Tenofovir as a drug of choice for the chronic hepatitis B treatment

EASL endorsed conference White Nights of Hepatology 2013 Symposium Perspectives of chronic viral hepatitis B and C treatment June 6-7 Saint-Petersburg Tenofovir as a drug of choice for the chronic hepatitis B treatment K. Zhdanov

Viread Clinical Trials Span All Populations of Chronic HBV Patients HBV Stages Quiescent Disease Treatment Naive Treatment Experienced Decompensated Liver Disease Patient Population Adults/Peds Peds Adolescents Adults Decomp. Liver Dz Liver Transplant Acute infection Chronic Infection Cirrhosis OLT Death Study 101 Immune Tolerant Study 144 Pediatrics 2-12 yr Study 115 Adolesc. 12-17 yr Studies 102 & 103 Tx Naïve Adults (HBeAg+, HBeAg-) Study 121 LAM- Resistant Study 106 ADV- Exper. Study 108 Decomp. Disease Study 107 Transplant Gilead Studies TDF vs. TVD TDF vs. PLB TDF vs. PLB TDF vs. ADV; OL TDF (8 yr) TDF vs. TVD TDF vs. TVD TDF vs. TDV vs. ETV TVD + HBIG vs. TVD AASLD 2012 (final) Start Q1 2012 EASL 2012 (72 wk) AASLD 2011, APASL 2012 (240 wk) AASLD 2012 (96 wk) AASLD 2010 (final) AASLD 2012 (final) Liver Transpl. (final)

Studies 102/103 Study designs Phase 3, randomised, double-blind, placebo-controlled trials in which adult patients received open-label tenofovir disoproxil fumarate (TDF) after Year 1 for a study duration of up to 8 years Chronic HBV patients (HBeAgand HBeAg+) N=641 TDF 300 mg (n=250, 176) ADV 10 mg (n=125, 90) Open-Label TDF 300 mg QD, N=585 Study Year 0 1 2 3 4 5 8 Liver Biopsies Patients had the option to add FTC at the discretion of the investigator if confirmed HBV DNA 400 copies/ml at Week 72 or beyond Neither Truvada (TVD = TDF + FTC) or emtricitabine (FTC) are licensed for use to treat CHB Marcellin P, et al. AASLD 2012; Boston. #374. Jacobson I, et al. AASLD 2012; Boston. #411.

Studies 102/103 Virologic Suppression at Year 6 Response HBeAg- Patients (Study 102) HBeAg+ Patients (Study 103) Year 5 Year 6 Year 5 Year 6 HBV DNA < 400 copies/ml Intent-to-treat *, % (n/n) 83 (291/350) 81 (281/345) 65 (160/248) 63 (157/251) HBV DNA < 400 copies/ml On treatment, % (n/n) 99 (292/295) 99.6 (283/284) 97 (170/175) 99 (167/169) * LTE-TDF (missing = failure/addition of FTC = failure) Observed (missing = excluded/addition of FTC = included) 80% of 585 patients entering the open-label phase remained on study at Year 6; 73% of enrolled patients remained on study HBeAg loss/seroconversion rates of 50% and 37%, respectively, through 6 years 11% of HBeAg+ patients had confirmed HBsAg loss (8% with seroconversion) No resistance to TDF was detected through 6 years Marcellin P, et al. AASLD 2012; Boston. #374. Neither Truvada (TVD = TDF + FTC) or emtricitabine (FTC) are licensed for use to treat CHB

Studies 102/103 Virologic Suppression at Year 6

Studies 102/103 Virologic Suppression at Year 6

Studies 102/103 Resistance Results Through Year 5 No resistance to TDF was detected through 6 years A. B. Number of Subjects 400 300 200 100 0 426 39 (9%) 389 (91%) 24 (6%) 364 (85%) 13* (3%) Year 348 (82%) 10* (3%) 323 (76%) 9* (3%) 0 0 0 0 0 1 2 3 4 5 250 200 150 100 50 0 ADV 196 192 (98%) 16 (8%) 9* (5%) 180 (92%) 2* (1%) 172 (88%) 3* (2%) 0 0 0 0 1 2 3 4 5 Year Total Subjects Subjects with Viremia Subjects with Confirmed Resistance *7, 5, and 5 subjects on FTC+TDF at Yrs 3, 4, and 5 *4, 1, and 1 subjects on FTC+TDF at Yrs 3, 4, and 5 Gordon SC, et al. APASL 2012; Poster #PP09-053. Emtricitabine (FTC) is not licensed for use to treat CHB

Studies 102/103 Liver Fibrosis in Regression over 5 Years of Treatment with TDF Patients with Ishak score 4: 38% at Baseline, 12% at Year 5 Patients with cirrhosis (Ishak score 5): 28% at Baseline, 8% at Year 5 P<0.001 P < 0.001 Percentage of patients 100 90 80 70 60 50 40 30 20 10 38% 39% 12% 63% Ishak Fibrosis Scores 6 5 4 3 2 1 0 0 Baseline Year 1 Year 5 Marcellin P, et al. Lancet. in press.

