1

Evalutation de Nouveaux Antirétroviraux

L’exemple de la Rilpivirine

Jean-Michel Molina

Université de Paris Diderot, Sorbonne Paris Cité

Hopital Saint-Louis, Paris

2

Liens d’Intérêt

Participation à des “réunions de conseils” pour les laboratoires Gilead, BMS, ViiV, Merck, Teva et Janssen Subventions de recherche: Laboratoires Merck et Gilead

Situation de l’Epidémie de VIH/SIDA Rapport ONUSIDA 2016 (1)

Nombre de personnes vivant avec le VIH - 2001: 28,6 Millions - 2015: 36,7 Millions

Décès liés au SIDA - 2001: 1,8 Millions - 2015: 1,1 Millions (-35% par rapport à 2005)

Personnes nouvellement infectées par le VIH

- 2001: 3,4 Millions - 2015: 2,1 Millions (diminution de 38%)

Situation de l’Epidémie de VIH/SIDA Rapport ONUSIDA 2016 (2)

Nombre de personnes traitées - 2015: 17 Millions (46% des personnes infectées)

Les 3 objectifs de l’ONUSIDA pour 2020 - 90% des personnes infectées connaissent leur statut - 90% des personnes infectées ont accès au traitement - 90% des personnes traitées ont une charge virale

indétectable

Situation en France Données de la FHDH (114000 personnes : 80% des

diagnostics)

Amélioration continue de l’efficacité des traitements

– 90% des patients traités ont ARN VIH < 200 cp/ml

– Médiane des CD4 à 430/mm3 (59% > 500 CD4)

Evolution des recommendations de mise sous traitement

– 90% des patients infectés par le VIH reçoivent un traitement

Très faible proportion de patients sans alternative thérapeutique: 1-2% (avec une disparité régionale)

Molécules antirétrovirales disponibles en 2017

Inhibiteurs non nucléosidiques de RT (NNRTIs)

Efavirenz (EFV) Nevirapine (NVP) Etravirine Rilpivirine

Inhibiteurs de protéase (IPs)

Amprenavir (APV) Atazanavir (ATV) Fosamprenavir (FPV) Indinavir (IDV) Lopinavir/ritonavir (LPV/RTV) Nelfinavir (NFV) Ritonavir (RTV) Saquinavir (SQV hgc) Tipranavir (TPV) Darunavir (DRV)

Abacavir (ABC) Didanosine (ddI) Emtricitabine (FTC) Lamivudine (3TC) Stavudine (d4T) Tenofovir (TDF) Zidovudine (ZDV) 3TC/ABC 3TC/ABC/ZDV 3TC/ZDV FTC/TDF TAF/FTC

Inhibiteurs nucléosidiques de RT (NRTIs)

Inhibiteurs de fusion (FIs)

Enfuvirtide (ENF)

Inhibiteurs d’intégrase (IIs)

Raltegravir (RTG) Elvitegravir/cobicistat Dolutegravir

Inhibiteurs d’entrée (EIs)

Maraviroc (MVC)

Recommendations Françaises 2017 6 combinaisons de molécules sont recommandées

•Rilpivirine + TDF/FTC : Eviplera (8183 Euros*)

•DRV/r + TDF/FTC : Prezista/ Norvir/Truvada (10423 Euros)

•Dolutegravir + ABC/3TC: Triumeq (11141 Euros)

•Elvitegravir/c + TDF/FTC: Stribild (11725 Euros)

•Raltegravir + TDF/FTC : isentress /Truvada (12240 Euros)

•Dolutegravir + TDF/FTC: Tivicay + Truvada (12724 Euros)

* Coût annuel

8

Overview of Rilpivirine

• Background • Trials in ARV naïve patients

• Phase 3 Pooled ECHO/THRIVE Week 96 • Phase 3 Star Trial

• Trials in ARV experienced patients (switch)

– Switch from PIs (Spirit) – Switch from EFV

• Cohort study in “real life”

9

Background

1. Azijn H, et al. AAC 2010;54:718–27 5. Hoetelmans R, et al. IAS 2005. Rio de Janeiro, Brazil. #WePe3.3C15 2. Desmidt M, et al. EACS 2009. Cologne, Germany. #PE7.1/4 6. Mathias A, et al. IAC 2010. Vienna, Italy. #LBPE17 3. Eviplera® (emtricitabine/rilpivirine/tenofovir disoproxil fumarate). 7. Janssen PA, et al. J Med Chem 2005;48:1901–9 Summary of Proeuct Characteristics. November 2011 8. Lachau-Durand S, et al. EACS 2009. Cologne, Germany. #PE7.1/3 4. Crauwels H, et al. IWCPHT 2008. New Orleans, LA. #P32

Rilpivirine (RPV) is an NNRTI with the following attributes: • Anti-HIV-1 activity, EC50=0.3ng/mL1 • No teratogenicity in preclinical studies2

