Potential conflict of interest: Sandra De Meyer, Inge Dierynck, Anne Ghys, Maria Beumont, Bjorn Daems, and Ben Van Baelen are full-time employees of Janssen Infectious Diseases BVBA. James C. Sullivan, Douglas J Bartels, and Tara L. Kieffer are full-time employees of Vertex Pharmaceuticals. Stefan Zeuzem has been a consultant for Abbott, Anadys, Achillion, Bristol-Myers Squibb, Gilead, Novartis, Merck, Pfizer, Pharmasset, Roche, Vertex Pharmaceuticals, Tibotec Inc., Santaris, and iTherX. Gaston Picchio is a full-time employee of Janssen Research and Development.
The clinical trial was sponsored by Janssen Pharmaceuticals and Vertex Pharmaceuticals. Medical writing support and general editorial assistance for this article was provided by Ryan Woodrow and Joanne Williams (Medical Writers, Gardiner-Caldwell Communications, Macclesfield, UK) and funded by Janssen Pharmaceuticals.
In the Phase 3 REALIZE study, 662 genotype 1 hepatitis C virus (HCV)-infected patients with prior peginterferon/ribavirin treatment failure (including relapsers, partial, and null responders) were randomized to 12 weeks of telaprevir given immediately (T12/PR48) or following 4 weeks of peginterferon/ribavirin (lead-in T12/PR48), or 12 weeks of placebo (PR48), combined with a total of 48 weeks of peginterferon alfa-2a/ribavirin. Sustained virologic response (SVR) rates were 64% (T12/PR48), 66% (lead-in T12/PR48), and 17% (PR48). This analysis aimed to characterize treatment outcomes and viral variants emerging in telaprevir-treated patients not achieving SVR. HCV NS3·4A population sequencing was performed at baseline, during treatment, and follow-up. Telaprevir-resistant variants were classified into lower-level (3- to 25-fold 50% inhibitory concentration [IC50] increase: V36A/M, T54A/S, R155I/K/M/T, and A156S) and higher-level (>25-fold IC50 increase: V36M+R155K and A156T/V) resistance. Resistant variants were uncommon at baseline. Overall, 18% (52%, 19%, and 1% of prior null and partial responders and relapsers, respectively) of telaprevir-treated patients had on-treatment virologic failure, with no significant difference with or without a lead-in. Virologic failure during the telaprevir-treatment phase was predominantly associated with higher-level resistance; virologic failure during the peginterferon/ribavirin-treatment phase was associated with higher- or lower-level, or wildtype variants, depending on genotype. Relapse occurred in 9% of patients completing assigned treatment and was generally associated with lower-level resistant variants or wildtype. Resistant variants were no longer detectable by study end (median follow-up of 11 months) in 58% of non-SVR patients. Conclusion: In REALIZE, variants emerging in non-SVR, telaprevir-treated patients were similar irrespective of the use of a lead-in and were consistent with those previously reported. In most patients, resistant variants became undetectable over time. (HEPATOLOGY 2012;56:2106–2115)
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Telaprevir is a potent and selective inhibitor of the nonstructural (NS) 3·4A protease of the hepatitis C virus (HCV).1 This direct-acting antiviral (DAA) recently demonstrated significantly higher efficacy over placebo in combination with peginterferon/ribavirin in randomized Phase 3 trials conducted in patients infected with HCV genotype 1,2-4 and is now approved in the United States and Europe for the treatment of genotype 1 chronic hepatitis in adult patients with compensated liver disease.5, 6 The efficacy of telaprevir-based treatment in patients for whom prior peginterferon/ribavirin therapy had failed was demonstrated in the Phase 3 REALIZE trial, which enrolled prior relapsers, partial responders, and null responders.4 Sustained virologic response (SVR) (undetectable plasma HCV RNA 24 weeks after the last planned administration of a study drug) with telaprevir-based regimens were significantly superior to peginterferon/ribavirin alone across all populations: 86% versus 24% in prior relapsers, 57% versus 15% in prior partial responders, and 31% versus 5% in prior null responders.4 Using the definition of HCV RNA <25 IU/mL at last observation within the week 72 visit window, SVR rates were 86% versus 22% in prior relapsers, 59% versus 15% in prior partial responders, and 32% versus 5% in prior null responders.5 No clinical benefit was observed in patients receiving a 4-week peginterferon/ribavirin lead-in before starting triple combination therapy, compared with those initiating all drugs simultaneously.
