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AASLD 2011- Feedback on HBV

AASLD 2011- Feedback on HBV. Dr Allister J Grant Consultant Hepatologist University Hospitals Leicester NHS Trust 62 th Annual Meeting November 4 – 8, 2011 San Francisco, CA. No Resistance to Tenofovir (TDF) Following up to 240 Weeks of Treatment in HBeAg + and HBeAg - CHB Infection.

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AASLD 2011- Feedback on HBV

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  1. AASLD 2011- Feedback on HBV Dr Allister J Grant Consultant Hepatologist University Hospitals Leicester NHS Trust 62th Annual Meeting November 4 – 8, 2011 San Francisco, CA

  2. No Resistance to Tenofovir (TDF) Following up to 240 Weeks of Treatment in HBeAg+ and HBeAg- CHB Infection Study 102 (HBeAg- Patients) and 103 (HBeAg+ Patients) Year 1 Year 8 Tenofovir DF 300 mg N=250& N=176 Tenofovir DF 300 mg N=235 N=154 RANDOMIZATION 2:1 Adefovir Dipivoxil 10 mg N=125 & N=90 Tenofovir DF 300 mg N=112 N=84 Year 1 Liver Biopsy1 Pre-treatment Liver Biopsy Year 5/ Week 240 Liver Biopsy Week 72 Year 8 Year 3 • At Week 72, patients with HBV DNA ≥ 400 copies/mL had the option at the discretion of the investigator to add emtricitabine (FTC) • Retention rate at Week 240: 81% for HBeAg-, 70% for HBeAg+ Marcellin, P, et al. AASLD 2011; Oral #238

  3. Study 102 (HBeAg-): Proportion of Patients with HBV DNA <400 copies/mL Week 240: TDF-TDF 83%ADV-TDF 84%Overall: 83% Long-term evaluation [LTE-TDF] (missing/ addition of FTC = failure) Marcellin, P, et al. 2011 AASLD, Poster #1375. Marcellin, P, et al. AASLD 2011; Oral #238.

  4. The Addition of FTC to TDF Between Weeks 72-240 Did Not Impact Subsequent HBV DNA Decline All subjects analyzed with >400 copies/mL had no evidence of TDF resistance Marcellin, P, et al. AASLD 2011; Oral #238.

  5. Virologic Breakthrough was Infrequent and Associated with Non-adherence • 4/495 (0.8%) of patients were classified as having virologic breakthrough during Year 5 • 3 patients had documented non-adherence during the time of breakthrough (TFV plasma levels undetectable) • All 4 patients had HBV DNA return to <400 copies/mL during Year 6 • Phenotypic analysis revealed isolates from all virologic breakthrough patients were sensitive to tenofovir (fold change values <2 compared to baseline) Marcellin, P, et al. AASLD 2011; Oral #238.

  6. Efficacy Summary Marcellin, P, et al. AASLD 2011; Oral #238.

  7. Five years of Treatment with Tenofovir DF for Chronic Hepatitis B Infection is Associated with Sustained Viral Suppression and Significant Regression of Histological Fibrosis and Cirrhosis P. Marcellin1, M. Buti2, E.J. Gane3, Z. Krastev4, R. Flisiak5, G. Germanidis6, M.K. Washington7, C.N. Barnes8, J.F. Flaherty8, J.D. Bornstein8, J.G. McHutchison8, E.J. Heathcote9 1Hôpital Beaujon, APHP, Clichy, France, 2Hospital General Universitari Vall d’Hebron and Ciberehd, Barcelona, Spain, 3Auckland City Hospital, Auckland, New Zealand ,4University Hospital “St. Ivan Rilsky”, Sofia, Bulgaria, 5Medical University ofBialystok, Bialystok, Poland, 6University Hospital of Thessaloniki, Thessaloniki, Greece, 7Vanderbilt University, Nashville, TN, United States, 8Gilead Sciences Inc., Foster City, CA, United States, 9University of Toronto, Toronto, ON, Canada Marcellin, P, et al. AASLD 2011; Poster #1375.

