Info: HCV Genotypes & Treatments

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HCV Genotypes and TreatmentNov 16 2011This summary is a collection of data from the latest medical news, clinical trial information, news articles, Web searches, and links to other related sources on the Web relating to the recent November 2011 liver meeting-AASLD.What Is a Genotype? Have you ever had a key copied and found that the new key did not work very well or did not work at all? If so, then you know that even a small difference can be very important. Although the keys may look the same, may be made from the same material, and have the same function, the shape of the new key may not match up as well with the keyhole.In much the same way, small genetic differences between viruses can make them very

different or only slightly different. In the case of hepatitis C, these differences can influence the way the virus responds to treatment.The hepatitis C virus has 6 major known types (called genotypes). Each type is assigned a number from 1 to 6. Different types are common in different parts of the world. For example, types 1, 2, and 3 are the most common types in North America and Western Europe, Australia, and the Far East. In the United States, type 1 accounts for most cases ofhepatitis C.Molecular differences between genotypes are relatively large, and they have a difference of at least 30% at the nucleotide level. The major HCV genotype worldwide is genotype 1, which accounts for 40-80% of all isolates. Genotype 1 also may be associated with more severe liver disease and a higher risk of HCC. Genotypes 1a and 1b are

prevalent in the United States, whereas in other countries, genotype 1a is less frequent. HCV genotype 1, particularly 1b, does not respond to therapy as well as genotypes 2 and 3. Genotype details are as follows:

Genotype 1a occurs in 50-60% of patients in the United States; this type is difficult to eradicate using current medications Genotype 1b occurs in 15-20% of patients in the United States; subtype 1b is also difficult to eradicate using current medications; this type is most prevalent in Europe, Turkey, and Japan Genotype 1c occurs in less than 1% of patients in the United States Genotypes 2a, 2b, and 2c occur in 10-15% of patients in the United States; these subtypes are widely distributed and are most responsive to medication Genotypes 3a and 3b occur in 4-6% of patients in the United States; these subtypes are most prevalent in India, Pakistan, Thailand, Australia, and Scotland Genotype 4 occurs in less than 5% of patients in the United States; it is most prevalent in the Middle East and Africa Genotype 5 occurs in less than 5% of patients in the United States; it is most prevalent in South Africa Genotype 6 occurs in less than 5% of patients in the United States; it is most prevalent in Southeast Asia, particularly Hong Kong and Macao SourceStandard TherapyYour genotype is important because it influences your treatment plan and response to therapy, Only your doctor can tell you how your genotype relates to your treatment, but generally when treating with standard therapy people with genotypes 1 and 4 require 48 weeks of treatment, and people with genotypes 2 and 3 need only 24 weeks of treatment. Genotype 1 has a lower cure rate than other HCV genotypes using the current standard treatment for chronic hepatitis C of 48 weeks Peg-IFN plus RBV. As evaluated by sustained virologic response (SVR [undetectable serum HCV RNA 24 weeks after end-of-treatment]), 48 weeks of Peg-IFN/RBV therapy

results in a SVR in only about 50% of treatment-naive patients with genotype 1 chronic hepatitis C, compared with 70% to 80% of patients with genotypes 2 and 3. FDA approved direct-acting antiviral agents The good news is that In May the first two direct-acting antiviral agents to treat hepatitis C- Boceprevir and Telaprevir were FDA approved, increasing SVR and cutting treatment duration in most genotype 1 patients. Both drugs are used with peginterferon and ribavirin. Telaprevir -Genotype 1 ShorterTreatment DurationAccording to a recent study the treatment duration of peginterferon and ribavirin can be cut in half—from 48 weeks to 24—following 12 weeks of treatment with telaprevir in patients with chronic hepatitis C virus (HCV) genotype 1 infection who have an extended rapid

