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Directly acting antivirals for the treatment of patients with hepatitis C infection: A clinical development update addressing key future challenges

Open AccessPublished:November 04, 2008DOI:https://doi.org/10.1016/j.jhep.2008.10.011
      Current therapy for chronic hepatitis C virus (HCV) infection is effective in less than 50% of genotype 1-infected patients. Antiviral agents specifically targeting either the HCV protease or polymerase, or other targets, are now in clinical development. In general, direct antivirals are potent inhibitors of HCV replication and can result in rapid declines in serum HCV RNA levels. Yet these agents drive selection pressure for mutant viruses that can reduce susceptibility to any given drug. Using pegylated interferon (PEG-IFN) and ribavirin (RBV) in combination with direct antivirals can suppress viral breakthrough and increase the likelihood of sustained virologic response. Direct antivirals also result in adverse events in a proportion of patients, adding to concerns of tolerability that exist with PEG-IFN and RBV. Direct antivirals are very likely to become an integral part of treatment within the next decade, and already their use in clinical trials has raised important issues related to duration of treatment, early stopping rules, retreatment of previously treated patients, and how or when direct antivirals should be combined. Here, we provide current information regarding the effectiveness of direct antivirals in treating chronic HCV infection and discuss the key questions and challenges now facing the field.

      Keywords

      1. Introduction

      The currently available therapy of peginterferon (PEG-IFN) combined with ribavirin (RBV) for suitable patients with chronic hepatitis C virus (HCV) infection can eradicate virus permanently in those patients who achieve a sustained virologic response (SVR). However, this treatment is only effective in approximately 40% of patients with genotype 1 infection, the most common genotype in Europe and North America [

      WHO. Global surveillance and control of hepatitis C. Report of a WHO consultation organized in collaboration with the Viral Hepatitis Prevention Board, Antwerp, Belgium. J Viral Hepat 1999;6: 35–47.

      ]. Therapy is also costly and frequently associated with side effects that to a variable degree limit eligibility for, and compliance with, therapy. For these reasons, alternative, more effective treatment strategies that would be more broadly available and applicable to patients with chronic HCV must be developed.
      While many new compounds interacting with a variety of targets are currently in development (Fig. 1) [
      • Pawlotsky J.M.
      • Chevaliez S.
      • McHutchison J.G.
      The hepatitis C virus life cycle as a target for new antiviral therapies.
      ,
      • Manns M.P.
      • Foster G.R.
      • Rockstroh J.K.
      • Zeuzem S.
      • Zoulim F.
      • Houghton M.
      The way forward in HCV treatment—finding the right path.
      ], in this review we focus only on the development of the HCV protease and polymerase inhibitors. These agents are currently the most promising in clinical development. Both classes are potent inhibitors of viral replication, and in clinical trials several candidates have significantly enhanced response rates compared with our current regimen. However, certain principles and methods related to optimizing treatment regimens and suppressing resistance must now be addressed to move the clinical trial framework forward successfully. While all direct antiviral agents and data relating to them cannot be covered in this review, we highlight specific examples and issues related to their use by addressing the following key and clinically relevant questions.
      Figure thumbnail gr1
      Fig. 1Specifically targeted antivirals currently in development. Most targets known to the authors are shown for completeness. While the list is incomplete, more than 50 clinical trials are currently underway in chronic hepatitis C patients. The direct antivirals active against the HCV protease and polymerase are depicted as separate groups, and are an area of intense interest and drug development with many “first” and subsequent generation compounds in a variety of earlier and latter stage clinical development.

      2. How effective are HCV protease and polymerase inhibitors?

      Inhibitors of the NS3/4a protease have been the most extensively studied direct antivirals to date, and two such agents, the peptidomimetic inhibitors telaprevir and boceprevir, have now progressed to phase 3 clinical trials. In genotype 1, treatment-naı¨ve HCV patients, telaprevir in combination with PEG-IFN and RBV can result in SVR rates (defined as HCV RNA negativity 24 weeks post therapy) as high as 68% [
      • Dusheiko G.M.
      • Hézode C.
      • Pol S.
      • Groeser T.
      • Bronowicki J.-P.
      • Bourliere M.
      • et al.
      Treatment of chronic hepatitis C with telaprevir (TVR) in combination with peginterferon alfa-2a with or without ribavirin: Further interim analysis results of the PROVE2 study.
      ]. Similarly, in genotype 1, treatment-naı¨ve HCV patients, the rate of HCV RNA negativity 12 weeks post therapy (an earlier and accurate surrogate of SVR), with boceprevir has been as high as 74% [

      Schering-Plough. Top-line results of boceprevir phase II study showed high rate of sustained response (SVR) in genotype 1 treatment-naı¨ve hepatitis C patients. Available from: http://www.schering-plough.com/schering_plough/news/release.jsp?releaseID=1182855. Accessed September 19, 2008.

      ].
      Inhibitors of the HCV NS5B RNA-dependent RNA polymerase (RdRp) include nucleos(t)ide inhibitors and non-nucleos(t)ide inhibitors. A total of at least five different target sites within the HCV polymerase have been identified. R1626, a prodrug of a cytidine analog, is a nucleoside inhibitor currently in phase 2 development. When used in combination with PEG-IFN and RBV for 4 weeks, the mean maximal viral load reduction from baseline was 5.2 log10 IU/mL [
      • Pockros P.J.
      • Nelson D.
      • Godofsky E.
      • Rodriguez-Torres M.
      • Everson G.T.
      • Fried M.W.
      • et al.
      R1626 plus peginterferon Alfa-2a provides potent suppression of hepatitis C virus RNA and significant antiviral synergy in combination with ribavirin.
      ]. R7128, another cytidine analog prodrug, has shown a similar mean reduction in HCV RNA, 5 log10 IU/mL, when used with PEG-IFN and RBV for 4 weeks in treatment-naı¨ve genotype 1 patients [
      • Lalezari J.
      • Gane E.
      • Rodriguez-Torres M.
      • De Jesús D.
      • Nelson G.
      • Everson G.
      • et al.
      Potent antiviral activity of the HCV nucleoside polymerase inhibitor R7128 with PEG-IFN and ribavirin: interim results of R7128 500 mg bid for 28 days.
      ].
      Non-nucleoside inhibitors target the NS5B RdRp at a site separate from the enzyme’s catalytic center. In a phase 1 study, treatment with the non-nucleoside inhibitor VCH-759 resulted in mean maximal decreases in HCV RNA of up to 2.5 log10 IU/mL [
      • Cooper C.
      • Lawitz E.J.
      • Ghali P.
      • Rodriguez-Torres M.
      • Anderson F.H.
      • Lee S.S.
      • et al.
      Antiviral activity of the non-nucleoside polymerase inhibitor, VCH-759, in chronic Hepatitis C patients: results from a randomized, double-blind, placebo-controlled, ascending multiple dose study.
      ], and the drug has progressed to phase 2 studies.
      Several other protease and polymerase inhibitors are in clinical development, and it is likely that many of them will also display rapid, highly effective and efficient, robust suppression of HCV replication.

