1. Anna LOK

2. Management of Antiviral Resistant Hepatitis B Clinical Case Anna S. F. Lok University of Michigan Ann Arbor, MI, USA

3. Clinical Case M/25, born in Taiwan, moved to USA 3 yr ago, single, attending graduate school 3/02 – incidental mild increase in ALT No past history of acute hepatitis or jaundice Denied risk factors for hepatitis B FH: uncle diagnosed liver cancer at age 55, mother and 1 brother HBV+ PE: Normal

4. M/25, asymptomatic LFT normal except for ALT 46 IU/L (N <40), AST 34 (N <35) CBC, PT, AFP – normal HBsAg+, HBeAg+ HBV DNA 8.7 log 10 c/mL US: normal liver size and texture, spleen not enlarged

5. M/25, perinatal infection, HBeAg+ Repeat labs 1 month later: ALT 42 IU/L (N <40), HBV DNA 9.4 log 10 c/mL Gastroenterologist concerned, HBV DNA doubled!!, ALT still increase, particularly by “new” standard Liver biopsy recommended but patient declined Treatment recommended: HBeAg+, high HBV DNA, abnormal ALT, family history of HCC Only approved therapies then: standard IFN and lamivudine

6. M/25, HBeAg+, ALT mild increase 6/02 - Lamivudine started, HBV DNA 9.4 log 9/02 - HBV DNA 5.8 log 12/02 – HBV DNA 4.5 log, ALT 29, HBeAg+ 7/03 – ALT 31, AFP 7.1, HBV DNA not tested Patient graduated and relocated

7. M/25, Lamivudine breakthrough after 20 months 2/04 – severe fatigue ALT 237 IU/L, bil 0.9 mg/dL, INR 1.0 HBeAg+, HBV DNA 8.7 log10 c/mL

8. M/25, HBeAg+, HBV DNA 9 log, ALT mild increase, lamivudine breakthrough after 20 months. What would you do at this time? A)Stop lamivudine and observe B)Continue lamivudine and observe C)Stop lamivudine and switch to adefovir D)Continue lamivudine and add adefovir E)Stop lamivudine and switch to entecavir

9. Lamivudine breakthrough, switched to Adefovir monotherapy in 3/04 3/04 – Patient advised to stop lamivudine and switch to adefovir 9/04 – HBV DNA decreased from 8.7 to 6.4 log10 c/mL 4/05 – HBV DNA 5.2 log10 c/mL

10. Lamivudine breakthrough, switched to Adefovir monotherapy, HBV DNA 5 log after 13 months What would you now do? A)Increase dose of adefovir to 20 mg B)Add lamivudine C)Add entecavir D)Add interferon E)Switch to tenofovir

11. Lamivudine breakthrough, switched to Adefovir monotherapy in 3/04 11/05 – HBV DNA 5.9 log10 c/mL, ALT 27 2/06 – HBV DNA 6.5 log10 c/mL, ALT 39 IU/mL, no symptoms –rtN236T mutation detected

12. Lamivudine breakthrough in 2/04 Adefovir breakthrough in 2/06 What to do now? A)Stop treatment and observe B)Add lamivudine C)Add entecavir D)Switch to Truvada: combination of emtricitabine + tenofovir E)Add interferon

13. Figure 1. Sequential monotherapy leading to sequential antiviral resistance HBV DNA (Log 10 copies/ml) 2002 2003 2004 2005 2006 ALT (IU/L) 300 0 200 100 LAMIVUDINE ADEFOVIR ALT HBV DNA

14. Management of Antiviral-Resistant HBV How often should patients be monitored during antiviral therapy? Should all patients with breakthrough infection be tested for resistance mutation? When should rescue therapy be implemented? Which is the most appropriate rescue therapy?

15. How often should patients be monitored during nucleos/tide analogue therapy? Quantitative HBV DNA by PCR assay and ALT (LFT) –Q 3 months – ideally –Q 1 month – initially, in patients with severe flare or decompensation –Q 6 months – minimum frequency HBeAg in those initially positive –Month 12, then every 6-12 months HBsAg in those HBeAg negative –Month 12, then yearly

16. Why is it necessary to monitor patients so frequently? To enable early detection of treatment failure –Primary treatment failure (primary nonresponse) –Secondary treatment failure (breakthrough) To enable timely adjustment of treatment –To prevent death and liver failure due to hepatitis flares associated with emergence of drug resistance –To ensure better response through early institution of rescue therapy in patients with drug resistance –To decrease the risk of drug resistance by adjusting treatment in patients with primary nonresponse

17. Primary Treatment Failure or Primary Non Response Definition: Serum HBV DNA decrease by 4 log 10 IU/mL after 6 months of treatment Estimated frequency (using >4 log 10 copies/mL at week 24) –Adefovir ~30-50%Lamivudine 10-35% –Telbivudine 8-30%Entecavir 5-10% Consequences: –Lower rates of response at year 1 and 2 –Higher rates of drug resistance

18. Entecavir vs. Lamivudine Treatment of Nucleoside-Naϊve Patients HBeAg+ patients Lai CL, NEJM 2006; 354:1010-20 HBeAg- patients Chang T, NEJM 2006; 354:1001-10

19. Week 24 HBV DNA Level is Predictive of Response to Telbivudine or Lamivudine at 2 years % of patients HBeAg seroconversionALT normalization PCR negative PCR neg 4 HBV DNA at wk 24 (log 10 copies /ml) Di Bisceglie A, AASLD 2006, Abstract 112 HBeAg+HBeAg-

