The Results of Phase III Clinical Trials With Telaprevir and Boceprevir Presented at the Liver Meeting 2010: A New Standard of Care for Hepatitis C Virus Genotype 1 Infection, But With Issues Still Pending
2011; Elsevier BV; Volume: 140; Issue: 3 Linguagem: Inglês
10.1053/j.gastro.2011.01.028
ISSN1528-0012
Autores Tópico(s)HIV/AIDS drug development and treatment
ResumoThe Liver Meeting 2010 was held in Boston, Massachusetts, from October 29 to November 2, 2010. At this meeting, the results of Phase III trials with 2 hepatitis C virus (HCV) protease inhibitors, telaprevir and boceprevir, in combination with pegylated interferon (IFN)-α and ribavirin in both treatment-naïve patients and nonresponders to a first course of pegylated IFN-α and ribavirin, were presented to a large audience and received extensive coverage by the media. Two Phase III trials have been performed with boceprevir, including SPRINT-2 in treatment-naïve patients and RESPOND-2 in treatment-experienced patients.1Poordad F. McCone J. Bacon B.R. et al.Boceprevir (BOC) combined with peginterferon alfa-2b/ribavirin (P/R) for treatment-naïve patients with hepatitis C virus (HCV) genotype 1: SPRINT-2 final results.Hepatology. 2010; 52: 402AGoogle Scholar, 2Bacon B.R. Gordon S.C. Lawitz E. et al.HCV RESPOND-2 final results: high sustained virologic response among genotype 1 previous nonresponders and relapsers to peginterferon/ribavirin when retreated with boceprevir plus PegIntron (peginterferon alfa-2b)/ribavirin.Hepatology. 2010; 52: 430APubMed Google Scholar Three Phase III trials have been performed with telaprevir, including ADVANCE and ILLUMINATE in treatment-naïve patients,3Jacobson I.M. McHutchison J.G. Dusheiko G.M. et al.Telaprevir in combination with peginterferon and ribavirin in genotype 1 HCV treatment-naïve patients: final results of Phase 3 ADVANCE study.Hepatology. 2010; 52: 427AGoogle Scholar, 4Sherman K.E. Flamm S.L. Afdhal N.H. et al.Telaprevir in combination with peginterferon alfa2a and ribavirin for 24 or 48 weeks in treatment-naive genotype 1 HCV patients who achieved an extended rapid viral response: final results of Phase 3 ILLUMINATE study.Hepatology. 2010; 52: 401APubMed Google Scholar and REALIZE in nonresponder patients. Results from the latter trial were not presented at The Liver Meeting, but a press release was issued a few weeks before the meeting reporting selected, non–peer-reviewed or otherwise filtered results (available: http://investors.vrtx.com/releasedetail.cfm?ReleaseID=505239). The results of these 5 trials raise hope that better cure rates will be achieved in patients infected with HCV genotype 1 when these combinations reach the market. They also raise a number of questions and several concerns. Here, the results of Phase III trials presented at The Liver Meeting will be summarized and the introduction of these new therapies into current clinical practice as well as a number of unresolved issues raised by these results will be discussed. Figure 1 summarizes the design of the 3 Phase III trials with pegylated IFN-α2a, ribavirin, and telaprevir (Figure 1A–C). In these telaprevir trials, the extended rapid virologic response (eRVR) was defined as an undetectable HCV RNA (<25 IU/mL) at week 4 of therapy that remained undetectable at week 12. The virologic results of ADVANCE presented at The Liver Meeting are summarized in Table 1.3Jacobson I.M. McHutchison J.G. Dusheiko G.M. et al.Telaprevir in combination with peginterferon and ribavirin in genotype 1 HCV treatment-naïve patients: final results of Phase 3 ADVANCE study.Hepatology. 