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Re: [GIWorld-Hepatitis] NATAP: Hepatitis C-Treatment for Peg Nonresponders

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  • avansi7465
    Gotta love my hepatologist! Go Doc Shiffman!!! Anne
    Message 1 of 2 , Mar 21, 2006
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      Gotta love my hepatologist! Go Doc Shiffman!!! Anne
      -----Original Message-----
      >From: claudine intexas <claudineintexas@...>
      >Sent: Mar 19, 2006 9:52 PM
      >To: giworld-hepatitis@yahoogroups.com, Web Warriors <HepCWebWarriors@yahoogroups.com>
      >Subject: [GIWorld-Hepatitis] NATAP: Hepatitis C-Treatment for Peg Nonresponders
      >
      >
      >Subject: NATAP: Hepatitis C-Treatment for Peg Nonresponders
      >
      >NATAP http://natap.org/
      >_______________________________________________
      >Chronic Hepatitis C: Treatment of Pegylated Interferon/Ribavirin Nonresponders
      >
      >Mitchell L. Shiffman, MD
      >Hepatology Section, Virginia Commonwealth University Medical Center, Box 980341, Richmond, VA 23298, USA.
      >
      >Current Gastroenterology Reports March 2006, 8:46-52
      >
      >TOPICS
      >Recognizing Nonresponse
      >o Null response
      >o Partial virologic response
      >o Virologic breakthrough
      >o Relapse
      >Assessing Factors Prior to Retreatment
      >o Fixed factors
      >o Correctable factors
      >More Aggressive Therapies with Currently Available Agents
      >o Consensus interferon and ribavirin
      >o Higher doses and longer duration of pegylated interferon and ribavirin
      >Antiviral Agents for Chronic HCV
      >Observation
      >Maintenance Therapy
      >o Maintenance therapy with interferon
      >
      >ABSTRACT. Patients with chronic hepatitis C virus (HCV) who were nonresponders to previous treatment with pegylated interferon and ribavirin are a growing population. The vast majority have genotype 1, a high viral load, advanced fibrosis or cirrhosis, and are of African-American race. The evaluation of these patients should include a thorough review of the previous treatment record and characterization of the previous nonresponse. Patients with prior null response are likely resistant to the effects of interferon. In contrast, patients with partial virologic response, breakthrough, and relapse could potentially achieve sustained virologic response if one or more correctable factors that contributed to the prior nonresponse are identified and addressed before and during retreatment. Many HCV nonresponders, especially those with no fibrosis or mild fibrosis, have an excellent prognosis, are at low risk to develop cirrhosis, and should simply be monitored at periodic intervals until
      > more effective therapy has been developed.
      >
      >Introduction
      >Patients with chronic hepatitis C virus (HCV) infection who were nonresponders to previous therapy with pegylated interferon and ribavirin represent a growing population within the HCV epidemic. The vast majority of these patients are often labeled as "difficult to treat" and are characterized as having genotype 1, a high viral load, and advanced fibrosis or cirrhosis. They have already failed to achieve a virologic response with the best therapy available to date [ 1, 2, 3]. As a result, the management of these patients is formidable. This
      >review discusses how HCV nonresponders to pegylated interferon and ribavirin should be evaluated and the various options available for these patients once this evaluation is complete. The management of specific HCV subpopulations at very high risk for nonresponse, those coinfected with HIV, those with advanced cirrhosis, and those patients who have recurrent HCV following liver transplantation, are not specifically addressed. However, many of the issues raised herein are also applicable to these populations.
      >
      >Recognizing Nonresponse
      >The first and single most important thing to do when evaluating an HCV patient with prior nonresponse to pegylated interferon and ribavirin is to review the previous treatment records and ensure that the "label" of nonresponse is in fact correct. If serum HCV RNA has not been measured since the patient discontinued therapy, a repeat HCV RNA test should be performed. We have seen patients referred at our center who were told they were not responding to treatment but had a marked decline in HCV RNA or were HCV RNA undetectable at the time treatment was discontinued. We have also seen patients who had stopped treatment prematurely due to adverse events without first having HCV RNA assessed to see if a virologic response had been achieved. Interestingly, in some cases these patients have been found to have undetectable HCV RNA when retested months later, indicating that the response to therapy had not been appreciated. Failure to recognize virologic response is an important cause of
      > presumed nonresponse. Characteristics of HCV RNA assays and the pitfalls encountered when assessing virologic response were recently reviewed [4, 5].