  8. Change in Ishak Fibrosis Scores at Year 5 by Baseline Fibrosis Score n=10 n=126 n=79 n=37 n=19 n=77 100% 90% Improvement No Change 80% Worsening 70% 348 paired biopsies at Year 5 (71%) 60% Percentage of Subjects 50% 40% 96% (335/348) of patients with paired biopsies either improved (≥ 1 unit decrease in fibrosis score) or did not change at Year 5 30% 20% 10% 0 Percentage of the population with cirrhosis (Ishak Score ≥5) progressively decreased from 28% at baseline to 8% at Year 5 1 2 3 4 5 6 Baseline Ishak Fibrosis Score Marcellin, P, et al. AASLD 2011; Oral #238.

  9. Distribution of Ishak Fibrosis Scores at Baseline, Year 1, and Year 5 • 344/348 patients had liver biopsy data available at all three time points • Percentage of the population with cirrhosis (Ishak Score ≥5) progressively decreased from 28% at baseline to 8% at Year 5 Marcellin, P, et al. AASLD 2011; Poster #1375.

  10. Authors’ Conclusions • Over 5 years, sustained virologic suppression is associated with histologic improvement and regression of liver fibrosis • Largest prospective dataset of chronic HBV patients with sequential biopsies • 96% of patients with paired biopsies had either improvement or no worsening of fibrosis • 74% of patients with cirrhosis at baseline were no longer cirrhotic at year 5 • 98% of patients on TDF had undetectable HBV DNA levels of < 400 copies/mL • Virologic and biochemical responses are maintained • Sustained virologic suppression maintained through 5 years • ALT normalization maintained in the majority of patients • 11% of patients had confirmed HBs-Ag loss (8% with seroconversion) with 5 years of TDF • No resistance detected to TDF through 5 years Marcellin, P, et al. AASLD 2011; Poster #1375.

  11. Effects of Tenofovir on Vitamin D Levelsin Chronic Hepatitis B Mono-infected Patients: A Single Centre “Real Life” Cohort Experience Huyen-Ly Nguyen, Mohammad A B Al-Freah, Roy Sherwood, Ivana Carey, Dorothy Joe, Abid Suddle, Phillip M. Harrison, Kosh Agarwal Institute of Liver Studies, King’s College Hospital, London, UK Nguyen, HL, et al. AASLD 2011; Poster #509.

  12. 1 Mueller NJ et al. AIDS 2010; 24(8):1127-34. Introduction Vitamin D deficiency has been shown to be prevalent in patients with viral diseases such as HIV. Data derived from HIV population demonstrate negative effects of Tenofovir (TDF) on vitamin D levels and bone mineral density1 To determine the impact of Tenofovir on vitamin D levels as well as metabolic bone parameters in patients mono-infected with HBV Nguyen, HL, et al. AASLD 2011; Poster #509.

  13. Methods Nguyen, HL, et al. AASLD 2011; Poster #509. Retrospective study of all patients treated with TDF or Entecavir (ETV) in our centre (n=313) from May 2006 to September 2010 Collected data included demographic, clinical variables, Vitamin D (VD), phosphate, calcium and alkaline phosphatase levels at baseline and at 12 months after initiation of TDF or ETV Data collection at baseline (initiation of TDF or ETV) and following 12 months of treatment (+/- 3 months) Patients on combination of TDF and ETV (n=22) and those that received VD supplementation within 3 months prior to initiation of antiviral therapy or at any point during the 12 months follow up (n=114) we excluded

  14. Baseline Vitamin D Analysis Nguyen, HL, et al. AASLD 2011; Poster #509. Median VDaccording to ethnicity Median VDaccording to season 20 20 18 18 16 16 16.9 16.5 16.45 14 14 15.7 14.3 12 12 13.8 Vitamin D μg/L Vitamin D μg/L 10 10 11.4 11 11.2 8 8 6 6 4 4 2 2 0 0 Winter Spring Summer Autumn Indian Other Afro-Caribbean SE Asian European Season Ethnic Group p = 0.015, Kruskal-Wallis, n = 272 p = 0.005 Kruskal-Wallis, n = 272 • Significant seasonal variability, with higher vitamin D levels detected during the Summer and lowest levels during the Winter • The prevalence of vitamin D deficiency in this cohort of patients was 71.7%, defined as vitamin D levels < 22 µg/L • There is a significant variability in vitamin D levels among the different racial groups of patients being treated at our centre in South East London • Vitamin D deficiency was more prevalent in men than women 85% vs 72%