2010; 52: 427AGoogle Scholar The sustained virologic response (SVR) rates achieved were 75% in T12PR, 69% in T8PR, versus 44% in the control PR arm (P < .0001 and P < .0001, respectively; Table 1). The 6% difference between T12PR and T8PR (95% confidence interval, −12.5% to +0.6%) was not significant. When the results were analyzed according to eRVR, fibrosis stage, or race, the SVR rates were always higher, although not significantly, in T12PR than in T8PR (Table 1).3Jacobson I.M. McHutchison J.G. Dusheiko G.M. et al.Telaprevir in combination with peginterferon and ribavirin in genotype 1 HCV treatment-naïve patients: final results of Phase 3 ADVANCE study.Hepatology. 2010; 52: 427AGoogle ScholarTable 1Summary of ADVANCE Virologic Results as Presented at The Liver Meeting, 20103Jacobson I.M. McHutchison J.G. Dusheiko G.M. et al.Telaprevir in combination with peginterferon and ribavirin in genotype 1 HCV treatment-naïve patients: final results of Phase 3 ADVANCE study.Hepatology. 2010; 52: 427AGoogle ScholarT12PR, % (n = 363)T8PR, % (n = 364)PR, % (n = 361)SVR (overall)756944Rapid virologic response RVR68669 eRVR58578SVR according to eRVR eRVR+898397 eRVR−545039Relapse Overall9928 Completed regimen6727Virologic failure813NASVR according to fibrosis stage No, mild or portal fibrosis787347 Bridging fibrosis or cirrhosis625333SVR according to race Caucasian757046 Black/African American625825 Hispanic/Latino746639eRVR, extended rapid virologic response, i.e. undetectable HCV RNA at week 4 that remains undetectable at week 12; NA, not applicable; RVR, rapid virologic response, i.e. undetectable HCV RNA at week 4; SVR, sustained virologic response.Virologic failure includes patients who met the stopping rule (HCV RNA >1000 IU/mL at week 4, HCV RNA decline 1000 IU/mL at week 12 even if HCV RNA decline ≥2 log10, and patients with detectable HCV RNA at the end of treatment. Open table in a new tab eRVR, extended rapid virologic response, i.e. undetectable HCV RNA at week 4 that remains undetectable at week 12; NA, not applicable; RVR, rapid virologic response, i.e. undetectable HCV RNA at week 4; SVR, sustained virologic response. Virologic failure includes patients who met the stopping rule (HCV RNA >1000 IU/mL at week 4, HCV RNA decline 1000 IU/mL at week 12 even if HCV RNA decline ≥2 log10, and patients with detectable HCV RNA at the end of treatment. Virologic failure was defined as patients who met the conditions of the stopping rule (HCV RNA >1000 IU/mL at week 4, HCV RNA decline 1000 IU/mL at week 12 even if HCV RNA decline ≥2 log10, or patients with detectable HCV RNA at the end of treatment. The virologic failure rate was 13% in T8PR versus 8% in T12PR; the difference was explained by a higher failure rate after telaprevir discontinuation in the former group, suggesting that longer telaprevir administration prevents subsequent failures.3Jacobson I.M. McHutchison J.G. Dusheiko G.M. et al.Telaprevir in combination with peginterferon and ribavirin in genotype 1 HCV treatment-naïve patients: final results of Phase 3 ADVANCE study.Hepatology. 2010; 52: 427AGoogle Scholar A virologic analysis of failures was presented in a complementary poster.5Kieffer T.L. Bartels D.J. Sullivan J. et al.Clinical virology results from telaprevir Phase 3 study ADVANCE.Hepatology. 2010; 52: 879AGoogle Scholar Based on population sequencing, on-treatment virologic failures during telaprevir administration were essentially associated with the presence of viral variants with substitutions conferring high-level resistance to telaprevir. By contrast, these variants were found in fewer than half of the cases when the on-treatment virologic failure occurred during subsequent pegylated IFN-α2a and ribavirin administration, the remaining cases being associated with the presence of low-level resistance and, rarely, wild-type variants.5Kieffer T.L. Bartels D.J. Sullivan J. et al.Clinical virology results from telaprevir Phase 3 study ADVANCE.Hepatology. 