Inhibiteurs d’Intégrase

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1 Inhibiteurs d’Intégrase
Dr Chloe Orkin

2 Etapes d’Intégration du VIH-1
2 Processing de l’extrémité 3’-OH 3a Attachement à l’ADN cible 3b Clivage et insertion de l’ADN cible 1 Assemblage de l’ADN viral au sein du complexe nucléoprotéique Synthèse de l’ADN viral Entrée Nucléaire Membrane Nucléaire Remplissage des “gaps” Provirus Hazuda D, et al Medicinal Chemistry 30th Annual National Symposium Copyright © 2006 Merck & Co., Inc., Whitehouse Station, NJ, USA. All rights reserved.

3 Inhibiteurs d’Intégrase
Raltegravir (dérivé du naphthyridine carboxamide, initialement MK- 0518)[1] Premier inhibiteur de l’intégrase Initialement approuvé chez les patients pré-traités ; récemment approuvé chez les patients naïfs Elvitegravir (dikéto acide dérivé de l’acide dihydroquinoline-3-carboxylique, initialement GS-9137)[2] Actuellement en phase III Dolutegravir[3] Nouveau inhibiteur d’intégrase actif in vitro contre les isolats résistants à raltegravir et elvitegravir Actuellement en phase IIb 1. Markowitz M, et al. J Acquir Immune Defic Syndr. 2006;43: DeJesus E, et al. J Acquir Immune Defic Syndr. 2006;43: Lalezari J, et al. IAS Abstract TUAB105.

4 Activité in Vitro de Raltégravir
H O - F K + Puissante activité in vitro IC95 (Moyenne  DS) = 31 nM  20 nM Activité contre les Souches VIH-1 multi-résistantes Souches VIH-1 à tropisme CCR5 et CXCR4 Les souches VIH-1 résistantes à raltégravir demeurent sensibles aux autres classes antirétrovirales Action additive/synergique in vitro avec les INRTIs, INNTIs, IPs, et enfuvirtide IAS 2009, Abstract # A

5 Protocole 005 Phase IIb: Raltégravir chez les patients pré-traités
Essai de phase IIb, randomisé, en double aveugle, contrôlé versus placebo, et en escalade de doses S 24 S 48 Phase de double aveugle Phase ouverte† Raltegravir 200 mg BID + TO* (n = 43) Raltegravir 400 mg BID + TO* (n = 100) Patients avec virus résistant aux 3 classes historiques, ARV-VIH1 > 5000 copies/mL et taux de CD4+ > 50 cellules/mm3 (N = 178) Raltegravir 400 mg BID + TO* (n = 45) †Patients autorisés à recevoir raltégravir 400 mg BID en phase ouverte après au moins 24 semaines de traitement en double aveugle ; la durée médiane de la phase en double aveugle était de 40 semaines pour le groupe raltégravir et de 24 semaines pour le groupe placebo BID, twice daily; DRV, darunavir; OBR, optimized background regimen; RAL, raltegravir; RTV, ritonavir. Raltegravir 600 mg BID + TO* (n = 45) Placebo + TO* (n = 45) *TO: traitement de fond optimisé. DRV/RTV n’était pas disponible Grinsztejn B, et al. ICAAC Abstract H-713. 5

6 Protocol 005: Résultats à 48 semaines
Raltegravir 200 mg BID Raltegravir 400 mg BID Raltegravir 600 mg BID Placebo ITT, NC = F BL Carried Forward for VFs Double aveugle Double aveugle + ouvert Double aveugle Double aveugle + ouvert 100 200 80 150 60 100 CD4+ Cell Count Change (cells/mm3) ARN VIH < 50 copies/mL (%) 40 50 BID, twice daily; ITT, intent-to-treat; NC = F, non-completers = failure; VF, virologic failure 20 -50 2 4 8 12 16 24 32 40 48 2 4 8 12 16 24 32 40 48 Semaine Semaine No. de Patients No. de Patients 43 43 42 43 41 37 45 45 44 45 43 44 45 45 45 45 42 43 45 45 45 43 Adapted with permission of Merck & Co., Inc., Whitehouse Station, NJ. Copyright © Merck & Co., Inc. Whitehouse Station, NJ. All rights reserved. 6

7 BENCHMRK-1 & -2: Design de l’essai
Randomisé, double aveugle, contrôlé versus placebo Analyse primaire à S16; analyse secondaire à S48; durée estimée à semaines Analyse actuelle à 156 semaines Current analysis: Week 156 Week 240 HIV-1-infected Triple-class resistant ARN VIH >1000 copies/mL Aucune limite de CD4 Protocole 018 (N=352) (Europe, Asie/Pacifique et Perou) Protocole 019 (N=351) Amérique Nord et Sud RAL 400 mg BID + TO P018 (n=234) P019 (n=232) RAL 400 mg BID + TO 2:1 Placebo + TO P018 (n=118) P019 (n=119) RAL 400 mg BID + TO After Week 156, double-blind phase was completed and all patients were offered open-label RAL until Week 240.

8 BENCHMRK 1: Caractéristiques à baseline
Raltegravir + TO (n = 234) Placebo + TO (n = 118) ARN VIH-1, log10 copies/mL (moyenne) 4.6 4.5 Taux de CD4+, cellules/mm3 (médiane) 140 105 SIDA, % 94 89 Durée d’exposition aux ARV (médiane), ans 11 10 GSS = 0, % 30 29 GSS = 1, % 33 41 PSS = 0, % 19 18 PSS = 1, % Première utilisation de DRV dans le TO, % 27 25 Première utilisation d’ENF dans le TO, % 21 20 GSS, genotypic sensitivity score; HBV, hepatitis B virus; HCV, hepatitis C virus; OBR, optimized background regimen; PSS, phenotypic sensitivity score; SD, standard deviation. Cooper DA, et al. CROI Abstract 788. 8

9 Pourcentage de Patients (95% IC) avec ARN VIH < 50 Copies/mL (NC=F)
57% 26% 62% 33% 50% 22% * * p-value< p-value was derived from a logistic regression model adjusted for baseline HIV RNA level (log10), first enfuvirtide use in OBT, first darunavir use in OBT, active PI in OBT.

10 Variation du taux de CD4 par rapport à baseline (celllules/mm3)
* 164 124 109 63 45 49 * p-value< For change from baseline in CD4 cell counts, p-value was derived from a mixed-effects model adjusted for: baseline CD4 cell count, stratum, treatment, visit, interactions between visit and previous variables.

