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  • Welcome to this CME-certified presentation, entitled “Managing the Difficult-to-Treat HCV Patient.” My name is K. Rajender Reddy, MD, and I am a Professor of Medicine and Surgery, Director of Hepatology, and Medical Director of Liver Transplantation at the University of Pennsylvania in Philadelphia, Pennsylvania.
  • Approximately 3.9 million people are infected with hepatitis C virus (HCV) in the United States. Approximately 35,000 new cases are known to occur yearly; however, the rate of new infections appears to be decreasing. Most individuals—approximately 85%—who are infected with HCV become chronically infected. Regarding mortality, there are 10,000-20,000 HCV-related deaths per year, and this rate is expected to triple within the next 10-20 years. Hepatitis C virus infection is the leading cause of chronic liver disease, cirrhosis, liver cancer, and liver transplantation. A liver transplantation is required in a large number of HCV-infected patients. Ultimately, many of these individuals have a recurrence of HCV that can result in death.
  • HCC, hepatocellular carcinoma. Effective therapy for hepatitis C is available and will be discussed later in more detail. The primary goal of HCV therapy is to eradicate the virus. In fact, eradication of HCV infection with sustained long-term absence of the virus is possible. Additional goals for HCV therapy include retarding disease progression, minimizing the risk of hepatocellular carcinoma, improving liver histology, enhancing the quality of life, preventing transmission of HCV infection, and reducing extrahepatic manifestations.
  • IFN, interferon; RBV, ribavirin; SVR, sustained virologic response;. The standard of treatment for HCV therapy began with the use of standard interferon. Initially, patients received standard interferon monotherapy 3 times weekly for a total of 24 weeks. Now, it is recognized that such therapy results in a suboptimal rate of sustained virologic response (SVR) of approximately 6% on average. Next, patients were administered standard interferon monotherapy for an extended duration of 48 weeks. This resulted in an improved SVR rate of approximately 19%. The rate of SVR was further improved by the introduction of ribavirin to standard interferon, resulting in an SVR rate of approximately 43% following 48 weeks of therapy.
  • GT, genotype; PegIFN, peginterferon; RBV, ribavirin; SVR, sustained virologic response. Further improvements in SVR rates were achieved by replacing standard interferon with peginterferon when used together with ribavirin. This slide illustrates the data from 2 large registration trials. Manns and colleagues evaluated the efficacy of peginterferon alfa-2b plus ribavirin whereas Fried and colleagues evaluated the efficacy of peginterferon alfa-2a plus ribavirin. The overall SVR rates were > 50% in both trials. Among genotype 1 patients, who typically respond less well to treatment, the SVR rates were 42% and 46% with the use of peginterferon alfa-2b plus ribavirin and peginterferon alfa-2a plus ribavirin, respectively. Among genotype 2/3 patients who traditionally achieve higher SVR rates, those who received peginterferon alfa-2b plus ribavirin had an SVR rate of 82% and those who received peginterferon alfa-2a plus ribavirin had an SVR rate of 76%. These data clearly demonstrate that patients infected with genotype 1 HCV are able to achieve a higher SVR rate with peginterferon plus ribavirin compared with the rates achieved with standard interferon plus ribavirin therapy. Therefore, peginterferon represents an advancement in the treatment of hepatitis C and is currently used as the standard of care.
  • While treating a patient for chronic C hepatitis, it is important to recognize the pattern of virologic response and to identify the predictors of response.
  • cEVR, complete early virologic response; EVR, early virologic response; PegIFN, peginterferon; RBV, ribavirin; RVR, rapid virologic response; SVR, sustained virologic response. After the initiation of hepatitis C treatment, it is important to assess viral clearance at various time points. The first key time point for assessing viral clearance is at Week 4. This should be conducted using a sensitive quantitative or qualitative assay. Rapid virologic response (RVR) is defined as the clearance of the virus by Week 4. Many HCV-infected patients who do not clear the virus by Week 4 will achieve viral clearance by Week 12. These patients are said to have achieved a complete early virologic response. Patients who experience a decline in HCV RNA of at least 2 log 10 IU/mL by Week 12 and then later clear the virus between Weeks 12-24 are known as partial early virologic responders or slow virologic responders. Given these differences in response rates in individuals, a fixed duration of therapy of 48 weeks in genotype 1 HCV–infected patients results in varied treatment efficacy. For example, 48 weeks of therapy among the rapid virologic responders would result in 44 weeks of therapy after virologic negativity was achieved whereas a fixed duration of 48 weeks among the slow virologic responders would result in only 24 weeks of therapy after virologic negativity was achieved. This variation in the duration of therapy following the achievement of virologic negatively has an impact on the eventual SVR rates such that the slow virologic responders tend to have a lower SVR rate when compared with the rapid virologic responders who would be predicted to have the highest SVR rate. This trend has been well documented in clinical trials and retrospective analyses of data.
  • PegIFN, peginterferon; RBV, ribavirin. Ultimately, some patients do not achieve SVR, and it is important to recognize that there are several patterns of suboptimal virologic response. For instance, a null response is defined as a decline in HCV RNA < 1 log 10 IU/mL by Week 12. If a patient experiences a decline in HCV RNA of at least 2 log 10 IU/mL but does not have a further decline in HCV RNA levels, he or she is classified as a partial responder. In addition, a patient who clears the virus while receiving treatment but later experiences a re-emergence in HCV RNA on treatment has undergone breakthrough. Breakthrough may occur in patients who maintain the same dosages of peginterferon and ribavirin throughout treatment as well as in patients who later receive a decreased dosage of one or both drugs. A relapser is a patient who becomes HCV RNA negative while receiving treatment and maintains virologic negativity throughout the entire duration of treatment but later experiences a re-emergence of virus after treatment is stopped. It is important to differentiate relapse from the other patterns of suboptimal virologic responses because a relapser has a better chance of responding with retreatment and has a better chance of achieving SVR with retreatment when compared with null responders, partial responders, and those who undergo virologic breakthrough.
