The decision to treat hepatitis C virus. Managing Hepatitis C REPORTS. Bruce R. Bacon, MD

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1 Bruce R. Bacon, MD Abstract Availability of a drug regimen that eradicates the hepatitis C virus (HCV) in more than half of treated patients provides the medical community with a powerful new weapon to diminish the anticipated future wave of HCV-related liver disease and cancer. Clinicians must understand the benefits, risks, and costs associated with the combination of peginterferon alfa and ribavirin. Major clinical trials with this new standard of HCV therapy have demonstrated sustained virologic responses of 54% and 56% with 48 weeks of combination therapy. Response is highest in those with genotype 2/3, with early virologic response by week 12, in patients with high adherence, and in patients receiving weight-appropriate ribavirin dosages. The most common side effects are manageable and include fatigue, headache, myalgia, rigors, fever, nausea, insomnia, and depression. Neutropenia associated with interferon and anemia associated with ribavirin are more serious side effects that can cause discontinuation or dose reduction. Clinicians can maximize results and reduce costs with a regimen of peginterferon alfa plus ribavirin by choosing patients carefully, educating patients thoroughly, stopping therapy early in those patients who do not respond by week 12 of therapy, and enhancing adherence by managing side effects with appropriate dose reductions and/or selective use of antidepressants or hematopoietic colony stimulators. (Am J Manag Care. 24;1:S3-S4). The decision to treat hepatitis C virus (HCV) infection can be complex and controversial. Some clinicians advocate treatment of practically all individuals who harbor the virus while others favor a more selective approach to treatment. In most cases, patients and clinicians weigh a variety of factors in deciding about therapy, including the severity of disease as indicated by liver fibrosis on biopsy and the presence of comorbid conditions. Patients with HCV genotypes 2 and 3 are also more likely to receive aggressive early drug therapy. The potential for drug side effects and the likelihood of therapeutic adherence to a course of therapy that may last 6 to 12 months are also factors. On an institutional or societal level, the cost effectiveness of HCV therapy versus preventive therapies for other costly long-term illnesses must also be considered in establishing guidelines and setting formulary policies. Helping patients sort through the pros and cons of HCV therapy requires an experienced staff capable of delivering consistent and accurate information in a thoughtful and supportive manner. Many patients still believe that HCV is completely untreatable, practically a death sentence, or they fear undergoing the liver biopsy. On the other hand, increasing numbers of patients have educated themselves about the new treatment options and insist on early therapy. Even some patients with mild levels of fibrosis on biopsy are now demanding treatment either to eradicate the long-term risk and worry or to improve perceived symptoms of fatigue or depression. The counseling provided to today s patients, and the treatment decisions based on that counsel, will shape the course of HCV outcomes for years to come. As outlined in this special supplement s accompanying article, the morbidity and mortality due to HCV cirrhosis and hepatocellular carcinoma (HCC) are expected to double or triple over the next 2 decades as a result of the coming wave of patients with mature HCV infections (ie, infections acquired between 196 and 1989). 1,2 The recent availability of an anti-hcv combination regimen that eradicates the virus in more than half of treated patients provides the medical community with a powerful new weapon to diminish the inevitable future wave of serious liver disease and cancer. The combi- S3 THE AMERICAN JOURNAL OF MANAGED CARE MARCH 24

