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Hepatitis C therapy in treatment-naı̈ve patients
Hepatitis C Therapy in Treatment-naı¨ve Patients John McHutchison, MD
Until recently, interferon was the only approved therapy for previously untreated patients with chronic hepatitis C. Unfortunately, the majority of patients do not respond to this regimen, and rates of sustained virologic response were a disappointingly low 15% to 20%. Clearly, more effective treatment for this infection was needed. The nucleoside analogue ribavirin is now approved for administration in combination with interferon to treatment-naı¨ve individuals with hepatitis C (HCV) infection as well as HCV-positive patients who have relapsed after interferon monotherapy. Results of a recent US multicenter trial in treatment-naı¨ve patients with chronic hepatitis C demonstrate that combination therapy with interferon plus ribavirin produces sustained virologic response rates that are two to three times higher than those obtained with interferon alone. Rates of sustained virologic response (defined as undetectable serum HCV-RNA levels 24 weeks after completion of treatment) were 6% vs 31% after 24 weeks of interferon alone vs interferon plus ribavirin, respectively. For 48 weeks of treatment, rates of sustained virologic response were 13% and 38% with monotherapy and combination therapy, respectively. These results, which are consistent with those obtained in smaller preliminary trials and in a recently completed international multicenter trial, suggest that combination therapy with interferon and ribavirin may be preferable to monotherapy as first-line treatment for patients with chronic HCV infection. Am J Med. 1999; 107(6B):56S– 61S. © 1999 by Excerpta Medica, Inc.
H
epatitis C has been identified as an enormous health-care problem in this country. Approximately 30,000 new infections are estimated to occur each year. In addition, the mortality rate, currently estimated at 8,000 to 10,000 deaths each year, is expected to triple in the next 10 to 15 years.1 Management of chronic hepatitis C is complex. Some of the difficulties stem from the wide individual variability that exists in the degree and rate of disease progression and the lack of reliable prognostic markers of disease progression. Another problem is the explosion of information accompanied by rapid advances in diagnosis and treatment that have occurred over the last few years. Even experts in the field have difficulty staying abreast of the changes. One major accomplishment in the past few years has been in defining the terminology used to describe treatment responses in clinical trials. An understanding of these terms is key to evaluating properly the results of clinical trials, such as the one presented here, as well as to communicating with other physicians about individual patients. A “response” is defined both biochemically and virologically: normalization of alanine aminotransferase (ALT) levels and disappearance of hepatitis C virus (HCV) RNA from serum during treatment. Responses are not considered “sustained responses” until 6 months after the discontinuation of therapy. Follow-up studies have determined that a response maintained for 6 months has a very low likelihood of relapse. “Relapsers” are patients in whom the virus comes back after an initial response. A proportion of such patients will respond to another course of treatment, but the likelihood of response decreases with each relapse. In “nonresponders,” the virus never disappears, and these patients are very difficult to manage. (See Bacon’s article “Available Options for Treatment of Interferon Nonresponders” in this supplement.) Other complexities in managing patients with chronic hepatitis C have been limited treatment options and the limitations of the treatments that are available.
LIMITATIONS OF INTERFERON MONOTHERAPY FOR CHRONIC HEPATITIS C
From Scripps Clinic and Research Foundation, Division of Gastroenterology/Hepatology, La Jolla, California, USA. Requests for reprints should be addressed to John McHutchinson, MD, Scripps Clinic and Research Foundation, Division of Gastroenterology/Hepatology, 10666 North Torrey Pines Road, La Jolla, California 92037. 56S © 1999 by Excerpta Medica, Inc. All rights reserved.
Until recently, interferon ␣ was the only available therapy for chronic hepatitis C. Unfortunately, this treatment has significant limitations and is effective in the minority of patients. Treatment with interferon ␣ at a dosage of 3 million units administered subcutaneously three times weekly for 6 months has produced biochemical treatment responses in approximately 40% of patients. In most, 0002-9343/99/$20.00 PII S0002-9343(99)00384-8
A Symposium: Hepatitis C Therapy in Treatment-naı¨ve Patients /McHutchison
however, the improvement is transient, and only 15% to 20% achieve a sustained response.1 In terms of virologic results, a 6-month course of treatment has produced an end-of-treatment response rate of 30% to 40%, but the response is sustained in only 10% to 15% of patients.1 This response rate is similar for all available type 1 interferons. Increasing the duration of treatment to 1 year increases the sustained response to 20% to 25%.1 In a meta-analysis of 20 randomized, controlled clinical trials including previously untreated patients who were randomly allocated to receive at least 2 million units of interferon ␣ three times weekly, a 6-month course of therapy was associated with sustained response rates of only 14%, whereas extending the duration of therapy to 12 to 24 months produced a sustained response rate of 27% (P ⬍0.001).2 For this reason, extended-duration interferon therapy is the standard of care for the treatment of chronic hepatitis C in the United States and throughout most of the world. In the relatively small proportion of patients who achieve a sustained response, the long-term prognosis is good. According to long-term follow-up data from Marcellin3 and from Lau4, the majority of sustained responders remain so for 5 years or more; their HCV RNA remains undetectable, and their liver histology continues to improve. Nevertheless, considering current efficacy rates, interferon monotherapy leaves the majority of HCV-infected patients without hope of viral eradication. In addition, the need for parenteral administration and the side effects associated with therapy, including flu-like symptoms, fatigue, alopecia, bone marrow suppression, and neuropsychiatric problems, pose further limitations to interferon treatment.
