1. Experience with first-line ARV regimens in Lusaka Jeff Stringer, MD Professor, Obstetrics and Gynecology, UAB Director, Centre for Infectious Disease Research in Zambia University of Alabama at Birmingham Ministry of Health Zambia The University of Alabama at Birmingham

2. Why MOH is changing to Tenofovir Tolerability Once daily dosing ARV sequencing Better outcomes as first-line

3. Patients enrolled at Project HEART-supported sites thru Aug ‘07 113,561 Enrolled 70,624 On ART

4. Background Patient data captured on forms Entered in real time into SmartCare EMR Every pharmacy prescription and dispensation captured (n=789,541) – Switching very well captured – Reasons for switching not well captured D4T and AZT commingled in every clinic Prescription by availability; anemia

5. Methods Comparison of D4T vs. AZT- containing regimens Outcome = Mortality – Post 90-days Cox Proportional Hazards Regression – Exposure categorized by initial regimen in crude analyses (ITT) – Adjusted analyses treat drug exposure as time- varying covariate

7. AZT (n=12,635) D4T (n=9,962) Age, median (IQR) 35 (30, 41)34 (29, 40) Female 58%70% CD4 count, median (IQR) 139 (77, 199)119 (58, 191) < 50 cells/  l 15%21% WHO I or II 39%30% III 54%60% IV 7%10% Hemoglobin, median (IQR) 11.6 (10.6, 12.8)9.6 (8.5, 10.7) < 8 g/dL 1.8%17% BMI, median (IQR) 20.4 (18.5, 22.8)19.4 (17.4, 21.6) <16 kg/m 2 5.0%12% Active TB 0.3%0.5% *p < 0.001 for all comparisons (except TB, p = 0.14) Comparison of patients by initial regimen

8. Switching from D4T and from AZT: 22,597 Adults in Lusaka AZT → D4T rate: 27.1 / 100 pt-yrs Median time to switch: 84 days D4T → AZT rate: 13 / 100 pt-yrs Median time to switch: 148 days

9. Post 90-Day Mortality Crude WHO I/II1.0 III1.97 (1.74 - 2.23) IV3.48 (2.96 - 4.09) CD4 >2001.0 50-2000.94 (0.82 - 1.07) <501.90 (1.65 - 2.19) Age >351.0 < 351.15 (1.04 - 1.26) Weight (continuous)0.95 (0.95 - 0.96) HgB >101.0 8-9.992.29 (2.04 - 2.57) <8.03.18 (2.73 - 3.70) Female1.0 Male1.43 (1.30 - 1.58) AZT1.0 D4T1.83 (1.66 - 2.02)

10. Post 90-Day Mortality CrudeAdjusted WHO I/II1.0 III1.97 (1.74 - 2.23)1.46 (1.27 - 1.69) IV3.48 (2.96 - 4.09)2.13 (1.76 - 2.58) CD4 >2001.0 50-2000.94 (0.82 - 1.07)0.90 (0.78 - 1.05) <501.90 (1.65 - 2.19)1.35 (1.15 - 1.59) Age >351.0 < 351.15 (1.04 - 1.26)1.20 (1.07 - 1.34) Weight (continuous)0.95 (0.95 - 0.96)0.96 (0.95 - 0.97) HgB >101.0 8-9.992.29 (2.04 - 2.57)1.91 (1.67 - 2.19) <8.03.18 (2.73 - 3.70)2.21 (1.84 - 2.65) Female1.0 Male1.43 (1.30 - 1.58)1.80 (1.60 - 2.02) AZT1.0 D4T1.83 (1.66 - 2.02)1.15 (1.01 - 1.31)

11. Post 90-Day Mortality CrudeAdjustedTime-varying WHO I/II1.0 III1.97 (1.74 - 2.23)1.46 (1.27 - 1.69)1.44 (1.25 - 1.66) IV3.48 (2.96 - 4.09)2.13 (1.76 - 2.58)2.11 (1.74 - 2.55) CD4 >2001.0 50-2000.94 (0.82 - 1.07)0.90 (0.78 - 1.05)0.90 (0.78 - 1.04) <501.90 (1.65 - 2.19)1.35 (1.15 - 1.59)1.33 (1.14 - 1.56) Age >351.0 < 351.15 (1.04 - 1.26)1.20 (1.07 - 1.34)1.19 (1.07 - 1.33) Weight (continuous)0.95 (0.95 - 0.96)0.96 (0.95 - 0.97) HgB >101.0 8-9.992.29 (2.04 - 2.57)1.91 (1.67 - 2.19)1.72 (1.51 - 1.97) <8.03.18 (2.73 - 3.70)2.21 (1.84 - 2.65)1.96 (1.64 - 2.33) Female1.0 Male1.43 (1.30 - 1.58)1.80 (1.60 - 2.02)1.83 (1.63 - 2.05) AZT1.0 D4T1.83 (1.66 - 2.02)1.15 (1.01 - 1.31)1.48 (1.30 - 1.69)

