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Advances in HCV treatment

Advances in HCV treatment

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  • PEGASYS ® HCV Global Slide Kit Slide . HCV treatment evolution
  • PEGASYS ® HCV Global Slide Kit Slide . The primary goal of HCV treatment is viral eradication
  • PEGASYS ® HCV Global Slide Kit Slide . HCV infection is considered eradicated when an SVR is achieved The durability of sustained virological response (SVR) following interferon-based treatment for chronic hepatitis C is an important question that can only be addressed by monitoring patients for a protracted period of time with periodic serum HCV RNA testing. As part of a long-term follow-up study to determine the durability of SVR in patients participating in phase III trials of peginterferon alfa-2a (40KD) (PEGASYS ® ) plus ribavirin (COPEGUS ® ), Swain et al. have reported that an SVR is durable for several years after the completion of treatment (patients assessed for 3.9 years [range 0.8–7.1] from the last date of treatment). 1. Swain M, et al. Gastroenterology 2010; 139: 1593.
  • PEGASYS ® HCV Global Slide Kit Slide 32. Definitions of on-treatment response Rapid virological response (RVR), defined as HCV RNA negative (<50 IU/mL) at week 4. Extended rapid virological response (eRVR), defined as HCV RNA negative (<50 IU/mL) at week 4–24. Complete EVR (cEVR), defined as HCV RNA positive at week 4 but negative at week 12. Partial EVR (pEVR), defined as HCV RNA positive at week 4 and 12 but ≥2 log 10 drop from baseline at week 12. Non-EVR, defined as <2 log 10 drop in HCV RNA from baseline at week 12.
  • PEGASYS ® HCV Global Slide Kit Slide . Patterns of virological response Virological response is determined first by the presence or absence of serum HCV RNA and then by the viral load in patients with HCV RNA positivity. Patients who fail to decrease HCV RNA level by < 2 logs after 24 weeks of therapy are termed null-responders. 1 Patients who exhibit an initial decline in HCV RNA levels (2 log decrease) during therapy but are still HCV RNA positive at Week 24 are deemed partial responders. 1 Patients who exhibit breakthrough are those who test HCV RNA negative and then test positive again before the end of treatment. 1,2 Patients who demonstrate end-of-treatment response (HCV RNA <50 IU/mL) and subsequently test positive for HCV RNA are considered relapsers. 1 Only those patients in whom HCV RNA levels are undetectable at the end of treatment and who maintain this response status throughout the follow-up period (to 24 weeks’ post-treatment) can be regarded as sustained virological responders. 1 1. Ghany M, et al. Hepatology 2009; 49: 1335 2. Farci P, et al. Proc Natl Acad Sci U S A 2002; 99: 3081
  • PEGASYS ® HCV Global Slide Kit Slide . Treatment failure: definitions Virological response is determined first by the presence or absence of serum HCV RNA and then by the viral load in patients with HCV RNA positivity. Patients who fail to decrease HCV RNA level by < 2 logs after 24 weeks of therapy are termed null-responders. 1 Patients who exhibit an initial decline in HCV RNA levels during therapy and subsequently return to near-baseline HCV RNA levels during the treatment period are deemed partial responders.1 Patients who exhibit breakthrough are those who test HCV RNA negative and then test positive again before the end of treatment. 1 Patients who demonstrate end-of-treatment response (HCV RNA <50 IU/mL) and subsequently test positive for HCV RNA are considered relapsers. 1 Only those patients in whom HCV RNA levels are undetectable at the end of treatment and who maintain this response status throughout the follow-up period (to 24 weeks’ post-treatment) can be regarded as sustained virological responders. 1 1. Ghany M, et al. Hepatology 2009; 49: 1335
  • PEGASYS ® HCV Global Slide Kit Slide . Biochemical and histological responses: definitions A biochemical response to treatment is the normalisation of previously elevated alanine aminotransferase (ALT) levels. 1 A sustained biochemical response is defined as normal serum ALT levels at the end of follow-up (24 weeks post-treatment). Patients who exhibit a biochemical response during therapy do not necessarily attain a virological response (i.e., HCV RNA clearance); nevertheless, the long-term prognosis (8 to 11 years post-therapy) of these patients has been reported to be as good as that of virological responders. 2 A histological response refers to an improvement (i.e., decrease) of at least 2 points in the 22-point Knodell Histologic Activity Index (HAI) score at the end of follow-up (24 weeks post-treatment). 3   1. Perry C, Jarvis B. Drugs 2001; 61: 2263 2. Shindo M et al. Hepatology 2001; 33: 129 3. Heathcote E, et al. N Engl J Med 2000; 343: 1673
  • Narrative: Using a model of patients infected with genotype 1, changing baseline variables dramatically changed the probability of achieving an SVR. A large difference was observed in hypothetical patients in whom five variables were changed to represent best and worst case scenarios of individuals infected with HCV. The best case scenario involved a patient with no cirrhosis/bridging fibrosis, an alanine aminotransferase (ALT) quotient of 7, age 20 years, a body mass index (BMI) of 20 kg/m2 and a viral load of 40,000 IU/mL. These factors were associated with an SVR probability of 97%. This can be compared to the worst case scenario, a patient with cirrhosis/bridging fibrosis, an ALT quotient of 1, age 60 years, BMI of 30 kg/m2 and a viral load of 9,000,000 IU/mL. This scenario was associated with a very low SVR probability of 7%. Treatment adherence and early virological response also increased the probability of an SVR. It appears that this logistical regression model can be used to predict the probability of achieving an SVR in individual patients. Reference: Foster GR, Fried MW, Hadziyannis SJ et al. Prediction of sustained virological response in chronic hepatitis C patients treated with peginterferon alfa-2a (40KD) and ribavirin. Scand J Gastroenterol. 2007;42:247-55.
