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AASLD 2013:  sofosbuvir & ledipasvir with or without ribavirin

Nov 28, 2013 - 0 comments
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AASLD 2013

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Sofosbuvir

,

Ledipasvir



According to information presented at AASLD 2013 in Washington D.C., results of the LONESTAR study demonstrated that sofosbuvir and ledipasvir with or without ribavirin 95-100% of treatment naive and treatment experienced G1 patients attained SVR 24.  Link is at bottom.

Advocate1955

AASLD 2013: Fixed-dose Sofosbuvir/Ledipasvir Cures Most Genotype 1 Hepatitis C

Published on Monday, 11 November 2013 00:00

Written by Liz Highleyman

At least 95% of newly treated genotype 1 hepatitis C patients and prior non-responders achieved sustained virological response using a fixed-dose combination of sofosbuvir plus ledipasvir, with or without ribavirin, according to findings from the LONESTAR study presented the 64th AASLD Liver Meeting last week in Washington, DC. While response rates were high overall, the 2 relapsers in the trial were not taking ribavirin.

The advent of direct-acting antiviral agents has revolutionized treatment of chronic hepatitis C. While these agents were initially tested as add-ons to interferon-based therapy, many people with HCV and their providers are awaiting all-oral regimens that dispense with pegylated interferon and its difficult side effects.

Eric Lawitz from the Texas Liver Institute reported results from the phase 2 LONESTAR trial, which evaluated a fixed-dose combination pill containing Gilead Sciences' HCV polymerase inhibitor sofosbuvir (formerly GS-7977) plus the NS5A inhibitor ledipasvir (formerly GS-5885), taken with or without ribavirin for 8 or 12 weeks.
LONESTAR enrolled 2 cohorts at a single center. Cohort 1 included 60 treatment-naive individuals without liver cirrhosis. Cohort 2 included 40 people, about half with cirrhosis, who did not achieve a cure with the current standard of care: triple therapy with the approved HCV protease inhibitors boceprevir (Victrelis) or telaprevir (Incivek) plus pegylated interferon/ribavirin.

Overall, two-thirds of participants were men, 9% were black, 40% were Hispanic, and the mean age was 50 years. Most (87%) had harder-to-treat HCV subtype 1a and only 15% had the favorable IL28B CC gene variant associated with interferon responsiveness. In Cohort 2, 55% had cirrhosis at study entry. Just over half (55%) had previously been treated with boceprevir while 45% had used telaprevir. All had experienced prior virological failure; people who stopped previous therapy due to adverse events were excluded.

Participants in Cohort 1 were randomly assigned (1:1:1) to receive the once-daily fixed-dose tablet containing 400 mg sofosbuvir and 90 mg ledipasvir, either with or without 1000-1200 mg/day weight-based ribavirin for 8 weeks, or without ribavirin for 12 weeks. Treatment-experienced patients were randomized to receive sofosbuvir/ledipasvir either with or without ribavirin for 12 weeks.

Results
• All participants completed therapy except for 1 who withdrew consent.
• In Cohort 1, 95% of treatment-naive patients treated with sofosbuvir/ledipasvir for either 8 or 12 weeks achieved sustained virological response, or continued undetectable HCV RNA at 12 weeks post-treatment (SVR12).
• The SVR12 rate was 100% in the 8-week sofosbuvir/ledipasvir plus ribavirin arm.
• In Cohort 2, SVR12 rates were 95% for sofosbuvir/ledipasvir and 100% for sofosbuvir/ledipasvir plus ribavirin given for 12 weeks.
• All patients without cirrhosis achieved sustained response, as did all but 1 of the cirrhotics (91%).
• Response rates for all arms remained the same at 24 weeks post-treatment (SVR24); comparing favorably to historical rates of about 70% for patients without cirrhosis and 44% for cirrhotics in pivotal trials of boceprevir or telaprevir plus pegylated interferon/ribavirin.
• The 95% response rates reflect 3 people who did not achieve SVR12/24: 1 patient in Cohort 1 who received sofosbuvir/ledipasvir alone for 8 weeks and 1 in Cohort 2 who received sofosbuvir/ledipasvir for 12 weeks experienced viral relapse, while 1 person in Cohort 1 who received sofosbuvir/ledipasvir for 12 weeks was lost to follow-up after reaching SVR8.
• Both relapsers had HCV subtype 1a.
• No one who took ribavirin relapsed.
• 7 of the 9 patients with NS5A resistance mutations and all 28 people with NS3/4A (protease) resistance mutations at baseline nevertheless achieved sustained response.
• 1 patient had evidence of the S282T mutation and multiple NS5A resistance mutations at the time of relapse at week 8; this person was retreated with sofosbuvir/ledipasvir plus ribavirin for 24 weeks and went on to achieve SVR12.
• Sofosbuvir/ledipasvir was generally safe and well-tolerated with or without ribavirin.
• 2 people receiving sofosbuvir/ledipasvir alone and 2 receiving ribavirin experienced serious adverse events, but no one discontinued treatment for this reason.
• Grade 3-4 adverse events (0% vs 14%) and grade 3-4 laboratory abnormalities (7% vs 14%) were more common among those taking ribavirin.
• Anemia was seen only in the ribavirin arms (19%).
Asked whether ribavirin is still important, Lawitz said these results confirm that "for a large proportion of patients we can remove ribavirin without impacting SVR," and "outside clinical trials anything we can do to improve compliance is a benefit."
The Phase 3 ION trials are currently underway, testing sofosbuvir/ledipasvir with or without ribavirin for 8, 12, or 24 weeks in genotype 1 treatment-naive patients and prior non-responders, Lawitz noted.

