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VIREAD (Tenofovir DF) Update. Viread Update  Pharmacokinetics  Safety & Tolerability  Efficacy  Virology.

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Presentation on theme: "VIREAD (Tenofovir DF) Update. Viread Update  Pharmacokinetics  Safety & Tolerability  Efficacy  Virology."— Presentation transcript:

1 VIREAD (Tenofovir DF) Update

2 Viread Update  Pharmacokinetics  Safety & Tolerability  Efficacy  Virology

3 Pharmacokinetics

4 Tenofovir DF Pharmacology  Once-daily dosing –Long intracellular half-life (tenofovir-DP) Activated cells: 10 hours; Resting cells: 50 hours –Serum t 1/2  17 hours  Renally cleared –interval adjustment for CrCl < 50 mL/min  Bioavailability –Can be given without regard to food* * US package insert August 2003

5 Tenofovir DF Pharmacology (cont’d)  Not a substrate or inhibitor of human CYP450 enzymes  No significant plasma drug interactions with: –FTC –3TC –ABC –EFV –LPV/r –IDV –FOS-APV –TPV  Clinically significant drug interactions with: –ddI (plasma levels increased  44-60%) –ATV (AUC  25%)

6 Background:  Previous PK studies with ddI EC 400 mg have demonstrated increased ddI exposures when co-administered with TDF 1 Objectives: To evaluate PK of ddI EC 250mg dosed:  Separated dosing –on an empty stomach two hours prior to TDF and a light meal  In a simplified dosing regimen –together with TDF and a light meal –together with TDF on an empty stomach 1 Viread Prescribing Information Kearney B, et al. 10th Conference on Retroviruses and Opportunistic Infection, Feb. 2003, Abstract 533 Study 984 Tenofovir DF and Didanosine EC Interaction: Background & Objectives

7 Kearney B, et al. 10th Conference on Retroviruses and Opportunistic Infection, Feb. 2003, Abstract 533 Viread Prescribing Information Study 984 Tenofovir DF and Didanosine EC Interaction: Results

8  ddI EC 250 mg dosed with TDF, in the presence or absence of food, results in drug exposures similar to ddI EC 400 mg dosed alone  When TDF and ddI is given, dose of ddI should be decreased to 250 mg in patients  60 kg* Kearney B, et al. 10th Conference on Retroviruses and Opportunistic Infection, Feb. 2003, Abstract 533 Viread Prescribing Information * US package insert August 2003 Study 984 Tenofovir DF and Didanosine EC Interaction: Results

9 Blum et al. ICAAC 2003, poster A-1621 No Interaction Observed TDF and FTC

10 TDF and LPV/r Steady-State LPV and RTV Concentrations LPV alone LPV + TDF mean  95%CI LPV IC 50(wt) Time (hr) Concentration (ng/mL) Kearney et al. ICAAC 2003, poster A-1617 RTV alone RTV+TDF

11 TDF and LPV/r Steady-State TDF Concentration TDF alone TDF + LPV/r mean  95%CITime (hr) Tenofovir Concentration (ng/mL) Kearney et al. ICAAC 2003, poster A-1617 TDF AUC  32%

12 TDF+LPV/r-Containing Regimens: Long-Term Safety Assessment (Study 908)  LPV/r was used in 271/296 (94%) of patients –mean duration of concomitant use: 63 weeks (maxiumum: 96 weeks)  The incidence of confirmed changes in serum creatinine to > 2.0 mg/dL or serum phosphorus < 1.5 mg/dL was < 1%  TDF discontinuation due to changes in serum creatinine occurred in 5 of 271 TDF+LPV/r-treated patients with advanced disease  Changes in serum creatinine and phosphorus similar to background incidence reported in advanced patient population 1 Kearney et al. ICAAC 2003, poster A Fisher et al. AIDS 2001, 15:

13 TDF and IDV Steady State IDV Pharmacokinetics with TDF (N=12) Flaherty JF, et al. 1 st IAS, Buenos Aires 2001, #336 AUC ss (  g*hr/mL) 27.5   12.5 C max (  g/mL) 9.46   % a -5% a a % Difference

14 TDF and ABC ABC alone ABC + TDF mean  95%CI Time (hr) Concentration (  g/ mL ) ABC was measurable in plasma for 6 to 8 hours following dosing Kearney et al. ICAAC 2003; poster A-1615 No Interaction Observed

15 Puzzle-2 Study Steady State ATV and RTV PK with TDF (N=11) Taburet AM, et al. 10 th CROI, Boston 2003, #537 Data on file, BMS Co., 2003 ATV/r 300/100 mg + TDF provides an IQ higher than ATV 400 mg alone and similar to historical data for ATV/r Historical data for boosted ATV Historical data for unboosted ATV

16 ATV and TDF + RTV Data on file with BMS and Gilead Taburet AM et al. 10CROI Feb Abstract # 537 ATV 400 TDF 300 % change C MAX (ng/ml) (  21) C MIN (ng/ml) (  40) AUC (ng*hr/ml) ,866 (  25) ATV 400 TDF 300 % change C MAX (ng/ml) (  21) C MIN (ng/ml) (  40) AUC (ng*hr/ml) 21,866 (  25) ATV 300 RTV 100 ATV 300 RTV 100 TDF 300 % change (  28) (  23) 46,07334,459 (  25)

