Hepatitis C Treatment: Tailoring Therapy To Maximize Response

PRINTER-FRIENDLY VERSION AT GASTROENDONEWS.COM Hepatitis C Treatment: Tailoring Therapy To Maximize Response PATRICK J. AMAR, MD Department of Gastroenterology and Hepatology Holy Cross Medical Group Fort Lauderdale, Florida EUGENE R. SCHIFF, MD Leonard M. Miller Professor of Medicine Chief, Division of Hepatology Director, Center for Liver Diseases University of Miami Leonard M. Miller School of Medicine Miami, Florida Approximately 4 million people in the United States are infected with the hepatitis C virus (HCV), and 70% will develop chronic liver disease. 1 Additionally, hepatitis C accounts for approximately 40% of deaths due to liver disease and 40% of transplants performed annually in the United States. 2 However, only 15% of those who need treatment are currently receiving it. Although a lack of aggressive screening programs may contribute to the underdiagnosis of hepatitis C in affected individuals, many patients are not receiving treatment because of the significant side effects of currently available medications and the duration of treatment required. The goal of hepatitis C therapy is to achieve a sustained virologic response (SVR), defined as undetectable levels of HCV 6 months after the cessation of treatment. Clinically, this is considered equivalent to a cure, with more than 99% of patients having no detectable HCV RNA after several years of follow-up. This review focuses on the importance of using viral kinetics and other patient characteristics to optimize treatment regimens and maximize SVR rates. Testing for HCV The US Centers for Disease Control and Prevention currently recommends that people who present with the following risk factors be tested for HCV: history of injection drug use; long-term hemodialysis; receipt of clotting factors before 1987; receipt of blood products or a transplanted organ before 1992; fetal exposure from an infected mother; occupational exposure (ie, needlestick); or evidence of chronic liver disease. Enzyme immunoassay (EIA) has a sensitivity and specificity of 99% for the detection of HCV antibodies GASTROENTEROLOGY & ENDOSCOPY NEWS SPECIAL EDITION 2008 7

Table 1. SVR Rates According to Pretreatment Characteristics Age, y 20 20 43 43 43 60 60 60 BMI, kg/m 2 20 20 26 26 26 30 30 30 HCV RNA, IU/mL x 10 3 40 40 40 1,200 9,000 9,000 9,000 9,000 Cirrhosis No No No No No No No Yes ALT quotient 7 2 2 2 2 2 1 1 Predicted SVR rate, % 97 85 74 52 36 19 14 7 The results of the SVR Calculator Project demonstrate that it is possible to estimate the probability that an individual patient will achieve an SVR when treated with the combination of PEG-IFN and RBV. ALT, alanine aminotransferase; BMI, body mass index; HCV, hepatitis C virus; PEG-IFN, pegylated interferon; RBV, ribavirin; SVR, sustained virologic response Based on reference 5. in immunocompetent individuals. Polymerase chain reaction (PCR) should be used to quantify levels of HCV RNA in all patients who test positive for antibodies to HCV because this can reliably determine if active viral replication is present; the lower limits of detection are now 10 to 50 IU/mL. Immunocompromised patients who are at risk for HCV infection should also undergo HCV RNA testing, even if they tested negative for the HCV antibody. Patients who test positive for HCV antibody but are negative for HCV RNA should be tested with HCV recombinant immunoblot assay (RIBA); a negative test result signifies a false-positive HCV antibody test result. A positive RIBA result and a negative HCV RNA test result most likely represent resolved infection. Once the diagnosis of HCV infection has been established, it is important to determine the HCV genotype because this is a major determinant of the length of treatment indicated and the likelihood of achieving an SVR. Sequelae and Standard Therapy The 2 most feared sequelae of long-standing HCV infection are the development of cirrhosis and the risk for hepatocellular carcinoma (HCC). Cirrhosis develops in approximately 15% to 20% of individuals infected with HCV for more than 20 years. 3 Nonetheless, it is HCC that poses the greatest threat to cirrhotic patients infected with HCV, rather than the complications of cirrhosis. 