      3. Can these antivirals be given as monotherapy, or can we dispense with PEG-IFN?

      Currently interferon remains a crucial backbone for HCV therapy. When the first direct antivirals entered clinical trials with HCV-infected patients, the “hope” was that they might replace PEG-IFN and/or RBV therapy by displaying potent viral suppression. However, early clinical trials indicated that monotherapy with direct antivirals selects for resistance mutations within a week, and as such, they cannot be given effectively alone.
      BILN-2061, the first NS34a protease inhibitor to enter clinical trials, produced a greater than 2-log10 IU/mL reduction in HCV RNA after only 2 days in HCV genotype 1-infected patients [
      • Hinrichsen H.
      • Benhamou Y.
      • Wedemeyer H.
      • Reiser M.
      • Sentjens R.E.
      • Calleja J.L.
      • et al.
      Short-term antiviral efficacy of BILN 2061, a hepatitis C virus serine protease inhibitor, in hepatitis C genotype 1 patients.
      ]. Yet early in vitro studies revealed the worrying concern of emergence of drug resistance to BILN-2061 [
      • Lin C.
      • Lin K.
      • Luong Y.P.
      • Rao B.G.
      • Wei Y.Y.
      • Brennan D.L.
      • et al.
      In vitro resistance studies of hepatitis C virus serine protease inhibitors, VX-950 and BILN 2061: structural analysis indicates different resistance mechanisms.
      ], which is no longer in development because of cardiac toxicity in laboratory animals. In a separate phase 1b study examining telaprevir monotherapy in genotype 1 patients, those who received 750 mg of drug every 8 h for 2 weeks had a median maximal viral load reduction of 4.4 log10 IU/mL [
      • Reesink H.W.
      • Zeuzem S.
      • Weegink C.J.
      • Forestier N.
      • van Vliet A.
      • van de Wetering de Rooij J.
      • et al.
      Rapid decline of viral RNA in hepatitis C patients treated with VX-950: a phase Ib, placebo-controlled, randomized study.
      ]. However, during the second week of treatment, virologic breakthrough, as evidenced by a rebound in HCV RNA, was noted in a significant number of patients who received lower doses. Subsequent clinical trials have established that adding PEG-IFN in combination with telaprevir increases HCV RNA suppression and reduces the emergence of resistance. In a small trial conducted in genotype 1-infected patients, combination therapy with telaprevir and PEG-IFN for 14 days led to a greater median HCV RNA reduction (5.5 log10 IU/mL) than either telaprevir (4.0 log10 IU/mL) or PEG-IFN (1.0 log10 IU/mL) alone [
      • Forestier N.
      • Reesink H.W.
      • Weegink C.J.
      • McNair L.
      • Kieffer T.L.
      • Chu H.M.
      • et al.
      Antiviral activity of telaprevir (VX-950) and peginterferon alfa-2a in patients with hepatitis C.
      ]. Viral sequence analysis identified resistance mutations in fewer (2 of 7) patients receiving combination therapy versus 7 of 8 receiving telaprevir monotherapy.
      Similar to telaprevir, the protease inhibitor boceprevir also results in more robust reductions in HCV RNA when used in combination with PEG-IFN. In a phase 1b crossover study, patients who received 400 mg of boceprevir tid and PEG-IFN had a mean maximum HCV RNA reduction of 2.88 log10 IU/mL, compared with 1.61 log10 IU/mL for those who received boceprevir alone at the same dose [
      • Sarrazin C.
      • Rouzier R.
      • Wagner F.
      • Forestier N.
      • Larrey D.
      • Gupta S.K.
      • et al.
      SCH 503034, a novel hepatitis C virus protease inhibitor, plus pegylated interferon alpha-2b for genotype 1 nonresponders.
      ].
      In contrast to protease inhibitors, nucleoside polymerase inhibitors theoretically have a higher genetic barrier to resistance. Unfortunately, those examined thus far in larger trials induce only modest viral suppression. Valopicitabine, a nucleoside analog of 2′-C-methylcytidine, has a documented up to 1.2 log10 IU/mL HCV RNA reduction in genotype 1-infected patients. But when used in combination with PEG-IFN, valopicitabine has a dose-dependent additive antiviral effect [
      • Afdhal N.H.
      • O’Brien C.
      • Godofsky E.
      • Rodriguez-Torres M.
      • Pappas S.C.
      • Pockros P.
      • et al.
      Valopicitabine (NM283), alone or with peg-interferon, compared to peg-interferon/ribavirin (PEGIFN/RBV) retreatment in hepatitis C patients with prior non-response to PEGIFN/RBV: week 24 results.
      ].
      The cytidine nucleoside analog R7128 has been reported to induce a mean maximum decline of 2.72 log10 IU/mL at 1500 mg bid for 14 days in genotype 1 prior nonresponders [
      • Reddy R.
      • Rodriguez-Torres M.
      • Gane E.
      • Robson R.
      • Lalezari J.
      • Everson G.T.
      • et al.
      Antiviral activity, pharmacokinetics, safety, and tolerability of R7128, a novel nucleoside HCV RNA polymerase inhibitor, following multiple, ascending, oral doses in patients with HCV genotype 1 infection who have failed prior interferon therapy.
      ]. Yet in an ongoing trial of treatment-naı¨ve, HCV genotype 1 patients, combining R7128 1500 mg bid with PEG-IFN and RBV has been reported to lead to a greater reduction in HCV RNA—5 log10 IU/mL at 4 weeks—similar to that observed with the current protease inhibitor trials [
      • Lalezari J.
      • Gane E.
      • Rodriguez-Torres M.
      • De Jesús D.
      • Nelson G.
      • Everson G.
      • et al.
      Potent antiviral activity of the HCV nucleoside polymerase inhibitor R7128 with PEG-IFN and ribavirin: interim results of R7128 500 mg bid for 28 days.
      ].
      Compared with the nucleoside inhibitors, both suboptimal antiviral suppression and drug resistance have so far been significant issues for non-nucleoside polymerase inhibitors. The inhibitor HCV-796 targets the non-nucleoside allosteric D site, in the hinge of the RdRp. In a phase 1b study, the highest dose of HCV-796 was reported to be associated with a peak mean HCV RNA reduction of 1.4 log10 IU/mL [
      • Chandra P.
      • Raible D.
      • Harper D.
      • Speth J.
      • Villano S.
      • Bichier G.
      Antiviral activity of the non-nucleoside polymerase inhibitor, HCV-796, in patients with chronic hepatitis C virus: preliminary results from a randomized double-blind, placebo-controlled, ascending multiple dose study.
      ]. Unfortunately, most patients relapsed after a few days of therapy. However, in a phase 2 trial in which HCV genotype 1 and non-1 infected patients received combination PEG-IFN and HCV-796 for 14 days, the HCV RNA level reduction was 3.3–3.5 log10 IU/mL in the combination groups, and no relapse caused by resistance was observed during therapy [
      • Villano S.A.
      • Raible D.
      • Harper D.
      • Speth J.
      • Chandra P.
      • Shaw P.
      • et al.
      Antiviral activity of the non-nucleoside polymerase inhibitor, HCV-769, in combination with pegylated interferon alpha-2b in treatment-naive patients with chronic HCV.
      ].
      There may be several important factors that contribute to suboptimal viral suppression by a direct antiviral. For example, poor drug bioavailability and other pharmacokinetic factors could limit the amount of drug delivered to infected hepatoctyes. Nonetheless, current clinical data support a trial model of including PEG-IFN in combination with individual antivirals and developing a clear understanding of the reasons any drug is associated with submaximal viral suppression.

