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Dec 15, 2010 - 0 comments
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.
Kwo PY, Lawitz EJ, McCone J, et al.
Lancet. 2010;376:705-716
Donald M. Jensen, MD
Professor of Medicine
Director, Center for Liver Diseases
Department of Medicine
University of Chicago Medical Center
Chicago, Illinois
Peginterferon and ribavirin given for 48 weeks is currently the standard care for patients chronically infected with genotype 1 hepatitis C virus (HCV). However, ≤ 50% of such patients treated with this regimen achieve a sustained virologic response (SVR), which is the most important endpoint for long-term clinical benefit.[1-4] Recently, newer therapies called direct-acting antiviral (DAA) agents have advanced in clinical development for HCV. These agents act in a more specific manner by inhibiting HCV proteins essential for replication. Boceprevir is a DAA that inhibits the HCV NS3 protease inhibitor and has previously demonstrated antiviral activity in patients who have failed peginterferon therapy with or without ribavirin.[5,6] Of note, telaprevir – another HCV protease inhibitor – has also demonstrated potent activity in both treatment-naive (Capsule Summary)[7] and treatment-experienced patients (Capsule Summary).[8]
To determine the efficacy of boceprevir in combination with peginterferon/ribavirin in treatment-naive patients with chronic genotype 1 HCV infection, Kwo and colleagues[9] randomized 595 patients in the open-label, phase II SPRINT-1 trial (Capsule Summary). The study was divided into 2 parts. Part 1 (n = 520) compared 4 different boceprevir-containing regimens vs a 48-week peginterferon/ribavirin (peginterferon alfa-2b 1.5 µg/kg plus ribavirin 800-1400 mg/day) control group. Two of the boceprevir (800 mg 3 times daily) arms had a 4-week lead-in with peginterferon/ribavirin, and then boceprevir was added for an additional 24 or 44 weeks. In the arms with no lead-in, boceprevir was combined with peginterferon/ribavirin for 28 or 48 weeks.
All 4 boceprevir-containing arms demonstrated significantly higher SVR rates (54% to 75%) as compared with the 48-week peginterferon/ribavirin control arm (38%), regardless of treatment duration or 4-week peginterferon/ribavirin lead-in. Although the differences between the SVR rates in the arms with and without lead-in were small and the necessity of the lead-in remains unclear, the rate of viral breakthrough did appear to be slightly lower with lead-in (4% vs 9%; P = .057). In all treatment groups, rapid virologic response (undetectable HCV RNA by Week 4 of boceprevir) was highly associated with achieving SVR. Those who achieved a rapid virologic response at Week 4 had similarly excellent results whether treated for 24 or 48 weeks (74% vs 84%), although the definition of rapid virologic response in those with a lead-in was actually Week 8 of total therapy. In general, shorter treatment durations with boceprevir led to higher relapse rates: 24% and 30% with 24 or 28 weeks of treatment vs 3% and 7% with 44 or 48 weeks of treatment, respectively. The relapse rate was 24% in the control group. Boceprevir was associated with higher rates of anemia and dysgeusia than the control arm.
Part 2 of the study was designed to determine whether low-dose ribavirin could reduce the incidence of anemia without compromising efficacy. In Part 2, 75 patients were randomly assigned to receive either standard weight-based dosing of ribavirin (800-1400 mg/day; n = 16; control arm) or low-dose weight-based ribavirin (400-1000 mg/day; n = 59), each combined with peginterferon and boceprevir for 48 weeks. Although rates of anemia (hemoglobin < 10 g/dL) were lower in the low-dose ribavirin arm vs the control arm (24% vs 63%, respectively), SVR rates were also lower (36% vs 50%, respectively). Therefore, full-dose ribavirin is necessary to achieve the higher responses found with boceprevir treatment.
Once new DAAs, such as boceprevir, become commercially available, they have the potential to revolutionize treatment of patients with genotype 1 HCV infection, particularly difficult-to-treat patients. Indeed, SVR rates for blacks treated in this study were as high as 53% (8 of 15) with boceprevir treatment vs 13% (2 of 16) for those treated with the standard 48-week peginterferon/ribavirin regimen. Patients with cirrhosis also achieved higher SVR rates with boceprevir treatment: 67% (10 of 15) vs 25% (2 of 8) of those treated in the control arm. However, the number of such patients enrolled in this study was low, and data from more patients will be needed to determine the true benefit of boceprevir in these difficult-to-treat populations.