4 Therefore, treatment with the combination of pegylated interferon (PEG-IFN) alfa and ribavirin (RBV) should be considered for all patients infected with HCV. However, current treatments for HCV can lead to numerous side effects, and patients often require a prolonged course of therapy. Newer and potentially less toxic therapies are on the horizon, but many patients cannot afford to wait for these agents. For the foreseeable future, HCV therapy will continue to require the use of PEG-IFN, despite its tendency to cause many adverse reactions. Therefore, the question arises: Can we do a better job with what we now have, specifically PEG-IFN and RBV, to improve SVR rates while minimizing side effects? Factors That Alter SVR Rates Numerous factors are known to alter individual responses to HCV therapy, and their relative effects need to be weighed when it is decided to begin treatment (Table 1). 5 Although the list of variables known to affect SVR rates is quite lengthy, it is worth highlighting several significant ones. Race: The Virahep-C study illustrated that rates of SVR are lower in blacks than in whites (28% vs 52%). 6 The WIN-R (Weight-Based Dosing of PEG- Intron and Rebetol) trial also showed decreased SVR rates in blacks and observed the same in Hispanics, but SVR rates in Asians were higher. 7 The reasons for these differences remain unclear, but continued investigation and consideration by physicians treating patients infected with HCV are warranted. Low viral load (LVL): The definition of an LVL has varied between studies. Analysis of the data from the WIN-R trial revealed significantly decreased SVR rates in patients infected with HCV who had viral loads above 500,000 copies per ml, 8 whereas data from Berg and colleagues showed viral loads above 400,000 copies per ml to be associated with lower SVR rates (46% vs 70%). 9 The exact cutoff for an LVL remains uncertain, but it is clear that patients with lower viral loads at baseline achieve higher SVR rates with treatment. Fibrosis: SVR rates are higher in patients with mild fibrosis (F0-F2) than in those with advanced fibrosis (F3-F4); 57% of patients with mild fibrosis and 44% of those with advanced fibrosis achieve an SVR. 10 However, the negative effect of fibrosis on SVR may be significant only in bridging fibrosis (F3) or cirrhosis (F4), with SVR rates estimated at 44% to 49% for F3 and 33% to 34% for F4. 11 8

Obesity: The WIN-R study, which evaluated nearly 5,000 patients receiving PEG-IFN alfa-2b and RBV, demonstrated that the SVR rate decreases as body weight increases, as long as doses of RBV are fixed 52% of patients who weighed less than 65 kg reached an SVR, whereas only 35% of those weighing more than 105 kg were able to do the same. 12 However, this effect is essentially eliminated if weight-based doses of RBV are employed. SVR rates for patients who received weight-based doses of RBV (800-1,400 mg/d) were similar in those who were obese and those who were not; an SVR was reached by 49% of patients weighing less than 65 kg and by 47% of those weighing more than 105 kg. Fried and colleagues conducted a study comparing standard doses with higher doses of PEG-IFN alfa-2a (180 vs 270 mcg/wk) and RBV (1,200 vs 1,600 mg/d) in various combinations in patients weighing more than 85 kg. They found that the SVR rate improved as doses of both medications were increased (SVR rate of 28% for low-dose PEG- IFN/RBV vs 47% for high-dose PEG-IFN/RBV). 13 Therefore, although the optimal dosing can vary among patients, it is appropriate to consider higher doses of anti-hcv medications when obese patients are treated. Tailoring Treatment to Viral Kinetics The focus of many recent studies has been to better understand viral kinetics and its significance in tailoring HCV therapy. It is critical to first establish a baseline HCV RNA level before initiating treatment because this serves as a reference point for any evaluation of the effectiveness of treatment. Failure to achieve an early viral response (EVR), defined as a decrease of 2 log10 in quantitative HCV RNA levels after 12 weeks of treatment, has been demonstrated to have a high negative predictive value for successful clearing of the virus. Indeed, not achieving an EVR correlates with a 98% likelihood of not achieving an SVR. Conversely, achieving a rapid virologic response (RVR), which is defined as undetectable HCV RNA at 4 weeks of treatment, has a high positive predictive value. Among patients infected with HCV genotype 1 who were treated with PEG- IFN alfa-2a and ribavirin, 91% attained an RVR at week 4 and then went on to achieve an SVR (Figure). 