  15. Nguyen, HL, et al. AASLD 2011; Poster #509. Comparison of Baseline Characteristics According to Anti-Viral Therapy (cont.) ALP = Alkaline phosphatase • The TDF cohort had a higher baseline phosphate level than those on ETV • There was no significant difference in the remaining metabolic bone parameters at baseline

  16. Nguyen, HL, et al. AASLD 2011; Poster #509. 12 Months Interval Data • No difference in vitamin D levels at baseline and at 12 months in either of the treatment groups • The TDF cohort showed a significant rise in alkaline phosphatase and a fall in calcium which may indicate development of metabolic bone disease

  17. Authors’ Conclusions Nguyen, HL, et al. AASLD 2011; Poster #509. Vitamin D deficiency is highly prevalent in this cohort of chronic hepatitis B mono-infected patients No significant decrease in vitamin D levels after 12 months of treatment with either TDF or ETV Significant rise in ALP and decline in calcium in the TDF cohort and a downward calcium trend in the ETV cohort suggesting adverse effects on bone metabolism Further long term follow-up with additional radiological assessment of bone mineral density is warranted to establish if AVT such as TDF and ETV are associated with a negative effect on bone metabolism

  18. Bone Mineral Density Results (Year 4 to Year 5) • No significant changes were observed in mean (SD) BMD results from year 4 to year 5 for hip and lumbar spine • No consistent trends were observed in T score (see Table) or Z score (data not shown) category shifts between year 4 and year 5 a. T Score ranges: normal > -1, osteopenia -1 to -2.5, osteoporosis < -2.5; pooled data (N=266 hip; N=276 spine) Marcellin, et al. AASLD 2011; Poster #1385.

  19. Entecavir (ETV) Monotherapy for 96 Weeks is Comparable to Combination Therapy with ETV Plus Tenofovir (TDF) in Nucleos(t)ide-naïve Patients with Chronic Hepatitis B (CHB): The BE-LOW Study A.S. Lok1, H. Trinh2, G. Carosi3, U. Akarca4, A. Gadano5, F. Habersetzer6, W. Sievert7, D. Wong8, M. Lovegren9, D. Cohen9, C. Llamoso9 1. University of Michigan, Ann Arbor, MI, United States. 2. Pacific Health Foundation, San Jose, CA, United States. 3. Institute of Infectious and Tropical Disease, University of Brescia, Brescia, Italy. 4. Department of Gastroenterology, Ege University, Izmir, Turkey. 5. Seccion Hepatologia, Hospital Italiano de Buenos Aires – Argentina, Ciudad de Buenos Aires, Argentina. 6. Service d’Hepato-gastroenterologie, Nouvel Hopital Civil, Strasbourg, France. 7. Department of Medicine, Monash University, Melbourne, VIC, Australia. 8. Toronto Western Hospital, University Health Network, Toronto, ON, Canada. 9. Research and Development, Bristol-Meyers Squibb Company, Wallingford, CT, United States Lok, AS, et al. AASLD 2011; Oral #223.

  20. ETV-110: Study Design Dosing x 100 weeks RANDOMIZATION 1:1 Further anti-HBV therapy at discretion of investigator – up to 24 weeks follow-up ETV 0.5 mg, once daily (N = 182) * ETV 0.5 mg + TDF 300 mg, once daily (N = 197) * Week 96 • Randomized, open-label, Phase IIIb trial • NA-naïve CHB, HBeAg(-) patients capped at 30% Baseline Primary endpoint *Modified intent-to-treat (ITT) population: received at least one dose of study medication Lok, AS, et al. AASLD 2011; Oral #223.

  21. HBV DNA <50 IU/mL at Weeks 48 and 96: Overall Difference 9.9% (95% CI 1.5, 18.4) Difference 6.9% (95% CI -1.0, 14.9) HBV DNA <50 IU/mL(% patients) * Number of 128158139164 Patients: 182197182197 Non-completer = failure *Primary endpoint Lok, AS, et al. AASLD 2011; Oral #223.