2 nation of peginterferon alfa and ribavirin is certainly not free of risks or costs. However, the higher efficacy of this combination regimen has led to an expansion of thinking about who should be treated. In particular, older patients and those with compensated cirrhosis groups formerly considered as uncertain candidates for therapy are increasingly seen as treatable patients. 3 Clearly, decisions about treating longterm HCV infection have grown more complex in recent years. Clinicians, pharmacists, and institutions need to balance the risks and costs of the new standards of therapy against the potential benefits to determine the best course of action for individual patients as well as for defined populations. This article will provide background on the goals, efficacy, safety, dosing, and practical prescribing concerns related to combination anti-hcv therapy. The New Standard of Therapy: Pegylated Interferon Alfa Plus Ribavirin The ideal therapy for long-term HCV infection should be highly effective, orally bioavailable, suitable for a majority of patients, safe with few side effects, inexpensive, and cost effective. Although the ideal HCV therapy does not exist, researchers have made noteworthy incremental advances since interferon alfa was approved more than 1 years ago. When first introduced, the recombinant forms of interferon alfa, a natural host protein with antiviral activities, were found to produce sustained virologic response (SVR) rates of approximately 6% and 16% when administered for 24 and 48 weeks, respectively. Pegylation of the molecule, which involves attachment of polyethylene glycol to the native protein (in this case, interferon) to prolong the half-life and improve HCV inhibition, boosted the interferon monotherapy SVR rates to approximately 25% to 39%. 4,5 The addition of ribavirin, an oral agent with multiple nonspecific antiviral actions, 6 to interferon therapy was found to boost SVR rates to about 34% and 41% at 24 and 48 weeks, respectively. In the most recent studies of pegylated interferon alfa and ribavirin, as detailed later in this article, SVR rates have been in the range of 54% to 61%. This decade-long trend of incremental gains in efficacy is similar even in the hard-to-treat population with HCV genotype 1, though the actual SVRs are consistently lower: 9% for interferon monotherapy at 48 weeks, 29% for interferon alfa plus ribavirin at 48 weeks, and 42% to 48% for pegylated interferon plus ribavirin. Thus, since the publication of the 1997 National Institutes of Health (NIH) consensus recommendations on HCV treatment, there have been dramatic improvements in HCV therapy options. Overall, combination therapy with recombinant interferon alfa plus ribavirin offers a 2- to 3-fold improvement over interferon monotherapy, and the use of pegylated interferon alfa boosts the SVR further. Based on these recent findings, the 22 NIH consensus committee recently recommended pegylated interferon alfa plus ribavirin as the standard of care for HCV infections. 7,8 The 2 forms of peginterferon available in the United States are peginterferon alfa-2b (Pegintron; Schering-Plough Corporation, Kenilworth, NJ) and peginterferon alfa-2a (Pegasys, Hoffmann-La Roche, Nutley, NJ). Ribavirin is available as Rebetol or Copegus from the same manufacturers, respectively. The main aim of anti-hcv therapy is to prevent progressive liver disease by eradicating the virus. The immediate goal of therapy is SVR, an easily measured and clinically relevant outcome that is defined as an HCV-ribonucleic acid (RNA) negative status 6 months after completing treatment. In successful treatment, antiviral therapy quickly lowers RNA in the blood to nondetectable levels where it remains for the duration of therapy and thereafter. More than 98% of patients with SVR are, in fact, considered to be clinically and histologically cured. 9 Directly related to this durable reduction of HCV-RNA titer, the other goals of drug therapy for HCV include reduction of hepatic inflammation and necrosis, reduction of liver enzymes, and overall slowing of cirrhotic disease progression. Combination therapy has even been associated with reversal of liver fibrosis in patients with METAVIR F4 (Figure 1). 1 Although sustained improvements in liver chemistry and histology have been associated with SVRs, the durability and long-term VOL. 1, NO. 2, SUP. THE AMERICAN JOURNAL OF MANAGED CARE S31

3 Figure 1. Reversal of Cirrhosis Observed in 75 (49%) Patients N = 31 paired biopsies 16 METAVIR Score 14 F 12 F1 1 F F3 6 F First Second # of Prognostic Factor Patients Source: Reference 1. clinical implications of these short-term benefits of anti-hcv therapy still require verification in large clinical trials. The evidence on long-term outcomes with interferon-based therapy is mixed and is based mostly on studies with methodologic limitations (eg, variable lengths of follow-up, different doses and durations of therapy, lack of control for alcohol consumption, etc). 