Options for HBV treatments in case of TDF toxicity

Transcription

1 Options for HBV treatments in case of TDF toxicity Pr Corinne Isnard Bagnis Pitie Salpetriere Hospital

2 Honorarium from Novartis BMS Gilead Abbvie GSK Roche Research funding BMS Interests

3 Renal diseases and HBV :The challenge for the coming years Improve our ability to screen for, diagnose and treat renal insult secondary to HBV/drug induced «renal» side effects Fight against comorbidities, ageing, hypertension, obesity, toxic co-treatments (NSAID S, anti cancer drugs)

4 Estimation of Glomerular filtration rate Glomerulus and Bowman s Capsule Proximal Tubule Urine Glomerular Filtration Tubular Secretion Creatinine is a product of skeletal muscle metabolism that is primarily filtered by the glomerulus and used for estimating/measuring creatinine clearance Because a small amount of creatinine undergoes tubular secretion, creatinine clearance usually overestimates the actual GFR 1,2 Anytime muscle mass is altered, creatinine is no more an accurate marker for GRF Anytime, body composition is altered, weight is no more a good marker for muscle mass 1 Calza L. HIV Clin Trials. 2012;13: NKF KDOQI. Frequently asked questions about GFR estimates _KBB_FAQs_AboutGFR-1.pdf. Accessed August 14, 2012.

5 Estimation of glomerular filtration rate in general population Cockcroft and Gault Formula ClCR = k x [(140-age) x weight] / SCr (µmol/l) Man k=1,23 et woman k=1,04 Performs better in general population, overweighed patients, older patients smdrd Formula GFR = k x 186 x [S Cr ] -1,154 x [age] -0,203 (mg/dl) Man k=1 et woman k=0,742 Cockcroft and Gault, 1976; 16: Levey et al, Ann Intern Med. 1999,130(6):

6 Dipstick Trace < 0.3 g/l g/l g/l g/l ++++ >10 g/l Hematuria Leukocyturia Dipstick If positive confirm by examination of urinary sediment and/or ACR

7 Albumin or protein over creatinine ratio protein/ creatinine Ratio Protein (mg/l) /creatinine (g/l) spot Protein (mg/l) /creatinine (mmol/l) 24 h urines (mg/24h) Normal <30 mg/g < 2mg/mmol < 30 mg/j Micro albuminuria mg/g 2-22 mg/mmol mg/j Proteinuria 300 mg/g 22 mg/mmol 300 mg/j

8 Estimating GFR in cirrhotic patients Creatinine : Dosage interferences with bilirubin above 3.7 mg/dl (67 µmol/l) Creatinine is synthetized by the liver and dehydrated (non enzymatic metabolism) in the muscle Creatinine varies on Muscular mass Hydration state (edema, ascitis) Nutritional status Creatinine clearance : always false because 24h urine collection is a pain. estimation of GFR with the formulae Gold standard : isotopic clearances Cystatine C? 8

9 Estimating GFR in cirrhotic patients Authors N Gold value Proulx etal 193 Inuline CrCl overestimates Gonwa et al I-iothamamate MDRD overestimates Woitas etal 44 Inuline Cyst C screening Orlando et al 36 cirr/56 controls Inuline Cyst C screening Demitras et al 26 hépatorenal 99 Tcm-DTPA Cystatine C+++ Samyn et al 62 children 51 Cr-EDTA Cystatine C+++ Poge et al Skluzacek et al 44 Inuline 125 I-iothamamate Cr, Cyst, MDRD overestimate MacAulay et al Tcm-DTPA overestimation ++ Cholongitas et al, Aliment Pharmacol Ther, 2007, 26,

10 Who took my kidneys? What is CKD? NKF: K/DOQI Clinical Practice Guidelines for Chronic Kidney Disease: Evaluation, Classification and Stratification. AJKD, Vol 39, No 2, Suppl 1 (February), 2002: pp S1-S

