Reviews/Evaluations. Chronic Hepatitis C. Introduction and Epidemiology. Natural Course of HCV. Recommendations for Treatment

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1 Reviews/Evaluations Chronic Hepatitis C Introduction and Epidemiology Hepatitis C virus (HCV) is one of the most common blood-borne infections and cause of chronic liver disease in the United States (1). Nearly 4 million Americans are infected with HCV, of which 3 million are chronically infected. The majority of cases result from illicit IV drug use. In Oregon, the number of voluntarily reported cases of Hepatitis C from 1993 to 2002 was 129. The prevalence in Oregon is likely much higher since reporting is presently voluntary and many individuals go undiagnosed. In Multnomah County from % of incident chronic liver disease cases were attributable to HCV. In January, the Statewide Viral Hepatitis Planning Group (SVHPG) was formed to address HB 2451 which mandates the Department of Human Services to design a plan for statewide education, prevention, and management of Hepatitis C by January 2005 (2). Unlike other viral hepatides there is no vaccination to prevent hepatitis C. Natural Course of HCV The natural course typically evolves over several decades. Eighty percent of persons have no signs or symptoms. Others may experience abdominal pain, nausea, anorexia, jaundice, fatigue or dark urine (3). After initial infection 15-30% recover, while 70-85% evolve into chronic infection (3). The clinical outcomes of chronic infection are variable; 70% of patients manifest chronic hepatitis which in many is mild to moderate. Others progress to cirrhosis, decompensation, hepatocellular carcinoma, and a need for liver transplantation or death. An estimated 1-5% die from liver disease. Factors known to influence progression are heavy alcohol consumption, male gender, obesity, coinfection with HIV or HBV, and >40 years of age at time of infection (4). HCV progression does not appear to be influenced by viral load, serum ALT, or mode of transmission. Because of the long delay between viral infection and the appearance of liver damage, the impact of hepatitis C is expected to grow, making early diagnosis and treatment desirable. Recommendations for Treatment The National Institutes of Health (NIH) Consensus Development Conference Statement: Management of Hepatitis C 2002 and the CDC define the optimal treatment of HCV infection and has set the standard of practice- shown in Table 1 (5). All HCV (+) persons should be evaluated for the presence and severity of liver disease, and advised on alcohol and illicit drug abstinence (1). Additionally, psychosocial issues must be addressed and those negative for hepatitis A and hepatitis B should be vaccinated. Antiviral therapy is recommended for patients with chronic infection defined as detection of HCV RNA ³ to 6 months after newly acquired infection and who are at greatest risk for progression to cirrhosis, including those with detectable HCV RNA levels, anti-hcv-(+), persistently elevated ALT levels, and a liver biopsy indicating either portal or bridging fibrosis, or moderate degrees of inflammation and necrosis (1). For individuals with persistently normal ALT levels, less severe histologic changes or compensated cirrhosis (without jaundice, ascites, variceal hemorrhage, or encephalopathy) indications for treatment are less clear because progression may not occur or is often slow or they may not benefit from treatment. In these individuals, careful clinical follow-up is an acceptable alternative (1). Treatment also is not recommended for patients with advanced cirrhosis who are at risk for decompensation, uncontrolled major depressive illness, cytopenias, hyperthyroidism, renal transplantation, and evidence of autoimmune disease; and pregnant or nursing women. Furthermore, treatment is not FDA-approved for patients aged less than 18 years, and more data are needed regarding treatment of persons aged less than 18 years or greater than 60 years (1). Finally treatment should be delayed for patients who are abusing alcohol or illicit IV drugs until these behaviors have been discontinued for ³ to 6 months.

