Download Long term adverse events of nucleos(t)ides analogues in patients

Joint Conference … 2015.11.10 (Tue)
Long term adverse events of nucleos(t)ides
analogues in patients with CHB
- Osteorenal toxicity Jae-Jun Shim, MD, PhD
Kyung Hee University Hospital
Department of Internal Medicine
Chronic hepatitis B
•
•
•
•
Serious health problem in Korea and in the world.
Long term complications: 30% progress to LC or HCC
Nucleos(t)ide analogues
Efficacy
• HBV suppression, seroconversion, LC regression, HCC prevention
• Adverse events, well-known
• Renal tubular disorders, hypophosphatemia, and osteomalacia
Today…
Osteorenal toxicity
• of oral antiviral agents against HBV
Nucleotide analogues
• Adefovir (Hepsera®)
• Tenofovir DF (Viread®)
Nucleoside analogues
• Lamivudine (Zeffix®)
• Telbivudine (Sebivo®)
Proximal renal tubular disorder
• Proximal tubular disorder (type 2 RTA), d/t loss of
bicarbonate
• Fanconi’s syndrome
• Renal tubular acidosis
Proximal renal tubular disorder
Clinical features
• Bicarbonate loss  acidosis
• Phosphate loss  bone formation defect
• Growth failure, osteomalacia
• Hypokalemia
• Hyperchloremia
• Polyuria, polydipsia
Renal tubular acidosis (RTA)
Type
Type 1
Type 2
Type 4
Location
Distal tubules
Proximal tubules
Adrenal
Acidemia
Yes (severe)
Yes
Mild when present
Potassium
Hypokalemia
Hypokalemia
Hyperkalemia
Pathophysiology
Failure of H+ secretion by t
he α intercalated cells and r
eclaim K
Failed HCO3− reabsorptio
n from the urine by the pr
oximal tubular cells
Deficiency of aldosterone, or
a resistance to its effects, (hy
poaldosteronism or pseudoh
ypoaldosteronism)
Drugs with high FDA adverse event
association with OSTEOMALACIA
 FOSAMAX (496 patients)
 FORTEO (37 patients)
 HEPSERA (149 patients)
 PREDNISONE (34 patients)
 AREDIA (72 patients)
 SYNTHROID (33 patients)
 VIREAD (65 patients)
 ACTONEL (30 patients)
 KALETRA (45 patients)
 NEXIUM (30 patients)
 ZOMETA (44 patients)
 LASIX (30 patients)
 BONIVA (43 patients)
 ZOFRAN (30 patients)
 LAMIVUDINE (43 patients)
 VIOXX (40 patients)
 THALIDOMIDE (37 patients)
 NEURONTIN (37 patients)
• Retrospectively enrolled 687 CHB patients (51.4% with compensated cirrhosis)
• Treated with ADV alone (18.2%) or in combination with lamivudine (81.8%) for
more than 12 months. Renal function was measured using the estimated
glomerular filtration rate (eGFR), and renal dysfunction was defined as mild (20–
30% decrease), moderate (30–50%), or severe (more than 50%).
• 72 (10.5%) developed renal impairment. Most of the cases were mild (77.8%) to
moderate (20.8%), and severe renal impairment developed in only one patient
Journal of Gastroenterology and Hepatology 27 (2012) 306–312
Journal of Gastroenterology and Hepatology 27 (2012) 306–312
 ADV에 의한 신독성(Renal toxicity)
•
대개 ADV 60 – 120 mg 고용량 사용하는 HIV 환자에서 발생
•
10 mg 의 저용량 사용에서 신독성 보고는 없었음
•
신장 독성  저인산혈증  골연화증  골 통증, ALP 상승, 골밀도 감소 및 가성
골절
•
42세 남성, LMV 2년 사용 후 내성  ADV 투약 (add-on), 6개월 후 ALP 상승
•
대사성산증이나 Fanconi 증후군 소견은 없었음
•
1년 이상 ADV 사용 환자 270명 중 131명분석  40명(14.8%)에서
hypophosphatemia (+) 소견 보임
Adefovir (Hepsera®)
• Drug labeling: nephrotoxicity, renal impairements
• Micromedex, UpToDate: short comments on
Fanconi’s syndrome, osteomalacia
Case report
Hypophosphatemic osteomalacia induced by low-dose adefovir therapy
•
•
•
•
•
A 62-year-old man
a 2-year history of bone pain
a history of chronic hepatitis B infection and liver cirrhosis,
lamivudine from 2003 to 2005
from 2005 to 2011, lamivudine was changed to adefovir (10 mg/ day) owing to lamivudine
resistance
J Bone Miner Metab (2013) 31:240–246
Case Report
Hypophosphatemic Osteomalacia Due to Drug-induced Fanconi’s Syndrome
Associated with Adefovir Dipivoxil Treatment for Hepatitis B
• 58-year-old man
• a 13-month history of progressive generalized bone pain involving the bilateral rib cage,
hips, knees and heels
• Lamivudine 2001 ~ 2003
• LMV resistance 2003
• ADV switch (2003-2009) and add on 2009-2011
Intern Med 53: 233-237, 2014)
Clinical course
The mechanisms of proximal renal
tubule damage by ADV
• Not fully understood.
• ADV is excreted mainly by proximal renal tubule
• The human renal organic anion transporter-1 (hOAT-1) on membrane of
renal tubular epithelial cells has a high affinity for ADV.
• Large doses or prolonged application of ADV can result in significant
increase of ADV concentration within renal tubular epithelial cells.
• The high concentration of ADV can inhibit mitochondrial DNA synthesis
and cause cytochrome oxidase deficiency, which will significantly inhibit
mitochondrial function.
