January 27, 2011

Liver International
Special Issue: Proceedings of the 4th Paris Hepatitis Conference. The publication of this supplement was supported by an unrestricted educational grant from F. Hoffmann-Laroche Ltd.
Volume 31, Issue Supplement s1, pages 53–57, January 2011

David R. Nelson

Article first published online: 4 JAN 2011
DOI: 10.1111/j.1478-3231.2010.02391.x
© 2011 John Wiley & Sons A/S

Author Information

Clinical and Translational Science Institute, University of Florida, FL, USA

* Correspondence: Correspondence David R. Nelson, Clinical and Translational Science Institute, University of Florida, 1600 SW Archer Rd, Gainsville, FL, 32610, USA Tel: +352 273 9500 Fax: +352 392 7393 e-mail: nelsodr@ufl.edu

Keywords:
boceprevir; direct-acting antiviral agents; hepatitis C; novel therapies; protease inhibitors; resistant mutations; telaprevir

Abstract

Abbreviations
BOC, boceprevir; DAA, direct acting antiviral agents; PEG-IFN, pegylated interferon; SOC, standard of care; SVR, sustained virological response; TPR, telaprevir.

Hepatitis C virus (HCV) infection is a global problem with an estimated prevalence of 170 million worldwide and 4 million (1.6%) in the US (1–3). Most patients with acute HCV infection become chronically infected, which increases the risk of developing further complications associated with advanced liver disease (4). Given the projected increase in HCV-related cirrhosis (the proportion of chronic HCV infection with cirrhosis is now 25% and projected to reach 45% in 2030) and hepatocellular carcinoma (HCC), optimal treatment of chronic HCV is a high priority (5). Current standard therapy for HCV includes pegylated interferon (PEG-IFN) and ribavirin (RBV), a combination which is effective in approximately 40–50% of genotype 1-infected patients and 80% of genotype 2 and 3-infected patients (6–8). Unfortunately, most patients in the US and Western Europe are infected with HCV genotype 1. The relatively low response rates in treating genotype 1-infected patients, as well as the long treatment durations and adverse side effects has meant that a small minority of patients opt for treatment. Less than 20% of the HCV-infected population in the US is estimated to have been treated. However, the introduction of oral, direct-acting antiviral agents (DAA) is now on the horizon with anticipated higher cure rates, and potentially shorter treatment durations. Approval of the first oral inhibitors is expected by mid-2011 and many patients are awaiting these new therapies.

Direct-acting antiviral agents: protease inhibitors

The class of drugs in the latest stages of development is HCV serine protease NS3–NS4A inhibitors. The NS3/4A protease is essential to viral replication and is responsible for cleaving the HCV polyprotein and releasing most of the nonstructural proteins. The design of NS3/4A inhibitors is complicated because the active site of the NS3/4A protease is located in a very shallow groove composed of three highly conserved amino acid residues. This key concept explains why most NS3/4A protease inhibitors under development display high antiviral efficacy but a low genetic barrier to resistance and will frequently cause the selection of resistant mutants which can lead to viral breakthrough. The most mature protease inhibitors are telaprevir (TVR) and boceprevir (BOC), which have now completed phase II and III trials and will probably be approved in mid 2011. These programmes have yielded some consistent early lessons for the protease inhibitor class. For naïve, genotype 1 patients, higher cure rates and a shorter duration of therapy can be expected, which will be partially offset by new issues of resistance and increased adverse events.

Protease Inhibition for Viral Evaluation 1 and 2: telaprevir trials

The recently published Protease Inhibition for Viral Evaluation (PROVE 1 and 2, evaluating TVR) and Serine Protease Inhibitor Therapy (SPRINT-1, evaluating BOC) studies evaluated protease inhibitors in combination with PEG-IFN/RBV in genotype 1, naïve patients. In PROVE 1, TVR was dosed at 750 mg every 8 h for 12 weeks in combination with PEG-IFN and RBV followed by an additional 12 weeks or 36 weeks of standard of care (SOC). The results were compared with 48 weeks of SOC (see Table 1). The sustained virological response (SVR) rate in SOC was 41%, compared with 61% (P=0.02) in the 24-week treatment group and 67% (P=0.002) in the 48–week treatment group (9). Relapse rates were highest in the control group (23%) compared with the 24- (2%) and 48-week TVR treatment group (6%). However, more patients discontinued therapy in the TVR treatment groups secondary to adverse side effects, with a rash being the most common reason for discontinuation. In the PROVE 2 trial, shorter treatment duration was investigated with treatment groups receiving triple therapy (TVR+PEG-IFN/RBV) for only 12 weeks (with and without RBV) compared with an additional 12 weeks of SOC (See Table 1). SVR was 46% in the control group, compared with 36% in the non-RBV group (P=0.20), 60% in the 12 weeks triple therapy TVR group (P=0.12) and 69% in the 24 weeks triple therapy TVR group (P=0.004) (10). Relapse rates were highest in the non-RBV treated group (48%) compared with the control group (22%), 12 weeks triple therapy group (30%) and 24 weeks triple therapy group (14%). The most important side effects with TVR were rash, gastrointestinal disorders and anaemia. Although severe rash may require treatment discontinuation, moderate forms can be successfully treated with topical steroids. The median decline in blood haemoglobin concentrations with TVR was approximately 1 g/dl.

