Optimized HBV Treatment Through Baseline and on-treatment Predictor Oral Antiviral Therapy. Watcharasak Chotiyaputta

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1 Optimized HBV Treatment Through Baseline and on-treatment Predictor Oral Antiviral Therapy Watcharasak Chotiyaputta

2 Progression of Liver Disease Goal of HBV Treatment: prevention the development of cirrhosis and HCC Intermediate endpoint: HBV DNA viral load HBeAg HBsAg quantitative

3 Oral NUCs for Treatment of CHB Drugs Lamivudine (LMV) Telbivudine (TBV) Entecavir (ETV) Adefovir (ADV) Tenofovir (TDF) Antiviral activity Drug resistance Specific side effects Pregnancy category Low 70% in 5 yrs Negligible C High 30% in 3 yrs Myopathy B High 1.2% in 5 yrs Negligible C Low High 29% in 5 yrs 0% in 6 yrs Nephrotoxicity Hypophosphatemia Nephrotoxicity, hypophosphatemia, bone loss C B Wong V and Chan HL. Semin Liver Dis 2013

4 HBV Replication Cycle Chan HLY, et al. J Hepatol 2011

5 Indication for NUC Treatment Chronic hepatitis Decompensated cirrhosis and OLT Patients with HCC Acute on chronic liver disease Acute or fulminant hepatitis Preemptive prophylaxis in immunocompromised host Pregnancy Extrahepatic manifestations of HBV

6 At baseline Selection of NUC Treatment Entecavir or tenofovir are preferred. Lamivudine HBeAg positive: HBV DNA < 9log 10 cpm, ALT 2 ULN 77% HBV DNA < 4log, 41% HBV DNA PCR negative, 88% ALT normalization, 82% HBeAg seroconversion, 35.5% YMDD mutation at 5 year Telbivudine HBeAg positive: HBV DNA <9 log 10 cpm or ALT 2 ULN HBeAg negative: HBV DNA <7 log 10 cpm Strong better outcome at 2 year Yuen MF, et al. Antivir Ther 2009 Zeuzem S, et al. J Hepatol 2009

7 HBV Roadmap Concept Assessment of Primary non-response at week 12 Virologic Response: 1log IU/mL reduction from baseline Primary treatment failure: < 1log IU/mL reduction from baseline Compliant: add more potent drug Non-compliant: counsel on adherence Assessment of early predictors of efficacy at week 24 Complete virologic response: PCR negative Partial virologic response: 60 to < 2,000 IU/mL Inadequate virologic response: 2,000 IU/mL Continue therapy with same drug: monitor every 6 mo Drug with low genetic barrier: add a second drug with different genetic mutation profile Drug with high genetic barrier: monitor every 3 mo; continue beyond 48 wks Drug with suboptimal antiviral potency: monitor every 3 mo; continue until 48 wks Add more potent drug: monitor every 3 mo If complete response at 48 wks, continue therapy If incomplete response at 48 wks, add a more potent drug that is not cross-resistant Keeffe EB, et al. Clin Gastroenterol Hepatol 2007

8 Predictor at Baseline and On Treatment HBeAg positive BL < 9log 10 cpm and ALT 2 ULN TBV PCR negative at week 24 ( 300 cpm) 2 year outcome 89% PCR negative 52% Seroconversion 81% ALT normalization 1.8% Resistance HBeAg negative BL < 7log 10 cpm PCR negative at week 24 ( 300 cpm) 2 year outcome 91% PCR negative 83% ALT normalization 2% Resistance Zeuzem S, et al. J Hepatol 2009

9 Predictor at Baseline and On Treatment LMV HBeAg positive BL < 9log 10 cpm and ALT 2 ULN DNA < 3log cpm at week 24 5 year outcome 60% Undetectable DNA 80% HBV DNA < 3log cpm 90% HBV DNA < 4 log cpm 90% Seroconversion 100% ALT normalization 10% Resistance Yeun MF, et al. Antivir Ther 2009

10 Schematic of Genotypic Resistance and Virological and Biochemical Breakthrough Virological breakthrough: 1log increase in HBV DNA from nadir in a compliant patient, confirmed with repeat testing at 1 month later Biochemical breakthrough: rise in ALT while on treatment, after having achieved normalization in a compliant patient Genotypic resistance: detection of viral populations bearing reverse transcriptase mutations previously shown to confer resistance to antiviral drugs in a phenotypic assay Phenotypic resistance: decreased susceptibility of an HBV polymerase to antiviral treatment in vitro Tana MM and Ghany MG. Clin Liv Dis 2013

11 Schematic of Genotypic Resistance and Virological and Biochemical Breakthrough Tana MM and Ghany MG. Clin Liv Dis 2013