  • PEGASYS ® HCV Global Slide Kit Slide . Evolution of hepatitis C treatment The hepatitis C virus (HCV) was identified in 1989. 1 There have been substantial improvements in the success of HCV treatment, and there are currently several approved treatments available. Initial treatment was with interferon alfa alone, administered as a three-times weekly subcutaneous injection for 24 or 48 weeks. The addition of the ribavirin to the treatment regimen further improved outcomes. Pegylation of interferon alfa has enhanced its pharmacokinetic profile, allowing more convenient once-weekly dosing, thereby improving therapeutic efficacy when used in combination with ribavirin. Pegylated interferon alfa plus ribavirin is now the treatment of choice for hepatitis C. 2 Rates of sustained virologic response (SVR) can be further optimised by tailoring treatment duration according to individual patients’ on-treatment responses, a concept termed response-guided therapy. 3 –9 Patients who achieve a virological response at week 4 and/or 12 can achieve high SVR rates with a shorter duration of therapy, 3 –6 whilst those who do not may benefit from treatment intensification. 7 –9 Among new antiviral treatments in development, inhibitors of the HCV RNA polymerase or the HCV protease are showing promise. 10 –16 Of these, the former show a lesser tendency towards the development of resistance. 10,13 In the future, these new molecules are likely to be used in combination with p egylated interferon alfa plus ribavirin. 11,14 –16 1. World Health Organization. Hepatitis C Fact Sheet No. 164, 2000 2. Ghany M, et al. Hepatology 2009; 49: 1335 3. Marcellin P, et al. 58th AASLD 2007; Abstract 1308 4. Jensen D, et al. Hepatology 2006; 43: 954 5. Ferenci P, et al. 58th AASLD 2007; Abstract 1301 6. Shiffman M, et al. N Engl J Med 2007; 357: 124 7. S á nchez-Tapias J, et al. Gastroenterology 2006; 131: 451 8. Berg T, et al. Gastroenterology 2006; 130: 1086 9. Willems B, et al. 42nd EASL 2007; Abstract 8 10. Sarrazin et al., Gastroenterology 2007;132:1767-77 11. Kieffer TL, et al. Hepatology 2007; 46:631 12. Roberts S, et al. 57th AASLD 2006; Abstract LB2 13. Le Pogam S, et al. EASL 2007; Abstract 622 14. Pockros P, et al. 58th AASLD 2007; Abstract 167 15. Jacobson et al, AASLD 2007: Abstract 177 16. Hezode C, et al. AASLD 2007: Abstract 80
  • PEGASYS ® HCV Global Slide Kit Slide . HCV treatment: pegylated interferon plus ribavirin is the current standard of care In the past decade, treatment for HCV infection has evolved considerably and there are now several agents approved for use in this indication. These are listed in the slide. Initially, the standard of care in HCV infection was to use interferon alfa three times a week with ribavirin twice daily for 48 weeks. Consensus interferon is a non-natural recombinant interferon that was developed by scanning subtypes of alpha interferon and assigning the most frequently observed amino acid at each position to form a consensus molecule. Pegylated interferons were then introduced and have proved to have superior efficacy to conventional interferon products. Like conventional interferons, pegylated interferons are usually used in combination with ribavirin. The rationale for pegylation is to prolong the plasma half-life, reduce clearance and reduce immunogenicity. 1 Two pegylated interferon products have been produced commercially. PEGASYS ® (peginterferon alfa-2a [40KD]) and pegylated interferon alfa-2b (12KD) have both shown superiority over conventional combination therapy. In two different but comparable studies, PEGASYS ® outperformed conventional therapy by 12%, whereas pegylated interferon alfa-2b (12KD) outperformed the same comparator by 7%. 2,3 1. Delgado C, et al. Clin Rev Ther Drug Carrier Syst 1992; 9: 249 2. Fried M, et al. N Engl J Med 2002; 347: 975 3. Manns M, et al. Lancet 2001; 358: 958
  • PEGASYS ® HCV Global Slide Kit Slide . Pegylated interferons lead to a significantly better treatment outcome There have been substantial improvements in the success of HCV treatment, and there are currently several approved treatments available. In a study published in 1998, treatment with interferon alfa-2b alone for 24 or 48 weeks resulted in SVRs of 6% and 13%, respectively. 1 In the same 1998 study, 48 weeks of treatment with the combination of interferon alfa-2b 3 MIU subcutaneously (sc) thrice weekly (tiw) with ribavirin 1000 or 1200 mg/day orally (po) resulted in SVRs in 38% (87/228) of patients. 1 In a second trial conducted in 1998 by the same group (International Hepatitis Interventional Therapy Group), treatment with this combination for 48 weeks produced SVRs in 43% (118/277) of patients. 2 Combining the results of these two trials yields an overall SVR of 41% (205/505). The combination of pegylated interferon plus ribavirin has been demonstrated to result in even higher SVRs. Manns et al. found that 48 weeks of treatment with the combination of pegylated interferon alfa-2b (12KD) 1.5  g/kg/wk plus ribavirin 800 mg/day produced an SVR in 54% of patients. 3 Fried et al. reported an SVR of 56% in patients treated for 48 weeks with peginterferon alfa-2a (40KD) (PEGASYS ® ) 180 μg/wk and plus ribavirin (COPEGUS ® ) 1000 or 1200 mg/day. 4 More recently, it has been reported that 48 weeks of treatment with the combination of PEGASYS ® 180  g/wk plus COPEGUS ® 1000 or 1200 mg/day produced an SVR in 63% of patients. 5 In a study by Zeuzem et al. (DITTO-HCV) the overall SVR rate with 48 weeks’ PEGASYS ® 180 mg/wk plus COPEGUS ® 1000–1200 mg/day was 66% and therefore, higher than in previous studies. 6 1. McHutchison J, et al. N Engl J Med 1998; 339: 1485 2. Poynard T, et al. Lancet 1998; 352: 1426 3. Manns M, et al. Lancet 2001; 358: 958 4. Fried M, et al. N Engl J Med 2002; 347: 975 5. Hadziyannis S, et al. Ann Intern Med 2004; 140: 346 6. Zeuzem S, et al. J Hepatol 2005; 43: 250
  • PEGASYS ® HCV Global Slide Kit Slide . Approved treatment duration is 48 weeks for genotype 1* and 24 weeks for genotype 2/3 Patients with HCV genotype 1 require treatment for 48 weeks and a standard dose of ribavirin. Patients with HCV genotypes 2 or 3 are adequately treated with 24 weeks’ treatment and a low dose of ribavirin. 24 weeks may now be considered for patients with a low viral load (≤800 000 IU/mL) at baseline and who achieve an RVR (EU only) Hadziyannis S, et al. Ann Intern Med 2004; 140: 346
  • PegIFN, peginterferon; RBV, ribavirin.   If we consider the evolution of HCV therapy, we can start by referring to the current standard, peginterferon and ribavirin, which was first introduced in 2001. The use of this combination increased sustained virologic response (SVR) rates to approximately 60% overall; however, in the genotype 1–infected population, the SVR rates have only been 40% to 50%.
  • PegIFN, peginterferon; RBV, ribavirin.   In 2011, we are entering the era of triple therapy. This will include the standard of care peginterferon/ribavirin as a backbone but will include the addition of a protease inhibitor, either boceprevir or telaprevir.
  • PegIFN, peginterferon; RBV, ribavirin.   In the future, we will have a large variety of different options that will include combining the peginterferon/ribavirin backbone with any of the different DAA drug classes but also the possibility of combining DAAs alone, omitting the use of ribavirin and/or peginterferon. The ultimate aim, of course, will be to achieve an all-oral treatment that eradicates the virus in almost every patient without side effects, but that is a goal for the future.
  • DAAs, direct-acting antivirals; ER, endoplasmic reticulum; HCV, hepatitis C virus; LD, luminal domain.   The elucidation of the life cycle of the hepatitis C virus (HCV) allowed for the identification of potential targets of antivirals that directly interrupt HCV replication. From the binding of the virus to the plasma membrane and its endocytosis through the membrane, all the way through uncoating and generating the membranous web to translation and replication, viral assembly, and transport and release again into the extracellular space, one may envision a variety of potential targets. The most obvious targets are the NS3/4 serine protease and the NS5B HCV polymerase. Therefore, our first DAAs have been protease inhibitors and nucleoside or nonnucleoside polymerase inhibitors.   Also interesting was the recent discovery of NS5A inhibitors that are inhibitors of the NS5A protein. However, the function of this protein in the hepatitis C life cycle is not yet well understood. Therefore, the inhibitory drugs may help to elucidate the involvement of this protein in the HCV life cycle rather than vice versa.  
  • DAAs, direct-acting antivirals. This is a list of some of the newly developed antivirals. It is not a complete list but includes many of the compounds with reported data at the major international meetings. They are listed by their clinical phase of development, from phase I to phase III. The majority of these different compounds in development can be categorized into classes of protease inhibitors, nucleoside or nonnucleoside polymerase inhibitors, and the NS5A inhibitors. Two drugs—the protease inhibitors boceprevir and telaprevir—that are in pivotal phase III programs are expected to be approved in 2011 in Europe and the United States.