11 Still, based on the best interpretation of the existing evidence, the longerterm benefits of successful therapy are presumed to include prolonged survival, prevention of cirrhosis and end-stage liver disease, reduction in rates of HCC, and reduced need for orthotopic liver transplant. Anecdotal evidence also suggests improvements in health-related quality of life in Figure 2. Common Side Effects with Pegylated Interferon Plus Ribavirin Fatigue Headache Myalgia Rigors Fever Nausea Insomnia Alopecia Arthralgia Irritability Depression Anorexia or pruritus Sources: References 19, Percentage Manns et al Fried et al patients with SVRs, although these positive reports will also require objective analysis and validation. Thus, clinicians and pharmacists need to be aware that the vast majority of clinical trials involving interferon and ribavirin have employed the surrogate outcomes of SVR and liver biopsy to define success; although reductions in HCV-related morbidity and mortality are very likely related to these short-term virological and histological responses, randomized clinical trials are needed to verify this assumption. 12 Based on various sets of assumptions that peginterferon alfa plus ribavirin will prevent cirrhosis, decrease mortality, prevent HCC, reduce the need for liver transplantation, and/or improve the quality of life, several studies have now estimated that this combination regimen is as cost-effective as other well-accepted clinical interventions Although the conclusions of these studies are very sensitive to the assumptions made and the populations defined, they illustrate how the sizable investment in therapy for patients with long-term HCV (eg, $24 - $3 per year per patient for drug costs alone 17 ) may be justifiable based on benefits that can be quantified in terms of prolonged survival, reduced hospitalizations, or improved quality of life. The predominant side effects of combination antiviral therapy for HCV are fatigue, influenza-like symptoms (headaches, fever, myalgia), hematologic abnormalities, and neuropsychiatric symptoms. 18 The incidences of side effects reported in the major registration trials for the 2 peginterferon alfa products are shown in Figure 2. 19,2 Each randomized controlled trial included more than 1 patients and compared pegylated interferon alfa with standard interferon alfa in combination therapy. Note that the criteria for detecting and recording side effects in these 2 trials were different and so results should not be used for a head-to-head comparison. In general, the safety profiles of the pegylated interferons are similar to those of the standard interferons, although the frequencies of specific adverse events may vary (eg, neutropenia being more common in those receiving peginterferon alfa 18 ). The main side effect of ribavirin as part of HCV combination therapy is dose-dependent S32 THE AMERICAN JOURNAL OF MANAGED CARE MARCH 24

4 reversible intravascular hemolytic anemia. Specific strategies for managing the most common side effects and maximizing adherence are discussed later. While most side effects can be managed symptomatically, some patients receiving interferon alfa plus ribavirin combination therapy will require discontinuation or dose reduction because of their adverse effects. Overall, about 1% to 14% of participants in the registration trials for combination therapy involving the peginterferons withdrew prematurely from therapy due to adverse events. 7,18 The overall discontinuation rates and the incidences of dose reductions for the most common specific reasons (eg, neutropenia and anemia) are shown in Figure 3. 19,2 Again, the varying criteria used in these trials preclude any direct comparisons of the interferon alfa products. The Decision to Treat All patients with long-term hepatitis C are potential candidates for antiviral therapy. 7 As described in the most recent consensus guidelines from the NIH, treatment is recommended for patients with an increased risk of developing cirrhosis (Table 1). The risks and benefits of anti-hcv therapy must be determined for each patient based on the individual s disease stage, symptoms, comorbid conditions, risk factors, and the likelihood of adherence and side effects. Treatment decisions are still controversial in several types of patients, especially those with normal alanine aminotransferase (ALT) levels, 21 mild liver disease (eg, persistent ALT elevations but no fibrosis and minimal necroinflammatory changes), acute HCV infection, and in children, elderly individuals, and those who are active injection drug users or heavy alcohol users. 7 In fact, current combination regimens have yet to be fully tested in many populations, often because of safety or socioeconomic issues (Table 2). Several patient factors predict a favorable response to combination therapy (Table 3). 