Journal of Clinical Pharmacy and Therapeutics, 2013, 38, 321–326
Summary
• ADV is an evidently nephrotoxic drug.
• Even in lower dosage (10 mg)
• Old age, concurrent nephrotoxic drugs, and
underlying renal diseases are major predisposing
factors for renal toxicity.
• Renal toxicity is reversible and manageable after
stopping ADV.
• Nucleoside analogues (lamivudine, telbivudine)
usually do not complicate renal toxicity.
Tenfovir and Renal toxicity
In patients with HIV or CHB
Case report from J Clin Virol 2014
Case #3, #4 after TDF therapy
• Previous exposure to ADV or hypertension, predisposing factors
• Occurred after 3-4 years of TDF therapy  late onset complication
Journal of Clinical Virology 61 (2014) 600–603
Cause of renal tubular toxicity?
• may be secondary to specific mtDNA toxicity within
the proximal tubules.
• This hypothesis is biologically plausible, as TDF is
secreted in the proximal renal tubules through a
mechanism involving the hOAT-1 and -3, and the MDR4
efflux pump. Polymorphisms in these transporters or
drug interactions could lead to a toxic increase in
intracellular concentrations of TDF
Therap Adv Gastroenterol. 2010 Mar;3(2):107-19
Lessons to learn from the HIV experience
Tenofovir
• Proximal renal tubular dysfunction
• After 5 years of FDA approval: 164 cases of Fanconi synd.
• OR of TDF for renal tubular dysfunction: 21.6 (4.1-113,
P<0.001) Ref. AIDS 2009;23:689
• Impairement of renal phosphate transport: 22% of
patients on TDF
• Bone toxicity
• Increased cases of osteomalacia in patients with TDF
induced Fanconi’s syndrome
• ALP elevation
Therap Adv Gastroenterol. 2010 Mar;3(2):107-19
Tenofovir-associated renal and bone toxicity
• Among 5,687 patients with HIV (2004-2006)
• Twenty two (1.6%): TDF-associated renal toxicity
- 10 of 22: other potential nephrotoxic drugs (acyclovir, cotrimoxazole,
NSAIDs…)
- TDF duration: 2.5 years
- 20 of 22: in combination with a ritonavir-boosted PI
HIV Medicine (2009), 10, 482–487
Tenofovir-associated renal and bone toxicity
• Among 5,687 patients with HIV (2004-2006)
• Twenty two (1.6%): TDF-associated renal toxicity
• Fall in eGFR (< 60 ml/min/1.73m2): 82%
• Proteinuria
-
Hypophosphatemia: 19/22 (86%)
ALP elevation: 17/19 (90%)
Bone pain and osteomalacia: 12 patients (54.5%)
Glycosuria: 8/9
•
HIV 환자에서는 TDF에 의한 신독성이 문제가 될 수 있음.
•
특히 다른 항바이러스제 병합요법을 받고 있거나 신독성 약물이 병용 사용 되고 있을 때 위험.
•
만성B형간염 환자에서 위험성은?
HIV Medicine (2009), 10, 482–487
*Definition: At least two parameters of tubular function were altered, being one of them nondiabetic
glucosuria, reduced tubular resorption of phosphorus or pathologic aminoaciduria.
AIDS 2009;23:689
AIDS 2009;23:689
Lessons to learn from the HIV experience
Tenofovir
• HBV vs HIV patients? : same scenario?
• HIV patients: exposed to multiple drugs [i.e. use of
several antivirals and antimicrobials, nonsteroidal antiinflammatory drugs (NSAIDs)], which significantly
increase the chances of having an adverse drug
reaction.
• TDF-induced renal toxicity in CHB?
• Very rare… hidden or unreported??
• Few case reports … 4 cases
Therap Adv Gastroenterol. 2010 Mar;3(2):107-19
Suggested algorithm for monitoring pat
ients using tenofovir for kidney toxicity
 Hypophosphatemia
•
a late complication in TDF toxicity
•
recommend measuring fractional excre
tion of phosphate, rather than serum ph
osphate alone.
Am J Kidney Dis. 2011;57(5):773-780
Tenofovir alafenamide fumarate (TAF)
• Genvoya (Gilead)
• Nov 5, 2015 (The U.S. Food and Drug Administration)
• A fixed-dose combination tablet
• Elvitegravir + cobicistat + emtricitabine + tenofovir alafenamide
• As a complete regimen for the treatment of HIV-1 infection in adults an
d pediatric patients 12 years of age and older
Journal of Hepatology 2015 vol. 62 j 533–540
Seven-Year Efficacy and Safety of Treatment with
Tenofovir Disoproxil Fumarate for Chronic Hepatitis B Virus
Infection
Dig Dis Sci (2015) 60:1457–1464
Differences in nephrotoxicity risk and renal effects
among anti-viral therapies against hepatitis B
• from Turkey
Aliment Pharmacol Ther 2015; 41: 310–319
Switch to TDF from LMV+ADV
- 60 patients
- For 1 year (1,3,6,9,12 months)(T0-T5)  eGFR reduction 7.5%
J Antimicrob Chemother 2015; 70: 1150–1154
Summary
• Renal toxicity is common in patients with HIV receiving TDF-based ART.
• Renal toxicity is rare in patients with CHB as compared with adefovir or
in HIV-infected patients.
• However, the risk can increase in high-risk patients such as old age,
hypertension, pre-existing renal diseases, combination of other
nephrotoxic drugs…
• Regular monitoring with serum Cr and urinary tests (for protein,
phosphate excretion) is recommended. Testing for serum ALP or
phosphate might miss early renal toxicity.