Management of HBV infection between Specialist and General Practitioners

Transcription

1 13 October 2016 Management of HBV infection between Specialist and General Practitioners Pietro Lampertico Gastroenterology and Hepatology Unit Fondazione IRCCS Cà Granda - Ospedale Maggiore Policlinico University of Milan

2 Financial disclosures Advisory Board/Speaker Bureau for - BMS, ROCHE, GILEAD SCIENCES, GSK, MSD

3 Natural History of Hepatitis B Virus Infection 5%-10% of chronic HBVinfected individuals 1 Liver Cancer (HCC) 3%/yr Acute Infection >90% of infected children progress to chronic disease <5% of infected immunocompetent adults progress to chronic disease 1 *ALT <ULN *anti-hbe pos *HBV-DNA <2000 IU/ml Chronic Infection Inactive carrier* 30% of chronic HBV-infected individuals 1 3%/yr Cirrhosis Liver Failure (Decomp.) 23% of patients decompensate within 5 years of developing cirrhosis 3 Liver Transplanta tion Death Chronic HBV is the 6th leading cause of liver transplantation in the US 4 1. Torresi, J, Locarnini, S. Gastroenterology. 2000; 2. Fattovich, G, Giustina, G, Schalm, SW, et al. Hepatology Moyer, LA, Mast, EE. Am J Prev Med. 1994; 4. Perrillo, R, et al. Hepatology

4 Inactive carriers

5 Management of Inactive Carriers A review What do we know 1) Most of the HBV carriers are inactive carriers 2) Diagnosis and follow-up of inactive carriers have been established by international guidelines (similar criteria) 3) Minimum criteria: normal ALT, HBV-DNA <2,000 IU/ml for 12 months (check for fibrosis, qhbsag, DNA <20,000 IU/ml) 4) Diagnosis remains challenging for some carriers 5) Favorable prognosis, long-term monitoring (no treatment) 6) During immunosuppression, high risk of reactivation, universal prophylaxis with NUC is mandatory. Invernizzi F, et al, Liver Int. 2016; 36 (Suppl. S1):

6 Management of Inactive Carriers From GPs to Specialist to GPs. 1) Phase I: GPC: referral to Specialist all HBsAg pos subjects 2) Phase II: Specialist for IC diagnosis (24-48 weeks) 3) Phase III: GPs for monitoring and follow-up of IC 4) Phase IV: GPs: re-referral selected cases to Specialist

7 Other phases of HBV infection

8 The decision to treat is historically based on phase of disease and risk of disease progression Phase HBeAg status HBV DNA Immune tolerant HBeAg-positive CHB Inactive carrier HBeAg-negative CHB Positive Positive Negative Negative Very high >200,000 IU/mL >2000 IU/mL <2000 IU/mL >2000 IU/mL (fluctuating) ALT Normal Elevated Normal Elevated (fluctuating) Liver histology Disease progression Normal or mild inflammation and limited fibrosis Low Inflammation and fibrosis: degree varies Moderate to high Normal or mild inflammation No, very low Inflammation and fibrosis: degree varies Moderate to high Treatment Not indicated* Indicated Not indicated Indicated * Treatment indicated in some patients EASL HBV Guidelines, J Hepatol 2012;57: ; EASL special HBV conference, J Hepatol 2015;63:

9 Therapeutic strategies for chronic hepatitis B Short-term "curative" treatment IFN Follow-up (mo/yrs) On treatment response HBV DNA < 2000 IU/ml ALT < UNL (anti-hbe) HBsAg Loss Long-term "suppressive" treatment NUC HBV DNA undetectable by PCR (<10-15 IU) HBsAg loss Years

10 8-10 years of ETV or TDF therapy for CHB Virological endpoints - Summary Viral suppression in >95% patients (ETV, TDF) HBeAg seroc. in 40-50%, HBsAg clearance in 1% ALT normalization in ~85%, no major safety issues Histological improvement (year 5) Reduced complications (HCC) Excellent 5-year survival Simple and inexpensive strategy (generics)

11 ETV or TDF therapy for CHB - Challenges Partial response in HVL naive and NUC-R patients Safey issues in selected TDF treated patients Low HBeAg/HBsAg seroconversion rates Limited stopping rules Long duration of therapy Cost, compliance, resistance, safety >8-10 years?? Young patients with mild liver disease

12 Patients wit HBV DNA < 69 IU/ml (%) 4 years TDF vs TDF+FTC in HBV patients with normal ALT and high HBV-DNA levels - ITT analysis e+ N=126 patients, HBV-DNA >1.7x10 7 IU/mL FTC/TDF 76% P=0.016 TDF 55% Study week Multivariate analysis for response: female (OR 6.0, CI ) and TDF+FTC (OR 3.9, CI ) Chan HL et al, Gastroenterology 2014