19,22,23 Although treatment should never be restricted only to those patients most likely to respond, these pretreatment factors must be considered in the overall assessment of risks and benefits of combination Figure 3. Discontinuations and Dose Reductions with Pegylated Interferon Plus Ribavirin Discontinuation of Therapy Dose Reductions (adverse events) Dose Reductions (neutropenia) Dose Reductions (anemia) Dose Reductions (low platelets) Sources: References 19, Percentage therapy for individual patients. The strongest predictors of response are infection with genotype 2 or 3, a viral RNA load <2 million copies per milliliter, and a minimal stage of fibrosis on liver biopsy. Patients under 4 years of age respond better than older patients and females do better than males. Bodyweight is another important predictor of SVR. Increasingly, studies are also showing that steatosis, the presence of fat in the liver, also worsens the response to treatment. As discussed later, an early virologic response and close adherence to therapy are key patient factors emerging during therapy that also predict favorable response. Table 1. Which Patients with Hepatitis C Should Be Treated? Manns et al Fried et al Treat patients with an increased risk of developing cirrhosis as indicated by all of the following: Detectable HCV RNA levels higher than 5 IU/mL Liver biopsy with portal or bridging fibrosis At least moderate inflammation and necrosis Note that the majority of these patients also have persistently elevated ALT values. Risks and benefits must be weighed on an individual basis. Source: National Institutes of Health 22 Consensus Statement. Management of Hepatitis C: 22. Available at: Consensus.nih.gov/ cons/116/116cdc_intro.htm. Accessed February 19, 24. HCV RNA indicates hepatitis C virus ribonucleic acid; ALT, alanine transaminase. VOL. 1, NO. 2, SUP. THE AMERICAN JOURNAL OF MANAGED CARE S33

5 Table 2. Special Patient Populations: Where Evidence Supporting HCV Treatment Is Still Needed Limited Data Children Elderly Normal ALT Hemophilia/thalassemia HIV coinfection Complex medical and socioeconomic issues Uninsured patients Patients on public assistance Incarcerated Institutionalized Safety Issues: Contraindicated Pregnancy Safety Issues: Unclear Methadone maintenance Drug user in recovery Active alcohol use/abuse Transplantation Decompensated cirrhosis Renal disease Neuropsychiatric illness Autoimmune disease Chronic anemia/neutropenia Source: Adapted with permission from Lindsay KL. Hepatology. 22;36:S114-S12. HCV indicates hepatitis C virus; ALT, alanine transaminase; HIV, human immunodeficiency virus. Table 3. Favorable Predictors of Response Genotype 2/3 Absence of fibrosis Low viral load Younger age Female Low weight (BMI or BSA) Lack of steatosis Sources: References 19, 22, 23. BMI indicates body mass index; BSA, body surface area. The results of the liver biopsy play a pivotal role in treatment decisions. Before initiating therapy, the biopsy provides unique insight into the individual s natural history and the likelihood of response. Contributing factors such as steatosis and alcoholic liver disease can also be evaluated. During therapy, information from the biopsy can help clinicians balance the likelihood of response against the presence of side effects. Thus, while not all patients require a liver biopsy before embarking on a long treatment course for HCV infection (eg, some patients may be extremely fearful of biopsy, others may have a contraindication such as a coagulopathy), it is generally advisable as part of the patient s informed consent process. 7 Randomized Clinical Trials with Peginterferon Plus Ribavirin Several randomized clinical trials have now established the efficacy and safety of peginterferon alfa plus ribavirin in treating HCV infection. 7 One recent review of the available clinical studies found that combination regimens employing pegylated interferons were especially beneficial in treating patients with the more common and harderto-eradicate genotype 1 HCV infections, where the overall SVR was 42% versus 33% for those receiving combinations using standard interferons. 12 Two large studies in particular have influenced the NIH to recommend the combination of pegylated interferon alfa plus ribavirin for patients with long-term HCV infection. 19,2 Because these trials helped define the most up-todate treatment standard, their findings are summarized here. In general, these pivotal clinical trials proved that pegylated interferon alfa plus ribavirin was more effective than standard interferon-ribavirin combination or peginterferon alone. In the trial of interferon alfa- 2b, 153 patients with HCV infection were assigned to (1) interferon alfa-2b (3 million units subcutaneously 3 times/week) plus ribavirin (1-12 mg/day), or (2) peginterferon alfa-2b (1.5 µg/kg/week) plus ribavirin (8 mg/day), or (3) peginterferon alfa-2b (1.5 µg/kg/week for 4 weeks then.5 µg/kg/week) plus ribavirin (1-12 mg/day) for 48 weeks. 19 The SVR was signif- S34 THE AMERICAN JOURNAL OF MANAGED CARE MARCH 24

