1. HAART for the treatment experienced patient Prema Menezes PA-C

2. Treatment Failure Definition and Reasons  Immunologic  No increase in CD4  Decrease in CD4  Clinical  HIV related event at least 3 months after ART  Virologic  HIV RNA >400 (24wks), >50 (48 weeks)  Virus  Resistant  Drug Therapy  Sub optimal  Sub therapeutic  Patient  Non adherence

3. Managing virologic failure: make a distinction between limited, intermediate, and extensive prior treatment exposure and resistance Goal of treatment: re-establish maximal virologic suppression  March 2004: Preservation of immune function and prevention of clinical progression  May 2006: Re-suppress HIV RNA levels maximally and prevent further selection of resistance mutations DHHS Treatment Guidelines

4. New Agents  Protease Inhibitors  Tipranavir  Darunavir  NNRTIs  Etravirine  Integrase Inhibitor  Raltegravir  CCR5 Inhibitor  Maraviroc

5. Limited Treatment Failure

7. Case 1: First Line Virologic Failure  31 yo woman s/p bilateral tubal ligation began [fdc ZDV/3TC] + EFV 36 months ago  Initial CD4 = 162; VL = 56,000  After starting HIV therapy, CD4 increased to 365 and VL fell to 340 and then to < 50 c/mL  Difficulty taking medication over the past 2 months due to relapse of substance abuse  Now returns with weight loss and thrush

8. What is your next step? 1. Obtain HIV RNA, CD4, continue therapy and have her return within a month 2. Obtain HIV RNA, CD4, stop therapy and have her return within a month 3. Obtain a resistance test 4. Choice 1 and 3 5. Choice 2 and 3

9. GS934: Resistance Development Through Week 96 TDF + FTC (n = 244) ZDV/3TC (n = 243) Patients genotyped, n1429 Wild-type, n47 Any resistance, n1020 EFV resistance mutations, n 1018 M184V/I, n29*9* TAMs, n01 K65R, n00 Gallant J, et al IAC 2006. Abstract TUPE0064. Comparative trial of ZDV/3TC/EFV vs. TDF/FTC/EFV in treatment naïve patients

10. KLEAN: Resistance FPV/r vs. LPV/r (with ABC/3TC FDC) Eron JJ Jr, Lancet 2006. FPV/r, n LPV/r, n Confirmed virologic failures 1624 Unable to sequence 23 No treatment-emergent mutations 914 Treatment-emergent mutations TAMs (M41M/L) 01 3TC-associated mutations (M184I, M184V, M184M/V) 34 NNRTI-associated mutations (V106V/A) 02 PI-associated mutations: all minor (I54I/L, I93I/L, K20K/R, I62I/V) 32

11. Case 1: First Line Virologic Failure  CD4 now = 98 and VL = 29,000  Genotype reveals 184V and 103N mutations  ART is discontinued and PCP prophylaxis prescribed. The patient enters in-patient detox and 6 weeks later returns to restart HIV medications.  She begins a series of adherence counseling sessions  What ART to use?

12. 1. Atazanavir + NRTIs 2. Atazanavir/ritonavir + NRTIs 3. Lopinavir/ritonavir + NRTIs 4. Fos-Amprenavir/ritonavir + NRTIs 5. [fdc ZDV/3TC/ABC] + tenofovir 6. Other Case 1: First Line Virologic Failure

13. If you chose NRTI + PI – which NRTIs 1. Abacavir + 3TC or FTC 2. Abacavir + tenofovir 3. Didanosine plus 3TC or FTC 4. Didanosine plus tenofovir 5. Tenofovir + 3TC or FTC 6. Tenofovir, ZDV + 3TC or FTC 7. Something else

14. 3TC Alone vs Treatment Interruption Castagna et al. AIDS 20:795 2006 -250 -200 -150 -100 -50 0 BL4812162024 Weeks 3TC TI 0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 BL4812162024 Weeks 3TC TI Mean CD4+ Decrease (ITT)Mean VL Increase (ITT) In contrast to treatment interruption arm, 3TC alone resulted in:  No recovery in RC  No increase in RT mutations  No reversion of PR mutations

15. Effects of M184V on other NRTI  Increases in susceptibility  Zidovudine  Stavudine  Tenofovir  Minimal Change or decrease in susceptibility  Abacavir  Didanosine −Both of these agents can select for M184V in vivo.

