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Maintenance Therapies for Hepatitis C Brett D. Kalmowitz, MD and Nezam H. Afdhal, MD 2004, 3:23-29 Current Science, Inc. ISSN Copyright © 2004 by Current Science, Inc. Despite improvements in antiviral therapy for hepatitis C virus, 50% of patients still fail to clear virus despite optimal therapy with pegylated interferon and ribavirin. No effective treatment has been identified for these nonresponders and consideration should be given to maintenance therapy in patients with advanced fibrotic liver disease. Maintenance therapy is focused on preventing liver failure, hepatocellular cancer, and progression of fibrosis. Multiple agents have been proposed and tried as maintenance therapy, but the leading candidate is low-dose pegylated interferon monotherapy, which is being studied in several large clinical trials. The clinician must individualize choice of maintenance therapy with risk of disease progression, and no definite guidelines exist for maintenance therapy at the present time. Introduction Hepatitis C is a worldwide epidemic; the World Health Organization describes hepatitis C as a "viral time bomb." It is estimated that there are approximately 170 million chronic carriers of hepatitis C (3% of the world's population) [1]. In the United States, the Centers for Disease Control estimates that 3.9 million Americans have been infected (1.8%) and that 2.7 million have active viremia [2]. There are even concerns that this data underestimates the prevalence of disease because these figures are based on the NHANES III (third National Health and Nutrition Examination Survey) study, which may under-represent sections of the population at higher risk for chronic hepatitis C [3]. Although the incidence is declining in the United States, there are a growing number of chronically infected patients who are at risk for complications related to hepatitis C virus (HCV) disease. Natural history studies suggest that 20% to 25% of those infected with hepatitis C progress to advanced fibrosis and cirrhosis [4, 5, 6]. Patients with long-standing, advanced disease are those most likely to use medical resources in the coming years. Estimates suggest that the proportion of patients with cirrhosis will increase from 16% to 32% within the next 20 years [7]. Complications related to cirrhosis will markedly rise, including hepatic decompensation, hepatocellular carcinoma (HCC), and liver-related deaths. Effective therapies focused on patients who are likely to progress are required. The current standard of care for medical treatment involves 24 to 48 weeks of therapy with pegylated interferon (IFN) with ribavirin (RBV). Sustained virologic response (SVR) rates for genotype 1 HCV range from 40% to 50%, and for genotypes 2 and 3 from 70% to 80% [8, 9]. Optimal dosage regimens, adherence to therapy, and aggressive side-effect management are required to achieve these rates of SVR. Early assessment of the effectiveness of the above therapy can be made at 12 weeks, and those patients who have not had a 2-log reduction in their viral load can have the option to discontinue therapy, because the ultimate likelihood of a positive response is extremely low [10]. Successful treatment accomplishes several goals of therapy. From a virologic point of view, we are able to eradicate HCV from hepatocytes and achieve a negative polymerase chain reaction (PCR), which is an undetectable virus to 50 copies/mL. At the present time, no occult HCV infection has been identified and no human reservoir of HCV is felt to exist. Studies with follow-up for 10 years after SVR have shown an extremely low recurrence or reactivation of 1% to 2% [11]. From a biochemical perspective, with SVR, there typically is a resolution of any transaminitis that accompanies active viral infection, suggesting a reduction in necroinflammation [12]. Although histologic improvement has also been described after SVR [12, 13, 14,15**, 16, 17], the critical unresolved issue is whether advanced fibrosis, cirrhosis, HCC risk, and survival can be improved by viral eradication. Until more data are available, patients with cirrhosis even after SVR should be considered to still be at risk for HCC and hepatic decompensation. We are left with approximately 50% of patients being nonresponders to IFN therapy, despite constant advances in medical treatment options. Nonresponders are identified by failure to clear virus by PCR after a minimum of 3 months of treatment. There are other classes of nonresponders, including partial responders who had a reduction of 1 log of HCV or biochemical improvement; breakthrough patients who have been PCR negative on treatment but virus appeared while still on treatment; and relapsers who had a negative PCR at some point during treatment but virus reoccurred or was detectable by PCR when treatment was stopped. In the United States, if all 4 million HCV patients, 70% of who are genotype 1, were treated with optimal therapy, optimistic outcomes would still yield approximately 1.5 million patients with persistent viremia. There are several identified