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Interferon-alpha therapy for hepatitis C virus (HCV) recurrence after liver transplantation: Long term response with maintenance therapy
132A
i01
103
AASLD
ABSTRACTS
HEPATOLOGY O c t o b e r 1995
SEVERE RECURRENT HCV AFTER LIVER TRANSPLANTATION: A DISTINCT HISTOLOGIC AND CLINICAL ENTITY? Reem Ghalib. Jon Ritter. Jeff Lowell. Todd Howard and Marion Peters. Depts Medicine, Pathology, Surgery. Washington University,St Louis MO. It is well established that HCV recurs in the majority of patients after liver transplant (OLT). However, >90% have mild recurrence without patient loss, graft loss or rapid progression to cirrhosis C. Aim: To study the histologic and clinical patterns of severe recurrent HCV post OLT. 66 patients underwent OLT for HCV between 1985- 1995. 8 patients had clinically severe recurrence as defined by ALT >500; cirrhosis < 2 years; graft failure or patient loss due to HCV. Four histologic patterns on liver biopsies emerged: Pattern A: Extensive periportal, portal and lobular inflammation, numerous acidophil bodies, minimal cholestasis and bridging fibrosis with marked necrosis was noted in one patient who died 13 months post-OLT. Pattern B. massive ballooning degeneration, marked cholestasis, acidophil bodies and mild portal and lobular inflammation were noted on two patients, one with ductal proliferation, the other with ductopenia. Both of these patients died of acute liver failure within one yr post OLT. Pattern C: moderate to marked portal and lobular inflammation, mild ballooning degeneration, scattered acidophil bodies and early severe bridging fibrosis and cirrhosis < 2 yrs post-OLT. Three patients fit this pattern, two re clinically stable while one has developed encephalopathy. pattern D: mild to moderate chronic active hepatitis, minimal cholestasis and gradual development of cirrhosis over 4-5 yrs were noted in two patients, both of whom died of complications of liver cirrhosis 4-5 yrs post transplant. Conclusions: All patients with severe recurrent HCV have varying degrees of significant ballooning degeneration, acidophil bodies, cholestasis and progressive bridging fibrosis. Only histologic pattern B has features resembling Fibrosing Cholestatic Hepatitis seen in severe forms of hepatitis B. The patients with that histologic pattern had the most acute rapidly deteriorating course early post-OLT.
102
TREATMENT OF HCV AFTER SOLID ORGAN TRANSPLANT WITH ALFA 2B- INTERFERON. Reem Ghalib. Peiain~ Oian. Jon Ritter. Heather White. Jeff Lowell. Todd Howard and Marion Peters. Departments of Medicine, Pathology and Surgery. Washington University School of Medicine, St Louis, MO. HCV is the most common cause of chronic hepatitis after solid organ transplantation. Treatment with co-interferon (IFN) is still being evaluated. Aims: To assess clinical, biochemical, virologic and histologic response of 14 HCV patients post solid organ transplant at our institution who were treated with ot-IFN. 14 patients with HCV post solid organ transplant (11 liver, 1 kidney, 1 heart) were included. Chronic active hepatitis C was documented by liver biopsy and HCV RNA in all patients. Therapy was initiated at 3 MU TIW for 6 months and dose was adjusted for toxicity. Liver function tests, liver biopsies and quantitative HCV RNA were performed. 14 patients Pre IFN end IFN >1 yr after IFN CR PR CR PR ALT normal 1 2 2 5 6 HCVRNAneg 0 0 0 1 1 Results: There were 2 complete (CR) and 2 partial (PR) biochemical responders by the end of therapy. None of these patients lost viremia. There were 5 CR and 6 PR >one year after therapy. Only 2 patients lost viremia. 4/14 (28.5%) patients had histologic improvement by the end of therapy with modest decrease in inflammation and acidophil bodies. 4/14 (28.5%) had rejection episodes while on therapy, in one of whom IFN was terminated. Dose limiting toxicity occurred in 8 patients (57%). Conclusions:. Dose limiting toxicity due to a-IFN is common in patients with HCV after solid organ transplant, but therapy is rarely terminated. Graft rejection is not more common than in the non HCV patients. Long term biochemical response occurs in about one third of the patients. This does not seem to correlate with HCV RNA levels or histologic response.