14 GENOTYPE 1 In recent years, patients infected with HCV genotype 1 who achieved an EVR have been treated with PEG-IFN and weight-based RBV for 48 weeks. The effectiveness of this regimen was well demonstrated in a study by Hadziyannis and colleagues. 15 The study of 1,311 patients infected with HCV genotype 1, 2, or 3 compared 24- and 48-week courses of therapy as well as fixed RBV doses of 800 mg daily and weight-based RBV doses of 1,000 to 1,200 mg daily. In patients infected with HCV genotype 1, weight-based RBV dosing for 48 weeks yielded an SVR rate of 52%, whereas the fixed dose of RBV given for 24 weeks yielded an SVR rate of 29%. However, the duration of therapy has come into question with the use of viral kinetics. Recent data suggest that patients infected with HCV genotype 1 who have an LVL ( 600,000 IU/mL) and achieve an RVR have an 89% chance of attaining an SVR when given only 24 weeks of treatment with PEG-IFN alfa-2b and RBV. 16 Conversely, patients negative for HCV RNA at 12 weeks had a 25% SVR rate, and those negative for HCV RNA at 24 weeks had a 17% SVR rate. Consequently, in the European Union, the treatment of patients infected with HCV genotype 1 who achieve an RVR is truncated at 24 weeks. Alternately, one can use the RVR as the point at which to lower doses of medication after 12 weeks, as opposed to ending therapy. Indeed, RBV, which is thought to help maintain the virologic response to IFN, may be unnecessary beyond a certain point in patients who rapidly clear the virus, such as those with an RVR. 17,18 Additional support for use of the RVR in reducing treatment dose or duration comes from an ad hoc analysis of treatment with PEG-IFN and low versus standard doses (800 vs 1,000-1,200 mg/d) of RBV for 24 or 48 weeks. 19 Patients with HCV genotype 1 who achieved an RVR at week 4 had an SVR rate of 89% despite a shorter duration of treatment. The benefits of the full 48-week treatment or standard RBV dosing were significant only in those who did not achieve an RVR. Subgroup analysis of the patients with an RVR revealed that the ability to achieve an RVR was strongly linked to the pretreatment viral load the RVR rate in the group with HCV RNA levels of less than 200,000 IU/mL at baseline was 49%, compared with 9% in those with baseline levels of HCV RNA above 600,000 IU/mL. Traditional treatment algorithms for patients infected with HCV dictated that those who achieved an EVR should complete 48 weeks of therapy. This included patients who achieved an RVR and those who cleared the virus anytime between 12 and 24 weeks. What has come to light, however, is that the length of time that the virus remains undetectable serves as a powerful tool for predicting relapse once therapy is complete (Table 2). 20 This has been demonstrated in the TeraViC-4 study, in which 326 patients who had detectable viremia at week 4 of treatment (lack of an RVR) were randomly assigned to receive either 48 or 72 weeks of treatment. 21 Although the end-of-treatment response was similar in the 2 arms, the SVR rate was significantly higher in the 72-week treatment group than in the 48-week group (45% vs 32%; P=0.01), reflecting a reduced relapse rate. Of all patients in whom the virus was cleared at the end of the treatment, 26% of those in the 72-week group had a relapse, compared with 48% of those in the 48-week group. However, those who were treated for 72 weeks were more likely to discontinue therapy (18% of those treated for 72 weeks vs 5% of those treated for 48 weeks). A similar study by Berg and colleagues found that patients who were negative for 9