  • GT, genotype; RBV, ribavirin. Key predictors of response have been identified and are expanding as we have more information. In the 1990s, it was recognized that genotype 2/3 patients respond well to treatment. Similarly, other predictors of response at that time included relatively mild fibrosis, low baseline HCV RNA levels, younger age, the female sex, and lighter body weight. Recently, additional predictors of response have been identified. It is still recognized that genotype 2/3 patients respond well to treatment; however, we have more recently learned that patients who do not have steatosis respond better than those who do have steatosis. Moreover, SVR is more likely among patients who adhere to therapy, among patients who achieve RVR, and among patients who receive adequate dosages of ribavirin. Race is another predictor of response, and it has been shown that the SVR rate among white patients is higher than the rate among black patients. For more information, go online to: http://clinicaloptions.com/Hepatitis/Journal%20Options/Articles/Muir-NEJM-2004-05/Capsule.aspx
  • IFN, interferon. Some key principles and fundamentals should be considered while assessing the causes and management of null response. Null response may occur because of inadequate dosing or an inadequate treatment duration, and certain patients may require higher treatment dosages. For example, heavier patients require higher doses of ribavirin than do lighter patients. There are also preliminary data to suggest that higher dosages of peginterferon may be helpful in heavier patients. Another cause of null response may be insufficient compliance. It is important to recognize that patients can experience adverse events that may lead to dose reductions or interruptions during treatment. To enhance the likelihood of achieving SVR, it is incumbent upon clinicians to help patients maintain treatment for the full duration through the effective management of adverse effects. For example, one may need to use growth factors to enhance treatment maintenance in patients with anemia. Improved compliance will ultimately result in a higher likelihood of the patient achieving an SVR. It is also important to recognize the role of steatosis in treatment nonresponse. Some patients have insulin resistance that leads to hepatic steatosis that eventually impairs the response to HCV therapy. Later in this presentation, we will discuss the mechanisms of steatosis, the management of steatosis among patients with various genotypes, as well as the impact of steatosis on SVR rates. In addition, some patients are inherently resistant to interferon therapy. These null responders do not experience any significant change in HCV RNA levels while receiving interferon-based therapy, making them very difficult to treat with the current standard of care.
  • It is important to recognize factors that may affect relapse and to identify methods to address these factors and to prevent relapse. Foresight is the most important factor in the appropriate management of hepatitis C patients.
  • GT, genotype; RBV, ribavirin. There are 2 key principles to consider regarding the occurrence of relapse among patients who undergo HCV therapy: viral kinetics and ribavirin dosage. It is important for clinicians to understand the role of the duration of HCV RNA negativity in treatment success. Clinicians should assess for RVR and complete early virologic response at Weeks 4 and 12, respectively. In addition, they should be aware that some patients may have partial early virologic response, and the duration of therapy is particularly critical to their success. Specifically, slow responders or patients who achieve HCV RNA negativity between Weeks 12-24 are likely to benefit from an extended duration of therapy. This is particularly true among patients infected with genotype 1 HCV. Furthermore, it is critical for clinicians to recognize that an inadequate ribavirin dosage is associated with high rates of relapse.
  • GT, genotype; PegIFN, peginterferon; RBV, ribavirin; SVR, sustained virologic response. Ferenci and colleagues conducted a retrospective analysis that demonstrated that patients who achieve HCV RNA negativity early during peginterferon plus ribavirin therapy have the highest chance of achieving SVR. This graph illustrates that as the timing of viral clearance decreases, the rate of SVR decreases following a fixed duration of therapy of 48 weeks. In fact, the SVR rate among patients who first became HCV RNA negative at Week 4 was 91%, the SVR rate among patients who first became HCV RNA negative at Week 12 was 66%, and the SVR rate among patients who first became HCV RNA negative at Week 24 was 45%. Furthermore, patients who remained HCV RNA positive at Week 24 had only a 2% rate of SVR. Therefore, following these results, investigators began to evaluate the use of longer durations of therapy in slower responders.
  • GT, genotype; PegIFN, peginterferon; RBV, ribavirin; RVR, rapid virologic response; SVR, sustained virologic response. Sanchez-Tapias and colleagues evaluated the rate of SVR following 48 and 72 weeks of peginterferon alfa-2a plus ribavirin therapy among treatment-naive patients. The left-hand side of this slide illustrates the rate of SVR following 48 and 72 weeks of peginterferon alfa-2a plus ribavirin therapy among all patients who failed to achieve RVR. Specifically, 72 weeks of therapy was associated with a higher rate of SVR compared with 48 weeks of therapy (45% vs 32%, respectively). The right-hand side of the slide is dedicated exclusively to genotype 1–infected patients who did not achieve RVR. Among these patients, a higher SVR rate was also achieved in those who received 72 weeks of therapy compared with those who received only 48 weeks of therapy (44% vs 28%, respectively).
  • cEVR, complete early virologic response; GT, genotype; PegIFN, peginterferon; pts, patients; RBV, ribavirin; SVR, sustained virologic response. Berg and colleagues conducted a post hoc analysis to examine the rates of SVR and relapse following 72 vs 48 weeks of peginterferon alfa-2a plus ribavirin therapy among genotype 1–infected patients who did not achieve a complete early virologic response but who became HCV RNA negative by Week 24 (ie, slow responders). The data indicate that the SVR rate was higher among those who received 72 weeks of therapy as opposed to those who received 48 weeks of therapy (29% vs 17%, respectively). This disparity is primarily because of differences in the rates of relapse. The relapse rate was 64% among those who received 48 weeks of therapy compared with only 40% among those who received 72 weeks of therapy. The importance of these data should be emphasized. Clearly, the results of this study demonstrate that patients who are slow responders are more likely to achieve SVR following 72 weeks of treatment as opposed to 48 weeks of treatment. The difference in SVR rates is primarily because of the variation in relapse rates among patients who receive 48 weeks of treatment as opposed to 72 weeks of treatment. It is important for clinicians to remember that treatment of slow responders for only 48 weeks will result in higher relapse rates, and clinicians can provide the best benefit to slow responders by prolonging treatment to 72 weeks.