RATIONALE FOR COMBINATION THERAPY Clearly, a more efficacious antiviral regimen is necessary for the treatment of this disease. In the absence of a single agent that provides improved efficacy against chronic hepatitis C, combination therapy holds the greatest promise. Combination therapy has the potential not only to overcome the limited efficacy of currently available therapy, but also to allow for therapeutic attack at various sites of viral replication and for enhancement of the host humoral responses. Numerous agents have been tried in combination with interferon for both initial and subsequent treatment of HCV infection; these agents include corticosteroids, nonsteroidal antiinflammatory drugs, pentoxifylline, quinolone antibiotics, ursodeoxycholic acid, thymosin, amantadine, granulocyte-macrophage colony-stimulating factor, and ribavirin. Except for ribavirin, these other agents have not demonstrated any significant benefit in terms of sustained biochemical or vi-
rologic response compared with interferon monotherapy.
THE ROLE OF RIBAVIRIN IN COMBINATION THERAPY Ribavirin is a nucleoside analogue that, when used alone, may produce some histologic improvement and transiently reduces levels of serum alanine aminotransferase (ALT, an indicator of liver cell injury) in approximately 50% of patients with chronic hepatitis C. Ribavirin monotherapy, however, does not lower serum HCVRNA levels.1 The mechanisms of action of ribavirin are not fully understood, but the agent is known to inhibit replication of many RNA and DNA viruses, including several related to HCV. Its antiviral actions include inhibition of viraldependent RNA polymerase, 5⬘ cap structure, and inosine monophosphate dehydrogenase, while its immunomodulatory actions include macrophage inhibition and alteration of the T1/T2 cytokine balance. Three initial randomized international trials have been conducted to compare a 6-month regimen of interferon monotherapy with a 6-month regimen of ribavirin plus interferon in treatment-naı¨ve patients. Although the sample sizes in each of the trials was small, the results were quite consistent (Figure 1). In the trial conducted by Reichard et al,5 the largest of the three studies (N ⫽ 100), the virologic sustained response rate (i.e., negative HCV RNA) was 42% in the combination-therapy group, compared with 20% in the interferon monotherapy group (P ⫽ 0.03). Lai et al,6 who studied 40 patients, obtained a 43% virologic response rate with combination therapy versus a 6% response rate with monotherapy at 48 weeks after treatment discontinuation; this response was maintained at 96 weeks. Finally, Chemello et al,7 in their study of 30 patients, obtained a 43% sustained virologic response rate in patients who received combination therapy, compared with a 7% response rate in monotherapytreated patients.
INTERFERON MONOTHERAPY VERSUS INTERFERON/RIBAVIRIN COMBINATION THERAPY: FINDINGS OF A US MULTICENTER TRIAL After these preliminary studies, a large multicenter trial was conducted in the United States.8 At the same time, a multicenter trial of nearly identical regimens and design was conducted internationally, with very similar results.9 The details of the pivotal US trial will be reviewed here. Study Design The aim of this double-blind, randomized, placebo-controlled US trial was to compare the safety and efficacy of interferon alone versus interferon with ribavirin for the initial treatment of chronic hepatitis C and to determine
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Figure 1. Percent of patients with sustained responses in three small randomized clinical trials of interferon plus ribavirin versus interferon alone in treatment-naı¨ve patients with chronic hepatitis C.5–7
the optimal duration of combination therapy.8 Adult patients were eligible for the study if they had chronic hepatitis C, as evidenced by elevated ALT values, detectable serum HCV RNA, and a liver biopsy consistent with chronic hepatitis C within 12 months of study entry. Individuals with documented anemia or cardiovascular disease that might be worsened by ribavirin-associated anemia were excluded. Because ribavirin is teratogenic, pregnant women and women of childbearing age unwilling to practice effective contraception were also excluded. The study enrolled 933 patients, and 912 were treated. Patients were stratified according to factors known to influence response to therapy, including the presence or absence of genotype 1, presence or absence of cirrhosis, and high or low baseline HCV-RNA levels. Patients were randomized to one of four regimens: interferon