By Liz Highleyman

Since about half of all chronic hepatitis C patients who receive standard therapy consisting of pegylated interferon plus ribavirin do not achieve a cure, or sustained virological response (SVR), researchers have explored whether maintenance therapy with lower doses of pegylated interferon alone might help slow or halt liver disease progression even in individuals who do not clear the virus.

Investigators with the HALT-C trial reported their latest findings at the 43rd annual meeting of the European Association for the Study of the Liver (EASL) last week in Milan.

The primary analysis of the HALT-C trial, reported at the American Association for the Study of Liver Diseases (AASLD) annual meeting last fall, demonstrated that pegylated interferon maintenance therapy did not reduce complications of cirrhosis, hepatocellular carcinoma (HCC), need for liver transplantation, or mortality in patients with chronic hepatitis C and advanced fibrosis or compensated cirrhosis at baseline.

The analysis presented at EASL assessed the relationship between HCV viral suppression and clinical outcomes in 764 patients who failed to achieve SVR with standard-dose 180 mg/week pegylated interferon alfa-2a (Pegasys) plus ribavirin during the HALT-C lead-in phase. Among these patients, half (n = 378) were randomly assigned to receive pegylated interferon maintenance monotherapy at a reduced dose of 90 mcg/week, while the remainder (n = 386) received no further treatment for 3.5 years of follow-up.

Results

• During lead-in treatment, 56% of patients experienced less than a 2 log decline in HCV RNA from their pre-treatment baseline level.

• 23% had a greater than 4 log decline in HCV RNA or achieved undetectable viral load, but subsequently experienced viral breakthrough or relapse.

• After randomization, serum HCV RNA remained within 1 log of pre-treatment levels in 99% of control patients and 72% of those receiving interferon maintenance therapy.

• Only 34% of patients with a greater than 4 log decrease in HCV RNA during lead-in treatment sustained this degree of viral suppression while on maintenance therapy.

• Clinical outcomes (2-point increase in Child-Turcotte-Pugh score, ascites, hepatic encephalopathy, variceal hemorrhage, HCC, liver transplantation, or death) occurred in significantly fewer patients who experienced a profound decline in HCV RNA during the lead-in treatment phase.

• These clinical outcomes occurred in 20% of patients with HCV RNA declines of less than 2 logs, 23% of patients with declines of 2 to 4 logs, and 7% of patients with decreases greater than 4 logs during pegylated interferon maintenance therapy.

• Corresponding rates in the untreated control group were 20%, 13%, and 10%, respectively (P < 0.05).

• When HCV RNA continued to be suppressed by these same amounts, clinical outcomes occurred in 18%, 22%, and 12% of patients on maintenance therapy (p = NS).

• 45% of patients with repeatedly undetectable HCV RNA over 3.5 years while on pegylated interferon maintenance monotherapy achieved SVR.

Conclusion

Based on these findings, the HALT-C investigators concluded that, "A significant decline in clinical outcomes was observed in patients with chronic HCV and advanced fibrosis or cirrhosis who achieved a profound decline in HCV RNA (> 4 log and/or undetectable with subsequent breakthrough or relapse) with full-dose [pegylated interferon] and ribavirin whether or not they remained on maintenance therapy."

"Whether additional clinical benefit can be derived when profound HCV RNA suppression is maintained with [pegylated interferon] remains unproven," they added.

Hepatology Section, Virginia Commonwealth University Medical Center, Richmond, VA; Department Of Laboratory Medicine, University Of Washington, Seattle, WA; Division Of Gastroenterology And Liver Disease, University Of Southern California, Los Angeles, CA; Division Of Gastroenterology, University Of California - Irvine, Irvine, CA; Gastrointestinal Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA; Liver Center, University Of Massachusetts Medical School, Worcester, MA; Division Of Digestive and Liver Diseases, University Of Texas Southwestern Medical Center, Dallas, TX;
Department Of Health And Human Services, National Institute Of Diabetes and Digestive And Kidney Diseases, Bethesda, MD.

4/29/08

Reference
ML Shiffman, C Morishima, KL Lindsay, and others. Suppression of Serum HCV RNA Levels During Maintenance Peginterferon (PegIFN) Alfa-2a Therapy and Clinical Outcomes in the HALT-C Trial. 43rd annual meeting of the European Association for the Study of the Liver (EASL 2008). Milan, Italy. April 23-27, 2008.