2010; 52: 879AGoogle Scholar Sixty-three percent of the patients with telaprevir-resistant variants after virologic failures lost these variants during follow-up (median follow-up, 45 weeks).5Kieffer T.L. Bartels D.J. Sullivan J. et al.Clinical virology results from telaprevir Phase 3 study ADVANCE.Hepatology. 2010; 52: 879AGoogle Scholar Adverse events that were more frequent (difference ≥10%) in the telaprevir-containing arms included pruritus (50%, 45%, and 36% in T12PR, T8PR, and PR, respectively), nausea (43%, 40%, 31%), rash (37%, 35%, 24% when reported as rash; 56%, 53%, and 37% when any event suggesting a rash was taken into consideration), anemia (37%, 39%, 19%), and diarrhea (28%, 32%, 22%).3Jacobson I.M. McHutchison J.G. Dusheiko G.M. et al.Telaprevir in combination with peginterferon and ribavirin in genotype 1 HCV treatment-naïve patients: final results of Phase 3 ADVANCE study.Hepatology. 2010; 52: 427AGoogle Scholar Seven percent, 8%, and 4% of patients discontinued all drugs owing to adverse events during the telaprevir/placebo phase in T12PR, T8PR, and PR, respectively. Eleven percent, 7%, and 1% of patients discontinued telaprevir/placebo only during the telaprevir/placebo phase in T12PR, T8PR, and PR, respectively.3Jacobson I.M. McHutchison J.G. Dusheiko G.M. et al.Telaprevir in combination with peginterferon and ribavirin in genotype 1 HCV treatment-naïve patients: final results of Phase 3 ADVANCE study.Hepatology. 2010; 52: 427AGoogle Scholar Severe rash events occurred in 6%, 3%, and 1% of patients during the telaprevir/placebo phase in T12PR, T8PR, and PR, respectively. They led to telaprevir/placebo discontinuation in 7%, 5%, and 1% of cases, respectively. On average, the hemoglobin drop was approximately 1 g/dL greater during telaprevir administration than with pegylated IFN-α2a and ribavirin only. No growth factors were allowed by the protocol and anemia was managed with ribavirin dose modifications. Nine percent, 9%, and 2% of patients had a hemoglobin drop below 8.5 g/dL during telaprevir/placebo administration in T12PR, T8PR, and PR, respectively, and 4%, 2%, and 0% of patients discontinued telaprevir/placebo owing to anemia.3Jacobson I.M. McHutchison J.G. Dusheiko G.M. et al.Telaprevir in combination with peginterferon and ribavirin in genotype 1 HCV treatment-naïve patients: final results of Phase 3 ADVANCE study.Hepatology. 2010; 52: 427AGoogle Scholar In the ILLUMINATE trial, 65% of the patients were reported to achieve an eRVR, 87% had undetectable HCV RNA at the end of therapy, and the overall SVR rate was 72%.4Sherman K.E. Flamm S.L. Afdhal N.H. et al.Telaprevir in combination with peginterferon alfa2a and ribavirin for 24 or 48 weeks in treatment-naive genotype 1 HCV patients who achieved an extended rapid viral response: final results of Phase 3 ILLUMINATE study.Hepatology. 2010; 52: 401APubMed Google Scholar The SVR rates in the patients with an eRVR who were randomized into T12PR24 and T12PR48 were 92% and 88%, respectively. The difference was 4.5% (2-sided 95% confidence interval, −2.1% to +11.1%) and met the criteria for non-inferiority. The relapse rate was 6% in T12PR24 and 3% in T12PR48. The SVR rate was 64% in the patients who did not achieve an eRVR and who received treatment for 48 weeks. The side effect profile was comparable with that observed in the ADVANCE trial.4Sherman K.E. Flamm S.L. Afdhal N.H. et al.Telaprevir in combination with peginterferon alfa2a and ribavirin for 24 or 48 weeks in treatment-naive genotype 1 HCV patients who achieved an extended rapid viral response: final results of Phase 3 ILLUMINATE study.Hepatology. 