Geoffrey DUSHEIKO

1. Geoffrey DUSHEIKO

2. Nucleosides for HBeAg-positive chronic hepatitis B G Dusheiko Centre for Hepatology Royal Free and University College School of Medicine London UK

3. Nucleosides for HBeAg positive chronic hepatitis B • Discuss • Efficacy • Safety • Utility • Resistance • outstanding questions

4. Nucleoside efficacy and pharmacologyHBeAg positive chronic hepatitis B • Nucleoside analogues well characterised • Results 1996-2007 • Ushered in new era of treatment for chronic hepatitis B • Extensive response data acquired • Can achieve desired end points of treatment • Relative efficacy and response established

5. Treatment of HBeAg positive chronic hepatitis B: • Goals and endpoints of treatment achieved with nucleosides • Suppression of HBV DNA • Improve abnormal ALT • Improve hepatic histology • Slows development of fibrosis • Accelerates HBeAg seroconversion in some • HBeAg loss can lead to HBsAg loss • Prevent serious disease

6. HBV TreatmentEnd points of Antiviral Response DNA decline/negativity ALT decline HBeAg neg Anti-HBe HBsAg neg HBeAg Positive Histology Improves Variable: RESISTANCE Variable T cell response

7. HBeAg Seroconversion after one year treatment 0 30 20 10 95% CI for Proportion With Seroconversion

8. Efficacy at Years 1 and 2: HBeAg(+) Patients(ITT Population) Telbivudine Lamivudine

9. PEG alpha 2a: Effect HBV Genotype on HBeAg seroconversionWeek 52 Genotype Cooksley G et al EASL 2005

10. Tenofovir vs Adefovir in LAM-Resistant CHB Week 24 Week 36 Week 48 0 Tenofovir 300 mg/day for 72-130 weeks (n = 35) Adefovir 10 mg/day for 60-80 weeks (n = 18) -2.6 -2.8 -3.0 % HBV DNA < 400 copies/mL at Week 48 • 100% of tenofovir patients • 44% of adefovir group -5.2* -5.4* -5.5* *P < .001 vs ADV -7 Mean change in log10 HBV DNA (PCR) van Bömmel F, et al. Hepatology. 2004;40:1421-1425.

11. Telbuvidine: Distribution of Patients antiviral response Baseline, Week 24 and Week 52: HBeAg-positive Patients 14 13 12 11 Serum HBV DNA Log10 Copies/mL 10 9 8 7 6 5 4 Assay LLOQ 300 Copies/mL 3 2 52% 67% 25% 38% Baseline Week 24 Week 52 Baseline Week 24 Week 52 Telbivudine Lamivudine Jia JD et al 2006 Chinese study

12. HBeAg Seroconversion at 2 Years vs Antiviral Effect at Week 24* Percent HBeAg seroconversion Serum HBV DNA level at Week 24 *HBeAg positive patients, telbuvidine and lamivudine groups.

13. Lamivudine (nucleosides) predictors of response • High baseline ALT • Higher HAI score • Early viral suppression • Lack of resistance • Cirrhosis ? • (High DNA) • (Genotype) • Need predictors of durability

14. 25 Placebo (n=215) 21% YMDDm (n=209) (49%) 20 Wild Type (n=221) Placebo % with Disease Progression 15 13% YMDDm 10 5% 5 WT 0 0 6 12 18 24 30 36 Time after Randomisation (months) Disease modification with lamivudine therapy: Time to Disease Progression by YMDD Status Liaw et al, NEJM 2004

15. Integral role liver transplantation Combination of LAM and HBIG In decompensated disease anti-HBc donors Fulminant hepatitis Prophylactic chemotherapy Extrahepatic disease Immunosuppressed patients HIV co-infected patients In pregnancy Utility of lamivudine (nucleosides)

16. Safety of nucleosides • Safe agents, with infrequent monitoring • Rare reports of • mitochondrial toxicity • renal impairment • peripheral neuropathy • CPK elevations and myositis • Use in cirrhosis and decompensated cirrhosis • Flares with initiation, withdrawal and resistance

17. Hepatitis Flares with (+) or without (-) lamivudine resistance Lok et al Gastroenterology 125: 1714 2003

18. Results offset by resistance Use of first line monotherapies restricted Avoid sequential therapy Appropriate salvage interventions Predictors resistance being identified Combination therapy Form backbone of therapy Expanding number of agents Grow experience Characterisation pol resistance mutations Mutational pathways New technologies Resistance to nucleoside analogues

19. Telbuvidine Viral Resistance at 2 Yearsvs Antiviral Effect at Week 24 HBeAg positive Percent with resistance n= 203 146 57 63 83 79 115 175

20. “Low resistance nucleosides” • Entecavir (naïve) • 152 treated for three years (from 673 naïve) • 3 developed point mutations conferring ETV resistance • ?? cumulative incidence 1.1 % • Prototypical substitution • Position S202G confers entecavir resistance in the setting of L180 - M204 - S202G • Tenofovir?

21. Drug Duration Yielding Identical Costs

22. Combination therapies with nucleosides • Naïve patients • Lamivudine and PEG interferon • Lamivudine and famciclovir • Lamivudine and adefovir • (Lamivudine and telbuvidine) • Lamivudine and tenofovir • FTC and tenofovir • Ideal complications in the offing • Two agents which do not share cross resistance • Prospective trials required with low resistance drugs

23. Nucleosides HBeAg positive Advantages • Effective, safe suppression of HBV replication • HBeAg seroconversion increments • 2 years = that of PEG IFN one year • HBsAg loss can follow • Can be used for long term treatment • Oral once daily dosing vs injection • Extended use in spectrum of disease • Disease modifying agents • Few side effects

24. Nucleosides for HBeAg positive chronic hepatitis • Results offset by resistance • Use of first line monotherapy restricted • Better use is indicated • We should investigate potential of (maintenance) combination therapy • Can agents with < 5% resistance at 3 years be utilised as monotherapies? • (HBeAg negative)