May 18, 2013

Fatty Liver Predicts Heart Risk Independent of Other Factors

Daniel M. Keller, PhD

May 16, 2013

AMSTERDAM, the Netherlands — In subjects at high risk for cardiovascular events, there is an increased prevalence of nonalcoholic fatty liver disease, and that prevalence correlates with predictors of atherosclerosis, according to a large cohort study.

We found that fatty liver disease independently predicts early atherosclerosis and 10-year risk for cardiovascular disease, beyond the traditional risk factors, said Raluca Pais, MD, from the Université Pierre et Marie Curie in Paris, France.

Dr. Pais presented the study results here at the International Liver Congress 2013.

The study cohort consisted of subjects with at least 2 cardiovascular risk factors, including dyslipidemia, hypertension, diabetes, high fasting glucose, obesity, and smoking. Subjects had no previous cardiovascular events, no known causes of chronic liver disease other than fatty liver disease, and alcohol intake was 50 g/day or less.

Of the 5685 study subjects, 2073 (36.5%) had fatty liver disease.

About half the study subjects were men, mean age was 55 years, and mean body mass index was 26.4 kg/m². Mean carotid intima-media thickness on ultrasound was 0.62 mm, and 26% had at least 1 carotid plaque. Mean Framingham risk score was 10.6.

Mean fatty liver index score was 45. This score is calculated on the basis of body mass index, waist circumference, triglyceride level, and gamma-glutamyl transferase level, and a score of 60 or more is a marker of hepatic steatosis.

Subjects with a fatty liver index score above 60 had a higher body mass index than those with a lower score, and higher levels of alanine transaminase, aspartate transaminase, and gamma-glutamyl transferase (P < .001 for all). They also had greater carotid intima-media thickness (0.64 vs 0.61 mm; P < .001) and higher 10-year Framingham risk scores (14.7 vs 8.3; P < .001).

The prevalence of carotid plaques was higher in subjects with fatty liver disease than in those without (29% vs 25%; P < .001).

The interaction between fatty liver index score and the presence of carotid plaques was age dependent.

For subjects 50 years and older, the prevalence of plaques was higher in those with a fatty liver index score above 60 than in those with a lower score (36% vs 32%; P = .01). For younger subjects, there was no significant difference (10% vs 12%). The index was independently associated with the Framingham risk score (P < .001).

On multivariate analysis, fatty liver index score was independently correlated with carotid intima-media thickness (P < .001) and carotid plaques (P = .01), independent of age, cholesterol level, or the presence of diabetes or hypertension.

Better Than Traditional Risk Predictors?

This study suggests that fatty liver disease is a heterogeneous entity requiring a multidisciplinary approach and modified screening strategies, Dr. Pais concluded.

Is the fatty liver index any better than traditional risk predictors for coronary heart disease?

"These data will have to be duplicated before you can really answer that question with certainty. But this is exactly what these authors were trying to show — that you can use this test in your daily practice, Jean-François Dufour, MD, told Medscape Medical News. Dr. Dufour, who is professor of hepatology at the University of Bern in Switzerland, was not involved in the study.

"Although patients with nonalcoholic fatty liver disease have long been known to suffer from excess cardiovascular disease," Dr. Dufour noted, "it was unclear whether this was mediated through a higher risk for earlier atherosclerotic lesions. This study shows that nonalcoholic fatty liver disease is an independent predictor of cardiovascular risk."

The authors have disclosed no relevant financial relationships. Dr. Dufour is an investigator with the Fatty Liver: Inhibition of Progression Consortium.

International Liver Congress 2013: 48th Annual Meeting of the European Association for the Study of the Liver (EASL). Abstract 1356. Presented April 26, 2013.


Summary from EASL 2013 for Hepatitis C - New HCV DAAs on their way soon: what do the phase III studies tell us?

Provided by NATAP

Jürgen K. Rockstroh M.D., Professor of Medicine
University of Bonn, Germany

Prof. Dr. J.K. Rockstroh
Department of Medicine I
University of Bonn
Sigmund-Freud-Str. 25
53105 Bonn


Ever since the first DAA based triple therapy for HCV became available treatment paradigms for HCV therapy have subsequently changed significantly and promise cure of HCV infection in around two thirds of treatment naïve HCV-genotype-1 infected patients undergoing triple therapy. Nevertheless, with more widespread use of boceprevir and telaprevir based triple therapy the current challenges of HCV therapy have become quite evident: Adherence issues due to high pill burden and food requirements with tablet intake, high rate of adverse events particularly in patients with more advanced liver disease, multiple drug-drug interactions and finally also significantly lower response rates in more challenging patient populations (cirrhosis, previous null-response to dual therapy, post-transplant treatment etc.). So not so surprisingly after an initial euphoria to offer triple therapy to HCV patients who had waited a long time for more efficacious HCV treatment options, many physicians and patients likewise now seem to wait for easier to take and potentially better tolerated and at best even interferon free new treatment options in the near future. At this year's EASL in Amsterdam with over 9600 delegates the phase III study results for the two "second wave HCV protease inhibitors" faldaprevir and simeprevir each in combination with pegylated interferon (PEG-IFN) and ribavirin (RBV) for HCV genotype 1 patients were presented as well as the phase III findings for the polymerase inhibitor sofosbuvir again in combination with PEG-IFN/RBV for treatment of genotypes 1,4,5 and 6. In addition phase III results of the first interferon free combination of sofosbuvir with ribavirin for treatment of genotype 2 and 3 were presented. As these new drugs have been or are about to be filed for licensing it can be expected that at least for the US, approval of these new HCV drugs can be expected 2013/2014. Therefore, with most likely less than a year ahead before these new drugs hit the market the question who to treat now and in whom to wait for improved HCV treatment options has become even more pertinent.