The PROVE 1 and 2 seem to indicate that TVR can help overcome negative host and viral factors. A recent pooled analysis looked at a subgroup of patients with characteristics associated with low virological response (11). The overall SVR for the pooled TVR treatment groups was 65 vs. 44% in the control group (P<0.001). SVR rates were significantly higher with TVR-based vs. SOC among patients with baseline HCV RNA ≥800 000 IU/ml (P<0.05), patients with genotype 1a HCV infection (P<0.05), patients with genotype 1b HCV infection (P<0.05), men (P<0.05), patients >50 years of age (P<0.05) and those with bridging fibrosis (P<0.05). The conclusion of this analysis is that TVR is effective in all subgroups of patients who have traditionally been considered difficult to treat. Another phase II trial with TVR was recently released (Study C208) that suggests that SVR rates in naïve patients may be higher than previously reported, especially when a response-guided duration is followed. In this study, treatment-naïve, genotype 1 patients (n=161) were administered triple therapy for 12 weeks with the subsequent PEG-IFN/RBV treatment duration determined according to a response-guided strategy (12). Patients who achieved a rapid virological response (RVR) received a total of 24 weeks of therapy and those who did not have RVR continued PEG-IFN/RBV to weeks 48. The SVR rates in this study ranged from 81 to 85%, higher than those observed in the phase II PROVE trials. These high overall SVR rates emphasize the potential of the triple therapy approach. Results may be explained in part by experienced study centres with very low discontinuation rates (5%) compared with the PROVE studies. In addition, treatment duration was shortened to 24 weeks in patients who achieved RVR, while the remaining patients received 48 weeks of therapy. Between 80 and 83% of patients treated with PEG-IFN-α2a, and 67–69% of patients treated with PEG-IFN-α2b achieved RVR and could therefore be treated for 24 weeks. This study clearly suggests that response-guided therapy based on RVR at week 4 may optimize SVR and provides a useful guide for determining which patients should be treated for 24 vs. 48 weeks.

Serine Protease Inhibitor Therapy-1: boceprevir trial

In the phase II SPRINT-1 trial, triple combination therapy with BOC and the current SOC, PEG-IFN and RBV, was found to induce high rates of SVR (54–75%) in genotype 1 treatment-naive patients, depending on the duration of therapy (13). Unlike TVR, BOC was administered for the duration of treatment. The treatment regimens included a control group treated with 48 weeks of SOC compared with five BOC treatment regimens (4 weeks of PEG-IFN/RBV lead-in followed by triple therapy for 24 or 44 weeks; triple therapy for 28 or 48 weeks; triple therapy, but with low-dose RBV for 48 weeks). The ideal duration of therapy appears to depend upon early viral kinetics. Patients who cleared the virus by week 4 of triple therapy had 82 and 94% chances of achieving SVR after 28 and 48 weeks of treatment respectively. If HCV RNA is detectable after week 4, but becomes undetectable by week 12, 48 weeks of treatment resulted in a 79% SVR rate; shortened treatment was significantly inferior, with only 21% of patients achieving SVR after 28 weeks. Clearance after week 12 was associated with a negligible chance of SVR and appears to indicate an early stopping rule at week 12. In addition to the expected side effects associated with the SOC, treatment with a BOC-containing regimen was associated with increased dysgeusia and anaemia. Anaemia (defined as a decline in haemoglobin level <10 g/dl) occurred in 52–56% of patients in the triple-therapy groups despite administration of epoetin-αat the investigator's discretion, compared with 34% in controls. Higher rates of discontinuation secondary to adverse side effects and viral breakthrough occurred in the BOC treatment groups compared with the control group and anaemia appeared to be a significant problem, with up to 50% of patients receiving erythropoietin. Of note, the highest reported viral breakthrough was seen in the low-dose RBV group.

