large scale tenofovir peg ifn combo trial aasld 2014 results

[studyforhope]

193
HBsAg Loss with Tenofovir Disoproxil Fumarate (TDF) plus Peginterferon alfa-2a (PEG) in Chronic Hepatitis B (CHB): Results of a Global Randomized Controlled Trial
Patrick Marcellin1, Sang Hoon Ahn2, Xiaoli Ma3, Florin A. Caruntu4, Won Young Tak5, Magdy Elkashab6, Wan-Long Chuang7, Fehmi Tabak8, Rajiv Mehta9, Joerg Petersen10, Eduardo B. Martins11, Phillip Dinh11, Amoreena C. Corsa11, Prista Charuworn11, Mani Subramanian11, John G. McHutchison11, Maria Buti12, Giovanni B. Gaeta13, George V. Papatheodoridis14, Robert Flisiak15, Henry Lik-Yuen Chan16; 1Hopital Beaujon, University Paris-Diderot, Cli- chy, France; 2Division of Gastroenterology, Yonsei University Col- lege of Medicine, Seoul, Republic of Korea; 3Drexel University College of Medicine, Philadelphia, PA; 4National Institute for Infec- tious Diseases “ Matei Bals”, Bucharest, Romania; 5Kyungpook National University Hospital, Daegu, Republic of Korea; 6Toronto Liver Center, Toronto, ON, Canada; 7Kaohsiung Medical Univer- sity Chung-Ho Memorial Hospital, Kaohsiung City, Taiwan; 8Uni- versity of Istanbul, Istanbul, Turkey; 9Liver Clinic, Surat, India; 10IFI Institute for Interdisciplinary Medicine at the Asklepios Klinik St. George, University of Hamburg, Hamburg, Germany; 11Gilead Sciences, Foster City, CA; 12Hepatology Unit, Hospital Universitari Vall d’Hebron, Barcelona, Spain; 13Viral Hepatitis Unit, Depart- ment of Infectious Diseases, Second University of Naples, Naples, Italy; 14Athens University Medical School, “Hippokration” General Hospital of Athens, Athens, Greece; 15Medical University of Bialys-
16
Background: Rates of HBsAg loss in CHB patients treated with nucleos(t)ide analogues (NA) or PEG therapy are relatively low. Studies comparing PEG+NA combination therapy versus PEG alone are inconclusive. Here we present the Week 48 analysis of an ongoing trial evaluating TDF+PEG as combina- tion therapy. Methods: 740 patients with non-cirrhotic CHB were randomized 1:1:1:1 to receive TDF+PEG x48 weeks (Arm A); TDF+PEG x16 weeks followed by TDF x32 weeks (Arm B); continuous TDF (Arm C); PEG x48 weeks (Arm D). The primary hypotheses compared the rates of HBsAg loss, estimated by Kaplan-Meier method, at Week 72 for arms A vs C, A vs D, B vs C, and B vs D. The Week 48 analysis was pre-specified. Results: Of the 740 patients randomized and treated, 58.4% were HBeAg(+), mean age 37 years, 74.9% Asians and HBV genotype distribution (A, B, C, D, E-H) was 8.2%, 27.3%, 42.3%, 20.8% and 1.1%, respectively. At week 48, patients receiving PEG+TDF for 48 weeks had significantly higher rates of HBsAg loss than either TDF or PEG alone (fig- ure). Arm A had higher rates of HBs seroconversion (5.9%)
than Arms B (0.6%), C (0%) or D (1.8%). Of the subjects with HBsAg loss, 73% were HBeAg(+) at baseline and had the following genotype distribution: 31.8% A, 36.4% B, 18.2% C, and 13.6% D. Rates of HBeAg loss were also higher in arms receiving PEG+TDF(Arm A 24.3%, Arm B 20.2%, Arm C 8.3%, Arm D 12.5%). HBV DNA suppression (HBV DNA < 15 IU/ml) was higher in the TDF-containing arms (Arm A 69.2%, Arm B 71.2%, Arm C 60.5%, Arm D 20.8%). No unexpected AEs were observed in the combination arms. Conclusion: CHB patients treated with TDF and PEG combination therapy for 48 weeks achieved significantly higher rates of HBsAg loss than either therapy given alone.