virologic response (eRVR). E. Sherman, MD, PhD, professor of medicine, University of Cincinnati, and colleagues reported their findings in the Sept. 15 issue of The New England Journal of Medicine (365:1014-1024). Read more here.Telaprevir and Boceprevir SVR Rates Compared To Standard TherpayIncreased SVR in genotype 1 patients with the addition of Telaprevir or Boceprevir .In genotype 1 patients Telaprevir Pegylated interferon + ribavirin alone = 44% SVRWith the addition of telaprevir = 69-75% SVR Boceprevir Pegylated interferon + ribavirin alone = 38% SVRWith the addition of boceprevir = 63-66% SVR Triple therapy for HCV geno1: telaprevir or boceprevir?February 2012The duration of protease inhibitor administration and the treatment paradigm are no doubt more streamlined with telaprevir. All patients begin telaprevir and PEG-IFN/RBV at the onset of treatment, receive 12 weeks of telaprevir and either 24 or 48 weeks of PEG-IFN/RBV. In contrast, the initiation of boceprevir is delayed by 4 weeks and is administered for 24, 32 or 44 weeks, whereas PEG-IFN/RBV IL combination is administered for 28, 32 or 48 weeks respectively. In contrast, boceprevir may have a somewhat more tolerable adverse event profile. Both agents exacerbate the anaemia of PEG-IFN/RBV to a similar extent. However, telaprevir is associated with a rash in over 50% of patients and several gastrointestinal symptoms..Read more...For Patients That Have Treated Previously In clinical trials the SVR in patients who have treated previously with telaprevir was at 65% and for boceprevir 66%. Although before Merck presented new data at this months liver meeting (AASLD) the trials with boceprevir did not include null responders. Vertex’s phase III REALIZE trial did test telaprevir in null responders, which produced a 31% SVR

rate.The new data presented at the 2011 November liver meeting from Merck showed that in an interim analysis, 38 per cent (16/42) of prior null responders achieved a sustained virologic response (SVR), meaning they were able to clear the virus from the body ,when treated with boceprevir in combination with peginterferon alfa and ribavirin.View Press ReleaseOther factors that contribute to decreased SVR rates in both the new drugs and standard Peg-IFN/RBV treatment, include IL28B genotype ( IL28B for the new drugs -(in Clinical trials) , high baseline HCV RNA levels, cirrhosis or bridging fibrosis, and black or Latino

ethnicity.More on IL28B genotypeIL28B is a gene related to the interferon system. A genetic region near the IL28B gene is referred to as an IL28B genotype.There are three variations of IL28B genotypes: CC, CT or TT. People with the two copies of the C allele of the gene respond best to treatment, while those with two copies of the T allele are most resistant. Those with one copy of each allele fall in the middle.To learn more see;Hey, I have a question about this IL28B gene and hepatitis c treatment.........These variations have been associated with a person's response to treatment for hepatitis C with pegylated-interferon and ribavirin.The CC

variation is more frequent in Caucasians compared to African Americans (39 percent versus 16 percent), which may partially explain the lower response to treatment observed among African Americans in most clinical trials of pegylated-interferon and ribavirin. A genetic factor: a single nucleotide polymorphism in the IL28b gene that has been shown to reduce the response to therapy, and may also cut the rate of spontaneous clearanceThe IL28B polymorphism is the strongest pretreatment predictor of sustained virologic response in patients with HCV genotype 1. Personalized HCV treatment regimens based on pretreatment factors such as IL28B or on-treatment response may improve the efficacy and tolerability of treatment.Re-treatment options with standard therapy There are no effective re-treatment options with standard

therapy . Patients who do not achieve a viral cure after treatment with 48 weeks of Peg-IFN/RBV therapy. Re-treatment with an additional 48 weeks of Peg-IFN/RBV results in SVR in only 5% to 20% of patients. Consequently.Again, the recently FDA Approved Direct-acting antivirals, such as telaprevir or boceprevir, have proven effective for patients who do not respond to first-line pegylated interferon alfa-ribavirin therapy or who relapse after the standard treatment.New Study TelaprevirIn October of 2011 Vertex announced a Phase 3b study called CONCISE that will evaluate the potential for treatment with INCIVEK- (telaprevir) combination therapy to be shortened to 12 weeks in people with genotype 1 chronic hepatitis C who have the 'CC' variation near the IL28B gene.

The study is expected to enroll 350 people in the United States and Europe who are new to treatment or who have relapsed after at least one prior course of treatment with pegylated-interferon and ribavirin alone. The primary endpoint of the study is the proportion of patients who achieve a sustained viral response 12 weeks after the last planned dose of study drug (SVR12). Click here for more information. Triple Therapy-Investigational inhibitors in combination with (SOC) peginterferon alfa 2a and ribavirinNaive genotype 1 PILLAR Phase 2b Study-TMC435/ Peginterferon alpha-2a/ribavirin

PILLAR, a phase 2b study of the investigational hepatitis C virus (HCV) NS3/4A protease inhibitor TMC435 in treatment-naive patients with chronic genotype 1 HCVWithin each TMC435 dosing group, patients were randomly assigned to get 12 or 24 weeks of the drug.In an intention-to-treat analysis, the researchers found:

82% of patients in the 12-week, 75-mg arm had undetectable hepatitis C RNA after 24 weeks. In the 150-mg dosing group, 81% in the 12-week arm and 86% in the 24-week arm reached the same endpoint. The differences from placebo were significant at P less then 0.005, P=0.013, and P less then 0.001, respectively.Interestingly, the 75% response in the 24-week, 75-mg arm was not significantly different from the "unexpectedly high" 65% response rate among the placebo patients, Fried said.A key finding was that between 79% and 86% of the patients receiving the drug qualified for shortened 24-week therapy, "which I think is quite beneficial," Fried said. Of those, he said, between 85% and 96% had undetectable hepatitis C RNA at week 24.Click Here for more information. InterMune / Genentech-Danoprevir(RG7227)- PEG IFN alfa-2a/RBV naïve genotype 1ATLAS StudyATLAS was a dose-ranging study of the NS3/4A protease inhibitor danoprevir when added to a background regimen of

pegylated interferon alfa-2a and ribavirin (PEG IFN alfa-2a/RBV) in treatment-naïve, noncirrhotic patients with hepatitis C virus (HCV) genotype 1.Patients were randomised to receive danoprevir 300 mg every 8 hours, danoprevir 600 mg every 12 hours, danoprevir 900 mg every 12 hours, or placebo for 12 weeks.All patients were continued on PEG IFN/RBV for an additional 12 weeks. Patients who did not achieve an early rapid virologic response (eRVR) and undetectable viral load (HCV RNA less then 15 IU/mL) between weeks 4 and 20 continued to receive PEG IFN alfa-2a/RBV through week 48. The highest dose arm of the study (danoprevir 900 mg) "was discontinued prematurely due to the development of ALT [alanine aminotransferase] elevations [grade 4] early in the course of the study," said Norah A. Terrault, MD, University of California at San Francisco, San Francisco, California. The elevations resolved upon

discontinuation. Patients who had started on danoprevir 900 mg were continued on PEG IFN alfa-2a/RBV, while those who had been randomised to it but not yet started were rerandomised to the remaining arms of the study. "Among those patients receiving danoprevir who had an extended RVR, the sustained virologic response rates were 87% to 96%," said Dr. Terrault. The highest rate of response was seen in the 600-mg arm, in part because only a portion of the higher dose group completed the full 12-week regimen prior to that dosage being discontinued. Overall response rates, as measured by undetectable HCV RNA, were high across all IL28B genotypes: 81% to 95% in those with the CC allele, 63% to 79% in the non-CC alleles. Response was better in patients with HCV genotype 1b (67%-93%) compared with genotype 1a (57%-79%). For complete article click hereAchillion Pharmaceuticals -ACH-1625/peginterferon alfa-2a/ribavirinACH-1625, is a once-daily NS3 protease inhibitorInterim results The majority of the 64 patients enrolled were HCV genotype 1a (73%), with a smaller percentage of HCV genotype 1b patients (25%). A total of 75% of the patients enrolled were genotype CT/TT, a marker of the patient's diminished response to interferon, and 25% were genotype CC. All patients receiving 4 weeks of treatment with ACH-1625 demonstrated continuous and substantial declines in HCV RNA with no viral breakthrough during therapy at any of the doses. Preliminary results for the 64 patients enrolled demonstrate RVR percent and viral load reduction as follows:Week 4 RVR Subjects with HCV RNA

Less Then 25 IU/mLACH-1625200 mg QD N=16 - 13/16 (81%)400 mg QD N=16 - 12/16 (75%)800 mg QD N=17 - 13/17 (76%)Placebo . N=15 - 3/15 (20%)Mean maximum HCV RNA decline through Week 4 (log10)ACH-1625200 mg QD N=16 - 13/16 4.90400 mg QD N=16 - 12/16 4.63800 mg QD N=17 - 13/17 4.96Placebo . N=15 - 3/15 2.25Genotype 1 treatment-naïve patients demonstrated that the number of patients who achieved an RVR (4-week HCV RNA undetectable) was 55 to 61% higher in the groups that received ACH-1625 compared to placebo.Click here for Abstract Boehringer Ingelheim -BI 201335, pegylated interferon/ribavirin in treatment-naïve genotype-1 The results from SILEN-C3 indicate that among

patients achieving an extended rapid viral response (eRVR), 12 weeks of treatment with BI 201335 was sufficient to achieve SVR. Patients with undetectable HCV RNA in the blood prior to week 12 had similar SVR rates, whether they were treated for 12 or 24 weeks with BI 201335 (82% and 81%, respectively).1In addition to the SILEN-C3 study, the overall analysis of the SILEN-C1 study shows that 83.1% of patients treated with BI201335 240 mg QD achieved SVR, compared with 56.3% of patients on PegIFN/RBV alone (p less then 0.0001). The majority of patients with difficult to treat HCV subtypes, such as patients with the viral GT1a or the IL-28B non-CC gene variant (polymorphism), achieved SVR:

Specifically, among patients with GT1a HCV (n=32), a virus type that is more likely to resist treatment than GT1b, 82% achieved SVR, while for GT1b HCV patients (n=38), 84% achieved SVR In addition, SVR was 71% for patients with the non-CC polymorphism of the IL-28B gene (n=29). While patients with the CC polymorphism (n=11) achieved 100% SVR and those where IL-28B genotyping was missing (n=31) achieved 86% SVR. Patients exhibiting the non-CC polymorphism are less likely to achieve SVR with PegIFN/RBV treatment2GT1 HCV is the most challenging genotype of HCV to treat3 and those carrying the IL-28B non-CC polymorphism are less likely to achieve SVR than those with the CC polymorphism, with some studies showing an almost seven fold difference in treatment response.View complete information - Press Release PSI-7977-with peginterferon alfa 2a and ribavirin -Naive Genotype 1 PSI-7977 plus

interferon/ribavirin shows "a rapid and complete suppression in 95% of patients," said PROTON lead investigator Lawitz, MD, from Alamo Medical Research in San , Texas. Nov 2011- Excerpt From MedscapePSI-7977, a uridine nucleotide analog polymerase inhibitor that is administered once daily with or without food, has previously shown activity in a broad range of HCV patient genotypes. There have been no drug-related viral breakthroughs reported to date, demonstrating a high barrier to resistance.Results showed a dramatic improvement with the triple drug combination, compared with placebo."The rapid viral response for the 200 mg dose was 98%, with an end-of- treatment response at 24 weeks of 91%," reported Dr. Lawitz. The same response rate was seen with the 400 mg dose. In the placebo group, the rapid viral response

was 19%, and end-of-treatment response was 50%. The reported sustained viral response at 12 weeks was 88% for the 200 mg group, 91% for the 400 mg group, and roughly 40% for the placebo group (an estimate because observation is ongoing).Significantly, a subanalysis of patients with the difficult-to-treat IL28B T/T mutation (n = 13) showed that "all had a rapid response and all became HCV-negative by week 3," said Dr. Lawitz.These cohorts went on to achieve a 100% sustained viral response.Read full article hereSeptember 6, 2011 More On The PROTON TrialPharmasset Announces 91% SVR12 From the PROTON Trial in Subjects With Hepatitis C Genotype 1 - Intent to-treat SVR12 of 91% (43 of 47) following a 24-week treatment regimen incorporating 12 weeks of PSI-7977

400 mg QD PRINCETON, N.J., Sept. 6, 2011 /PRNewswire/ -- Pharmasset, Inc., announced today sustained virologic response (SVR) results from its phase 2b PROTON study with PSI-7977 400 mg dosed once daily in combination with peginterferon alfa 2a and ribavirin (Peg-IFN/RBV) in subjects with hepatitis C virus (HCV) genotype 1 who have not been treated previously. 43 out of 44 (98%) evaluable subjects achieved an SVR12, defined as HCV RNA below the limit of detection (<15 IU/mL) 12 weeks after the completion of treatment. All enrolled subjects will be followed to determine SVR24, the primary efficacy endpoint of the study.Ninety five treatment-naive patients with HCV genotype 1 were enrolled into two open-label arms of the PROTON trial, receiving either PSI-7977 200 mg QD (N=48) or 400 mg QD (N=47) for 12 weeks. Individuals in both arms received Peg-IFN/RBV for 24 weeks and were followed post-treatment to assess SVR12. Twenty-six subjects

were enrolled in a placebo control arm and are receiving 48 weeks of Peg-IFN/RBV. Results from this study through the SVR12 endpoint are scheduled to be presented as part of a Presidential Plenary Session at the American Association for the Study of Liver Diseases (AASLD) meeting on Tuesday, November 8, 2011."I am very pleased with the results of this study which clearly demonstrate the benefit of the 400 mg dose of PSI-7977 with only 24 weeks of interferon for all subjects," stated Dr. Lawitz, the study's principal investigator. "HCV therapy is becoming overly complex, and the elimination of 24 weeks of interferon and ribavirin as well as all response guided criteria for patients with HCV genotype 1 would be a welcomed simplification." At the European Association for the Study of the Liver (EASL) in April 2011, Dr. presented interim results from the PROTON trial showing that 43 out of 47 subjects receiving the 400 mg