But clearly there is an even more promising future behind these new HCV agents, suggesting interferon free regimens will become available even in more difficult to treat patient populations and for all genotypes in the upcoming years. Again several studies which were presented at EASL allowed a glimpse into this highly promising future. Nevertheless, issues around the potential cost of the HCV drugs to come as well as the question which prediction factors allow us to decide which patient needs how many DAAs and what kind of combination suits which type of patient remain unanswered to the very day. Indeed the high number of compounds and combinations makes it increasingly difficult to follow all studies. Also 100% sustained virological response rates in easy to treat naïve HCV patients with early fibrosis stages and an IL28b CC genotype as well as a 1b infection cannot be automatically transferred to more challenging patient populations. In summary, the HCV field is moving fast and new HCV compounds promising simpler treatment regimens with increased tolerability and shortened treatment durations can be expected soon. In addition first interferon-free treatment approach for genotype 2 and 3 will be available shortly. A successful interferon-free HCV treatment strategy for all patients however, still has not yet arrived.

Why treat hepatitis C?

In consideration of the high costs of HCV therapy many countries in Europe have restricted the use of HCV protease inhibitor based triple therapy to more advanced fibrosis stages. Therefore, it is important that studies look at the impact of HCV therapy on survival in HCV infected individuals in order to demonstrate the benefits of HCV therapy and ultimately demonstrate cost-effectiveness of these treatment approaches. Interesting data in this context was presented at the EASL conference from a retrospective cohort study using the Electronically Retrieved Cohort of HCV Infected Veterans (ERCHIVES) (1). Within this study the predictors of mortality among US HCV infected veterans were evaluated. Overall they were able to compare an impressive number of 195,585 HCV Patients with 202,739 non-HCV infected veterans. The all-cause mortality rate among Veterans with HCV infection was much higher with 43.9 (43.4-44.3) per 1000 person-years (PY) than in Veterans without HCV infection (all-cause mortality was 24.0 (23.7-24.4) per 1000 PY). The table 1 shows the relevant predictors found to impact mortality. Among Veterans with HCV infection, decompensated liver disease, anemia, cancer, chronic kidney disease and COPD were the strongest predictors of higher risk of mortality, while HCV treatment was associated with over 50% reduction in mortality in this group. These findings once again underline the importance of HCV therapy to significantly lower risk of mortality in HCV infected individuals.

Continue to full article here ….

New HCV Drugs presented at EASL 2013, Reported by NATAP

Provided by NATAP

EASL NEW Oral HCV Drugs - Report 1 of 3

Reported by Jules Levin

Original reported filed April 26 from EASL in real-time live. Yesterday Abbvie reported results from a phase 2b study of their oral IFN-free 4-drug regimen with 99% SVR rate with 12 weeks therapy in genotype 1 and 98% SVR with 24 weeks in null responders, see the table in this email of the results & click the link to read the entire slide presentation. Abbvie is in phase 3 with this regimen. In the Late Breaker poster session SVR12 results were reported from the QUEST-1 phase 3 study looking at the Janssen once-daily new protease TMC435+Peg/Rbv in treatment-naive patients, with phase 3 QUEST-2 being reported tomorrow at EASL, with an overal SVR12 rate of 80%, with 80% of patients achieving a RVR, rapid viral response (undetectable at week 4) & with 91% of these patients thus being able to shorten therapy to 24 weeks & achieve SVR. TMC435 is being studied in numerous IFN-free studies that contain 2 orals without IFN. Also in the same oral session Gilead reported results from phase 3 the Fusion & Fission studies which were published wednesday in the New England Jnl of Medicine & below are links to this publication & the pdfs with a breakout of the data & links to the slides presented yesterday, with 12 weeks therapy achieving a 98% SVR rate with GS7977+Rbv in genotype 2 non-cirrhotic patients & 91% in cirrhotic patients in the phase 3 FISSION Study. For genotype 3 61% of noncirrhotics & 34% of cirrhotics achieving SVR, so gt3 did not achieve good results, a different strategy will be studied for gt3 by Gilead & others. Then in the phase 3 FUSION Study 12 vs 16 weeks GS7977+Rbv was explored, with 96% SVR for gt2 noncirrhotics with 12 weeks therapy & 100% with 16 weeks. For gt2 cirrhotics 78% SVR was achieved with 16 weeks GS7977+Rbv therapy and 60% with 12 weeks. Again for GT3 SVR rates were less with 16 weeks performing much better than 12 weeks: 63% vs 37% in noncirrhotics & 61% vs 19% in cirrhotics. Again a better treatment strategy for GT3 will be examined by Gilead & others, but clearly gt2 patients achieved great results. Here are links to key data reported Thursday in the first HCV oral session on new HCV drugs. A poster Late Breaker was reported yesterday showing SVR results with the BMS 3-oral drug IFN/-Rbv free regimen including their protease Asunaprevir+the NS5A BMS052 (declatavir)+ their non-nuc polymerase inhibitor BMS325 showing high SVR rates of 94% perhaps higher because of lost to followup, see the data & link below. There are 2 additional Late Breaker posters from Thursday not are not reported here in my original reported I filed & distributed in real time at EASL as it was too late & I was too tired last night to write the reports but I did them & one is on the BMS protease BMS032 Asunaprenavir + PegRBv. This is a phase 2b study with patients receiving 200mg bid + Peg/Rbv for 24 weeks. The other was a poster from BMS on their development of a new "synergy" NS5A "molecule" that would be administered along with BMS052 & intended to prevent NS5A resistance. Both Janssen & Gilead have just recently submitted New Drug Applications to the FDA for indications for the use of GS7977 and for TMC435 with approvals expected by the end of the year. Other companies are completing phase 3 now & will be submitting NDAs to the FDA soon. Many additional studies are ongoing with these drugs in various types of IFN & Rbv free regimens with 2 or 3 oral HCV drugs., by all the companies, so as we move forward over the next few years the regimens will improve, will become more potent, efficient & effective. Gilead's coformulated combination of GS7977+ their NS5A GS5885 is in phase 3 now with an expected NDA application to the FDA in 2014. At CROI in April Janseen reported 96% SVR rates with the combination of TMC435+GS7977+Rbv for 12 weeks & 93% without Rbv in the COSMOS Study in null responders. BMS has reported 100% SVR rates with with their NS5A BMS052, now in phase 3, + GS7977 in treatment naives without Rbv & are reporting data here in telaprevir/boceprevir failures showing an expected 100% SVR rate. Of note, at EASL Gilead reported from the QUANTUM Study that patients who did not achieve an SVR with GS7977 were retreated & 76% achieved SVR.

