Tuesday Case Conference
Introduction
• What is Tenofovir disoproxil fumarte
(TDF)?
• How Nucleotide RTI work
• Nephrotoxicity of NtRTI
• Is TDF Nephrotoxic?
– In vitro evidence
– Epidemiologic evidence
What is tenofovir disoproxil
fumarate (TDF)?
• Orally administered pro-drug of tenofovir
• Tenofovir is a nucleotide analogue inhibitor of reverse
transcriptase (NtRTI)
– Others in the family are Adefovir and Cidofovir, well described
nephrotoxins
– Tenofovir similar to Adefovir
– The only NtRTI used for treatment of HIV
TDF
• Single Agent
– Viread
• marketed for the treatment of HIV since 2001
• Combination
– Truvada
• Fixed-dose combination
– TDF and emtricitabine (NRTI), 2004
– Atripla
• Fixed-dose triple combination of
– TDF, emtricitabine (NRTI) and efavirenz (NNRTI), 2006
Reverse Transcriptase Inhibitors
• Competitive substrate
inhibitors
– Nucleoside RTI (NRTI)
– Nucleotide RTI (NtRTI)
• Non-competitive
substrate inhibitor
– Non-nucleoside RTI
(NNRTI)
www.web-books.com/.../Images/HIV_Cycle.jpg
How does NtRI work?
• Nucleoside+Phosphate
– Prolonged action
– Low resistance profile
• TDF
– Compete with normal
substrate for viral DNA
polymerase (HIV-1 RT)
– Minimally interfere with
nuclear DNA synthesis
Clercq-Holy_Acyclic nuc phosphonates_Nat Rev Pharm_2005
TDF in treatment of HIV infection
Clercq-Holy_Acyclic nuc phosphonates_Nat Rev Pharm_2005
Regimen with TDF
• >80% of patients with HIV
RNA (<50 copies per ml)
at 48 weeks
Is TDF nephrotoxic?
• Potential for nephrotoxicity
– Similar structure to Adefovir,
known nephrotoxin
– Accumulation in renal
proximal tubule
• Vd of 0.8 L/kg
• Minimally protein bound (<8%)
• Mainly excreted in urine,
unchanged pro-drug from
– The Mitochondrial Cytopathy
Hypothesis
Blood
TDF
Proximal
Tubule
OAT1
MRP
Lumen
TDF is eliminated through the
Kidney
ATP
MRP 2 / 4
Tenofovir
Tenofovir
Potential for
accumulation of high
concentration of TDF
in proximal tubule
cells
Mechanisms of Tubular Toxicity
The Mitochondrial Cytopathy Hypothesis
http://www.retroconference.org/2002/Posters/13560.pdf
In vitro study
In vitro assessment of mitochondrial toxicity
The effect of TDF and other NRTIs on mtDNA synthesis
Tenofovir has little mitochondrial toxicity
Birkus-Cihlar_Assmt of Mitochondrial Toxicity in Human CellsTreated with Tenofovir_AAC_2002
In vitro study
In vitro study
Effects of tenofovir and cidofovir on the human renal proximal
tubule epithelial cells
Inhibition of cell proliferation
Effects on viability
TDF with low cytotoxicity in proximal tubule epithelial cells
Cihlar-Hitchcock_TFV exhibits low cytotoxicity in various human cell types comariosn with other NRTI_Antiviral Res_2002
Does TDF have nephrotoxic effect?
• in vitro study
– TDF is a weak inhibitor of mamalian DNA
polymerases
• Has not decreased mtDNA levels
• Shows low cytotoxicity
• Epidemiologic study…
Epidemiology
• Phase I/II
–
–
–
–
–
Barditch-Crovo P et al, Antimicrob Agents Chemother. 2001
The Johns Hopkins University School of Medicine
N = 49
Tenofovir: 75mg, 150 mg, 300 mg, or 600 mg
No renal abnormalities at 28 days
• Phase II
–
–
–
–
–
–
Schooley, et al, AIDS. 2002
University of Colorado
RCT
N = 181
Tenofovir: 75mg, 150 mg, or 300 mg
No renal abnormalities after 48 weeks
Clinical Trials
Gilead-Sponsored Clinical Studies of TDF
Study
Tx-
Comparison
N
Results Available
GS903
Naive TDF vs. d4T
600
Week 144
GS902
Exp.