  • PEGASYS ® HCV Global Slide Kit Slide . PEGASYS ® plus COPEGUS ® : SVR rates of up to 61% in genotype 1 This slide displays the SVR rates achieved with pegylated interferon plus ribavirin combination therapy in genotype 1. 1–5 The highest SVR rate to date in an international, multicentre study has been reported with PEGASYS ® plus COPEGUS ® . 5 1. Manns M, et al. Lancet 2001; 358: 958 2. Fried M, et al. N Engl J Med 2002; 347: 975 3. Hadziyannis S, et al. Ann Intern Med 2004; 140: 346 4. Ferenci P, et al. J Hepatol 2006; 44: 275 5. Zeuzem S, et al. J Hepatol 2005; 43: 250
  • PEGASYS ® HCV Global Slide Kit Slide . PEGASYS ® plus COPEGUS ® : SVR rate of >90% in genotype 2/3 This slide displays the SVR rates achieved with pegylated interferon plus ribavirin combination therapy in genotype 2 or 3. 1–5 High rates of SVR have been achieved with PEGASYS ® plus COPEGUS ® . 1. Yu M-L, et al. Gut 2007; 56: 553 2. Hadziyannis S, et al. Ann Intern Med 2004; 140: 346 3. Von Wagner M, et al. Gastroenterology 2005; 129: 522 4. Zeuzem S, et al. J Hepatol 2004; 40: 993 5. Mangia A, et al. N Engl J Med 2005; 352: 2609
  • PEGASYS ® HCV Global Slide Kit Slide . Safety/tolerability
  • PEGASYS ® HCV Global Slide Kit Slide . Management of patients treated with interferon plus ribavirin Haemolytic anaemia (haemoglobin <10 g/dL) has been observed in approximately 10% of patients treated with interferon plus ribavirin; therefore, complete blood counts should be performed early in the course of therapy and whenever clinically indicated. It is recommended that a patient whose haemoglobin level falls below 10 g/dL should have his or her ribavirin dose reduced and that a patient whose haemoglobin level falls below 8.5 g/dL be permanently discontinued from ribavirin therapy. Decreases in neutrophil counts have been noted in patients treated with interferon or interferon plus ribavirin. It has been recommended that interferon or interferon plus ribavirin treatment be discontinued when the neutrophil count falls below 0.5 x 10 9 /L, respectively. Combination therapy with interferon plus ribavirin should not be used by women who are pregnant or by men whose female partners are pregnant. Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients taking interferon plus ribavirin. Patients must undergo a pregnancy test monthly during therapy and for 6 months post-therapy. Women of childbearing potential must be counselled about use of effective contraception (two reliable forms) prior to initiating therapy. Therapy with interferon may also decrease platelet counts, and treatment should be discontinued when levels fall to below 25 x 10 9 /L. Severe psychiatric adverse events, including depression, psychoses, aggressive behaviour, hallucinations, violent behaviour (suicidal ideation, suicidal attempts, suicides) and rare instances of homicidal ideation have occurred during treatment with interferon plus ribavirin. These treatments should be used with extreme caution in patients with a history of pre-existing psychiatric disorders. All patients should be carefully monitored for evidence of depression and other psychiatric symptoms. REBETRON™. PDR ®
  • PEGASYS ® HCV Global Slide Kit Slide . Safety/tolerability: summary
  • PEGASYS ® HCV Global Slide Kit Slide . The role of ribavirin
  • PEGASYS ® HCV Global Slide Kit Slide 135. Ribavirin is a critical component of HCV therapy Pegylated interferon plus ribavirin has been clearly established as the standard of care in the treatment of chronic hepatitis C although the mode of action of ribavirin is not fully understood.
  • PEGASYS ® HCV Global Slide Kit Slide 136. Ribavirin: exact MOA not fully understood The mode of action of ribavirin is not fully understood but several potential mechanisms of action have been proposed including direct antiviral activity, inhibition of the enzyme inosine-monophosphate-dehydrogenase (IMPDH) leading to depletion of intracellular guanosine triphosphate (GTP) pools, immunomodulation or induction of error catastrophe as a result of accumulation of mutations in the viral genome. Despite the uncertainty over the actual mode of action of ribavirin, clinical practice has clearly shown that ribavirin plays a crucial role in combination with pegylated interferon at all stages of the treatment of hepatitis C. Dixit N & Perleson A, Cell Mol Life Sci 2006; 63: 832
  • PEGASYS ® HCV Global Slide Kit Slide 137. Significantly faster viral decay with addition of ribavirin The effect of ribavirin on the kinetics of viral suppression during the first 1–2 months of therapy was reported by Hermann and colleagues in 2003. Compared to patients receiving PEGASYS ® alone, patients receiving PEGASYS ® plus COPEGUS ® demonstrated a greater and more rapid decline in HCV RNA leading to an earlier undetectable viral load. Herrmann E, et al. Hepatology 2003; 37: 1351
  • PEGASYS ® HCV Global Slide Kit Slide 138. Increase in SVR by prevention of relapse with addition of ribavirin Fried and colleagues reported the effect of combining COPEGUS ® (1000–1200 mg/day) with PEGASYS ® (180 µg/week) compared to therapy with PEGASYS ® alone. COPEGUS ® contributed a relatively modest increase of 10% to the end of treatment response rates but a large 27% improvement in the rate of SVR driven by an even larger 32% reduction in the rate of relapse. Fried M, et al. NEJM 2002; 347: 975
  • PEGASYS ® HCV Global Slide Kit Slide 152. Maintaining ribavirin exposure prevents breakthrough* and relapse Similarly, if we look at patients experiencing viral relapse it was significantly more common in patients who discontinued COPEGUS ® compared with patients who maintained both PEGASYS ® and COPEGUS ® . The results of this study therefore demonstrate the importance, in genotype 1 patients, of maintaining both PEGASYS ® and COPEGUS ® therapy for the full duration of planned therapy. *Defined as achievement of HCV RNA negativity during treatment but becoming positive again before the end of treatment Bronowicki J-P, et al. Gastroenterology 2006; 131: 1040
  • PEGASYS ® HCV Global Slide Kit Slide . Treatment intensification in difficult-to-cure patients
  • PEGASYS ® HCV Global Slide Kit Slide . A number of factors influence response to therapy
  • PEGASYS ® HCV Global Slide Kit Slide . Genotype is the most important predictor of response Among independent host factors predictive of achieving a sustained virological response (SVR) with PEGASYS ® therapy, the strongest association by a large margin is seen for HCV genotype (non-1 vs 1). Additional predictive factors for achieving an SVR include age ( ≤ 40 years), baseline viral load (≤2 x 10 6 copies/mL), and baseline histology (F0/1/2). 1. Lee S, et al. J Hepatol 2002; 37: 500 2. Roche data on file
  • PEGASYS ® HCV Global Slide Kit Slide . Treatment intensification Treatment intensification can be through increasing treatment dose and/or duration
  • PEGASYS ® HCV Global Slide Kit Slide 234. Re-treatment of previous non-responders and relapsers: maximising success with PEGASYS ® plus COPEGUS ®
