Interferon is generally contraindicated in patients with Child Pugh B or C status cirrhosis and even carries risk in patients with milder decompensation (4). During the past several years, a number of studies have shown that lamivudine is well tolerated and often improves the clinical status of patients with decompensated cirrhosis (5-10). Long-term data, however, on the use of lamivudine in patients with advanced chronic hepatitis B are not available. The current article primarily focuses on the experience using nucleoside analogues to treat HBV-related cirrhosis. It should be mentioned at the outset that in the vast majority of instances, liver transplantation is still the preferred option (Figure 2). This is underscored by a very low rate of recurrent hepatitis B when liver allograft recipients are treated with hepatitis B immune globulin, either given alone or in conjunction with nucleoside analogue therapy (11,12).

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Interferon

Patients with end stage liver disease due to chronic HBV infection have a reduced parenchymal mass and therefore, are more easily subject to liver failure whenever immunologic-mediated liver injury is enhanced. Interferon use is accompanied by flares of serum aminotransferase levels in approximately one third of patients, and these flares are poorly tolerated in patients who already have hepatic decompensation (4,13,14). Initiation of interferon with lower doses (0.5-1 MU on alternate days) appears to be less frequently associated with flares of serum aminotransferase levels, but not with serious bacterial and fungal infections (4). Thus, this can only be recommended in patients with stable cirrhosis or mild hepatic decompensation (i.e., Child-Pugh status A). In the latter instance, starting with low doses on alternate days and gradually titrating therapy to the level of serum HBV DNA may be a safer way of administration.

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Nucleoside Analogues

These drugs block viral replication by inhibiting negative or positive strand HBV DNA synthesis or both. They do not have any direct immunologic activity and only rarely precipitate serious flares of aminotransferase levels (15). Due to a lack of effect on granulocyte and platelet count, they are also appreciably safer in patients with advanced cirrhosis.

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Lamivudine. The advantages of using lamivudine in patients with decompensated chronic hepatitis B are that it has few side effects and only rarely induces disease exacerbations (15). The latter have been shown not to occur any more frequently than in placebo treated controls. However, in vitro studies have shown that lamivudine is restorative of CD4 and CD8 positive cellular immune responses (16,17). The potential effect that immunologic reconstitution has on the occasional flares during treatment needs further study.

A number of studies have shown that lamivudine often improves the clinical status in patients with decompensated cirrhosis (5-10). The patients in these studies have either been transplant ineligible or otherwise treated while awaiting transplantation. Long term studies on the use of lamivudine in patients with decompensated cirrhosis have yet to be published, however. One of the earliest reports to define the benefit of lamivudine was that of Villeneuve et al from Quebec, Canada (6). In this study, 35 patients with end stage hepatitis B were treated with lamivudine, 10 of whom were Child Pugh class C. Five patients died and an additional 7 patients underwent transplantation within six months of starting lamivudine. In the majority of the remaining 23 cases there was slow improvement that was most evident after nine months of therapy. In another study in which 133 patients with decompensated cirrhosis were treated with lamivudine, the authors found a biphasic survival pattern (10). In that study, most of the deaths (25/32 or 78%) occurred within the first 6 months of treatment due to complications of liver failure. In multivariate modelling, pre-treatment serum bilirubin and creatinine levels as well as the presence of detectable HBV DNA by the branched nucleotide assay were significantly associated with 6 month survival. Taken together, these data indicate that there may be a subgroup of individuals with extremely advanced disease who require urgent transplantation and do not benefit from lamivudine monotherapy.

The advantages of lamivudine therapy in patients with decompensated cirrhosis can also be evaluated using transplant-free survival as an endpoint. There are no firm data with respect to the latter, but a study from the University of California, San Francisco, indicates that time to death or transplantation was significantly longer (P < .001) in lamivudine treated patients when compared to a historical cohort that was matched for age, sex, and baseline Child Pugh status (18).

The major downside of long term lamivudine monotherapy is the tendency for lamivudine resistance to occur due to one or more mutations in the YMDD motif of the HBV DNA polymerase gene. The rate of lamivudine resistance increases with time on drug, appearing in approximately 15% of patients after one year of treatment and in as many as two thirds of patients who are treated for four years (19). HBV DNA and serum aminotransferase levels often remain lower than baseline after the emergence of lamivudine resistance, and the disease can be quite variable in extent (20). However, there are several case descriptions of progressive liver injury and even severe liver failure in patients infected with drug resistant mutants (21, 22). Most of these cases have been described after liver or kidney transplantation.