The phase II SPRINT-1 addressed several important questions surrounding treatment duration, the potential utility of a lead-in, and the importance of coadministering full-dose ribavirin with boceprevir. It remains to be determined how a peginterferon/ribavirin lead-in phase would be handled in clinical practice, where turnaround time for HCV RNA testing can be up to 2 weeks. It is hoped that these issues will be addressed further in ongoing phase III trials. It seems clear that a new treatment paradigm will emerge with DAAs with significantly higher rates of SVR, but they will come at the price of more side effects and increased cost. Finally, these regimens will continue to require the use of peginterferon/ribavirin therapy.
______________________________
Capsule Summary
Higher SVR Rates When Boceprevir Added to PegIFN/RBV Therapy for Patients With Chronic Genotype 1 HCV Infection
Posting Date: October 25, 2010
Phase II SPRINT-1 trial: open-label, randomized trial[1]
Summary of Key Conclusions
Addition of boceprevir to peginterferon (pegIFN)/ribavirin (RBV) led to higher sustained virologic response (SVR) rates vs standard pegIFN/RBV alone in treatment-naive genotype 1 HCV patients
Rapid virologic response (RVR) and early virologic response (EVR) predictive of SVR
Nonblack race, genotype 1b infection, lower baseline HCV RNA (≤ 600,000 IU/mL), and lower platelet count significantly predictive of SVR in boceprevir treatment arms
Boceprevir improved SVR for blacks and patients with cirrhosis relative to pegIFN/RBV
Potential for treatment duration to be modified according to HCV RNA decline in first 4 weeks of treatment
Reduction in HCV RNA from baseline to Week 4
< 1.5 log10 IU/mL: longer 48-week treatment duration improved SVR
≥ 1.5 log10 IU/mL: 28 weeks of treatment likely sufficient
Boceprevir treatment associated with higher rates of anemia and dysgeusia
Low-dose RBV with boceprevir and pegIFN reduced incidence of anemia, but SVR similar to standard care
Treatment-emergent anemia associated with higher SVR rates
Background
Current standard treatment for HCV genotype 1 infection: pegIFN/RBV for 48 weeks
However, ≤ 50% of genotype 1 HCV patients achieve SVR
Boceprevir, an HCV NS3 protease inhibitor with potent antiviral activity[2,3]
SPRINT-1 trial evaluated efficacy and safety of adding boceprevir to standard care for treatment-naive patients with chronic genotype 1 HCV infection[1]
Efficacy of lead-in phase, treatment duration, and dosing of RBV analyzed
Kwo PY, Lawitz EJ, McCone J, et al.
Lancet. 2010;376:705-716
Donald M. Jensen, MD
Professor of Medicine
Director, Center for Liver Diseases
Department of Medicine
University of Chicago Medical Center
Chicago, Illinois
Peginterferon and ribavirin given for 48 weeks is currently the standard care for patients chronically infected with genotype 1 hepatitis C virus (HCV). However, ≤ 50% of such patients treated with this regimen achieve a sustained virologic response (SVR), which is the most important endpoint for long-term clinical benefit.[1-4] Recently, newer therapies called direct-acting antiviral (DAA) agents have advanced in clinical development for HCV. These agents act in a more specific manner by inhibiting HCV proteins essential for replication. Boceprevir is a DAA that inhibits the HCV NS3 protease inhibitor and has previously demonstrated antiviral activity in patients who have failed peginterferon therapy with or without ribavirin.[5,6] Of note, telaprevir – another HCV protease inhibitor – has also demonstrated potent activity in both treatment-naive (Capsule Summary)[7] and treatment-experienced patients (Capsule Summary).[8]
To determine the efficacy of boceprevir in combination with peginterferon/ribavirin in treatment-naive patients with chronic genotype 1 HCV infection, Kwo and colleagues[9] randomized 595 patients in the open-label, phase II SPRINT-1 trial (Capsule Summary). The study was divided into 2 parts. Part 1 (n = 520) compared 4 different boceprevir-containing regimens vs a 48-week peginterferon/ribavirin (peginterferon alfa-2b 1.5 µg/kg plus ribavirin 800-1400 mg/day) control group. Two of the boceprevir (800 mg 3 times daily) arms had a 4-week lead-in with peginterferon/ribavirin, and then boceprevir was added for an additional 24 or 44 weeks. In the arms with no lead-in, boceprevir was combined with peginterferon/ribavirin for 28 or 48 weeks.