  • PEGASYS ® HCV Global Slide Kit Slide 235. Introduction It has been more than six years since pegylated interferon plus ribavirin supplanted conventional interferon plus ribavirin as the standard of care. There is a large and growing number of non-responders to the standard of care and effective treatment for these individuals is urgently required today. 1. Ghany M, et al. Hepatology 2009; 49: 1335 2. Dienstag J. & McHutchison J. Gastroenterology 2006; 130: 225
  • PEGASYS ® HCV Global Slide Kit Slide 236. SVR rates increase over time but 30 – 50% of patients do not achieve SVR The percentage of patients achieving SVR has steadily increased with the standard of care treatment in HCV infection: PEGASYS ® + COPEGUS ® . In 2005 66% of patients treated with PEGASYS ® + COPEGUS ® achieved an SVR 1 compared to 63% in 2004 2 and 56% in 2002. 3 A large cohort of patients (30 – 50%), however, do not achieve an SVR and remain infected with HCV. 1. Zeuzem S, et al. J Hepatol 2005; 43: 250 2. Hadziyannis S, et al. Ann Intern Med 2004; 140: 346 3. Fried M, et al. N Engl J Med 2002; 347: 975
  • PEGASYS ® HCV Global Slide Kit Slide 238. Definition of non-response and relapse Non-response defines patients who have positive HCV RNA levels at every assessment throughout the course of treatment. In virological relapse, patients initially respond to treatment and HCV RNA levels drop below the limit of detection but, upon cessation of treatment, RNA levels become detectable again. If the relapse happens before the end of the treatment protocol a virological breakthrough is said to have occurred. 1. Jensen D, et al. Ann Intern Med 2009; 150: 528 2. Ghany M, et al. Hepatology 2009; 49: 1335 3. Farci P, et al. PNAS 2002; 99: 3081
  • PEGASYS ® HCV Global Slide Kit Slide 239. PEGASYS ® is indicated for re-treatment of treatment-experienced patients PEGASYS ® is indicated for the re-treatment of treatment-experienced patients The recommended treatment duration is 48 weeks except for genotype 1 non-responders to prior pegylated interferon plus ribavirin where the recommended treatment duration is 72 weeks. The 12-week stopping rule: all patients are recommended to commence therapy. If there is detectable HCV RNA at week 12, treatment should be stopped. PEGASYS ® SPC, October 2009
  • PEGASYS ® HCV Global Slide Kit Slide 256. Re-treatment of relapsers: the Kaiser study
  • PEGASYS ® HCV Global Slide Kit Slide 260. Kaiser study: summary An SVR rate of 50% was achieved with 72 weeks of re-treatment with PEGASYS ® in patients who had previously relapsed with peginterferon plus ribavirin therapy. Achieving an RVR or negative HCV-RNA at week 12 of therapy is highly predictive of achieving an SVR. A 72-week re-treatment regimen was well tolerated in these relapser patients. Based on these data an extended 72-week treatment duration for relapsers should be considered. Kaiser S, et al. Hepatology 2008; 48 (4, Suppl); 1140A
  • PEGASYS ® HCV Global Slide Kit Slide . Other patient populations
  • PEGASYS ® HCV Global Slide Kit Slide . Patients with cirrhosis
  • PEGASYS ® HCV Global Slide Kit Slide 311. Higher SVR rates are achieved in patients without cirrhosis Patients with HCV infection and advanced fibrosis/cirrhosis show lower SVR rates compared to patients without cirrhosis; however, it is currently not known which baseline and on-treatment factors influence the SVR rates in patients with advanced fibrosis/cirrhosis. In their retrospective study, Bruno and colleagues used data from three large phase III studies of PEGASYS ® (peginterferon alfa-2a [40KD]) and COPEGUS ® (ribavirin) to determine the predictive values of baseline and on-treatment factors associated with SVR in patients with advanced fibrosis/cirrhosis.1 Patients were classified by liver staging (non-cirrhotic: Metavir ≤2, Knodell ≤2, Ishak ≤3; advanced fibrosis/cirrhotic: Metavir 3/4, Knodell 3/4, Ishak 4/5/6).1 Patients with genotype 1/4 infection received PEGASYS ® 180 µg/week plus COPEGUS ® 1000/1200 mg/day for 48 weeks.1 Patients with genotype 2/3 infection were randomised to PEGASYS ® 180 µg/week plus COPEGUS ® 800 mg/day for 24 or 16 weeks, respectively.1 Results: In the HCV genotype 1/4 group, the SVR rates were 60% (n=242) in patients without bridging fibrosis/cirrhosis, 51% (n=63) in those with bridging fibrosis (excluding cirrhosis) and 33% (n=36) in patients with cirrhosis (trend test: p=0.028).1 In the HCV genotype 2/3 group, the SVR rates following 24 week’s treatment were 76 % (n=629) in patients without bridging fibrosis/cirrhosis, 61% (n=119) in those with bridging fibrosis (excluding cirrhosis) and 57% (n=70) in patients with cirrhosis (trend test: p=0.0001).1 SVR rates were lower for genotype 2/3 patients with bridging fibrosis or cirrhosis treated for 16 weeks than for 24 weeks (48% versus 57%);1 however, among patients without bridging fibrosis/cirrhosis, an SVR rate of 67% was reported for genotype 2/3 patients treated for 16 weeks.2 References 1. Bruno S, et al. Hepatology 2009; 51: 388 2. Bruno S, et al. 43rd EASL 2008; Abstract 774
  • PEGASYS ® HCV Global Slide Kit Slide . PEGASYS ® + COPEGUS ® : improved efficacy in cirrhotic patients In the study by Fried and associates, PEGASYS ® plus COPEGUS ® was superior to conventional interferon alfa-2b plus ribavirin in patients with cirrhosis. Fried M, et al. N Engl J Med 2002; 347: 975
  • PEGASYS ® HCV Global Slide Kit Slide . Chronic hepatitis C and ‘normal’ alanine aminotransferase (ALT) levels
  • PEGASYS ® HCV Global Slide Kit Slide . Chronic hepatitis C and alanine aminotransferase (ALT) Up to 46% of patients with chronic hepatitis C have ALT levels within the currently defined ‘normal’ range. 1 These patients were historically excluded from treatment and clinical trials because they were considered ‘healthy’ or ‘asymptomatic’, not thought to have progressive fibrosis and there was concern that treatment may cause ALT flares. Although these patients were characterised historically as ‘asymptomatic’, the majority have some degree of liver damage and some show advanced fibrosis or cirrhosis. 2 Quality of life is significantly impaired in patients with chronic hepatitis C compared to healthy controls, irrespective of whether they have elevated or ‘normal’ ALT levels. 3 1. Alberti A, et al. Ann Intern Med 2002; 137: 961 2. Puoti C, et al. J Hepatol 2002; 37: 117 3. Foster G, et al. Hepatology. 1998; 27: 209
  • PEGASYS ® HCV Global Slide Kit Slide . ALT levels do not always correlate with degree or severity of liver disease ALT, a non-specific biochemical marker of liver damage, is released from damaged cells into the blood. Importantly, not all damaged liver cells release ALT. Therefore, although elevated levels are a reasonable indicator of liver damage, lower levels do not necessarily indicate a healthy liver. Levels of ALT tend to drop as cirrhosis develops and they can be affected by many factors such as alcohol consumption, concurrent medication, other viral infections or other liver diseases such as non-alcoholic fatty liver disease. As ALT levels can fluctuate during the course of disease, a single ‘normal’ ALT level may not be representative of the true pattern of ALT levels for a particular patient.
