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Study Design

CPCRA GART Study (046) A Randomized Study of Antiretroviral Management Based on Plasma Genotypic Antiretroviral Resistance Testing (GART) in Patients Failing Antiretroviral Therapy. GART (N = 78). No-GART (N = 75). Follow-up Wks 4, 8, & 12. Follow-up Wks 4, 8, & 12. Study Design.

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Study Design

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  1. CPCRA GART Study (046)A Randomized Study of Antiretroviral Management Based on Plasma Genotypic Antiretroviral Resistance Testing (GART) in Patients Failing Antiretroviral Therapy

  2. GART (N = 78) No-GART (N = 75) Follow-up Wks 4, 8, & 12 Follow-up Wks 4, 8, & 12 Study Design 3-fold rise in HIV RNA on >16 weeks 2 NRTIs + PI Baseline Virologists review genotype + AR HxPrepare GART report with Tx suggestions Randomization (N = 153)

  3. Algorithm For Interpretation Of Resistance Mutations: RTIs Reverse Transcriptase Mutation Expected Drug Resistance 75T stavudine 215F/Y ± (41L, 67N, 70R, 210W, 219E/Q) zidovudine 74V or 65R or 69D didanosine, zalcitabine 184V lamivudine, didanosine, zalcitabine 215F/Y + [74V or 65R or 69D] zidovudine, didanosine, zalcitabine 151M ± (62V, 75I, 77L, 116Y) zidovudine, didanosine, zalcitabine, stavudine possible lamivudine 103N or 106A or 181C/I or 188C nevirapine, delavirdine

  4. Algorithm For Interpretation Of Resistance Mutations: PIs Protease Mutation Expected Drug Resistance 90M or 48V ± (63P, 71T/V) saquinavir possible nelfinavir 30N ± (36I/L, 46I/L, 71T/V, 77I, 88D) nelfinavir 50V ± (46 I /L, 47V) amprenavir 90M + 48V saquinavir possible: ritonavir, indinavir, nelfinavir > Any 3 of the following: indinavir, ritonavir possible: nelfinavir, saquinavir 10 I/ R/V, 20M/R, 24I, 36I/L, 46I/L, 48V, 54V, 63P, 64V, 71T/V, 82A/F/T, 84V, 90M (either 46 I /L, 82A/F/T or 84V must be present)

  5. Baseline GART Report PID: 023-0004 Date: 05-23-97 Resistance Mutations These mutations indicate the following drug sensitivities RT gene Protease gene 67N 48V ZDV resistance 70R 90M 3TC resistance 184V 215Y SQV resistance IDV/RTV possible resistance … Based on a review of this patient’s genotypic resistance mutations and antiretroviral history, we suggest the following treatment recommendations: 1. ddI + HU + nevirapine + indinavir 2. ddI + HU + delavirdine + nelfinavir 3. d4T + nevirapine + nelfinavir + indinavir 4. d4T + delavirdine + nelfinavir + indinavir

  6. Baseline Characteristics GART No-GART CD4 (mean cells/mm3) 230229 HIV RNA (median copies/mL) 28,78525,860 Entry regimen (%)NRTI Component ZDV + 3TC 4544 d4T + 3TC 4139PI Component Indinavir 5453 Nelfinavir 3333 Ritonavir 68 Saquinavir 65 Failing on first PI (%) 5344

  7. Major Mutations (%) 69S (S-S) 1 151M 3 184V 82 215F/Y 61 Any NNRTI 4 Other 12 RT Protease 30N 14 46I/L 31 48V 1 82A/F/T 34 84V 8 90M 31 Distribution of Major Mutations

  8. Impact of GART Report on RegimenPrescribed in the GART Group GART report influenced choice of 83 regimen* A regimen suggested by the study 54 virologists was prescribed Percent * After review of the GART report, the site clinician altered their initial proposed regimen

  9. HIV RNA (log10) Change from Baseline No-GART GART Dif.* P-value* Avg (4 & 8 wks) -1.19-0.61 -0.53 .00001 95% CI: (-0.29 to -0.77) * Adjusted for baseline HIV RNA and baseline regimen.