  • RBV, ribavirin. The guanosine analogue ribavirin is a unique drug that is orally administered. By itself, ribavirin does little to reduce HCV RNA. Ribavirin alone may cause a decline in HCV RNA of 0.5 log 10 IU/mL and improves the levels of alanine aminotransferase and aspartate aminotransferase. However, ribavirin monotherapy does not lead to SVR. The role of ribavirin in a successful outcome is not only because of its antiviral activity but also because of its ability to prevent relapse. These 2 benefits will be addressed shortly. There are several questions that must be asked regarding ribavirin. First of all, how can treatment best be optimized with the use of ribavirin? How important is the initial dose of ribavirin? How can the ribavirin dosage be maintained for the duration of treatment?
  • ETR, end-of-treatment response; pegIFN, peginterferon; RBV, ribavirin; SVR, sustained virologic response. The next study by Fried and colleagues evaluated the use of peginterferon alfa-2a plus ribavirin vs peginterferon alfa-2a monotherapy to treat chronic hepatitis C. The set of bars on the left-hand side of this graph represent the end-of-treatment responses. The end-of-treatment response rate was 59% among the peginterferon alone arm compared with 69% among the peginterferon plus ribavirin arm ( P = .01). Therefore, there was a 10% difference among the 2 treatment arms, which illustrates that ribavirin adds very little to the end-of-treatment response. However, regarding the rates of SVR, there was a large difference among those who received peginterferon alone and those who received combination therapy. Specifically, as illustrated by the bars in the middle of the graph, the SVR rate was 29% among the monotherapy arm and 56% among the combination therapy arm ( P < .001). The difference in SVR is primarily because of a difference in relapse rates. As illustrated by the bars on the right-hand side of the graph, 51% of the monotherapy group experienced relapse after cessation of therapy compared with only 19% of the combination therapy arm. These data illustrate that ribavirin slightly adds to the antiviral activity of peginterferon, as seen by the small difference in the end-of-treatment response. However, a major difference in relapse rates was seen among the monotherapy vs the combination therapy arms.
  • GT, genotype; pegIFN, peginterferon; RBV, ribavirin; SVR, sustained virologic response. This slide addresses the question about the optimal dose of ribavirin among genotype 1 patients. Hadziyannis and colleagues conducted a trial in which patients infected with genotype 1 HCV received 800 mg/day of ribavirin or 1000-1200 mg/day of weight-based ribavirin, both together with peginterferon. The graph illustrates that the SVR rate was higher among those receiving the higher dose of ribavirin. Based on the results of this study, it became standard practice to use a higher dose of ribavirin for genotype 1 patients in order to increase the likelihood of achieving SVR. For more information, go online to: http://clinicaloptions.com/Hepatitis/Journal%20Options/Articles/Hadziyannis-AIM-2004-03/Capsule.aspx
  • GT, genotype; pegIFN, peginterferon; RBV, ribavirin; SVR, sustained virologic response. Snoeck and colleagues conducted a study to determine if the ribavirin dosage should be increased further. Using modeling data, they showed that there is a dose-dependent increase in SVR rates with the use of ribavirin dosages above 10 mg/kg/day. Therefore, higher ribavirin dosages are needed to increase the probability of achieving SVR.
  • pegIFN, peginterferon; RBV, ribavirin. However, increasing the ribavirin dosage is associated with an elevated incidence of severe anemia, defined as hemoglobin < 10 g/dL. At a ribavirin dosage of 15 mg/kg/day of body weight or greater, the incidence of severe anemia is approximately 20%. With ribavirin dosages > 15 mg/kg/day, the incidence of anemia increases exponentially. Therefore, in clinical practice, the ideal dose of ribavirin for genotype 1 patients is no more than 15 mg/kg/day of body weight.
  • GT, genotype; pegIFN, peginterferon; RBV, ribavirin; SVR, sustained virologic response. Now, we will discuss the importance of ribavirin exposure and the impact on SVR. This slide illustrates the results of a retrospective analysis of 569 genotype 1 patients who completed combination therapy with peginterferon alfa-2a plus ribavirin. Cumulative ribavirin exposure was classified according to 1 of 4 categories which included 0% to 60%, > 60% to 80%, > 80% to 97%, and > 97% of the planned dosage. Among patients who received > 97% of their expected dose of ribavirin for 48 weeks, the SVR rate was 67% and the relapse rate was only 19%. On the other hand, among patients who received < 60% of their expected ribavirin dose during the course of treatment, the relapse rate was the highest at 54% and the SVR rate was the lowest at 33%. Clearly, with increasing exposure to ribavirin, there is an increase in the rate of SVR from 33% to 67% and there is a decrease in the rate of relapse from 54% to 19%.
  • pegIFN, peginterferon; RBV, ribavirin; SVR, sustained virologic response. This slide addresses another important practical point concerning the treatment response among patients who receive the full dose of ribavirin for the first 12 weeks of therapy followed by a modified dose during Weeks 13-48 of therapy. The graph illustrates that in this scenario, there is still a decrease in the SVR rate with decreased cumulative ribavirin exposure during the latter portion of therapy. Specifically, the SVR rate declined from 67% among patients who received > 97% of their ribavirin dose to 36% among patients who received < 60% of their ribavirin dose. Therefore, the use of full-dose ribavirin is important not only initially but throughout the duration of treatment. Clinicians should attempt to maintain adequate ribavirin exposure throughout therapy to give patients the best chance of achieving an SVR.
  • Steatosis is a common comorbidity in patients with HCV infection, occurring in 50% to 60% of HCV-infected patients. Younossi and colleagues demonstrated the prevalence of steatosis and nonalcoholic steatohepatitis (NASH) as well as the absence of steatosis among 121 HCV-infected patients with available liver biopsies. Forty one percent of the patients had steatosis, 18% had NASH, and 41% did not have steatosis. In my opinion, these data are quite representative of the HCV-infected population in the United States.
  • Some HCV-infected patients have metabolic syndrome that is defined according to the presence of at least 3 of the following 5 characteristics: an abdominal circumference > 40 inches for men and > 35 inches for women, elevated triglycerides (≥ 150 mg/dL), low levels of high density lipoprotein (< 40 mg/dL in men and < 50 mg/dL in women), hypertension (blood pressure ≥ 130 mm Hg systolic or ≥ 85 mm Hg diastolic), and hyperglycemia (fasting glucose ≥ 100 mg/dL).