dose of PSI-7977 achieved an eRVR, defined as HCV RNA below the limit of detection (<15 IU/ml) at week 4 through week 12. Of those not achieving eRVR, 3 discontinued therapy early due to unrelated adverse events and 1 was lost to follow-up, as previously reported. Notably, one of these individuals went on to achieve an SVR12 in spite of the shortened course of therapy. The combination of PSI-7977, pegylated interferon and ribavirin was generally safe and well tolerated.Naive, genotype 1 and 4Bristol-Myers Squibb Daclatasvir (BMS-790052) peginterferon alfa/ribavirin in naive, genotype 1 and 4COMMAND-1 Phase IIb clinical trial - In this study 395 treatment-naive, genotype 1 and 4 hepatitis C infected patients in which two doses of the investigational NS5A replication complex inhibitor daclatasvir (BMS-790052), in combination with

peginterferon alfa and ribavirin (alfa/RBV), achieved higher virologic response rates through Week 12 than the alfa/RBV control group, with comparable rates of adverse events.Interim results - Genotype 1Of the 365 patients with HCV genotype 1 in the study, 54% in each of the daclatasvir dose groups (20 mg and 60 mg) achieved eRVR vs. 14% in the control group.The proportion of HCV genotype 1 patients with undetectable viral load at Week 12 was 78% (115/147) and 75% (110/146) in the daclatasvir 20 mg and 60 mg groups, respectively, compared with 43% (31/72) in the control groupInterim results - Genotype 4Of the 30 patients with HCV genotype 4, undetectable viral load at Week 12 was achieved in 58% (7/12) and 100% (12/12) of patients in the daclatasvir 20 mg and 60 mg groups, respectively, compared with 50% (3/6) of patients in the control group. View Press ReleasePharmasset - PSI-7977 genotype 1, 4, 5 or 6 who have not been treated previouslyPharmasset Initiates Phase 2b ATOMIC Trial of PSI-7977 for Multiple HCV GenotypesMarch 30, 2011 /PRNewswire/ -- Pharmasset, Inc. (Nasdaq: VRUS) announced today that screening has begun in a Phase 2b study of PSI-7977, a nucleotide analog polymerase inhibitor for the treatment of chronic hepatitis C (HCV). "The trial will evaluate PSI-7977 400mg QD with pegylated interferon and ribavirin in patients with HCV genotype 1, 4, 5 or 6 who have not been treated previously.""We are encouraged by the early efficacy and safety

data being generated with our nucleotide analogs, PSI-7977 and PSI-938," stated Berrey, MD, MPH, Pharmasset's Chief Medical Officer. "The ATOMIC trial is designed to explore 12 and 24 week durations of PSI-7977. The potency, high barrier to resistance, and consistent antiviral activity across genotypes provided the data to support an interferon free dosing period in this trial, as well as enabling us to enroll multiple genotypes in this trial." About the Phase 2b ATOMIC Trial This Phase 2b trial is planned to enroll approximately 300 patients with chronic HCV genotype 1 who have not been treated previously. The primary endpoint of the trial will be the safety and tolerability of PSI-7977 in combination with peginterferon and ribavirin over 12 or 24 weeks. The trial will be conducted in the U.S. Patients will be randomized (1:2:3) into the following arms: PSI-7977 400mg QD with peginterferon and ribavirin for 12

weeks;PSI-7977 400mg QD with peginterferon and ribavirin for 24 weeks;PSI-7977 400mg QD with peginterferon and ribavirin for 12 weeks, followed by either PSI-7977 400mg QD monotherapy for 12 weeks or PSI-7977 400mg QD plus ribavirin for 12 weeks.HCV GT1 patients will be stratified by IL28B status and baseline HCV RNA to ensure balance across cohorts. An additional 25 treatment-naïve patients with HCV genotype 4, 5, 6 or indeterminate genotype, will receive PSI-7977 400mg QD with peginterferon and ribavirin for 24 weeks. Additional details on this and all Pharmasset trials can be found at http://www.clinicaltrials.gov/View Press ReleaseInvestigational all-oral

