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    <recommendedItem id="20100101_19_277"
                     title="Liver Cell Culture System Might Test New HCV Drugs (CME/CE)"
                     score="0.002"
                     href="http://www.medpagetoday.com/InfectiousDisease/Hepatitis/tb/18133?impressionId=1265792240458"
                     
      &lt;p&gt;Researchers say they can now grow liver cells that maintain their functions long enough to test potential treatments for hepatitis C.&lt;/p&gt;
&lt;p&gt;The method uses so-called &quot;micropatterned co-cultures&quot; of primary human hepatocytes and supportive stroma, according to Sangeeta N. Bhatia, MD, PhD, of MIT, and colleagues.&lt;/p&gt;
&lt;p&gt;The co-cultures were able to support the entire life cycle of hepatitis C, including infection and replication, Bhatia and colleagues reported online in the &lt;em&gt;Proceedings of the National Academy of Sciences&lt;/em&gt;.&lt;/p&gt;
&lt;p&gt;Coupled with reporter systems, the co-cultures have &quot;potential as a high-throughput platform for simultaneous assessment of in vitro efficacy and toxicity&quot; of antiviral drugs, the researchers said.&lt;/p&gt;
&lt;p&gt;The lack of such a system has been a roadblock to testing potential treatments for the virus, which affects 130 million people around the world, the researchers noted in the journal.&lt;/p&gt;
&lt;p&gt;Recently, they added, researchers have been able to propagate the virus in human hepatoma cells, but those cells, among other issues, proliferate abnormally and have disturbed gene expression.&lt;/p&gt;
&lt;p&gt;To overcome those obstacles, the researchers turned to primary hepatocytes, which would make a better test system, except that they are notoriously hard to maintain in culture.&lt;/p&gt;
&lt;p&gt;To form the co-cultures, Bhatia and colleagues seeded multi-well plates with human hepatocytes, followed several hours later by murine fibroblasts.&lt;/p&gt;
&lt;p&gt;&quot;If you just put cells on a surface in an unorganized way, they lose their function very quickly,&quot; Bhatia said in a statement. &quot;If you specify which cells sit next to each other, you can extend the lifetime of the cells and help them maintain their function.&quot;&lt;/p&gt;
&lt;p&gt;In a series of experiments, Bhatia and colleagues found:&lt;ul&gt; &lt;li&gt;Pseudoparticles bearing the hepatitis C glycoproteins E1 and E2 were able to infect between 1% and 3% of the hepatocytes, but did not infect the fibroblasts.&lt;/li&gt; &lt;li&gt;A hepatitis C virus modified to express a fluorescent protein persistently replicated over a two-week period.&lt;/li&gt; &lt;li&gt;Infectious virus was found in the co-culture supernatant from four through 12 days after initial infection.&lt;/li&gt; &lt;/ul&gt;&lt;/p&gt;
&lt;p&gt;The researchers also tested some possible therapeutics, including antibodies against viral entry factors and viral protease inhibitors, and were able to show effects on replication of hepatitis C.&lt;/p&gt;
&lt;p&gt;They were also able to test two or more drugs simultaneously to show the feasibility of combination drug studies using the system.&lt;/p&gt;
&lt;p&gt;Although the system is &quot;an important step forward,&quot; Bhatia and colleagues said, the co-cultures have some limitations, including the relatively inefficient uptake of virus.&lt;/p&gt;
&lt;p&gt;But they concluded that the co-cultures have the potential to be a &quot;highly valuable system for studies of (hepatitis C) biology.&quot;&lt;/p&gt;
&lt;div style=&quot;float:left;border-style:solid;border-width:1px;border-color:#8dabbc;font-family:arial;font-size:12px;background-color:#DBE9F2;padding:5px;&quot;&gt;&lt;p&gt;This study had support from the Greenberg Medical Research Institute, the Ellison Medical Foundation, the Starr Foundation, the Ronald A. Shellow Memorial Fund, the Richard Salomon Family Foundation, and the NIH. The researchers said they had no conflicts.&lt;/p&gt;&lt;/div&gt;&lt;div style=&quot;clear:both;&quot;&gt;&lt;/div&gt;
    </recommendedItem>
    <recommendedItem id="20090101_19_3520"
                     title="AASLD: Once-Daily HCV Protease Inhibitors Show Early Promise (CME/CE)"
                     score="-0.005"
                     href="http://www.medpagetoday.com/MeetingCoverage/AASLD/tb/16766?impressionId=1265792240458"
                     
      BOSTON  --  Two investigational drugs targeting the hepatitis C virus (HCV) protease enzyme helped patients clear the virus with once-daily dosing, contrasting with the three-times-per-day schedule needed for similar drugs in development, researchers reported here in separate studies.&lt;br&gt;
