Posted: 10-May-2006 << BACK
Reports from the 41st Annual Meeting of the European Association for the Study of the Liver, 26-30 April 2006, Vienna
Jenny Bryan, freelance medical writer
Sustained viral response means cure for hepatitis C patients.
Hepatitis C patients who have no sign of virus 24 weeks after completing treatment (sustained virological response, SVR) can be told they are cured, agreed leading liver specialists attending the recent annual congress of the European Association for the Study of the Liver (EASL), in Vienna, Austria.
Their conclusion follows presentation of new data from a five year follow up of over 1000 patients treated with interferon alfa-2b (Intron A), alone or in combination with ribavirin therapy. At five years, 97% of the 493 patients who had achieved an SVR remained free of hepatitis C. They continued to have no evidence of viral infection, or progression of liver disease.
Previous small studies have shown similar results. But this was the largest prospective follow up to show that patients were clinically and virologically free of hepatitis C at five years, so we are happy to use the term cure, commented Dr John McHutchison, medical director of the Duke Clinical Research Institute at Duke University, North Carolina, USA, and lead investigator of the study. Furthermore, this finding may help motivate hepatitis C patients to seek treatment and complete their prescribed regimen, he said.
One in seven genotype 1 patients can be cured by shorter course treatment.
Genotype 1 hepatitis C patients with low viral load (< 600,000) and undetectable virus by week 4 of peginterferon alfa-2b and ribavirin combination therapy (rapid virological response, RVR) only need a 24 week course of therapy to achieve an SVR, according to final results from a key study of 237 genotype 1 patients, presented at EASL.
Speaking at a satellite symposium sponsored by Schering-Plough, lead investigator of the study, Professor Stefan Zeuzem, head of internal medicine at the University Hospital Saarland, Homburg/Saar, Germany, reported that 89% of genotype 1, low viral load patients who had undetectable virus at week 4 went on to achieve an SVR with a 24 week course of treatment. This compared with 85% of rapid responders treated for the standard 48 weeks in previous studies.
Professor Zeuzem explained that one in three genotype 1 patients has a low viral load, and about 50% of these are so-called fast responders, ie: have undetectable hepatitis C virus (HCV) after four weeks of treatment. This means that about one in seven genotype 1 patients will benefit from the shorter, 24 week course of treatment. He added that patients undergoing shorter course treatment are less likely to discontinue therapy or require a dose reduction because of side effects than those who need 48 weeks of treatment.
He advised delegates to measure viral load twice before starting genotype 1 patients on anti-HCV treatment due to fluctuations in virus levels, in order to be sure that they fall into the category of low viral load patients who may be eligible for the shorter course of therapy. In the recent study, 18% of patients who had a low viral load during screening for the trial no longer fell into that category when their baseline measurement was carried out at entry to the study.
Can HCV non responders be responders?
Doctors treating hepatitis C patients should take a more positive approach to their hard-to-treat patients, and consider how best to tailor treatment to their needs. Speaking at the EASL-VIRGIL (Vigilance against Viral Resistance) joint meeting at the congress, Professor Christian Trepo, from INSERM U271, Lyon, France, urged delegates to broaden their treatment strategies and to consider prolonged courses of treatment for slow responders, and maintenance and re-treatment options for those who fail to clear HCV.
We are not using the right terms. If we tell patients that they are non-responders, they think they are finished. Non responders are partial responders and we must stop saying they are non responders, he said.
He pointed out that some patients can achieve a good biochemical response, with normalisation of liver transaminases, even if they cannot achieve a good virological response. He added that studies, such as the COPILOT (Colchicine versus PEG-INTRON Long-Term) study of low-dose maintenance therapy with peginterferon alfa-2b and the EPIC3 (Evaluation of PegIntron in Control of Hepatitis C Cirrhosis) retreatment and maintenance therapy studies, have demonstrated that it is never too late to treat. For example, in EPIC3, one in five refractory genotype 1 HCV patients achieved an SVR following retreatment with peginterferon alfa-2b and ribavirin for up to 48 weeks, and around half of genotype 2/3 patients.
Every patient should be given a chance, and we should go la carte in the way we treat them. Patients with cirrhosis should be offered maintenance treatment until new treatments come along, concluded Professor Trepo.
New study to show optimal time to treat acute hepatitis.
A multicentre German study is comparing the effects of immediate versus delayed therapy for acute hepatitis C. About half of the 150 patients acutely infected with hepatitis C who will take part in the study have been randomised to:
Immediate peginterferon alfa treatment alone for 24 weeks or
A 12 week wait to see if they spontaneously clear the virus, followed by peginterferon alfa+ribavirin for 24 weeks, if they remain infected
Professor Michael Manns, chairman of the Center for Internal Medicine at the University of Hannover, Germany, explained that eligible patients for the study include those with acute jaundice or needle stick injury who are found to be infected with hepatitis C. Results of an earlier study, published in February 2006*, showed that 70-90% of acute hepatitis C patients can be successfully treated with peginterferon alfa+ribavirin, so that they dont develop chronic disease. However, as Professor Manns explained, usual practice is to wait for 12 weeks to see if they clear the virus spontaneously. But if the new study shows that immediate treatment with peginterferon is as effective as delayed combination therapy, patients may prefer the better tolerated single drug regimen even though they may not need it than waiting to see if they must have the longer combination regimen which is likely to give them more side effects.
Results of the study are expected at the end of 2007.