      >
      >When assessing the previous treatment records of a patient with nonresponse, three distinct patterns should be recognized: null response, partial virologic response, and breakthrough. These patterns are graphically depicted in Figure 1. A third group of patients, those with relapse, are not true nonresponders. However, they are an important group to discuss because they are the easiest group to manage among those who failed to achieve sustained virologic response (SVR).
      >
      >Null response
      >A null response is defined as the failure to have any meaningful decline in serum HCV RNA during treatment. This term is typically reserved for those patients who have had less than a 2-log decline in the serum level of HCV RNA from the pretreatment baseline 12 weeks after treatment was initiated. Approximately 20% of patients with HCV genotype 1 and 5% of patients with HCV genotype 2 or 3 have a null response to pegylated interferon and ribavirin therapy. Patients with a null response rarely have a further decline in the serum level of HCV RNA with continued therapy, and treatment should be discontinued as soon as this response pattern is recognized.
      >
      >It is important to recognize patients with null response because they appear resistant to the antiviral effects of interferon. In a previous study in which interferon nonresponders were retreated with higher doses of standard interferon and ribavirin, no patient with prior null response achieved SVR during retreatment [6]. Although retreatment of null responders with higher doses of interferon or pegylated interferon has never been evaluated, such an approach is unlikely to be successful in many of these patients. The use of interferon maintenance therapy is also unlikely to benefit patients with prior null response. Because histologic improvement is associated with a marked decline in HCV RNA, null responders in general do not exhibit histologic improvement [7**]. Such patients were therefore excluded from the only study of maintenance therapy reported to date [8**]. The best treatment option for patients with null response is to participate in clinical trials of antiviral agents,
      > which could lower HCV RNA and render them more sensitive to the effects of interferon and ribavirin. In the absence of clinical trials, patients with null response should simply be monitored at periodic intervals.
      >
      >Partial virologic response
      >Patients with partial virologic response have a decline in serum HCV RNA by 2 log units (100-fold) or more from the pretreatment baseline but do not become HCV RNA undetectable by treatment week 24. Previous studies have suggested that this decline in HCV RNA is associated with an improvement in hepatic inflammation [7**, 8**] and that continuing interferon long term in these patients can maintain this improvement in hepatic inflammation and possibly reduce fibrosis [8**]. Partial virologic response is likely to be more common in patients who require reduction in the dose of pegylated interferon and/or ribavirin during the first 12 weeks of therapy [9, 10].
      >
      >It is very important to recognize patients with partial virologic response. Such patients are close to becoming HCV RNA undetectable and could potentially achieve a virologic response with higher doses of interferon or pegylated interferon or with antiviral agents. Such patients are also potential candidates for maintenance therapy and to date are the only group of nonresponders in which interferon maintenance therapy has been shown to be effective [8**].
      >
      >Virologic breakthrough
      >Virologic breakthrough is defined as the reappearance of HCV RNA in serum after HCV RNA had initially become undetectable despite ongoing interferon therapy. Breakthrough most commonly occurs when the dose of pegylated interferon and/or ribavirin is reduced in response to adverse events that develop during therapy [11]. More effective management of the particular adverse events that required dose reduction is likely to allow the patient to remain on full-dose therapy, and if this occurs the potential to achieve SVR will be significantly increased. Many patients with breakthrough may not be candidates for treatment with higher doses of interferon or pegylated interferon because they were unable to tolerate the previous course of therapy.
