Retreatment of persons with chronic hepatitis C is a challenging and controversial issue. In an article from Hepatology, Mitchell Shiffman, MD, presents an examination of approaches to retreatment based on a consideration of which patients can benefit and a careful assessment of other factors such as genotype and stage of liver disease. Following is a summary review of Dr. Shiffman’s article:

The combination of standard interferon alfa (3 MU 3 times a week) and ribavirin (1,000 to 1,200 mg daily) for 24 to 48 weeks yielded SVR rates between 36% and 47%, 2-fold to 3-fold higher than that observed with standard interferon monotherapy.

More recently, pegylated interferons alfa-2a and alfa-2b (Pegasys and PEG-Intron, respectively) have been developed, and 2 large clinical trials using peginterferon and ribavirin yielded SVR rates of 54% to 56%, which were 7% to 12% higher than those achieved with standard interferon and ribavirin.

Peginterferon alfa-2b (PEG-Intron) and ribavirin was approved by the FDA for the treatment of chronic hepatitis C in 2001. Peginterferon alfa-2a (Pegasys) was approved in October 2002.

With the introduction of each new, more effective therapeutic regimen for hepatitis C, the issue of retreatment arises. The major rationale for retreatment has been that a more effective regimen is likely to lead to an SVR in at least a proportion of patients who failed to respond to the previous, less effective regimen.

Unfortunately, preliminary studies have demonstrated that the overall rates of response during retreatment tend to be limited. Several clinical and virological factors can be helpful in predicting the likelihood of a response to retreatment and higher response rates can be achieved by carefully selecting patients for retreatment. Only prospective trials can address the issue of whether retreatment is beneficial and for which groups of patients.

Categories of Patients for Retreatment
Retreatment of Non-responders
Appropriate Candidates for Retreatment
Options for Patients with Continued Non-response
Summary and Future Research Needs

Categories of Patients for Retreatment

Patients being considered for retreatment can be categorized into 2 groups: relapsers and non-responders. Relapsers are patients who become HCV RNA negative during a course of therapy, but then relapse and redevelop HCV RNA after stopping treatment.

Non-responders are patients who do not become HCV RNA negative during therapy. These definitions require regular timed testing for HCV RNA using a sensitive and reliable method.

A third pattern of response is referred to as breakthrough, in which patients become HCV RNA negative initially and then redevelop HCV RNA while still receiving therapy. Patients with this pattern are identified only by repeat HCV RNA testing during therapy and for general discussion should be considered non-responders.

In recent years, it has become clear that virological response rates are more predictive than biochemical responses of both short-term and long-term outcome. Sensitive and specific assays for HCV RNA are now widely available, and current definitions for relapse and non-response are generally based on virological criteria alone.

Within the group of non-responders are 2 different virological patterns of response. A proportion of patients have little or no decrease in HCV RNA levels during therapy, the decrease being less than 2 log10 units (null or flat response). In another proportion, serum HCV RNA levels decrease at least 2 log10 units, but still remain detectable during therapy (partial response).

The differences between these 2 patterns may be important, as patients with a significant decrease in HCV RNA levels may have improvements in serum ALT levels and hepatic histology, as well. These patients may also have a greater likelihood of achieving a SVR when retreated with a more effective therapeutic regimen.

Table 1. Factors to consider when assessing the usefulness of retreatment

The efficacy of the previous therapy

The efficacy of the therapy to be used for retreatment

The character of the response to previous therapy

Race

HCV genotype

Severity of liver disease

The ability to tolerate and/or comply with the previous and current therapy

Ongoing alcohol consumption

The major predictive factors for an SVR with retreatment are the type of responses that occurred with the previous course of therapy and the difference in efficacy between the initial and the repeat course of treatment. Several studies have shown that re-administration of the same regimen of therapy is unlikely to be beneficial, unless the previous course was stopped early or was not adequately administered.

New treatment regimens have utilized higher doses of interferon, a different type of interferon, a longer duration of therapy, or the addition of a second medication, such as ribavirin and its dose and duration of treatment. The likelihood that retreatment will be successful is directly related to the differences in efficacy between the initial and the retreatment regimens.

The expected range for SVR during retreatment can be estimated by calculating the difference in end-of-treatment virological response rates between the 2 therapies and the relapse rate of the newer treatment.

For example, patients who were non-responders to interferon monotherapy (which has an end-of-treatment-response rate of 24% to 29%) would be expected to have a 21% to 37% chance of an end-of-treatment response to interferon and ribavirin (which in naïve subjects has an end-of-treatment-response rate of 50% to 61%).

These same non-responders to interferon monotherapy would have a 36% to 54% chance of an end-of-treatment response to peginterferon and ribavirin (which in naïve subjects has an end-of-treatment response rate of 65% to 68%). In contrast, patients who failed to respond to interferon and ribavirin would have only a 21% to 37% chance of responding to peginterferon and ribavirin.

Because relapse rates to combination therapy have averaged 20%, the expected range for SVR after reatreatment can also be calculated. The actual sustained response rates observed during retreatment studies were well within what would be expected based on these calculations.