17 ATV 300 mg QD RTV 100 mg QD ATV 400 mg QD SQV 1200 mg QD LPV 400 mg BID RTV 100 mg BID Weeks 1 and 2: Maintain NRTIs & Replace PI / NNRTI Wks : Replace NRTIs With Tenofovir 300 mg QD + 1 NRTI Patients Who Failed  2 Regimens &  1 ARV From Each Class 1:1:1 Randomization (N = 358) Randomized Treated BMS 045 Study Design

18 ATV 300/RTV – LPV/RTV Time-Averaged Difference Estimate (97.5% Cl) = 0.14 (-0.09, 0.37) ATV 400/SQV – LPV/RTV Time-Averaged Difference Estimate (97.5% Cl) = 0.31 (-0.07, 0.55) –1.52 –1.86 –1.89 Badaro R, et al. 2 nd IAS, Paris 2003, #118 Regimens (all with TDF+NRTI) BMS 045 Mean Change from Baseline HIV RNA through Week 24

19 LPV/RTV N = *Time to Loss of Virologic Response ATV 300/RTV N = 120 % Responders ATV 400/SQV N = LOQ = 400 c/mL LOQ = 50 c/mL BMS 045 Virologic Response (ITT)* at Week 24

20 B/L Weeks Percent Responders ATV 300/RTV (N = 120) ATV 400/SQV (N = 115) LPV/RTV (N = 123) For LOQ = 400 c/mL: ATV 300/RTV – LPV/RTV Difference Estimate (95% Cl) = 2.4 (-9.8, 14.5) *Time to Loss of Virologic Response  400 c/mL  50 c/mL BMS 045 Virologic Response (ITT)* at Week 24 Regimens (all with TDF+NRTI)

21 Other PK Studies  No Interaction Observed: –Methadone 1 –Oral Contraceptive 2, 3 –Ribavirin 4 1 Smith P et al. 2nd IAS, July 2003, Poster 869; 2 Viread Prescribing Information; 3 Kearney et al. 43rd ICAAC, September 2003, Poster A Margot and Miller. 2nd IAS, July 2003, Poster 980

22 TDF and Oral Contraceptive Interaction Viread Prescribing Information

23 Summary of Tenofovir Drug Interaction Data Consider ATV/r 300/100 ddl 250 mg Dose Change w/ TDF No Systemic PK Interaction Oral contraceptives Methadone EFV ATV RTV LPV IDV FosAPV/r ddl ABC d4T 3TC FTC Agent Studied

24 Renal Safety

25  Two year data from Study 903 –Active-controlled in treatment-naive patients  Long-term follow up in treatment-experienced patients from Studies 902 and 907 –Placebo-controlled, intensification design  Recent retrospective analyses and case reports  Renal dosing guidelines

26 Study 903 Study Design ART-naive patients (N = 600) randomized 1:1 Staszewski S. 10th CROI, Boston, MA, Feb 10-14, 2003, Abstract # 564b Stratification by: plasma HIV RNA >/  100,000 c/ml CD4 count  /< 200 cells/mm³ 144 wks

27     Maximum Toxicity Grade 0-96 Weeks in mg/dL TDF + 3TC + EFV (n=296) d4T + 3TC + EFV (n=296) 1 (0.5 from baseline) 10 ( 3%)7 ( 2%) 2 ( ) 2 (1%) 0 (0%) 3 ( )0 (0%) 2 (1%) 4 (6.0) 0 (0%) Gallant et al. ICAAC Abstract H840. Study 903 Serum Creatinine through Week 96

28 Study 903 Consecutive Visits with Graded Creatinine Consecutive Visits Number of Patients TDF+3TC+EFV d4T+3TC+EFV Gallant et al. ICAAC Abstract H840.

29 Maximum Toxicity Grade 0-96 Weeks in mg/dL TDF + 3TC + EFV (n=296) d4T + 3TC + EFV (n=296) 1 (2.0-  2.2) 9 (3%) 2 ( )8 (3%)7 (2%) 3 ( ) 1 (  1%)1 (  1%) 4 (  1.0) 0 (0%) Study 903 Serum Phosphorus through Week 96 Gallant et al. ICAAC Abstract H840.

30 Study 903 Consecutive Visits with Graded Serum Phosphorus through Week Consecutive Visits Number of Patients TDF+3TC+EFV d4T+3TC+EFV Gallant et al. ICAAC Abstract H840.

31 Maximum Toxicity Grade 0-96 Weeks in mg/dL TDF + 3TC + EFV (n = 296) d4T + 3TC + EFV (n = 296) 1 (30-99)35 (12%)46 (16%) 2 ( )18 (6%)17 (6%) 3 (  300) 0 (0%) 4Nephrotic Syndrome0 (0%) Study 903 Proteinuria through Week 96 Gallant et al. ICAAC Abstract H840.

32 Maximum Toxicity Grade 0-96 Weeks in mg/dL TDF + 3TC + EFV (n = 296) d4T + 3TC + EFV (n = 296)      1 (250)2 (1%) 3 (1%) 2 ( ) 2 (1%)1 (1%) 3 ( ) 2 (1%) 3 (1%) 4 (1000) 0 (0%) Study 903 Glucosuria through Week 96 Gallant et al. ICAAC Abstract H840.