      >
      >Relapse
      >Relapse is defined as the reappearance of HCV RNA in serum after interferon and ribavirin are discontinued in a patient who was HCV RNA undetectable at the completion of therapy. The risk of relapse appears to be increased in those patients who require a reduction in the dose of ribavirin during treatment [9, 10, 12], especially during the first 24 weeks of therapy and before the patient becomes HCV RNA undetectable. In contrast, reducing the dose of pegylated interferon and/or ribavirin after week 20 in patients who were already HCV RNA undetectable did not affect the rate of relapse [12].
      >
      >It is very important to recognize patients with relapse. If a patient develops relapse in response to dose reduction during the first 24 weeks of therapy, more effective management of adverse events is likely to allow the patient to remain on full-dose therapy during retreatment and increase the chance for SVR. Preliminary data also suggest that relapse could be significantly reduced if treatment is extended for several additional months [13]. Thus, retreatment of patients with relapse for a longer period, possibly 72 weeks or even longer, is another potential option for these patients if they were able to tolerate the previous therapy with minimal adverse events. The use of pegylated interferon maintenance therapy to keep HCV RNA undetectable is simply a variation of long-term therapy and is a good alternative for some of these patients, particularly those who can tolerate pegylated interferon but not ribavirin. Retreatment with higher doses of interferon or pegylated interferon can
      > also be considered. However, data regarding the likelihood that this approach would be effective in the absence of also prolonging therapy are currently unavailable.
      >
      >Assessing Factors Prior to Retreatment
      >All HCV nonresponders have a series of factors that have contributed to their negative outcome. These factors are of two types: fixed or correctable (Table 1). Fixed factors are those characteristics that cannot be altered or corrected. In contrast, correctable factors can be modified, and this could significantly enhance the chance that retreatment with the same or a more aggressive regimen could achieve SVR.
      >
      >
      >Fixed factors
      >Fixed factors associated with nonresponse include HCV genotype 1, a null response to treatment with pegylated interferon and ribavirin, and African-American race [14*]. A nonresponder with one or more of these fixed factors who has completed at least 12 to 24 weeks of full-dose pegylated interferon and ribavirin without dose reduction and without becoming HCV RNA undetectable should not be retreated with the same regimen. This is true for patients with null response, partial virologic response, or breakthrough. Whether antiviral agents or higher doses of interferon or pegylated interferon could overcome these fixed factors is being evaluated in clinical trials. Such patents should either be monitored or offered enrollment in clinical trials if possible.
      >
      >Correctable factors
      >Correctable factors that may have contributed to nonresponse during initial treatment include dose reduction or premature discontinuation of pegylated interferon and/or ribavirin in response to adverse events [9, 10, 11], the ongoing use of alcohol or illicit drugs during therapy [15, 16], and noncompliance with the prescribed therapy. Many of these factors are related to adverse events that develop during treatment. The management of adverse events has been addressed in a recent review [11].
      >
      >Recognizing that a patient had a correctable factor that may have contributed to a nonresponse is one of the most important aspects in the evaluation of these patients. For example, we have had patients referred to our center for nonresponse, and only after careful questioning was it established that the patient was taking the wrong dose of pegylated interferon and/or ribavirin, missed several doses within the first 12 weeks of treatment because of work or family activities, and/or used illicit drugs or large amounts of alcohol to combat the side effects of therapy. These factors are relatively easy to address and correct.
      >
      >Approximately 20% of patients develop a severe hemolytic anemia, neutropenia, or thrombocytopenia during treatment with pegylated interferon and ribavirin [1, 2, 3]. This is frequently managed by dose reduction and/or premature discontinuation of therapy. Two randomized controlled trials have demonstrated that the use of epoetin alfa can correct anemia induced by these medications [17, 18*]. Retreatment of such patients with epoetin alfa, instituted at the onset of pegylated interferon and ribavirin therapy or as soon as the decline in hemoglobin occurs, can potentially prevent the need to either reduce the dosage or discontinue treatment a second time and enhance the likelihood of SVR during retreatment. Although no clinical trials have evaluated the efficacy of filgrastim to correct interferon-induced neutropenia, this agent is nevertheless effective in this situation [11]. No effective therapy is available for interferon-induced thrombocytopenia. However, many experienced
      > hepatologists will allow the platelet count to decline into the 25,000-to-30,000 range before reducing the dose or discontinuing treatment.