16. First Line Virologic Failure  Good news  Lots of treatment options  Considerations  Keep 3TC/FTC in new regimen  Genotype  Resistance appears to be limited in first HAART failure

17. ART Options for Extensively Treatment Experienced Patients Newer Agents DarunavirTipranavir

18. * Based on IAS-USA March 2003 at start of studies; updated to October 2004 list during studies VL = viral load, OBR = optimized background regimen (NRTIs ± enfuvirtide [ENF]) Investigator- selected CPI(s) + OBR (without NNRTIs) POWER 1 and 2 trials: design Investigator-selected CPI(s) + OBR TMC114/r 400/100mg qd + OBR TMC114/r 800/100mg qd + OBR TMC114/r 400/100mg bid + OBR TMC114/r 600/100mg bid + OBR PI-, NRTI- and NNRTI- experiencedPI-, NRTI- and NNRTI- experienced ≥1 PI mutation*≥1 PI mutation* PI-based regimenPI-based regimen VL >1,000 copies/mLVL >1,000 copies/mL Randomization The highest dose of TMC114/r (600/100mg bid) provided the greatest virologic response in the Week 24 analysis and is the selected dose for treatment-experienced patients The combined 48-week efficacy and safety interim analysis at this dose versus CPI(s) is reported here Lazzarin A, et al. XVI IAC 2006. Abstract TUAB0104

19. POWER 1 and 2: BL characteristics TMC114/r 600/100mg bid n=131 CPI(s) n=124 Demographics Gender (% male) Mean age (years) 89 44 88 44 Disease characteristics CDC class C (%) Mean duration of infection (years) Mean VL (log 10 copies/mL; SD) Median CD4 count (cells/mm 3 ; range) 36 12.0 4.61 (0.69) 153 (3–776) 43 12.9 4.49 (0.78) 163 (3–1,274) Previous ARV experience Mean duration (months; SD) NRTI NNRTI PI Fusion inhibitor (ENF) 100 (48) 28 (24) 65 (29) 14 (11) 106 (45) 23 (15) 65 (28) 11 (9) Genotypic and phenotypic information Median primary PI mutations* (n; range) Median PI resistance-associated mutations* (n; range) ≥1 sensitive † PI available (%) ≥1 sensitive † NRTI in OBR (%) 3 (0–5) 8 (0–12) 36 72 3 (0–5) 8 (1–13) 39 73 ARV = antiretroviral; SD = standard deviation *IAS-USA October 2004, † susceptibility was determined by Antivirogram ® Lazzarin A, et al. XVI IAC 2006. Abstract TUAB0104

20. POWER 1 and 2: patients with VL <50 copies/mL over time to Week 48 (ITT-TLOVR) TMC114/r 600/100mg bid CPI(s) 45%* (n=59/131) 12% (n=15/124) 46%* (n=50/110) 10% (n=12/120) 0 20 40 60 80 100 04812162024283236404448 Weeks Patients (%) 12 *p<0.001 vs CPI(s) ITT = intent-to-treat, TLOVR = time to loss of virologic response Not all patients had reached Week 48 at the time of analysis; patients who had not reached Week 48 were censored at their last available visit TMC114/r n= 131 131 131 130 120 110 CPI(s)n= 124 124 124 124 121 120 Lazzarin A, et al. XVI IAC 2006. Abstract TUAB0104

21. POWER 1 and 2: virologic response defined as VL <50 copies/mL by BL subgroups at Week 48 (ITT-TLOVR) Patients (%) 70 60 50 40 30 20 10 0 ENF used (naïve) ENF used (non-naïve) ENF not used TMC114/r 600/100mg bid CPI(s) 21/36 1/15 7/70 0 sensitive ARV in OBR ≥1 sensitive ARV in OBR 5/25 0/18 44/82 11/100 4/35 2/13 27/61 ARV = antiretroviral drug; OBR = optimized background regimen; ENF = enfuvirtide. Use of ENF was not randomized in POWER 1 and 2. Lazzarin A, et al. XVI IAC 2006. Abstract TUAB0104