2010; 52: 401APubMed Google Scholar The results of the REALIZE trial were not presented at The Liver Meeting 2010. A non–peer-reviewed press release issued on September 7, 2010 (available: http://investors.vrtx.com/releasedetail.cfm?ReleaseID=505239) indicates that the SVR rate was 65% in the telaprevir containing arms versus 17% in the control arm (P < .0001). The SVR rates were 86% in prior relapsers, 57% in partial responders, and 31% in null responders in the telaprevir groups, versus 24%, 15%, and 5% in the control arm, respectively. No difference was seen between the arm with a lead-in phase (66%) and the arm without a lead-in phase (64%). The reported safety profile was in concert with what has been reported in the ADVANCE and ILLUMINATE trials. These data should be considered with caution because they have not yet been presented in a peer-reviewed format. Figure 2 summarizes the design of the 2 Phase III trials with pegylated IFN-α2b, ribavirin and boceprevir (Figure 2A, B). In the boceprevir trials, the rapid virologic response (RVR) was defined as an undetectable HCV RNA (<9.3 IU/mL) at week 4 of boceprevir administration, that is, at week 8 of therapy as a "lead-in" phase of 4 weeks with pegylated IFN-α2b and ribavirin preceded boceprevir intake. The patients were split into 2 cohorts: non-black and black patients. There were 316, 311, and 311 non-black patients in the BOC/RGT (response-guided therapy), BOC/PR48, and 48/PR (control) arms, respectively; there were 52, 55, and 52, black patients, respectively, (Figure 2A). The virologic results of SPRINT-2 presented at The Liver Meeting are summarized in Table 2.1Poordad F. McCone J. Bacon B.R. et al.Boceprevir (BOC) combined with peginterferon alfa-2b/ribavirin (P/R) for treatment-naïve patients with hepatitis C virus (HCV) genotype 1: SPRINT-2 final results.Hepatology. 2010; 52: 402AGoogle Scholar In the non-black cohort, the SVR rates were 67% in BOC/RGT and 68% in BOC/PR48 versus 40% in 48P/R (P < .0001 and P < .0001, respectively). In the black cohort, the SVR rates were 42% and 53% versus 23%, respectively (P = .044 and P = .004, respectively; Table 2).1Poordad F. McCone J. Bacon B.R. et al.Boceprevir (BOC) combined with peginterferon alfa-2b/ribavirin (P/R) for treatment-naïve patients with hepatitis C virus (HCV) genotype 1: SPRINT-2 final results.Hepatology. 2010; 52: 402AGoogle ScholarTable 2Summary of SPRINT-2 Virologic Results as Presented at The Liver Meeting, 20101Poordad F. McCone J. Bacon B.R. et al.Boceprevir (BOC) combined with peginterferon alfa-2b/ribavirin (P/R) for treatment-naïve patients with hepatitis C virus (HCV) genotype 1: SPRINT-2 final results.Hepatology. 2010; 52: 402AGoogle ScholarBOC/RGT, % (n = 368)BOC/PR48, % (n = 366)48P/R, % (n = 363)SVR Non-black676840 Black425323Relapse Non-black9823 Black121714SVR according to lead-in (week 4) Non-black ≥1 Log10 HCV RNA decline828252 <1 Log10 HCV RNA decline29395 Black ≥1 Log10 HCV RNA decline676146 <1 Log10 HCV RNA decline25310SVR according to RVR (week 8)aMore than 3 times as many patients (60%) receiving boceprevir achieved an RVR compared with controls. Non-black RVR (HCV RNA undetectable)899186 No RVR (HCV RNA detectable)374331 Black RVR (HCV RNA undetectable)788275 No RVR (HCV RNA detectable)322821Discontinuations owing to stopping rule (detectable HCV RNA at week 24) Non-black8927 Black171546RVR, rapid virologic response, i.e. undetectable HCV RNA at week 4 of boceprevir administration (week 8 of therapy); SVR, sustained virologic response.a More than 3 times as many patients (60%) receiving boceprevir achieved an RVR compared with controls. Open table in a new tab RVR, rapid virologic response, i.e. undetectable HCV RNA at week 4 of boceprevir administration (week 8 of therapy); SVR, sustained virologic response. Boceprevir-resistant variants were found in 4% of patients who achieved a decrease of HCV RNA ≥1 log10 in both BOC/RGT and BOC/PR48 arms, and in 47% and 35% of those who achieved a decrease of HCV RNA <1 log10 during the lead-in phase in arms BOC/RGT and BOC/PR48, respectively.1Poordad F. McCone J. Bacon B.R. et al.Boceprevir (BOC) combined with peginterferon alfa-2b/ribavirin (P/R) for treatment-naïve patients with hepatitis C virus (HCV) genotype 1: SPRINT-2 final results.Hepatology. 