State of the ART: Integrase Inhibitors (clinical overview)

Transcription

1 State of the ART: Integrase Inhibitors (clinical overview) Mauro Schechter, MD PhD Principal Investigator, Projeto Praça Onze Professor, Infectious Diseases Universidade Federal do Rio de Janeiro Rio de Janeiro, Brasil Global HIV Clinical Forum 2018 Amsterdam July 21, 2018

2 Disclosures Honoraria for ad boards and lectures: Abbvie, Gilead, GSK/ViiV, Janssen, Merck,

3 Disclosures There is no now. There are only immediate memories of an extremely recente past (Anonymous and numerous)

4 BENCHMRK: Viral Suppression (NC=F) and CD4 Cell Count (OF) Patients With HIV RNA <400 copies/ml, % Patients With HIV RNA <50 copies/ml, % Change from Baseline % 41% 72% 37% Double-Blind 62% 28% Weeks Open-Label OLRAL 54% 23% 49% 18% 45% 17% CD4 Cell Count, cells/mm Double-Blind Weeks Open-Label OLRAL Double-Blind Open-Label OLRAL % 33% 57% 26% 51% 22% 45% 16% 42% 16% Weeks Raltegravir group Placebo group BENCHMRK = Blocking Integrase in Treatment Experienced Patients with a Novel Compound against HIV, Merck; F = failure; NC = noncompleter; OBT = optimized background therapy; OF = observed failure; OLRAL = open-label raltegravir; PBO = placebo; RAL = raltegravir. 1. Eron JJ et al. Lancet Infect Dis. 2013;13(7): Steigbigel RT et al. N Engl J Med. 2008;359(4):

5 Integrase Inhibitors Metal-Chelating Core Halogenated Phenyl Ring Side Chain RAL EVG DTG BIC Metal-Chelating Core: Oxygen atoms chelate a pair of Mg 2+ ions and bind the integrase catalytic active site Halogenated Phenyl: Interacts with the integrase pocket that is normally occupied by the terminal 3 base of viral DNA 1. Lazerwith SE, et al. ASM Poster # Gallant J, et al. ASM Poster # Tsiang M, et al. ASM Poster # Tsiang M, et al., AAC 2016;60:7086.

6 First Line Therapy (May, 2018) Nukes Non-nukes Instis PIs GUIDELINES TDF ou TAF/ FTC/3TC ABC/ 3TC AZT/ 3TC EFV NVP RPV DTG EVG RAL BIC ATV DRV LPV IAS-USA (2016) 6 DHHS (2018) 7 EACS (2017) 8 WHO (2016) 9 * Brazil (2017) 4 Preferential Not recommended, only special situationss Alternative Not available *400 mg 4. BRASIL. Ministério da Saúde. Protocolo Clínico e Diretrizes Terapêuticas para Manejo da Infecção pelo HIV em Adultos Disponível em: < Acesso em: 24 abr ; 6. GÜNTHARD, HF. JAMA; 316(2): , 2016.; 7. DHHS. Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents Living with HIV Disponível em: < Acesso em: 24 abr 2018.; 8. EACS. Guidelines. Version 9.0. Disponível em: < Acesso em: 24 abr ; 9. WHO. Consolidated Guidelines on the use of antiretroviral drugs for treating and preventing HIV infection: Recommendations for a public health approach Disponível em: < Acesso em: 24 abr ;

7 Integrase Inhibitors Metal-Chelating Core Halogenated Phenyl Ring Side Chain RAL EVG DTG BIC Metal-Chelating Core: Oxygen atoms chelate a pair of Mg 2+ ions and bind the integrase catalytic active site Halogenated Phenyl: Interacts with the integrase pocket that is normally occupied by the terminal 3 base of viral DNA 1. Lazerwith SE, et al. ASM Poster # Gallant J, et al. ASM Poster # Tsiang M, et al. ASM Poster # Tsiang M, et al., AAC 2016;60:7086.

8 STARTMRK: RAL vs EFV Plus TDF/FTC in Treatment-Naive Adult HIV-1 Patients Study Design Study overview International, multicenter, double-blind, double-dummy, randomized (1:1), active-controlled, noninferiority, phase 3 study Endpoints The primary endpoint was noninferiority with respect to the percentage of patients with HIV-1 RNA <50 copies/ml at Week 48, with a secondary time point at 96 weeks A prespecified exploratory analysis examined results at Weeks 156, 192, and 240 Eligibility criteria: 18 years old Treatment naïve HIV-1 infected Viral load >5000 copies/ml Without genotypic resistance to EFV, TDF, or FTC Patients with stable, chronic hepatitis could be enrolled if serum aminotransferase was 5-fold the ULN range 1:1 Screening baseline HIV- 1 RNA: >50,000 copies/ml vs 50,000 copies/ml Viral hepatitis coinfection status: positive for hepatitis B, hepatitis C, or both vs negative for both RAL 400 mg BID + TDF/FTC (n=281) EFV 600 mg QHS + TDF/FTC (n=282) BID = twice daily; EFV = efavirenz; FTC = emtricitabine; QHS = every night; RAL = raltegravir; TDF = tenofovir. 1. Rockstroh JK et al. J Acquir Immune Defic Syndr. 2013;63(1): Patients Treated With 71 Patients (25.2%) Discontinued 6 Lack of efficacy 14 Adverse events RAL-Based Regimen 210 Patients (74.5%) Completed Entire 5-Year Study 563 Enrolled Patients Randomized 1:1 to RAL/EFV Arms 282 Patients Treated With EFV-Based Regimen 184 Patients (64.8%) Completed Entire 5-Year Study 98 Patients (34.5%) Discontinued 10 Lack of efficacy 28 Adverse events