  • GT, genotype. There are 2 types of steatosis in patients with hepatitis C. Some HCV-infected patients develop metabolic steatosis as a result of the presence of the metabolic syndrome and insulin resistance. This can occur among patients with obesity or diabetes as well as among patients who abuse alcohol. On the other hand, some HCV-infected patients develop a unique type of viral-related steatosis. This occurs among patients with genotype 3 infection; however, the precise mechanism associated with viral steatosis remains unclear. Interestingly, viral steatosis may disappear following successful hepatitis C therapy. By contrast, metabolic steatosis may have an adverse impact on hepatitis C therapy that results in a suboptimal likelihood of obtaining SVR.
  • HOMA, homeostasis model assessment; QUICKI, quantitative insulin sensitivity check index. In practice, there are several ways to calculate insulin resistance. The homeostasis model assessment (HOMA), which is commonly quoted in the literature, is easily calculated by determining the levels of fasting insulin and fasting glucose. As indicated in the formula, these 2 values are multiplied and then divided by 22.5. HOMA values > 1.8-2.0 are consistent with insulin resistance. The quantitative insulin sensitivity check index is another method of determining insulin resistance. The values for fasting insulin and fasting glucose are multiplied by each other. The log of this product is then divided into 1. Values < 0.35 are consistent with insulin resistance. Lastly, an estimate of insulin resistance can be determined by multiplying the values of fasting insulin by fasting glucose. In this case, values > 700 are typically consistent with insulin resistance.
  • HOMA, homeostasis model assessment; IR, insulin resistance. Insulin resistance is common among nondiabetic, HCV-infected patients. In this study, Moucari and colleagues demonstrated that 35% of HCV-infected patients (n = 240) had insulin resistance whereas only 5% of HBV-infected patients (n = 80) had insulin resistance. Insulin resistance was defined as a HOMA insulin resistance score of > 3.
  • GT, genotype; SVR, sustained virologic response. In addition, the presence of insulin resistance in HCV-infected patients may have an impact on their likelihood of achieving an SVR. For example, Romero‑Gomez and colleagues demonstrated that patients with insulin resistance achieved a lower SVR rate when compared with patients without insulin resistance (33% vs 61%, respectively).
  • BMI, body mass index; GT, genotype; HOMA, homeostasis model assessment; pegIFN, peginterferon; RBV, ribavirin. The next question to be addressed is how to overcome insulin resistance in HCV-infected patients. Intuitively, clinicians may believe that weight loss will help their patients overcome insulin resistance. Preliminary results from Tarantino and colleagues, who evaluated the effects of weight loss on antiviral response in a small study involving 32 treatment-naive, genotype 1 HCV–infected patients with metabolic syndrome, suggested that this is true. Participants were randomized to either a low-calorie diet to reduce their body mass index by 10% before treatment (n = 15) or to the control arm (n = 17). Among the patients who reduced their body mass index by 10% before initiating therapy, there was an improvement in the HOMA scores ( P = .0018) and 60% responded to treatment with peginterferon alfa-2b plus ribavirin. By contrast, among the control patients who did not reduce their body mass index before initiating therapy, only 17% responded to treatment with peginterferon alfa-2b plus ribavirin. Although this is a proof-of-concept study, it is very effective in illustrating that weight loss before treatment is associated with a higher rate of response following peginterferon plus ribavirin therapy. In fact, it suggests that even a weight loss of as little as 10% can improve the likelihood of treatment response. Often the question arises as to the impact of insulin sensitizers on achieving SVR. The role of insulin sensitizers in this regard is still under investigation, and definitive results are awaited.
  • Now, we will identify retreatment options for patients with previous treatment failure.
  • IFN, interferon; pegIFN, peginterferon; RBV, ribavirin; SVR, sustained virologic response. An examination of the aggregated literature reveals that the rate of SVR among previous nonresponders to interferon monotherapy following retreatment with peginterferon plus ribavirin ranges from 25% to 30%. Previous nonresponders to standard interferon plus ribavirin therapy who are later retreated with peginterferon plus ribavirin achieve an overall SVR rate of 10% to 15%. In addition, there is a high relapse rate (> 50%) among those who have an on-treatment virologic response. The highest SVR rate following retreatment with peginterferon plus ribavirin has been illustrated among relapsers to previous standard interferon plus ribavirin therapy. The SVR rate among these patients is 40% to 50%. Therefore, relapsers clearly have the best chance of achieving SVR after retreatment with peginterferon plus ribavirin.