33 mL/min TDF + 3TC + EFV (n = 296) d4T + 3TC + EFV (n = 296) Baseline Week 4828 Week 9614 Study 903 Mean Increase from Baseline in Calculated Creatinine Clearance (Calc Cr Cl): Week 96 Gallant et al. ICAAC Abstract H840.

34 Parameters through 96 weeks TDF+3TC+EFV (n = 296) d4T+3TC+EFV (n = 296) Graded SerumCreatinine12 ( 4%)9 ( 3%) Graded Serum Phosphorus18 ( 6%)17 ( 6%) GradedProteinuria53 (18%)63 (21%) GradedGlucosuria 6 ( 2%)7 ( 2%) BaselineCalcCrCl* (mL/min) Mean Change from Baseline in CalcCrCl* (mL/min) +1+4 Patients withFanconi’s Syndrome00 *Using Cockcroft-Gault Equation Study 903 Summary of Results: Parameters Through Week 96 Gallant et al. ICAAC Abstract H840.

35 Tenofovir DF 300 mg Placebo Tenofovir DF 300 mg Stable ART  8 weeks randomized 24 wks 48 wks 24 wks Double- blind Open- label Study 902: HIV RNA 400 to 100,000 copies/mL; no CD4 criteria Study 907: HIV RNA 400 to 10,000 copies/mL; no CD4 criteria Studies 902 and 907 Study Designs

36 Mean Duration of Treatment (Weeks) Maximum Grade of Laboratory Abnormality Grade 1 (  0.5 mg/dL over BL*) 1% 7% Grade 2 (2.1 – 3.0 mg/dL) 0% Grade 3 (3.1 – 6.0 mg/dL)0% Grade 4 (>6.0 mg/dL) 0% *BL=Baseline Placebo (0 ‑ 24 Weeks) (N= 210) TDF 300 mg (0 ‑ 24 Weeks) (N = 443) All TDF (N = 687) Maximum Grade of Laboratory Toxicity– Serum Creatinine (Pooled Studies) Data on file. Gilead Sciences, Inc

37 No. of patients 11 22 3 Visits Studies 902 and 907 Consecutive Visits Serum Phosphate <2.0 mg/dL Data on file. Gilead Sciences, Inc

38 *Patient had pyelonephritis *1* 1*1* No. of patients 11 22 33 4 Visits Studies 902 and 907 Consecutive Visits with Grade 1 Creatinine Data on file. Gilead Sciences, Inc

39 Recent Retrospective Analysis Harris Analysis 1 - Canada Expanded Access  Population –Patient population not well-matched –TDF patients older and longer time on previous ARVs  Increases in serum creatinine –At 6 months, increases in serum creatinine (1.5x baseline) observed in 8% TDF vs 4% ABC patients (p<0.001) –Consecutive (confirmed) increases were observed in 4% TDF vs 9% ABC patients (p=0.004)  Discontinuations –At least 1-2% discontinued TDF during first year –Patients more likely to discontinue TDF than ABC due to increased creatinine 1 Harris M, et al. 2nd IAS. Abstract 55.

40  3 cases of Fanconi’s syndrome among 81 ART-experienced patients initiated on a TDF-containing regimen 1 –Glycosuria, hypophosphatemia, proteinuria, decrease in CrCl –Initial signs appeared after 8, 9, and 11 months of TDF exposure –2/3 cases had low Cr clearance at baseline  3 patients developed hypophosphatemia on TDF 2 –Phosphate levels remain stable in two patients who continued TDF with phosphate supplementation –3/3 patients previously on ADV 60 or 120mg and diagnosed with renal tubular acidosis with hypophosphatemia Recent Reports 1 Reynes J, et al. 10th CROI. February 10-14, Abstract Blick G, et al. 10th CROI. February 10-14, Abstract 718

41 CPCRA 039 Background Incidence of Renal Abnormalities in HIV+ Patients  Renal abnormalities observed in placebo arm –8% hypophosphatemia –6% serum creatinine increase  0.5 mg/dL –0.8% Fanconi Syndrome –4 patients with renal-related serious adverse events  A placebo-controlled study of Adefovir 120 mg in HIV-infected patients with CD4 <50 –1:1 randomization, 505 patients –at study termination ~ 11 months follow-up Fisher et al. AIDS 2001, 15:

42 Viread in Patients with Renal Impairment  Dosing interval adjustment is recommended in all patients with creatinine clearance < 50 mL/min  The majority of reported cases of renal impairment in patients taking VIREAD occurred in patients with underlying systemic or renal disease, or in patients taking nephrotoxic agents  VIREAD should be avoided with concurrent or recent use of a nephrotoxic agent  Patients at risk for, or with a history of, renal dysfunction and patients receiving concomitant nephrotoxic agents should be carefully monitored Viread Package Insert August 2003

43 *Calculated using ideal (lean) body weight ** Generally once weekly assuming three hemodialysis sessions a week of approximately 4 hours duration. VIREAD should be administered following completion of dialysis. Dosing Interval Recommendations for Viread in Patients with Renal Impairment Creatinine Clearance (mL/min)* Hemodialysis Patients Every 7 days or after a total of approximately 12 hours of dialysis ** > Every 24 hEvery 48 hTwice/wk