      4. Can the addition of a direct antiviral allow us to dispense with ribavirin?

      Experience with both protease and polymerase inhibitors suggests that ribavirin will remain an essential component of HCV therapy for the foreseeable future. The phase 2 PROVE2 study of telaprevir included four treatment groups, two of which included triple therapy with PEG-IFN and RBV, one standard of care, and the remaining arm only telaprevir and PEG-IFN. The telaprevir and PEG-IFN arm had a higher virological breakthrough rate, 26%, versus 2% in the triple therapy arms [
      • Dusheiko G.M.
      • Hézode C.
      • Pol S.
      • Groeser T.
      • Bronowicki J.-P.
      • Bourliere M.
      • et al.
      Treatment of chronic hepatitis C with telaprevir (TVR) in combination with peginterferon alfa-2a with or without ribavirin: Further interim analysis results of the PROVE2 study.
      ]. RBV therefore has an important effect in limiting the emergence of resistant variants. Within this study, two groups received identical regimens except for the presence or absence of ribavirin. Between those groups, the triple therapy regimen resulted in an SVR of 62% and a relapse rate of 29%, whereas double therapy without ribavirin demonstrated a lower SVR rate of 36% and a significantly higher relapse rate of 48% (Table 1). The value of RBV therefore extends beyond preventing resistance, to also limiting relapse.
      Table 1Virologic responses to telaprevir- or boceprevir-based treatment regimens
      RVR (%)EVR (%)SVR12 (%)SVR24 (%)Relapse (%)
      PEG-IFN + RBV (control arms)
       PROVE111454123
       PROVE213414820
       SPRINT-138
      Telaprevir + PEG-IFN, 12 weeks
       PROVE251623648
      Telaprevir + PEG-IFN + RBV
       12 weeks
        PROVE159713533
        PROVE280796229
       24 weeks
      Telaprevir was administered only during the first 12 weeks of therapy [4,19,23].
        PROVE18168612
        PROVE269736814
       48 weeks
      Telaprevir was administered only during the first 12 weeks of therapy [4,19,23].
        PROVE18180676
      Boceprevir + PEG-IFN + RBV (SPRINT-1)
       28 weeks
        Induction
      Boceprevir was not administered for the first 4 weeks of therapy [5].
      56
        No induction55
       48 weeks
        Induction
      Boceprevir was not administered for the first 4 weeks of therapy [5].
      74
        No induction66
      EVR, early virologic response (12 weeks); PEG-IFN, pegylated interferon; RBV, ribavirin; RVR, rapid virologic response (4 weeks); SVR12, sustained virologic response week 12 post-treatment; SVR24, sustained virologic response week 24 post-treatment.
      a Telaprevir was administered only during the first 12 weeks of therapy
      • Dusheiko G.M.
      • Hézode C.
      • Pol S.
      • Groeser T.
      • Bronowicki J.-P.
      • Bourliere M.
      • et al.
      Treatment of chronic hepatitis C with telaprevir (TVR) in combination with peginterferon alfa-2a with or without ribavirin: Further interim analysis results of the PROVE2 study.
      ,
      • McHutchison J.G.
      • Everson G.T.
      • Gordon S.C.
      • Jacobson I.
      • Kauffman R.
      • McNair L.
      • et al.
      PROVE1: results from a phase 2 study of telaprevir with peginterferon alfa-2a and ribavirin in treatment-naive subjects with hepatitis C.
      ,

      McHutchison JG, Everson GT, Gordon SC, Jacobson IM, Sulkowski M, Kauffman R, et al. A phase 2b study of the protease inhibitor telaprevir with peginterferon and ribavirin in treatment-naı¨ve subjects with genotype 1 chronic hepatitis C. Submitted for publication.

      .
      b Boceprevir was not administered for the first 4 weeks of therapy

      Schering-Plough. Top-line results of boceprevir phase II study showed high rate of sustained response (SVR) in genotype 1 treatment-naı¨ve hepatitis C patients. Available from: http://www.schering-plough.com/schering_plough/news/release.jsp?releaseID=1182855. Accessed September 19, 2008.

      .
      Additionally, a phase 2 study of valopicitabine in genotype 1 prior nonresponder patients included three study arms: valopicitabine and PEG-IFN; valopicitabine, PEG-IFN, and RBV; and PEG-IFN and RBV. At day 36, 23% of patients treated with triple combination therapy were HCV RNA negative, compared with 11% of patients treated with the standard of care, and 14% of patients treated with valopicitabine and PEG-IFN [

      HIVandHepatitis.com. Valopicitabine (NM283) produces greater suppression of HCV when added to pegylated interferon plus ribavirin. Available from: http://www.hivandhepatitis.com/hep_c/news/2007/062207_b.html. Accessed September 18, 2008.

      ].
      And finally, in a third phase 2 study, dual therapy with PEG-IFN and the nucleoside inhibitor R1626 at 1500 mg bid resulted in a week 4 HCV RNA undetectable response rate of 29%, compared with 74% for triple therapy including ribavirin [
      • Pockros P.J.
      • Nelson D.
      • Godofsky E.
      • Rodriguez-Torres M.
      • Everson G.T.
      • Fried M.W.
      • et al.
      R1626 plus peginterferon Alfa-2a provides potent suppression of hepatitis C virus RNA and significant antiviral synergy in combination with ribavirin.
      ]. At week 4, the mean HCV RNA decrease from baseline for the dual therapy group was 3.6 log10 IU/mL, versus 5.2 log10 IU/mL for triple therapy. The difference of 1.6 log10 IU/mL again suggests that RBV has a synergistic effect in terms of antiviral efficacy for both protease and polymerase inhibitors, driving higher on-treatment and sustained response rates and limiting resistance.
      In the future, it may be theoretically possible to combine protease and polymerase inhibitors, or other targeted drugs, and dispense with ribavirin, but for now, ribavirin seems an essential component of these newer HCV therapeutic regimens in development.

