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Editor-in-Chief, HCV Advocate
The Digestive Disease Weekly Conference is being held in San Francisco from May 19 – 22, 2002. This report begins the HCV Advocate’s daily coverage of clinical data related to hepatitis C. These reports will focus on live plenary presentations with a summary of posters and abstracts to follow upon completion of this daily conference coverage.
May 20, 2002
Treatment of Chronic Hepatitis C in Decompensated Cirrhotics
Gregory T. Everson, M.D. University of Colorado School of Medicine, Denver, CO
There are two main reasons to treat patients with decompensated cirrhosis. First, effective treatment could clear the virus prior to transplantation and avoid post-transplant recurrence of hepatitis C. Second, viral eradication may halt disease progression and possibly avoid the need for transplantation.
Currently, hepatitis C is the leading indication for liver transplantation in the United States and the proportion of patients with end stage liver disease due to hepatitis C is increasing. Many studies have demonstrated that patients who are HCV RNA positive prior to transplant will experience post-transplant recurrence of infection and many of these may require retransplantation due to progressive hepatitis and cirrhosis. Post-transplant treatment of recurrent hepatitis C is problematic due to effects of immunosuppression and intolerance to side effects of interferon-based treatment. For these reasons, pre-transplant treatment and viral eradication is potentially the most effective strategy in limiting the impact of post-transplant recurrence of hepatitis C.
Combination therapy with standard interferons plus ribavirin in clinically stable populations without advanced liver disease clears hepatitis C RNA in 50% to 60% on treatment, and clearance is sustained in approximately 40%. Results with peginterferon plus ribavirin are even more encouraging with on-treatment clearance rates of 70 to 80% and sustained viral clearance of approximately 55%.
Most studies, but not all, have indicated that rates of viral clearance are lower in cirrhotic patients, due, in part, to dose reductions and side effects of treatment. Nonetheless, many cirrhotic patients experience both on-treatment and sustained response. Those that clear virus may experience reduction or abolition of liver inflammation, arrest of disease progression, and even resolution of fibrosis. The published experience has mainly focused on compensated cirrhotics as interferon-based treatment has generally been considered to be contraindicated in those with clinical evidence of advanced liver disease.
The expanding numbers of patients with hepatitis C on the waiting list coupled with the problems of post transplant recurrence of disease, stimulated us to consider treatment of decompensated cirrhotics. Our treatment protocol was dubbed LADR (low-accelerating dose regimen) to indicated initiation of therapy at half doses of IFN and ribavirin followed by dose increases based upon patient tolerance. G-CSF and erythropoietin analogue, were used to treat cytopenias. Efficacy was defined by clearance of HCV RNA and tolerance was assessed by occurrence of side effects, adjustments in dose of interferon and ribavirin, frequency of dropouts from treatment, and use of G-CSF or erythropoeitin to correct cytopenias.
Our initial group of 86 candidates for treatment was male-predominant with 50% reporting significant past alcohol use or abuse. The population was enriched in hepatitis C genotype 1 and 86% had either biopsy-proven or obvious clinical signs of cirrhosis. The remaining 14% had bridging fibrosis on biopsy or other features suggesting advanced disease (spider telangiectasia (a vascular lesion formed by dilatation of a group of small blood vessels), thrombocytopenia). Sixty three percent had experienced clinical decompensation with either variceal hemorrhage, ascites, spontaneous bacterial peritonitis, or encephalopathy. Two-thirds of patients who had upper endoscopy, had esophageal varices.
Treatment was difficult in this patient population. There were 21 dropouts, mainly for side effects of fatigue, neuropsychiatric symptoms, or cytopenias. The rate of serious inter-current illness was what one might expect in this population. 28% required G-CSF and only 1 required erythropoeitin.
Eleven of the 86 patients elected not to enroll in the trial. Of the remaining 75, 21 dropped from treatment due to side effects, 29 were nonresponders. 25 cleared RNA on treatment. Of the 25 on-treatment responders, 12 relapsed. RNA was positive by 3 months in all who relapsed. The other 13 remain RNA negative but 4 were still on treatment and 3 others were followed for less than 6 months post-treatment. Overall, the on-treatment rate of clearance of RNA was 29% for all eligible patients, 33% for enrolled patients, and 46% for those who enrolled and did not drop from treatment. Responders and nonresponders were similar in terms of age, gender distribution, % with obvious cirrhosis, or frequency of clinical decompensation.
In this initial experience, two factors seemed to be most important in determining response. Nonresponders were enriched in genotype 1 and a lower percentage of responders were able to achieve full doses of treatment for at least 3 months. The effect of dose on response was observed primarily in genotype 1.
Of the 57 patients with genotype 1, 23 never achieved full dose for at least 3 months. Only 2 of these 23 patients cleared RNA on treatment and neither sustained this response. The only sustained responses in patients with genotype 1 occurred in those who were able to take at least 6 months of full dose treatment. In contrast to patients with genotype 1, those with other genotypes cleared RNA more frequently and there was less dependency upon dose. In fact, 2 sustained responders, who were treated for 12 months, never received full dose therapy for over 3 months.