11 ARN VIH à Baseline (copies/mL) Taux de CD4 à Baseline (cells/mm3)
% de Patients avec ARN VIH <50 copies/mL à S96 en fonction de la charge virale et du taux de CD4 à Baseline* Sous-groupe N % de Patients Total ARN VIH à Baseline (copies/mL) >100,000 ≤100,000 Taux de CD4 à Baseline (cells/mm3) ≤50 >50 and ≤200 >200 Raltegravir + TO Placebo + TO *Virologic failures carried forward

12 % de Patients avec ARN VIH <50 copies/mL à S96 en fonction du Score Génotypique de Sensibilité (GSS)* Sous-groupe N % de Patients Total GSS 1 2 ou plus Raltegravir + TO Placebo + TO *Virologic failures carried forward Pour les patients avec un GSS=1 à baseline, les agents actifs dans le TO étaient : darunavir (52%, 52% dans les groupes raltégravir et placebo, respectivement), enfuvirtide (8%, 16%), tenofovir (12%, 6%), et tipranavir (11%, 11%)

13 % de Patients avec ARN VIH <50 copies/mL à S96 en fonction des ARVs présents dans le TO*
Subgroup N % de Patients Total Enfuvirtide Darunavir + + + - - + - - + : Utilisation de novo dans le TO - : absent dans le TO Raltegravir + TO Placebo + TO *Virologic failures carried forward

14 Cancer – Risque Relatif (IC95%)
Raltegravir + TO Placebo + TO Risque Relatif N Cas/PA† (taux‡ ) (95% IC) Total 462 24/801 (3.0) 237 7/264 (2.6) 1.1 (0.5, 3.1) BENCHMRK-1 232 12/417 (2.9) 118 2/133 (1.5) BENCHMRK-2 230 12/384 (3.1) 119 5/131 (3.8) † Patient-années à risque. ‡ Par 100 PA. Pour évaluer le risque de cancer, une analyse semblable a été effectuée incluant toutes les data en double aveugle des études de phase II et III (Protocoles 004, 005, BENCHMRK-1 and -2 et STARTMRK). Le taux de mailignités était de 1.7 /100 PA pour raltégravir et de 2.2 /100 PA pour le groupe comparateur, résultant d’un risque relatif (IC95%) de 0.8 (0.4, 1.5). (D. Cooper et al, CROI 2009 Abs R-106, Poster 859).

15 Autres usages potentiels de Raltegravir
Naïve Switch Épargne de NRTIs Once Daily Grossesse (Categorie C)

16 STARTMRK Phase III: RAL vs EFV chez les Patients Naïfs
Essai randomisé, contrôlé versus comparatif actif Critère principal d’efficacité : ARN HIV-1 < 50 copies/mL à S48 Wk 96 planned follow-up S48 Critère primaire RAL 400 mg BID + TDF/FTC (n = 281) Patients naïfs de traitement avec ARN VIH-1 > 5000 copies/mL et absence de résistance à EFV, TDF, ou FTC (N = 563) BID, twice daily; FTC, emtricitabine; QHS, dosed at bedtime; TDF, tenofovir. EFV 600 mg QD+ TDF/FTC (n = 282)

17 STARTMRK: % de Patients avec ARN VIH < 50 copies/mL (IC95%)
(Non-Completer = Failure) 100 86% 80 82% 60 % de patients avec ARN VIH <50 copies/mL 40 20 Valeur de P pour non infériorité < 0.001 2 4 8 12 16 24 32 40 48 Weeks Nombre de patients Raltegravir 400 mg b.i.d.* 281 279 281 279 281 279 278 280 280 Efavirenz 600 mg q.d.* 282 282 282 282 281 282 280 281 281 *En combinaison avec TDF/FTC. Lennox J et al. 48th ICAAC Abstract H-896. 17 17

18 (MK-###) (PN###) "CONFIDENTIAL - LIMITED ACCESS", Interim Deck-Expires when CSR Deck is Available
Proportion (%) of Patients Achieving HIV RNA <50 copies/mL (95% CI) Over Time 4/27/2017 1:28 AM Non-Completer = Failure Approach 86 82 81 79 75 69 76 67 281 278 279 280 277 282 Raltegravir 400 mg bid. Efavirenz 600 mg qHS. 12 24 48 72 96 120 144 168 192 216 240 Weeks 20 40 60 80 100 Percent of Patients with HIV RNA Levels <50 Copies/mL Number of Contributing Patients 71% 61% White Template MASTER ppt 18

19 Yearly Efficacy Analyses
(MK-###) (PN###) "CONFIDENTIAL - LIMITED ACCESS", Interim Deck-Expires when CSR Deck is Available Yearly Efficacy Analyses 4/27/2017 1:28 AM Study Week % (n/N) of Patients with vRNA <50 copies/mL Change (cells/mm3) from BL CD4 Count RAL (N=281) EFV (N=282) RAL – EFV (95% CI) 48 86.1 (241/280) 81.9 (230/281) 4.2 (-1.9, 10.3)* 189 163 26 (4, 47) 96 81.1 (228/281) 78.7 (222/282) 2.4 (-4.3, 9.0)* 240 225 15 (-12, 43) 156 75.4 (212/281) 68.8 (194/282) 6.6 (-0.8, 14.0)* 331 295 36 (3, 68) 192 76.2 (214/281) 67.0 (189/282) 9.0 (1.6, 16.4)*° 361 301 60 (24, 95) 71.0 (198/279) 61.3 (171/279) 9.5 (1.7, 17.3)*° 374 312 62 (22, 102) * P-value for non-inferiority <0.001. ° Met criteria for superiority. n/N, number of pts with vRNA <50 c/mL over Number of evaluable pts at each time point.  Non-Completer=Failure (NC=F): Pts who discontinued for any reason were considered as failures thereafter. ¶ Observed Failure (OF): Pts who discontinued for lack of efficacy were considered as virologic failures thereafter, & BL CD4 values were carried forward.  Difference calculated as RAL minus EFV (95% CI). A positive value favors RAL over EFV. The treatment difference & 95% CIs were weighted proportionally by the size of screening HIV RNA stratum (> or ≤50,000 c/mL).  Difference calculated as RAL minus EFV (95% CI). A positive value favors RAL over EFV. The 95% CIs were calculated based on a t- distribution. § RAL would be considered non-inferior to EFV if the lower bound of the 95% CI for the difference in response rates was above -12%, & superior to EFV if the entire 95% CI was >0. * P-value for non-inferiority <0.001. ° Met criteria for superiority. White Template MASTER ppt 19