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Adefovir dipivoxil. This is an oral prodrug of adefovir, a nucleotide analogue with antiviral activity against both wild type and YMDD mutant HBV. The remarkable thing about this agent is that there has been no evidence of drug resistance in patients who have been treated in excess of 136 weeks. Studies have shown that adefovir (10 mg) can be used safely and effectively in patients with YMDD mutant HBV irrespective of whether the patient has clinically stable cirrhosis, decompensated cirrhosis or recurrent hepatitis B after liver transplantation (23-25). The preliminary data from these studies are encouraging because 2 to 6 log10 reductions in serum HBV DNA have been observed at 24 weeks of treatment (23). Further experience with this agent has shown that the benefits are maintained when therapy is prolonged to 48 weeks (26). The decrease in HBV DNA level has been associated with a favourable effect on the Child Pugh status as well as improvement in biochemical parameters of liver dysfunction (Figure 4).

Due to potential for nephrotoxicity when adefovir is used in higher doses (30 mg or more), there may be some concern about the long term application of this agent in patients with concomitant renal dysfunction, particularly in patients who are treated after liver transplantation.

Other agents. There are several alternative nucleosides in various phases of development that have antiviral activity against both the wild type and YMDD mutant HBV (27, 28). Early clinical trials with entecavir look promising. As this nucleoside is devoid of renal toxicity, it may play a particularly important role in the future management of renally compromised patients with decompensated cirrhosis. Recently, the author has seen marked improvement (Child Pugh status C conversion to Child A) in a decompensated cirrhotic after 4 months of treatment with tenofovir, a nucleoside agent which is licensed for HIV-1 infection (unpublished observations). It is clear that in the relatively near future a number of therapeutic options will become available for patients with HBV-associated decompensated cirrhosis.

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REFERENCES:

