HOME

JANIS AND FRIENDS HEPATITIS C WEB SITE 

 

Hepatitis C Research

Back to Index

  Optimal Therapy of Hepatitis C
  Retreatment of Patients With Chronic Hepatitis C
  Treatment for Hepatitis C: A Systematic Review
  Utilization of Virologic Testing in the Treatment of Chronic Hepatitis C
  The Role of Liver Biopsy in Therapy of Chronic Hepatitis C
  Children with Hepatitis C

 

 

Optimal Therapy of Hepatitis C

Adrian M. Di Bisceglie, M.D.

Considerable progress has been made in therapy since the last Consensus Development Conference on Management of Hepatitis C in 1997. Using the sustained virologic response (SVR) rate as the standard definition of beneficial outcome of therapy, different treatments can be compared in various categories of patients. The combination of interferon alfa-2b and ribavirin resulted in SVR rates of 31–35 percent after a 24-week course and 38–43 percent after a 48-week course of therapy. (1) The use of pegylated rather than standard interferon with ribavirin increased the response rate to 54–56 percent. (2,3)

The efficacy of two different formulations of peginterferon combined with ribavirin were assessed in two recent pivotal trials. The first of these compared two different doses of peginterferon alfa-2b plus ribavirin to standard interferon alfa-2b plus ribavirin for the initial treatment of chronic hepatitis C. (2) In the trial, 1,530 patients were randomized to receive either: (1) peginterferon alfa-2b (1.5 mcg weekly: higher dose) plus ribavirin (800 mg daily), (2) peginterferon alfa-2b (1.5 mcg weekly for 4 weeks followed by 0.5 mcg weekly: lower dose) plus ribavirin (1,000–1,200 mg daily), or (3) standard interferon alfa-2b (3 million units thrice weekly) plus ribavirin (1,000–1,200 mg daily). The treatment duration in all groups was 48 weeks. End-of-treatment virologic responses were achieved in 65 percent of patients treated with higher dose peginterferon, 56 percent treated with lower dose peginterferon, and 54 percent treated with standard interferon and ribavirin. Sustained virologic responses occurred in 54 percent of patients in the higher dose peginterferon group, 47 percent in the lower dose group, and 47 percent in the standard interferon group. Among patients treated with the higher dose of peginterferon, SVRs were significantly higher in patients infected with HCV genotype 2 or 3 (82 percent) than in those with genotype 1 (42 percent). The initial level of HCV RNA in serum also correlated with the SVR rates. Patients with high initial levels of HCV RNA, defined as greater than 2 million copies/ml, had significantly lower response rates than those with lower levels of virus (less than 2 million copies /ml) (42 percent vs. 78 percent). The degree of hepatic fibrosis had a lesser impact on the outcome of therapy: the SVR rate was 57 percent in those with no or minimal fibrosis compared to 44 percent among those with bridging hepatic fibrosis or cirrhosis.

A second recent large, randomized controlled trial compared peginterferon alfa-2a (180 mcg weekly) plus ribavirin 1,000 - 1,200mg daily) to the same dose of peginterferon alfa-2a alone, or standard interferon alfa-2b (3 million units thrice weekly) plus ribavirin (1,000–1,200 mg daily) in 1,121 patients. (3) End-of-treatment virologic responses occurred in 69 percent of patients treated with peginterferon alfa-2a plus ribavirin, 59 percent with peginterferon alone, and only 52 percent with standard interferon and ribavirin. Sustained virologic response rates were 56 percent, 30 percent, and 45 percent, respectively. As in virtually all studies of antiviral therapy, HCV genotype was a strong predictor of SVR, which occurred in 46 percent of those with genotype 1 compared to 76 percent with genotypes 2 or 3 in the peginterferon plus ribavirin group.

Thus, two large pivotal trials have shown that the combination of peginterferon and ribavirin given for 48 weeks yields the highest rate of sustained response. While this may be the most effective regimen overall, it may not be optimal for all patients and in all situations. At issue is the optimal dose of peginterferon, the optimal dose of ribavirin, and the optimal duration of therapy.