20 REFLATE TDF245 mg qd + 3TC 300mg qd + EFV 600 mg qd
HIV RNA>1000 cp/mL ART naïve Confirmed or probable TB RIF containing regimen 1:1:1 TDF245mg qd + 3TC 300mg qd + RAL 400 mg bid TDF245 mg qd + 3TC 300 mg qd + RAL 800 mg bid + RAL 400 mg bid J’ai enlevé les effectifs par bras : le nombre calculé figure en dessous (c’est la dia de méthodes pas de résultats) Critère de jugement : ce sont les composantes de TLOVR mais pas une analyse TLOVR (à S24 ce serait impossible et TLOVR = Time to = analyse de survie, Ce qui n’est pas le cas ici, on analyse des proportions) J’ai enlevé « mITT » ici car cela ne présente pas d’intérêt et on comprend mieux que c’est une « mITT » dans la dia d’après (puisque on voit directement Que l’on enlève uniquement ceux qui n’ont pas débuté le traitement) J’ai également enlevé la rando par pays, cela n’apporte rien dans cette dia très chargée et peut être dit à l’oral ou en réponse à une question. De fait, vu le petit nombre inclus en France, Cela ne change pas grand-chose Abréviations : RHZE, RH : pas clair, sera dit à l’oral ? Mo = months? TB drugs RHZE 2mo followed by RH 4mo W 24 W0 W48 Primary endpoint mITT HIV RNA<50copies/mL Sample size : 50 patients/arm, 80% power to show ≥70% success at W24 20

21 % Participants with HIV RNA<50 cp/mL at each visit (M=F, study treatment discontinuation=F)
Measures after strategy discontinuation (RIF, RALTE, EFV) considered as > 50cp/ml 21

22 Efficacy outcomes, W24 Primary endpoint : HIV RNA<50 cp/mL at W20 and W24, mITT (M=F, D/C=F) EFV N = 51 RAL 400 N = 51 RAL 800 PRIMARY ENDPOINT n % [95% CI] % [95% CI] Success 32 63 [49-76] 39 76 [65-88] 40 78 [67-90] Failure 19 37 [24-51] 12 24 [12-35] 11 22 [10-33] Virologic failure 15 4 AE leading to treatment discontinuation 2 3 Death Withdrawal / Lost to Follow-up Secondary endpoint : HIV RNA<400 cp/mL at W20 and W24, mITT (M=F, D/C=F) EFV N = 51 RAL 400 RAL 800 SECONDARY ENDPOINT n % [95% CI] Success 39 76 [65-88] 41 80 [69-91] 42 82 [72-93] Failure 12 24 [12-35] 10 20 [9-31] 9 18 [7-28] Virologic failure 8 2 AE leading to treatment discontinuation 3 Death Withdrawal / Lost to Follow-up 22

23 Variation moyenne des lipides à S12 ARN VIH-1 < 50 copies/mL à S24
SWITCHMRK-1 et -2: Switch par RAL d’un traitement efficace contenant LPV/RTV Stratification par durée de traitement contenant LPV/RTV (≤ vs > 1 an) Variation moyenne des lipides à S12 ARN VIH-1 < 50 copies/mL à S24 Patients avec ARN VIH-1 indétectable et schéma thérapeutique stable contenant LPV/RTV depuis au moins 3 mois (Protocole 032: N = 348; Protocole 033: N = 354) Switch par RAL* (Protocole 032: n = 174; Protocole 033: n = 176) Poursuite de LPV/RTV* (Protocole 032: n = 174; Protocole 033: n = 178) *Tous les patients ont continué à recevoir au moins 2 INTIs. Les patients ayant des antécédents d’échec virologique n’ont pas été exclus et le nombre de traitements antirétroviraux antérieurs n’était pas limité. Eron J et al. CROI Abstract 70aLB. 23

24 SWITCHMRK-1 and -2: Diminution significative des Lipides avec RAL
Protocole 032 Protocole 033 Mean Change From BL at Week 12 (%) NS NS nps nps * * * * nps, not prespecified for test; NS, not significant * * Fasting Cholesterol Non HDL-C Fasting TG† Fasting LDL-C Fasting HDL-C Fasting Cholesterol Non HDL-C Fasting TG† Fasting LDL-C Fasting HDL-C Mean mg/dL: At BL At Wk 12 *P < 0.001; †Variation médiane à S12 à partir de BL, %. Eron J et al. CROI Abstract 70aLB. Adapted with permission of Merck & Co., Inc., Whitehouse Station, New Jersey, USA. Copyright © 2009 Merck & Co., Inc., Whitehouse Station, NJ, USA. All rights reserved. 24 24 24

25 SWITCHMRK-1 et -2: Réponse virologique à S24, NC = F
Critère prédéfini de non infériorité: limite inférieure de l’IC à 95% CI pour la différence entre les traitements > -12% Protocol 032 Protocol 033 100 100 94% 87% 90 90 80 80 88% ARN VIH-1 < 50 c/mL (%) ARN VIH-1 < 50 c/mL (%) 70 81% 70 60 60 ∆ : -6.6 (IC à 95%: to 1.2) ∆ : -5.8 (IC à 95%: to 0.2) 50 50 4 8 12 24 4 8 12 24 Weeks Weeks RAL + ARVs, n LPV/RTV + ARVs, n Eron J et al. CROI Abstract 70aLB. Adapted with permission of Merck & Co., Inc., Whitehouse Station, New Jersey, USA. Copyright © 2009 Merck & Co., Inc., Whitehouse Station, NJ, USA. All rights reserved. 25

26 SWITCHMRK-1 et -2: Caracteristiques des patients à Baseline
Characteristic Protocole 032 Protocole 033 RAL (n = 174) LPV/RTV (n = 174) RAL (n = 176) LPV/RTV (n = 178) Age moyen, ans 44.4 43.6 42.0 41.9 Femelle, % 16.1 25.9 22.2 22.5 Nonwhite, % 19.0 51.7 54.5 ARN VIH-1 ≤ 50 copies/mL, % 94.3 92.5 96.0 95.5 Taux moyen de CD4, cellules/mm3 478 508 471 482 Usage de lopinavir/ritonavir ≤ 1 yr, % 16.7 17.8 17.6 18.5 Durée médiane des traitements ARV antérieurs, ans (limites) 3.3 ( ) 3.6 ( ) 3.7 ( ) 4.6 ( ) Median previous antiretroviral drugs, n (limites) 5.0 ( ) 5.0 ( ) 5.5 ( ) 6.0 ( ) Eron J et al. CROI Abstract 70aLB.