Ribavirin is required to maximize efficacy with protease inhibitors

As shown above, early phase II studies strongly suggest that RBV is needed in protease inhibitor drug regimens. Patients who did not receive RBV in the PROVE trials and those with low-dose RBV (400–1000 mg) in the SPRINT-1 trial had increased viral breakthrough, higher relapse and lower SVR. This data strongly indicates that standard-dose RBV is needed to optimize response to these first generation protease inhibitors by reducing the development of resistance/breakthrough. It is also clear that the initial rapid decrease in HCV viral levels with protease combination therapy is because of inhibition of wild type virus that then leads to the ‘uncovering’ of pre-existing resistant variants. Resistant variants are present in most patients at very low rates (<1%) and are usually detected after near complete suppression of the dominant, wild type virus. The continued replication of these variants can then lead to a virological breakthrough. To date, mutations conferring TVR-resistance have been identified at four positions, V36A/M/L, T54A, R155K/M/S/T and A156S//T (14). A detailed kinetic analysis of TVR-resistant variants was performed in genotype 1 patients during 14 days of TVR monotherapy and combination therapy with PEG-IFN. TVR monotherapy initially led to a rapid decline in HCV RNA in all patients as a result of a strong reduction in the wild-type virus. In patients who developed a viral rebound during TVR monotherapy, the single mutation variants R155K/T and A156/T were mainly uncovered by wild-type reduction and became dominant after day 8. These single mutation variants were selected from pre-existing quasispecies. The combination of TVR and PEG-IFN was sufficient to inhibit the breakthrough of resistant mutations in a 14-day study (15). It is important to note that low to medium levels of V36 and R155 variants were still observed in single patients up to 3 years after TVR treatment. Antiviral resistance is also a concern with BOC. Mutations were frequently associated with virological breakthrough, and most substitutions occurred at locations comparable to those with TVR. Of note, the time to revert back to wild type varied with the specific mutation in patients who developed resistance mutations. Another important finding from the TVR Phase II trials is the different rates of viral resistance and breakthrough detected between genotype 1a and 1b (much higher for 1a). This can be explained by a difference in the genetic barrier to resistance between the subtypes. For example, the mutation most frequently associated with resistance to TVR is R155K; changing R to K at position 155 requires one nucleotide change in HCV subtype 1a and 2 nucleotide changes in subtype 1b isolates. Thus HCV subtyping may play an important role in helping to select future treatment regimens and predict the development of resistance.

Phase III data for telaprevir and boceprevir

Phase III clinical trials evaluating TVR in combination with PEG-IFN and RBV have now been completed with top-line SVR data being released. The ADVANCE trial enrolled treatment-naïve HCV genotype 1 patients to evaluate 24 weeks of TVR-based therapy. TVR was dosed at 750 mg every 8 h and given for 8 or 12 weeks in combination with PEG-IFN and RBV followed by PEG-IFN and RBV alone until treatment week 24. Patients who did not achieve RVR were treated with PEG-IFN and RBV until week 48. A significantly greater proportion of patients achieved SVR with 12-week and 8-week TVR-based combination regimens (75 and 69% respectively) than in the SOC arm (44%) (16). Relapse rates were reduced three-fold (9%) compared with SOC (28%). In the ILLUMINATE trial, TVR was given for 12 weeks in combination with PEG-IFN and RBV followed by PEG-IFN and RBV alone until treatment week 24 or 48. The aim of the ILLUMINATE trial was to assess whether extending treatment beyond 24 weeks of total therapy improves SVR rates in patients with RVR or EVR. 72% of all subjects achieved SVR, while those with extended RVR (virus negative from week 4 to week 12) achieved SVR rates of 92 and 88% in randomized 24- and 48-week treatment groups respectively (17). Thus, data from these two phase III trials support the use of 24-week TVR-based therapy in a response-guided regimen for patients with RVR. Of note, treatment discontinuation from adverse events were double that of SOC but were much lower than that in Phase 2 trials. The most common adverse events reported in the ILLUMINATE study, were, in order of frequency, fatigue, pruritus, nausea, anaemia, rash and headache. Most of these adverse events were mild or moderate. Adverse events leading to discontinuation of all study drugs during the 12-week TVR dosing period occurred in 6.9%, while treatment discontinuation of all drugs because of anaemia and rash occurred in 1.1 and 0.6% of people in this study, respectively, during the TVR dosing period (Figs 1 and 2).

Figure 1. ILLUMINATE: Phase 3: response-guided therapy optimal for eRVR Patients. eRVR, extended rapid virological response; SVR, sustained virological response.

Figure 2ADVANCE: Phase 3: 12-week duration telaprevir optimal. PEG-IFN, pegylated interferon; RBV, ribavirin; RVR, rapid virological response; SVR, sustained virological response; TVR, telaprevir.

