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Treatment guidelines have recently been modified inline with the considerable therapeutic advances made regarding combination therapy with RBV and the introduction of pegylated IFNα molecules (French Consensus Conference Statement: Treatment of Hepatitis C, 2002; National Institutes of Health Consensus Statement, 2002). The guidelines conclude that combination therapy with IFNα / RBV results in better treatment responses than with monotherapy, and that the highest response rates are achieved when RBV is combined with a pegylated IFNα.
Pegylated IFNα / RBV combination therapy is recommended for patients who are naïve to treatment and for whom pegylated IFNα and RBV are not contraindicated (French Consensus Conference: Treatment of Hepatitis C, 2002; National Institutes of Health Consensus Statement, 2002).
Based on data from the clinical trials of PEGASYS®, it was recommended that treatment regimens be based on the infecting genotype (French Consensus Conference: Treatment of Hepatitis C, 2002; National Institutes of Health Consensus Statement, 2002). Patients with genotype 1 infection require 48 weeks of combination treatment with a standard dosage of 1000 or 1200 mg/day RBV, while a 24-week course of treatment with a reduced dose of RBV (800 mg/day) is sufficient for patients infected with genotype 2 or 3. Recent data have shown that the optimal treatment regimen for patients infected with genotype 4 is the same as that for genotype 1 (Diago et al, 2004). Using this regimen, it is possible to achieve high SVRs, similar to those reported for genotypes 2 and 3. Specific data are lacking for patients infected with genotypes 5 and 6 and thus the same regimen is recommended as for genotype 1.
It has been suggested by Foster (2002) that a liver biopsy for patients infected with HCV genotype 2 or 3 is no longer necessary. The French guidelines support this proposal and state that liver biopsy may not be necessary if the decision to treat has already been taken and does not depend on the histological result. Liver biopsy at the end of the treatment-free follow-up period is only indicated in patients who did not respond virologically but whose histological result may affect their subsequent management, for example, initiation of ‘maintenance’ therapy with pegylated IFN monotherapy aimed at slowing down the progression of fibrosis. The duration of ‘maintenance’ therapy would depend on tolerability.
Predictors of Response
Viral Factors
It is becoming increasingly apparent that several virus-specific factors are highly predictive of the response of HCV-infected patients to IFNα-based treatments. Viral genotype and high viral load are known to be the two most important factors that influence success rates to treatment (Trepo, 2000: Lee S, et al. J Hepatol 2002; 37: 500). Patients with HCV genotypes 1 and 4 are regarded as being more difficult-to-treat than those infected with genotypes 2 and 3 (Davis and Lau, 1997; Koshy et al, 2000; Shiratori and Omata, 2000; Zylberberg et al, 2000; Nishiguchi et al, 2001). Current guidelines therefore recommend that treatment decisions are primarily made according to HCV viral genotype (Strader D, et al. Hepatology 2004; 39: 1147).
A low baseline viral load is more likely to be cleared from the blood more quickly than higher HCV titres. Consequently, it is generally accepted that an early decline in viral RNA levels is associated with a high chance of SVR and thus a good prognosis. Conversely, those patients who do not demonstrate an early response to therapy are less likely to achieve an SVR (Karino et al, 1997; Fallows et al, 2000; Lee et al, 2000; Min et al, 2000; Neumann et al, 2000; Saito et al, 2000; Ferenci et al, 2001, Fried et al, 2002).
Patient-specific Factors
Studies have also identified several patient-specific baseline factors that are predictive of patients’ responses to therapy. For example, factors that negatively influence treatment outcomes include male gender, African descent, older age, alcohol abuse, high body weight and the presence and severity of fibrosis/cirrhosis or other co-morbidities (Davis and Lau, 1997; Schalm et al, 1997; Poynard et al, 1998; Lee et al, 2000; Zeuzem et al, 2000a; Lee S, et al. J Hepatol 2002; 37: 500). Awareness of the influence of these factors on treatment success is increasing, and more consideration is being given to them when making important treatment decisions.
Treatment success also depends upon on-treatment responses to therapy. Indeed, pivotal studies supportive of these observations influenced the current treatment guidelines. For example, the discontinuation of treatment in patients who have at least a 2 log10 drop in viral load by week 12 of treatment - the so-called ‘12-week stopping rule’ (Fried M, et al. N Engl J Med 2002; 347: 975; Strader D, et al. Hepatology 2004; 39: 1147).
