Undetectable: A crucial goal of therapy

1. Undetectable:A crucial goal of therapy January 2007

2. New data lead guidelines to change their recommendations for treatment experienced patients • In pivotal clinical trials conduced in treatment-experienced patients (TORO, RESIST, POWER), reaching a ≥ 1 log drop was the endpoint to enable statistical comparison between groups • Secondary endpoints were more stringent • As a result of these trials, the recommendations made by international treatment guidelines have been revised • However, in clinical practice different goals may exist

3. HIV treatment guidelines recognize the importance of adding FUZEON: DHHS • The goal of treatment for patients with prior drug exposure and drug resistance is to re-establish maximal virological suppression • Adding a drug with activity against drug-resistant virus (e.g., a potent PI/r) and a drug with a new mechanism of action (e.g., HIV entry inhibitor) to an optimized background ARV regimen can provide significant ARV activity • One should design a regimen with two or more fully active drugs (on the basis of resistance testing or new mechanistic class) http://AIDSinfo.nih.gov

4. HIV treatment guidelines recognize the importance of adding FUZEON: IAS-USA • The virological target for patients with treatment failure is now a plasma HIV-1 RNA level < 50 copies/mL • Trials with newer ARV agents (e.g., TPV and DRV) have shown that it is possible to achieve HIV-1 RNA levels < 50 copies/mL even in highly treatment-experienced patients • The likelihood of reaching an HIV-1 RNA level < 50 copies/mL was highest if more than two active drugs were in the regimen, especially if one of the drugs was enfuvirtide Hammer S et al. JAMA 2006; 296:827-43

5. In treatment-experienced patients access to sufficient active drugs may be problematic

6. The dilemma: When a viraemic patient does not have two active drugs, a choice must be made Choice Add the single active agent Wait for two active drugs

7. The dilemma: When a viraemic patient does not have two active drugs, a choice must be made Choice Add the single active agent Wait for two active drugs Advantages: Short-term immunological and clinical benefits Advantages: Preserve activity Enabling durable suppression when a second active drug becomes available

8. The dilemma: When a viraemic patient does not have two active drugs, a choice must be made Choice Add the single active agent Wait for two active drugs Advantages: Short-term immunological and clinical benefits Advantages: Preserve activity Enabling durable suppression when a second active drug becomes available Disadvantages: Lose future opportunity for durable suppression Disadvantages: Potential clinical progression

9. What is the risk of keeping a patient on a failing ARV regimen?

10. Risks of keeping a patient on a failing regimen Accumulating resistance mutations and lossof treatment options Decreasing CD4 cell counts Disease progression

11. Relationship between viraemia and disease progression Detectable viral load High viral load Low viral load Resistanceaccumulation CD4 cell count decrease and HIV disease progression

12. Relationship between viraemia and disease progression Detectable viral load Undetectable viral load High viral load Low viral load No resistanceaccumulation No HIV diseaseprogression Resistanceaccumulation CD4 cell count decrease and HIV disease progression

13. Delayed impact of resistance accumulation on clinical progression Resistance mutations Increasing viral load Decreasing CD4 cell count Clinical progression Time (years)

14. Delayed impact of resistance accumulation on clinical progression Resistance mutations Increasing viral load Decreasing CD4 cell count Clinical progression T1 Time (years)

15. Delayed impact of resistance accumulation on clinical progression Resistance mutations Increasing viral load Decreasing CD4 cell count Clinical progression T1 T2 Time (years)

16. Risks of keeping a patient on a failing regimen Accumulating resistance mutations and lossof treatment options Decreasing CD4 cell counts Disease progression

17. Cumulative resistance mutations arise on a non-suppressive regimen e.g., ZDV/3TC/ABC M184V + any TAM(s) M184V only or wild-type 100 90 80 60 % of patients with mutation 40 20 10 0 0–8 n = 39 Number of weeks on therapy after viral rebound Melby T et al. 8th CROI 2001; Poster 448

18. Cumulative resistance mutations arise on a non-suppressive regimen e.g., ZDV/3TC/ABC M184V + any TAM(s) M184V only or wild-type 100 90 76 75 80 67 60 56 60 44 % of patients with mutation 40 33 40 25 24 20 10 0 0–8 n = 39 9–16 n = 34 17–24 n = 28 25–32 n = 24 33–40 n = 20 41–48 n = 16 Number of weeks on therapy after viral rebound Melby T et al. 8th CROI 2001; Poster 448

19. Maintaining patients on a failing regimen diminishes future treatment options • After a median of 14 months, 75% of patients acquired new drug resistance mutations and had a significantly lower GSS Kantor R et al. AIDS 2004; 18:1503–1511