The phase III clinical trial (SPRINT-2) evaluating BOC in over 1000 treatment-naïve patients was also recently completed. Equivalent to the SPRINT-1 study design, patients (two separate cohorts were enrolled; one African American and the other non) received 800 mg BOC three times daily in combination with PEG-IFN and weight-based RBV for 24 or 48 weeks. A lead-in strategy for 4 weeks with PEG-IFN and RBV was utilized in all investigational arms. In this study, 66% of the patients in the BOC 48-week treatment group and 63% of the patients in the response-guided therapy group achieved SVR respectively, compared with 38% of patients in the control group (18). Among the non-African American patients in the BOC 48-week treatment group, 69% achieved SVR, and 67% achieved SVR in the response-guided therapy, compared with 40% in the control SOC group. Among African American patients, 53% of patients in the 48-week treatment group and 42% of patients in the response-guided therapy group achieved SVR, compared with 23% in the control group. This data is less clear than TVR phase 3 studies on the utility of response-guided therapy in all genotype 1 populations and suggest that extending therapy may be beneficial in African Americans. Further details from this study will help clarify the importance of host factors in response-guided therapy durations. In the HCV SPRINT-2 study, the most common treatment-emergent adverse events reported for the BOC 48-week treatment group, BOC response-guided therapy group and control group, respectively, were: fatigue (57, 53 and 60%), headache (46, 46 and 42%), nausea (43, 48 and 42%), anaemia (49, 49 and 29%) and pyrexia (fever) (32, 33 and 33%). Treatment was discontinued because of anaemia in 2% of each of the BOC groups compared with 1% in the control group, although erythropoietin use was allowed to maintain RBV dosing. Overall treatment discontinuations from adverse events were 16 and 12% for the BOC groups, respectively, compared with 16% for the control group. The utility of erythropoietin in these patients is currently under investigation in another phase 3 trial.

Conclusion

In conclusion, clinical trials have shown that the addition of protease inhibitors to standard therapy results in potent viral suppression and shortened duration of therapy. SVR rates approaching 75% can now be anticipated for genotype 1 patients, which should lead to increased treatment opportunities for many HCV populations. However, new issues of viral resistance and increased adverse events will increase the importance of close medical management. A new era of DAA is upon us and offers new hopes for HCV-infected patients.

Conflicts of interest

David Nelson has received research funding and is on advisory boards or a consultant for Vertex, Merck, Genentech, Pharmassett, Bayer-Onyx and GSK. He has received research funding from BMS, Gilead and Tibotech and is a consultant for Abbott.

References

1 Armstrong GL, Wasley A, Simard EP, et al. The prevalence of Hepatitis C virus infection in the United States, 1999 through 2002. Ann Intern Med 2006; 144: 705–14.

2 Seeff LB. Natural history of chronic hepatitis C. Hepatology 2002; 36: S35–46.

3 Marcellin P, Asselah T, Boyer N. Fibrosis and disease progression in hepatitis C. Hepatology 2002; 36: S47–56.

4 Verna EC, Brown RS. Hepatitis C and liver transplantation: enhancing outcomes and should patients be retransplanted. Clin Liver Dis 2008; 12: 637–59.

5 Davis GL, Alter MJ, El-Serag H, et al. Aging of hepatitis C-infected persons in the United States: a multiple cohort model of HCV prevalence and disease progression. Gastroenterology 2010; 138: 513–21.

6 Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon alfa-2a plus ribavirin for chronic Hepatitis C virus infection. N Engl J Med 2002; 347: 975–82.

7 Manns MP, McHutchison JG, Gordon SC, et al. Peginterferon alfa-2b plus ribavirin compared with Interferon alfa-2b plus ribavirin for initial treatment of chronic Hepatitis C: a Randomised Trial. Lancet 2001; 358: 958–65.

8 Asselah T, Benhamou Y, Marcellin P. Protease and polymerase inhibitors for the treatment of hepatitis C. Liver Int 2009; 29 (Suppl. 1): 57–67.

9 McHutchison JG, Everson GT, Gordon SC, et al. Telaprevir with Peginterferon and ribavirin for chronic HCV genotype 1 infection. N Engl J Med 2009; 360: 1827–38.

10 Hézode C, Forestier N, Dusheiko G, et al. Telaprevir and peginterferon with or without ribavirin for chronic HCV infection. N Engl J Med 2009; 360: 1839–50.

11 Everson GT, Dusheiko GM, Ferenci P, et al. Telaprevir, peginterferon alfa-2a and ribavirin improved rates of sustained virologic response (SVR) in ‘difficult-to-cure’ patients with chronic Hepatitis C (CHC): a pooled analysis from the PROVE1 and PROVE2 trials. Hepatology 2009; 50: 1565.

