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Antivirals Are Poorly Tolerated, Largely Ineffective Against HCV After Liver Transplantation
July 13, 2010 (Hong Kong, China) — Results from a new study suggest that antiviral therapy should be used more judiciously in patients with hepatitis C virus (HCV) infection who have undergone liver transplantation.
Specifically, these patients should not be started on antiviral therapy in the first postoperative year unless there is clear evidence of histologic recurrence of HCV infection, investigator Michael Charlton, MD, from the Mayo Clinic College of Medicine in Rochester, Minnesota, told attendees here at the International Liver Transplantation Society 16th Annual International Congress.
The most common indication for liver transplantation in North America is HCV-related end-stage liver disease. Most of these transplant recipients go on to experience virological recurrence, which is a major cause of morbidity and mortality. Cirrhosis is diagnosed in 20% to 40% of patients in the 5 years after transplantation, Dr. Charlton noted during an interview with Medscape Medical News.
"I think the study highlights the difficulties we face in treating HCV infection in liver transplant recipients with our current tools — peginterferon and ribavirin. Most patients don't tolerate treatment and most of those who do tolerate treatment don't respond to it."
In the PHOENIX study, the Mayo Clinic team looked at the safety, tolerability, and safety of prophylactic peginterferon alfa-2a plus ribavirin therapy after liver transplantation in 115 patients randomized to treatment (55 patients) or observation (60 patients) 10 to 26 weeks after transplantation. The mean age in the prophylaxis group was 51.0 years (range, 35 to 68 years) and in the observation group was 53.5 years (range, 38 to 66 years). Patients in the prophylaxis group received peginterferon alfa-2a (135 µg/week for 4 weeks followed by 180 µg/week for 44 weeks) and ribavirin (initially dosed at 400 mg/day and escalated to 1200 mg/day).
Dr. Charlton reported sustained virologic response in 22% of the patients in the prophylaxis group and 21% of those in the observation group, who were treated if histologic recurrence was demonstrated.
When analyzed at 120 weeks on an intent-to-treat basis, the frequency of histologically confirmed HCV recurrence was similar in both groups (P = .725).
Prophylactic antiviral therapy had no effect on patient or graft survival. Antiviral therapy was poorly tolerated, and only 55.6% of the prophylaxis group and 28.6% of the observation group were able to tolerate more than 80% of the intended antiviral dosing.
Dr. Charlton added: "I hope the results will provoke new studies of strategies to improve the tolerability and efficacy of posttransplant antiviral therapy. The near-term advents of IL28b testing and the addition of protease inhibitors are eagerly awaited."
Brian B. Borg, MD, MHSc, from the Ochsner Multi-Organ Transplant Institute in New Orleans, Louisiana, added that after liver transplantation, "patients are on multiple immune suppressive regimens, especially in the early posttransplant period, and are prone to other comorbidities making them less optimal candidates for treatment. The treatment response is not as good as in pretransplant patients and adherence to current combination therapy is poor because of side effects and potential complications." Dr. Borg is not affiliated with the study, but spoke with Medscape Medical News about the implications of the research.
Other transplantation centers have found alternative strategies for dealing with this problem. Luca Cicalese, MD, from the Texas Transplant Center at the University of Texas Medical Branch in Galveston, told Medscape Medical News that "at the Texas Transplant Center, we start treatment for hepatitis C after liver transplant only when there is evidence of active infection. We are also using a particular immunosuppressive protocol (to reduce the risk of rejection) that is particularly designed to reduce the risk of recurrence of hepatitis C posttransplant in our patients, which has drastically reduced such occurrence." Dr. Cicalese was not involved with the study.
Dr. Charlton's study was funded entirely by Roche/Genentech, the makers of peginterferon alfa-2a and ribavirin. Dr. Borg and Dr. Cicalese have disclosed no relevant financial relationships.
International Liver Transplantation Society (ILTS) 16th Annual International Congress: Abstract 0-162. Presented June 19, 2010.
