1. Cohen_MDS218_final1 Second Regimens: Issues in Improving Success Calvin Cohen, MD, MS Clinical Instructor Harvard Medical School Research Director Community Research Initiative of New England Boston, MA

2. Cohen_MDS218_final2 Treatment-Experienced Patients n What is failure? n Why did first regimen fail?

3. Cohen_MDS218_final3 Success n Ample data on how to create a successful regimen

4. Cohen_MDS218_final4 Multiple Regimens Multiple Paths to Success d4T + ddI + EMV (MKC-302) AZT + 3TC + APV (PROAB 3301) AZT + 3TC + IDV (DMP-006) AZT + 3TC + ABC (CNA3005) d4T + ddI + IDV (START II) AZT + 3TC + IDV (AVANTI 2) AZT + ddI + NVP (INCAS) AZT + 3TC + IDV (START II) AZT + 3TC + NFV (AVANTI 3) AZT + 3TC + IDV (CNA3005) AZT + 3TC + IDV (START I) d4T + 3TC + EMV (MKC-302) d4T + ddI + 3TC (Atlantic) d4T + 3TC + IDV (START I) d4T + ddI + NVP (Atlantic) 2 NRTIs + SQV-SGC (NV-15355) AZT + 3TC + ABC (CNAB3003) d4T + ddI + IDV (Atlantic ) AZT + 3TC + EFV (DMP-006) d4T + 3TC + EFV (DMP-043) 0102030405060708090100 Regimen (Trial) %With HIV RNA  50 at 48 Weeks: ITT Analysis Bartlett. 7th CROI; 2001; San Francisco. Poster 519.

5. Cohen_MDS218_final5 Success n Ample data on how to create a successful regimen —Active given any preexisting resistance

6. Cohen_MDS218_final6 Prevalence of HIV Drug Resistance in Recently Infected Cohorts SitenNRTINNRTI PI Madrid 1 3023%3%7% Boston 2 4511%2%2% Spain 3 1123%02% 1. Briones C, et al. 40th ICAAC, Toronto, 2000. Abstract 1245; 2. Balaguera HU, et al. 40th ICAAC, Toronto, 2000. Abstract 1247; 3. Guerrero A, et al. 40th ICAAC, Toronto, 2000. Abstract 1250; 4. Routy JP, et al. 40th ICAAC, Toronto, 2000. Abstract 1244

7. Cohen_MDS218_final7 Success n Ample data on how to create a successful regimen —Active given any preexisting resistance —Adequate adherence

8. Cohen_MDS218_final8 Success n Ample data on how to create a successful regimen —Active given any preexisting resistance —Adequate adherence —Ample potency l intrinsic vs. “boosted”

9. Cohen_MDS218_final9 Who Has Drug Failure? Impact of High Baseline HIV RNA *Statistically significant difference from IDV + AZT + 3TC, P<.05. Tashima. 6th CROI; 1999; Chicago. Abstract LB16. On Treatment ITT:NC=F Baseline Plasma HIV RNA 0 20 40 60 80 100 All<100,000>100,000All<100,000>100,000 EFV + AZT + 3TC EFV + IDV IDV + AZT + 3TC Patients <50 (%) 90 74 79 87 83 97 55 68 65 48 54 64 43 47 66 35 34 * * * * * Patients With HIV RNA <50 at wk 48

10. Cohen_MDS218_final10 DMP 006: Impact of Low vs High CD4 in HIV RNA Response HIV RNA <50 CD4 100 EFV + AZT + 3TC58.1%66.6%* (25/43)(223/335) EFV + IDV23.8%56.1% †,‡ (10/42)(189/337) IDV + AZT + 3TC40.9%47.2% (18/44)(161/341) *P =.05 EFV + AZT + 3TC vs IDV + AZT + 3TC. † P =.05 EFV + IDU vs IDV + AZT + 3TC. ‡ P =.05 comparing CD4 100 within each treatment group.