risk factors for nonresponse to IFN therapy. Viral genotype plays a major factor as described earlier; patients with genotype 1 achieve SVR approximately one-half as often as those with genotype 2 or 3 [8, 9]. Progressive disease with advanced fibrosis or cirrhosis is noted to show decreased response rates to IFN [18]. African Americans also do not appear to respond as favorably as white or Asian patients [19]. Elevated initial viral loads (> 2 million copies/mL) and coinfection with HIV [20] are also negative prognostic factors. High body mass index [21] and hepatic steatosis are comorbidities that lend to decreased response rates. Other considerations include hepatic iron concentration, because high levels correspond to less response to therapy [22]. Of this population, there are some patients who may benefit from retreatment with a pegylated IFN-RBV cocktail, namely those treated with IFN monotherapy, especially those who had good virologic response while on therapy and achieved HCV RNA negativity. As time passes, this is becoming the minority because increasing numbers of patients receive pegylated IFN and RBV as their first-line therapy. There is no current effective therapy for either Rebetron (Schering Plough, Kenilworth, NJ) or pegylated IFN/RBV failures. These nonresponder patients with advanced fibrosis present a significant clinical challenge to the clinician. In reviewing the medical literature, it is clear that there are little data regarding management of these patients. There are no current guidelines or recommendations addressing the treatment of nonresponders. The National Institutes of Health Consensus Development Conference Panel Statement on the Management of Hepatitis C address this group of patients briefly, but indicate that no recommendations for maintenance therapy can be made at this time until the results of large-scale multicenter trials are reported [10]. Patients with mild disease showing minimal to moderate fibrosis on biopsy may be followed serially and expectantly. These patients are at little risk for the complications of end-stage liver disease. However, there is a pressing need to address treatment strategies for the growing number of patients with advanced fibrosis or cirrhosis who have failed attempts at curative therapy. It is this population of patients who are at risk for the potential chronic effects of hepatitis C, including portal hypertension and the complications inherent within, HCC in approximately 4% of patients per year, and hepatic decompensation in 3% of cirrhotic patients per year [7]. Who Needs Maintenance Therapy? The patient best suited for maintenance therapy is the patient who will derive the most benefit from it. Those patients who have aggressive or advanced disease are most in need of some form of intervention to halt the progression of complications of cirrhosis, such as portal hypertension, ascites, gastrointestinal bleeding, encephalopathy, and HCC. The other group in whom maintenance therapy is an option is those patients with symptomatic extracellular complications such as cryoglobinemia, which can be controlled by viral suppression. It could be suggested that any patient who has failed therapy is a candidate for maintenance treatment as a bridge to more definitive action, provided the therapy is effective at slowing or halting the rate of progression of disease. However, studies have shown that patients with benign initial biopsies and mild elevations of alanine aminotransferase (ALT) typically have slow progression of disease and may benefit from a watchful waiting policy [23*]. There is a subset of patients who cannot psychologically tolerate waiting and would prefer to be doing something rather then doing nothing. Patients who are not candidates for curative doses of current therapy because of comorbid medical conditions (eg, renal or cardiac impairment), psychiatric illness, or an inability to tolerate therapy secondary to lack of social support may be considered for maintenance therapy. The pre- and post-transplant hepatitis C populations are other groups to be considered, but a review of that literature is beyond the scope of this article. Goals of Maintenance Therapy The primary goal of maintenance therapy is to prevent disease progression. Reduction in hepatic fibrosis has been accepted as a surrogate for measurement of effective maintenance therapy, but the real measure is prevention of clinical outcomes such as death, transplant, liver failure, and HCC. Secondary goals include symptom control and improvement in quality of life, including the psychological benefits of a proactive approach for some patients. Effective maintenance therapy should have a positive financial impact on the reduction of both direct and indirect health care costs. Potential Interventions for Maintenance Therapy There are numerous approaches to arresting the progression of hepatitis C. Although IFNs have been the most widely studied agents for maintenance therapy, there are other agents and techniques that have been used (Table 1). Table 1:  Potential alternative interventions for maintenance therapy