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Beneficial effect of lamivudine for hepatitis B transplant recipients
EDITORIAL
Beneficial Effect of Lamivudine for Hepatitis B Transplant Recipients David Mutimer
I
n this issue of Liver Transplantation, Fontana et al describe the outcome of 309 patients with chronic hepatitis B virus (HBV) infection who were listed for transplantation at 20 transplant centers between January 1996 and June 1998. Patients were followed up until May 2000. Lamivudine was prescribed according to the discretion of each center, and approximately half the cohort was treated with lamivudine after listing (group 1 of the study) and half remained untreated (group 2). Each group included patients with or without serum markers of ongoing viral replication. Thus, a large number of patients with replication markers were not administered lamivudine before transplantation, but lamivudine was prescribed for a significant number of patients who were lacking replication markers. Lamivudine is a potent inhibitor of HBV replication, and there is no clear rationale for its use in the treatment of patients who lack serum markers of HBV replication. However, clinicians’ practice may have been influenced by published protocols of lamivudine prophylaxis in liver transplantation that have prescribed lamivudine from the time of listing, regardless of replication status (hence, treatment for patients without replication).1-3 Also, many patients included in this study would have been listed before the presentation of these trial data that encouraged the use of lamivudine before and after liver transplantation (hence, failure to treat patients despite evidence of viral replication). However, overall, treated patients were more likely to have serum markers of ongoing viral replication. This was the principal difference between the two groups at the time of listing. In my opinion, this difference explains many results of the investigators’ analysis and also explains the From the Liver and Hepatobiliary Unit, Queen Elizabeth Hospital, Birmingham, England. Address reprint requests to David Mutimer, MD, Liver and Hepatobiliary Unit, Queen Elizabeth Hospital, Edgbaston, Birmingham, England B15 2TH. Telephone: 011-44-121-472-2337; FAX: 011-44121-627-2412; E-mail: [email protected] Copyright © 2002 by the American Association for the Study of Liver Diseases 1527-6465/02/0805-0063$35.00/0 doi:10.1053/jlts.2002.32987
440
investigators’ somewhat downbeat conclusions, which seem at variance with the enthusiasm inspired by other published data.4-8 The meat in the report can be picked from the bones of Figures 2 and 3 and Table 3. Figures 2 and 3 of the report examine actuarial survival pretransplantation and actuarial transplantationfree survival, respectively. The figures demand close scrutiny and cautious interpretation. As long as organ allocation is determined by the clinical need for transplantation (regardless of whether the patient is on antiviral therapy), it should be difficult to show a difference in pretransplantation survival between the two groups (Fig. 2). Comparison of clinical (laboratory) characteristics at the time of listing of patients who underwent transplantation with those of patients still waiting at the end of follow-up (Table 3) confirms that sicker patients were more likely to undergo transplantation, and clinical need was associated with likelihood of transplantation. Under this circumstance, clinical benefit of lamivudine treatment might be manifested by a delay in the need for liver transplantation. Consistent with that prediction, pretransplantation follow-up of lamivudinetreated patients was significantly longer than that of untreated patients. Thus, the two curves of Figure 2, although not statistically separated, suggest an advantage for lamivudine-treated patients. For me, Figure 3 is more relevant, easier to understand, and more likely to show the advantage (if it exists) of antiviral therapy. Figure 3 shows the proportion of patients who survived without transplantation 1, 2, and 3 years after listing. The majority of listed patients underwent transplantation during the first 12 months after listing; thus, absolute numbers at risk for dying before transplantation but more than 12 months after listing are relatively few. Nevertheless, there is apparent separation of the curves that begins at 6 months and appears maximal at 12 months. Although the log-rank test for comparison of the two survival curves did not achieve statistical significance, it seems likely that significant separation of the curves may have been achieved during the second half of the first year of treatment. This suggests a benefit of lamivudine treatment for group 1 patients and is consistent with the observations of Villeneuve et al,4 who found that clini-
