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EASL Prague Special Conference on Therapy of Hepatitis C: Clinical Application and Drug Development Sept 14-16
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Download the PDF here: Full EASL Prague Report
Reported by Jules Levin
Excerpts from report:
Professor Wedemeyer said that clinicians have a responsibility to use current and upcoming treatments in a responsible way, making best use of limited resources to help patients. "In the end, what counts is not treatment efficacy but effectiveness at a population level. This means identifying patients to be treated, helping patients to understand the need for treatment and good adherence, educating primary care physicians about how to reduce the condition and advocating at a political level to ensure we have the resources in all countries to cure HCV."
IDUs - Healthcare-associated transmission is the major route of HCV in less economically developed countries, with one of the major risks being re-use of needles and syringes by medical practitioners and blood transfusions also being a common cause of infection. This results in very high HCV prevalence in many developing countries. "We need to improve healthcare practices to reduce this burden,"
from Jules: Well-Designed Screening Programs LINKING HCV+ IDUs to Care is NEEDED with rapid HCV testing, by strong patient navigators, strongly defined support services, education to increase the numbers of strong clinical care providers as being done now with weekly webcast/telemedicine in the NY Check Hep C Program, a 1-year $2 mill demonstration project doing 5,000 rapid HCV tests.
If all countries used screening alongside the deployment of new treatments, hepatitis C could be halved, according to a modeling study in six European countries reported by Sylvie Deuffic-Burban, INSERM, Lille, France. She concluded that new treatments that can reduce transmission of HCV and therefore reduce the burden of HCV disease might save costs
in the long-term.
HIV-HCV co-infected patients - even in the HAART era - show faster
progression to cirrhosis and increased liver-related mortality compared to HCV patients without HIV, warned Professor Juergen Rockstroh, University of Bonn, Germany. "Unfortunately, only about 25% of coinfected patients in European cohorts and 11% of the VA cohort in the US
ever receive HCV treatment," he reported. "There is a tremendous need to
improve treatment in this challenging patient population."
"HCV infection is curable...Sustained virologic response in HCV translates into both short and long-term benefits, according to the longest follow-up study yet to assess treatment......Results
showed that 94% of patients maintained a virological response and
markers of liver disease improved over time. Only three patients relapsed, giving a 10-year relapse rate of 5.7%.
"Both boceprevir and telaprevir have dramatically improved SVR compared
to interferon/ribavirin," he told the meeting. The ADVANCE study showed a marked improvement in SVR adding telaprevir compared to control (75% vs 44%) and SPRINT-2 showed a 28% increase in SVR adding boceprevir to IFN+RBV. He suggested that all HCV patients are potential candidates for triple therapy but careful monitoring is needed in those with advanced fibrosis who are more at risk for treatment-related adverse events. What is the frequency and severity of HCV therapy side-effects in real life clinical practice? Dr. Christophe Hezode, Hopital Henri Mondor, Creteil, France, warned that the safety record of triple therapy is poor but this has to be balanced against its good virologic response. "The majority of patients should be treated, but cautiously," he suggested. Particular care is needed in patients with high-risk complications, including cirrhosis
- with the French real-life CUPIC study of teleprevir in patients with HCV and cirrhosis showing severe adverse events in 48.6% of patients. He noted that life-threatening complications such as severe infection are not uncommon in patients with advanced cirrhosis and that 2-3% of this highly selected cohort died during treatment.
New HCV drugs in development
Combinations including NS5A inhibitors appear likely to address many of the current unmet medical needs in HCV, especially for patients who remain difficult to treat with currently available therapies, including those with cirrhosis and patients undergoing liver transplant, according to Dr. Stanislas Pol, Hopital Cochin, France. Reviewing the data with daclatasovir, the first agent in the class, he said it is very potent, has broad genotypic coverage and has a pharmacokinetic profile supportive of once daily dosing, making it easy to take. A recent study with quadruple therapy including daclatasovir, asapravir and peg-interferon/ ribavirin has shown 'fantastic results,' he said, with SVR4 of 90-100% in a difficult to treat group of genotype 1 null responders. Moreover, NS5A
inhibitors are part of many IFN-free treatment regimens.
Newer NS3/4A protease inhibitors in combination with peg-IFN and ribavirin achieve high rates of SVR with simpler dosing schedules and generally better tolerability than older agents, according to Dr. Michael Fried, University of North Carolina, USA. He said that two years of clinical experience with the currently available PIs have shown that ribavirin is required for achieving SVR, rapid virological response is associated with highest SVR and adverse events can generally be managed but that certain populations are less responsive. New PIs in development include simeprevir and faldeprevir (phase 3) and asuneprevir and ABT-450/r (phase 2), mostly with peg-INF + RBV backbone. Trials so far show
encouragingly high rates of SVR and generally good tolerability, but we have to wait for more data, he concluded.
"It's becoming clear that nucleoside/nucleotide analogues provide a very strong backbone for future HCV therapies," argued Dr. David Nelson, University of Florida, USA. They work by causing premature chain termination during viral nucleic acid synthesis. The active binding site in the target - NS5B RNA-dependent RNA polymerase - is highly conserved across HCV genotypes, conferring pangenotypic activity and there is a high barrier to resistance. Three agents are currently in development: sofosbuvir (phase 3), mericitabine (phase 2) and ALS-2200 (phase 2), while some others have been put on hold due to toxicity. "Sofosbuvir (previously GS-7977) will be the most important compound during the next 2-4 years," predicted Professor Wedemeyer. He noted that sofosbuvir therapy was successful in various IFN-free regimens and may also help to shorten IFNa-based therapies. "However, we have learned over the last few months that there will be no 'one-size-fits-all' regimen with sofosbuvir."
Non-nucleoside inhibitors of HCV RNA polymerase have no role in monotherapy and limited role in triple therapy, but they may be useful in quadruple therapy, suggested Dr. Paul Pockros, La Jolla, USA. Reviewing
the available data, he noted that these agents have low to moderate potency, a low barrier to resistance and are unlikely to have crossgenotype activity. "Of the 13 non-nucleoside inhibitors in development in 2008, a lot have given disappointing results, with only six remaining," he said. Of these, Vx-222 is the most potent, achieving a 3.4 log10 reduction in viral load (at a dose of 400mg bid) and is currently in phase 2. However, some compounds may still be used in IFN-free treatment regimens if combined with other highly potent DAAs.
Cyclophilin inhibitors offer the benefits of a high barrier to resistance and no cross-resistance with protease or polymerase inhibitors, Professor Robert Flisiak, Medical University of Bialystok, Poland, told the meeting. They act on NS5A, NS5B and NS2 HCV viral proteins, as well as preventing HCV-mediated mitochondrial and endogenous interferon production. Alisporivir - the most advanced agent in the class - has shown effects in treatment naïve, previous non-responders and in HIV/HCV coinfected patients. It has demonstrated antiviral efficacy against the four most prevalent genotypes (1,2,3 and 4). It is effective in interferon-free regimens, as well as providing additional antiviral effects in combination with peg-interferon plus ribavirin, and is well tolerated. However, it is currently on hold due to toxicity in combination with PEG-IFNa. Future trials may therefore focus on IFN-free regimens including alisporivir.
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