2010; 52: 402AGoogle Scholar Adverse events that were more frequent in the boceprevir-containing arms were anemia (49% and 49% in BOC/RGT and BOC/PR48, respectively, vs 29% in PR48) and dysgeusia (37% and 43% vs 18%).1Poordad F. McCone J. Bacon B.R. et al.Boceprevir (BOC) combined with peginterferon alfa-2b/ribavirin (P/R) for treatment-naïve patients with hepatitis C virus (HCV) genotype 1: SPRINT-2 final results.Hepatology. 2010; 52: 402AGoogle Scholar Serious adverse events were reported in 11%, 12%, and 9% of cases, discontinuations due to adverse events in 12%, 16%, and 16% of cases, and dose modifications owing to adverse events in 40%, 35%, and 26% of cases in the BOC/RGT, BOC/PR48, and PR48 arms, respectively. Hemoglobin drops below 8.5 g/dL were observed in 5%, 9%, and 4% of cases, respectively. Erythropoietin was allowed in the study; it was used in 43%, 43%, and 24% of cases, respectively. Discontinuations owing to anemia occurred in 2%, 2%, and 1% of cases, respectively.1Poordad F. McCone J. Bacon B.R. et al.Boceprevir (BOC) combined with peginterferon alfa-2b/ribavirin (P/R) for treatment-naïve patients with hepatitis C virus (HCV) genotype 1: SPRINT-2 final results.Hepatology. 2010; 52: 402AGoogle Scholar The virologic results of RESPOND-2 presented at The Liver Meeting are summarized in Table 3.2Bacon B.R. Gordon S.C. Lawitz E. et al.HCV RESPOND-2 final results: high sustained virologic response among genotype 1 previous nonresponders and relapsers to peginterferon/ribavirin when retreated with boceprevir plus PegIntron (peginterferon alfa-2b)/ribavirin.Hepatology. 2010; 52: 430APubMed Google Scholar Null responders (patients who achieved a <2 log10 IU/mL HCV RNA decrease at week 12 during the first course of therapy) had been excluded from the trial. The SVR rates were 59% in BOC/RGT and 66% in BOC/PR48 versus 21% in the control PR48 arm (P < .0001 and P < .0001, respectively; Table 3). At different time points during therapy (weeks 8, 12, 24, and 36), the proportion of patients with undetectable HCV RNA was always higher by 9–12% in the BOC/PR48 arm than in the BOC/RGT arm. As expected, previous relapsers responded better than previous nonresponders (i.e., patients with a >2 log10 drop who kept detectable HCV RNA throughout therapy; Table 3).2Bacon B.R. Gordon S.C. Lawitz E. et al.HCV RESPOND-2 final results: high sustained virologic response among genotype 1 previous nonresponders and relapsers to peginterferon/ribavirin when retreated with boceprevir plus PegIntron (peginterferon alfa-2b)/ribavirin.Hepatology. 2010; 52: 430APubMed Google ScholarTable 3Summary of RESPOND-2 Virologic Results as Presented at The Liver Meeting, 20102Bacon B.R. Gordon S.C. Lawitz E. et al.HCV RESPOND-2 final results: high sustained virologic response among genotype 1 previous nonresponders and relapsers to peginterferon/ribavirin when retreated with boceprevir plus PegIntron (peginterferon alfa-2b)/ribavirin.Hepatology. 