SAN DIEGO — Dr. Mitchell Shiffman views therapy for hepatitis C as an accordion in which treatment with pegylated interferon and ribavirin is compressed for early responders and extended for slow responders.
“The single best predictor for sustained viral response is the time at which the patient becomes HCV RNA undetectable,” he said at a meeting on chronic liver disease sponsored by Scripps Clinic. “Time to response is everything.”
Clinicians are starting to modify the duration of therapy with pegylated interferon and ribavirin based on time to respond. Five published studies have examined extending therapy to 72 weeks in patients who are slow to respond. The best-designed study found that the sustained virologic response (SVR) in these patients was 52% by week 48 and 69% by week 72. Other studies have shown that rapid responders may not require therapy beyond 24 weeks (Hepatology 2006;43:954-60).
“So if you have a complete early virologic responder who is negative for disease at 12 weeks, then the optimal duration of therapy appears to be 48 weeks. On the other hand, if you [have] a rapid responder who is negative for disease at 4 weeks, you can compress that therapy down to 24 weeks in most of these patients, with minimal risk of relapse. The worst that can happen is that if you do have a relapse, you can re-treat for 48 weeks. We've done that on occasion,” said Dr. Shiffman, chief of the hepatology section at Virginia Commonwealth University, Richmond.
For patients who do not become virus negative until week 24, “you stretch out the duration of therapy to 72 weeks to limit relapse,” he said.
Among patients treated with pegylated interferon and ribavirin, those with a virologic response by week 4 are referred to as rapid virologic responders and have the highest SVR and the lowest rates of relapse. Because of that, a shorter period of treatment may suffice, Dr. Shiffman said.
Complete early virologic responders have a virologic response by week 12. “You would not expect this group to have as high a cure rate as the rapid responders,” he said.
Among slow responders, HCV becomes undetectable by week 24 and a log2 drop is reached by week 12. “Therefore, you continue therapy in these patients” and monitor viral load, he said. “It's important to differentiate the slow responder from the partial responder.”
Patients with a partial response also have a log2 drop by week 12, he said, “but then the virus does not continue to fall; it plateaus. … They never become virus negative. It is irrational to treat this patient beyond week 24.”
Recognizing response patterns enables clinicians to predict a patient's chances of achieving a virologic response. Among patients with genotype 1 disease, 15% achieve a virologic response by week 4, compared with 35% by week 12 and 15% by week 24 (J. Hepatol. 2005;43:453-71). The remainder has a null response (20%) or partial response (15%). The SVR rate is highest among those who achieve a virologic response by week 4 (91%), compared with those who achieve a virologic response by weeks 12 and 24 (66% and 45%, respectively).
“So if you have a patient who is slow to respond, they become virus negative at week 24, their chance of relapsing is higher than their chance of getting a sustained response,” Dr. Shiffman said.
Among patients with genotypes 2 and 3 disease, 66% achieve a virologic response by week 4, 31% achieve virologic response by week 12, and 3% are nonresponders (N. Engl. J. Med. 2007;357:124-34). The SVR rate is highest among those who achieve a virologic response by week 4 (90%), compared with those who achieve a virologic response by week 12 (49%).
Poor prognostic features that are correlated with a low SVR rate include African American race, body mass index of greater than 27 kg/m2, viral loads that exceed 400,000 IU/mL, and cirrhosis. “The reason this occurs is because these features are associated with slower responses,” Dr. Shiffman explained. “But if a patient with a poor prognostic factor achieves a rapid response, their cure rate is just as good as anybody else with a rapid response,” Dr. Shiffman said, citing data from a retrospective analysis of six studies that he and his associates conducted involving a total of 894 patients with HCV infection; the SVR rates were similar among patients who achieved a virologic response by week 4 “regardless of any of these poor prognostic factors” (75%, compared with 63% and 33% for those who achieved a virologic response by weeks 12 and 24, respectively).