All 4 boceprevir-containing arms demonstrated significantly higher SVR rates (54% to 75%) as compared with the 48-week peginterferon/ribavirin control arm (38%), regardless of treatment duration or 4-week peginterferon/ribavirin lead-in. Although the differences between the SVR rates in the arms with and without lead-in were small and the necessity of the lead-in remains unclear, the rate of viral breakthrough did appear to be slightly lower with lead-in (4% vs 9%; P = .057). In all treatment groups, rapid virologic response (undetectable HCV RNA by Week 4 of boceprevir) was highly associated with achieving SVR. Those who achieved a rapid virologic response at Week 4 had similarly excellent results whether treated for 24 or 48 weeks (74% vs 84%), although the definition of rapid virologic response in those with a lead-in was actually Week 8 of total therapy. In general, shorter treatment durations with boceprevir led to higher relapse rates: 24% and 30% with 24 or 28 weeks of treatment vs 3% and 7% with 44 or 48 weeks of treatment, respectively. The relapse rate was 24% in the control group. Boceprevir was associated with higher rates of anemia and dysgeusia than the control arm.
Part 2 of the study was designed to determine whether low-dose ribavirin could reduce the incidence of anemia without compromising efficacy. In Part 2, 75 patients were randomly assigned to receive either standard weight-based dosing of ribavirin (800-1400 mg/day; n = 16; control arm) or low-dose weight-based ribavirin (400-1000 mg/day; n = 59), each combined with peginterferon and boceprevir for 48 weeks. Although rates of anemia (hemoglobin < 10 g/dL) were lower in the low-dose ribavirin arm vs the control arm (24% vs 63%, respectively), SVR rates were also lower (36% vs 50%, respectively). Therefore, full-dose ribavirin is necessary to achieve the higher responses found with boceprevir treatment.
Once new DAAs, such as boceprevir, become commercially available, they have the potential to revolutionize treatment of patients with genotype 1 HCV infection, particularly difficult-to-treat patients. Indeed, SVR rates for blacks treated in this study were as high as 53% (8 of 15) with boceprevir treatment vs 13% (2 of 16) for those treated with the standard 48-week peginterferon/ribavirin regimen. Patients with cirrhosis also achieved higher SVR rates with boceprevir treatment: 67% (10 of 15) vs 25% (2 of 8) of those treated in the control arm. However, the number of such patients enrolled in this study was low, and data from more patients will be needed to determine the true benefit of boceprevir in these difficult-to-treat populations.
The phase II SPRINT-1 addressed several important questions surrounding treatment duration, the potential utility of a lead-in, and the importance of coadministering full-dose ribavirin with boceprevir. It remains to be determined how a peginterferon/ribavirin lead-in phase would be handled in clinical practice, where turnaround time for HCV RNA testing can be up to 2 weeks. It is hoped that these issues will be addressed further in ongoing phase III trials. It seems clear that a new treatment paradigm will emerge with DAAs with significantly higher rates of SVR, but they will come at the price of more side effects and increased cost. Finally, these regimens will continue to require the use of peginterferon/ribavirin therapy.
______________________________
Capsule Summary
Higher SVR Rates When Boceprevir Added to PegIFN/RBV Therapy for Patients With Chronic Genotype 1 HCV Infection
Posting Date: October 25, 2010
Phase II SPRINT-1 trial: open-label, randomized trial[1]
Summary of Key Conclusions
Addition of boceprevir to peginterferon (pegIFN)/ribavirin (RBV) led to higher sustained virologic response (SVR) rates vs standard pegIFN/RBV alone in treatment-naive genotype 1 HCV patients
Rapid virologic response (RVR) and early virologic response (EVR) predictive of SVR
Nonblack race, genotype 1b infection, lower baseline HCV RNA (≤ 600,000 IU/mL), and lower platelet count significantly predictive of SVR in boceprevir treatment arms
Boceprevir improved SVR for blacks and patients with cirrhosis relative to pegIFN/RBV
Potential for treatment duration to be modified according to HCV RNA decline in first 4 weeks of treatment
Reduction in HCV RNA from baseline to Week 4
< 1.5 log10 IU/mL: longer 48-week treatment duration improved SVR
≥ 1.5 log10 IU/mL: 28 weeks of treatment likely sufficient
Boceprevir treatment associated with higher rates of anemia and dysgeusia
Low-dose RBV with boceprevir and pegIFN reduced incidence of anemia, but SVR similar to standard care
Treatment-emergent anemia associated with higher SVR rates
Background
Current standard treatment for HCV genotype 1 infection: pegIFN/RBV for 48 weeks
However, ≤ 50% of genotype 1 HCV patients achieve SVR
Boceprevir, an HCV NS3 protease inhibitor with potent antiviral activity[2,3]
SPRINT-1 trial evaluated efficacy and safety of adding boceprevir to standard care for treatment-naive patients with chronic genotype 1 HCV infection[1]
Efficacy of lead-in phase, treatment duration, and dosing of RBV analyzed