Given the limitations of retreatment with peginterferon/ribavirin in HCV genotype 1-infected patients,7, 8 the HCV protease inhibitors telaprevir4 and boceprevir9 represent an important clinical advance. However, these and other DAAs are associated with new management issues, including the potential for the development of resistance. HCV infection is characterized by the presence of a viral population consisting of genetically distinct but closely related variants, due to the high rate of replication,10 which is inherently error-prone as the RNA-dependent RNA polymerase lacks a proof-reading function.11, 12 Unlike peginterferon and ribavirin, the DAAs specifically target HCV proteins. Therefore, during treatment with DAAs, such as telaprevir and boceprevir, there is the potential for selection of preexisting viral variants with decreased susceptibility to DAAs with a similar mechanism of action.13-15 In HCV genotype 1-infected patients, the use of telaprevir was associated with the emergence of resistant variants at NS3 amino acid positions 36, 54, 155, and 156.13, 15, 16 In addition to these positions, the use of boceprevir has been associated with the emergence of resistance at positions 55 and 170.14
Here we report the findings from a subanalysis of the Phase 3 telaprevir REALIZE trial, in which treatment outcomes and the emergence of viral variants were further characterized in patients with prior peginterferon/ribavirin treatment failure who did not achieve an SVR with subsequent telaprevir-based therapy. We explored whether the use of a peginterferon/ribavirin lead-in, HCV genotype subtype, or prior peginterferon/ribavirin response category had an effect on treatment outcome or the emergence of variants. The impact of baseline variants on treatment outcome and the persistence of resistant variants after the end of therapy were also studied.
DAA, direct-acting antiviral; IC50, 50% inhibitory concentration; ITT, intent-to-treat; HCV, hepatitis C virus; LLOQ, lower limit of quantification; NS, nonstructural; SVR, sustained virologic response.
Patients and Methods
The methodology for this randomized, double-blind, placebo-controlled Phase 3 trial in HCV genotype 1-infected patients with prior peginterferon/ribavirin treatment failure has been described fully elsewhere.4 The protocol was approved by all relevant independent ethics committees and the study was performed in accordance with provisions of the Declaration of Helsinki and Good Clinical Practice guidelines. All patients provided written informed consent. The trial was registered with clinicaltrials.gov (NCT00703118).
Patients with chronic HCV genotype 1 infection were enrolled. Eligible patients must have failed at least one prior course of peginterferon/ribavirin therapy (prior relapsers: undetectable HCV RNA at the end of previous treatment but detectable HCV RNA thereafter; prior partial responders: ≥2 log10 reduction in HCV RNA at week 12 of prior therapy but never achieving undetectable HCV RNA; prior null responders: <2 log10 reduction in HCV RNA at week 12 of prior therapy).
Patients were stratified by baseline HCV RNA and category of prior peginterferon/ribavirin response. Patients were randomized to receive one of two telaprevir-based regimens (with or without a lead-in) or a peginterferon/ribavirin (control) schedule in a 2:2:1 ratio. This subanalysis excluded patients in the control arm because it specifically investigated the virologic aspects of telaprevir-based therapy. Patients in the lead-in T12/PR48 arm received placebo plus peginterferon/ribavirin for 4 weeks, followed by telaprevir plus peginterferon/ribavirin for 12 weeks, then peginterferon/ribavirin alone for 32 weeks. Patients in the T12/PR48 arm (without a lead-in) received telaprevir plus peginterferon/ribavirin for 12 weeks, followed simultaneously by placebo for 4 weeks and peginterferon/ribavirin for 36 weeks. Telaprevir was taken orally at 750 mg every 8 hours, with ribavirin at 1,000-1,200 mg/day, and peginterferon alfa-2a administered subcutaneously at a dose of 180 μg/week.
