Triple therapy with telaprevir, PEG-IFN plus RBV
In 2011, two NS3/4A protease inhibitors, telaprevir and boceprevir, were approved in Europe and the United States for use in combination with PEG-IFN/RBV [([17-21], commented in [16, 22]] for the treatment of genotype 1 chronic hepatitis C in both treatment-naïve and experienced patients. The Advance study was a 3-arm double-blind, randomized, placebo-controlled Phase 3 study assessing the efficacy and safety of two telaprevir-based response-guided regimens compared with PEG-IFN alfa-2a/RBV in treatment-naïve patients with chronic genotype 1 HCV infection . A significantly greater proportion of patients achieved SVR with the 12-week and 8-week telaprevir-based combination regimens (75% and 69% respectively) compared to the PEG-IFN alfa-2a/RBV 48 week control arm (44%, P < 0.001) (Fig. 3).
Figure 3. The ADVANCE study is a 3-arm double-blind, randomized, placebo-controlled Phase 3 study assessing the efficacy and safety of two telaprevir-based response-guided regimens compared with PEG-IFNalfa-2a and RBV in treatment-naïve patients with chronic genotype 1 HCV infection. A total of 1050 patients were randomized into three arms (a) telaprevir 750 mg q8 h combined with PEG-IFN alfa-2a/RBV for 8 weeks, followed by additional weeks of standard of care (SOC); (b) telaprevir 750 mg q8 h combined with PEG-IFNalfa-2a/RBV for 12 weeks, followed by additional weeks of SOC; (c) PEG-IFNalfa-2a/RBV for 48 weeks (control arm). Patients in the telaprevir arms achieving an extended rapid viral response (eRVR, undetectable HCV RNA at weeks 4 and 12) received a total of 24 weeks of therapy although those who did not, received a total of 48 weeks of therapy . A significantly greater proportion of patients achieved SVR with the 12-week and 8-week telaprevir-based combination regimens (75% and 69% respectively) compared to the PEG-IFNalfa-2a/RBV 48 week control arm (44%, P < 0.001).
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The most common adverse events in the telaprevir arms were fatigue, pruritus, nausea, headache, anaemia, rash, influenza-like illness, insomnia, pyrexia and diarrhoea. Discontinuation of treatment because of adverse events occurred in 7% and 8% of patients in the telaprevir regimens and 4% in PEG-IFN alfa-2a/RBV.
Finally, SVR rates improved with telaprevir-based therapy in genotype 1 treatment-naïve patients. The benefit-risk profile with a 12-week telaprevir-based regimen was better than with an 8-week regimen. With response guided treatment (RGT) nearly two-thirds of treatment-naïve patients were eligible for a 24-week treatment regimen, and achieved high SVR rates. Discontinuation of treatment because of rash was minimized by stopping medication sequentially.
The Illuminate study was a phase 3 open label study which randomized patients who achieved an eRVR into two durations of therapy . RVR was achieved in 72% of patients; 65.2% of patients achieved an eRVR. A total of 322 (59.6%) patients were randomized (1:1) to either a 24 or 48-week arm. The SVR rate was 92% in patients randomized to 24 weeks and 87.5% in patients randomized to 48 weeks (Fig. 4). Thirty-six patients (6.7%) discontinued treatment owing to virological failure. Ninety-four patients (17.4%) permanently discontinued all study drugs because of adverse events. Fatigue and anaemia were the most common adverse events leading to discontinuation.
Figure 4. The Phase 3 open label ILLUMINATE study evaluated genotype 1 treatment-naïve patients randomized into two durations of therapy (telaprevir plus PEG-IFNalfa-2a and RBV) among those who achieved extended rapid viral response (eRVR). A total of 540 HCV genotype 1 treatment-naïve patients were treated with telaprevir (12 weeks, 750 mg po q8 h) with PEG-IFNalfa-2a/RBV. Patients who achieved an eRVR were randomized at week 20 to continue receiving PEG-IFN alfa2a/RBV for 24 or 48 weeks of total treatment. Patients who did not achieve an eRVR were assigned to 48 weeks of treatment . SVR was 92% in patients randomized to 24 wks (n = 162). SVR was 87.5% (Δ4.5%, 2-sided 95% C.I. = –2.1 to + 11.1%) in patients randomized to 48 wks (n = 160). Overall, SVR was 71.9% (ITT analysis). In patients who achieved an eRVR, a 24-week telaprevir-based regimen was non-inferior to the 48-week telaprevir-based regimen (92% SVR compared to 87.5%).
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Finally, the 24-week telaprevir-based regimen was non-inferior to the 48-week telaprevir-based regimen in patients who achieved an eRVR, (92% SVR compared to 87.5%). Thus, RGT resulted in an overall SVR of 71.9% SVR and nearly two-thirds of the patients were eligible for shorter treatment. These results support the use of RGT for telaprevir-based regimens in treatment-naïve patients.
What have we learned from the telaprevir studies in treatment-naïve genotype 1 patients?