2 Table 1: CDC Treatment Recommendations (1) Should be treated Should not be treated Caution in Persistently elevated ALT levels with histologic changes or Normal ALT levels with severe (grade ³ 2) fibrosis and Detectable HCV RNA Liver biopsy indicating portal or bridging fibrosis or moderate degrees of inflammation and necrosis and No active decompensation including: ascites, encephalopathy, or variceal bleeding Goals of Treatment Pregnant or nursing women Current substance or alcohol abusers Concomitant/Uncontrolled Cytopenias Hyperthyroidism Renal transplantation Evidence of autoimmune disease Prior psychiatric illness Decompensated cirrhosis Persistent ALT elevations, with less severe histologic changes Age < 18 or > 60 yrs The long-term goals of antiviral therapy include: prevention of overt cirrhosis, hepatocellular carcinoma, liver failure and need for transplantation, and improved quality of life. The primary short-term goal of therapy is a sustained virologic response (SVR) which is defined as undetectable HCV RNA 6 or more months following treatment. Factors predictive of sustained response are shown in table 2. While more than 95% of individuals who achieve SVR show improvements in liver histology and appear to maintain viral clearance in follow-up studies of up to 6 years, the long-term impact on complications such as morbidity (e.g. need for transplant) and mortality remains unknown (6). Antiviral Therapy Antiviral therapy has rapidly evolved. Pegylated alpha-interferon (PEG-IFN) in combination with ribavirin (RBV) is now considered the standard of care. Prior to the advent of PEG-IFN, treatment consisted of non-pegylated alpha 2b-interferon (IFN; Intron-A) monotherapy. In clinical trials of Intron-A 3 MIU SQ tiw for 12 months, approximately 50% of treated patients had biochemical response (normalization of ALT) and 15-22% had virologic response at the end of therapy (7-9). However, ³ 50% patients relapsed when therapy was stopped. The addition of RBV to IFN improved SVRs to 40-50% (1). Finally, the introduction of once-daily PEG-IFNs [peginterferon alpha-2b (Peg-Intron) and later peginterferon alpha-2a (Pegasys)] further increased response rates. Advantages of PEG-IFN include convenience of once-weekly dosing and enhanced response. Brief Review of Evidence- Pegylated Interferon Reported SVRs of PEG-IFN have ranged from 25-39% suggesting PEG-IFN monotherapy does not produce a significant advantage over standard IFN + RBV therapy. However PEG-IFN + RBV combination therapy induces an overall SVR of 52-56% in treatment-naïve patients. A recent Canadian systematic review pooled results from 51 and 2 RCTs evaluating standard IFN and PEG-IFN therapy respectively and concluded that 1 additional patient avoided chronic C infection for every 14 patients treated with PEG-IFN + RBV compared to standard IFN + RBV (21). A summary of the key clinical trials follows. A large randomized trial in 1,530 patients with chronic HCV infection compared Peg-Intron + RBV to Intron-A + RBV for 48 weeks (10). Patients were assigned to three treatment groups, as follows: Peg-Intron 1.5mcg/kg/wk + RBV 800mg qd ( high dose Peg-Intron), Peg-Intron 1.5mcg/kg/wk for 4 weeks then 0.5mcg/kg/wk + RBV 1,000mg to 1,200mg qd ( low dose Peg-Intron), or Intron-A 3mu tiw + RBV 1,000mg to 1,200mg qd. In the two groups receiving RBV 1,000mg to 1,200mg qd, the

3 dose was based on patient weight- patients < 75kg received 1,000mg and ³ 75kg received 1,200mg. Eligible patients had compensated liver disease, detectable HCV RNA, elevated ALT, and liver histopathology consistent with chronic hepatitis. The primary endpoint was SVR (undetectable HCV RNA) at 24 weeks post-treatment and patients with missing data were classified as nonresponders. The Peg-Intron 1.5mcg/kg + RBV 800mg regimen produced an overall SVR of 54% compared to 47% with the low-dose Peg-Intron and IFN + RBV (p=.01). HCV genotype (non-1), baseline HCV RNA viral load ( 2 x 106/mL), baseline