  • PEGASYS ® HCV Global Slide Kit Slide . A single ALT value may not be representative of the true ALT status A single ALT value may not be representative of the true pattern of ALT levels for a particular patient. Persistently ‘normal’ ALT can only be defined following serial measurements over a period of time. Although it is recommended that ‘normal’ ALT status be determined by three measurements over a 6-month period, 1 this may not be adequate to discriminate between patients with persistently ‘normal’ ALT and those with transient remissions. 2 Patients with ALT levels within the ‘normal’ range may show further reductions in ALT levels following treatment. In a study of retreatment with conventional interferon alfa plus ribavirin, a subgroup of patients with ALT levels within the ‘normal’ range before retreatment showed further decreases in ALT after treatment, which were associated with a sustained response. 3 1. Marcellin P, et al. Hepatology 1997; 26: 133S 2. Puoti C, et al. J Hepatol. 2002; 37: 117 3. Di Bisceglie A, et al. Hepatology. 2001; 33: 704
  • PEGASYS ® HCV Global Slide Kit Slide . 77% of patients with ‘normal’ ALT have some degree of liver damage Patients with chronic hepatitis C and ‘normal’ levels of ALT have been characterised historically as ‘healthy’ or ‘asymptomatic’. However, the majority of these patients have some degree of liver damage 1,2 and some show advanced fibrosis or cirrhosis. 3,4 Shiffman, et al. assessed the degree of liver damage in a group of 95 consecutive patients who presented for evaluation and treatment for chronic hepatitis C infection. Patients were divided into two groups, ‘normal’ or elevated ALT, on the basis of a review of their medical records. 1. Puoti C, et al. Hepatology 1997: 26: 1393 2. Pradat P, et al. Hepatology 2002; 36: 973 3. Puoti C, et al. J Hepatol 2002; 37: 117 4. Shiffman M, et al. J Infect Dis 2000; 182: 1595
  • PEGASYS ® HCV Global Slide Kit Slide . Fibrosis progression occurs in patients with persistently ‘normal’ ALT Fibrosis progression occurs in patients with persistently ‘normal’ ALT. Patients with chronic hepatitis C and persistently ‘normal’ ALT have a substantial lifetime risk of developing cirrhosis. Inability to predict which patients are going to have more accelerated progression; progression may not be linear. Therefore, treatment should not be withheld in patients with persistently ‘normal’ ALT because of a mistaken perception that their disease is benign. Hui et al compared the histological progression of fibrosis in 40 patients with chronic hepatitis C and persistently ‘normal’ ALT and 41 patients with chronic hepatitis C and elevated ALT. Nine patients (22.5%) with persistently ‘normal’ ALT had progression of fibrosis compared to 17 with elevated ALT (41.5%). There was a trend towards a significantly higher cumulative probability of fibrosis progression in patients with elevated ALT levels (p=0.06). Hui C-K, et al. J Hepatol 2003; 38: 511
  • PEGASYS ® HCV Global Slide Kit Slide . PEGASYS ® plus COPEGUS ® in patients with ‘normal’ ALT levels Previous clinical trials established the superiority of PEGASYS ® and COPEGUS ® combination therapy compared to conventional interferon-based therapy in patients with chronic hepatitis C and elevated ALT levels, in terms of both efficacy and safety. 1 PEGASYS ® and COPEGUS ® combination therapy showed significant improvement over conventional interferon across all genotypes and regardless of viral load. 1 The first and only major clinical trial of a pegylated interferon in patients with chronic hepatitis C who have persistently normal ALT levels was completed by Zeuzem et al. 2 1. Fried M, et al. N Engl J Med. 2002; 347: 975 2. Zeuzem S, et al. Gastroenterology 2004; 127: 1724
  • PEGASYS ® HCV Global Slide Kit Slide . Treatment and ALT levels
  • PEGASYS ® HCV Global Slide Kit Slide 385: Children and adolescents
  • PEGASYS ® HCV Global Slide Kit Slide 386. Chronic hepatitis C in children and adolescents The scale of the HCV infection in children is not well understood. In the paediatric population under 12 years of age the seroprevalence is estimated to be 0.2%. In adolescents between 12 and 19 years of age the seroprevalence is estimated to be 0.4%. 1 Thirty to sixty percent of children with HCV develop chronic HCV 1 The main route of HCV transmission in children is blood transfusion. Other risk factors include circumcision, vertical transmission and living in a house with a family member infected with HCV. However, up to 70% of HCV infection in children is caused by unidentified risk factors. 2 Children with HCV respond better to interferon than adults. Sustained response rates in patients with HCV genotype 1 infection: 27% vs. 8 – 10% for children and adults respectively. 3 1. Mushtaq M et al. Curr Pediatr Res 2009; 13(1 & 2): 35 2. El-Raziky MS et al. World J Gastroenterol 2007; 13(12): 1828 3. Jacobson IM et al. J Pediatr Gastroenterol Nutr 2002; 34(1): 52
  • PEGASYS ® HCV Global Slide Kit Slide 388. CHIPS: virological response in children and adolescents with PEGASYS ® plus COPEGUS ® In CHIPS good sustained virological response (SVR) rates were achieved with PEGASYS ® (peginterferon alfa-2a [40KD]) plus COPEGUS ® (ribavirin). The overall SVR rate was 66% which is similar to that reported for adults. Early virological response is predictive of SVR. Among patients who achieved an EVR, 83% reported an SVR; however, among patients who did not achieve an EVR, only 22% achieved an SVR. 1. Sokal EM, et al. J Hepatol. 2010; 52: 827
  • PEGASYS ® HCV Global Slide Kit Slide 389. CHIPS: PEGASYS ® plus COPEGUS ® was generally well tolerated in children and adolescents Treatment related adverse events that occurred at a frequency >10% are listed on this slide. The treatment was generally well tolerated; however, it was frequently associated with flu-like and gastrointestinal symptoms. There were two SAEs that led to treatment discontinuation resulting from acute hepatitis and (acute hepatitis and laboratory abnormality/thyreotoxicosis. 1. Sokal EM, et al. J Hepatol. 2010; 52: 827
  • Transcript

    • 1. Advances in HCV TREATMENT DR. SADIQ ZIA
    • 2. ALT DOES NOT MEAN ABSOLUTE LIVER TEST DR. SADIQ ZIA
    • 3. AND
    • 4. SGPT SHOULD NOT MEAN SIMPLE G.P. TEST
    • 5. The primary goal of HCV treatment is viral eradication Primary objective  Viral eradication – SVR  Arrest progression of necrosis/fibrosis Secondary objective  Reduce progression of fibrosis/cirrhosis  Prevent decompensation  Prevent HCC SVR = sustained virological response HCC = hepatocellular carcinoma
    • 6. HCV infection is considered eradicated when an SVR is achieved  SVR is defined as absence of HCV RNA in the serum at the end of treatment and 6 months later1  >99% of patients remained HCV RNA-negative after completion of treatment with pegylated interferon alfa- 2a (40KD) plus ribavirin when assessed for 3.9 years (range 0.8–7.1) from the last date of treatment • SVR is long lasting and clinical relapse is extremely rare in patients who are ‘cured’ of chronic hepatitis C 1. Ghany M, et al. Hepatology 2009; 49: 1335 2. Swain M, et al. Gastroenterology 2010; 139: 1593.
    • 7. Response Definition RVR* HCV RNA negative (<50 IU/mL) at week 4 eRVR HCV RNA negative (<50 IU/mL) at week 4–24 EVR** Complete EVR HCV RNA positive at week 4 but negative at week 12 Partial EVR HCV RNA positive at week 4 and 12 but ≥2 log10 drop from baseline at week 12 Non-EVR <2 log10 drop from baseline at week 12 Definitions of on-treatment response * RVR = rapid virological response ** EVR = early virological response
    • 8. Patterns of virological response Sustained responder (SVR) Null responder Baseline Treatment Time Relapser Partial responder Undetectable HCV RNA HCVRNA Breakthrough Detection limit 6 months 1. Ghany M, et al. Hepatology 2009; 49: 1335 2. Farci P, et al. Proc Natl Acad Sci U S A 2002; 99: 3081
    • 9. Treatment failure: definitions Non-response • Detectable HCV RNA levels at the end of treatment or end of follow-up. Includes: – Null responders: failure to decrease HCV RNA by at least 2 logs after 24 weeks – Partial responders: ≥2 log decrease in HCV RNA but positive at week 24 – Relapsers: HCV RNA-negative at the end of treatment but subsequently positive during the follow-up period Breakthrough • HCV RNA levels become undetectable during treatment, but virus reappears while still on treatment Ghany M, et al. Hepatology 2009; 49: 1335
    • 10. Biochemical and histological responses: definitions Biochemical response • Normalisation of serum alanine aminotransferase (ALT) levels1 (if elevated at baseline) Histological response • Improvement of ≥2 points in total Histology Activity Index (HAI) score at the end of follow-up (24 weeks post-treatment), using the Knodell scoring system2 1. Perry C, Jarvis B. Drugs 2001; 61: 2263 2. Heathcote E, et al. N Engl J Med 2000; 343: 1673
    • 11. Probability of SVR Interactions of Multiple Factors Cirrhosis No No No No No No No Yes ALT quotient 7 2 2 2 2 2 1 1 Age (years) 20 20 43 43 43 60 60 60 BMI (kg/m2 ) 20 20 26 26 26 30 30 30 HCV RNA (IU/mL ×103 ) 40 40 40 1200 9000 9000 9000 9000 ProbabilityofAchievinga SustainedVirologicResponse 97 89 74 52 36 19 14 7 0 10 20 30 40 50 60 70 80 90 100 1 2 3 4 5 6 7 8Patient Number Foster GR et al. Scand J Gastroenterol. 2007;42:247-255.