Firstly, the duration of therapy can be shortened in treatment-naive genotype 1 patients who achieve an eRVR. One major result of these studies was that approximately two-thirds of patients achieved an RVR and remained HCV RNA negative through 24 weeks, thus benefiting from 24 weeks of treatment. Treatment-naïve patients with cirrhosis who have undetectable HCV RNA at weeks 4 and 12 may benefit from an additional 36 weeks of PEG-IFN/RBV (48 weeks total).
Secondly, knowledge of the stopping rules is important. Discontinuation of therapy is recommended in all patients with HCV RNA levels of 1000 IU/ml or more at treatment week 4 or 12; or those with confirmed detectable HCV RNA levels at treatment week 24, because of the high risk of resistance.
Can either interferon (2a or 2b) be used with either protease inhibitor?
Yes, certainly. In a prospective, multicentre, randomized, open label, phase 2 clinical trial study including 161 HCV genotype 1 patients, a high proportion (> 80%) of patients achieved a SVR regardless of the frequency of telaprevir dosing (q8 or q12 h) or type of PEG-IFN alfa used (alfa-2a or alfa-2b) . Since each PEG-IFN results in approximately the same SVR , either IFN can be utilized with either protease inhibitor.
The Realize study was a phase 3, randomized, double-blind, placebo-controlled study in 662 genotype 1 experienced chronic hepatitis C patients . SVR rates for the telaprevir simultaneous start arm and the delayed start arm were 64% and 66% respectively, overall, based on an intent-to-treat analysis. Primary analysis showed that the SVR rates for the telaprevir simultaneous start arm, delayed start arm and control arm respectively, were 83%, 88% and 24% in relapsers; 59%, 54% and 15% in partial responders; and 29%, 33% and 5% in non-responders (Fig. 5). Prior relapsers could be treated for 24 weeks if they achieved an eRVR. About 76% of prior relapsers achieved an eRVR and 95% of these achieved a SVR. Partial responders and non-responders should be treated for 48 weeks. Non-responders could wait for future combination treatments. Although the mechanisms of non-response to IFN are not well understood the addition of a protease inhibitor could partially restore IFN responsiveness .
Figure 5. The REALIZE study was a Phase 3, randomized, double-blind, placebo-controlled study in 662 genotype 1 chronic HCV non-responder patients with at least prior treatment with IFN-based therapy. There were two telaprevir-based arms (simultaneous and delayed start) and one control arm. SVR rates for the telaprevir simultaneous start arm and the delayed start arm were 64% and 66% respectively, overall, based on an intent-to-treat (ITT) analysis. For the primary analysis, the SVR rates for the telaprevir simultaneous start arm, delayed start arm and control arm, respectively, were 83%, 88% and 24% in relapsers (P < 0.001); 59%, 54% and 15% in partial responders, (P < 0.001); and 29%, 33% and 5% in non-responders, (P < 0.001).
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Approximately 90% of all rashes were mild or moderate (grades 1 and 2), although severe rash (grade 3) developed in 6% of patients, leading to discontinuation of telaprevir . Grade 3–4 skin lesions require immediate treatment discontinuation and consultation with an experienced dermatologist. Frequent physical examinations and laboratory testing for anaemia must be performed to adapt dosing in these regimens. HCV RNA must be measured frequently with real-time PCR to monitor drug resistance. A viral breakthrough in a compliant patient is very likely to be drug resistance and is a stopping rule.
Triple therapy with boceprevir, PEG-IFN plus ribavirin
Boceprevir is a linear peptidomimetic ketoamide serine protease inhibitor that binds reversibly to the HCV non-structural 3 (NS3) active site.
The Sprint-2 study was a phase 3 international double-blind randomized study including genotype 1 treatment-naïve patients that compared triple therapy with boceprevir (with or without a 4-week lead-in treatment with PEG-IFN alfa-2b/RBV) to PEG-IFN alfa-2b/RBV plus placebo . The SVR in non-Black patients was 40% for 48 weeks of PEG-IFN alfa-2b/RBV and was significantly higher in both boceprevir arms: 67% for RGT and 68% for the lead-in phase followed by 44 weeks of boceprevir plus PEG-IFN alfa-2b/RBV. The corresponding SVR in Black patients was 23%, 42% and 53% respectively. SVR rates in non-Black patients receiving ≥ 1 dose of boceprevir or placebo were 42%, 70% and 71% (Fig. 6). Anaemia was reported in 29% of controls vs. 49% in the boceprevir arms, leading to a dose reduction in 13% and 21% and discontinuation in 1% and 2% respectively.
Figure 6. The SPRINT-2 study is a phase 3 international double-blind randomized study including genotype 1 treatment-naïve patients (938 non-Black & 159 Black) and comparing a 4-week lead-in treatment with PEG-IFNalfa-2b/RBV, followed by (1) PEG-IFNalfa-2b/RBV plus placebo for 44 weeks; (2) response-guided therapy: boceprevir plus PEG-IFNalfa-2b/RBV for 24 weeks, with an additional 20 weeks of PEG-IFNalfa-2b/RBV if HCV RNA remains detectable during weeks 8-24; or (3) boceprevir plus PEG-IFNalfa-2b/RBV for 44 weeks. Boceprevir plus PEG-IFNalfa-2b/RBV significantly increased SVR (approximately 70%) in both arms over standard of care. Compared to 44 weeks of triple therapy after the lead-in period, response-guided therapy with lead-in plus 24 boceprevir plus PEG-IFN α-2b/RBV ± 20 PEG-IFNalfa-2b/RBV produced comparable SVR.