22. POWER 1 and 2: mean change from BL in CD4 count over time to Week 48 (LOCF) TMC114/r 600/100mg bid CPI(s) 92* 102* 17 19 *p<0.001 vs CPI(s) LOCF = last observation carried forward 2 20 40 60 80 100 120 140 04812162024283236404448 Weeks Mean change in CD4 count (cells/mm 3 ) 0 TMC114/r n= 131 131 131 130 120 110 CPI(s) n= 124 124 124 124 121 120 Lazzarin A, et al. XVI IAC 2006. Abstract TUAB0104

23. Baseline Resistance and Response to DRV/r  Baseline fold-change was strongest predictor of Week 24 response  11 mutations associated with reduced response  V11I, V32I, L33F, I47V, I50V, I54L, I54M, G73S, L76V, I84V and L89V  73% of pts had  2 of these mutations DeMeyer S, et al. Resistance Workshop 2006. Abstract 73. Δ VL at Wk 24, (NC = F) FC  10 (n = 255) (70% of pts) FC 11-40 (n = 65) (17% of pts) FC > 40 (n = 48) (13% of pts) VL < 50 c/mL at Wk 24 50%25%13% Baseline DRV FC No. of BL mutations 0123  4 4 4 4 % with VL < 50, Wk 24 6450422210 -2.04 -1.08 -0.78 -2.5 -2.0 -1.5 -0.5 0

24. POWER 1 and 2: observed incidence of the most common treatment-emergent AEs* during treatment, regardless of severity and causality *AEs = adverse events reported in ≥10% of patients and excluding ENF-associated injection site reaction (TMC114/r: 28%; CPI: 22%) 80 70 60 50 40 30 20 10 0 Diarrhea NauseaHeadache Naso- pharyngitis Fatigue Patients (%) Pyrexia TMC114/r 600/100mg bid CPI(s) Upper respiratory tract infection Herpes simplex Lazzarin A, et al. XVI IAC 2006. Abstract TUAB0104

25. TITAN DRV/RTV vs LPV/RTV in Tx-Experienced, LPV-Naive Patients  Intermediate treatment experience  Stratified by treatment site, NNRTI in OBR, HIV RNA > or or < 50,000 c/mL  Darunavir/ritonavir met criteria for superiority to lopinavir/ritonavir in proportions with HIV-1 RNA < 400 copies/mL and < 50 copies/mL at week 48  Safety comparable between darunavir/ritonavir and lopinavir/ritonavir

26. The Randomized Evaluation of Strategic Intervention in Multidrug Resistant Patients With Tipranavir (RESIST)

27. Proportion of patients with viral load <400 and <50 copies/ml at week 96 Resist 1 and 2 – 96 weeks

28. Proportion of patients who took Enfuvirtide as a new drug and achieved virologic suppression.

31. Safety - laboratory abnormalities  Patients with Grade 3/4 elevations in liver enzymes or lipids were able to continue TPV/r therapy without developing clinical AEs

32. Highly Treatment Experienced Patients

33. Highly Treatment Experienced  48 yo white man HIV + since 1991 (CD4 180)  Received ZDV from 1994 to 1996, added 3TC then indinavir  VL on this regimen was initially BDL and CD4 rose to 300 cells over two years.  VL rose to 5,600 then 10,100, CD4 was 390.  In 2000 treatment was interrupted VL peaked at 386,000 and CD4 fell to 220

34. Case: Multi-drug Resistance  Over several years he was on a series of regimens:  EFV, SQV/RTV, d4T  Abacavir, ddI, LPV/r  TDF, FTC, LPV/r plus SQV  HIV RNA rebound was eventually observed on each regimen  He feels well and has had no AIDS defining illness. His current CD4 is 310 and his VL repeated several times is between 10,000 and 15,000 on therapy

35. Case: Multi-drug Resistance  Given long treatment history with only intermittent suppression of HIV RNA to BDL you order a genotype  This is the test available to you  RT mutations include:  41L, 74V, 118I, 184V, 215Y and 219Q  Protease mutations include:  10V, 20R, 33F, 46L,54V, 82A, 84V and 90M

36. Case: Multi-drug Resistance What will you do at this point? 1. Change to > 1 NRTI, tipranavir/r and enfuvirtide 2. Change to > 1 NRTI, darunavir/r and enfuvirtide 3. Interrupt therapy and after 6 months begin > 1 NRTI, darunavir/r and enfuvirtide 4. Continue current therapy 5. Holding regimen