Lara C. Pullen, PhD
http://www.medscape.com/viewarticle/725000
Specifically, these patients should not be started on antiviral therapy in the first postoperative year unless there is clear evidence of histologic recurrence of HCV infection, investigator Michael Charlton, MD, from the Mayo Clinic College of Medicine in Rochester, Minnesota, told attendees here at the International Liver Transplantation Society 16th Annual International Congress.
The most common indication for liver transplantation in North America is HCV-related end-stage liver disease. Most of these transplant recipients go on to experience virological recurrence, which is a major cause of morbidity and mortality. Cirrhosis is diagnosed in 20% to 40% of patients in the 5 years after transplantation, Dr. Charlton noted during an interview with Medscape Medical News.
"I think the study highlights the difficulties we face in treating HCV infection in liver transplant recipients with our current tools — peginterferon and ribavirin. Most patients don't tolerate treatment and most of those who do tolerate treatment don't respond to it."
In the PHOENIX study, the Mayo Clinic team looked at the safety, tolerability, and safety of prophylactic peginterferon alfa-2a plus ribavirin therapy after liver transplantation in 115 patients randomized to treatment (55 patients) or observation (60 patients) 10 to 26 weeks after transplantation. The mean age in the prophylaxis group was 51.0 years (range, 35 to 68 years) and in the observation group was 53.5 years (range, 38 to 66 years). Patients in the prophylaxis group received peginterferon alfa-2a (135 µg/week for 4 weeks followed by 180 µg/week for 44 weeks) and ribavirin (initially dosed at 400 mg/day and escalated to 1200 mg/day).
Dr. Charlton reported sustained virologic response in 22% of the patients in the prophylaxis group and 21% of those in the observation group, who were treated if histologic recurrence was demonstrated.
When analyzed at 120 weeks on an intent-to-treat basis, the frequency of histologically confirmed HCV recurrence was similar in both groups (P = .725).
Prophylactic antiviral therapy had no effect on patient or graft survival. Antiviral therapy was poorly tolerated, and only 55.6% of the prophylaxis group and 28.6% of the observation group were able to tolerate more than 80% of the intended antiviral dosing.
Dr. Charlton added: "I hope the results will provoke new studies of strategies to improve the tolerability and efficacy of posttransplant antiviral therapy. The near-term advents of IL28b testing and the addition of protease inhibitors are eagerly awaited."
Brian B. Borg, MD, MHSc, from the Ochsner Multi-Organ Transplant Institute in New Orleans, Louisiana, added that after liver transplantation, "patients are on multiple immune suppressive regimens, especially in the early posttransplant period, and are prone to other comorbidities making them less optimal candidates for treatment. The treatment response is not as good as in pretransplant patients and adherence to current combination therapy is poor because of side effects and potential complications." Dr. Borg is not affiliated with the study, but spoke with Medscape Medical News about the implications of the research.
Other transplantation centers have found alternative strategies for dealing with this problem. Luca Cicalese, MD, from the Texas Transplant Center at the University of Texas Medical Branch in Galveston, told Medscape Medical News that "at the Texas Transplant Center, we start treatment for hepatitis C after liver transplant only when there is evidence of active infection. We are also using a particular immunosuppressive protocol (to reduce the risk of rejection) that is particularly designed to reduce the risk of recurrence of hepatitis C posttransplant in our patients, which has drastically reduced such occurrence." Dr. Cicalese was not involved with the study.
Dr. Charlton's study was funded entirely by Roche/Genentech, the makers of peginterferon alfa-2a and ribavirin. Dr. Borg and Dr. Cicalese have disclosed no relevant financial relationships.
International Liver Transplantation Society (ILTS) 16th Annual International Congress: Abstract 0-162. Presented June 19, 2010.
Lara C. Pullen, PhD
http://www.medscape.com/viewarticle/725000
Yes, the tolerability problems in transplant recipients is a big issue because, as we know, if a patient is not compliant the odds of successful treatment are not good.