9 Change from Baseline Patients with HIV RNA Levels < 50 copies/ml, % STARTMRK: Viral Suppression and CD4 Cell Counts at Week 240 Viral Suppression (NC=F Analysis) Primary endpoint Secondary endpoint Exploratory analysis % 61% RAL 400 mg BID EFV 600 mg QHS 20 Difference (95% Cl) = 9.5 (1.7,17.3) P<0.001 Superiority concluded Weeks Number of Contributing Patients CD4 Cell Count, cells/mm RAL EFV Weeks BID = twice daily; EFV = efavirenz; F = failure; FTC = emtricitabine; NC = noncompleter; OF = observed failure; QHS = every bedtime; RAL = raltegravir; TDF = tenofovir. 1. Lennox JL et al. Lancet. 2009;374(9692): Lennox JL et al. J Acquir Immune Defic Syndr. 2010;55(1): Rockstroh JK et al. Clin Infect Dis. 2011;53(8): DeJesus E et al. HIC Clin Trials. 2012;13(4): Rockstroh JK et al. J Acquir Immune Defic Syndr. 2013;63(1):77-85.

10 ACTG 5257: Ritonavir-Boosted DRV or ATV versus RAL: Study Design Study overview: Phase 3, prospective, randomized, open label trial Hypothesis: FTC/TDF QD with ATV/r QD, RAL BID, or DRV/r QD will be equivalent in terms of virologic efficacy and tolerability over 96 weeks Co-primary End Points Virologic Failure: time to HIV-1 RNA >1,000 c/ml at or after Week 16 to before Week 24, or >200 c/ml at or after Week 24 Tolerability Failure: time to DTC of randomized component for toxicity Secondary Endpoint: the earlier occurrence of either virologic failure or tolerability failure Substudies: Mean change from baseline in fasting lipid profile over time Percentage bone mineral density change at total hip, lumbar spine, and total body Eligibility criteria: 18 years old ART naïve HIV-1 infected Plasma HIV-1 RNA >1000 copies/ml 1:1:1 Stratified by screening baseline HIV-1 RNA: 100,000 copies/ml vs <100,000 copies/ml with balancing by institution. Stratified by metabolic substudy participation and Framingham 10-yr risk of MI or coronary death (<6% vs 6%) ATV/r 300/100 mg QD + FTC/TDF 200/300 mg QD (n=605) RAL 400 mg BID + FTC/TDF 200/300 mg QD (n=603) DRV/r 800/100 mg QD + FTC/TDF 200/300 mg QD (n=601) 605 patients ATV/r 5 never started ART 89 patients (14.7%) discontinued 10 death 29 lost to follow up 28 unable to travel to clinic 22 nonadherent or other 556 patients (91.9%) completed 96 weeks 1814 patients randomized 1:1:1 to ATV/r:RAL:DRV/r 1809 patients included in all analyses 603 patients RAL 4 never started ART 72 patients (11.9%) discontinued 6 death 23 lost to follow up 35 unable to travel to clinic 8 nonadherent or other 560 patients (92.9%) completed 96 weeks 5 patients excluded 1 acute illness, 1 prior ART, and 3 prior ART and resistance 601 patients DRV/r 4 never started ART 101 patients (16.8%) discontinued 13 death 34 lost to follow up 30 unable to travel to clinic 24 nonadherent or other 546 patients (90.8%) completed 96 weeks ART = antiretroviral; ATV/r = atazanavir/ritonavir; BID = twice daily; DRV/r = darunavir/ritonavir ; DTC discontinuation; FTC = emtricitabine; QD = once daily; RAL = raltegravir; TDF = tenofovir disoproxil fumarate. 1. Lennox JL et al. Ann Intern Med. 2014;161(7): Ofotokun I et al. Clin Infect Dis. 2015;60(12): Brown TT et al. J Infect Dis. 2015;212(8):

11 ACTG 5257 Primary endpoint analyses at Week 96 VF Regimens equivalent in time to VF Tolerability failure Significantly greater incidence of treatment failure with ATV/r vs RAL or DRV/r in part due to a high proportion of patients with hyperbilirubinemia Composite endpoint RAL superior to either boosted PI DRV/r superior to ATV/r ATV/r vs RAL 3.4% ( 0.7 to 7.4) DRV/r vs RAL 5.6% (1.3 to 9.9) ATV/r vs DRV/r 2.2% ( 6.7 to 2.3) Favours RAL ATV/r vs RAL 13% (9.4 to 16.0) DRV/r vs RAL 3.6% (1.4 to 5.8) Favours DRV/r ATV/r vs DRV/r 9.2% (5.5 to 13.0) Difference in 96-week cumulative incidence (97.5% CI) Favours RAL ATV/r vs RAL 15% (10to 20) Favours RAL DRV/r vs RAL 7.5% (3.2 to 12.0) Favours DRV/r ATV/r vs DRV/r 7.5% (2.3 to 13.0) Lennox JL et al. Ann Intern Med 2014;161:

12 ONCEMRK Study: raltegravir 1200 mg QD vs 400 mg BID, with TDF/FTC Design > 18 years ARV-naïve HIV RNA > 1000 c/ml Randomisation* 2 : 1 Double-blind N = 531 N = 266 RAL 1200 mg ** QD + RAL 400 mg BID placebo TDF/FTC fdc QD RAL 400 mg BID + RAL 1200 mg ** QD placebo TDF/FTC fdc QD W48 W96 *Randomisation was stratified by baseline HIV RNA (< or > c/ml) and viral hepatitis co-infection status ** Reformulated RAL 600 mg tablet Objective Non inferiority of RAL QD: % HIV RNA < 40 c/ml by ITT, NC=F (lower margin of the 2-sided 95% CI for the difference = - 10%, 90% power) Cahn P. AIDS 2016, Durban, Abs. FRAB0103LB

13 ONCEMRK Study: raltegravir 1200 mg QD vs 400 mg BID, with TDF/FTC % 53.5 HIV RNA < 40 c/ml (NC = F ; snapshot), % (95% CI) RAL 1200 mg QD + TDF/FTC RAL 400 mg BID + TDF/FTC Difference QD vs BID = 0.5% (- 4.2 ; 5.2) 20 0 Patients with baseline HIV RNA > c/ml: % HIV RNA < 40 c/ml (observed failure): QD = 86.7% vs BID = 83.8% ; difference = 2.9% (- 6.5 ; 14.1) Week CD4/mm 3 increase at W48 (observed failure): QD = vs BID = ; -2 (- 31 ; 27) Cahn P. AIDS 2016, Durban, Abs. FRAB0103LB

14 ONCEMRK: Adverse Events by Race/Ethnicity White Black % Subjects With RAL 1200 mg QD (N=301) RAL 400 mg BID (N=172) RAL 1200 mg QD (N=98) Any adverse event (AE) Drug-related (DR) AE Serious AE Serious & DR AE Discontinued owing to AE Determined by the investigator to be related to study drug. Study medication withdrawn. AE = adverse event; BID = twice daily; DR = drug-related; QD = once daily; RAL = raltegravir. 1. Cahn P et al. Oral presentation at HIV Glasgow Glasgow, UK. Abstract # RAL 400 mg BID (N=36) Asian Hispanic/Latino % Subjects With RAL 1200 mg QD (N=83) RAL 400 mg BID (N=40) RAL 1200 mg QD (N=126) RAL 400 mg BID (N=52) Any adverse event (AE) Drug-related (DR) AE Serious AE Serious & DR AE Discontinued owing to AE

15 Integrase Inhibitors Metal-Chelating Core Halogenated Phenyl Ring Side Chain RAL EVG DTG BIC Metal-Chelating Core: Oxygen atoms chelate a pair of Mg 2+ ions and bind the integrase catalytic active site Halogenated Phenyl: Interacts with the integrase pocket that is normally occupied by the terminal 3 base of viral DNA 1. Lazerwith SE, et al. ASM Poster # Gallant J, et al. ASM Poster # Tsiang M, et al. ASM Poster # Tsiang M, et al., AAC 2016;60:7086.

16 The QUAD Pill: Study Design Elvitegravir 150 mg Cobicistat 150 mg Emtricitabine 200 mg Tenofovir disoproxil fumarate 300 mg n=350 Treatment- naive Any CD4 count Quad QD EFV/FTC/TDF QHS Placebo n=350 EFV/FTC/TDF QHS Quad Placebo QD Week 48 Week 192

17 Percentage of subjects (%) Quad Vs Efavirenz: 48 and 96 weeks results % 84% 84% 82% % 7% 9% 6% 8% 9% 11% 5% W48 W96 W48 W96 W48 W96 Virologic Success Virologic Failure No data at W48 (or 96) QUAD (STBD) EFV/FTC/TDF (ATR)

18 Change from BL in Serum Creatinine (mg/dl) (IQR) Median Change from Baseline 0.35 in Serum Creatinine BL Week

19 Two Phase 3, International, randomized, double-blind, active-controlled studies comparing TDF vs TAF N =866 E/C/F/TAF QD Tx-Naïve Adults Treatment HIV-1 RNA Naïve 1000 Patients c/ml Study egfr and ml/min 103 1:1 E/C/F/TDF Placebo QD E/C/F/TDF QD (STB) Stratification by HIV-1 RNA />100,000 c/ml CD4 cell count Geographic region N =867 E/C/F/TAF Placebo QD Week 48 Week 96 Primary Endpoint Secondary Endpoints Primary Endpoint HIV-1 RNA <50 copies/ml* at Week 48 by FDA Snapshot analysis (12% Non-inferiority margin of E/C/F/TAF to E/C/F/TDF) Secondary Endpoints Efficacy, safety** and tolerability observed through Week 96, Week 144 Week 144 *Taqman 2.0 assay Combined efficacy analysis was pre-specified. **SCr, proteinuria, hip and spine BMD were pre-specified week 48 safety endpoints. Study 104 (North America, EU, Asia) and Study 111 (North America, EU, Latin America) E/C/F/TAF: elvitegravir 150 mg / cobicistat 150 mg / emtricitabine 200 mg / tenofovir alafenamide 10 mg STB: Stribild; elvitegravir 150 mg / cobicistat 150 mg / emtricitabine 200 mg / tenofovir DF 300 mg 1. Wohl D, et al. JAIDS Ward, D., HIV and Aging 2016, Poster # Sax P, et al. Lancet Arribas J, et al. CROI Seattle, WA. Poster #453 ClinicalTrials.gov Identifier: NCT and NCT

