Title | FACTORS ASSOCIATED WITH REGRESSION OF CIRRHOSIS IN PATIENTS WITH CHORNIC HEPATITIS B (CHB) INFECTION TREATED WITH TENOFOVIR DISOPROXIL FUMARATE (TDF) |
Speaker: | Nezam Afdhal |
Author: | N. Afdhal1*, M. Buti2, S. Fung3, E. Gane4, J. Flaherty5, E. Martins5, N. Bekele5, J. Bornstein5, P. Marcellin6 |
Affiliation: | 1Harvard Medical School, Boston, MA, USA, 2Servei de Medicina Interna-Hepatologia, Vall d'Hebron Hospital General, Barcelona, Spain, 3Univeristy of Toronto, Toronto, ON, Canada, 4Auckland City Hospital, Auckland, New Zealand, 5Gilead Sciences, Foster City, CA, USA, 6Hopital Beaujon, Clichy, France. *[email protected] |
Regression of fibrosis is an important clinical outcome for patients with CHB who achieve long term viral suppression with nucleos(t)ide therapy. It has been previously reported that up to 5 years of TDF therapy results in a regression of cirrhosis in 74% of patients. The clinical and pathophysiologic differences between those that had reversal and those that did not has not been described.
Methods: A retrospective analysis was conducted on 96 cirrhotic patients (Ishak fibrosis stage ≥ 5) who had liver biopsies at baseline and at year 5 in 2 studies that compared the safety and efficacy of TDF to adefovir for 48 weeks in HBeAg negative (Study 0102) and HBeAg positive (Study 0103) patients, followed by open-label TDF treatment for an additional 7 years.
Results: 96 patients with cirrhosis at baseline had follow-up biopsies at year 5. 71 of the 96 (74%) were no longer cirrhotic (Ishak fibrosis stage ≤ 4). Among the different baseline covariates assessed, elevated body weight (87.4 kg vs. 76.8 kg, p=0.013) and body mass index (BMI) (29.0 kg/m2 vs 25.7 kg/m2, p< 0.001) were the only variables that were significantly correlated with persistent cirrhosis. Age, gender, race, viral genotype, inflammation, platelet count, albumin, ALT, and DNA and HBsAg titers did not correlate. There was a trend showing that patients with a shorter time since diagnosis and those with Ishak fibrosis stage 5 were more likely regress than those with longer duration of infection and Ishak stage 6 fibrosis. Subjects who were no longer cirrhotic were more likely than those with persistent cirrhosis to have a normal ALT at year 5, but no other differences were noted in outcomes for those that resolved cirrhosis vs. those that did not. Both groups had similar increases in platelet counts and albumin levels, similar rates of HBeAg loss, viral suppression, and HCC rates. No patient in either group had ascites, variceal bleeding or hepatic encephalopathy.
Conclusion: TDF therapy results in a high rate of cirrhosis reversal. Persistence of cirrhosis is most likely when risk factors for a 2nd disease such as obesity induced liver disease co-exists. |
Title | CLINICAL, VIROLOGICAL, SEROLOGICAL AND HISTOLOGICAL OUTCOMES IN CIRRHOTIC PATIENTS WITH CHRONIC HEPATITIS B (CHB) TREATED WITH TENOFOVIR DISOPROXIL FUMARATE (TDF) FOR UP TO 5 YEARS |
Speaker: | Maria Buti |
Author: | M. Buti1*, S. Fung2, E. Gane3, N. Afdhal4, J. Flaherty5, E. Martins5, N. Bekele5, J. Bornstein5, P. Marcellin6 |
Affiliation: | 1Servei de Medicina Interna-Hepatologia, Vall d'Hebron Hospital General, Barcelona, Spain, 2Univeristy of Toronto, Toronto, ON, Canada, 3Auckland City Hospital, Auckland, New Zealand, 4Harvard Medical School, Boston, MA, 5Gilead Sciences, Foster City, CA, USA, 6Hopital Beaujon, Clichy, France. *[email protected] |
CHB suppression with TDF improves transaminases, results in a regression of liver fibrosis and increases HBeAg seroconversion. Long term data in cirrhotic patients is needed.
Methods: A retrospective analysis of 2 pivotal studies of TDF was conducted to assess whether cirrhotic patients had different clinical outcomes than non-cirrhotic patients. In these studies, the safety and efficacy of TDF compared to adefovir was assessed for 48 weeks in HBeAg negative (Study 0102) and HBeAg positive (Study 0103) patients, followed by open-label TDF treatment.
Results: A total of 634 subjects were included. Cirrhotics had outcomes comparable to non-cirrhotics (see tables).