      >
      >Psychiatric factors are also common during treatment and a frequent reason for reducing the dose, skipping doses, or prematurely discontinuing treatment. The most common psychiatric adverse events include depression, insomnia, and irritability [11, 19, 20]. Aggressive management of these symptoms prior to and at the onset of retreatment by a psychiatrist or non-physician mental health provider working in close communication with the physician or mid-level provider treating HCV may prevent the need to either reduce the dose or discontinue treatment and enhance the likelihood of SVR. A randomized placebo-controlled trial has demonstrated that antidepressant therapy can be used successfully in this manner [21].
      >
      >The best candidates with correctable factors for retreatment are those patients with partial virologic response, breakthrough, or relapse. As noted previously, such patients had a marked reduction in HCV RNA during therapy and in some cases became HCV RNA undetectable. Careful attention to ensure that these correctable factors do not recur during retreatment frequently allows such patients to complete therapy and achieve an SVR. In contrast, patients with prior null response are less likely to achieve SVR, even if these factors can be successfully addressed. However, if the correctable factor occurred within the first 12 weeks after the onset of therapy, retreatment of the patient with null response would not be unreasonable.
      >
      >In summary, patients with adverse events or noncompliant behavior that contributed to nonresponse, but that can be corrected prior to and during retreatment, are the only patients who should be treated a second time with the same standard doses of pegylated interferon and ribavirin.
      >
      >More Aggressive Therapies with Currently Available Agents
      >
      >Consensus interferon and ribavirin
      >Consensus interferon (CIFN) is a synthetic interferon product with an amino acid sequence that reflects all alfa interferons. CIFN has been shown to be effective for retreatment of patients who have failed to achieve SVR after 24 weeks of treatment with standard IFN monotherapy [22]. In that study, SVR was achieved in 58% of patients with prior relapse and 13% with previous nonresponse. High-dose daily CIFN and ribavirin has recently been evaluated in pegylated interferon/ribavirin nonresponders in two small single-center trials [23, 24]. In these studies CIFN was initiated at doses of 27, 18, or 15 mg daily for 4 to 12 weeks followed by a stepwise reduction in the dosage to 18 and then 9 mg daily. Patients treated with the highest dose of CIFN received this as monotherapy until the dosage was reduced to 9 or 15 mg, at which point ribavirin was added. Preliminary data from these studies have suggested that 37% to 42% of pegylated interferon/ribavirin nonresponders could achieve SVR
      > with this approach. One of these studies suggests that high-dose daily CIFN may be particularly helpful in African Americans [24]. Based on these single-center preliminary studies, a large multicenter clinical trial has been initiated in which CIFN (15 or 9 mg/day) plus ribavirin (1000-1200 mg/day) is being evaluated for treatment of pegylated interferon/ribavirin nonresponders.
      >
      >Higher doses and longer duration of pegylated interferon and ribavirin
      >Another approach to treatment of pegylated interferon/ribavirin nonresponders is to use a higher dose of pegylated interferon. In a preliminary study in which patients with prior nonresponse to standard interferon and ribavirin were retreated with higher dosages of pegylated interferon (270 and 360 mg/week) and ribavirin, a significant increase in SVR was observed compared with retreatment with a standard dose of pegylated interferon (180 mg/week) and ribavirin [25]. These data have led to the initiation of a multicenter trial in which higher doses of pegylated interferon and ribavirin are used for treatment of pegylated interferon/ribavirin nonresponders.