Liver Transplantation, Vol 8, No 5 (May), 2002: pp 440-442
Editorial
cal benefit for lamivudine-treated decompensated patients with cirrhosis was most apparent after 9 months of treatment. Table 3 of the report compares characteristics (at listing, then at either transplantation or most recent follow-up without transplantation) of lamivudinetreated with untreated patients. Statistical analysis shows that the two groups differ with respect to serum HBV DNA positivity at time of listing (for both transplant recipients and waiting patients who did not undergo transplantation) and at the time of most recent follow-up for waiting patients who did not undergo transplantation. Also apparent from Table 3 is the significant improvement in liver function observed for surviving lamivudine-treated patients who did not undergo transplantation despite adverse evolution of some clinical parameters for the untreated group. Studies of the natural history of HBV chronic hepatitis and cirrhosis have highlighted the importance of ongoing viral replication as an adverse prognostic factor.9,10 Previously published studies of lamivudine treatment for decompensated HBV cirrhosis have focused on patients with serum HBV DNA positivity at baseline.4-8 All patients included in studies cited in the report were serum HBV DNA positive. It seems much less likely that benefit would be observed for the treatment of cirrhotic patients who lack evidence of ongoing viral replication. Although none of the studies were prospective randomized studies, Yao et al7 identified a historic control group of untreated patients who matched the treated cohort with respect to age, sex, and baseline liver disease severity. In that study, treated patients and untreated controls were serum HBV DNA positive at baseline. In comparison to untreated patients, lamivudine treatment was associated with significant clinical improvement and prolongation in time to death or transplantation. It seems likely that the benefit of lamivudine therapy in the cohort presented by Fontana et al may have been obscured by inclusion in the analysis of a significant number of transplant candidates who lacked serum markers of ongoing viral replication. It would be interesting to repeat the analysis of their data after exclusion of patients who were negative for HBV DNA and/or hepatitis B e antigen at listing. Thus, in my opinion, Fontana et al show improved outcome for lamivudine-treated patients, a group with baseline characteristics that may have predicted an inferior outcome. These and other published data support the use of lamivudine for patients with decompensated
441
cirrhosis who have serum markers of ongoing viral replication. When liver transplantation is contraindicated (e.g., significant nonhepatic comorbidity), lamivudine treatment may effect an improvement in liver status and prolongation of life. For the potential transplant recipient, disease improvement or stabilization may be observed. Herein lies a dilemma. Allocation of organs should be determined by clinical need. However, clinical need may be diminished by lamivudine treatment. The associated delay in transplantation may permit the emergence of lamivudine-resistant HBV species before transplantation. In turn, resumption of HBV replication might cause further decompensation and compromise the success of posttransplantation prophylaxis.11 However, it seems likely that this management dilemma may be resolved by the use of new antivirals that can suppress lamivudine-resistant virus before or after liver transplantation.12-14