Results from the phase 2 ELECTRON trial, also reported at the Liver Meeting, showed that Gilead'snon-nucleoside polymerase inhibitor GS-9669 as a third agent instead of ribavirin also led to SVR12 rates of 100% for difficult-to-treat genotype 1 patients.

11/11/13

Reference

E Lawitz, F Poordad, RH Hyland, et al. Once Daily Sofosbuvir/Ledipasvir Fixed Dose Combination with or without Ribavirin Resulted in >95% Sustained Virologic Response In Patients with HCV Genotype 1, Including Patients with Cirrhosis: the LONESTAR trial. 64th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2013). Washington, DC, November 1-5, 2013. Abstract 215.

http://www.hivandhepatitis.com/hcv-treatment/experimental-hcv-drugs/4402-aasld-2013-fixed-dose-sofosbuvirledipasvir-cures-most-genotype-1-hepatitis-c-lonestar-shows




AASLD 2013:  sofosbuvir, ledispavir plus ribavirin or GS9669

Nov 28, 2013 - 0 comments
Tags:

AASLD 2013

,

Sofosbuvir

,

Ledipasvir

,

Ledispavir

,

GS9669



According to information presented at AASLD 2013 in Washington D.C. this month, results of the ELECTRON Study demonstrated a 100% rate of SVR12 in G1 patients who were previous non-responders with fibrosis and Cirrhosis.  Link is at the bottom.
Advocate1955

AASLD 2013: 100% of Hard-to-treat Patients Cured with Sofosbuvir/Ledipasvir + Ribavirin or GS-9669
Published on Sunday, 03 November 2013 00:00

Written by Liz Highleyman

Interferon-free regimens of sofosbuvir and ledipasvir plus either ribavirin or GS-9669 taken for 12 weeks produced sustained response in 100% of treatment-experienced genotype 1 chronic hepatitis C patients with advanced liver fibrosis or cirrhosis, according to the latest findings from the ELECTRON trial presented yesterday at the 64th AASLD Liver Meeting in Washington, DC. A related analysis of previously untreated people without cirrhosis found that reducing treatment duration to 6 weeks led to relapses.

Gilead Science's Phase 2 ELECTRON trial program has tested the nucleotide HCV polymerase inhibitor sofosbuvir (formerly GS-7977) in various all-oral regimens for increasingly difficult-to-treat patient populations.
A 12-week dual regimen of sofosbuvir plus ribavirin cures most people with easier-to-treat HCV genotypes 2 or 3, and an advisory committee of the U.S. Food and Drug Administration last month recommended approval for this indication.

The dual regimen was not adequate, however, for prior non-responders with HCV genotype 1. Researchers then tried adding the NS5A inhibitor ledipasvir (GS-5885), finding that the triple regimen taken for 12 weeks produced a sustained virological response rate at 12 weeks post-treatment (SVR12) of 100% for both treatment-naive patients and prior non-responders without cirrhosis.

The analysis presented at the Liver Meeting by Edward Gane of Auckland Clinical Studies evaluated a once-daily fixed-dose tablet containing 400 mg sofosbuvir and 90 mg ledipasvir, taken with either ribavirin or the non-nucleoside polymerase inhibitor GS-9669, for the most difficult-to-treat group: treatment-experienced genotype 1 patients with advanced fibrosis or cirrhosis.