Parameter | Baseline Cirrhotic (n=152) | Baseline Non-cirrhotic (n=482) | P-Value | % >40 years old | 68% | 45% | <0.001 | % male | 81% | 72% | 0.022 | Mean BMI (kg/m^2) | 26.5 | 25.1 | <0.001 | Mean platelets (x10^3) | 178 | 219 | <0.001 | Mean albumin (g/dL) | 4.0 | 4.2 | <0.001 |
[Baseline Characteristics of Cirrhotics vs. Non-cir]
Parameter | Baseline Cirrhosis (n=152) | Baseline Non-cirrhosis (n=482) | P-Value | HBV DNA < 400 copies/ml | 99% | 98% | NS | ALT < ULN | 80% | 82% | NS | HBeAg loss | 62% | 45% | 0.066 | HBsAg loss | 2% | 3% | NS | Mean increase in platelets (x10^3) | 31 | 20 | 0.03 | Mean increase in albumin (g/dL) | 0.27 | 0.1 | <0.001 | Fibrosis: regression | 74% | 42% | NA | Fibrosis: no change | 25% | 54% | NA | Fibrosis: worsening | 1% | 1% | NA |
[Year 5 Comparison of Cirrhotics and Non-cirrhotics]
There were no cases of hepatic encephalopathy or variceal bleeding in either group, and ascites occurred in one non-cirrhotic patient with HCC. The incidence of HCC was 1.5% in non-cirrhotics and 3.3% in cirrhotics (p=NS).
Conclusions: Cirrhotic patients differed from non-cirrhotic subjects at baseline, but demonstrated significant treatment benefits with 74% experiencing regression of cirrhosis. Cirrhotic patients treated with TDF had similar rates of viral suppression and serological responses as non-cirrhotics and derived comparable clinical benefit after 5 years of viral suppression. |
Title | IS HBeAg LOSS ASSOCIATED WITH AN IMPROVED OUTCOME IN HEPATITIS B PATIENTS TREATED WITH TENOFOVIR DISOPROXIL FUMARATE (TDF)? |
Speaker: | Scott Fung |
Author: | S. Fung1*, M. Buti2, E. Gane3, N. Afdhal4, J. Flaherty5, E. Martins5, N. Bekele5, J. Bornstein5, P. Marcellin6 |
Affiliation: | 1University of Toronto, Toronto, ON, Canada, 2Servei de Medicina Interna-Hepatologia, Vall d'Hebron Hospital General, Barcelona, Spain, 3Auckland City Hospital, Auckland, New Zealand, 4Harvard Medical School, Boston, MA, 5Gilead Sciences, Foster City, CA, USA, 6Hopital Beaujon, Clichy, France. *[email protected] |
In patients with chronic hepatitis B (CHB) infection, spontaneous HBeAg seroconversion is a key event in the transition from active hepatitis to the inactive carrier state, which is associated with improved prognosis. It is unclear whether nucleos(t)ide analogue-induced HBeAg loss produces a similar benefit and whether therapy should be stopped once this outcome is achieved.
Methods: A retrospective analysis was conducted on HBeAg positive subjects enrolled in study GS-US-0174-103 that compared TDF to adefovir for 1 year followed by open-label TDF for up to 7 years. Subjects who lost HBeAg were compared to those remained HBeAg-positive at the end of year 5.
Results: 165 subjects were included, of whom 81 (49%) became HBeAg negative while 84 (51%) remained HBeAg positive. Baseline characteristics associated with a higher likelihood of HBeAg loss on treatment included age > 40 years (46% vs. 24%, p=0.003), genotype A (37% vs. 10%, p< 0.001), higher hepatic necroinflammatory score (mean Knodell 9 vs. 8, p=0.038), lower serum HBV DNA (8.42 vs. 8.90 Log10 copies/ml, p=0.002) and lower HBsAg levels (55,000 vs. 65,000 IU/ml, p=0.052). Subjects who achieved HBeAg loss at year 5 were more likely to have undetectable HBV DNA (100% vs. 94%, p=0.026) as well as HBsAg loss (10% vs. 0%, p=0.003) and HBsAg seroconversion to anti-HBs (7% vs. 0%, p=0.011). No significant differences were observed between the groups in terms of reduction of hepatic inflammation, regression of fibrosis, development of hepatocellular carcinoma and or hepatic decompensation.
