clinicaloptions.com/hiv

Terapia del paciente naive con un régimen de Inhibidor de la proteasa

Dr. Jose R ArribasIX Curso de avances en

Infección VIH y hepatitis virales

Eficacia en Ensayos Clínicos pivotales en naïves

RAL DTGEVG/c

EFV

ATV/r DRV/r

RPV

Single4

DTG>EFV

Spring-26

DTG=RAL

Flamingo8

DTG>DRV/r

ACTG 52579

DRV/r>ATV/r

ACTG 52579

RAL>ATV/rRAL>DRV/r

ACTG52025

ATV/r=EFV

1037

EVG/C=ATV/r

1022

EVG/C=EFV

Echo/Thrive1

RPV=EFV

Startmrk3

RAL>EFV

1. Cohen CJ et al. JAIDS 2012; 60 (1): 33-42 ; 2. Sax PE et al. Lancet 2012; 379: 2439–48; Rockstroh JK et al. JAIDS 2013; 63 (1); 4. Walmsley SL et al. N Engl J Med 2013; 369:1807-1818; 5. Daar ES, et al. Ann Intern Med 2011;154:445–56; 6. Raffi F et al. Lancet. 2013 Mar 2;381(9868):735-43; 7. DeJesus E, et al. Lancet 2012;379:2429–38; 8. Feinberg J et al. 52 ICAAC, September 9-12, 2012, H-1464a; 9. Landovitz RJ et al. CROI 2014. Abstract 85. 10. Cohen C. AIDS 2014, 28:989–997.

STAR10

RPV=EFV

Study DesignStudy 103

Conducted in parallel with Study 102 comparing STB to ATR

Randomized, double-blind, double dummy, active-controlled, international study

Treatment Naïve HIV-1 RNA ≥ 5000 c/mL

Any CD4 cell count

eGFR ≥70 mL/min

HIV-1 RNA < 50 c/mL by snapshot analysis (ITT)Non-inferiority margin (Wk48): 12%

STB QD

ATV/r+TVD Placebo QD

ATV+RTV+TVD QD

STB Placebo QD

(n=350)

(n=350)

Week 48

1:1*

Week 144

Primary Endpoint Secondary Endpoint

*Randomization stratified by screening HIV-1 RNA

(≤ vs >100,000 c/mL)

Efficacy Endpoint: HIV-1 RNA <50 c/mL Study 103 – Primary (Wk 48) and Secondary (Wk 96 and 144)

Virologic Success * Virologic Failure * No data *

Per

cent

age

of s

ubje

cts

(%)

STB (n=353) ATV+RTV+TVD (n=355)

95% CI for Difference

Favors ATV+RTV+TVD Favors STB

W48

0 -12%

-2.1% 7.5%

2.7%

W96-4.5% 6.7%

1.1%

12%

11

W144-3.2% 9.4%

3.1%11

*Virologic outcome as defined by FDA Snapshot algorithm

A5257 Study Design*

RAL 400 mg BID + FTC/TDF 200/300 mg QD

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

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

Study Conclusion 96 weeks after final participant e nrolled

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

Cumulative Incidence of Virologic Failure

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

Cumulative Incidence of Tolerability Failure

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

Cumulative Incidence of Virologic or Tolerability Failure

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

Proportion VL ≤50 copies/mLITT, regardless of ART change ITT, off-ART=failure ( SNAPSHOT)

24 48 96 144

ATV/r 83% 90% 88% 90%

RAL 90% 92% 94% 94%

DRV/r 83% 88% 89% 90%

24 48 96 144

ATV/r 70% 73% 63% 62%

RAL 84% 83% 80% 76%

DRV/r 77% 77% 73% 71%

14th European AIDS Conference; October 16-19, 2013; Brussels, Belgium

FLAMINGO (ING114915) Study Design

Clotet et al. EACS 2013; Brussels, Belgium. Abstract LBPS4/6.

Primary endpoint: proportion with HIV-1 RNA <50 c/mL at Week 48, FDA Snapshot

analysis, -12% non-inferiority (NI) margin

Secondary endpoints: antiviral activity, safety, tolerability, health outcomes and viral

resistance

HIV+ ART-naiveVL ≥1,000 c/mL

Stratified by screening plasma HIV-1 RNA

(≤ vs >100,000 c/mL) and background dual NRTI (ABC/3TC or TDF/FTC*)

Week 96 analysis

Randomization Week 48

analysis

DRV/r 800 mg/100 mg QD

+ 2 NRTIs

DTG + ART

Open-label randomized phase

DTG 50 mg QD +

2 NRTIs

Extension phase

*Investigator selected backbone of choice

Orkin C et al HIV Med 2012; 14:49–59.