      5. Are there additional side effects when adding a direct antiviral to PEG-IFN and RBV therapy?

      In most trials conducted to date, combining an oral antiviral with PEG-IFN and RBV has increased the likelihood of side effects and treatment discontinuation. In the PROVE1 and PROVE2 studies of telaprevir, gastrointestinal events, skin rashes, and anemia were more frequent in the triple therapy arms compared with PEG-IFN and RBV alone [
      • Dusheiko G.M.
      • Hézode C.
      • Pol S.
      • Groeser T.
      • Bronowicki J.-P.
      • Bourliere M.
      • et al.
      Treatment of chronic hepatitis C with telaprevir (TVR) in combination with peginterferon alfa-2a with or without ribavirin: Further interim analysis results of the PROVE2 study.
      ,
      • McHutchison J.G.
      • Everson G.T.
      • Gordon S.C.
      • Jacobson I.
      • Kauffman R.
      • McNair L.
      • et al.
      PROVE1: results from a phase 2 study of telaprevir with peginterferon alfa-2a and ribavirin in treatment-naive subjects with hepatitis C.
      ]. In PROVE1, the discontinuation rate in the first 12 weeks with triple therapy was 18%, versus 4% with PEG-IFN and RBV. In the phase 2 studies of boceprevir, rates of anemia and “dysgeusia” were higher with triple therapy than with standard therapy, as were discontinuation rates (26–28% vs. 14%) [
      • Kwo P.
      • Lawitz E.
      • McCone J.
      • Schiff E.
      • Vierling J.
      • Pound D.
      • et al.
      Interim results from HCV SPRINT-1: RVR/EVR from phase 2 study of boceprevir plus Pegintron (peginterferon alfa-2b)/ribavirin in treatment-naive subjects with genotype-1 CHC.
      ,
      • Schiff E.
      • Poordad F.
      • Jacobson I.
      • Flamm S.
      • Bacon B.
      • Lawitz E.
      • et al.
      Boceprevir (B) combination therapy in null responders (NR): response dependent on interferon responsiveness.
      ].
      For the nucleoside inhibitor R1626, dose-limiting gastrointestinal adverse effects and mild to moderate reversible leukopenia have been noted with monotherapy [
      • Roberts S.K.
      • Cooksley G.
      • Dore G.J.
      • Robson R.
      • Shaw D.
      • Berns H.
      • et al.
      Robust antiviral activity of R1626, a novel nucleoside analog: a randomized, placebo-controlled study in patients with chronic hepatitis C.
      ]. In combination with PEG-IFN, further significant hematologic toxicity has been observed. The rate of grade 4 neutropenia was 78% when R1626 was administered at a dose of 3000 mg bid with PEG-IFN. Even at lower doses of R1626, the rates of grade 4 neutropenia were 42–52%. Thirty-nine percent of patients treated with R1626 and PEG-IFN therapy also experienced grade 3 or 4 anemia. Most of the hematologic toxicities reversed upon removal of R1626, despite continuation with PEG-IFN. Gastrointestinal adverse events and rash are also more common with R1626 plus PEG-IFN than with PEG-IFN alone [
      • Pockros P.J.
      • Nelson D.
      • Godofsky E.
      • Rodriguez-Torres M.
      • Everson G.T.
      • Fried M.W.
      • et al.
      R1626 plus peginterferon Alfa-2a provides potent suppression of hepatitis C virus RNA and significant antiviral synergy in combination with ribavirin.
      ].
      In contrast, R7128 appears to be generally well tolerated in combination with PEG-IFN and RBV. In an ongoing study, albeit with a small sample size, grade 3/4 hematological toxicity has been rare, with rates similar to treatment with PEG-IFN and RBV. Headache, fatigue, and chills have been more common than with control, yet all events have been categorized as mild [
      • Lalezari J.
      • Gane E.
      • Rodriguez-Torres M.
      • De Jesús D.
      • Nelson G.
      • Everson G.
      • et al.
      Potent antiviral activity of the HCV nucleoside polymerase inhibitor R7128 with PEG-IFN and ribavirin: interim results of R7128 500 mg bid for 28 days.
      ].
      Clinical development for the polymerase inhibitors valopicitabine and HCV-796 have both been placed on hold because of concerns regarding toxicity: gastrointestinal toxicities (nausea, vomiting and diarrhea) for valopicitabine, and liver toxicity for HCV-796.
      Therefore, in all early phase clinical trials of direct antivirals, management plans which incorporate careful evaluation of differences in adverse events will be critical to avoid exposing patients to potential serious toxicities and to develop an early and accurate evaluation of the tolerability of new compounds.

      6. What is the value of a lead-in strategy with PEG-IFN and RBV?

      A lead-in phase could accurately discriminate PEG-IFN and RBV responders and nonresponders, and reducing viral burden prior to initiating a direct antiviral could theoretically minimize or at least reduce the development of drug resistant variants. Only one such study has addressed this to date. The SPRINT-1 trial of boceprevir in HCV genotype 1 naive patients included study arms that received 4 weeks of PEG-IFN plus RBV followed by the addition of boceprevir, 800 mg tid, for an additional 24 or 44 weeks. Preliminary data suggest patients who received 28 weeks of therapy had an SVR rate of 56%, which is similar to the rate of 55% for patients without the lead-in [

      Schering-Plough. Top-line results of boceprevir phase II study showed high rate of sustained response (SVR) in genotype 1 treatment-naı¨ve hepatitis C patients. Available from: http://www.schering-plough.com/schering_plough/news/release.jsp?releaseID=1182855. Accessed September 19, 2008.

      ]. Among patients who received 48 weeks of therapy, there did appear to be some benefit of the lead-in strategy: SVR12 rates were 74% versus 64% for patients with and without a lead-in phase. However, these results should be interpreted with some caution, as the sample size is relatively small.
      It is therefore unclear at this stage whether a lead-in strategy will be effective with these or other antivirals or suitable for all patient groups. Also unanswered is what would theoretically be the most effective length of treatment in a lead-in strategy (for example 1, 2, 4, 6, or 8 weeks, most of which have not been tested) and what duration of triple therapy is then required for consolidation therapy?