100 91 91 90 90 End-of-Treatment Response 80 SVR Patients, % 60 40 60 48 20 0 13 2 Week 4 Week 12 Week 24 Decrease <2 log 10 HCV RNA Levels Decrease <2 log 10 Decrease >2 log 10 Any decrease Any decrease Detectable Figure. SVR rates according to virologic response at 4, 12, and 24 weeks. Detection limit: HCV RNA <50 IU/mL HCV, hepatitis C virus; SVR, sustained virologic response Based on reference 14. HCV RNA at 12 weeks did not benefit from extended treatment (SVR rate, 17%), whereas those who were negative only at 24 weeks had a better SVR rate with 72 weeks of therapy (SVR rate, 29%). 22 GENOTYPES 2 AND 3 Patients infected with HCV genotype 2 or 3 have generally been treated with PEG-IFN and fixed-dose RBV (800 mg/d) for 24 weeks, with an excellent overall response. This treatment paradigm has been validated by data from the WIN-R trial, in which the SVR rates of patients infected with HCV genotype 2 or 3 did not show any difference whether they were treated for 24 or 48 weeks or whether they received a fixed or weightbased dose of RBV. 12 However, data on the effects of viral kinetics in the treatment of HCV genotypes 2 and 3 are challenging this standard of treatment. A number of clinical trials have considered the RVR in patients infected with HCV genotype 2 or 3 to determine whether to shorten therapy. 23-26 Altogether, these studies seem to support cessation of therapy at 12 to 16 weeks in patients infected with HCV genotype 2 or 3 who achieve an RVR. SVR rates in these studies ranged from 82% to 90% after 12 to 16 weeks of therapy, compared with 80% to 91% after the standard 24 weeks of therapy. Slight differences in SVR rates, however, may warrant the continued use of 24 weeks of therapy in these groups. In the ACCELERATE trial, the largest of these studies (1,469 patients), the difference between SVR rates among those who achieved an RVR reached statistical significance in favor of 24 weeks of treatment (82% vs 90%). 26 An alternate approach is to use the RVR to tailor the duration of treatment and combine this with weightbased RBV dosing (1,000-1,200 mg daily) rather than fixed dosing. Using this approach in patients with HCV genotype 2, investigators in one study achieved SVR rates of 94% with 16 weeks and of 95% with 24 weeks of treatment. 27 Given the relatively small size of the study (150 patients), however, the available data support the continued use of 800 mg per day in these patients. At the opposite end of the spectrum, prospective data on the use of extended treatment for slow responders among patients infected with HCV genotype 2 or 3 are insufficient to recommend this. Nonresponders to Therapy The population of patients who have not cleared the virus despite treatment, including the combination of PEG-IFN and RBV, is growing. Approximately 20% of patients infected with HCV genotype 1 are null responders that is, their HCV RNA levels decrease minimally or not at all despite adequate dosing and adherence to treatment. These patients are unlikely to respond to changes in the dose of IFN and may require newer therapies to resolve their viremia. Partial responders who do achieve an EVR but fail to clear the virus by week 24 may benefit from re-treatment with PEG-IFN and RBV. One study examined the effect of PEG-IFN and RBV in patients who had previously been treated with IFN monotherapy; the investigators found that 10% of partial responders were able to reach an SVR. 28 Of note, none of the prior null responders achieved an SVR on re-treatment in this study. In anoth- 10

er study, patients who had previously received combination therapy with IFN and RBV and were subsequently treated with PEG-IFN and RBV achieved an SVR rate of 21%. 29 Finally, in the REPEAT trial, an SVR rate of 9% was achieved in partial responders to PEG-IFN and RBV therapy when they were given the standard dose of PEG-IFN, but the SVR rate increased to 16% when they received a double dose of the drug. 30 Presently, it remains difficult to recommend a particular approach to the treatment of partial responders or patients who relapse unless the initial treatment has ended or was shortened prematurely. The results of maintenance therapy in non-responders has been equally disappointing. The long-awaited HALT-C (Hepatitis C Antiviral Long-term Treatment against Cirrhosis) trial, which enrolled 1,050 non-responders with advanced fibrosis, sought to determine if extended therapy with pegylated interferon monotherapy could prevent progressive liver disease among patients with HCV who did not respond to combination therapy. 