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The recent development of direct-acting antiviral (DAA) molecules that are active on hepatitis C virus (HCV) has raised the concern that resistance may undermine therapy based on DAAs. A new standard-of-care treatment is now available for treatment-naive patients and treatment-experienced patients infected with HCV genotype 1. This treatment is based on a triple combination of pegylated interferon α (IFNα), ribavirin and a protease inhibitor (either telaprevir or boceprevir).

Principles of HCV Resistance to DAAs

  1. Top of page
  2. Abstract
  3. Principles of HCV Resistance to DAAs
  4. Resistance to Telaprevir or Boceprevir Monotherapy
  5. Mechanisms of Treatment Failure During Triple-Combination Therapy With Pegylated IFNα, Ribavirin, and Telaprevir or Boceprevir
  6. Posttreatment Behavior of Protease Inhibitor–Resistant HCV Variants
  7. Consequences of Treatment Failure for the Outcome of Liver Disease
  8. Implications of Treatment Failure for Future DAA-Based Therapy
  9. References

Viral resistance to a DAA drug corresponds to the selection (during treatment) of viral variants that bear amino acid substitutions altering the drug target and that are, therefore, less susceptible to the drug's inhibitory activity. These DAA-resistant variants preexist as minor populations within the patient's quasispecies (i.e., the ensemble of all viral variant populations present in a given individual). However, preexisting drug-resistant variants are rarely detected with current techniques before therapy because the amino acid substitutions that confer resistance also generally reduce replicative capacity in the absence of the drug.

Drug exposure profoundly inhibits the replication of the dominant, wild-type, drug-sensitive viral population, and the resistant variants gradually occupy the vacant replication space. Resistance is usually associated with a typical escape pattern (with a rapid recovery of pretreatment levels of viral replication) when amino acid substitutions confer a high level of resistance without impairing fitness in the presence of the drug (Fig. 1). Viral replication may resume more gradually if the resistant virus is not very fit. Cross-resistance (i.e., overlapping resistance) between two antiviral drugs that target the same site or function is due to amino acid substitutions that confer reduced susceptibility to both drugs.

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Figure 1. Schematic representation of the dynamics of wild-type (sensitive) and resistant HCV variants during treatment with a DAA with a low barrier to resistance (e.g., telaprevir or boceprevir) when it is administered alone. The wild-type (sensitive) viral population, which is dominant at the start of therapy, is efficiently inhibited by the DAA and shows a biphasic decline. Resistant viruses, which are present at the start of therapy as minor, less fit, and most often undetectable viral populations (with currently available techniques), grow exponentially during DAA administration at rates depending on their relative in vivo fitness, which may improve in a stepwise manner with the accumulation of novel mutations. The wild-type virus may be cleared entirely if the DAA is administered for a sufficient amount of time. Otherwise, the wild-type viral population generally grows back and again becomes the dominant population within a period of months to years.

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Resistance to Telaprevir or Boceprevir Monotherapy

  1. Top of page
  2. Abstract
  3. Principles of HCV Resistance to DAAs
  4. Resistance to Telaprevir or Boceprevir Monotherapy
  5. Mechanisms of Treatment Failure During Triple-Combination Therapy With Pegylated IFNα, Ribavirin, and Telaprevir or Boceprevir
  6. Posttreatment Behavior of Protease Inhibitor–Resistant HCV Variants
  7. Consequences of Treatment Failure for the Outcome of Liver Disease
  8. Implications of Treatment Failure for Future DAA-Based Therapy
  9. References

Telaprevir and boceprevir bind tightly to the catalytic site of the HCV protease, compete with its natural substrates, the polyprotein cleavage sites, and thereby inhibit polyprotein processing (i.e., the generation of mature viral proteins). HCV protease inhibitors have a low genetic barrier to resistance, and they have been shown to select resistant HCV variants in vitro and in vivo.1, 2 These variants bear amino acid substitutions that are located in close vicinity to the protease catalytic triad, alter the affinity of the drugs for the enzyme's catalytic site, and thereby attenuate their inhibitory activity. Boceprevir and telaprevir share extensive cross-resistance. The most frequent resistance substitutions that they select are V36A/M, T54A/S, R155K/T/Q, V36A/M+R155K/T, A156V/T, and V36A/M+A156V/T; however, numerous other substitutions have been reported during the administration of these drugs. HCV subtypes 1a and 1b are associated with slightly different resistance patterns.