Continue to full article here …..

New HCV Drugs: Report 2

Reported by Jules Levin
EASL 48th Annual Meeting
April 24th - 28th 2013
The Netherlands, Amsterdam

This report is an updated version that was originally distributed live in real-time from EASL on April 28. 2 days ago I reported & distributed by email "New HCV Drugs - report 1" which was a report from the first 2 days on new study data reported for new HCV drugs, this report is a followup on new study data reported for new HCV drugs in the last 2 days of the conference EASL. There are many more reports to be prepared from this conference coming. Daclatasvir, TMC435, Faldaprevir & MK5172 reports below are from studies in combination with Peg/Rbv, but IFN-free all oral combination studies with 2 or perhaps 3 orals are also being studied, one study is reported below: Daclatasvir+GS7977 in 41 patients who previously were treated with boceprevir or telaprevir & did not achieve SVR, this is the first study treating patients who did not achieve SVR when treated previously with a protease triple therapy. Yesterday from 3:30 to 5:30pm, was the oral Late-Breaker session here at EASL in Amsterdam, the city of canals & lots of people using bikes to get around this relatively small but very cosmopolitan urban and yet still old European-style city of 850,000 people, that has a very nice bustling downtown with squares & lots of shopping, clothing stores and walking malls. Presented in the Late Breaker session was (see links below to the study data reports.

- GS7977(nucleotide)+Peg/Rbv for 12 weeks for genotypes 1/4/5/6 in the phase 3 NEUTRINO Study
- TMC435 (protease)+Peg/Rbv for GT1 in the phase 3 QUEST-2 Study
- Faldaprevir (BI335, protease)+Peg/Rbv in the phase 3 study STARTVERS01
- NS5A BMS052+GS7977 in GT1 patients who previously did not achieve an SVR with boceprevir or telaprevir (this captured a lot of attention)
- Daclatasvir (BMS052) + Peg/Rbv for GT2/3 for 12 or 16 weeks

The day before a phase 2 study on MK5172 (Merck 2nd generation protease) + Peg/Rbv for Gt1 was presented.

In the NEUTRINO Study with GS7977+Rbv taken for 12 weeks the overall SVR rate was 90%, there were 327 patients in this study, mostly Gt1 with 89% SVR rate in Gt1, 96% in Gt4, and 100% for Gt5/6. The overall SVR for non-cirrhotics was 92% & 80% for cirrhotics. Regarding resistance they looked at 28 patients who relapsed & 1 patient who discontinued treatment with HCV RNA>1000 IU/Ml and they reported "no S282T mutations, the signatory GS7977 mutation, observed by population or deep sequencing (1%) cutoff, no change in susceptibility to GS7977 or Rbv observed by phenotype amnalyses of other NS5B substitutions". There was a poster here on the QUANTUM Study, I distributed by email yesterday, wherein they retreated 132 patients who had not achieved SVR who were previously treated with GS938 (the discontinued sister drug of GS7977) or GS7977+GS938 and they reported high SVR rates of 76-85%, the point being it is hard to get resistance to GS7977. See link to study below. Gilead has submitted an initial New Drug Application to the FDA for approval of GS7977+Rbv for GT2/3 and for GS7977+Peg/Rbv for Gt1 and I think additional GTs 4....And here at EASL they reported phase 3 results in GT2/3:

EASL: All Oral Therapy With Sofosbuvir + Ribavirin for 12 or 16 Weeks in Treatment-Experienced Genotype 2/3 HCV-Infected Patients: Results of the Phase 3 FUSION Trial - (04/25/13)

EASL: Phase 3 Randomized Controlled Trial of All-Oral Treatment With Sofosbuvir + Ribavirin for 12 Weeks Compared to 24 Weeks of PEG + Ribavirin in Treatment-Naïve GT 2/3 HCV-Infected Patients (FISSION) - (04/25/13)

EASL: No S282T Mutation Detected by Deep Sequencing in a Large Number of HCV Patients Who Received Sofosbuvir With RBV and/or GS-0938: the Quantum Study - (04/29/13)