20 Treatment Difference in Virologic Outcomes at Week 144 by Pre-specified Subgroups Age Sex Race Region <50 yrs 50 yrs* Male Female* Black Nonblack* US* Non-US % (n/n) of Participants Difference (95% CI) E/C/F/TDF n= (602/753) 81 (92/114) 82 (603/740) 72 (91/127) 71 (152/213) 83 (542/654) 80 (423/532) 81 (271/335) E/C/F/TAF n= (647/777) 92 (82/89) 84 (616/733) 85 (113/133) 75 (168/223) 87 (561/643) 84 (447/532) 84 (282/334) E/C/F/TDF E/C/F/TAF * Statistically significant Arribas J, et al. CROI Seattle, WA. Poster #

21 Median (IQR) % Change From BL Renal Parameters through Week n= n= 50 0 BL, mg/g UPCR Week E/C/F/TAF E/C/F/TDF p <0.001* for all * p-values calculated using 2-sided Wilcoxon rank-sum test to compare treatment groups BL, baseline; β2m, β2 microglobulin; IQR, interquartile range; RBP, retinol binding protein; UPCR, urine protein:cr ratio BL, µg/g RBP:Cr Week BL, µg/g β2m:cr Week At Week 144, median decrease from baseline in egfr CG was significantly smaller with E/C/F/TAF vs E/C/F/TDF (-1.6 vs -7.7 ml/min; p<0.001) Arribas J, et al. CROI Seattle, WA. Poster #

22 Median Change (Q1,Q3) Median Change in Spine and Hip BMD through Week Spine E/C/F/TAF E/C/F/TDF 2 Hip 0-1,22-1,20-0,97-0,89 0-0,45-0,76-0,90-0,93-2 P <0.001 for all -2-1,56 P <0.001 for all -4-2,72-2,76-2,82-2, ,00-3,57-3,53 E/C/F/TAF: (n=) Week Week E/C/F/TDF: (n=) Through Week 144, significantly greater losses in spine and hip BMD in TDF group No D/C due to bone AEs in TAF arm vs 6 in TDF arm Initiated meds during the study to increase BMD: 16% TAF vs. 21% TDF; p=0.018 Arribas J, et al. JAIDS E-pub. DOI: /QAI *p-value calculated using analysis of variance model including treatment as a fixed effect.

23 Integrase Inhibitors Metal-Chelating Core Halogenated Phenyl Ring Side Chain RAL EVG DTG BIC Metal-Chelating Core: Oxygen atoms chelate a pair of Mg 2+ ions and bind the integrase catalytic active site Halogenated Phenyl: Interacts with the integrase pocket that is normally occupied by the terminal 3 base of viral DNA 1. Lazerwith SE, et al. ASM Poster # Gallant J, et al. ASM Poster # Tsiang M, et al. ASM Poster # Tsiang M, et al., AAC 2016;60:7086.

24 Spring-2: A double-dummy, multicentre study comparing Dolutegravir to Raltegravir in Treatment Naïve Patients Treatment-naïve, HIV-1-infected adults HIV-1 RNA 1000 c/ml Stratified by NRTI and viral load DTG (50 mg QD) plus RAL placebo (BID) + 2 NRTIs* (n=411) RAL (400 mg BID) plus DTG placebo (QD) + 2 NRTIs* (n=411) DTG (50 mg QD) + 2 NRTIs Screening Visit (Day -14) Randomisation (Day 1) Analysis Week 48 Analysis Week 96 Screening period Randomised phase Open-label phase Primary endpoint: proportion of subjects with HIV-1 RNA <50 c/ml at Week 48 (FDA Snapshot), with a -10% non-inferiority margin *Investigator s selection ABC/3TC or TDF/FTC FDA, Food and Drug Administration

25 Spring-2: A double-dummy, multicentre study comparing Dolutegravir to Raltegravir in Treatment Naïve Patients Number of responders/ total assessed, n (%) Difference in proportion (95% CI) (DTG - RAL) Adjusted difference in proportion (95% CI) (DTG - RAL) Treatment DTG 50 mg QD 332/411 (81) 4.4% ( 1.2%, 10.0%) 4.5% ( 1.1%, 10.0%) RAL 400 mg BID 314/411 (76) DTG and RAL were associated with similar increases in CD4+ cell count from baseline over time. Error bars indicate 95% CI Adaptado a partir das referências 3, 4, 6

26 SPRING-2: Adverse Events Discontinuations due to AEs were 2% for DTG vs 2% for RAL at Week 96 AEs, n (%) WEEK 48 DTG 50 mg QD (n=411) RAL 400 mg BID (n=411) Any event 339 (82) 340 (83) Nausea 59 (14) 53 (13) Headache 51 (12) 48 (12) Nasopharyngitis 46 (11) 48 (12) Diarrhoea 47 (11) 47 (11) WEEK 96 Any event 349 (85) 349 (85) Nausea 60 (15) 56 (14) Nasopharyngitis 55 (13) 58 (14) Diarrhoea 57 (14) 55 (13) Headache 56 (14) 55 (13)

