By Liz Highleyman

A substantial proportion of chronic hepatitis C patients -- especially those with HCV genotype 1 -- do not achieve a sustained response to standard interferon-based therapy, leading researchers to study tailored treatment utilizing higher drug doses and/or extended duration. Two such studies were reported at the recent 59th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2008) in San Francisco.

Prior Relapsers

In the first study, Stephan Kaiser and colleagues evaluated at 72-week re-treatment regimen in patients who relapsed after an earlier 48-week course of therapy. Relapse refers to individuals who achieve HCV RNA suppression during therapy, but experience viral rebound after completing treatment, and therefore do not achieve a sustained virological response (SVR), or continued undetectable viral load 24 weeks post-treatment.

As background, the researchers noted that 20%-30% of genotype 1 patients who receive standard therapy with pegylated interferon plus ribavirin for 48 weeks experience relapse, with the highest rates seen in partial or slow responders (those with HCV RNA >15 IU/mL at weeks 4 and 12, but at least a 2 log drop at week 12).

The present study included 107 chronic hepatitis C patients who experienced prior relapse after 48 weeks of treatment with pegylated interferon alfa-2a (Pegasys) or alfa-2b (PegIntron) plus ribavirin. Most (74%) were men, the average weight was 81 kg (about 179 lb), 81% had HCV genotype 1, and about 20% had advanced liver fibrosis or cirrhosis.

All patients were treated with 180 mcg/week Pegasys plus 1000-1200 mg/day weight-adjusted ribavirin for 72 weeks. Virological response was assessed at week 4 (rapid virological response or RVR; HCV RNA < 15 IU/mL), week 12 (early virological response or EVR; HCV RNA > 15 IU/mL at week 4 but at least a 2 log drop at week 12), week 24 (HCV RNA < 15 IU/mL), week 72 (end of treatment response or EOT, HCV RNA < 15 IU/mL), and week 96 (SVR; HCV RNA < 15 IU/mL 24 weeks after completing treatment).

Results

• The overall SVR rate was 51%.

• Overall, 27% of patients achieved RVR, of whom 97% went on to achieve SVR.

• 43% had HCV RNA < 15 IU/mL at week 12, of whom 93% achieved SVR.

• 92% had undetectable HCV RNA at week 24.

• 79% achieved an EOT response.

• Viral breakthrough during treatment occurred in 4 patients.

• The total relapse rate (during and after treatment) was 36%.

• 9 patients discontinued treatment prematurely, 6 of them due to adverse events or laboratory abnormalities.

• 16% of patients required a dose reduction of pegylated interferon and 21% reduced their doses of ribavirin.

Based on these findings, the researchers concluded, "A treatment duration of 72 weeks with peginterferon alfa-2a plus ribavirin in patients that had relapsed to previous therapy resulted in high SVR rate, particularly in those who were negative at weeks 4 and 12."
Therefore, they continued, "with 72 weeks of re-treatment, sustained virological response can be achieved in approximately half of patients that previously relapsed with 48 weeks of treatment."

REPEAT Analysis

As previously reported, the REPEAT study found that 72 weeks of treatment with Pegasys plus ribavirin was more effective than 48 weeks in more than 900 prior non-responders, with SVR rates of 16% and 8%, respectively.

However, these sustained response rates remain low, and interferon-based therapy is associated with potentially severe side effects. At AASLD, Patrick Marcellin and colleagues reported results from an analysis of the risk-benefit ratio of treating non-responders for 72 versus 48 weeks, comparing adverse event (AE) rates and outcomes for the 2 treatment durations.

A total of 942 REPEAT participants were randomly assigned to receive double-dose Pegasys (360 mcg/week) for 12 weeks, followed by 180 mcg/week for a total of either 72 weeks (Arm A) or 48 weeks (Arm B). Other arms received only the standard dose of 180 mcg/week for either 72 weeks (Arm C) or 48 weeks (Arm D). All received 1000-1200 mg/day weight-adjusted ribavirin.

The risk-benefit ratio of treatment was assessed by calculating AE incidence per case of SVR, and by calculating the number of total treatment days and treatment days with AEs per SVR.

Results

• 4047 on-treatment AEs were reported among 473 patients in the 72 week arms (A& C), compared with 3814 AEs among 469 patients in the 48-week arms (B & D).

• The total number of on-treatment AEs and cumulative treatment days with any AEs or serious AEs were slightly higher in patients randomized to receive treatment for 72 weeks versus 48 weeks.

• However, AE incidence per treatment year was lower for patients receiving 72 weeks of treatment (8.1 vs 10.1 AEs per year).

• This difference became more favorable for 72 weeks of treatment when the cumulative treatment duration required to achieve SVR (6.7 vs 10.0 years) and AE burden per SVR (55 vs 100 AEs) were taken into consideration.

"A treatment duration of 72 weeks compared with 48 weeks of [Pegasys] plus ribavirin did not impose a large additional adverse event burden on patients who were previous non-responders to [PegIntron] plus ribavirin undergoing retreatment with [Pegasys] plus ribavirin in REPEAT," the investigators concluded.

"When the significantly higher SVR rate is considered, extended treatment has a favorable risk: benefit ratio," they continued. "These data demonstrate that a 72-week regimen of [Pegasys] plus ribavirin is the preferred treatment duration for non-responders to previous [PegIntron]/ribavirin therapy."

11/25/08

References

S Kaiser, B Lutze, HG Hass,and others. High sustained virologic response rates in HCV genotype 1 relapser patients retreated with peginterferon alfa-2a (40KD) plus ribavirin for 72 weeks. 59th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2008). San Francisco. October 31-November 4, 2008. Abstract 1860.

P Marcellin, A Craxi, CE Brandao-Mello, and others. 1873. A 72-week treatment duration with peginterferon alfa-2a (40KD) (PEGASYS) plus ribavirin (COPEGUS) has a favorable risk:benefit ratio in non-responders to pegylated interferon alfa-2b (12KD) plus ribavirin: findings of the multinational REPEAT study. 59th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2008). San Francisco. October 31-November 4, 2008. Abstract 1873.