Outcome in LADR Patients who were Transplanted.
Twenty six patients treated by LADR underwent transplantation. Six were sustained responders prior to transplantation and none have experienced post-transplant recurrence. Seven had on-treatment response but relapsed prior to transplant. One was retreated, became HCV RNA negative, was transplanted, and remains HCV RNA negative for one year post-transplant. The other 6 relapsers were not retreated, underwent transplant, and all recurred. All thirteennon responders have post-transplant recurrence of hepatitis C.
Implications for Living Donor Liver Transplantation.
Twenty eight patients infected with HCV have received LDLT (living donor liver transplantation) at our center between 8/97 - 4/2001. Fourteen received no treatment and remained HCV positive pre- and post-transplant. Two of the remaining twelve were non responders to interferon monotherapy and recurred post-transplant. The 12 remaining patients received either standard combination therapy or LADR. Four of the 12 were complete responders on-treatment (33%) and remain free of HCV 6 months or more post-transplant.
HCV RNA can be cleared in at least 33% of cirrhotics with advanced liver disease using the LADR protocol. Best response is achieved in non-1 genotypes and in genotype 1 patients able to take full dose treatment for at least 3 months. Relapse, after discontinuation of treatment, is more frequent in this group of patients but retreatment of relapse prior to transplantation may clear virus and prevent post-transplant recurrence. Those who experience sustained response will not relapse post-transplant. LADR treatment may be well-suited for application in the setting of LDL T where the timing of transplantation in relation to treatment can be fixed. Treatment is difficult in this population, dropouts are common, serious complications can occur, and G-CSF or erythropoeitin may be needed.
LADR may be warranted in decompensated cirrhotics, but genotype 1 patients who become RNA negative should be maintained on treatment until time of transplantation. In addition, if treatment is withdrawn in a responder, HCV RNA should be monitored for relapse and consideration of reinstitution of therapy. We also speculate that clearance or suppression of hepatitis C RNA will slow disease progression, improves hepatic function, and possibly reduces the need for transplantation.
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Hepatitis C and Liver Transplantation. Natural history and predictors of disease progression
Marina Berenguer, Hospital Universitario La Fe, Valencia, Spain
The leading indication for liver transplantation is currently HCV-related end-stage liver disease. Recurrence of infection occurs in virtually all patients with a 10-to 20-fold increase in the levels of viremia. Early short-term survival is comparable to that obtained with other etiologies. Emerging data are however demonstrating that the long-term outcome is not as benign as previously thought. Indeed, infection of the graft leads to the development of histologic hepatitis in the vast majority of patients with progression to cirrhosis in a percentage of patients which ranges from 10% to 30% at 5 years post-transplantation. The development of this cirrhosis is associated with reduced graft and patient survival. Moreover, disease progression is more aggressive and accelerated compared to the natural history of primary chronic hepatitis C infection observed in immunocompetent patients. In that sense, a recent study has estimated that the median time to reach the stage of cirrhosis after transplantation is approximately 9-12 years, a duration significantly shorter than that described in the immunocompetent population. The high agressivity of hepatitis C in the transplant setting is also evident once the cirrhosis is established, with a truncated natural history of clinically compensated HCV-related graft cirrhosis compared to that observed in immunocompetent patients. The one-year actuarial risk of decompensation has been established in 42%, a percentage significantly higher than the 28% at 10 years in HCV -infected non-transplant cirrhotic patients. Finally, in a proportion of patients albeit less than 5%, an accelerated course of liver-injury leading to rapid development of liver failure has been observed, reminiscent of that previously described in HBV-infected recipients with fibrosing cholestatic hepatitis. Altogether, these data explain the reduced graft and patient survival compared with patients transplanted for non-viral causes that has been recently evidenced in several series.
The natural history of recurrent hepatitis C is however highly variable and while there are patients developing cirrhosis in less than a year, others (= 30%) continue stable for many years. Factors which may determine a worse outcome include viral factors such as high viral load at transplantation (> 1 Meq/mL) and/or early following transplantation (> 10 Meq/mL at 4 months) and the infecting genotype (1 b); host–related factors such as a weak immune response mounted towards the virus (lack of multispecific CD4 response) and the genetic background (non Caucasian race, HLA-B14, HLA-DRB1 *04, DRB1 donor/recipient mismatching); and external factors such as the type and amount of immunosuppression used to preventing rejection. Other variables include the timing (< 12 months) and severity/type of early histological findings (hepatic activity index> 3, steatosis, ballooning degeneration, cholestasis), the age of the donor (> 45 years), and the presence of steatosis. Of all the variables involved, the immune status per se likely represents the main significant one in influencing disease severity and/or progression in HCV-infected patients.
Preliminary data suggest that disease progression has increased in recent years. Possible reasons which explain this worse outcome include (a) the use of new and more potent immunosuppressive agents with early steroid withdrawal, likely provoking an "abrupt immune reconstitution" which in turns leads to an immune-mediated liver damage; and (b) the increasing use of marginal organs, in an effort to expand the donor pool (i.e. old donors).