27 Mean change from baseline of CR (μmol/l) SPRING-2: Effect of Dolutegravir on Creatinine Serum Levels These changes are not considered to be clinically relevant as the glomerular filtration rate is unchanged Change in serum CR, Mean (+/- SD) 2, * +4.7* Week mg/dl Creatinine clearance by Cockcroft-Gault, mean (SD) DTG 50 mg QD + NRTIs* RAL 400 mg BID + NRTIs* n ml/min n ml/min Baseline (25.8) (31.2) Week (13.4) (13.8) Week (14.2) (13.9) Baseline (µmol/l): DTG: 74.7 versus RAL: 75.2 A small initial increase in creatinine was observed with DTG, due to the blockade of creatinine secretion. There was no further increase in mean serum CR from Week 48 to Week 96 (Week 0 to 96: DTG mmol/l; RAL +8.2 mmol/l) 5 *Mean change in serum CR (mg/dl): DTG, +0.14mg/dL, RAL, mg/dl; based on conversion rate 0.011mg/dL = 1 µmol/l CR, creatinine Adaptado a partir das referências 3, 4, 5, 7, 8

28 abstract 948 Unexpectedly High Rate of Intolerance for Dolutegravir in Real Life Setting Guido van den Berk, Josephine Oryszczyn, Willem Blok, Narda van der Meche, Rosa Regez, Daoud Ait Moha, Kees Brinkman dept internal medicin OLVG, Amsterdam, The Netherlands background - Integrase inhibitors (INSTI)are now preferred antiretrovirals in first line cart. - Dolutegravir (DTG) is possibly considered as one of the most efficacious, convenient and tolerated INSTI, with hardly any chance for drug-drug interactions. - Since we encountered many patients who stopped DTG because of intolerance, we analyzed the experience with DGV in our whole patient population since licensing in the Netherlands (aug 2014) methods - OLVG cohort: ±3000 patients, (97,4% on cart) - retrospective analysis of all patients who started DTG, either as initial therapy or after switching from other antiretrovirals for any reason. - Baseline characteristics at the moment of DTG start were recorded. - We calculated the proportion of patients who stopped DTG, analyzed the reason for interruption and evaluated potential risk factors. - Chi-squared test and Z-score to check for significant differences between groups and proportions. results total (N=387) naives(n=65) non-naives (N=322) median age (IQR) (22) 48 (13) ns female 44 11,4% 8 12,3% 36 11,2% ns dutch origin ,1% 28 43,1% ,5% ns median CD4/mm3 (IQR) (395) 655 (345) ns median DTG days (IQR) (147) 221 (148) ns DTG separate DTG in STR DTG stopped 62 16,0% 13 20,0% 49 15,2% ns median DTG days (IQR) (71) 75 (99) ns female 5 11,4% 3 37,5% 2 5,6% p=0.01 DTG separate 24 15,4% 1 6,7% 23 16,3% ns DTG in STR 38 16,6% 12 24,0% 26 14,4% ns reason for interruption other than toxicity* 6 9,7% 1 7,7% 5 10,2% toxicity 56 90,3% 12 92,3% 44 89,8% ns sleeping ,3% 5 38,5% 14 28,6% ns gastro-intestinal ,5% 4 30,8% 14 28,6% ns neuro-psychiatric ,7% 3 23,1% 9 18,4% ns paresthesia.. 6 9,7% 0 0,0% 6 12,2% ns headache ,9% 0 0,0% 8 16,3% ns fatigue ,6% 1 7,7% 8 16,3% ns allergy.. 1 1,7% 1 7,7% 0 0,0% ns other.. 5 8,2% 1 7,7% 4 8,2% ns *LTFU, HBV protection, insurance, induction, patient request, interaction results DTG treatment was stopped in 62/387 (16,0%) patients. There were no virological failures. Main reason for DGV interruption was intolerance in 56/62 (90,3%) patients: 19/56 (31,3%) sleeping problems, 18/56 (29,5%) gastrointestinal problems, 12/56 (19,7%) psychiatric problems, 8/56(12,9%) headache, 9/56 (14,6%) fatigue and 6/55 (10,9%). Some patients reported more than one toxicity. Psychiatric reason to stop (n=12) varied from anxiety, depression and agitation to psychosis (n=2) conclusion In a real life setting a substantial proportion of patients unexpectedly interrupted DTG treatment for reasons of intolerance, in particular sleeping, gastrointestinal and psychiatric problems. This was much higher than reported in clinical trials.

29 Integrase Inhibitors Metal-Chelating Core Halogenated Phenyl Ring Side Chain RAL EVG DTG BIC Metal-Chelating Core: Oxygen atoms chelate a pair of Mg 2+ ions and bind the integrase catalytic active site Halogenated Phenyl: Interacts with the integrase pocket that is normally occupied by the terminal 3 base of viral DNA 1. Lazerwith SE, et al. ASM Poster # Gallant J, et al. ASM Poster # Tsiang M, et al. ASM Poster # Tsiang M, et al., AAC 2016;60:7086.