Mechanisms of Treatment Failure During Triple-Combination Therapy With Pegylated IFNα, Ribavirin, and Telaprevir or Boceprevir

  1. Top of page
  2. Abstract
  3. Principles of HCV Resistance to DAAs
  4. Resistance to Telaprevir or Boceprevir Monotherapy
  5. Mechanisms of Treatment Failure During Triple-Combination Therapy With Pegylated IFNα, Ribavirin, and Telaprevir or Boceprevir
  6. Posttreatment Behavior of Protease Inhibitor–Resistant HCV Variants
  7. Consequences of Treatment Failure for the Outcome of Liver Disease
  8. Implications of Treatment Failure for Future DAA-Based Therapy
  9. References

In treatment-adherent patients, the failure of the triple combination of pegylated IFNα, ribavirin, and a protease inhibitor to eradicate an HCV infection results primarily from an inadequate response to pegylated IFNα and ribavirin, which leads to uncontrolled outgrowth of resistant variants selected by the protease inhibitor. Indeed, phase 2 and 3 clinical trials have shown that the outcome of triple-combination therapy strongly depends on the ability of pegylated IFNα and ribavirin to induce a sufficiently strong antiviral response in host cells,3-6 as detailed in Table 1. Figure 2 shows schematic representations of the dynamics of wild-type (sensitive) and resistant HCV variants during treatment with a DAA with a low barrier to resistance (e.g., telaprevir or boceprevir) that is administered in combination with pegylated IFNα and ribavirin according to the antiviral effects of IFNα and ribavirin.

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Figure 2. Schematic representation of the dynamics of wild-type (sensitive) and resistant HCV variants during treatment with a DAA with a low barrier to resistance (e.g., telaprevir or boceprevir) when it is administered in combination with pegylated IFNα and ribavirin according to the antiviral effects of IFNα and ribavirin. (A) A DAA in combination with pegylated IFNα and ribavirin exerts a potent antiviral effect. The wild-type virus is efficiently inhibited by the additive or synergistic actions of pegylated IFNα/ribavirin and the DAA, and this results in its rapid clearance. The minor preexisting DAA-resistant viral population is controlled by pegylated IFNα and ribavirin and is rapidly eliminated. The patient is cured. (B) A DAA in combination with pegylated IFNα and ribavirin exerts a modest antiviral effect. In this case, the treatment duration is crucial because DAA-resistant viruses may take months to be cleared by the weak combined action of pegylated IFNα and ribavirin. The patient either may be cured or may experience a breakthrough or relapse because of the DAA-resistant viral population. (C) A DAA in combination with pegylated IFNα and ribavirin exerts virtually no antiviral effect. In effect, the patient is receiving virtual monotherapy with the DAA, and the outcome is similar to that shown in Fig. 1.

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Table 1. Rates of Treatment Failure (No Sustained Virological Response) in Phase 2 and 3 Clinical Trials of Combination Therapy With Pegylated IFNα2b, Ribavirin, and BOC or With Pegylated IFNα2a, Ribavirin, and Telaprevir According to the HCV RNA Decline During a 4-Week Lead-In Phase With Pegylated IFNα and Ribavirin Dual-Agent Therapy
  • Abbreviations: BOC, boceprevir; PR48, peginterferon and ribavirin for 48 weeks; RESPOND-2, Retreatment With HCV Serine Protease Inhibitor Boceprevir and Peginterferon/Rebetol 2; RGT, response-guided therapy; SPRINT, Serine Protease Inhibitor Therapy; T12PR48, telaprevir for 12 weeks and peginterferon and ribavirin for 48 weeks.

  • *

    Treatment-naive patients in the 28-week arm received 24 weeks of the triple combination after the 4-week lead-in phase; patients in the 48-week arm received 44 weeks of the triple combination after the 4-week lead-in phase.4

  • b

    The results for the nonblack treatment-naive cohort are presented. Patients in the BOC/RGT arm received 24 weeks of the triple combination after the 4-week lead-in phase if HCV RNA was undetectable (<9.3 IU/mL) at weeks 8 and 24 of therapy (weeks 4 and 20 of BOC administration) or 44 weeks of the triple combination after the 4-week lead-in phase if it was not; patients in the BOC/PR48 arm received 44 weeks of the triple combination after the 4-week lead-in phase.5

  • c

    Treatment-experienced patients in the BOC/RGT arm received 32 weeks of the triple combination after the 4-week lead-in phase if HCV RNA was undetectable (<9.3 IU/mL) at week 8 of therapy (week 4 of BOC administration) or 44 weeks of the triple combination after the 4-week lead-in phase if it was not; patients in the BOC/PR48 arm received 44 weeks of the triple combination after the 4-week lead-in phase.3

  • d

    Treatment-experienced patients in the T12PR48 group received the triple combination of pegylated IFNα2a, ribavirin, and telaprevir for 12 weeks, which was preceded by a lead-in phase of 4 weeks with pegylated IFNα2a and ribavirin dual-agent therapy and was followed by pegylated IFNα2a and ribavirin dual-agent therapy until week 48.7