  • EPIC3, Evaluation of Peginterferon alfa-2b in Control of Hepatitis C Cirrhosis; GT, genotype; HALT-C, Hepatitis C Antiviral Long-term Treatment Against Cirrhosis; IFN, interferon; pegIFN, peginterferon; RBV, ribavirin; RENEW, Retreatment of Nonresponders With Escalating Weight-Based Therapy; SVR, sustained virologic response. Several studies have evaluated outcomes in nonresponders to interferon-based therapy. In these studies, patients have been retreated with regimens containing peginterferon alfa-2b plus ribavirin or peginterferon alfa-2a plus ribavirin. The majority of the participants was infected with genotype 1 HCV as these patients are less likely to respond to interferon-based therapy. This table illustrates that the SVR rate following peginterferon plus ribavirin retreatment is approximately 20% among genotype 1 patients who have previously failed interferon monotherapy. However, among patients who failed previous interferon plus ribavirin therapy, the SVR rates following peginterferon alfa plus ribavirin retreatment ranged from 8% to 18%, and up to 37% for those infected with genotype 2/3 HCV. Together, these data suggest that the best SVR rate one can expect to achieve in genotype 1 HCV–infected patients who previously failed interferon-based therapy and who are retreated with peginterferon plus ribavirin is 20%. Therefore, 1 in 5 of these patients will achieve SVR. For more information, go online to: http://clinicaloptions.com/Hepatitis/Conference%20Coverage/San%20Francisco%202005/Tracks/HCV%20Management%20Facing%20New%20Challenges/Capsules/60.aspx For more information, go online to: http://clinicaloptions.com/Hepatitis/Conference%20Coverage/Milan%202008/Tracks/Hepatitis%20C%20Update/Capsules/988.aspx
  • AlbIFN, albumin interferon; CIFN, consensus interferon; DIRECT, Daily-Dose Consensus Interferon and Ribavirin: Efficacy of Combined Therapy; EPIC3, Evaluation of Peginterferon alfa-2b in Control of Hepatitis C Cirrhosis; GT, genotype; IFN, interferon; PegIFN, peginterferon; RBV, ribavirin; REPEAT, Retreatment With Peginterferon alfa-2a in Patients Not Responding to Prior Peginterferon alfa-2b/Ribavirin Combination Therapy; SVR, sustained virologic response. The next table illustrates outcomes among patients who previously failed peginterferon plus ribavirin therapy and were retreated in various separate studies with either peginterferon alfa-2a plus ribavirin, consensus interferon plus ribavirin, albumin interferon plus ribavirin, or peginterferon alfa-2b plus ribavirin. Various doses of these regimens were used. We will discuss the importance of dosages later in the presentation. The result of these 4 studies show that the SVR rates achieved among nonresponders to peginterferon plus ribavirin who were retreated ranged from 5.3% to 16.0%. Therefore, < 1 in 5 nonresponders to peginterferon plus ribavirin will respond to retreatment with various combination therapies. For more information, go online to: http://clinicaloptions.com/Hepatitis/Conference%20Coverage/Boston%202007/Tracks/Approved%20HCV/Capsules/LB4.aspx For more information, go online to: http://clinicaloptions.com/Hepatitis/Conference%20Coverage/Boston%202007/Tracks/Approved%20HCV/Capsules/168.aspx For more information, go online to: http://clinicaloptions.com/Hepatitis/Conference%20Coverage/Boston%202007/Tracks/Investigational%20HCV/Capsules/51.aspx For more information, go online to: http://clinicaloptions.com/Hepatitis/Conference%20Coverage/Milan%202008/Tracks/Hepatitis%20C%20Update/Capsules/988.aspx
  • EPIC3, Evaluation of Peginterferon alfa-2b in Control of Hepatitis C Cirrhosis; GT, genotype; IFN, interferon; PegIFN, peginterferon; RBV, ribavirin; SVR, sustained virologic response. Regarding relapsers, these patients achieve a higher SVR rate following retreatment with peginterferon alfa plus ribavirin. This table illustrates the outcomes among relapsers to previous interferon-based therapy. The SVR rate ranged from 42% to 63% following retreatment with peginterferon alfa plus ribavirin. For more information, go online to: http://clinicaloptions.com/Hepatitis/Conference%20Coverage/San%20Francisco%202005/Tracks/HCV%20Management%20Facing%20New%20Challenges/Capsules/60.aspx
  • CIFN, consensus interferon; EPIC3, Evaluation of Peginterferon alfa-2b in Control of Hepatitis C Cirrhosis; GT, genotype; PegIFN, peginterferon; RBV, ribavirin; SVR, sustained virologic response. The table on this slide illustrates the outcomes following retreatment of relapsers to peginterferon-based therapy. Among these patients, SVR rates of 32% to 69% have been demonstrated following retreatment with consensus interferon plus ribavirin, peginterferon alfa-2a plus ribavirin, or peginterferon alfa-2b plus ribavirin. For more information, go online to: http://clinicaloptions.com/Hepatitis/Conference%20Coverage/San%20Francisco%202005/Tracks/HCV%20Management%20Facing%20New%20Challenges/Capsules/60.aspx
  • CIFN, consensus interferon; DIRECT, Daily-Dose Consensus Interferon and Ribavirin: Efficacy of Combined Therapy; PegIFN, peginterferon; RBV, ribavirin; SVR12, sustained virologic response by Week 12. Now, we will discuss specific trials involving the retreatment of nonresponders. The Daily-Dose Consensus Interferon and Ribavirin: Efficacy of Combined Therapy (DIRECT) trial evaluated the use of consensus interferon dosed at 9 μg/day or 15 μg/day for 48 weeks, along with ribavirin, to retreat previous peginterferon plus ribavirin nonresponders. The results indicated that the SVR rate 12 weeks after treatment end (SVR12) was 5.3% among those who received consensus interferon 9 μg daily and 9.5% among those who received consensus interferon 15 μg daily. Therefore, this study suggests that < 10% of patients with previous nonresponse to peginterferon plus ribavirin are expected to achieve SVR following retreatment with consensus interferon plus ribavirin. For more information, go online to: http://clinicaloptions.com/Hepatitis/Conference%20Coverage/Boston%202007/Tracks/Approved%20HCV/Capsules/168.aspx