INTERFERON-ALPHA THERAPY FOR HEPATITIS C VIRUS (HCV) RECURRENCE AFTER LIVER TRANSPLANTATION: LONG TERM RESPONSE WITH MAINTENANCE THERAPY. T Gavowski*, N Singh, CF Wannstedt, IR Marino, MM Wa~ener. VA Medical Center, Pittsburgh, PA.
104
OKT3 USE ASSOCIATED WITH DIMINISHED GRAFT AND PATIENT SURVIVAL IN PATIENTS TRANSPLANTED FOR CHRONIC HEPATITIS C. HR Rosen. P Martin. CR Shackleton, DA Farmer. C Holt. RW Busuttil. Dumont - UCLA Liver Transplant Program, UCLA School of Medicine, Los Angeles, CA.
Interferon-alpha is currently the only available treatment for HCV hepatitis. Because of a high rate of relapse after 6 months of interferon-alpha, longer duration of treatment has been proposed. Short-term response has been documented in 9% to 28% of liver transplant recipients receiving 6 months of interferon-alpha. No study, to our "knowledge, has evaluated the efficacy of interferon-alpha treatment of longer than 6 months in liver transplant recipients. We assessed the safety and efficacy of 6 month course of interferon therapy in 18 consecutive liver transplant recipients with recurrent HCV hepatitis and report the long-term response with maintenance interferon; median followup after the institution of interferon was 24 months. Complete response was defined as normalization of both aspartate and alanine aminotransferase. Complete response after 6 months of interferon was observed in 28% (5/18); an additional 33% (6/18) of the patients were late responders (i.e., responded after 6 months). Overall, 61% (1 !/l 8) of the patients had long-term sustained normal response at a median followup of 24 months. Long-term sustained response was observed in 73% (8/11) of the patients who continued interferon beyond 6 months versus 43% (3/7) in those who received 6 months of interferon. Fatigue, headache, and eytopenia were the most connnonly observed side-effects occurring in 39%, 22% and 28% of the patients, respectively. Discontinuation of interferon, however, was not required in any of the patients. Rejection was documented in 6% (1/18) patients receiving interferon; this incidence was not higher than rejection episodes occurring >6 months post-transplant in other liver transplant recipients transplanted during the same period and who did not receive interferon. In conclusion, maintenance interferon was well tolerated and appeared to improve the long-term outcome in our patients; however, future studies should evaluate this in a controlled trial.
Viremia due to hepatitis C virus (HCV) is detectable in most patients following orthotopic liver transplantation (OLT) for cirrhosis due to chronic HCV. The spectrum of allograft injury related to HCV recurrence ranges from no evidence of biochemical or histologic injury to mild abnormalities to graft failure requiring retransplantation. Both viral and host factors have been proposed to explain these differences in response to recurrent HCV infection. Augmented immunosuppression for the treatment of rejection seems to be associated with a higher incidence (or greater virulence) of recurrent HCV in the allograft. We sought to determine the consequences of recurrent HCV infection after OLT with regard to liver graft histology and graft and patient survival in patients treated with OKT3 for steroidresistant rejection. METHODS: Between 1991 and 1994, 372 patients underwent OLT at our institution for end-stage liver disease due to HCV. For our study, patients with a pre-OLT diagnosis of hepatocellular carcinoma were excluded; none of the patients received OKT3 induction. In 22 patients, OKT3 was used for steroid-resistant rejection (group 1). 22 age- and sex-matched historical controls underwent OLT for HCV and developed rejection which was treated with steroid taper but not OKT3 (group 2). Protocol liver biopsies were Obtained within 1st month, at 3 months, 12 months and yearly thereafter or when clinically indicated. Recurrent HCV was defined either virologically (HCV RNA by RT-PCR) or histologically. Histologic severity was graded: 0 (normal liver), 1 (mild portal inflammation), 2 (moderate portal + Iobular inflammation), and 3 (cirrhosis). RESULTS: Median follow-up was 643 days. One year actuarial survival was 86% vs. 91% for groups' 1 and 2, respectively (P=NS). However, one year actuarial graft survival was significantly lower in patients receiving OKT3 (75% vs. 91% for groups I and 2 respectively, P=0.05). Recurrence free survival was significantly poorer in patients treated with OKT3 as compared to those without (at 1 year, 45% vs. 80%, P<0.01). 4 of 22 (18%) of patients treated with OKT3 demonstrated cirrhosis on their most recent biopsy as compared to 0 of 22 (0%) controls, (P=0.05). CONCLUSION: Use of OKT3 for steroid-resistant rejection in patients transplanted for HCV is associated with significantly poorer recurrence-free survival and one year actuarial graft survival.
