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Abstract The vast number of patients with hepatitis C represent a huge medical and economic burden. While 20–30% of these patients progress and develop advanced liver disease, the majority do not. Thus, it is crucial to identify patients suitable for treatment and those who may benefit most from therapy. Anti-viral therapy is recommended for those patients with chronic hepatitis C who also have elevated liver tests, detectable hepatitis C virus ribonucleic acid and significant inflammation and/or fibrosis on liver biopsy. Currently, the most effective initial therapy is the combination of interferon plus ribavirin. The sustained viral response rate (SVR) is 36–41% following a 24- or 48-week course of therapy. In general, patients with the genotype 1 infection should receive 48 weeks of therapy, and those with genotypes 2 or 3 infection only 24 weeks. Viral load estimations are problematic because of normal fluctuations (up to 0.5–10 log), assay variability and lack of a universally accepted standard; thus, viral load testing is not recommended routinely at present. The sustained viral response rate produces improvements in quality of life and liver histology (including reversal of bridging fibrosis and cirrhosis is some), and durable responses lasting 5–11 years in 95–97% of cases. While the optimal dose of ribavirin is currently unknown, available data suggest that higher doses increase efficacy (albeit with a greater degree of anemia). The dose of 800 mg/day may be the most appropriate lower dose for those patients who require dosage modification for anemia or other side-effects. Patients who have relapsed after interferon monotherapy can be successfully retreated with higher doses of interferon for 1 year or the combination of interferon and ribavarin for 24–48 weeks. Preliminary data suggest that patients with an unfavorable profile, including those with genotype 1 infection, should probably be retreated with interferon and ribavirin for 48 rather than 24 weeks.
With our current best therapies, the majority of patients still do not achieve the benefits of a sustained response. Re-treatment with interferon and ribavirin may achieve a sustained response in approximately 10–25% of these patients. In the immediate future, once-weekly pegylated interferons will replace standard interferons. Initial data suggest that SVR achieved with these drugs in combination with ribavirin is increased to 54–61%, but dose modifications and side-effects are more frequent. They will thus provide an incremental benefit in terms of efficacy, particularly for genotype 1-infected patients.
© 2002 Blackwell Publishing Asia Pty Ltd
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Over the last decade, impressive advances have been made in antiviral therapy for suitable patients with chronic hepatitis C. With the recent approval of combination therapy with interferon and ribavirin and, subsequently, the introduction of pegylated interferons, recommendations regarding therapy are likely to change frequently. The goal of this presentation was to highlight recent advances in antiviral therapy, and to overview what is currently the accepted and most reasonable treatment for those patients with chronic hepatitis C who are appropriate candidates for therapy.
While this topic includes a discussion of patients who are recognized as candidates for therapy (i.e. those with elevated liver tests and significant liver disease with histological fibrosis), other subgroups of patients, including those with persistently normal liver tests, those with minimal histological disease, and those with contraindications to currently available therapies, are also addressed.
Our current best therapy
Data from at least five randomized controlled trials, including two large trials (Fig. 1) of more than 1700 patients, indicate that compared to interferon monotherapy for 1 year, the two-drug regimen of interferon plus ribavirin enhances sustained viral response rates (SVR) to 33% when given for 24 weeks of therapy, and to 41% for 48 weeks of therapy.1,3–5 Despite this increased efficacy, drawbacks with the two-drug regimen include side-effects associated with ribavirin (cough, shortness of breath, rash, itch, insomnia, and hemolytic anemia), the fact that ribavirin is teratogenic, the higher cost of the two-drug combination, and the need for more frequent dose modifications. Despite these drawbacks, the enhanced SVR with this two-drug regimen is approximately two to threefold higher than that which could previously be achieved with 12 or 18 months of interferon monotherapy (Fig. 1).
