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A few things...
... from today's 'Expert Analysis' module on Cliical Care Options site
Boceprevir:
"The phase II HCV SPRINT-1 trial investigated the efficacy and safety of combining the investigational NS3 protease inhibitor boceprevir with peginterferon alfa‑2b plus ribavirin in 520 treatment‑naive patients with genotype 1 infection. Although interim results of this study were reported previously (Capsule Summary),[1] Kwo and colleagues[2] presented the final sustained virologic response (SVR) data at EASL 2009 (Capsule Summary). The trial was designed to compare several boceprevir, peginterferon, and ribavirin dosing strategies with the standard of care: peginterferon alfa-2b plus ribavirin for 48 weeks. Although the study design was quite complicated, the goals included an evaluation of 28 vs 48 weeks of the triple-combination regimen and a comparison of boceprevir and peginterferon alfa-2b plus low-dose ribavirin (400-1000 mg/day) vs standard-dose ribavirin (800-1400 mg/day). Another key aspect of this trial was the assessment of a 4-week peginterferon plus ribavirin lead‑in phase before the introduction of boceprevir. The rationale for this approach was to establish antiviral activity before adding boceprevir with the hope of minimizing the risk of emergent drug resistance. Therefore, 2 additional treatment arms compared 24 vs 44 weeks of triple therapy, each following a 4-week peginterferon/ribavirin lead-in phase.
The key finding from this analysis was that 44 weeks of boceprevir plus peginterferon/ribavirin following a lead-in phase was associated with the highest sustained virologic response (SVR) rate of 75% (vs 38% with standard of care; P < .0001). The next highest SVR rate was 67%, which was achieved by patients receiving the 48‑week triple-combination regimen that did not include lead‑in treatment (P < .0001 vs standard of care). The proportion of patients who achieved SVR with 24 weeks of triple therapy following a lead-in phase was 56% (P = .0005 vs standard of care) vs 54% with 28 weeks of triple therapy and no lead-in treatment (P = .013 vs standard of care).
Another important finding concerns the incidence and extent of anemia. The investigators observed that adding boceprevir to standard of care resulted in an approximately 1 g/dL hemoglobin decrease in addition to that associated with peginterferon/ribavirin treatment. Among patients treated with lead-in boceprevir and standard-dose ribavirin, approximately 50% received erythropoietin to maintain normal hemoglobin levels vs only 26% in the control group. Although only 15% of patients received erythropoietin in the boceprevir plus peginterferon and low-dose ribavirin arm, the SVR rate was much lower at 36%. Erythropoietin therapy was associated with lower treatment discontinuation rates."
Telaprevir:
"Most studies on small molecule antiviral agents involve treatment-naive patients infected with genotype 1 HCV. The PROVE 3 trial of telaprevir is one of the first large, randomized phase II studies to examine an investigational protease inhibitor exclusively in previously treated HCV-infected patients (Capsule Summary).[4] In this study, 453 patients with genotype 1 HCV who did not achieve SVR to previous peginterferon-based therapy were randomized to 4 treatment arms: 12 weeks of telaprevir plus peginterferon alfa-2a/ribavirin followed by another 12 weeks of peginterferon alfa-2a/ribavirin (T12/PR24); 24 weeks of telaprevir plus peginterferon alfa-2a/ribavirin followed by an additional 24 weeks of peginterferon alfa-2a/ribavirin (T24/PR48); 24 weeks of telaprevir plus peginterferon alfa-2a and no ribavirin (T24/P24); or 48 weeks of peginterferon alfa-2a/ribavirin (the control arm) (PR48).
The patients enrolled in this study included all types of previous nonresponders, including nonresponders who never achieved undetectable HCV RNA, relapsers (those who achieved undetectable HCV RNA at the end of treatment but had detectable HCV RNA during the follow‑up period), and breakthrough patients (those who achieved undetectable HCV RNA at some point during therapy, but then experienced an increase in HCV RNA to detectable levels before treatment completion). The proportions of each type of nonresponse were comparable among all treatment arms. In addition, both cirrhotic and noncirrhotic patients were included in the trial—approximately 20% of the patients had cirrhosis and 23% to 29% had bridging fibrosis.
The investigators found that the SVR rate was 9% in the control arm, which is to be expected among previous nonresponders. Of note, however, 39% of subjects treated with T12/P24 and 38% treated with T24/PR48 achieved SVR (both P < .001 vs control). In addition, SVR rates were comparable between patients with vs without baseline cirrhosis."