  1. Weissberg JI, Andres LL, Smith CI, Weick S, Nichols JE, Garcia G, Robinson WS, Merigan TC, Gregory PB. Survival in chronic hepatitis B. An analysis of 379 patients. Ann Intern Med 1984;101: 613-616.
  2. De Jongh FE, Janssen HLA, De Man RA, Hop WCJ, Schalm SW, Blankenstein MV. Survival and prognostic indicators in hepatitis B surface antigen-positive cirrhosis of the liver. Gastroenterology 1992; 103:1630-1635.
  3. Ladenheim J, Yao F, Martin PB, Gregory P, Mangels C, Garcia G. Survival in chronic hepatitis B: A 15 year follow up. Hepatology (abstract) 1993; 18:119A.
  4. Perrillo R, Tamburro C, Regenstein F, Balart L, Bodenheimer H, Silva M, Schiff E, Bodicky C, Miller B, Denham C, Brodeur C, Roach K, Albrecht J. Low dose, titratable interferon alfa in decompensated liver disease caused by chronic infection with hepatitis B virus. Gastroenterology 1995; 109:908-916.
  5. Perrillo R, Wright T, Rakela J, Levy G, Schiff E, Gish R, Martin P, Dienstag J, Adams P, Dickson R, Anschuetz G, Bell S, Condreay L, Brown N, and the Lamivudine North American Transplant Group. A multicenter United States-Canadian trial to assess lamivudine monotherapy before and after liver transplantation for chronic hepatitis B. Hepatology 2001; 33:424-432.
  6. Villeneuve J-P, Condreay LD, Willems B, Pomier-Layrargues G, Fenyves D, Bilodeau M, Leduc R, Peltekian K, Wong F, Margulies M, Heathcote EJ. Lamivudine treatment for decompensated cirrhosis resulting from chronic hepatitis B. Hepatology 2000; 31:207-210.
  7. Hann H-WL, Fontana RJ, Wright T, Everson GT, Schiff ER, Riely C, Riker M, Hamedani A, Brown NA. Lamivudine treatment for decompensated cirrhosis due to hepatitis B: A multicenter longitudinal study. (Abstract). Gastroenterology 118; 2000:A1004.
  8. Kapoor D, Guptan RC, Wakil SM, Kazim SN, Kaul R, Agarwal SR, Raisuddin S,Hasnain SE, Sarin SK. Beneficial effects of lamivudine in hepatitis B virus-related decompensated cirrhosis. J Hepatol 2000; 33:508-512.
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  11. Markowitz JS, Martin P, Conrad AJ, Markmann JF, Seu P, Yersiz H, Goss JA, Schmidt P, Pakrasi A, Artinian L, Murray NG, Imagawa DK, Holt C, Goldstein LI, Stribling R, Busutil RW. Prophylaxis against hepatitis B recurrence following liver transplantation using combination lamivudine and hepatitis B immune globulin. Hepatology 1998; 28:585-589.
  12. Rosen H. Hepatitis B and C in the liver transplant recipient: Current understanding and treatment. Liver Transplant 2001; 7:S87-98.
  13. Nair S, Perrillo RP. Serum alanine aminotransferase flares during interferon treatment of chronic hepatitis B: Is sustained clearance of HBV DNA dependent on levels of pre-treatment viremia? Hepatology 2001; 34:1021-1026.
  14. Hoofnagle JH, Di Bisceglie AM, Waggoner JG, Park Y. Interferon alfa for patients with clinically apparent cirrhosis due to chronic hepatitis B. Gastroenterology 1993; 104:1116-1121.
  15. Perrillo RP. Acute flares in chronic hepatitis B: the natural and unnatural history of an immunologically mediated disease. Gastroenterology 2001; 120:1009-1022.
  16. Boni C, Bertoletti A, Penna A, Cavalli A, Pilli M, Urbani S, Scognamiglio P, Boehme R, Panebianco R, Fiaccadori F, Ferrari C. Lamivudine treatment can restore T cell hyporesponsiveness in chronic hepatitis B. J Clin Invest 1998; 102:968-975.
  17. Boni C, Penna A, Ogg GS, Bertoletti A, Pilli M, Cavallo C, Cavalli A, Urbani S, Boehme R, Panebianco R, Fiaccadori F, Ferrari C. Lamivudine treatment can overcome cytotoxic T-cell hyporesponsiveness in chronic hepatitis B: new perspectives for immune therapy. Hepatology 2001; 33:963-971.
  18. Yao FY, Terrault NA, Freise C, Maslow L, Bass NM. Lamivudine treatment is beneficial in patients with severely decompensated cirrhosis and actively replicating hepatitis B infection awaiting lliver transplantation: A comparative study using a matched, untreated cohort. Hepatology 2001; 34:411-416.
  19. Chang TT, Liaw YF, Guan R. Incremental increases in HBeAg seroconversion and continued ALT normalization in Asian chronic HBV (CHB) patients treated with lamivudine for four years. Antiviral Therapy 2000; 5:44.
  20. Perrillo R, Rakela J, Dienstag J, Levy G, Martin P, Wright T, Caldwell S, Schiff E, Gish R, Villeneuve JP, Farr G, Anschuetz G, Crowther L, Brown N, and the Lamivudine Transplant Group. Multicenter study of lamivudine therapy for hepatitis B after liver transplantation. Hepatology 1999; 29:1581-1586.
  21. Peters MG, Singer G, Howard T, Jacobsmeyer S, Xiong X, Gibbs CS, Lamy P, Murray A. Fulminant hepatic failure resulting from lamivudine-resistant hepatitis B virus in a renal transplant recipient: Durable response after orthotopic liver transplantation on adefovir dipivoxil and hepatitis B immune globulin. Transplantation 1999; 68:1912-1914.
  22. Mutimer D, Pillay D, Shields P, Cane P, Ratcliffe D, Martin B, Buchan S, Boxall L, O’Donnell K, Shaw J, Hubscher S, Elias E. Outcome of lamivudine resistant hepatitis B virus infection in the liver transplant recipient. Gut 2000; 46:107-113.
  23. Perrillo R, Schiff E, Yoshida E, Statler A, Hirsch K, Wright T, Gutfreund K, Lamy P, Murray A. Adefovir dipivoxil for the treatment of lamivudine-resistant hepatitis B mutants. Hepatology 2000; 32:129-134.
  24. Perrillo R., Schiff E, Hann H-W L, Buti M, Strasser S, Watkins KM, Moorat AE, Woessner M, Vig P, Brosgart CL, Bourne EC, Atkins MC. The addition of adefovir dipivoxil to lamivudine in decompensated chronic hepatitis B patients with YMDD variant HBV and reduced response to lamivudine- Preliminary 24 week results. (Abstract) Hepatology 2001; 34: 349A.
  25. Schiff ER, Neuhaus P, Tillmann H, Samuel D, Terrault N, Marcellin P, Lama N, James C, Fry J, Namini H, Brosgart C. Safety and efficacy of adefovir dipivoxil for the treatment of lamivudine resistant HBV in patients post liver transplantation. (Abstract) Hepatology 2001; 34:446A.
  26. Mutimer D, Hann H-WL, Buti M, Strasse S, Watkins K, Woessner M, Brosgart C.Bourne E, Tait D, Perrillo R. Significant clinical improvement following the addition of adefovir dipivoxil to lamivudine in decompensated patients with YMDD variant HBV and a reduced response to lamivudine- 1 year results. (Abstract). Hepatology 2002; 36:in press.
  27. Tassopoulos N, Hadziyannis S, Cianciara J, Rizzetto M, Schiff ER, Pastore G, Rutkiewicz V, Thomas N, Denisky G, Joshi Shobha. Entecavir is effective in treating patients with chronic hepatitis B who have failed lamivudine therapy. (Abstract) Hepatology 2001; 34: 340 A.
  28. Dunkle LM. ACH-126, 443: A second generation anti-HBV and anti-HIV L-nucleoside analogue. (Abstract) Antiviral Research (Suppl) 2001; 52:47.

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