plus placebo for 24 weeks (n ⫽ 231), interferon plus placebo for 48 weeks (n ⫽ 225), interferon plus ribavirin for 24 weeks (n ⫽ 228), or interferon plus ribavirin for 48 weeks (n ⫽ 228). Ribavirin was administered twice daily at the standard dose of 1,000 mg/day for patients weighing less than 75 kg and 1,200 mg/day for patients weighing more than 75 kg/day. Interferon was administered at the standard dose of 3 million units subcutaneously three times a week. Patients were monitored frequently throughout treatment, with HCV-RNA testing and liver biopsy performed 24 weeks after the end of treatment. The primary end point of the study was a sustained virologic response, defined as the absence of serum HCV RNA 24 weeks after completion of treatment. Secondary end points included normalization of serum ALT levels and reduction of histologic inflammation of at least 2 points, as graded by a modified Knodell Histologic Activity Index (HAI). The mean age of the study participants was 44 to 45 58S December 27, 1999 THE AMERICAN JOURNAL OF MEDICINE威
years, and two thirds were male. Both HCV-RNA levels and ALT values were moderately elevated at baseline, and 70% of the patients were infected with HCV genotype 1. Mild to moderate inflammatory scores were obtained on liver biopsy, and cirrhosis was noted in only 4% to 7% of patients in each group. Results Sustained virologic response rates were significantly higher in patients who had been treated with interferon plus ribavirin for 48 weeks (38%) or 24 weeks (31%) than in patients who had received interferon alone for 48 weeks (13%) or 24 weeks (6%; P ⬍0.001; Figure 2).8 Similarly, end-of-treatment response, that is, the proportion of patients who had undetectable HCV RNA at the conclusion of treatment, was approximately doubled in patients who had received the combination regimen. Relapse after treatment was less frequent among patients receiving combination therapy (42% at 24 weeks and 24% at 48 weeks) than among those receiving interferon alone (80% at 24 weeks and 46% at 48 weeks). Thus, it appears that the addition of ribavirin to interferon not only initially increases the number of patients who can achieve virologic remission during treatment, but also subsequently prevents relapse. Biochemical response rates, as measured by ALT levels, mirrored virologic response rates (Figure 3). Histologic improvement occurred in all four groups and was significantly more common in both combination-therapy groups than in the monotherapy group that was treated for 48 weeks (P ⬍0.001). The degree of histologic improvement was greatest in the patients who received combination therapy with interferon and ribavirin for 48 weeks. Interestingly, even among patients considered nonresponders, 35% to 40% had some improvement in histologic inflammation. As expected, none of the treatVolume 107 (6B)
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Figure 2. Percent of patients with sustained virologic responses in US Multicenter Trial at 24 weeks versus 48 weeks with interferon alone or interferon plus ribavirin.8
Figure 3. Percent of patients with sustained biochemical (ALT) responses in US Multicenter Trial at 24 weeks versus 48 weeks with interferon alone or interferon plus ribavirin.8
ments had an effect on fibrosis over the short duration between liver biopsies. In patients infected with genotype 1, sustained virologic response rates with combination therapy was four times higher than that after interferon alone after 48 weeks of treatment. Among patients with this genotype, 48 weeks of combination therapy was significantly more effective than 24 weeks of combination therapy (P ⫽ 0.01; Table 1). This finding may suggest that 48 weeks of combination therapy is preferable for patients with HCV genotype 1. Conversely, the sustained virologic response rates for 24 and 48 weeks were similar for patients with genotype non-1, suggesting that 24 weeks of therapy may
be sufficient for such patients. These data provide a rationale for genotyping of patients to determine the duration of therapy. Data from the US multicenter study also demonstrates that late clearance of HCV RNA during combination therapy is frequently associated with a sustained response. This observation has been very rare in patients treated with interferon alone, and it suggests that discontinuing therapy at week 12 because of persistent viremia, as is recommended for monotherapy,1 may be inappropriate when combination therapy is used. Thus, combination interferon/ribavirin therapy should be continued for 24 weeks before considering discontinuation.
