CROI 2014-ACTG 5257 e NEAT001/ANRS 143

quali nuove opportunità per i pazienti

Marco Borderi

U. O. Malattie Infettive – Bologna

Roma, 8 Maggio 2014

Seminario Nadir 2014 - Iniziativa resa possibile grazie al supporto di MSD Italia.

Ma Nino non aver paura di sbagliare un calcio di rigore,

non è mica da questi particolari che si giudica un giocatore,

un giocatore lo vedi dal coraggio, dall'altruismo e dalla fantasia.

NRTI NRTI

NNRTI

PI/r

INI

HIV

Linee Guida DHHS 2014

Linee Guida IAS 2012

Component Recommended Regimens

NNRTI plus nRTIs • Efavirenz/tenofovir/emtricitabine (AIa)

• Efavirenz plus abacavir/lamivudine (AIa) in HLA-B*5701-negative patients with baseline plasma HIV-1 RNA <100,000 copies/mL

PI/r plus nRTIs • Darunavir/r plus tenofovir/emtricitabine (AIa)

• Atazanavir/r plus tenofovir/emtricitabine (AIa)

• Atazanavir/r plus abacavir/lamivudine (AIa) in patients with plasma HIV-1 RNA <100,000 copies/mL

InSTI plus nRTIs • Raltegravir plus tenofovir/emtricitabine (AIa)

Thompson et al, JAMA, 2012.

Linee Guida EACS 2013

Linee Guida Italiane 2013

Gravidanza:Linee Guida EACS 2013

PEP:Linee Guida Italiane 2013

Interazioni farmacologiche:Linee Guida Italiane 2013

Perché sempre 3?

• Immagini + Colonna sonora

• Dialoghi + Colonna sonora

• Immagini + Dialoghi

Perché sempre 3?

NRTI NRTI

PI/r

INI

HIV

Efficacy and Tolerability of Atazanavir, Raltegravir, or Darunavir

with FTC/TDF: ACTG A5257

Landovitz RJ, Ribaudo HJ, Ofotokun I, Wang H, Baugh BP, Leavitt RY, Rooney JF, Seekins D, Currier JS, and Lennox JL for the A5257

Study Team

Disegno dello studio*

RAL 400 mg BID + RAL 400 mg BID + FTC/TDFFTC/TDF 200/300200/300 mgmg QDQD

DRV 800DRV 800 mgmg QDQD ++ RTV 100RTV 100 mgmg QD QD + FTC/TDF 200/300 mg QD+ FTC/TDF 200/300 mg QD

ATV 300ATV 300 mg QD + RTV 100mgmg QD + RTV 100mg QDQD+ FTC/TDF 200/300 mg QD+ FTC/TDF 200/300 mg QD

Study Conclusion 96 weeks after final participant enrolled

Follow-up continued for 96 weeks after randomization of last subject (range 2-4 years) regardless of status on randomized ART

HIV-infected patients, ≥18 yr, with no previous ART, VL ≥ 1000 c/mL at US Sites

Randomized 1:1:1 to Open Label TherapyStratified by screening HIV-1 RNA level (≥ vs < 100,000 c/mL), A5260s metabolic substudy participation, cardiovascular risk

*With the exception of RTV, all ART drugs were provided by the study

Disegno dello studio• Hypothesis

– FTC/TDF with ATV/r, RAL, or DRV/r will be equivalent in terms of virologic efficacy and tolerability over 96 weeks

• Primary Endpoints*– Time to HIV-1 RNA >1000 c/mL wk 16 to before wk 24, or

>200 c/mL at or after wk 24 (VF)– Time to discontinuation of randomized component for

toxicity (TF)

• Pre-planned Composite Endpoint– The earlier occurrence of either VF or TF in a given

participant

* Time measured from date of study entry/randomization

Considerazioni per l’analisi

• Equivalence shown if 97.5% CI on the pairwise difference in 96-week cumulative incidence falls entirely within -10% and +10%.

• If equivalence not demonstrated, superiority shown if 97.5% CI excludes zero. -20 0-10% 20%10%

Difference in 96-week cumulative incidence

Equivalence region

* 97.5% CI controls type I error at 5% for 3 pairwise equivalence comparisons.