HCV RNA Decline During Lead-In (log10 IU/mL)Treatment Failure Rate (%): SPRINT-1 (Phase 2, Treatment-Naive, BOC)*
28-Week Arm (n = 103)48-Week Arm (n = 103)
<0.57156
0.5 to <1.07638
1.0 to <1.57035
1.5 to <2.02720
2.0 to <3.03321
3.0 to <4.01718
≥4.008
Undetectable (<15 IU/mL)00
 Treatment Failure Rate (%): SPRINT-2 (Phase 3, Treatment-Naive, BOC)†
BOC/RGT Arm (n = 368)BOC/PR48 Arm (n = 366)
<1.07161
≥1.01818
 Treatment Failure Rate (%): RESPOND-2 (Phase 3, Treatment-Experienced, BOC)‡
BOC/RGT Arm (n = 162)BOC/PR48 Arm (n = 161)
<1.06766
≥1.02721
 Treatment Failure Rate (%): REALIZE (Phase 3, Treatment-Experienced, Telaprevir)§
T12PR48 Arm (n = 266)
Overall 
 <1.067
 ≥1.018
Prior responders/relapsers 
 <1.038
 ≥1.06
Prior partial responders 
 <1.044
 ≥1.041
Prior null responders 
 <1.085
 ≥1.046

In approximately 50% to 70% of patients whose treatment failed to eradicate the infection and who experienced a breakthrough during treatment or a relapse after the end of therapy in phase 2 and 3 clinical trials of telaprevir or boceprevir, protease inhibitor–resistant viral populations were dominant at the time of relapse.4, 8-10 In the remaining cases, the wild-type virus was still dominant when the protease inhibitor administration was stopped, but the protease inhibitor–resistant viral population had also been enriched.

Posttreatment Behavior of Protease Inhibitor–Resistant HCV Variants

  1. Top of page
  2. Abstract
  3. Principles of HCV Resistance to DAAs
  4. Resistance to Telaprevir or Boceprevir Monotherapy
  5. Mechanisms of Treatment Failure During Triple-Combination Therapy With Pegylated IFNα, Ribavirin, and Telaprevir or Boceprevir
  6. Posttreatment Behavior of Protease Inhibitor–Resistant HCV Variants
  7. Consequences of Treatment Failure for the Outcome of Liver Disease
  8. Implications of Treatment Failure for Future DAA-Based Therapy
  9. References

Follow-up studies of patients who were included in phase 2 and 3 clinical trials of pegylated IFNα, ribavirin, and telaprevir or boceprevir and whose treatment failed to eradicate HCV showed that after several months to 2 years, the vast majority of the patients had lost the resistant virus, whereas the wild-type, telaprevir-sensitive virus had returned as the dominant population.11, 12 HCV variants resistant to the protease inhibitor still replicated but did so as minor viral populations (a situation close to the pretherapeutic one).

Consequences of Treatment Failure for the Outcome of Liver Disease

  1. Top of page
  2. Abstract
  3. Principles of HCV Resistance to DAAs
  4. Resistance to Telaprevir or Boceprevir Monotherapy
  5. Mechanisms of Treatment Failure During Triple-Combination Therapy With Pegylated IFNα, Ribavirin, and Telaprevir or Boceprevir
  6. Posttreatment Behavior of Protease Inhibitor–Resistant HCV Variants
  7. Consequences of Treatment Failure for the Outcome of Liver Disease
  8. Implications of Treatment Failure for Future DAA-Based Therapy
  9. References

After triple-combination therapy fails to eradicate HCV, the rate of disease progression appears similar to the rate observed before treatment, at least in the short to medium term. This is explained by the fact that the circulating HCV RNA level does not correlate with the severity of liver disease, which progresses slowly. Because HCV is not cytopathic, there is no reason to believe that resistant HCV variants would be more aggressive than the wild-type virus for the liver. It is also unlikely that the selection of protease inhibitor–resistant variants present for years as minor viral populations could trigger a strong intrahepatic cellular immune response and the associated production of proinflammatory cytokines that would accelerate liver disease progression. Thus, although long-term follow-up studies of these patients are needed to draw firm conclusions, there is currently no reason to think that a failure to clear HCV with the triple combination of pegylated IFNα, ribavirin, and a protease inhibitor is harmful. Patients for whom this regimen has failed should be reassured because many other therapeutic options will be available in the near future.

