1. On-treatment management for chronic hepatitis B (CHB) in patients receiving oral antiviral therapy Byung-Ho Kim Kyung Hee University School of Medicine 2009. 9. 1.

2. Oral nucleos(t)ides (NUCs) for CHB AgentsTypeAbbreviations Lamivudine Nucleoside analogue LAM Clevudine CLV Telbivudine TLV Entecavir ETV Adefovir dipivoxil Acyclic nucleotide analogue ADV Tenofovir disoproxil fumarate TDF

3. Importance of serum HBV DNA levels in clinical outcomes of patients with CHB

4. Cumulative incidence of HCC (n = 3653) Chen CJ, et al. JAMA. 2006;295:65. Iloeje UH, et al. Gastroenterology 2006;130:678. REVEAL study: HBV DNA levels and long-term outcomes (11.4 years) 1.37% 3.57% 14.89% 1.30% 12.17% 0 5 10 15 20 3.6% 9.7% 2.0% 1.0% 10.6% 0 2 4 6 8 10 12 Relative risk of LC (n = 3482) < 300 (Undetectable) 300-9,999 10,000-99,999 100,000-999,999  1 Million Viral Load at Baseline (copies/mL) HR=2.3

5. Past HBV viral load as predictor of mortality and morbidity from HCC and CLD in a prospective study (11 years) Chen G, et al. Am J Gastroenterol 2006;101:1797.

6. Impact of treatment-induced viral suppression on clinical outcomes

7. Time to disease progression Percentage with disease progression Time to disease progression (months) Lamivudine Placebo P=0.001 17.7% 7.8% Liaw et al, N Engl J Med, 2004 ITT population Lamivudine, n=436 Placebo, n=215

8. Time to diagnosis of HCC Percentage with diagnosis Time to diagnosis (months) P=0.047 Excluding 5 cases in year 1: HR=0.47; P=0.052 Liaw et al, N Engl J Med, 2004 Placebo 7.4% Lamivudine 3.9% Lamivudine, n=436 Placebo, n=215

9. Summary on importance of serum HBV DNA level in clinical outcomes 1.A serum HBV DNA level ≥ 4 log 10 copies/mL is a strong risk factor for disease progression and HCC. 2.Sustained HBV eradication may be the important factor to determine therapeutic outcomes.

10. Limited efficacy of current NUCs Weak antiviral potency –ADV < LAM < TLV < ETV < TDF Long-term treatment is required. Drug resistance –Frequent with LAM –Less frequent with ADV and TLV –Rare with ETV and TDF

11. Rates of undetectable HBV DNA at 1 year of NUCs therapy HBeAg (+) patientsHBeAg (-) patients EASL guidelines. J Hepatol 2009;50:227 not head-to-head comparisons

12. 70 Entecavir: Gish RG, et al. Gastroenterology 2007;133:1437 Adefovir: Hadziyannis S, et al. Gastroenterology 2006;131:1743 Incidence/Probability of Resistance Substitutions (%) Duration of Therapy (Years) Lamivudine Adefovir in HBeAg (-) Entecavir Rates of drug-resistance in treatment-naïve patients < 1 2 3 4 5 24 42 53 70 03 11 18 <1 0 10 20 30 40 50 60 70 80 90 100 <1 29 <1

13. ETV resistance in HBeAg-positive patients with LAM-resistance Cumulative Probability (%) 1 yr (n=187) 2 yr (n=146) 3 yr (n=80) 4 yr (n=53) 0% 25% 50% 75% 100% 6 1 41 11 27 15 36 46 5 yr (n=33) 43 51 72/187 (39%) achieved HBV DNA < 300 copies/mL 3/72 (4%) had subsequent genotypic ETV resistance Tenney et al, APASL 2008 ETVr = LAMr (M204V ± L180M) + T184, S202 and/or M250 substitutions ETVr + Virologic Breakthrough

14. Time after randomisation (months) Time to disease progression by mutant status during LAM treatment Liaw et al, N Engl J Med, 2004 Percentage with disease progression

15. On-treatment monitoring for predicting therapeutic outcomes during early treatment period

16. Zöllner B, et al. J Med Vriol 2001;65:659. PPV 54% NPV 100% From month 6 onward during LAM tx, HBV PCR negativity was predictive of HBeAg loss

17. HBV load & resistance during LAM therapy Zöllner B, et al. J Med Vriol 2001;65:659. PPV 100% NPV 53%

18. HBV DNA level at week 24 is useful to predict viral resistance during LAM therapy HBV DNA ≤10 3 copies/mL –A 21% chance of the developing YMDD mutant HBV DNA >10 3 copies/mL –63% Yuen, et al. Hepatology 2001;34:785.