&lt;br&gt;At least 85% of patients adding narlaprevir (formerly called SCH 900518) to pegylated interferon-alfa-2b (PEGIntron) and ribavirin (Rebetol) after four weeks achieved rapid virological responses, compared with no patients receiving only interferon and ribavirin, according John Vierling, MD, of Baylor College of Medicine in Houston.&lt;br&gt;
&lt;br&gt;Early virologic responses, defined as viral clearance after 12 weeks of treatment, also occurred in 85% to 87% of patients receiving narlaprevir after the interferon-ribavirin lead-in, versus 17% of patients in the control arm.&lt;br&gt;
&lt;br&gt;Comparable results were reported for another investigational compound, BI 201355, by Mark Sulkowski, MD, of Johns Hopkins University. The drug, also given once daily with interferon-ribavirin, led to HCV RNA becoming undetectable by week 12 in up to 90% of patients.&lt;p&gt;&lt;/p&gt;
&lt;p&gt;Vierling and Sulkowski reported interim results from ongoing Phase II trials of the two drugs here in a late-breaking abstract session at the American Association for the Study of Liver Disease&apos;s annual meeting.&lt;/p&gt;
&lt;p&gt;&lt;strong&gt;Narlaprevir&lt;/strong&gt;&lt;/p&gt;
&lt;p&gt;By itself, narlaprevir is eliminated rapidly from circulation, as are boceprevir and telaprevir, the HCV protease inhibitors farthest along in development (now in Phase III testing). Those drugs must be given three times daily. Vierling said the multiple dosing schedule is a source of compliance problems for HCV-infected patients.&lt;/p&gt;
&lt;p&gt;But co-administering narlaprevir with 100 mg of the anti-HIV drug ritonavir  --  one-twelfth the dose normally given to HIV patients  --  interferes with narlaprevir&apos;s metabolism by the CYP3A4 enzyme, prolonging its half-life enough that a single daily dose is feasible, Vierling said.&lt;/p&gt;
&lt;p&gt;In the current study, called NEXT-1, several permutations of the narlaprevir-ritonavir and interferon-ribavirin combinations are being tested.&lt;/p&gt;
&lt;p&gt;The study has enrolled 111 patients, all with HCV genotype 1.&lt;/p&gt;
&lt;p&gt;Three dose levels of narlaprevir (200 or 400 mg once daily or 100 mg twice daily), combined with 100 mg of ritonavir, were initiated simultaneously with pegylated interferon and ribavirin at standard doses.&lt;/p&gt;
&lt;p&gt;Two other treatment arms were established in which the two once-daily doses of narlaprevir plus ritonavir were started after patients had been on the interferon-ribavirin combination for four weeks.&lt;/p&gt;
&lt;p&gt;A sixth group took only interferon and ribavirin, which is the current standard of care for HCV antiviral treatment.&lt;/p&gt;
&lt;p&gt;In the five groups receiving narlaprevir, the drug was given for 12 weeks, with interferon and ribavirin continued for an additional 12 or 36 weeks, depending on patients&apos; virologic responses after the first four weeks of treatment.&lt;/p&gt;
&lt;p&gt;In the two arms involving delayed narlaprevir, virologic clearance within four weeks occurred in 85% to 87% of patients, Vierling reported.&lt;/p&gt;
&lt;p&gt;Starting narlaprevir and ritonavir simultaneously with interferon and ribavirin appeared to be a less successful strategy, with 58% to 75% of patients in those arms achieving rapid virologic responses.&lt;/p&gt;
&lt;p&gt;Vierling said that dosing narlaprevir twice daily actually reduced its efficacy, presumably because maximal plasma levels of the drug were about half those seen with the once-daily administration of higher doses.&lt;/p&gt;
&lt;p&gt;Mild to moderate anemia and mild neutropenia were the main adverse events that appeared to be related to the narlaprevir-ritonavir treatment. Vierling said no patients discontinued treatment because of anemia, and the neutropenia had no clinical consequences.&lt;/p&gt;
&lt;p&gt;Dizziness was also seen more often with narlaprevir, but also was relatively mild, Vierling said.&lt;/p&gt;
&lt;p&gt;Other adverse effects, such as fatigue, nausea, headache, and skin rashes occurred in the control arm and with narlaprevir.&lt;/p&gt;
&lt;p&gt;&lt;strong&gt;BI 201355&lt;/strong&gt;&lt;/p&gt;
&lt;p&gt;The other once-daily protease inhibitor described here, BI 201355, does not require co-administration of another agent to keep it active for a full day.&lt;/p&gt;
&lt;p&gt;Sulkowski reported that the drug led to rapid virological responses in most patients, with 62% to 77% showing viral clearance within four weeks of starting the drug.&lt;/p&gt;