      7. By adding a direct antiviral, can the duration of therapy be shortened?

      As described above, it appears that for boceprevir, 48 weeks of therapy may be needed to maximize rates of SVR. For telaprevir, results from PROVE1 suggest 24 weeks of therapy may be sufficient. In PROVE1, the group that received triple therapy for 12 weeks followed by PEG-IFN plus RBV alone for an additional 12 weeks had an overall SVR of 61%, comparable to the SVR of 67% seen with triple therapy for 12 weeks followed by PEG-IFN plus RBV for an additional 36 weeks [
      • McHutchison J.G.
      • Everson G.T.
      • Gordon S.C.
      • Jacobson I.
      • Kauffman R.
      • McNair L.
      • et al.
      PROVE1: results from a phase 2 study of telaprevir with peginterferon alfa-2a and ribavirin in treatment-naive subjects with hepatitis C.
      ,

      McHutchison JG, Everson GT, Gordon SC, Jacobson IM, Sulkowski M, Kauffman R, et al. A phase 2b study of the protease inhibitor telaprevir with peginterferon and ribavirin in treatment-naı¨ve subjects with genotype 1 chronic hepatitis C. Submitted for publication.

      ]. In PROVE2, patients who received triple therapy for 12 weeks followed by 12 weeks of PEG-IFN and RBV had an SVR of 68%. Those who received only 12 weeks of triple therapy had an SVR of 62%, which again is comparable, except the rate of relapse was higher in the 12-week group (29%) versus the 24-week group (14%) [
      • Dusheiko G.M.
      • Hézode C.
      • Pol S.
      • Groeser T.
      • Bronowicki J.-P.
      • Bourliere M.
      • et al.
      Treatment of chronic hepatitis C with telaprevir (TVR) in combination with peginterferon alfa-2a with or without ribavirin: Further interim analysis results of the PROVE2 study.
      ].
      Clinical trials of polymerase inhibitors have not yet addressed duration of combination therapy to the same extent as those with protease inhibitors have. Given the potential observed differences between boceprevir and telaprevir regarding duration of treatment, it may be that optimal duration will need to be evaluated for each antiviral in direct comparative trials. Also, these different duration strategies may not apply equally to patients who have previously not responded or relapsed to prior therapy with IFN and RBV based regimens. These issues will need to be addressed carefully in subsequent clinical trials in these patient populations.

      8. What is the observed early virologic response with direct antivirals, and how does this translate into different or similar stopping rules?

      With telaprevir, suppression of HCV occurs early, and in the PROVE1 study rates of week 4 undetectability (rapid virologic response, RVR), and week 12 response (early virologic response, EVR), exceeded the rates of SVR. Among patients who received triple therapy for 12 weeks followed by either 12 or 36 weeks of PEG-IFN plus RBV, the rate of RVR was 81%, EVR was 74%, and SVR was 63% [
      • McHutchison J.G.
      • Everson G.T.
      • Gordon S.C.
      • Jacobson I.
      • Kauffman R.
      • McNair L.
      • et al.
      PROVE1: results from a phase 2 study of telaprevir with peginterferon alfa-2a and ribavirin in treatment-naive subjects with hepatitis C.
      ,

      McHutchison JG, Everson GT, Gordon SC, Jacobson IM, Sulkowski M, Kauffman R, et al. A phase 2b study of the protease inhibitor telaprevir with peginterferon and ribavirin in treatment-naı¨ve subjects with genotype 1 chronic hepatitis C. Submitted for publication.

      ]. In PROVE2, rates of virologic response were more consistent over time, and the study arm that received 12 weeks triple therapy followed by 12 weeks PEG-IFN plus RBV had an RVR of 69%, an EVR of 73%, and an SVR of 68% [
      • Dusheiko G.M.
      • Hézode C.
      • Pol S.
      • Groeser T.
      • Bronowicki J.-P.
      • Bourliere M.
      • et al.
      Treatment of chronic hepatitis C with telaprevir (TVR) in combination with peginterferon alfa-2a with or without ribavirin: Further interim analysis results of the PROVE2 study.
      ].
      With boceprevir, the effect of rapid virologic response is less clear. In SPRINT-1, in the non-lead-in arms, virological response increased from an RVR of 37% to a 12-week SVR of 55% [
      • Kwo P.
      • Lawitz E.
      • McCone J.
      • Schiff E.
      • Vierling J.
      • Pound D.
      • et al.
      Interim results from HCV SPRINT-1: RVR/EVR from phase 2 study of boceprevir plus Pegintron (peginterferon alfa-2b)/ribavirin in treatment-naive subjects with genotype-1 CHC.
      ]. However, among patients who received the lead-in and achieved RVR, SVR was 82% with the 28-week regimen and SVR12 was 92% with the 48-week regimen [

      Schering-Plough. Top-line results of boceprevir phase II study showed high rate of sustained response (SVR) in genotype 1 treatment-naı¨ve hepatitis C patients. Available from: http://www.schering-plough.com/schering_plough/news/release.jsp?releaseID=1182855. Accessed September 19, 2008.

      ]. The definition of RVR in this trial was also different; the timepoint for RVR assessment was after 4 weeks of triple therapy; by which stage patients in the “lead-in” arms had received 8 weeks of PEG-IFN and RBV.
      While there is substantial evidence that rapid and early virologic response may be predictive of SVR with PEG-IFN and RBV, at this time it seems premature to develop solid accurate stopping rules for any given new antiviral, and rules developed for one drug regimen may not apply to another. Additionally, whether a response can be predicted earlier, for example, within the first few days or a week of treatment, needs to be fully explored utilizing modeling techniques in larger data sets. It will also be necessary to confirm in follow-up studies that SVR rates 24 weeks post-treatment translate into long-term viral eradication and that late relapse does not occur.

      9. Clinically, how common is virologic resistance?

      In vitro analyses have shown that resistance mutations develop in the NS5B gene in response to polymerase inhibitors and in the NS3 gene in response to protease inhibitors, as expected with HCV’s high viral replication rate, quasispecies diversity, and error-prone reverse transcriptase. Preliminary data analyses from the telapravir clinical development program also suggest that virologic breakthrough is associated, in general terms, with lower trough serum levels of both telaprevir and PEG-IFN [
      • Reesink H.W.
      • Zeuzem S.
      • Weegink C.J.
      • Forestier N.
      • van Vliet A.
      • van de Wetering de Rooij J.
      • et al.
      Rapid decline of viral RNA in hepatitis C patients treated with VX-950: a phase Ib, placebo-controlled, randomized study.
      ,

      Sulkowski M, McHutchison JG, on behalf of the PROVE1study team. Interim analysis results and viral variant evaluation from a phase 2 study of telaprevir with peginterferon alfa-2A and ribavirin in treatment-naı¨ve subjects with hepatitis C. ICAAC, Chicago, USA, September 19, 2007.

