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Extended HCV Treatment After Liver Transplant Has Benefits
November 2, 2009 (Boston, Massachusetts) — After orthotopic liver transplantation for hepatitis C virus (HCV), extending antiviral therapy for 52 weeks after a first HCV-negative result leads to low relapse rates, according to research reported here during an oral presentation at The Liver Meeting 2009: American Association for the Study of Liver Diseases (AASLD) 60th Annual Meeting.
"In patients responding slowly to antiviral therapy following orthotopic liver transplant, the 'stop rules' at weeks 12 and 24 should be reconsidered," lead investigator Kimberly Brown, MD, head of the Division of Gastroenterology at the Henry Ford Hospital in Detroit, Michigan, and colleagues report in their meeting abstract.
In an interview with Medscape Gastroenterology just prior to her presentation, Dr. Brown said: "There are some data in the pretransplant population that, if you extend antiviral therapy, you reduce relapse rates, especially in patients who are responding slowly. The purpose of our study was to extend therapy to see if we could do that in a posttransplant population, and the results suggest that we could."
The study involved 241 consecutive patients who underwent orthotopic liver transplant from 1999 to 2006 for HCV. Patients were offered therapy if they tested positive for HCV RNA, had recurrent HCV with at least stage 1 fibrosis, and had stable immunosuppression for at least 3 months.
Patients received either nonpegylated interferon 3 times weekly or pegylated interferon in combination with ribavirin in standard doses. Treatment was continued for 52 weeks after patients became HCV-negative.
According to Dr. Brown, of the 241 patients, 66 were treated, 22 achieved sustained virologic response, and only 2 (8%) relapsed. "A relapse rate of 8% is quite a bit lower than the 30% that is commonly cited in the literature," she told Medscape Gastroenterology.
She also noted that patients who achieved sustained virologic response were more likely to have had extended treatment than those who did not (97.5 vs 59.9 weeks; P < .014).
Moreover, "35% of the patients who went on to have a sustained virologic response actually became virus-negative after week 24," Dr. Brown said. "This suggests that even if patients are positive at 24 weeks, there is still a 35% chance that they can achieve sustained viral clearance."
Stuart C. Gordon, MD, also from the Department of Gastroenterology and Transplant Surgery at the Henry Ford Hospital, but who was not involved in the study, said: "These are very provocative data that challenge a lot of long-held paradigms. The standard of care has always taught us that failure to achieve viral negativity by 24 weeks is the end of the line. This study shows that this is not the case."
"In light of these findings, our preconceived notions about antiviral therapy need to be re-explored," he concluded.
The study was funded by Henry Ford Health System in Detroit, Michigan. Dr. Brown and Dr. Gordon have disclosed no relevant financial relationships.
The Liver Meeting 2009: American Association for the Study of Liver Diseases (AASLD) 60th Annual Meeting: Abstract 187. Presented November 2, 2009.
"In patients responding slowly to antiviral therapy following orthotopic liver transplant, the 'stop rules' at weeks 12 and 24 should be reconsidered," lead investigator Kimberly Brown, MD, head of the Division of Gastroenterology at the Henry Ford Hospital in Detroit, Michigan, and colleagues report in their meeting abstract.
In an interview with Medscape Gastroenterology just prior to her presentation, Dr. Brown said: "There are some data in the pretransplant population that, if you extend antiviral therapy, you reduce relapse rates, especially in patients who are responding slowly. The purpose of our study was to extend therapy to see if we could do that in a posttransplant population, and the results suggest that we could."
The study involved 241 consecutive patients who underwent orthotopic liver transplant from 1999 to 2006 for HCV. Patients were offered therapy if they tested positive for HCV RNA, had recurrent HCV with at least stage 1 fibrosis, and had stable immunosuppression for at least 3 months.
Patients received either nonpegylated interferon 3 times weekly or pegylated interferon in combination with ribavirin in standard doses. Treatment was continued for 52 weeks after patients became HCV-negative.
According to Dr. Brown, of the 241 patients, 66 were treated, 22 achieved sustained virologic response, and only 2 (8%) relapsed. "A relapse rate of 8% is quite a bit lower than the 30% that is commonly cited in the literature," she told Medscape Gastroenterology.
She also noted that patients who achieved sustained virologic response were more likely to have had extended treatment than those who did not (97.5 vs 59.9 weeks; P < .014).
Moreover, "35% of the patients who went on to have a sustained virologic response actually became virus-negative after week 24," Dr. Brown said. "This suggests that even if patients are positive at 24 weeks, there is still a 35% chance that they can achieve sustained viral clearance."
