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Response Rates in Heavily Pretreated HIV+ Patients

Response Rates in Heavily Pretreated HIV+ Patients. Roy M. Gulick, MD, MPH Cornell Clinical Trials Unit. Clinical Cohort Studies: Virologic Failure Rates. Clinical Cohort Studies: Predictors of Virologic Failure. prior antiretroviral treatment higher baseline/peak viral load level

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Response Rates in Heavily Pretreated HIV+ Patients

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  1. Response Rates in Heavily Pretreated HIV+ Patients Roy M. Gulick, MD, MPH Cornell Clinical Trials Unit

  2. Clinical Cohort Studies: Virologic Failure Rates

  3. Clinical Cohort Studies: Predictors of Virologic Failure • prior antiretroviral treatment • higher baseline/peak viral load level • lower baseline/nadir CD4 cell count • specific antiretroviral regimen used • more missed clinic appointments

  4. GART: HIV RNA Changes by Number of Active Drugs Change (log) HIV RNAchanges(log) 0 -0.25 -0.50 -0.75 % of patients GART n=78 No GART n=75 -1.00 -1.25   No. of active drugs Baxter, et al., AIDS 2000

  5. Therapeutic Drug Monitoring: VIRADAPT HIV RNA Decreases in PI-Treated Patients Time, mo 0 3 6 0.05 -0.15 -0.35 -0.55 -0.75 -0.95 -1.05 -1.35 -1.55 SOC SOC + GT HIV RNA, log decrease OC OC + GT S/OC = suboptimal/optimal drug concentration GT = genotypic testing done Control = Standard of care. Source: Garraffo. Antiviral Ther; 1999;4(1):75.

  6. Clinical Cohort Studies: Limitations • Heterogeneous patient populations (e.g., prior antiretroviral experience) • Reflects antiretroviral rx use in 1996-98 • Fewer antiretrovirals available • More complex regimens • Sequential monotherapy • ?virologic = immunologic = clinical failure

  7. UCSF Cohort (N=380):Virologic +Immunologic Responses Deeks, et al, J Infect Dis 2000

  8. French Cohort (N=2236):Viro., Immun. + Clinical Responses 100 95 IR+/VR+ IR+/VR- 90 IR-/VR+ Percent alive and AIDS-free 85 IR-/VR- 80 75 6 12 18 24 30 . Months since introduction of PI Grabar, et al, Ann Intern Med 2000

  9. Treatment Failure at 2 years: EuroSIDA Cohort (N=8507) Mocroft, et al. 3rd Salvage Workshop, 2000

  10. Prospective Studies of Salvage Rx: First Failures • ACTG 333: SQV-experienced • ACTG 372b: IDV-experienced • ACTG 359: IDV-experienced • ABT-765: Single PI-experienced

  11. ACTG 333: SQV-experienced • Study population: >48 wks SQVhc, no other PI, stable antivirals X 2 mos (N=72) • Baseline: HIV RNA 21K, CD4 222 • Results (interim analysis at 8 wks): Para, et al. J Infect Dis 2000

  12. ACTG 372b: IDV-experienced • Population: HIV+, on AZT or d4T + 3TC + IDV with VL >500 cps/ml (N = 84) • Duration: 48 weeks • Rx: EFV + ADV + ABC (or new NRTI) +/- NFV • Results: Overall, 29 (35%) had HIV RNA <500 copies/ml at week 16 • Factorial analyses: • ABC (37%) vs. 1-2 new NRTI’s (32%) (p=0.62) • NFV (45%) vs. placebo (24%) • favored nelfinavir group (p=0.046) Hammer, et al, 6th CROI, #490.