The phase 3 QUEST-2 Study reported on TMC435, the new once-daily HCV protease from Janssen, + Peg/Rbv, with an SVR12 rate of 81%, and 94% of patients were eligible for shortened 24 weeks therapy & among them 86% achieved SVR, see link below to the data report that includes the slide presentation, in the report is a slide with an interesting list of studies in the TMC435 development program, of note including numerous IFN-free multi-oral combination studies being conducted. Of note 88% achieved SVR with Pegasys while 77% achieved SVR with PegIntron, and of course this was noted with comments after the presentation with the presenter Michael Manns saying this was not a properly randomized study to address the question of which peg has superior efficacy, Pegasys & Pegintron. 96% IL28B CC achieved SVR, 80% with CT & 57% with TT. Of note SVR rates were the same for GT1a & GT1b: 80.4% & 82% respectively. SVR rate by stage of disease reflecting again that cirrhotics are harder to treat with lower SVR rates seen here & in other studies, thus needing more potent regimens & with null cirrhotics being the hardest to treat: 84.6% with early disease (F0-F2) achieved SVR, 66.7% with F3 & 64.7% with F4. There was some rash & photosensitivity associated with TMC435 but apparently manageable, 97% grade 1/2. and "mild, transient bilirubin increases not accompanied by changes in other liver parameters". Janssen has submitted to the FDA a New Drug Application for TMC435. A FDA hearing is scheduled for mid-October, perhaps to hear & review both the Gilead & Jansssen submissions simultaneously as they did 2 years ago for both telaprevir & boceprevir, apparently it is posted online that the FDA is holding hearings Oct 24 & 25. A 2nd phase 2 study QUEST-1 was presented here at EASL as well.

Faldaprevir is the new once-daily HCV protease from Boehringer Ingelheim, also called BI335. They reported SVR results from the phase 3 study STARTVERS01, they studied 2 doses 120 & 240 mg once daily + Peg/Rbv in over 600 patients, reporting overall SVR12 rates of 79% with the 120mg dose & 80% with the 240mg dose, with 88% achieving what they called ETS, early treatment success at week 4, permitting a shortened therapy of 24 weeks & of these patients 86% with 120mg & 89% with 240mg achieving SVR12. GT1a SVR12s were 69% with 120mg & 76% with 240mg & for Gt1b 84% with 120mg & 83% with 240mg. Boehringer is planning to submit to the FDA their NDA soon. See link below to slide presentation. Those with IL28b, 90% receiving 120mg & 95% receiving 240mg achieved SVR12, for CT 70% & 69% achieved SVR12, and for TT 76% & 79%. There was GI upset, rash & bilirubin increases. Of note several additional phase 3 studies are near completion including one in HCV/HIV coinfection and will be presented publicly later at a conference. BI reported at CROI ART HIV drug-drug interactions which generally are favorable and so they appear to be headed to be the first with a FDA indication for coinfection.

CROI: Pharmacokinetic interactions of darunavir/ritonavir, efavirenz, and tenofovir with the HCV protease inhibitor faldaprevir in healthy volunteers - (03/04/13)

CROI: STARTVerso 4: High rates of early virologic response in HCV genotype 1/HIV-co-infected patients treated with faldaprevir plus pegIFN and RBV - (03/04/13)

CROI: Boerhinger Ingelheim Announes Interim Results Evaluating Virologic Response Rates in HCV/HIV Coinfected Patients Treated with HCV Protease BI201335, and Drug Drug Interaction Studies with HIV ARTs - (03/04/13) press announcement

The first retreatment study of patients who failed (nonresponse, relapse, breakthrough) a triple therapy with either boceprevir or telaprevir with an IFN-free regimen was presented at yesterday's Late Breaker session & perhaps this garnered the most attention & discussion, although all the new data here on all the new oral HCV drugs captured everyone's delight & everyone was very pleased with the great progress in treating HCV. 21 patients received the BMS NS5A BMS052 (Daclatasvir) + GS7977 (Gilead's nucleotide) and 20 patients received this 2 drug combination along with Rbv, treatment was 24 weeks. Of note 81-85% had F2 disease stage or greater and Mark Sulkowski, who presented the data, said some of these patients may have had cirrhosis, the stages of disease by some of these patients varied based on when the test was done etc. At the end of treatment 100% HCV RNA < LLOQ, SVR4 was 100%, and SVR12 was 95%, there was 1 patient who was missing at post-treatment week 12, but "HCV RNA was undetectable at post-treatment week 4 & post-treatment week 24 (preliminary). 21/41 patients have reached PT week 24, all have achieved SVR24. see link below to full slide presentation. Side effects included headache, fatigue. By the way, in the presentation Sulkowski mentioned that it has been I think I recall he said as long as 1.5 or more years, perhaps as much as 2 yrs, since some patients had stopped boceprevir or telaprevir therapy & of note baseline resistance mutations were still detected, but apparently with 95-100% SVR rates, this resistance did not affect outcomes in this regimen with 2 orals from 2 different classes, but this raises a concern that protease resistance may not disappear as easily as has been reported previously in some studies, see the report link to read the slide on baseline mutations.

Results were reported in the Late Breaker session yesterday from the COMMAND GT2/3 Study where 150 patients with Gt2/3 were studied & 100 received the BMS NS5A Dacaltasvir (BMS052) + Peg/Rbv for either 12 or 16 weeks. In the 12 week arm at the End Of Treatment for GT2 100% had < LLOQ-TD (target detected, detectable but < LLOQ) and 96% had < LLOQ-TND (target not detected, undetectable), with 100% & 91% for the 16-week arm, and of note the 24-week Peg/Rbv-placebo arm had similar SVR rates of 96 & 91% (which changed in SVR rates). SVR24 for GT2 in the 12-week group was 88% < LLOQ-TD & 83% < LLOQ-TND, and for the 16 week arm 83% for both measures, they called this modified ITT analysis, so they also said in the graph legend SVR24 observed values (excluding patients with missing post-treatment data: 95% (DCV 12 weeks), 100% DCV 16 weeks). IL28b CC GT2 patients had 100% SVR with 16 weeks (7/7) byt CT & TT had lower SVR rates, see slide graph. Response rates were less for GT3 patients, SVR24 rates of 67-70% & 69-72% after excluding missing post-treatment data and SVR24 for Peg/Rbv-placebo arm was 59%, so clearly GT3 patients did not perform well here either as in the GS7977 study and need extra potency with therapy directed at GT3. For patients with PDR, protocol defined responses (HCV RNA < LLOQ at week 4 & < LLOQ-TND at week 10, SVR24 rates were 81% with 12 weeks for GT2 & 94% with 16 weeks for GT2 & for GT3 73% with 12 weeks or 16 weeks. See link below to the slides presented.