In the large trial of peginterferon alfa-2b, two doses of peginterferon were compared, both based upon body weight. (2) While the higher dose yielded a better overall response rate, SVR rates for patients with genotypes 2 and 3 were similar with the higher and the lower peginterferon doses (82 percent vs 80 percent). In the trial of peginterferon alfa-2a, a single dose not adjusted to body weight (180 mcg weekly) was tested, based upon previous studies which identified this to be the most effective dose when given alone without ribavirin. (4) Yet, in all of these studies, dose modifications because of side effects were common, and it is, therefore, possible that lower doses of peginterferon are just as effective and perhaps better tolerated.

The optimal dose of ribavirin for use in combination with either form of peginterferon is also not clear. In the study of peginterferon alfa-2b, two doses were used: 800 mg of ribavirin per day with the higher dose of peginterferon alfa-2b was compared to the more standard dose of ribavirin of 1,000–1,200 mg daily (based on body weight) with the lower dose of peginterferon. Post-hoc analyses suggested that the 800 mg dose of ribavirin was suboptimal, in that response rates correlated with body weight, so that SVR rates increased as the ribavirin dose per kg body weight increased up to the highest rates, which were achieved at 13 mg/kg. Only the standard dose of ribavirin was used in the studies of peginterferon alfa-2a. (3) Clearly, the effects of these small differences in ribavirin doses need to be properly assessed in prospective controlled trials.

In both of the pivotal trials of peginterferon, therapy was given for 48 weeks. Thus, the relative efficacies of shorter or longer courses are not known. A full 48 weeks of therapy is clearly not needed to achieve SVR in all patients. Evidence from earlier studies of standard interferon with ribavirin suggested that 24 weeks of therapy was sufficient for patients with genotypes 2 or 3 and in patients with genotype 1 and low levels of HCV RNA. (1) Furthermore, sequential testing for HCV RNA levels suggests that patients who do not respond can be identified as early as 24 or even 12 weeks of therapy; (2,3) if so, their therapy could be curtailed early, thus minimizing side effects and cost. Future studies are needed to assess the optimal duration of therapy in different categories of patients as well as to assess the possible role of sequential measurements of HCV RNA levels as a means of determining the optimal duration of treatment.

References

  1. McHutchison JG, Poynard T. Combination therapy with interferon plus ribavirin for the initial treatment of chronic hepatitis C. Semin Liver Dis 1999;19:57–65.
  2. Manns MP, McHutchison JG, Gordon SC, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomized trial. Lancet 2001;358:958–65.
  3. Fried MW, Shiffman ML, Reddy K, et al. Pegylated (40 kDa) interferon alfa-2a (PEGASYS) in combination with ribavirin: Efficacy and safety results from a phase II, randomized, actively-controlled, multicenter study. Gastroenterology 2001;120:A-55 (abstract).
  4. Zeuzem S, Feinman SV, Rasenack J, et al. Peginterferon alfa-2a in patients with chronic hepatitis C. N Engl J Med 2000;343:1666–72.

 

Retreatment of Patients With Chronic Hepatitis C

Mitchell L. Shiffman, M.D.

A large number of patients with chronic hepatitis C have been treated with alpha interferon with or without ribavirin since the 1997 Consensus Development Conference. Unfortunately, a majority of these patients probably did not achieve a sustained virologic response (SVR). As new therapies are developed for hepatitis C, the issue of retreatment of these non-responders will continue to arise. Recommendations regarding retreatment should be based upon several factors: (1) the previous type of response, (2) the previous therapy and the difference in potency of the new therapy, (3) the severity of the underlying liver disease, (4) viral genotype and other predictive factors for response, and finally (5) tolerance of previous therapy and compliance. (1)

Types of Non-Response

Patients who fail to achieve SVR can be categorized as either relapsers or non responders. In general, relapsers are more likely to achieve SVR during retreatment with a more potent regimen than are non-responders. Yet among patients referred to as non-responders, there is the subset who have a marked reduction without disappearance of HCV RNA (1–2 log units or more) during therapy. These partial responders may also be good candidates for retreatment, if a more potent regimen of therapy is being applied, such as the currently recommended combination of peginterferon and ribavirin. In at least one study of retreatment, only non-responders who had a decline in HCV RNA to an absolute titer <100,000 copies/ml during previous treatment with interferon alone achieved SVR when retreated with interferon and ribavirin. (2)

Retreatment of Non-Responders

The likelihood that non-responder patients will respond to retreatment depends in large part upon the previous therapy. Retreatment of non-responders with the same therapy will not result in viral clearance, whereas retreatment with a more potent regimen can result in SVR in a proportion of patients. Thus, preliminary results suggest that up to 30 percent of non-responders to the standard interferon/ribavirin combination became HCV RNA negative on retreatment using the peginterferon/ribavirin combination. (3,4) Higher rates occurred in patients with HCV genotypes 2 or 3 compared to genotype 1. Unfortunately, relapse was common once therapy was discontinued, so that the rate of SVR was only 15–20 percent overall.