Implications of Treatment Failure for Future DAA-Based Therapy

  1. Top of page
  2. Abstract
  3. Principles of HCV Resistance to DAAs
  4. Resistance to Telaprevir or Boceprevir Monotherapy
  5. Mechanisms of Treatment Failure During Triple-Combination Therapy With Pegylated IFNα, Ribavirin, and Telaprevir or Boceprevir
  6. Posttreatment Behavior of Protease Inhibitor–Resistant HCV Variants
  7. Consequences of Treatment Failure for the Outcome of Liver Disease
  8. Implications of Treatment Failure for Future DAA-Based Therapy
  9. References

It is possible that protease inhibitor–resistant HCV variants acquire additional substitutions that further improve their fitness in the presence of a protease inhibitor during its administration. Nevertheless, 2 years after a triple-combination treatment failure, a situation close to the pretherapeutic one is restored, with a dominant wild-type viral population and the presence of minor variants bearing amino acid substitutions conferring resistance to protease inhibitors. Thus, a new treatment with telaprevir and boceprevir or a first-generation protease inhibitor sharing cross-resistance with these drugs is not contraindicated as long as the drug is combined with another drug or several drugs that potently inhibit HCV replication while sharing no cross-resistance with protease inhibitors (this excludes retreatment in combination with pegylated IFNα and ribavirin only). Two options can be envisaged: quadruple combinations with two non–cross-resistant DAAs, pegylated IFNα, and ribavirin and all-oral, IFN-free drug regimens. Ongoing studies will define the optimal retreatment strategies for patients for whom the triple combination of pegylated IFNα, ribavirin, and telaprevir or boceprevir fails to eradicate HCV.

References

  1. Top of page
  2. Abstract
  3. Principles of HCV Resistance to DAAs
  4. Resistance to Telaprevir or Boceprevir Monotherapy
  5. Mechanisms of Treatment Failure During Triple-Combination Therapy With Pegylated IFNα, Ribavirin, and Telaprevir or Boceprevir
  6. Posttreatment Behavior of Protease Inhibitor–Resistant HCV Variants
  7. Consequences of Treatment Failure for the Outcome of Liver Disease
  8. Implications of Treatment Failure for Future DAA-Based Therapy
  9. References
  • 1
    Kieffer TL, Sarrazin C, Miller JS, Welker MW, Forestier N, Reesink HW, et al. Telaprevir and pegylated interferon-alpha-2a inhibit wild-type and resistant genotype 1 hepatitis C virus replication in patients. Hepatology 2007; 46: 631-639.
  • 2
    Sarrazin C, Kieffer TL, Bartels D, Hanzelka B, Muh U, Welker M, et al. Dynamic hepatitis C virus genotypic and phenotypic changes in patients treated with the protease inhibitor telaprevir. Gastroenterology 2007; 132: 1767-1777.
  • 3
    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.
  • 4
    Kwo PY, Lawitz EJ, McCone J, Schiff ER, Vierling JM, Pound D, et al. Efficacy of boceprevir, an NS3 protease inhibitor, in combination with peginterferon alfa-2b and ribavirin in treatment-naive patients with genotype 1 hepatitis C infection (SPRINT-1): an open-label, randomised, multicentre phase 2 trial. Lancet 2010; 376: 705-716.
  • 5
    Poordad F, McCone J Jr, Bacon BR, Bruno S, Manns MP, Sulkowski MS, et al. Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med 2011; 364: 1195-1206.
  • 6
    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.
  • 7
    Foster GR, Zeuzem S, Andreone P, Pol S, Lawitz EJ, Diago M, et al. Subanalyses of the telaprevir lead-in arm in the REALIZE study: response at week 4 is not a substitute for prior null-response categorization. J Hepatol 2011; 54(suppl 1): S3-S4.
  • 8
    Hezode C, Forestier N, Dusheiko G, Ferenci P, Pol S, Goeser T, et al. Telaprevir and peginterferon with or without ribavirin for chronic HCV infection. N Engl J Med 2009; 360: 1839-1850.
  • 9
    Zeuzem S, Barnard RJ, Howe JA, Ogert RA, Ralston R, Boparai N, et al. Boceprevir resistance-associated variants (RAVs) are observed more frequently in HCV (GT1)-infected patients with poor response to peginterferon alfa-2b/ribavirin. J Hepatol 2011; 54(suppl 1): S4-S5.
  • 10
    Sullivan JC, De Meyer S, Bartels DJ, Dierynck I, Zhang E, Spanks J, et al. Evolution of treatment-emergent resistant variants in telaprevir phase 3 clinical trials. J Hepatol 2011; 54(suppl 1): S4.
  • 11
    Zeuzem S, Sulkowski M, Zoulim F, Sherman KE, Alberti A, Wei LJ, et al. Long-term follow-up of patients with chronic hepatitis C treated with telaprevir in combination with peginterferon alfa-2a and ribavirin: interim analysis of the EXTEND study [abstract]. Hepatology 2010; 52(suppl): 436A.
  • 12
    Vierling JM, Ralston R, Lawitz EJ, McCone J, Gordon SC, Pound D, et al. Long-term outcomes following combination treatment with boceprevir plus Peg-Intron/ribavirin (P/R) in patients with chronic hepatitis C, genotype 1 (CHC-G1). J Hepatol 2010; 52(suppl 1): S470.