Studies 102/103 Change in Ishak Scores at Year 5 for Patients with Cirrhosis at Baseline 74% (71/96) had no histologic evidence of cirrhosis (Ishak score <5) at Year 5 1% (3/252) of non-cirrhotics (Ishak score 4) progressed to cirrhosis at Year 5 (P <0.001; McNemar s test) Change in Ishak Scores at Year 5 for Patients with Cirrhosis at Baseline 3 2 1 73% of patients had 2 unit reduction n=1 0-1 -2-3 -4-5 n=15 n=41 n=14 n=1 n=24 In multivariate analysis, only low BMI was associated with fibrosis regression at Year 5 (Age, gender, origin and ALT level: no significant association) Afdhal N et al. EASL 2012, Poster 497

Distribution of Ishak Fibrosis Scores at Baseline and Year 5 in Lamivudine-Experienced Patients Fibrosis Score 6 5 4 3 2 1 0 72% (54/75) of LAM-experienced patients had baseline and year 5 biopsies 33% (18/54) of patients had cirrhosis (Ishak score 5) at baseline; only 4% (2/54) remained cirrhotic at year 5 Tsai N, et al. APASL 2012; Poster #PP09-008.

High viral load patients can achieve HBV DNA negativity with long-term TDF 100 129 patients with HBV DNA >9 log 10 IU/mL (20% of overall population) 90 Percentage with HBV DNA <400 copies/ml (%) 80 70 60 50 40 30 20 10 0 Patients with HBV DNA <400 copies/ml at week 240: Non-HVL: 99.2% HVL: 98.3% Non-high viral load (non-hvl) High viral load (HVL) 0 8 16 24 32 40 48 56 64 72 80 88 96 108 120 132 144 156 168 180 192 204 216 228 240 Weeks on study Gordon SC et al. Hepatology 2013; doi: 10.1002/hep.26277.

Dealing with PVR in real-life practice: Patients treated with TDF 3-year TDF in naïve CHB patients in clinical practice Outcome of patients with PVR* Patients with viraemia (%) 20 15 10 5 0 16% N=44 12 6% N=16 18 3% N=7 24 1% N=3 30 Months *277 patients evaluated at Month 12 Lampertico P et al. AASLD 2012; Abstract 401 (oral).

Long-term therapy with TDF decreased incidence of HCC vs predicted risk Data to 5 years (studies 102 and 103) HCC developed in only 8/585 patients 6 of the 8 with HCC had cirrhosis at baseline and showed no histological improvement from baseline to Week 48 6-year long-term follow-up from pivotal TDF studies compared with predicted rate of HCC using the REACH-B model Cumulative number of HCC cases 25 20 15 10 5 Predicted Observed * Progressive divergence after 3.3 years *Standardised incidence ratio between observed and predicted was statistically significant at 5.5-year follow-up (0.55; CI: 0.32 0.94) 0 0 1 2 3 4 5 6 Years Kim WR et al. EASL 2013; Oral 43.

Antiviral therapy in HBeAg(+) patients with ALT <2xULN PRO Maintenance of high HBV replication increasing number of infected hepatocytes High risk of HBV transmission Patients with high HBV DNA levels are at risk of HCC regardless of ALT level Lower HBV DNA (10 4 <10 9 ) and ALT at high end of normal reflect cumulative hepatocyte damage CON Belief that there s no disease progression, minimal histological lesions Immune tolerance low probability of anti-hbe seroconversion (PEG-)ΙFN : not effective; NAs: inhibition of HBV replication Resistance during first years of therapy? Probably life-long therapy in young patients: long-term safety, patient reluctance, family planning? Zoulim F, Mason WS. Gut 2012;61:333 336; EASL Clinical Practice Guidelines: Management of Chronic Hepatitis B Virus Infection. J Hepatol 2012;57:167 185.