12 Management of HBV Resistance Drug Resistant mutation EASL APASL LMV rtm204v/i, rt A181V/T Switch to TDF Switch to TDF Add ADV Add ADV Switch ETV (not preferred) ADV rtn236t Switch to ETV or TDF (LMV naïve) Add LMV, TBV, ETV Switch to ETV (LMV naïve + high VL) Switch to TDF rt181t/v Add ETV Switch ETV plus TDF or Truvada TBV rtm204i Switch to TDF Add ADV ETV rts184g, rts202i, rtm204v/i, rtm250v Add ADV Switch to TDF Add ADV Switch to TDF Add TDF or ADV TDF Unknown Switch to ETV (LMV naïve) Unknown Add ETV (LMV resist) Switch to ETV + TDF (LMV and ADV resist) EASL. J Hepatol 2012 Liaw YF, et al. Hepatol Int 2012

13 Recommendation of Guidelines for Discontinuation of NUC Treatment Guideline EASL APASL AASLD THASL HBeAg (+) HBeAg (-) Anti-HBe positive and undetectable DNA for 12 mo HBsAg loss Anti-HBe positive and undetectable DNA for 12 mo Minimum 2 yrs with undetectable DNA X 3 times Anti-HBe positive and undetectable DNA for 6 mo HBsAg loss Anti-HBe positive and undetectable DNA for 12 mo HBsAg loss Lok AS and McMahon BJ. Hepatology 2009 EASL. J Hepatol 2012 Liaw YF, et al. Hepatol Int 2012 แนวทางการด แลร กษาผ ป วยไวร สต บอ กเสบบ และซ เร อร งในประเทศไทย ป 2555

14 Clinical Efficacy of Antiviral Agents for CHB, HBeAg positive Efficacy LMV ADV TBV ETV TDF Log 10 HBV DNA decline at 1 yr HBV DNA undetectable (%) at 1 yr HBeAg seroconversion (%) at Year Year 2 27 NA NA Year 3 40 NA 46 NA 26 Year 4 47 NA Year NA NA NA Kao JH. Liver Int 2014

15 Response rate at wk 48 (%) Response rate at wk 48 (%) Switch Study: CHB, HBeAg Positive Peg-IFN 180 mcg/wk for 48 wks (n=100) Peg-IFN 180 mcg/wk for 48 wks (n=27) ETV 0.5 mg OD (n=200) 9-36 mo HBV 10 3 cpm ETV for 8 wks ETV 0.5 mg OD (n=57) At least 96 wk HBV < 500 cpm ETV for 12 wks ETV 0.5 mg OD for 48 wks (n=100) ETV 0.5 mg OD for 48 wks (n=30) ** ** ** n = 97 n = 100 P= NS n = 27 n = 30 ** = P significant Ning Q, et al. Hepatology 2012;56 (suppl 1):35-88A Chen X, et al. EASL Abstract 741

16 Durability of HBeAg Seroconversion Durability of response 46-72% after discontinuation of antiviral 3 years Author, year Lee HW, 2010 Ryu SH, 2003 Dai CY, 2013 Study Retrospective Prospective Retrospective No of patients Medication LMV LMV LMV Duration of treatment (mo) (consolidation 24 mo) 23.7 Definition of SVR Normal ALT, HBV undetectable, HBeAg (-) at least 6 mo. HBeAg negative at least 1 yrs HBeAg positive or detectable HBV at 6 mo Duration of follow up (mo) Relapsed rate Predictor of SVR yr 15.9% 5 yr 30.2% Age 40 yrs Consolidation 12 mo 1 yr 12% 2 yr 20% Young age Absence of precore mutation 59.4% Low HBV VL at baseline Consolidation 18 mo Lee HW, et al Hepatology 2010, Ryu SH, et al. J Hepatol 2003 Dai CY, et al. J Antimicrob Chemother 2013, Liaw YF, et al Dig Dis Sci 2010

17 Treatment Strategies for CHB Patients with NUC HBeAg positive HBeAg seroconversion No HBeAg seroconversion May stop after consolidation therapy 12 mo later Continue therapy until seroconversion is achieved For cirrhotic patients treat until HBsAg negative For suboptimal response consider alternative therapy Consolidation may prolonged > 1 yr in patients with history of relapse, decompensation, immunocompromised status, and old age

18 HBsAg, log 10 IU/mL Kinetics of HBsAg Decline During 3 Year of Telbivudine HBeAg+ve CHB patients with effective viral suppression during TBV treatment 5 Rapid decline ( 0.5 log 10 IU/mL) Slow decline (0 0.5 log 10 IU/mL) Steady ( 0 log 10 IU/mL) N = 162, HBsAg loss 6%, HBeAg seroconversion 57% 4 HBsAg loss 0% 3 HBsAg loss 4% 2 HBsAg loss 13% 1 Baseline Week 24 Year 1 Year 2 Year 3 A rapid HBsAg decline (>0.5 log) after successful HBV DNA suppression (< 100 IU/mL) with LdT therapy may predict a higher probability of HBsAg loss Wursthorn K, et al. Hepatology 2010