• Half-life of ~ 50 hours3

• Food increases RPV’s bioavailability by approximately 60% – RPV should be taken with a meal4

• No significant drug interaction with TDF5 or FTC6

• >99.7% protein-bound in vitro7

• Metabolised primarily via the CYP3A pathway8

• Eviplera (RPV + TDF/FTC) or Edurant (RPV)

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Effect of Food Type on Mean RPV PK Profile

Standard breakfast (533 kcal)

Fasting conditions (0 kcal)

High-fat breakfast (928 kcal)

Nutritional drink (300 kcal)

Crauwels HM, et al. IWCPHT 2008. New Orleans, LA. #P32

Time (hours)

Mea

n R

PV p

lasm

a co

ncen

tratio

n (n

g/m

L) 300

250

200

150

100

50

0 0 4 8 12 16 20 24

Taking RPV with food increases RPV exposure by 57% compared to fasting. RPV AUC was similar when administered after a high-fat or standard breakfast.

Drug Interactions: Contra-indications

Drug that may decrease RPV plasma concentrations 1. Drugs that increase gastric pH

– PPIs (esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole)

Alternative #1: H2 blocker given at least 12h before or 4h after RPV Alternative #2: Antacids given ≥ 2h before or ≥ 4h after RPV

2. CYP3A4 inducers – Anticonvulsants (carbamazepine, oxcarbazepine, phenobarbital,

phenytoin) – Antimycobacterials (rifabutin, rifampin, rifapentine) – St. John’s Wort (Hypericum perforatum) – System glucocorticoid dexamethasone (more than a single dose)

12

• Objectives: to assess the potential effects of oral RPV on embryo-foetal development in rats and rabbits

• RPV did not show teratogenic potential in rat and rabbit models at exposures 13- to 80-times higher than those seen in HIV-1-infected patients receiving 25mg qd RPV at steady-state

• These animal data suggest that further studies of RPV in women of child bearing potential are warranted

Desmidt M, et al. EACS 2009. Cologne, Germany. #PE7.1/4

Teratogenicity Preclinical Safety

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RPV 25mg qd (n=93) RPV 75mg qd (n=95) RPV 150mg qd (n=91) EFV 600mg qd (n=89)

RPV: high and sustained virologic response rate in combination with 2 NRTIs over 96 weeks in Phase II study

76% 72% 71% 71%

100

80

60

40

20

0

Time (weeks)

Viro

logi

c re

spon

ders

(%, 9

5% C

I)

Viral load

14 14

† From 39 NNRTI RAMs based on list of 441; ‡ Based on Virco®TYPE HIV-1 test; Tambuyzer L et al. Antivir Ther 2009;14:103–9

Randomized, double-blind, double-dummy, multicenter, 96-week study

690 patients RPV 25mg qd + TDF/FTC qd + EFV placebo qd (n=346)

EFV 600mg qd + TDF/FTC qd + RPV placebo qd (n=344)

ECHO (TMC278-C209)

678 patients

RPV 25mg qd + 2 NRTIs + EFV placebo qd (n=340)

EFV 600mg qd + 2 NRTIs + RPV placebo qd (n=338) THRIVE (TMC278-C215)

ARV-naïve HIV RNA > 5,000 c/mL

No NNRTI RAMs† Sensitivity to the NRTIs‡

• Primary objective: to demonstrate non-inferiority (12% margin) vs. EFV in confirmed virologic response (viral load [VL]

15

Baseline parameter RPV

N=686 EFV

N=682

Female, % 25 24

Median age, years 36 36 Race, % Caucasian Black Asian Other races/not stated

61 24 11 3

60 23 14 3

Median log10 VL, copies/mL (min–max) 5 (2–7) 5 (3–7)

% viral load

Efficacy results

16

Time (weeks)02 8 1216 24 32 40 48 60 72 84 96

RPV EFV

77%77%

Res

pond

ers

(%,9

5%C

I)

40

20

40

60

80

100

• RPV+FTC/TDF was non-inferior to EFV+FTC/TDF at weeks 48 & 96 • Mean change in CD4 cell count from baseline (NC=F)

• 48 weeks RPV: +193 vs. EFV: +182 cells/mm3 • 96 weeks RPV: +226 vs. EFV: +222 cells/mm3

Difference (95% CI) in response rates (RPV–EFV)

-5.4 -0.4 4.6

–12 –10 –8 –6 –4 –2 0 2 4 6 8 10 12

Favours EFV Favours RPV

Pooled ECHO & THRIVE (wk 96 FTC/TDF Dataset) HIV RNA

0

10

20

30

40

50

60

70

80

90

100

0

10

20

30

40

50

60

70

80

90

100

≤100K

Patie

nts

(%)

