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    <recommendedItem id="20100101_19_277"
                     title="Liver Cell Culture System Might Test New HCV Drugs (CME/CE)"
                     score="0.003"
                     href="http://www.medpagetoday.com/InfectiousDisease/Hepatitis/tb/18133?impressionId=1265789727728"
                     
      &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_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=1265789727728"
                     
      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_19_3563"
                     title="AASLD: HCV Response Linked Strongly to Gene Variant (CME/CE)"
                     score="-0.005"
                     href="http://www.medpagetoday.com/MeetingCoverage/AASLD/tb/16829?impressionId=1265789727728"
                     
      &lt;p&gt;BOSTON  --  Additional analysis has confirmed that a polymorphism in an interferon-related gene is strongly associated with responses to standard treatments for hepatitis C virus (HCV) infection, a researcher said here.&lt;/p&gt;
&lt;p&gt;Not only is the so-called CC variant of the &lt;em&gt;IL28B&lt;/em&gt; gene associated with long-term responses to treatment with pegylated interferon (Pegasys, PEGIntron) and ribavirin (Rebetol), but it also predicts the speed of response, said Alexander J. Thompson, MD, of Duke University.&lt;/p&gt;
&lt;p&gt;Thompson was part of a group that, in August, reported online in &lt;em&gt;Nature&lt;/em&gt; that the CC genotype of &lt;em&gt;IL28B&lt;/em&gt;, which encodes the lambda-3 form of interferon, is associated with sustained suppression of HCV. (See &lt;a href=&quot;http://www.medpagetoday.com/InfectiousDisease/Hepatitis/15564&quot; mce_href=&quot;http://www.medpagetoday.com/InfectiousDisease/Hepatitis/15564&quot; target=&quot;_blank&quot;&gt;Gene Variant Predicts HCV Treatment Success&lt;/a&gt;)&lt;/p&gt;
&lt;p&gt;Speaking here at the American Association for the Study of Liver Diseases meeting, Thompson reported on further analyses of the group&apos;s data, focusing on virologic responses after four and 12 weeks, referred to as rapid and early responses, respectively.&lt;/p&gt;
&lt;p&gt;Thompson also provided additional insights into the effects on sustained responses, which were assessed 24 weeks after a 48-week treatment period with interferon and ribavirin.&lt;/p&gt;
&lt;p&gt;As in the &lt;em&gt;Nature&lt;/em&gt; report, the analysis used data on more than 1,600 participants in a clinical trial called IDEAL which compared the 2a and 2b forms of pegylated interferon in patients infected with HCV genotype 1. Genome-wide association studies were performed on tissue samples from these individuals, correlating their virologic responses to a large number of gene polymorphisms.&lt;/p&gt;
&lt;p&gt;As Thompson reported here, sustained virologic response rates in patients with the CC genotype of &lt;em&gt;IL28B&lt;/em&gt; were 69% in Caucasians, 48% in African-Americans, and 56% in Hispanics. For each group, these response rates were substantially higher than for two other genotypes, TC and TT.&lt;/p&gt;
&lt;p&gt;Those ranged from 27% to 33% in whites, 13% to 15% in blacks, and 27% to 38% in Hispanics.&lt;/p&gt;
&lt;p&gt;Overall, the adjusted odds ratio for sustained virologic response associated with CC versus the other genotypes was 5.2 (95% CI 4.1 to 6.7), the largest odds ratio of any pretreatment predictor.&lt;/p&gt;
&lt;p&gt;Other baseline factors predicting sustained response rates included viral loads, white or Hispanic versus black ethnicity, baseline liver fibrosis, and fasting blood sugar.&lt;/p&gt;
&lt;p&gt;Thompson said the &lt;em&gt;IL28B&lt;/em&gt; genotype explained about half the difference in sustained response rates between Caucasians and African-Americans  --  a difference that had been observed previously and which had never been adequately explained.&lt;/p&gt;
&lt;p&gt;He reported that CC-genotype patients also responded more quickly to treatment in each ethnic group, compared with the TC and TT genotypes. At treatment week two, whites with the CC variant already showed log&lt;sub&gt;10&lt;/sub&gt; reductions in viral loads of 2.5, whereas white patients with the other genotypes had not yet achieved one-log reductions.&lt;/p&gt;
&lt;p&gt;Differences were also apparent at weeks four and 12, Thompson said. However, the rate of decline in viral loads was about the same for all genotypes after week four.&lt;/p&gt;
&lt;p&gt;The same pattern was seen in African-Americans and Hispanics, he said.&lt;/p&gt;
&lt;p&gt;Another new finding was that the CC genotype predicted sustained responses in white patients who had not shown viral clearance by week four.&lt;/p&gt;
&lt;p&gt;Those patients were 86% of the sample. More than half had the TC genotype and another 13% had the TT variant. In contrast, those who did achieve rapid virologic responses were predominantly the CC genotype (77%).&lt;/p&gt;
&lt;p&gt;Nevertheless, in those not achieving rapid responses, 66% of those with the CC variant eventually obtained a sustained response, compared with 31% of TC and 24% of TT genotypes (&lt;em&gt;P&lt;/em&gt;&amp;lt;0.0001), Thompson said.&lt;/p&gt;
&lt;p&gt;Other researchers said the findings, when validated, would likely be practice-changing.&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, predicted that &lt;em&gt;IL28B&lt;/em&gt; genotype testing would become part of the standard of care once a test becomes clinically available.&lt;/p&gt;
&lt;p&gt;Schering-Plough, which sells pegylated interferon-alfa-2b (PEGIntron), owns commercial rights to develop the genotype test.&lt;/p&gt;
&lt;p&gt;A spokesman said the company was evaluating how best to bring it to market. He said Schering-Plough, which has little experience in developing or marketing diagnostic tests, was primarily interested in making it available as soon as possible.&lt;/p&gt;
&lt;p&gt;He said the company had discussed nonexclusive licensing arrangements with other firms with the relevant capabilities, but no decisions had been made.&lt;/p&gt;
&lt;p&gt;Friedman pointed out that, although genotype testing looked to be extremely useful in the short term, whether it would remain so when direct antiviral drugs for HCV become available  --  expected in the next several years  --  was unclear.&lt;/p&gt;
&lt;p&gt;Thompson agreed that the &lt;em&gt;IL28B&lt;/em&gt; polymorphism&apos;s effect on treatment response would have to be reevaluated for regimens including direct antivirals.&lt;/p&gt;
&lt;p&gt;Other research needs include studies of the polymorphism in patients with nongenotype 1 HCV and whether it predicts responses to personalized duration of therapy.&lt;/p&gt;
&lt;p&gt;In his presentation here, Thompson offered no new insights into the mechanism underlying the &lt;em&gt;IL28B&lt;/em&gt; polymorphism&apos;s effects on treatment responses, beyond what the &lt;em&gt;Nature&lt;/em&gt; paper had suggested  --  namely, that interferon-lambda-3 helps mediate innate control of HCV.&lt;/p&gt;
&lt;p&gt;This form of interferon appears to have its own unique receptor, but the downstream signalling path is believed to converge with that of interferon-alfa, the researchers said.&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 IDEAL study was funded by Schering-Plough.&lt;/p&gt;&lt;p&gt;Thompson reported no potential conflicts of interest other than the research funding. Several co-authors were employees of Schering-Plough. Others reported relationships with a large number of other firms including Roche, Gilead, Vertex, Globimmune, Human Genome Sciences, Boehringer Ingelheim, GlaxoSmithKline, Tibotec, Novartis, Pharmasset, Salix, Pfizer, and Bristol-Myers Squibb, among others.&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="