      >
      >It has been hypothesized that HCV patients with genotype 1 who relapse following treatment with pegylated interferon and ribavirin may not have been treated long enough to achieve long-lasting viral suppression or clearance. Preliminary results from a trial in which patients were randomly assigned to receive either 48 or 72 weeks of therapy have demonstrated that relapse was reduced from 48% to 13% in those patients treated for a longer period of time [13]. Retreatment with the same dose of pegylated interferon and ribavirin but for a longer period of time is therefore a reasonable option for patients with prior relapse. Such an approach should not be used in patients with nonresponse.
      >
      >Antiviral Agents for Chronic HCV
      >Among the most promising therapies for patients with prior nonresponse to pegylated interferon and ribavirin are antiviral agents directed against HCV. Protease and polymerase inhibitors have been evaluated to date. Helicase inhibitors and inhibitors of other proteins important for HCV replication are likely to be evaluated in the future. Which of these agents will evolve into an effective therapy for chronic HCV remains speculative. Furthermore, it remains unclear if these agents will be used with pegylated interferon or with pegylated interferon and ribavirin as triple therapy. However, it is already apparent that no antiviral agent will be used alone as single agent for HCV.
      >Table 2 lists several antiviral agents currently being evaluated in clinical trials (this Table was not available. The furthest along in development are these 3 drugs. Three new HCV antiviral orally administered drugs are in studies in patients: Vertex's HCV protease inhibitor showed a 4.4 log reduction in HCV viral load in a 2-week study & is now entering larger phase II studies in combination with Pegasys; Schering's HCV protease inhibitor showed a 2 log reduction in HCV viral load in a 2-week study in treatment-experienced patients and is in phase II now looking at various doses including a higher dose; Idenix's polymerase inhibitor showed about a 1 log reduction in viral load, and is in large phase III study). Even if these experimental therapies show promise, many more years will pass before any are widely available as treatments for chronic HCV. Although some patients with nonresponse to pegylated interferon and ribavirin may choose to enter clinical trials and assist in the
      > development of these agents, the vast majority of HCV nonresponders are either ineligible to enter these trials or live too far from centers where these trials are being conducted.
      >
      >Observation
      >Many patients with chronic HCV and nonresponse to pegylated interferon and ribavirin have no, mild, or moderate degrees of fibrosis and mild inflammation and are therefore at low risk to develop fibrosis progression to cirrhosis within the next decade
      >[26, 27]. (NOTE from Jules: HCV/HIV coinfected patients are at risk for accelerated progression 2 to 5 times more quickly than HCV monoinfected patients, therefore delaying therapy can be risky). The risk of hepatic decompensation in patients with stable cirrhosis appears to be about 5% yearly, and the risk of hepatocellular carcinoma about 3% yearly [28]. Thus, after 5 years of follow-up, approximately 15% to 25% of patients would be expected to develop either hepatocellular carcinoma or hepatic decompensation. It is therefore reasonable for many nonresponders simply to be observed at periodic intervals until significant improvements to therapy have been established. During this time the focus should be on modifying lifestyle factors that enhance fibrosis progression, including totally eliminating or severely limiting alcohol consumption [29]. The minimum amount of alcohol that is safe and not associated with an enhanced rate of fibrosis progression in HCV patients remains
      > undefined. At our own center we allow patients to consume a limited amount of alcohol on special occasions only (eg, birthdays, anniversaries, weddings). The presence of co-existent nonalcoholic fatty liver disease has been associated with more rapid fibrosis progression and a higher prevalence of cirrhosis in patients with chronic HCV [30, 31]. It is therefore rational to recommend that HCV nonresponders lose weight, exercise regularly, and improve the control of their diabetes mellitus and hyperlipidemia if possible. All patients with chronic HCV should be assessed for prior exposure to viral hepatitis A and B and vaccinated to prevent acute infection if immunity is not already present [32**, 33]. Patients with cirrhosis should undergo screening for hepatocellular carcinoma at regular intervals [34]. If patients with cirrhosis develop liver cancer or evidence of hepatic decompensation, they should be considered for liver transplantation.