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In conclusion, boceprevir plus PEG-IFN alfa-2b/RBV significantly increased the SVR (approximately 70%) in both arms compared to PEG-IFN alfa-2b/RBV. Although anaemia occurred more often with boceprevir it rarely led to treatment discontinuation. Compared to 44 weeks of triple therapy after the lead-in period, RGT with lead-in plus 24 weeks of boceprevir plus PEG-IFN alfa-2b/RBV ± 20 PEG-IFN alfa-2b/RBV resulted in comparable SVR rates.
What have we learned from this study of boceprevir in genotype 1 treatment-naïve patients?
Firstly, there was a very high response rate. Boceprevir plus PEG-IFN alfa-2b/RBV significantly increased SVR (to approximately 70%) in both treatment arms compared to SOC. The treatment duration in treatment-naïve genotype 1 patients who achieve an RVR can be shortened. Approximately two-thirds of patients achieved an RVR and remained HCV RNA negative through 24 weeks of treatment, thus benefiting from 24 to 28 weeks of treatment.
Baseline predictors of non-response were age over 40 years, Black ethnicity, baseline HCV RNA levels > 400 000 IU/ml, the presence of cirrhosis and not receiving boceprevir. A decrease in HCV RNA levels by 1 log10 IU/ml or more at the end of the 4-week lead-in period was strongly predictive of a SVR. In an expanded model that included response data during the treatment period, the highest odds ratio was found when HCV RNA levels were undetectable at week 4 or had decreased by 1 log10 IU/ml or more from baseline. SVR rates in patients with advanced fibrosis were lower than in those with mild fibrosis, although the numbers of patients with a Metavir fibrosis score of 3 or 4 (indicating bridging fibrosis or cirrhosis) were small, particularly in the cohort of Black patients.
The RVR was a strong predictor of SVR and failure to achieve an EVR was a strong predictor of non-SVR, independent of the patients’ pretreatment status . When RVR was added to baseline characteristics, prediction of SVR was more accurate. The combination of RVR and EVR provided complementary information, and thus provides a key opportunity to individualize treatment and improve the benefit/risk ratio of therapy.
Secondly, lessons obtained from the strategy of the lead-in phase. In one arm, boceprevir was added after lead-in treatment with PEG-IFN/RBV alone. Theoretically, a lead-in phase could lower HCV RNA levels before exposure to the protease inhibitor, thus reducing the risk of viral breakthrough or resistance to DAA, as noted in a phase 2 study which compared lead-in plus boceprevir to boceprevir without a lead-in. Patients with a poor response to IFN, defined as a reduction in HCV RNA levels of less than 1log10 IU/ml after 4 weeks could wait for multiple DAA combinations and avoid protease monotherapy, unless they have cirrhosis. The SVR rates in patients with an RVR are high and they might not require a protease inhibitor, but could benefit from PEG-IFN/RBV alone.
Thirdly, the safety profile. Dysgeusia, and anaemia were more frequent in the boceprevir groups than in the control group. Boceprevir regimens were associated with increased rates of anaemia, and nearly twice as many boceprevir recipients as controls had a haemoglobin level of less than 9.5 g/dl or received erythropoietin (43% vs. 24%). In patients receiving erythropoietin, the average duration of use was shortest in group 2. Neither the incidence of serious adverse events nor the frequency of discontinuation due to adverse events differed significantly between patients receiving boceprevir and those receiving SOC.
The SVR rates in patients with a poor response to IFN, defined as a reduction in HCV RNA of less than 1log10 IU/ml after 4 weeks of PEG-IFN/RBV therapy, were sufficiently high to dispel concern that the addition of a protease inhibitor to the treatment regimen would be equivalent to functional monotherapy. However, these patients were less likely than patients with a strong response to IFN to have a SVR after boceprevir. Thus, patients with a poor response to IFN should be monitored closely to determine who can benefit from better therapies, once they are available.
During monotherapy, viral variants with substitutions at the six main positions (36, 54, 55, 155, 156 and 170) within the NS3 protease have been selected. Phenotypic analyses of resistance based on in vitro replicons showed different levels of resistance conferred by substitutions at these different positions. Changes at positions 36, 54, 55, 155 and 156 conferred moderate resistance . Cross resistance studies have shown that most of the known resistance mutations confer resistance to most of the protease inhibitors under development.
HCV resistance to boceprevir is significantly less frequent when administered in combination with PEG-IFN/RBV. The Sprint-1 phase II study showed that administering a standard dose PEG-IFN/RBV and boceprevir are crucial to improve SVR in genotype 1 treatment-naïve patients, and that RBV is needed to prevent resistance . In the past with the PEG-IFN plus RBV treatment, premature discontinuation of RBV was associated with a significant increase in relapse , and even though the mechanism of action of RBV is poorly understood, this drug appears to be important in future and near future combinations.