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Tuesday Case Conference

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

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Tuesday Case Conference

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  1. Tuesday Case Conference

  2. Introduction • What is Tenofovir disoproxil fumarte (TDF)? • How Nucleotide RTI work • Nephrotoxicity of NtRTI • Is TDF Nephrotoxic? • In vitro evidence • Epidemiologic evidence

  3. 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

  4. 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

  5. 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

  6. 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

  7. 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

  8. 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 Proximal Tubule Lumen TDF OAT1 MRP

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

  10. Mechanisms of Tubular ToxicityThe Mitochondrial Cytopathy Hypothesis http://www.retroconference.org/2002/Posters/13560.pdf

  11. In vitro study

  12. In vitro assessment of mitochondrial toxicityThe 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

  13. In vitro study

  14. In vitro studyEffects 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

  15. 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…

  16. 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

  17. Clinical TrialsGilead-Sponsored Clinical Studies of TDF In all of these studies the rates of renal abnormalities were similar between TDF and control arms.

  18. Clinical Trial • Multicenter, RCT • FU of 144 weeks TDF + 3TC + EFV vs. d4T + 3TC + EFV

  19. GS903 Izzedine-Deray_Long-term renal safety of TFV_NephDialTranp_2005

  20. GS903Incidences of elevated serum creatinine and hypophosphatemia (-0.1) (-0.2) Izzedine-Deray_Long-term renal safety of TFV_NephDialTranp_2005

  21. GS903Calculated 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

  22. 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

  23. Case Reportfirst 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

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

  25. Literature search for published case reports of TDF related ARF • 1990 - 2005

  26. Tenofovir- associated Renal Dysfunctionliterature review Zimmermann-Braden_TFD associated acute and ckd, HIV / AIDS, 2006

  27. Tenofovir- associated Renal Dysfunctionliterature review Mean (range) unless otherwise specified Zimmermann-Braden_TFD associated acute and ckd, HIV / AIDS, 2006

  28. Tenofovir-induced Fanconi syndromeliterature 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)

  29. Tenofovir-induced Fanconi syndrome • Retrospective review of the FDA Adverse Event Reporting System • 2001-2006

  30. Gupta_Tenofovir associated fanconi_AIDS pt care_2008

  31. 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

  32. The End

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