Figure 1. The most effective therapy for initial treatment of patients with chronic hepatitis C is the combination of interferon plus ribavirin. Response rates for this combination in the two published trials shown are 33% and 41% for 24 and 48 weeks of therapy, respectively, compared to only 16% for 48 weeks of interferon monotherapy. Despite this greater efficacy, certain side-effects are more common with the two-drug combination.1,2
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Benefits of successful therapy
The short-term benefits of a SVR to therapy include normalization of alanine aminotransferase (ALT) values, serum hepatitis C virus (HCV) ribonucleic acid (RNA) becomes and remains undetectable, and liver inflammation, as observed histologically, improves (Table 1). These responses are durable in 95% of patients followed over a 5–12-year follow-up period, and are associated with an improvement in health-related quality of life, which is impaired in untreated patients with hepatitis C.10–12 A number of published reports have also indicated that treatment with either interferon monotherapy or interferon and ribavirin is a cost-effective strategy for preventing the future costs that would be incurred by the development of chronic liver disease and its complications.6,13
Table 1. Sustained virologic response is associated with short-term improvement in biochemical and histological markers of disease, as well as being durable over 5–10 years. Successful treatment is also associated with improvement in quality of life and has been shown to be cost-effective. Other long-term outcomes such as delaying time to transplantation and prevention of hepatocellular carcinoma have yet to be proven prospectively.
|Chronic hepatitis C: benefits of successful therapy6–9|
| Short-term improvement|
| Alanine aminotransferase|
| Hepatitis C virus ribonucleic acid|
| 95% long-term durable response|
| Improvement in health-related quality of life|
| Cost-effective strategy|
| Prevent development of cirrhosis|
| Prevent development of hepatocellular carcinoma|
| Improve mortality and morbidity|
| Delay transplantation|
While these short-term and longer-term benefits are easily reconciled, it is unknown whether successful therapy will always prevent the development of cirrhosis or hepatocellular carcinoma, although more recent retrospective data indicate that successful therapy is associated with a reduction in the development of liver cell cancer. In addition, improvements in mortality and morbidity, and delaying the time to transplantation following successful therapy, have not been established, but are the subject of a number of ongoing long-term clinical treatment trials.
Factors predictive of treatment response
As for interferon monotherapy, factors predictive of the response to combination therapy are similar. Those most likely to respond and achieve a SVR are those infected with HCV genotypes 2 or 3, those with low viral load (< 800 000 IU/mL), those with an absence of significant fibrosis, women, and those who are young1,3 (Table 2). The two most important and clinically useful of these favorable predictors of response are HCV genotype and viral load. When treated with interferon and ribavirin, patients with genotype 1 infection respond less well than those with genotype 2 and 3 infections. Thus, SVR rates of 29% are observed when genotype 1-infected patients receive 48 weeks of combination therapy, as compared to 17% when this therapy is given for a 24-week period (Fig. 2). In contrast, patients with genotype 2 or 3 infection respond equally when given the combination of interferon and ribavirin for either 24 or 48 weeks, with SVR of 66% and 65%, respectively. Hence, it is logical to perform HCV genotyping prior to therapy. Those patients with genotype 2 or 3 infection should receive 24 weeks of therapy and those with genotype 1 infection, 48 weeks of therapy.1,3
Table 2. Favorable predictors of a successful outcome (sustained viral response) after antiviral therapy1,3
|Genotype 2 or 3|
|Low viral load|
|Age: ≤ 40 years|
Figure 2. Hepatitis C patients with (a) genotype 1 infection have the greatest chance of a sustained response if they receive interferon and ribavirin (I/R) for 48 weeks, as shown. By contrast, (b) genotype 2- or 3-infected patients have higher response rates, which are similar, irrespective of whether therapy is for 24 or 48 weeks.1,2
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For these reasons, pretreatment HCV genotyping is an important tool in determining the duration of therapy with interferon and ribavirin. While different methods are available, they produce comparable results. Also, while costly (approximately $US150–200), genotyping to determine the duration of therapy has been shown to be the most cost-effective treatment strategy,6 and may aid in the decision-making process. For example, a patient with milder disease and a favorable genotype may be more likely to be considered for therapy, whereas a marginal candidate for treatment with an unfavorable genotype may be less likely to be offered therapy.