27 % de Patients avec ARN VIH < 50 copies/mL (NC = F)
Par historique thérapeutique- P032 & 033 Combinés Δ (CI à 95%) -1.0 (-6.9, 4.9) Δ (IC à 95%) -15.3 (-24.9, -6.2) Absence d’échec virologique antérieur Echec virologique antérieur

28 PROGRESS: RAL vs TDF/FTC, + LPV/RTV chez les patients naïfs (analyse intermédiaire)
Essai de phase III, randomisé, en ouvert Analyse intermédiaire S48 S96 RAL 400 mg BID + LPV/RTV 400/100 mg BID (n = 101) Patients naïfs avec ARN VIH-1 > 1000 copies/mL (N = 206) BID, twice daily; FTC, emtricitabine; LPV, lopinavir; QD, once daily; RAL, raltegravir; RTV, ritonavir; TDF, tenofovir. TDF/FTC 300/200 mg QD + LPV/RTV 400/100 mg BID (n = 105) Podsadecki T, et al. British HIV Association Abstract P31.

29 Proportion de patients répondeurs à S96 (FDA-TLOVR)
For reference: The FDA time to loss of virologic response (TLOVR) algorithm: Subjects are considered responders when they achieve two consecutive HIV-1 RNA values <40 copies/mL. Subjects are classified as non-responders at all subsequent visits if they demonstrate 2 consecutive rebound HIV-1 RNA values ≥40 copies/mL, or if they discontinue the study for any reason prior to week 48 Results generally similar to ITT NC=F primary endpoint Primary endpoint: plasma HIV-1 RNA <40 copies/mL at week 48 (FDA-TLOVR) FDA-TLOVR week 48: LPV/r + RAL=83.2%, LPV/r + TDF/FTC=84.8% P=0.850, difference -1.6%, 95% exact confidence interval [CI] -12.0%, 8.8% Week 96 FDA-TLOVR response for subjects with high and low baseline viral loads For subjects with baseline HIV-1 RNA level <100,000 copies/mL, LPV/r + RAL= 61/86 (70.9%), LPV/r + TDF/FTC= 62/86 (72.1%) For subjects with baseline HIV-1 RNA level ≥100,000 copies/mL, LPV/r + RAL= 6/15 (40.0%), LPV/r + TDF/FTC= 10/19 (52.6%) PROGRESS 96 Week Results April 9, 2011

30 ACTG 5262 Study Design Multicenter, single arm, open-label, 52-week pilot study HIV-infected Men and Women, 18 years and older ARV Naive N=112 RAL 400 mg BID + DRV 800mg/RTV 100mg QD TRANSITION The next Single Table Regimen that is anticipated in 2011 is TDF/FTC with RPV. Now let’s look at the data for the components of ATR vs. the components of that next STR. MAIN MESSAGES BACKGROUND 2/11 update - Goal is to fully enroll by Q2 2011 Primary Endpoint: Virologic failure prior to or at week 24 30 30

31 ACTG 5262 Time to Virologic Failure (ITT approach)
Time to Virologic Failure (VF) Time to VF by Baseline HIV-1 RNA 1.0 0.8 0.6 0.4 0.2 0.0 1.0 0.8 0.6 0.4 0.2 0.0 Probability of not having a VF Probability of not having a VF Log Rank Test p=0.0002 HIV-1 RNA ≤ 100,000 copies/mL HIV-1 RNA > 100,000 copies/mL BACKGROUND Patients were excluded if they had DM, were on meds for DM, or were on meds known to affect bone or body composition These baseline characteristics are similar to the overall cohort of ACTG 5202. MAIN MESSAGES The median age of the population was 38, mostly men, with just under one half being White non-Hispanic race A high proportion of patients had baseline VL > 100,000 and CD4 < 200 cells, with a median CD4 count of 233 Of note, one third of the patients had osteopenia at baseline The median limb fat was in the normal range TRANSITION The BMD findings comparing the pooled ATV/r and EFV arms are shown on the next slide Time (weeks) Time (weeks) n with VF: n at risk: HIV-1 RNA ≤ 100,000 copies/mL n with VF: n at risk: HIV-1 RNA > 100,000 copies/mL n with VF: n at risk: Taiwo B, et al. CROI Boston. #551.

32 RADAR

33 Can RAL Be Dosed Once Daily?
ClinicalTrials.gov. Available at:

34 QDMRK: Raltegravir QD vs. BID chez les patients naïfs
Critère primaire S48 Critère secondaire S96 Raltegravir 800 mg QD + TDF/FTC n=382 Patients naïfs ARN VIH >5000 copies/mL Raltegravir 400 mg BID + TDF/FTC n=388 Study design: Phase III Study of the Safety and Efficacy of Once Daily vs Twice Daily RAL in Combination Therapy for Treatment-naïve HIV-infected Patients Background:  Based on prior pharmacokinetic and in vitro data suggesting that once-daily dosing of raltegravir (RAL) might be effective as an alternative to twice-daily RAL in treatment-naive patients, QDMRK was initiated to evaluate once-daily RAL (800 mg once daily) vs twice-daily RAL (400 mg twice-daily) regimens. Methods:  QDMRK was a non-inferiority study with prespecified –10% margin, where treatment-naive patients with HIV RNA levels >5000 copies/mL and no resistance to tenofovir (TDF) or emtricitabine (FTC) were randomized to receive once-daily vs twice-daily RAL, each with TDF/FTC. The primary efficacy endpoint was percentage of patients with HIV RNA <50 copies/mL at week 48 (non-completer = failure analysis). Enrollment began with a vanguard cohort of 150 patients followed by the first of 2 completed interim analyses monitored by an external DMC; a total of 770 patients were randomized and treated. Results:  Of 382 once-daily and 388 twice-daily RAL-treated patients, 40% and 39% had baseline HIV RNA >100,000 copies/mL, respectively. Week 48 results appear in the table:  88 patients experienced virologic failures (non-response or rebound) by week 48:  53 of 382 (13.9%) and 35 and 388 (9.0%) in the once-daily and twice-daily groups, respectively. Of patients with available resistance data, there were 9 vs 2 patients from the once-daily and twice-daily groups, respectively, with integrase (and FTC) -resistant virus. Higher Ctrough and Call (geometric mean of all sparse pharmacokinetics for an individual) were associated with a greater probability of a successful treatment outcome. Serious clinical adverse events and discontinuations occurred at a similar and infrequent rate in both arms. Conclusions:  Both once-daily and twice-daily RAL in combination with TDF/FTC achieved high virologic response rates and similar immunologic effects. However, once-daily was inferior in virologic efficacy as compared to twice-daily RAL; with once-daily, higher pharmacokinetic and lower baseline viral load were associated with treatment success. RAL-based regimens in treatment-naive patients continue to demonstrate a favorable tolerability and safety profile. Essai en double aveugle, randomisé, multicentrique Analyse: Non-inferiorité (marge de 10%) Eron J, et al. 18th CROI; Boston, MA; February 27-March 2, Abst. 150LB. 34

