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21, July 2010

Antiretroviral Regimen and Pharmacogenetic Determinants of Tenofovir-associated Change in Creatinine Clearance in ACTG Protocol A5142 (NWCS 291). Miguel Goicoechea, Yu Zheng, Michael Hughes, Sharon Riddler, Michael Neely, David Haas, Stan Louie and Richard Haubrich. 21, July 2010. Background.

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21, July 2010

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  1. Antiretroviral Regimen and Pharmacogenetic Determinants of Tenofovir-associated Change in Creatinine Clearance in ACTG Protocol A5142(NWCS 291) Miguel Goicoechea, Yu Zheng, Michael Hughes, Sharon Riddler, Michael Neely, David Haas, Stan Louie and Richard Haubrich 21, July 2010

  2. Background • Phase 3 trials of Tenofovir (903 & 934)1 • EFV-based regimens for 144 weeks • No difference in CrCl changes between arms • Case reports of Fanconi2 • Majority (83%) received TDF in PI-based regimens3 • Retrospective studies with greater CrCl declines with PI+TDF4,5 • Biphasic decline in CrCl 1Gallant JAMA 2004; 2Verhelst Am J Kidney Dis 2002; 3Gupta AIDS Patient Care STDs 2008; 4Goicoechea JID 2008; 5Gallant AIDS 2009;

  3. PI/r Renal clearance of tenofovir 80% 20% MRP-4 MRP-2 TFV OAT-1 & 3 TFV

  4. Objectives - Hypothesis • (Primary) Regimen type and change in CrCl over 96 weeks • LPV/r + TDF regimens will be associated with greater declines in CrCl. • Tenofovir plasma concentration and CrCl over 96 weeks • Higher tenofovir concentrations (weeks 4-16) will be associated with greater declines in CrCl. • Polymorphisms in drug transporters and CrCl over 96 weeks • SNPs associated with increased influx (i.e. OAT-1) or decreased efflux (i.e. Pgp, MRP-2 and MRP-4) transporter expression/ function will be associated with greater CrCl decline.

  5. Study Design of A5142 Riddler SA, Haubrich R et al., NEJM 2008 LPV/r BID + 3TC + d4T XR or TDF or ZDV LPV/r 533/133 mg BID + EFV 600 mg QD Multicenter Randomized Open-label LPV/r BID + EFV QD 96 weeks Screening ARV-naïve HIV RNA >2,000 c/mL Any CD4 count EFV 600 mg QD+ 3TC + d4T XR or TDF or ZDV N  250/arm In A5142 renal events were rare: • 9 subjects with grade 2 or less serum creatinine increase • No TDF treatment discontinuations due to renal toxicity concerns

  6. NWCS 291 - Study Design Four treatment groups: • TDF with (or without) a ‘pharmacologic inhibitor’ • LPV/r + TDF/3TC • EFV + TDF/3TC * a priori main comparison • Nucleoside-containing (Non-TDF) • LPV/r or EFV + 2 NRTIs • Nucleoside-sparing • LPV/r + EFV

  7. Methods • Inclusion criteria: • Subjects on randomized regimen until at least week 48 • Stored serum at BL & w48 • Estimated creatinine clearance (CrCl) • Bun, Cr, albumin (BL and weeks 24, 48, 72 and 96) • Cockcroft-Gault (ml/min) & MDRD (ml/min/1.73 m2) • Tenofovir exposure • Plasma tenofovir (weeks 4, 12, 16) • Single nucleoside polymorphisms • ABCB1 (P-gp), ABCC2 (MRP-2), ABBC4 (MRP-4), SLC22A6 (OAT-1)

  8. Baseline Characteristics No significant differences between treatment groups

  9. Regimen type – Mean change and 95% CI

  10. Regimen type and change in CrCL(Mixed effects model with repeated measures at weeks 24, 48, 72 and 96)

  11. Tenofovir concentration - percentile For every 10% increase in the mean tenofovir percentile there was a 2.3 ml/min/1.73m2 decrease in CrCl over 96 weeks (P<0.01). *Adjusted for: race, age, sex, treatment arm, time, baseline CrCl, CD4 count and HIV RNA **Black lines represent the median for each treatment group

  12. 17 Polymorphisms associated with change in CrCl only among TDF-treated patients • PgP (ABCB1) and OAT-1 (SLC22A6) • No significant associations • MRP-2 (ABCC2) • 12 of 43 SNPs (28%) • MRP-4 (ABCC4) • 5 of 86 SNPs (6%) Adjusted for: race, age, sex, treatment arm, time, baseline CrCl, CD4 count and HIV RNA Adjustment for multiple comparisons using False Discovery Method

  13. ABCC2 rs2273697 (1249 G>A) • In a prior study by Izzedine et al. Homozygote of minor allele at a higher frequency among patients with TDF-associated renal tubular dysfunction Izzedine et al. JID 2006

  14. ABCC4 rs1751034 (3463A>G) • In prior study by Kiser et al. Minor allele associated with 35% higher intracellular TFV-DP levels and reduced tenofovir renal clearance Kiser JJ et al. JAIDS 2008

  15. Summary (1) • Biphasic decline in CrCl among LPV/r+TDF+3TC • Possibly slowly progressive decline beyond 6 months • Traditional risk factors • Age (per 10 yrs): -2.3 ml/min/1.73m2 • Female: -3.2 ml/min/1.73m2 (P=0.07) • CD4 (per 100 cell/mm3 dec): -1.0 ml/min/1.73m2 • HIV RNA level (per log10 c/ml): -2.9 ml/min/1.73m2 • Regimen type (vs. EFV/TDF/3TC) • LPVr/TDF/3TC: -11.4 ml/min/1.73m2

  16. Summary (2) Dose-response relationship with early tenofovir exposure (weeks 4, 12 and 16) and CrCl change over 96 weeks Minimum plasma TFV (per 10%): -2.1 ml/min/1.73m2 Possible mechanistic role of genetic variants in ABBC2 (MRP-2) and ABBC4 (MRP-4) in TDF-associated renal toxicity Homozygous carriers of minor alleles in drug transporters ABCC2 (rs2273697): -27 ml/min/1.73m2 ABCC4 (rs1751034): -28 ml/min/1.73m2

  17. A5142 participants A5142 study team Richard Haubrich Sharon Riddler Statisticians Yu (Evelyn) Zheng Michael Hughes TFV pharmacokinetics Stan Louie Michael Neely Genetic testing David Haas Grant support UCSD Department of Medicine HIV/AIDS Clinical Trials Unit (5 U01 AI069432-04), National Institute of Allergy and Infectious Diseases (K24 AI064086 and K23 AI066901), University California San Diego Center for AIDS Research (5P30 AI 36214); Acknowledgements

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