Equivalence

Equivalence

Superiority

Caratteristiche al basale Treatment group

Characteristic  Total

(N=1809)ATV/r

(N=605)RAL

(N=603)DRV/r

(N=601)Sex Female 435 (24%) 144 (24%) 148 (25%) 143 (24%)

 

Age (years) Mean 37 38 37 38 

Race/Ethnicity White Non-His. 615 (34%) 212 (35%) 212 (35%) 191 (32%)  Black Non-His. 757 (42%) 252 (42%) 254 (42%) 251 (42%)  Hispanic 390 (22%) 125 (21%) 117 (19%) 148 (25%) 

HIV-1 RNA (log10 c/ml)

Median (Q1-Q3) 4.6 (4.1-5.1) 4.6 (4.1-5.2) 4.7 (4.1-5.1) 4.6 (4.1-5.1)

(copies/ml) <100,000 70% 68% 68% 72%100,000-500,000 23% 25% 24% 22%>500,000 7% 7% 8% 6%

CD4+ cells(/mm³) Median (Q1-Q3) 308 (170-425) 309 (176-422) 304 (158-427) 310 (171-424)

%<200 30% 29% 31% 29%

Incidenza cumulativa diFallimento Virologico

Difference in 96 wk cumulative incidence (97.5% CI)

-20 0-10 10 20

3.4% (-0.7%, 7.4%)

5.6% (1.3%, 9.9%)

-2.2% (-6.7%, 2.3%)

ATV/r vs RAL

DRV/r vs RAL

ATV/r vs DRV/r

96 week cumulative incidence of VF:•ATV/r: 13%•RAL: 10%•DRV/r: 15%

Incidenza cumulativa diFallimento per Tollerabilità

Difference in 96 wk cumulative incidence (97.5% CI)

-20 0-10 10 20

13% (9.4%, 16%)

3.6% (1.4%, 5.8%)

9.2% (5.5%, 13%)

ATV/r vs RAL

DRV/r vs RAL

ATV/r vs DRV/r

Favors RAL

Favors DRV/r

96 week cumulative incidence of TF:•ATV/r: 14%•RAL: 1%•DRV/r: 5%

Fallimento per TollerabilitàCause di discontinuazione*

ATV/r(N=605)

RAL(N=603)

DRV/r(N=601)

Any toxicity discontinuation 95 (16%) 8 (1%) 32 (5%)

Gastrointestinal toxicity 25 2 14

Jaundice/Hyperbilirubinemia 47 0 0

Other hepatic toxicity 4 1 5

Skin toxicity 7 2 5Metabolic toxicity 6 0 2Renal toxicity (all nephrolithiasis) 4 0 0

Abnormal chem/heme (excl. LFTs) 0 0 2

Other toxicity 2 3 4

*Participants allowed to switch therapy for intolerable toxicity

% di discontinuazione di ATV/r per iperbilirubinemia/subittero negli studi

A52571++

n=605*

CASTLE2-5++

n=440A52026-7++

n=928**

1038,10++

n=3550459++

n=119

D/C due to toxicity % (n) 15.7% (95)

7.1% (33)

3.0% (13$)

7% (24)

8% (10)

D/C due to HBR/jaundice % (n) 7.8% (47^)

2.9% (19)a

0.7% (3)

1.7% (6)

5.9%(7)

• D/C due to lab HBR % (n)

• D/C due to clinical jaundice % (n)

2.6% (16)

5.0% (30)

#

#

#

#

#

1.7% (6)

#

#

Consequences of Discontinuation Off study Switch to LPV/r or FPV/r Off study # Off study

+Week 48 analysis + + Week 96 analysis *600 in analysis **646 in analysis. #Data not available. $ N=438 aDiscontinuations due to bilirubin-associated issues in sub-analysis; N=646. ^1 subject discontinued due to hyperpigmentation

1. Landovitz RJ, et al. CROI 2014; oral presentation 85; Available from: http://www.natap.org/2014/CROI/croi_30.htm (accessed March 2014). 2. Molina JM, et al. Lancet. 2008;372:646-655. 3. Molina JM, et al. JAIDS. 2010;53:323-332. 4. Uy et al. HIV10, 2010, poster P93. 5. CASTLE CSR (Table 5.3.1). 6. Daar et al. Ann Int Med 2011 154 (7) 445-456 7. Ribaudo H, et al. J Infect Dis. Feb (3):420-425 8. DeJesus et al. Lancet. 2012;379(9835):2429-2438 9. Johnson et al AIDS 2006, 20:711–718 10. Rockstroh et al JAIDS 2013;62:483–486)