35 QDMRK: ARN VIH <50 copies/mL (NC=F)
BID 88.9% QD 83.2% Δ (QD-BID) [IC à 95%] = -5.7 [-10.7, -0.83] 4 8 12 16 24 36 48 Semaines 20 40 60 80 100 % de patients avec ARN VIH <50 copies/mL Note: RAL QD NOT non-inferior to RAL BID QDMRK, a Phase III Study of the Safety and Efficacy of Once Daily vs Twice Daily RAL in Combination Therapy for Treatment-naïve HIV-infected Patients Joseph Eron*1, J Rockstroh2, J Reynes3, J Andrade-Villanueva4, J Madruga5, J Zhao6, P Sklar6, B-Y Nguyen6, and QDMRK Study Team 1Univ of North Carolina at Chapel Hill, US; 2Univ of Bonn, Germany; 3Ctr Hosp Univ Montpellier, France; 4Univ of Guadalajara, Mexico; 5Ctr de Referencia e Treinamento DST/AIDS, Sao Paulo, Brazil; and 6Merck Res Labs, North Wales, PA, US Background:  Based on prior pharmacokinetic and in vitro data suggesting that once-daily dosing of raltegravir (RAL) might be effective as an alternative to twice-daily RAL in treatment-naive patients, QDMRK was initiated to evaluate once-daily RAL (800 mg once daily) vs twice-daily RAL (400 mg twice-daily) regimens. Methods:  QDMRK was a non-inferiority study with prespecified –10% margin, where treatment-naive patients with HIV RNA levels >5000 copies/mL and no resistance to tenofovir (TDF) or emtricitabine (FTC) were randomized to receive once-daily vs twice-daily RAL, each with TDF/FTC. The primary efficacy endpoint was percentage of patients with HIV RNA <50 copies/mL at week 48 (non-completer = failure analysis). Enrollment began with a vanguard cohort of 150 patients followed by the first of 2 completed interim analyses monitored by an external DMC; a total of 770 patients were randomized and treated. Results:  Of 382 once-daily and 388 twice-daily RAL-treated patients, 40% and 39% had baseline HIV RNA >100,000 copies/mL, respectively. Week 48 results appear in the table:  88 patients experienced virologic failures (non-response or rebound) by week 48:  53 of 382 (13.9%) and 35 and 388 (9.0%) in the once-daily and twice-daily groups, respectively. Of patients with available resistance data, there were 9 vs 2 patients from the once-daily and twice-daily groups, respectively, with integrase (and FTC) -resistant virus. Higher Ctrough and Call (geometric mean of all sparse pharmacokinetics for an individual) were associated with a greater probability of a successful treatment outcome. Serious clinical adverse events and discontinuations occurred at a similar and infrequent rate in both arms. Conclusions:  Both once-daily and twice-daily RAL in combination with TDF/FTC achieved high virologic response rates and similar immunologic effects. However, once-daily was inferior in virologic efficacy as compared to twice-daily RAL; with once-daily, higher pharmacokinetic and lower baseline viral load were associated with treatment success. RAL-based regimens in treatment-naive patients continue to demonstrate a favorable tolerability and safety profile. 382 377 381 379 380 388 386 387 RAL 800 mg QD RAL 400 mg BID Nombre de Patients Eron J, et al. 18th CROI; Boston, MA; February 27-March 2, Abst. 150LB. 35

36 QDMRK: Histogrammes pour les MG des Ctrough et % avec ARN VIH <50 copies/mL (Observed Failure)
MG C12hr (nM) MG C24hr (nM) Note low rate of success in the RAL QD quartile with lowest RAL trough levels QDMRK, a Phase III Study of the Safety and Efficacy of Once Daily vs Twice Daily RAL in Combination Therapy for Treatment-naïve HIV-infected Patients Joseph Eron*1, J Rockstroh2, J Reynes3, J Andrade-Villanueva4, J Madruga5, J Zhao6, P Sklar6, B-Y Nguyen6, and QDMRK Study Team 1Univ of North Carolina at Chapel Hill, US; 2Univ of Bonn, Germany; 3Ctr Hosp Univ Montpellier, France; 4Univ of Guadalajara, Mexico; 5Ctr de Referencia e Treinamento DST/AIDS, Sao Paulo, Brazil; and 6Merck Res Labs, North Wales, PA, US Background:  Based on prior pharmacokinetic and in vitro data suggesting that once-daily dosing of raltegravir (RAL) might be effective as an alternative to twice-daily RAL in treatment-naive patients, QDMRK was initiated to evaluate once-daily RAL (800 mg once daily) vs twice-daily RAL (400 mg twice-daily) regimens. Methods:  QDMRK was a non-inferiority study with prespecified –10% margin, where treatment-naive patients with HIV RNA levels >5000 copies/mL and no resistance to tenofovir (TDF) or emtricitabine (FTC) were randomized to receive once-daily vs twice-daily RAL, each with TDF/FTC. The primary efficacy endpoint was percentage of patients with HIV RNA <50 copies/mL at week 48 (non-completer = failure analysis). Enrollment began with a vanguard cohort of 150 patients followed by the first of 2 completed interim analyses monitored by an external DMC; a total of 770 patients were randomized and treated. Results:  Of 382 once-daily and 388 twice-daily RAL-treated patients, 40% and 39% had baseline HIV RNA >100,000 copies/mL, respectively. Week 48 results appear in the table:  88 patients experienced virologic failures (non-response or rebound) by week 48:  53 of 382 (13.9%) and 35 and 388 (9.0%) in the once-daily and twice-daily groups, respectively. Of patients with available resistance data, there were 9 vs 2 patients from the once-daily and twice-daily groups, respectively, with integrase (and FTC) -resistant virus. Higher Ctrough and Call (geometric mean of all sparse pharmacokinetics for an individual) were associated with a greater probability of a successful treatment outcome. Serious clinical adverse events and discontinuations occurred at a similar and infrequent rate in both arms. Conclusions:  Both once-daily and twice-daily RAL in combination with TDF/FTC achieved high virologic response rates and similar immunologic effects. However, once-daily was inferior in virologic efficacy as compared to twice-daily RAL; with once-daily, higher pharmacokinetic and lower baseline viral load were associated with treatment success. RAL-based regimens in treatment-naive patients continue to demonstrate a favorable tolerability and safety profile. Intervalle Médiane Intervalle Médiane Eron J, et al. 18th CROI; Boston, MA; February 27-March 2, Abst. 150LB.