37. Need to Know Likelihood of Success CD4 310, clinically stable

38. Let’s Look at Genotype  RT mutations include:  41L, 74V, 118I, 184V, 215Y and 219  Resistance predicted to 3TC, FTC, ddI, ABC, ZDV  Intermediate activity to TDF and d4T  Protease mutations include:  10V, 20R, 33F, 46L,54L, 82A, 84V and 90M

39. TPV Score and Treatment Response Valdez H, et al. Resistance Workshop 2005. Abstract 27. -2 0 -3 Median Change in VL at Wk 24* (log 10 copies/mL) 0-12-34-56-78-9 -2.10 (n = 144) -0.89 (n = 242) -0.45 (n = 260) -0.49 (n = 68) -0.08 (n = 4) TPV Score Median FC:0.7-0.91.1-1.42.0-3.13.3-3.9 14.7-52.5 *24-week data from patients in RESIST-1 and -2 given TPV/r TPV Score Mutations 10V, 13V, 20M/R/V, 33F, 35G, 36I, 43T, 46L, 47V, 54A/M/V, 58E, 69K, 74P, 82L/T, 83D, 84V 10V, 20R, 33F, 46L,54L, 82A, 84V, and 90M

40. Baseline Resistance and Response to DRV/r  Baseline fold-change was strongest predictor of Week 24 response  11 mutations associated with reduced response  V11I, V32I, L33F, I47V, I50V, I54L, I54M, G73S, L76V, I84V and L89V  73% of pts had  2 of these mutations DeMeyer S, et al. Resistance Workshop 2006. Abstract 73. Δ VL at Wk 24, (NC = F) FC  10 (n = 255) (70% of pts) FC 11-40 (n = 65) (17% of pts) FC > 40 (n = 48) (13% of pts) VL < 50 c/mL at Wk 24 50%25%13% Baseline DRV FC No. of BL mutations 0123  4 4 4 4 % with VL < 50, Wk 24 6450422210 -2.04 -1.08 -0.78 -2.5 -2.0 -1.5 -0.5 0 10V, 20R, 33F, 46L,54L, 82A, 84V, and 90M

41. Multi-Drug Resistance  This case illustrates several points to consider when making the difficult decision of when to switch  This patient is in no clinical danger.  His CD4 cell count is above 300  His viral load is over 1 log 10 lower than a peak off therapy.  He has had no AIDS defining illness and feels well  On the other hand his current therapy is not optimal with sustained viral replication  Continued current therapy may lead to CD4 cell decline and further accumulation of resistance mutations

42. Case: Multi-drug Resistance  There is no clinical urgency; what are treatment options?  He is naïve to T-20 therefore likely very active initially −T-20 low barrier to resistance; incomplete suppression leads to rapid resistance evolution  He has no NNRTI mutations −By history he had previous viral rebound while on EFV −NNRTI may add modest activity, −NRTI will likely have modest ADDITIONAL activity  There are substantial PI mutations limiting PI options −He has 5 TPV-associated mutations decreasing the likelihood of a sustained response −He has 3 DRV mutations which will impact activity

43. Should He Wait for New Agents? How quickly will new mutations evolve?

44. Risk of Delayed Switch on Stable HAART  SCOPE cohort of ART-experienced subjects (n = 106) [1]  Stable HAART for  120 days  HIV-1 RNA > 1000 c/mL   1 resistance mutation  Resistance testing every 4 mos until HAART modification  Emergence of new mutns at 1 yr  Any: 44% (95% CI: 33%-56%)  NAMs: 23% (95% CI: 15%-34%)  PI: 18% (95% CI: 9%-34%)  Those with persistent viremia on HAART run risk of limiting future treatment options  Other studies show similar results [2- 4] 1. Hatano H, et al. CROI 2006. Abstract 615. 2. Lafeuillade A, et al. IAC 2004. Abstract WeOrB1293. 3. Margot NA, et al. JAIDS. 2003;33:15-21. 4. Napravnik S, et al. JAIDS. 2005;40:34-40. Proportion Without New Mutation 1 new major PI mutation 1 new NRTI mutation* Any new mutation Number of available antiretrovirals from the following: ZDV, 3TC, ddI, ABC,TDF, EFV, IDV, NFV, SQV, RTV, APV, LPV 0 0.25 0.50 0.75 1.00 04812162024 Time (Mos) Time to loss of 1 drug equivalent 04812162024 *PI-treated subjects (n = 71) 0 0.25 0.50 0.75 1.00 Proportion Without Loss of 1 Drug