12 Marcellin P, Forns X, Goeser T, et al. Virologic analysis of patients receiving telaprevir administered q8h or q12h with Peginterferon-alfa-2a or -alfa-2b and ribavirin in treatment-naïve patients with genotype 1 hepatitis: study C208. Hepatology 2009; 50: 194.

13 Kwo P, Lawitz E, McCone J, et al. Efficacy of boceprevir, an NS3 protease inhibitor, in combination with peginterferon alfa-2b and ribavirin in treatment-naive patients with genotype 1 hepatitis C infection (SPRINT-1): an open-label, randomised, multicentre phase 2 trial. Lancet 2010; 376: 705–16.

14 Sarrazin C, Kieffer TL, Bartels D, et al. Dynamic hepatitis C virus genotypic and phenotypic changes in patients treated with the protease inhibitor telaprevir. Gastroenterology 2007; 132: 1767–77.

15 Kieffer TL, Sarrazin C, Miller JS, et al. Telaprevir and pegylated interferon-alpha 2a inhibit wild-type and resistant genotype 1 hepatitis C virus replication in patients. Hepatology 2007; 46: 631–9.

16 Vertex Pharmaceuticals. 75% of treatment-naive patients with chronic hepatitis C achieve SVR (viral cure) with telaprevir-based treatment in Phase 3 trial. Press release, 25 May 2010.

17 Vertex Pharmaceuticals. Phase 3 ILLUMINATE Study supports 24-week telaprevir-based therapy within a response-guided regimen for people with hepatitis C who had not received prior treatment. Press release, 10 August 2010.

18 Poordad F, McCone J, Bacon BR, et al. Boceprevir combined with peginterferon alfa-2b/Ribavirin for treatment-naïve patients with hepatitis C virus genotype. 1: SPRINT-2 final results. Hepatology 2010; 52: 107A.

Source

The role of triple therapy in HCV genotype 1-experienced patients

Liver International
Special Issue: Proceedings of the 4th Paris Hepatitis Conference. The publication of this supplement was supported by an unrestricted educational grant from F. Hoffmann-Laroche Ltd.
Volume 31, Issue Supplement s1, pages 58–61, January 2011

Michael W. Fried

Article first published online: 4 JAN 2011
DOI: 10.1111/j.1478-3231.2010.02410.x
© 2011 John Wiley & Sons A/S

Author Information
UNC Liver Center, University of North Carolina, Chapel Hill, NC, USA

* Correspondence: Correspondence Michael W. Fried, University of North Carolina, CB# 7584, Room 8015 Burnett-Womack Building, Chapel Hill, NC 27514, USA Tel: +1 919 966 2516 Fax: +1 919 966 1700 e-mail: mfried@med.unc.edu

Keywords:
boceprevir; hepatitis C; non-responder; peginterferon; relapser; telaprevir

Abstract

The ability to achieve a sustained virological response (SVR) to peginterferon (PEG-IFN) and ribavirin (RBV) depends on numerous host and virological factors, as well as adherence to a prescribed treatment regimen. Patients who have failed to achieve a SVR to PEG-IFN and RBV have limited options for retreatment. Emerging data from phase II and phase III clinical trials of direct-acting antiviral agents suggest that new therapeutic regimens will be available for many patients. Treatment with protease inhibitors such as PEG-IFN, RBV, ribavirin. and boceprevir, combined with PEG-IFN and RBV, has been shown to produce high rates of virological response in both prior relapsers and, to a lesser extent, prior non-responders. The benefits of these novel treatment regimens for each individual patient must be weighed against the side effects, costs and potential of developing viral resistance. Regulatory approval of telaprevir and boceprevir is expected to begin in mid-late 2011.

Treatment-experienced patients with genotype 1 who do not achieve a sustained virological response (SVR) to peginterferon (PEG-IFN) and ribavirin (RBV) represent a continuing challenge for management. Permanent eradication of hepatitis C virus (HCV) from these patients remains the only acceptable goal of future therapeutic combinations. The ability to achieve SVR is dependent upon numerous factors including host and virological factors, a well as the efficacy of the therapeutic regimens for these difficult-to-treat patients.

Defining non-sustained response

A non-SVR includes patients who have relapsed or those who were non-responders to an initial course of therapy with PEG-IFN and RBV. Data from preliminary studies of triple therapy combinations including a protease inhibitor (telaprevir or boceprevir) combined with PEG-IFN and RBV in treatment-experienced patients reinforce the importance of correctly categorizing the initial response to dual combination therapy since it is an important predictor of the likelihood of response to triple combination therapy.