      ]. Hence, promoting and evaluating adherence to therapy with the goals of optimizing pharmacokinetics and suppressing resistance will become important aspects of all clinical trial programs involving direct antivirals. In addition, the effect of suboptimal adherence on viral resistance and breakthrough will also need to be evaluated in detail.
      To date, in vivo resistance has been most extensively studied with telaprevir. A phase 1b study of 16 treatment-naı¨ve, genotype 1 patients that compared telaprevir monotherapy with telaprevir plus PEG-IFN included a detailed kinetic analysis of viral variants over 14 days of treatment [
      • Kieffer T.L.
      • Sarrazin C.
      • Miller J.S.
      • Welker M.W.
      • Forestier N.
      • Reesink H.W.
      • et al.
      Telaprevir and pegylated interferon-alpha-2a inhibit wild-type and resistant genotype 1 hepatitis C virus replication in patients.
      ]. Of 8 patients who received telaprevir alone, 4 experienced HCV RNA rebound, which was detected in 3 patients at day 8, and in the fourth at day 12. Among these 4 patients, virus isolated at day 4 was mostly wild-type but also contained low levels (5–20%) of V36A/M, R155K/T, and A156V/T single mutants, which were ultimately replaced by high-level resistant double mutants (36/155). Four patients who received telaprevir monotherapy experienced a continuous decline in HCV RNA. Two of them had sequence data available for days 8 and 12, and both had resistant variants in spite of the decline. Thus, the presence of resistance variants alone does not necessarily indicate failure of therapy. Genotypic resistance, as detected by sequence analyses, appears to be separate from phenotypic or clinical resistance, in which HCV RNA increases after an initial decline.
      A major concern is that continued monotherapy drives the selection of more resistant variants, with progressive accumulation of mutations. Based on phenotypic characterization of many of the substitutions, V36A/M or T54A confer less than eightfold resistance to telaprevir. However, variants with double substitutions at Val36 plus Thr54 have approximately 20-fold resistance to telaprevir, and variants with double substitutions at Val36 plus Arg155 or Ala156 have >40-fold resistance [
      • Zhou Y.
      • Bartels D.J.
      • Hanzelka B.L.
      • Müh U.
      • Wei Y.
      • Chu H.M.
      • et al.
      Phenotypic characterization of resistant Val36 variants of hepatitis C virus NS3-4A serine protease.
      ]. Even among single mutants, there can be a substantial difference in sensitivity to drug compared with wild-type virus. Some variants have a similar sensitivity to telaprevir as wild-type, but others can be more than 10,000-fold resistant [
      • Kieffer T.
      • Sarrazin C.
      • Bartels D.
      • Hanzelka B.
      • Muh U.
      • Welker M.
      • et al.
      Wild-type HCV NS3 protease re-emerges during follow-up after 14 days of dosing with VX-950 in patients with genotype 1 HCV.
      ]. Whether this predicted in vitro reduced sensitivity results in significant reduced efficacy for this drug and other active compounds in this class remains to be determined.
      Finally, in vitro studies of various protease inhibitors have identified variants cross-resistant to both boceprevir and telaprevir, suggesting a class effect (Fig. 2) [
      • Kieffer T.L.
      • Sarrazin C.
      • Miller J.S.
      • Welker M.W.
      • Forestier N.
      • Reesink H.W.
      • et al.
      Telaprevir and pegylated interferon-alpha-2a inhibit wild-type and resistant genotype 1 hepatitis C virus replication in patients.
      ,
      • Lin C.
      • Gates C.A.
      • Rao B.G.
      • Brennan D.L.
      • Fulghum J.R.
      • Luong Y.P.
      • et al.
      In vitro studies of cross-resistance mutations against two hepatitis C virus serine protease inhibitors, VX-950 and BILN 2061.
      ]. The selection of these variants has complicated monotherapy with both drugs independently in vivo, allowing the prediction that telaprevir would not be suitable as salvage therapy for boceprevir resistance, or vice versa. These crucial repeat exposure experiments have not yet been performed but can be expected to demonstrate the rapid development of the same drug resistant variants. Although not yet characterized in vivo, several mutations to polymerase inhibitors—especially non-nucleoside inhibitors—have been described [
      • Gilden D.
      Resistance to HCV protease and polymerase inhibitors and to novel compounds. Report from the 2nd international workshop on hepatitis C resistance and new compounds.
      ]. As resistant mutations are further observed and analyzed, of interest is whether other members of this class—nucleoside analog, non-nucleoside inhibitors, thumb inhibitors, or allosteric binding site inhibitors—will exhibit distinct genotypic and phenotypic profiles. Further, the role of polymerase inhibitors in treating variants resistant to protease inhibitors and vice versa will need to be explored, sooner rather than later.
      Figure thumbnail gr2
      Fig. 2In vitro resistance to protease (A) and polymerase (B) inhibitors. The list does not contain all inhibitors or identified variants but highlights variants identified for more than one drug (for summaries see Kieffer et al., 2007
      [
      • Kieffer T.L.
      • Sarrazin C.
      • Miller J.S.
      • Welker M.W.
      • Forestier N.
      • Reesink H.W.
      • et al.
      Telaprevir and pegylated interferon-alpha-2a inhibit wild-type and resistant genotype 1 hepatitis C virus replication in patients.
      ]
      and Gilden, 2008
      [
      • Gilden D.
      Resistance to HCV protease and polymerase inhibitors and to novel compounds. Report from the 2nd international workshop on hepatitis C resistance and new compounds.
      ]
      ). Cross resistance may be expected to limit the efficacy of retreating nonresponders or relapsers with antivirals of the same class, as depicted.

