Options for HBV treatments in case of TDF toxicity

Pr Corinne Isnard Bagnis Pitie Salpetriere Hospital

corinne.bagnis@psl.aphp.fr

Interests

• Honorarium from – Novartis – BMS – Gilead – Abbvie – GSK – Roche

• Research funding – BMS

Renal diseases and HBV :The challenge for the coming years

Fight against comorbidities, ageing, hypertension, obesity, toxic co-treatments (NSAID’S,

anti cancer drugs)

Improve our ability to screen for, diagnose and treat renal insult secondary to HBV/drug induced « renal » side effects

Estimation of Glomerular filtration rate

• 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 GFR1,2

• 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

Glomerular Filtration Tubular Secretion

Urine

Proximal Tubule Glomerulus and

Bowman’s Capsule

1 Calza L. HIV Clin Trials. 2012;13:189-211. 2 NKF KDOQI. Frequently asked questions about GFR estimates. http://www.kidney.org/professionals/kls/pdf/12-10- 4004_KBB_FAQs_AboutGFR-1.pdf. Accessed August 14, 2012.

Estimation of glomerular filtration rate in general population

sMDRD Formula GFR = k x 186 x [SCr]-1,154 x [age]-0,203 (mg/dl)

Man k=1 et woman k=0,742

Cockcroft and Gault Formula ClCR = k x [(140-age) x weight] / SCr (µmol/l)

Man k=1,23 et woman k=1,04

Cockcroft and Gault, 1976; 16: 31-41. Levey et al, Ann Intern Med. 1999,130(6):461-70. www.mdrd.com

Performs better in general population,

overweighed patients, older patients

Dipstick

Hematuria Leukocyturia

Dipstick If positive confirm by examination of urinary sediment and/or ACR

Trace < 0.3 g/L + 0.3-1 g/L

++ 1-3 g/L +++ 3-10 g/L

++++ >10 g/L

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 30-300 mg/g 2-22 mg/mmol 30-300 mg/J

Proteinuria ≥ 300 mg/g ≥ 22 mg/mmol ≥ 300 mg/J

Albumin or protein over creatinine ratio

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 ?

9

Estimating GFR in cirrhotic patients

Authors

N

Gold

value

Proulx etal 193 Inuline CrCl overestimates

Gonwa et al 1447 125I-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 99Tcm-DTPA Cystatine C+++

Samyn et al 62 children 51 Cr-EDTA Cystatine C+++

Poge et al Skluzacek et al

44 Inuline 125I-iothamamate

Cr, Cyst, MDRD overestimate

MacAulay et al 57 99Tcm-DTPA overestimation ++

Cholongitas et al, Aliment Pharmacol Ther, 2007, 26, 969-978

10

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-S266.

Who took my kidneys?

11

Chronic kidney disease is a strong cardiovascular risk factor

x 15 x 15

Go et al. Nejm 2004;351:1296

1 120 295 adults > 20 years – mean follow up : 2,84 years Multivariate analysis : eGFR, %death, %CVE, %Hosp

Deaths CV events

Renal Function* Is Abnormal In An Important % of Patients With End-stage Liver Disease, N=19 261

67%

22%

8% 3%

Normal RF >70 mL/min,N=12,778Mild RF 56 mL/min,N=4,419Moderate RF 30 mL/min,N=1,560Severe RF, 14 mL/min,N=504

Nair S, et al. Hepatology 2002;35:1179-1185.

