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Hepatitis C Treatment
   the correctable factors of treatment failure during the previous course of therapy.
Consistent with the change in HCV RNA during the previous course of therapy, four different patterns of treatment failure
   with crucial implications for the buy fluconazole 150 mg no prescription  regimen, duration and likelihood of response to retreatment  can be distinguished:
1.   Patients with less than 2 log10UI/ml decline in HCV RNA from baseline to treatment week 12 are defined as nonresponders. Within this group, null responders show a minimal reduction in HCV RNA level (usually less than 1 log10UI/ml), being considered the most refractory group to treatment with pegylated interferon alfa (PegIFN) and ribavirin (RBV). SVR rates during retreatment rarely surpass 15% in this population. Therefore, unless other compelling reasons impose therapy in these fungal infection  patients (such as control of extrahepatic manifestations or advanced liver disease), the best option may be to closely monitor them while waiting for triple therapy (PegIFN/RBV + a directacting antiviral).
2.   Patients with >2 log10UI/ml decline in HCV RNA from baseline to treatment week 12, who remain HCV RNA detectable at week 24 are partial virological responders.
3.   Breakthrough is order fluconazole 100mg  online defined as detectable HCV RNA during therapy, after an initial virologic response (HCV RNA undetectable or >2 log10UI/ml decline at week 12).
4.   In contrast to previous categories, relapsers are those who, during therapy, achieved and maintained undetectable HCV RNA (measured by a high sensitive assay), but HCV RNA become again measurable during the first 6 months after the end of therapy. Relapsers have the best chance of achieving SVR during retreatment with PegIFN/RBV, with a SVR rate of approximately 40%. Triple therapy with a protease inhibitor further increase this rate.
Numerous host and virological factors strongly influence the response to therapy. A complex constellation of fixed factors related to virus, such as genotype 1 or high pretherapeutic viral
Antiviral therapy in nonresponders, relapsers and special populations | 45
load (VL) or to the patient, such as AfricanAmerican or Hispanic race, severity of liver fibrosis/cirrhosis, hepatic steatosis or insulin resistance (IR), negatively impact the therapeutic outcome during a subsequent course of treatment. On the contrary, identifying correctable factors that may have contributed to prior treatment failure can help the decision of retreatment and subsequent management. The most common correctable factors that can significantly diminish the rate of SVR include:
Dose reduction, transient discontinuation or premature interruption of therapy, due to side effects such as anemia, neutropenia or depression. Close monitoring and judicious interventions (modest dose reduction, use of growth factors, prophylactic antidepressants) could minimize these factors.
Lack of adherence to the prescribed medication regimen. Rigorous adherence should be stressed and monitored.
Therapeutical strategies
The following strategies for prior genotype 1 nonresponders and relapsers can be distinguished:
1.   Retreatment with PegIFN/RBV
2.   Extended treatment duration for slow virological responders
3.   Increasing PegIFN dose and longer treatment duration
4.   Optimizing PegIFN and RBV dosing during retreatment
5.   Maintenance therapy with lowdose of PegIFN
6.   Triplecombination therapy
1.   Retreatment with the previous regimen (PegIFN/RBV). In
the EPIC3 study, nonresponders and relapsers to previous therapy with interferon alfa (n=1203) or PegIFN alfa2a/2b (n=820) with or without RBV were retreated with PegIFN alfa2b (1.5pg/kg/week) and weightbased RBV (8001400 mg/day) for 48 weeks (Poynard 2009). SVR was higher in prior relapsers vs. nonresponders (38% vs. 14%) and in patients who achieved
46 | Hepatitis C Treatment
an EVR (56%) during the second course of therapy (Poynard 2008; Poynard 2009).
2.   Extended treatment duration for slow virological responders. Slow virological responders are patients with >2 log10 decline in HCV RNA at treatment week 12, who achieve undetectable HCV RNA between 12 and 24 weeks of therapy. In this group, standard 48week course of therapy has been associated with a high rate of virological relapse after therapy. Despite differences in study design (different criteria of randomization to extended therapy, different doses of RBV), several randomized controlled trials comparing 72 weeks to 48 weeks of treatment among slow virological responders have shown consistently that prolonged therapy significantly improves rates of SVR (44% vs. 28% [SanchezTapias 2006]; 38% vs. 18% [Pearlman 2007]), largely by decreasing the rate of relapse (40% vs. 64% [Berg 2006]; 20% vs. 59% [Pearlman 2007]). However, extending therapy has been associated with a higher rate of AEs and premature discontinuation beyond 48 weeks of treatment, a finding that temper this approach in many patients.
3.   Increasing PegIFN dose and longer treatment duration. Trials of intensified regimen with higher fixeddose of PegIFN and/or longer treatment duration have demonstrated only modest increases in SVR in prior nonresponders to PegIFN/RBV. In the REPEAT trial (Jensen 2009) prior nonresponders received PegIFN alfa2a higherdose induction (360^g/week) for 12 weeks, followed by the usual 180^g/week for a further 60 or 36 weeks (total duration 72 and 48 weeks, respectively) with RBV 10001200 mg/day. The SVR rate was higher for those treated for 72 weeks; no difference was found between the induction and noninduction arms. This confirms that retreatment of nonresponders with extended therapy may improve SVR rates, while induction therapy with higher
Antiviral therapy in nonresponders, relapsers and special populations | 47
dose of PegIFN has no beneficial effect. Multiple logistic regression analysis indicated that EVR at 12 weeks consistently predicts SVR in retreated nonresponders (Marcellin 2008).