Retreatment of Relapsers

Several studies have shown that patients with prior relapse have a high rate of SVR when retreated with more effective therapy. Thus, 50 percent of patients who relapsed following treatment with interferon alone achieved SVR when retreated with interferon/ribavirin combination. (5) The ability to achieve SVR following retreatment with peginterferon/ribavirin in patients who relapsed following interferon monotherapy or standard interferon/ribavirin therapy is currently being evaluated. The majority of relapsers become HCV RNA negative during retreatment, even when the regimen is the same. When the same regimen is used, however, virtually all patients relapse again after treatment is stopped. Extending the duration of retreatment without changing the dose or regimen may reduce relapse, but this has not been prospectively proven.

Severity of Liver Disease and Retreatment

Knowledge of the severity of the underlying liver disease is important in recommending retreatment of chronic hepatitis C. Patients with no or minimal fibrosis probably have an excellent long-term prognosis and low risk for developing cirrhosis or complications of chronic hepatitis C. These patients, therefore, could forgo retreatment and await further advances in therapy. On the other hand, patients with advanced fibrosis or cirrhosis are at increased risk for developing hepatic decompensation and should be considered for retreatment, especially if the previous treatment was interferon alone. For patients with intermediate degrees of fibrosis and disease activity, recommendations for retreatment should weigh the type of initial response, the improvement in treatment regimen, factors such viral genotype, initial titer of HCV RNA, as well as tolerance of therapy.

Non-Responders to Combination Therapy with Peginterferon and Ribavirin

Patients who fail to respond even to the current optimal therapy with peginterferon/ ribavirin are a great challenge for management, particularly those with advanced fibrosis or cirrhosis. In several studies of standard interferon, up to 40 percent of non-responders developed evidence of a histological response despite persistence of HCV RNA. (6,7) These histological responses occurred largely among patients with a partial virological response as shown by a significant reduction in HCV RNA titer. In a prospective, randomized controlled trial, these histological improvements were shown to be maintained by continuation of interferon monotherapy. (8) The possible role of maintenance therapy with peginterferon alone in preventing further progression of cirrhosis, clinical decompensation, or development of hepatocellular carcinoma is currently the focus of a large-scale, multi-center U.S. trial, referred to as HALT-C. Until the results of that study or similar studies are available, the role of long-term, continuous therapy with peginterferon (or ribavirin or both) for non-responder patients must be considered experimental.

Tolerance and Compliance

An important reason for relapse and non-response to interferon therapy of hepatitis C is non-compliance. Non-compliance can be the result of severe side effects or lack of commitment by the patient, but also can be due to poor counseling regarding side effects and inadequate management. If the causes of non-compliance can be corrected or lessened, retreatment can be successful. In contrast, if side effects are intolerable despite adequate counseling and management, retreatment is unlikely to be successful and should not be encouraged. 

References

  1. Shiffman ML. Management of interferon therapy non-responders. Clin Liver Dis 2001;5:1025–43.
  2. Shiffman ML, Hofmann CM, Gabbay J, et al. Treatment of chronic hepatitis C in patients who failed interferon monotherapy: Effects of higher doses of interferon and ribavirin combination therapy. Am J Gastroenterol 2000;95:2928–35.
  3. Minuk GY, Reddy KR, Lee SS, et al. Enhanced virologic response to treatment with 40KDA peginterferon-alpha-2a (Pegasys) in patients previously unresponsive to treatment with interferon-alpha-2a. Hepatology 2001;34:330A.
  4. Shiffman ML, for the HALT-C trial investigators. Retreatment of interferon and interferon-ribavirin non-responders with peginterferon-alpha-2a and ribavirin: Initial results from the lead-in phase of the HALT-C trial. Hepatology 2001;34:243A.
  5. Davis GL, Esteban-Mur R, Rustgi V, et al. Interferon alfa-2b alone or in combination with ribavirin for the treatment of relapse of chronic hepatitis C. N Eng J Med 1998;339:1493–9.
  6. Shiffman ML, Hofmann CM, Thompson EB, et al. Relationship between biochemical, virologic and histologic response during interferon treatment of chronic hepatitis C. Hepatology 1997;26:780–5.
  1. Shiffman ML. Histologic improvement in response to interferon therapy in chronic hepatitis C. Viral Hepatitis Reviews. 1999;5:27–43.
  2. Shiffman ML, Hofmann CM, Contos MJ, et al. A randomized, controlled trial of maintenance interferon for treatment of chronic hepatitis C non-responders. Gastroenterology 1999;117:1164–72.