44 Bone Safety

45 Study 903 Baseline Incidence of Osteopenia in HIV+ Patients  HIV disease associated with osteopenia  At baseline –24% patients were osteopenic at the lumbar spine (p=0.007) –23% patients were osteopenic at the femoral neck (p=0.011)  Analyses done WHO Definitions by T Score: Normal > -1 SD, Osteopenia -1 SD to -2.5 SD, Osteoporosis < -2.5 SD McGowan et al. 8th CROI, 2001, Abstract #628

46 Study 903 Median (IQ) % Change in Spine BMD

47 Study 903 Median (IQ) % Change in Hip BMD

48 Study 903 Bone Fractures Summary Fractures 1 7 (0-96 Weeks) TDF+3TC+EFV d4T+3TC+EFV (n=299) (n=301) *All fractures involved significant trauma Data on file. Gilead Sciences, Inc. Feb 2003

49 Possible contributing factors to decreased BMD in HIV-infected Patients M. Glesby, CID supplement, Sept. 2003

50 Lipid Safety

51 Study 903 Mean (95% CI) Change in Fasting Cholesterol Weeks Change from Pre-Baseline (mg/dL) Wk 96, p < – TDF+3TC+EFV – d4T+3TC+EFV mg/dL 51 mg/dL Staszewski S. 10th CROI, Boston, MA, Feb 10-14, 2003, Abstract # 564b

52 Study 903 Mean (95% CI) Change in Fasting Triglycerides Weeks Change from Pre-Baseline (mg/dL) – TDF+3TC+EFV – d4T+3TC+EFV : mg/dL 5 mg/dL Wk 96, p < Staszewski S. 10th CROI, Boston, MA, Feb 10-14, 2003, Abstract # 564b

53 Study 903 Fasting HDL and LDL Cholesterol Mean (95% CI) Change at Week 96 – TDF+3TC+EFV – d4T+3TC+EFV * p < Mean Change (mg/dL) Direct LDL HDL * **p = * * * ** Staszewski S. 10th CROI, Boston, MA, Feb 10-14, 2003, Abstract # 564b

54 TDF+3TC+EFV: d4T+3TC+EFV: % Taking Lipid Drug Weeks BL Study 903 Time to First Lipid Lowering Drug – TDF+3TC+EFV – d4T+3TC+EFV *p < % 2% Staszewski S. 10th CROI, Boston, MA, Feb 10-14, 2003, Abstract # 564b

55 Tenofovir DF 300 mg Placebo Tenofovir DF 300 mg Stable ART  8 weeks randomized 2:1 24 wks 48 wks n= wks Double- blind Open- label HIV RNA 400 to 10,000 copies/mL; no CD4 criteria Squires K et al (2003) Annals of Internal Medicine In Press Study 907 Study Design

56 TDF PLB PLB->TDF Weeks on Study Change from Baseline in Cholesterol (mg/dL) BL Study 907 Mean (95% CI) Change from Baseline in Cholesterol through Week 48 – Tenofovir DF – Placebo * * – Placebo to Tenofovir DF *p< Data on file. Gilead Sciences, Inc. February 2003.

57 Recover Study Dyslipidemia Improvement in Patients Switching from d4T to TDF  1350 heavily pretreated patients switched single NRTI to TDF –d4T (65%), ddI (13%), AZT (13%), ABC (6%), 3TC (2%), ddC (1%)  Reason for switch –Peripheral neuropathy (13%), lipodystrophy (50%)  d4T most frequently switched (n=886, 65%) –Hypertriglyceridemia (n=271) –Hypercholestrolemia (n=193)  No virologic rebound  No significant changes in CD4 Moreno S. 43 rd ICAAC, Chicago 2003, #H-855b.

58 Recover Study Lipid Changes Following d4T to TDF Switch Baseline 12 weeks Baseline 12 weeks mg/dL * Mean + 95% CI Triglycerides (N=94)* Cholesterol (N=70)* p <0.001 Moreno S. 43 rd ICAAC, Chicago 2003, #H-855b.

59 All Grades Through Week 96 TDF+3TC+EFV d4T+3TC+EFV (n=299)(n=301) Patients (%) with events4%*20%* Peripheral neuritis/neuropathy3%*10%* Lipodystrophy**1%*12%* Lactic acidosis**01% Pancreatitis00 Relative risk (95% CI) for toxicity (d4T/TDF)5.5 (3.0, 10.3) *p< ** Investigator defined Staszewski S, et al. Presented at 10th Conference on Retroviruses and Opportunistic Infections; February 10-14, 2003; Boston, Mass. Abstract 564b. Study 903 Toxicities Potentially Associated with Mitochondrial Dysfunction

60 Study 903 Mean Change from Baseline in Weight through Week 96 Pounds TDF+3TC+EFV: d4T+3TC+EFV: – TDF+3TC+EFV – d4T+3TC+EFV Weeks 6.1* 0.8 *p = Staszewski S. 2nd IAS Conference, Paris 2003, Poster # 562