Merck's once-daily MK5172 is a 2nd generation protease with activity against resistant virus. In this study of 332 non-cirrhotic patients, several MK5172 doses were looked at: 100mg, 200mg, 400mg & 800mg, all once daily, + Peg/Rbv. Patients received 12 weeks of MK5172 and the comparison arm was boceprevir+Peg/Rbv. At AASLD in Nov 2012 SVR12 was reported & here SVR24 & HCV-RNA (TND) is reported with 311/332 (94%) patients have reached followup week 24 or have discontinued before week 24 followup. SVR24 & HCV-RNA TND* at last visit with 100mg (the dose to be used) +PR was 86% (55/64) & 92% (61/66), (*HCV RNA TND at last visit: patients who discontinued for reasons other than virologic failure, who completed therapy and are in follow-up, or who completed therapy but did not return for the followup week 24 visit). 91% of patients receiving MK5172 100mg had HCV-RNA TND at week 4 & were eligible for the short-duration of therapy and 98% had HCV-RNA TND at last visit & 90% had SVR 24. See link below to full slide report. Merck & BMS recently announced an agreement to study a 2 oral once-daily regimen IFN-free in genotype 1 with this protease MK5172 + the BMS NS5A BMS052.

Continue to full article here ….

HCV New Drugs - Report 3 (ELECTRON Study phase 2: GS7977+Rbv GT1)

Reported by Jules Levin

This report was also originally filed & distributed via the NATAP listserve live & real-time from EASL on Sunday the day EASL ended.

EASL: ELECTRON: All-Oral Sofosbuvir-Based 12-Week Regimens for the Treatment of Chronic HCV GT 1 Infection - (04/27/13)

Gilead Announces Update on Phase 3 Study of Oral Fixed-Dose Combination of Sofosbuvir and Ledipasvir for Genotype 1 Hepatitis C Patients - (04/01/13) Phase 3 ION-1 and ION-2 studies GS7977+GS5885 with & without Rbv in treatment-naives & patients who failed previous therapy with either Peg/Rbv or triple therapy with a protease+Peg/Rbv.


EASL: Treatment With Sofosbuvir + Peginterferon + Ribavirin for 12 Weeks Achieves 90% SVR12 in Treatment-Naïve Genotype 1, 4, 5, and 6 HCV-Infected Patients: The NEUTRINO Study - (04/27/13)

EASL: Once-Daily Sofosbuvir Plus Ribavirin Given for 12 or 24 Weeks in Treatment-Naïve Patients With HCV Infection: the QUANTUM Study - (04/28/13)

I count I think 6 phase 3 studies for Gilead in HCV covering across the genotypes, take a look at the 2 links above listing the various phase 3 studies. The ELECTRON Study is a phase 2 of about 94 patients looking at both treatment-naives & null responders with each of 3 treatment arms for 12 weeks therapy: GS7977+Rbv, GS7977+GS5885 (NS5A)+Rbv and GS7977+GS9669 (non-nuc)+Rbv. These were 90% Gt1a patients without cirrhosis, phase 3 will include cirrhotics. You can view the ELECTRON slide presentation here at EASL with the link above. Here is the results slide just below showing 100% in naives (25/25) with the 3-drug regimen of GS7977+GS5885+Rbv & 100% in nulls with the same regimen, phase 3 ION studies will look at with & without Rbv with the coformulation of GS7977+GS5885. You can see this study also looked at GS7977+GS9669 (non-nuc)+Rbv with 92% SVR in naives (23/25) & 3/3 SVR in nulls all with 12 weeks, ION-2 will look at treatment-experienced with 12 and 24 weeks therapy.

Continue to full article here ….

New Oral HCV Drugs at EASL - Report 4A

Gilead Reports Interim Data From Phase 2 LONESTAR Study - (05/03/13)