PI Resistance Rare at VF in First-line Studies of Boosted PIsStudy n PI Wk Genotypes Major PI Mutations

CASTLE[1] 440443

ATV/RTVLPV/RTV

962626

10

ACTG 5202[2] 463465

ATV/RTV 968357

10

Study 103[3] 355 ATV/RTV 144 NR 0

ARTEMIS[4] 343346

DRV/RTVLPV/RTV

963146

00

FLAMINGO[5] 242 DRV/RTV 48 NR 0

ACTG 5257[6] 605601

ATV/RTVDRV/RTV

967599

00

1. Molina JM, et al. Lancet. 2008;372:646-655. 2. Daar ES, et al. Ann Intern Med. 2011;154:445-456.3. Clumeck N, et al. EACS 2013. Abstract LBPS7/2. 4. Mills A, et al. AIDS. 2009;23:1679-1688. 5. Clotet B, et al. Lancet. 2014;[Epub ahead of print]. 6. Landovitz R, et al. CROI 2014. Abstract 85.

� Among 4303 pts in these trials, only 2 pts developed major PI mutations at initial VF

Patient with bad adherence

Dual therapy with Lopinavir/ Ritonavir (LPV/r) and Lamivudine (3TC) is

non-inferior to standard triple drug therapy in Naïve HIV-1 infected

subjects : 48-week results of the GARDEL Study.

ClinicalTrials.gov : # NCT01237444

Pedro Cahn on behalf of the GARDEL study group

Study design

Phase III, randomized, international , controlled, open-label study

• Study included adult patients from Argentina, Chile, Mexico, Peru, Spain, US.

DT:

LPV/r 400/100mg BID

+ 3TC 150 mg BID

(n=217)

TT:LPV/r 400/100mg BID

+ 3TC or FTC and a third investigator-selected NRTI in

fixed-dose combination(n=209)

ARV- naive patients,

≥18 years

HIV-1 RNA >1000 copies/ml

No IAS-USA defined NRTI or PI resistance at screening*

HB(s)Ag negative

(N = 426)

Stratified by screening

HIV-1 RNA

(≤ or > 100,000 copies/mL)

Wk 48

primary endpoint

*Defined as > 1 major or > 2 minor LPV/r mutations)

LPV major mutations include the following mutations: V32I; I47V/A; L76V; V82A/F/T/S

Wk 24

interim analysis

Viral load <50 copies/mL

at week 48 (ITTe)

88.3%

83.7%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

BSL W4 W8 W12 W24 W36 W48

DT TT

(p= 0.171, difference +4.6%

[CI95%:-2.2% to +11.8%])

Viral load <50 copies/mL

at week 48 (ITTe), baseline VL

> 100.000 copies/mL

87.2%

77.9%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

BSL W4 W8 W12 W24 W36 W48

DT TT

(p= 0.145, difference +9.3%

[CI95%:-2.8% to +21.5%])

Protocol-Defined Virologic Failure and

Emergent Resistance Mutations

Number of patients, n (%)DT

(N=214)

TT

(N=202)

Confirmed virological failures 10 (4.6 %) 12 (5.9 %)*

HIV-1 RNA at failure (copies/ml) (median-

IQR)

236

(183-17,687)

1027

(123-4,880)

Never suppressed 2 8

Rebounders 8 4

Primary PI RAMs 0 0

NRTI RAMs (M184V) 2 0

*p=0.72

PDVF: 2 measurements of HIV-1 RNA at least 1 week apart

>400 copies/mL at week 24

> 50 copies/mL at week 48

Emergent resistance mutations, in samples successfully amplified:

DT: 2 out of 5 both M184V

TT: 0 out of 8

Milestones in the Evolution of the PI Class

PAST PRESENT(Not-too-distant)