    • 12. Evolution of hepatitis C treatment Discovery of HCV genome Addition of RBV to IFN alfa improved outcomes Peg-IFN alfa plus RBV becomes gold standard Treatment with IFN alfa for 24 or 48 weeks – 3x weekly dosing – Poor outcomes Peg-IFN mono – once-weekly dosing 20101989 Response-guided therapy emerging New antivirals enter development
    • 13. HCV treatment Pegylated interferon plus ribavirin is the current gold standard
    • 14. Pegylated interferons lead to a significantly better treatment outcome 6% 13% 41% 66% 0 10 20 30 40 50 60 70 IFN 24 weeks1 IFN 48 weeks1 IFN+RBV 48 weeks1,2 PEGASYS® + COPEGUS® 48 weeks3 SVR(%) 1. McHutchison J, et al. N Engl J Med 1998; 339: 1485 2. Poynard T, et al. Lancet 1998; 352: 1426 3. Zeuzem S, et al. J Hepatol 2005; 43: 250 1998 2004
    • 15. Approved treatment duration is 48 weeks for genotype 1* and 24 weeks for genotype 2/3 84% 79% 0 20 40 60 SVR(%) Genotype 1 80 81% 80% 100 Genotype 2/3 24-LD 24-SD 48-LD 48-SD 96 144 99 153 Hadziyannis S, et al. Ann Intern Med 2004; 140: 346 PEGASYS® 180 µg plus COPEGUS® 29% 41%42% 52% n= 101 118 250 271 LD = RBV 800 mg/day; SD = RBV 1000–1200 mg/day * 24 weeks may now be considered for patients with a low viral load (≤800 000 IU/mL) at baseline and who achieve an RVR (EU only)
    • 16. Treatment of Chronic Hepatitis C with Peginterferon and Ribavirin SVR Rates in Pivotal Trials Pegasys1,2 PEG-Intron3 Overall 56% & 63% 54% (61%) Genotype 1 46% & 52% 42% (48%) Genotype 1, HVL 41% & 47% 30% (37%) Genotype 2 & 3 76% & 84% 1 Fried MW, et al. N Engl J Med 2002;347:975-982. 2 Hadziyannis S, et al. Ann Intern Med 2004;140:346-355. 3 Manns MP, et al. Lancet 2001;358:958-965. (RBV > 10.6 mg/kg by post-hoc analysis)
    • 17. Side Effects of PegIFN/Ribavirin • Depression ranging from mild to suicidality • Irritability, aggressive behavior • Worsening of mania • Fatigue • Insomnia • Myalgias, fever, flu- like symptoms • Hair loss • Cytopenias“Interferon Man” Slide courtesy Chia Wang
    • 18. To Treat or not to Treat: A Constellation of Considerations Duration of infection Personal plans (marriage, pregnancy) Age ALT HIV coinfection Extrahepatic Features (Fatigue, EMC, PCT) Patient "mindset" Genotype virus Genotype Patient (IL28) Contraindications & comorbidities Insulin Resistance Histologic stage 20%+ life time risk Of cirrhosis Family and other support Occupation PinK AALSD CME 2009
    • 19. clinicaloptions.com/hepatitis Change Folio Title on Master /Arial 15pt /Unbold White clinicaloptions.com/hepatitis Future Generations: Direct-Acting Antivirals for Hepatitis C Evolution of HCV Therapy 2001 PegIFN/RBV
    • 20. clinicaloptions.com/hepatitis Change Folio Title on Master /Arial 15pt /Unbold White clinicaloptions.com/hepatitis Future Generations: Direct-Acting Antivirals for Hepatitis C Evolution of HCV Therapy 2001 2011 PegIFN/RBV Protease inhibitor
    • 21. clinicaloptions.com/hepatitis Change Folio Title on Master /Arial 15pt /Unbold White clinicaloptions.com/hepatitis Future Generations: Direct-Acting Antivirals for Hepatitis C Evolution of HCV Therapy 2001 2011 Beyond PegIFN/RBV Protease inhibitor Nucleos(t)ide polymerase inhibitor Nonnucleoside polymerase inhibitor NS5A inhibitor
    • 22. clinicaloptions.com/hepatitis Change Folio Title on Master /Arial 15pt /Unbold White clinicaloptions.com/hepatitis Future Generations: Direct-Acting Antivirals for Hepatitis C New Therapies  Nucleoside and nucleotide polymerase inhibitors  Non-nucleoside polymerase inhibitors  NS5a inhibitors  Novel Interferons  Other Immune Modulators  Anti-fibrotics
    • 23. Role of Genes
    • 24. SOME OF THE NEW NAMES YOU WOULD COME ACROSS SOON BOCEPRAVIR TELEPRAVIR Vaniprevir Danoprevir Filibuvir Narlaprevir
    • 25. THANKS
    • 26. clinicaloptions.com/hepatitis Change Folio Title on Master /Arial 15pt /Unbold White clinicaloptions.com/hepatitis Future Generations: Direct-Acting Antivirals for Hepatitis C Oral drugs (known as direct-acting antivirals, or DAAs) that specifically target certain steps in the hepatitis C virus life cycle are in late-stage development. New Therapies
    • 27. clinicaloptions.com/hepatitis Change Folio Title on Master /Arial 15pt /Unbold White clinicaloptions.com/hepatitis Future Generations: Direct-Acting Antivirals for Hepatitis C HCV Life Cycle and DAA Targets Adapted from Manns MP, et al. Nat Rev Drug Discov. 2007;6:991-1000. Receptor binding and endocytosis Fusion and uncoating Transport and release (+) RNA Translation and polyprotein processing RNA replication Virion assembly Membranous web ER lumen LD LD ER lumen LD NS3/4 protease inhibitors NS5B polymerase inhibitors Nucleoside/nucleotide Nonnucleoside *Role in HCV life cycle not well defined NS5A* inhibitors
    • 28. clinicaloptions.com/hepatitis Change Folio Title on Master /Arial 15pt /Unbold White clinicaloptions.com/hepatitis Future Generations: Direct-Acting Antivirals for Hepatitis C  HCV-specific protease inhibitors will be the first DAA class available. – Protease inhibitors block cleaving of viral proteins New Therapies
    • 29. clinicaloptions.com/hepatitis Change Folio Title on Master /Arial 15pt /Unbold White clinicaloptions.com/hepatitis Future Generations: Direct-Acting Antivirals for Hepatitis C Select DAAs in Clinical Development Phase I Phase II Phase III Protease Inhibitors ABT-450 ACH-1625 GS 9451 MK-5172 VX-985 BMS-650032 CTS-1027 Danoprevir GS 9256 IDX320 Vaniprevir BI 201335 Boceprevir Telaprevir TMC435 Nonnucleoside polymerase inhibitors BI 207127 IDX375 ABT-333 ABT-072 ANA598 BMS-791325 Filibuvir Tegobuvir VX-759 VX-222 Nucleoside polymerase inhibitors IDX184 PSI-7977 RG7128 NS5A inhibitors A-831 PPI-461 BMS-790052 BMS-824393 CF102
    • 30. PEGASYS® plus COPEGUS® : SVR rates of up to of 61% in genotype 1 0 10 20 30 40 50 60 70 80 SVR(%) 60% 46% 52% 52% 2005 Zeuzem5 2002 2004 298 271 95 90 Fried2 Hadziyannis3 2006 Ferenci4 1. Manns M, et al. Lancet 2001; 358: 958 2. Fried M, et al. N Engl J Med 2002; 347: 975 3. Hadziyannis S, et al. Ann Intern Med 2004; 140: 346 4. Ferenci P, et al. J Hepatol 2006; 44: 275 5. Zeuzem S, et al. J Hepatol 2005; 43: 250; 6. Sakai T, et al. EASL 2006; Abstract 605 n= 99 61% 2006 Sakai6 0 10 20 30 40 50 60 70 80 SVR(%) 42% 348 2001 Manns1 n= Peg-IFNα-2b (12KD) + RBV PEGASYS® + COPEGUS® 48-week treatment duration