Researchers first enrolled 20 treatment-experienced genotype 1 patients with cirrhosis (Metavir stage F4) who were randomly assigned to receive the sofosbuvir/ledipasvir fixed-dose combination either with or without ribavirin for 12 weeks.

Next, 50 treatment-experienced genotype 1 patients with advanced fibrosis or cirrhosis (stage F3-F4) were randomized to receive the sofosbuvir/ledipasvir fixed-dose tablet plus either ribavirin or GS-9669, again for 12 weeks.

About 70% of treatment-experienced participants were men, about 90% were white, and the mean age was approximately 56 years. About three-quarters had harder-to-treat HCV subtype 1a and about one-quarter had the favorable IL28B CC gene pattern.

Researchers also aimed to determine a minimum effective duration of sofosbuvir/ledipasvir/ribavirin for easier-to-treat patients. This analysis enrolled 25 genotype 1 treatment-naive participants with absent-to-moderate fibrosis (stage F0-F2). All were treated with the sofosbuvir/ledipasvir fixed-dose tablet plus ribavirin for 6 weeks and compared against previously studied patients.

Just over half of the treatment-naive group were men, most were white, and the average age was 51 years. Most (84%) had HCV subtype 1a and 20% had the favorable IL28B variant.

Results
• In the first comparison, 100% of cirrhotic patients treated with sofosbuvir/ledipasvir plus ribavirin achieved SVR12, compared to only 70% of those treated with sofosbuvir/ledipasvir alone.
• In the second comparison, 100% of patients with advanced fibrosis or cirrhosis achieved SVR12 when treated with sofosbuvir/ledipasvir plus either ribavirin or GS-9669.
• While response rates were the same in both arms, hemoglobin levels dropped significantly among people taking ribavirin but remained stable among GS-9669 recipients.
• Among the easier-to-treat patients, several people treated for only 6 weeks relapsed after the end of therapy, resulting in an SVR12 rate of just 68%, compared with 100% of patients previously treated with the same regimen for 8 or 12 weeks.
• No baseline factors predicted which individuals would relapse and all had good initial viral declines on treatment.
• Across all treatment arms sofosbuvir/ledipasvir alone or with ribavirin or GS-9699 was generally safe and well tolerated.
• Just 1 participant experienced a serious adverse event and no one discontinued treatment early due to side effects.
• About 9% of treatment-experienced patients receiving any study regimen experienced grade 3-4 laboratory abnormalities, but this rose to 36% in the treatment-naive group.
• 15% of treatment-experienced and 40% of treatment-naive people taking ribavirin saw their hemoglobin levels fall below 10 g/dL, indicating anemia, compared with none in the ribavirin-sparing arms.
• The most common side effects were headache (30% in the sofosbuvir/ledipasvir only arm, 35% in the sofosbuvir/ledipasvir/ribavirin treatment-experienced arm, 32% in the sofosbuvir/ledipasvir/ribavirin treatment-naive group, and 25% in the sofosbuvir/ledipasvir/GS-9669 arm), fatigue (10%, 18%, 24%, and 35%, respectively) and nausea (0%, 32%, 20%, and 42%).

"In treatment-experienced patients with advanced fibrosis/cirrhosis, either ribavirin or GS-9669 may enhance the efficacy of sofosbuvir/ledipasvir given for 12 weeks," the investigators concluded.

"The optimal duration of sofosbuvir/ledipasvir in treatment-naive genotype 1 patients (even with the addition of ribavirin) is more than six weeks," they added.

11/4/13

Reference

EJ Gane, CA Stedman, RH Hyland, et al. Once Daily Sofosbuvir/Ledipasvir Fixed Dose Combination with or without Ribavirin: the ELECTRON trial. 64th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2013). Washington, DC, November 1-5, 2013. Abstract 73.

http://www.hivandhepatitis.com/hcv-treatment/experimental-hcv-drugs/4387-100-of-hard-to-treat-patients-cured-with-sofosbuvirledipasvir-plus-ribavirin-or-gs-9669





AASLD 2013: Simeprevir + Sofosbuvir

Nov 28, 2013 - 0 comments
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aasld

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simeprevir

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Sofosbuvir

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Cosmos Study



According to information presented at AASLD 2013 in Washington, D.C. this month, results of the Phase 2 trial called Cosmos Study shows high rates of SVR in G1 patients with mild - moderate fibrosis as well as null responders.  Patients included both mild - moderate fibrosis and advanced fibrosis, treatment naive, and prior null responders.  The trial included 12 weeks of treatment with simeprevir and sofosbuvir with or without ribavirin.  Link is the bottom.