6 icantly higher in the high-dose peginterferon group (274/511, 54%) than in the standard interferon group (235/55, 47%) (P =.1) (Figure 4). The SVR was also increased by 9% in those patients with genotype 1 receiving the pegylated interferon (P =.1). By contrast, among patients with genotypes 2/3, the SVRs were similar (82% and 79% in the pegylated and nonpegylated interferon groups, respectively). Secondary analysis showed that weight-based dosing of ribavirin would have enhanced the overall SVR to 61%. Adherent patients had the highest SVRs. The side effects (see Figure 2) consisted mainly of neutropenia, fever/nausea, and injection-site reactions and were generally manageable. Similarly, in the trial of pegylated interferon alfa-2a, 1121 patients received (1) 18 µg peginterferon alfa-2a once weekly plus daily ribavirin (1 or 12 depending on body weight), (2) 18 µg peginterferon alfa- 2a once weekly plus daily placebo, or (3) interferon alfa-2b (3 million units 3 times/week) plus ribavirin weight-based dosing for 48 weeks. 2 Significantly more patients receiving the peginterferon combination achieved SVR versus patients receiving the standard interferon combination (Figure 5). As in the other trial just described, the SVR was also significantly increased in those patients with genotype 1. The SVRs for genotypes 2 and 3 were 76% and 61% in the pegylated and nonpegylated interferon groups, respectively. The results of these large trials have major implications for clinicians. They show that anti-hcv drug treatment is now effective in more than half of all patients and in at least 8% of those patients with genotype 2 or 3. These results mean that practically all patients with long-term HCV infections should be considered candidates for combination therapy. Which combination? At this point, the choice between the pegylated interferon alfa-2a and -2b products is not clear. No head-to-head studies have been completed, and comparing results from the major studies just reviewed would be dangerous since the designs, dosing, and study populations were so different. One of the major differences in study methodologies was the use of Figure 4. Pegylated Interferon alfa-2b (Peg) Plus Ribavirin: Comparison with Standard Interferon (IFN) Plus Ribavirin % Sustained Virologic Response % Source: Reference % IFN/Ribavirin 54% 42% Peg/Ribavirin weight-based dosing for pegylated interferon alfa-2b and fixed dosing for pegylated interferon alfa-2a. The patient populations in these trials also had differences in viral-load characteristics and genotype distributions, the prevalence of fibrosis, and the number of European versus non-european patients. In terms of safety evaluations, as mentioned previously, the criteria for dose reductions and discontinuations were also quite different in these trials. However, until the results of an ongoing trial directly comparing different regimens of peginterferon alfa-2b plus ribavirin versus peginterferon alfa-2a plus ribavirin are published, either peginterferon is considered appropriate. There is a study All genotypes Genotype 1 Figure 5. Pegylated Interferon alfa-2a (Peg) Plus Ribavirin: Comparison with Standard Interferon (IFN) Plus Ribavirin % Sustained Virologic Response % IFN/Ribavirin Source: Reference 2. 37% 56% Peg/Ribavirin 46% All genotypes Genotype 1 VOL. 1, NO. 2, SUP. THE AMERICAN JOURNAL OF MANAGED CARE S35

7 Figure 6. Combination Therapy in Patients with HCV Genotypes 2 and 3: 24 Weeks versus 48 Weeks due to start soon that will have pegylated interferon alfa-2b and ribavirin compared to pegylated interferon alfa-2a and ribavirin. This study will enroll approximately 3 US genotype-1 patients from about 1 sites. Another prospective study has recently shed light on the significance of genotype in determining outcomes in anti-hcv combination therapy. In this soon-to-be-published study, the SVRs with pegylated interferon alfa-2a plus ribavirin at varying dosages were uniformly high (73%-78%) and essentially Figure 7. Pegylated Interferon alfa-2b Plus Ribavirin: The Influence of Ribavirin Dose % Sustained Virologic Response % Sustained Virologic Response Ribavirin dose Duration Peg IFN alfa-2a % >1.6 mg/kg 61* * 54 IFN alfa-2b 3 MU 78% 8 mg 1/12 mg 8 mg 1/12 mg 24 wks 24 wks 48 wks 48 wks 18 µg 18 µg 18 µg 18 µg 1.6 mg/kg Intention to Treat N = % Source: Hadziyannis et al as reported by Di Bisceglie et al. HCV indicates hepatitis C virus; Peg IFN, pegylated interferon Overall Genotype 1 Peg IFN alfa-2b 1.5 µg/kg Source: Reference 19. Peg IFN indicates pegylated interferon. *P =.2 chi-squared; P <.3 logistic regression % Genotype 2/3 identical at weeks 24 and 48 in patients with genotypes 2 and 3 (Figure 6). 