2010; 52: 430APubMed Google ScholarBOC/RGT, % (n = 162)BOC/PR48, % (n = 161)48P/R, % (n = 80)SVR (overall)596621Relapse (overall)151232SVR according to previous response Nonresponders40527 Relapsers697529SVR according to lead-in (week 4) ≥1 Log10 HCV RNA decline737925 <1 Log10 HCV RNA decline33340SVR according to RVR (week 8)aOf patients in BOC/RGT, 46% achieved an RVR and were eligible for shorter therapy; 52% in BOC/PR48, and 9% in 48P/R. RVR (HCV RNA undetectable)8688100 No RVR (HCV RNA detectable)404312RVR, rapid virologic response, i.e. undetectable HCV RNA at week 4 of boceprevir administration (week 8 of therapy); SVR, sustained virologic response.a Of patients in BOC/RGT, 46% achieved an RVR and were eligible for shorter therapy; 52% in BOC/PR48, and 9% in 48P/R. Open table in a new tab RVR, rapid virologic response, i.e. undetectable HCV RNA at week 4 of boceprevir administration (week 8 of therapy); SVR, sustained virologic response. Boceprevir-resistant variants were found in 8% and 6% of patients who achieved a decrease of HCV RNA ≥1 log10 by population sequencing, and in 28% and 32% of those who achieved a decrease of HCV RNA <1 log10 during the lead-in phase in arms BOC/RGT and BOC/PR48, respectively.2Bacon B.R. Gordon S.C. Lawitz E. et al.HCV RESPOND-2 final results: high sustained virologic response among genotype 1 previous nonresponders and relapsers to peginterferon/ribavirin when retreated with boceprevir plus PegIntron (peginterferon alfa-2b)/ribavirin.Hepatology. 2010; 52: 430APubMed Google Scholar As in SPRINT-2, anemia and dysgeusia were more frequent in the boceprevir-containing arms than in the control arm (43%, 46%, and 20%, and 43%, 45%, and 11% in BOC/RGT, BOC/PR48, and 48P/R, respectively).2Bacon B.R. Gordon S.C. Lawitz E. et al.HCV RESPOND-2 final results: high sustained virologic response among genotype 1 previous nonresponders and relapsers to peginterferon/ribavirin when retreated with boceprevir plus PegIntron (peginterferon alfa-2b)/ribavirin.Hepatology. 2010; 52: 430APubMed Google Scholar Serious adverse events were reported in 10%, 14%, and 5% of cases, discontinuations owing to adverse events in 8%, 12%, and 3% of cases, and dose modifications due to adverse events in 29%, 33%, and 14% of cases, respectively. Hemoglobin drops below 8.5 g/dL were observed in 5%, 14%, and 1% of cases, respectively. Erythropoietin was used in 41%, 46%, and 21% of cases, respectively. Discontinuations because of anemia occurred in 3%, 0%, and 0% of cases, respectively.2Bacon B.R. Gordon S.C. Lawitz E. et al.HCV RESPOND-2 final results: high sustained virologic response among genotype 1 previous nonresponders and relapsers to peginterferon/ribavirin when retreated with boceprevir plus PegIntron (peginterferon alfa-2b)/ribavirin.Hepatology. 2010; 52: 430APubMed Google Scholar First, it is important to note that the presentations at The Liver Meeting 2010 did not include the full data sets and it will be difficult to draw definitive conclusions before the full articles are published in peer-reviewed journals. Nevertheless, both telaprevir and boceprevir will be available soon in early access programs in various areas of the world, and it is likely that both drugs will be approved for clinical use before the full reports are published. It is thus important to examine carefully the data presented to address practical questions of importance for future prescribers. The design of these Phase III trials, although criticizable in several aspects, will inevitably govern the way telaprevir and boceprevir will be prescribed in combination with pegylated IFN-α and ribavirin. Telaprevir will be used at the dose of 750 mg 3 times per day in combination with pegylated IFN-α2a 180 μg/week, and ribavirin 1.0–1.2 g/d according to body weight. In treatment-naïve patients, telaprevir will be administered for the first 12 weeks of therapy, and response-guided therapy will be used to tailor the duration of additional