Telaprevir was stopped in patients with HCV RNA >100 IU/mL at weeks 4, 6, and 8 after the start of telaprevir; these individuals could continue peginterferon/ribavirin. All treatment was discontinued in patients with <2 log10 HCV RNA decrease from baseline to week 12 in the T12/PR48 group or week 16 in the lead-in T12/PR48 group, or in those with detectable HCV RNA at weeks 24 or 36.
Plasma HCV RNA quantification was performed using the COBAS TaqMan assay, v. 2.0 (Roche, Switzerland). The lower limit of quantification (LLOQ) was 25 IU/mL. Results below the LLOQ were reported as “<25 IU/mL, detected,” or “<25 IU/mL, target not detected.” HCV RNA “<25 IU/mL, target not detected” is also described as undetectable HCV RNA in the study. HCV RNA levels were measured at the following study visits: screening, baseline, day 3, weeks 1, 2, 4, 5, 6, 8, 10, 12, 14, 16, 20, 24, and 36, end of treatment (week 48 or time of early discontinuation), and at follow-up visits 4, 12, and 24 weeks after the end of treatment. HCV RNA levels were also assessed at week 72 for all patients, including those who discontinued early. In line with the primary efficacy analysis, SVR was defined as undetectable HCV RNA 24 weeks after the last planned dose of study medication. An NS3-based genotyping method was used for genotype and subtype determination in this virologic analysis.
To study HCV variants, sequencing analysis of the HCV NS3·4A regions was performed on all baseline samples. HCV RNA was extracted from plasma virions under denaturing conditions and viral RNA was isolated on a standard commercial silica-gel membrane using a modified QIAamp Virus BioRobot 9604 method (Qiagen, Valencia, CA). The NS3·4A protease regions were amplified using a nested reverse-transcriptase polymerase chain reaction assay. The resulting DNA was purified and sequenced; the lower limit of detection for the sequencing assay was ∼1,000 IU/mL of HCV RNA. Population sequencing can typically detect down to about 25% of the viral population.
In addition to baseline samples, sequencing analyses were conducted at the time of failure in cases of on-treatment virologic failure (i.e., in patients with viral breakthrough or who met a virologic stopping rule) or relapse and in patients with detectable HCV RNA at the end of treatment. Furthermore, sequencing analyses were conducted after treatment, at follow-up visits 4 and 24 weeks after the actual end of treatment, at week 72, and in case of relapse also at follow-up visit 24 weeks after relapse. Viral breakthrough was defined as an HCV RNA increase of ≥1 log10 IU/mL from the lowest level reached during treatment, or HCV RNA >100 IU/mL in patients who previously had <25 IU/mL during treatment. Relapse was defined as detectable HCV RNA during the follow-up period after having undetectable HCV RNA at the end of treatment.
On the basis of previous studies,13, 15 commonly observed substitutions in NS3 after treatment failure considered to confer lower-level in vitro resistance to telaprevir (3- to 25-fold increase in replicon 50% inhibitory concentration [IC50]) were: V36A/M, T54A/S, R155I/K/M/T, and A156S. Substitutions considered to confer higher-level in vitro resistance to telaprevir (>25-fold increase in replicon IC50) were A156T/V and the combination of V36M+R155K.16 Other changes within the NS3·4A region were also investigated.
Following sequencing, amino acid positions were assigned with hidden Markov models using HMMer2 software (Howard Hughes Medical Institute, Chevy Chase, MD), which was trained on multiple sequence alignments of HCV reference sequences from the Los Alamos National Laboratory database.17 Pretreatment sequence and sequence at time of failure were compared for all patients with on-treatment virologic failure or relapse. Potential new resistance-associated mutations were identified as amino acid states whose frequencies were significantly different between pretreatment and failure sequences. Statistical significance was defined as a one-tailed P < 0.05 using Fisher's exact test for unpaired pretreatment and failure sequences, and Liddell's exact test18 for paired sequences. A Bonferroni correction was applied for multiple comparisons.
For each patient not achieving an SVR, any nonwildtype variants at positions known to be associated with telaprevir treatment failure (36, 54, 155, and 156) were indexed from the failure visit. The proportion of patients losing these variants was recorded until the end of study visit (i.e., last available sequence during the study). To ascertain the median time to loss of variants as compared to time of failure at each position, nonparametric (Kaplan-Meier) survival analyses were performed.