      10. What are the consequences of resistance, and how can they be curtailed?

      Given that antivirals have only been used in trials, the long-term consequences can only be speculated on, but resistance can hopefully be curtailed by using a multiple-target approach.
      With respect to treatment outcome, there is evidence that some patients who experience viral breakthrough during telaprevir monotherapy can subsequently respond to standard therapy with PEG-IFN plus RBV, although only a small number of patients have been studied thus far, and a minority of them went on to achieve undetectable HCV RNA at week 12 after standard therapy [
      • Kieffer T.L.
      • Sarrazin C.
      • Miller J.S.
      • Welker M.W.
      • Forestier N.
      • Reesink H.W.
      • et al.
      Telaprevir and pegylated interferon-alpha-2a inhibit wild-type and resistant genotype 1 hepatitis C virus replication in patients.
      ]. Drug resistant variants also remain sensitive to IFN in vitro, supporting these clinical observations.
      In vivo, PEG-IFN appears to abrogate the proliferation of resistant variants. In the Kieffer et al study [
      • Kieffer T.L.
      • Sarrazin C.
      • Miller J.S.
      • Welker M.W.
      • Forestier N.
      • Reesink H.W.
      • et al.
      Telaprevir and pegylated interferon-alpha-2a inhibit wild-type and resistant genotype 1 hepatitis C virus replication in patients.
      ] comparing telaprevir monotherapy with telaprevir and PEG-IFN, of the 8 patients who received PEG-IFN and telaprevir, 6 had a continuous decline in HCV RNA, with only wild-type virus detected at day 15. One patient had HCV RNA <10 IU/mL at day 13, which rose to <30 IU/mL at day 15. This patient had wild-type virus at day 4, and the high-level resistant mutant A156T was detected at day 8. Yet after subsequent treatment with standard therapy, this patient was HCV RNA negative at week 12 post-treatment, as were the remaining 7 in the treatment group. RBV also appears to be important in suppressing viral breakthrough, as adding it to combination therapy with telaprevir and PEG-IFN reduces virological breakthrough rates from 26% to 2% [
      • Dusheiko G.M.
      • Hézode C.
      • Pol S.
      • Groeser T.
      • Bronowicki J.-P.
      • Bourliere M.
      • et al.
      Treatment of chronic hepatitis C with telaprevir (TVR) in combination with peginterferon alfa-2a with or without ribavirin: Further interim analysis results of the PROVE2 study.
      ].
      Whether viral variants are archived is not clear, and if so, the long-term clinical consequences are unknown. After telaprevir monotherapy is ceased, in the absence of selective pressure the majority of resistant variants are replaced by wild-type virus within 3–7 months [
      • Sarrazin C.
      • Kieffer T.L.
      • Bartels D.
      • Hanzelka B.
      • Müh U.
      • Welker M.
      • et al.
      Dynamic hepatitis C virus genotypic and phenotypic changes in patients treated with the protease inhibitor telaprevir.
      ]. Yet several issues remain to be addressed: does the replicative fitness of variants change over time, will the presence of variants influence the rate of disease progression, and will patients who do not respond to one antiviral respond to subsequent therapy with drugs of the same or different classes?

      11. How should resistance testing be standardized?

      Experience with telaprevir suggests that the probability of detecting resistance mutations depends upon the method of detection and its sensitivity. For example, in a serum sample from a patient at day 2 of telaprevir dosing, clonal sequencing analysis detected the variant V36M at a frequency of about 5%, while the population sequencing analysis revealed no mutants, only wild-type virus.
      Thus, the method of testing, frequency of testing, and definitions of outcomes all influence the ability to detect and interpret development of resistance to any given drug. Yet none of these factors is currently standardized, making it difficult to fully understand the prevalence and consequences of resistance, as well as compare resistance profiles among various drugs of the same class.
      The FDA has recommended that resistance testing begin in preclinical development [

      US food and drug administration. Guidance for industry. Antiviral drug development—conducting virology studies and submitting data to the agency. May 2005. Available from: http://www.fda.gov/cder/guidance/6568dft.htm#_Toc103416124. Accessed September 30, 2008.

      ], with in vitro selection of resistant mutants, phenotypic and genotypic characterization of the mutants, and cross-resistance analyses to be completed before initiating clinical studies in infected patients. Resistance testing should subsequently be continued in all phases of clinical development, and definitions of virologic failures (breakthrough, relapse, nonresponse) be clearly defined for each protocol. These definitions should be standardized across drugs of the same class and trials, but no such rigorous standardization is currently in place.
      We agree that resistance testing, even in patients responsive to therapy, should be a routine part of clinical development (Table 2). Initial studies should use the most sensitive techniques available, such as clonal sequencing, with 30–80 clones analyzed oer sample per time point. Later stage clinical trials could more reasonably shift to a population sequencing approach.
      Table 2Strategies for detecting and analyzing drug resistant HCV variants that require standardization and guideline development
      Strategy
      Development phase
       PreclinicalIdentification of resistant mutants via serial passage
      Genotypic analyses
      Cross-resistance analyses
       Early phase clinical trialsResistance testing using clonal sequencing at pre-specified time intervals, optimally with 30–80 clones to detect minority species
      Consistent cross-study definitions of (a) virologic failure (breakthrough, relapse, nonresponse) and (b) testing schedules
       Later phase clinical trialsResistance testing using population sequencing
      Clinical practiceIntegrate resistance testing evaluations with multiple agents and predictive models for drug sensitivity
      All phasesPublic data storage and sharing of data
      Societal and other interested groups, along with regulatory agencies, will need to work together to devise meaningful guidelines that should be universally followed. Subsequent storage and sharing of data would allow a broader understanding of the extent and effects of resistance and would provide additional insight for modeling and prediction. Resistance testing will likely become integrated into clinical practice once direct antiviral agents are approved, as it has for HIV and hepatitis B virus, but the need for resistance testing outside of clinical development is unclear at present.

      12. What data currently exist for retreating prior nonresponders to PEG-IFN and RBV with direct antivirals?

      Preliminary data with telaprevir suggest that patients who did not achieve SVR with IFN and RBV therapy may benefit from triple therapy. The data are especially encouraging for patients who experienced breakthrough or relapse with their prior course of therapy.
      In an open-label study of telaprevir triple therapy in 60 previous nonresponders to PEG-IFN plus RBV from the control arms of the PROVE studies, patients were categorized as null responders (<1 log10 IU/mL HCV RNA decline at week 4 or <2 log10 IU/mL by week 12), partial responders (⩾2 log10 IU/mL decline by week 24), relapsers, or breakthrough patients [
      • Poordad F.
      • Shiffman M.
      • Sherman K.
      • Smith J.
      • Yao M.
      • George S.
      • et al.
      A study of telaprevir (TVR) with peginterferon alfa-2a (P) and ribavirin (R) in subjects with well-documented prior PR null response, non-response or relapse: preliminary results.
      ]. Overall, 83% achieved an RVR at week 4 during retreatment. Patients with previous breakthrough or relapse had RVR rates of 100%, whereas those with prior null response had RVR rates of 70% to 75%. Rates of SVR are awaited.
      PROVE 3 is also an ongoing phase 2b study evaluating telaprevir-based triple therapy in genotype 1 HCV patients who did not achieve SVR with at least one prior PEG-IFN and RBV regimen. At the interim analysis, 52% of patients who received 12 weeks of telaprevir with PEG-IFN and RBV followed by 12 weeks of PEG-IFN and RBV alone achieved SVR at 12 weeks post treatment. In the various categories of prior response, SVR12 rates were as follows: 41% for prior nonresponders, 73% for prior relapsers, and 44% for prior breakthroughs [
      • McHutchison J.G.
      • Shiffman M.L.
      • Terrault N.
      • Manns M.P.
      • Di Bisceglie A.M.
      • Jacobson I.M.
      • et al.
      A phase 2b study of telaprevir with peginterferon-alfa-2a and ribavirin in hepatitis C genotype 1 null and partial responders and relapsers following a prior course of peginterferon-alfa-2a/b and ribavirin therapy: PROVE3 interim results.
      ].
      Boceprevir has also been evaluated in prior nonresponders. In a phase 2, dose-finding study, boceprevir with PEG-IFN and RBV therapy was used to treat prior nonresponders to PEG-IFN plus RBV. Unfortunately, the regimen yielded low SVR rates, 7–14% [
      • Schiff E.
      • Poordad F.
      • Jacobson I.
      • Flamm S.
      • Bacon B.
      • Lawitz E.
      • et al.
      Boceprevir (B) combination therapy in null responders (NR): response dependent on interferon responsiveness.
      ]. However, protocol changes during the course of the trial, including a boceprevir dose increase, limit the interpretation of the data, and further definitive ongoing studies are underway with this agent in the nonresponder setting.