Non-responders are patients who fail to achieve undetectable viraemia at any point during treatment (1). Non-responders may be further categorized as null responders or partial responders. Null responders are those who achieve minimal viral suppression (usually less than one-log fold decrease in HCV RNA) during the first 4 weeks of treatment while partial responders are those with a greater decrease in HCV RNA (usually multiple log-folds) but who remain HCV RNA positive throughout treatment. In contrast, relapsers are patients who achieve undetectable viraemia during the prescribed treatment regimen with PEG-IFN and RBV, but then relapse with the reappearance of HCV RNA once treatment is discontinued (1). As we shall see below, patients who relapse with PEG-IFN and RBV have a greater chance of responding to triple therapy combinations than non-responders.

Host interferon pathways are critical for triple therapy combinations

On-treatment viral kinetics are highly predictive of treatment outcome in both treatment-naïve and treatment-experienced patients, and may be considered a surrogate for the responsiveness of host IFN pathways. Rapid virological response (RVR), defined as undetectable viraemia at week 4 of treatment, is associated with an ∼90% rate of SVR and has been shown to be more predictive of treatment success than other pretreatment demographical, virological or histological factors (2, 3). Conversely, a slow virological response, with delayed or lack of clearance of HCV RNA, is a pharmacodynamic marker for suboptimal IFN/RBV-associated therapeutic response.

Recent data suggest that polymorphisms in the interleukin (IL)28B region are highly associated with a SVR as well as an early virological response to PEG-IFN and RBV (4). Approximately 80% of treatment-naïve patients with the favourable IL28B CC genotype will achieve a SVR to combination therapy. The presence of the CC genotype is also associated with a higher probability of achieving an RVR, which occurred in almost 30% of patients treated with PEG-IFN and RBV (5). The IL28B genotype has also been associated with the differential expression of IFN signalling genes in hepatic tissue (6, 7). The impact of the IL28B genotype on treatment-experienced patients has just begun to be explored but a similar relationship seems to exist for this population as well. However, since the minority of non-responders will be CC genotype, other factors will also be important.

The presence of a robust IFN signalling pathway is important for triple therapy combinations since the IFN–RBV backbone minimizes the viral resistance that is inevitable with protease inhibitor monotherapy (8). Thus, previous non-responders to PEG-IFN and RBV have a greater likelihood of virological breakthrough to triple combination therapy with a protease inhibitor than prior relapsers.

Telaprevir for treatment-experienced patients: phase II results

Prove-3 was a study of the protease inhibitor telaprevir in treatment-experienced patients that enrolled both non-responders (∼60%) and relapsers (∼40%) (9). A schematic of the study design is shown in Figure 1. The various treatment arms evaluated the impact of different durations of triple therapy, different total treatment durations and the importance of RBV for this difficult-to-treat population.

Figure 1. PROVE 3 study design in prior non-responders and relapsers. PEG-IFN, peginterferon; RBV, ribavirin; TVR, telaprevir. Adapted from McHutchison et al. (9).

Strict stopping rules were used to minimize the development of viral resistance and exposure to therapy in case of no response. Thus, in patients treated with telaprevir, HCV RNA was required to be undetectable by week 4 in order to continue treatment. The final results of the study are shown in Figure 2.

Figure 2. Final results of PROVE 3 in prior non-responders and relapsers. P, PEG-IFN; PEG-IFN, peginterferon; R, RBV; RBV, ribavirin; T, telaprevir. Adapted from McHutchison et al. (9).

Prior relapsers had the best chance of achieving SVR, with a rate of 76% in those treated with 24 weeks of triple therapy, followed by 24 weeks of dual PEG-IFN and RBV (total duration=48 weeks) (9). The SVR rate in patients treated with only 12 weeks of triple therapy and an additional 12 weeks of dual combination therapy (total duration=24 weeks) was 69%. Prior non-responders had substantially lower rates of SVR, although nearly 40% achieved SVR with similar regimens. Interestingly, when telaprevir and PEG-IFN were used without RBV, the rate of SVR was substantially diminished, emphasizing the importance of RBV in triple therapy combinations.
 
As discussed previously, the risk of virological breakthrough, defined as an increase of HCV RNA of more than one-log from baseline or to more than 100 IU/ml if previously undetectable, was more frequent in previous non-responders than previous relapsers. By week 24 of treatment, up to 13% of prior relapsers and 45% of prior non-responders had evidence of virological breakthrough (9).
 
Telaprevir for treatment-experienced patients: phase III results
 
Phase III data from the REALIZE trial of telaprevir in treatment-experienced patients have only been reported to date as a company press release (10), but we will describe it briefly to provide the most current data. Nevertheless, it must be remembered that this is a preliminary non-peer-reviewed report. The study design included triple therapy with PEG-IFN, RBV and telaprevir for 12 weeks begun simultaneously or with a prior lead-in of PEG-IFN and RBV, followed by PEG-IFN and RBV for a total of 48 weeks. In previous non-responders, the SVR rate was 86% in the combined telaprevir arms and 57% in partial responders. The SVR rate in previous null responders was only 31%, showing the differential response based on prior experience with dual combination therapy.
 