However, the approach of response-guided therapy takes this concept further, redefining the definitions of on-treatment responses and allowing the customization of individual patient’s therapy according to their on-treatment responses.
For G1/4 patients, levels of serum HCV RNA are measured at weeks 4 and 12. If serum HCV RNA levels are undetectable (<50 IU/mL) at treatment week 4, patients are said to have achieved a rapid virological response (RVR). If however, an RVR is not achieved but HCV RNA levels are detectable (>50 IU/mL) but a ≥2log10 reduction from baseline levels has been achieved at week 12, the patient is said to have a partial early virological response (pEVR). On the other hand, if HCV RNA is undetectable at week 12, then a complete early virological response (cEVR) has been achieved. Finally, non-EVR patients are defined as those with <2 log10 drop in HCV RNA levels from baseline at week 12. Since 97% of G2/3 patients achieve a cEVR or pEVR at week 12 (Shiffman M, et al. 57th AASLD 2006; Abstract 340), these patients are only assessed at week 4 to determine their RVR status.
The predictive value of these newer definitions of on-treatment responses has been demonstrated in a recent study, in which very high rates of SVR (87%) were observed in G1 patients with an RVR (Marcellin P, et al. 18th APASL 2008; Abstract FP022). Similarly, G1 patients with a cEVR had a high SVR rate (68%), whilst the SVR rate for those with a pEVR was just 27% (Marcellin P, et al. 18th APASL 2008; Abstract FP022).
Outcomes of such studies into the predictive value of RVR, cEVR and pEVR have thus lead to a more tailored approach to individual patients’ therapy. For example, G1 patients with low baseline viral loads who achieve an RVR can achieve an SVR even if the standard treatment duration is reduced from 48 to 24 weeks, a finding that lead to the revision of the EU PEGASYS® license (Jensen D, et al. Hepatology 2006; 43: 954; PEGASYS® EU SPC, revised 2007). On the other hand, G1 patients who achieve a pEVR have improved rates of SVR (up to 69%) if their treatment duration is extended from 48 to 72 weeks (Sánchez-Tapias JM, et al. APASL 2007; Abstract 0-196).
A similar approach has also proven valuable for G2/3 patients: those patients with an RVR who had a low or high baseline viral load have demonstrated SVR rates of 94% or 88%, respectively (Shiffman M et al. 18th APASL 2008; Abstract FP023). In contrast, less than half (49%) of G2/3 patients without an RVR achieved a subsequent SVR (Shiffman M et al. 18th APASL 2008; Abstract FP023). Consequently, studies have demonstrated that these G2/3 patients with low viral loads who achieve an RVR may be treated successfully for shorter durations (Shiffman M, et al. N Engl J Med 2007;357:124-34; Yu M-L, et al. Gut 2007: 56: 553). For example, SVR rates of up to 90% were achieved in G2/3 patients who had the standard treatment duration shortened from 24 to 16 weeks (Shiffman M, et al. N Engl J Med 2007;357:124-34). Conversely, for G2/3 patients without an RVR, extension of their treatment duration from 24 to 48 weeks has been shown to result in SVR rates of up to 76% (Willems B, et al. 42nd EASL 2007; Abstract 8).
Thus, the application of response-guided therapy, which takes into account patient- and viral baseline factors together with their on-treatment response, can allow therapy to be tailored to the needs of individual patients. This customised approach to HCV therapy can further improve SVR rates for particular sub-sets of patients.
Response-guided therapy has also found a place in the treatment of prior non-responders to interferon therapy. The REPEAT study investigated the efficacy of PEGASYS® plus COPEGUS for the treatment of prior non-responders to PegIntron plus ribavirin for 48 or 72 weeks, with or without an induction phase of PEGASYS® 360μg. The results demonstrated that extension of the treatment duration to 72 weeks improved SVR rates for these patients (Jensen D, et al. 58th AASLD 2007; Abstract LB4). Furthermore, achievement of HCV RNA negativity at week 12, during both the initial and re-treatment phases, was found to be predictive of SVR even in this difficult-to-treat patient sub-set (Marcellin P, et al. 43rd EASL 2008, Abstract # 805).