      13. For patients who have received a direct antiviral agent alone, should triple therapy with that agent and PEG-IFN and RBV be considered?

      There is modest evidence that some patients who experience viral breakthrough during telaprevir monotherapy can subsequently respond to telaprevir in combination with PEG-IFN plus RBV [
      • Kieffer T.L.
      • Sarrazin C.
      • Miller J.S.
      • Welker M.W.
      • Forestier N.
      • Reesink H.W.
      • et al.
      Telaprevir and pegylated interferon-alpha-2a inhibit wild-type and resistant genotype 1 hepatitis C virus replication in patients.
      ], but the long-term sustained response rates are unknown (see consequences of resistance, above).
      It is also unknown whether the same holds true for other direct antiviral agents. Because the antiviral treatment paradigm now includes therapy with PEG-IFN and RBV, patients receiving monotherapy represent a minority, yet because of such patients, this question remains important and must be addressed in clinical trials in the near future.

      14. What options are available for patients who have failed to achieve a sustained virologic response with direct antiviral-based regimens?

      One option is to attempt a triple therapy regimen that includes an alternate antiviral, although the issues of re-emergence of resistance need to be considered carefully, especially in re-exposing patients to agents of same class. There is a need for well-designed clinical trials to investigate this area now. Frequent monitoring with sensitive molecular techniques will be needed to detect the emergence of resistant variants. Combination therapy with multiple direct antivirals (such as combining protease and polymerase inhibitors) is an alternate strategy that may be effective for patients who fail “triple” therapy. Again, resistance will be an important issue, and no such data on these regimens is currently available.

      15. How will the presence of viral variants affect long-term virologic response?

      Data from long-term follow-up of sustained responders to IFN plus RBV therapy suggest that at 5 years after treatment, the vast majority of patients, approximately 99%, remain HCV RNA negative and are considered cured and have no clinically related outcomes of note [
      • McHutchison J.G.
      • Davis G.
      • Esteban-Mur R.
      • Poynard T.
      • Ling M.-H.
      • Garaud J.J.
      • et al.
      Durability of sustained virologic response in patients with chronic hepatitis C after treatment with interferon alpha-2b alone or in combination with ribavirin.
      ]. However, IFN and RBV do not induce specific viral variants and are thus unlikely to result in variants that have a potential long-term consequence. As described above, telaprevir withdrawal removes the selection pressure for viral variants [
      • Sarrazin C.
      • Kieffer T.L.
      • Bartels D.
      • Hanzelka B.
      • Müh U.
      • Welker M.
      • et al.
      Dynamic hepatitis C virus genotypic and phenotypic changes in patients treated with the protease inhibitor telaprevir.
      ], yet we cannot exclude a long-term effect of harboring resistant variants. Thus, long-term follow-up studies evaluating disease progression, relative fitness of variants over time, effects of various classes of direct antivirals, and re-exposure, as well as retreament outcomes, are needed. Shared databases and registries will be required to evaluate these issues critically.

      16. What are the weaknesses and exigencies of the current direct antiviral trials?

      As discussed elsewhere in this review, the published data so far are limited, reflecting the current early stage of drug development in this therapeutic area. Early phase studies to date have been heterogeneous in design, included small numbers of patients, and there has been a lack of standardization of resistance testing between different trials and drugs, making generalizability and development of themes or principles difficult. For example, the benefit of lead-in pegIFN and RBV will need to be assessed for individual agents and different patient populations. In addition, the optimal duration of a three drug combination therapy, the duration of pegIFN and RBV “consolidation”, and the most effective doses of pegIFN and RBV that maximize response must be clarified in future trial designs. Studies using combinations of direct antivirals of different classes must also be urgently performed. Other patient populations will need to be evaluated, including patients with non-genotype 1 infection, as well as ‘difficult-to-treat’ populations most in need of more efficacious therapies (such as post-liver transplant HCV-infected patients, those with decompensated liver disease, renal failure or HIV co-infection). These and other issues will need to be addressed sooner, rather than later in clinical development.

      17. Ideally, how should therapy look in 5 or 10 years time?

      In 5 years, it is likely that the first direct antivirals will be approved for use in combination with PEG-IFN and RBV for HCV patients. Based on existing data, we can predict that combination triple therapy will increase SVR rates in HCV genotype 1 patients from 40% to approximately 60%, or more (Fig. 3). At the same time, relapse rates should decline to 5–10%. Although treatment duration may be shortened for a proportion of patients, rates of discontinuation may well increase because of the increased risk of side effects with triple therapy.
      Figure thumbnail gr3
      Fig. 3Getting from A to B to C for treating chronic HCV infection in the next decade. With specifically targeted antivirals expected to enter the market in the next 5 years, sustained virologic response (SVR) rates in HCV genotype 1 patients will likely increase from 40% currently with pegylated interferon (PEG-IFN) and ribavirin (RBV) to approximately 60% or more with a targeted antiviral and PEG-IFN and RBV (with or without a shortened duration of therapy). Relapse rates are expected to decline, as they have been documented to in trials to date, although rates of discontinuation may well increase because of the increased risk of adverse effects with triple therapy. In the more distant future, higher response rates will hopefully be achieved, theoretically, by multiple drug regimens that limit discontinuation rates, enhance efficacy and tolerability, and with some possible small enhancement in relapse and nonresponder (NR) rates, as shown.
      In 10 years, the treatment landscape will almost certainly look very different, with specifically targeted antivirals a regular component of treatment regimens. Combination therapy with two or more antivirals and PEG-IFN may replace triple therapy with an antiviral, PEG-IFN, and RBV. If multiple antivirals are available in the marketplace, treatment decisions regarding combination therapies and retreatment options may become increasing complex, especially with the background of resistance.

      Acknowledgment

      We thank Jennifer King, PhD, for her assistance in preparing this manuscript.

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