      >
      >Maintenance Therapy
      >Fibrosis progression in patients with chronic HCV is mediated by hepatic inflammation [26, 27]. Reducing hepatic inflammation may therefore prevent fibrosis progression. Both HCV RNA and hepatic inflammation are reduced in many nonresponders during treatment with interferon [7**, 8**]. The long-term use of interferon or pegylated interferon as maintenance therapy may therefore prevent fibrosis progression. Other agents that selectively reduce apoptosis, inflammation, or fibrosis are also being considered as long-term maintenance treatment in HCV nonresponders. Ribavirin monotherapy has also been used for treatment of HCV nonresponders [35]. Although it is well tolerated, additional studies of ribavirin maintenance therapy have not been pursued.
      >
      >Maintenance therapy with interferon
      >Maintenance therapy with standard interferon was evaluated in a randomized, controlled trial of patients who achieved partial virologic response and a reduction in hepatic inflammation after an initial course of standard interferon therapy [8**]. These patients were randomly assigned either to continue standard interferon for an additional 2 years or to stop treatment. Patients who remained on standard interferon maintained the initial reduction in serum HCV RNA and improvement in hepatic inflammation observed after the initial treatment. No patients became persistently HCV RNA undetectable. In contrast, both serum HCV RNA and hepatic inflammation returned to the pretreatment baseline level in those patients randomized to stop therapy. After 2.5 years, patients given maintenance therapy had a mild decline in fibrosis score, whereas the control group had a slight increase in fibrosis. However, the difference in fibrosis scores between these two groups was not significant. Several
      > large multicenter clinical trials are currently investigating the benefits of pegylated interferon maintenance therapy. The dosages of pegylated interferon alfa-2a and pegylated interferon alfa-2b in these trials are 90 mg/week and 0.5 mg/kg/week, respectively. The goal of these studies is to determine if pegylated interferon maintenance therapy can prevent fibrosis progression; reduce hepatic decompensation, hepatocellular carcinoma, and the need for liver transplantation; and improve survival. In a preliminary report, one of these trials showed a significant reduction in the incidence of variceal hemorrhage in patients receiving pegylated interferon maintenance therapy, compared with colchicine. However, no reduction in hepatocellular carcinoma, the need for liver transplantation, or death was observed [36].
      >
      >Final results from the various clinical trials evaluating pegylated interferon maintenance therapy will not be available for several years. However, based on available data, it is possible to consider maintenance therapy for patients with advanced fibrosis or stable cirrhosis who have relapsed after treatment with pegylated interferon and ribavirin and those who have a partial virologic response associated with a marked reduction in HCV RNA. In contrast, maintenance therapy should probably not be considered in those patients who had a null response in previous therapy and those who have developed complications of cirrhosis.
      >
      >Conclusions
      >Patients who do not respond to pegylated interferon and ribavirin represent a diverse group that can be categorized based on the pattern of HCV RNA change during therapy and whether factors that were potentially responsible for this response can be corrected. Patients with a null response pattern are likely resistant to the effects of pegylated interferon and are unlikely to benefit from retreatment strategies. In contrast, patients with a partial virologic response, breakthrough, or relapse could potentially achieve SVR if any factors that may have contributed to this result can be identified and corrected both prior to and during retreatment. Higher daily dosages of standard interferons, higher dosages of pegylated interferon, longer duration of pegylated interferon and ribavirin, antiviral agents, and pegylated interferon maintenance therapy are currently being evaluated in patients with nonresponse. Many patients with mild fibrosis have an excellent prognosis and can be monitored
      > at regular intervals until more effective therapy for chronic HCV has been developed.
      >
      >References and Recommended Reading
      >Recently published papers of particular interest have been highlighted as:
      >* Of importance
      >** Of major importance
      >1. Manns MP, et al.: Peginterferon-alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomized trial. Lancet 2001, 358:958-965. View the PubMed notation for this reference.
      >
      >2. Fried MW, et al.: Combination of peginterferon alfa-2a (40 kd) plus ribavirin in patients with chronic hepatitis C virus infection. N Engl J Med 2002, 347:975-982. View the PubMed notation for this reference.