4.   Optimizing PegIFN and RBV dosing during retreatment.
When combined with PegIFN, RBV is critical to prevent relapse after treatment cessation. A small prospective study on 10 patients with HCV genotype 1 infection and high baseline VL (>800, 000 IU/ml) showed feasibility and high efficacy of treatment with high RBV doses (Lindhal 2005). RBV was calculated to achieve a steadystate concentration above 15 pmol/ml. Prophylactic and asneeded administration of erythropoietin and blood transfusions were required in a single patient. SVR was achieved in 9 of 10 patients without major treatment regimen violation. RBV dosing at 1315 mg/kg appears to be the best balance between optimized efficacy and intolerable hemolytic anemia that develops at high doses. SVR is significantly diminished when RBV dose is below 11 mg/kg. Therefore, maximizing RBV dosing, particularly in overweight patients, has the potential to improve SVR during the second course of therapy. In a retrospective analysis of a large database of patients treated with PegIFN/RBV, it has been demonstrated that RBV dose reduction led to a stepwise decrease in SVR. The cumulative dose of RBV below 60% is associated with an evident decline in SVR (Reddy 2007). Thus, not only maximizing RBV dosing, but also maintaining a cumulative RBV dose higher than 80% of the overall dose, with or without erythropoietin, improves SVR in previous nonresponders and relapsers.
Other trials (Fried 2006) demonstrated improved SVR in patients with body weight above 85 kg treated with higher dose of PegIFN/RBV. Patients treated with PegIFN alfa2a, 270 pg/week and RBV 1600 mg/day, showed an SVR of 48% versus 28% in those treated with standard dosing regimen (relapse rates 19% vs. 40%). However, higher dose regimen was associated with an increased rate of hematological AEs.
48 | Hepatitis C Treatment
5.   Maintenance therapy with lowdose of PegIFN. Nonsustained responders to SoC, with advanced fibrosis or cirrhosis, have a high risk for disease progression and complications. Two large multicentre trials have evaluated the benefits of maintenance therapy with lowdose PegIFN in this group:
   the COPILOT study (Colchicine vs. PegIFN alfa2b 0.5 ^g/kg/week Long Term) (Afdhal 2008)
   the HALTC study (Hepatitis C Antiviral LongTerm Treatment Against Cirrhosis with PegIFN alfa2a 90 ^g/week) (Di Bisceglie 2008)
In the COPILOT study 555 patients with prior failure to interferonbased therapy were randomized to receive either PegIFN alfa2b 0.5 ^g/kg/week (n=286) or colchicine 0,6 mg twice daily (n=269). No differences were observed between the two groups with respect to progression of the CP score, development of complications of portal hypertension or HCC.
The HALTC trial was a prospective, randomized, controlled study of longterm maintenance therapy with PegIFN alfa2a 90 ^g/week (n=517) or no treatment (n=533) for 3.5 years in patients with chronic hepatitis C (CHC) and advanced fibrosis or cirrhosis (Ishak score 36) who did not achieve SVR after interferonbased therapy. By the end of the study period, there was no difference between the control and treated groups in the frequency of death, hepatic decompensation or development of HCC. Overall, the COPILOT and HALTC trials showed that maintenance therapy with lowdose PegIFN alfa2a or alfa2b does not reduce the rate of liverrelated death, clinical disease progression and complications over a period of up to 4 years.
6.   Triplecombination therapy. Triple therapy combination of PegIFN/RBV with a protease inhibitors (telaprevir or boceprevir) in HCV genotype 1experienced patients has been shown to produce high rates of virological response in both prior relapsers
Antiviral therapy in nonresponders, relapsers and special populations | 49
and, to a lesser extent, prior nonresponders in phase III trials. A detailed presentation of the newly aproved directacting antivirals (DAAs) is given in chapter 4.
Prove3 trial evaluated triplecombination therapy with telaprevir in treatmentexperienced patients (~60% nonresponders and ~40% relapsers) (McHutchison 2010). Patients were randomized on four treatment arms in order to assess the impact of different durations of triple therapy, different total treatment duration and the importance of RBV for this difficulttotreat population. Prior relapsers treated with 24 weeks of triple therapy followed by 24 weeks of PegIFN/RBV (total duration of therapy 48 weeks) had a SVR rate of 76%, while prior nonresponders had lower rates of SVR (~40% ).
RESPOND2 evaluated triple therapy combination with boceprevir in nonresponders and relapsers (Bacon 2011). The results indicate that 75% of prior relapsers and 52% of prior nonresponders treated with a fixed triple therapy boceprevir regimen achieved SVR. In the responseguided arm, SVR was 69% in prior relapsers and 40% in prior nonresponders.
Curent available data clearly show that that triple therapies including a protease inhibitor provide higher chance of SVR for relapsers and nonresponders. The benefits of these novel treatment regimens for each individual patient must be weighed against the side effects, costs and potential of developing viral resistance.
Practical approach to retreatment
When deciding retreatment of previous nonsustained responders to standard therapy, the following practical issues should be considered:
   Patient’s motivation for another course of therapy. Lower likelihood of SVR in treatmentexperienced patients, side effects, poor QoL should be discussed with the patient;
   Severity of liver disease (clinical, biochemical, histological). Patients with minimaltomoderate fibrosis
50 | Hepatitis C Treatment
may wait for triple therapy while patients with advanced fibrosis should be treated immediately with available regimens;
   Virological response during the initial course of therapy. Null and partial responders achieve lower SVR rates as compared with relapsers, irrespective of therapeutic regimen. Slow virological responders who have relapsed may benefit from extending duration of therapy;
   Previous dose regimen and adherence assessment. Optimizing RBV dosing, minimizing dose reductions by use of growth factors and avoiding premature discontinuations are important issues during retreatment;
   Correctable factors that may affect the subsequent response to therapy: steatosis, insulinresistance, chronic alcohol consumption etc.
How to manage genotype 2 and 3 nonresponders and relapsers.