37 Elvitegravir vs. Raltegravir: Study Design
Elvitegravir (EVG) QD Protease Inhibitor/r 3rd ARV RAL Placebo BID Choice of fully active PI and 3rd agent were based on resistance testing If M184V or M184I, optional to also add FTC or 3TC N = 702 1:1 randomization RAL 400 mg BID Protease Inhibitor/r 3rd ARV EVG Placebo QD Background: Elvitegravir is an investigational once-daily integrase inhibitor with a long half life, and robust PK with trough levels of over 10-fold in excess of IC95. Methods: Adults with plasma HIV-1 RNA ≥1,000 copies/mL, and either resistance or six months experience to > 2 classes of antiretroviral drugs were randomized to receive blinded elvitegravir (EVG) 150 mg QD (85 mg if with atazanavir/lopinavir) or raltegravir (RAL) 400mg BID, in addition to a background regimen (BR) of a fully active ritonavir-boosted protease inhibitor and a second agent (investigator choice). The primary endpoint was the proportion of subjects achieving and maintaining HIV RNA < 50 copies/mL through Week 48 by TLOVR algorithm, with a non-inferiority threshold set at -10% (EVG-RAL). Primary Endpoint: HIV-1 RNA <50 c/mL through 48 weeks (FDA TLOVR) Non-inferiority Study Lower limit of the 95% Conf Interval: -10% Molina JM, et al. 6th IAS; Rome, Italy; July 17-20, Abst. WELBB05. 37

38 Efficacy Endpoint: HIV-1 RNA <50 c/mL (ITT, TLOVR) Study 145 – Primary (Week 48) and Secondary (Week 96) EVG (n=351) RAL (n=351) 95% CI for Difference 100 Favors RAL Favors EVG 80 59 58 60 1.1 Percentage of subjects (%) 48 45 W48 -6.0 8.2 40 29 26 26 26 22 23 19 19 2.6 20 W96 -4.6 9.9 -10% 10% W48 W96 W48 W96 W48 W96 Virologic Response Virologic Failure* Others# Once-daily EVG was comparable to twice-daily RAL at Week 96 *Virologic failure includes never suppressed, rebound, switch of background regimen, and discontinuation due to lack of efficacy #Others include death, discontinuation due to AE, investigator’s discretion, lost to follow up, pregnancy, protocol violation, subject non-compliance, withdrawal of consent. 38 Elion R, et al., IAC 2012; Washington, DC. Oral TUAB0105. 38 38

39 Integrase Resistance Study 145 – Week 96
EVG (n=351) RAL Non-responders by TLOVR, n 184 (52%) 193 (55%) Resistance analysis population*, n 87 (25%) 93 (26%)ˆ Any Primary Integrase-R, n 23 (7%) 26 (7%) T66I/A 8 E92Q/G 7 3 T97A 4 Y143R/H/C 1 S147G Q148R Q148H N155H 5 16 Rates of primary integrase-R between at Week 48 were EVG 5% vs RAL 4% Any NRTI-R, n 9 (3%) 12 (3%) Any Primary PI-R, n 5 (1%) Any Primary NNRTI-R, n 8 (2%) ˆ One subject was a responder at Week 96 but analyzed for resistance due to a confirmed virologic rebound early in the study. *Subjects who experienced either suboptimal virologic response (HIV-1 RNA ≥50 c/mL and <1 log10 below baseline at Week 8 and confirmed at the subsequent visit), virologic rebound (two consecutive visits with HIV-1 RNA either ≥400 c/mL after achieving HIV-1 RNA <50, or >1 log10 increase from nadir), or had HIV-1 RNA ≥400 c/mL at their last visit. 39 Elion R, et al., IAC 2012; Washington, DC. Oral TUAB0105. 39

40 EVG vs. RAL: Week 48 Results
Outcomes, % EVG (n=351) RAL Responder1 (Per Protocol Analysis)* 59 58 Virologic Failure 20 22 Rebound 11 16 Never suppressed 8 5 Switched background regimen 1 Deaths <1 2 Drug discontinuation due to AE 3 Drug discontinuation due to Other2 19 15 95%CI: -6% to 8.2%, p=0.001 for noninferiority Integrase Resistance: RAL: 21% EVG: 27% Key 48 Week Results: for Elvitegravir vs. Raltegravir HIV RNA < 50 copies/mL(TLOVR) Responder, n (%) 207/351 (59%) 203/351 (58%) 95% CI, -6.0% to 8.2%, * p= for non inferiority Increase in CD4 cells/mm3, mean 138 vs 147 cells/mm Development of Integrase Resistance 16/62 vs 15/76 Discontinuations due to Adverse Events, n (%) 9/354 vs. 15/358   Adverse events (AE) and laboratory abnormalities were similar. Conclusion: This study demonstrated that once daily EVG was non-inferior to twice daily RAL in treatment-experienced HIV-1 infected subjects with similar AE profiles overall. CD4 Change: RAL: +147/mm3 EVG: +138/mm3 * 1. Responder: achieved and maintained confirmed HIV-1 RNA <50 copies/mL through Week 48 2. Drug DC due to Other: Lack of Efficacy, Lost to Follow-up, Non-compliance, Investigator Discretion, Pregnancy, Protocol Violation, Withdrew Consent Molina JM, et al. 6th IAS; Rome, Italy; July 17-20, Abst. WELBB05. 40 40

41 Cross-resistance between EVG and RAL
From: McColl, et al., 2007, 16th International HIV Drug Resistance Workshop, Barbados, Abstract #9