7,24 These surprisingly similar results at 24 and 48 weeks contrast sharply with the lower and varying SVRs reported for patients with genotype 1: 29% to 41% at 24 weeks versus 4% to 51% at 48 weeks. Patients with the reduced ribavirin dosage (8 mg daily) at either time point had lower responses. The conclusion from this trial was that 24 weeks of treatment and an 8-mg dose of ribavirin are sufficient for patients with genotypes 2 and 3 while those with genotype 1 require 48 weeks of treatment and standard doses of ribavirin. 7 This conclusion is supported by a secondary analysis of calculated weight-based dosing in the Manns et al 19 study. In this analysis, the overall intention-to-treat SVR with pegylated interferon alfa-2b was 54%. In those patients who received < 1.6 mg/kg of ribavirin (about 8 mg for an average-sized person weighing 75 kg), the SVR was only 5%; patients who received more than this 1.6-mg/kg cutoff had a mean SVR of 61% (P =.2) (Figure 7). This influence of ribavirin dose was especially apparent in patients with HCV genotype 1. Strategies for Enhancing Response and Reducing Total HCV Costs Although interferon-based combination therapy has dramatically improved outcomes for patients with long-term HCV infection, clinicians face challenges in implementing this regimen and duplicating the results demonstrated in controlled clinical trials. The complexity of the 2-drug regimen, the 6- to 12-month duration of treatment, and the frequent and sometimes serious side effects are the main hurdles. As outlined in this section, managed care organizations can institute several practical guidelines to overcome these challenges and maximize results with the expensive combination regimens. 1. Identify Nonresponders and Stop Treatment Early. One relatively simple strategy for limiting patient exposure to side effects and reducing drug costs involves prediction of nonresponse early in therapy. This tactic is based on retrospective analyses from the major peginterferon trials showing that practically none of the patients S36 THE AMERICAN JOURNAL OF MANAGED CARE MARCH 24

8 with minimal reductions in viral load at week 12 went on to develop SVR after a full year of therapy. In the peginterferon alfa-2a trial, 98 patients (18%) failed to attain a 2-log reduction in HCV RNA by week 12, and all of these 98 patients (1%) had no SVR at week 48 of therapy. 2 In the trial involving the alfa-2b variant of peginterferon, 63 patients (14%) had no 2-log reduction in HCV RNA at 12 weeks, and 61 of these patients (97%) had no SVR at week 48 of therapy. 25 Based on these results, the NIH now recommends assessment of early virologic response (EVR) at week 12 in patients with HCV. 7,8 This early assessment of efficacy is most important in patients with genotype 1 in whom a full 48 weeks of therapy is usually required. If the HCV RNA has not fallen by 2 log units (ie, a 1-fold reduction, such as from 2 million IU to 2 IU or from 5 IU to 5 IU or less), therapy should be discontinued. The rationale is straightforward and evidence-based: if a patient has not responded by week 12, he or she is very unlikely to benefit from a full year of therapy. Therefore, discontinuing therapy early will spare many patients from unnecessary side effects. As indicated in a series of recent economic analyses, early discontinuation policies may also reduce a health system s overall antiviral drug costs In an economic model, the 12-week assessment and early discontinuation policy led to a projected 44% to 45% reduction in lifelong antiviral costs (Figure 8). 