Role of pretreatment liver biopsy
Current management of patients with hepatitis C would be incomplete without a discussion of liver biopsy. Advocates of liver biopsy suggest that as hepatitis C is a liver disease, a biopsy is important to stage the degree of hepatitis (extent or stage of fibrosis) and to exclude the occasional unexpected diagnosis. In addition, biopsy is valuable over the years as a baseline to monitor progression, and it may help to modify the decision-making process in deciding who should and who should not receive therapy (Table 3). In addition, the risk of liver biopsy is acceptably low (approximately 0.3%), and in the absence of reliable non-invasive tests to determine the degree of fibrosis and inflammation in the liver, most hepatologists still advocate pretreatment liver biopsy.14
Table 3. The advantages and disadvantages of liver biopsy before treatment in chronic hepatitis C patients should be weighed in each patient. In general, biopsy should not be mandated, but is acceptable to most patients after an informed discussion of the risks and benefits, treatment response and the natural history of this disease
|Pretreatment liver biopsy|
| ‘Liver disease’|
| Very small risk (approximately 0.3%)|
| Unexpected diagnoses|
| Valuable over years as ‘baseline’|
| Monitor progression (years)|
| Modify treatment decision|
| Lack of reliable non-invasive tests|
| ‘Viral disease’|
| Occasional death, transfusion|
| Not cost-effective|
| Those most likely to respond have mild disease|
Alternatively, a growing group of experts suggest that liver biopsy is overutilized. As the disease is viral, and biopsy causes an occasional death or need for blood transfusion, perhaps it should not be routinely performed. Others suggest that liver biopsies may not be cost-effective, and those most likely to respond have mild liver disease, so why should they be excluded by performing liver biopsy (Table 3)?15 Currently, consensus indicates that a liver biopsy is generally still advisable, although it should not be made mandatory. If explained in the context of the natural history of the disease, the risks and benefits and response to treatment, most hepatitis C patients are willing to undergo liver biopsy before making a decision about antiviral therapy.
Viral load testing before therapy
Quantification of serum HCV-RNA levels before therapy has been widely advocated and is currently recommended. However, certain problems exist that should be clarified in order to understand the value and utility of viral-load testing as a prelude to starting combination therapy.16 Currently available assays to quantify viral load are associated with intrapatient variability of approximately 0.5 log, and the assays themselves differ by approximately 10–20-fold. In addition, the precision of current assays is also approximately 0.5 log. Some authorities have suggested that patients with ‘high’ viral or ‘low’ viral load receive different durations of combination therapy (cut-off values of 2 million or 3.5 million viral equivalents/mL have been suggested; or 800 000 IU/mL). However, these relatively arbitrary cut-off values represent log 6.3 and 6.5, respectively, and can thus not be accurately separated with currently available assays (Table 4).
Table 4. While viral load testing before therapy provides a guide to the likelihood of response, interassay and within-patient variability and the precision of these tests make them difficult to use as a guide to the duration of therapy17
|Viral load testing pretreatment: problems|
|Within-patient variability ≤ 0.5 log|
|Assay differences × 10–20-fold|
|Assay precision approximately 0.5 log|
| 2.0 million (log106.3)|
| 3.5 million (log106.5)|
Examples of two untreated patients with viral load values over a 3-month period of time are shown in Fig. 3. While one patient had persistently high viral load, any decision regarding treatment duration based on viral load would have been relatively simple. However, the example of another patient with fluctuating viral load around the cut-off values of 2 and 3.5 million viral equivalents/mL indicate that this patient would have been differently classified as having high or low viral load depending on the time of testing. They would therefore have been treated with different durations of therapy according to the month tested and the cut-off value used. These problems should be clearly understood if viral-load testing before therapy is to be utilized in patients with chronic hepatitis C. Clinicians should be careful when using viral-load measurement around the accepted cut-off values and, in these situations, giving the patient the benefit of doubt and retesting if the clinical situation is unclear. Hopefully, with future World Health Organization (WHO) recommendations to standardize HCV-RNA testing, these assays will be more clinically useful.
Figure 3. Shown here are two untreated patients with viral load estimates performed at monthly intervals. Depending upon the ‘cut-off’ value for high or low viral load, the patient depicted by the lower line would have been classified as having high or low viral load at different time intervals. Thus a decision to treat this patient for either 24 or 48 weeks based on baseline viral load would be problematic.