Conclusions: Older patients with more hepatic inflammation, lower HBV DNA and HBsAg levels and HBV genotype A infection were more likely to become HBeAg negative on TDF therapy. Subjects who lost HBeAg were more likely to have undetectable HBV DNA and to also lose HBsAg . No difference in long-term clinical outcomes was noted, although longer follow-up and long-term therapy are likely necessary to detect such differences. |
Title | A European field study of the efficacy and safety of Tenofovir disoproxil fumarate (TDF) as monotherapy in patients with prior failure to other nucleoside/nucleotide analogues |
Speaker: | Florian van Bömmel |
Author: | F. van Bömmel1*, R. Zoutendijk2, R. de Man3, J.-P. Bronowiki4, K. Rutter5, P. Ferenci5, H. Janssen2, B. Fülöp1, A. Brodzinski1, J. Wiegand1, H. Wedemeyer6, K. Deterding6, A. Erhardt7, D. Hüppe8, M. Bourlière9, C. Sarrazin10, J. Trojan10, P. Buggisch11, J. Petersen11, U. Spengler12, A. Kamp13, S. Mauss13, M. Schuchmann14, K. van Nieuwkerk15, T. Gerlach16, D. Moradpour17, A. Schweinberger1, H. Wasmuth18, T. Berg1 |
Affiliation: | 1Klinik und Poliklinik für Gastroenterologie und Rheumatologie, Universitätsklinik Leipzig, Leipzig, Germany, 2Erasmus MC Rotterdam, 3Gastroenterology, Erasmus MC University Hospital, Rotterdam, The Netherlands, 4Service d'Hépato-Gastroentérologie, CHU de Nancy, Nancy, France, 5Medical University of Vienna, Vienna, Austria, 6Medizinische Hochschule Hannover, Hannover, 7Universitätsklinikum der Heinrich-Heine-Universität Düsseldorf, Düsseldorf, 8Gastroenterologische Gemeinschaftspraxis Herne, Herne, Germany, 9Hôpital St Joseph, Marseille, France, 10Johann Wolfgang Goethe University Medical Center, Frankfurt/Main, 11IFI Institut Asklepios Klinik St Georg, Hamburg, 12Universitätsklinikum Bonn, Bonn, 13Center for HIV and Hepatogastroenterology, Düsseldorf, 14Universitätsklinikum Mainz, Mainz, Germany, 15VU Medisch Centrum, Amsterdam, The Netherlands, 16Klinik Augustinum, München, Germany, 17Centre Hospitalier Universitaire Lausanne, Lausanne, Switzerland, 18University Hospital Aachen, Aachen, Germany. *[email protected] |
Background: Monotherapy with tenofovir disoproxil fuarate (TDF) is effective in patients who are treatment naïve and in patients after failure to treatment with other nucleoside/nucleotide analogues (NUCs). In this study, we have assessed the efficacy of long term TDF treatment in patients with preceding failure to other NUCs in a real life setting.
Methods: Patients receiving monotherapy with TDF 245 mg per day after failure to other NUCs were identified in 22 European centres. Inclusion criteria were: age ≥ 18 years, duration of TDF treatment ≥ 6 months, re-increase of HBV DNA > 1 log10 from nadir during preceding NUC treatment, exclusion of non compliance as stated by the treating physician. HBV DNA was measured using a real time PCR based assay (Roche Amplicor, lower detection limit 400 copies/mL).
Results: 589 patients receiving monotherapy with TDF for a mean duration of 44±24 [range, 9-122] months after failure to NUC treatment were retrospectively analyzed in 18 European centers (mean age 44±13[range, 18-76] years, 74% male, 54% HBeAg positive). Pre-treatment included lamivudine (n=426), adefovir (n=374), telbivudine (n=13) and entecavir (n=16). HBV DNA levels decreased from 5.6±2.3 [2.8-10.3] to 2.6±13 [2.6-4.4] after 12 and to 2.6±0.9 [18-3.1] after 24 months, respectively. HBV DNA was detectable in 6 patients at months 24, all of them who had been pre-treated with ADV. No re-increase of HBV DNA levels > 1 log10 was observed. HBeAg and HBsAg losses was observed in 60 (20%) and 11 (2%, all HBeAg positive) patients after a mean duration of 12±12 [1-55] and 15±12 [range, 1-36] months, respectively. Mean glomerular filtration rates changed from 67±35 [34-124] to 63±55 [36-118] at months 24 (p=0.87). No patient with initial glomerular filtration rate > 50 ml/min showed a decrease to values < 50 ml/min. TDF treatment was stopped in one patient due to enteritis.
Conclusion: In a real life setting, TDF as monotherapy represents an effective and safe option for long term treatment for patients with prior failure to NUC treatment. |
-----Clinical, Virological, Serological and Histological Outcomes in Cirrhotic Patients with Chronic Hepatitis B (CHB) Treated with Tenofovir Disoproxil Fumarate (Tdf) for up to 5 Years