19. 74 HBeAg (+) patients Ideal response at 5 years: n=17 (23%) Best cut-off levels Week 4: 4.0 log copies/mL (AUC 0.89) PPV 100%, NPV 83.8% Week 16: 3.6 log copies/mL (AUC 0.94) PPV 100%, NPV 87.7% Optimal cut-off HBV DNA levels for prediction of excellent response during 5 years of LAM treatment Yuen et al, Hepatology 2007;46;1695.

20. Early viral suppression of TLV vs LAM: GLOBE study Serum HBV DNA after 24 weeks of treatment Lai et al, NEJM, 2007;357:2576.

21. Undetectable HBV DNA by PCR (%) Serum HBV DNA level at week 24 (log 10 copies/mL) Low HBV DNA levels at wk 24 predict favorable 1-year efficacy outcomes

22. HBeAg seroconversion in HBeAg (+) patients Serum HBV DNA level at week 24 (log 10 copies/mL)

23. Resistance at week 48 (%) Serum HBV DNA level at week 24 (log10 copies/mL) Low HBV DNA levels at wk 24 predict favorable 1-year efficacy outcomes

24. Viral response to long-term ADV monotherapy n=76 VR: HBV DNA<3 log 10 copies/mL Reijnders JGP, et al, J Viral Hept 2009;16:113.

25. Virologic response to ADV can be assessed at 24 weeks Reijnders JGP, et al, J Viral Hept 2009;16:113.

26. HBV DNA levels at week 24 after switching to ADV monotherapy predict an optimal response in patient with LAM resistance (n=43) (n=30) Area under the ROC curve HBV DNA level at wk 12 HBV DNA level at wk 24 HBV DNA reduction from the baseline at wk 12 HBV DNA reduction from the baseline at wk 24 Shim, et al. 2009 APASL STC

27. Prediction of response at weeks 48 by HBV DNA levels measured at week 24 HBV DNA cutoff level (log 10 copies/mL) PV indexPPVNPV 2.80.71983.3%88.6% 3.00.76679.2%97.4% 3.30.73376.0%97.3% 3.60.64564.5%100% 4.00.51351.3%100% PV (predictive value) index means PPV plus NPV minus 1. Shim, et al. 2009 APASL STC

28. On-treatment predictors for ETV or TDF The 24-week on-treatment HBV DNA level achieved in patients with LAM resistance also may be predictive of long-term outcomes and the eventual emergence of resistance to this drug Colonno, et al. Hepatology 2005;42(Suppl 1):573A.

29. 2009 EASL definition of viral response to NUCs HBV DNA (log 10 IU/mL) Duration of treatment (wks) 0 2 4 6 8 12 24 36 48 Primary non-response Virologic breakthrough Virologic response (VR) Partial VR EASL guidelines. J Hepatol 2009;50:227.

30. Factors related to primary non-response Host factors –Compliance –Enzyme polymorphism Viral factors –High viral load –Viral quasispecies with lower drug susceptibility –Intrinsic mutation Drug-related factors –Drug potency More frequent with ADV: 10-20% Rare with LAM, TLV, ETV or TDF: 1-3%

31. Summary Potent drugs with a high genetic barrier should be used as first-line monotherapy. Early virological response is of value in predicting likely long-term outcomes. –Primary response to NUCs should be checked at week 12 to modify management. –Monitoring the serum HBV DNA level at week 24 may be crucial to maximize treatment outcomes.

32. Tailoring oral antiviral therapy Primary non-response (PNR) at week 12 Compliance (+) EducationChange tx option Compliance (-) Monitoring at week 24 for drugs with a low genetic barrier or moderately potent drugs (LAM, TLV, ADF) Complete VR Incomplete VR Change tx option Continue tx Responder PNR

33. Primary non-response (PNR) at week 12 Compliance (+) Educatio n Change tx option Compliance (-) Monitoring at week 24 for less potent drugs CVR PVR Continue tx PNR (-) PNR (+) IVR HBV treatment roadmap concept

34. CVR PVR IVR - Continued therapy - Monitor every 6 months Drugs with low genetic barrier - add a second drug with different resistant profile Drugs with high genetic barrier or suboptimal potency – monitor every 3 months beyond 48 weeks - Switch to potent drug or Add more potent drug with no cross-resistance - Monitor every 3 months If complete response at 48 weeks - Continued therapy If incomplete response at 48 weeks - Add a more potent drug with no cross-resistant profile Tailoring oral antiviral therapy at week 24