13 Registration studies (8 years) showed minimal renal events on TDF Real-life studies with TDF showed controversial results 8 cases of TDF-induced Fanconi syndrome have been described Higher risk of TDF renal toxicity in older patients, previously exposed to ADV, with comorbidities, longer duration of TDF Need for more research with more sensitive markers of tubular damage Lampertico P et al, Aliment Pharmacol Ther 2016; 44: 16 34

14 Patients (%) High rates of renal tubular damage in 281 HBV patients long-term treated with TDF a real life study Age 62 yr, 95% Caucasian, 81% GT D, 74% males, 94% normal ALT, 91% negative HBV DNA, egfr 68 ml/min, 45% cirrhotics, 36% HTA, 15% diabetes, TDF therapy for 82 (1-118) months. Hypophosphatemia (<2.7 mg/dl) Increased UBCR* (>300 mg/g) Hyperphosphaturia (TmPO4/GFR ratio <0.80) Hypercalciuria (>0.11 UCA/Cr ratio) *urinary B2-microglobulin Lampertico P et al, manuscript in preparation 2016

15 Tenofovir Alafenamide (TAF) Prodrug of TFV Reduces Circulating TFV Tenofovir (TFV) Parent Nucleotide DIANION GI TRACT TFV PLASMA TFV HBV HIV TFV-DP Tenofovir disoproxil fumarate (TDF) ESTER TDF 300 mg T 1/2 = 0.4 min TFV-MP Tenofovir alafenamide (TAF) TAF 25 mg T 1/2 = 90 min TFV TFV HEPATOCYTE AMIDATE TAF is more stable in plasma compared with TDF 1-2 TAF 25 mg has 92% lower circulating plasma TFV levels compared to TDF 300mg 1 T 1/2 based on in vitro plasma data 1. Agarwal K, et al. J Hepatology. 2015; 62; Lee W et. Antimicr Agents Chemo 2005;49(5): Agarwal K et al. J Hepatology 2015; 62: Murakami E et al. Antimicrob. Agents Chemother.13 Apr 2015 (epub). doi: /aac Kearney BP, Flaherty JF, Shah J. Clin Pharmacokinet. 2004;43(9):

16 Proportion of Patients, % Study 108 and 110: Phase 3 CHB Studies: TAF vs TDF HBV DNA Response at 48 Weeks (<29 IU/ml) HBeAg Study 108 negative (HBeAg negative) Study 110 (HBeAg positive) 100 Treatment difference -3.6% (-9.8, +2.6); p= TAF: 64% (Wk 48) TDF: 67% (Wk 48) Study Week Similar and non-inferior rates of virologic suppression with TAF and TDF at Week 48 No resistance detected in either treatment group Buti M et al, EASL 2016, Oral GS06; Chan H et al, EASL 2016, Oral GS12; Buti M et al, Lancet Gastroenterol Hepatol Chan H et al, Lancet Gastroenterol Hepatol

17 M e a n ( S D ) c h a n g e i n Mean (±SD) change e G F R in C G egfr (m L /m CG in )(ml/min) Study 108 and 110: Phase 3 CHB Studies: TAF vs TDF Results: Renal Safety 2 0 T A F T D F p < S tu d y W e e k TAF n=866 TDF n=432 P-value Change in scr, mg/dl (0.11) (0.10) Subjects receiving TAF experienced significantly less change in egfr CG scr at Week 48 compared to TDF Continuous data are expressed as mean (SD) scr, serum creatinine; egfr CG, creatinine clearance by Cockcroft-Gault and Buti EASL 2016, Oral GS06; Chan, EASL 2016, Oral GS12; Buti Lancet Gastroenterol Hepatol Chan Lancet Gastroenterol Hepatol

18 Median (Q1, Q3) Change From Baseline, % Study 108 and 110: Phase 3 CHB Studies: TAF vs TDF Results: Quantitative Proteinuria at Week 48 Total protein Glomerular biomarkers Proximal tubular biomarkers 7 5 Protein (UPCR) Albumin (UACR) Retinol-Binding Protein 2-Microglobulin p=0.010 p=0.073 p <0.001 p < TAF TDF Changes in tubular proteinuria were significantly lower with TAF compared to TDF UPCR: Urine Protein Creatinine Ratio UACR: Urine Albumin Creatinine Ratio Buti EASL 2016, Oral GS06; Chan, EASL 2016, Oral GS12; Buti Lancet Gastroenterol Hepatol Chan Lancet Gastroenterol Hepatol