pegylated IFN-α2a and ribavirin administration: 12 weeks in patients who achieve an eRVR, that is, a total duration of 24 weeks; and 36 weeks in those who do not, for a total duration of 48 weeks. In treatment-experienced patients, telaprevir will most likely be administered for 12 weeks in combination with pegylated IFN-α2a and ribavirin without a lead-in phase, and treatment with pegylated IFN-α2a and ribavirin will be continued for an additional 36 weeks, that is, until week 48, pending presentation of the final results of the REALIZE trial. Boceprevir will be used at the dose of 800 mg 3 times per day in combination with pegylated IFN-α2b, 1.5 μg/kg per week, and ribavirin, 0.8–1.4 g/d according to body weight. In treatment-naïve patients, boceprevir will be administered for 24 weeks, after a lead-in phase of 4 weeks with pegylated IFN-α2b and ribavirin alone. Thus, the total treatment duration will be 28 weeks in patients who achieve an RVR (undetectable HCV RNA at week 4 of boceprevir administration; i.e., at week 8 of therapy), whereas patients who do not achieve an RVR will receive pegylated IFN-α2b and ribavirin for an additional 20 weeks, namely, until week 48. In treatment-experienced patients, the triple combination of boceprevir, pegylated IFN-α2b, and ribavirin will be administered for 32 weeks after a lead-in phase of 4 weeks with pegylated IFN-α2b and ribavirin in patients who achieve an RVR (total treatment duration, 36 weeks), and 44 weeks in those who do not (total treatment duration, 48 weeks). It is unlikely that prior null responders to pegylated IFN-α and ribavirin alone (<2 log10 HCV RNA level drop at week 12 of the first course of therapy) will be eligible for treatments including boceprevir as they were excluded from the Phase III trial.2Bacon B.R. Gordon S.C. Lawitz E. et al.HCV RESPOND-2 final results: high sustained virologic response among genotype 1 previous nonresponders and relapsers to peginterferon/ribavirin when retreated with boceprevir plus PegIntron (peginterferon alfa-2b)/ribavirin.Hepatology. 2010; 52: 430APubMed Google Scholar The use of protease inhibitors in combination with pegylated IFN-α and ribavirin is generally claimed to yield higher SVR rates with shorter treatment duration. In reality, among treatment-naïve patients, only those who will achieve an eRVR with telaprevir (undetectable HCV RNA at weeks 4 and 12) or an RVR with boceprevir (undetectable HCV RNA at week 4 of boceprevir administration—i.e., at week 8 of therapy) will be eligible for shorter therapy. Based on the presented results, this represents approximately 50–60% of treatment-naïve patients who will receive 24 weeks of therapy with telaprevir and 28 weeks with boceprevir, and 46–52% of treatment-experienced patients who will receive 32 weeks of boceprevir.1Poordad F. McCone J. Bacon B.R. et al.Boceprevir (BOC) combined with peginterferon alfa-2b/ribavirin (P/R) for treatment-naïve patients with hepatitis C virus (HCV) genotype 1: SPRINT-2 final results.Hepatology. 2010; 52: 402AGoogle Scholar, 2Bacon B.R. Gordon S.C. Lawitz E. et al.HCV RESPOND-2 final results: high sustained virologic response among genotype 1 previous nonresponders and relapsers to peginterferon/ribavirin when retreated with boceprevir plus PegIntron (peginterferon alfa-2b)/ribavirin.Hepatology. 2010; 52: 430APubMed Google Scholar, 3Jacobson I.M. McHutchison J.G. Dusheiko G.M. et al.Telaprevir in combination with peginterferon and ribavirin in genotype 1 HCV treatment-naïve patients: final results of Phase 3 ADVANCE study.Hepatology. 2010; 52: 427AGoogle Scholar, 4Sherman K.E. Flamm S.L. Afdhal N.H. et al.Telaprevir in combination with peginterferon alfa2a and ribavirin for 24 or 48 weeks in treatment-naive genotype 1 HCV patients who achieved an extended rapid viral response: final results of Phase 3 ILLUMINATE study.Hepatology. 