11. Cohen_MDS218_final11 Drug Class Issues in Managing Resistance n NRTIs n NNRTIs n PIs

12. Cohen_MDS218_final12 Drug Class Issues in Managing Resistance n NRTIs n NNRTIs n PIs

13. Cohen_MDS218_final13 M184V 17/23 3TC AZT + 3TC + IDV 1 orAZT + 3TC + IDV 2 IDV + EFV 2 AZT + 3TC + APV 3 IDV Monotherapy 1 Havlir. JAMA 2000; 283:229. 2 Holder. 6th CROI; 1999; Chicago. Abstract 492. 3 De Pasquale. Antivir Ther 1998;3(suppl 1):50. Isolates With Resistance (%) 0 25 50 75 100 AZT not reported IDV 10/14 IDV 5/23 3/14 EFVAZT 14/16 4/16 3TCAPV 2/16 M184V 0/26 IDV M184V 14/17 3TC AZT not reported RTI Resistance Without PI Resistance Differential Development of Mutations Following ART Failure

14. Cohen_MDS218_final14 Kuritzkes D, et al. AIDS 1996;10:975-81. (n=14) HIV-1 RNA Response in Subjects With M184V (M184V present by Week 12)

15. Cohen_MDS218_final15 CNA3005: Detection of Mutations on Therapy, ABC + CBV M184V + any TAM(s) 10 24 25 33 40 56 90 76 75 67 60 44 0 20 40 60 80 100 0-817-2425-3233-4041-48 Number of Weeks on Therapy After First Genotype (n = 16) (n = 39)(n = 34)(n = 28) (n = 24)(n = 20) Patients (%) 9-16 Patients With Given Genotype M184V only or WT

16. Cohen_MDS218_final16 Effect of RT Mutations on Response to ABC 53 66 37 22 79 84 57 52 21 16 43 48 0 20 40 60 80 100 <400 >0.5 log or <400 Nonresponders WT (n = 19) 184V only (n = 50) 1-2 muts (n = 35)  3 muts (n = 50) ART-Experienced Adults

17. Cohen_MDS218_final17 ddI Use in Second Regimens: HU as Booster in Experienced Patients? 0 20 40 60 80 100 04812162024283236404448 Week 3D + HU 3D + placebo HU/Placebo added 0 20 40 60 80 100 04812162024283236404448 Week 3D + HU 3D + placebo Treatment NaiveTreatment Experienced 1 Murphy. 13th IAC; 2000; Durban. Abstract 603. Proportion of Patients With HIV RNA <400 copies/mL (%)

18. Cohen_MDS218_final18 Regimen Sequencing: NRTIs n Determine impact of baseline NRTI mutations on virologic response among heavily NRTI- treated patients receiving 2 new NRTIs + EFV, NFV, or both Previous NRTIsNew NRTIs AZT + 3TC (n = 40) d4T + ddI vs vs AZT + ddI or ddC (n = 43)d4T + 3TC Katzenstein. Antivir Ther 1999;4(suppl 1):47. ACTG 364: Objective

19. Cohen_MDS218_final19 n Virologic success (HIV RNA <2000) by week 16 —AZT + 3TC  d4T + ddI: 22/40 (55%) —AZT + ddI or ddC  d4T + 3TC: 35/43 (82%) n Initiating ART with ddI (or ddC) may enhance second-line virologic response n d4T  55%-82% success rate after AZT- containing first-line regimen Katzenstein. Antivir Ther 1999;4(suppl 1):47. Regimen Sequencing: NRTIs

20. Cohen_MDS218_final20 Drug Class Issues in Managing Resistance n NRTIs n NNRTIs n PIs

21. Cohen_MDS218_final21 Drug Class Issues in Managing Resistance n NRTIs n NNRTIs n PIs

22. Cohen_MDS218_final22 ACTG 359: Suppression After IDV Prospective, Randomized, Partially Blind Study 33 47 31 38 20 16 50 40 30 20 10 0 RTV + SQV + DLV RTV + SQV + DLV + ADV RTV + SQV + ADV NFV + SQV + DLV NFV + SQV + DLV + ADV NFV + SQV + ADV Patients with HIV RNA <500 (%) Acosta. 6th CROI; 1999; Chicago. Abstract 365.