Therapy Proposed mechanism Studies Results Ribavirin Antiviral Placebo-controlled trial Improvement of necroinflammatory scores; improvement in ALT Iron reduction therapy Decrease free radical production Retrospective Improvement in histology; stability of histology scores Interleukin-10 Anti-inflammatory cytokine Pilot trial Normalize ALT; improve inflammation; decrease fibrosis Phase 2 Above results not confirmed Silymarin Alters hepatocyte cell membrane; promotes regeneration; anti-inflammatory Ongoing NA d-a-tocopherol Antioxidant Short term No improvement Glycyrrhizin Antiviral, anti-inflammatory Retrospective Decrease ALT; decrease HCC rates Ginseng, complete thymic formula, oxymatrine, bing gan ling Unknown None NA ALT--alanine aminotransferase; HCC--hepatocellular carcinoma; NA--not available. The use of RBV monotherapy as maintenance therapy in a short-term 48-week study has recently been evaluated [24*]. IFN and RBV failures were randomized to either RBV or placebo and followed for 48 weeks. There were 17 patients in each arm of this small study and all but one patient had genotype 1 disease. From a histologic perspective, necroinflammatory scores improved significantly in both groups but were numerically and statistically greater in the RBV group versus placebo. Fibrosis scores were not changed in either the placebo or RBV arms. During the treatment phase with RBV, mean serum ALT remained in the near normal range for these patients and was statistically reduced from baseline values, compared with the rise in ALT in those patients receiving placebo toward pretreatment levels. RBV was well tolerated, with no effect on fatigue or sense of well-being compared to placebo. There was no virologic impact from RBV therapy. There was an apparent categorical response to RBV therapy because eight of 17 patients had a histologic response that compared favorably to those with SVR from phase 1 of the study, with a decrease of inflammatory score to less then three or a decrease by five points from baseline. It is unclear why RBV was particularly effective in this group of patients. Although there was stability in several patients in this study, the follow-up period is relatively short and the ultimate use of RBV in clinical practice for nonresponders has yet to be defined [25]. Iron reduction therapy is known to reduce serum ALT levels in patients with hepatitis C. Hepatic iron concentrations have been noted as predictors to response to IFN therapy and excess iron may accentuate the liver damage caused by hepatitis C [26]. The mechanism is unclear but iron may act as a cofactor in the production of oxygen-derived free radicals. A retrospective study of 13 IFN nonresponders undergoing 5 years of maintenance phlebotomy compared with historical nonresponder control subjects demonstrated statistically significant improvement in histology and stabilization in fibrosis scores [27]. The control group had statistical worsening of their fibrosis scores. This result allowed the authors to speculate that iron reduction therapy may play a role in preventing progression in patients with chronic hepatitis C. There has been no randomized controlled trial to answer this question to date and phlebotomy is not recommended as part of routine maintenance therapy. Interleukin-10 (IL-10) is an anti-inflammatory cytokine that may modulate hepatocyte proliferation and fibrosis [28] and has been evaluated in IFN nonresponders. A pilot trial of IFN nonresponders with subcutaneous IL-10 for 24 weeks showed normalization of ALT and improvement in hepatic inflammation in 19 of 22 patients. Fibrosis decreased in 14 of these patients. There was an associated reduction in serum levels of tumor necrosis factor-a (TNF-a) and an increase in TNF-soluble receptors [29]. A larger phase 2 study was not able to confirm these findings and use of IL-10 will require further research. Patients requiring maintenance therapy for hepatitis C are also using alternative therapies. Many are using silymarin, the active ingredient in milk thistle. According to some literature, silymarin alters the hepatocyte membrane preventing the entrance of hepatotoxic substances into the cell [30, 31]. Also, polymerase "A" is stimulated, which increases ribosomal protein synthesis leading to an increase in regeneration of the liver and the formation of new hepatocytes [31]. There is also an anti-leukotriene effect that may reduce inflammation [30]. Studies looking at this medication long term are lacking, but the side-effect profile appears benign. We do not advise against the use of silymarin but rarely encourage patients to begin de novo. There are several phase I and II trials funded by the National Institutes of Health that are in process and we await the results of these studies. Oxidative stress induces activation of stellate cells and treatment with d-a-tocopherol, an antioxidant, can interrupt this activation and prevent the deposition of collagen. Although 8 weeks of therapy did not show statistical improvement in fibrosis or inflammation, longer studies are warranted and this may be an option for patients