There is also concern about interferon triggered organ rejection.
Yes there is a difference in HCV+ transplant recipients' livers. The progression of fibrosis in liver transplant recipients is generally significantly faster than in native livers. This article suggests that 20% to 40% of HCV+ transplant recipients will show cirrhosis within 5 years of their surgery. Yes, I believe that the anti-rejection drugs do play a part but I am not clear on the extent of the role they play or how different anti-rejection meds may impact the rate of fibrosis progression and/or treatment outcome.
I know of no reason why the PIs will not be effective in transplant patients. I haven't seen any studies in support of this so it's just speculation on my part. I haven't seen anything that suggests that protease/polymerase inhibitors wouldn't confer significant benefits when combined with SOC. Of course, we will still have the tolerability problems but I believe that those can be mitigated to some extent if rescue drugs are more generously prescribed.
The article doesn't mention whether epoetin alfa was used and that makes a big difference. The SVR rate of 22% is disappointing but I don't think very much of the treatment protocol either. There was a 4 week lead in period with only low dosed Peg(135 µg/week) and no ribavirin. Then peg was increased to 180 µg/week and ribavirin was added at 400 mg per day and escalated to 1200 mg per day and treatment continued for another 44 weeks. We have no information regarding when patients achieved undetectable VL and I believe that is critical when designing treatment duration. We hear more and more about individualizing treatment and I think it is critical to approach transplant recipients individually.
Really, what this article tells me is that HCV+ liver transplant patients have a tough road ahead. But, I have several problems with what else this article says. For instance:
"Dr. Charlton reported sustained virologic response in 22% of the patients in the prophylaxis group and 21% of those in the observation group, who were treated if histologic recurrence was demonstrated."
Basically SVR was achieved at the same rate in the treatment group and the patients in the non-treatment group who treated.
I also have trouble understanding/believing this:
"Antiviral therapy was poorly tolerated, and only 55.6% of the prophylaxis group and 28.6% of the observation group were able to tolerate more than 80% of the intended antiviral dosing. "
Why such a disparity between the 2 groups' ability to tolerate treatment? Could it be because the patients in the observation were only treated after displaying fibrosis and therfore had poorer liver histology which made treatment more difficult? I can't think of any other factor that would produce such a disparity in tolerability. And if the tolerability was so low in the observation group how did that group achieve the same SVR rate as the treatment group? That seems strange to me.
I also was surprised that there was no mention of genotype. I generally assume that genotype 1 makes up the majority of the study cohort but I always see some reference to genotype makeup. There is also no mention of viral load which would seem relevant. Basically there is no detail to this "study".
There was also this statement:
"Prophylactic antiviral therapy had no effect on patient or graft survival."
That statement makes no distinction between patients who achieved SVR and those who didn't and I believe it this was based on 120 weeks post transplant - which really isn't much time to evaluate and especially those patients who did achieve SVR.
I apologize for rambling. I tend to do that when talking about this stuff.
Be well,
Mike
There is also concern about interferon triggered organ rejection.
Yes there is a difference in HCV+ transplant recipients' livers. The progression of fibrosis in liver transplant recipients is generally significantly faster than in native livers. This article suggests that 20% to 40% of HCV+ transplant recipients will show cirrhosis within 5 years of their surgery. Yes, I believe that the anti-rejection drugs do play a part but I am not clear on the extent of the role they play or how different anti-rejection meds may impact the rate of fibrosis progression and/or treatment outcome.
I know of no reason why the PIs will not be effective in transplant patients. I haven't seen any studies in support of this so it's just speculation on my part. I haven't seen anything that suggests that protease/polymerase inhibitors wouldn't confer significant benefits when combined with SOC. Of course, we will still have the tolerability problems but I believe that those can be mitigated to some extent if rescue drugs are more generously prescribed.