>100K

Patie

nts

(%) 4.0 (–1.7, 9.7)§

RPV

Responders

Discontinued due to other reasons†

VFeff

Discontinued due to AE/death

EFV

75 84 80

RPV N’=318

EFV N’=353

RPV N’=368

EFV N’=329

-5.2 (-12, 1.5)§

70 Non responders

Pooled ECHO and THRIVE: ITT-TLOVR outcome at Week 96 by baseline VL

• Responses by baseline CD4 cell count were (≥200 cells/mm3): RPV 82% vs EFV 79%, (≥50–

Pooled ECHO and THRIVE: ITT-TLOVR outcome at Week 96 by self-reported M-MASRI adherence

M-MASRI = Modified Medication Adherence Self-Report Inventory

0

10

20

30

40

50

60

70

80

90

100

0

10

20

30

40

50

60

70

80

90

100

Adherent (>95%)

Patie

nts

(%)

Suboptimally adherent (≤95%)

Patie

nts

(%)

*Responders = patients with viral load

Resistance

Pooled ECHO/THRIVE: Week 48 Full Dataset Incidence of Treatment-emergenta NNRTI and N(t)RTI RAM

in Virologic Failures by Baseline Viral Load Category

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Incidence, n (%) RPV

(N = 686) EFV

(N = 682) All virologic failure with genotypic datab n = 62 n = 28

NNRTI RAM 39 (63) 15 (54) N(t)RTI RAM 42 (68) 9 (32) NNRTI and N(t)RTI RAM 37 (60) 8 (29)

a Not present at screening or baseline and present at time of failure while on treatment. b At time of failure.

Baseline viral load ≤100K c/mL (RPV n=368), (EFV, n =330) n = 16 n =12 NNRTI RAM 6 (38) 5 (42) N(t)RTI RAM 7 (44) 2 (17) NNRTI and N(t)RTI RAM 5 (31) 1 (8)

Baseline viral load >100K c/mL (RPV, n=318), (EFV, n=352) n = 46 n = 16 NNRTI RAM 33 (72) 10 (63) N(t)RTI RAM 35 (76) 7 (44) NNRTI and N(t)RTI RAM 32 (70) 7 (44)

Rimsky L, et al. IWHHC 2011; Los Cabos, Mexico. Abstract 9.

Baseline viral load ≤100K c/mL n = 16 n =12 NNRTI RAM 1.6% 1.5%

N(t)RTI RAM 1.9% 0.6%

NNRTI and N(t)RTI RAM 1.4% 0.3% Baseline viral load >100K c/mL n = 46 n = 16

NNRTI RAM 10.4% 2.8% N(t)RTI RAM 11% 2% NNRTI and N(t)RTI RAM 10% 2%

22 22

RPV 25mg qd (n=62) EFV 600mg qd (n=28)

*Not present at screening or baseline and present at time of failure while on treatment †Occurring in ≥5% of VF with available resistance data

• Among RPV VFs with emerging NNRTI RAMs, 46%, 31% and 23% had 1, 2, or 3 NNRTI RAMs, respectively, at failure

• Non-clade B VFs (n=13, including 8 clade C) did not exhibit any distinctive pattern of NNRTI RAMs

Pooled ECHO & THRIVE (wk 48 Full Dataset) Treatment-emergent* NNRTI RAMs

45

0

E138K

0

39

K103N

0 7

0

11

V106M Y188C

13 4

10 0

8 0

8 0 0

8

K101E H221Y V189I Y181C V90I Most frequent NNRTI RAMS †

63 54

0 10 20 30 40 50 60 70 80 90

100

Any

Adapted from Eron J et al. ICAAC 2010. Boston. Abstract H-1810

Viro

logi

c fa

ilure

s w

ith

NN

RTI

RAM

s (%

)

68

15

39

8 5

32

18

4 4 7

0

20

40

60

80

100

Any M184V M184I M184I/V K65R

Virolo

gicfai

lures

with

N(t

)RTI R

AM (%

)

Most frequent N(t)RTI RAMs*

23 23

RPV 25mg (n=62) EFV 600mg qd (n=28)

• 18/62 RPV VFs and 12/28 EFV VFs failed with wild-type virus

• 37/62 RPV VFs and 6/28 EFV VFs had both treatment-emergent NNRTI and N(t)RTI RAMs

Pooled ECHO & THRIVE (wk 48 Full Dataset) Treatment-emergent IAS-USA N(t)RTI RAMs

Adapted from Eron J et al. ICAAC 2010. Boston. Abstract H-1810

Safety and tolerability

• RPV+FTC/TDF demonstrated a more favourable overall safety profile, with significantly less discontinuations due to AEs

– Fewer discontinuations for rash with RPV+FTC/TDF (p=0.003) • Majority of AEs occurred in the first year

– In Year 2, the incidence of treatment-related grade 2-4 AEs was 2.5% (RPV+FTC/TDF) and 3.7% (EFV+FTC/TDF)