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Viral load testing during therapy
Hepatitis C virus RNA testing is also recommended to manage patients receiving therapy. Persistence of serum HCV-RNA during therapy has been shown to be a better predictor of non-response than the absence of HCV-RNA as a predictor of sustained response.2,18 Hepatitis C virus RNA measurements are also more accurate than ALT in terms of predicting response or non-response.19 However, as discussed above for viral testing pretherapy, one must be aware of the pitfalls, and be conservative in using ‘cut-off’ values of viral-load reduction or levels to determine who should or should not continue therapy at certain time-points during therapy.
Discordant ALT and HCV-RNA response
A proportion of patients have a discordant response between ALT values and serum HCV-RNA during and after therapy (Fig. 4). During therapy, some patients eradicate serum HCV-RNA, but their ALT values remain elevated or actually increase. This may be due to drug toxicity and has been described in some instances with peginterferon; it is also more common among those with cirrhosis. However, these occasional occurrences may also be a result of the induction or exacerbation of autoimmune liver disease, or an alternative unassociated cause of hepatotoxicity.20 After therapy, 12–15% of patients who have eradicated serum HCV-RNA and are sustained virologic responders have persistently elevated ALT values. While some of these patients have been shown to have fatty infiltration of the liver, other causes of persistently elevated liver tests should be sought in these clinical situations.18
Figure 4. Occasionally, some patients have an increase in their alanine aminotransferase (ALT) values during therapy, without viremia, associated with eradication of serum hepatitis C virus (HCV) RNA. This may be due to drug toxicity, the induction or exacerbation of autoimmune liver disease, or other etiologies. More frequently, patients who achieve a sustained viral response have persistently elevated liver tests. This is most commonly associated with fatty liver.
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Optimal dosing of ribavirin
The recommended dose of ribavirin to be given in combination therapy is 1000 mg per day for those weighing <75 kg and 1200 mg per day for those weighing >75 kg.1,3 As ribavirin causes a dose-dependent hemolytic anemia, smaller studies have evaluated whether lower doses of ribavirin could be given with equal efficacy, while diminishing the problems associated with the hemolytic anemia. Two small studies in non-responders have evaluated 600 mg of ribavirin per day; one study suggested equal efficacy in terms of sustained response rates and the other suggested that this lower ribavirin dose was ineffective.21 A subsequent study of triple-therapy with amantadine, interferon and ribavirin in non-responders, utilizing 800–1000 mg per day of ribavirin, suggested less anemia with an equivalent SVR.22 A re-analysis of over 1000 patients who received interferon and ribavirin indicated that those patients who received >10.6 mg/kg per day of ribavirin (equivalent to 800 mg per day for an average 75 kg patient) had a significantly higher SVR (44% compared to 28%) than patients who received less than 10.6 mg/kg per day (Fig. 5). Also, a 4-week trial combining interferon α-2b with either 400, 600, 800 or 1000–1200 mg of ribavirin indicated that lower doses of ribavirin were associated with lower reductions in hemoglobin, but also lower reductions in serum HCV-RNA ( JG McHutchison, unpubl. data, 2000).
Figure 5. A retrospective analysis of 1009 patients who received more or less than 10.6 mg/kg of ribavirin (equivalent to a total dose of 800 mg ribavirin per day for a 75 kg person) indicated that those patients who received higher doses of ribavirin based upon bodyweight had higher sustained response rates (P = 0.048), as shown. (Schering Plough, unpubl. data, 2000.)
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Thus, while the optimal dose of ribavirin is still unclear from large randomized controlled trials, available data indicate 800 mg per day is associated with less anemia but 600 mg per day is associated with less efficacy; more is better on a per weight basis. As such, recommendations should be to initiate treatment at 1000–1200 mg per day according to the patient’s bodyweight and, probably, to dose-reduce to 800 mg for those patients who require dose modification because of the development of significant hemolytic anemia or other side-effects.
Are more intensive interferon regimens currently advisable?