61 Study 903 Mean (95% CI) Total Limb Fat at Week 96 Total Limb Fat (DXA) n=126, n=132 Pounds – TDF+3TC+EFV – d4T+3TC+EFV * p < * Staszewski S. 2nd IAS Conference, Paris 2003, Poster # 562

62 Study 418: Once-daily vs. twice-daily lopinavir/r in antiretroviral-naive patients 24-week results D Podzamczer, J Gathe, M Johnson, R Schwartz, J Villacian, T Marsh, C Naylor, M King, R Tressler, S Brun Hospital de Bellvitge, Barcelona; Therapeutic Concepts, Houston, TX; Royal Free Hospital, London; Private Practice, Ft. Myers, FL; Tan Tock Seng Hospital, Singapore, Abbott Laboratories, Abbott Park, IL

63 Study 418: Rationale  QD dosing of LPV/r (vs. BID) in ARV naïve patients: –No efficacy difference in pilot study 1 –C trough /IC 50 of wild type HIV (IQ) compares favorably to that of other QD PIs  Thus, QD LPV/r warrants further study as a useful alternative for patients who require a QD regimen as initial therapy IQ values for QD protease inhibitor regimens 2 1 Eron J, et al. 9 th Conf Retroviruses and OI, Seattle WA #409W 2 Stevens R, et al. 4 th Internat Workshop on Clin Pharm of HIV Therapy, Cannes, 2003, #4.2

64 Study 418: Study design ARV-naive HIV RNA >1000 c/mL Any CD4 cell count LPV/r 800/200 mg QD + TDF 300 mg/FTC 200 mg QD (n=115) LPV/r 400/100 mg BID + TDF 300 mg/FTC 200 mg QD (n=75)

65 Study 418: Baseline characteristics Gender Male Female Age (years) Mean (Range) Race Caucasian Black Hispanic Other HIV RNA (log 10 copies/mL) Median (IQR) Range CD4 count (cells/mm 3 ) Median (IQR) Below 200 cells/mm 3 81% 19% 39 (19-75) 56% 27% 10% 7% 4.8 ( ) ( ) 44% 75% 25% 38 (19-75) 51% 36% 5% 8% 4.6 ( ) (95-339) 47% LPV/r 800/200 QD (n=115) LPV/r 400/100 BID (n=75)

66 Study 418: Week 4 pharmacokinetic results  QD vs. BID LPV/r dosing: –Higher Cmax –Similar AUC –Lower trough concentrations –(Chiu, et al., 2 nd IAS, 2003)  Median (IQR) Week 4 LPV IQ –49 (15-88) for the QD group –94 (44-131) for the BID group

67 Study 418: Disposition through week 24 Subjects discontinued Adverse event Death Lost to follow-up Withdrew consent Nonadherence LPV/r 800/200 mg QD (n=115) 18 (16%) 13 (11%) 0 (0%) 1 (1%) 3 (3%) 1 (1%) 12 (16%) 2 (3%) 1 (1%) 5 (7%) 1 (1%) 3 (4%) LPV/r 400/100 mg BID (n=75)

68 Study 418: HIV RNA <50 copies/mL (ITT M=F) 57% Week 24 difference (QD minus BID) and 95% CI: 0.1% (-14.3%, 14.4%)

69 Study 418: HIV RNA <50 copies/mL (observed data) Sample SizeQD: BID: % 68%

70 84% 80% 70% 68% Sample SizeQD: BID: Study 418: HIV RNA <50 copies/mL (observed data)

71 Study 418: CD4 cell count Mean (±SE) change from baseline

72 Study 418: Most common adverse events Diarrhea Nausea Abdominal Pain Vomiting LPV/r 800/200 QD (n=115) 12% 9% 3% LPV/r 400/100 BID (n=75) 5% 9% 3% 5% Moderate or severe LPV/r- related adverse events Includes all events occurring in >3% of patients in either group p-value ns

73 Study 418: Distribution of total cholesterol Baseline vs. Week 24 LPV/r QD + TDF/FTCLPV/r BID + TDF/FTC mg/dL (mmol/L)

74 Study 418: Distribution of triglycerides (Grade 0-1 to 3) Baseline vs. Week 24 LPV/r QD + TDF/FTCLPV/r BID + TDF/FTC mg/dL (mmol/L)

75 Study 418: Distribution of LDL-cholesterol Baseline vs. Week 24 by NCEP Guidelines 3 LPV/r QD + TDF/FTCLPV/r BID + TDF/FTC mg/dL (mmol/L) 3 JAMA 2001, 285:

76 Study 418: Distribution of HDL-cholesterol Baseline vs. Week 24 by NCEP Guidelines 3 LPV/r QD + TDF/FTCLPV/r BID + TDF/FTC mg/dL (mmol/L) 3 JAMA 2001, 285:

77 Study 418: No change in mean LDL:HDL cholesterol ratio from baseline to Week 24 p=0.76p=0.38

78 Study 418: Conclusions  Week 24 HIV RNA <50 copies/mL was similar in patients receiving LPV/r QD vs. BID –ITT (M=F): 57% (QD), 57% (BID) –Observed data: 68% (QD), 70% (BID)  Patients continued to achieve HIV RNA <50 copies/mL after Week 24  Gastrointestinal events were the most common AEs, with a somewhat higher rate of diarrhea in the QD arm.  At Week 24, over 90% of patients demonstrated LDL cholesterol values <160 mg/dL.  LDL:HDL cholesterol ratio was unchanged from baseline to Week 24