The article doesn't mention whether epoetin alfa was used and that makes a big difference. The SVR rate of 22% is disappointing but I don't think very much of the treatment protocol either. There was a 4 week lead in period with only low dosed Peg(135 µg/week) and no ribavirin. Then peg was increased to 180 µg/week and ribavirin was added at 400 mg per day and escalated to 1200 mg per day and treatment continued for another 44 weeks. We have no information regarding when patients achieved undetectable VL and I believe that is critical when designing treatment duration. We hear more and more about individualizing treatment and I think it is critical to approach transplant recipients individually.
Really, what this article tells me is that HCV+ liver transplant patients have a tough road ahead. But, I have several problems with what else this article says. For instance:
"Dr. Charlton reported sustained virologic response in 22% of the patients in the prophylaxis group and 21% of those in the observation group, who were treated if histologic recurrence was demonstrated."
Basically SVR was achieved at the same rate in the treatment group and the patients in the non-treatment group who treated.
I also have trouble understanding/believing this:
"Antiviral therapy was poorly tolerated, and only 55.6% of the prophylaxis group and 28.6% of the observation group were able to tolerate more than 80% of the intended antiviral dosing. "
Why such a disparity between the 2 groups' ability to tolerate treatment? Could it be because the patients in the observation were only treated after displaying fibrosis and therfore had poorer liver histology which made treatment more difficult? I can't think of any other factor that would produce such a disparity in tolerability. And if the tolerability was so low in the observation group how did that group achieve the same SVR rate as the treatment group? That seems strange to me.
I also was surprised that there was no mention of genotype. I generally assume that genotype 1 makes up the majority of the study cohort but I always see some reference to genotype makeup. There is also no mention of viral load which would seem relevant. Basically there is no detail to this "study".
There was also this statement:
"Prophylactic antiviral therapy had no effect on patient or graft survival."
That statement makes no distinction between patients who achieved SVR and those who didn't and I believe it this was based on 120 weeks post transplant - which really isn't much time to evaluate and especially those patients who did achieve SVR.
I apologize for rambling. I tend to do that when talking about this stuff.
Be well,
Mike
You asked: "Why on earth would they be put on antiviral therapy if they DIDN'T have hcv?"
The article stated: ""Specifically, these patients should not be started on antiviral therapy in the first postoperative year unless there is clear evidence of histologic recurrence of HCV infection".
So basically the article is saying that until there is histological evidence of recurrent HCV liver transplant recipients should not treat. That really isn't anything new because most centers have not been treating until they see fibrosis.
My situation was in line with that because the virus recurred very aggressively in me and there was histological evidence early. The problem was differentiating HCV recurrence from acute cellular rejection because the two disorders look identical on biopsy. When I started treatment I responded and that signaled that HCV was the problem. I was ribavirin under-dosed like most transplant recipients so I did not clear but my enzymes did normalize. I treated again and then a third time and finally cleared and have been SVR since June 2004. I am an extremely lucky man.
When I was transplanted in June 2000 I knew nothing at all about HCV. I thought the transplant was a cure. Had I known what I know now I would have been exponentially more apprehensive about the surgery. Maybe it was good that I went into it knowing absolutely nothing. It was MedHelp that educated me and I really believe that this place saved my life. There were very brilliant people here then and they gave me the basics and encouraged me to start educating myself. After that all I did for the next 4 years was study about and discuss HCV and treatment. That's a big part of the reason that I stick around. I feel like I owe this place a lot and maybe here and there I might just help someone along the way.
It sure is nice to see you here, by the way.
Mike
The article stated: ""Specifically, these patients should not be started on antiviral therapy in the first postoperative year unless there is clear evidence of histologic recurrence of HCV infection".
So basically the article is saying that until there is histological evidence of recurrent HCV liver transplant recipients should not treat. That really isn't anything new because most centers have not been treating until they see fibrosis.
My situation was in line with that because the virus recurred very aggressively in me and there was histological evidence early. The problem was differentiating HCV recurrence from acute cellular rejection because the two disorders look identical on biopsy. When I started treatment I responded and that signaled that HCV was the problem. I was ribavirin under-dosed like most transplant recipients so I did not clear but my enzymes did normalize. I treated again and then a third time and finally cleared and have been SVR since June 2004. I am an extremely lucky man.