2010; 52: 401APubMed Google Scholar All treatment-experienced patients will be retreated with the triple combination of pegylated IFN-α2a, ribavirin, and telaprevir for 48 weeks. Unfortunately, shorter treatment duration has not been tested in patients who did not achieve an eRVR with telaprevir or an RVR with boceprevir. Such an experiment may have identified a subgroup of treatment-experienced patients who may benefit from shorter treatment duration in the absence of an eRVR or an RVR. This experiment will have to be performed post-approval. Response-guided therapy will allow treatment-naïve patients to stop therapy at week 24 or 28 with telaprevir or boceprevir when they achieve and eRVR or an RVR, respectively, eliminating side effects and saving costs while likely improving adherence. In treatment-experienced patients, the RESPOND-2 trial showed that treatment-experienced patients (excluding prior null-responders) can stop therapy at week 36 when they achieve an RVR.2Bacon B.R. Gordon S.C. Lawitz E. et al.HCV RESPOND-2 final results: high sustained virologic response among genotype 1 previous nonresponders and relapsers to peginterferon/ribavirin when retreated with boceprevir plus PegIntron (peginterferon alfa-2b)/ribavirin.Hepatology. 2010; 52: 430APubMed Google Scholar Response-guided therapy has not been tested with telaprevir in REALIZE. There was already some confusion in the definition of on-treatment responses used to tailor treatment duration with pegylated IFN-α and ribavirin. The results of the Phase III trials with these protease inhibitors will add more confusion and make everyday practice difficult, especially for non-expert practitioners. Indeed, response-guided therapy is based on different definitions of "rapid virologic responses" assessed at different time points of therapy for telaprevir and boceprevir. Different lower limits of detection have been used in the trials (25 IU/mL for telaprevir, 9.3 IU/mL for boceprevir).1Poordad F. McCone J. Bacon B.R. et al.Boceprevir (BOC) combined with peginterferon alfa-2b/ribavirin (P/R) for treatment-naïve patients with hepatitis C virus (HCV) genotype 1: SPRINT-2 final results.Hepatology. 2010; 52: 402AGoogle Scholar, 2Bacon B.R. Gordon S.C. Lawitz E. et al.HCV RESPOND-2 final results: high sustained virologic response among genotype 1 previous nonresponders and relapsers to peginterferon/ribavirin when retreated with boceprevir plus PegIntron (peginterferon alfa-2b)/ribavirin.Hepatology. 2010; 52: 430APubMed Google Scholar, 3Jacobson I.M. McHutchison J.G. Dusheiko G.M. et al.Telaprevir in combination with peginterferon and ribavirin in genotype 1 HCV treatment-naïve patients: final results of Phase 3 ADVANCE study.Hepatology. 2010; 52: 427AGoogle Scholar, 4Sherman K.E. Flamm S.L. Afdhal N.H. et al.Telaprevir in combination with peginterferon alfa2a and ribavirin for 24 or 48 weeks in treatment-naive genotype 1 HCV patients who achieved an extended rapid viral response: final results of Phase 3 ILLUMINATE study.Hepatology. 2010; 52: 401APubMed Google Scholar Although the difference is modest, it is likely that other thresholds will be used in clinical practice in the future, including "lower limits of detection" or "lower limits of quantification" for different commercial assays. Practically, bleeding the patients and having to wait several days to weeks for the results may delay or alter the treatment decision. Overall, at a time when screening programs and better cure rates will lead an increased number of nonspecialists to treat f
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