1. De Luca A 1,2, Bracciale L 1, Doino M 1, Fabbiani M 1, Sidella L 1, Marzocchetti A 1, Farina S 1, D’Avino A 1, Cauda R 1, Di Giambenedetto S 1 Safety and efficacy of treatment simplification to Atazanavir/ritonavir plus Lamivudine in patients on two NRTIs plus Atazanavir/ritonavir with optimal virologic control: 24 weeks results from a pilot study (Atazanavir and Lamivudine Simplification Study, ATLAS) 1 Institute of Clinical Infectious Diseases, Catholic University of Sacred Heart, Rome, Italy 2 Infectious Diseases Unit, Siena University Hospital, Siena, Italy

2. Introduction Long term toxicity and costs of cART highlight the need of treatment simplification strategies Monotherapy with boosted PIs has been investigated with controversial results Dual therapy could be a suitable option in certain patients

3. Atazanavir/ritonavir + lamivudine Tolerability: –ATV is a PI with a low metabolic impact; –3TC generally very well tolerated. Once daily administration Relatively limited pill burden Relatively limited costs

4. ATLAS Pilot study (40 patients) –Prospective single-arm, single center, 48 weeks –Safety and tolerability –Max allowed failure rate (confirmed VL>50 cp/mL): 12.5% –Enrolment June 2009 – May 2010 –Clinicaltrials.gov NCT00885482 Inclusion criteria: –Patients on ATV/rit + 2 NRTIs from at least 3 months –HIV-RNA <50 copies/mL from at least 3 months –CD4 >200 cells/µL from at least 6 months

5. ATLAS Exclusion criteria: –Previous virological failure of 3TC or PI- containing regimens or exposure to mono-dual NRTI –Virological failure with other regimens but a GRT with any RAM to 3TC or ATV –Proton pump inhibitors co-administration –HBsAg positive –Pregnancy

6. ATLAS: study procedures At baseline simplification to ATV/rit 300/100 mg OD + 3TC 300 mg OD Follow up visits at 4, 12, 24, 36 and 48 weeks At each visit: chemistry, CD4 and HIV-RNA, TDM, self reported adherence (VAS) At baseline and at 48 weeks: Quality of Life, self-reported symptoms, Neurocognitive assessment, Bone density (DXA), Fat distribution (DXA, Liposound), carotid IMT and endothelial function (brachial FMD)

7. Population: baseline characteristics (n=40) n (%) Age (years)*45 (41-52) Male sex23 (57.5) Foreign born2 (5) Injecting drug users9 (22.5) HCV co-infection8 (20) Past AIDS-defining events9 (22.5) Time from HIV diagnosis (years)*11.4 (7.1-15.2) Time (years) from starting cART*8.5 (6.3-10.2) Time (years) from starting last cART regimen*2.6 (1.7-4.2) Tenofovir-containing NRTI backbone39 (97.5) CD4 cells count (cells/µL)*598 (483-778) CD4 cells count nadir (cells/µL)*108 (45-223) Time (months) with viral load <50 copies/mL*21 (10-30) Values are expressed as n (%) except for *median (IQR)

8. 40/40 patients completed Week 4, 38/40 Week 12, 36/40 week 24 All patients maintained an HIV-RNA<50copies/mL, without viremic blips No significant modifications of CD4 cells count Results of 24 weeks interim analysis P=0.277 P=0.402 P=0.458 100% Proportion of patients with HIV-RNA<50copies/mL Changes in CD4 cells count

9. Severe clinical adverse events A total of 5 severe adverse events were observed in 5 patients : 2 renal colic 1 hypertensive crisis 1 brain hemorrhage 1 pregnancy (the only dropped patient)

10. Laboratory toxicity 14 patients with baseline grade 3 elevation of total bilirubin New grade 3 laboratory toxicities were observed in 18 pts Grade 3 toxicities at baseline New Grade 3 toxicities Week 4Week 12Week 24Total patients Total bilirubin14/40 (35%)6/25 (24%)9/24 (37.5%)6/21 (28.6%)13 Total Cholesterol 2/38 (5.3%)3/38 (7.9%)1/36 (2.8%)3 LDL 2/35 (5.7%)4/33 (12.2%)2/35 (5.7%)4 Triglycerides 1/38 (2.6%) 1 Amylases 1/33 (3%)1

11. Cholesterol changes from baseline Mean change (mg/dL) BaselineWeek 4Week 12Week 24p TC/HDL4.3 (3.5-5.4)4.2 (3.5-5.5)4.4 (3.5-5.6) ns HDL/LDL0.4 (0.3-0.5) ns +20 +18 +21 +4 +3 +4 +13 +9 +17 P<0.01 for all parameters at all time points

12. Triglycerides changes from baseline P=0.342 P=0.126 P=0.442

13. Renal function change from baseline Mean change (mg/dl) Mean change (mL/min/1.73m 2 ) -0.04 P=0.020 -0.06 P=0.012 -0.08 P<0.001 +6 P=0.097 +4 P=0.017 +6 P<0.001

14. Bilirubin change from baseline Mean change (mg/dL) +0.3 P=0.07 +0.1 P=0.7 +0 P=0.8 +0.3 P=0.04 +0.1 P=0.5 +0.1 P=0.6

15. Changes in ATV plasma levels (C 24h or C 12h ) BLW4W12W24 Patients36322825 ATV geometric mean (GM) concentration (95% CI), mg/L 2.21 (0.22-5.76)2.46 (0.63-5.70)2.82 (0.48-7.58)2.20 (0.04-10.2) GM relative changes-+11.3%+27.6%-0.5% P=0.925 P=0.469 P=0.664

16. Conclusions Simplification regimen with ATV/rit+3TC maintained virological suppression through 24 weeks 2 severe adverse events possibly related to drugs (renal colic); no severe laboratory adverse event; bilirubin increased temporarily. TC, HDL and LDL increased (a lipid-lowering effect of TDF was recently suggested) * ; TC/HDL and HDL/LDL ratios were unchanged. Renal function improved significantly (probably due to TDF discontinuation) * Tungsiripat M. AIDS. 2010 Jul 17;24:1781-4

17. Conclusions 48 weeks efficacy and safety results are necessary to confirm preliminary safety and efficacy of simplification to ATV/r+3TC Results will form the basis for definitive testing of this strategy in a randomized controlled trial.