31 Patients were randomly assigned to receive 90 mcg of PEG-IFN alfa-2a once weekly for 3.5 years or no treatment. In this trial, maintenance therapy failed to reduce the rate of disease progression or the frequency of death, hepatic decompensation, HCC, or progression of fibrosis. In the COPILOT (Colchicine versus Peg-Intron Long-term) trial, presented at the 2008 annual meeting of the European Association for the Study of the Liver, a potential benefit of maintenance therapy was observed with PEG-IFN alfa-2b in patients with portal hypertension, although this result was revealed in a subgroup analysis. 32 Treatment of HCV HIV Coinfection Because HIV therapy has become very effective, the number of coinfected patients who die of liver disease resulting from HCV has now surpassed those who die of complications of HIV. 33 The prevalence of HCV infection among HIV-infected individuals is approximately 25% and approaches 80% in those with a history of injection drug use. 34 Although coinfection with HIV is associated with lower response rates to HCV therapy, it is now well established that treatment should be considered in most HIV-coinfected individuals. Results from several studies of people coinfected with HIV and HCV demonstrated that SVR rates of 27% to 44% can be achieved with standard treatment. 35-38 Although CD4+ cell counts of more than 200/mm 3 are preferred before HCV therapy is initiated, treatment can be considered for patients with lower levels. Patients must be monitored closely when taking RBV in conjunction with zidovudine because the resulting anemia can be quite severe. Additionally, patients should not be given didanosine in conjunction with RBV (an absolute contraindication) because severe mitochondrial toxicity is associated with this combination. Table 2. Proposed Treatment Algorithm For Patients Infected With HCV Genotype 1, Based on Viral Kinetics Week 4 HCV RNA Positive Positive HCV, hepatitis C virus; RBV, ribavirin Based on reference 20. On the Horizon There is a great deal of excitement regarding the development of new antiviral agents aimed primarily at treating patients infected with HCV genotype 1. Many of these agents show significant promise and appear to be effective in reducing HCV levels in a short period of time. They are likely several years from being approved, however, and concomitant administration with IFN and RBV will be required for the foreseeable future. Although the future of HCV therapy may lie in the combination of different HCV inhibitors without IFN, most patients cannot afford to wait for these potentially less toxic regimens. In this new era of treatment, multidrug therapy, similar to that used for HIV infection, will likely be required to minimize the already emerging reality of HCV resistance. Until such a time, however, we must strive to better utilize our currently available therapies in order to stem the epidemic of chronic liver disease resulting from HCV infection. References Week 12 HCV RNA Positive Week 24 HCV RNA Significant Adverse Effects No Yes No No 1. Centers for Disease Control and Prevention. National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention. Viral hepatitis C fact sheet. http://www.cdc.gov/hepatitis/index.htm. Accessed August 27, 2008. 2. Kim WR. The burden of hepatitis C in the United States. Hepatology. 2002;36(5 suppl 1):S30-S34. Duration of Therapy, wks 3. National Digestive Diseases Information Clearinghouse. Chronic hepatitis C: current disease management. http://digestive.niddk.nih.gov/ddiseases/pubs/chronichepc/ index.htm. Accessed August 27, 2008. 4. Schiff ER. Prevention of mortality from hepatitis B and hepatitis C. Lancet. 2006;368(9539):896-897. 5. Weiland O. Combination therapy with peginterferon alfa-2a (40 KD) (Pegasys) plus ribavirin (Copegus) in treatment-naïve patients with chronic hepatitis C and genotype 1 infection: individual estimated probability of sustained virological response (SVR). Abstract presented at: European Association for the Study of the Liver; April 14-18, 2004; Berlin, Germany. 48 24, or lower RBV dose 48 72 11