11 Chronic kidney disease is a strong cardiovascular risk factor adults > 20 years mean follow up : 2,84 years Multivariate analysis : egfr, %death, %CVE, %Hosp Deaths CV events x 15 x 15 Go et al. Nejm 2004;351:

12 Renal Function* Is Abnormal In An Important % of Patients With End-stage Liver Disease, N= % 3% 22% 67% Normal RF >70 ml/min, N=12,778 Mild RF 56 ml/min, N=4,419 Moderate RF 30 ml/min, N=1,560 Severe RF, 14 ml/min, N=504 *Calculated creatinine clearance (CCr) at the time of OLT Nair S, et al. Hepatology 2002;35:

13 Important % Of Cirrhotic Patients With Diabetes and Renal Dysfunction (Taiwanese Cohort) Patients with HE, N=375 Cirrhotic patients without HE, N=3764 N % N % Median age, year (Range) 53 (20-100) 53 (20-100) Age, year < Female Male Comorbidity Diabetes Chronic heart failure Myocardial infarction Chronic kidney disease Chronic pulmonary disease Dementia Cerebrovascular disease Osteoporosis Tsai C-G, et al. Journal of Hepatology 2013;58:

14 Main Pathologic Conditions And Treatments That May Cause Kidney Injury In Chronic Hepatitis B Patients HBV Membranous glomerulonephritis MGN Antivirals Nucleotides analogues Nucleosides analogues Protease inhibitors? Co-morbidities Diabetes mellitus Arterial hypertension Older age H.I.V Nephropathy of heroin abuse Other drugs Aminosides NSAID +++ Amphotericin Sulfadiazine Valproïc acid 14

15 Antiviral B drugs Nucleos(t)ide analogs (nucs) L-Nucleoside analogues D cyclopentanes Acyclic nucleotide phosphonates L-nucleoside pyrimidine analogue Lamivudine Entecavir Adefovir Clevudine Telbivudine Tenofovir disoproxil fumarate

16 Tubular Toxicity of Nucleotides Analogs 120 In vitro toxicity of nucleotides in cultures of human cells of the proximal tubule. Low direct tubular toxicity of Tenofovir in vitro. 120 Control growth (%) Cidofovir Control growth (%) Adefovir Concentration (µm) Concentration (µm) CC 50 = 260±42 µm EC 50 (HCMV) = µm Tl = CC 50 = 495±120 µm EC 50 (HBV) = µm Tl =1,000-2,500 CC 50 > 2,000 µm EC 50 (HIV-1) = µm Tl >1,000 Cihlar T, et al. Nucleosides Nucleotides Nucleic Acids Apr-Jul;20(4-7):641-8.

17 TDF renal safety in CHB mono-infected patients and in co-infected, naive or experienced Majority of evidence supporting TDF renal safety derived from two Phase III, doubleblind studies Large experience with long term follow up At 144 weeks TDF patient creatinine clearance remained stable 2 But in real life conditions? 1 : Manns M, et al. J Hepatol 2009;50 Suppl 1:S335 S336 [abstract 923]. 2. Marcellin P, et al. Hepatology 2009;50(4 Suppl):532A 533A [abstract 481].1

18 Only A Very Small % of Patients With Abnormal Renal Function Are Included In The Tenofovir Pivotal Studies* <50 ml/min ml/min >80 ml/min Baseline characteristics Overall 1% 8% N 675 Median age (range) 41 (18-69) HBeAg+, % 41.9 Medical history of hypertension, % 14.5 Medical history of diabetes, % 5.2 Median HBV DNA (log 10 copies/ml) 6.74 (2.23, 10.92) *Studies 102 and % Marcellin P et al. EASL March 30 - April 3, 2011, Berlin. Poster #739.