Boceprevir for treatment-experienced patients
 
Full results of a comparable phase II study with boceprevir in treatment-experienced patients have not been reported. However, data from the Sprint-1 study of treatment-naïve patients suggest that the protease inhibitor boceprevir also benefited patients with a poor early response to PEG-IFN and RBV (11). The study design of Sprint-1, and subsequent phase III studies with boceprevir, used a lead-in phase of treatment for 4 weeks with PEG-IFNα-2b+RBV, followed by the addition of boceprevir. Kwo et al. (11) performed a retrospective analysis of patients based on the HCV RNA response during these first 4 weeks of dual combination therapy. Patients with less than a one-log decrease in viraemia by week 4 had only a 24% rate of SVR when treated with PEG-IFN and RBV alone, while those patients who received boceprevir at week 4 subsequently achieved an SVR of 62% (Fig. 3).
 
Figure 3. SPRINT 1: analysis of virological response and sustained virological response. P, PEG-IFN; R, RBV; T, telaprevir. aOne patient who was positive at week 24 became undetectable at week 30 onwards. bTwo patients were missing polymerase chain reaction (PCR) at week 24, but later had detectable PCR. Adapted from Kwo et al. (11). Presented at: AASLD; 30 October–3 November 2009, Boston, MA, USA.

It should be noted that this analysis did not include non-responders who had completed a previous full course of treatment. Nevertheless, the strong association of treatment failure with null response during the first 4 weeks of antiviral therapy suggests that these results are of interest.
 
RESPOND-2 is a recent phase III trial reported at the 2010 AASLD in non-responders and relapsers treated with boceprevir (12). The three-arm study compared a response-guided regimen including boceprevir to a fixed-duration 48-week triple regimen vs 48 weeks of PEG-IFN and RBV. Top-line results indicate that 75% of prior relapsers and 52% of prior non-responders treated with a fixed triple therapy boceprevir regimen achieved SVR. Relapsers and non-responders in the response-guided arm also had significant SVR rates of 69 and 40% respectively (12).
 
Considerations for the selection of candidates for triple therapy
 
Recommendations for the use of protease inhibitor triple therapy combinations are still evolving and will be dependent upon rigorous peer-reviewed analyses of phase III clinical trial data, as well as the interpretation and recommendations of various pharmaceutical regulatory agencies worldwide, such as the US Food and Drug Administration and the European Medicines Agency. Nevertheless, currently available data clearly show that triple therapies including a protease inhibitor provide exciting new therapeutic options for treatment-experienced individuals. These therapies will be most useful in prior virological relapsers, although many prior non-responders, particularly partial responders, will achieve successful viral eradication with triple therapies. The benefits of these novel treatments for each individual patient must be weighed against the side effects, cost and potential of developing viral resistance.
 
Conflicts of interests
 
Dr Fried is funded, in part, by K24 DK066144, NIH Mid-Career Mentoring Award. Dr Fried serves as a consultant for and/or receives research grants from Genentech, Vertex, Merck, Tibotec, Bristol Myers Squibb, Anadys. He is a consultant and stockholder of Pharmasset.

References

1 Ghany MG, Strader DB, Thomas DL, Seeff LB. Diagnosis, management, and treatment of hepatitis C: an update. Hepatology 2009; 49: 1335–74.

2 Fried MW, Hadziyannis S, Shiffman ML, Messinger D, Zeuzem S. Rapid virological response is the most important predictor of sustained virological response across genotypes in patients with chronic hepatitis C virus infection. J Hepatol 2010 (in press).

3 Ferenci P, Shiffman ML, Fried MW, et al. Early prediction of response to 40KDA peginterferon alfa-2a (PEGASYS) plus ribavirin in patients with chronic hepatitis C. J Hepatology 2005; 43: 425–33.

4 Ge D, Fellay J, Thompson AJ, et al. Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance. Nature 2009; 461: 399–401.

5 Thompson AJ, Muir AJ, Sulkowski MS, et al. Interleukin-28B polymorphism improves viral kinetics and is the strongest pretreatment predictor of sustained virologic response in genotype 1 hepatitis C virus. Gastroenterology 2010; 139: 120–9.e118.

6 Urban TJ, Thompson AJ, Bradrick SS, et al. IL28B genotype is associated with differential expression of intrahepatic interferon-stimulated genes in patients with chronic hepatitis C. Hepatology 2010; 52: 1888–96.