P-values for other analyses mentioned in this article were generated using the chi-squared test and were not calculated where sample sizes were low.
The disposition of patients in the REALIZE trial, and the baseline characteristics of the two telaprevir treatment arms included in this virologic analysis, have been published elsewhere.4 Briefly, 662 patients were randomized: 266 to the T12/PR48 arm, 264 to the lead-in T12/PR48 arm, and 132 to the PR48 control arm. Regarding previous peginterferon/ribavirin response, 53% were prior relapsers, 19% were prior partial responders, and 28% were prior null responders. Fifty-four percent of patients had HCV genotype 1a, 46% had genotype 1b, and 26% had cirrhosis.
Patients who did not achieve an SVR (i.e., undetectable plasma HCV RNA 24 weeks after the last planned administration of a study drug) following telaprevir-based treatment did so for the following reasons: on-treatment virologic failure (viral breakthrough or patients who met a virologic stopping rule); detectable HCV RNA at the end of treatment (for reasons other than virologic stopping rules) without viral breakthrough; relapse (completers or noncompleters of assigned treatment); or having undetectable HCV RNA at the end of treatment but subsequently being lost to follow-up before week 72.
No significant difference was observed between the telaprevir treatment arms with or without a peginterferon/ribavirin lead-in phase in terms of categories of treatment outcome, including SVR and virologic failure rates (Fig. 1A). SVR rates of 64% (171/266) and 66% (175/264) were observed in the T12/PR48 and lead-in T12/PR48 arms, respectively. On-treatment virologic failure rates were 20% (52/266) in the T12/PR48 arm versus 17% (45/264) in the lead-in T12/PR48 arm (P = 0.46). On-treatment virologic failure was more frequent in patients with HCV genotype 1a versus 1b (24% [69/285] versus 12% [28/239]; Fig. 1B) and in those with prior null response versus prior partial response or relapse (52% [76/147], 19% [18/97], and 1% [3/286] respectively; Fig. 1C). Relapse after completing telaprevir-based treatment occurred in 9% (14/162) of patients in the T12/PR48 arm and 10% (18/178) in the lead-in arm (P = 0.64; calculated based on patients with undetectable HCV RNA at end of treatment). No differences in relapse rates were seen between patients with genotype 1a and 1b.
Patients With Telaprevir-Resistant Variants at Baseline.
Population-based sequencing of the NS3·4A protease domain at baseline was successful for 98% (652/662) of patients. Of these patients, 97% (634/652) had wildtype virus (no telaprevir-resistant variants) at baseline. It was uncommon for patients to have a predominant telaprevir-resistant variant prior to treatment: 1.8% had T54S (n = 12, including two patients in the PR48 arm who are excluded from the subsequent analyses), 0.6% R155K (n = 4), and 0.3% V36M (n = 2). No predominant higher-level resistant variants were observed at baseline. Treatment outcomes following telaprevir-based therapy in patients with baseline variants is shown in Table 1. Overall, 6/9 of prior relapsers with baseline variants achieved an SVR with telaprevir-based treatment, whereas 0% (0/5) of prior null responders with baseline variants achieved an SVR and all of these patients experienced on-treatment virologic failure. There were only two prior partial responders with baseline variants, and one achieved an SVR. For comparison, in the overall population SVR rates with telaprevir-based regimens were 86% in prior relapsers, 57% in prior partial responders, and 31% in prior null responders.
Table 1. Outcome of Telaprevir-Based Therapy According to Baseline Variants Detectable by Population Sequencing and Prior Response to Peginterferon/Ribavirin
Detectable at end of treatment – no viral breakthrough
Undetectable at end of treatment – lost to follow-up
Characterization of Viral Variants in Patients Without SVR.