% RPV N=550 EFV N=546 P-value

Any serious AEs 9.5 11.2 ND Grade 2-4 treatment-related AEs 17 33

Pooled ECHO and THRIVE: Wk 96 FTC/TDF Dataset Lipid Changes Over 96 Weeks

RPV+FTC/TDF

EFV+FTC/TDF

mm

ol/L

TC* LDL* HDL* TG*

*P 7 . 7 8 G rade 3: > 6 . 2 -7 . 7 8 G rade 2: > 5 . 2-6 . 2 G rade 1:

mmol / L < 5 . 2 G rade 0:

> 7 . 7 8 G rade 3: G rade 2:

> 5 . 2-6 . 2 G rade 1:

mmol / L < 3 . 4 G rad e 0 :

> 4 . 9 G rad e 3 : > 4 . 1-4 . 9 G rad e 2 : > 3 . 4-4 . 1 G rad e 1 :

mmol / L < 3 . 4 G rad e 0 :

> 4 . 9 G rad e 3 : > 4 . 1-4 . 9 G rad e 2 : > 3 . 4-4 . 1 G rad e 1 :

mmol / L Total Cholesterol LDL

RPV+FTC/TDF

EFV+FTC/TDF

RPV+FTC/TDF

EFV+FTC/TDF

† P

Pooled ECHO and THRIVE: Conclusions at Week 96

• RPV showed sustained overall efficacy that was similar to EFV over 96 weeks (78% overall response in each group)

– Suboptimal adherence was associated with reduced responses in both groups

– Response was numerically higher in the RPV group with baseline VL ≤100K

– The effect of suboptimal adherence and higher baseline viral load on VFeff was more apparent with RPV than with EFV

• At Week 48 the overall VFres rate was higher with RPV than EFV, however, beyond Week 48 there were similar increases in VFres for both groups

• RPV showed lower incidences than EFV of

– Grade 2–4 overall AEs†

– Dizziness, abnormal dreams/nightmares and rash (any grade)†

– Discontinuations due to AEs (mainly rash and dizziness)

– Grade 2 to 4 lipid abnormalities

• From Week 48 to 96, there were no new safety concerns with either NNRTI

• RPV was efficacious and well tolerated in a large and diverse group of treatment-naïve patients

• RPV + TDF/FTC approved in Europe in naïve patients with

28

STaR Study: Single-Tablet Regimen

Emtricitabine/Rilpivirine/Tenofovir DF is Non-Inferior to Efavirenz/Emtricitabine/Tenofovir DF

in ART-Naïve Adults Week 48 Results

Calvin Cohen, David Wohl, Jose Arribas, Keith Henry, Jan van Lunzen, Mark Bloch, William Towner,

Edmund Wilkins, Hui Wang, Kirsten White, Danielle Porter, Bill Guyer, Todd Fralich

Eleventh International Congress on Drug Therapy in HIV Infection

Glasgow, Scotland 15 November 2012

Published in AIDS, 2014

STAR Study Design

RPV/FTC/TDF STR

EFV/FTC/TDF STR

ARV-naive HIV-1 RNA >2500 c/mL

Sensitivity to EFV, FTC, RPV, TDF (N=786)

Stratified by HIV RNA (≤ or >100,000 c/mL)

n=394

n=392

96 Weeks

Primary endpoint: Efficacy of the 2 STRs by proportion with HIV-1 RNA

Baseline Demographics and Characteristics

RPV/FTC/TDF EFV/FTC/TDF

Median age, years (IQR) 37 (29, 45) 35 (28, 45)

Male % 93% 93%

White % 68% 67%

Black % 25% 24%

Latino ethnicity % 15% 19%

Mean CD4 cell count, cells/mm3 (SD) 396 (180) 385 (187)

HIV-1 RNA, log10 c/mL, (SD) 4.8 (0.7) 4.8 (0.6)

≤100,000 c/mL, n (%) 260 (66%) 250 (64%)

>100,000 to ≤500,000 c/mL, n (%) 98 (25%) 117 (30%)

>500,000 c/mL, n (%) 36 (9%) 25 (6%)

95% CI for Difference 86

8 6

82

613

0102030405060708090

100

VirologicSuppression

Virologic Failure No W48 Data

Prop

ortio

n of

Par

ticip

ants

, %

4.1 -1.1 9.2

-12 0 12

Favors EFV/FTC/TDF

Favors RPV/FTC/TDF

% %

RPVFTC//TDF is non-inferior to EFV/FTC/TDF

Virologic Suppression and CD4 Change at Week 48 FDA Snapshot Analysis – ITT Population

■ RPV/FTC/TDF ■ EFV/FTC/TDF

(HIV-1 RNA

Virologic Suppression by FDA Snapshot Analysis Stratified by Baseline HIV-1 RNA 100,000 c/mL