weight (lower- according to logistic regression analysis), and age (younger) were associated with SVR (p<.0001). Patients with genotype 1 and genotypes 2 or 3 had SVR rates of 42% and 82% respectively in the high-dose Peg-Intron group and the rates compared to IFN+RBV were significantly better for only those with genotype 1. Thus, patients with genotype 2 or 3 received no additional benefit from PEG-IFN + RBV over standard IFN + RBV treatment. Those with both poor prognostic factors of genotype 1 and high viral load had a response rate of 29-30%. Histologic improvement (a secondary outcome defined as an improvement in the Knodell fibrosis score) was observed in 21% of patients overall in the high-dose Peg-Intron group. A large blinded, randomized, multicenter trial evaluated the safety and efficacy of fixed-dose Pegasys + RBV, Intron-A + RBV, and Pegasys monotherapy in 1121 treatment-naïve patients with chronic hepatitis C (11). Patients were excluded if they had HIV infection, decompensated liver disease, neutropenia, thrombocytopenia, anemia, SrCr > 1.5 times the upper limit of normal, poorly controlled psychiatric disease, alcohol or drug dependence within 1 year before entry, or significant coexisting medical conditions. Patients were randomized to one of three treatment groups: Pegasys 180mcg/wk + RBV po qd, Pegasys 180mcg/wk + placebo, and Intron A 3mu tiw + RBV po qd. The RBV dose was weight-adjusted- patients 75kg received RBV 1,000mg qd; patients > 75kg received RBV 1,200mg qd. All patients were treated for 48 weeks and followed for an additional 24 weeks. In an intent-to-treat analysis, the SVR in the Pegasys + RBV group was 56% overall and 46% in genotype 1 compared to 44% overall and 36% in genotype 1 in the Intron A + RBV group (p<.001 and p=.01 respectively). Three factors independently and significantly increased the odds of achieving an SVR: an HCV genotype other than 1 (OR 3.25; 95% CI= ; p<0.001), age of 40 years or less (OR 2.60; 95% CI= ; p<0.001), and a body weight of 75 kg or less (odds ratio, 1.91; 95% CI= ; p=0.002). Furthermore, early virologic reponse (at least a 2-log decrease in HCV RNA from baseline at week 12 was predictive of SVR. Of patients with early virologic responses, 65% achieved an SVR while those that did not had an SVR rate of 3%. Recently, a randomized, double-blind, multicenter study evaluated the effects of the duration (24 vs. 48 weeks) and RBV dose (800mg vs mg) with Pegasys + RBV combination therapy in 1,284 treatment-naïve patients with chronic heptatitis C (12,13). Treatment groups were stratified by genotype and viral load to Pegasys180 mcg/wk + low-dose RBV 800 mg qd or standard weight-based RBV mg qd for weeks. As observed in other trials, HCV genotype was the predominant predictor of response (odds ratio for a genotype other than genotype 1 vs. genotype 1 was 5.4 (CI= , p< 0.001). The SVR (primary endpoint) after 48 weeks was 63% (CI: 59%-68%) overall and 52% (CI= 46%-58%) in patients with genotype 1 (n=740). Furthermore, weight-based RBV and increased treatment duration (48 v. 24 weeks) produced significantly higher SVRs in patients with genotype 1. In patients with genotypes 2 or 3 (n=492), an overall SVR rate of approximately 80% was achieved and did not vary significantly based on duration of treatment or dose suggesting that low-dose RBV 800 mg qd for 24 weeks of therapy is adequate. Study differences such as patient demographics, severity or stage of disease, protocols for dose reduction and discontinuation, HCV RNA assays, and RBV dosing (fixed vs. weight-based) prevent definitive SVR comparisons of PEG-IFN alpha-2b and PEG-IFN + RBV combination therapy (14). Clinical trials comparing Peg-Intron and Pegasys have been conducted but are published only in abstract form (15). Factors predictive of response to PEG-IFN + RBV therapy observed in clinical trials are summarized in Table 2. Table 2: Factors Predictive of a Sustained Virologic Response Non-Genotype-1 infection Low HCV RNA titers