*Calculated creatinine clearance (CCr) at the time of OLT

12

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

<60 2330 71.9 2330 71.9 ≥60 1434 38.1 1434 38.1

Female 1292 34.3 1292 34.3 Male 2472 65.7 2472 65.7 Comorbidity

Diabetes 1209 32.1 1202 31.9 Chronic heart failure 375 10.0 359 9.5 Myocardial infarction 71 1.9 50 1.3 Chronic kidney disease 645 17.1 599 15.9 Chronic pulmonary disease 1372 36.5 1363 36.2 Dementia 109 2.9 78 2.1 Cerebrovascular disease 620 16.5 601 16.0 Osteoporosis 340 9.0 392 10.4

Tsai C-G, et al. Journal of Hepatology 2013;58:706–714. 13

Main Pathologic Conditions And Treatments That May Cause Kidney Injury In Chronic Hepatitis B Patients

Membranous glomerulonephritis

MGN

Aminosides NSAID +++

Amphotericin Sulfadiazine

Valproïc acid…

Diabetes mellitus Arterial hypertension

Older age H.I.V

Nephropathy of heroin abuse

?

Nucleotides analogues Nucleosides analogues

Protease inhibitors

HBV

Co-morbidities Other drugs

Antivirals

14

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

Tubular Toxicity of Nucleotides Analogs

0

20

40

60

80

100

120

1 10 100 1000 10000

Cont

rol g

row

th (%

)

Concentration (µM)

Cidofovir

0

20

40

60

80

100

120

1 10 100 1000 10000

Cont

rol g

row

th (%

)

Concentration (µM)

Adefovir

CC50 = 260±42 µM EC50 (HCMV) = 0.7-2.0 µM

Tl =130-370

CC50 = 495±120 µM EC50 (HBV) = 0.2-0.5 µM

Tl =1,000-2,500

CC50 > 2,000 µM EC50 (HIV-1) = 1.0-2.0 µM

Tl >1,000

In vitro toxicity of nucleotides in cultures of human cells of the proximal tubule. Low direct tubular toxicity of Tenofovir in vitro.

Cihlar T, et al. Nucleosides Nucleotides Nucleic Acids. 2001 Apr-Jul;20(4-7):641-8.

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, double-blind 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

Only A Very Small % of Patients With Abnormal Renal Function Are Included In The Tenofovir Pivotal Studies*

Baseline characteristics Overall

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 (log10 copies/mL)

6.74 (2.23, 10.92)

*Studies 102 and 103

1% 8%

91%

<50 mL/min 50-80 mL/min >80 mL/min

Marcellin P et al. EASL March 30 - April 3, 2011, Berlin. Poster #739.

Tenofovir induced acute renal failure

Herlitz et al, Kidney Int, sept 2010

Herlitz et al, Kidney Int, sept 2010

Tenofovir induced acute renal failure

Herlitz et al, Kidney Int, sept 2010

Tenofovir induced acute renal failure

Sydney PATH meeting, September 2010

Tenofovir and CKD

GFR Worsens During Tenofovir Treatment Over 60 Months

0

20

40

60

80

100

120

140

0 12 24 36 48 60

Mea

n GF

R (m

L.m

in/1

.73

m2 )

Month

-10.3 mL/min/1.73 m2 = -11% P=0.01

GFR estimated by MDRD formula

0

20

40

60

80

100

120

140

0 12 24 36 48 60

Mea

n GF

R (m

L.m

in/1

.73

m2 )

Month

-16 mL/min = -13% P=0.002

GFR estimated by Cockcroft-Gault formula

van Bömmel F, et al. AASLD 2009; Oral #221.

ADV renal safety in CHB

• Renal safety of ADV has been assessed treatment-naive

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 combination2 • Age (>50 years) and renal function at study enrolment were

important predictors of renal impairment5 • Few studies assessed tubular function with long-term ADV

therapy • One case of Fanconi syndrome associated with ADV

treatment has been reported2

1. Izzedine H, et al. Kidney Int 2004;66:1153−1158. 2.Tamori A, et al. J Viral Hepat 2010;17:123−1292. Marcellin P, et al. Hepatology 2008;48:750−758. 4 . Marcellin P, et al. N Engl J Med 2008;359:2442−2455. 5. Ha NB, et al. Hepatology 2009;50:727−734

Deterioration In Renal Function In Real-Life Patients Treated With Adefovir and Entecavir, N=290

0

20

40

60

80

100

ADV, N=145 ETV, N=145

% o

f pat

ient

s

Significant decrease (greater than 30%)

Moderate decrease (20%-30%)

Mild decrease (10%-20%)

Minor to no decrease (0-10%)

Ha NB, et al. Hepatology 2009;50:727-734.

