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

2. Clinical Cohort Studies: Virologic Failure Rates CohortN(% above LD, time) Amsterdam (Wit JID 99) 27140%, 48 wks Cleveland (Valdez Arch IM 99) 31053%, 1 yr Hopkins (Lucas Ann IM 99) 27363%, 1 yr Swiss (Ledergerber Lancet 99) 151738%, 2 yrs UCSF (Deeks AIDS 99)33750%, 48 wks

3. Clinical Cohort Studies: Predictors of Virologic Failure prior antiretroviral treatment higher baseline/peak viral load level lower baseline/nadir CD 4 cell count specific antiretroviral regimen used more missed clinic appointments

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

5. Therapeutic Drug Monitoring: VIRADAPT Time, mo 036 0.05 -0.15 -0.35 -0.55 -0.75 -0.95 -1.05 -1.35 -1.55 HIV RNA, log decrease Control = Standard of care. Source: Garraffo. Antiviral Ther; 1999;4(1):75. HIV RNA Decreases in PI-Treated Patients SOC SOC + GT OC OC + GT S/OC = suboptimal/optimal drug concentration GT = genotypic testing done

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

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

9. Mocroft, et al. 3rd Salvage Workshop, 2000 Treatment Failure at 2 years: EuroSIDA Cohort (N=8507) Regimen Cohort Virologic failure (VL >500) Immune + clinical failure Clinical events 1 st HAART40%20%5% 2 nd HAART50%30%24% 3 rd HAART67%40%25%

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. Para, et al. J Infect Dis 2000 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): RxVL change % <200 cps/ml CD4 change SQVhcnone 9%none SQVsgc-0.2 logs10%+37 IDV-0.6 logs37%+22

12. Hammer, et al, 6th CROI, #490. 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)

13. Gulick, et al, J Infect Dis 2000 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)

14. Feinberg, et al. Glasgow Meeting, 2000 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)

15. log 10 copies/mL Week M97-765: HIV RNA Mean Change from Baseline At Week 2, NRTIs were switched and NVP added At Baseline, PI was switched to lopinavir/r

16. Percent Week M97-765: HIV RNA <400 copies/mL (ITT M=F) Sample Size 400/100 mg36 400/200 mg34 65% 61%

17. Rockstroh, Glasgow Meeting, 2000 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)

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

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. Mocroft, et al. 3rd Salvage Workshop 2000 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)

21. Mocroft, et al. 3rd Salvage Workshop 2000 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

22. Eron, et al, AIDS 1998, #OP5.2 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

23. Eron, et al, AIDS 1998, #OP5.2 CNAA 2007: PI-experienced Results 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%)

24. Hammer, et al, 7th CROI, #LB7 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

25. Hammer, et al, 7th CROI, #LB7 ACTG 398: PI-experienced Results 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)

26. Raffi, et al., Glasgow Meeting 2000 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

27. DAPD-101: Median Change in HIV-1 RNA Treatment Experienced Cohorts Study Day DAPD BID TREATMENT WASHOUT -2 -1.5 -0.5 0 0.5 05101520 HIV-1 RNA Median Change from BL 200 mg BID 300 mg BID 500 mg BID Add-On

28. Schooley, et al, Glasgow Meeting 2000 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

29. Tenofovir: Gilead 902 Study

30. Lalezari, et al, Durban AIDS Meeting 2000 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

31. n=71 n=66 n=64 n=50 n=46 T20-205: Phase I follow-up Viral Load Reduction -- Week 32 Viral Load Change from Baseline (log 10 copies / mL)

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.