References 1. Grellier L, Mutimer D, Ahmed M, Brown D, Burroughs AK, Rolles K, et al. Lamivudine prophylaxis against reinfection in liver transplantation for hepatitis B cirrhosis [published erratum in Lancet 1997;349:364]. Lancet 1996;348:1212-1215. 2. Mutimer D, Dusheiko G, Barrett C, Grellier L, Ahmed M, Anschuetz G, et al. Lamivudine without HBIg for prevention of graft reinfection by hepatitis B: Long-term follow-up. Transplantation 2000;70:809-815. 3. Perrillo RP, Wright T, Rakela J, Levy G, Schiff E, Gish R, et al. A multicenter United States-Canadian trial to assess lamivudine monotherapy before and after liver transplantation for chronic hepatitis B. Hepatology 2001;33:424-432. 4. Villeneuve JP, Condreay LD, Willems B, Pomier-Layrargues G, Fenyves D, Bilodeau M, et al. Lamivudine treatment for decompensated cirrhosis resulting from chronic hepatitis B. Hepatology 2000;31: 207-210. 5. Sponseller CA, Bacon BR, Di Bisceglie AM. Clinical improvement in patients with decompensated liver disease caused by hepatitis B after treatment with lamivudine. Liver Transpl 2000; 6:715-720. 6. Yao FY, Bass NM. Lamivudine treatment in patients with severely decompensated cirrhosis due to replicating hepatitis B infection. J Hepatol 2000;33:301-307. 7. 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 liver transplantation: A comparative study using a matched, untreated cohort. Hepatology 2001;34:411-416. 8. Kapoor D, Guptan RC, Wakil SM, Kazim SN, Kaul R, Agarwal SR, et al. Beneficial effects of lamivudine in hepatitis B virusrelated decompensated cirrhosis. J Hepatol 2000;33:308-312. 9. Fattovich G, Brollo L, Giustina G, Noventa F, Pontisso P, Alberti A, et al. Natural history and prognostic factors for chronic hepatitis type B. Gut 1991;32:294-298. 10. de Jongh FE, Janssen HL, de Man RA, Hop WC, Schalm SW,
442
David Mutimer
van Blankenstein M. Survival and prognostic indicators in hepatitis B surface antigen-positive cirrhosis of the liver. Gastroenterology 1992;103:1630-1635. 11. Rosenau J, Bahr JM, Tillmann HL, Trautwein C, Klempnauer J, Manns MP, Boker KHW. Lamivudine and low-dose hepatitis B immune globulin for prophylaxis of hepatitis B reinfection after liver transplantation. Possible role of mutations in the YMDD motif prior to transplantation as a risk factor for reinfection. J Hepatol 2001;34:895-902. 12. Perrillo R, Schiff E, Yoshida E, Statler A, Hirsch K, Wright T, et
al. Adefovir dipivoxil for the treatment of lamivudine-resistant hepatitis B mutants. Hepatology 2000;32:129-134. 13. Walsh KM, Woodall T, Lamy P, Wight DG, Bloor S, Alexander GJ. Successful treatment with adefovir dipivoxil in a patient with fibrosing cholestatic hepatitis and lamivudine resistant hepatitis B virus. Gut 2001;49:436-440. 14. Mutimer D, Feraz-Neto BH, Harrison R, O’Donnell K, Shaw J, Cane P, Pillay D. Acute liver graft failure due to emergence of lamivudine resistant hepatitis B virus: Rapid resolution during treatment with adefovir. Gut 2001;49:860-863.
Beneficial Effect of Lamivudine for Hepatitis B Transplant Recipients David Mutimer
I
n this issue of Liver Transplantation, Fontana et al describe the outcome of 309 patients with chronic hepatitis B virus (HBV) infection who were listed for transplantation at 20 transplant centers between January 1996 and June 1998. Patients were followed up until May 2000. Lamivudine was prescribed according to the discretion of each center, and approximately half the cohort was treated with lamivudine after listing (group 1 of the study) and half remained untreated (group 2). Each group included patients with or without serum markers of ongoing viral replication. Thus, a large number of patients with replication markers were not administered lamivudine before transplantation, but lamivudine was prescribed for a significant number of patients who were lacking replication markers. Lamivudine is a potent inhibitor of HBV replication, and there is no clear rationale for its use in the treatment of patients who lack serum markers of HBV replication. However, clinicians’ practice may have been influenced by published protocols of lamivudine prophylaxis in liver transplantation that have prescribed lamivudine from the time of listing, regardless of replication status (hence, treatment for patients without replication).1-3 Also, many patients included in this study would have been listed before the presentation of these trial data that encouraged the use of lamivudine before and after liver transplantation (hence, failure to treat patients despite evidence of viral replication). However, overall, treated patients were more likely to have serum markers of ongoing viral replication. This was the principal difference between the two groups at the time of listing. In my opinion, this difference explains many results of the investigators’ analysis and also explains the From the Liver and Hepatobiliary Unit, Queen Elizabeth Hospital, Birmingham, England. Address reprint requests to David Mutimer, MD, Liver and Hepatobiliary Unit, Queen Elizabeth Hospital, Edgbaston, Birmingham, England B15 2TH. Telephone: 011-44-121-472-2337; FAX: 011-44121-627-2412; E-mail: [email protected] Copyright © 2002 by the American Association for the Study of Liver Diseases 1527-6465/02/0805-0063$35.00/0 doi:10.1053/jlts.2002.32987
