De Luca A1,2, Bracciale L1, Doino M1, Fabbiani M1, Sidella L1, Marzocchetti A1, Farina S1, D’Avino A1,

Cauda R1, Di Giambenedetto S1

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)

1Institute of Clinical Infectious Diseases, Catholic University of Sacred Heart, Rome, Italy

2Infectious Diseases Unit, Siena University Hospital, Siena, Italy

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

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

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

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

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)

Population: baseline characteristics (n=40)  n (%)Age (years)* 45 (41-52)Male sex 23 (57.5)Foreign born 2 (5)Injecting drug users 9 (22.5)HCV co-infection 8 (20)Past AIDS-defining events 9 (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 backbone 39 (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)

• 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=0.277P=0.402

P=0.458

BL Week 4 Week 12

Week 24

0

20

40

60

80

100

120

100% 100% 100% 100%

Proportion of patients with HIV-RNA<50copies/mL Changes in CD4 cells count

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)

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 4 Week 12 Week 24 Total patients

Total bilirubin 14/40 (35%) 6/25 (24%) 9/24 (37.5%) 6/21 (28.6%) 13Total Cholesterol   2/38 (5.3%) 3/38 (7.9%) 1/36 (2.8%) 3LDL   2/35 (5.7%) 4/33 (12.2%) 2/35 (5.7%) 4Triglycerides   1/38 (2.6%) 1/38 (2.6%)   1Amylases       1/33 (3%) 1

Cholesterol changes from baselineM

ean

ch

ange

(m

g/d

L)

  Baseline Week 4 Week 12 Week 24 pTC/HDL 4.3 (3.5-5.4) 4.2 (3.5-5.5) 4.4 (3.5-5.6) 4.4 (3.5-5.6) nsHDL/LDL 0.4 (0.3-0.5) 0.4 (0.3-0.5) 0.4 (0.3-0.5) 0.4 (0.3-0.5) ns

+20+18

+21

+4 +3 +4

+13

+9

+17P<0.01 for all parameters at all time points

Triglycerides changes from baseline

P=0.342

P=0.126

P=0.442

Renal function change from baselineM

ean

ch

ange

(m

g/d

l)

Mea

n c

han

ge (

mL

/min

/1.7

3m2 )

-0.04P=0.020

-0.06P=0.012

-0.08P<0.001

+6P=0.097

+4P=0.017

+6P<0.001

Bilirubin change from baselineM

ean

ch

ange

(m

g/d

L)

+0.3P=0.07

+0.1P=0.7

+0P=0.8

+0.3P=0.04

+0.1P=0.5

+0.1P=0.6

Changes in ATV plasma levels (C24h or C12h)

  BL W4 W12 W24Patients 36 32 28 25

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

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

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.