Could higher sustained rates of SVR be obtained with higher doses of interferon in combination with ribavirin? The rationale for such an approach is based upon known HCV dynamics, where the viral half-life is measured in hours and large viral burdens exist.23 Recent preliminary reports from two studies suggest that higher, more intensive interferon regimens in association with ribavirin have been unsuccessful in achieving higher SVR. Further, they are associated with significantly higher rates of discontinuation of therapy.24 Thus, at this time, the utility of combining higher doses or more intensive interferon regimens in combination with ribavirin cannot be recommended as an approach to enhance SVR.
Importance of ribavirin side-effects
Certain side-effects, apart from those traditionally observed with interferon, are more common in patients who receive the combination of interferon and ribavirin. These include cough, dyspnea, insomnia, rash, pruritus, and anemia. The latter is dose dependent, and an extravascular hemolytic anemia accompanied by reticulocytosis. The average reduction in hemoglobin in the first 4–6 weeks of therapy is 2.5–3 g, after which time hemoglobin levels stabilize through the remainder of the course of therapy.25 After ending therapy, hemoglobin values return to their baseline within 4–8 weeks of follow up (Fig. 6). Seven to 10 percent of patients require discontinuation of therapy because of this anemia. Studies are currently evaluating the role of administering erythropoietin to prevent this anemia, and thus allowing ribavirin to be continued without dose reduction. While these trials are in progress, no data are available to indicate that this approach enhances sustained response rates and is cost-effective.
Figure 6. Ribavirin is associated with a dose-dependent extravascular hemolytic anemia as shown. Hemoglobin values fall to their lowest levels (usually a 2.5–3.0 g reduction) in the first 6–8 weeks of therapy, and then stabilize. This is associated with a compensatory reticulocytosis. The anemia is reversible, and hemoglobin values return to pretreatment levels 1–2 months after cessation of therapy.1,2 (s) Hemoglobin (IFN/Riba); (□) hemoglobin (IFN/P); (d) reticulocytes (IFN/Riba); (▪) reticulocytes (IFN/P). IFN, interferon; P, placebo; Riba, ribavarin.
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Cost-effectiveness of therapy
Despite the higher costs, a number of analyses indicate that combination therapy with interferon and ribavirin for initial treatment of patients with hepatitis6,14 is a cost-effective approach, and more cost-effective than interferon monotherapy. In addition, the costs per life years gained compare well with those of other accepted medical interventions, including fecal occult blood screening, pneumococcal vaccination, treatment of asymptomatic patients with hypertension, coronary artery bypass grafting and screening mammography (Fig. 7).6
Figure 7. The economic value of combination therapy compares well with other accepted medical interventions, as shown, and is below the ‘acceptable’ level of $US50 000 in terms of cost per year of life gained.1,8 Anti-HTN, anti-hypertensive treatment; CABG, coronary artery bypass grafting; FOB, fecal occult blood screening; IFN + Riba 48 w, interferon and ribavarin treatment for 48 weeks; Pneum vacc, pneumococcal vaccination.
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Adherence to therapy
As in human immunodeficiency virus (HIV) therapy, recent data indicate that adherence or compliance with therapy enhances SVR in patients receiving interferon and ribavirin. A retrospective analysis of patients in randomized controlled trials who received more than 80% of both of these medications for more than 80% of the time indicated that this subgroup of patients had a significantly higher SVR compared to the intent-to-treat response rates, or to those who received less than 80% of their medications (JG McHutchison, unpubl. data, 2001) (Fig. 8). Thus, the best chance of a SVR and a good outcome is among those patients with chronic hepatitis C who are most compliant. While prospective studies have not been conducted on how to improve adherence in patients with hepatitis C receiving therapy, simple measures, including patient education, exercise, hydration, regular follow up and phone contact, the use of antidepressants for mood changes, minimizing dose-reductions, as other modalities currently under further evaluation, will hopefully enhance SVR rates.
Figure 8. Patients who are most adherent and receive more than 80% of the doses of interferon and ribavirin for more than 80% of the duration of therapy (80 + 80 + 80) have higher sustained viral response (SVR) to treatment than those who do not achieve these goals. Adherence may be enhanced by patient education, close follow up and the other factors indicated.26 ITT, intention-to-treat.