6. Conjeevaram HS, Fried MW, Jeffers LJ, et al, and the Virahep-C Study Group. Peginterferon and ribavirin treatment in African American and Caucasian American patients with hepatitis C genotype 1. Gastroenterology. 2006;131(2):470-477. 7. Jacobson IM, Brown RS Jr, McCone J, et al. Impact of weightbased ribavirin with peginterferon alfa-2b in African Americans with hepatitis C virus genotype 1. Hepatology. 2007;46(4): 982-990. 8. Jacobson IM, Brown RS, Freilich B, et al. Stratification of high viral load: impact on sustained virologic response in the WIN-R trial [abstract T1806]. Gastroenterology. 2006;130(4 suppl 2):A-837. 9. Berg T, von Wagner M, Hinrichsen H, et al. Definition of a pretreatment viral load cut-off for an optimized prediction of treatment outcome in patients with genotype 1 infection receiving either 48 or 72 weeks of peginterferon alfa-2a plus ribavirin [abstract 350]. Hepatology. 2006;44(4 suppl 1):321A. 10. Manns MP, McHutchison JG, Gordon SC, et al. Peginterferon alfa- 2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet. 2001;358(9286):958-965. 11. Afdhal N, Jacobson IM, Brown R, et al. The effect of liver fibrosis and cirrhosis on SVR in 4913 patients with hepatitis C: results from the WIN-R trial [abstract 655]. Gastroenterology. 2006; 130(4 suppl 2):A-771. 12. Jacobson IM, Brown RS Jr, Freilich B, et al. Peginterferon alfa-2b and weight-based or flat-dose ribavirin in chronic hepatitis C patients: a randomized trial. Hepatology. 2007;46(4):971-981. 13. Fried M, Jensen D, Rodriguez-Torres M, et al. Improved sustained virological response (SVR) rates with higher, fixed doses of peginterferon alfa-2a (40 KD) (Pegasys) plus ribavirin (RBV) (Copegus) in patients with difficult-to-cure characteristics [abstract 335]. Hepatology. 2006;44(4 suppl 1):314A. 14. Ferenci P, Fried MW, Shiffman ML, et al. 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Impact of ribavirin dose reductions in hepatitis C virus genotype 1 patients completing peginterferon alfa-2a/ribavirin treatment. Clin Gastroenterol Hepatol. 2007;5(1):124-129. 19. Jensen DM, Morgan TR, Marcellin P, et al. Early identification of HCV genotype 1 patients responding to 24 weeks peginterferon alpha-2a (40 KD)/ribavirin therapy. Hepatology. 2006;43(5): 954-960. 20. Davis GL. Tailoring antiviral therapy in hepatitis C. Hepatology. 2006;43(5):909-911. 21. Sánchez-Tapias JM, Diago M, Escartín P, et al. Peginterferon-alfa2a plus ribavirin for 48 versus 72 weeks in patients with detectable hepatitis C virus RNA at week 4 of treatment. Gastroenterology. 2006;131(2):451-460. 22. Berg T, von Wagner M, Nasser S, et al. Extended treatment duration for hepatitis C virus type 1: comparing 48 versus 72 weeks of peginterferon-alfa-2a plus ribavirin. Gastroenterology. 2006; 130(4):1086-1097. 23. Dalgard O, Bjøro K, Hellum KB, et al. 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Torriani FJ, Rodriguez-Torres M, Rockstroh JK, et al, and the APRI- COT Study Group. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection in HIV-infected patients. N Engl J Med. 2004;351(5):438-450. 36. Chung RT, Andersen J, Volberding P, et al, and the AIDS Clinical Trials Group A5071 Study Team. Peginterferon alfa-2a plus ribavirin versus interferon alfa-2a plus ribavirin for chronic hepatitis C in HIV-coinfected persons. N Engl J Med. 2004;351(5):451-459. 37. Carrat F, Bani-Sadr F, Pol S, et al, and the ANRS HCO2 RIBAVIC Study Team. Pegylated interferon alfa-2b vs standard interferon alfa-2b, plus ribavirin, for chronic hepatitis C in HIV-infected patients: a randomized controlled trial. JAMA. 2004;292(23): 2839-2848. 38. Laguno M, Murillas J, Blanco JL, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for treatment of HIV/HCV co-infected patients. AIDS. 2004; 18(13):F27-F36. DISCLAIMER This review is designed to be a summary of information and represents the opinions of the author. Although detailed, the review is not exhaustive. Readers are strongly urged to consult any relevant primary literature, the complete prescribing information available in the package insert of each drug, and the appropriate clinical protocols. No liability will be assumed for the use of this review, and the absence of typographical errors is not guaranteed. Copyright 2008, McMahon Publishing, 545 West 45th Street, 8th Floor, New York, NY 10036. Printed in the USA. All rights reserved, including right of reproduction, in whole or in part, in any form. 12