Advocate1955

AASLD 2013: Simeprevir + Sofosbuvir Produces High Sustained Response Rates for Hard-to-treat Patients

Published on Sunday, 03 November 2013 00:00

Written by Liz Highleyman

A 12-week all-oral combination of simeprevir plus sofosbuvir led to sustained virological response in 93% of genotype 1 prior null responders with mild-to-moderate liver fibrosis, working as well as a longer course of treatment or triple therapy including ribavirin, according to late-breaking findings from the COSMOS trial presented this week at the 64thAASLD Liver Meeting in Washington, DC. The study also showed that 100% of treatment-naive patients and null responders with advanced fibrosis or cirrhosis achieved early sustained response at 4 weeks post-treatment using the same dual regimen.

The advent of next-generation direct-acting antivirals (DAAs) has been described as a revolution in the treatment of chronic hepatitis C virus (HCV) infection. While the first of these new agents will initially be approved as add-ons to interferon-based therapy, people with hepatitis C and their clinicians are eagerly awaiting interferon-free regimens.
Multiple DAAs developed by several major drug companies have performed well in all-oral regimens in trials to date, but their effectiveness varies based on a bewildering array of factors including HCV subtype (1b vs 1a), host IL28B gene pattern (CC vs non-CC), prior treatment status (untreated, relapser, prior partial or null responder). and extent of liver damage (absent, mild, or moderate fibrosis vs advanced fibrosis or cirrhosis).

Ira Jacobson from Weill Cornell Medical College presented findings from the Phase 2a COSMOS trial, evaluating oral regimens containing Janssen/Medivir's HCV protease inhibitor simeprevir (formerly TMC435) and Gilead Science’s nucleotide polymerase inhibitor sofosbuvir (formerly GS-7977), taken with or without ribavirin.
This open-label study enrolled 2 cohorts of genotype 1 chronic hepatitis C patients:
• Cohort 1: 80 prior interferon null responders with absent-to-moderate fibrosis (Metavir stage F0-F2);
• Cohort 2: 87 treatment-naive individuals and prior null responders with advanced fibrosis or compensated cirrhosis (F3-F4).

About 60% of participants in Cohort 1 were men, 29% were black, and the median age was 56 years. Just over three-quarters had harder-to-treat HCV subtype 1a, and half of these had the Q80K resistance mutation at baseline. Only 6% had the favorable IL28B CC gene variant associated with good interferon responsiveness -- typical of null responders. About 40% had stage F0-F1 fibrosis while 60% had F2.

In Cohort 2, two-thirds were men, 9% were black, and the median age was 58 years. Again, 78% had subtype 1a, 40% with the Q80K mutation. Participants were about evenly divided between treatment-naives and null responders, and 21% had the favorable CC variant. Just over half had advanced fibrosis, the rest cirrhosis.
Participants were randomly assigned to receive a dual regimen of 150 mg once-daily simeprevir plus 400 mg once-daily sofosbuvir, or else a triple regimen of these 2 drugs plus 1000-1200 mg weight-based ribavirin taken twice-daily. In addition, they were randomized to receive these regimens for either 12 or 24 weeks.

Jacobson presented results from a planned interim analysis. Cohort 1 started earlier and had long enough follow-up to determine sustained virological response at 12 weeks after completing treatment (SVR12), which is considered a cure. Cohort 2 started later and had 4-week post-treatment follow-up results (SVR4), which is too soon to declare them cured as relapses could still occur.

All participants treated for 12 week completed therapy in both cohorts. In Cohort 1, about 87% treated for 24 weeks finished therapy; 2 people in the dual therapy arm and 3 in the triple therapy arm stopped early, 1 in each arm due to adverse events. More than 90% of Cohort 2 participants treated for 24 weeks were still in treatment or follow-up; again 1 in each arm discontinued due to adverse events.