42 Cobicistat: potentialisation pharmacocinétique en l’absence de Ritonavir
Cobicistat: Puissant inhibiteur spécifique du CYP3A sans activité anti-VIH Boost d’EVG semblable à celui obtenu avec RTV Cobicistat (150 mg) a maintenu des concentrations minimales d’EVG à des niveaux 11-fois supérieurs à la CI95 (44.5 ng/mL) Bien toléré avec un impact minime sur les adipocytes et la résistance à l’insuline La combinaison fixe de Cobicistat + EVG + TDF/FTC est en cours d’évaluation 100mg 150mg RTV COBICISTAT Elvitegravir Ctau (ng/mL) 1200 1000 800 600 400 200 GS-9350 is an experimental agent that displays potent CYP-3A boosting without anti-HIV activity. The boosting ability of the agents appears comparable to Ritonavir based on the ability to boost elvitegravir (GS integrase inhibitor). GS-9350 had a favorable toxicity profile with minimal impact on either insulin resistance or adipocytes and is quite soluble , so could be utilized in a fixed dose combination with other ARV agents. Future studies are planned to compare the boosting ability of this compound with Atazanavir vs. Ritonavir, and to compare the levels of elvitegravir and efficacy in a fixed dose combination with TDF/FTC vs. EFV/TDF/FTC. Bars represent geometric mean (±95% Cl) Kearnew B, et al. 16th CROI; Montreal, Canada; February 8-11, Abst. 40. 42

43 Snapshot analysis (HIV-1 RNA < 50 c/mL) Non-inferiority margin: 12%
Study Design Study 114 Randomized, double-blind, double dummy, active-controlled, international study (n=350) ATV + COBI + FTC/TDF Placebo: RTV Treatment Naïve HIV-1 RNA ≥5000 c/mL Any CD4 cell count eGFR ≥70 mL/min 1:1* (n=350) ATV + RTV + FTC/TDF Placebo: COBI *Randomization stratified by screening HIV-1 RNA (≤ vs >100,000 c/mL) 48 Weeks 192 Weeks Primary Endpoint Snapshot analysis (HIV-1 RNA < 50 c/mL) Non-inferiority margin: 12% 43

44 Percentage of Subjects (%)
Primary Endpoint: HIV-1 RNA <50 c/mL Study 114 – FDA Snapshot Week 48 (ITT) 95% CI for Difference Favors ATV + RTV Favors ATV + COBI Percentage of Subjects (%) -2.2 -7.4 3.0 -12% 12% ATV + COBI + FTC/TDF was non-inferior to ATV + RTV + FTC/TDF at Week 48 *No W48 data include three categories: 1)DC study drug due to AE/death; 2)DC study drug due to other reasons and last available HIV-1RNA < 50c/mL; 3) Missing data during window but on study drug 44 44

45 EFV/FTC/TDF QHS Placebo
Study Design: n=350 Quad QD EFV/FTC/TDF QHS Placebo Treatment- naive Any CD4 count (N = 700 planned) n=350 EFV/FTC/TDF QHS Quad Placebo QD Randomized 1:1 Stratification by HIV-1 RNA (>100,000 c/mL) Conducted in US and Puerto Rico Week 48 Week 192 Primary Endpoint: Proportion with HIV-1 RNA < 50 copies/mL at Week 48 FDA snapshot analysis (ITT), 12% noninferiority margin HIV-1 RNA: Amplicor HIV-1 Monitor Test, version 1.5 Conducted in parallel with Study comparing Quad to FTC/TDF + ATV/r (DeJesus et al, Poster #627)

46 Primary Endpoint: HIV-1 RNA < 50 copies/mL Study 236-0102
Quad was non-inferior to EFV/FTC/TDF at Week 48 95% CI for Difference Favors EFV/FTC/TDF Favors Quad -1. 6 3.6 8.8 -12% 12% 46

47 ATV/r+FTC/TDF Placebo QD
Study Design (n=350) Quad QD ATV/r+FTC/TDF Placebo QD Treatment naive (N = 700 planned) (n=350) International Randomized 1:1 Stratification by HIV-1 RNA (>100,000 c/mL) ATV/r + FTC/TDF QD Quad Placebo QD Week 48 Week 192 Primary Endpoint: Proportion with HIV-1 RNA < 50 c/mL at Week 48 FDA snapshot analysis, 12% non-inferiority margin HIV-1 RNA: Amplicor HIV-1 Monitor Test, version 1.5 Conducted in parallel with Study comparing Quad to EFV/FTC/TDF 47 DeJesus E, et al., CROI 2012; Seattle. Poster 627. 47

48 HIV-1 RNA < 50 c/mL through Week 48 (M=F) 236-0103
100 90 80 70 60 50 40 30 20 10 Quad: 92% ATV/r + FTC/TDF: 88% Diff: 3.5% (95% CI: -1.0 to 8.0) Subjects with HIV-1 RNA <50 c/mL (%) BL Week QUAD (n=): ATV/r (n=): 48 DeJesus E, et al., CROI 2012; Seattle. Poster 627.

49 Efficacy by Baseline HIV-1 RNA Subgroups
Gilead_Slide Template_(25Jan12).ppt CORE_Efficacy_Safety_Feb-14_SLB.ppt 4/27/2017 4/27/2017 Efficacy by Baseline HIV-1 RNA Subgroups QUAD (n=353) ATV/r + FTC/TDF (n=355) P=0.30 P=0.50 P=0.85 Virologic Success* at Wk 48 (%) 188/ / / / / /29 HIV-1 RNA (c/mL) * Virologic success (HIV-1 RNA <50 copies/mL) as defined by FDA Snapshot algorithm BioScience Communications Gilead 49 49 49

50 Résistance aux inhibiteurs d’intégrase
Les inhibiteurs d’intégrase sélectionnent des mutations de résistance spécifiques sur le gène de l’intégrase du VIH-1 3 profils de résistance identifiés pour raltegravir N155H Q148K/R/H Y143C/R Résistance croisée importante entre raltegravir et elvitegravir

51 Signature and Secondary Mutations Affecting Susceptibility to Raltegravir
Q148 Pathway Q148 key mutation emerges, associated with secondary mutations Q148H 600 Q148H/G140S Q148K 500 Q148K/E138A 400 Q148K/G140A Fold Change IC50 Q148K/E138A/G140A 300 Q148R 200 Q148R/G140S 100 N155 Pathway N155H key mutation emerges, associated with secondary mutations N155H 70 N155H/L74M 60 N155H/T97A N155H/E92Q 50 Fold Change IC50 40 30 20 10 Hazuda DJ, et al. HIV Resistance Workshop Abstract 8. Adapted with permission of Merck & Co., Inc., Whitehouse Station, New Jersey, USA. Copyright © 2007 Merck & Co., Inc., Whitehouse Station, NJ, USA. All rights reserved.

