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Low prevalence of danoprevir resistance identified in genotype 1b HCV patients with prior null response treated with danoprevir plus low-dose ritonavir plus peginterferon alfa-2a (40KD)/ribavirin for 12 weeks
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Reported by Jules Levin
Presented at the International Liver Congress 2011 [46th Annual Meeting of the European Association for the Study of the Liver (EASL)], March 30-April 3, 2011, Berlin, Germany
S. Le Pogam,1 J.M. Yan,1 M. Chhabra,2 M. Ilnicka,1 D. Chin,1 Y. Ji,2 Y. Zhang,3 N. Shulman,3 K. Klumpp,1 I. Najera1
1Roche, Nutley, NJ, USA; 2Roche, Palo Alto, CA, USA; 3Roche, South San Francisco, CA, USA
EASL: Activity of danoprevir plus low-dose ritonavir in combination with peginterferon alfa-2a (40KD) plus ribavirin in previous null responders - (04/01/11)
Conclusions
· In treatment naive patients danoprevir/r at a dose of 100/100 mg q12h, 200/100 mg q12h or 200/100 mg q24h plus peginterferon alfa-2a (40KD)/
ribavirin provided a robust virological response in treatment-naive genotype 1b and 1a patients with no viral breakthrough observed.
· In prior null responders, robust response was observed in genotype 1b patients, with only 1 of 16 patients showing evidence of
resistance-related viral breakthrough, whereas resistance-related viral breakthrough was observed in 4 of 8 genotype 1a patients.
· R155K resistance mutation persisted in three of the genotype 1a patients, while one genotype 1a patient lost the R155K resistance
mutation at the last time point of follow-up (follow-up week 24, 240 days after stopping the danoprevir treatment).
· In prior null responders there may be a need for a more intensified regimen including a second direct-acting antiviral, particularly one
with a high barrier to resistance.
Introduction
The combination of a hepatitis C virus (HCV) NS3/4A protease inhibitor (PI) in combination with peginterferon plus ribavirin has the potential to increase cure rates and reduce the required duration of treatment for patients with HCV genotype 1 infection, including treatment-naive and previous non-responders to peginterferon plus ribavirin.[1 8]
Viral resistance has emerged during treatment and is associated with viral breakthrough in patients treated with a PI. Danoprevir is a potent, highly selective and well-tolerated oral HCV NS3/4A protease inhibitor that has been studied, not only in combination with peginterferon alfa-2a (40KD) plus ribavirin,[9] but also in combination with mericitabine (RG7128), a nucleoside analogue inhibitor of the HCV NS5B polymerase in the proof of concept study of a dual oral interferon-free regimen in patients with chronic hepatitis C (INFORM-1 study).[10]
The resistance profile of danoprevir has been characterised and, unlike other HCV protease inhibitors, is largely restricted to a single amino acid substitution in the NS3 protease sequence (R155K), as observed in a 14-day monotherapy study,[11] and in a 12-week combination therapy study of danoprevir plus peginterferon alfa-2a (40KD) and ribavirin.[12] In contrast, when administered for 2 weeks in combination with mericitabine in INFORM-1, R155K was not detected in any patient, suggesting a role for mericitabine in preventing resistance to danoprevir.[10]
Objective
The objective of this study was to monitor the potential emergence of resistance to danoprevir in HCV genotype 1 patients, including both treatment-naive and prior null responders to peginterferon alfa-2a (40KD) plus ribavirin treatment, before, during and after treatment for up to 12 weeks with danoprevir plus low-dose ritonavir (r) in combination with peginterferon alfa-2a (40KD) plus ribavirin.
Methods
Three cohorts of treatment-naive HCV genotype 1 patients (n=34; 24 genotype 1a; 10 genotype 1b) were randomised to receive danoprevir/r, danoprevir (900 mg q12h) or placebo/r in combination with peginterferon alfa-2a (40KD) (PEGASYS®) plus ribavirin
(COPEGUS®) for 15 days (Figure 1). There were three danoprevir/r dosage cohorts:
- Cohort 1: danoprevir/r 100/100 mg q12h
- Cohort 2: danoprevir/r 200/100 mg q24h
- Cohort 3: danoprevir/r 200/100 mg q12h
A fourth cohort (n=24; 8 genotype 1a and 16 genotype 1b) included HCV genotype 1 patients with a prior null response to peginterferon/ribavirin who were re-treated with 100/100 mg q12h danoprevir/r in combination with peginterferon alfa-2a (40KD) plus
ribavirin for 12 weeks (Figure 1).