  13. ACTG 359: IDV-experienced • Population: HIV+, > 6 mo prior IDV, HIV RNA 2-200K, naïve to other PI and NNRTI, (N = 277) • Baseline: VL 32K, CD4 229 • Rx: SQVsgc + RTV or NFV + DLV, ADV, or both • Overall, 77 (30%) had HIV RNA <500 copies/ml at week 16 • Factorial analyses: • SQV/RTV (28%) vs. SQV/NFV (33%) (p=0.50) • DLV (40%) vs. ADV (18%) vs. both (33%) • favored DLV-containing regimens (p=0.006) Gulick, et al, J Infect Dis 2000

  14. Abbott M97-765: PI-experienced • Study population: HIV+, single PI failure, NNRTI naïve, HIV RNA 1-100K (N=70) • Baseline: VL 4.1 logs, CD4 372 • Study treatment: lopinavir 400 mg bid + ritonavir 100 or 200 mg bid + NVP + nucs X 96 weeks • Preliminary results: 4 d/c for rx-related effects (3 GI, 1 rash) Feinberg, et al. Glasgow Meeting, 2000

  15. M97-765: HIV RNA Mean Change from Baseline At Baseline, PI was switched to lopinavir/r At Week 2, NRTIs were switched and NVP added log10 copies/mL Week

  16. M97-765: HIV RNA <400 copies/mL (ITT M=F) 65% 61% Percent Sample Size 400/100 mg 36 400/200 mg 34 Week

  17. Abbott M97-957: >2 PI-experienced • Study population: HIV+, >2 PI failure, NNRTI naïve, HIV RNA >1000 (N=57) • Baseline: VL ~4.5 logs, CD4 ~245 • Study treatment: lopinavir 400 or 533 mg bid + ritonavir 100 or 133 mg bid + EFV + nucs X 48 weeks • Preliminary results: 3 d/c for rx-related effects (2 CNS sx, 1 lactic acidosis) Rockstroh, Glasgow Meeting, 2000

  18. 400/100mg BID 533/133mg BID M98-957: Proportion <400 copies/mL (ITT M=F) 71% 59% Percentage of patients Week: 400/100mg n = 29 533/133mg n = 28

  19. Heavily Pretreated Patients:A Definition • Patients with: • a loss/lack of virologic response to at least 2 HAART regimens • have taken at least one member of each of the approved antiretroviral drug classes (NRTI, NNRTI, PI)

  20. Heavily Pretreated Patients:EuroSIDA Cohort (1) • 266 pts had 3-class experience; had taken >2 HAART regimens and started new salvage rx: • 40% decreased VL <1000, and 30% maintained this decrease at 6 months • 55% had >1 log decrease and 45% maintained this decrease at 6 months (55-70% virologic failure at 6 months) • 55% decreased CD4 below baseline (imm.failure at 1 year) • 5% had a new AIDS event/death (clinical failure at 1 year) Mocroft, et al. 3rd Salvage Workshop 2000

  21. Heavily Pretreated Patients:EuroSIDA Cohort (2) • Predictors of virologic response: • Prior VL <500 cps/ml • Less prior rx (28% decline in probability/year rx) • Higher latest CD4 count • Central Europe resident • Predictors of immunologic/clinical response: • Female • Lower latest VL • Fewer prior antiretrovirals Mocroft, et al. 3rd Salvage Workshop 2000

  22. CNAA 2007: PI-experienced • Population: HIV+, >20 weeks combination therapy with a PI; HIV RNA >500 cps/ml (N=99) • Baseline experience: 72% 4-5 NRTI, 44% NNRTI; 60% 3-4 PI • Duration: 48 weeks • Treatment: open label ABC + EFV + APV • Primary endpoint: safety/tolerability, antiviral activity at 16 weeks Eron, et al, AIDS 1998, #OP5.2

  23. CNAA 2007: PI-experiencedResults • Overall, 19 (26%) had HIV RNA <400 copies/ml at week 16 • Subgroup analyses: • NNRTI naïve, VL <40K (53%) • NNRTI naïve, VL >40K (23%) • NNTRI experienced, VL <40K (33%) • NNRTI experienced, VL >40K (7%) Eron, et al, AIDS 1998, #OP5.2