26 For patients taking peginterferon alfa plus ribavirin, the average savings attributed to the early discontinuation policy was $ to $16 268; for patients taking interferon alfa plus ribavirin, the savings was $ Since most patients with genotypes 2 and 3 only require a total of 24 weeks of combination therapy, 23 the reductions in morbidity and costs associated with early discontinuation at 12 weeks are obviously most apparent in patients with HCV genotype Improve Adherence. Adherence to the treatment regimen is a critical part of anti- HCV treatment success. One retrospective analysis of data from the peginterferon alfa- Figure 8. Reduction in Antiviral Drug Costs Associated With Early Discontinuation: Pegylated Interferon alfa-2b Plus Ribavirin (>1.6 mg/kg) US ($) Full Source: Reference 26. Intention to Treat Stop 24 2b plus ribavirin study showed that patients who received >8% of their total interferon doses and >8% of their ribavirin doses for more than 8% of the duration of therapy ( ) had significantly higher SVRs compared with those who fell below these adherence criteria (Figure 9). 28 In patients with genotype 1 who received weight-based ribavirin at >1.6 mg/kg, the SVR was 63% in the 67 patients with high adherence versus 34% in the 32 patients with low adherence (P =.8). Avoiding dose reductions in the 44% to 45% Reduction Stop 12 Figure 9. Pegylated Interferon alfa-2b Plus Ribavirin: Effect of Adherence on Response % Sustained Virologic Response vs 63 All Patients Peg IFN 1.5 µg/kg + RBV 8 mg P< All Patients Peg IFN 1.5 µg/kg + RBV >1.6 mg/kg Genotype 1 Peg IFN 1.5 µg/kg + RBV >1.6 mg/kg Source: Reference 28. Peg IFN indicates pegylated interferon alfa-2b; RBV, ribavirin. Intention to Treat <8/<8/< VOL. 1, NO. 2, SUP. THE AMERICAN JOURNAL OF MANAGED CARE S37

9 first 12 weeks is probably most critical since, as just discussed, the EVR is directly related to long-term outcomes. How can providers and health systems improve adherence rates? A range of management options are available. It begins with careful patient selection to focus on motivated patients who are willing to educate themselves and remain adherent for up to 1 year of drug therapy. Careful assessment of patients for comorbidities and contraindications is required. Educating patients about depression and substance abuse is an absolutely critical first step in building longterm drug adherence since these are prime blockers of successful HCV treatment. Of course, education about HCV disease itself, the treatment regimen, and the consequences of nonadherence are also fundamental elements of the educational package. Very specific and simplified messages about the drug regimen itself are essential. To facilitate this pharmacy instruction and adherence, patients may be given pill organizers, reminders, and accessible refills. Visits every 4 weeks during therapy are appropriate. To help deliver and sustain this long course of HCV education and encouragement, the patient s support system should widen beyond the clinician to include family, peers, nurses, nurse practitioners, and physician assistants. Management of drug side effects is an especially critical component in boosting adherence. In most cases, the side effects can be managed effectively with dose reductions rather than discontinuation. One of the most costly errors for a health plan is to discontinue therapy because of side effects and then restart therapy from the beginning. 17 This is why educating patients upfront about the possibility of depression, fatigue, and other common side effects is so critical in preventing dropouts. Treating the side effects on an as-needed basis is another relatively recent phenomenon that appears to facilitate adherence. Liberal use of antidepressants such as selective serotonin reuptake inhibitors, for example, is becoming more common as a method for maintaining anti-hcv drug coverage in the third of patients who develop this side effect of interferon therapy. Similarly, to combat the less frequent but more serious ribavirin-induced anemia, recombinant erythropoietin is increasingly employed. Recombinant granulocyte colony-stimulating factors are also now considered in patients who develop persistent interferon-induced neutropenia despite dose reductions. The optimal dosage of costly hematopoietic growth factors in this special setting is unknown, as is any documented association with improved SVRs; prospective trials will be required to guide selective use of this potentially valuable add-on therapy. 7 Combination-drug therapies for preventing the long-term complications of HCV disease and the health system strategies required to maximize outcomes with these complex regimens will require considerable institutional resources. However, as the incidence of advanced HCV liver disease grows over the coming decades, this investment in HCV drug therapy will become increasingly necessary. Future Strategies Retreatment and Maintenance Therapy. Hundreds of thousands of HCV-infected patients will fail to respond to interferon plus ribavirin combination therapy. When these nonresponders are retreated with conventional doses of pegylated interferon alfa plus ribavirin, about 3% clear the virus while on treatment and 15% to 2% achieve SVR. Patients with genotype 2 or 3 respond better to retreatment but the full range of host and viral factors that shape response to retreatment has not yet been elucidated. 