Albuferon:
"Albinterferon alfa-2b vs Peginterferon alfa-2a in Treatment-Naive Patients With Genotype 1 HCV
Stefan Zeuzem, MD:
The 2 peginterferon agents currently approved for the treatment of HCV have improved stability relative to standard interferons as a result of the covalent attachment of polyethylene glycol moieties to the parent interferon molecule. This pegylation prolongs the molecular half‑life in vivo, allowing less frequent weekly dosing.
Albinterferon represents a different strategy for increasing the stability of interferon. This recombinant polypeptide is synthesized from a genetic fusion of the genes encoding human serum albumin and interferon alpha. Expressing both molecules together as a single fused protein combines the antiviral activity of interferon with the long half‑life of human serum albumin, thereby enabling a biweekly dosing schedule. Albinterferon is the most advanced albumin-containing fusion drug under investigation, and this innovative technology has been described in several publications.[15,16]
Our group conducted a randomized, open-label phase III study to directly compare weekly peginterferon alfa-2a with 2 different doses of biweekly albinterferon alfa-2b (900 and 1200 μg), all of which were administered with weight-based ribavirin for 48 weeks (Capsule Summary).[17] This pivotal study included 1323 treatment-naive patients with chronic genotype 1 HCV infection. Baseline characteristics of the treatment arms were well balanced and the results showed that albinterferon alfa-2b met the criteria for noninferiority to peginterferon alfa-2a based on SVR rates (P = .0008 for noninferiority of the 900-μg dose; P = .0029 for noninferiority of the 1200-μg dose).
Unfortunately, the data and safety monitoring board discovered that 2 patients in the albinterferon alfa-2b 1200-μg treatment arm had evidence of interstitial lung disease at Week 24 and recommended that the albinterferon alfa-2b dose be reduced to 900 μg in this arm. Further investigation revealed that interstitial lung complications were present on computed tomography scans taken before therapy initiation for both patients. However, the safety review prompted additional lung analyses including spirometry and chest x‑rays. Encouragingly, no differences in spirometry, lung function, or a blinded review of chest x‑rays were observed between the 3 treatment arms. In general, interstitial lung disease is an adverse effect that has been described with all (peg)interferons—it is a class-specific effect. But, with the higher albinterferon alfa-2b dose used in this study, there was concern that it could be greater. Nevertheless, the study results showed that the 900-μg albinterferon alfa-2b dose was safe and exhibited equivalent efficacy to peginterferon alfa-2a."
Boceprevir:
"The phase II HCV SPRINT-1 trial investigated the efficacy and safety of combining the investigational NS3 protease inhibitor boceprevir with peginterferon alfa‑2b plus ribavirin in 520 treatment‑naive patients with genotype 1 infection. Although interim results of this study were reported previously (Capsule Summary),[1] Kwo and colleagues[2] presented the final sustained virologic response (SVR) data at EASL 2009 (Capsule Summary). The trial was designed to compare several boceprevir, peginterferon, and ribavirin dosing strategies with the standard of care: peginterferon alfa-2b plus ribavirin for 48 weeks. Although the study design was quite complicated, the goals included an evaluation of 28 vs 48 weeks of the triple-combination regimen and a comparison of boceprevir and peginterferon alfa-2b plus low-dose ribavirin (400-1000 mg/day) vs standard-dose ribavirin (800-1400 mg/day). Another key aspect of this trial was the assessment of a 4-week peginterferon plus ribavirin lead‑in phase before the introduction of boceprevir. The rationale for this approach was to establish antiviral activity before adding boceprevir with the hope of minimizing the risk of emergent drug resistance. Therefore, 2 additional treatment arms compared 24 vs 44 weeks of triple therapy, each following a 4-week peginterferon/ribavirin lead-in phase.
The key finding from this analysis was that 44 weeks of boceprevir plus peginterferon/ribavirin following a lead-in phase was associated with the highest sustained virologic response (SVR) rate of 75% (vs 38% with standard of care; P < .0001). The next highest SVR rate was 67%, which was achieved by patients receiving the 48‑week triple-combination regimen that did not include lead‑in treatment (P < .0001 vs standard of care). The proportion of patients who achieved SVR with 24 weeks of triple therapy following a lead-in phase was 56% (P = .0005 vs standard of care) vs 54% with 28 weeks of triple therapy and no lead-in treatment (P = .013 vs standard of care).
Another important finding concerns the incidence and extent of anemia. The investigators observed that adding boceprevir to standard of care resulted in an approximately 1 g/dL hemoglobin decrease in addition to that associated with peginterferon/ribavirin treatment. Among patients treated with lead-in boceprevir and standard-dose ribavirin, approximately 50% received erythropoietin to maintain normal hemoglobin levels vs only 26% in the control group. Although only 15% of patients received erythropoietin in the boceprevir plus peginterferon and low-dose ribavirin arm, the SVR rate was much lower at 36%. Erythropoietin therapy was associated with lower treatment discontinuation rates."