regimensThe Nov 2011 liver meeting-AASLD brought us updated data on future interferon free therapies which could be available in the near future. Below is a glance at some of the Investigational all-oral regimens, additional data on these agents presented at this months meeting is available here.Interferon-Free For ALL Genotypes September 13, 2011 QUANTUM TRIALPharmasset Initiates QUANTUM, a Phase 2b Interferon-Free Trial of PSI-7977 and PSI-938 for All HCV Genotypes PRINCETON, N.J., Sept. 13, 2011 /PRNewswire/ -- Pharmasset, Inc. announced today that screening has begun in a Phase 2b, international study

of PSI-7977 and PSI-938, two nucleotide analog polymerase inhibitors for the treatment of chronic hepatitis C (HCV). The QUANTUM trial will evaluate interferon-free regimens of PSI-7977 400mg QD and PSI-938 300mg QD with and without ribavirin over 12 or 24 weeks in patients with HCV who have not been treated previously. The trial will also evaluate the use of PSI-938 monotherapy."We are encouraged by the early efficacy and safety data being generated with our nucleotide analogs, PSI-7977 and PSI-938," stated Berrey, MD, MPH, Pharmasset's Chief Medical Officer. "The QUANTUM trial is the first interferon-free, all-nucleotide study with an SVR endpoint. The ability to include all HCV genotypes was supported by data from the NUCLEAR study and the interferon free arms of the ELECTRON trial. Data from ELECTRON are expected later this

year."About the Phase 2b QUANTUM Trial This study is designed to enroll approximately 450 patients with chronic HCV of all viral genotypes who have not been treated previously. The primary endpoint of the trial will be sustained virological response (SVR24). Patients will be equally randomized across the following arms:

PSI-938 only PSI-938 and PSI-7977 PSI-7977 and ribavirin PSI-938, PSI-7977, and ribavirinAll arms will be study for both 12 and 24 weeks with a placebo control of 24 weeks.

Placebo for 24 weeksHCV patients will be stratified by IL28B status and baseline HCV RNA to ensure balance across cohorts. Cirrhotic and non-cirrhotic patients will be enrolled in the study.Additional details on this and all ongoing Pharmasset sponsored trials can be found at www.clinicaltrials.gov.The DATAInterferon Free Therapies- Genotype 2/3AASLD-Pharmasset - PSI-7977 UpdateTwelve Weeks Interferon-Free PSI-7977 Regimen Cures 100 Percent Hep C Genotype 2/3A twelve-week course of Pharmasset’s once-daily experimental nucleotide analog PSI-7977, combined with ribavirin, cured 10 of 10 people living with genotype 2/3

hepatitis C virus (HCV) who used the regimen—without pegylated interferon—in a Phase II clinical trial. The highly encouraging results were reported Sunday, November 6, at the 62nd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD) in San Francisco.....For more information click here. Pharmasset - Clinical trials in 2011-2012Pharmasset Announces the Initiation of an Interferon-Free Phase 3 Program with PSI-7977 for HCVThe first trial, FISSION, will enroll approximately 500 treatment-naive patients with HCV genotype 2 or 3, and will evaluate the safety and efficacy of a 12-week interferon-free regimen

of PSI-7977 and ribavirin compared to 24 weeks of pegylated interferon and ribavirin. The primary endpoint of the study is sustained virologic response 12 weeks after the completion of treatment (SVR12). Pharmasset plans to initiate a second 12-week duration, interferon-free Phase 3 trial, POSITRON, in early 2012. This trial will enroll approximately 225 patients with HCV genotype 2 or 3 who cannot take interferon.In mid-2012, Pharmasset intends to initiate a third 12-week duration, interferon-free Phase 3 trial, NEUTRINO. This trial will enroll patients who cannot take interferon, and will include patients with HCV regardless of viral genotype, including those with HCV genotype 1. The final study design will be based on emerging data from ELECTRON and from PSI-7977 plus RBV-containing arms in the ongoing QUANTUM study."Based on encouraging results to

date, we have selected an IFN-free regimen of PSI-7977/RBV for our registrational program," said Berrey, MD, MPH, Pharmasset's Chief Medical Officer. "We continue to believe that interferon remains the greatest impediment to care for a majority of the millions of individuals living with HCV. PSI-7977 has demonstrated high cure rates, without viral resistance, and across HCV genotypes; we hope to confirm these benefits in these registrational studies." About FISSON FISSION will be conducted at more than 100 centers in the US, Europe and other territories. The trial will enroll approximately 500 treatment-naive patients with HCV genotype 2 or 3 into one of two open-label regimens:

PSI-7977 400 mg QD with ribavirin for 12 weeks the current standard-of-care for HCV GT2/3, pegylated interferon and ribavirin for 24 weeksThe study will include patients with and without cirrhosis, and will enroll a greater proportion of patients with HCV genotype 3, who are less likely to achieve an SVR with the currently available therapy, pegylated interferon and ribavirin. The primary endpoint of the trial will be SVR12. Enrollment is anticipated to begin by the end of 2011.About POSITRONPOSITRON will be conducted at more than 100 centers in the US, Europe and other territories. The trial will enroll patients with HCV genotype 2 or 3 who cannot take interferon into one of two blinded regimens:

PSI-7977 400 mg QD with ribavirin for 12 weeks placebo PSI-7977 and placebo ribavirinPOSITRON will enroll approximately 225 patients with or without cirrhosis. The primary endpoint of the trial will be SVR12. Enrollment is anticipated to begin in the first quarter of 2012.About NEUTRINONEUTRINO will enroll approximately 280 patients who cannot take interferon. The study will be conducted at more than 100 centers in the US, Europe and other territories. The final design of the trial will be based on emerging data from ongoing studies, including ELECTRON and QUANTUM. We anticipate the study will enroll patients with HCV regardless of viral genotype, and including those with HCV GT1. Enrollment is anticipated to begin in mid-2012.Pharmasset anticipates submitting data from all three phase 3 trials in the second half of 2013 to support the marketing approval of PSI-7977

in the US and European Union.Read More HereOctober 10, 2011 Pharmasset Announces Further Expansion of ELECTRON Trial in Hepatitis C**Added PSI-7977 monotherapy arm in treatment-naive patients with HCV GT1**Added PSI-7977/RBV arm in treatment experienced patients with HCV GT2/3**Modified previously-announced treatment regimen in HCV GT1 prior null responders to explore IFN-free regimen of PSI-7977/RBVAlisporivir-DEB025- Naive Genotype 2 and 3AASLD-Novartis’ alisporivir may become first interferon-free oral for hepatitis C G2/G3 The international, multicenter, open-label study led by Dr Pawlotsky and colleagues included 334 G2/3 patients (ratio 3:7) who had not been treated previously for HCV infection. They were randomized to five treatment arms:• alisporivir 1,000mg daily monotherapy (ALV1000) (n=82),• alisporivir 600mg daily plus ribavirin ® (ALV600R) ( n=84],• alisporivir 800mg daily plus R (ALV800R) (n=94),• alisporivir 600mg daily plus pegylated interferon (P) (ALV+P) (n=39), or• P plus R (P+R) (n=35).In week one, all alisporivir-treated patients received ALV 600mg twice daily. Patients receiving alisporivir as IFN-free treatment who achieved undetectable HCVRNA (<25 IU/mL) at week four remained on initial treatment,

while those with detectable HCVRNA had add-on IFN and continued with ALV+PR triple therapy from week six to week 24.Dr Pawlotsky reported a greater than 3 log reduction in mean HCV-RNA levels over the first four weeks of treatment with alisporivir-based IFN-free therapy. Also, rapid virologic responses (RVRs) were achieved by 28%, 37% and 42% of patients in the AlV1000, ALV600R and ALV800R groups, respectively. RVR patients on IFN-free treatment maintained responses to week 12, with minimal incidence of viral rebound.From week four to six, the proportion of patients with undetectable HCV RNA with alisporivir-based, IFN-free therapy increased further to 32%, 49% and 46% in the AlV1000, ALV600R and ALV800R groups, respectively.The proportion of patients with undetectable HCV-RNA levels was higher with alisporivir plus R than with alisporivir monotherapy. The RVR rate was about 60% higher for patients with lower

baseline HCV RNA (less then 800,000 IU/mL) than for the overall group. However, for those alisporivir patients who did not achieve RVR by week four, add-on IFN as triple therapy (alisporivir 600mg daily plus PR plus IFN) from week six resulted in rapid HCV clearance with more than 90% of patients having undetectable HCV-RNA levels at week 12.Click here to read press release.Daclatasvir (BMS-790052) and asunaprevir (BMS-650032) in HCV genotype 1b patients who had previously not responded to peginterferon alfa and ribavirinAASLD-All-Oral Regimen of daclatasvir (BMS-790052) and (BMS-650032) 90% SVR at 12wks Nov 8