95% CI for Difference

Favors EFV/FTC/TDF

< 100K

> 100K

Favors RPV/FTC/TDF

-12 0 +12

1.1 13.4

-1.8 -11.1 7.5

7.2

◙

◙

RPV/FTC/TDF compared to EFV/FTC/TDF Superior for subjects with baseline HIV-1 RNA 100,000 c/mL

898082 82

0

20

40

60

80

100

100K

HIV

-1 R

NA

<50

c/m

L (%

)

RPV/FTC/TDF EFV/FTC/TDF

Baseline HIV-1 RNA copies/mL

231/260 204/250 107/134 116/142

Virologic Suppression at Week 48 FDA Snapshot Analysis by Baseline HIV-1 RNA

8983

7282 82 80

0

20

40

60

80

100

≤100K >100 - 500K >500K

HIV

-1 R

NA

< 5

0 c/

mL

(%)

RPV/FTC/TDF EFV/FTC/TDF

204/ 250

81/ 98

96/ 117

26/ 36

20/ 25

* Post hoc analyses; analyses for non-inferiority only pre-specified for ≤100,000 c/mL and >100,000 c/mL

*

231/ 260

Baseline HIV-1 RNA copies/mL

*

Virologic Failure at Week 48 FDA Snapshot Analysis by Baseline HIV-1 RNA

Virologic failure: Week 48 HIV-1 RNA >50 copies/mL, or discontinued study drug due to lack of efficacy, or discontinued study drug due to other reasons and last available HIV-1 RNA >50 copies/mL *ECHO/THRIVE: Two Phase III double-blinded, double dummy, mulitcenter 96 week studies in treatment-naïve HIV-1 infected subjects randomized to receive either RPV (25mg) or EFV (600mg) in combination with 2 NRTIs (ECHO, FTC/TDF; THRIVE, Investigator’s choice [FTC/TDF, n=406; 3TC/AZT, n=204; 3TC/ABC, n=68]). In the pooled TVD subset analysis (N=1096), RPV+TVD was non-inferior to EFV+TVD (HIV-1 RNA 500K

Viro

logi

c Fa

ilure

(%)

RPV/FTC/TDFEFV/FTC/TDFRPV+FTC/TDFEFV+FTC/TDF

≤100K >100-500K

Resistance Analysis Through Week 48

RPV/FTC/TDF (n=394)

EFV/FTC/TDF (n=392)

RPV+FTC/TDF (n=550)

EFV+FTC/TDF (n=546)

Subjects with Resistance Data 5% 2% 11% 3% Subjects with Resistance to ARVs 4% 1% 7% 2%

Any Primary NNRTI-R 4% 1% 6% 2% Key NNRTI-R E138K/Q (2%) K103N (0.3%) E138K/Q (4%) K103N (1%)

Y181C/I (2%) Y181C/I (1%) K101E (1%) K101E (1%)

Any Primary NRTI-R 4% 0.3% 7% 1% Key NRTI-R M184V/I (4%) M184I (0.3%) M184V/I(6%) M184V/I (1%)

K65R/N (1%) K65R/N (1%) K65R/N (0.4%)

Within Baseline (BL) HIV-1 RNA ≤100,000 copies/mL at BL 2% 1% 2% 1% >100,000–500,000 copies/mL at BL 5% 0 9% 2% >500,000 copies/mL at BL 19% 4% 21% 7%

STaR* ECHO/THRIVE TVD Subset†

The STRs used in STaR, compared to the components of the regimens used in ECHO and THRIVE, demonstrated less emergent resistance

All Grades Treatment-Emergent Adverse Events* of Importance

Psychiatric Events, n (%) 62 (16%) 147 (38%) p< 0.001 Events >5% of subjects†, either arm

Abnormal Dreams 23 (6%) 96 (25%) Depression 26 (7%) 35 (9%) Anxiety, nervousness 20 (5%) 34 (9%)

*prespecified evaluation for common adverse events, US Efavirenz Prescribing Information † 1 (0.3%) suicide occurred in the EFV/FTC/TDF arm, day 36 of study

RPV/FTC/TDF (n=394)

EFV/FTC/TDF (n=392)

Nervous System Events, n (%) 117 (30%) 198 (51%) p< 0.001 Events >5% of subjects, either arm

Dizziness, vertigo, balance disorder 30 (8%) 100 (26%)

Insomnia 38 (10%) 55 (14%)

Somnolence 10 (3%) 27 (7%)

Headache 49 (12%) 53 (14%)

Adverse Events Leading to Discontinuation of Study Drug

RPV/FTC/TDF (n=394)

EFV/FTC/TDF (n=392)