  • PegIFN, peginterferon; REPEAT, Retreatment With Peginterferon alfa-2a in Patients Not Responding to Prior Peginterferon alfa-2b/Ribavirin Combination Therapy; RBV, ribavirin. The Retreatment With Peginterferon alfa-2a in Patients Not Responding to Prior Peginterferon alfa-2b/Ribavirin Combination Therapy (REPEAT) trial evaluated the use of peginterferon alfa-2a plus ribavirin therapy in those who previously failed peginterferon alfa-2b plus ribavirin therapy. The first 2 treatment regimens consisted of induction with peginterferon alfa-2a 360 μg/week plus ribavirin for the first 12 weeks. Arm A received a total of 72 weeks of treatment and arm B received 48 weeks of treatment. After Week 12, both arms received standard-dose peginterferon alfa-2a plus ribavirin. Arms C and D received standard-dose peginterferon alfa-2a plus ribavirin for 72 and 48 weeks, respectively. For more information, go online to: http://clinicaloptions.com/Hepatitis/Conference%20Coverage/Boston%202007/Tracks/Approved%20HCV/Capsules/LB4.aspx
  • ITT, intent to treat; REPEAT, Retreatment With Peginterferon alfa-2a in Patients Not Responding to Prior Peginterferon alfa-2b/Ribavirin Combination Therapy; SVR, sustained virologic response. The REPEAT study sought to examine the impact of a high-dose induction regimen and a longer duration of therapy with peginterferon alfa-2a plus ribavirin among peginterferon alfa-2b plus ribavirin nonresponders. The results indicated that regardless of whether patients received the induction regimen or not, 72 weeks of therapy was associated with a higher SVR rate vs 48 weeks of therapy (16% vs 8%, respectively). Therefore, these data demonstrate that a longer duration of therapy is more important than the use of an induction regimen among nonresponders who are retreated with peginterferon alfa-2a plus ribavirin. Again, it is disappointing that < 20% (1 in 6) of previous nonresponders achieved SVR with retreatment. For more information, go online to: http://clinicaloptions.com/Hepatitis/Conference%20Coverage/Boston%202007/Tracks/Approved%20HCV/Capsules/LB4.aspx
  • REPEAT, Retreatment With Peginterferon alfa-2a in Patients Not Responding to Prior Peginterferon alfa-2b/Ribavirin Combination Therapy. However, the REPEAT data did illustrate that patients who achieve HCV RNA < 50 IU/mL by Week 12 are more likely to achieve SVR. The graph on the right-hand side of this slide shows that among the 17% of patients who cleared the virus by Week 12, the SVR rate ranged from 53% to 68% after 72 weeks of therapy, regardless of whether the patients received induction therapy or not. Clinicians can use this information to better manage their patients who are initially nonresponsive to peginterferon plus ribavirin. If a patient initiates retreatment and achieves HCV RNA < 50 IU/mL by Week 12, the duration of therapy can be extended to 72 weeks. On the other hand, if the patient does not achieve HCV RNA < 50 IU/mL by Week 12, this patient is unlikely to achieve SVR. For example, as noted with the graph on the left-hand side of the slide, the SVR rates among patients who did not clear the virus ranged from 2% to 6%. Obviously, this low rate is undesirable in our patients. For more information, go online to: http://clinicaloptions.com/Hepatitis/Conference%20Coverage/Boston%202007/Tracks/Approved%20HCV/Capsules/LB4.aspx
  • EPIC3, Evaluation of Peginterferon alfa-2b in Control of Hepatitis C Cirrhosis; IFN, interferon; PegIFN, peginterferon; RBV, ribavirin; SVR, sustained virologic response. The next slide illustrates the SVR rates achieved according to previous treatment regimens and response in the EPIC3 study. In this study, previous nonresponders and relapsers were retreated with peginterferon alfa-2b plus weight-based ribavirin. Overall, 22% of the participants achieved SVR. However, only 14% of previous nonresponders achieved SVR compared with 38% of previous relapsers. Again, these results indicate that previous relapsers are more likely to respond to retreatment. The data were also analyzed according to the previous regimens. There were no major differences in response among patients who received either peginterferon alfa-2b plus ribavirin or peginterferon alfa-2a plus ribavirin as their initial regimen. The SVR rates among previous nonresponders to peginterferon alfa-2b plus ribavirin and peginterferon alfa-2a plus were 7% and 6%, respectively. However, the SVR rates among previous relapsers to peginterferon alfa-2b plus ribavirin and peginterferon alfa-2a plus were 32% and 34%, respectively. The best benefit to retreatment was observed in patients with previous nonresponse or relapse to standard interferon plus ribavirin therapy. Specifically, 18% of those with nonresponse to standard interferon plus ribavirin therapy achieved SVR, and 43% of those with previous relapse to standard interferon plus ribavirin therapy achieved SVR on retreatment. For more information, go online to: http://clinicaloptions.com/Hepatitis/Conference%20Coverage/Milan%202008/Tracks/Hepatitis%20C%20Update/Capsules/988.aspx
  • EPIC3, Evaluation of Peginterferon alfa-2b in Control of Hepatitis C Cirrhosis; GT, genotype; IFN, interferon; OR, odds ratio; pegIFN, peginterferon; RBV, ribavirin; SVR, sustained virologic response. Certain predictors of SVR were identified in the Evaluation of Peginterferon alfa-2b in Control of Hepatitis C Cirrhosis (EPIC3) trial. Not surprisingly, patients infected with genotype 2 or 3 HCV had a higher SVR rate when compared with patients infected with genotype 1 HCV. Patients with minimum fibrosis were also more likely to achieve SVR. For example, the odds ratio among patients with stageF2 vs F4 fibrosis was 2.2 ( P < .0001) and the odds ratio among patients with stage F3 vs F4 fibrosis with 1.4 ( P = .0183). Therefore, patients with stage F2 or F3 fibrosis responded better than those with stage F4 fibrosis. Patients with lower baseline HCV RNA levels also were more likely to achieve SVR. Patients who failed previous treatment with standard interferon plus ribavirin had higher SVR rates than those who failed previous treatment with peginterferon plus ribavirin. Lastly, patients classified as previous relapsers were more likely to respond to retreatment than those classified as previous nonresponders. For more information, go online to: http://clinicaloptions.com/Hepatitis/Conference%20Coverage/Milan%202008/Tracks/Hepatitis%20C%20Update/Capsules/988.aspx
  • Now, we will discuss the role of maintenance therapy. Often the question arises as to the benefit of maintenance therapy in patients who previously failed peginterferon plus ribavirin therapy. The results of 2 studies illustrate that maintenance therapy is not an effective strategy for preventing progression of fibrosis.