2011Bristol-Myers Squibb Company today announced results from a ten patient sentinel cohort of an ongoing Phase II study in which treatment with a dual, all-oral direct-acting antiviral (DAA) regimen of the investigational NS5A replication complex inhibitor daclatasvir (BMS-790052) and the investigational NS3 protease inhibitor asunaprevir (BMS-650032) achieved undetectable viral load at 12 weeks post-treatment (SVR12) in 90% (n=9/10) of genotype 1b hepatitis C (HCV) patients who had previously not responded to peginterferon alfa and ribavirin (alfa/RBV).Read more hereBoehringer Ingelheim- BI 201335 plus BI 207127-with and without ribavirin in genotype 1 naïve patients.Phase IIb study/SOUND-C2-combination of two oral direct acting anti hepatitis C virus compounds (the protease

inhibitor BI 201335 and the polymerase inhibitor BI 207127, with and without ribavirin in genotype 1 naïve patients.Interferon-free combination of BI 201335 plus BI 207127 and ribavirin shows up to 76% of patients achieve a virological response at week 12, and 59% achieve SVR12 with 16 weeks treatment View Press ReleaseVIDEO-Hepatitis C : Protease Inhibitor BI 201335, Polymerase Inhibitor BI 207127 and RibavirinMerck MK-5172 second-generation NS3 protease inhibitor Monotherapy-Genotype 1 and 3MK-5172, a second-generation NS3 protease inhibitor from Merck Sharpe & Dohme, was administered in several

doses, by itself (monotherapy), for seven days. MK-5172 was designed to have activity against strains of HCV that are resistant to the first-generation HCV protease inhibitors and against multiple HCV genotypes.In the study, researchers gave doses ranging from 50 milligrams (mg) to 800mg once daily to 40 men with HCV genotype 1, and doses ranging from 100mg to 800mg in 24 men with HCV genotype 3. In both groups, the drug was compared with placebo.Anti-HCV activity was quite high. In those with genotype 1, MK-5172 lowered HCV levels by up to 5.39 logs in those taking the 200mg dose. In those with genotype 3, the 600mg dose lowered HCV levels by 5.22 logs. When researchers looked at the percentage of people whose HCV levels became undetectable after only 7 days of dosing, 75% of those with genotype 1 and 38% of those with genotype 3 reached undetectable.More On GenotypesGenotype

Geography Patterns: It is believed that the hepatitis C virus has evolved over a period of several thousand years. This would explain the current general global patterns of genotypes and subtypes: 1a - mostly found in North & South America; also common in Australia 1b - mostly found in Europe and Asia. 2a - is the most common genotype 2 in Japan and China. 2b - is the most common genotype 2 in the US and Northern Europe. 2c - the most common genotype 2 in Western and Southern Europe. 3a - highly prevalent here in Australia (40% of cases) and South Asia. 4a - highly prevalent in Egypt 4c - highly prevalent in Central Africa 5a - highly prevalent only in South Africa 6a - restricted to Hong Kong, Macau and Vietnam 7a and 7b - common in Thailand 8a, 8b & 9a - prevalent in Vietnam 10a & 11a - found in Indonesia Articles Of Interest The Origin Of Hepatitis:HCV and HBVProtons, Electrons, and Hepatitis CWhy do most persons remain infected?Persons infected with HCV mount an antibody response to parts of the virus, but changes in the virus during infection result in changes that are not recognized by preexisting antibodies. This appears to be how the virus establishes and maintains long-lasting infection. Can persons become infected with different genotypes?Yes. Because of the ineffective immune response described above, prior infection does not protect against reinfection with the same or different genotypes of the virus. For the same reason, there is no effective pre- or postexposure prophylaxis

(i.e, immune globulin) available. What is a Quasispecies?As the virus continues to replicate in each person, there is the potential for quasispecies to form. Quasispecies are very closely related mutations of the original virus they were infected with. Over time the diversity of quasispecies increases and may affect response to treatment. View more here - HCV and QuasispeciesFor a summary of the AASLD Nov 2011 Meeting Click Here . Updates On Interferon Free Combinations, Click Here For The Hepatitis C Treatments in Current Clinical Development, Click Here

and HereRelated On The Web SiteRole of HCV Genotype 3 in Liver Fibrosis ProgressionTreatment and Genotype 4Telaprevir Genotype 2Individualizing Treatment Duration in Hepatitis C Virus Genotype 2/3-infected Patients

Role of HCV genotypes in severity of liver diseaseMay you be in heaven half an hour before the devil knows you're dead