&lt;p&gt;Unlike narlaprevir, however, a four-week lead-in with interferon and ribavirin did not boost BI 201355&apos;s effectiveness. The highest response rates at weeks four and 12 were seen with 240 mg of the drug started simultaneously with interferon-ribavirin, at 77% and 90%, respectively.&lt;/p&gt;
&lt;p&gt;Response rates among patients receiving the same dosage of BI 201355 with the four-week lead-in were 62% and 80%, respectively.&lt;/p&gt;
&lt;p&gt;Approximately 450 patients took part in the four-arm trial, which also included a control group receiving only interferon and ribavirin. Viral clearance after four and 12 weeks in the control group was seen in 4.2% and 42% of patients, respectively, significantly lower than in the groups taking BI 201355 (&lt;em&gt;P&lt;/em&gt;&amp;lt;0.05).&lt;/p&gt;
&lt;p&gt;As in the NEXT-1 trial, all patients had HCV genotype 1.&lt;/p&gt;
&lt;p&gt;Sulkowski said skin rashes were the chief adverse effects of concern with the drug. Most cases were mild and patients were able to stay on the drug. But 27% to 33% of patients in the higher-dose BI 201355 groups developed rashes, compared with about 13% of the control group.&lt;/p&gt;
&lt;p&gt;Jaundice was also seen in up to 20% of patients treated with BI 201355. Less than 2% of the control patients developed the condition.&lt;/p&gt;
&lt;p&gt;Scott Friedman, MD, of Mount Sinai School of Medicine in New York City, who was not involved in the study, said he was skeptical about the need for once-daily dosing in HCV infected patients.&lt;/p&gt;
&lt;p&gt;He said his experience is that most patients understand the importance of keeping to their dosing schedules.&lt;/p&gt;
&lt;p&gt;&quot;The patients I see, they get it,&quot; Friedman said.&lt;/p&gt;
&lt;p&gt;But he added that compliance may be more of a problem with new patients, compared with those who have been on therapy for a while.&lt;/p&gt;
&lt;div style=&quot;float:left;border-style:solid;border-width:1px;border-color:#8dabbc;font-family:arial;font-size:12px;background-color:#DBE9F2;padding:5px;&quot;&gt;&lt;p&gt;The narlaprevir study was funded by Schering-Plough.&lt;/p&gt;&lt;p&gt;The BI 201355 study was funded by Boehringer Ingelheim.&lt;/p&gt;&lt;p&gt;Vierling reported relationships with Schering-Plough, Abbott, Bristol-Myers Squibb, Gilead, Roche, Salix, Vertex, Hepa-Life Technologies, Arbios Systems, Axcan, Indenix, Novartis, Wyeth, GlobeImmune, Zymogenetics, Ocera, Intercept, Conatus, Pharmasset, and Pfizer.&lt;/p&gt;&lt;p&gt;Several co-authors were employees of Schering-Plough.&lt;/p&gt;&lt;p&gt;Sulkowski reported relationships with Boehringer Ingelheim, Roche, Schering, Merck, Human Genome Sciences, Gilead, Vertex, Tibotec, Bristol-Myers Squibb, Pfizer, Medarex, Peregrine, Debiopharm, and Abbott. Several co-authors were employees of Boehringer Ingelheim.&lt;/p&gt;&lt;p&gt;Friedman reported relationships with Exalenz, sanofi-aventis, Axcan, Angion, Intercept, 7TM, Stromedix, and Celera.&lt;/p&gt;&lt;/div&gt;&lt;div style=&quot;clear:both;&quot;&gt;&lt;/div&gt;
    </recommendedItem>
    <recommendedItem id="20090101_19_3555"
                     title="AASLD: Direct Antivirals Can Beat HCV Without Interferon (CME/CE)"
                     score="-0.005"
                     href="http://www.medpagetoday.com/MeetingCoverage/AASLD/tb/16818?impressionId=1265792240458"
                     
      BOSTON  --  The first clinical trial of direct antiviral drugs against hepatitis C virus (HCV) without interferon was a success, researchers said, although the FDA currently won&apos;t permit such a strategy in the U.S.&lt;br&gt;
&lt;br&gt;A combination of two investigational antivirals, one an HCV protease inhibitor and the other targeting the HCV polymerase, led to dramatic reductions in viral loads during a 13-day pilot trial, according to Edward Gane, MD, of Auckland Clinical Studies in Auckland, New Zealand, where the study took place.&lt;br&gt;
&lt;br&gt;The drugs&apos; lead developer, Roche, announced that Phase II testing would begin in early 2010. But for now, the studies must be conducted outside the U.S. because of an FDA policy requiring HCV drug testing to include interferon-alfa.&lt;/p&gt;
&lt;p&gt;Along with ribavirin (Rebetol), interferon is the only agent currently proved to control HCV infection. The FDA believes it is unethical to withhold it from infected patients, though researchers close to the situation said Roche was talking with the agency about relaxing its stance.&lt;/p&gt;
