Screening
Mass screening for hepatitis C by means of hepatitis C antibody testing does not appear to be a cost-effective strategy. However, an abstract presented at the AASLD meeting in October reported that alanine aminotransferase screening for chronic hepatitis C is cost- effective in individuals between 15 and 58 years of age (ie, across broad age groups). Improvements in cost efficiency may be obtained through identification of risk factors for HCV prior to screening.
Saturday, September 12, 2009
Hepatitis Cost Effectiveness
The Role of Pegylated Interferon
Rationale:
Pegylated IFNs are currently under investigation, and at this time are not approved for the treatment of hepatitis C in the United States. The concept behind the pegylation of IFN is to produce a molecule that can maintain longer-lasting therapeutic concentrations by optimizing both the absorption and distribution while decreasing the rate of clearance and reducing proteolysis at the same time. This is accomplished by the addition of a polyethylene glycol molecule (PEG) to standard IFN by means of a covalent bond. This PEG molecule is a nontoxic polymer that is readily excreted in the urine and this moiety may be either linear or branched. Larger PEG molecules lead to a greater reduction in renal clearance and provide greater subcutaneous absorption. Pegylated IFN is metabolized primarily in the liver, and its excretion is not affected by renal abnormalities.
Clinical Trials:
Two pegylated formulations of IFN are currently under investigation in the United States:
A linear 12-kD peginterferon-alfa-2b (Pegintron) and a branched chain 40-kD peginterferon-atfa-2a (Pegasys).
A double-blind, randomized, controlled trial was presented at the 2000 meeting of the European Association for the Study of the Liver that compared 3 regimens of peginterferon-alfa-2b (0.5, 1.0, and 1.5 mcg/kg per week) with standard IFN-alfa-2b 3 MU given 3 times weekly in previously untreated patients with hepatitis C. The sustained response rates for patients who received 0.5, 1.0, and 1.5 mcg/kg of the pegylated IFN were 18%, 25%, and 23%, respectively, compared with a 12% sustained response rate found in patients who received the conventional IFN. The overall genotype 1 response rate was 14% in both the 1.0- and 1.5-mcg/kg groups.
EOT = end-of-treatment response;
SVR = sustained virologic response
Zeuzem and colleagues reported the results of a trial comparing once-weekly peginterferon-alfa-2a at a dose of 180 mcg with standard-dose interferon-alfa-2a 3 times weekly for 48 weeks in previously untreated patients with hepatitis C. All patients were assessed at week 72 for a sustained virologic response. These investigators obtained a sustained response rate of 39% for the pegylated-IFN group compared with a 19% response rate for the standard-IFN group. A sustained response rate of 28% was seen in patients infected with HCV genotype 1 who received peginterferon-alfa-2a. The frequency and severity of adverse events were similar in both treatment groups. Pretreatment factors associated with a sustained response, in order of significance, included genotype other than type 1, alanine aminotransferase quotient> 3, HCV RNA level <2>
EOT = end-of-treatment response; SVR = sustained virologic response
In the largest trial of cirrhotic hepatitis C patients receiving IFN therapy performed to date, Heathcote and colleagues reported on the use of pegylated IFN-alfa-2a in the treatment of patients with bridging fibrosis or cirrhosis. Patients were randomized to receive IFN-alfa-2a 3 MU 3 times per week, 90 mcg of peginterferon-alfa 2a weekly, or 180 mcg of peginterferon-alfa-2a weekly, for a total of 48 weeks, and were followed up for 24 weeks. In an intention-to-treat analysis, a sustained response (response at week 72) was seen in 8%, 15%, and 30% of patients treated with standard IFN-alfa-2a, 90 mcg of peginterferon-alfa-2a, and 180 mcg of peginterferon-alfa-2a, respectively. The difference in rate of response between the standard-IFN and 180-mcg of peginterferon groups was statistically significant. The sustained response of patients infected with genotype 1 and non-1 who were treated with the higher dose of peginterferon was 13% and 51%, respectively.