In the overall intent-to-treat (ITT) study population, the proportion of patients with telaprevir-resistant variants at time of failure was comparable between the treatment arms with or without a peginterferon/ribavirin lead-in. In total, 21% (57/266) versus 22% (58/264) in the T12/PR48 and lead-in T12/PR48 arms, respectively, had telaprevir-resistant variants (P = 0.92; Fig. 2A). Also in the overall ITT population, resistant variants occurred more frequently in patients with genotype 1a (31%; 89/285) versus genotype 1b (11%; 26/239) (Fig. 2B). Finally, telaprevir-resistant variants were detected in 50% (74/147) of all prior null responders, 25% (24/97) of all prior partial responders, and 6% (17/286) of all prior relapsers (Fig. 2C).
Telaprevir-resistant variants were present in the majority of patients who did not achieve an SVR. Telaprevir-resistant variants were detected by population sequencing in 71% (115/161) of these patients with available sequencing data, including 82% (77/94) of on-treatment virologic failures, 33% (5/15) of patients with detectable HCV RNA at end of treatment without viral breakthrough, 61% (19/31) of patients who relapsed after completing treatment, and 67% (14/21) of patients who relapsed and did not complete their assigned treatment (Fig. 3). Resistant variants were detected in 80% (74/93) of prior null responders, 62% (24/39) of prior partial responders, and 59% (17/29) of prior relapsers who did not achieve an SVR with telaprevir-based therapy. The number of patients with telaprevir-resistant variants (Fig. 3) and the specific type of variants seen (Fig. 4) was generally comparable between the arms with or without a peginterferon/ribavirin lead-in phase.
The variants that emerged most frequently in patients with telaprevir treatment failure were consistent with those defined previously: V36M and R155K in genotype 1a patients and V36A, T54A, and A156T in genotype 1b patients (Fig. 4). No new significant resistant variants were detected in this study.
On-treatment virologic failure during the telaprevir/placebo triple therapy phase was predominantly associated with higher-level resistant variants (Fig. 4A). During the peginterferon/ribavirin treatment phase (after telaprevir treatment ended), on-treatment virologic failure was associated with higher- or lower-level resistant variants in genotype 1a patients, and lower-level resistant variants or wildtype virus in genotype 1b patients (Fig. 4B). Relapse was generally associated with lower-level resistant variants or wildtype HCV (Fig. 4C). All patients who received <4 weeks of telaprevir-based therapy failed to achieve an SVR and were found to have wildtype virus.
Persistence of Viral Variants in Patients Who Did Not Achieve an SVR.
Among patients with detectable resistant variants by population sequencing at the time of treatment failure, 58% (60/104) no longer had detectable levels of resistant variants at the end of study (median follow-up time as compared to time of failure was 11 months). When examined according to prior response category, variants were no longer detected in 63% (42/67) of prior null responders, 32% (7/22) of prior partial responders, and 73% (11/15) of prior relapsers. The median time to loss of resistant variants was 13 months overall (Table 2) (13, 15, and 9 months for prior null and partial responders, and relapsers, respectively). The median time to loss of the common genotype 1b variants (position 54 and 156; 3-4 months) was generally less than that of the common genotype 1a variants (position 36, 155, and 36+155; 13-15 months).
Table 2. Persistence of Variants Following Discontinuation of Telaprevir Treatment (Population Sequencing)
Patients with No Detectable Variants at End of Study, n (%)
Median Time-to-Loss of Variant, Months (95% CI)
Categories are not mutually exclusive.
Only patients with available follow-up data were included in the analysis.
CI = confidence interval.
Any telaprevir-resistant variant
This subanalysis of peginterferon/ribavirin treatment-experienced patients treated with the HCV protease inhibitor telaprevir in the REALIZE trial explored the effect of peginterferon/ribavirin lead-in, prior peginterferon/ribavirin treatment response, genotype subtype, and baseline variants on treatment outcome, and further characterized the emergence of resistance in patients who did not achieve an SVR. No new telaprevir-resistant variants were detected and the pattern of resistance pathways was consistent with that seen in treatment-naïve patients.19 Importantly, this analysis also showed that resistant variants could no longer be detected by population sequencing in the majority of patients after a median follow-up time of 11 months.
Prior to treatment in the REALIZE trial, predominant variants resistant to protease inhibitors were generally detectable by population sequencing in only a very small percentage (typically <3%) of patients, which is in agreement with other studies including those in the treatment-naïve setting.19-21 Also in line with other studies,20, 22, 23 the presence of resistant variants at baseline does not necessarily preclude successful treatment (i.e., SVR) in all patient groups, especially in prior relapsers. However, there might have been an effect in prior null responders.