 

Treatment for Hepatitis C: A Systematic Review

Geetanjali Chander, Mark S. Sulkowski, Mollie W. Jenckes, Kelly A. Gebo, Khalil G. Ghanem, H. Franklin Herlong, Michael Torbenson, Kirk A. Harris, Samer El-Kamary, and Eric B. Bass

Introduction

Hepatitis C is a spherical enveloped RNA virus of the Flaviviridae family, which has been recognized as a major cause of chronic hepatitis and hepatic fibrosis that progresses in some patients to cirrhosis and hepatocellular carcinoma (HCC). In the United States, approximately 4 million people have been infected with hepatitis C (HCV) and 10,000 HCV-related deaths occur each year. Effective treatment strategies are needed to prevent hepatitis C-related morbidity and mortality.

Objective

We conducted a systematic review of the literature to determine: (1) the extent to which randomized controlled trials have shown the efficacy and safety of current treatment options for chronic hepatitis C in treatment-naive patients, including: pegylated interferon plus ribavirin; pegylated interferon alone; interferon plus ribavirin; and interferon plus amantadine; (2) the extent to which randomized controlled trials have shown the efficacy and safety of current interferon based treatment options (including interferon alone) for chronic hepatitis C in selected subgroups of patients, especially those defined by the following characteristics: age less than or equal to 18 years, race/ethnicity, HCV genotype, presence or absence of cirrhosis, minimal vs. decompensated liver disease, concurrent hepatitis B or HIV infection, non-response to initial interferon based therapy, and relapse after initial interferon based therapy; and (3) the long-term outcomes of current treatment options for chronic hepatitis C infection.

Methods

Literature Sources

Seven electronic databases were searched through DIALOG for the period from January 1996 to March 2002. Additional articles were identified by searching references in pertinent articles, hand searching relevant journals, and querying technical experts.

Eligibility Criteria

Exclusion criteria for review included: non-English language, articles limited to basic science or non-human data, previously reported data, and meeting abstracts. Inclusion criteria for review were: study designed to address our key question, information pertinent to management of hepatitis C, and 30 or more study subjects with hepatitis C. In addition, treatment articles reviewed were limited to randomized controlled trials. To explore modern treatment options, we limited eligible studies to those evaluating interferon alone or in combination with other treatment options, e.g., ribavirin, amantadine, etc., and where outcomes were assessed by virologic and/or histologic measures of outcomes. Studies of interferon alone were only included when the study participants were subgroups of interest, e.g., renal disease, HIV co-infection. Studies evaluating long-term followup could be either randomized controlled trials or cohorts but required at least 60 months of observation.

Assessment of Study Quality

Each eligible article was reviewed by a pair of reviewers, including at least one team member with relevant clinical training and/or one with training in epidemiology and research methods. Paired reviewers independently rated the quality of each study in terms of the following categories: representativeness of study subjects (5 items); bias and confounding (4 items); description of therapy (4 items); outcomes and follow-up (5 items); statistical quality and interpretation (4 items). Reviewers assigned each response level a score of 0 (criterion not met), 1 (criterion partially met), or 2 (criterion fully met) to each relevant item on the quality form. The score for each category of study quality was the percentage of the total points available in each category and therefore could range from 0–100 percent. The overall quality score was the average of the five categorical scores. We also documented source of funding.

Extraction of Data

The paired reviewers also abstracted data on type of study and geographical location; study groups; specific aims; inclusion and exclusion criteria, screening regimen; demographic, social and clinical characteristics of subjects, and results. Differences between the two reviewers in either quality or content abstraction were resolved by consensus.