20. SCOPE: Accumulation of resistance mutations in treatment-experienced patients • 160 patients on stable ART for ≥ 120 days, with HIV RNA > 1000 copies/mL and ≥ 1 resistance mutation • Resistance testing every 4 months until ART modification 1.00 1 new major PI mutation 0.75 1 new NRTI mutation Without new mutation 0.50 Any new mutation 0.25 0 0 4 8 12 16 20 24 Time (months) Hatano et al. 13th CROI 2006; Poster 615

21. Risks of keeping a patient on a failing regimen Accumulating resistance mutations and lossof treatment options Decreasing CD4 cell counts Disease progression

22. Differences in CD4 cell count according to viral load in treatment-experienced patients Rodes et al., J Med Virol. 2005, 77:23-8

23. Detectable viral load leads to decreasing CD4 cell count Total n = 79 (29 Group A; 50 Group B) Lo Re et al., AIDS Pat Care STDs 2004, 18: 436-442

24. Time to immunological failure after virological failure 1.0 0.8 0.6 Proportion not inimmunologic failure 0.4 0.2 0.0 0 6 12 18 24 30 36 42 Months since onset of virologic failure Deeks et al. AIDS 2002; 16:201-207

25. Risks of keeping a patient on a failing regimen Accumulating resistance mutations and lossof treatment options Decreasing CD4 cell counts Disease progression

26. Increased disease progression with class-wide drug resistanceSurviving or remaining free of AIDS events 1.0 0.9 0 CWR 1 CWR 2 CWR 0.8 Cumulative proportion surviving 0.7 3 CWR 0.6 0 10 20 30 40 50 60 Months from genotype resistance test CWR = class-wide resistance Zaccarelli et al. AIDS 2005; 19:1081–1089

27. Increased disease progression with class-wide drug resistanceAIDS-related death 1.0 0 CWR 0.9 1 CWR 2 CWR Cumulative proportion surviving 0.8 3 CWR 0.7 0.6 0 10 20 30 40 50 60 Months from genotype resistance test CWR = class-wide resistance Zaccarelli et al. AIDS 2005; 19:1081–1089

28. Increased disease progression with class-wide drug resistanceOverall survival 1.0 0 CWR 0.9 1 CWR 2 CWR Cumulative proportion surviving 0.8 3 CWR 0.7 0.6 0 10 20 30 40 50 60 Months from genotype resistance test CWR = class-wide resistance Zaccarelli et al. AIDS 2005; 19:1081–1089

29. Relationship between virological suppression and survival % measurements detectable(0–18 months after starting HAART) 0.25 100% 0.20 0.15 Cumulative mortality 0.10 0.05 0.00 0 18 36 54 72 Months after baseline* Lohse et al. CID 2006; 42:136-44 *Baseline was 18 months after HAART initiation

30. Relationship between virological suppression and survival % measurements detectable(0–18 months after starting HAART) 0.25 100% 0.20 51% – 75% 76% – 99% 0.15 Cumulative mortality 0.10 0.05 0.00 0 18 36 54 72 Months after baseline* Lohse et al. CID 2006; 42:136-44 *Baseline was 18 months after HAART initiation

31. Relationship between virological suppression and survival % measurements detectable(0–18 months after starting HAART) 0.25 100% 0.20 51% – 75% 76% – 99% 0.15 26% – 50% Cumulative mortality 1% – 25% 0.10 0.05 0.00 0 18 36 54 72 Months after baseline* Lohse et al. CID 2006; 42:136-44 *Baseline was 18 months after HAART initiation

32. Relationship between virological suppression and survival % measurements detectable(0–18 months after starting HAART) 0.25 100% 0.20 51% – 75% 76% – 99% 0.15 26% – 50% Cumulative mortality 1% – 25% 0.10 0% 0.05 0.00 0 18 36 54 72 Months after baseline* Lohse et al. CID 2006; 42:136-44 *Baseline was 18 months after HAART initiation

33. Benefits of achieving undetectable viraemia

34. Longitudinal, clonal genotypic analysis of treated patients with viral loads < 50 copies/mL Adapted from Kieffer et al., JID 2004, 189: 1452–1465

35. TORO: Relationship between quality of life and viral load at 48 weeks Physical healthsummary score p= 0.07 VL < 400 copies/mL VL > 400 copies/mL Mental healthsummary score p= 0.0007 -0.5 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 Difference in score from baseline (ITT; Adjusted for baseline HRQoL score, treatment, stratum and treatment*stratum) Clumeck et al., HIV7 2004 Poster P102

36. When is waiting to switch therapy appropriate?

37. When is waiting to switch therapy appropriate? • When the chance of resuppression is low it may be appropriate to delay a treatment switch • Reasons include • If the patient has one or no “active” drugs for a regimen • If newer drugs are anticipated “soon enough” • If the patient clinically stable