[studyforhope]

HERE IS THE ITALIAN TRIAL OF PEG INTERFERON ADD ON...
Late breaker abstract. it is not completed yet, but interim results are interesting...

Final ID: LB-31
Add-on Peginterferon Alfa-2a significantly reduces HBsAg levels in chronic hepatitis B, HBeAg-negative, genotype D patients fully suppressed on nucleot(s)ide analogues treatment: HERMES Study Interim Analysis
P. Lampertico; 1; M. R. Brunetto; 2; A. Craxì; 3; G. B. Gaeta; 4; M. Rizzetto; 5; G. Palmieri; 6; M. Colombo; 1; 1. Division of Gastroenterology and Hepatology, Ospedale Maggiore Policlinico, University of Milan, Milan, Italy. 2. Liver Unit, Reference Centre for Chronic Liver Desease and HCC of the Tuscany Region, University Hospital of Pisa, Pisa, Italy.
3. Gastroenterology and Hepatology, Di.Bi.M.I.S., University of Palermo, Palermo, Italy.
4. Department of Internal Medicine, Section of Infectious Desease, Second University of Naples, Naples, Italy. 5. Department of Gastroenterology, University of Turin, Turin, Italy.
6. Roche S.p.A., Monza, Italy.
Abstract Body: Objective: Nucleos(t)ide Analogues (NA) suppress viral replication in Chronic Hepatitis B (CHB) HBeAg-negative patients without inducing significantly HBsAg loss. Several studies investigating the impact to HBsAg levels of Peginterferon alfa-2a (PEG-IFN) addition to NA treated patients. Here we present the week 24 analysis of an ongoing trial evaluating PEG-IFN add-on in NA treated CHB, HBeAg-negative, genotype D, Caucasians patients (HERMES study).
Methods: In this phase IIb, open label, single arm, multicenter study 13 sites in Italy enrolled patients who were receiving NA monotherapy, with HBV-DNA persistently below 20 IU/ml for at least 12 months and HBsAg >100 IU/ml. Prior to the addition of PEG-IFN, eligible patients were observed for 3 months and those with HBsAg decrease <0.5 log10 IU/ml at the end of the observational period, initiated add-on treatment with Peginterferon alfa-2a 180 μg sc once weekly for 48 weeks. Patients without any HBsAg decrease at week 24 or those who will complete the add-on treatment period (week 48) are going to discontinue PEG-IFN and be followed-up for additional 48-weeks. Serum HBsAg decline at the end of treatment with PEG-IFN plus NA combination (week 48) is the primary study endpoint. Results: 70 Caucasians, had completed 24 weeks of combination treatment and were included in this analysis. Median age was 50.5 (29-64) and 81% were males. At week 24 of combination treatment, 27.1% decreased serum HBsAg ≥ 50% from baseline, while 15.7% discontinued study due to lack of response. The median HBsAg count significantly decreased from baseline to week 24 (p<0.0001). The proportion of patients with HBsAg < 500 or < 1000 IU/ml increased from baseline up to week 24 (table). Fifty-seven patients (81.4%) experienced adverse events (AEs), 4.3% and 5.7% of the patients discontinued or temporarily interrupted PEG-IFN due to AEs respectively, while in 8.6% of patients PEG-IFN dosage was adjusted due to AEs.
Conclusion: In HBeAg-negative, CHB, genotype D patients treated with nucleot(s)ide analogues, add-on treatment with PEG-IFN results in significant reduction of serum HBsAg levels.
Table: HBsAg kinetics following 24 weeks of PEG-IFN and NA combination treatment
.
Baseline (n=70)
Week 12 (n=67)
Week 24 (n=66)
HBsAg, IU/ml
.
Change from baseline
Change from baseline
Mean (SD)
1742.4 (1747.1)
-213.8 (1108.9)
-533.9 (1141.3)
Median (Q1-Q3)
1159.7 (571.9 to 2321.0)
-85.7 (-414.9 to 85.8)
-220.1 (-649.3 to - 91.7)*

[yibok]

Hi Stef

HBsAg clearance at the end of PEGIFN treatment (W48) was associated with (1) baseline HBsAg titer (p= 0.018) and (2) history of HBeAg seroconversion prior to randomization (4/17 (23.5%) vs 2/61(3.3%))(p=0.0185).

