Retreatment and Long-Term Follow-Up of Nonresponders

By Liz Highleyman

Treatment with adequate doses of pegylated interferon plus ribavirin for an adequate length of time is crucial to ensure optimal response to hepatitis C therapy. Fortunately, patients who previously received suboptimal therapy may achieve sustained response with subsequent treatment attempts.

A study published in the July 2006 Journal of Viral Hepatitis found that more than half of patients who relapsed after 24-week treatment achieved sustained virological response (SVR) when retreated for 48 weeks.

The researchers conducted a randomized multinational study to determine whether 48 weeks of retreatment with pegylated interferon alpha-2a (Pegasys) plus ribavirin would produce sustained response in 64 chronic hepatitis C patients who previously relapsed after achieving end-of-treatment virological response with 24 weeks of Pegasys plus ribavirin in another trial. Standard doses were the same as those used in the 24-week treatment trial, although adjustments were permitted.

Results

After retreatment for 48 weeks plus a 24-week post-treatment follow-up period, 55% of patients achieved SVR.

The SVR rate for patients with genotype 1 HCV was 51%, compared with 63% for those with non-1 genotypes.

61% of patients achieved early virological response at week 12, and this was predictive of SVR.

The most frequently reported adverse events were fatigue (5%) and abdominal pain (3%).

Dosages of pegylated interferon were modified due to adverse events in 3% of patients and due to laboratory abnormalities in 23%. Corresponding rates of ribavirin dose reduction were 13% and 5%.

Conclusion

The authors concluded that a 48-week course of pegylated interferon plus ribavirin induces SVR in 55% of patients who relapsed during follow-up after 24 weeks of combination therapy. "Physicians should not hesitate to offer re-treatment to patients who relapse after an initial, 24-week course of combination therapy, or who have prematurely stopped treatment because, for example, of laboratory abnormalities," they recommended.

Are They Really Cured?

It remains unclear whether individuals who achieve SVR are truly "cured" of hepatitis C. Some research using ultrasensitive tests has shown that HCV genetic material remains in the body in miniscule amounts, but most studies have found that if viral load is undetectable 24 weeks after the completion of therapy (using standard tests), later relapse is rare.

A recent study published in the June 16, 2006 online edition of the American Journal of Gastroenterology, however, suggested that initial nonresponders to suboptimal therapy who achieve SVR following retreatment may still experience HCV reactivation with longer follow-up.

The researchers prospectively followed 97 chronic hepatitis C patients who had previously failed to respond to treatment with conventional interferon monotherapy. Conventional interferon produces poorer response rates than pegylated interferon, and combination therapy with ribavirin is superior to interferon monotherapy.

All patients achieved SVR 24 weeks after the completion of retreatment attempts using various combinations of conventional interferon plus ribavirin. Patients were followed for seven years, and HCV viral load was measured every six months.

Results

At the end of follow-up, 11 patients (11.3%) showed evidence of HCV rebound.

Late HCV relapse rates (for all HCV genotypes combined) varied with retreatment regimen:

- 0% for patients retreated with 3 MU interferon plus ribavirin for 48 weeks.
- 13% for those retreated with 5 MU interferon plus ribavirin for 48 weeks.
- 20% for those retreated with 3 MU interferon plus ribavirin for 24 weeks.
- 12% for those retreated with 3 MU interferon plus ribavirin for 24 weeks

The response rate was significantly greater when using the higher interferon dose for 48 weeks compared with the lower dose for 24 weeks, both overall (P = 0.005) and for patients with genotypes 1 or 4 (15% vs 3%; P = 0.03).

In patients with genotypes 2 or 3, the long-term virological response rate did not differ significantly across the different regimens.

Virological relapse occurred within two years after the completion of retreatment.

Conclusion

The authors concluded that, "Nonresponders to interferon monotherapy who achieve a sustained virologic response after retreatment with interferon plus ribavirin stand a discrete risk of HCV reactivation" within two years after completing therapy.

Combination therapy using pegylated interferon plus ribavirin is too new to have received such extensive follow-up. However, since it produces higher end-of-treatment and sustained virological response rates, it may well lead to higher long-term response rates as well.

7/11/06

References

C Berg, F L Goncales, D E Bernstein, and others. Re-treatment of Chronic Hepatitis C Patients After Relapse: Efficacy of Peginterferon-alpha-2a (40 kDa) and Ribavirin. Journal of Viral Hepatitis 13(7): 435-440. July 2006.

A Ciancio, A Smedile, C Giodanino, and others. Long-Term Follow-Up of Previous Hepatitis C Virus Positive Nonresponders to Interferon Monotherapy Successfully Retreated with Combination Therapy: Are They Really Cured? American Journal of Gastroenterology. June 16, 2006 [Epub ahead of print].