Maintenance therapy with Trizivir® after 6 months induction with Trizivir® plus either efavirenz or lopinavir/r in naïve patients. Trizefal study J. Mallolas* Infectious Diseases Service Hospital Clínic Barcelona * on behalf of the TRIZEFAL study group

AZT+3TC+IDV AZT+3TC AZT+IDV AZT or D4T+3TC+IDV AZT or D4T+3TC IDV D4T+3TC+SQV+NFV D4T+NFV SQV+NFV ACTG 343. Havlir. N Engl J Med 1998 Trilege.Pialoux. N Engl J Med 1998 ADAM.Reijers. Lancet 1998 Maintenance < 3 drugs: Contraindicated

ESS40013: Induction/Maintenance With Trizivir® ± EFV  High drop-out rate prior to randomization: 37%. 63% were randomized.  No difference in proportions with VL < 50 at Week 96 (ITT:M=F) 79% in +EFV, 77% in –EFV; 42% vs 40% all pts enrolled More virologic failures in -EFV: n = 16 (13%) vs 8 (6%) More dropouts in +EFV  Trend for improvement in self-reported adherence in -EFV Markowitz et al. JAIDS 2005; 39: Treatment-naive pts VL > 5000 Induction: Trizivir® + efavirenz (N = 448) Continued 4-drug therapy (+EFV arm) Trizivir® + efavirenz (n = 121) Maintenance therapy (-EFV arm) Trizivir® alone (n = 121) Week 96 Randomize if VL < 50 at Week 48

TRIZEFAL. Methods  Randomized, multicenter, open-label clinical trial including HIV naïve patients > HIV-RNA cp/mL.  Randomization was stratified: HIV-RNA copies/mL  Sample size: 220 patients provided 80% power to detect 20 percentual points differences assuming a success rate of 80% in the best arm and a lost to follow-up rate of 25%.  = 0.05  Primary end-point: Proportion of pts with HIV-RNA viral load undetectable at week 72 (by ITT s=f)

TRIZEFAL: Trial profile “Screening” Randomization Trizivir  + EfaTrizivir  + Lop/r Week 24 (if VL < 50 cp/mL) Trizivir  (48 week maintenance phase)

TRIZEFAL: Demographic baseline characteristics EFV (n=104) LPV/RTV (n=105) Age, years median (IQR) 38.5 ( ) 37.6 ( ) Gender M, n (%)79 (76)89 (85) Risk group, n (%) Heterosexual Homosexual IVDU Transfussion Other Unknown 40 (40) 34 (34) 21 (21) 2 (2) 5 (5) 48 (48) 33 (33) 18 (18) 0 (0) 2 (2) 4 (4) AIDS, n (%)25 (24)23 (22) CD4, cells/mm 3 median (IQR) ( ) 205 ( ) CV, copies/mL Median (IQR) ( ) ( )

TRIZEFAL: Patient´s disposition (I) 220 Patients included 109 EFV 111 LPV/r 5 patients: Consent withdrawn 6 patients: Consent withdrawn 209 Patients evaluables 104 EFV 105 LPV/r

TRIZEFAL: Patient ´s disposition (II) Lost: 6 Adverse event: 33 Clinical progression: 2 Virologic failure 3 Other: 6 50 No simplif. TZV 104 EFV + TZV 54 Simplif. a TZV 105 LPV/r + TZV 60 Simplif. TZV 45 No simplif. TZV Lost: 6 Adverse event: 1 Virologic failure: 14 Lost: 8 Adverse event: 25 Clinical progression: 2 Virological failure: 3 Other: 7 Lost: 5 Virologic failure: 7

TRIZEFAL. Outcome at 72 weeks p= p= p= 0.172

TRIZEFAL: Time to failure (ITT) (S or M=F) Log Rank test, p= Cumulative probability Months since start ARV EFALOP/r Kaplan-Meier estimation EFA LOP/r At risk

TRIZEFAL: Time to failure (ITT) (M=F) Cumulative probability Months since start ARV EFALOP/r Kaplan-Meier estimation EFA LOP/r At risk Log Rank test, p= 0.199

TRIZEFAL: Time to failure (OT) Log Rank test, p= Cumulative probability Months since start ARV EFALOP/r Kaplan-Meier estimation EFA LOP/r At risk

TRIZEFAL: Median Absolute Change in CD4 Count from Baseline * * Wilcoxon Rank Sum test, p= *

TRIZEFAL: Treatment-emergent viral resistance Virological failure during induction: N: 6 Wild-type: 2 N/A:4 Virological failure during maintenance: N: 21 N/A: 5 EFV (n=11) LPV/RTV (n=5) Wild type52 NNRTI mutations00 M184V63 M184V + TAMs (*)41 PI mutations00 At baseline: no primary resistance mutations were detected in 10 pts who developed virological failure and in 18 controls who did not developed virological failure. Thymidine analogue-associeted mutations seen at failure included: M41L, D67N, K70R, V118I, L210W, L 215Y and K219E.

TRIZEFAL: Side effects leading to treatment discontinuation EFV (n=104) LPV/RTV (n=105) Hypersensitivity reaction1510 GI Disorders38 Hematological Disorders55 Neurological Disorders71  Transaminases -1 Toxic Hepatitis1- Opioid Withdrawal Syndrome1- Hyperlactatemia1- Skin Reaction1- TOTAL3425

Conclusions  ARV naïve patients undergoing a 6 months induction regimen with Trizivir® plus either Efavirenz or Lopinavir/r followed by maintenance with Trizivir® achieved a non statistical significant difference in immunological and virological response after 72 weeks.  Virological failure rate was higher than expected during maintenance with Trizivir® and there was a trend to a higher rate in the efavirenz induction arm as compared with lopinavir/r.  Side effects leading to treatment discontinuation were frequent and mostly during induction phase.

Acknowledments Investigators of the TRIZEFAL study group: León A Riera M Domingo P Knobel H Pedrol E Gutiérrez F Barrufet P Peraire J Dalmau D Ribera E Ocampo A Muniaín MA Alonso C Estrada V Blanco JR Cucurull J Pich E De Lazzari E Llibre JM Carmena J Galindo MJ Pumarola T Gil C Gatell JM Mallolas J *** To the Patients