  10. Mean HIV RNA by Study Week 5.0 Study Group 10 4.5 4.0 HIV RNA (log ) 3.5 p = .003 p = .0001 p = .0003 3.0 = Study Week

  11. Percent of Patients with Undetectable HIV RNA, by Study Week P=.0001 P=.004 Percent P=.10 No-GART No-GART No-GART GART GART GART Week 4 (N = 150) Week 8 (N = 148) Week 12 (N = 148)

  12. HIV RNA Changes byNumber of Active Drugs Prescribed Change (log10) 0 HIV RNAChanges(log10) -0.10 -0.25 -0.59 -0.50 -0.75 -1.04 -1.00 -1.25 Percent -1.25 GART No-GART Number of Active Drugs

  13. No. Drugs Prescribedby Randomization Group 3 or moreactive drugs No. Patients 67% 30% 91% 62% 100% 60% 3 >5 4 Total No. Drugs

  14. No. Patients(Average Change in log10 HIV RNA) Treatment Difference (GART vs. No-GART and 95% CI) Characteristicat Entry GART No-GART 39 (-1.24)36 (-0.55) 50 - 199 38 (-1.14)39 (-0.66) 200 - 500 35 (-0.90)37 (-0.56) <25,000 copies/mL 42 (-1.43)38 (-0.66) >25,000 copies/mL All Patients -2 -1.5 -1 -0.5 0 0.5 1 Treatment Differences by Selected Baseline-Defined Subgroups CD4+ Count (cells/mm ) 3 Baseline HIV RNA (log10 RNA)

  15. No. Patients(Average Change in log10 HIV RNA) Treatment Difference (GART vs. No-GART and 95% CI) Characteristicat Entry GART No-GART 40 (-1.23)33 (-0.69) One Indinavir 41 (-1.12)40 (-0.55) 37 (-1.15)42 (-0.55) Two or More 26 (-1.29)25 (-0.67) Nelfinavir 5 (-1.18)6 (-0.77) Ritonavir 5 (-1.29)4 (-0.55) All Patients Saquinavir -2 -1.5 -1 -0.5 0 0.5 1 Treatment Differences by Selected Baseline-Defined Subgroups Prior PI Treatment Protease Inhibitor (log10 RNA)

  16. No. Patients(Average Change in log10 HIV RNA) Treatment Difference (GART vs. No-GART and 95% CI) Characteristicat Entry GART No-GART Yes 38 (-1.38)42 (-0.63) Yes 55 (-1.21)56 (-0.65) No 39 (-1.01)33 (-0.58) No 22 (-1.16)19 (-0.49) All Patients -2 -1.5 -1 -0.5 0 0.5 1 (log10 RNA) Treatment Differences by Selected Baseline-Defined Subgroups Major RT/PI Mutations NNRTI Proposedby Site Clinician

  17. Log10change* Log10change* P-value P-value Change in HIV RNA (from Baseline to Average of 4 and 8 Weeks) Associated with Selected Protease Mutations Unadjusted for Prior PI Treatment Adjusted for Prior PI Treatment Protease Mutation 30N -0.41 0.04 -0.47 0.06 46I/L -0.03 0.84 -0.01 0.93 82A/F/T 0.11 0.48 0.15 0.36 84V -0.22 0.39 -0.22 0.40 90M 0.31 0.04 0.25 0.13 * Adjusted for baseline HIV RNA and CD4+ count; positive change indicates increase from baseline relative to those without the indicated mutation

  18. Conclusion GART with expert advice in patients failing antiretroviral therapy was superior to No-GART, as measured by short-term viral load responses

  19. Conclusions (continued) • The greater viral load reduction with GART is attributed to a greater number of active drugs prescribed in the GART arm • The impact of GART was similar for patients failing their first protease inhibitor and for those who had received multiple protease inhibitors • Baseline genotype was associated with virologic response to salvage therapy

  20. Protocol Team John Baxter, M.D., Chair Douglas Mayers, M.D., Co-chair Thomas Merigan, M.D., Co-chair Donald Abrams, M.D. Barbara Brizz, B.S.N., M.H.S.Ed. Kathy Canaday, R.N. Timothy Day Marie Hoover, Ph.D. John Ioannidis, M.D. Leslie Johnston-Dow, Ph.D. Sharon Mannheimer, M.D. Ana Martinez, R.Ph. Robert Munk, Ph.D. James Neaton, Ph.D. Elizabeth Perelli, R.N., M.S. Carla Pettinelli, M.D., Ph.D. Melanie Thompson, M.D. Deborah Wentworth, M.P.H.

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