7 Higher doses of the combination lead to 5% rates of on-treatment viral clearance, but the longer-term SVRs are still being studied. At present, patients with advanced fibrosis or cirrhosis, who are at highest risk of hepatic decompensation, should be considered for retreatment. 7 In patients who fail to achieve SVR even after the best available interferon alfa plus ribavirin therapy, researchers are also evaluating the potential benefits of ongoing maintenance therapy with low doses of interferon monotherapy. The goal in these experiments is no longer to induce SVR, but to prevent progression of fibrotic liver disease. The related goals of course are to pre- S38 THE AMERICAN JOURNAL OF MANAGED CARE MARCH 24

10 vent liver decompensation and HCC, to reduce the need for liver transplantation, and to improve survival. Several large multicenter trials are currently under way in the United States to evaluate the role of lowdose pegylated interferon alfa therapy in preventing cirrhosis in patients with advanced fibrosis. Therapies in Development. The variety of drug development strategies aimed at enhancing HCV treatment are listed in Table Many of these new strategies involve variations on the existing mainstays of anti-hcv therapy interferons and ribavirin. Second-generation nucleoside analogues with reduced hemolysis compared with ribavirin, for example, are a high priority. Also being evaluated are new delivery systems for interferons (eg, disposable infusion pumps, controlledrelease polymer matrices in intramuscular or subcutaneous formats, encapsulation in liposomes) and novel interferon preparations such as omega interferon and albumin-bound interferon. Specific agents closest to phase 3 testing in long-term HCV infection include: Inhibitors of inosine 5 -monophosphate dehydrogenase, 1 of the enzymes involved in nucleotide synthesis and blocked by ribavirin. Thymosin alpha 1, a synthetic peptide that promotes T-cell maturation and natural killer cell activity and stimulates immunomodulatory pathways including interferon production. Gamma interferon, a recombinant protein with multiple potential antifibrotic activities. Finally, milk thistle (silymarin, or Silybum marianum) deserves special mention as a complementary medicine since it has recently reemerged as a popular therapy for liver disease. Almost every patient diagnosed with HCV will eventually ask about it, and as many as a third of patients are taking it. Although it does not have antiviral properties, milk thistle may have some beneficial antioxidant effects and is considered safe. Table 4. Future Therapeutic Strategies for HCV Enhance Current Therapy Modification of interferon regimens Alternative ribavirin-like drugs IMPDH inhibitors Additional agents Amantadine Histamine HCI Thymosin Molecular-based Therapies Specific HCV viral enzyme inhibitors Antisense oligonucleotides Ribozymes Antifibrotic Agent Gamma interferon Source: Reference 29. HCV indicates hepatitis C virus; IMPDH, inosine 5 -monophosphate dehydrogenase. Conclusions Therapy for long-term HCV has improved dramatically over the past 5 years. More than half of HCV-infected patients can now be cured with the combination of pegylated interferon alfa plus ribavirin. To get the most out of this complex drug regimen, however, the clinical team will need to pay careful attention to patient education and monitoring. Recent studies suggest that halting therapy in patients who fail to respond adequately after 12 weeks can reduce patient exposure to side effects and reduce the overall health system budget. Managing common side effects with either dose reduction or specific drug therapy (eg, antidepressants or hematopoietic growth factors) may also enhance adherence and improve SVRs. By implementing system-wide treatment guidelines and patient education on HCV drug therapy, managed care organizations can maximize the benefits of the current standards of care for HCV infection. These incremental gains in HCV outcomes will become ever more critical as health plan members with HCV infection continue to age and enter a period of increasingly high risk for serious symptomatic liver disease. VOL. 1, NO. 2, SUP. THE AMERICAN JOURNAL OF MANAGED CARE S39

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