    • 31. PEGASYS® plus COPEGUS® : SVR rate of >90% in genotype 2/3 *Patients had undetectable HCV RNA at Week 4 1. Hadziyannis S, et al. Ann Intern Med 2004; 140: 346 2. Von Wagner M, et al. Gastroenterology 2005; 129: 522 3. Yu M-L, et al. Gut 2007; 56: 553 4. Zeuzem S, et al. J Hepatol 2004; 40: 993 5. Mangia A, et al. N Engl J Med 2005; 352: 2609 Von Wagner*2 84% 80% n=0 10 20 30 40 50 60 70 100 90 80 SVR(%) 20042004 Hadziyannis1 2006 Yu3 95% 96 71 100 Peg-IFNα-2b (12KD) + RBV PEGASYS® + COPEGUS® 24-week treatment duration 81% 76% n=0 10 20 30 40 50 60 70 100 90 80 SVR(%) 2004 2005 Mangia5 Zeuzem4 224 70
    • 32. Safety/tolerability
    • 33. Management of patients treated with interferon plus ribavirin  Monitoring and dose reduction for ribavirin-related anaemia  Monthly monitoring for pregnancy; emphasis on prevention  Monitoring white blood cell and platelet counts  Monitoring for evidence of depression REBETRON™. PDR®
    • 34. Safety/tolerability  Compared with conventional combination therapy, fewer patients receiving PEGASYS® plus COPEGUS® report ’flu-like symptoms such as pyrexia, myalgia and rigors  The incidence of depression is significantly lower among patients receiving PEGASYS® plus COPEGUS® than among those receiving conventional combination therapy (22% versus 30%; p=0.01)  Better tolerability should encourage better patient adherence Fried M, et al. N Engl J Med 2002: 347: 975 Conventional combination therapy refers to interferon alfa plus ribavirin
    • 35. The role of ribavirin
    • 36. Ribavirin is a critical component of HCV therapy  Pegylated interferon plus ribavirin is the current standard of care for the treatment of chronic hepatitis C  Ribavirin plays an important role in combination with pegylated interferon but what is it and how does it work?
    • 37. Ribavirin: exact MOA not fully understood  Potential mechanisms for antiviral activity of ribavirin:1 • Direct inhibition of HCV replication • Inhibition of the enzyme inosine-monophosphate- dehydrogenase (IMPDH) • Immunomodulation • Mutagenesis  Ribavirin plays an important role in combination with pegylated interferon during all stages of HCV therapy 1. Dixit N & Perleson A, Cell Mol Life Sci 2006; 63: 832
    • 38. Significantly faster viral decay with addition of ribavirin 6 Viralload(log10IU/mL) 5 4 3 2 1 0 7 14 21 28 42 Limit of detection PEGASYS® 180µg/wk plus COPEGUS® 1000–1200 mg/day (n=10) PEGASYS® 180µg/wk (n=17) 56 Days Herrmann E, et al. Hepatology 2003; 37: 1351
    • 39. Increase in SVR by prevention of relapse with addition of ribavirin Patients(%) 56% 29% Fried M, et al. NEJM 2002; 347: 975 0 10 20 30 40 50 60 70 80 90 100 n= 224 453 224 453 132 313 SVR Relapse PEGASYS® 180 µg/wk + COPEGUS® 1000–1200 mg/day PEGASYS® 180 µg/wk 51% 19% 48 weeks’ treatment; all patients 69% 59% ETR ETR = end-of-treatment response
    • 40. Maintaining ribavirin exposure prevents breakthrough* and relapse 0 10 20 30 40 50 PEGASYS® 180 µg/wk plus COPEGUS® 800 mg/day PEGASYS® 180 µg/wk 30 36 48 Bronowicki J-P, et al. Gastroenterology 2006; 131: 1040 2% 5% 2% 6% 12% p=0.010 52 60 72 14% 32% 26% 42% 29% 42% p<0.001 p=0.004 p=0.020 Week DetectableHCVRNA(%) 3% * Defined as achievement of HCV RNA negativity during treatment but becoming positive again before the end of treatment
    • 41. Treatment intensification in difficult-to-cure patients
    • 42. A number of factors influence response to therapy Host factors • Race • Age • Gender • Body weight* • Insulin resistance* • Substance abuse* • Comorbidities* Treatment • Adherence* • Side effects* • Type of regimen* • Dose* • Duration* • Experience of MD* Viral factors • Genotype • Viral load Disease factors • Coinfection* • Fibrosis • Cirrhosis Reasons for treatment failure * Factors which can be influenced
    • 43. Genotype is the most important baseline predictor of response 1. Lee S, et al. J Hepatol 2002; 37: 500 2. Roche data on file 0 20 40 60 80 100 120 140 160 180 G enotype (1 versus non-1) Pre-treatm entviralload AgeALT quotient H istology R ace B ody w eight 800 versus 1000 or 1200 m g C O PEG U S® U S vs non-U S G ender WaldChi-square Patients treated with PEGASYS®
    • 44. Treatment intensification Treatment intensification Increase COPEGUS® dose Increase PEGASYS® dose PEGASYS® 270 µg/wk + COPEGUS® for 48 weeks Fixed-dose induction: PEGASYS® 360 µg/wk + COPEGUS® for 12 weeks followed by 180 µg/wk + COPEGUS® for 36 weeks Increase PEGASYS® + COPEGUS® treatment duration (Response-guided therapy) PROGRESS G1 HVL pilot study G1 HVL pilot study PROGRESS
    • 45. Re-treatment of previous non-responders and relapsers: maximising success with PEGASYS® plus COPEGUS®
    • 46. Introduction  There is a large and growing number of patients not achieving a sustained virological response (SVR) with the current standard of care  Effective treatment strategies for these patients are needed today 1. Ghany M, et al. Hepatology 2009; 49: 1335 2. Dienstag J & McHutchison J. Gastroenterology 2006; 130: 225
    • 47. 1. Manns M, et al. Lancet 2001; 358: 958; 2. Fried M, et al. N Engl J Med 2002; 347: 975 3. Hadziyannis S, et al. Ann Intern Med 2004; 140: 346 4. Zeuzem S, et al. J Hepatol 2005; 43: 250 SVR rates increase over time but 30–50% of patients do not achieve SVR 2002 2004 2005 511 453 436 134 Fried2 Hadziyannis3 Zeuzem4 56% 63% 66% 54% 2001 Manns1 Peg-IFNα-2b (12KD) + RBV PEGASYS® + COPEGUS®48-week treatment duration n= 0 10 20 30 40 50 60 70 100 90 80 SVR(%) All genotypes
    • 48. Definition of non-response and relapse  Non-response: occurs when a positive serum HCV RNA test result is observed at every assessment after initiation of treatment  Relapse: occurs if HCV RNA falls below the limit of detection (<50 IU/mL) during treatment but becomes detectable after end of treatment • If relapse occurs before the treatment regimen is complete this is termed virological breakthrough 1. Jensen D, et al. Ann Intern Med 2009; 150: 528 2. Ghany M, et al. Hepatology 2009; 49: 1335 3. Farci P, et al. PNAS 2002; 99: 3081