52 BENCHMRK 1 & 2 Longitudinal Data by Pathway
Mutations N=64 N=51 19% 10% # of patients with genotype 27% 53% 45% 18% First Genotype Subsequent Genotype *Based data form P005, VFs with 140/148 mutations were not re-analysed The post VF genotype is imputed from VF

53 Dolutegravir

54 ING112276 Study Design 572 Selected Dose after Week 96 EFV 600 mg
Phase IIb dose-ranging, partially-blinded, N~200 ART-naïve patients All arms include 2 NRTI backbone given once daily Primary endpoint: % <50 copies/mL at 16 weeks (TLOVR) Confirmatory endpoint: % <50 copies/mL at 24 weeks (TLOVR) mg 572 Selected Dose after Week 96 mg HIV-1 RNA >1000c/mL, CD4 ≥ 200 cells/mm3 1:1:1:1 Randomization mg EFV 600 mg EFV 600 mg Wk 24 dose confirmation Wk 16 dose selection 54

55 Dolutegravir: Antiviral Activity Week 96 Efficacy Analysis (<50 c/mL)
Percent Subjects with HIV-1 RNA <50 c/mL (TLOVR) 88% 78% 79% 72% Week 95% confidence intervals are derived using the normal approximation. 55

56 SPRING-2 (ING113086) Study Design
Phase III, randomized, double-blind, double-placebo, multicenter, parallel- group, non-inferiority study, ART-naive patients All arms include 2 NRTI backbone given once daily (ABC/3TC or TDF/FTC) Primary endpoint: % <50 c/mL at 48 weeks (“snapshot”) , non-inferiority margin 10% Randomized phase Nonrandomized phase HIV ART-naive HIV-1 RNA ≥1000 c/mL 1:1 Randomization Stratified by VL and NRTI DTG 50 mg QD+ RAL PBO BID + 2 NRTIs* DTG 50 mg QD open-label + 2 NRTIs DTG PBO QD + RAL 400 mg BID + 2 NRTIs* Randomization Week 48 Week 96 *Investigator’s selection ABC/3TC or TDF/FTC SPRING2_48wk IAC_v3+sa lmcv3_CB_L1.2_PAZ6_19 56

57 Virologic success over time
DTG 88% RAL 85% 100 90 80 70 60 50 40 30 20 10 BL W4 W8 W12 W16 W24 W32 W40 W48 Week Proportion <50 c/mL (%) DTG 50 mg QD RAL 400 mg BID Median (IQR) Change From Baseline CD4+ Cell Count (cells/mm3) W4 W24 W48 DTG 50 mg QD 87 (26, 149) 183 (100, 295) 230 (128, 338) RAL 400 mg BID 88 (32, 163) 182 (94, 296) (139, 354) SPRING2_48wk IAC_v3+sa lmcv3_CB_L1.2_PAZ6_19 57

58 VIKING Study Design Current or historic RAL-failures with evidence of RAL-resistance At least 3 ART-class resistant (includes INI) Subjects receive DTG 50mg QD (Cohort I), 50mg BID (Cohort II) Cohort II subjects must have ≥1 fully active ART in OBR Q148H/K/R + one or more secondary resistance mutations* N~ 10 (cohort II) Allocated to one of two groups based on genotype at screen to ensure broad sensitivity range Functional Monotherapy Phase Replace RAL with DTG or add, if RAL already stopped Continuation Phase DTG + OBR All other mutations (including codon 148 single mutation)** N~ 10 (cohort II) Day 1 Day 11 Week 24 *Q148H/K/R plus changes in L74 and/or E138 and/or G140 **N155H and Y143H pathways or Q148H/K/R single mutants Dolutegravir (DTG, S/GSK , 572) Joseph Eron et el CROI LB 58 58

59 Baseline (Day 1) Viral IN Mutation Pathways and Phenotypic Susceptibility to S/GSK1349572
Fold Change, median (range): RAL (0.6 - >166) S/GSK ( ) 20 Mixtures: n=1 Q148H + G140S / Y143H n=1 Q148H+ E138A+G140S / Y143H Others: n=1 E92Q (screen: E92Q, N155H) n=1 none (screen: G140G/S, Q148H/Q) 10 6 Baseline 572 Fold Change 4 2 1 0.6 Q148+2 n=3 Q148+1 n=4 Mixture n=2 N155 n=4 Y143 n=12 Other IN mutations n=2 Baseline Mutation Pathway More advanced Q148 pathway genotypes exhibit higher fold change to S/GSK 59 59 59

60 Change from Baseline in Plasma HIV1-RNA at Day 11 (log10 c/mL) Against Baseline Dolutegravir FC
DTG 50mg QD 0.0 -0.5 -1.0 -1.5 -2.0 -2.5 Change from Baseline in HIV1-RNA -3.0 DTG 50mg BID 0.0 -0.5 -1.0 -1.5 -2.0 -2.5 -3.0 0.5 1 2 4 8 16 32 Baseline DTG FC in IC50 Relative to Wild Type Virus Q Mixture Y143 Q N155 Other IN mutations Dolutegravir (DTG, S/GSK , 572) 60

61 Response to DTG at Week 24 in Subjects with RAL-resistant virus at Screening
Proportion (%) No. Subjects 11/27 18/24 14/27 20/24 In an exploratory analysis* through Week 24, 11% and 38% of subjects receiving DTG 50 mg QD and BID respectively achieved <2 c/mL *Modified BioMerieux EasyQ HIV-1 SuperLow assay (lower limit of detection 2 c/mL)

62 DTG Response at Week 24 (<50 c/mL by TLOVR) Increases with OBR activity
No. of subjects 1/ / / / /14 PSS=0* PSS=1 PSS≥2 *: 1 subject in Cohort II with PSS=0.5 responded Baseline PSS of OBR Increasing background drug activity remained as independent predictor of virologic response at Week 24 after adjusting for other variables

63 Integrase inhibitors are effective in salvage therapy
Studies suggest available integrase inhibitors have a relatively low genetic barrier to resistance and they must always be combined with other active agents Raltegavir resistant virus may be susceptible to second generation integrase inhibitors such as dolutegravir but are probably cross resistant to elvitegravir Continuation of a failing rategravir containing regimen may increase the risk of dolutegravir cross resistance