79 Acknowledgments  Study 418 Patients  Study 418 Study Coordinators  Study 418 Investigators  Gilead Sciences for provision of tenofovir and emtricitabine  Abbott Laboratories: –N Travers, K Luff, J Hairrell, A Cekander, KR King JR Arribas C Barros L Bush P Cimoch B Clotet JR Delfraissy P Dellamonica P Domingo P Easterbrook G Fatkenheuer T File M Fisher PM Girard S Green D Haas R Landman B Lutz A Mestre JM Molina K Mounzer R Myers G Pierone A Pozniak F Pulido E Ribera G Richmond R Rubio J Sampson S Schneider M Sension L Smith S Staszewski D Sweet M Thompson A Wilkin P Wolfe C Workman D Wright B Yangco V Yeh

80 Efficacy

81 Weeks 78% 74% % Patients with HIV-1 RNA < 50 c/mL TDF+3TC+EFV d4T+3TC+EFV Intent to Treat (Missing=Failure) Study 903 % Patients < 50 Copies/mL through Week 96 Staszewski S. 10th CROI, Boston, MA, Feb 10-14, 2003, Abstract # 564b

82 Study 903 % Patients < 50 Copies/mL through Week 96 As-Treated % Patients with HIV-1 RNA < 50 c/mL TDF+3TC+EFV d4T+3TC+EFV 95% 91% Weeks Data on file. Gilead Sciences, Inc. February 2003.

83 Study 903 % Patients < 50 Copies/mL at 96 Weeks  100, /161 (80%) 127/172 (74%) > 100, /138 (75%) 95/129 (74%) CD4 Cells/mm 3 < /118 (74%) 78/113 (69%)  /181 (80%) 144/188 (77%) TDF+3TC+EFVd4T+3TC+EFV (n=299)(n=301) HIV RNA c/mL Data on file. Gilead Sciences, Inc. February Intent to Treat (Missing=Failure)

84 Study 903 Mean Change from Baseline in CD4 through Week Weeks Change in CD4 Cell Count Intent to Treat TDF+3TC+EFV d4T+3TC+EFV Staszewski S. 10th CROI, Boston, MA, Feb 10-14, 2003, Abstract # 564b

85 Role of Triple NRTIs? ACTG 5095: Virologic Failure Randomized, evaluable: n=1147 Virologic failure (confirmed viral load  200 copies/mL  week 16) ZDV/3TC/ABC (Trizivir ® ) (n=382) 21% (n=82 failures) Pooled EFV (+ZDV/3TC or ZDV/3TC/ABC) (n=765) 11% (n=85 failures) Time to virologic failure greater for EFV arms than ZDV/3TC/ABC for viral load >100K, <100K and all patients Gulick RM 2nd IAS; 2003; Paris, France. Abstract 41.

86 Triple-NRTI Regimen ABC/3TC QD + TDF

87 ESS30009 ABC/3TC+TDF vs ABC/3TC+EFV ABC/3TC FDC QD + EFV 600mg QD n=180 planned ABC/3TC FDC QD + TDF 300mg QD n=180 planned Screening Primary Endpoint Proportion with HIV-1 RNA <50 c/mL at week 48 * Randomization (1:1) stratified by HIV-1 RNA <100K or ≥100K c/mL Gallant JE, et al. 43 rd ICAAC, Chicago 2003, #H-1722a. 48 weeks Randomize* Entry criteria > 18 years old ART-naïve (<14 days ART) VL > 5000 copies/mL No CD4+ restrictions Open-label, randomized, multicenter trial

88 ESS30009 Virologic Non-Response for Subjects with at least 8 Weeks HIV-1 RNA Data Total #2: ≥1.0 log rebound from nadir 50/102 (49%) 2 5/92 (5.4%) 2 8/102 (7.8%)0/92 (0%) 10/102 (9.8%)2/92 (2.2%)Both criteria #1 and #2 met 32/102 (31.4%)3/92 (3.3%) #1: <2.0 log decline from baseline by week 8 ABC/3TC + EFV (N=92) ABC/3TC + TDF (N=102) Criteria 1 Gallant JE, et al. 43 rd ICAAC, Chicago 2003, #H-1722a. 1. No subjects met virologic non-response criteria #3 2. Difference between arms p<0.001, 95% CI (-54.3%, -32.8%)

89 ESS30009 Week 12 NRTI Genotypic Mutations (N=36 ) Number of subjects (%) Mutations M184V Total M184V + K65R + V118I 36 (100%) 3 (8%) M184V + K65R + Y118I 17 (47%)M184V + K65R 13 (36%) M184V alone Gallant JE, et al. 43 rd ICAAC, Chicago 2003, #H-1722a.