Reported by Jules Levin

Results from many phase 2 & phase 3 studies of new oral HCV drugs were reported at EASL, which just took place in Amsterdam April 24-28. Abbott, Boehringer Ingelheim, Gilead, Janssen, & BMS all reported new data on their drugs. About 8-9 clinical/patient Gilead studies were reported at EASL with GS-7977 in Gt1 and Gt2/3, with therapy taken for as little as 12 weeks. ELECTRON & QUANTUM looked at Gt1 & both were phase 2 studies using GS-7977+rbv, but ongoing are ION phase 3 studies looking at the coformulated 2 oral regimen of GS7977+GS5885 with & without Rbv for 12 & 24 weeks including naives & treatment-experienced & those who failed to respond to triple therapy with a protease. You can read brief summaries of the results from the Gilead studies below & if you scroll down to the bottom of this report you will see links to the full slide & poster presentations. Abbott reported phase 2 results from their 4-drug IFN-free regimen taken for 12 weeks with 99% SVR in naives & 98% in nulls, see link below to read the slide presentation. Boehringer Ingelheim reported phase 3 results of their protease Faldaprevir (BI1335) from 1 study with 80% SVR rates, in combination with Peg/Rbv, several additional phase 3 studies including the coinfection study will be presented later this year. Janssen reported SVR rates of 81% from their 2 QUEST phase 3 studies, links below. BMS reported phase 2 results on their 3 drug IFN/RBV free all oral regimen given for 12 or 24 weeks with 90-94% SVR rates, they are planning a larger phase 3 study, see link below to read full poster. Merck reported phase 2 data with their 2nd generation protease MK5172+Peg/Rbv with 92% SVR rate, they just announced a deal with BMS for a study of the IFN-free regimen of MK5172 plus the BMS NS5A BMS052, plus they have further back in development a study with MK5172 plus their 2nd generation NS5A MK8742. Janssen & Boehringer are planning IFN-free studies looking at combinations of new oral drugs. Boehringer is looking at their protease in combination with their non-nuc BI127 plus the Presidio NS5A, recently announced. Janssen is involved in multiple oral regimen studies including one with their own non-nuc TMC055+the protease TMC435, another one with TMC435+TMC055+IDX719, TMC435+IDX719, one with TMC435+BMS052, & with TMC435 & Vertex in combination with their nucleotide VX135. Vertex is conducting numerous studies with their nucleotide VX135 in combinations with various oral HCV drugs from other companies, see links below to VX135 studies presented at EASL including with GSK NS5A GSK805. BMS just announced a study of their NS5A BMS052 in combination with VX135. Roche, don't forget Roche, they have ongoing, started last spring 2012, a 4-drug oral regimen, IFN-free- called ANNAPURNA, link to information below. Achillion has a protease, a 2nd generation NS5A & a 2nd generation protease in early development & Idenix has their NS5A & a nucleotide program in preclinical with studies perhaps to start with a nucleotide later this year. Presidio has a pangenotypic non-nuc & a NS5A, links below. Gilead submitted a New Drug Application for GS-7977 for 2 indications including for GS7977+Peg/rbv for Gt1, they are expected to be submitting a NDA next year for the coformulation of GS7977+GS5885. Janssen submitted their NDA TMC435. An FDA hearing for both drugs is expected in October this year. Boehringer is expected to an NDA submit to the FDA including for coinfection. As well, BMS will file a NDA including for BMS052, their NS5A. Abbott started their phase 3 program for their 4-drug IFN-free regimen in the Fall of 2012.

Genotype 1:

Treatment With Sofosbuvir + Peginterferon + Ribavirin for 12 Weeks Achieves 90% SVR12 in Treatment-Naïve Genotype 1, 4, 5, and 6 HCV-Infected Patients: The NEUTRINO Study....relapse accounted for all resistance (deep sequencing) was seen among relapsers

327 total patients (genotypes 1, 4, 5, 6) were treated with GS-7977+Peg/Ribavirin for 12 weeks in the phase 3 NEUTRINO Study, results reported at EASL. 292 patients with GT1 received GS-7977+Peg/Rbv for 12 weeks with 89% achieving SVR12. For GT4, 96% (27/28) patients achieved SVR12. And 100% (7/7) with genotypes 5/6 achieved SVR. Overall, 92% without cirrhosis achieved SVR12 & 80% without cirrhosis achieved SVR12. Among the 28 patients who relapsed & the 1 patient who discontinued with HCV RNA viral load >1000 no S282T mutation was observed, this is the signature mutation for GS-7977, and no change in susceptibility by phenotypic analyses of other NS5B substitutions was observed. Side effects reported appeared to be mostly related to ribavirin with 21% anemia.

phase 2: ELECTRON: All-Oral Sofosbuvir-Based 12-Week Regimens for the Treatment of Chronic HCV GT 1 Infection

GS-7977+Rbv was taken for 12 weeks in this small phase 2 study of genotype 1 patients, 25 treatment-naives & 10 null responders with 84% of the naives achieving SVR12 & only 10% of the nulls achieving SVR. But GS-7977+GS5885 (once daily NS5A) + Rbv was given to 25 naives with 100% SVR & 9 nulls with 100% SVR, and the large ION-1 & ION-2 ongoing phase 3 studies are looking at these regimens & will provide more results. This study also looked at the Gilead non nuc Gs-9669+GS7977+Rbv for 12 weeks duration of therapy and 23/25, 92%, of naives & 3/3 nulls achieved SVR12.

Genotype 2/3:

Phase 3 Randomized Controlled Trial of All-Oral Treatment With Sofosbuvir + Ribavirin for 12 Weeks Compared to 24 Weeks of PEG + Ribavirin in Treatment-Naïve GT 2/3 HCV-Infected Patients (FISSION)

This study of 500 treatment-naive genotype 2/3 patients compared 12 weeks GS-7977+Rbv to 24 weeks of Peg/RBV. After 12 weeks of GS-7977+Rbv 99% had undetectable viral load but SVR12 was 67%. For those receiving 24 weeks Peg/Rbv 99% had undetectable viral load after 24 weeks but 67% SVR12. Certainly GS-7977+Rbv is more tolerable & safe than Peg/Rbv. For those genotype 2 patients receiving GS7977+Rbv for 12 weeks 92% had SVR12 but only 56% Gt3 had SVR12. For Gt2 patients taking Peg/rbv for 24 weeks 78% achieved SVR12 but 63% with Gt3 achieved SVR12. For Gt2 patients receiving GS7977+Rbv both cirrhotics & non-cirrhotics did well, there was not much of a difference in SVR rate with 98% of non-cirrhotics & 91% of cirrhotics achieving SVR12. But fot Gt3 patients the degree of liver disease affected outcomes with 61% without cirrhosis achieving SVR12 vs 34% with cirrhosis. There were no unusual side effects reported, SOF+Rbv was well tolerated, safety profile consistent with Rbv.