Efficacy of TDF in immune tolerant patients TDF (N=64) FTC/TDF* (N=62) p value HBV DNA <400 copies/ml, % (n/n) 55 (35/64) 76 (47/62) 0.016 Mean HBV DNA, log 10 copies/ml (SD) -6.32 (1.46) -6.70 (0.91) 0.07 HBeAg seroconversion, % (n/n) 5 (3/63) 0 0.244 No mutations associated with TDF resistance Treatments well tolerated (2% discontinued due to AEs, 1 patient had an ALT flare associated with non-adherence) Treatment did not affect clinical endpoints, therefore no decision to treat can be made based on these data *Neither Truvada (TVD=FTC/TDF) nor emtricitabine (FTC) are licensed for use in CHB Chan HL et al. EASL 2013; Oral 101.

Low risk of fibrosis or fibrosis progression in immune tolerant patients Mild fibrosis (F1) detected in 50% of immune tolerant patients; no fibrosis in remainder 1 No change in fibrosis score in 42 of 48 patients who remained in the immune tolerant phase for 5 years 2 Stage Initial biopsy, n Final biopsy, n p value F0 15 16 F1 33 31 0.58 F2 0 1 1 Andreani T et al. Clin Gastroenterol Hepatol 2007;5:636 641; 2 Hui CK et al. Hepatology 2007;46:395 401.

NA characteristic in pregnancy Drug FDA pregnancy category Experience in pregnant HBV mothers Lamivudine С Two meta-analyses > 15 RCTs. Two costeffectiveness studies. Risk of birth defects No Remarks Recommended Telbivudine В Two RCTs No Recommended Tenofovir В No studies No May be recommended Entecavir С No studies In animal studies Not recommended Adefovir С No studies In animal studies Not recommended Kumar A. et al. Indian J Gastroenterol. 2012; 31 (2): 43-54

Tenofovir for prevention of vertical transmission of HBV in high HBV viremic pregnant women HBV DNA, log copies/ml 10 9 8 7 6 5 4 3 2 1 0 11 Asian mothers received TDF at 28-32 weeks of pregnancy 8,87 5,25 0/11 Baseline At delivery Infants with HBsAg+ at 28-36 weeks after birth No obstetric complications or birth defect 8/11 mothers discontinued TDF 0-12 weeks postpartum without severe ALT flare Pan CQ et al., Dig Dis Sci. 2012

Studies 102/103 Safety Summary During the Open-Label Period By Prior Treatment Assignment TDF-TDF (n=389) ADV-TDF (n=196) Total (N=585) AEs leading to drug discontinuation, n (%) 9 (2.3) 2 (1.0) 11 (1.9) Deaths, n (%) 6 (1.5) 3 (1.5) 9 (1.5) Serious AEs, n (%) 5 (1.3) 2 (1.0) 7 (1.2) Grade 3 or 4 AEs, n (%) 3 (0.8) 3 (1.5) 6 (1.0) scr 0.5 mg/dl above baseline *, n (%) 5 (1.3) 4 (2.0) 9 (1.5) PO 4 < 2 mg/dl *, n (%) 5 (1.3) 3 (1.5) 8 (1.4) CrCl < 50 ml/min *, n (%) 3 (0.8) 3 (1.5) 6 (1.0) * Confirmed upon retest Marcellin P, et al. AASLD 2012; Boston. #374.

Studies 102/103 Bone Mineral Density Results from Year 4 to Year 6 Year 4 to Year 6 shifts in BMD T scores * Hip (n=294) Spine (n=308) normal osteopenia 7 patients 10 patients osteopenia normal 6 patients 11 patients osteopenia osteoporosis 2 patients 3 patients osteoporosis osteopenia 1 patient 5 patients * T score ranges: normal >-1; osteopenia -1 to -2.5; osteoporosis <-2.5 No significant changes were observed in mean BMD results from Year 4 through Year 6 for either hip or lumbar spine No consistent trends were observed in T score or Z score category shifts between Year 4 and Year 6 Marcellin P, et al. AASLD 2012; Boston. #374.

Conclusions Long-term TDF treatment is well tolerated and results in high rates of response (HBV DNA, HBeAg, HBsAg) without resistance development through 6 years, high rates of fibrosis/cirrhosis reversion both naїve and lamivudineexperienced patients Proportion of patients with PVR during TDF after 48 weeks depends on baseline viral load and no alteration in treatment regimen is required in the vast majority of patients Long-term antiviral therapy in the absence of resistance results in HCC reduction, but need to continue HCC surveillance even in treated cirrhotic patients! In general, patients in the immune tolerant phase do not require treatment; if signs of advanced fibrosis, treatment with TDF associated with a high genetic barrier to resistance should be considered TDF should be considered during pregnancy in high HBV DNA levels both for treatment and in third trimester for prevention of HBV perinatal transmission