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Prophylaxis and Treatment of Recurrent Hepatitis C
K. Rajender Reddy, M.D. University of Pennsylvania, Philadelphia, PA
- Hepatitis C related end stage liver disease is the most common indication for liver Transplantation (L T) and the number of patients transplanted for this condition continues to increase.
- Recurrence of hepatitis C after liver transplantation is universal. The course of recurrent hepatitis C following transplantation is variable. A progressive liver disease may be seen in some of these patients with the dreaded complication of cholestatic hepatitis evolving in approximately 5-10 % of the patients.
- Currently therapeutic strategies for treating hepatitis C prior to transplant or following transplantation are not well defined. Limited success has been seen with combination of interferon and ribavirin.
- Selection of optimal therapy, timing of intervention, candidate selection, safety and efficacy of the therapies, need to evaluated in large trials. Combination of pegylated interferons and ribavirin is the next line therapy.
Over the past 10 years there has been a steady increase in the number of patients transplanted for HCV end stage liver disease with this condition accounting for 30 to 50 % of transplants across the transplant centers in the United States. Virologic recurrence of hepatitis C is universal although histological chronic hepatitis evolves in approximately 50% of HCV-infected recipients. Progressive chronic hepatitis is responsible for allograft failure leading to death or graft loss in approximately 10% of recipients by the fifth postoperative year. Although, the survival of patients and grafts following transplantation for HCV disease has been similar to overall patient and graft survival following transplantation for most other indications, recurrence of hepatitis C is a substantial cause of morbidity, mortality and graft loss. Most studies on survival of grafts and patients following L T have been for a mean period of 3-5 years. With increasing length of post-transplantation follow-up of HCV-infected recipients, it is expected that the long-term patient and graft survival of these patients may deteriorate through the effects of HCV recurrence. With an exponential increase in patients listed for liver transplantation in the background of a relatively static state of the availability of cadaveric donor organs, there is an increasing need and a big challenge to the transplant community to optimize outcomes following liver transplantation for hepatitis C.
Currently there is a lack of data on therapeutic strategies to decrease the morbidity and mortality associated with post-transplant recurrence of hepatitis C. Critical questions remain and these include, the patient population to be targeted, timing of the intervention, safety and efficacy of the therapy, the need to modify therapy, and the role of growth factors to enhance efficacy. Higher pre-LT HCV RNA titers have been associated with higher rates of graft loss and death when compared to recipients with lower pre-L T HCV RNA titers. Thus in light of this observation, HCV therapy in the pre-transplant period, in patients with decompensated liver disease has been evaluated in small trials. Although some success has been reported, serious adverse events has limited the enthusiasm for this strategy.
Treatment of recurrent hepatitis C following liver transplantation has been widely reported using non-pegylated interferon monotherapy and lately interferon and ribavirin. The data would suggest that interferon monotherapy does not achieve sustained virologic response, although there appears to be a transient decrease in HCV RNA. Following traditional interferon and ribavirin therapy, encouraging response rates, particularly on therapy, have been observed: however they are not to the extent seen in the non-transplanted HCV population. On combination therapy for recurrent hepatitis C on treatment virologic response rates of 30-50 % have been observed although relapse rates have been >50%. Reversal of fibrosing cholestatic hepatitis has been infrequently observed with the use of Interferon and ribavirin.
Intuitively, a prophylactic strategy would appear attractive given the rationale that the viral load immediately following transplantation might be low and thus be more susceptible to therapy, as opposed to established disease. An interferon monotherapy prophylactic study by Scheiner et al, did not report clearance of HCV with such a strategy, although histologic benefit was observed in recipients of interferon. Prophylactic therapy has been more encouraging with combination of interferon and ribavirin. Reddy et al, in a multi-center randomized early intervention therapy with interferon and ribavirin achieved a sustained virologic response of 16 % after 48 weeks of therapy and all patients in the control group became viremic. Therapy was initiated as early as 14-28 days but tolerability of therapy, particularly ribavirin, was a major issue which primarily was of anemia requiring transfusions.
The advent of 40 Kda pegylated interferon alpha 2a and 12 Kda pegylated interferon alpha 2b, has been a significant advance in the therapy of chronic hepatitis C. Higher response rates with combination of pegylated interferons and ribavirin, when compared with traditional interferon and ribavirin, have been reported in non-cirrhotics and cirrhotics, in the non-transplant population. While these studies are encouraging there is a need to evaluate pegylated interferons in combination with ribavirin in the HCV transplant population.
Recognizing that HCV disease will continue to contribute and increase as an indication for liver transplantation and that it is associated with significant graft loss and mortality, there is a great need to develop treatment strategies in this group. One approach might be a continuum of therapy initiated in the pre-transplant period with extension into post transplant stage with the goal of achieving sustained virologic response. Histologic benefit in the virologic non-responders would also be meaningful. Only large scale studies are likely to address several questions of optimal therapy, tolerability, timing of intervention. Pegylated interferons and ribavirin are the therapeutics on the horizon that are to be evaluated in HCV transplant population.
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