A previous small dose-finding study by Glue and coworkers showed that peginterferon-alfa-2b and ribavirin were safe when used in combination. The results of a larger trial using combination peginterferon-alfa-2b plus ribavirin in previously untreated patients with hepatitis C were reported in October 2000 at the annual meeting of the American Association for the Study of Liver Diseases (AASLD) in Dallas, Texas. Results showed that the overall sustained response of patients to peginterferon-alfa-2b given at 1.5 mcg/kg per week, plus ribavirin 1000-1200 mg/day, was 54%. The response rates of patients with genotype 1 and non-1 to this regimen were 42% and 82%, respectively.
The FDA approved pegylated IFN-alfa 2b mono therapy in January 2001. The use of combination pegylated IFN plus ribavirin is still under investigation, with several large trials currently underway to determine the effectiveness of this new regimen.
Treatment of the Post- Liver Transplant Patient
Hepatitis C is the leading indication for liver transplantation in the United States. In patients who undergo liver transplantation secondary to hepatitis C, the reappearance of HCV RNA post transplantation is an almost universal occurrence.
The natural history of post transplantation hepatitis C appears to be rapid, with as many as 20% of recipients developing cirrhosis within 5 years of transplantation. Studies with IFN mono therapy in this setting have reported biochemical responses in up to 25% of patients, but virologic response is rare. One study reported a sustained response rate of 24% with a 6-month course of combination IFN and ribavirin. After loss of HCV RNA with combination therapy, ribavirin mono therapy has been used as maintenance therapy. Although combination therapy has not been associated with rejection, significant anemia secondary to hemolysis is common. Larger trials are needed to better address the issue of recurrence of hepatitis C after transplantation.
The natural history of post transplantation hepatitis C appears to be rapid, with as many as 20% of recipients developing cirrhosis within 5 years of transplantation. Studies with IFN mono therapy in this setting have reported biochemical responses in up to 25% of patients, but virologic response is rare. One study reported a sustained response rate of 24% with a 6-month course of combination IFN and ribavirin. After loss of HCV RNA with combination therapy, ribavirin mono therapy has been used as maintenance therapy. Although combination therapy has not been associated with rejection, significant anemia secondary to hemolysis is common. Larger trials are needed to better address the issue of recurrence of hepatitis C after transplantation.
Hepatitis - Treatment of the Non responder:
Non response to antiviral therapy is defined as the persistence of detectable HCV RNA throughout therapy, with detectable serum HCV RNA at the end of the therapeutic course. The sustained response to re-treatment of non responders to any form of antiviral therapy has been disappointing.
Re-treatment of non responders to IFN mono therapy was evaluated in several small studies. In the consensus interferon trial, non responders to IFN mon otherapy showed a 13% sustained virologic response rate at 48 weeks of therapy with IFN-alfa con-1. The use of combination IFN and ribavirin therapy in FN non responders has resulted in sustained response rates ranging from 0% to 15%. Of interest, a recent trial reported a 42% sustained response to intravenous recombinant IFN-bEIA in previous IFN non responders.
Approximately 60% of all patients treated with combination IFN and ribavirin are non responders. The approach to this group represents a growing challenge to the treating clinician. Although it seems reasonable that higher doses of IEN plus ribavirin or a weight-based system of ribavirin dosing should improve response to treatment in these patients, there are little if any published data to support such an approach. The peginterferons may, however, prove useful in combination with IFN and ribavirin, and clinical trials designed to test this notion are currently ongoing.
Virologic non responders to antiviral therapy may derive some benefit from re-treatment that is aimed at preventing histologic disease progression. Patients with underlying bridging fibrosis or cirrhosis are at a greater risk for developing complications of cirrhosis than are those without fibrosis. In addition to its antiviral effect, IFN was shown to have anti proliferative and anti fibrotic activity through its down regulation of transforming growth factor b. Recent studies showed improvement in underlying histology in non responders to antiviral therapy. Several studies have also demonstrated a significant reduction in the relative risk of developing HCC among non responders to IFN mono therapy.
These studies have brought the issue of IFN maintenance therapy for prevention of fibrotic progression to the fore. Shiffman and colleagues’95’ reported that a 2-year course of IFN mono therapy administered to non responders stabilized fibrosis and improved inflammation on serial biopsies. This concept has now led to the launch of a National Institutes of Health-sponsored trial -- the Hepatitis C Antiviral Long-term Treatment against Cirrhosis or HALT-C trial -- to evaluate the effect of long-term peginterferon-alfa2a therapy in patients with advanced fibrosis or cirrhosis who did not respond to combination pegylated IEN plus ribavirin.
