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Treatment failure with pegylated interferon (PEG-IFN)/ribavirin (RBV) dual therapy can be due to either the persistence of hepatitis C virus (HCV) RNA throughout treatment (nonresponse) or the reappearance of the virus after the end of treatment (relapse; Table 1). Nonresponses can be subdivided according the drop in the viral load at week 12: a partial response (>2 log) or a null response (<2 log). These definitions are important when the retreatment of treatment-experienced patients is being considered. One important limitation in practice is that data on viral quantification are not available for many patients. As an alternative, the week 4 decline in the viral load during a lead-in phase with PEG-IFN/RBV can be used to differentiate null responders from partial responders.

Table 1. Types of Treatment-Experienced Patients
PatientsHCV RNA
Week 12Week 24End of TreatmentEnd of Follow-Up
Null responders<2 log [RIGHTWARDS ARROW] stop   
Partial responders>2 logDetectable [RIGHTWARDS ARROW] stop  
RelapsersNegative or >2 logNegativeNegativePositive

Retreatment of Nonresponders to Dual Therapy and Relapsers

  1. Top of page
  2. Abstract
  3. Retreatment of Nonresponders to Dual Therapy and Relapsers
  4. Treatment of Nonresponders to Triple Therapy and Relapsers
  5. References

Retreatment With PEG-IFN/RBV

Before the initiation of treatment, it is mandatory to identify and, if possible, correct factors that may explain the failure of the previous treatment (see Table 2).

Table 2. Factors Affecting the Treatment Response
Treatment-Related Factors
 Inadequate dose (PEG-IFN and RBV)
 Inadequate duration of treatment
 Poor adherence and side effects
Host Factors
 Interleukin-28B T allele carrier
 Advanced fibrosis
 Age > 40 years
 Male sex and race
 Obesity, high body mass index, and steatosis
 Insulin resistance
 Excessive alcohol consumption
 Vitamin D deficiency?
 Coinfection (human immunodeficiency virus and hepatitis B virus)
Viral Factors
 HCV genotype
 High baseline viral load

Except for relapsers, the retreatment of nonresponders with PEG-IFN/RBV is limited in value, even when the dose of PEG-IFN is increased and/or the duration of treatment is extended. Even the proportion of relapsers who benefit from dual therapy is small.

Retreatment With Triple Therapy

With the availability of the first generation of protease inhibitors (telaprevir and boceprevir), retreatment has become more successful for patients infected with HCV genotype 1. In phase 3 trials, up to 90% of relapsers, approximately 50% of partial responders, and approximately 35% of null responders achieved a sustained virological response (SVR).

In the Retreatment With HCV Serine Protease Inhibitor Boceprevir and Peginterferon/Rebetol 2 trial,1 the overall SVR rates were significantly higher for patients randomized to boceprevir versus patients randomized to a placebo (59%-66% versus 21% in the PEG-IFN/RBV control group), for previous relapsers (61%-67% versus 22%), and for patients with a previous partial response (40%-52% versus 7%). The magnitude of the change in the HCV RNA level at the end of the 4-week lead-in phase was predictive of SVR. SVR rates were higher for patients who had at least a 1-log10 drop in the HCV RNA level by week 4 (73%-79% in the two boceprevir-treated groups versus 25% in the placebo group) and were lower in patients who had less than a 1-log drop at this time point (33%-34% versus 0%). Approximately half of the patients (53%) who were enrolled in the REALIZE trial2 were previous relapsers, 19% had a previous partial response, and 28% were previous nonresponders to PEG-IFN/RBV (Table 2). The overall SVR rates were significantly higher for both telaprevir groups versus the PEG-IFN/RBV control group (64%-66% versus 17%) and for previous relapsers (83%-88% versus 24%), partial responders (54%-59% versus 15%), and nonresponders (29%-33% versus 5%). Among patients with bridging fibrosis or cirrhosis and a prior nonresponse, the SVR rate was 28%. Thus, although protease inhibitors have advanced HCV therapy overall, the much-in-need-of-therapy population of patients with cirrhosis and a demonstrated lack of interferon sensitivity still remains a major challenge.

Furthermore, it should be stressed that in the phase 3 trials, the number of patients with cirrhosis was limited. The role of baseline factors and on-treatment predictors has not been studied in detail. Because the success of triple therapy requires a sufficient response to PEG-IFN/RBV, null responders will do worse than relapsers and partial responders. The boceprevir trial did not include null responders. However, it is unclear how much interferon effect is required to achieve SVR with triple therapy.3 As far as it can be judged from the available data, patients with advanced fibrosis and a null response (those with the greatest need for an effective treatment) receive the lowest benefit but have the highest risk of developing resistant viral mutants. Thus, the results of retreating patients with compensated cirrhosis and a previous null response with telaprevir have been disappointing. Patients with more advanced cirrhosis (who have the greatest need for treatment) have not been studied at all. Preliminary data from the French Compassionate Use of Protease Inhibitors in viral C cirrhosis (CUPIC) cohort,4 which included patients with portal hypertension (approximately 20%), showed a high rate of severe adverse events when telaprevir or boceprevir was used.

Many direct-acting antivirals are in phase 2 or 3 trials, and their results are expected to further improve the response rates. New hope is coming from the excellent results of phase 2a trials with quadruple therapies combining 2 direct-acting antivirals with or without PEG-IFN/RBV. The combination of PEG-IFN/RBV with daclatasvir (a nonstructural protein 5A inhibitor) and asunaprevir (a protease inhibitor) led to a 100% SVR rate in null responders. The same combination without PEG-IFN/RBV in Japanese patients with genotype 1b was equally effective.

Treatment of Nonresponders to Triple Therapy and Relapsers

  1. Top of page
  2. Abstract
  3. Retreatment of Nonresponders to Dual Therapy and Relapsers
  4. Treatment of Nonresponders to Triple Therapy and Relapsers
  5. References

This new group of nonresponders has not been studied so far; only anecdotal data about intravenous silibinin as a successful rescue treatment have been published.

In summary, the development of new antivirals has allowed significant improvements in the effectiveness of the management of treatment-experienced patients. It is important to determine the pattern of previous nonresponsiveness in order to choose the optimal treatment regimen. The rich pipeline of new antivirals promises to provide further improvements in this difficult-to-treat population.

References

  1. Top of page
  2. Abstract
  3. Retreatment of Nonresponders to Dual Therapy and Relapsers
  4. Treatment of Nonresponders to Triple Therapy and Relapsers
  5. References
  • 1
    Bacon BR, Gordon SC, Lawitz E, Marcellin P, Vierling JM, Zeuzem S, et al. Boceprevir for previously treated chronic HCV genotype 1 infection. N Engl J Med 2011; 364: 1207-1217.
  • 2
    Zeuzem S, Andreone P, Pol S, Lawitz E, Diago M, Roberts S, et al. Telaprevir for retreatment of HCV infection. N Engl J Med 2011; 364: 2417-2428.
  • 3
    Ferenci P. Treatment of chronic hepatitis C - are interferons really necessary? Liver Int 2012; 32 Suppl 1: 108-112.
  • 4
    Hezode C, Dorival C, Zoulim F, et al. Safety of telaprevir or boceprevir in combination with peginterferon alfa/ribavirin, in cirrhotic non responders. First results of the French Early Access Program (ANRS CO20-CUPIC) in real-life setting. HEP DART. Hawaii: Global Antiviral Journal; 2011: p. 54. http://www.informedhorizons.com/hepdart2011/default.aspx.