Retreatment of Nonresponders & Relapsers and Maintenance Therapy
Reported by Jules Levin
HALT-C Study Preliminary Results: non-responders
Mitch Shiffman presented long preliminary results from the HALT-C study (Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis Trial) at the just completed AASLD liver conference in Boston Nov 1-5, 2002. The results from the lead-in phase of this study are reported here.
The aim of this study is to determine if maintenance therapy with low dose Pegasys (pegylated interferon a-2a) can prevent fibrosis progression and hepatic decompensation in patients who failed to achieve a sustained virologic response following treatment with peginterferon and ribavirin. The results from the maintenance therapy phase are not available yet.
The purpose of the lead-in phase of the study: non-responders to either interferon or interferon and ribavirin were treated with peginterferon a-2a and ribavirin. And to determine the efficacy of Pegasys retreatment in previous non-responders.
In the lead-in phase patients received Pegasys 180 mcg/week plus ribavirin 1000-1200 mg/day. The patientıs responses are evaluated at week 20 and week 72 (6 months after stopping 48 weeks therapy) and are reported below. Patients who are responders to therapy at wek 20 are treated for 48 weeks and evaluated at week 72 for sustained response. After the lead-in phase patients who were HCV RNA negative continued treatment and are followed for up to 72 weeks for sustained viral response (SVR) or relapse. Patients who are HCV RNA positive receive 90 mcg/week without ribavirin as maintenance therapy.
To qualify for this study patients had to have bridging fibrosis or cirrhosis, and Ishak score of 3 or more; and non-response to interferon or interferon plus ribavirin. Exclusionary criteria for study: HIV-infected patients; hemoglobin <12 gm/dl; platelet count <70,000/cc; Child-Pugh score of 7 or more; previous complication of cirrhosis: variceal hemorrhage, ascites, hepatic encephalopoathy; active alcohol or substance abuse; advanced non-hepatic chronic disease.
Patient characteristics before the study:
Average age: 50; 72% male; 80% Caucasion, 6% Hispanic, 12 Black; 63% had prior interferon plus ribavirin; ALT: 124; HCV RNA 4.96 million IU/ml; 90% have genotype 1; 42% have cirrhosis; white blood cell count 5,700/uL; platelet count 161,000 u/L.
LEAD-IN PHASE VIROLOGIC RESPONSE
Overall 37% of patients were HCV RNA negative at week 20; 33% were negative at week 48; and 18% were negative at week 72.
--Drop-outs: 5% (16/293) of patients dropped out before week 20
--Breakthroughs: 9% (11/107) of patients who were HCV RNA negative at week 20 became positive before week 48
--Relapsers: 45% (44/97) of patients who were HCV RNA positive at week 48 became positive after therapy was stopped. In the PegIbtron study reported below the relapse rate was also high showing nonresponders appear to have high relapse rates if the achieve end-of-treatment responses to undetectable.
Virologic Response By Prior Treatment: interferon alone or IFN+RBV
Interferon monotherapy prior treatment (n=108): 44% of these patients were HCV RNA negative at the end of 48 weeks re-treatment with Pegasys/ribavirin and 30% had a sustained viral response (SVR) at week 72 (31% relapsed).
Interferon + ribavirin combination therapy prior treatment (n=185): 30% were HCV RNA negative at the end of 48 weeks treatment, and 11% had a sustained response.
As you can see the relapse rates were high, particularly in prior nonresponders to combination therapy (63% relapsed).
Viral Response By Baseline Viral Load: viral load matters
Patients with <1.5 million IU/ml (n-42) had better viral responses than patients with >1.5 million IU/ml).
Patients with <1.5 million: 33% were HCV RNA negative at end of treatment and 31% had an SVR; they were able to maintain their response, low relapse rate.
Patients with >1.5 million had a high relapse rate: 24% were HCV RNA negative at the end of treatment but only 6% had a sustained viral response (80% relapse rate).
Viral Response By Genotype
Patients with genotype 2/3 (n=29) had a better response than genotype 1 patients.
Genotype 1: 29% were HCV RNA negative at the end of treatment and 14% were sustained responders.
Genotype 2/3: 72% had undetectable viral load at the end of treatment and 52% had a sustained response.