4 Early disappearance of HCV RNA Low hepatic iron stores Absence of cirrhosis or minimal hepatitic fibrosis Short duration of disease post-infection Younger age Safety Combination therapy with IFN or PEG-IFN + RBV is not benign. Influenza-like symptoms (myalgia, arthralgia, rigors, fever, fatigue), nausea, anorexia, depression and anemia and neutropenia are common adverse effects, rendering some HCV(+) individuals to elect non-conventional treatment or nonadherence in those who do commence therapy. In clinical trials, adverse events and withdrawals due to adverse events (14-32%) were similar among patients treated with PEG-IFN + RBV and standard IFN + RBV. In the Canadian systematic review, there was no statistically significant difference in mortality; however, a marginally significantly higher rate of non-fatal adverse effects was observed in patients on PEG-IFN + RBV compared to standard IFN + RBV (OR: 1.24, CI=1.01 to 1.51). Yet, a significant difference in adverse effect-related withdrawals was not detected. The most common types of adverse events leading to withdrawal were psychiatric disorders (mainly depression). RBV-induced anemia is a particularly problematic adverse effect. Product labeling recommends dose-reduction in this setting. In one trial, the mean decrease in Hgb was 25 g/l and resulted in 9-13% of overall adverse event withdrawals (10). Another trial reported that of patients who had an early response and a substantial dose reduction due to anemia had similar SVR rates compared to patients who maintained the full dosing schedule (11). However, some experts assert that a reduction in RBV dose may compromise the probability of an SVR and recommend the use of epoetin in combination to treatment as an alternative to dose-reduction. However, published clinical trials are lacking to support this practice at present. Proper identification of good candidates, education and support, and close follow-up is critical. Cost Two PEG-IFN products are currently available (Pegasys and Peg-Intron) and 3 products of RBV are available (Rebetol, Copegus, and the recently approved generic RBV (Ribasphere). The cost of therapy is shown in Table 3. Data are lacking to support the use of one PEG-IFN or RBV over another. Ribavirin products are not interchangeable by the dispensing pharmacist; one product is a capsule and the other is a tablet, although one recent review suggests that Rebetol and Copegus may be bioequivalent (16). Table 3: Cost of Therapy* Generic Brand Cost/unit Dose Cost/24 wks Cost/48 wks Interferon alfa-2b (recombinant) Intron-A $42.63/ dose 3 MIU SQ tiw $3070 $6139 Peginterferon alpha 2b Peginterferon alpha 2a Peg-Intron Pegasys $369.11/dose $387.54/dose $406.94/dose $427.94/dose $ / 1 month box Ribavirin Rebetol $11.04/capsule 50 mcg SQ qw 80 mcg SQ qw 120 mcg SQ qw 150 mcg SQ qw 180 mcg SQ qw mg qd $8859 $9301 $9767 $10,271 $17,717 $18,602 $19,533 $20,541 $9167 $18,333 $7419-$11,128 $14,838-$22,257

5 Ribavirin Copegus $6.64/capsule Ribavirin Interferon alfa-2b (recombinant) + Rebetol Ribasphere $9.93/capsule Rebetron $804.32/ 2 week box mg qd mg qd Intron-A 3 MIU SQ tiw + Rebetol 1000mg qd $4462-$6693 $8924-$13,386 $6673-$10,009 $13,346-$20,019 $9652 $19,304 * Cost is based on OMAP FFS AWP-15% Discussion The current standard of care is PEG-IFN in combination with RBV. Factors predictive of response are summarized in Table 2. Baseline HCV genotyping is used to predict a patient s response to therapy and to determine the duration of therapy. Those with genotype 1 are less likely to respond to therapy and require longer treatment periods (48 weeks) and higher doses of RBV ( mg qd). Patients with genotype 1 who continue to be HCV-RNA positive at 24 weeks of treatment are unlikely to respond and the recommendation is to stop treatment. Those with genotype 2 or 3 are inherently more likely to response and the recommended duration of therapy is 24 weeks with a lower RBV dose of 