Stuart C. Gordon, MD, also from the Department of Gastroenterology and Transplant Surgery at the Henry Ford Hospital, but who was not involved in the study, said: "These are very provocative data that challenge a lot of long-held paradigms. The standard of care has always taught us that failure to achieve viral negativity by 24 weeks is the end of the line. This study shows that this is not the case."
"In light of these findings, our preconceived notions about antiviral therapy need to be re-explored," he concluded.
The study was funded by Henry Ford Health System in Detroit, Michigan. Dr. Brown and Dr. Gordon have disclosed no relevant financial relationships.
The Liver Meeting 2009: American Association for the Study of Liver Diseases (AASLD) 60th Annual Meeting: Abstract 187. Presented November 2, 2009.
looks like the whole link won't fit
Abstract
Background. Hepatitis C virus (HCV) recurrence after orthotopic liver transplantation (OLT) is universal. We aimed to evaluate the efficacy and safety of pegylated interferon (PEG-IFN) and ribavirin (RIB) in the treatment of post-OLT HCV recurrence.
Methods. Thirty-seven patients with recurrent HCV after OLT were screened and began treatment. Nineteen patients have completed therapy. PEG-IFN was started at a dose of 0.5 μg/kg per week and titrated toward a maximum dose of 1.5 μg/kg per week. RIB was started at a dose of 400 mg per day and titrated toward a maximum of 1000 mg per day, as tolerated. Therapy continued for 1 year after HCV replication was undetectable by reverse transcriptase-polymerase chain reaction and was discontinued if there was no virologic clearance at 48 weeks.
Results. Twelve patients (63%) completed the combination regimen. Therapy was discontinued in seven (37%) patients. Seven patients (37%) had undetectable viral load at the end of treatment. Of those, five patients (26%) had sustained viral response 6 months after discontinuation of therapy. Five patients (26%) had no virologic response. Necro-inflammatory score declined from 5.22 to 2.89 (P =0.05) in nonresponders versus 6.8 to 2.6 (P <0.01) in responders. Fibrosis stage did not change in either group. Genotype 1-infected patients had a lower likelihood of attaining end of treatment or sustained viral response (P <0.05 for both).
Conclusions. Post-OLT HCV recurrence can be safely treated with PEG-IFN and RIB. Bone marrow toxicity, depression, and rejection are limiting factors that require aggressive management. There was short-term histologic benefit to the use of this regimen, even in those patients without viral clearance.
End-stage liver disease associated with hepatitis C virus (HCV) infection has become the leading indication for orthotopic liver transplantation (OLT) in the United States, accounting for 35% to 40% of cases. This indication is expected to increase fivefold by the year 2008 (1). After liver transplantation, recurrence of HCV infection is an almost universal phenomenon, with a 10- to 20-fold increase in viral levels compared with pre-OLT levels (2,3). Histologic evidence of recurrence is apparent in approximately 50% of patients as early as 1 year after OLT (3,4).
The natural history of post-OLT HCV is accelerated and is characterized by progression to cirrhosis in 6% to 23%, at a median of 3 to 4 years after OLT (5). The cumulative probability of developing HCV-related graft cirrhosis is estimated to reach 30% at 5 years (5,6). Twenty percent of the patients with recurrent disease will require re-OLT within 5 years. An additional 2% to 5% will develop early graft failure because of severe cholestatic hepatitis without cirrhosis (7). The 1-year actuarial risk for decompensation is estimated at 42% (5).
Various therapeutic options have been used to address this problem, with limited impact (8-10). Interferon α2b in combination with ribavirin (RIB) has been associated with a 25% to 30% end-of-treatment (EOT) response but only a 9% to 13% sustained response (11,12). All efforts at using interferon/RIB-based regimens for treatment of recurrent HCV have been hindered by a high incidence of adverse effects requiring use of expensive adjuvant therapy or outright discontinuation, thus limiting access to the therapy (11-14).
The recent success of pegylated interferons (PEG-IFN) in treating nonimmunosuppressed patients, coupled with recent reports of acceptable tolerability of PEG-IFN in the post-OLT setting, prompted our center to consider management of HCV after OLT with a combination of PEG-IFN and RIB (15-17). Our study is the first to evaluate the safety and efficacy of treatment with PEG-IFN and RIB in the post-OLT population with recurrence of HCV.
"
Abstract
Background. Hepatitis C virus (HCV) recurrence after orthotopic liver transplantation (OLT) is universal. We aimed to evaluate the efficacy and safety of pegylated interferon (PEG-IFN) and ribavirin (RIB) in the treatment of post-OLT HCV recurrence.