in the future [32]. Other commonly used antioxidants include vitamin E. Other alternative therapies include glycyrrhizin, an aqueous extract from licorice. It is felt that there are antiviral and anti-inflammatory properties as well with a protective effect on the hepatic cellular membrane [30]. In some retrospective studies done in Japan, there was evidence of decreased ALT levels and lower HCC rates in patients treated with glycyrrhizin [33]. The side-effect profile is not as benign as silymarin, and includes hypokalemia, hypertension, and edema. There is no prospective evidence at this time to support its use. Ginseng, complete thymic formula, oxymatrine, and bing gan ling have all been suggested as an alternative therapy for hepatitis C, but there are no studies in humans to date to validate these herbal remedies. A recent systematic review demonstrated that there is insufficient evidence for treating HCV infection with medicinal herbs [34]. This is due to a small number of randomized trials conducted, lack of adequate patient numbers, and the poor methodologic quality of the trials. Rationale for Interferon Interferon is the leading choice of agents with a potential role for maintenance therapy of hepatitis C. It is a biologically active agent with anti-inflammatory, antiviral, anti-angiogenesis, and anti-oncogenic properties. It is modestly effective in achieving eradication of hepatitis C as monotherapy, albeit at high doses. There have been numerous trials depicting the benefits achieved with IFN therapy from a virologic, biochemical, and histologic standpoint [12, 13, 14,15**, 16, 17]. With viral clearance, there is usually an improvement in fibrosis. This is dramatically highlighted by a reversal of cirrhosis in 49% of 153 patients treated with IFN [15**]. SVR was the only factor that was statistically associated with reversal of cirrhosis. Poynard et al. [35] described the response to IFN specifically in "nonresponders." The mean viral load decreased by approximately 50% in patients throughout the treatment period and returned to baseline within 3 months after coming off therapy. ALT levels were also improved during treatment with IFN to a significant degree [35]. There is evidence that the natural progression rate of fibrosis is altered by this medication. Meta-analyses of trials from Japan suggest that a course of treatment with IFN reduces HCC risk and mortality, particularly in patients with advanced fibrosis [36]. Mechanism of Action of Interferon The specific role IFN alpha has in hepatitis C is still not completely understood and there are complex interactions with both the virus and host [37, 38]. IFN alpha has a direct antiviral effect. At a cellular level, it activates numerous IFN-inducible genes that directly inhibit HCV replication. However, it also interacts and alters the inflammatory cascade. There is downregulation of TNF-a and transforming growth factor-b after treatment with IFN and upregulation of IL-10, leading to an anti-inflammatory and antifibrotic effect. IFN also has antiproliferative, anti-angiogenesis, and anticarcinogenic properties, and it is all these properties that make it a natural choice for maintenance therapy. Clinical Studies Interferon and fibrosis progression We have known from the clinical trials with paired biopsies that IFN can improve hepatic histology, particularly necroinflammation [13]. The relationship between persistent viremia, chronic inflammation, and hepatic fibrosis is complex and not fully elucidated. In one study by Shiffman et al. [12] using 6 months of IFN, improvements in histology were associated with reductions in viral load, but this data has not been replicated and it is unclear whether an effect of IFN on fibrosis and inflammation can occur separately from viral suppression. Fibrosis occurs in a nonlinear pattern, with other cofactors such as alcohol, HIV, age, and concomitant liver disease playing a role [39, 40]. However, fibrosis progression is highly variable. A cross-sectional study designed to describe the natural history of hepatitis C suggested the presence of at least three populations of patients: rapid fibrosers, intermediate fibrosers, and slow fibrosers [4]. However, the majority of these cohort studies suffer from their retrospective nature and methodologic shortcomings. Interferon treatment can alter liver fibrosis progression rates [13, 14, 15**, 16, 17]. In a study looking at fibrosis development, there was a decrease in the median fibrosis progression rate after treatment with IFN regardless of biochemical response [17]. A statistically significant proportion of patients, when compared to control subjects, had stabilization or improvement in fibrosis even if their ALT remained elevated at 3 months. Repeat biopsies ranged from 20 to 36 months. This suggested that discontinuing therapy at 3 months for patients without virologic or biochemical response may be premature because there are other benefits of IFN therapy. Emphasis was placed on treating biochemical (and likely virologic) nonresponders because these patients have higher fibrosis progression rates