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Table 1. Sustained Virologic Response Rates Achieved With Interferon Monotherapy Versus Interferon Plus Ribavirin in a US Multicenter Trial, Stratified by Viral Genotype Interferon ⫹ Ribavirin
Interferon Viral Genotype Genotype 1 Non–Genotype 1
N
24 Weeks
48 Weeks
24 Weeks
48 Weeks
659 253
2% 16%
7% 29%
16% 69%
28% 66%
Table 2. Treatment Discontinuations or Dosage Reductions Because of Adverse Effects With Interferon Monotherapy Versus Interferon Plus Ribavirin in a US Multicenter Trial Interferon
Discontinuation Dosage reduction due to anemia Dosage reduction due to other adverse events
Interferon ⫹ Ribavirin
24 Weeks
48 Weeks
24 Weeks
48 Weeks
9% 0 12%
14% 0 9%
8% 7% 13%
21% 9% 17%
Table 3. Characteristics of Patients Who Should or Should Not Be Considered for Combination Interferon/Ribavirin Therapy Consider Adult ⱖ 18 years of age Documented chronic hepatitis C with detectable HCV RNA Elevated ALT levels Treatment-naı¨ve or relapsed Compensated hepatitis
Step-wise regression analyses revealed that the most important factors associated with greater efficacy were combination therapy with interferon plus ribavirin (P ⬍0.001), extended-duration (48-week) therapy (P ⫽ 0.002), genotype non-1 (P ⬍0.001), and low viral burden (P ⬍0.001). Female sex and absence of cirrhosis were also significantly associated with better outcome, but to a lesser degree (P ⫽ 0.05 and 0.04, respectively). The need for dose reduction or treatment discontinuation because of anemia or other adverse events was more common among patients treated with combination therapy (Table 2). Adverse effects that were more common with combination therapy included hemolytic anemia, cough, pruritus, rash, and insomnia. None of the latter four adverse effects were dose limiting. Hemolytic anemia is a concern with ribavirin, and 25% of patients experienced a decrease in hemoglobin levels of greater than 4 g. However, hemoglobin levels returned to baseline values within 4 to 8 weeks after treatment discontinuation. The ribavirin dose was reduced to 600 mg daily for patients whose hemoglobin concentrations decrease below 10 g/dL and discontinued for concentrations below 8.5 g/dL. Hemoglobin concentrations increased by 1 to 1.5 60S December 27, 1999 THE AMERICAN JOURNAL OF MEDICINE威
Do Not Consider Pregnant Unable/unwilling to use effective contraception History of significant or unstable cardiac disease Hemoglobinopathies Autoimmune hepatitis Children
g/dL and then remained stable throughout treatment for patients (8%) requiring dose reductions. One patient required ribavirin discontinuation and transfusion.
SUMMARY The first approved therapy for treatment-naı¨ve patients with chronic HCV infection was interferon for a duration of at least 24 weeks. However, the rates of sustained virologic response to this regimen generally did not exceed 10% to 15%. Data from the US multicenter trial of combination interferon/ribavirin therapy confirm earlier findings from smaller preliminary trials that combination therapy with interferon and ribavirin for either 24 or 48 weeks is superior to treatment with interferon alone with respect to all endpoints, virologic, biochemical, and histologic. These responses will hopefully be sustained beyond 5 to 10 years and be accompanied by progressive histologic improvement. Dual therapy with interferon and ribavirin should be considered for first-line therapy in treatment-naı¨ve patients with chronic hepatitis C who are suitable candidates (Table 3). Volume 107 (6B)
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REFERENCES 1. National Institutes of Health Consensus Development Conference Panel Statement: management of hepatitis C. Hepatology. 1997;26(suppl 1):2S–10S. 2. Carithers RL Jr, Emerson SS. Therapy of hepatitis C: metaanalysis of interferon alfa-2b trials. Hepatology. 1997;26(3 suppl 1):83S– 88S. 3. Marcellin P, Boyer N, Gervais A, et al. Long-term histologic improvement and loss of detectable intrahepatic HCV RNA in patients with chronic hepatitis C and sustained response to interferon-alpha therapy. Ann Intern Med. 1997;127:875– 871. 4. Lau DT-Y, Kleiner DE, Ghany MG, Schmid P, Hoofnagle HJ. Sustained virologic response to interferon alpha (IFN1␣) in chronic hepatitis C is associated with long-term histologic improvement and lack of hepatic HCV RNA. Gastroenterology. 1998;114(suppl A):1284. Abstract. 5. Reichard O, Norkrans G, Fryden A, et al. Randomized, double-blind, placebo-controlled trial of interferon a-2b with
6.
7.
8.
9.
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and without ribavirin for chronic hepatitis C. Lancet. 1998; 351:83– 87. Lai M-Y, Kao J-H, Yang P-M, et al. Long-term efficacy of ribavirin plus interferon alfa in the treatment of hepatitis C. Gastroenterology. 1996;111:1307–1312. Chemello L, Cavalletto L, Bernardinello E, et al. The effect of interferon alfa and ribavirin combination therapy in naı¨ve patients with chronic hepatitis C. J Hepatol. 1995;23(suppl 2):8 –12. McHutchison JG, Gordon SC, Schiff ER, et al. Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. N Engl J Med. 1998;339:1485– 1492. Poynard T, Marcellin P, Lee SL, et al. Randomized trial of interferon ␣2b plus ribavirin for 48 weeks or for 24 weeks versus interferon ␣2b plus placebo for 48 weeks for treatment of chronic infection with hepatitis C virus. Lancet. 1998;352:1426 –1432.