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In summary, for initial treatment of patients with hepatitis C there are certain changes in practice that have been brought about by the improved SVR rates achieved with interferon and ribavirin. For patients who are candidates for therapy and are suitable for ribavirin, there is no place for interferon monotherapy; HCV genotyping should be performed before therapy to determine the duration of therapy. In addition, hemoglobin should be monitored frequently and at monthly intervals throughout therapy to assess the degree of hemolytic anemia. Because of the teratogenicity of ribavirin, pregnancy testing should be performed frequently and dual contraception (both partners) mandated in all patients.
Treatment of patients with persistently normal ALT values
Approximately 25–30% of patients with chronic hepatitis C have been documented to have persistently normal liver tests, and most have detectable serum HCV-RNA. Available literature suggests that the rate of histological progression in these patients is approximately half that of those with elevated liver tests (or even less).27,28 From biopsy studies, less than 1% of these patients have histological cirrhosis but 20% do have some degree of chronic hepatitis, predominantly those with a history of significant alcohol intake or those with concomitant obesity (Table 5). Treatment of patients with persistently normal ALT values with interferon monotherapy has indicated overall SVR rates of approximately 13%,29 similar to those response rates observed in patients with elevated liver tests. While there are few data in this subgroup of patients for initial treatment with interferon and ribavirin, retreatment of non-responders with interferon and ribavirin indicated sustained response rates of approximately 25%.31
Table 5. Approximately 25–30% of patients with hepatitis C have persistently normal alanine aminotransferase values and are viremic. These patients have a slower rate of disease (fibrotic) progression, and infrequently have advanced liver disease histologically. Those with more advanced disease tend to be obese, or have had significant alcohol intake in the past27,29,30,
|Persistently normal alanine aminotransferase values|
|≥ 25–30% of patients|
|Most are hepatitis C virus ribonucleic acid positive|
|Approximately half rate of, or no, fibrosis progression|
|< 1% have cirrhosis|
|20% have mild chronic hepatitis|
| Predominantly those with alcohol/obesity|
Thus, therapy of patients with chronic hepatitis C and persistently normal ALT values is unclear at the current time. It would seem advisable to discuss the natural history with these patients and to consider the role of liver biopsy in those with a past history of moderate or significant alcohol intake or obesity, in order to identify the minority of patients with some degree of significant chronic liver disease. If more advanced disease is present on biopsy, then patients should be considered for a clinical trial or potential treatment with interferon and ribavirin (Table 6).
Table 6. Patients with hepatitis C and persistently normal alanine aminotransferase values over time should be told that their disease progression is slower, that data regarding the efficacy of treatment in this setting is currently unclear, and that they may consider liver biopsy to determine if they have significant liver disease
|Therapy of chronic hepatitis C for those with persistently normal alanine aminotransferase values|
|Unclear whether valuable or necessary|
|Discuss natural history|
|Consider liver biopsy|
| Identify minority with fibrosis, moderate/severe activity|
|More advanced disease on biopsy|
| Consider clinical trial|
Since the introduction of highly active antiretroviral therapy (HAART), the natural history of HIV infection has changed significantly. Patients who are coinfected with HIV and HCV have higher rates of fibrosis progression and significantly greater liver-related mortality compared to HIV-infected patients without HCV infection, despite control of HIV infection with HAART (Table 7). Unfortunately, there are inadequate data on HCV treatment efficacy in this population. Because as many as 40% of HIV-infected patients also have HCV infection, it seems prudent at this time to test for the presence of HCV, evaluate these individuals for the presence of liver disease and consider therapy if their HIV disease is stable, with a CD4 count > 400, and if there is significant hepatic fibrosis histologically.