How much is p=0.018 corresponds to Hbsag value in IU/ML , Is there any coversion calculation that we can do .

and what does HbeAg seroconveriosn prior to randomization means , Just trying to read more and more getting  clarification on HBV.

Thanks

[stef2011]

http://www.aasld.org/livermeeting/Documents/Late-Breaking%20Abstracts%20TLM14.pdf

I prefer reports from italian researchers even if study is not finished yet pointing to the hbsag decline kinetics, i dont think hbsag clearance is possible to improve with just few years on nucs or just 1 year

did they report hbsag declines on that poster?

[studyforhope]

HERE IS A RELATED PEGASYS ADD ON STUDY WHERE PATIENTS HAD TO BE UND ON ANTIVIRALS FOR AT LEAST ONE YEAR PRIOR TO IFN START.

HBsAg clearance after addition of 48 weeks of PEGIFN in HBeAg negative CHB patients on Nucleos(t)ide therapy with undetectable HBV DNA for at least one year: a multicenter randomized controlled phase III trial ANRS-HB06 PEGAN study: preliminary findings

Marc Bourliere1, Pascaline Rabiega2, Nathalie Ganne-Carrie4, Lawrence Serfaty5, Patrick Marcellin6, Noelle Pouget2, Dominique Guyader7, Christophe Hezode8, Magali Picon9, Xavier Causse10, Vincent Leroy11, Jean-Pierre Bronowicki12, Ghassan Riachi13, Isabelle Rosa14, Pierre Attali15, Jean-Michel Molina16, Yannick Bacq17, Albert Tran18, Jean Didier Grange19, Fabien Zoulim20, Helene Fontaine21, Inga Bertucci22, Magali Bouvier-Alias23, Fabrice Carrat2, Yves Benhamou3;

1hepato-gastroenterology, hopital saint joseph, Marseille, France; 2INSERM UMR-S1136, Medical school Saint Antoine, Paris, France; 3Hepato-Gastroenterology, Pitie Salpetriere University Hospital, Paris, France; 4Hepato-Gastroenterology, Jean Verdier Hospital, Bondy, France; 5Hepato-Gastroenterology, Saint Antoine hospital, Paris, France; 6Hepatology, Beaujon Hospital, Clichy, France; 7Hepatology, Pontchaillou University Hospital, Rennes, France; 8Hepato-Gastroenterology, Henri Mondor University Hospital, Creteil, France; 9Hepato-Gastroenterology, Aix General Hospital, Aix en provence, France; 10Hepato-Gastroenterology, La source Hospital, Orleans, France; 11Hepato-Gastroenterology, University Hospital, Grenoble, France; 12Hepato-Gastroenterology, Brabois University Hospital, Nancy, France; 13Hepato-Gastroenterology, Charles Nicolle Hospital, Rouen, France; 14Hepato-Gastroenterology, Intercommunal Hospital, Creteil, France; 15Hepato-Gastroenterology, Bicêtre Hospital, Le Kremlin Bicêtre, France; 16Infectious diseases, Saint Louis Hospital, Paris, France; 17Hepato-Gastroenterology, Trousseau Hospital, Tours, France; 18Hepato-Gastroenterology, Archet Hospital, Nice, France; 19Hepato-Gastroenterology, Tenon Hospital, Paris, France; 20Hepato-Gastroenterology, Hotel Dieu Hospital, Lyon, France; 21Hepato-Gastroenterology, Cochin Hospital, Paris, France; 22Viral hepatitis, INSERM-ANRS, Paris, France; 23Bacteriology and Immunology, INSERM U 635, Creteil, France

