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Triple therapy for HCV genotype 1 infection: telaprevir or boceprevir?
Special Issue: Proceedings of the 5th Paris Hepatitis Conference. International Conference of the Management of Patients with Viral Hepatitis: Special Edition Hepatitis C
Review Article
Mitchell L. Shiffman1,2,*, Rafael Esteban3,4
Article first published online: 29 DEC 2011
DOI: 10.1111/j.1478-3231.2011.02718.x
© 2012 John Wiley & Sons A/S
Abstract
Boceprevir and telaprevir are the first two protease inhibitors available for the treatment of patients infected with hepatitis C virus (HCV) genotype 1. A sustained virological response (SVR) of 70–80% is observed when either of these protease inhibitors is utilized with pegylated interferon (PEG-IFN) and ribavirin (RBV) in treatment naïve patients. Both agents are also highly effective in patients who failed to achieve a SVR during previous treatment with PEG-IFN/RBV. A rapid virological response (RVR) is observed in 56–60% of treatment naïve patients. Patients who achieve a RVR can be treated with a shorter course of therapy (24–28 weeks) and still achieve a SVR rate of 90% or higher. Patients who do not achieve a RVR, those with cirrhosis and certain prior non-responders should be treated for 48 weeks. Although the SVR rates observed with boceprevir and telaprevir are quite similar both globally and within sub-populations, the treatment algorithms for the two agents are unique. The decision of which protease inhibitor to use should assess several factors including the treatment scheme, duration of therapy, adverse event profile, cost and the likelihood of achieving a RVR. The latter is highly dependent upon IFN sensitivity and the IL28B genotype.
Boceprevir and telaprevir were the first two and are currently the only protease inhibitors to be approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for the treatment of patients infected with hepatitis C virus (HCV) genotype 1. For the past decade, only 40–45% of these patients achieved a SVR when treated with PEG-IFN/RBV [1, 2, 3, 4]. The duration of therapy was for a fixed 48 weeks. In contrast, when either of these two protease inhibitors is added to PEG-IFN/RBV, the SVR rate in treatment naïve patients increases to 70–80% [5, 6, 7]. Boceprevir and telaprevir are also highly effective in patients who fail to achieve a SVR during previous treatment with PEG-IFN/RBV [8, 9]. The availability of these two protease inhibitors has therefore revolutionized the treatment of chronic HCV. For the first time, physicians can tell their patients that it is much more likely they will be ‘cured’ of HCV following treatment.
It has been recognized in recent years that the likelihood of achieving a SVR during treatment with PEG-IFN/RBV was directly related to when the patient became HCV RNA undetectable during therapy [10]. Patients with a RVR, who became HCV RNA undetectable within 4 weeks after initiating treatment, had SVR rates in the 85–90% range and several studies strongly suggested that these patients could receive only 24 weeks of PEG-IFN/RBV [11, 12, 13, 14]. This observation forms the cornerstone of response guided therapy (RGT) [10, 15, 16]; a concept that was readily incorporated into the treatment schemes developed for boceprevir and telaprevir.
This manuscript will review data from the phase 3 clinical trials performed with boceprevir and telaprevir in the treatment naïve population [5, 6, 7] and in patients who previously failed to achieve a SVR with PEG-IFN/RBV [8, 9]. We conclude by discussing issues that may lead to the selection of a specific protease inhibitor. Throughout this discussion, the reader must keep in mind that the phase 2 and 3 clinical trials that led to the approval of boceprevir and telaprevir were each performed against a placebo control (with PEG-IFN/RBV) and that these two protease inhibitors have never been directly compared. It is therefore impossible to conclude that either protease inhibitor is universally superior for the treatment of patients with chronic HCV genotype 1.