19 Tenofovir induced acute renal failure Herlitz et al, Kidney Int, sept 2010

20 Tenofovir induced acute renal failure Herlitz et al, Kidney Int, sept 2010

21 Tenofovir induced acute renal failure Herlitz et al, Kidney Int, sept 2010

22 Tenofovir and CKD Sydney PATH meeting, September 2010

23 GFR Worsens During Tenofovir Treatment Over 60 Months 140 GFR estimated by MDRD formula GFR estimated by Cockcroft-Gault formula Mean GFR (ml.min/1.73 m 2 ) ml/min/1.73 m 2 = -11% P=0.01 Mean GFR (ml.min/1.73 m 2 ) ml/min = -13% P= Month Month van Bömmel F, et al. AASLD 2009; Oral #221.

24 ADV renal safety in CHB Renal safety of ADV has been assessed treatment-nai ve and LAM- experienced CHB patients trials Renal dysfunction has been seen in CHB patients receiving long-term treatment with ADV, although not common:1 5 Higher doses (>30mg) 1 LAM combination 2 Age (>50 years) and renal function at study enrolment were important predictors of renal impairment 5 Few studies assessed tubular function with long-term ADV therapy One case of Fanconi syndrome associated with ADV treatment has been reported 2 1. Izzedine H, et al. Kidney Int 2004;66: Tamori A, et al. J Viral Hepat 2010;17: Marcellin P, et al. Hepatology 2008;48: Marcellin P, et al. N Engl J Med 2008;359: Ha NB, et al. Hepatology 2009;50:

25 Deterioration In Renal Function In Real-Life Patients Treated With Adefovir and Entecavir, N= % of patients Significant decrease (greater than 30%) Moderate decrease (20%-30%) Mild decrease (10%-20%) Minor to no decrease (0-10%) 20 P< between groups 0 ADV, N=145 ETV, N=145 Ha NB, et al. Hepatology 2009;50:

26 Safety Issues With Oral Nucleos(t)ide Analogues In Decompensated HBV Cirrhosis References Drugs used Safety issue Fontana RJ, et al. Gastroenterology 2002;123: Lamivudine (100 mg), N=154 Schiff E, et al. Liver Transpl 2007;13: Adefovir (10 mg), N=226 Entecavir (1 mg), N=100 Liaw YF, et al. Hepatology 2011;54: Adefovir (10 mg), N=91 Tenofovir (300 mg), N=450 Liaw YF, et al. Hepatology 2011;53: Truvada (200 mg/300 mg), N=45 Entecavir (0.5 or 1 mg), N=22 Lamivudine (100 mg), N=116 Chan H, et al. J Viral Hepat Oct;19(10): Telbivudine (600 mg), N=116 Disease flare with LAM-R HBV Nephrotoxicity 6% Nephrotoxicity 17% Nephrotoxicity 24% Nephrotoxicity 9% Nephrotoxicity 7% Nephrotoxicity 5% Nephrotoxicity 2% Nephrotoxicity None reported

27 CN04E1 Chinese 015 Safety population: GFR from baseline during 6 yrs telbivudine ,9 24,7 31,9 26,8 41,9 44, Increase GFR (median) 40 82, Baseline Year 1 Year 2 Year 3 Year 4 Year 5 Year 6 Baseline GFR ml/min: improved in 37/39 (95%) improved in 25/26 HBeAg positive CHB (96%) improved in 12/13 HBeAg negative CHB (92%) E Gane EDTA 2011 E Gane EDTA 2011

28 Korean Real-life Study On Effect Of Different Antiviral Regimes On Renal Function Enrolled in study, N=1043 Analyzed patients, N=831 Patients excluded due to MDRD egfr <50 ml/min (N = 31) CKD-EPI egfr <50 ml/min (N = 28) History of ADV or ETV therapy (N = 101) De novo ADV plus LMV therapy (N = 21) HCV co-infection (N = 21) HIV co-infection (N = 10) Control group N=292 ADV exposed group, N=539 These patients received LAM therapy and showed resistance ETV mono, N=292 ADV+LdT, N=43 ADV+LAM, N=297 ADV+ETV, N=59 ADV mono, N=140 Lee MJ, et al. Journal of Viral Hepat [epub ahead of print]. 28

29 Significant Improvement In Renal Function Over 2 Years Among ADV+LdT Treated Patients 15 ADV+LdT ADV+LAM ADV+ETV ADV mono ETV mono CKD-EPI change, ml/min/1.73 m Months Lee MJ, et al. Journal of Viral Hepat [epub ahead of print].