When I was transplanted in June 2000 I knew nothing at all about HCV. I thought the transplant was a cure. Had I known what I know now I would have been exponentially more apprehensive about the surgery. Maybe it was good that I went into it knowing absolutely nothing. It was MedHelp that educated me and I really believe that this place saved my life. There were very brilliant people here then and they gave me the basics and encouraged me to start educating myself. After that all I did for the next 4 years was study about and discuss HCV and treatment. That's a big part of the reason that I stick around. I feel like I owe this place a lot and maybe here and there I might just help someone along the way.
It sure is nice to see you here, by the way.
Mike
"Specifically, these patients should not be started on antiviral therapy in the first postoperative year unless there is clear evidence of histologic recurrence of HCV infection"
Sometimes I see these news quotes and I'm like... huh? Why on earth would they be put on antiviral therapy if they DIDN'T have hcv? I mean... isn't that part a given? Are the PI's supposed to help post TP patients with TX? better efficacy or shorter tx or anything?
You treated after tp didn't you Mike? Geez, I knew you had a difficult time of it, but with those numbers you're showing it seems like it was prob a lot harder than I realized making it through everything post tp. I had no idea the odds were as bad as that. That's just pitiful. I don't know how someone psyches themself up for a liver tp knowing they have to treat after and looking at long odds like that. I HOPE that the PI's offer some help there. Please tell me they do.
Sometimes I see these news quotes and I'm like... huh? Why on earth would they be put on antiviral therapy if they DIDN'T have hcv? I mean... isn't that part a given? Are the PI's supposed to help post TP patients with TX? better efficacy or shorter tx or anything?
You treated after tp didn't you Mike? Geez, I knew you had a difficult time of it, but with those numbers you're showing it seems like it was prob a lot harder than I realized making it through everything post tp. I had no idea the odds were as bad as that. That's just pitiful. I don't know how someone psyches themself up for a liver tp knowing they have to treat after and looking at long odds like that. I HOPE that the PI's offer some help there. Please tell me they do.
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Definitely the same thing here. I came here newly infected, just diagnosed, about to treat and not knowing anything. And completely unaware of how extreme tx was going to be for me personally. I would never have made it through tx without the knowledge, support and advice of the folks here, yourself very much included (and good to see you too btw!). People here had more information than my doctors did, and they were able to refer my doctors to other hcv specialists when things got really complicated and dicey during my tx.
I still have a series of very ignorant ?'s about tx after transplant if I can prevail on you a little bit. It's just not a topic I know much about but its interesting. In my mind, I'm thinking that logically, the person who has hcv pre-tp still has hcv after tp. That's the reason I didn't quite understand the statement about clear evidence of "histological recurrence" because my view was, hey, it's a blood disorder. The person had it pre tp, so they've got it post tp. The liver is shiny and new NOW, but at some point in the future, it'll start tanking at least to some extent. And regardless, the person still has hcv (which in my view is a systemic disease - albeit one which does the most hefty bit of its damage to the liver).
BUT after reading the explanation you wrote, I think (maybe) I understand what you mean. Are you saying though that due to the harshness of the antiviral portion of the tx on the liver and the low response/success rate of the current SOC, the policy is to wait until there is fibrosis to try treatment?
Is there any difference that you know of, commonly - or on average, in post tp patients in how quickly hcv progresses in terms of liver damage? For instance, does it tend to advance any more or less quickly in the new liver than it did prior to tp? I just wondered if the anti-rejection drugs might have an effect on how quickly the disease might be able to progress.
Also, will they be able to use PI's along with SOC to benefit tp patients - is this something that is hopeful in terms of increasing response/success rates? Because those are some terrible numbers you've posted. Makes me happy that you were able to SVR and sad knowing what an uphill battle it is for so many people out there.