Telaprevir
Three phase 3 clinical trials led to the approval of telaprevir, PEG-IFN/RBV for the treatment of patients with chronic HCV genotype 1 [6, 7, 9]. The ADVANCE study was a randomized placebo controlled trial designed to compare 8 weeks vs 12 weeks of telaprevir triple therapy (with PEG-IFN/RBV). Patients who achieved a RVR and remained HCV RNA undetectable throughout the first 24 weeks of treatment were referred to as having an extended RVR (eRVR). These patients were treated for a total of 24 weeks: 8 or 12 weeks of telaprevir-based triple therapy followed by an additional 16 or 12 weeks of PEG-IFN/RBV respectively. Patients who failed to achieve an eRVR received a total of 48 weeks of treatment (8 or 12 weeks of telaprevir-based triple therapy followed by 36 weeks of PEG-IFN/RBV). Patients who received 12 weeks of telaprevir had about a 5% higher SVR rate compared to patients who received only 8 weeks whether they achieved an eRVR and received 24 weeks of treatment (89 vs 83%) or they failed to achieve an eRVR and received 48 weeks of treatment (54% vs 50%). The conclusion of ADVANCE was that 12 weeks of telaprevir was superior and preferable to 8 weeks.The ILLUMINATE study was a randomized controlled trial designed to compare 24 vs 48 weeks of treatment in patients with an eRVR. All patients were treated with telaprevir-based triple therapy for 12 weeks and then continued PEG-IFN/RBV. Patients who achieved an eRVR were randomized to receive a total of 24 weeks of treatment (12 weeks of telaprevir-based triple therapy plus 12 weeks of PEG-IFN/RBV) or a total of 48 weeks of treatment (an additional 36 weeks of PEG-IFN/RBV). The SVR rates in these two groups were identical (92 vs 90% respectively). Patients who did not achieve an eRVR but did become HCV RNA undetectable by treatment week 24 were treated for a total of 48 weeks. The SVR rate in these patients was 64%. The conclusion of ILLUMINATE was that patients with an eRVR should be treated for only 24 weeks. In both ADVANCE and ILLUMINATE, about 60% of patients treated with telaprevir-based triple therapy achieved an eRVR.
The REALIZE study was a randomized, placebo-controlled trial designed to document the impact of telaprevir-based triple therapy in patients who had failed to achieve a SVR during previous treatment with PEG-IFN/RBV and to determine if 4 weeks of lead-in therapy with PEG-IFN/RBV affected SVR. Patients were randomized to receive ether 12 weeks of telaprevir-based triple therapy followed by 36 weeks of PEG-IFN/RBV or 4 weeks of PEG-IFN/RBV lead-in followed by 12 weeks of telaprevir-based triple therapy, followed by an additional 30 weeks of PEG-IFN/RBV. Both groups were treated for a total of 48 weeks. Overall, the SVR rates in patients with prior relapse, partial response and non-response were 86, 58 and 32% respectively. No significant difference in SVR was apparent between the two treatment arms in any of the three non-responder categories. The conclusion of REALIZE was that 4 weeks of a PEG-IFN/RBV lead-in prior to adding telaprevir did not influence SVR.
The most common adverse events in patients who received telaprevir-based triple therapy compared to PEG-IFN/RBV in these phase 3 clinical trials included anaemia, nausea, diarrhoea, anal-rectal discomfort, rash and pruritus. The average decline in haemoglobin during telaprevir-based triple therapy was approximately 1 g/dl more than that observed with PEG-IFN/RBV; and nearly 40% of patients had a decline in haemoglobin to below 10 g/dl. Over half the patients receiving telaprevir developed a rash and once this occurred it generally worsened over time. In most cases, this was mild-moderate in severity and could be managed symptomatically. Severe rash requiring premature discontinuation of telaprevir occurred in 7% of patients.
The recommended treatment paradigm for telaprevir is illustrated in Fig. 1. Telaprevir is initiated along with PEG-IFN/RBV for the first 12 weeks of treatment. Patients then continue PEG-IFN/RBV for a total of either 24 or 48 weeks based upon the concepts of RGT [14, 15]. Patients who are treatment naïve or with prior relapse to PEG-IFN/RBV can be treated for only 24 weeks if they achieve eRVR. These patients achieve SVR rates that exceed 90%. In contrast, patients who become HCV RNA undetectable after week 4 should be treated for a total of 48 weeks (12 weeks of telaprevir-based triple therapy and 36 weeks of PEG-IFN/RBV). These patients achieve SVR rates of about 64%. It is recommended that all patients with cirrhosis also be treated for 48 weeks. Treatment should be discontinued in any patient with an HCV RNA level of >1000 IU/ml at treatment weeks 4 or 12 and any detectable HCV RNA at treatment week 24.