FUTURE

Many pills per day Multiple doses necessary

Improved tolerabilitySome boosted

1 pill per day (+ RTV & NRTIs)Boosting gold standard

Manageable toxicity

More coformulations Single-tablet regimens

High toxicity

Once-daily dosingCoformulation

Some treatment-limiting toxicity

SQVRTVIDV

APVNFV

FPV/RTVLPV/RTV

ATVATV/RTVDRV/RTV

ATV/COBIDRV/COBI

DRV/COBI/TAF/FTC

SQV/RTVIDV/RTV

8000

DRV/COBI FDC Bioequivalent to DRV + RTV and to DRV + COBI� PK analyses in healthy subjects

DRV Concentration When DRV and COBI Administered as Single Agents or as

Coformulation [2]

DRV Concentration When Administered as DRV + RTV or as DRV/COBI Coformulation [1]

1. Kakuda TN, et al. Clin Pharmacol. 2012. Abstract O_20. 2. Kakuda TN, et al. IAS 2013. Abstract MOPE029.

HrsPla

sma

Con

cent

ratio

n of

DR

V

(ng/

mL;

Mea

n ±± ±±

SD

)

Hrs

DRV/RTV 800/100 mg QD as single agents (n = 32)DRV/COBI 800/150 mg QD as FDC (n = 33)DRV/COBI 800/150 mg QD as FDC (n = 33)

Single agents; fed (n = 38)FDC; fed (n = 40)Single agents; fasted (n = 72)FDC; fasted (n = 74)

6000

4000

2000

0240 6 12 18

8000

6000

4000

2000

00 4 8 12 16 20 24

Ongoing Studies of COBI-Boosted DRV Plus 2 NRTIs� Phase IIIb study in tx-naive tx-exp’d pts

with no DRV RAMs[1]

– Primary endpoint: grade 3 or grade 4 AEs by Wk 24

– Secondary endpoints: HIV-1 RNA at Wk 24 and Wk 48

� Randomized, double-blind phase II trial[2]

– Primary endpoint: HIV-1 RNA < 50 copies/mL at Wk 24

Pts with HIV-1 RNA≥ 500; naive or on stable

ART for 12 wks and sensitive to

2 NRTIs with no DRV RAMS

(N = 300)

DRV + COBI + 2 NRTIs

Wk 48

1. ClinicalTrials.gov. NCT01440569. 2. ClinicalTria ls.gov. NCT01565850.

ART-naive pts, HIV-1 RNA ≥ 5000 c/mL,

eGFR ≥ 70 mL/min(N = 150)

DRV/COBI/TAF/FTC QD(n = 75)

DRV/COBI + TDF/FTC(n = 75)

Wk 48Wk 24

Wk 24

� Coformulation of DRV and COBI being considered for approval by FDA

EIMC . En prensa

Lennox JL et al. Annals of internal medicine 2014

Conclusiones

� Los IPs potenciados son apropiados para muchos pacientes naïve

� Gran experiencia clínica

� Prácticamente no hay resistencia primara

� Alto grado de supresión virológico en terapia de inicio.

� No selección de resistencias tras fracaso.

� Buen perfil metabólico (ATV y DRV)

� Cobicistat puede ofrecer una nueva oportunida de coformulación

� FLEXIBILIDAD

– Terapias duales

Emergent Resistance Through Week 144Study 102/103 – Week 144

STB(n=701)

EFV/TVD(n=352)

ATV/r + TVD (n=355)

n (%) W96 W144 W96 W144 W96 W144

Population Analyzed

36 (5.1%) +6 (0.9%) 23 (6.5%) +5 (1.4%) 16 (4.5%) +3 (0.8%)

EmergentResistance

16 (1.9%) +2 (+0.3%) 10 (2.8%) +4 (+1.1%) 0 +2 (+0.6%)

Primary INSTI-R

14 (2.0%) +1 (+0.1%) 10 (2.8%) +4 (+1.1%) 0 0

or NNRTI-R E92Q 9 0 K103N 9 +4 I50L 0 0

or PI-R N155H 5 0 K101E 3 +2 I84V 0 0

Q148R 3 0 V108I 2 +2 N88S 0 0

T66I 2 0 Y188F/H/L 2 +1

T97A 0 +1 M230L 2 +0

V90I 1 +0

G190A/S 1 +0

P225H 1 +0

Primary NRTI-R

15 (2.1%) +2 (+0.3%) 3 (0.9%) +1 (+0.3%) 0 +2 (+0.6%)

M184V/I 15 +2 M184V/I 3 +1 M184V/I 0 +2

K65R 5 0 K65R 3 +0 K65R 0 0