30 % of Isolates by FC Categories Phenotypic Analysis of Clinical Isolates Stratification of 47 HIV-1 Clinical Isolates Based on Fold Change in Resistance < to < 5 5 to < EC 50 Fold Change (FC) vs Reference Wild Type 6% 2% 2% 4% 4% 0 49% 92% 89% 17% 17% 17% EVG RAL DTG 70% 15% 13% 2% BIC Each of 47 patient-derived clinical isolates (from Monogram Biosciences) had 1 primary and/or other INSTI mutations with phenotypic resistance to INSTIs and comprised all available INSTI resistant variants in the Monogram library). Mean fold changes: BIC 2.8 (ref) ; DTG 5.8, p=0.042; RAL >100, p<0.001; EVG >106, p<0.001 EC 50 =effective concentration of half maximal response; FC=fold change; IN=Integrase; T 1/2 =half-life. 1. White K, et al., European Workshop HIV & Hep Rome, Italy. Poster O Tsiang M, et al., AAC 2016;60:

31 B/F/TAF Vs DTG in Treatment-Naïve Randomized Double-Blind Randomized Double-Blind Study ,2 * ART-naive Adults HIV-1 RNA 500 c/ml egfr CG 50 ml/min HLA B*5701 negative 1:1 n=314 n=315 B/F/TAF QD ABC/3TC/DTG Placebo QD ABC/3TC/DTG QD B/F/TAF Placebo QD Week Study ,4 * ART-naive Adults HIV-1 RNA 500 c/ml egfr CG 30 ml/min 1:1 n=320 n=325 B/F/TAF QD DTG + FTC/TAF Placebo QD DTG + FTC/TAF QD B/F/TAF Placebo QD Week Gallant J, et al. IAS Paris, France. Oral #MOAB0105LB; Gallant J, et al. Lancet 2017;390: ; Sax P, et al. IAS Paris, France. Poster Discussion #TUPDB0201LB; Sax P, et al. Lancet 2017;390: ;

32 Virologic Efficacy: HIV-1 RNA <50 copies/ml, Missing=Excluded Analysis Pooled ART-naïve Studies 1489 and Participants (%) B/F/TAF displayed rapid viral suppression (M=E) 1 and non-inferior efficacy 2,3 * vs. DTG-based regimens at Week 48 * Based on Snapshot analysis White K, et al. CROI Boston, MA. Poster 532; Gallant J, et al. Lancet 2017;390: ;. Sax P, et al. Lancet 2017;390:

33 Drug-Related Adverse Events (AEs) through Week 48 Study Study All grade ( 2% in either arm) B/F/TAF n=314 DTG/ABC/3TC n=315 Any Drug-related AEs 26%* 40% Diarrhea 6% 4% Nausea 5% 17% Headache 5% 5% Fatigue 3% 3% Abnormal dreams 3% 3% Dizziness 2% 3% Insomnia 2% 3% Difference between treatment arms: * p< , p<0.0001, and ** p=0.01 All grade ( 1% in either arm) B/F/TAF n=282 DTG/ABC/3TC n=281 Any Drug-related AEs 8% ** 16% Headache 3% 3% Abnormal dreams <1% 2% Diarrhea <1% 1% Fatigue <1% 1% Flatulence 0% 2% Nausea 0% 2% Insomnia 0% 1% B/F/TAF was well tolerated with significantly fewer drug-related AEs than DTG/ABC/3TC in ART-naïve and suppressed patients, largely due to GI and CNS AEs White K, et al. CROI Boston, MA. Poster 532; Gallant J, et al. Lancet 2017;390: ;. Sax P, et al. Lancet 2017;390:

34 Integrase Inhibitors: Clinical Pharmacology Profile RALTEGRAVIR ELVITEGRAVIR DOLUTEGRAVIR BICTEGRAVIR Clinical dose 400 mg BID* OR 1200 mg QD 150 mg QD with cobi and FTDF or FTAF 50 mg QD 50 mg BID (INI-resistant) 50 mg QD with FTAF Metabolism UGT1A1 CYP3A (major), UGT1A1/3 (minor) UGT1A1 (major), CYP3A (minor) UGT1A1 and CYP3A (equal) DDI Potential Least Highest Slightly greater than RAL Slightly greater than DTG 1. Tivicay SmPC updated October Min S, et al. Antimicrob Agents Chemother 2010;54: Min S, et al. AIDS 2011;25: Isentress SmPC July 2015; 5. Stribild SmPC updated June 2015); 6. Ramanathan S, et al. Clin Pharmacokinet 2011;50:

35 Legend primarily applies to drug therapy

36 Drug class Corticosteroids Antidepressants Benzodiazepines Chemotherapy drugs Anticoagulants; Vit K antagonists Direct acting anticoagulant (DOAC) Calcium channel blockers Statins Selected DDI for Boosted Regimens (PI/r; PI/c; EVG/c) Comment Risk of Cushing syndrome. Avoid PI/r, PI/c, EVG/c. Risk not just oral but inhaled, eye drops, injection, topical. Triamcinolone, budesonide, fluticasone, mometasone contraindicated. Avoid tricyclics - can cause anticholinergic effects, sedation, orthostatic hypotension. Caution - increased sensitivity in elderly with risk of cognitive impairment, falls etc. AEs increased by inhibition of CYP metabolism. Use lowest dose for short duration. Midazolam, triazolam contraindicated. Many chemotherapy drugs metabolised by CYP. Increased risk of chemo related toxicities. Monitor INR and adjust dose accordingly. Dose adjustment may be required if switching from ritonavir to cobicistat. Significant effect expected (limited data). Effect not routinely measured. Recommended - avoid with boosted regimens Increased exposure and potential hypotensive effect. Start with lowest dose and titrate based on response Increased exposure of some statins. Simva-, lovastatin contraindicated. Pitavastatin can be used. Others start with low dose and titrate. Smith JM et al. AIDS 2017, Burgess MJ et al. HIV AIDS 2015; Nachega JB et al. AIDS 2012,