TDF vs. Placebo
186
Week 48*
GS907
Exp.
TDF vs. Placebo
550
Week 48
GS934
Naive TDF/FTC vs. CBV
517
Week 24
TOTAL
1853
In all of these studies the rates of renal abnormalities were similar between TDF
and control arms.
Clinical Trial
• Multicenter, RCT
• FU of 144 weeks
TDF + 3TC + EFV vs. d4T + 3TC + EFV
GS903
Izzedine-Deray_Long-term renal safety of TFV_NephDialTranp_2005
GS903
Incidences of elevated serum creatinine and hypophosphatemia
(-0.2)
Izzedine-Deray_Long-term renal safety of TFV_NephDialTranp_2005
(-0.1)
GS903
Calculated Creatinine Clearance Through Week 144
Conclusion:
-Renal safety profile between 2 groups was similar
-Incidence of renal failure and hypophosphatemia were reversible
-No patient developed Fanconi syndrome
Izzedine-Deray_Long-term renal safety of TFV_NephDialTranp_2005
Conclusion from Clinical Trial
• Double-blind, placebo-controlled studies
– No difference in incidence of renal events
between TDF and placebo groups
• No TDF-related toxic side effects were
noted in the recommended drug
combination regimes of TDF
Case Report
first report of TDF associated fanconi syndrome
• Renal failure
– Verhelst et al, AJKD,
2002
• First report of TDF
related renal failure,
nephrogenic DI and
Fanconi syndrome
• Reversible renal failure
with withdrawal of
tenofovir
• Nephrogenic DI
• histology demonstrated
mainly proximal tubular
cell abnormalities
Fanconi Syndrome
Proximal Tubule Cell
Glucose
Phosphate
Bicarbonate
Sodium
Amino Acids
X
X
X
Phosphate
Hypophosphatemia, acidosis, glycosuria, aminoaciduria, hypokalemia = FANCONI SYNDROME
• Literature search for published case reports
of TDF related ARF
• 1990 - 2005
Tenofovir- associated Renal Dysfunction
literature review
Characteristic
N=27
Age; years
45.5 (31 – 65)
Concurrent ARV; n(%)
Ritonavir
Didanosine
21 (77)
9 (33)
Time to diagnosis; months
11.3 (1 – 29)
Diabetes insipidus; n (%)
5 (18)
Zimmermann-Braden_TFD associated acute and ckd, HIV / AIDS, 2006
Tenofovir- associated Renal Dysfunction
literature review
Characteristic (N=27)
Baseline creatinine; mg/dL
0.9 (0.5 – 2.1)
Peak creatinine; mg/dL
3.9 (0.89 – 20) P < .05
Post creatinine; mg/dL
1.2 (0.67 – 2.6) P < .05
Fanconi Syndrome; n (%)
16 (59)
Return to baseline creatinine; n (%)
22 (81)
Urine protein; n (%)
6/17 (35)
Hemodialysis; n (%)
2 (7)
Mean (range) unless otherwise specified
Zimmermann-Braden_TFD associated acute and ckd, HIV / AIDS, 2006
Tenofovir-induced Fanconi syndrome
literature review
• Other features
– Acidosis, Hypokalemia
– When checked TDF levels were elevated
• In all cases acidosis, hypokalemia,
hypophosphatemia and glycosuria resolved after
discontinuation of TDF
• Biopsy findings (8)
– Proximal acute tubular necrosis (ATN)
Tenofovir-induced Fanconi
syndrome
• Retrospective review of the FDA Adverse
Event Reporting System
• 2001-2006
Gupta_Tenofovir associated fanconi_AIDS pt care_2008
Conclusion from case reports
• Potential role of drug interactions
– Ritonavir
• has been shown to increase serum TDF by >30%
• Inhibitor of MRP-2 -> increase proximal tubular concentration
of TDF by decreasing secretion
– Didanosine
• Coadministration with TDF may increase serum
concentration of didanosine -> proximal tubular dysunfction
• Polymorphism in the renal tublar drug
transporter
– variant MRP 2 or 4
The End