Discontinuations* Due to Adverse Event (AE), n (%) 10 (2.5%) 34 (8.7%) P1 subject in either arm Nervous System Events Dizziness 0 Abnormal Dreams or Nightmare 0 Insomnia 1 (0.3%) Psychiatric Disorders Depression, Anxiety or Depressed Mood 0 Suicidal Ideation 0 GI, General, Skin Disorders Diarrhea 0 Fatigue 0 Pyrexia 0 Toxic Skin Eruption 0

5 (1.3%) 6 (1.5%) 3 (0.8%)

9 (2.3%) 2 (0.5%)

2 (0.5%) 2 (0.5%) 2 (0.5%) 2 (0.5%)

23 (6%) 96 (25%)

• Overall, RPV/TDF/FTC was non-inferior to EFV/FTC/TDF through 48 weeks for the primary endpoint of virologic suppression

– Superior when baseline HIV-1 RNA ≤100,000 copies/mL – Non-inferior when baseline HIV-1 RNA >100,000 copies/mL

• Overall, low and similar rates of virologic failure occurred for RPV/FTC/TDF (8%) and EFV/FTC/TDF (6%)

– Similar rates observed for virologic failure with baseline HIV-1 RNA ≤100,000 c/mL (RPV/FTC/TDF 5%, EFV/FTC/TDF 3%) and for >100,000 to 500,000 c/mL (RPV/FTC/TDF 10%, EFV/FTC/TDF 9%); low rates of resistance

– Higher rates of virologic failures for baseline HIV-1 RNA >500,000 c/mL (RPV/FTC/TDF 25%, EFV/FTC/TDF 16%); resistance rate higher for RPV/FTC/TDF (19% vs EFV/FTC/TDF 4%)

• RPV/FTC/TDF is well-tolerated compared to EFV/FTC/TDF – Significantly fewer nervous system and rash adverse events – Significantly fewer discontinuations due to adverse events

• Significant differences for change in lipids – TC, LDL, and TG favoring RPV/FTC/TDF – HDL favoring EFV/FTC/TDF – Similar change to TC:HDL ratio for both arms

Star Conclusions

Switch Studies

40 40

Switch d’EFV vers RPV (GS 111)

FTC/RPV/TDF STR

Primary endpoint: % of subjects with HIV-1 RNA

41 41

Primary Endpoint: HIV-1 RNA

42

Primary Endpoint: Non-inferiority (12% margin) of RPV/FTC/TDF to PI+RTV+2 NRTIs by FDA snapshot analysis HIV RNA

43

Baseline Characteristics

RPV/FTC/TDF N = 317

PI+RTV+ 2NRTIs N = 159

Median age, years (IQR) 42 (35, 48) 43 (36, 49) Male 86% 91% White race 76% 78% Black race 19% 14% Latino ethnicity 16% 20% Median time since first ART, years (IQR) 2.9 (1.9, 4.4) 2.6 (1.7, 4.8) Mean CD4 cell count, cells/mm3 (SD) 576 (237) 600 (259)

44

3TC/ZDV

ABCFTC

3TC

TDF

d4TZDV

SQV

APV

Antiretroviral Therapy at Screening (n=476)

RTV-boosted PI† NRTI

3TC: lamivudine; d4T: stavudine; ABC: abacavir; APV: amprenavir; ATV: atazanavir; DRV: darunavir; FPV: fosamprenavir; FTC: emtricitabine; LPV: lopinavir; RTV: ritonarvir; SQV: saquinavir; TDF: tenofovir disoproxil fumarate; ZDV: zidovudine

3.4 1.1

0.8 0.8 0.6

0.2 0.2

1.7

0.2

% Subjects

FTC/TDF 81%

3TC/ABC 13%

ATV 37%

LPV 33%

DRV 20% FPV

8%

% Subjects

† Includes all treated subjects. 2 subjects enrolled on EFV/FTC/TDF instead of a boosted PI (protocol violation)

45

Switching to RPV/FTC/TDF was non-inferior* to remaining on PI+RTV+2NRTIs for 24 weeks. Similar rates of virologic suppression were also seen with 48 weeks

of treatment with RPV/FTC/TDF

Virologic Suppression at Weeks 24 and 48 FDA Snapshot Analysis – ITT Population

Prop

ortio

n of

Sub

ject

s, %

(HIV-1 RNA

46

Grade 3 or 4 Adverse Events and Laboratory Abnormalities

RPV/FTC/TDF N = 317

(Immediate switch, at W48)

PI+RTV +2NRTIs N = 159 (at W24)

RPV/FTC/TDF N = 152

(Delayed switch, at W24)

Grade 3 or 4 Adverse Events 18 (5.7%) 11 (6.9%) 12* (7.9%)

Grade 3 or 4 Laboratory Abnormalities 28

† (8.8%) 18‡

(11.3%) 23§ (15.2%)

Adverse events and laboratory abnormalities occurring in ≥1% of subjects: * creatine kinase increase † ALT, AST, creatine kinase, hematuria ‡ AST, bilirubin, creatine kinase, triglycerides § ALT, AST, creatine kinase, glycosuria