  24. ACTG 398: PI-experienced • Population: HIV+, >4 months of up to 3 prior PI; HIV RNA >1000; prior NNRTI OK; (N=481) • Duration: 72+ weeks • Treatment: • open label APV + ABC + EFV + ADV with • SQV sgc 1600 mg bid • IDV 1200 mg bid • NFV 1250 mg bid or • matching placebo (for 2nd PI) • Primary endpoint: safety/antiviral activity/24 wks Hammer, et al, 7th CROI, #LB7

  25. ACTG 398: PI-experiencedResults • Overall, 149 (31%) had HIV RNA <200 copies/ml at week 24 • Subgroup analyses: • NNRTI-naïve (43%) vs. experienced (16%) • favors naïve subjects (p<0.001) • 1 PI exp (37%) vs. >2 PI exp (29%) • no difference (p=0.16) • Dual PI rx (35%) vs. APV alone rx (23%) • favors dual PI rx (p=0.002) Hammer, et al, 7th CROI, #LB7

  26. New Drug in Experienced Pts: DAPD (nucleoside analog) DAPD-101 Study • Study population: Failed prior ZDV or d4T + 3TC; VL 5-250K cps/ml, CD4 >50 (N=24) • Baseline: VL 5 logs, CD4 ~350 • Prior treatment experience: • average number of antivirals – 6 • average prior length of rx -- 4 years • 100% NRTI, >60% NNRTI, >80% PI • Rx: DAPD at 200, 300, 500 mg bid; 3 groups washed out X 7d, 1 group added on X 15 days Raffi, et al., Glasgow Meeting 2000

  27. DAPD-101: Median Change in HIV-1 RNA Treatment Experienced Cohorts 0.5 DAPD BID TREATMENT WASHOUT 0 -0.5 HIV-1 RNA Median Change from BL -1 200 mg BID 300 mg BID 500 mg BID 500 mg BID Add-On -1.5 -2 0 5 10 15 20 Study Day

  28. New Drug in Experienced Pts: Tenofovir (nucleotide analog) Gilead 902 Study • Study population: On stable antiretroviral regimen with VL >5K (N=189) • Baseline: VL 3.7 logs; CD4 ~350 • Prior treatment experience: • average prior length of rx – 4.6 years • Baseline mutations: 97% NRTI, 32% NNRTI, 57% PI • Rx: tenofovir at 75, 150, or 300 mg qd (or placebo) X 48 weeks Schooley, et al, Glasgow Meeting 2000

  29. 300 mg TDF started 0.2 Placebo 0.1 75 mg 150 mg 0 300 mg -0.1 Mean HIV RNA Change (log10 copies./mL) from Baseline -0.2 -0.3 -0.4 -0.5 -0.6 -0.7 -0.8 -0.9 Weeks: 0 4 8 12 16 20 24 28 32 N = 189 175 181 176 170 164 164 105 Tenofovir: Gilead 902 Study

  30. New Drug in Experienced Pts: T-20 (fusion inhibitor) T-20 205 Study • Study population: Prior T-20 experience (N=71) • Baseline: VL 4.8 logs, CD4 133 • Prior treatment experience: • average number of antivirals – 10 • 80% were three-drug class experienced • Rx: T-20 50 mg bid sq + other antiretrovirals chosen by hx and genotype X 48 wks • Results: 14/71 (20%) had <0.5 log reduction; • 23/70 (33%) had >1 log reduction or VL <400 Lalezari, et al, Durban AIDS Meeting 2000

  31. T20-205: Phase I follow-upViral Load Reduction -- Week 32 n=71 Viral Load Change from Baseline (log10 copies / mL) n=66 n=64 n=46 n=50

  32. Salvage Therapy: Conclusions • Virologic failure occurs commonly; immunologic and clinical failure also occur; all should be evaluated. • Predictors of response include adherence, VL, CD4, resistance profile, number of active drugs, drug levels. • Newer drugs with novel resistance patterns and/or mechanisms demonstrate activity, even in heavily pretreated patients. • Novel study design may demonstrate activity AND provide benefit for the subjects. • Further clinical research is needed.

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