All Oral Therapy With Sofosbuvir + Ribavirin for 12 or 16 Weeks in Treatment-Experienced Genotype 2/3 HCV-Infected Patients: Results of the Phase 3


This study of about 200 patients compared 12 vs 16 weeks of GS-7977+Rbv for treatment-experienced patients (Peg/Rbv). 30% of study subjects had cirrhosis, 70% were non-CC IL28b. At the end of treatment in both groups 100% had undetectable SVR, all patients finished treatment, relapse accounted for all failures. SVR12 was 50% for 12 weeks & 73% for 16 weeks. The difference in response between GT2 & Gt3 reflected results: for Gt2 patients, 86% receiving 12 weeks & 94% receiving 16 weeks achieved SVR12 while for Gt3 patients 30% receiving 12 weeks & 62% receiving 16 weeks achieved SVR. And the presence of cirrhosis affected outcomes. Gt2 patients without cirrhosis had 96% with 12 weeks & 100% with 16 weeks SVR12, but for cirrhotics 60% (6/10) with 12 weeks & 78% (7/9) with 16 weeks achieved SVR12. For Gt3 without cirrhosis 37% with 12 weeks & 63% with 16 weeks achieved SVR12 & for those with cirrhosis 19% with 12 weeks (5/26) & 61% with 16 weeks achieved SVR12. Again resistance to GS7977 was not an issue and there were no unusual side effects.

Treatment With Sofosbuvir + Ribavirin for 12 Weeks Achieves SVR12 of 78% in GT 2/3 Interferon-Ineligible, -Intolerant, or -Unwilling Patients: Results of the Phase 3 POSITRON Trial

207 patients received GS-7977+rbv. SVR was 93% for Gt2 & 61% for Gt3. Relapse accounted for all failures, no resistance seen in any relapse patient, and Gs-7977+Rbv was well tolerated. At the end of treatment 100% of patients had undetectable viral load & SVR12 was 78% with 92% for Gt2 & 61% for Gt3. Gt2 patients with or without cirrhosis did well, cirrhosis did not affect their outcomes with both groups achieving the same SVR, but cirrhosis did affect outcomes for Gt3 with 68% without cirrhosis achieving SVR12 % 21% with only cirrhosis achieving SVR12. Side affects were again consistent with those expected from Rbv.

Ongoing phase 3 studies ION-1 & ION-2 with coformulated once-daily GS7977+GS5885 :

ION-1, a Phase 3 clinical trial evaluating a once-daily fixed-dose combination of the nucleotide sofosbuvir and the NS5A inhibitor ledipasvir with and without ribavirin (RBV) for 12 or 24 weeks among treatment-naïve genotype 1 patients with hepatitis C virus (HCV) infection (n=800)

ION-2 initiated in January 2013, which is now fully enrolled. ION-2 is evaluating sofosbuvir/ledipasvir with RBV for 12 weeks, and with and without RBV for 24 weeks, among 400 treatment-experienced genotype 1 HCV patients. Participants in this study failed to respond to past therapy containing pegylated interferon (peg-IFN) or peg-IFN plus a protease inhibitor.


Amsterdam, The Netherlands, April 23, 2013 - Gilead Sciences, Inc. (Nasdaq: GILD) today announced that detailed results from four Phase 3 clinical trials (NEUTRINO, FISSION, POSITRON and FUSION) evaluating sofosbuvir, the company's investigational once-daily nucleotide NS5B inhibitor for the treatment of chronic hepatitis C virus (HCV) infection, will be presented this week in oral sessions at the 48th Annual Meeting of the European Association for the Study of the Liver (International Liver Congress 2013) in Amsterdam, The Netherlands. In addition, detailed results from the four clinical studies have also been published online in two papers, ahead of print, in The New England Journal of Medicine (NEJM).

In the four trials, sofosbuvir was administered to nearly 1,000 patients with chronic HCV infection as part of an all-oral 12-week or 16-week treatment regimen in combination with ribavirin (RBV) in genotypes 2 and 3, or with RBV and pegylated interferon (peg-IFN) for 12 weeks in genotypes 1, 4, 5 and 6. Overall SVR12 rates (sustained viral response 12 weeks after completing therapy) from 50 to 90 percent were observed. Patients who achieve SVR12 are considered cured of their HCV infection.

A description of the four Phase 3 studies and SVR12 results are summarized in the table below. Detailed results from the Phase 3 studies of sofosbuvir are available at, you can read the published articles on the 4 studies with links to them below, scroll down.


Continue to full article here ….

To read further reports and view posters please visit NATAP for full EASL 2013 coverage

Triple Therapy for Hepatitis C is Effective After Liver Transplantation, but Side-Effects Are Common