12. Normal (n=13,111) Mild insufficiency (n=5,249) Moderate insufficiency (n=1,752) Severe insufficiency (n=227) Baseline renal function 20,339 patients initiating ART in Lusaka, Zambia Creatinine clearance calculated by Cockroft-Gault equation (Mild = 61 – 90 mL/min; Moderate = 31 – 60 mL/min; Severe = < 30 mL/min)

13. Mortality by baseline renal function 20,339 patients initiating ART in Lusaka, Zambia Creatinine clearance calculated by Cockroft-Gault equation

14. Mortality risk according to baseline renal function Crude HR (95% CI) n=16,646 Adjusted HR * (95% CI) n=15,051 Normal renal function Ref Renal Insufficiency Mild 1.7 (1.5, 1.9)1.5 (1.3, 1.7) Moderate 3.0 (2.7, 3.5)2.3 (2.0, 2.7) Severe 6.2 (4.8, 8.0)4.4 (3.4, 5.8) * Adjusted for baseline CD4 count, WHO stage, hemoglobin and adherence to antiretroviral drugs

15. Summary Why we’re switching to Tenofovir DF –Truvada is better than combivir Gallant et al NEJM 2006 –D4T ass’d with worse outcomes than AZT in our data Why we’re worried –Many patients have underlying renal disease –Monitoring of renal function can be difficult in some settings

16. End

17. Study 934 Preliminary 48 week analyses February 25, 2005

18. Study 934 Study Design ART-naïve patients (n = 517) randomized 1:1 96 wks Any CD4 cell count HIV RNA > 10,000 c/mL TDFQD FTCQD EfavirenzQD AZT/3TCBID EfavirenzQD Adequate Renal and Hepatic Function at baseline FTC/TDF Fixed dose combination tablet was not used

19. Study 934 Statistical Analysis Non inferiority Trial 85% power to detect a 13% difference between arms Primary Endpoint-Time to Loss Virologic Response (TLOVR) –FDA-required endpoint –Similar to ITT Missing = Failure, Switch = Failure –Requires confirmation for success –Used by FDA for presentation in U.S. Prescribing Information of newly approved antiretrovirals

20. a. Median values Study 934 Baseline Characteristics (ITT) FTC/TDF (n = 255) CBV (n = 254) Age a 3637 % Female14%13% % White56%61% % Black25%20% % Hispanic15%16% HIV RNA (log 10 copies/mL) a 5.0 % HIV RNA > 100,00052%50% CD4+ (cells/mm 3 ) a 233241 % < 20042%41% % < 5015%11%

21. Study 934 Baseline NNRTI Resistance (ITT) 22 patients (11 FTC/TDF vs. 11 CBV) Investigators notified if affected FDA recommended excluding these patients for Week 48 primary endpoint analysis (n = 487) Primary Efficacy Endpoint (HIV RNA < 400 c/mL) at Week 48 analyzed for both populations, excluding NNRTI-R (n = 487) and ITT (n = 509)

22. Study 934 Proportion with HIV-RNA <400 c/mL (TLOVR) ITT (n = 509) 0 20 40 60 80 100 BL81624324048 Weeks % Responder FTC/TDF 81%* CBV 71%* *95% CI: (+3.4%, +18.1%) p = 0.005 Exclude NNRTI-R (n=487): FTC/TDF 84%, CBV 73%, p=0.002 (+4.3%,18.6%)

23. a. p value 0.016 b. p value 0.021 Study 934 Summary Outcomes Wk 48 TLOVR < 400 c/mL FTC/TDF (N = 255) CBV (N = 254) Permanent Study Regimen Discontinuation19%29% Adverse Event4%9% a Lost to Follow Up5% 7% Withdrawal Consent/Non Compliance3%4% Other3% Virologic Rebound<1%4% b Insufficient Virologic Response2%1% Pregnancy2%1% Death<1%