    • 49. PEGASYS® is indicated for re-treatment of treatment-experienced patients  PEGASYS® plus RBV is indicated for patients who have failed previous treatment with IFN alpha (pegylated or non-pegylated) alone or in combination with RBV • Recommended treatment duration is 48 weeks – 72 weeks for genotype 1 PegIFN/RBV non-responders • Patients who have detectable virus at week 12 should stop therapy PEGASYS® SPC, October 2009
    • 50. Re-treatment of relapsers: the Kaiser study
    • 51. Kaiser study: summary  SVR rate of 50% achieved with 72 weeks of re-treatment with PEGASYS® in patients who had previously relapsed  Achieving an RVR or negative HCV-RNA at week 12 of therapy is highly predictive of achieving SVR  A 72 week re-treatment regimen was well tolerated in these relapser patients  Based on these data an extended 72 week treatment duration for relapsers should be considered Kaiser S, et al. Hepatology 2008; 48 (4, Suppl); 1140A
    • 52. Other patient populations
    • 53. Patients with cirrhosis
    • 54. Higher SVR rates are achieved in patients without cirrhosis Bruno S, et al. Hepatology 2009; 51: 388 Patients without bridging fibrosis/cirrhosis Patients with bridging fibrosis Patients with cirrhosis Genotype 2/3 24 weeks† n= 60 51 33 242 63 36 76 61 57 629 119 70 * 48 weeks PEGASYS® 180 µg/wk plus COPEGUS® 1000/1200 mg/day † 24 weeks PEGASYS® 180 µg/wk plus COPEGUS® 800 mg/day Trend test: p=0.0028 (Genotype1/4) and p=0.0001 (Genotype 2/3) Genotype 1/4 48 weeks* SVR(%) 0 40 60 80 20
    • 55. PEGASYS® + COPEGUS® : improved efficacy in cirrhotic patients Fried M, et al. N Engl J Med 2002; 347: 975 IFN alfa-2b + ribavirin 0 10 20 30 40 33% 50 n=54 SVR(%) PEGASYS® plus COPEGUS® 0 10 20 30 40 43% 50 n=56 SVR(%)
    • 56. Chronic hepatitis C and ‘normal’ alanine aminotransferase (ALT) levels
    • 57. Chronic hepatitis C and alanine aminotransferase (ALT)  Up to 46% of patients with chronic hepatitis C have ALT levels within the currently defined ‘normal’ range1  These patients were historically considered ‘healthy’ or ‘asymptomatic’ and have not received treatment  However, >80% have some degree of liver damage on biopsy2  Quality of life is significantly impaired in patients with chronic hepatitis C (and elevated or persistently ‘normal’ ALT)3 1. Alberti A, et al. Ann Intern Med 2002; 137: 961 2. Puoti C, et al. J Hepatol 2002; 37: 117 3. Foster G, et al. Hepatology 1998; 27: 209
    • 58. ALT levels do not always correlate with degree or severity of liver disease  Although elevated ALT levels are generally associated with hepatocellular damage, lower levels are not always associated with mild liver disease  ALT levels fall as cirrhosis develops  Many factors, independent of liver damage, can affect ALT levels  ALT levels may fluctuate throughout the course of chronic hepatitis C
    • 59. A single ALT value may not be representative of the true ALT status  It is recommended that ALT status be defined by three measurements over a 6-month period1  However, studies suggest that this time period may not be adequate2  Patients with ALT levels within the ‘normal’ range may show further reduction in serum ALT levels following treatment3 1. Marcellin P, et al. Hepatology 1997; 26: 133S 2. Puoti C, et al. J Hepatol 2002; 37: 117 3. Di Bisceglie A, et al. Hepatology. 2001; 33: 704
    • 60. 77% of patients with ‘normal’ ALT have some degree of liver damage ‘Normal’ ALT Shiffman M, et al. J Infect Dis 2000; 182: 15 Elevated ALT No Fibrosis 23% Mild 39% Portal 26% Bridging 6% Cirrhosis 6% No Fibrosis 19% Mild 19% Cirrhosis 22% Bridging 16% Portal 24%
    • 61. Fibrosis progression occurs in patients with ‘normal’ ALT 2 4 6 8 10 12 Years 0 20 40 60 80 100 Cumulativeprobabilityoffibrosis(%) ‘Normal’ ALT Elevated ALT p=0.06 Hui C-K, et al. J Hepatol 2003; 38: 511
    • 62. PEGASYS® plus COPEGUS® in patients with ‘normal’ ALT levels  In chronic hepatitis C patients with elevated ALT levels • PEGASYS® plus COPEGUS® therapy shows significant improvement in efficacy and tolerability over conventional interferon-based therapy across all HCV genotypes, irrespective of viral load1  PEGASYS® is the first and only pegylated interferon approved in the European Union for the treatment of patients with ALT levels persistently within the current ‘normal’ range 1. Fried M, et al. N Engl J Med 2002; 347: 975
    • 63. Treatment and ALT levels  AASLD 2009 guidelines state: • Regardless of the serum ALT level, the decision to initiate therapy with pegylated interferon and ribavirin should be individualized based on the severity of liver disease by liver biopsy, the potential for serious side effects, the likelihood of response, and the presence of comorbid conditions Ghany MG, et al. Hepatology 2009; 49: 1335
    • 64. Children and adolescents
    • 65. Chronic hepatitis C in children and adolescents  The prevalence of HCV in children is approximately: • 0.2% in those younger than 12 years old1 • 0.4% in those between 12 and 19 years old1  The main route of transmission of HCV in children is blood transfusion2  Of those infected, 30-60% will develop chronic HCV infection1  Children with HCV respond better to IFN than adults: • Sustained response rates in patients with HCV genotype 1 infection: 27% vs. 8–10% for children and adults respectively3 1. Mushtaq M et al. Curr Pediatr Res 2009; 13 (1 & 2): 35 2. El-Raziky MS et al. World J Gastroenterol 2007; 13(12): 1828 3. Jacobson IM et al. J Pediatr Gastroenterol Nutr. 2002 Jan; 34(1): 52
    • 66. 57% 57% Genotype 2/3 (24 weeks) Genotype 1/4/5/6 (48 weeks) Sokal EM, et al. J Hepatol 2010; 52: 827 Early response (12 weeks) EOT SVR 83% 15/18 27/47 94% 17/18 27/47 89% 57% 16/18 27/47n/N CHIPS: virological response in children and adolescents with PEGASYS® plus COPEGUS® Virologicalresponserate(%) 60 0 40 80 100 20
    • 67. CHIPS: PEGASYS® plus COPEGUS® was generally well tolerated in children and adolescents Sokal EM, et al. J Hepatol 2010; 52: 827 *Includes fever † Includes irritability, depression and change of mood N number shown at the bottom of each bar Flu-like sym ptom s*H eadache Abdom inalpain FatiguePsychiatricD erm atitis N ausea/vom iting D ecreased appetiteInsom niaSore throatD iarrhoea Injection site reactions B acterialinfectionsB reathless Thyroid problem Incidence(%) 54 45 38 34 34 29 23 22 18 15 14 14 14 11 11 222935 1215 925 22 1419 10 7 799 30 0 20 50 60 10 40