Figure 1. Treatment paradigm recommended by the FDA for telaprevir. (A) Treatment naïve and patients with prior relapse. (B) Patients with prior partial response, null response and all patients with cirrhosis. Hepatitis C virus (HCV) RNA is tested at week 4. If HCV RNA is undetectable and remains undetectable at week 12 and 24, the patient requires only 24 weeks of treatment. If HCV RNA is under 1000 (log10 3) IU/ml at weeks 4 and 12 and undetectable for HCV RNA at week 24 the patient should be treated for 48 weeks. Therapy is stopped if HCV RNA is greater than log10 3 (1000 IU/ml) at treatment weeks 4 and 12 and any detectable HCV RNA at week 24.
Boceprevir
Two phase 3 clinical trials led to the approval of boceprevir, PEG-IFN/RBV for the treatment of patients with chronic HCV genotype 1 [5, 8]. The SPRINT-2 study was a randomized placebo-controlled trial performed in treatment naïve patients and designed to compare RGT to a fixed 48 weeks of treatment. Patients randomized to the 48 week treatment arm received a 4 week lead-in with PEG-IFN/RBV followed by 44 weeks of boceprevir-based triple therapy (48 weeks of total treatment). Patients randomized to the RGT arm received the 4 week PEG-IFN/RBV lead-in followed by 24 weeks of boceprevir-based triple therapy. Patients who achieved RVR (HCV RNA undetectable 4 weeks after the addition of boceprevir; 8 weeks after the start of treatment) and remained HCV RNA undetectable through week 24 received a total of 28 weeks of treatment (4 weeks of PEG-IFN/RBV and 24 weeks of boceprevir-based triple therapy). Patients who became HCV RNA undetectable more than 4 weeks after the addition of boceprevir and before treatment week 24 received an additional 20 weeks of PEG-IFN/RBV for a total treatment duration of 48 weeks (4 weeks of PEG-IFN/RBV, 24 weeks of boceprevir triple therapy and 20 weeks of PEG-IFN/RBV). The SVR rate achieved with the RGT approach was identical to that observed in patients who received 48 weeks of therapy (70 vs 71%). Patients who achieved a RVR had SVR rates of 96% with 28 weeks of total treatment. Patients who did not achieve a RVR but became HCV RNA undetectable after treatment week 8 (4 weeks after the start of boceprevir) had SVR rates of about 70% when treated for 48 weeks. The conclusion of SPRINT-2 was that the duration of HCV treatment should be determined according to the principles of RGT. Approximately 60% of patients achieved a RVR and could be treated for the shorter duration.The RESPOND-2 study was a randomized placebo-controlled trial conducted in patients with a prior partial virological response or relapse to PEG-IFN/RBV. The study was designed to document the SVR rate with boceprevir triple therapy retreatment and like SPRINT-2 to compare RGT to a fixed 48 weeks of treatment. Although patients with documented prior non-response were not enrolled in this study a significant proportion of the patients had less than a 1 log10 decline in HCV RNA during the 4 week lead-in and thus behaved biologically as non-responders. Patients were randomized to receive either 48 weeks of treatment (4 weeks PEG-IFN/RBV lead-in and 44 weeks of boceprevir-based triple therapy) or RGT. Patients randomized to the RGT arm received the 4-week PEG-IFN/RBV lead-in followed by 32 weeks of boceprevir-based triple therapy. Patients who achieved RVR (HCV RNA undetectable 4 weeks after the addition of boceprevir; 8 weeks after the start of treatment) and remained HCV RNA undetectable through week 24 received a total of 36 weeks of boceprevir-based triple therapy (4 weeks of PEG-IFN/RBV and 32 weeks of boceprevir-based triple therapy). Patients who became HCV RNA undetectable more than 4 weeks after the addition of boceprevir and before treatment week 24 received an additional 12 weeks of PEG-IFN/RBV for a total treatment duration of 48 weeks (4 weeks of PEG-IFN/RBV, 32 weeks of boceprevir triple therapy and 12 weeks of PEG-IFN/RBV).