Telaprevir:
"Most studies on small molecule antiviral agents involve treatment-naive patients infected with genotype 1 HCV. The PROVE 3 trial of telaprevir is one of the first large, randomized phase II studies to examine an investigational protease inhibitor exclusively in previously treated HCV-infected patients (Capsule Summary).[4] In this study, 453 patients with genotype 1 HCV who did not achieve SVR to previous peginterferon-based therapy were randomized to 4 treatment arms: 12 weeks of telaprevir plus peginterferon alfa-2a/ribavirin followed by another 12 weeks of peginterferon alfa-2a/ribavirin (T12/PR24); 24 weeks of telaprevir plus peginterferon alfa-2a/ribavirin followed by an additional 24 weeks of peginterferon alfa-2a/ribavirin (T24/PR48); 24 weeks of telaprevir plus peginterferon alfa-2a and no ribavirin (T24/P24); or 48 weeks of peginterferon alfa-2a/ribavirin (the control arm) (PR48).
The patients enrolled in this study included all types of previous nonresponders, including nonresponders who never achieved undetectable HCV RNA, relapsers (those who achieved undetectable HCV RNA at the end of treatment but had detectable HCV RNA during the follow‑up period), and breakthrough patients (those who achieved undetectable HCV RNA at some point during therapy, but then experienced an increase in HCV RNA to detectable levels before treatment completion). The proportions of each type of nonresponse were comparable among all treatment arms. In addition, both cirrhotic and noncirrhotic patients were included in the trial—approximately 20% of the patients had cirrhosis and 23% to 29% had bridging fibrosis.
The investigators found that the SVR rate was 9% in the control arm, which is to be expected among previous nonresponders. Of note, however, 39% of subjects treated with T12/P24 and 38% treated with T24/PR48 achieved SVR (both P < .001 vs control). In addition, SVR rates were comparable between patients with vs without baseline cirrhosis."
Albuferon:
"Albinterferon alfa-2b vs Peginterferon alfa-2a in Treatment-Naive Patients With Genotype 1 HCV
Stefan Zeuzem, MD:
The 2 peginterferon agents currently approved for the treatment of HCV have improved stability relative to standard interferons as a result of the covalent attachment of polyethylene glycol moieties to the parent interferon molecule. This pegylation prolongs the molecular half‑life in vivo, allowing less frequent weekly dosing.
Albinterferon represents a different strategy for increasing the stability of interferon. This recombinant polypeptide is synthesized from a genetic fusion of the genes encoding human serum albumin and interferon alpha. Expressing both molecules together as a single fused protein combines the antiviral activity of interferon with the long half‑life of human serum albumin, thereby enabling a biweekly dosing schedule. Albinterferon is the most advanced albumin-containing fusion drug under investigation, and this innovative technology has been described in several publications.[15,16]
Our group conducted a randomized, open-label phase III study to directly compare weekly peginterferon alfa-2a with 2 different doses of biweekly albinterferon alfa-2b (900 and 1200 μg), all of which were administered with weight-based ribavirin for 48 weeks (Capsule Summary).[17] This pivotal study included 1323 treatment-naive patients with chronic genotype 1 HCV infection. Baseline characteristics of the treatment arms were well balanced and the results showed that albinterferon alfa-2b met the criteria for noninferiority to peginterferon alfa-2a based on SVR rates (P = .0008 for noninferiority of the 900-μg dose; P = .0029 for noninferiority of the 1200-μg dose).
Unfortunately, the data and safety monitoring board discovered that 2 patients in the albinterferon alfa-2b 1200-μg treatment arm had evidence of interstitial lung disease at Week 24 and recommended that the albinterferon alfa-2b dose be reduced to 900 μg in this arm. Further investigation revealed that interstitial lung complications were present on computed tomography scans taken before therapy initiation for both patients. However, the safety review prompted additional lung analyses including spirometry and chest x‑rays. Encouragingly, no differences in spirometry, lung function, or a blinded review of chest x‑rays were observed between the 3 treatment arms. In general, interstitial lung disease is an adverse effect that has been described with all (peg)interferons—it is a class-specific effect. But, with the higher albinterferon alfa-2b dose used in this study, there was concern that it could be greater. Nevertheless, the study results showed that the 900-μg albinterferon alfa-2b dose was safe and exhibited equivalent efficacy to peginterferon alfa-2a."
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