800mg qd (15, 19, 20). With the improvement in the reproducibility and availability of sensitive quantitative PCR HCV RNA testing, evaluation of viral response is recommended at 12 weeks as a means of reducing antiviral treatment morbidity and costs, particularly in patients with genotype 1. The goal is to avoid unnecessary treatment morbidity and expense in as many nonresponders as possible. Recommendations Consider prior authorization of HCV interferon-based therapy to ensure appropriate use and maximization of Oregon Health Plan resources. Proposed criteria are in Appendix 1. References 1. Center for Disease Control. MMWR. 1998;47 (no. RR-19): Thomas DL, Astemborski J, Rai RM, et al. The national history of hepatitis C infection: Host, viral, and environmental factors. Am J Med 2000; 284(4): National Institutes of Health. NIH Consensus Development Conference Statement: Management of Hepatitis C 2002; June 10-12, 2002; Bethesda, MD: NIH Consensus Development Program. 2002;19(1). Available at Accessed on April 1, Lindsay KL. Hepatology 1997;26(suppl 1):75S. 7. Keeffe EB, Hollinger FB and the Consensus Interferon Study Group. Therapy of hepatitis C: consensus interferon trials. Hepatology 1997;26(suppl 1): 101S-107S. 8. Poynard T. Marcellin P, Lee SS, et al. Randomized trial of interferon alpha 2b + ribavirin for 48 weeks or for 24 weeks versus interferon alpha 2b plus placebo for 48 weeks for treatment of chronic infection with hepatitis C virus. International Hepatitis Interventional Therapy Group. Lancet 1998;352: McHutchison JG, Gordon, SC, Schiff ER, et al. Interferon alfa-2a alone or in combination with ribavirin as initial treatment for chronic hepatitis C. NEJM 1998; 339: Manns MP, McHutchison JG, Gordon SC, Rustgi VK, Shiffman M, Reindollar R, Goodman ZD, Koury K, Ling MH, Albrecht JK. Peginterferon alfa-2b plus ribavirin compared to interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomized trial. Lancet 2001;358: Fried MW, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N

6 Engl J Med. 2002;347: Hadziyannis SJ, Sette H, Morgan T, Balan V, Diago M, Marcellin P, 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: Baker R. Pegasys plus ribavirin produces highest sustained virological response (SVR) rate ever achieved for patients with HCV genotype 1. April 18, hep_c/news/041902a.html, Accessed on December 12, FDA Advisory Committee Briefing Document. Food and Drug Administration Website,available at Accessed January Trepo C, Lindsay K, Niederau C. et al. Pegylated interferon alfa-2b monotherapy is superior to interferon alfa-2b for the treatment of chronic hepatitis C (abstract GS2/07). Journal of Hepatology. 2000;32(suppl 2); Anon. Peginterferon alfa-2a (Pegasys) for chronic hepatitis C. The Medical Letter 2003 March 3;45(1151): Siebert et al. Cost effectiveness of peginterferon alfa-2b plus ribavirin versus interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C. Gut 2003;52: Salomon JA et al. Cost-effectiveness of treatment for chronic hepatitis C infection in an evolving patient population. JAMA 2003;290(2): Brau N. Pegylated interferons and advances in therapy for chronic hepatitis C. Medical Education Collaborative. November Available at Accessed on November 15, Leung NWY. Management of viral hepatitis C. J Gastroenterol Hepatol 2002;17(suppl):S146-S Husereau D, Bassett K, Koretz R. Inteferon-based therapies for chronic hepatitis C virus infection: an assessment of clinical outcomes. Canadian Coordinating Office of Health Technology Assessment (CCOHTA). Available at Accessed on May 13, Additional References: Gebo K, Jenckes M, Changer G, et al. Management of chronic hepatitis C [Evidence report/technology assessment no.60]. Rockville, MD: Agency for Health Care Research and Quality; Publ no 02-E030. Pharmacy home Drug Info & Policy Eval Oregon DUR Board Reviews/Evaluations Interventions Newsletter Provider Tools Comments or Questions: pharmacy@orst.edu Copyright 2002 Oregon State University