37 Integrase Inhibitors and Cation Containing Medications: Recommendations Coadministered Drug Raltegravir Dolutegravir Elvitegravir/c Bictegravir Mg/Al containing antacid Not recommended (NR) bd & qd Separate well (6h before/2h after Separate by least 4h Take BIC under fasting 2h before Calcium supplements No dose adjustment (bd) NR - qd Separate well (6h before/2h after Not stated BIC and supplement can be taken with food Multivitamins Not stated Separate well (6h before/2h after Separate by least 4h Not stated Iron supplements Not stated Separate well (6h before/2h after Not stated BIC and supplement can be taken with food Genvoya SmPC 03/18; Tivicay SmPc 03/18.; Isentress SmPC 02/18; Bictarvy PI 02/18

38 Drug Class Antacids Calcium, Mineral supplements Selected DDI for Integrase Inhibitors (RAL; DTG; EVG/c; BIC) Comment Integrase inhibitors form complex with divalent cations in the g.i.tract which limits absorption. Potential risk of treatment failure. Metformin DTG increases metformin exposure (inhibits OCT2 in kidney). EVG/c probably increases metformin exposure. RAL has no effect. BIC increases metformin exposure - but less than DTG. Note: No DDIs with most other antidiabetic drugs. Rifampicin Rifabutin DTG Rifampicin decreases DTG exposure. RAL Rifampicin decreases RAL exposure EVG/c Rifampicin decreases EVG exposure BIC Rifampicin decreases BIC exposure DTG and RAL no clinically significant change in exposure EVG/c Rifabutin decreases EVG exposure BIC Rifabutin decreases BIC exposure Smith JM et al. AIDS 2017, Burgess MJ et al. HIV AIDS 2015; Nachega JB et al. AIDS 2012,

39 REFLATE Trial (Missing = Failure, Study drug discontinuation = Failure)

40 INSPIRING: Phase IIb, randomized, multicenter, open-label, noncomparative, active-control parallel-group study TB therapy HRZE (2 months) HR (4 months) a DTG dose switch 2 weeks post-completion of TB treatment HIV/TB coinfected ART-naive adults DTG (50 mg BID) + 2 NRTIs (n = 69) EFV (600 mg QD) + 2 NRTIs (n = 44) DTG (50 mg QD) + 2 NRTIs Screening 28 to 14 days Day 1 24 weeks Interim analysis: % <50 c/ml (Snapshot) 52 weeks End of randomized phase Primary endpoint at Week 48: % <50 c/ml (Snapshot) Inclusion criteria HIV-1 RNA 1000 copies/ml and CD4+ 50 cells/mm 3 Pulmonary, pleural, or lymph node tuberculosis with RIFsensitive MTB confirmed by culture or GeneXpert RIF-containing TB treatment started up to a maximum of 8 weeks before randomization and no later than the screening date DTG:EFV 3:2 randomization stratified by Screening plasma HIV-1 RNA 100,000 or >100,000 copies/ml Screening CD cells/mm 3 or >100 cells/mm 3 Adapted from reference 1 ART, antiretroviral therapy; DTG, dolutegravir; EFV, efavirenz; HR, isoniazid, rifampin; HRZE, isoniazid, rifampin, pyrazinamide, ethambutol; NRTI, nucleoside reverse transcriptase inhibitor; RIF, rifampin; TB, tuberculosis. a Duration of continuation phase of TB treatment according to local guidelines (continuation phase up to 7 months in some countries). 1. DOOLEY, KE. et al. INSPIRING: Safety and efficacy ClinTrials.gov of dolutegravir-based NCT ART in TB/HIV coinfected adults at week 24. In: CROI, Disponível em: < Acesso em: 28 mar

41 Percentage, % Virologic and Immunologic Results in the ITT-E Population Through Week Modified FDA snapshot analysis (ITT-E) Proportion of Participants With HIV-1 RNA <50 copies/ml, % (95% CI) 89 (79, 98) 81 (72, 90) INSPIRING Pharmacokinetic Data Pre-dose concentration: DTG 50 mg BID with RIF Time n DTG Conc (ng/ml) Geomean (90%CI) %CV Wk ( ) 118 Wk ( ) DTG (n=69) 0 EFV (n=44) Week Pre-dose concentration: DTG 50 mg QD without RIF (post-tb treatment phase) Time n DTG Conc (ng/ml) Geomean (90%CI) %CV Wk ( ) 151 Wk ( ) 359 INSPIRING DTG C tau when administered twice daily with RIF were similar to DTG 50 mg once daily without RIF and to previously reported data for DTG 50 mg once daily in Phase 2/3 HIV trials. Median change from Baseline CD4+ cell count (Q1, Q3) at Week 24: DTG, 146 cells/mm 3 (71, 214); EFV 93 cells/mm 3 (47, 178) Adapted from reference 1 1. DOOLEY, KE. et al. INSPIRING: Safety and efficacy of dolutegravir-based ART in TB/HIV coinfected adults at week 24. In: CROI, Disponível em: < Acesso em: 28 mar