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Until recently, interferon was the only approved therapy for previously untreated patients with chronic hepatitis C. Unfortunately, the majority of patients do not respond to this regimen, and rates of sustained virologic response were a disappointingly low 15% to 20%. Clearly, more effective treatment for this infection was needed. The nucleoside analogue ribavirin is now approved for administration in combination with interferon to treatment-naı¨ve individuals with hepatitis C (HCV) infection as well as HCV-positive patients who have relapsed after interferon monotherapy. Results of a recent US multicenter trial in treatment-naı¨ve patients with chronic hepatitis C demonstrate that combination therapy with interferon plus ribavirin produces sustained virologic response rates that are two to three times higher than those obtained with interferon alone. Rates of sustained virologic response (defined as undetectable serum HCV-RNA levels 24 weeks after completion of treatment) were 6% vs 31% after 24 weeks of interferon alone vs interferon plus ribavirin, respectively. For 48 weeks of treatment, rates of sustained virologic response were 13% and 38% with monotherapy and combination therapy, respectively. These results, which are consistent with those obtained in smaller preliminary trials and in a recently completed international multicenter trial, suggest that combination therapy with interferon and ribavirin may be preferable to monotherapy as first-line treatment for patients with chronic HCV infection. Am J Med. 1999; 107(6B):56S– 61S. © 1999 by Excerpta Medica, Inc.
H
epatitis C has been identified as an enormous health-care problem in this country. Approximately 30,000 new infections are estimated to occur each year. In addition, the mortality rate, currently estimated at 8,000 to 10,000 deaths each year, is expected to triple in the next 10 to 15 years.1 Management of chronic hepatitis C is complex. Some of the difficulties stem from the wide individual variability that exists in the degree and rate of disease progression and the lack of reliable prognostic markers of disease progression. Another problem is the explosion of information accompanied by rapid advances in diagnosis and treatment that have occurred over the last few years. Even experts in the field have difficulty staying abreast of the changes. One major accomplishment in the past few years has been in defining the terminology used to describe treatment responses in clinical trials. An understanding of these terms is key to evaluating properly the results of clinical trials, such as the one presented here, as well as to communicating with other physicians about individual patients. A “response” is defined both biochemically and virologically: normalization of alanine aminotransferase (ALT) levels and disappearance of hepatitis C virus (HCV) RNA from serum during treatment. Responses are not considered “sustained responses” until 6 months after the discontinuation of therapy. Follow-up studies have determined that a response maintained for 6 months has a very low likelihood of relapse. “Relapsers” are patients in whom the virus comes back after an initial response. A proportion of such patients will respond to another course of treatment, but the likelihood of response decreases with each relapse. In “nonresponders,” the virus never disappears, and these patients are very difficult to manage. (See Bacon’s article “Available Options for Treatment of Interferon Nonresponders” in this supplement.) Other complexities in managing patients with chronic hepatitis C have been limited treatment options and the limitations of the treatments that are available.
LIMITATIONS OF INTERFERON MONOTHERAPY FOR CHRONIC HEPATITIS C
From Scripps Clinic and Research Foundation, Division of Gastroenterology/Hepatology, La Jolla, California, USA. Requests for reprints should be addressed to John McHutchinson, MD, Scripps Clinic and Research Foundation, Division of Gastroenterology/Hepatology, 10666 North Torrey Pines Road, La Jolla, California 92037. 56S © 1999 by Excerpta Medica, Inc. All rights reserved.
Until recently, interferon ␣ was the only available therapy for chronic hepatitis C. Unfortunately, this treatment has significant limitations and is effective in the minority of patients. Treatment with interferon ␣ at a dosage of 3 million units administered subcutaneously three times weekly for 6 months has produced biochemical treatment responses in approximately 40% of patients. In most, 0002-9343/99/$20.00 PII S0002-9343(99)00384-8
A Symposium: Hepatitis C Therapy in Treatment-naı¨ve Patients /McHutchison
however, the improvement is transient, and only 15% to 20% achieve a sustained response.1 In terms of virologic results, a 6-month course of treatment has produced an end-of-treatment response rate of 30% to 40%, but the response is sustained in only 10% to 15% of patients.1 This response rate is similar for all available type 1 interferons. Increasing the duration of treatment to 1 year increases the sustained response to 20% to 25%.1 In a meta-analysis of 20 randomized, controlled clinical trials including previously untreated patients who were randomly allocated to receive at least 2 million units of interferon ␣ three times weekly, a 6-month course of therapy was associated with sustained response rates of only 14%, whereas extending the duration of therapy to 12 to 24 months produced a sustained response rate of 27% (P ⬍0.001).2 For this reason, extended-duration interferon therapy is the standard of care for the treatment of chronic hepatitis C in the United States and throughout most of the world. In the relatively small proportion of patients who achieve a sustained response, the long-term prognosis is good. According to long-term follow-up data from Marcellin3 and from Lau4, the majority of sustained responders remain so for 5 years or more; their HCV RNA remains undetectable, and their liver histology continues to improve. Nevertheless, considering current efficacy rates, interferon monotherapy leaves the majority of HCV-infected patients without hope of viral eradication. In addition, the need for parenteral administration and the side effects associated with therapy, including flu-like symptoms, fatigue, alopecia, bone marrow suppression, and neuropsychiatric problems, pose further limitations to interferon treatment.
