High-efficacy results from non–interferon-based therapies for hepatitis C virus (HCV) dominated the discussion at the EASL meeting, leading to widespread talk of a new era emerging in treatment. Also notable among the research presented were developments in controlling adverse effects of interferon-based HCV treatments. The sessions took place in Barcelona from April 18 to 22, 2012. More than 7,000 clinicians and researchers participated.
. 2012 Jun;37(6):362–363.
P T. 2012 Jun;37(6):362.
Results from the phase 2, three-arm CO-PILOT study suggest that a combination of ABT-450 (Abbott, Enanta) with ritonavir (Norvir; ABT-450/r) plus ABT-333 (Abbott) plus ribavirin (e.g., Copegus, Genentech, RBV) was well tolerated and produced high sustained virological responses (SVRs) in treatment-naive patients with hepatitis C virus (HCV) genotype 1 infection. The investigators also reported high SVRs in previous non-responders to interferon-based therapy.
Arms 1 and 2 included treatment-naive patients who received ABT-333 400 mg twice daily plus RBV 1,000 to 1,200 mg once daily plus ABT-450/r either 250/100 mg once daily (n = 19) or 150/100 mg once daily (n = 14).
Treatment in arm 3 was the same as in arm 2, but it included prior partial or null responders to previous pegylated interferon plus RBV treatments (n = 17).
Subjects were treated for 2 weeks, with 48 weeks of follow-up. The primary endpoint of the trial was extended rapid virological response (eRVR) based on HCV–RNA counts lower than the limit of detection from treatment weeks 4 to 12.
Dr. Poordad reported that eRVRs were 90% in arm 1, 79% in arm 2, and 59% in arm 3. Notably, for SVRs at week 4 (SVR4) and at week 12 (SVR12), arm 1 achieved SVR4 at a rate of 95% and SVR12 at a rate of 93%.
For arm 2, the SVR4 rate was 95% and the SVR12 rate was 93%. The investigators reported SVR4 and SVR12 of 47% for the previously non-responding patients in arm 3.
No deaths or serious adverse events were noted, but one adverse event in arm 1 led to discontinuation of therapy.
Dr. Poordad concluded, “ABT-450 with ritonavir plus ABT-333 and ribavirin for 12 weeks has the potential to achieve a sustained virological response in a high proportion of subjects without interferon.”
The study was supported by Abbott.
P T. 2012 Jun;37(6):362–363.
A phase 2 study of an interferon-free combination daclatasvir (BMS-790052, Bristol-Meyers Squibb) plus GS-7977 (formerly PSI-7977, Pharmasset/Gilead), with or without ribavirin, showed that this regimen was well tolerated and that treatment-naive patients with hepatitis C virus (HCV) genotype 1, 2, and 3 infection achieved high rates of early sustained virological responses (SVRs).
Investigators enrolled treatment-naive adults without cirrhosis who had chronic HCV infection type 1, 2, or 3 (n = 88). The patients were randomly assigned to three treatment cohorts for 24 weeks.
Subjects in cohort A (n = 31) received GS-7977 400 mg once daily for 7 days, then daclatasvir 60 mg once daily. Subjects in group B (n = 28) received GS-7977 400 mg once daily plus daclatasvir 60 mg once daily. Subjects in group C (n = 29) received the same regimen as group B plus ribavirin 1,000 to 1,200 mg once daily according to weight (HCV genotype 1) or 800 mg once daily (HCV genotype 2 or 3).
In this interim analysis, researchers evaluated data for the secondary endpoint of SVRs at week 4 (SVR4), defined as HCV–RNA counts below the lower limit of quantification (25 IU/mL). They reported that all genotype 1 subjects in groups A, B, and C achieved SVR4 at a rate of 100%. Patients with HCV genotypes 2 and 3 achieved SVR4 at rates of 88% for cohort A, 100% for cohort B, and 86% for cohort C.
“Overall sustained virological responses at week 4 were 95.5% across genotypes 1, 2, and 3,” said Dr. Thurz at the opening EASL press briefing. “There was no difference in sustained virological response at 4 weeks by the hepatitis C genotype 1 subtype or by the interleukin-28B genotype. Ribavirin did not increase the magnitude of hepatitis C RNA decline or influence sustained virological response.”
The most frequent adverse events were fatigue, reported in 26% to 50% of subjects; headache, in 16% to 31%; and nausea, in 16% to 32%. Bristol-Meyers Squibb funded the study.
P T. 2012 Jun;37(6):363.
Patients with hepatitis C virus (HCV) genotype 2 or 3 infection who received investigative pegylated interferon lambda-1a (peg-IFN-lambda 1, Bristol-Myers Squibb) in combination with ribavirin achieved a rate of 75% for sustained virological responses (SVRs) at 24 weeks (SVR24) after treatment in the phase 2 EMERGE trial.
Flu-like musculoskeletal symptoms in the investigative arm were less frequent compared with those occurring with standard pegylated interferon alfa-2a (Pegasys, Genentech). Rates of anemia and decreased white blood cell and platelet counts were lower as well.