42 Participants With TB and Non TB-Associated IRIS n (%) Participants with events sent to adjudication committee for TB-associated IRIS Met criteria for TB-associated IRIS Possibly met criteria for TB-associated IRIS Participants with events sent to adjudication committee for non TB-associated IRIS Met criteria for non-tb-associated IRIS Possibly met criteria for non-tb-associated IRIS DTG (n=69) 9 (13) 4 a (6) 0 2 (3) 1 c (1) 1 d (1) EFV (n=44) 12 (27) 4 b (9) 0 3 (7) 0 0 No participant in either arm permanently discontinued treatment due to IRIS a 1 x Grade 1, 2 x Grade 2 and 1 x Grade 3. b 3 x Grade 2 and 1 x Grade 4. c Grade 2 (IRIS and strongyloidiasis; also experienced TB-associated IRIS). d Grade 1 (Herpes zoster). Adapted from reference 1 1. DOOLEY, KE. et al. INSPIRING: Safety and efficacy of dolutegravir-based ART in TB/HIV coinfected adults at week 24. In: CROI, Disponível em: < Acesso em: 28 mar

43 REALITY: RAL Intensification in First-line ART Randomized, open-label phase III trial in Uganda, Kenya, Zimbabwe, and Malawi Primary endpoint: 24-wk mortality; endpoints assessed via blinded adjudication Wk 12 Wk 24 ART-naive adults, adolescents, and children with HIV infection; 5 yrs with CD4+ count < 100 cells/mm 3 (N = 1805) RAL intensified: 2 NRTI + NNRTI + additional RAL (n = 902) Standard ART: 2 NRTI + NNRTI (n = 903) Standard ART: 2 NRTI + NNRTI Follow-up to Wk 48 Baseline characteristics well balanced between arms Gibb DM, et al. CROI Abstract O23.

44 HIV-1 RNA < 50 c/ml, % (95% CI) RAL Intensification of First-line ART: HIV-1 RNA and All-Cause Mortality 100 HIV-1 RNA < 50 copies/ml at Wk 48 (ITT) RAL Intensified 80.7% 76.7% 71.9% 79.2% 74.7% Standard ART 41.0% 51.7% 40 Overall P < % P value: <.0001 < Wks Since Randomization (ART Initiation) 24-wk mortality rate RAL intensified: 10.9% Standard ART: 10.2% HR: 1.10 (95% CI: ; P =.53) 48-wk mortality rate RAL intensified: 12.4% Standard ART: 13.0% HR: 0.98 (95% CI: ; P =.91) Gibb DM, et al. CROI Abstract O23. Reproduced with permission.

45 RAL Intensification of First-line ART: IRIS- Compatible Events and Prophylaxis Outcomes IRIS-Compatible Events,* n (%) All fatal events TB-IRIS Cryptococcal-IRIS Other of known etiology Unknown etiology All fatal/nonfatal events TB-IRIS Cryptococcal-IRIS Other of known etiology Unknown etiology *P >.05 for all comparisons. RAL Intensified 36 (4.0) 20 (2.2) 8 (0.9) 5 (0.6) 3 (0.3) 89 (9.9) 53 (5.9) 15 (1.7) 17 (1.9) 4 (0.4) Standard ART 31 (3.4) 21 (2.3) 5 (0.6) 4 (0.4) 1 (0.1) 86 (9.5) 54 (6.0) 16 (1.8) 14 (1.6) 2 (0.2) No impact of additional RAL on IRIS-compatible events Gibb DM, et al. CROI Abstract O23. Independent Predictor of Fatal/Nonfatal IRIS Events RAL intensified vs standard ART Enhanced vs standard prophylaxis CD4+ count (per 10 cells/mm 3 higher) shr (95% CI) 1.08 ( ) 0.60 ( ) 0.87 ( ) P Value <.001 Age at last birthday (per yr older) yrs 1.07 ( ) 30 yrs 0.99 ( ) Current TB disease at ART initiation 1.62 ( ) Slide credit: clinicaloptions.com

46 Data from: ; Descovy SmPC Oct 017; Custodio JM, EACS Differences in the DDI Profile of TDF & TAF TDF TAF Potential Mechanism Rifabutin NR Induction of P-gp Rifampicin NR* Induction of P-gp Rifapentine NR Induction of P-gp Carbamazepine CA Induction of P-gp Oxcarbazepine CA Induction of P-gp Phenobarbitone CA Induction of P-gp Phenytoin CA Induction of P-gp St John s Wort NR Induction of P-gp NR = Not Recommended CA = Consider Alternative *TAF BD + RIF data presented at EACS 2017

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51 Conclusions INSTIs are widely recommended as the preferred third drug in first line therapy All INSTIs are generally well tolerated* Occasional reports of insomnia, depression, and suicidal ideation, primarily in patients with a history of psychiatric illnesses Treatment-emergent mutations that confer resistance are very uncommon in patients receiving INSTIs as part of a three-drug regimen for initial therapy In addition to differences in resistance profile, INSTIs differ considerably in potential drug-drug interactions that can have important clinical implications Drug-drug interactions, safety profile, and cost may affect the choice of the backbone and of INSTI *Except for DTG in some European cohorts, with up to 16% discontinuation rates due to AEs

52 Acknowledgements David Back Mark Boyd Kees Brinkman Carlos Brites Ricardo Diaz Valdez Madruga Anton Pozniak Jonathan Shapiro

53 OBRIGADO!!!!