RATIONALE FOR COMBINATION THERAPY Clearly, a more efficacious antiviral regimen is necessary for the treatment of this disease. In the absence of a single agent that provides improved efficacy against chronic hepatitis C, combination therapy holds the greatest promise. Combination therapy has the potential not only to overcome the limited efficacy of currently available therapy, but also to allow for therapeutic attack at various sites of viral replication and for enhancement of the host humoral responses. Numerous agents have been tried in combination with interferon for both initial and subsequent treatment of HCV infection; these agents include corticosteroids, nonsteroidal antiinflammatory drugs, pentoxifylline, quinolone antibiotics, ursodeoxycholic acid, thymosin, amantadine, granulocyte-macrophage colony-stimulating factor, and ribavirin. Except for ribavirin, these other agents have not demonstrated any significant benefit in terms of sustained biochemical or vi-
rologic response compared with interferon monotherapy.
THE ROLE OF RIBAVIRIN IN COMBINATION THERAPY Ribavirin is a nucleoside analogue that, when used alone, may produce some histologic improvement and transiently reduces levels of serum alanine aminotransferase (ALT, an indicator of liver cell injury) in approximately 50% of patients with chronic hepatitis C. Ribavirin monotherapy, however, does not lower serum HCVRNA levels.1 The mechanisms of action of ribavirin are not fully understood, but the agent is known to inhibit replication of many RNA and DNA viruses, including several related to HCV. Its antiviral actions include inhibition of viraldependent RNA polymerase, 5⬘ cap structure, and inosine monophosphate dehydrogenase, while its immunomodulatory actions include macrophage inhibition and alteration of the T1/T2 cytokine balance. Three initial randomized international trials have been conducted to compare a 6-month regimen of interferon monotherapy with a 6-month regimen of ribavirin plus interferon in treatment-naı¨ve patients. Although the sample sizes in each of the trials was small, the results were quite consistent (Figure 1). In the trial conducted by Reichard et al,5 the largest of the three studies (N ⫽ 100), the virologic sustained response rate (i.e., negative HCV RNA) was 42% in the combination-therapy group, compared with 20% in the interferon monotherapy group (P ⫽ 0.03). Lai et al,6 who studied 40 patients, obtained a 43% virologic response rate with combination therapy versus a 6% response rate with monotherapy at 48 weeks after treatment discontinuation; this response was maintained at 96 weeks. Finally, Chemello et al,7 in their study of 30 patients, obtained a 43% sustained virologic response rate in patients who received combination therapy, compared with a 7% response rate in monotherapytreated patients.
INTERFERON MONOTHERAPY VERSUS INTERFERON/RIBAVIRIN COMBINATION THERAPY: FINDINGS OF A US MULTICENTER TRIAL After these preliminary studies, a large multicenter trial was conducted in the United States.8 At the same time, a multicenter trial of nearly identical regimens and design was conducted internationally, with very similar results.9 The details of the pivotal US trial will be reviewed here. Study Design The aim of this double-blind, randomized, placebo-controlled US trial was to compare the safety and efficacy of interferon alone versus interferon with ribavirin for the initial treatment of chronic hepatitis C and to determine
December 27, 1999
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Figure 1. Percent of patients with sustained responses in three small randomized clinical trials of interferon plus ribavirin versus interferon alone in treatment-naı¨ve patients with chronic hepatitis C.5–7
the optimal duration of combination therapy.8 Adult patients were eligible for the study if they had chronic hepatitis C, as evidenced by elevated ALT values, detectable serum HCV RNA, and a liver biopsy consistent with chronic hepatitis C within 12 months of study entry. Individuals with documented anemia or cardiovascular disease that might be worsened by ribavirin-associated anemia were excluded. Because ribavirin is teratogenic, pregnant women and women of childbearing age unwilling to practice effective contraception were also excluded. The study enrolled 933 patients, and 912 were treated. Patients were stratified according to factors known to influence response to therapy, including the presence or absence of genotype 1, presence or absence of cirrhosis, and high or low baseline HCV-RNA levels. Patients were randomized to one of four regimens: interferon