Retreatment of Non-responders

Higher response rates to retreatment were associated with HCV genotype non-1, treatment duration of 48 rather than 24 weeks, lower baseline HCV RNA levels, non-black race, absence of cirrhosis, use of standard doses of ribavirin (1,000 to 1,200 mg/d), and previous partial virological response to interferon monotherapy.

Preliminary results suggest that approximately 25% to 40% of non-responders to interferon monotherapy will achieve an SVR with peginterferon-ribavirin combination therapy, but only 10% to 11% of non-responders to standard interferon-ribavirin combination therapy have a sustained response to retreatment with peginterferon-based combination therapy.

Data regarding the effectiveness of peginterferon and ribavirin for retreatment of patients who relapsed after initial treatment with interferon and ribavirin are available only from a single study, which is still ongoing. Of 15 patients retreated with peginterferon alfa-2b at a dose of 1.5 µg/kg/wk and ribavirin 800 mg/d, 87% achieved an end-of-treatment response and 60% an SVR. The effect of continuing therapy for a longer period of time requires further study.

Appropriate Candidates for Retreatment

The recent increase in response rates to treatment with peginterferon and ribavirin in chronic hepatitis C has renewed enthusiasm for retreatment in both physicians and patients. Unfortunately, the actual increase in SVR with peginterferon combination over rates with standard interferon combination therapy is only 10% to 11%. For these reasons, combination retreatment using peginterferon should probably be limited to the patients in greatest need for therapy and/or those with the greatest likelihood of responding (Table 3).

Table 3. Factors associated with a favorable response during retreatment

Previous relapse

Partial virological response during the previous treatment

Previous treatment with only interferon monotherapy

HCV genotype 2 or 3

Non-African American race

Patients in greatest need of therapy are those with advanced fibrosis or cirrhosis or patients with symptoms or extrahepatic manifestations of hepatitis C. Patients with the greatest likelihood of a response to retreatment are relapsers or those who had a significant decline (at least 2 log10 units) in serum HCV RNA levels during previous therapy. Response to retreatment is also more likely in non-responders to interferon monotherapy and those infected with HCV genotypes 2 or 3.

Options for Patients with Continued Non-response

As noted above, the number of non-responders who achieve a sustained virological response after retreatment, even with peginterferon and ribavirin, is limited. These patients should be classified into 2 groups, those with advanced fibrosis or cirrhosis and those with either none or only mild degrees of fibrosis.

This later group of patients has an excellent long-term prognosis and is at low risk for development of cirrhosis within the next 5 to 10 years or possibly longer. There is, therefore, no imminent need to retreat these patients, especially if they exhibit characteristics suggestive of continued non-response. Careful observation over several years with retreatment only after more effective therapies are available is an appropriate approach to management of such patients.

This approach underscores the importance of performing a liver biopsy and assessing hepatic histology before initial therapy, especially in patients with HCV genotype 1 in whom the likelihood of not achieving an SVR is at least 50%.

Non-responders after retreatment who have advanced fibrosis or cirrhosis are at significant risk for developing cirrhosis and/or hepatic decompensation in the subsequent 5 to 10 years.

Continuing low-dose peginterferon as maintenance therapy has been proposed as a possible treatment for these patients. The concept of maintenance therapy is based on the observation that up to 40% of non-responders have a histological response during treatment.

Maintenance therapy with interferon may lead to continued viral suppression and improvements in necroinflammatory changes in the liver and prevention of progression of fibrosis.

This important hypothesis is the focus of 2 large multicenter, randomized, controlled trials using low doses of peginterferon in patients with advanced fibrosis or cirrhosis due to hepatitis C. Endpoints in these trials are prevention of worsening of fibrosis and prevention of cirrhosis, clinical decompensation, and hepatocellular carcinoma.

Until results from these studies are available, use of maintenance interferon therapy should be considered experimental and of unproven benefit.

Summary and Future Research Needs

Unfortunately, sustained responses to retreatment occur in only a limited number of patients. For these reasons, retreatment with peginterferon and ribavirin should be reserved for patients with favorable factors for achieving an SVR. These include patients with prior relapse or a partial virological response, infection with HCV genotypes 2 or 3, and previous therapy with interferon alone.

The decision to retreat a patient should not only be based on the likelihood for response, but also on the severity of the liver disease, which determines the overall risk that the patient may develop cirrhosis or advanced liver disease in the future.

This underscores the need to perform a liver biopsy before therapy, especially in patients with HCV genotype 1 who have a significantly lower likelihood for non-response. Patients who remain viremic despite retreatment can be safely observed without continued therapy if their liver disease is mild.

Maintenance therapy utilizing low-dose peginterferon is currently being evaluated as a possible way to prevent cirrhosis and decompensation in patients with advanced fibrosis and cirrhosis who fail to have a sustained response to treatment.

The limited benefit of peginterferon and ribavirin in the population of non-responders underscores the need for better treatments for chronic hepatitis C.

This is almost certain to be in the form of oral, direct antiviral agents. A better understanding of those host immunologic and genetic factors, which favor non-response, could also provide important insight into the development of more effective therapies for these patients.

In the meantime, ongoing studies should clarify the role of maintenance therapy and that subset of non-responders who are most likely to benefit from this approach.

Reference
M Shiffman. Retreatment of patients with chronic hepatitis C. Hepatology 36(5): S128-S134. November 2002, part 2.