Incidenza cumulativa diFallimento Virologico o per Tollerabilità

Difference in 96 wk cumulative incidence (97.5% CI)

-20 0-10 10 20

15% (10%, 20%)

7.5% (3.2%, 12%)

7.5% (2.3%, 13%)

ATV/r vs RAL

DRV/r vs RAL

ATV/r vs DRV/r

Favors RAL

Favors RAL

Favors DRV/r

*Consistent results seen with TLOVR at a 200 copies/ml threshold

0 TDF+FTC

1 RAL

0 RAL+FTC

0 RAL+FTC+TDF

1 TDF+FTC

1 RAL

0 RAL+FTC

0 RAL+FTC+TDF

Insorgenza di resistenza

75/94 VFAvailable

RAL

99/115 VFAvailable

9 Any Resistance(1.5%)

18 Any Resistance(3%)

4 Any Resistance(<1%)

2 TDF 0 TDF 0 TDF

5 FTC 7 FTC 3 FTC

0 TDF+FTC

ATV/r DRV/r

295 Virologic Failures1 Baseline Missing

56 VF Failed to Amplify

1809 Participants

1 RAL

7 RAL+FTC

3 RAL+FTC+TDF

65/85 VFAvailable

Conclusioni• ATV/r, RAL, and DRV/r were equivalent for virologic

efficacy• ATV/r was less well tolerated than DRV/r or RAL

– Largely due to cosmetic hyperbilirubinemia

• RAL was superior to both PI/r regimens for combined tolerability and virologic efficacy– DRV/r was superior to ATV/r

• VF with resistance was rare– More frequently observed with RAL

• Analyses are ongoing to evaluate:– Cardiovascular, metabolic, skeletal, fat, inflammatory

biomarkers, behavior, adherence, and key subgroup differences

Sottostudio lipidicoFigure 1. Mean of Changes from Baseline in Fasting Lipid Profile (mg/dL) Over Time with 95% CI

30

602600595

ATV/RTVRAL

DRV/RTV

541527529

521542507

490505490

364397363

20

10

0

Dif

f fr

om

Bas

elin

e:

Fas

tin

g T

C (

mg

/dL

)

0 24 48 96 144Study week

Number of subjects contributing data

ATV/RTV RAL DRV/RTV

(A) Fasting Total Cholesterol (TC)40

602600595

ATV/RTVRAL

DRV/RTV

542527528

522542507

490505490

364397363

20

0

-20

Dif

f fr

om

Bas

elin

e:

Fas

tin

g

Tri

gly

ceri

des

(m

g/d

L)

0 24 48 96 144Study week

Number of subjects contributing data

ATV/RTV RAL DRV/RTV

(B) Fasting Triglycerides (TG)

15

596593581

ATV/RTVRAL

DRV/RTV

529518508

512531486

480493468

360385346

10

0

-5

Dif

f fr

om

Bas

elin

e:

Fas

tin

g L

DL

-C (

mg

/dL

)

0 24 48 96 144Study week

Number of subjects contributing data

ATV/RTV RAL DRV/RTV

(C) Fasting LDL-C

5

10.0

602600595

ATV/RTVRAL

DRV/RTV

541527529

522542506

490505488

364397363

7.5

2.5

0.0

Dif

f fr

om

Bas

elin

e:

Fas

tin

g H

DL

-C (

mg

/dL

)

0 24 48 96 144Study week

Number of subjects contributing data

ATV/RTV RAL DRV/RTV

(D) Fasting HDL-C

5.0

• Testo testo, testo

Sottostudio osseo

Sottostudio cardiovascolare

NRTI NRTI

HIV

JFK & BMD

JFK & BMD → BMD & JFK

ACTG 5202 (wk 48) Median Changein Fasting Lipids (mg/dL)