Viral Response By Race and Ethnicity
Caucasians (n=235): 37% had an end of treatment response (EOT), 20% SVR
Hispanics (n=18): 22% had EOT, 17% had SVR. Pretty good response for Hispanics. They have not been studied much. And it is difficult to study this group because of genetic and ethnic variability.
African-Americans (n=35): 14% had EOT, 6% had SVR
Viral Response Based on Early 12 Week HCV RNA is Predictive
59% (n=160) of patients were HCV RNA negative at week 12, and 32% had an SVR. 2% (n=133) of patients who were not HCV RNA negative had an SVR.
Effect of Dose Reduction on Sustained Viral Response
A dose reduction in ribavirin reduces response and interferon reduction did not reduce response, but reducing dose of both drugs has more effect in reducing response.
Patients with no dose reductions (n=118): 39% EOT, 23% SVR
Interferon only dose reduction (n=70): 37% EOT, 23% SVR
Ribavirin dose reduction (n=36): 25% EOT, 11% SVR
Dose reductions in both drugs (n=59): 20% EOT, 8% SVR
Effect of Average Dose During First 20 Weeks on SVR
Patients unable to achieve an SVR had a lower average ribavirin dose (1082 mg/day vs 962 mg/day, p<0.05) during the 20-week period. But regarding interferon, patients not able to achieve an SVR had the same average interferon dose as responders during the 20 week period. Again suggesting that reducing the ribavirin dose but not interferon dose affected ability to achieve SVR. But perhaps more importantly suggesting that maintaining full ribavirin dose during the first 20 weeks of therapy may be important to achieving a sustained response. Using EPO to address anemia due to ribavirin appears to help maintain ribavirin dose. Dose reduction in ribavirin during the first 20 weeks may impair the ability to achieve an SVR.
Summary and Conclusions by Authors
Patients with advanced fibrosis/cirrhosis who failed previous interferon therapy, with or without ribavirin, can be successfully re-treated with peginterferon a-2a and ribavirin.
Sustained viral response was observed in only:
--18% of all non-responders (14% genotype 1, 52% genotype 2/3)
--11% if previously treated with interferon/ribavirin combination therapy
--6% if high viral load (>1.5 million IU/ml)
--less than 2% of patients had sustained response if they did not have early 12 week response
--SVR declined significantly when dose of ribavirin but not peginterferon was reduced
--it is not unreasonable to re-treat previous non-responders with Pegasys and ribavirin
--those patients with the greatest likelihood of response to re-treatment include: genotype 2/3, previous treatment with interferon monotherapy, low levels of HCV RNA viral load, patients with early 12 week response
--when re-treating patients with peginterferon and ribavirin, efforts should be made not to lower the dose of ribavirin, particularly during the first 12 weeks of therapy.
Ira Jacobson reported results from his study of PegIntron plus ribavirin in patients with hepatitis C who were prior non-responders to interferon monotherapy or combination therapy and in combination therapy relapsers. Here is a sampling of his findings with more details to follow.
Genotype 1 combination non-responders: PegIntron 1.5 mcg/week plus 800 mg/day ribavirin (group 1: n=102), 9% of patients had an SVR; PegIntron 1.0 mcg/week plus ribavirin 1000-1200 mg/day (group 2: n=96), 5% of patients had an SVR
Genotype 2/3: for these patients the number of evaluable patients was too small but genotype 2/3 appear to have better response.
Treatment breakthrough and relapse was high occurring in about 40% of patients.
There were several studies presented at AALD suggesting ways to improve response rates in non-responders and hard to treat patients, but these were pilot studies and the approaches are relatively experimental. The RENEW study gave patients double the dose of PegIntron and found better preliminary viral responses but we donıt have data yet following patients after stopping therapy. Data from this study is in the AASLD Conference report section on the NATAP website. Another experimental approach was suggested by a study presented at the Viral Hepatitis Workshop and the data is on the website in the Conference Reports section. They found better responses by using interferon for a day and then starting peginterferon on the second day. The theory is to achieve better viral response in first day by using standard interferon. They used Consensus Interferon in this study. There are no other studies I know of on this subject so it has not really been explored yet. Perhaps some combination of daily interferon up front plus peginterferon might increase response rates in hard to treat patients including non-responders.