Synthesis

Results of Literature Search

We identified 3,104 potentially relevant citations and 1,731 of these were deemed eligible for abstract review. Through the abstract review process, we identified 486 articles that could have been related to one of our key questions regarding treatment. After reviewing these 486 articles, we found 231 studies including 165 randomized controlled trials reporting on current treatment and 66 reporting on long-term outcomes. Data from these eligible studies will be presented in a series of evidence tables and figures highlighting their distinguishing characteristics, methodological strengths and limitations, and key findings.

 

Utilization of Virologic Testing in the Treatment of Chronic Hepatitis C

Gary L. Davis, M.D.

Slightly fewer than half of patients with chronic hepatitis C fail to eradicate hepatitis C virus (HCV) when treated with the current regimen of combination therapy with pegylated interferon and oral ribavirin (PEG-R). (1,2) With past treatment regimens including interferon monotherapy or the combination of standard interferon with ribavirin, patients who remained HCV RNA positive by qualitative testing by RT-PCR after 12 or 24 weeks, respectively, had little or no chance of achieving a sustained virologic response (SVR). (3,4) Preliminary data from one of the PEG-R studies suggested that the most appropriate time point for assessing response with the current regimen was also 24 weeks. (1). Thus, treatment could be discontinued early in viral non-responders, saving them the inconvenience and expense of the latter half of the treatment course. However, several papers also reported that the lack of an even earlier reduction in viral level was predictive of non-response despite continued treatment. (5,6) Unfortunately, these reports examined small numbers of patients and used quantitative assays for HCV RNA that were neither reliable or commercially available. Recently, several standardized commercial assays for quantitating HCV RNA have become available. The role of these quantitative tests in assessing early virologic response (or non-response) to PEG-R has not been studied.

The goal of the current analysis was to determine whether reduction of the level of HCV RNA during the first weeks of PEG-R treatment predicted response and non-response at the end of treatment and whether this information would be used to formulate early stopping rules before 24 weeks of treatment. Data from two recent large international clinical studies of pegylated interferon plus oral ribavirin was made available by the study sponsors, Schering Plough and Roche Pharmaceuticals, after agreement of the study investigators. (1,2) Only those treatment groups receiving the optimal regimen were included (PEG-IFNα2a 180 mcg q wk + ribavirin1000–1200 mg daily; PEG-IFNα2b 1.5 mcg/kg qwk + ribavirin 800 mg daily). Quantitative HCV RNA was measured at baseline, 4 weeks, 12 weeks, and 24 weeks by the NGI method (Schering study) or Amplicor with appropriate dilutions of high titer samples (Roche study). (7,8) This data was analyzed to answer the following questions: (a) Can serial quantitative HCV RNA testing predict a lack of virologic response to PEG-R? (b) Can serial quantitative HCV RNA testing predict a sustained virologic response to PEG-R? (c) What is the optimal time to determine early virologic response?

The analysis of the 2 data sets with respect to the ability of the week 12 viral response to predict non-response is shown in the table below. The results with the 2 different interferon regimens are nearly identical. Early virologic response (EVR) was best defined as a fall in HCV RNA level after the first 12 weeks of treatment to less than the lower limit of detection (PCR) or by at least 2 logs compared to the pre-treatment level. Overall, 82.7 percent of patients treated with this combination achieved EVR and 68 percent of these cases eventually achieved SVR. SVR was more than 50 percent more likely to occur in patients who were able to receive at least 80 percent of the recommended dose and duration of drugs. Failure to achieve an early virologic response was highly predictive of non-response; only 2 of 161 (1.2 percent) patients without EVR ultimately achieved SVR. Viral response at 4 weeks was less predictive than the 12 week response; failure to achieve a 4 week EVR was associated with a 4 percent chance of SVR. A quantitative cutoff of more than 2 logs (e.g. 3 logs) missed some patients who ultimately achieved SVR while a less rigorous cutoff (e.g. 1 log) allowed too many non-responders to continue on treatment.

 

Early Virological Response

Treatment Response

SVR                                                             NR

Study #1

 

Yes

71.8%                                                  28.2%

No

0.0%                                                 100.0%

Study #2

 

Yes

64.9%                                               35.1%

No

3.2%                                                 96.8%

Combined Data

 

Yes

68.3%                                               31.7%

No

1.2%                                                 98.8%