45. Case 1  Patient now has CD4 cell count of 120  VL is 15,000  Repeat Genotype – virtual phenotype show no new mutations  DRV fold change = 45 (cut-offs 3.4 – 96.8)  TPV fold change = 4.0 (cut-offs 1.2 – 5.4)  Intermediate susceptibility to TDF resistant to all NRTI  No NNRTI mutations (failed EFV in the past)

46. Case 1  If you were to start the patient on new drugs which would you use? A. Maraviroc B. Raltegravir C. Etravirine D. Raltegravir/Etravirine E. Maraviroc/Etravirine F. Maraviroc/Raltegravir

47. HIV-infected patients with VF on current HAART regimen, history of ≥ 1 NNRTI resistance mutations, ≥ 3 primary PI mutations, HIV-1 RNA > 5000 copies/mL (DUET-1: N = 612; DUET-2: N = 591) Placebo + DRV/RTV-containing OBR* (n = 604) Etravirine 200 mg BID + DRV/RTV-containing OBR* (n = 599) Week 48 *Investigator-selected OBR to consist of DRV/RTV (600/100 mg/mL) + ≥ 2 NRTIs ± enfuvirtide. † Planned Week 24 analysis: primary endpoint HIV-1 RNA < 50 copies/mL (TLOVR). Week 24 † DUET-1 and -2: Etravirine + DRV/RTV- Containing OBR Phase III Trials Madruga JV, et al. Lancet. 2007;370:29-38. Lazzarin A, et al. Lancet. 2007;370:39-48. Mills A, et al. IAS 2007. Abstract WESS204.1. Katlama C, et al. IAS 2007. Abstract WESS204.2. Cahn P, et al. ICAAC 2007. Abstract H-717.

48. DUET-1 and -2: Pooled Virologic and Immunologic Responses Outcome at Week 24Etravirine (n = 599) Placebo (n = 604) P Value HIV-1 RNA < 50 copies/mL, % 5941<.0001 Mean change in HIV-1 RNA from baseline, log 10 copies/mL -2.4-1.7<.0001 Mean change in CD4+ cell count from baseline, cells/mm 3 +86+67<.0001  In patients using enfuvirtide for the first time (n = 201), the difference between treatment arms (67% and 62% for etravirine vs placebo, respectively) was not significant (P =.427) Cahn P, et al. ICAAC 2007. Abstract H-717.

49. DUET-1 and -2: Response Based on Active Agents in OBR Cahn P, et al. ICAAC 2007. Abstract H-717. 0 20 40 60 80 100 HIV-1 RNA < 50 copies/mL at Week 24 (%) 45 8 60 74 30 67 Etravirine + OBR Placebo + OBR n = 8825725821119991 No. of Fully Active Agents in OBR (assessed by PSS) 01≥ 2

50. DUET-1 and -2: BL ETR Mutations and Virologic Response at Week 24 012 3 Patients With HIV-1 RNA < 50 copies/mL (%) 0 10 20 30 40 50 60 70 80 90 100 45 No. of BL ETR Mutations Patients (%)403016851  13 mutations associated with ETR resistance V90IA98G L100IK101E/P V106IV179D/F Y181C/I/VG190A/S  Presence of ≥ 3 ETR mutations associated with response similar to placebo + OBR –70% of patients had 0 or 1 ETR resistance mutations at BL – 14% of patients had ≥ 3 ETR resistance mutations at BL –Response diminished by ~ 20% in presence of 1 or 2 mutations Katlama C, et al. IAS 2007. Abstract WESS204.2.