Regarding the use of a 4-week peginterferon/ribavirin lead-in phase before the initiation of telaprevir, no differences in the rates of on-treatment virologic failure or relapse were observed between the concurrent and delayed initiation of telaprevir. Further, the use (or not) of a peginterferon/ribavirin lead-in had no significant effect on the number of patients who had emergent telaprevir-resistant variants, or on the type of variants observed following virologic failure. The data from this virologic analysis are in agreement with results from the primary analysis of the REALIZE trial,4 in which SVR rates were similar between the telaprevir-based treatment arms with and without a lead-in. Therefore, our findings confirm that a peginterferon/ribavirin lead-in is not required with telaprevir. In contrast, a Phase 2 study of boceprevir previously suggested that lowering HCV RNA levels with a 4-week peginterferon/ribavirin pretreatment may reduce the emergence of protease-resistant variants, decrease viral breakthrough rates during treatment, and increase SVR rates.24
Regarding previous peginterferon/ribavirin response, on-treatment virologic failure and the emergence of resistant variants were more frequent in prior null responders than in prior partial responders and prior relapsers. This is not surprising given that, by definition, prior null responders failed to achieve a ≥2 log10 reduction in HCV RNA by week 12 of previous peginterferon/ribavirin treatment, and therefore two components of the telaprevir triple therapy regimen would not have been fully functional in these patients. Virologic failure and the emergence of resistance with current telaprevir-based therapy is therefore probably primarily due to an insufficient peginterferon/ribavirin response. Despite this, in the REALIZE trial, telaprevir plus peginterferon/ribavirin still increased SVR rates in prior null responders from 5% (in the control arm) to 29%-33% (across the two telaprevir combination arms).4 However, further improvements for managing prior null responders are warranted and may potentially be achieved in the future by adding another DAA with an alternative mechanism of action to the treatment regimen.
With respect to HCV genotype subtype, on-treatment virologic failure was more frequent in telaprevir-treated patients with HCV genotype 1a (24%) versus 1b (12%). There were also differences between genotypes in the pattern of variants observed upon virologic failure. In the peginterferon/ribavirin treatment phase (i.e., after telaprevir dosing was ended), virologic failure was associated with higher- or lower-level variants in genotype 1a patients (most frequently V36M and R155K), and lower-level resistant variants or wildtype HCV in genotype 1b patients. Similar data were observed in patients who received boceprevir-based treatment in Phase 3 trials; resistance-associated variants were detected more frequently and SVR rates were lower in patients with HCV genotype 1a versus 1b.25 These observations with telaprevir and boceprevir might be explained by the higher genetic barrier to resistance with 1b versus 1a subtypes. In genotype 1a isolates, amino acid substitutions at positions 36 (V to M) and 155 (R to K) of the NS3 region require only one nucleotide change.26 Conversely, in genotype 1b isolates, two nucleotide changes are required to generate a change at these positions, making these variants less likely to exist in chronically infected patients. Furthermore, the V36M+R155K double-mutant variant that shows higher-level resistance and is commonly found in genotype 1a patients is more fit than the single-mutant, higher-level resistant variants A156T/V that are commonly found in genotype 1b patients. Peginterferon/ribavirin activity may be sufficient to slow or prevent replication of less fit variants, potentially also explaining the differences in rates of virologic failure between the genotypes.
During therapy, the phase of treatment in which virologic failure occurred had an impact on the proportion of patients with higher- versus lower-level resistant variants. If during the telaprevir treatment phase, the peginterferon/ribavirin component of the regimen fails to provide sufficient viral inhibition (i.e., null responders), then the DAA pressure would be anticipated to immediately select for preexisting variants that can replicate in its presence. This may explain why, in our analysis, virologic failure that occurred during triple therapy was predominantly associated with higher-level resistant variants. These higher-level resistant variants were present in a lower proportion of patients with failure during the peginterferon/ribavirin treatment phase and in an even lower proportion of patients with failure during follow-up (i.e., with relapse). These differences could be in part explained by different fitness requirements. In the absence of DAA pressure, higher-level resistance is not necessary and therefore, lower-level variants with improved fitness over those with higher-level resistance may be favored. All patients who received less than 4 weeks of telaprevir had wildtype HCV at the time of failure, suggesting that a 4-week treatment duration is not sufficient to fully eradicate wildtype virus.