Re-treatment of non responders to IFN mono therapy was evaluated in several small studies. In the consensus interferon trial, non responders to IFN mon otherapy showed a 13% sustained virologic response rate at 48 weeks of therapy with IFN-alfa con-1. The use of combination IFN and ribavirin therapy in FN non responders has resulted in sustained response rates ranging from 0% to 15%. Of interest, a recent trial reported a 42% sustained response to intravenous recombinant IFN-bEIA in previous IFN non responders.
Approximately 60% of all patients treated with combination IFN and ribavirin are non responders. The approach to this group represents a growing challenge to the treating clinician. Although it seems reasonable that higher doses of IEN plus ribavirin or a weight-based system of ribavirin dosing should improve response to treatment in these patients, there are little if any published data to support such an approach. The peginterferons may, however, prove useful in combination with IFN and ribavirin, and clinical trials designed to test this notion are currently ongoing.
Virologic non responders to antiviral therapy may derive some benefit from re-treatment that is aimed at preventing histologic disease progression. Patients with underlying bridging fibrosis or cirrhosis are at a greater risk for developing complications of cirrhosis than are those without fibrosis. In addition to its antiviral effect, IFN was shown to have anti proliferative and anti fibrotic activity through its down regulation of transforming growth factor b. Recent studies showed improvement in underlying histology in non responders to antiviral therapy. Several studies have also demonstrated a significant reduction in the relative risk of developing HCC among non responders to IFN mono therapy.
These studies have brought the issue of IFN maintenance therapy for prevention of fibrotic progression to the fore. Shiffman and colleagues’95’ reported that a 2-year course of IFN mono therapy administered to non responders stabilized fibrosis and improved inflammation on serial biopsies. This concept has now led to the launch of a National Institutes of Health-sponsored trial -- the Hepatitis C Antiviral Long-term Treatment against Cirrhosis or HALT-C trial -- to evaluate the effect of long-term peginterferon-alfa2a therapy in patients with advanced fibrosis or cirrhosis who did not respond to combination pegylated IEN plus ribavirin.
Hepatitis - Treatment of the Relapse Patient
Relapse is defined as the reappearance of serum HCV RNA in a patient who had previously undetectable levels at the end of antiviral therapy. Occurrence of relapse following IEN mono therapy is more common than following combination IFN and ribavirin therapy.
While re-treatment of IFN-mono therapy relapse patients with a repeat course of similar therapy is ineffective, treatment with higher doses may improve sustained response rates. A large, multi center trial evaluated the use of high-dose consensus IFN (IFNalfa con-1) in patients who had relapse following a 24-week course of standard dose IFN-alfa-2b or IFN-alfa con-1. Subjects were randomized to receive 15 mcg of IFN alfa con-1 for either 24 or 48 weeks. The sustained viral response was 28% at 24 weeks and 58% at 48 weeks. Re-treatment at this higher dose was not associated with more significant side effects than treatment with the standard IFN regimen. Factors predictive of a sustained virologic response in this trial included low initial viral load, HCV genotype 2 or 3, and the absence of cirrhosis.
A second large study evaluated the use of combination IFN and ribavirin therapy in IFN mono therapy relapse patients. Patients were treated for a total of 6 months and randomized to receive standard-dose IFN-alfa-2b with or without ribavirin. A sustained virologic response was seen in 49% of patients treated with combination therapy and in only 8% of those treated with IFN mono therapy. Genotype other than type 1 and low pretreatment HCV-RNA levels were positive predictive factors of a sustained response in this trial. Twelve percent of subjects treated with ribavirin required a dose reduction or interruption secondary to anemia, whereas only 3% of those receiving IEN mono therapy required dose reduction.
As previously indicated, patients who relapse following IFN mono therapy may be effectively re-treated with either higher-dose IFN mono therapy or with combination IFN and ribavirin. But the increasing problem facing physicians today is how to approach the patient who relapses following combination therapy. At present, there are no large published studies to help answer this question. Several studies are ongoing with either pegylated interferon (peginterferon) alfa-2a or peginterferon alfa-2b in patients who relapsed following treatment with combination therapy of IFN plus ribavirin.
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