      >
      >3. Hadziyannis SJ, et al.: Peginterferon-alfa 2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose. Ann Intern Med 2004, 140:346-355. View the PubMed notation for this reference.
      >
      >4. Ferreira-Gonzalez A: Use of diagnostic testing for managing hepatitis C virus infection. Semin Liver Dis 2004, 24(Suppl 2):9-18.
      >View the PubMed notation for this reference.
      >
      >5. Sethi A: Approach to the management of patients with chronic hepatitis C who failed to achieve sustained virologic response. Clin Liver Dis 2005, 9:453-471. View the PubMed notation for this reference.
      >
      >6. Shiffman ML, et al.: Treatment of chronic hepatitis C in patients who failed interferon monotherapy: effects of higher doses of interferon and ribavirin combination therapy. Am J Gastroenterol 2000, 95:2928-2935. View the PubMed notation for this reference.
      >
      >7. Shiffman ML, et al.: Relationship between biochemical, virologic and histologic response during interferon treatment of chronic hepatitis C. Hepatology 1997, 26:780-785.
      >First study to demonstrate that a decline in HCV RNA during interferon therapy is associated with a decline in hepatic inflammation. View the PubMed notation for this reference.
      >
      >8. Shiffman ML, et al.: A randomized, controlled trial of maintenance interferon for treatment of chronic hepatitis C non-responders. Gastroenterology 1999, 117:1164-1172.
      >First study to demonstrate the potential benefits of maintenance interferon therapy. Patients who had a reduction in hepatic inflammation during treatment with interferon were able to maintain this histologic improvement if interferon therapy was continued long term. View the PubMed notation for this reference.
      >
      >9. McHutchison JG, et al.: Adherence to combination therapy enhances sustained response in genotype 1 infected patients with chronic hepatitis C. Gastroenterology 2002, 123:1061-1069.
      >View the PubMed notation for this reference.
      >
      >10. Davis GL, et al.: Early virologic response to treatment with peginterferon alfa 2b plus ribavirin in patients with chronic hepatitis C. Hepatology 2003, 38:645-652. View the PubMed notation for this reference.
      >
      >11. Shiffman M: Side effects of medical therapy for chronic hepatitis C. Ann Hepatol 2004, 3:5-10. View the PubMed notation for this reference.
      >
      >12. Shiffman ML, et al.: Peginterferon alfa-2a and ribavirin in patients with chronic hepatitis C who have failed prior treatment. Gastroenterology 2004, 126:1015-1023. View the PubMed notation for this reference.
      >
      >13. Sanchez-Tapias JM, et al.: Sustained virologic response after prolonged treatment with peginterferon alfa-2a and ribavirin. Hepatology 2004, 40 (Suppl 1):218A.
      >
      >14. Muir AJ: Peginterferon alfa-2b and ribavirin for the treatment of chronic hepatitis C in blacks and non-hispanic whites. N Engl J Med 2004, 350:2265-2271.A controlled trial demonstrating that African Americans have a significantly lower rate of sustained virologic response compared with Caucasians. View the PubMed notation for this reference.
      >
      >15. Peters MG: Alcohol use and hepatitis C. Hepatology 2002, 36:S220-S225. View the PubMed notation for this reference.
      >
      >16. Sylvestre DL: Treating hepatitis C virus infection in active substance users. Clin Infect Dis 2005, 40(Suppl 5):S321-S324.
      >View the PubMed notation for this reference.
      >
      >17. Dieterich DT, et al.: Once weekly epoetin alfa improves anemia and facilitates maintenance of ribavirin dosing in hepatitis C virus infected patients receiving ribavirin plus interferon alfa. Am J Gastroenterol 2003, 98:2491-2499. View the PubMed notation for this reference.
      >
      >18. Afdhal NH, et al.: Correction of anemia With epoetin alfa maintains ribavirin dose in HCV-infected patients: A prospective, double-blind study. Gastroenterology 2004, 126:1302-1311.