Important clinical questions regarding resistance include whether resistant variants that emerge during DAA treatment persist, and if patients with these variants can be retreated in the future with the same DAA class. In our analysis, variants that had developed in non-SVR patients became undetectable by population sequencing during the study follow-up period (median 11 months) in the majority (58%) of patients. Some common genotype 1b mutations (positions 54 and 156) became undetectable very quickly after a median of 3-4 months, whereas common genotype 1a mutations (positions 36, 155, and 36+155) persisted for longer (up to a median of 15 months). This suggests that the genotype 1b variants are generally less fit than the common genotype 1a variants, and are therefore more rapidly replaced by wildtype. Although the results from our analysis and from a boceprevir study that also showed a loss of resistant variants in treatment-naïve and treatment-experienced patients posttherapy27 are somewhat reassuring; a limitation is that a relatively small number of patients were included and the analysis was based on population sequencing only. Therefore, it is possible that resistant variants may have persisted at levels below the assay's sensitivity. However, clonal analysis, which can detect variants at considerably lower levels than population sequencing (5% versus 25%, respectively),28 was used in the EXTEND trial, a multinational, 3-year follow-up study of patients treated with telaprevir-based regimens in Phase 2 and Phase 3 clinical trials (NCT00916474). Interim findings using this approach showed that HCV populations returned to the pretreatment state during long-term follow-up (median 22 months).29 The EXTEND trial is continuing to follow up a subset of non-SVR patients from Phase 2 and 3 telaprevir studies. Additional research is needed to evaluate whether these patients can be successfully retreated with the same DAA class.
In conclusion, in the REALIZE trial treatment outcome and the emergence of telaprevir-resistant variants were similar irrespective of the use of a peginterferon/ribavirin lead-in phase and were consistent with what has been reported in other telaprevir studies, including those in treatment-naïve patients. Virologic failure occurring during telaprevir-based triple therapy tended to be associated with higher-level resistant variants, whereas these were less frequent when failure occurred during the peginterferon/ribavirin treatment phase or during follow-up (relapse). Prior relapsers to prior peginterferon/ribavirin treatment showed less frequent on-treatment virologic failure and emergence of resistant variants than prior null responders, highlighting the importance of the peginterferon/ribavirin response. Furthermore, virologic failure and the emergence of resistance were less frequent in patients with genotype 1b than in patients with genotype 1a. These data may inform risk-benefit treatment decisions in patients who could have a higher risk of virologic failure. Importantly, and in agreement with previously published data, resistant variants were no longer detectable in most patients during follow-up, and became undetectable most rapidly in patients with HCV genotype 1b.
We thank the study coordinators, nurses, and patients involved in the study. We thank Isabelle Lonjon-Domanec, MD from Janssen Pharmaceuticals, for editorial assistance. We also thank Ryan Woodrow and Joanne Williams from Gardiner-Caldwell Communications for providing an initial outline and draft of this article and for providing general editing and styling support with funding from Janssen Pharmaceuticals. Prior/Concurrent Publications: The data from the analysis reported in the article have not been published elsewhere. The data have been presented at the following congresses: De Meyer S, Dierynck I, Ghys A, et al. Characterization of HCV variants in non-SVR Patients in the REALIZE study suggests that telaprevir exhibits a consistent resistance profile irrespective of a lead-in. 46th Annual Meeting of the European Association for the Study of the Liver, Berlin, Germany, 30 March-3 April 2011. Poster 1202. De Meyer S, Dierynck I, Ghys A, et al. Similar incidence of virologic failure and emergence of resistance with or without a lead-in: results of a telaprevir Phase 3 study in patients who did not achieve SVR with prior Peg-IFN/RBV treatment. International Workshop on HIV and Hepatitis Virus Drug Resistance and Curative Strategies, Los Cabos, Mexico, 7-11 June 2011. Poster 19.