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Experience with first-line ARV regimens in Lusaka

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

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Experience with first-line ARV regimens in Lusaka

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

  6. Comparison of patients by initial regimen *p < 0.001 for all comparisons (except TB, p = 0.14)

  7. 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

  8. Post 90-Day Mortality

  9. Post 90-Day Mortality

  10. Post 90-Day Mortality

  11. Baseline renal function20,339 patients initiating ART in Lusaka, Zambia Mild insufficiency (n=5,249) Normal (n=13,111) Moderate insufficiency (n=1,752) Severe insufficiency (n=227) Creatinine clearance calculated by Cockroft-Gault equation (Mild = 61 – 90 mL/min; Moderate = 31 – 60 mL/min; Severe = < 30 mL/min)

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

  13. Mortality risk according to baseline renal function * Adjusted for baseline CD4 count, WHO stage, hemoglobin and adherence to antiretroviral drugs

  14. 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

  15. End

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

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

  18. Study 934Statistical 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

  19. Study 934 Baseline Characteristics (ITT) a. Median values

  20. Study 934Baseline 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)

  21. 100 80 60 % Responder 40 20 0 BL 8 16 24 32 40 48 Weeks Study 934Proportion with HIV-RNA <400 c/mL (TLOVR)ITT (n = 509) p = 0.005 FTC/TDF 81%*CBV 71%* *95% CI: (+3.4%, +18.1%) Exclude NNRTI-R (n=487): FTC/TDF 84%,CBV 73%, p=0.002 (+4.3%,18.6%)

  22. Study 934Summary Outcomes Wk 48 TLOVR < 400 c/mL a. p value 0.016 b. p value 0.021

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

  24. 90 80 70 60 50 % Responder 40 30 20 10 0 BL 8 16 24 32 40 48 Weeks Study 934Proportion with HIV-RNA <50 c/mL (TLOVR)ITT (n = 509) p = 0.042 FTC/TDF 77%*CBV 69%* *95% CI: (+0.5%, +15.8%) Exclude NNRTI-R (n=487): FTC/TDF 80%,CBV 71%, p=0.027 (+1.2%,16.1%)

  25. 225 ) 3 175 125 Mean Change (cells/mm 75 0 BL 8 16 24 32 40 48 Weeks Study 934CD4 Mean Absolute Change from BaselineAs Treated FTC/TDF 189CBV 158 p = 0.002 at Week 48 p < 0.001 by AAUCMB FTC+TDF+EFV 238 234 223 218 209 198 CBV+EFV 222 216 199 188 175 164

  26. Study 934 Resistance Development at Week 48 (mITT) • 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). • Genotyping of 1 additional Combivir patient failed due to technical reasons. • K103N developed in 21/25 patients; other NNRTI mutations that developed included K101E, K103E, V108I, V179D, G190A/S, P225H, M230L

  27. Rates of K65R in TDF Clinical Trials Time Period Study 903 TDF/3TC/EFV n=299 n ( %) Study 418 TDF/FTC/LPV n=190 n (%) Study 934 TDF/FTC/EFV n=255 n (%) Week 0-24 5 (2%) 0 0 Week 24-48 2 (2%) 0 0 Week 48-96 1 (3%) pending pending Week 96-144 0

  28. Study 934 Adverse Events Leading to Study Drug Discontinuation Through Week 48 • Occurring in more than 1 patient in either arm; patients may have > 1 event • p = 0.016

  29. 20 60 20 55 18 18 50 16 47 16.0 45 16 16.0 14 40 40 13.8 14 13.8 12 35 33 12 31 10.8 Hematocrit % 10 30 10.8 Hemoglobin (g/dL) 10 9.3 22 25 9.3 Hemoglobin (g/dL) 8 8 20 6.9 6 6.9 15 11 6 4 10 3.7 4 3.7 2 5 2 0 0 Nadir Baseline Nadir Baseline 0 Nadir Baseline Study 934Median (Range) Hemoglobin and Hematocrit ValuesDiscontinuations due to Anemia on CBV arm (n=14)

  30. Study 934Calculated Creatinine Clearance (CLcr) FTC/TDF (n=257) CBV (n=254)

  31. Study 934Serum Creatinine a. Confirmed toxicity grade = two consecutive visits

  32. Study 934Serum Phosphorus a. Confirmed toxicity grade = two consecutive visits

  33. Study 934Week 48 Summary • 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

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