plus placebo for 24 weeks (n ⫽ 231), interferon plus placebo for 48 weeks (n ⫽ 225), interferon plus ribavirin for 24 weeks (n ⫽ 228), or interferon plus ribavirin for 48 weeks (n ⫽ 228). Ribavirin was administered twice daily at the standard dose of 1,000 mg/day for patients weighing less than 75 kg and 1,200 mg/day for patients weighing more than 75 kg/day. Interferon was administered at the standard dose of 3 million units subcutaneously three times a week. Patients were monitored frequently throughout treatment, with HCV-RNA testing and liver biopsy performed 24 weeks after the end of treatment. The primary end point of the study was a sustained virologic response, defined as the absence of serum HCV RNA 24 weeks after completion of treatment. Secondary end points included normalization of serum ALT levels and reduction of histologic inflammation of at least 2 points, as graded by a modified Knodell Histologic Activity Index (HAI). The mean age of the study participants was 44 to 45 58S December 27, 1999 THE AMERICAN JOURNAL OF MEDICINE威
years, and two thirds were male. Both HCV-RNA levels and ALT values were moderately elevated at baseline, and 70% of the patients were infected with HCV genotype 1. Mild to moderate inflammatory scores were obtained on liver biopsy, and cirrhosis was noted in only 4% to 7% of patients in each group. Results Sustained virologic response rates were significantly higher in patients who had been treated with interferon plus ribavirin for 48 weeks (38%) or 24 weeks (31%) than in patients who had received interferon alone for 48 weeks (13%) or 24 weeks (6%; P ⬍0.001; Figure 2).8 Similarly, end-of-treatment response, that is, the proportion of patients who had undetectable HCV RNA at the conclusion of treatment, was approximately doubled in patients who had received the combination regimen. Relapse after treatment was less frequent among patients receiving combination therapy (42% at 24 weeks and 24% at 48 weeks) than among those receiving interferon alone (80% at 24 weeks and 46% at 48 weeks). Thus, it appears that the addition of ribavirin to interferon not only initially increases the number of patients who can achieve virologic remission during treatment, but also subsequently prevents relapse. Biochemical response rates, as measured by ALT levels, mirrored virologic response rates (Figure 3). Histologic improvement occurred in all four groups and was significantly more common in both combination-therapy groups than in the monotherapy group that was treated for 48 weeks (P ⬍0.001). The degree of histologic improvement was greatest in the patients who received combination therapy with interferon and ribavirin for 48 weeks. Interestingly, even among patients considered nonresponders, 35% to 40% had some improvement in histologic inflammation. As expected, none of the treatVolume 107 (6B)
A Symposium: Hepatitis C Therapy in Treatment-naı¨ve Patients /McHutchison
Figure 2. Percent of patients with sustained virologic responses in US Multicenter Trial at 24 weeks versus 48 weeks with interferon alone or interferon plus ribavirin.8
Figure 3. Percent of patients with sustained biochemical (ALT) responses in US Multicenter Trial at 24 weeks versus 48 weeks with interferon alone or interferon plus ribavirin.8
ments had an effect on fibrosis over the short duration between liver biopsies. In patients infected with genotype 1, sustained virologic response rates with combination therapy was four times higher than that after interferon alone after 48 weeks of treatment. Among patients with this genotype, 48 weeks of combination therapy was significantly more effective than 24 weeks of combination therapy (P ⫽ 0.01; Table 1). This finding may suggest that 48 weeks of combination therapy is preferable for patients with HCV genotype 1. Conversely, the sustained virologic response rates for 24 and 48 weeks were similar for patients with genotype non-1, suggesting that 24 weeks of therapy may
be sufficient for such patients. These data provide a rationale for genotyping of patients to determine the duration of therapy. Data from the US multicenter study also demonstrates that late clearance of HCV RNA during combination therapy is frequently associated with a sustained response. This observation has been very rare in patients treated with interferon alone, and it suggests that discontinuing therapy at week 12 because of persistent viremia, as is recommended for monotherapy,1 may be inappropriate when combination therapy is used. Thus, combination interferon/ribavirin therapy should be continued for 24 weeks before considering discontinuation.