440
investigators’ somewhat downbeat conclusions, which seem at variance with the enthusiasm inspired by other published data.4-8 The meat in the report can be picked from the bones of Figures 2 and 3 and Table 3. Figures 2 and 3 of the report examine actuarial survival pretransplantation and actuarial transplantationfree survival, respectively. The figures demand close scrutiny and cautious interpretation. As long as organ allocation is determined by the clinical need for transplantation (regardless of whether the patient is on antiviral therapy), it should be difficult to show a difference in pretransplantation survival between the two groups (Fig. 2). Comparison of clinical (laboratory) characteristics at the time of listing of patients who underwent transplantation with those of patients still waiting at the end of follow-up (Table 3) confirms that sicker patients were more likely to undergo transplantation, and clinical need was associated with likelihood of transplantation. Under this circumstance, clinical benefit of lamivudine treatment might be manifested by a delay in the need for liver transplantation. Consistent with that prediction, pretransplantation follow-up of lamivudinetreated patients was significantly longer than that of untreated patients. Thus, the two curves of Figure 2, although not statistically separated, suggest an advantage for lamivudine-treated patients. For me, Figure 3 is more relevant, easier to understand, and more likely to show the advantage (if it exists) of antiviral therapy. Figure 3 shows the proportion of patients who survived without transplantation 1, 2, and 3 years after listing. The majority of listed patients underwent transplantation during the first 12 months after listing; thus, absolute numbers at risk for dying before transplantation but more than 12 months after listing are relatively few. Nevertheless, there is apparent separation of the curves that begins at 6 months and appears maximal at 12 months. Although the log-rank test for comparison of the two survival curves did not achieve statistical significance, it seems likely that significant separation of the curves may have been achieved during the second half of the first year of treatment. This suggests a benefit of lamivudine treatment for group 1 patients and is consistent with the observations of Villeneuve et al,4 who found that clini-
Liver Transplantation, Vol 8, No 5 (May), 2002: pp 440-442
Editorial
cal benefit for lamivudine-treated decompensated patients with cirrhosis was most apparent after 9 months of treatment. Table 3 of the report compares characteristics (at listing, then at either transplantation or most recent follow-up without transplantation) of lamivudinetreated with untreated patients. Statistical analysis shows that the two groups differ with respect to serum HBV DNA positivity at time of listing (for both transplant recipients and waiting patients who did not undergo transplantation) and at the time of most recent follow-up for waiting patients who did not undergo transplantation. Also apparent from Table 3 is the significant improvement in liver function observed for surviving lamivudine-treated patients who did not undergo transplantation despite adverse evolution of some clinical parameters for the untreated group. Studies of the natural history of HBV chronic hepatitis and cirrhosis have highlighted the importance of ongoing viral replication as an adverse prognostic factor.9,10 Previously published studies of lamivudine treatment for decompensated HBV cirrhosis have focused on patients with serum HBV DNA positivity at baseline.4-8 All patients included in studies cited in the report were serum HBV DNA positive. It seems much less likely that benefit would be observed for the treatment of cirrhotic patients who lack evidence of ongoing viral replication. Although none of the studies were prospective randomized studies, Yao et al7 identified a historic control group of untreated patients who matched the treated cohort with respect to age, sex, and baseline liver disease severity. In that study, treated patients and untreated controls were serum HBV DNA positive at baseline. In comparison to untreated patients, lamivudine treatment was associated with significant clinical improvement and prolongation in time to death or transplantation. It seems likely that the benefit of lamivudine therapy in the cohort presented by Fontana et al may have been obscured by inclusion in the analysis of a significant number of transplant candidates who lacked serum markers of ongoing viral replication. It would be interesting to repeat the analysis of their data after exclusion of patients who were negative for HBV DNA and/or hepatitis B e antigen at listing. Thus, in my opinion, Fontana et al show improved outcome for lamivudine-treated patients, a group with baseline characteristics that may have predicted an inferior outcome. These and other published data support the use of lamivudine for patients with decompensated