i01
103
AASLD
ABSTRACTS
HEPATOLOGY O c t o b e r 1995
SEVERE RECURRENT HCV AFTER LIVER TRANSPLANTATION: A DISTINCT HISTOLOGIC AND CLINICAL ENTITY? Reem Ghalib. Jon Ritter. Jeff Lowell. Todd Howard and Marion Peters. Depts Medicine, Pathology, Surgery. Washington University,St Louis MO. It is well established that HCV recurs in the majority of patients after liver transplant (OLT). However, >90% have mild recurrence without patient loss, graft loss or rapid progression to cirrhosis C. Aim: To study the histologic and clinical patterns of severe recurrent HCV post OLT. 66 patients underwent OLT for HCV between 1985- 1995. 8 patients had clinically severe recurrence as defined by ALT >500; cirrhosis < 2 years; graft failure or patient loss due to HCV. Four histologic patterns on liver biopsies emerged: Pattern A: Extensive periportal, portal and lobular inflammation, numerous acidophil bodies, minimal cholestasis and bridging fibrosis with marked necrosis was noted in one patient who died 13 months post-OLT. Pattern B. massive ballooning degeneration, marked cholestasis, acidophil bodies and mild portal and lobular inflammation were noted on two patients, one with ductal proliferation, the other with ductopenia. Both of these patients died of acute liver failure within one yr post OLT. Pattern C: moderate to marked portal and lobular inflammation, mild ballooning degeneration, scattered acidophil bodies and early severe bridging fibrosis and cirrhosis < 2 yrs post-OLT. Three patients fit this pattern, two re clinically stable while one has developed encephalopathy. pattern D: mild to moderate chronic active hepatitis, minimal cholestasis and gradual development of cirrhosis over 4-5 yrs were noted in two patients, both of whom died of complications of liver cirrhosis 4-5 yrs post transplant. Conclusions: All patients with severe recurrent HCV have varying degrees of significant ballooning degeneration, acidophil bodies, cholestasis and progressive bridging fibrosis. Only histologic pattern B has features resembling Fibrosing Cholestatic Hepatitis seen in severe forms of hepatitis B. The patients with that histologic pattern had the most acute rapidly deteriorating course early post-OLT.
102
TREATMENT OF HCV AFTER SOLID ORGAN TRANSPLANT WITH ALFA 2B- INTERFERON. Reem Ghalib. Peiain~ Oian. Jon Ritter. Heather White. Jeff Lowell. Todd Howard and Marion Peters. Departments of Medicine, Pathology and Surgery. Washington University School of Medicine, St Louis, MO. HCV is the most common cause of chronic hepatitis after solid organ transplantation. Treatment with co-interferon (IFN) is still being evaluated. Aims: To assess clinical, biochemical, virologic and histologic response of 14 HCV patients post solid organ transplant at our institution who were treated with ot-IFN. 14 patients with HCV post solid organ transplant (11 liver, 1 kidney, 1 heart) were included. Chronic active hepatitis C was documented by liver biopsy and HCV RNA in all patients. Therapy was initiated at 3 MU TIW for 6 months and dose was adjusted for toxicity. Liver function tests, liver biopsies and quantitative HCV RNA were performed. 14 patients Pre IFN end IFN >1 yr after IFN CR PR CR PR ALT normal 1 2 2 5 6 HCVRNAneg 0 0 0 1 1 Results: There were 2 complete (CR) and 2 partial (PR) biochemical responders by the end of therapy. None of these patients lost viremia. There were 5 CR and 6 PR >one year after therapy. Only 2 patients lost viremia. 4/14 (28.5%) patients had histologic improvement by the end of therapy with modest decrease in inflammation and acidophil bodies. 4/14 (28.5%) had rejection episodes while on therapy, in one of whom IFN was terminated. Dose limiting toxicity occurred in 8 patients (57%). Conclusions:. Dose limiting toxicity due to a-IFN is common in patients with HCV after solid organ transplant, but therapy is rarely terminated. Graft rejection is not more common than in the non HCV patients. Long term biochemical response occurs in about one third of the patients. This does not seem to correlate with HCV RNA levels or histologic response.
INTERFERON-ALPHA THERAPY FOR HEPATITIS C VIRUS (HCV) RECURRENCE AFTER LIVER TRANSPLANTATION: LONG TERM RESPONSE WITH MAINTENANCE THERAPY. T Gavowski*, N Singh, CF Wannstedt, IR Marino, MM Wa~ener. VA Medical Center, Pittsburgh, PA.