The SVR rate in patients with prior relapse was 72%. Patients who were sensitive to interferon and had more than a 1 log10 decline in HCV RNA during the 4 week lead-in had an SVR rate of 76%. Patients who were insensitive to interferon and had less than a 1 log10 decline in HCV RNA during the 4 week lead-in had a SVR of 32%. No significant differences in SVR rates were evident between a fixed 48 week treatment and the RGT approach. Patients who achieved RVR (HCV RNA undetectable 4 weeks after the addition of boceprevir) had SVR rates of 88% with the shorter duration of therapy. Patients who did not achieve RVR but became HCV RNA undetectable after treatment week 8 (4 weeks after the start of boceprevir) had SVR rates of about 75% when treated for 48 weeks. The conclusion of RESPOND-2 was that the duration of HCV treatment should be determined by the principles of RGT even in patients with prior non-response to PEG-IFN/RBV.
The most common adverse events in patients who received boceprevir-based triple therapy compared to PEG-IFN/RBV in these phase 3 clinical trials included anaemia and dysgusea. The average decline in haemoglobin during treatment with boceprevir-based triple therapy was approximately 1 g/dl greater than that observed with PEG-IFN/RBV; nearly half had a decline in haemoglobin to below 10 g/dl. Although 43% of patients in these two phase 3 clinical studies received epoetin alfa to treat anaemia, no significant difference in SVR rates was observed between patients who received epotin alfa and those patients whose anaemia was managed by ribavirin dose reduction.
The recommended treatment paradigm for boceprevir is illustrated in Fig. 2. Boceprevir is initiated after 4 weeks of lead-in therapy with PEG-IFN/RBV. After the 4 week lead-in, patients are treated with boceprevir triple therapy. Patients who are HCV RNA undetectable at treatment week 8 (an RVR 4 weeks after adding boceprevir) and remain HCV RNA undetectable at treatment weeks 12 and 24 can be treated for a total of 28 weeks (4 weeks of PEG-IFN/RBV lead-in and 24 weeks of boceprevir-based triple therapy). These patients have SVR rates which exceed 90%. In contrast, patients who become HCV RNA undetectable more than 4 weeks after the addition of boceprevir (after treatment week 8) should be treated for a total of 48 weeks. This consists of 4 weeks of PEG-IFN/RBV lead-in, 32 weeks of boceprevir triple therapy and another 12 weeks of PEG-IFN/RBV. These patients achieve SVR rates of about 70%. It is recommended that patients who are interferon resistant (less than a 1 log10 decline in HCV RNA during the lead-in), prior non-responders and patients with cirrhosis receive 44 weeks of boceprevir-based triple therapy following the 4 week PEG-IFN/RBV lead-in. Treatment should be discontinued in patients with an HCV RNA level of >100 IU/ml at treatment week 12 and any detectable HCV RNA at treatment weeks 24.
Figure 2. Treatment paradigm recommended by the FDA for boceprevir. (A) Treatment naïve. (B) Patients with prior relapse and partial response. (C) Patients with prior null response, interferon insensitivity as assessed by lead-in and all patients with cirrhosis. Hepatitis C virus (HCV) RNA is tested at week 8. If HCV RNA is undetectable and remains undetectable at week 24 the patient requires only 28 weeks of treatment. If HCV RNA is positive for HCV RNA at week 8, under 100 (log10 2) IU/ml at week 12 and undetectable at week 24 the patient should be treated for 48 weeks. Therapy is stopped if HCV RNA is greater than log10 2 (100) IU/ml at treatment week 12 and any detectable HCV RNA at week 24. * HCV RNA may also be measured at week treatment 4, at end of lead-in, to assess interferon sensitivity. In patients with prior null response, interferon insensitivity and cirrhosis who are treated for 48 weeks there is no formal stopping rule for being HCV RNA detectable at week 24. However, most experts would stop treatment if HCV RNA were still positive at this time.