      >A controlled, randomized, double-blinded trial demonstrating that the use of epoetin alfa can improve serum hemoglobin in patients who develop anemia during treatment with interferon and ribavirin.
      >View the PubMed notation for this reference.
      >
      >19. Fontana RJ: Neuropsychiatric toxicity of antiviral treatment in chronic hepatitis C. Dig Dis 2000, 18:107-116. View the PubMed notation for this reference.
      >
      >20. Asnis GM: Interferon induced depression: strategies in treatment. Prog Neuropsychopharmacol Biol Psychiatry 2005, 29:808-818. View the PubMed notation for this reference.
      >
      >21. Musselman DL, et al.: Paroxetine for the prevention of depression induced by high-dose interferon alfa. N Engl J Med 2001, 344:961-966. View the PubMed notation for this reference.
      >
      >22. Heathcote EJ, et al.: Retreatment of chronic hepatitis C with consensus interferon. Hepatology 1998, 27:1136-1143. View the PubMed notation for this reference.
      >
      >23. Kaiser S: Successful retreatment of peginterferon nonresponders with chronic hepatitis C with high dose consensus interferon induction therapy. Gastroenterology 2003, 124(Suppl 1):A700.
      >
      >24. Leevy C II: Comparison of African American and non-African American patient end of treatment response for PEGIFN alpha-2a and weight based ribavirin nonresponders retreated with IFN alfacon-1 and weight based ribavirin. Hepatology 2004, 40 (Suppl 1):240A.
      >
      >25. Diago M, et al.: Peginterferon alfa-2a and ribavirin in patients infected with HCV genotype 1 who failed to respond to interferon and ribavirin: Final results of the Spanish high dose induction pilot trial. Hepatology 2004, 40(Suppl 1):389A.
      >
      >26. Yano M, et al.: The long term pathological evolution of chronic hepatitis C. Hepatology 1996, 23:1334-1340. View the PubMed notation for this reference.
      >
      >27. Ghany MG, et al.: Progression of fibrosis in chronic hepatitis C. Gastroenterology 2003, 124:97-104. View the PubMed notation for this reference.
      >
      >28. Fattovich G, et al.: Morbidity and mortality in compensated cirrhosis type C: a retrospective follow up study of 384 patients. Gastroenterology 1997, 112:463-472. View the PubMed notation for this reference.
      >
      >29. Schiff ER: Hepatitis C and alcohol. Alcohol Res Health 2003, 27:232-239. View the PubMed notation for this reference.
      >
      >30. Ramesh S: Hepatitis C and nonalcoholic fatty liver disease. Semin Liver Dis 2004, 24:399-413. View the PubMed notation for this reference.
      >
      >31.Younossi ZM, et al.: Obesity and non-alcoholic fatty liver disease in chronic hepatitis C. J Clin Gastroenterol 2004, 38:705-709. View the PubMed notation for this reference.
      >
      >32.Reiss G: Review article: Hepatitis vaccination in patients with chronic liver disease. Aliment Pharmacol Ther 2004, 19:715-727.
      >Review outlining the benefits of vaccinating patients with chronic liver disease against viral hepatitis A and B. View the PubMed notation for this reference.
      >
      >33.Strader DB: Diagnosis, management, and treatment of hepatitis C. Hepatology 2004, 39:1147-1171. View the PubMed notation for this reference.
      >
      >34.Daniele B: Alpha-fetoprotein and ultrasonography screening for hepatocellular carcinoma. Gastroenterology 2004, 127(Suppl 1):S108-S112.
      >
      >35.Hoofnagle JH, et al.: Maintenance therapy with ribavirin in patients with chronic hepatitis C who fail to respond to combination therapy with interferon alfa and ribavirin. Hepatology 2003, 38:66-74. View the PubMed notation for this reference.
      >
      >36.Afdhal N, et al.: Colchicine versus Peg-Intron long term (CoPilot) trial: Interim analysis of clinical outcomes at year 2. Hepatology 2004, 40 (Suppl 1):239A.
      >
      >
      >
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