In cohorts 1 to 3 serum HCV RNA was measured by the Roche COBAS® TaqMan® HCV Test (detection limit = 15 IU/mL) at baseline and at days 1, 2, 3, 6, 9, 12, 14, 15 and 16 of danoprevir/r, danoprevir, or placebo/r plus peginterferon alfa-2a (40KD)/ribavirin treatment and also at week 4, 12 and 24 during follow-up treatment with peginterferon alfa-2a (40KD) plus ribavirin.
In cohort 4, serum HCV RNA was measured by the Roche COBAS® TaqMan® HCV Test (detection limit = 15 IU/mL) at baseline and at days 1, 2, 3, 6, 9, 12, 14, 15 and 16, and week 4, 8 and 12 of danoprevir/r + peginterferon alfa-2a (40KD)/ribavirin
treatment, at week 16, 20, 24, 36 and 48 of peginterferon alfa-2a (40KD)/ribavirin follow-up treatment, and at week 52, 60 and 72 during the follow-up treatment-free period (i.e. follow-up weeks 4, 12 and 24, respectively).
![EASL1.gif](../images/040611/040611-20/EASL1.gif)
Sample selection
Population sequencing and phenotypic analyses were performed for both on treatment and follow-up samples from patients who received danoprevir/r plus peginterferon alfa-2a (40KD) plus ribavirin and who experienced one of the following:
- Viral breakthrough during danoprevir/r treatment, defined as a sustained increase (i.e. for two or more consecutive measurements) in viral load of ≥1 log10 IU/mL above a nadir that was ≥0.5 log10 IU/mL below baseline.
- Partial response during danoprevir/r treatment, defined as an initial decrease in viral load to a nadir of ≥0.5 log10 IU/mL below baseline, followed by stabilisation (i.e. at least three consecutive measurements within 0.5 log10 IU/mL of nadir), and/or an end of treatment viral load of >1000 IU/mL in a patient who has received at least 4 weeks of treatment.
-- Non-response during danoprevir/r treatment, defined as a decrease in viral load of <0.5 log10 IU/mL in a patient who has received at least 2 weeks of treatment.
Sequencing
Amplification and population sequencing covering the entire NS3/4A and/or NS3 protease coding regions was performed on baseline samples from all patients, and on-treatment and follow-up samples from selected patients treated with danoprevir/r.
Phenotyping
Phenotypic characterisation was performed by cloning the NS3 protease gene from samples collected at day 1 and at the point after viral load rebound (viral breakthrough patients) and/or at the end of danoprevir treatment (partial responders) into the NS3 protease shuttle replicon and measuring the susceptibility to danoprevir and to peginterferon alfa-2a (40KD).
Results
A total of 58 patients were enrolled, of whom 53 received either danoprevir/r + peginterferon alfa-2a (40KD)/ribavirin (25 treatment-naive patients and 24 treatment-experienced patients) or danoprevir + peginterferon alfa-2a (40KD)/ribavirin (n=4; all treatment-naive patients).
Overall danoprevir/r at a dose of 100/100 mg q12h and 200/100 mg q12h or q24h plus peginterferon alfa-2a (40KD) plus ribavirin elicited a robust virological response.
Treatment-naive patients (cohorts 1-3)
· In cohorts 1-3 all 29 treatment-naive patients that received either danoprevir/r plus peginterferon alfa-2a (40KD)/ribavirin or danoprevir plus
peginterferon alfa-2a (40KD)/ribavirin experienced a continuous viral load decline; none experienced viral breakthrough, partial response or non-response during 2 weeks of combination therapy (20 genotype 1a; 9 genotype 1b).
Treatment-experienced patients (cohort 4)
· Of the 24 prior null responder patients (8 genotype 1a; 16 genotype 1b) treated with 100/100 mg danoprevir/r + peginterferon alfa-2a (40KD)/ribavirin, viral breakthrough was observed in 5 individuals (4 genotype 1a, 1 genotype 1b), all of whom had a baseline viral load >6 log10 IU/mL (range 6.44-7.27 log10 IU/mL).
· Viral breakthrough was observed by week 3 in two genotype 1a patients, by week 4 in one genotype 1a patient, by week 8 in one genotype 1a and by week 8 in one genotype 1b patient (Figure 2).
· Viral breakthrough was associated with the selection of the R155K variant in the NS3 protease region in all cases (Table 1).