104
OKT3 USE ASSOCIATED WITH DIMINISHED GRAFT AND PATIENT SURVIVAL IN PATIENTS TRANSPLANTED FOR CHRONIC HEPATITIS C. HR Rosen. P Martin. CR Shackleton, DA Farmer. C Holt. RW Busuttil. Dumont - UCLA Liver Transplant Program, UCLA School of Medicine, Los Angeles, CA.
Interferon-alpha is currently the only available treatment for HCV hepatitis. Because of a high rate of relapse after 6 months of interferon-alpha, longer duration of treatment has been proposed. Short-term response has been documented in 9% to 28% of liver transplant recipients receiving 6 months of interferon-alpha. No study, to our "knowledge, has evaluated the efficacy of interferon-alpha treatment of longer than 6 months in liver transplant recipients. We assessed the safety and efficacy of 6 month course of interferon therapy in 18 consecutive liver transplant recipients with recurrent HCV hepatitis and report the long-term response with maintenance interferon; median followup after the institution of interferon was 24 months. Complete response was defined as normalization of both aspartate and alanine aminotransferase. Complete response after 6 months of interferon was observed in 28% (5/18); an additional 33% (6/18) of the patients were late responders (i.e., responded after 6 months). Overall, 61% (1 !/l 8) of the patients had long-term sustained normal response at a median followup of 24 months. Long-term sustained response was observed in 73% (8/11) of the patients who continued interferon beyond 6 months versus 43% (3/7) in those who received 6 months of interferon. Fatigue, headache, and eytopenia were the most connnonly observed side-effects occurring in 39%, 22% and 28% of the patients, respectively. Discontinuation of interferon, however, was not required in any of the patients. Rejection was documented in 6% (1/18) patients receiving interferon; this incidence was not higher than rejection episodes occurring >6 months post-transplant in other liver transplant recipients transplanted during the same period and who did not receive interferon. In conclusion, maintenance interferon was well tolerated and appeared to improve the long-term outcome in our patients; however, future studies should evaluate this in a controlled trial.
Viremia due to hepatitis C virus (HCV) is detectable in most patients following orthotopic liver transplantation (OLT) for cirrhosis due to chronic HCV. The spectrum of allograft injury related to HCV recurrence ranges from no evidence of biochemical or histologic injury to mild abnormalities to graft failure requiring retransplantation. Both viral and host factors have been proposed to explain these differences in response to recurrent HCV infection. Augmented immunosuppression for the treatment of rejection seems to be associated with a higher incidence (or greater virulence) of recurrent HCV in the allograft. We sought to determine the consequences of recurrent HCV infection after OLT with regard to liver graft histology and graft and patient survival in patients treated with OKT3 for steroidresistant rejection. METHODS: Between 1991 and 1994, 372 patients underwent OLT at our institution for end-stage liver disease due to HCV. For our study, patients with a pre-OLT diagnosis of hepatocellular carcinoma were excluded; none of the patients received OKT3 induction. In 22 patients, OKT3 was used for steroid-resistant rejection (group 1). 22 age- and sex-matched historical controls underwent OLT for HCV and developed rejection which was treated with steroid taper but not OKT3 (group 2). Protocol liver biopsies were Obtained within 1st month, at 3 months, 12 months and yearly thereafter or when clinically indicated. Recurrent HCV was defined either virologically (HCV RNA by RT-PCR) or histologically. Histologic severity was graded: 0 (normal liver), 1 (mild portal inflammation), 2 (moderate portal + Iobular inflammation), and 3 (cirrhosis). RESULTS: Median follow-up was 643 days. One year actuarial survival was 86% vs. 91% for groups' 1 and 2, respectively (P=NS). However, one year actuarial graft survival was significantly lower in patients receiving OKT3 (75% vs. 91% for groups I and 2 respectively, P=0.05). Recurrence free survival was significantly poorer in patients treated with OKT3 as compared to those without (at 1 year, 45% vs. 80%, P<0.01). 4 of 22 (18%) of patients treated with OKT3 demonstrated cirrhosis on their most recent biopsy as compared to 0 of 22 (0%) controls, (P=0.05). CONCLUSION: Use of OKT3 for steroid-resistant rejection in patients transplanted for HCV is associated with significantly poorer recurrence-free survival and one year actuarial graft survival.