38. TORO: Waiting may be appropriate if a patient has one or no “active” drugs for a regimen Median viral load decline over the first 28 days of therapy, OB GSS = 0 Day 7 14 21 28 0 OB −0.04 −0.06 −0.07 -0.5 HIV-1 RNA change from baseline (log10 copies/mL) FUZEON + OB -1.0 −0.92 −1.19 -1.5 −1.42 -2.0 FUZEON + OB 112 104 106 108 OB 53 51 52 51 Bartlett et al. XV IAC 2004; Poster TuPeB4484

39. Approaches to consider when waiting to switch therapy • Options when a decision to delay a treatment switch is made include • Complete treatment interruption • Partial treatment interruption

40. Complete treatment interruption:SMART study Log rank = 31.1 p < 0.0001 20 DC Group VS = viral suppression DC = discontinue according to CD4 cell count 15 Patients with event (%) (HIV disease progression or death) 10 VS Group 5 0 0 4 8 12 16 20 24 28 32 36 40 44 Months from randomization 322 589 DC 2720 1170 VS 2752 334 625 1167 Wafaa El-Sadr et al. 13th CROI 2006; Oral LB106

41. Partial treatment interruption: 3TC monotherapy vs. treatment interruption • Prospective, open-label, randomized study (n = 29 in both groups); on 3TC-containing regimen • HIV RNA > 1000 copies/mL • CD4 > 500 cells/mm3 • Have M184V mutation Mean change in HIV RNA (log10 copies/mL) Mean change in CD4 count (cells/mm3) 0 2.00 1.75 –50 1.50 –100 1.25 –150 1.00 0.75 –200 0.50 –250 p = 0.0015 p = 0.122 0.25 –300 0 0 4 8 12 16 20 24 36 48 0 4 8 12 16 20 24 36 48 Weeks Weeks Treatment interruption 3TC Castagna et al. AIDS 2006 20(6):795-803

42. How can we maximize the likelihood of reaching < 50 copies/mL?

43. Response seen in control arms of clinical trials in treatment-experienced patients Katlama et al. IAS 2003. Abstract LB2; Hill and Moyle BHIVA 2006. Poster 1 Grinsztejn et al. 46th ICAAC 2006, Abst. H-1670b

44. Baseline mutations reduce the response to new drugs

45. NNRTI mutations and virological response to TMC125 (800 mg BID) at week 24 Baseline NNRTI mutations in TMC125 arm TMC125 Control 0* 1 2 ≥ 3 0 n=40 n=79 n=15 n=17 n=29 n=18 –0.19 –0.5 –0.66 Mean change in viral load (log10 copies/mL) –1.0 –1.00 –1.18 Relevant NNRTI mutations: K101P, V179E, V179F, Y181I, Y181V, G190S, M230L –1.5 –1.65 –1.82 –2.0 *All subjects had NNRTI mutations from prior genotyping TM125 is an investigastigational agent and has not been approved Vingerhoets et al. 13th CROI 2006; Oral 154

46. PI mutations and virologic response to TPV/r (500/200 mg BID) at week 24 *Change in viral load was the change in HIV RNA from baseline through week 2 (OT) or week 24 (LOCF) in log10 copies/mL Valdez et al. Antivir Ther. (2005) 10 Suppl 1:S29

47. Limitations ofresistance testing

48. Adding a new class will increase the response, even when resistance testing shows three or more “active” drugs TORO1 RESIST2 FUZEON + OB OB TPV/r Control PI/r 100 100 80 75 55 60 52 % patients 1 log10 drop, 24 weeks % patients < 400 copies/mL, 48 weeks 46 46 50 44 37 40 34 32 25 20 20 19 19 20 13 13 9 9 8 0 0 0 0 1 2 3 4 0 1 2  3 Baseline GSS Number of active background ARVs Interruptions during screening excluded 1Miralles et al. HIV7 2004. Abstract P17 2Cooper et al. CROI 2005. Abstract 560

49. TORO: Patients with three “active” agents show increased response when a new class is added Patients with active LPV/r and  2 other “active” ARVs 100 80 With FUZEON (n = 98) 52% 60 % of patients reaching <400 copies/mL 40 27% No FUZEON (n = 59) 20 0 0 4 8 12 16 20 24 28 32 36 40 44 48 Week p < 0.05 ; ITT Miralles and DeMasi. IDSA 2004. Abstract 921

50. Single genotypic tests underestimate resistance • Interpretation of resistance testing results should be donewith caution in treatment-experienced patients Harrigan PR et al., J. Infect. Dis. 2005 15;191(8):1325–30.