7 Honda M, Sakai A, Yamashita T, et al. Hepatic ISG expression is associated with genetic variation in interleukin 28B and the outcome of IFN therapy for chronic hepatitis C. Gastroenterology 2010; 139: 499–509.

8 Kieffer TL, Sarrazin C, Miller JS, et al. Telaprevir and pegylated interferon-alpha-2a inhibit wild-type and resistant genotype 1 hepatitis C virus replication in patients. Hepatology 2007; 46: 631–9.

9 McHutchison JG, Manns MP, Muir AJ, et al. Telaprevir for previously treated chronic HCV infection. N Engl J Med 362: 1292–303.

10 Anonymous. Vertex press release: REALIZE study. 2010.

11 Kwo PY, Lawitz EJ, McCone J, et al. Efficacy of boceprevir, an NS3 protease inhibitor, in combination with peginterferon alfa-2b and ribavirin in treatment-naive patients with genotype 1 hepatitis C infection (SPRINT-1): an open-label, randomised, multicentre phase 2 trial. Lancet 376: 705–16.

12 Bacon BR, Gordon SC, Lawitz EJ, et al. HCV respond-2 final results: high sustained virological response among genotype 1 previous non-responders and relapsers to peginterferon/ribavirin when retreated with boceprevir plus pegintron(peginterferon alfa-2a)/ribairinv. Hepatology 2010; 52: 430, (abstract).

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For immediate release

January 24, 2011 - The San Francisco Hepatitis C Task Force today released a report expressing grave concern about the hepatitis C epidemic in the City and outlining a series of recommendations for the Mayor and Board of Supervisors to mount a comprehensive effort to fight the disease. The report, entitled "Recommendations for Strategically Addressing Hepatitis C in San Francisco" is the result of a year-long process by the Task Force to identify gaps to addressing hepatitis C in San Francisco and create a set of strategic directions for San Francisco to have an immediate impact in the following areas of hepatitis C: Research and Surveillance; Prevention, Education, Awareness and Testing; Care and Treatment; and Public Policy. The report can be viewed at http://hepcsf.org/uploads/Recommendations_Document.pdf.

Some recommendations in the document include: establishing a hepatitis C coordinator position at the San Francisco Department of Public Health; ensuring full access to hepatitis C treatment and care through Healthy San Francisco; developing citywide educational/awareness campaigns; and creating a pilot legal supervised injection facility as part of a comprehensive hepatitis C prevention strategy. The report is dedicated to the memory of Randy Allgaier, who served as the Task Force's co-chair until his untimely death in November, 2010.

"This report highlights significant gaps in services for people like me living with hepatitis C and others at risk of infection," said Dominique Leslie, Task Force Co-Chair. "We urge Mayor Lee and the Board of Supervisors to take swift action to implement our recommendations."

The Task Force was convened in September, 2009, by then-Mayor Gavin Newsom and includes over 30 advocates, medical and social service providers, public health officials, and people living with hepatitis C. The group was formed in response to growing concern about the hepatitis C epidemic in the City. There are an estimated 12,000 San Franciscans infected with hepatitis C, with most not aware of their status. The disease disproportionately affects African-Americans, Latinos, veterans, people involved with the criminal justice system, injection drug users, men who have sex with men, people with HIV, immigrants, and low-income people. Hepatitis C can lead to liver disease, cirrhosis, liver cancer, liver failure and death. In January of 2010, the Institutes of Medicine (IOM) released a national report highlighting the severity of the hepatitis B and C epidemics in the United States and calling on public officials to participate in efforts to prevent, control, and care for the diseases.

"Hepatitis C is a growing epidemic that puts a significant burden on our public health and medical systems," said Todd Frederick, M.D., of California Pacific Medical Center Department of Transplantation and Task Force member. "The lifetime cost of treating one person with hepatitis C is estimated to be between $100,000 and $300,000. Those who go untreated face increased risks of developing cirrhosis and liver cancer, and the cost for a liver transplant, for which HCV is the leading cause, is estimated at $500,000. By implementing the Task Force's recommendations, San Francisco has a unique opportunity to prevent new infections and save money for the City, provide care and treatment for those living with hepatitis C, prevent long-term complications of the disease and be a leader in the national fight against this disease."

The San Francisco Hepatitis C Task Force will continue as a community coalition focused on advocating for full implementation of all recommendations and educating public officials, medical and social service providers, at-risk communities, and the general public about hepatitis C and its impact on San Francisco. For more information about the Task Force, visit www.hepcsf.org.

Contact: Ryan Clary, 415-235-8593 (cell), rclary@projectinform.org Laura Thomas, 415-241-9800, lthomas@drugpolicy.org

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