Interferon sensitivity
In patients who fail treatment, several interferon-stimulated genes are upregulated before treatment, indicating a blunted response to interferon [17]. At least some degree of interferon sensitivity is necessary for patients to achieve SVR and those who are interferon insensitive are at risk of having protease-resistant strains of HCV emerge during treatment [18, 19]. Interferon sensitivity is largely a genetic trait of the host and this is modulated by nucleotide polymorphisms within the interleukin (IL) 28B gene. Patients who have cytosine-cytosine (CC) at a specific site within this gene are highly sensitive to interferon [20, 21, 22]. Nearly 80% of these patients achieve RVR, can be treated for a shorter duration with either boceprevir or telaprevir-based triple therapy and enjoy SVR rates that exceed 90% [23, 24]. In contrast, patients with thymidine-thymidine (TT) at this specific site within the IL28B gene are far less sensitive to interferon. Only about 50% of these patients will achieve a RVR and could be treated for a shorter duration. The interferon sensitivity and response characteristics of patients with IL28B-CT fall somewhere between these two extremes. Patients who do not become HCV RNA undetectable during treatment with boceprevir or telaprevir triple therapy are at high risk of developing protease resistant virus [5, 18, 19].Approximately 15% of all patients with HCV genotype 1 achieve a RVR when treated with PEG-IFN/RBV [10, 16]. Most of these patients have IL28B genotype CC [21]. Patients who achieve a RVR with PEG-IFN/RBV also have very high SVR rates which vary from 85 to 95% in most studies [12, 13, 14]. Recognizing that patients with RVR could be treated for only 24 weeks with an IFN containing regimen is one of the cornerstones of RGT [10, 15, 16].
Differences in the treatment paradigm
The paradigms utilized to treat chronic HCV with boceprevir and telaprevir are summarized and compared in Table 1-see below.Telaprevir is started with PEG-IFN/RBV at the onset of therapy and used for only 12 weeks. In contrast, boceprevir is initiated after the 4 week PEG-IFN/RBV lead-in. Measuring HCV RNA after 4 weeks of treatment with PEG-IFN/RBV makes it possible to assess interferon responsiveness, the likelihood of SVR and the emergence of resistance after boceprevir is added. In both the telaprevir and boceprevir studies patients who were HCV RNA undetectable at treatment week 4 had very high and nearly identical SVR rates whether treated with PEG-IFN/RBV or with protease inhibitor triple therapy [5, 6]. Do patients who are already HCV RNA undetectable at the conclusion of the 4 week PEG-IFN/RBV lead-in really need a protease inhibitor? Only the lead-in treatment paradigm provides the opportunity to avoid the additional adverse events of a costly protease inhibitor in patients who have a high likelihood of achieving a RVR.
| Boceprevir | Telaprevir | |
|---|---|---|
| ||
| Interferon | ||
| Utilized in clinical trials | Peginterferon alpha-2b | Peginterferon alpha-2a |
| Approved for use by FDA and EMA | Either peginterferon | Either peginterferon |
| When initiated | After 4 weeks of treatment with PEG-IFN/RBV | At the start of therapy with PEG-IFN/RBV |
| Duration of protease inhibitor use (weeks)/duration of PEG-IFN/RBV (weeks) | ||
| Treatment naïve | ||
| With RVR | 24/28 | 12/24 |
| Without RVR | 32/48 | 12/48 |
| Retreat with prior relapse | ||
| With RVR | 32/36 | 12/24 |
| Without RVR | 32/48 | 12/48 |
| Retreat with prior partial response | ||
| With RVR | 32/36 | 12/48 |
| Without RVR | 32/48 | 12/48 |
| Retreat prior null response | 44/48 | 12/48 |
| Retreatment with previous non-response and interferon insensitivity during lead-inb | 44/48 | NA |
| Cirrhosis | 44/48 | 12/48 |
| Times to measure HCV RNA (weeks) | ||
| Prior to starting treatment | 0 | 0 |
| At end of lead-in phase | 4 | NA |
| During treatment with protease inhibitor | 8, 12, 24 | 4, 12, 24 |
| Other time pointsc | 2, 16, 20, 36 | 2,16, 20, 36 |
| At end of treatment | 28, 36 or 48 | 24 or 48 |