  • COPILOT, Colchicine vs Peginterferon alfa-2b Long-term; CTP, Child-Turcotte-Pugh; HCC, hepatocellular carcinoma; HTN, hypertension; ITT, intent to treat; OLT, orthotopic liver transplantation; PegIFN, peginterferon. The Colchicine vs Peginterferon alfa-2b Long-term (COPILOT) study evaluated the impact of maintenance therapy on several endpoints. In this study, patients received either peginterferon alfa-2b 0.5 µg/kg/week maintenance therapy or the control drug colchicine. Colchicine produces no antiviral affect but may act as an antifibrotic agent. Regarding the number of deaths, there were no differences between the 2 groups—4 patients in the peginterferon alfa-2b arm and 4 patients in the colchicine arm died. Likewise, there were no differences between the 2 arms regarding the number of liver transplantations. One patient in each arm required a liver transplantation. Interestingly, there was a higher incidence of hepatocellular carcinoma among the peginterferon alfa-2b group compared to the colchicine group, which was diagnosed in 22 vs 13 patients, respectively. Changes in the Child-Turcottte-Pugh score were also similar among the 2 groups. In total, 27 patients in the colchicine arm and 23 patients in the peginterferon alfa-2b arm had a Child-Turcottte-Pugh score > 2. One important point illustrated in this study is that variceal bleeding events were more common in the control group vs the peginterferon alfa-2b group. Moreover, portal hypertension events were less common in the peginterferon alfa-2b group vs the colchicine group (23% vs 32%, respectively). It should be noted that portal hypertension was not an initial endpoint and a post hoc analysis was conducted. Therefore, one should be careful in interpreting the data and translating it into clinical practice. Overall, there were no differences in the primary endpoints between the peginterferon alfa-2b maintenance group and the colchicine control group. For more information, go online to: http://clinicaloptions.com/Hepatitis/Conference%20Coverage/Milan%202008/Tracks/Hepatitis%20C%20Update/Capsules/3.aspx
  • HALT-C, Hepatitis C Antiviral Long-term Treatment Against Cirrhosis; PegIFN, peginterferon; RBV, ribavirin. Now, we will examine the results of another maintenance study called the Hepatitis C Antiviral Long-term Treatment Against Cirrhosis (HALT-C) trial. In this study, patients with advanced fibrosis and cirrhosis and previous nonresponse to peginterferon plus ribavirin underwent a lead-in treatment phase consisting of peginterferon alfa-2a plus ribavirin. Those patients who achieved viral clearance on treatment were then treated for 48 weeks. On the other hand, those who did not achieve a response to peginterferon alfa-2 plus ribavirin were randomized to receive either peginterferon alfa-2a 90 µg/week for 3.5 years or no treatment. For more information, go online to: http://clinicaloptions.com/Hepatitis/Conference%20Coverage/Boston%202007/Tracks/Approved%20HCV/Capsules/LB1.aspx
  • CI, confidence interval; HALT-C, Hepatitis C Antiviral Long-term Treatment Against Cirrhosis; HCC, hepatocellular carcinoma; HR, hazard ratio; NS, nonsignificant; PegIFN, peginterferon. Di Bisceglie and colleagues presented the results of the HALT-C study at the 2007 Annual Meeting of the American Association for the Study of Liver Diseases. This slide illustrates that there were no differences in the rates of mortality, decompensation, hepatocellular carcinoma, or fibrosis between the peginterferon alfa-2a maintenance group and the control group. These results were understandably very disappointing as it was hoped that maintenance therapy might provide a benefit to nonresponsive patients. Unfortunately, the HALT-C study demonstrated that maintenance therapy over 3.5 years provides no benefit in decreasing certain clinical events that are relevant to our patients. For more information, go online to: http://clinicaloptions.com/Hepatitis/Conference%20Coverage/Boston%202007/Tracks/Approved%20HCV/Capsules/LB1.aspx
  • HALT-C, Hepatitis C Antiviral Long-term Treatment Against Cirrhosis. The next slide illustrates the impact of viral suppression on outcomes in the HALT-C trial. The left-hand side of the slide demonstrates the impact of viral suppression during the lead-in phase on the achievement of viral suppression during the maintenance phase. The right-hand side of the slide shows that there was no significant difference in clinical events among patients who achieved a decline in HCV RNA of > 4 log 10 IU/mL during the maintenance phase vs those who had a decline in HCV RNA of < 1 log 10 IU/mL during the maintenance phase. Similarly, the rate of fibrosis progression was no different regardless of the magnitude of viral suppression during the maintenance phase. Therefore, viral suppression during the maintenance phase of this study was associated with no benefit in clinical outcomes or fibrosis progression. For more information, go online to: http://clinicaloptions.com/Hepatitis/Conference%20Coverage/Milan%202008/Tracks/Hepatitis%20C%20Update/Capsules/144.aspx
  • Now, we will discuss studies concerning future options for retreatment.
  • AlbIFN, albinterferon; IFN, interferon; RBV, ribavirin. One study by Nelson and colleagues evaluated the use of albinterferon alfa-2b plus ribavirin in previous nonresponders. Patients were randomized to 1 of 5 different regimens. In 4 of the treatment arms, albinterferon alfa-2b was administered as doses ranging from 900 µg every 2 weeks to 1800 µg every 2 weeks. One arm, as indicated at the top of the schematic, received albinterferon alfa-2b 1200 µg every 4 weeks. All of the treatment arms received ribavirin 1000-1200 mg/day. The study included 115 participants who had previously failed to achieve SVR following interferon-based regimens. Albinterferon alfa-2b plus ribavirin was administered for a total of 48 weeks followed by 24 weeks of follow-up. For more information, go online to: http://clinicaloptions.com/Hepatitis/Conference%20Coverage/Boston%202007/Tracks/Investigational%20HCV/Capsules/51.aspx
  • AlbIFN, albumin interferon; GT, genotype; IFN, interferon; PegIFN, peginterferon; RBV, ribavirin; SVR, sustained virologic response. The rate of SVR among all patients ranged from 9% to 30%. However, among genotype 1 patients, the rate of SVR ranged from 6% to 15%. Therefore, no more than 15% of peginterferon alfa plus ribavirin nonresponders with genotype 1 HCV achieved SVR following retreatment with albinterferon alfa-2b plus ribavirin. For more information, go online to: http://clinicaloptions.com/Hepatitis/Conference%20Coverage/Boston%202007/Tracks/Investigational%20HCV/Capsules/51.aspx