The EMERGE investigators enrolled 526 treatment-naive subjects with HCV genotypes 1, 2, 3, and 4. Dr. Zeuzem reported on 118 patients with HCV genotype 2 or 3 infection who had received either weekly Pegasys injections or one of three weekly doses of peg-IFN-lambda (240, 180, or 120 mcg) in combination with ribavirin for 24 weeks.
Subjects in the Pegasys group achieved a 53.3% SVR24 rate, whereas those in the 250-mcg peg-IFN-lambda group achieved a 60% SVR24 rate. Patients in the 120-mcg group achieved a 65.5% SVR24 rate; those receiving 180 mcg achieved a 75.9% SVR24 rate.
Dr. Zeuzem noted that the 180-mcg dose of peg-IFN-lambda will be used in phase 3 studies.
Serious side effects and other adverse events were similar in all arms up to week 24, after therapy ended. Flu-like symptoms, however, were reported less frequently in the peg-IFN-lambda groups at 17.2% and 23.3%, respectively, compared with 40% among patients receiving Pegasys. Similarly, 16.7% to 27.6% of peg-IFN-lambda subjects reported musculoskeletal symptoms, compared with 63.3% of Pegasys subjects.
Notably, only 6.9% of patients receiving 180 mcg of peg-IFN-lambda required dose reductions of interferon because of side effects, compared with 26.7% of the Pegasys patients. The ribavirin dosage had to be reduced in 6.9% of patients receiving 180 mcg of peg-IFN-lambda and in 43.3% in the Pegasys group. Furthermore, it was necessary to reduce the ribavirin dosage in 23.3% of the Pegasys patients because of anemia but in none of those receiving peg-IFN-lambda 180 mcg.
Dr. Zeuzem concluded, “Pegylated interferon lambda-1a was associated with a comparable sustained virological response 24 rate in patients with HCV genotype 2 and 3 with fewer musculoskeletal and flu-like symptoms, less hematological toxicity, and fewer peg-interferon or ribavirin dose modifications versus Pegasys ribavirin.”
Bristol-Meyers Squibb supported the study.
P T. 2012 Jun;37(6):363.
Researchers who conducted a phase 3, open-label study reported no difference in rates of viral clearance between two anemia-management strategies for patients with chronic hepatitis C virus (HVC) genotype 1 infection. Boceprevir (Victrelis, Merck), a protease inhibitor, was combined with peginterferon alfa-2b (PegIntron, Merck) and ribavirin (P/R). Boceprevir is indicated for the treatment of chronic HCV genotype 1 infection in combination with P/R.
Dr. Poordad reported that anemia was managed equally well by a reduction of ribavirin or by the addition of erythropoietin (EPO).
The investigators enrolled 687 treatment-naive adults with chronic HCV genotype 1 who had baseline hemoglobin levels of 15 g/dL or lower. Patients were monitored for the development of anemia, a common side effect of P/R treatment.
Patients received a 4-week lead-in of PegIntron (1.5 mcg/kg per week) and an investigational dose of ribavirin (600–1,400 mg/day), followed by the addition of boceprevir (800 mg three times daily) after week 4 for 24 or 44 weeks, based on HCV–RNA levels at treatment week 8. Dr. Poordad said that when 16% of the subjects (111/687) had been enrolled and treatment was initiated among them, a protocol amendment was introduced allowing the use of response-guided therapy rather than fixed-dose therapy only. Those 111 subjects were assigned to a fixed-dose regimen of 4 weeks of P/R, followed by 44 weeks of boceprevir plus P/R. Results for subjects receiving the fixed-dose regimen and for those receiving response-guided therapy were the same, and the data from both groups were combined in the presentation of the trial at EASL. The remaining patients were enrolled in cohort 2.
Anemia developed in 500 subjects, who were then randomly assigned to receive either a ribavirin dose reduction of 200 to 400 mg/day or the addition of EPO at 40,000 IU/week.
A secondary method of anemia management (e.g., adding EPO), a dose reduction of ribavirin, or transfusion was possible if hemoglobin levels dropped to 8.5 g/dL or lower. Treatment was stopped if the hemoglobin level fell to 7.5 g/dL or below. If the initial hemoglobin measurement qualifying a patient as anemic was 8.5 g/dL or lower, that patient was not assigned to receive one of the anemia-management strategies.
The primary endpoint was the comparison of sustained virological responses (SVRs) in patients who were assigned to the reduced ribavirin dose or to the addition of EPO. SVR rates were 71% for both the ribavirin dose-reduction group (178/249) and the EPO group (178/251). Relapse rates were also the same (10% in each group), and safety profiles were similar for both strategies.
Dr. Poordad concluded, “There were no meaningful differences in sustained virological response rates between either of the two anemia-management strategies. These data support the use of ribavirin dose reduction as the primary strategy for anemia management.”
Merck & Co. supported the research.