19 Study 110 Patients, % Study 108 Patients, % Study 108 and 110: Phase 3 CHB Studies: TAF vs TDF Results: BMD Changes at Week 48 TAF TDF Spine Hip p <0.001* p <0.001* >3% >3% No Decrease >3% >3% No Decrease p <0.001* p <0.001* * All categories >3% >3% No Decrease >3% >3% No Decrease Higher proportion of TAF patients had significantly less or no BMD decrease compared to TDF patients Buti EASL 2016, Oral GS06; Chan, EASL 2016, Oral GS12; Buti Lancet Gastroenterol Hepatol Chan Lancet Gastroenterol Hepatol

20 Stopping rules for NUC therapy

21 When to stop NUC therapy? CHB Treatment Guidelines EASL 2012 guidelines HBeAg positive A) confirmed anti-hbe seroconversion (and undectable HBV DNA) after at least 12 months of consolidation* B) confirmed HBsAg loss and anti-hbs seroconversion HBeAg negative confirmed HBsAg loss and anti-hbs seroconversion Cirrhotics confirmed HBsAg loss and anti-hbs seroconversion *A proportion of patients who discontinue NUC therapy after anti-hbe seroconversion may require retreatment, since they fail to sustain their serological and/or virological response adapted from EASL HBV Guidelines, J Hepatol 2012; Reijnders JG and Janssen HL. Hepatology 2013, EASL Special HBV conference, J Hepatol 2015

22 Virological remission after NUC discontinuation in HBeAg pos CHB - A systematic review e+ 14 studies, 733 initially HBeAg+ patients HBV DNA <20,000 IU/mL (% pts) Months after NUC discontinuation Pooled HBsAg loss: 1%; Durable biochemical remission: 76% Papatheodoridis G. et al, Hepatology 2016

23 Virological remission after NUC discontinuation in HBeAg neg CHB - A systematic review e studies, 967 HBeAg- patients 80 HBV DNA <20,000 IU/mL (% pts) months after NUC discontinuation Pooled HBsAg loss: 1.7%; Durable biochemical remission: 57% Papatheodoridis G. et al, Hepatology 2016

24 New treatment endpoints?

25

26 How to improve HBsAg decline/loss in long-term NUC treated patients? Stop NUC (before HBsAg loss) to flare New strategies based on current drugs - switch NUC to PEG - add-on PEG to NUC New strategies based on new drugs

27 How to improve HBsAg decline/loss in long-term NUC treated patients? Stop NUC (before HBsAg loss) to flare (NO) New strategies based on current drugs - switch NUC to PEG (YES in selected pts) - add-on PEG to NUC (YES in selected pts) New strategies based on new drugs

28 Future HBV therapies: new targets, new drugs Immunomodulation Toll-like receptors agonists, e.g. GS-9620 Anti-PD-1 mab, e.g. BMS CYT107 GI13000 Vaccine therapy RNA interference, (sirna) e.g. ARC-520 HBx cccdna Inhibition of HBsAg release, e.g. REP 9AC Surface proteins Polymerase Core pgrna Polymerase inhibitors Nucleoside analogues, e.g. TAF, amdoxovir, MIV-210 Non-nucleoside, e.g. LB80380 Entry inhibitors (HBV/HDV) Lipopeptides, e.g. Myrcludex-B Endosome rcdna Targeting cccdna HAPs Chromatinmodifying enzymes Inhibition of Nucleocapsid Assembly, e.g. Bay , NVR1221 Inhibition of Prenylation (HDV) Lonafarnib Development stage: preclinical, clinical ; modified and updated from Zoulim F, et al. Antiviral Res 2012;96(2):256 9; HBV Drug Watch, Available at:

29 Future HBV therapies: new targets, new drugs Immunomodulation Toll-like receptors agonists, e.g. GS-9620 Anti-PD-1 mab, e.g. BMS CYT107 GI13000 Vaccine therapy RNA interference, (sirna) e.g. ARC-520 HBx cccdna Inhibition of HBsAg release, e.g. REP 9AC Surface proteins Polymerase Core pgrna Polymerase inhibitors Nucleoside analogues, e.g. TAF, amdoxovir, MIV-210 Non-nucleoside, e.g. LB80380 Entry inhibitors (HBV/HDV) Lipopeptides, e.g. Myrcludex-B Endosome rcdna Targeting cccdna HAPs Chromatinmodifying enzymes Inhibition of Nucleocapsid Assembly, e.g. Bay , NVR1221 Inhibition of Prenylation (HDV) Lonafarnib Development stage: preclinical, clinical ; modified and updated from Zoulim F, et al. Antiviral Res 2012;96(2):256 9; HBV Drug Watch, Available at:

30 Management of HBV From Specialist to General Practitioners Limited interaction General Practitioner: - Referral to Specialist of all new HBsAg pos subjects - Follow-up of ICs (after consolidated diagnosis) - Re-referral selected ICs to Specialist Management of HBV remains challenging Anti-HBV treatments improved significant New endpoints as functional cure (HBsAg loss) New anti-hbv treatments coming

31 Back-up slides