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)

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 TDF BloodLumen OAT1 MRP Proximal Tubule

TDF is eliminated through the Kidney Tenofovir Potential for accumulation of high concentration of TDF in proximal tubule cells MRP 2 / 4 ATP

Mechanisms of Tubular Toxicity The Mitochondrial Cytopathy Hypothesis

In vitro study

In vitro assessment of mitochondrial toxicity The effect of TDF and other NRTIs on mtDNA synthesis Birkus-Cihlar_Assmt of Mitochondrial Toxicity in Human CellsTreated with Tenofovir_AAC_2002 Tenofovir has little mitochondrial toxicity

In vitro study

In vitro study Effects of tenofovir and cidofovir on the human renal proximal tubule epithelial cells Cihlar-Hitchcock_TFV exhibits low cytotoxicity in various human cell types comariosn with other NRTI_Antiviral Res_2002 Inhibition of cell proliferationEffects on viability TDF with low cytotoxicity in proximal tubule epithelial cells

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 –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 –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 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 Izzedine-Deray_Long-term renal safety of TFV_NephDialTranp_2005 (-0.2) (-0.1)

GS903 Calculated Creatinine Clearance Through Week 144 Izzedine-Deray_Long-term renal safety of TFV_NephDialTranp_2005 Conclusion: -Renal safety profile between 2 groups was similar -Incidence of renal failure and hypophosphatemia were reversible -No patient developed Fanconi syndrome

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 Glucose Phosphate Bicarbonate Sodium Amino Acids Hypophosphatemia, acidosis, glycosuria, aminoaciduria, hypokalemia = FANCONI SYNDROME X X X Phosphate Proximal Tubule Cell

Literature search for published case reports of TDF related ARF

Tenofovir- associated Renal Dysfunction literature review Characteristic N=27 Age; years45.5 (31 – 65) Concurrent ARV; n(%) Ritonavir Didanosine 21 (77) 9 (33) Time to diagnosis; months11.3 (1 – 29) Diabetes insipidus; n (%) 5 (18) Zimmermann-Braden_TFD associated acute and ckd, HIV / AIDS, 2006

Characteristic (N=27) Baseline creatinine; mg/dL0.9 (0.5 – 2.1) Peak creatinine; mg/dL3.9 (0.89 – 20) P <.05 Post creatinine; mg/dL1.2 (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 Tenofovir- associated Renal Dysfunction literature review 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

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