* Wiegand J, Buggisch P, Boecher W et al. Early monotherapy with pegylated interferon alpha-2b for acute hepatitis C infection: the HEP-NET acute-HCV-II study. Hepatology 2006;43(2):250-6.
VISER1 shows mixed benefits for viramidine.
Viramidine, the new prodrug of ribavirin, under development by Valeant Pharmaceuticals, is significantly less likely to cause anaemia than ribavirin when administered in a flat-dosing schedule, but appears to be less effective at treating hepatitis C. Results of the phase III VISER1 (Viramidines Safety and Efficacy vs. Ribavirin) study in 970 treatment nave hepatitis C patients, show an anaemia rate of 5% in those treated with viramidine 600mg BID, compared to 24% (p<0.0001) in those treated with a weight-based 1000/1200 mg daily dose of ribavirin, both in combination with peginterferon alfa-2b.
But the overall ITT SVR rate for viramidine+peginterferon alfa-2b was 38% compared to 52% for the ribavirin combination.
Viramidine has been developed to target the liver, with minimal effects on red blood cells, and has a 3-6 fold higher liver:red blood cell ratio than ribavirin.
Presenting the results, Dr John McHutchison, medical director of the Duke Clinical Research Institute at Duke University, North Carolina, USA, suggested that, like ribavirin, viramidine may need to be dosed according to the weight of patients, and he pointed out that a significant proportion of US patients are obese (Body Mass Index>30). However, VISER2 a second phase III study in hepatitis C which is using peginterferon alfa-2a has the same flat dosing schedule for viramidine. Dr McHutchison estimated that about 25-30% of US hepatitis C patients are currently given erythropoietin (EPO) to combat anaemia something which approximately doubles the cost of their anti-viral treatment.
Is shorter duration of therapy better for genotype 2/3?
Genotype 2/3 patients who are treated with the combination of peginterferon alfa-2a and ribavirin do need the full 24 weeks of treatment, widely used in everyday practice. According to results of the ACCELERATE study, 76% of patients treated with the combination for 24 weeks achieved an SVR, compared with only 65% who had a shorter, 16 week course of treatment. The difference was attributed to an approximate two-fold increase in relapse in patients undergoing 16 weeks of treatment with peginterferon alfa-2a and ribavirin.
However, another study is underway to determine the optimal dose and duration of peginterferon alfa-2b and ribavirin therapy for hepatitis C genotype 2 and 3 patients.
More than 650 previously untreated patients are to take part in a comparison of 24 weeks treatment with peginterferon alfa-2b 1.5mg/kg/week+ribavirin 800-1200mg/day or peginterferon alfa-2b 1.0mg/kg/week+ribavirin 800-1200mg/day, or 16 weeks treatment with peginterferon alfa-2b 1.5mg/kg/week+ribavirin 800-1200mg/day.
The goal is to achieve better tolerability of hepatitis C treatment, without compromising virological response rates.
Genes predict risk of bridging fibrosis/cirrhosis in hepatitis C.
A 7 SNP (single nucleotide polymorphism) signature has been shown to predict hepatitis C patients who are most at risk of developing bridging fibrosis/cirrhosis. The genetic test, in development by Celera Diagnostics, was shown to be a better predictor than clinical risk factors (age, gender and daily alcohol intake). It was found to be 73% predictive of risk, compared with 53% for clinical factors.
Celera is proposing that the test, which uses 6 SNPs already in the public domain, and 1 SNP isolated by company researchers, should initially be used after liver biopsy to identify high risk patients with stage 0-1 disease, so that they can be treated to prevent progression.
If further studies confirm the accuracy of the test, it is proposed that it should be used before liver biopsy to identify high risk patients. Only those with negative tests would then need a liver biopsy to check that they had not been missed by the SNP test thus reducing biopsy rates. The test is currently being validated in non-Caucasian populations.
Good progress with novel anti-HCV agents.
Patient enrolment has been completed in the first part of the ongoing phase II trial of the novel HCV protease inhibitor, SCH 503034, in combination with peginterferon alfa-2b, in genotype 1 patients unresponsive to peginterferon and ribavirin combination therapy. The study has been expanded to include an 800mg TID treatment arm for SCH 505034 in combination with peginterferon alfa-2b for 24 weeks.
In phase I dose-ranging studies of SCH 503034 as monotherapy or in combination with peginterferon alfa-2b, four out of 10 patients in the 400mg TID combination group became HCV RNA negative during the 14 day treatment period, with virus levels returning to baseline following treatment. Mean maximum log10 reductions in HCV RNA were 2.4IU/ml and 2.9IU/ml for 200mg and 400mg SCH 503034 respectively.
Twenty four week data from a phase IIb study of the HCV polymerase inhibitor, valopicitabine, in non responders to peginterferon+ribavirin, have confirmed the significant reductions in viral load seen at an earlier 12 week datapoint. Mean reductions in HCV RNA at 24 weeks of around 3 log10 IU/ml were seen in patients treated with valopicitabine 800mg and peginterferon. Continuing follow-up will assess whether these viral responses at 24 weeks result in viral clearance and SVR.
HCV protease mutations seen in HIV/HCV coinfected patients.
Two out of 25 HIV/HCV coinfected patients undergoing anti-retroviral therapy including HIV protease inhibitor therapy have been found to have mutations in the NS3 protease domain that confer resistance to HCV protease inhibitor treatment.
Dr Sabrina Bagaglio, from the San Raffaele Scientific Institute in Milan, Italy, and co-workers, urge that management of HIV/HCV coinfected patients should take account of the effects of protease inhibitors against the two viruses.