47

Changes from Baseline in Fasting Lipids M

ean

Cha

nges

from

BL,

mm

ol/L

(mg/

dL)

TC LDL TG HDL

TC - total cholesterol, LDL - low-density lipoprotein, TG - triglycerides, HDL - high-density lipoprotein

RPV/FTC/TDF (immediate, D1-W24) PI+RTV+2NRTIs (D1-W24) RPV/FTC/TDF (delayed, W24-W48) RPV/FTC/TDF (immediate, D1-W48)

(-16) (-14)

(-16)

(-53)

(3)

(-80)

(-64)

(-4)

(-1) (-2)

0

-0.03

-.41

-0.05 -0.1

-.60

-.41

-.65

-.03

.03

-0.05

-.90

-.36

-.65 -.72

-.62

-0.9 -0.8 -0.7 -0.6 -0.5 -0.4 -0.3 -0.2 -0.1

0 (-1)

(-24) (-25) (-25)

(-2)

Switching to RPV/FTC/TDF resulted in improvement in fasting lipids, including TC, LDL, TGs, and TC:HDL ratio at Week 24 and maintained through Week 48

48

• Through 24 weeks, switching to RPV/FTC/TDF was non-inferior to remaining on PI+RTV+2NRTIs (93.7% versus 89.9%) – In the delayed switch arm, virologic suppression was maintained through

24 weeks with RPV/FTC/TDF (92.1%) – In the immediate switch arm, virologic suppression was maintained through

48 weeks after switching to RPV/FTC/TDF (89.3%) • Lower rate of virologic failure observed in subjects switching to

RPV/FTC/TDF (0.9%) compared to remaining on PI+RTV+2NRTIs (5.0%) at Week 24 – Low rate of virologic failure (1.3%) was also seen in the delayed

switch arm – Through 48 weeks, RPV/FTC/TDF maintained a low rate (2.5%)

of virologic failure • Resistance development was infrequent with switching to RPV/FTC/TDF • Switching to RPV/FTC/TDF resulted in improvement in fasting lipids,

including TC, LDL, TGs, and TC:HDL ratio at Week 24 and was maintained through Week 48

Conclusions

Efficacy and Safety of a switch to RILPIVIRINE-Based Regimens in Treatment-Experienced HIV-1

Infected Patients a Prospective Cohort Study.

S. Gazaignes1, M. Resche-Rigon1, C. Yang2, C. Gatey1, A-L Munier1, K. Desseaux1, W.

Rozenbaum1, J-M. Molina1.

1Saint-Louis Hospital and University of Paris Diderot, Paris, France, 2University of Toronto, Toronto, Canada;

Gazaignes S. et al Antiviral Therapy 2016

BACKGROUND AND OBJECTIVES • Rilpivirine (RPV) is a second-generation NNRTI given once daily,

available in France since September 2012. • In treatment-naïve patients, RPV has shown non-inferior antiviral

activity versus efavirenz (EFV) in three large phase III clinical trials (ECHO, THRIVE and STAR).

• The SPIRIT trial evaluated in virologically suppressed patients the switch from a boosted PI to RPV/TDF/FTC.

• At week 48, among 317 patients who switched to RPV, 283 (89.3%) had VL< 50 cp/mL, 8 (2.5%) had VF and 8.2% had no data. 4/7 patients with VF developed RAM. (Pallela et al. AIDS 2014)

• We wished to assess the efficacy and safety of RPV in treatment-experienced patients with suppressed HIV-1 replication switching to a RPV-based regimen in a “real-life” setting.

METHODS • Study design: observational, longitudinal, prospective, monocentric

cohort study at Saint-Louis hospital (Paris-France) • Patients:

– All antiretroviral therapy (ART) experienced HIV-1 infected patients switching to a RPV-based regimen

– With a plasma HIV-RNA level 50 cp/mL and RPV discontinuation Window period M12 = M12+/- 8 weeks. A sensitivity analysis was performed with available data beyond M12. – Secondary endpoints: To describe:

• Reasons for the switch • Virologic and immunological efficacy • Virologic failure and emergence of resistant associated mutation (RAM) • Clinical and biological tolerability.