30 The 104-Week Efficacy and Safety of Telbivudine-Based Optimization Strategy in CHB Patients HBeAg(+) Nai ve CHB patients randomized, N=599 OPTIMIZE Telbivudine OPTIMIZE-combo: Week 24 HBV DNA 300 copies/ml Add-on Adefovir OPTIMIZE-mono: Week 24 HBV DNA <300 copies/ml Telbivudine monotherapy Adefovir will be added if viral breakthrough is confirmed MONO -Telbivudine monotherapy Baseline Week 12 Week 24 Week 52 Week 104 Sun J, et al. Hepatology 2014, 59:

31 The 104-Week Efficacy and Safety of Telbivudine-Based Optimization Strategy in CHB Patients OPTIMIZE Group N=300 MONO Group N=299 P value Virological response, % 76.7 (230/300) 61.2 (183/299) <0.001 Serum HBV DNA (median change in log 10 copies/ml from baseline ALT normalization, % 80.7 (234/290) 79.2 (232/293) HBeAg loss, % 29.0 (87/300) 31.1 (93/299) HBeAg seroconversion, % 23.7 (71/300) 22.1 (66/299) HBsAg loss, % 0.7 (2/300) 0.7 (2/299) HBsAg seroconversion, % 0.3 (1/300) 0.3 (1/299) Virological breakthrough, %) 6.0 (18/300) 30.4 (91/299) <0.001 Genotypic resistance, % 2.7 (8/300) 25.8 (77/299) <0.001 Patients with impaired renal function at baseline showed greater egfr improvement after 104 weeks of treatment compared to the overall population. The changes in egfr levels from baseline (in patients with baseline egfr <90 ml/min/1.73 m 2 ) were ml/min/1.73 m 2 with telbivudine monotherapy and ml/min/1.73 m 2 with telbivudine plus adefovir treatment. Sun J, et al. Hepatology 2014, 59:

32 Wait and see

33 2012 EASL Guidelines: Enhanced Attention To Risk Associated With Long-term Use Of NAs NAs are cleared by the kidneys, and appropriate dosing adjustments are recommended for patients with creatinine clearance <50 ml/min (A1). Therefore, all patients starting NA therapy should be tested for serum creatinine levels and estimated creatinine clearance before treatment (A1). In addition, the baseline renal risk should be assessed for all patients. High renal risk includes one or more of the following factors: decompensated cirrhosis, creatinine clearance <60 ml/min, poorly controlled hypertension, proteinuria, uncontrolled diabetes, active glomerulonephritis, concomitant nephrotoxic drugs, solid organ transplantation. Minimal rates of renal function decline have been reported with all NAs, except perhaps for telbivudine which seems to improve the creatinine clearance [144] (C1). The nephrotoxic potential seems to be higher for nucleotide analogues, particularly adefovir [145] (B1). Therefore, it seems appropriate for now to monitor for adverse renal effects with serum creatinine (estimated creatinine clearance) and serum phosphate levels during adefovir or tenofovir therapy in all CHB patients and with serum creatinine levels (estimated creatinine clearance) during nucleoside analogue therapy in CHB patients at high renal risk (C1). Adapted from EASL guidelines. Journal of Hepatology 2012;57: Adapted from EASL guidelines. Journal of Hepatology 2012;57:

34 Nephroprotective care Control blood pressure Check for diabetes No nephrotoxic drugs associated to adefovir/tenofovir Careful with contrast media injection Refrain from N SAIDS Monitor renal parameters