19 Serum HBsAg / HBV DNA (log IU/mL) ALT (U/l) Log HBV DNA (copies/ml) Log HBsAg (IU/ml) Quantitative HBsAg Levels in CHB Patients with NUC Treatment N=322, on LMV N=166, on ETV 9-7- HBsAg ALT HBsAg HBV DNA HBV DNA Baseline Year 5 Year 10 Median HBsAg levels 4,780 1, (IU/mL) Median HBV DNA levels 6.38x (IU/mL) Baseline Year 1 Year Predictor of HBsAg loss: HBsAg at BL < 1,000 IU/mL and reduction > log IU/ml/yr Seto WK, et al. Hepatology 2013 Fung J, et al. Am J Gastroenterol 2011

20 HBsAg Decline During NUC Treatment Years to 1 log HBsAg decline, medican (range) Years to HBsAg loss, median (range) HBeAg (+) HBeAg (-) HBeAg (+) High ALT 6.6 ( ) 8.0 ( ) 3.6 ( ) 36.4 ( ) 38.9 ( ) 19.5 ( ) Zoutendijk R, et al. J Infect Dis 2011

21 When to Stop NUC Study Chan HL, 2011 Liu F, 2011 Ha M, 2012 Jeng WJ, 2013 Hadziyannis SJ, 2012 Method Retrospective Prospective Prospective Retrospective Prospective No of patient Drug LMV LMV ADV ETV ADV Baseline DNA (log 10 IU/mL) Duration of treatment (mo) Duration of F/U (mo) Sustained response Predictor of good response Response rate ± (24-66) 26 (24-66) 24 ± ± (1-84) 16 (1-88) (67-72) SR 12: DNA < 200 IU/mL at 12 mo SR last: last visit HBsAg 100 IU/mL HBsAg reduction > 1 log IU/mL 9 (17%) HBsAg loss 23% in 5 yrs DNA < 2,000 IU/mL DNA < 2,000 IU/mL Age 20 Age (49.2%) 50 (34.5%) HBsAg seroconversion 12 (8.3%) DNA < 2,000 IU/mL ALT < 2ULN DNA BL < 5.3 log Consolidation phase > 16 mo 52 (55%) DNA 2,000 IU/mL Normal ALT Low HBsAg at EOT Low DNA at BL High ALT at BL and EOT Previous INF treatment 18 (54.5%) HBsAg loss 13 (39.4%) Chan HL, et al. Antiviral Ther 2011, Liu F, et al. JGH 2011, Ha M, et al. Arch Virol 2012, Jeng WJ, et al. Hepatology 2013, Hadziyannis SJ, et al. Gatroenterology 2012

22 When: end of therapy (NAs) Prediction of outcome after NUC therapy discontinuation (APASL guideline) % Cumulative probability of virologic relapse HBsAg >1000 IU/ml at end of therapy HBsAg IU/ml at end of therapy HBsAg <100 IU/ml at end of therapy months Liang Y, et al. Aliment Pharmacol Ther 2011

23 Algorithm for Monitoring NUC Renal Safety Before NUC treatment, all patients should be tested for serum cr to estimate GFR High renal risk* Normal renal risk ETV, LMV, TBV GFR at baseline and every 3 mo until 1 yr and then every 6 mo ADV, TDF GFR and phosphate at baseline and at month 1, 2, 3, 6, 9, 12, and then every 6 mo ETV, LMN, TBV GFR at baseline and every 3-6 mo ADV, TDF GFR and phosphate at baseline and every 3 mo until year 1 and then every 6 mo High renal risk: decompensated cirrhosis, GFR<60 cc/min, poorly controlled HT and DM, proteinuria, active GN, concomitant nephrotoxic drug TBV: monitor CPK every 3-6 mo ADV, TDF: glycosuria, proteinuria, urine phosphate Modified from EASL Clinical Practice Guideline, J Hepatol 2012

24 Algorithm for Monitoring NUC Renal Safety Marcellin P, et al. Lancet 2013

25 Conclusions Baseline and on treatment predictors HBV DNA most important Baseline: LMV < 9log 10 cpm in HBeAg positive TBV < 9log 10 cpm in HBeAg positive, < 7log 10 cpm in HBeAg negative During treatment: Road map concept HBeAg Increase consolidation phase to increase durability HBsAg No HBsAg titer to predict response of treatment Stop in HBeAg negative - low DNA at BL, HBsAg less than 100 IU/mL Monitor side effects from NUC

26 Thank You for Your Attention

27 % HBeAg seroconversion Add on Study HBeAg (+), who achieved undetable HBV DNA with at least 1 year of NUC therapy without seroconversion Combination therapy with NUC and Peg-IFN Monotherapy: remaining on NUC therapy ** ** ** ** n= 56 n= 19 Weeks of therapy ** p significant Li Q, et al EASL Abstract 757