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A Symposium: Hepatitis C Therapy in Treatment-naı¨ve Patients /McHutchison
Table 1. Sustained Virologic Response Rates Achieved With Interferon Monotherapy Versus Interferon Plus Ribavirin in a US Multicenter Trial, Stratified by Viral Genotype Interferon ⫹ Ribavirin
Interferon Viral Genotype Genotype 1 Non–Genotype 1
N
24 Weeks
48 Weeks
24 Weeks
48 Weeks
659 253
2% 16%
7% 29%
16% 69%
28% 66%
Table 2. Treatment Discontinuations or Dosage Reductions Because of Adverse Effects With Interferon Monotherapy Versus Interferon Plus Ribavirin in a US Multicenter Trial Interferon
Discontinuation Dosage reduction due to anemia Dosage reduction due to other adverse events
Interferon ⫹ Ribavirin
24 Weeks
48 Weeks
24 Weeks
48 Weeks
9% 0 12%
14% 0 9%
8% 7% 13%
21% 9% 17%
Table 3. Characteristics of Patients Who Should or Should Not Be Considered for Combination Interferon/Ribavirin Therapy Consider Adult ⱖ 18 years of age Documented chronic hepatitis C with detectable HCV RNA Elevated ALT levels Treatment-naı¨ve or relapsed Compensated hepatitis
Step-wise regression analyses revealed that the most important factors associated with greater efficacy were combination therapy with interferon plus ribavirin (P ⬍0.001), extended-duration (48-week) therapy (P ⫽ 0.002), genotype non-1 (P ⬍0.001), and low viral burden (P ⬍0.001). Female sex and absence of cirrhosis were also significantly associated with better outcome, but to a lesser degree (P ⫽ 0.05 and 0.04, respectively). The need for dose reduction or treatment discontinuation because of anemia or other adverse events was more common among patients treated with combination therapy (Table 2). Adverse effects that were more common with combination therapy included hemolytic anemia, cough, pruritus, rash, and insomnia. None of the latter four adverse effects were dose limiting. Hemolytic anemia is a concern with ribavirin, and 25% of patients experienced a decrease in hemoglobin levels of greater than 4 g. However, hemoglobin levels returned to baseline values within 4 to 8 weeks after treatment discontinuation. The ribavirin dose was reduced to 600 mg daily for patients whose hemoglobin concentrations decrease below 10 g/dL and discontinued for concentrations below 8.5 g/dL. Hemoglobin concentrations increased by 1 to 1.5 60S December 27, 1999 THE AMERICAN JOURNAL OF MEDICINE威
Do Not Consider Pregnant Unable/unwilling to use effective contraception History of significant or unstable cardiac disease Hemoglobinopathies Autoimmune hepatitis Children
g/dL and then remained stable throughout treatment for patients (8%) requiring dose reductions. One patient required ribavirin discontinuation and transfusion.
SUMMARY The first approved therapy for treatment-naı¨ve patients with chronic HCV infection was interferon for a duration of at least 24 weeks. However, the rates of sustained virologic response to this regimen generally did not exceed 10% to 15%. Data from the US multicenter trial of combination interferon/ribavirin therapy confirm earlier findings from smaller preliminary trials that combination therapy with interferon and ribavirin for either 24 or 48 weeks is superior to treatment with interferon alone with respect to all endpoints, virologic, biochemical, and histologic. These responses will hopefully be sustained beyond 5 to 10 years and be accompanied by progressive histologic improvement. Dual therapy with interferon and ribavirin should be considered for first-line therapy in treatment-naı¨ve patients with chronic hepatitis C who are suitable candidates (Table 3). Volume 107 (6B)
A Symposium: Hepatitis C Therapy in Treatment-naı¨ve Patients /McHutchison
REFERENCES 1. National Institutes of Health Consensus Development Conference Panel Statement: management of hepatitis C. Hepatology. 1997;26(suppl 1):2S–10S. 2. Carithers RL Jr, Emerson SS. Therapy of hepatitis C: metaanalysis of interferon alfa-2b trials. Hepatology. 1997;26(3 suppl 1):83S– 88S. 3. Marcellin P, Boyer N, Gervais A, et al. Long-term histologic improvement and loss of detectable intrahepatic HCV RNA in patients with chronic hepatitis C and sustained response to interferon-alpha therapy. Ann Intern Med. 1997;127:875– 871. 4. Lau DT-Y, Kleiner DE, Ghany MG, Schmid P, Hoofnagle HJ. Sustained virologic response to interferon alpha (IFN1␣) in chronic hepatitis C is associated with long-term histologic improvement and lack of hepatic HCV RNA. Gastroenterology. 1998;114(suppl A):1284. Abstract. 5. Reichard O, Norkrans G, Fryden A, et al. Randomized, double-blind, placebo-controlled trial of interferon a-2b with
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and without ribavirin for chronic hepatitis C. Lancet. 1998; 351:83– 87. Lai M-Y, Kao J-H, Yang P-M, et al. Long-term efficacy of ribavirin plus interferon alfa in the treatment of hepatitis C. Gastroenterology. 1996;111:1307–1312. Chemello L, Cavalletto L, Bernardinello E, et al. The effect of interferon alfa and ribavirin combination therapy in naı¨ve patients with chronic hepatitis C. J Hepatol. 1995;23(suppl 2):8 –12. McHutchison JG, Gordon SC, Schiff ER, et al. Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. N Engl J Med. 1998;339:1485– 1492. Poynard T, Marcellin P, Lee SL, et al. Randomized trial of interferon ␣2b plus ribavirin for 48 weeks or for 24 weeks versus interferon ␣2b plus placebo for 48 weeks for treatment of chronic infection with hepatitis C virus. Lancet. 1998;352:1426 –1432.
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