Background and Aims: Uncontrolled studies suggest that addition of PEGIFN in CHB patients receiving NUCs with unde-tectable serum HBV DNA may increase HBsAg clearance. We conducted a multicenter randomized controlled study to evaluate this strategy. Patients and methods: The key inclusion criteria were: HBeAg negative CHB and documented negative HBV DNA while on stable NUC regimens for at least 1 year. Patients with PEGIFN contra-indications were excluded. From Jan 2011 to July 2012, 183 patients (86 %male, mean age 47.6 years range 28-74, HBV DNA undetectable for 192 weeks range 17-685) were randomized to receive a 48 weeks course of 180 μg/w PEGIFN-alfa-2a (Pegasys) in addition to the backbone NUC regimens (Group 1: n=90) or no additional therapy (Group 2: n=93). Patients were stratified according to the HBsAg titers (< or ≥ 2.25 log IU/ml). NUC regimens remained unchanged during the study period up to week 144. Treatments discontinuation was allowed if HBsAg clearance was sustained for 24 weeks. Patients were seen monthly during the first 48 weeks, then every 3 months. The primary end point was the proportion of patients with serum HBsAg clearance at week 96. Secondary endpoints included HBsAg clearance at Week 48. Preliminary Results: 85 patients initiated PEGIFN in group 1, 17 patients discontinued prematurely PEGIFN due to adverse events, and 4 patients had a dose reduction to 135μg/w. There was no discontinuation of the NUC regimens in all the patients of both groups. At week 48, 6 patients had an HBsAg clearance in group 1 and 1 in group 2 (p= 0.061). Demographic and baseline characteristics, CHB history and history of anti-HBV therapies were studied. HBsAg clearance at the end of PEGIFN treatment (W48) was associated with (1) baseline HBsAg titer (p= 0.018) and (2) history of HBeAg seroconversion prior to randomization (4/17 (23.5%) vs 2/61(3.3%))(p=0.0185). Conclusion: Addition of a 48 weeks course of PEGIFN alfa-2a to oral anti-HBV therapy in HBeAg negative CHB patients with undetectable serum HBV DNA for at least 1 year: (1) Results in a low rate of HBsAg clearance (6/90 (6.6%)) and (2) Suggests that low baseline HBs Ag titers and a history of HBeAg seroconversion either spontaneously or under HBV therapy may increase HBsAg clearance rate.

[studyforhope]

This study was selected for a plenary presentation, with thousands of doctors and researchers attending. Only a few of the oral presentations get this honor, so at least the aasld committee must have judged it as very important.

[stef2011]

yes genotype E is the less responsive but on sequential it is not virus that counts but rescue of t cells reactivity to hbv by years of antivirals, so genotype is indipendent

on sequential studies they said hbsag clearance is indipendent of genotype only the number of years on antivirals counts and possibly on the most potent tdf

the study of this post is not the most interesting, check the studies on 10years of antivirals and the studies on sequential peg add on

[bigmoviebuff]

did they break it up by genotype?
I Have genotype E which my doctor says is more aggressive and inteferon does not respond well to it. Less that 1-2% cure with Peg is what he told me.

[stef2011]

actually not hbsag loss for all but trend to very low/undetectable cccdna already at 10 years use, at this stage hbsag can be cleared easily by immune system in the following years or by peg add on

actually i d never thought antivirals could clear cccdna but these are very good results

[mer971]

I agree with Steff, as 20 people, as 100 is the same,results are excellent,it doesn't matter the number, purpose is how many of them have loss hbsag

[stef2011]

when you have such clear results it doesn t matter the number of patients, if trend is close to 90-100% even 10 patients are enough.other trials showed exactly the same

the trend is very clear between 10-15years of tdf there is a rescue of tcell function and loss of cccdna

[melcul]

Stef's trial has5-10 years period results, very encouraging but only on 40 people. This one has 740 patients but only on 2 years stll ongoing ..we need large scale trials for 5-10 years ..anyway, i think for 2 years trial on 740 patients the results are not very encouraging

[StephenCastlecrag]

Thank you for the posting. Yes, there are sure a lot of abstracts to go read. Sometimes, it is a puzzle to read about research studies with results that are pulling in different directions.The #1855 abstract:
Profound Reduction of HBV Covalently Closed Circular DNA with Long-term Nucleoside/tide Analogue Therapy
by researchers from Hong Kong seems to be more encouraging, although the sample size was small.

I also read a abstract that used the phrase "HBsAg negative phase" and the use of a ultra-sensitive assay for serum HBsAg.

Please select more ASSLD abstracts and post them with your comments.

[studyforhope]

all the 2014 abstracts are available now.

but the conference book has 1300 pages, hard work to find ones way around.

these trial patients were a broad mix, very representative of the average hbv patient.
but they did not have long tenofovir pretreatment times.
overall a little bit disappointing for the combo treatment, but in line with previous similar smaller trials.