  22. HBV DNA <50 IU/mL at Weeks 48 and 96: By Baseline HBeAg Status HBeAg(+) HBeAg(-) Lok, AS, et al. AASLD 2011; Oral #223.

  23. Authors’ Conclusions • At Week 96, both treatment arms (ETV monotherapy and ETV + TDF combination therapy) showed comparable antiviral efficacy in a mixed population (70% HBeAg[+]) of NA-naïve CHB patients • Both treatments were well tolerated with comparable safety profiles • Combination of ETV + TDF did not provide an overall benefit compared to ETV monotherapy. However, it may • Provide incremental benefit in HBeAg(+) patients with baseline viral load ≥ 108 IU/mL • Have a role in clinical settings in patients with high viral load where rapid HBV DNA decline is important Lok, AS, et al. AASLD 2011; Oral #223.

  24. Quantitative HBsAg as Predictor of Outcomes in Chronic Hepatitis B • Patients with chronic hepatitis B enrolled 1991-1992 (N = 4155) and followed until 2004 • Natural history study of previously untreated patients • In multivariate analysis, baseline HBsAg level independently predicted spontaneous HBV DNA and HBsAg clearance Baseline HBV DNA ≥ 104 copies/mL (N = 1449) HBsAg Seropositives (N = 2946) 1.0 1.0 Baseline HBsAg (IU/mL) Baseline HBsAg (IU/mL) 86.0% 86.6% ≥ 10,0001000-9999 100-999< 100 ≥ 10,0001000-9999100-999 10-99< 10 0.8 0.8 0.6 0.6 Cumulative Incidence of HBV DNA Seroclearance Cumulative Incidence of HBsAg Seroclearance 49.1% 42.2% 45.9% 0.4 0.4 41.9% P < .001 P < .001 32.1% 0.2 0.2 17.4% 3.3% 0 0 0 2 4 6 8 10 12 14 0 2 4 6 8 10 12 14 Yrs Yrs Liu J, et al. AASLD 2011. Abstract 239.

  25. Initiation of LAM in 2nd vs 3rd Trimester in Pregnant Women With High HBV Viremia • Retrospective analysis of lamivudine initiated in 2nd vs 3rd trimester in women with HBV DNA > 6 log10 copies/mL • All babies received HBIG and appropriate vaccinations • Vertical transmission determined by HBsAg and HBV DNA status at 7-12 month • Significant reduction of perinatal transmission with similar efficacy when LAM administered in 2nd or 3rd trimester among highly viremic women Infants’ HBsAg status at birth Infants’ HBsAg status at 28 wks 60 P = .003 40 P = .004 30.4 Infants With HBsAg+ in the Venous Blood (%) 24.4 P < .001 20 11.8 8.7 14/119 11/45 28/92 8/92 0 0 0 LAM Usein the 2T LAM Usein the 3T Untreated Han GR, et al. AASLD 2011. Abstract 236.

  26. HBV Reactivation Among Patients With Cancer • Retrospective cohort, chart review of 10,729 patients with solid or hematologic cancers who received initial chemotherapy between 2004-2007 • 17% of patients at risk for HBV reactivation screened • HBsAg: 87 • HBsAg and anti-HBc: 1665 • Anti-HBc: 35 Hwang JP, et al. AASLD 2011. Abstract 172.

  27. High HBV Reactivation Rate Among Patients With Cancer • 34 patients experienced HBV reactivation • HBsAg+: 14/26 (54%) • Anti-HBc+: 20/125 (16%) • Leukemia: 14 • Lymphoma: 8 • Myeloma: 1 • Solid tumors (eg, lung, colon, HCC): 11 • Rituximab treated: 10 • 26% prophylaxis Rx and 32% rescue Rx • All cause mortality • 22% prophylaxis • vs. 71% Rescue • vs. 72% No Rx 100 80 60 Patients With Reactivation (%) 40 28 20 14 0 Solid(9/63) Hematologic(23/82) Cancer Type • Mean age: 47 yrs with reactivation vs 54 yrs for no reactivation Hwang JP, et al. AASLD 2011. Abstract 172.

  28. Thank you

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