90  Inadequate pharmacokinetics of once-daily dosing of ABC and/or 3TC?  Intracellular pharmacologic interaction?  Overlapping resistance profiles? –3TC & ABC select for M184V –TDF & ABC select for K65R –ABC selects for both M184V and K65R  Insufficient potency of using only one class of ARVs (NRTIs) to attack the virus? ESS30009 Proposed Explanations for Response

91 Triple-NRTI Regimen ddI+3TC+TDF  24-week, single-site, open-label pilot study (N=24)  Safety & efficacy of triple-NRTI regimen: ddI+3TC*+TDF  Results: –91% had < 2 log 10 reduction in HIV RNA by Week 12 –Resistance testing in 21 patients: 20 patients (95%) with M184V 10 patients (50%) with M184V + K65R  Action: –Study enrollment stopped –Dear Health Care Provider Letter (Oct 14): ddI+3TC+TDF not recommended * 3TC dosed once-daily in this study Jemsek et al. Oral Communication. September 2003

92 Study 903 % Patients < 50 Copies/mL through Week 96 As-Treated % Patients with HIV-1 RNA < 50 c/mL TDF+3TC+EFV d4T+3TC+EFV 95% 91% Weeks Data on file. Gilead Sciences, Inc. February 2003.

93 Virology

94 Incidence of K65R 0% 10% 20% Q4 '01Q1 '02Q2 '02Q3 '02Q4 '02Q1 '03 Percent of Genotyped Samples 1 Miller MD. 43 rd ICAAC, Chicago 2003, #H-904; 2 Bacheler L. ibid, #H-917. K65R Incidence in 2003: 4.0% (ViroLogic) 1, 3.6% (Virco) 2 Incidence of K65R in HIV-1 Genotyped at ViroLogic, Q Q % 4%

95 Study 903 Study Design ART-naive patients (N = 600) randomized 1:1 Staszewski S. 10th CROI, Boston, MA, Feb 10-14, 2003, Abstract # 564b Stratification by: plasma HIV RNA >/  100,000 c/ml CD4 count  /< 200 cells/mm³ 144 wks

96 Study 903 Week 96 Clinical Virology  Genotypically and phenotypically analyzed HIV from all patients with virologic failure (ITT analysis)  Virologic failure was defined as patients with > 400 copies/mL of HIV RNA at week 48, 96 or early study drug discontinuation –includes both suboptimal suppression and HIV RNA rebound  Last on-study plasma sample analyzed –median time from virologic failure to analysis: 12 weeks

97 1 K103N, V106M, Y188C/L or G190A/S/E/Q (K103N in 19/28; others > 50 fold EFV-R with other mutations) 2 Three patients (all in TDF arm) had > 4-fold EFV-R at baseline and developed additional EFV-R 3 One patient developed D67G+K70E+V75L and >20-fold 3TC resistance, but no tenofovir susceptibility change Miller et al., 6th Int’l Congress on Drug Therapy in HIV Infection, 2002, Glasgow, UK, Abstract P205 Study 903 Development of Resistance Mutations through Week 48 (ITT)

98 Study 903 Development of Resistance Mutations through Week 96 (ITT) 1 K103N, V106M, Y188C/L or G190A/S/E/Q (K103N in 19/28; others > 50 fold EFV-R with other mutations) 2 Three patients (all in TDF arm) had > 4-fold EFV-R at baseline and developed additional EFV-R 3 One patient developed D67G+K70E+V75L and >20-fold 3TC resistance, but no tenofovir susceptibility change 4 Combined K65R comparison: p=0.06 Data on file. Gilead Sciences, Inc. Feb 2003

99 EFV-R = efavirenz resistance. 1. K103N, V106M, Y188C/L or G190A/S/E/Q (K103N in 19/28; others >50 fold EFV-R with other mutations). 2. Three patients (all in TDF arm) had >4-fold EFV-R at baseline and developed additional EFV-R. Miller MD. 2nd IAS Conf HIV; 2003; Paris, France. Abstract n% of% of totalfailures % 175.6%45% %34% 20.7%5% %47% n% of% of totalfailures % %61% %39% 8 2.7%22% %30% Virologic failures Any EFV-R 1 Any M184V/I Any K65R K65R alone Wild type or as baseline p value d4T+3TC+EFV (n=301) TDF+3TC+EFV (n=299) Development of Resistance Mutations Through Week 96 (ITT) (Study 903)

100 Study 903 Phenotypic Susceptibility of NRTIs in Presence of K65R Fold ChangePhenosense Assay (ViroLogic cut-off) Fully Susceptible Intermediate Susceptibility Resistant Patient AZT (2.5) d4T (1.7) ddI (1.7) ABC (4.5/6.5) 3TC (2.5) TDF (1.4/4.0) 1(+M184V) >>1.2 2(+M184V) >>1.3 3(+M184V) >> (+M184V) >> Miller MD, XII International HIV Drug Resistance Workshop, June 2003, Abstract 135

101 Study 903 Outcomes of TDF-Treated Patients with K65R Miller MD, XII International HIV Drug Resistance Workshop, June 2003, Abstract 135