Table 7. Forty percent of human immunodeficiency virus (HIV)-infected patients are coinfected with hepatitis C. These patients have a higher rate of disease or fibrosis progression, and higher rates of liver-related mortality, despite the fact that the HIV disease can now be effectively controlled with highly active antiretroviral therapy (HAART)
|HIV/ hepatitis C virus coinfection|
|HAART: natural history has changed|
| Increased rate of fibrosis progression32|
| Increased liver-related mortality (approximately 17-fold)33|
|Mortality due to end-stage liver disease increasing|
| 55% of deaths in 1998 were a result of end-stage liver disease|
| HIV ribonucleic acid negative or CD4 > 20034|
Patients with stable cirrhosis
While response rates in patients with cirrhosis who receive interferon monotherapy have generally been disappointing, results can be obtained with the combination of interferon and ribavirin.35,36 Thus, there has been a renewal of interest in treating patients with stable Child’s A cirrhosis and platelet count ≥ 75 000/mm3 to achieve the potential benefits of SVR. Treatment in these patients seems to be tolerable, and may lower the risk of hepatocellular cancer and/or slow rates of fibrosis progression.37 In theory, eradication of HCV in patients with Child’s Class A cirrhosis could also potentially decrease the risk of recurrent HCV post-transplantation. While treatment of patients with cirrhosis can be undertaken, the approach to those patients with more advanced disease should be considered carefully and, probably in collaboration with a tertiary referral liver transplantation center.
Initial therapy of chronic hepatitis C patients with pegylated interferons
The addition of a polyethylene glycol molecule to available α-interferons produces a biologically and immunologically active interferon with a longer half-life and more favorable pharmacokinetics. Both pegylated interferon α-2a and α-2b have now been developed. This allows for a more convenient once-weekly dosing, and these agents have been studied in clinical trials. While these peginterferons have different physical and structural characteristics, in randomized controlled trials where they have been given alone for 48 weeks, they exhibited similar side-effect profiles to standard interferon, but double the SVR rate compared to their regular interferon counterparts.38–40 Unfortunately, relapse rates after cessation of therapy are the same as standard interferon, and the majority of genotype 1-infected patients do not respond. Because of these deficiencies and because ribavirin decreases relapse, the next most likely approach to the treatment of hepatitis C is the combination of pegylated interferons in combination with ribavirin.
A recent large randomized controlled trial of 1530 patients has compared pegylated interferon α-2b at a dose of 1.5 µg/kg per week in combination with ribavirin, compared to standard interferon α-2b plus ribavirin.41 Overall, SVR rates were incrementally enhanced from 47% to 54% and genotype 1 patients benefited most, with a 9% increase in SVR to 42% when receiving the combination of pegylated interferon α-2b plus ribavirin. Dosing both drugs according to bodyweight further enhanced the rate of SVR in a retrospective analysis of this study, from 54% to 61%. The combination of peginterferon α-2b and ribavirin allows for a more convenient approach, although a higher frequency of neutropenia, fever, nausea, and injection-site reactions were observed.
In another recently completed study, the combination of pegylated interferon α-2a plus ribavirin was compared to standard interferon and ribavirin.42 The results of this study were similar: SVR with pegylated interferon/ribavirin combination was 56%, compared to 45% with standard interferon and ribavirin, and those with genotype 1 infection also achieved 9% benefit when treated with the long-acting interferon combination.
Both the above studies indicated that patients with genotype 2 or 3 infection respond well to the combination of peginterferon and ribavirin, as they do to standard interferon and ribavirin, with SVR rates of 75–80%. In summary, the combination of pegylated interferon and ribavirin incrementally enhances and improves the SVR for initial treatment of patients with hepatitis C. The greatest benefit appears to be for those with genotype 1 infection. This therapy is associated with a similar side-effect profile to conventional interferon/ribavirin, but once-weekly interferon dosing is more convenient. Discontinuation rates in both studies were similar, although more frequent dose modifications were required for neutropenia with pegylated interferons. The combination of pegylated interferon α-2b and ribavirin has received Federal Drug Administration (FDA) and European approval and is now the treatment of choice for the majority of HCV-infected patients in the USA and throughout Europe.