ATV/r ATV/r ATV/r ATV/r ATV/r ATV/r ATV/r ATV/rEFV EFV EFV EFV EFV EFV EFV EFV

ABC/3TC ABC/3TC ABC/3TC ABC/3TCTDF/FTC TDF/FTC TDF/FTC TDF/FTC

N= 326 290 326 300 303 270 310 281 322 288 324 299 325 289 324 300

p<0.001

p=0.07

Cholesterol LDL HDL Triglycerides

p<0.001p<0.001

p=0.002p<0.001

p<0.001

p=0.26

p-values: ATV/r vs. EFV

Sax PE et al, J Infect Dis. 2011 Oct 15;204(8):1191-201

p=0.003

January 2012 | Volume 7 | Issue 1 | e29977

PRT: proximal renal tubulopathyFE(p): fractional excretion of phosphate >20% ->10% if hypophosphatemiccGFR: calculated Glomerular Filtration Rate (Cockroft-Gault)

Fux C. et al., CROI 2009; p743Fux C. et al., CROI 2009; p743

Tenofovir and Protease Inhibitor Use Are Associated with an Increased Prevalence of Proximal Renal Tubular Dysfunction in the Swiss HIV

Cohort Study (SHCS)

Cumulative survival probability after any type of fracture (Center JR et al. Lancet 1999)

0

Lu

mb

ar s

pin

e B

MD

per

cen

t ch

ang

e fr

om

wee

k 0

-1-2

-3-4

-5

0 24 48 96 144 192Visit Week from Randomization

p=0.004*

0

Hip

BM

D p

erce

nt

chan

ge

fro

m w

eek

0

-1-2

-3-4

-50 24 48 96 144 192

Visit Week from Randomization

p=0.025*

TDF/FTC

ABC/3TC

No. of subjectsTDF/FTC 128 111 106 97 87 53ABC/3TC 130 122 106 101 80 53

No. of subjectsTDF/FTC 126 109 105 96 85 53ABC/3TC 128 119 104 99 79 54

*linear regression

ACTG 5224s: BB and BMD

McComsey G, et al. Journal of Infectious Diseases 2011;203:1791–801

A5224s

Association between current ABC use and MI risk

Overall Pre-March 2008

Post-March 2008

GFR → CVA

• CKD is associated with higher risk of AMI and CVA

– HR for AMI: 2.41 (95% CI: 1.73-3.36)

– HR for CVA: 1.80 (95% CI: 1.44-2.24)

Estimated GFR, mL/min/1.73 m2

AMI CVA

Rate per 1000 Pt-Yrs

Unadjusted HR

P Value Rate per 1000 Pt-Yrs

Unadjusted HR

P Value

• < 60 11.33 3.85 < .0001 30.58 2.95 .002

• 60-89 3.89 1.33 .048 12.57 1.28 < .0001

• ≥ 90 2.92 Ref -- 9.74 Ref --

Bedimo R. Clin Infect Dis. 2011 Jul 1;53(1):84-91

J Acquir Immune Defic Syndr. 2011 oct 1;58(2):163-172

Tankó LB. et al. JBMR. 2005;20:1912-1920

Osteoporosi

Osteopenia

BMD → CVD

NRTI NRTI

PI/r

INI

HIV

Perché ancora 3?

First-Line Raltegravir (RAL) + Darunavir/Ritonavir (DRV/r) is Non-inferior to Tenofovir/Emtricitabine (TDF/FTC) + DRV/r: The NEAT 001/ANRS 143 Randomised Trial

François Raffi1, Abdel G Babiker2, Laura Richert3, Jean-Michel Molina4, Elizabeth

C George2, Andrea Antinori5, Jose Arribas6, Stefano Vella7, Geneviève

Chêne3, Anton L Pozniak8,

and the NEAT001/ANRS143 Study Group21st CROI, Boston, March 3-6,2014, Abs 84LBClinicaltrials.gov identifier: NCT01066962

Disegno dello studio• Phase III, randomised, open-label, multicenter, parallel-group, non-inferiority, strategic trial• 78 sites, 15 countries (Austria, Belgium, Denmark, France, Germany, Great Britain, Greece, Hungary, Ireland, Italy,

Netherlands, Poland, Portugal, Spain, Sweden)