102 * Change from baseline (log 10 copies/mL) RT Resistance Mutations Viral Load (  RNA * ) Before Next Regimen 1) 229,511 (-0.2) W24 2) 7,047 (-0.8) W24 3) 5,623 (-1.6) W48 4) 80,600 (-0.6) W24 V106M; M184V; K65R V179I; Y188L M184V; K65R K103N; L100I; M184V; K65R V179G; Y181C; G190E; K65R TDF/AZT/LPV/r TDF/3TC/ddI/ LPV/r ddI/d4T/IDV/r ddI/IDV <50, W32 <50, W36 <50, W72 <50, W44 <50, W96 <50, W72 On study; no additional follow-up yet <50, W80 Next Regimen CommentsResponse Miller et al., 6th Int’l Congress on Drug Therapy in HIV Infection, 2002, Glasgow, UK, Abstract P205 Study 903 Outcomes of TDF-Treated Patients with K65R (n=8)

103 Study 903 Outcomes of TDF-Treated Patients with K65R (n=8) (continued) * Change from baseline (log 10 copies/mL) 5) 18,332 (-1.2) W24 6) 40,903 (-0.5) W48 7) 34,295 (-1.1) W24 8) 2,945 (-1.4) W96 G190E/Q; K65R K103N; M184I; K65R K103N; Y188C; K65R V108I; Y181C; G190A; K65R AZT/3TC/SQV/r AZT/ddI/NFV AZT/3TC/APV AZT/3TC/LPV/r <50, W48 423, W , W32 NA D/C W48, lost to follow-up D/C W68; lost to follow-up Developed M184V at W48, non-adherence Next Regimen RT Resistance Mutations CommentsResponse Viral Load (  RNA * ) Before Next Regimen Mean Baseline Viral Load: 235,962 (median 245,727) Mean Viral Load Before Next Regimen: 52,407 (mean -0.9 log from baseline) On study; no additional follow-up yet

104 K65R Mutation Effects of K65R Mixtures and M184V on TDF Phenotype K65R mix? Yes No Yes No Yes No Yes No Yes No Yes No n=8 n=42 n=24 n=34 n=2 n=21 n=6 n=18 n=44 n=32 n=28 n=29 K65R alone K65R+Q151M K65R+other mut + M184V Bars = median for each group Fold Change from Wild-Type TDF Clinical Cutoffs Miller MD. 43 rd ICAAC, Chicago 2003, #H-904. K65R+M184V K65R+Q151M K65R + other mut + M184V no M184V

105 Susceptibility of K65R Viruses Relative to TDF Clinical Cutoffs *TDF clinical cutoff of 1.4-fold for beginning of reduced response and 4-fold for no clinically significant responses 1 Miller MD. 43 rd ICAAC, Chicago 2003, #H-904. HIV-1 in plasma samples submitted to ViroLogic from Q through Q in which K65R was detected were analyzed (n=288)

106 Susceptibility of K65R Viruses Relative to TDF Clinical Cutoffs *TDF clinical cutoff of 1.4-fold for beginning of reduced response and 4-fold for no clinically significant responses 1 Miller MD. 43 rd ICAAC, Chicago 2003, #H-904.

107 Phenotypic Susceptibilities of K65R Viruses to NRTIs Above cutoffBelow cutoff K65R alone (n=50) K65R + M184V (n=58) % of viruses ZDV d4T TDF ABC ddI ddC 3TC 100% 90% 30% 100% 50% 18% 16% 100% 100% 90% 55% 42% 18% 3% Miller MD. 43 rd ICAAC, Chicago 2003, #H-904.

108 Study 903 Week-96 Resistance Analysis Conclusions  EFV resistance and M184V were the most commonly observed mutations at failure  K65R emerged less frequently –Observed only with EFV resistance –Maintained mean 0.9 log 10 HIV RNA decrease from baseline  Effective second-line regimens constructed in patients developing K65R Miller MD. XII International HIV Drug Resistance Workshop; 2003; Los Cabos, Mexico. Abstract 135.

109 Studies 902 and 907 Response by Baseline Tenofovir Susceptibility (Virco Antivirogram) Baseline Tenofovir Susceptibility (fold-change from wild-type) <1.0 >4.0 >2.0 to <3.0 >1.0 to <2.0 >3.0 to <4.0 Mean DAVG 24 (log 10 copies/mL) (n=79) (n=66) (n=19) (n=204) (n=27) (n=13) Miller et al., 9th CROI, Oral #43

110 ViroLogic Clinical Cut-off Analyses: Summary  Cut-off of 1.4-fold established as the beginning of reduced response to tenofovir DF therapy using the PhenoSense assay –1.4 to 4-fold defines intermediate response level  Cut-off of 4-fold established for no clinically significant response to tenofovir DF therapy Lu B et al, 11th Resistance Workshop; 2002; Seville, Spain

111 The Future: TDF/FTC Fixed Dose Combination Tablet Tenofovir and Emtricitabine fixed dose combination Study 934 in progress TDF/FTC/EFV vs COM/EFV Bioequivalence and stability studies in progress

112 Study 934 Study Design ART-naive patients (N = 300) randomized 1:1 48 wks

113 Emtriva & Viread Summary of Similar Characteristics  Durable efficacy in clinical trials –Both Emtriva and Viread have shown efficacy in both treatment-naïve and treatment-experienced patients  Tolerability and safety  Convenience –Both one tablet dosed once-daily  Pharmacokinetics –Both have long intracellular half-lives, true once-daily dosing –Both can be taken without regard to food  Co-infection –Though not indicated for hepatitis B, both have demonstrated potency against hepatitis B in co-infected patients


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