P<0.0001 between groups

25

Safety Issues With Oral Nucleos(t)ide Analogues In Decompensated HBV Cirrhosis

References Drugs used Safety issue

Fontana RJ, et al. Gastroenterology 2002;123:719–727. Lamivudine (100 mg), N=154 Disease flare with LAM-R HBV

Schiff E, et al. Liver Transpl 2007;13:349–360. Adefovir (10 mg), N=226 Nephrotoxicity 6%

Liaw YF, et al. Hepatology 2011;54:91–100. Entecavir (1 mg), N=100 Nephrotoxicity

17%

Adefovir (10 mg), N=91 Nephrotoxicity 24%

Liaw YF, et al. Hepatology 2011;53:62–72.

Tenofovir (300 mg), N=450 Nephrotoxicity 9%

Truvada (200 mg/300 mg), N=45 Nephrotoxicity 7%

Entecavir (0.5 or 1 mg), N=22 Nephrotoxicity 5%

Chan H, et al. J Viral Hepat. 2012 Oct;19(10):732-743.

Lamivudine (100 mg), N=116 Nephrotoxicity 2%

Telbivudine (600 mg), N=116 Nephrotoxicity None reported

E Gane EDTA 2011

0

20

40

60

80

100

120

140

Baseline Year 1 Year 2 Year 3 Year 4 Year 5 Year 6

82,7

20,9 24,7 31,9 26,8 41,9 44,1

Increase

GFR (median)

CN04E1 Chinese 015 Safety population: ∆GFR from baseline during 6 yrs telbivudine

• Baseline GFR 60-90 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

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

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. 2013 [epub ahead of print]. 28

These patients received LAM therapy and showed resistance

Significant Improvement In Renal Function Over 2 Years Among ADV+LdT Treated Patients

Lee MJ, et al. Journal of Viral Hepat. 2013 [epub ahead of print].

-10

-5

0

5

10

15

0 6 12 18 24

CKD-

EPI c

hang

e, m

L/m

in/1

.73

m2

Months

ADV+LdT ADV+LAM ADV+ETV ADV mono ETV mono

The 104-Week Efficacy and Safety of Telbivudine-Based Optimization Strategy in CHB Patients

Baseline Week 24 Week 52 Week 104

MONO -Telbivudine monotherapy

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

HBeAg(+) Naive CHB

patients randomized,

N=599

Week 12

Sun J, et al. Hepatology 2014, 59: 1283-1292

Week 104

• 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 m2) were 125.1 mL/min/1.73 m2 with telbivudine monotherapy and 114.4 mL/min/1.73 m2 with telbivudine plus adefovir treatment.

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 log10 copies/mL from baseline -6.3 -6.1 0.009

ALT normalization, % 80.7 (234/290) 79.2 (232/293) 0.649

HBeAg loss, % 29.0 (87/300) 31.1 (93/299) 0.574

HBeAg seroconversion, % 23.7 (71/300) 22.1 (66/299) 0.643

HBsAg loss, % 0.7 (2/300) 0.7 (2/299) 1.000

HBsAg seroconversion, % 0.3 (1/300) 0.3 (1/299) 1.000

Virological breakthrough, %) 6.0 (18/300) 30.4 (91/299) <0.001

Genotypic resistance, % 2.7 (8/300) 25.8 (77/299) <0.001

Sun J, et al. Hepatology 2014, 59: 1283-1292

The 104-Week Efficacy and Safety of Telbivudine-Based Optimization Strategy in CHB Patients

Wait and see…

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;57:167–185. Adapted from EASL guidelines. Journal of Hepatology 2012;57:167–185.

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