and, thus, the impact of IFN is greater (Fig. 1). A large retrospective study using pooled data from 1452 patients who were nonresponders to IFN-based therapies also noted the impact of IFN-based therapies on fibrosis [15**]. Paired liver biopsies were examined before and after a fixed course of IFN treatment. They demonstrated that 17% of patients had improvement in fibrosis and 62% showed stability on post-treatment biopsies. Activity progression also showed stability (43%) or improvement (36%) in a majority of patients not achieving virologic response. In their discussion, the authors again suggest that other considerations besides biochemical and virologic normalization should be considered, especially in patients with advanced fibrosis on initial biopsy. Maintenance therapy was suggested as an option to be validated in prospective trials. Interferon and hepatocellular carcinoma Hepatocellular carcinoma develops in 3% to 5% of cirrhotic patients per year [41]. The exact mechanism as to the pathogenesis of HCC from HCV is not clear, but there is evidence that HCV proteins can activate cell genes. Furthermore, HCV may be indirectly oncogenic because a subset of patients will have chronic active inflammation, activation of cytokines and stellate cells, fibrosis, hepatocyte regeneration, and cirrhosis. It is speculated that cells that are damaged replicate at higher rates, and that this increase in cell division influences the likelihood of carcinogenesis [42]. HCV accounts for an estimated 33% of HCC cases in the United States [10]. Figure 1 Responders versus nonresponders. Impact of interferon according to observed fibrosis progression rate among 40 matched control responders (0.098 fibrosis U/y) and 46 control nonresponders (0.154 fibrosis U/y). These rates were applied to the median age at infection observed in the treated group (30 years) and to the median age at first biopsy in the matched control groups (41 years in responders, 48 years in nonresponders). The expected rates for the next years are represented by dotted lines for 3-month nonresponders and for 3-month responders (0.000 fibrosis U/y observed for matched treated responders and nonresponders during 20 months), for sustained responders (-0.042 fibrosis U/y observed in 32 sustained responders), and for untreated patients (assumption of constant fibrosis rates). (Adapted from Sobesky et al. [17].) View larger image Studies from Japan looking at 90 cirrhotic patients from HCV were randomized to either IFN therapy for 12 to 24 weeks or expectant follow-up [42]. These patients were followed from 2 to 7 years; only one patient had genotype 1 disease. A final diagnosis of HCC was made in 19 cases, two in the IFN arm and 17 in the control arm. The difference was statistically significant. Although this cohort of patients did not consist of the genotype 1 patients typically seen as nonresponders and the therapy arm was only for 2 to 6 months, it did have a relatively long follow-up (mean 4.4 years for treated arm, 5.5 years for the control arm) and an impressive outcome. In an Italian study, 193 patients with HCV cirrhosis were treated with various forms of IFN therapy for 24 to 48 weeks and then followed for over 2.5 years [43]. Five of these patients developed HCC over the time course, all in patients that did not demonstrate virologic response. In the control group of 92 patients, there were nine incidences of HCC. There was a significant decrease in the incidence of HCC in those who were treated. Specifically, among HCV patients who were male and over 50 years of age, treatment with IFN alpha dramatically lowered the incidence of HCC as compared to untreated control subjects. It is precisely these patients who would be considered candidates for maintenance therapy. Interferon and portal hypertension The development of portal hypertension is an indicator of clinical progression of liver disease. Prospective studies have shown that the risk of developing varices in patients with cirrhosis is between 35% to 80%, but no specific data are available for HCV-induced cirrhosis [44, 45]. Portal hypertension is a product of intrahepatic sinusoidal resistance to flow and a hyperdynamic splanchnic circulation. Fibrosis in HCV would result in increased sinusoidal resistance and inflammation increases the release of vasodilatory mediators such as TNF-a, which increases nitric oxide levels and may contribute to increased inflow into the portal circulation. IFN may decrease both inflammation and fibrosis and could theoretically affect both resistance and inflow by decreasing fibrosis and reducing vasodilatory neuromediators or cytokines such as TNF-a and nitric oxide. Therefore, the effect of IFN versus placebo on the clinical development of portal hypertension is a potential benefit of long-term therapy. Interferon and maintenance therapy A pilot study by Shiffman et al. [46] investigated the use of maintenance IFN in patients with persistent viremia. The study was a well-designed, randomized control trial looking at 53 patients who did not respond to standard IFN alfa-2b for 6 months but did have