| After treatment has completedd | 4, 12 and 24 | 4, 12 and 24 |
| Time points and HCV RNA values at which treatment should be discontinued | ||
| Week 4 | HCV RNA > 1000 IU/ml | |
| Week 8 | ||
| Week 12 | HCV RNA > 100 IU/ml | HCV RNA > 1000 IU/ml |
| Week 24 | HCV RNA detectable | HCV RNA detectable |
Selecting a paradigm for treatment of HCV
The factors used to select a protease inhibitor include efficacy, the duration of protease inhibitor administration, the total duration of therapy, the adverse event profile and cost. The efficacy of these two agents is summarized in Table 2. For treatment naïve patients, the rates of SVR appear very similar in patients who achieve a RVR (89–96%) and in patients with a delayed virological response who become HCV RNA negative more than 4 weeks after the initiation of the protease inhibitor (64–75%). A similar percentage of treatment naïve patients achieve a RVR (56–60%) and can be treated for a shorter duration. When divided by IL28B status, SVR rates also appear to be quite similar [23, 24]. Response rates are more difficult to compare in the retreatment population because true non-responders were not evaluated in the RESPOND-2 study. However, if one accepts that patients who are IFN insensitive during the lead-in are biologically similar to non-responders [4] than similar rates of SVR are observed during retreatment as well.
The duration of protease inhibitor administration and the treatment paradigm are no doubt more streamlined with telaprevir. All patients begin telaprevir and PEG-IFN/RBV at the onset of treatment, receive 12 weeks of telaprevir and either 24 or 48 weeks of PEG-IFN/RBV. In contrast, the initiation of boceprevir is delayed by 4 weeks and is administered for 24, 32 or 44 weeks, whereas PEG-IFN/RBV IL combination is administered for 28, 32 or 48 weeks respectively. In contrast, boceprevir may have a somewhat more tolerable adverse event profile. Both agents exacerbate the anaemia of PEG-IFN/RBV to a similar extent. However, telaprevir is associated with a rash in over 50% of patients and several gastrointestinal symptoms.
The final issue that could be considered is cost. The published cost for telaprevir is just under 50 000 USD for 12 weeks of medication. The published cost of boceprevir is 1100 USD per week or $26 400, $35 200 or $48 400 for 24, 32 and 44 weeks of treatment respectively. The costs of treatment are therefore similar in patients who require 32–44 weeks of boceprevir. In contrast, the cost of therapy is considerably reduced in patents who achieve a RVR and receive only 24 weeks of boceprevir. This reduced cost is possible in most patients with IL28B genotype CC who have high rates of RVR [23, 24]. In addition, approximately 30% of patients with this IL28B genotype are already HCV RNA undetectable by the end of the 4 week lead-in with PEG-IFN/RBV alone. Simply continuing these patients on PEG-IFN/RBV will yield SVR rates that are similar to those observed with either telaprevir or boceprevir triple therapy without any additional cost [5, 6]. Such a strategy is certainly reasonable in countries or in patients with limited financial resources.
Conflicts of interest
Dr Shiffman has received consulting fees from Conatus, Genentech/Roche, Human Genome Sciences and Romark; has attended advisor meetings with Bristol Myers-Squibb, Gilead, Merck, Pfizer, Vertex and Zymogenetics; has received grant support from Abbott, Achillion, Anadys, Conatus, Genentech/Roche, Gilead, Globeimmune and Zymogenetics; has provided lectures on behalf of Genentech/Roche, Merck and Vertex; and has served on a Data Safety Monitoring Board for Anadys and Abbott.
Dr Estaban has attended advisor meetings with Abbott, Boehringer Ingelheim, Boeriiher, Bristol Myers-Squibb, Glaxo, Gilead, Janssen Merck, and Novartis; has provided lectures on behalf of Abbott, Boeriiher, Bristol Myers-Squibb, Glaxo, Gilead, Janssen, Merck, Novartis and Roche; and has served on a Data Safety Monitoring Board for Novartis.
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