![EASL2.gif](../images/040611/040611-20/EASL2.gif)
![EASL3.gif](../images/040611/040611-20/EASL3.gif)
Emergence of the R155K variant was associated with at least a 218-fold shift in EC50 for danoprevir compared with baseline samples (Figure 3).
The R155K resistance mutation persisted through week 24 of the follow-up period after danoprevir had been discontinued in three genotype 1a patients.
The R155K resistance mutation persisted through at least week 4 of the follow-up period for genotype 1b patients (only data available at the time of reporting) (Table 1).
Interestingly, one (1/4) genotype 1a patient (patient 4 in Table 1) lost the R155K resistance at the last time point of follow-up (week 24), which corresponds to 240 days after stopping danoprevir treatment.
![EASL4.gif](../images/040611/040611-20/EASL4.gif)
Actual EC50 values are shown for day -1 samples, and the fold-change in EC50 relative to day -1 is shown for on-treatment and follow-up time points. EC50 determination was not possible for samples from patient 2 at the week 4 time point due to very low replication capacity. Baseline sample for this patient (patient 2; day -1) was sensitive to danoprevir (0.13 ± 0.012 nM). Phenotypic characterisation of the genotype 1b samples was not available at the time of reporting.
Analysis of baseline samples in all patients (cohorts 1-4)
Population sequence analysis of the NS3/4A region from baseline samples from all 58 recruited patients did not identify any pre-existing danoprevir resistance mutations at baseline.
References
1. 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
2. Hezode 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
3. McHutchison JG, Manns MP, Muir AJ, et al. Telaprevir for previously treated chronic HCV infection. N Engl J Med 2010; 362: 1292-1303
4. 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 2010; 376: 705-16
5. Sherman K, Flamm S, Afdhal N, et al. Telaprevir in combination with peginterferon alfa2a and ribavirin for 24 or 48 weeks in treatment-naive genotype 1 HCV patients who achieved an extended rapid viral response: final results of Phase 3 illuminate study [abstract LB-2]. Hepatology 2010; 52 (Suppl 1): 401A-2A
6. Jacobson I, McHutchison J, Dusheiko G, et al. Telaprevir in combination with peginterferon and ribavirin in genotype 1 HCV treatment-naive patients: final results of phase 3 ADVANCE study [abstract 211]. Hepatology 2010; 52 (Suppl 1): 427A
7. Bacon B, Gordon S, Lawitz E, et al. HCV RESPOND-2 final results: high sustained virologic response among genotype 1 previous non-responders and relapsers to peginterferon/ribavirin when re-treated with boceprevir plus Pegintron (peginterferon alfa-2b)/ribavirin [abstract 216]. Hepatology 2010; 52 (Suppl 1): 430A
8. Bronowicki J-P, McCone J, Bacon B, et al. Response-guided therapy (RGT) with boceprevir (BOC) + peginterferon alfa-2b/ribavirin (P/R) for treatment-naive patients with hepatitis C virus (HCV) genotype (G) 1 was similar to a 48-wk fixed-duration regimen with BOC + P/R in SPRINT-2 [abstract LB-15]. Hepatology 2010; 52 (Suppl 1): 881A
9. Gane E, Rouzier, R, Stedman C, et al. Ritonavir boosting of low dose RG7227/ITMN-191, HCV NS3/4A protease inhibitor results in robust reduction in HCV RNA at lower exposures than provided by unboosted regimens [abstract 38]. J Hepatol 2010; 52 (Suppl 1): S16-17
10. Gane EJ, Roberts SK, Stedman CA, et al. Oral combination therapy with a nucleoside polymerase inhibitor (RG7128) and danoprevir for chronic hepatitis C genotype 1 infection (INFORM-1): a randomised, double-blind, placebo-controlled, dose-escalation trial. Lancet 2010; 376: 1467-75
11. Sarrazin C, Lim S, Qin X, et al. Kinetic analysis of viral rebound and drug-resistant viral variant dynamics in patients treated with ITMN-191 (R7227) monotherapy suggests a high barrier to viral escape [abstract 1411]. Hepatology 2009; 50 (Suppl. 4): 953A.
12. Le Pogam S, Chhabra M, Yan JM, et al. Low rate of viral load rebound observed among treatment-naive genotype 1 patients with chronic hepatitis C treated with danoprevir (RG7227) plus Peg IFN α-2a (40KD) (PEGASYS®) plus ribavirin: interim analysis [abstract 802]. Hepatology 2010; 52 (Suppl 1):703A.
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