evidence of histologic improvement after this initial therapy. Twenty-six of these patients were randomized to low-dose IFN alfa-2b for an additional 24 months, whereas 27 were followed serially with repeated biopsy at 1 and 2 years. There was a statistical improvement in both patient groups after the 6 months of high-dose IFN therapy with regard to inflammation. However, the patients randomized to stop IFN had an increase in the hepatic inflammation score toward their pretreatment baseline. This increase nullified the statistical significance originally achieved. In fact, 35% of patients had a worsening of their score by at least two points. In contrast, the patients randomized to maintenance therapy continued to have significantly reduced inflammation compared to pretreatment baseline; 85% had improvement in their inflammation score by at least two points. There was a trend toward improvement with respect to hepatic fibrosis in patients on maintenance IFN. Patients randomized to stop IFN showed an increased hepatic fibrosis and 39% had an increase in fibrosis of at least one stage. This is in contrast with the patients on maintenance therapy who had an overall decrease in their hepatic fibrosis score, with 55% having a reduction by at least one stage (neither value significant). Table 2:  Clinical trials of maintenance therapy HALT-C COPILOT EPIC 3 Patients Ishak 4-6 Ishak 3-6 Metavir 2-4 N 1000 600 1000 End point Fibrosis Clinical Fibrosis + clinical Treatment arms Alfa-2a 90 mg/kg, placebo Alfa-2b 0.5 mg/kg, colchicine 0.6 mg bid Alfa-2b 0.5 mg/kg, placebo Run-in period Yes No Yes Treatment duration, y 3.5 4 4 Current status Recruitment complete Year 2 of maintenance Enrolling bid--twice a day; COPILOT--Colchicine vs PegIntron Long-Term; EPIC 3--Evaluation of Peg-Intron in Control of hepatitis C cirrhosis; HALT-C--Hepatitis C Antiviral Long-term Treatment against Cirrhosis. Studies in Progress Three large, prospective, randomized control trials with pegylated IFN as maintenance therapy are currently underway (Table 2). The populations of patients included in these trials are those with significant amounts of fibrosis on pretherapy biopsy (stages 3 to 4). Peginterferon alfa-2a is used at 90 mg once a week in HALT-C (Hepatitis C Antiviral Long-term Treatment against Cirrhosis) and peginterferon alfa-2b at 0.5 g/kg weekly is used in the other two studies. The National Institutes of Health-sponsored HALT-C trial is designed predominantly to look at fibrosis progression in a cohort of 1000 patients who failed a run-in period with pegylated IFN/RBV and are randomized to pegylated IFN or placebo for 3.5 years. COPILOT (Colchicine vs PegIntron Long-Term) is a comparative study of colchicine versus pegylated IFN with clinical primary end points and EPIC 3 (Evaluation of Peg-Intron in Control of hepatitis C cirrhosis) is evaluating both histologic and clinical end points. No major data are yet available from the maintenance phases of these trials. The safety profile of low-dose maintenance IFN appears acceptable. Conclusions There is both a strong need and a strong rationale for maintenance therapy. While the results of the clinical trials are eagerly awaited, the clinician is left with difficult decisions. Low doses of pegylated IFN appear well tolerated but still unproven. Simple treatments such as antioxidants and herbals are cheap and well tolerated, but again unproven. At the present time, we cannot fully endorse maintenance therapy but feel that the decision is one that needs to be individualized between physician and patient until more data are available. References and Recommended Reading Recently published papers of particular interest have been highlighted as: * Of importance ** Of major importance 1.   Hepatitis C: global prevalence [no authors listed]. Wkly Epidemiol Rec 1997, 72:341-344. 2.   Alter MJ: Epidemiology of hepatitis C. Hepatology 1997, 26(3 suppl 1):62S-65S. 3.   Kim WR: The burden of hepatitis C in the United States. Hepatology 2002, 36(5 suppl 1):S30-S34. 4.   Poynard T: Natural history of liver fibrosis progression in patients with chronic hepatitis C. 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Randomized, double-blind trial establishing the potential efficacy of RBV in a maintenance role.   View the PubMed notation for this reference. 25.   Patel K: Ribavirin as maintenance therapy for hepatitis C patients: an interim peacekeeper? Hepatology 2003, 38:21-24.   View the PubMed notation for this reference. 26.   Di Bisceglie AM, et al.: Iron reduction as an adjuvant to interferon therapy in patients with chronic hepatitis C who have previously not responded to interferon: a multicenter, prospective, randomized, controlled trial. Hepatology 2000, 32:135-138.   View the PubMed notation for this reference. 27.   Yano M, et al.: Long term effects of phlebotomy on biochemical and histological parameters of chronic hepatitis C. Am J Gastroenterol 2002, 97:133-137.   View the PubMed notation for this reference. 28.   Louis H: Modulation of liver injury by interleukin-10. 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