20. Better viral suppression reduces the risk of genotypic resistance Lamivudine Resistance (median 29 mos) vs. wk 24 HBV DNA Adefovir Resistance at wk 144 vs. wk 48 HBV DNA % Resistance 8 % 13 % 32 % 64 % 4 % 26 % 67 % Wk 24 HBV DNA (log10 c/ml) N = 159 HBeAg+ patients Yuen M, Hepatology 2001; 34:785 < ND 3-6>6< ND> 4< 4< 3 Wk 48 HBV DNA (log10 c/ml) N = 114, primarily HBeAg- patients Locarnini S, J Hepatol 2005; 42(Suppli 2):17

21. Should All Patients with Breakthrough Infection be Tested for Antiviral Resistant Mutations? Not all patients with breakthrough infection are confirmed to have resistant mutations –~70% in clinical trials, likely less in practice Rescue therapy can be tailored to pattern of resistant mutations –More important in patients who had been exposed to sequential monotherapy

22. When Should Rescue Therapy be Initiated? Detection of resistant mutations through surveillance program –Impractical in practice –Overall benefit not established, may consider for patients with decompensated cirrhosis or immunosuppressed patients Virologic breakthrough – HBV DNA increase by >1 log10 from nadir –More effective Viral rebound – HBV DNA increase to >5 log10 –Not as effective Biochemical breakthrough – ALT increase –Not as effective Hepatitis flare or hepatic decompensation –May not reverse outcome

23. Manifestations of Antiviral Resistance HBV DNA (Log 10 IU/ml) Biochemical Breakthrough ULN Viral Breakthrough 0 123 Years Antiviral Treatment 0 2 4 6 8 Hepatitis Flare Viral Rebound Genotypic Resistance

24. Early Addition of Adefovir is More Effective in Patients with Lamivudine Resistance Lampertico P, Hepatology 2005;42:1414 Months % Patients with undetectable HBV-DNA Virologic BT <6 log HBV-DNA Virologic BT 6-8 log HBV-DNA Biochemical BT >8 log HBV DNA p<0.0001 Patients still at risk 2831 322214106 13 12 11 914 0 0 0 5 6 10 0 9 4 4 0 2 3 0

25. Choice of Rescue Therapy Depends on knowledge of Prior therapy Pattern of resistant mutations In vitro data on susceptibility of mutants to other antiviral therapies and any cross- resistance

26. Location of Primary Antiviral-Resistant HBV Mutations in the HBV Polymerase/RT Domain LAM Resistance rtA181TrtM204V/I/S ADV ResistancertA181T/VrtN236T ETV Resistance*rtI169TrtT184S/A/I/LrtS202G/IrtM250I/V L-dT ResistancertM204I * In association with LAM-resistant mutations 845 a.a. Terminal Protein Spacer POL/RT RNaseH ABCED 1 183 349 (rt1)692 (rt 344) YMDD F__V__LLAQ__ I(G) II(F)

27. Selection of lamivudine-resistant mutations limits future treatment options L180M A181V/T T184G/S/A/C S202G M204V/1 N236T M250V LAM FTC LdT ADV ETV

28. In Vitro Cross-Resistance LAMLdTETVADVTDF M 204 I┼┼┼┼┼┼┼?┼┼ L 180M+ M 204 V ┼┼┼┼┼┼┼┼┼ A 181 T/V┼┼ ┼ ? N 236 T┼┼┼┼┼ I 169+ M 250V* ┼┼┼┼ ┼┼ T 184G+ S202 I* ┼┼┼┼ ┼┼ * (+ L180M + M 204 V/I)

29. Management of Lamivudine- or Telbivudine- Resistant HBV Add Adefovir Add Tenofovir or Switch to Truvada (FTC+Tenofovir) –Not yet approved for HBV Switch to Entecavir –Response not as good as wild type HBV, increase risk of ETV resistance Switch to Adefovir –Response not as good as add-on therapy (some studies), increase risk of ADV resistance Switch to Interferon –Limited data

30. Lamivudine resistant HBV: Add-on Adefovir is less likely to be associated with subsequent resistance to Adefovir 5/5 (100%) 9/29 (31%) % patients switched to ADV Fung et al, J Hepatol 2006; 44:283-90 p=0.01 0 10 20 30 40 50 60 70 80 90 100 ADV-RNo ADV-R 5/5 5/5100% 9/2931%

31. Management of Adefovir-Resistant HBV Lamivudine-naïve patients –Add Lamivudine: long-term efficacy unknown –Switch to Truvada: limited data –Add or switch to Entecavir: limited data –Switch to IFN: no data –Switch to Tenofovir: partial response

32. Management of Adefovir-Resistant HBV Lamivudine-experienced patients –Add Lamivudine: long-term efficacy unknown Rapid re-emergence of LAM-resistant mutations reported –Switch to Truvada: limited data –Add or switch to Entecavir: limited data Possibility of subsequent ETV-resistance unknown –Switch to IFN: no data –Switch to Tenofovir: partial response

33. Management of Entecavir-Resistant HBV Add or switch to Adefovir Add or switch to Tenofovir Switch to IFN Little or no data on all options

34. Prevention of Antiviral-resistant HBV Judicious use of antiviral treatment Initiate treatment with combination therapy – what agents to combine? Use most potent agent with highest genetic barrier to resistance Monitor viral response – switch therapy if response suboptimal Counsel on medication compliance Avoid sequential monotherapy Avoid cross-resistant drugs