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

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

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

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

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

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

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

Post 90-Day Mortality Crude WHO I/II1.0 III1.97 ( ) IV3.48 ( ) CD4 > ( ) < ( ) Age >351.0 < ( ) Weight (continuous)0.95 ( ) HgB > ( ) < ( ) Female1.0 Male1.43 ( ) AZT1.0 D4T1.83 ( )

Post 90-Day Mortality CrudeAdjusted WHO I/II1.0 III1.97 ( )1.46 ( ) IV3.48 ( )2.13 ( ) CD4 > ( )0.90 ( ) < ( )1.35 ( ) Age >351.0 < ( )1.20 ( ) Weight (continuous)0.95 ( )0.96 ( ) HgB > ( )1.91 ( ) < ( )2.21 ( ) Female1.0 Male1.43 ( )1.80 ( ) AZT1.0 D4T1.83 ( )1.15 ( )

Post 90-Day Mortality CrudeAdjustedTime-varying WHO I/II1.0 III1.97 ( )1.46 ( )1.44 ( ) IV3.48 ( )2.13 ( )2.11 ( ) CD4 > ( )0.90 ( )0.90 ( ) < ( )1.35 ( )1.33 ( ) Age >351.0 < ( )1.20 ( )1.19 ( ) Weight (continuous)0.95 ( )0.96 ( ) HgB > ( )1.91 ( )1.72 ( ) < ( )2.21 ( )1.96 ( ) Female1.0 Male1.43 ( )1.80 ( )1.83 ( ) AZT1.0 D4T1.83 ( )1.15 ( )1.48 ( )

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)

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

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

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

End

Study 934 Preliminary 48 week analyses February 25, 2005

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

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

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 % < 20042%41% % < 5015%11%

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)

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

a. p value b. p value 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%

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

Study 934 Proportion with HIV-RNA <50 c/mL (TLOVR) ITT (n = 509) BL Weeks % Responder FTC/TDF 77%* CBV 69%* *95% CI: (+0.5%, +15.8%) p = Exclude NNRTI-R (n=487): FTC/TDF 80%, CBV 71%, p=0.027 (+1.2%,16.1%)

Study 934 CD4 Mean Absolute Change from Baseline As Treated FTC/TDF 189 CBV 158 FTC+TDF+EFV CBV+EFV BL Weeks Mean Change (cells/mm 3 ) p = at Week 48 p < by AAUCMB

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 Failure 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%)

Rates of K65R in TDF Clinical Trials Study 934 TDF/FTC/EFV n=255 n (%) Study 418 TDF/FTC/LPV n=190 n (%) Week (3%) pending pending Week (2%)00 Week (2%)00 Study 903 TDF/3TC/EFV n=299 n ( %) Time Period Week

a.Occurring in more than 1 patient in either arm; patients may have > 1 event b. p = 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%)

Study 934 Median (Range) Hemoglobin and Hematocrit Values Discontinuations due to Anemia on CBV arm (n=14) Hematocrit % Baseline Nadir Baseline Nadir Hemoglobin (g/dL) Baseline Nadir Hemoglobin (g/dL)

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

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

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 ( ) 01 (<1%) 3 ( ) 00 4 (<1.0) 00 a. Confirmed toxicity grade = two consecutive visits

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