DRV+r 800+100 mg QD + TDF/FTC FDC QD

DRV+r 800+100 mg QD + RAL 400 mg BID

Minimum

Week 96Randomisation 1:1 stratified by country and participation in virology/immunology substudy

HIV-1 ART-naïve≥ 18 years

HIV-1 RNA > 1000 c/mlCD4 ≤ 500/mm3

HBs Ag negativeNo major IAS-USA resistance mutations

• Composite virological and clinical primary endpoint (6 components)

NEAT 001/ANRS 143

• Primary endpoint : Time to failure, as the first occurrence of any of the following components: Virological

– V1. change of treatment before W32 because of insufficient virologic response • HIV-1 RNA reduction < 1 log10 c/ml by W18*

• or HIV-1 RNA ≥ 400 c/ml at W24*

– V2. HIV-1 RNA ≥ 50 c/ml at W32*

– V3. HIV-1 RNA ≥ 50 c/ml at any time after W32*

Clinical– C1 death due to any cause

– C2. any new or recurrent AIDS defining event**

– C3. any new serious non AIDS defining event**

• All patients followed-up until last patient reached W96, events recorded until end of F-U• Non-inferiority margin: absolute difference of at most 9% for the failure rate of RAL vs.

TDF/FTC by W96 (estimated by Kaplan-Meier methods) in the ITT analysis• Major secondary endpoints: safety, changes in CD4 and HIV RNA, genotypic resistance

Obiettivi

* confirmed by a subsequent measurement ; ** confirmed by the Endpoint Review Committee

NEAT 001/ANRS 143

Tempo dalla randomizzazione all’obiettivo primario

Primary endpoint

* confirmed by a subsequent measurement

Estimated proportion reaching primary endpoint at W96RAL: 17.4% vs TDF/FTC: 13.7%

Adjusted difference: 3.7% (95% CI: -1.1, 8.6%)

log rank p=0.12

0

0.25

0.50

0.75

1.00

Probability of reaching primary endpoint

402 395 393 361 350 340 331 215 90 12400 384 375 347 329 317 308 211 90 11

0 8 18 32 48 64 80 96 112 128 144Time (weeks)

RAL + DRV/r TDF/FTC + DRV/r

N at risk

NEAT 001/ANRS 143

RAL

+ DRV/r

TDF/FTC + DRV/r

N 401 404

N with primary endpoint 76 (19%) 61 (15%)

V1. Regimen change for insufficient response

< 1 log10 c/ml HIV RNA reduction W18*

1 0

HIV RNA ≥ 400 c/ml W24* 1 0

V2. HIV RNA ≥ 50 c/ml at W32*

27 28

V3. HIV RNA ≥ 50 c/ml after W32*

32 22

C1. Death 3 1

C2. AIDS event 5 3

C3. SNAIDS event 7 7

0

0 4 8 12 18 24 32 48 64 80 96

401404

385389

377385

382387

376388

356374

RAL + DRV/r

TDF/FTC + DRV/r

20

40

60

80

100

Weeks

Percentage of participants with available data

89 %

91 % 93 %

89 %

HIV-1 RNA < 50 cp/mLHIV-1 RNA < 50 cp/mL

n

Mean (95% CI) Change From Baseline CD4+ Cell Count (cells/mm3)W48 W96

RAL + DRV/r + 197 (184, 210) + 267 (250, 285)TDF/FTC + DRV/r

+ 193 (180, 206) + 266 (249, 283)

NEAT 001/ANRS 143

Overall analysis: RAL + DRV/r non inferior to TDF/FTC + DRV/r

Obiettivo primario per HIV-RNA e CD4+ al basale

n = 805

n = 530

n = 275

n = 123

n = 682

Overall

< 100,000 c/ml

> 100,000 c/ml

< 200/mm3

> 200/mm3

Baseline HIV-1 RNA

Baseline CD4+

17.4 %

7 %

36 %

39.0 %

13.6 %

13.7 %

7 %

27 %

21.3 %

12.2 %

RAL + DRV/r

TDF/FTC + DRV/r

100-10 20 30

9

Difference in estimated proportion (95% CI) RAL – TDF/FTC; adjusted

* Test for homogeneity

p = 0.09*

p = 0.02*

-1.1 8.6

-3.9 3.5

-0.05 19.3

4.7 30.8

-3.4 6.3

NEAT 001/ANRS 143

Fallimenti virologici e insorgenza di resistenza

Protocol-defined virological failure change of any component of the initial randomised regimen before W32 because of confirmed insufficient virological response, defined as HIV-1 RNA reduction < 1 log10 copies/ml by W18 or HIV-1 RNA ≥ 400 copies/ml at W24 ; failure to achieve virological response by W32 (confirmed HIV-1 RNA ≥ 50 copies/ml at W32) ; confirmed HIV-1 RNA ≥ 50 copies/ml at any time after W32