  • GT, genotype; IFN, interferon; PegIFN, peginterferon; RBV, ribavirin; SVR, sustained virologic response. The next slide illustrates the results of a study using a new molecule to retreat previous nonresponders. Schiff and colleagues conducted a phase II study using the protease inhibitor boceprevir. This study included difficult-to-treat, HCV-infected patients who failed previous peginterferon alfa plus ribavirin therapy. Genotype 1 patients with detectable HCV RNA or a < 2 log 10 decline in HCV RNA at ≥ 12 weeks of previous peginterferon alfa plus ribavirin therapy were administered peginterferon alfa-2b plus ribavirin or boceprevir plus peginterferon alfa-2b plus ribavirin. The doses of boceprevir ranged from 100-800 mg 3 times daily. The SVR rates among the boceprevir-treated patients were only 7% to 14%, which is lower than one might have hoped. For more information, go online to: http://clinicaloptions.com/Hepatitis/Conference%20Coverage/Milan%202008/Tracks/Investigational%20HCV/Capsules/104.aspx
  • PegIFN, peginterferon; RBV, ribavirin; RVR, rapid virologic response. On the other hand, some impressive data have been presented on the use of another protease inhibitor, telaprevir, in combination with peginterferon alfa-2a plus ribavirin. This open-label study by Poordad and colleagues included previous nonresponders or relapsers from the PROVE 1-3 trials. These patients had received peginterferon alfa-2 plus ribavirin and were rolled over into triple therapy consisting of telaprevir plus peginterferon alfa-2 plus ribavirin. The bar graph on this slide illustrates the rate of undetectable HCV RNA (< 10 IU/mL) at Weeks 4, 8, or 12 of triple therapy among various categories of prior nonresponders. A Week 4 nonresponder was defined as a patient who previously achieved an HCV RNA decline of < 1 log 10 IU/mL at Week 4. A Week 12 nonresponder was defined as a patient who previously achieved a HCV RNA decline of < 2 log 10 IU/mL at Week 12. A partial responder was defined as a patient who previously had a HCV RNA decline of ≥ 2 log 10 IU/mL at Week 12 but who remained detectable at Week 24. Among the Week 4 nonresponders to previous therapy, the rate of RVR following the addition of telaprevir was 33%. Moreover, 67% of the Week 4 nonresponders to previous therapy achieved viral clearance by Week 8 and 89% by Week 12. Among the Week 12 nonresponders to previous therapy, 50% achieved RVR, and all of the patients achieved viral clearance by Weeks 8 and 12. Among the partial responders to previous therapy, 79% achieved viral negativity by Week 4 of triple therapy, and 100% of these patients had undetectable HCV RNA by Weeks 8 and 12. As expected, the previous relapsers demonstrated the best response to triple therapy with telaprevir. Eighty percent of previous relapsers achieved RVR, and all of these patients had undetectable HCV RNA by Weeks 8 and 12. These data are impressive considering that the study included a population of difficult-to-treat nonresponders to peginterferon alfa-2a plus ribavirin. Remarkably, a good response was achieved with the use of triple therapy including telaprevir plus peginterferon alfa-2a plus ribavirin. Of course, it remains to be seen whether the initial impressive response rates will translate into high SVR rates. For more information, go online to: http://clinicaloptions.com/Hepatitis/Conference%20Coverage/Milan%202008/Tracks/Investigational%20HCV/Capsules/1000.aspx
  • In conclusion, there are several principles to consider during retreatment.
  • IFN, interferon; pegIFN, peginterferon; RBV, ribavirin. Relapsers are the best candidates for retreatment. Studies indicate that these patients have a better chance of response following retreatment compared with nonresponders. Even among nonresponders, there are categories of patients who are likely to achieve good response rates with retreatment. For example, nonresponders who failed standard interferon monotherapy are likely to achieve a reasonably high SVR rate. I recognize that many clinicians no longer see patients who have previously failed standard interferon monotherapy. However, these patients should be considered for retreatment with peginterferon plus ribavirin as there is a reasonable expectation that they will achieve SVR. Clearly, those who have failed therapy with peginterferon plus ribavirin are less likely to achieve SVR following retreatment with peginterferon plus ribavirin. Negative predictors of response include advanced fibrosis and insulin resistance. Patients with negative predictors of response may not be good candidates for retreatment unless a strategy is developed to address these poor predictors before initiating therapy. Maintenance therapy has not been shown to be effective for reducing fibrosis progression or other disease outcomes such as the development of liver cancer or the evolution of hepatic decompensation. However, new compounds offer promise even in the setting of nonresponse. This has been demonstrated with the use of telaprevir plus peginterferon alfa plus ribavirin.
  • GT, genotype. In summary, there are several questions that should be considered before initiating retreatment. First of all, clinicians must determine what the patient was treated with, at what dosage, and for how long. For slow responders, 48 weeks of therapy is not adequate and 72 weeks of therapy is needed. Patients with slow response who receive only 48 weeks of therapy are more likely to relapse. Therefore, clinicians must also determine what kind of response a patient previously had. A rapid virologic responder may have relapsed not because of a shortened duration of therapy but because of a compromise in the dosage of ribavirin. It is important also to consider genotype. Genotype 2/3 nonresponders or relapsers are more likely to achieve SVR with retreatment than individuals infected with genotype 1 or 4 HCV. Dose reductions and treatment interruptions can also play a role in nonresponse. Adverse effects, such as depression, can lead to treatment interruptions. Therefore, before retreating patients who have previously experienced dose reductions and treatment interruptions, it is important to address those factors or adverse events that initially caused the patient to undergo a reduction in dosage or an interruption in therapy. For example, if the development of anemia caused a patient to receive a reduced dose of ribavirin during initial treatment, the clinician should be sure that the patient is receiving growth factors before undergoing retreatment so as to prevent the likelihood of needing another ribavirin dose reduction. Similarly, if the development of depression led to treatment interruptions during initial treatment, the clinician should be sure that the patient is treated with an antidepressant before undergoing retreatment. Another question to consider before retreatment is whether the patient experienced any adherence issues during initial therapy. It also is conceivable that the patient previously received an inadequate dose of ribavirin. For genotype 1 patients, the ideal ribavirin dosage should be 15 mg/kg/day of body weight. Therefore, a 100-kg patient may require a higher dose of ribavirin at 1500 mg to prevent relapse from occurring. Lastly, it is important for clinicians to consider whether the patient had a good support system during previous therapy. The lack of a support system can lead to dose reductions and treatment interruptions. All of these will compromise the likelihood of SVR.

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