51.  Proportion of patients achieving HIV-1 RNA < 50 copies/mL significantly greater in etravirine arms  CD4+ cell count increase from baseline significantly greater in ETR arm in DUET-1  DUET-1: 89 vs 64 cells/mm 3 (P =.0002)  DUET-2: 78 vs 66 cells/mm 3 (P =.3692)  Presence of ≥ 3 mutations from list of 13 ETR RT mutations associated with decreased response  K103N not associated with ETR resistance  Incidence of adverse events and laboratory abnormalities similar to placebo arm DUET-1 and -2: Study Conclusions

52. BENCHMRK-1 and -2: Raltegravir in Treatment-Experienced Pts Cooper D, et al. CROI 2007. Abstract 105aLB. Steigbigel R, et al. CROI 2007. Abstract 105bLB.  Randomized, double-blind, placebo-controlled, parallel phase III studies Raltegravir 400 mg twice daily + OBR BENCHMRK-1 (n = 232) BENCHMRK-2 (n = 230) Placebo + OBR BENCHMRK-1 (n = 118) BENCHMRK-2 (n = 119) HIV infected; triple-class resistant; VL > 1000 copies/mL BENCHMRK-1 (N = 350) (Europe, Asia/Pacific, Peru) BENCHMRK-2 (N = 349) (North, South America) Primary endpoints: Week 16 Planned duration: Week 48

53. Benchmark 1 and 2 Patient Disposition at study entry

54. BENCHMRK 1 and 2: HIV-1 RNA < 50 copies/mL (ITT, NC = F) Cooper D, et al. CROI 2007. Abstract 105aLB. Steigbigel R, et al. CROI 2007. Abstract 105bLB. P <.001 at Week 16 Percent of Patients with HIV RNA <50 Copies/mL P <.001 at Week 16 BENCHMRK-2 Weeks 0248121624 0 20 40 60 80 100 0248121624 0 20 40 60 80 100 BENCHMRK-1 Weeks 61% 33% 62% 36% Raltegravir + OBRPlacebo + OBR

55. BENCHMRK 1 and 2: HIV-1 RNA < 400 c/mL at Wk 16 by Agents in OBR Cooper D, et al. CROI 2007. Abstract 105aLB. Steigbigel R, et al. CROI 2007. Abstract 105bLB. + : First use in OBR – : No use in OBR Overall Efficacy Data –– % of Patients 020406080100 n 447 230 Efficacy by Agents in OBR EnfuvirtideDarunavir + + + + – – 87 98 44 23 63 90 42 24 55 90 80 47 29 74 191 90 79 43 Raltegravir + OBRPlacebo + OBR

56. BENCHMRK 1 and 2: HIV-1 RNA < 400 c/mL at Wk 16 by PSS/GSS of OBR Cooper D, et al. CROI 2007. Abstract 105aLB. Steigbigel R, et al. CROI 2007. Abstract 105bLB. (PSS) 0 1 2 or more (GSS) 0 1 2 or more Overall Efficacy Data % of Patients 61 5 62 44 76 41 141 68 87 57 222 110 57 10 111 63 85 43 170 93 89 71 159 70 020406080100 n 447 230 79 43 Raltegravir + OBRPlacebo + OBR

57. Case Summary  CD4 now 200 cell/mm 3, VL is 65,000; patient is symptomatic  RT mutations include:  41L, 74V, 118I, 184V, 215Y and 219  Resistance to 3TC, FTC, ddI, ABC, ZDV  Intermediate activity to TDF and d4T  Protease mutations include:  10V, 20R, 33F, 46L,54L, 82A, 73S, 84V and 90M  Predicted phenotype TPV = 4.0 (1.2, 5.4) DRV 64 (3.4, 96.9)  above upper cut-off for all other PI.  Previous NNRTI experience  Raltegravir, etravirine and maraviroc are now available.  Entry phenotype is dual-mixed

58. Summary Treatment experienced patients  Re-suppress HIV RNA levels maximally and prevent further selection of resistance mutations  Need to know likelihood of success  Must have at least two active drugs

59. World AIDS Day 2006

60. What Is the “Resistance Penalty” of Continued Nonsuppressive Therapy?  Studies of resistance accumulation in states of “incomplete viral suppression”  68% with new mutations after median of 22 mos [1]  33% with new TAMs, 2% K65R during 96 wks of FU [2]  60% with new mutations after median of 9.3 mos, but no shift on virtual phenotype [3]  Studies lack results of subsequent switches  No fully powered randomized studies of early vs deferred switching 1. Lafeuillade A, et al. IAC 2004. Abstract WeOrB1293. 2. Margot NA, et al. J Acquir Immune Defic Syndr. 2003;33:15-21. 3. Napravnik S, et al. J Acquir Immune Defic Syndr. 2005;40:34-40.