23. Cohen_MDS218_final23 0 20 40 60 80 100 IDV (n = 70)NFV (n = 155) IDV NFV APV SQV RTV Distribution of Susceptibility to PIs if >4-fold Resistance to IDV or NFV Susceptible (%)

24. Cohen_MDS218_final24 Suppression After Resistance to IDV vs NFV 55% 63% 28% 50% 0 20 40 60 80 100 IDVNFV PRT SOC Patients (%) n =30/48 23/4630/62 23/55 Impact of Phenotype Resistance Testing on % <400 wk 16

25. Cohen_MDS218_final25 Probability of Maintaining HIV RNA* <500 Based on HIV RNA at Time of Switch Week 0481216202428323640 44 <30 000 (n = 12) >30 000 (n = 12) Patients <500 (%) HIV RNA at Switch 100 80 60 40 20 0 *bDNA. Tebas. AIDS 1999;13:F23.

26. Cohen_MDS218_final26 Drug Concentration (µg/mL) EC 50 WT* EC 50 range of wild-type viral isolates 4 x EC 50 WT* 0.01 0.1 1 10 700 Impact of PK: PIs Usually Dosed Near the EC 90 for WT Virus *Adjusted for 50% serum. Sun. Antivir Ther 2000;5(suppl 3):70.

27. Cohen_MDS218_final27 Drug concentration (µg/mL) EC 50 WT* EC 50 range of resistant viral isolates 4 x EC 50 WT* 0.01 0.1 1 10 700 Impact of PK: Can We Increase Drug Concentration to Overcome Resistance? *Adjusted for 50% serum. Sun. Antivir Ther 2000;5(suppl 3):70.

28. Cohen_MDS218_final28 Drug Concentration (µg/mL) EC 50 WT* EC 50 range of resistant viral isolates 4 x EC 50 WT* 0.01 0.1 1 10 Impact of PK: Can We Increase Drug Concentration to Overcome Resistance? *Adjusted for 50% serum. Sun. Antivir Ther 2000;5(suppl 3):70.

29. Cohen_MDS218_final29 RTV intensification of IDV n Detectable HIV RNA on IDV regimen n Inclusion —On 2 NRTIs + IDV —HIV RNA >50-50,000 n Dose: 400/400 RTV + IDV (dose escalation used) n NRTI changes allowed after 3 weeks

30. Cohen_MDS218_final30 IDV C min Following Change From IDV 800 TID  RTV + IDV 400/400 BID *Crixivan ® package insert, Merck and Co., Inc. C 0 is predose concentration. Study is ongoing; results subject to change. Shulman. 7th CROI; 2000; San Francisco. Abstract 534. P<.001 0.001 0.01 0.1 1 Baseline C 0 Week 3 C 0 IDV Concentration, (  g/mL) Wild Type EC 50 *

31. Cohen_MDS218_final31 Virologic Response: Stratified by Increase in IDV C min at Week 3 of RTV Intensification The median IDV C 0 at 800 mg q8h was 0.106 mcg/mL increased to 0.792 mcg/mL at week 3 with RTV/IDV 400/400 mg BID. Study is ongoing; results subject to change. 0 20 40 60 80 100 0369121624  Median >Median Patients (%) n = 12 16 15 16 14 100 80 38 57 RTV Addition Without NRTI Change NRTI Change Allowed 14 100 40 19 86 88 63 38 100 56 36 Week

32. Cohen_MDS218_final32 Time Postdose (hours) 024681012 100 1000 10,000 IDV + RTV BID PK Study IDV + RTV q12h: 800/200 High-fat Meal 800/100 High-fat Meal 400/400 High-fat Meal IDV q8h: 800 mg Fasted IDV Plasma Concentration (nM) Saaha. 6th CROI; 1999; Chicago. Abstract 362.. Highly Resistant Virus 800 nM 3000 nM IC 95 of wild strain HIV-1 susceptible to IDV (100 nM)

33. Cohen_MDS218_final33 SQV dosage with mini dose of ritonavir: PK trough at 12 hrs Actual and Predicted C min for Different Doses of SQV/rtv Hill. Antivir Ther 2000;5(suppl 3):50.