Provided by CDCNPIN


Researchers, including Elizabeth Verna of Columbia University and others from the Consortium to Study Health Outcomes in Hepatitis C Virus (HCV) Liver Transplant Recipients (CRUSH-C) study evaluated triple therapy in liver transplant recipients at six US centers. The researchers reported on their study results at the 48th International Liver Congress in Amsterdam, the Netherlands, on April 24–28, 2013. The research included 112 patients with HCV genotype 1 (55 percent with harder-to-treat subtype 1a). Of these, 80 percent were men, the majority were white, their median age was 58 years, and 26 percent had the favorable IL28B CC gene variant. Half of the patients had been treated previously with interferon-based therapy post-transplant, 25 percent were relapsers, 27 percent were partial responders, and 48 percent were null responders. Most had moderate-to severe fibrosis and all participants were being treated with immunosuppressive drugs to prevent organ rejection. Triple therapy for HCV consisted of pegylated interferon, ribavirin, and either telaprevir or boceprevir. Median time from liver transplantation to the start of therapy was 3.7 years. At week 4 of treatment, 66 percent of patients had undetectable HCV RNA, which increased to 84 percent of patients at week 12. Altogether, 64 percent of patients had extended rapid virological response (eRVR). Of the 43 patients who completed therapy with at least 4 weeks of post treatment follow-up, 65 percent achieved sustained virological response (SVR) 4. Among those with eRVR, the SVR4 rate rose to 93 percent of patients. For patients with advanced disease, 44 percent achieved SVR4 compared with 71 percent without advanced disease. Adverse events were common and 11 percent discontinued treatment. One in five experienced serious adverse events requiring hospitalization, 4 percent experienced liver graft rejection, and 6 percent died during follow-up. The researchers concluded that high eRVR rates can be achieved with triple therapy, exceeding previous rates with pegylated interferon/ribavirin alone, even with hard-to-treat patients. They acknowledged that SVR4 rates may be lower in patients with advanced disease, and that the results must be balanced against high rates of adverse events. They also noted that improving tolerability and identifying predictors of SVR are critical to optimizing the risks-benefits of post liver transplant triple therapy. The full report, “ A Multicenter Study of Protease Inhibitor-Triple Therapy in HCV-Infected Liver Transplant Recipients; Report from the CRUSH-C Group,” was published online in the Journal of Hepatology (2013; doi:10.1016/S0168-8278(13)60025-2).


Date of Publication 05/16/2013

Author Liz Highleyman

Disclaimer: NPIN provides this information as a public service only. The views and information provided about the materials, funding opportunities, and organizations do not necessarily state or reflect those of the U.S. Department of Health and Human Services, CDC, or NPIN.


Coffee Consumption Associated with Reduced Risk of Autoimmunue Liver Disease

A Range of New Research Studies Presented at DDW® 2013

Orlando, FL (May 18, 2013) — Research presented today at Digestive Disease Week® (DDW) explores new discoveries in liver disease research, with findings about the impact of coffee on autoimmune disease and palliative care for cirrhotic patients.

While coffee consumption recently has been associated with reduced risk of fibrosis, a new study found that even a few more cups of java each month also correlate with lower risk for a particular autoimmune liver disease. Researchers at the Mayo Clinic, Rochester, MN, linked coffee consumption with reduced risk of primary sclerosing cholangitis (PSC), a disease of the bile ducts that causes inflammation and subsequent duct obstruction that ultimately can lead to cirrhosis of the liver, liver failure and biliary cancer.

“While rare, PSC has extremely detrimental effects,” said Craig Lammert, MD, instructor of medicine at Mayo Clinic. “We are always looking for ways to mitigate risk, and our first-time finding points to a novel environmental effect that might also help us to determine the cause of this and other devastating autoimmune diseases.”

Funded by grants from the National Institutes of Health and the American Liver Foundation, the study examined the largest cohort of patients with PSC and primary biliary cirrhosis (PBC) in the U.S. as well as a healthy control group. Data showed that coffee consumption was associated with reduced risk of PSC, but not PBC. PSC patients were much more likely to never consume coffee compared with the control group. The control group also spent nearly 20 percent more of their life regularly drinking coffee.

Study highlights need of terminally ill cirrhotic patients

Other DDW research illuminates the need for better palliative care for terminally ill cirrhotic patients who are rejected for a liver transplant. A retrospective cohort review of patients previously assessed or listed for liver transplant by the University of Alberta in Canada found that only 3 percent of patients in the study died while in hospice, a hallmark of palliative care.

“In our study, less than 10 percent of patients had even been referred to palliative care,” said Constantine Karvellas, assistant professor of medicine at the University of Alberta. “We need to be better about ensuring quality of life for these patients.”

Palliative care is specialized medical care for people with serious, often terminal, illnesses. Its goal is to improve patients’ quality of life by concentrating on relief from symptoms, pain and stress.

The patients in Dr. Karvellas’s study had been de-listed or declined for liver transplantation. The most common reason was noncompliance with restrictions on substance use, but other reasons related to cancer and multiple organ dysfunction. Researchers examined patients’ medical trajectory and the symptoms prominent at their end of life and found that more than half had pain and nausea. Others had symptoms of depression, anxiety, breathlessness and anorexia. Eighty percent required repeat hospital admissions and invasive procedures such as paracentesis, in which fluid accumulation is drained from the abdomen.

“Palliative care offers a way to avoid some of these costly procedures and at the same time improve the quality of life for these patients. This data helps to start the conversation on how we can make a positive difference in the lives of many patients and families,” Dr. Karvellas said.

Dr. Lammert will present data from the study “Coffee consumption is associated with reduced risk of primary sclerosing cholangitis but not primary biliary cirrhosis,” abstract 630, on Monday, May 20, at 10 a.m. ET in Room 205A of the Orange County Convention Center.

Dr. Karvellas will present data from the study “Paucity of palliation in cirrhotic patients: a retrospective study and needs assessment,” abstract 796, on Monday, May 20, at 4:30 p.m. ET in Room 202AB of the Orange County Convention Center.

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Digestive Disease Week® (DDW) is the largest international gathering of physicians, researchers and academics in the fields of gastroenterology, hepatology, endoscopy and gastrointestinal surgery. Jointly sponsored by the American Association for the Study of Liver Diseases (AASLD), the American Gastroenterological Association (AGA) Institute, the American Society for Gastrointestinal Endoscopy (ASGE) and the Society for Surgery of the Alimentary Tract (SSAT), DDW takes place May 18 to 21, 2013, at the Orange County Convention Center, Orlando, FL. The meeting showcases more than 5,000 abstracts and hundreds of lectures on the latest advances in GI research, medicine and technology. More information can be found at

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