24. Study 934 Proportion with HIV-RNA <400 c/mL (TLOVR) by Baseline HIV-RNA

25. Study 934 Proportion with HIV-RNA <50 c/mL (TLOVR) ITT (n = 509) 0 10 20 30 40 50 60 70 80 90 BL81624324048 Weeks % Responder FTC/TDF 77%* CBV 69%* *95% CI: (+0.5%, +15.8%) p = 0.042 Exclude NNRTI-R (n=487): FTC/TDF 80%, CBV 71%, p=0.027 (+1.2%,16.1%)

26. Study 934 CD4 Mean Absolute Change from Baseline As Treated FTC/TDF 189 CBV 158 FTC+TDF+EFV 238 234 223 218 209 198 CBV+EFV 222 216 199 188 175 164 0 75 125 175 225 BL81624324048 Weeks Mean Change (cells/mm 3 ) p = 0.002 at Week 48 p < 0.001 by AAUCMB

27. Study 934 Resistance Development at Week 48 (mITT) 1.All patients with confirmed >400 copies/mL of HIV RNA at Week 48 or early discontinuation analyzed. Patients with baseline NNRTI-resistance excluded (n = 22). 2.Genotyping of 1 additional Combivir patient failed due to technical reasons. 3.K103N developed in 21/25 patients; other NNRTI mutations that developed included K101E, K103E, V108I, V179D, G190A/S, P225H, M230L FTC/TDF, n=244 N, (% mITT, % VF) CBV, n=243 N (% mITT, % VF) Virologic Failure1223 2 Any EFV-R 3 9 (4%, 75%) 16 (7%, 73%) Any M184V/I 2 (0.8%, 17%) 7 (3%, 32%) Any TAMs0 1 (0.4%, 5%) K65R00 Wild-type 3 (1%, 25%) 5 (2%, 23%)

28. Rates of K65R in TDF Clinical Trials Study 934 TDF/FTC/EFV n=255 n (%) Study 418 TDF/FTC/LPV n=190 n (%) Week 48-96 1 (3%) pending pending Week 24-48 2 (2%)00 Week 0-24 5 (2%)00 Study 903 TDF/3TC/EFV n=299 n ( %) Time Period Week 96-1440

29. a.Occurring in more than 1 patient in either arm; patients may have > 1 event b. p = 0.016 Study 934 Adverse Events Leading to Study Drug Discontinuation Through Week 48 Safety Population FTC/TDF (n = 257) CBV (n = 254) No. w/ any Adverse Event a 10 (4%)23 (9%) b Adverse Event Anemia/ ↓ Hgb014 (6%) Nausea1(<1%)4 (2%) Fatigue03 (1%) Vomiting02 (<1%) Dermatitis (NNRTI)2 (<1%)0 Neutropenia02 (<1%)

30. Study 934 Median (Range) Hemoglobin and Hematocrit Values Discontinuations due to Anemia on CBV arm (n=14) Hematocrit % 0 5 10 15 20 25 30 35 40 45 50 55 60 Baseline Nadir 40 47 31 22 33 11 0 2 4 6 8 10 12 14 16 18 20 Baseline Nadir Hemoglobin (g/dL) 13.8 16.0 10.8 6.9 3.7 9.3 0 2 4 6 8 10 12 14 16 18 20 Baseline Nadir Hemoglobin (g/dL) 13.8 16.0 10.8 6.9 3.7 9.3

31. Study 934 Calculated Creatinine Clearance (CLcr) CBV (n=254) FTC/TDF (n=257) Baseline CLcr, Mean (ml/min)129126 CLcr at week 48, Mean127134

32. Study 934 Serum Creatinine Maximum Confirmed Toxicity Grade (mg/dL) a FTC/TDF (n = 257) CBV (n = 254) 1 (>1.5 - 2.0)01 (<1%) 2 (2.1 - 3.0)01 (<1%) 3 (3.1 - 6.0)00 4 (>6.0)00 a. Confirmed toxicity grade = two consecutive visits

33. Study 934 Serum Phosphorus Maximum Confirmed Toxicity Grade (mg/dL) a FTC/TDF (n = 257) CBV (n = 254) 1 (2.0-<2.2) 00 2 (1.5-1.9) 01 (<1%) 3 (1.0-1.4) 00 4 (<1.0) 00 a. Confirmed toxicity grade = two consecutive visits

34. Superior overall response in the FTC/TDF arm compared to CBV arm No patient developed K65R M184V developed less frequently in the TDF/FTC arm than in the Combivir arm. Significantly more CBV patients discontinued due to adverse events Similar renal safety profile No confirmed abnormalities serum creatinine or phosphorus in FTC/TDF arm Study 934 Week 48 Summary