281 Patients included

3491 Patients followed at Saint-Louis hospital

385 Patients treated with RPV

Exclusion of patients treated in trials: 9

Exclusion of treatment-naive patients : 46

Exclusion of patients without RPV: 7

Exclusion of patients with VL> 50 cp/ml: : 42

38 (14%) Patients discontinued RPV - 7 due to VF - 23 due to AEs - 6 due to other reasons - 2 patients died

211 (75%) Patients remained on RPV at M12

32 (11%) Patients lost to follow-up

Baseline Characteristics of the 281 patients N or median % or (range)

Male gender 214 76%

Age, years 47 (22-78)

Ethnicity

Sub-saharan Africa 57 20%

Europe 156 56%

North Africa 27 10%

Mode of HIV infection

Homosexual 169 60%

Heterosexual 90 32%

Intravenous drug users, transfusion, others 13 5%

Duration of HIV infection, years 10 (0-29)

CD4 cell count at baseline, cells/mm3 630 (81-1800)

Duration of undetectable HIV RNA before switch, months 38 (0-200)

Time between first ART and switch, years 7 (0-23)

CDC category C 61 22%

Hepatitis co-infection

HBV (AgHbS +) 17 6%

HCV (Ac anti HCV positive/PCR +) 11 4%

273 (97%) patients received a combination of 2 N(t)RTIs associated with a third agent before the switch.

3TC-ABC 15%

3TC-AZT 5%

3TC-ddi

Reasons for the switch

6 (2%)

5 (2%)

7

2

3

4

12 (4%)

65 (23%)

177 (63%)

Others

Switch to avoid drug-drug interaction

Other AEs

Renal toxicity

Lipodystrophy

Dyslipidemia

Gastrointestinal

Neuropsychiatric

Simplification of treatment regimen

Switch due to

AEs

93 (33%)

Primary endpoint at M12 (Snapshot and with available data beyond M12)

• Median CD4 count remained stable around 630 cells/mm3 from M0 to M12

Virologicsuppression

Virologicalfailure No data

> M12 202 16 63

Snapshot at M12

72%

6% 22%

Parameters Virologic failures

N=16 N/median (%/IQR)

Virologic suppression

N=202 N /median (%/IQR)

p-value

Age, years 47 [42;48] 47[40;53] p=0.90

Gender, male 10 (63%) 156 (77%) p=0.22

Mode of HIV infection -Heterosexual -MSM

9 (56%) 6 (38%)

65 (32%)

119 (59%)

p=0.15

Highest HIV VL, log cp/mL 4.9 [4.6;5.2] 5 [4.6;5.5] p=0.59

CD4 count nadir, cells/mm3 210 [140; 310] 260 [160;350] p=0.37

Undetectable plasma VL before the switch, months 38 [17;56] 37 [17;78] p=0.67

NNRTI-based ART before switch 2 (13%) 83 (41%) p=0.03

Previous RAMs to NNRTIs* 1/10 (10%) 3/109 (2%) p= 0.30

Previous M184V* 3/10 (30%) 5/109 (5%) p=0.02

Baseline risk factors associated with virologic failure

Incidence of clinical AEs N=281 %

Number of patients with AEs leading to RPV discontinuation 23 8% Neuropsychiatric (sleep disturbances, dizziness, vertigo) 16 6% Gastrointestinal (abdominal pain) 7 2% Cutaneous (rashs) 5 2% Hepatitis 3 Renal failure 1

Most common clinical adverse events Sleeping disorders 12 4% Abdominal pain/bloating 11 4% Rash 9 3% Nausea/vomiting 6 2% Insomnia 5 2% Vertigo 4 Diarrhea 3 Abnormal dreams 3 Headache 2 Depression 2 Death due to suicide 2

Median changes in biological parameters from baseline to M12

• A small but significant increase from BL in serum creatinine was seen with RPV: + 6 µmol/L [-0.087; 13] (p

Summary • RPV was overall well tolerated. Only 23 (8%) discontinued for AEs, 16 (70%) of whom with neuropsychiatric AEs.

• 16 (6%) patients experienced virological failure, 5 (2%) of whom developed new NRTI or NNRTI RAMs. • RPV is indicated in France for naive patients with no baseline resistance and VL < 100,000 cp/ml and in well suppressed patients on a PI-based regimen with no previous failure or resistance • Patients with unknwon resistance genotype or a history of virological failure or with NNRTI and/or NRTIs (M184V) RAM should not be switched to RPV based regimen.

Evalutation de Nouveaux Antirétroviraux ��L’exemple de la RilpivirineLiens d’IntérêtSituation de l’Epidémie de VIH/SIDA�Rapport ONUSIDA 2016 (1)Situation de l’Epidémie de VIH/SIDA�Rapport ONUSIDA 2016 (2)Situation en FranceMolécules antirétrovirales disponibles en 2017Recommendations Françaises 2017 Overview of RilpivirineBackground � ��� �� Effect of Food Type on Mean RPV PK ProfileDrug Interactions: Contra-indicationsDiapositive numéro 12RPV: high and sustained virologic response rate in combination with 2 NRTIs over 96 weeks in Phase II studyECHO and THRIVE – Phase 3 Studies�Study DesignsPooled ECHO and THRIVE�Demographics and Baseline CharacteristicsEfficacy resultsPooled ECHO & THRIVE (wk 96 FTC/TDF Dataset) �HIV RNA