Methods. Thirty-seven patients with recurrent HCV after OLT were screened and began treatment. Nineteen patients have completed therapy. PEG-IFN was started at a dose of 0.5 μg/kg per week and titrated toward a maximum dose of 1.5 μg/kg per week. RIB was started at a dose of 400 mg per day and titrated toward a maximum of 1000 mg per day, as tolerated. Therapy continued for 1 year after HCV replication was undetectable by reverse transcriptase-polymerase chain reaction and was discontinued if there was no virologic clearance at 48 weeks.
Results. Twelve patients (63%) completed the combination regimen. Therapy was discontinued in seven (37%) patients. Seven patients (37%) had undetectable viral load at the end of treatment. Of those, five patients (26%) had sustained viral response 6 months after discontinuation of therapy. Five patients (26%) had no virologic response. Necro-inflammatory score declined from 5.22 to 2.89 (P =0.05) in nonresponders versus 6.8 to 2.6 (P <0.01) in responders. Fibrosis stage did not change in either group. Genotype 1-infected patients had a lower likelihood of attaining end of treatment or sustained viral response (P <0.05 for both).
Conclusions. Post-OLT HCV recurrence can be safely treated with PEG-IFN and RIB. Bone marrow toxicity, depression, and rejection are limiting factors that require aggressive management. There was short-term histologic benefit to the use of this regimen, even in those patients without viral clearance.
End-stage liver disease associated with hepatitis C virus (HCV) infection has become the leading indication for orthotopic liver transplantation (OLT) in the United States, accounting for 35% to 40% of cases. This indication is expected to increase fivefold by the year 2008 (1). After liver transplantation, recurrence of HCV infection is an almost universal phenomenon, with a 10- to 20-fold increase in viral levels compared with pre-OLT levels (2,3). Histologic evidence of recurrence is apparent in approximately 50% of patients as early as 1 year after OLT (3,4).
The natural history of post-OLT HCV is accelerated and is characterized by progression to cirrhosis in 6% to 23%, at a median of 3 to 4 years after OLT (5). The cumulative probability of developing HCV-related graft cirrhosis is estimated to reach 30% at 5 years (5,6). Twenty percent of the patients with recurrent disease will require re-OLT within 5 years. An additional 2% to 5% will develop early graft failure because of severe cholestatic hepatitis without cirrhosis (7). The 1-year actuarial risk for decompensation is estimated at 42% (5).
Various therapeutic options have been used to address this problem, with limited impact (8-10). Interferon α2b in combination with ribavirin (RIB) has been associated with a 25% to 30% end-of-treatment (EOT) response but only a 9% to 13% sustained response (11,12). All efforts at using interferon/RIB-based regimens for treatment of recurrent HCV have been hindered by a high incidence of adverse effects requiring use of expensive adjuvant therapy or outright discontinuation, thus limiting access to the therapy (11-14).
The recent success of pegylated interferons (PEG-IFN) in treating nonimmunosuppressed patients, coupled with recent reports of acceptable tolerability of PEG-IFN in the post-OLT setting, prompted our center to consider management of HCV after OLT with a combination of PEG-IFN and RIB (15-17). Our study is the first to evaluate the safety and efficacy of treatment with PEG-IFN and RIB in the post-OLT population with recurrence of HCV.
"
http://journals.lww.com/transplantjournal/Abstract/2004/01270/Treatment_of_recurrent_hepatitis_C_infection_after.5.aspx
full link
full link
Somewhat similar study from '04, titrated dosing though
http://journals.lww.com/transplantjournal/Abstract/2004/01270/Treatment_of_recurrent_hepatitis_C_infection_after.5.aspx
http://journals.lww.com/transplantjournal/Abstract/2004/01270/Treatment_of_recurrent_hepatitis_C_infection_after.5.aspx
52 weeks after UND for transplant then? that's not so bad if it increases the SVR rates like it would appear, I'd totally do it (but I'm nuts with ribavirin anyway ;)
I don't know how many dropped out because of sides and how many just didn't respond. I have seen high drop out rates in post transplant treatment.
22 out of 66 (33%) SVR is actually better than I usually see in transplant patients - it is often around 26%. The 2 relapsers obviously were UND at EOT but what happened to the rest of the patients is certainly unclear.
The 2 relapsers represent 8% which suggests that the cohort was made up of 25 patients. If you approximate, I guess you could say that 2 is roughly 8% of 24 and that makes some sense but it sure isn't as clear as it could be.
I think there will be some clarification in time.
Mike
22 out of 66 (33%) SVR is actually better than I usually see in transplant patients - it is often around 26%. The 2 relapsers obviously were UND at EOT but what happened to the rest of the patients is certainly unclear.
The 2 relapsers represent 8% which suggests that the cohort was made up of 25 patients. If you approximate, I guess you could say that 2 is roughly 8% of 24 and that makes some sense but it sure isn't as clear as it could be.
I think there will be some clarification in time.
Mike
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