Retreatment of patients following interferon relapse
When patients in whom hepatitis C relapses after interferon monotherapy are treated with interferon and ribavirin for 24 weeks there is a good chance of SVR, depending on baseline viral factors.43 The overall SVR rate in this study was 50%, and favorable patients with low viral load and genotypes 2 or 3 were essentially all sustained responders, whereas those with a less favorable profile, particularly the genotype 1-infected patients, had lower sustained response rates (Fig. 9).43 Other prospective data support the concept that a longer duration of combination therapy in the setting of interferon relapse may enhance SVR rates. DiMarco et al. have shown that for these patients, effective retreatment with 12 months of interferon plus ribavirin enhances the SVR rate above that with 24 weeks of therapy, and leads to SVR in two out of three genotype 1-infected patients with interferon relapse (Fig. 10).44 Thus, retreatment of interferon relapse patients is effective. These patients should be retreated with interferon and ribavirin, and treated with a longer duration of therapy, particularly if they are infected with HCV genotype 1.
Figure 9. Retreatment of interferon relapse patients with interferon plus ribavirin for 24 weeks results in sustained viral eradication in nearly 50% of patients. Those most likely to respond are those with genotype 2 or 3 infection.43
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Figure 10. Retreatment of interferon relapse patients for a longer duration, 48 weeks, in this randomized controlled trial resulted in significantly higher sustained response rates, especially for those more difficult to treat patients with genotype 1 infection or high viral load.44
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Retreatment of non-responder patients
Despite improvements in initial therapy with interferon and ribavirin and, more recently, pegylated interferon and ribavirin, the majority of HCV genotype 1-infected patients are still non-responders to therapy.
Retreatment of interferon non-response with fixed higher doses of conventional interferon, extended duration of interferon, induction regimens or combining interferon with other agents including non-steroidal anti-inflammatory drugs, ursodeoxycholic acid, pentoxifylline, corticosteroids, cyclosporine, quinolone antibiotics, or phlebotomy have been largely unsuccessful in terms of enhancing the SVR rates, although some of these regimens may enhance end-of-treatment response or improve transaminases. Retreatment of interferon non-response patients with interferon and ribavirin has been shown in two large separately published meta-analyses to result in SVR in only 14% of patients. Factors predictive of which subgroup of patients is likely to benefit from retreatment in this setting should be investigated, so as to further characterize which interferon non-responder patients should receive retreatment with interferon and ribavirin.
Retreatment of interferon–ribavirin non-response and relapse patients is an increasing population of patients for whom little data are available to guide us in terms of which therapies these patients should receive. Amantidine, in combination with interferon alone or with interferon and ribavirin for treatment of combination therapy non-responders, has been studied in several small randomized controlled trials. While the results are conflicting, the general consensus is that this non-specific antiviral agent does not lead to enhanced sustained response rates and should not be recommended at this time in this retreatment setting.
Finally, the concept of ‘maintenance’ low-dose interferon therapy for patients who have failed to respond to therapy, in an attempt to prevent disease progression, has recently received attention. Interferon is known to inhibit activation of stellate cells, and other clinical studies have indicated reduced inflammation in non-responder patients and reduced fibrosis progression in non-responders to previous therapy.45 Only one randomized long-term retreatment trial has shown reduced inflammation and a trend to less fibrosis in patients with an early reduction in histological inflammation. As such, the concept of maintenance interferon therapy has a sound basis, and two national 4-year USA-based trials are currently evaluating the use of low-dose pegylated interferons to prevent disease progression. In practice, there is little evidence to support this approach currently, and in individual situations it is appropriate only to consider this type of therapy in patients with bridging fibrosis or cirrhosis.
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Treatment of hepatitis C has evolved significantly in the last decade. With the addition of ribavirin to interferon, and, subsequently, the introduction of peginterferon and ribavirin, a sustained response rate and its potential benefit can now be achieved in approximately 55–60% of suitable patients who receive initial treatment for chronic hepatitis C. Future treatment options for hepatitis C are likely to involve interferon-based regimens as the mainstay over the next 5 years. We are likely to see further rapid developments, and recommendations regarding therapy are likely to change frequently and require careful regular updates. It is hoped that, with the development of other agents, in the future, effective therapy will be available for the majority of patients with hepatitis C who need it.