Results
• In Cohort 1, all participants who completed therapy had undetectable HCV RNA at the end of treatment and no viral breakthroughs occurred.
• Among those treated for 12 weeks, 93% taking simeprevir/sofosbuvir and 96% taking simeprevir/sofosbuvir/ribavirin achieved SVR12; there was 1 relapser in each regimen arm.
• Among those treated for 24 weeks, SVR12 rates were 93% and 79%, respectively; there was 1 relapser and 4 people with "non-virological failure" in the ribavirin arm.
• In Cohort 2, all 14 participants who completed therapy had undetectable end-of-treatment viral load with no breakthroughs.
• 100% of both treatment-naive patients and null responders taking simeprevir/sofosbuvir who had adequate follow-up (7 of each) achieved SVR4, as did 100% of naive participants and 93% of null responders treated with simeprevir/sofosbuvir/ribavirin.
• In both cohorts, 100% of people with HCV subtype 1b or with subtype 1a but lacking the Q80K mutation achieved SVR12 or SVR4; 3 relapsers in Cohort 1 and 1 in Cohort 2 had subtype 1a with the mutation (SVR12 of 89% and SVR4 of 91%, respectively).
• Looking at the effect of adding ribavirin to the 12-week course of therapy for difficult-to-treat subgroups in both cohorts combined:
o   Among people with unfavorable IL28B status, 96% taking either the ribavirin-sparing or ribavirin-containing regimen achieved SVR4;
o   Among prior null responders, the SVR4 rate was 95% using either regimen;
o   Among people with cirrhosis, SVR4 rates were 100% without and 91% with ribavirin.
• Treatment was generally safe and well tolerated.
• Among people treated for 12 weeks in both cohorts combined, there were no serious adverse events, grade 3-4 laboratory abnormalities, or discontinuations due to adverse events with either regimen.
• Among people treated for 24 weeks, serious adverse events were rare (3%-4%) and there were 2 discontinuations due to adverse events in both regimen arms.
• The most common side effects were fatigue, headache, nausea, and insomnia, which occurred with similar frequency in both the ribavirin-sparing and ribavirin-containing arms.
• Anemia and elevated bilirubin, however, were more common among ribavirin recipients.

Based on these findings, the researchers concluded that treatment with simeprevir plus sofosbuvir, with or without ribavirin, resulted in high SVR12 rates (79%-96%) in HCV genotype 1 null responders with stage F0-F2 fibrosis, as well as high SVR4 rates (96%-100%) in naive and null responder patients with stage F3 fibrosis or F4 cirrhosis.
Addition of ribavirin to simeprevir and sofosbuvir "may not be needed to achieve high rates of SVR in this patient population," they added. "12 weeks of treatment may confer similar SVR rates compared with 24 weeks of treatment."

A press release issued by Medivir went further, stating that the interim results "show no benefit from adding ribavirin to simeprevir and sofosbuvir."

Given last month's recommendation for approval of both simeprevir and sofosbuvir by a U.S. Food and Drug Administration advisory committee, Jacobson was asked about the prospect of using these drugs together off-label as an interferon-free regimen, especially for patients with advanced disease who need treatment now but cannot tolerate ribavirin.

"It's difficult to provide definitive guidance," Jacobson replied. "But all of us want to help our patients, and it's not difficult to imagine extrapolating from these data."

11/4/13

Reference

IM Jacobson, RM Ghalib, M Rodriguez-Torres, et al.SVR results of a once-daily regimen of simeprevir (TMC435) plus sofosbuvir (GS-7977) with or without ribavirin in cirrhotic and non-cirrhotic HCV genotype 1 treatment-naive and prior null responder patients: the COSMOS study. 64th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2013). Washington, DC, November 1-5, 2013. AbstractLB-3.

Other Source
Medivir. Results from the COSMOS study with Simeprevir and Sofosbuvir in cirrhotic and non-cirrhotic HCV genotype 1 patients presented at AASLD. Press release. November 4, 2013.

http://hivandhepatitis.com/hcv-treatment/experimental-hcv-drugs/4394-aasld-2013-simeprevir-sofosbuvir-produces-high-sustained-response-rates-for-hard-to-treat-patients



May 16, 2013

May 16, 2013 - 0 comments
Tags:

Hepatitis C

,

cirrhosis



Husband had ultrasound, labwork, and check back appointment with hepatologist on May 16, 2013.  All is well.  Ultrasound showed little to no change in small, benign cyst with septation measuring 6.8 x 5.5 x 5.0 cm.

Liver Function is good, given Hep C and Cirrhosis, and liver is still compensated:
PT=13.1
INR=1.1
BILI=0.7
AST=51
ALT=87
ALB=3.5
AFP is pending

Ultrasound is good:  no signs of liver cancer, no signs of ascites.  

Blood counts are all good, following failed triple tx with Incivek last April, 2012.  
WBC=6.96
Hgb=16.3
Hct=47
Plt=154

Next follow up imaging, labwork, and appt with hepatologist is in December, 2013.
Hopeful for new HCV treatment (12 wks of sofosbuvir, interferon, and ribavirin) will be approved and available by then.

Advocate1955


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