441
cirrhosis who have serum markers of ongoing viral replication. When liver transplantation is contraindicated (e.g., significant nonhepatic comorbidity), lamivudine treatment may effect an improvement in liver status and prolongation of life. For the potential transplant recipient, disease improvement or stabilization may be observed. Herein lies a dilemma. Allocation of organs should be determined by clinical need. However, clinical need may be diminished by lamivudine treatment. The associated delay in transplantation may permit the emergence of lamivudine-resistant HBV species before transplantation. In turn, resumption of HBV replication might cause further decompensation and compromise the success of posttransplantation prophylaxis.11 However, it seems likely that this management dilemma may be resolved by the use of new antivirals that can suppress lamivudine-resistant virus before or after liver transplantation.12-14
References 1. Grellier L, Mutimer D, Ahmed M, Brown D, Burroughs AK, Rolles K, et al. Lamivudine prophylaxis against reinfection in liver transplantation for hepatitis B cirrhosis [published erratum in Lancet 1997;349:364]. Lancet 1996;348:1212-1215. 2. Mutimer D, Dusheiko G, Barrett C, Grellier L, Ahmed M, Anschuetz G, et al. Lamivudine without HBIg for prevention of graft reinfection by hepatitis B: Long-term follow-up. Transplantation 2000;70:809-815. 3. Perrillo RP, Wright T, Rakela J, Levy G, Schiff E, Gish R, et al. A multicenter United States-Canadian trial to assess lamivudine monotherapy before and after liver transplantation for chronic hepatitis B. Hepatology 2001;33:424-432. 4. Villeneuve JP, Condreay LD, Willems B, Pomier-Layrargues G, Fenyves D, Bilodeau M, et al. Lamivudine treatment for decompensated cirrhosis resulting from chronic hepatitis B. Hepatology 2000;31: 207-210. 5. Sponseller CA, Bacon BR, Di Bisceglie AM. Clinical improvement in patients with decompensated liver disease caused by hepatitis B after treatment with lamivudine. Liver Transpl 2000; 6:715-720. 6. Yao FY, Bass NM. Lamivudine treatment in patients with severely decompensated cirrhosis due to replicating hepatitis B infection. J Hepatol 2000;33:301-307. 7. 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 liver transplantation: A comparative study using a matched, untreated cohort. Hepatology 2001;34:411-416. 8. Kapoor D, Guptan RC, Wakil SM, Kazim SN, Kaul R, Agarwal SR, et al. Beneficial effects of lamivudine in hepatitis B virusrelated decompensated cirrhosis. J Hepatol 2000;33:308-312. 9. Fattovich G, Brollo L, Giustina G, Noventa F, Pontisso P, Alberti A, et al. Natural history and prognostic factors for chronic hepatitis type B. Gut 1991;32:294-298. 10. de Jongh FE, Janssen HL, de Man RA, Hop WC, Schalm SW,
442
David Mutimer
van Blankenstein M. Survival and prognostic indicators in hepatitis B surface antigen-positive cirrhosis of the liver. Gastroenterology 1992;103:1630-1635. 11. Rosenau J, Bahr JM, Tillmann HL, Trautwein C, Klempnauer J, Manns MP, Boker KHW. Lamivudine and low-dose hepatitis B immune globulin for prophylaxis of hepatitis B reinfection after liver transplantation. Possible role of mutations in the YMDD motif prior to transplantation as a risk factor for reinfection. J Hepatol 2001;34:895-902. 12. Perrillo R, Schiff E, Yoshida E, Statler A, Hirsch K, Wright T, et
al. Adefovir dipivoxil for the treatment of lamivudine-resistant hepatitis B mutants. Hepatology 2000;32:129-134. 13. Walsh KM, Woodall T, Lamy P, Wight DG, Bloor S, Alexander GJ. Successful treatment with adefovir dipivoxil in a patient with fibrosing cholestatic hepatitis and lamivudine resistant hepatitis B virus. Gut 2001;49:436-440. 14. Mutimer D, Feraz-Neto BH, Harrison R, O’Donnell K, Shaw J, Cane P, Pillay D. Acute liver graft failure due to emergence of lamivudine resistant hepatitis B virus: Rapid resolution during treatment with adefovir. Gut 2001;49:860-863.