34. Cohen_MDS218_final34 APV 20001: Median Steady-State Plasma Amprenavir Levels Wood. 8th CROI; 2001; Chicago. Abstract 332. 0 1 2 3 4 5 6 7 024681012141618202224 Hour APV 1200 mg BID (n = 61) APV 1200/rtv 200 mg QD (n = 15) APV 600/rtv 100 mg BID (n = 12) Total Plasma APV Concentration (  g/mL)

35. Cohen_MDS218_final35 Clumeck. 13th IAC; 2000; Durban. Abstract 3196 Multiple PI Experience: LPV/rtv + EFV at 24 Weeks M97-957 Design n n = 57, multiple PI exp, NNRTI naive n LPV/rtv (400/100 mg BID or 533/133 mg BID) + EFV 600 mg QD n 3 D/C for virologic failure n No significant changes in lipids from baseline n CD4 cell increase +45 Patients (%) 400/100 mg BID 533/133 mg BID 400/100 mg n = 292626 25 533/133 mg n = 282624 25 0 20 40 60 80 100 04812162024 OT92%80% ITT 82% 69%

36. Cohen_MDS218_final36 “Boosted” PI Options for Second Regimens n APV 600/100 BID n IDV 800/100 BID n SQV 1000/100 BID n LPV/rtv 400/100 BID n Note: NFV not usually “boosted”

37. Cohen_MDS218_final37 0 20 40 60 80 100 0 - 56 - 78 - 10 96% 76% 33% Percent Response ABT-378 Mutation Score Virologic Response to LPV/rtv in Multiple PI-Experienced Patients at Week 24 n No difference in susceptibility with 0-5 PI mutations n Moderate decrease in susceptibility with 6-7 PI mutations n Significant decrease with >8 PI mutations Kempf. Antivir Ther 2000; 5(suppl 3):29.

38. Cohen_MDS218_final38 ACTG: 2 PIs Are Better Than 1 NNRTI Naive NNRTI Experienced Overall SQV sgc 471534 (n = 116) IDV501936 (n = 69) NFV462134 (n = 139) Placebo33823 (n = 157) OVERALL: 2 PIs better than 1 (P =.002) Hammer. 7th CROI, San Francisco, 2000. Abstract LB7 % With HIV RNA <200 at Week 24 (ITT)

39. Cohen_MDS218_final39 28 53 51 54 TNV in ARV-Experienced Patients: HIV RNA Changes 23 48 43 48 19 42 39 41 Placebo 75 mg 150 mg 300 mg –0.9 –0.8 –0.7 –0.6 –0.5 –0.4 –0.3 –0.2 –0.1 0.0 0.1 0.2 081624324048 Weeks Placebo75 mg150 mg300 mg Mean  Log From Baseline Placebo roll-over to 300 mg TDF Schooley. 40th ICAAC; 2000; Toronto. Abstract 692.

40. Cohen_MDS218_final40 T20-205 48-Week Responder Analysis Patients Responding (%) *Intent-to-treat (ITT) analysis: non-completer = failure. 17 10 0 20 30 40 50 60 Intent-to-Treat* (n = 70) All patients who completed 48 weeks (n = 41) >400 and >1 log change from baseline 17 22 10 13 >50 and <400 <50

41. Cohen_MDS218_final41 Therapeutic Drug Monitoring Month 036 Control suboptimal concentration Genotypic suboptimal concentration Control optimal concentration Genotypic optimal concentration 0.05 –0.15 –0.35 –0.55 –0.75 –0.95 –1.05 –1.35 –1.55  Log HIV RNA, Log Decrease Control = Standard of care. Source: Garraffo. Antiviral Ther 1999;4(1):75. HIV RNA Decreases in PI-Treated Patients

42. Cohen_MDS218_final42 Resistance Testing n Does it help? —Several studies suggest it does —Especially when there still are treatment options to choose from —Both phenotype and genotype have favorable data —Need to know what the test results mean Cohen. 13th IAC; 2000; Durban. Abstract 1433.

43. Cohen_MDS218_final43 HAVANNA ITT Analysis No Genotype Genotype No Expert Expert n = 317 36% 46% 69% 49% 42% 58% 59% 41% P =.02 Meynard. 40th ICAAC; 2000; Toronto. Abstract 698.

44. Cohen_MDS218_final44 Summary n Not all rebound is failure n If rebound occurs, why? n What did we lose to viral resistance? n What works against that resistance virus? —New agents: more than 1! —Boosted drug levels —Don’t just guess—test n Progress continues...