&lt;p&gt;Gane, speaking here at the American Association for the Study of Liver Diseases&apos; annual meeting, reported data from a placebo-controlled Phase Ib trial called INFORM-1, testing various dosing regimens of two oral drugs co-developed by Roche and two other companies.&lt;/p&gt;
&lt;p&gt;The drugs were RG7128, a nucleoside agent inhibiting the HCV polymerase enzyme, and RG7227, a small-molecule compound that inhibits the virus&apos;s protease enzyme.&lt;/p&gt;
&lt;p&gt;Gane said the combination was attractive for several reasons. The differing targets and mechanisms discourage development of resistance, and in vitro studies confirmed that RG7128 suppressed emergence of resistance to the protease inhibitor.&lt;/p&gt;
&lt;p&gt;There is no cross-resistance between molecules, he added, and the drugs have different routes of elimination and no signs of pharmacokinetic interaction or overlapping toxicities.&lt;/p&gt;
&lt;p&gt;The clinical study encompassed seven treatment arms, four of which involved RG7128 given twice daily and RG7227 three times daily in treatment-naive patients. Gane reported results from those regimens earlier this year at a European liver disease meeting.&lt;/p&gt;
&lt;p&gt;He focused his presentation here on the other three treatment arms, in which both drugs were given twice daily and the 30 patients involved included people who had previously shown incomplete (partial or relapsing) or null responses to standard treatment with interferon and ribavirin as well as previously untreated patients.&lt;/p&gt;
&lt;p&gt;Eight patients in each group received active drugs for 13 days, and two received placebo pills. The RG7128 dose was 1,000 mg twice daily in all groups. RG7227 was given at 600 mg twice daily to the incomplete initial responders, while those with null responses or who were treatment-naive received 900 mg twice daily.&lt;/p&gt;
&lt;p&gt;Median reductions in HCV viral loads from baseline, measured in log&lt;sub&gt;10&lt;/sub&gt; increments on day 13, were as follows: &lt;ul&gt; &lt;li&gt;Incomplete initial responders: 4.0 (range 2.5 to 6.0)&lt;/li&gt; &lt;li&gt;Null initial responders: 4.9 (range 3.5 to 5.3)&lt;/li&gt; &lt;li&gt;Treatment-naive: 5.1 (range 3.0 to 5.9)&lt;/li&gt; &lt;/ul&gt;&lt;/p&gt;
&lt;p&gt;Gane said half of the previously-treated patients in both groups had viral loads suppressed below the lower limit of quantification. This level of virologic response was seen in seven of eight treatment-naive patients.&lt;/p&gt;
&lt;p&gt;HCV RNA was undetectable in five treatment-naive patients, two of the null responders, and one of the partial responders.&lt;/p&gt;
&lt;p&gt;Gane said there was no evidence of resistance to the drugs in any of the seven INFORM-1 treatment groups. Adverse effects did not appear to differ between placebo and the active drug, although the study was not powered to detect differences. No severe adverse events were noted, Gane said.&lt;/p&gt;
&lt;p&gt;Scott Friedman, MD, president of AASLD and a hepatologist at Mount Sinai School of Medicine in New York City, said the prospect of an interferon-free, all-oral drug regimen for HCV was intriguing.&lt;/p&gt;
&lt;p&gt;&quot;Interferon is a nasty drug,&quot; he said, adding that patients with advanced disease often can&apos;t tolerate it.&lt;/p&gt;
&lt;p&gt;On the other hand, Friedman said, there is some chance that treatment based solely on direct antiviral drugs could provoke resistance to those agents  --  resistance that would not develop if interferon were also given.&lt;/p&gt;
&lt;p&gt;That outcome could leave patients worse off, even taking the toxicities of interferon into account, he suggested.&lt;/p&gt;
&lt;div style=&quot;float:left;border-style:solid;border-width:1px;border-color:#8dabbc;font-family:arial;font-size:12px;background-color:#DBE9F2;padding:5px;&quot;&gt;&lt;p&gt;The study was funded by Roche, Pharmasset, and InterMune.&lt;/p&gt;&lt;p&gt;Gane reported no potential conflicts of interest other than the research funding. Several co-authors were employees of Roche, Pharmasset, or InterMune.&lt;/p&gt;&lt;p&gt;Friedman reported relationships with Exalenz, sanofi-aventis, Axcan, Angion, Intercept, 7TM, Stromedix, and Celera.&lt;/p&gt;&lt;/div&gt;&lt;div style=&quot;clear:both;&quot;&gt;&lt;/div&gt;
    </recommendedItem>
    <recommendedItem id="20090101_1_454"
                     title="Livers Under Wrap: AASLD 2005"
                     score="-0.005"
                     href="