According to the protocol, genotypic testing was carried out by local laboratories when patients had a single VL > 500 copies/ml at or after W32.

* 1 additional patient with T97A

NEAT 001/ANRS 143

RAL + DRV/rn=401

TDF/FTC + DRV/rn=404

Protocol-defined virological failure (PDVF), n 66 52

Number of PDVF who met criteria for genotype testing (HIV RNA > 500 copies/ml at or after W32)

33 9

Number of patients with single unconfirmed value of HIV RNA > 500 copies/ml at or after W32 (meeting criteria for genotype testing)

3 6

Genotype done, n 28/36 13/15

Major resistance mutations, n 5 0

NRTI 1 (K65R) 0

PI 0 0

INI 5 (N155H)* -

6.2

0

10

8

6

4

2

5.0

0.9

0.5

0.0 0.0

0.40.5

%

Grade 3-4 CK elevation

LDL-cTotal chol:HDL-c ratio

Total cholesterol

RAL (n = 401) TDF/FTC (n = 404)

2

1.5

1

0.5

Grade 3-4 ALT elevation

Mean changes in fasting lipidsat W96 from baseline (mmol/l)

Proportion with graded toxicity

p < 0.001

HDL-c

p = 0.02

0.10.2

p < 0.001 p = 0.7

3.0

1.0

Triglycerides

p = 0.49

0.30.2

0

NEAT 001/ANRS 143

Risultati di laboratorioRisultati di laboratorio

Creatinine clearance (eGFR, ml/min [Cockroft-Gault formula]

Mean (95% CI) change from baseline

No grade 2-4 creatinine elevation in either arm

-15

-10

-5

0

5

0 4 8 12 18 24 3232 48 64 80 96

Weeks

RAL + DRV/r TDF/FTC + DRV/r

- 3.8

+ 0.9

p=0.02

NEAT 001/ANRS 143Tollerabilità renaleTollerabilità renale

RADAR: BMD

ConclusioniIn this well powered, open-label randomised study

• Overall twice daily RAL was well tolerated and had comparable efficacy to once daily TDF/FTC, when co-administered with once daily DRV/r, over 96 weeks in first-line ARV therapy

– Primary endpoint incidence over 96 weeks was 17.4 % (RAL) vs. 13.7 % (TDF/FTC); adjusted absolute difference was 3.7%

– The upper 95% CI of 8.6% was below the pre-specified non-inferiority margin

– In a planned subgroup analysis of the outcome for patients with low CD4 (<200/mm3) RAL + DRV/r was inferior to TDF/FTC + DRV/r

• Comparable safety between the 2 strategies– Similar rate of SAE, Grade 3-4 AE, AE leading to treatment modification

• Treatment-emergent resistance was seen in 5/28 (RAL) vs. 0/13 (TDF/FTC) patients with available genotype at failure

RAL + DRV/r represents an alternative option to TDF/FTC + DRV/r for first line therapy, particularly in patients with CD4 > 200/mm3

Cosa guida la scelta del regime?Iter diagnostico

Anamnesi

Esame obiettivo

Algoritmi interpretativi

Studio laboratoristico

Studio morfometrico, QUS, DXA

Perché sempre e ancora 3?

Ma Nino non aver paura di sbagliare un calcio di rigore,

non è mica da questi particolari che si giudica un giocatore,

un giocatore lo vedi dal coraggio, dall'altruismo e dalla fantasia.

Marco Borderi

U. O. Malattie Infettive – Bologna

Roma, 8 Maggio 2014

Seminario Nadir 2014 - Iniziativa resa possibile grazie al supporto di MSD Italia.