Switch da regimi NN based – l’esperienza dei trial e la clinica Stefano Bonora Università di Torino XIV SIMIT8-11 novembre, Catania

Real-World ART Persistence with Single Tablet Regimens: Stribild vs Eviplera vs Atripla vs. Multi-Tablet Regimens (MTRs) To evaluate real-world persistence with different backbones (FTC/TDF vs. ABC/3TC) STRs vs. MTRs as initial ART and between STRs (STB vs. EPA vs. ATR) using data from the US Truven MarketScan ® claims database between 10/2008 and 03/2014 Sweet D, et al. HIV Glasgow, UK. Poster #P5 STR vs. MTR: US Analysis of Claims Database Treatment Persistence Among Different STRs and MTRs Stribild and Eviplera were associated with the highest rates of persistence throughout 18 months

Study Design Study 111 Phase 2b, open-label, multicenter, 48-week study of immediate switch from EFV/FTC/TDF to RPV/FTC/TDF in stable, virologically controlled subjects Stable EFV/FTC/TDF for ≥ 3 mos VL <50 c/mL for ≥ 8 wks Switch due to EFV intolerance No resistance to study drugs (N=50) Primary endpoint: HIV-1 RNA <50c/mL at week 12 after switching Secondary endpoints: Safety and tolerability of RPV/FTC/TDF STR over 24 & 48 wks HIV-1 RNA <50 c/mL at week 24 and week 48 post-switch Pharmacokinetics of RPV after switching from EFV Pre-dose PK samples obtained: Wks 1, 2, 4, 6, 8, and week 24 week 48 week Mills A, et al. BHIVA Birmingham, UK. #P186 RPV/FTC/TDF STR EFV/FTC/TDF STR 3

Virologic Outcomes through Week 48 - Snapshot Analysis Study 111 % HIV-1 RNA < 50 c/mL % 49/49 49/49 46/49 n/N Weeks 94% Virologic Suppression Maintained in majority of subjects who switched from EFV/FTC/TDF to RPV/FTC/TDF thru W48 Mills A, et al. HIV Clinical Trials 2013;14(5):216–223 * Virologic failure defined as confirmed HIV-1 RNA >50 c/mL at least 2 weeks apart † Wk 48 window spanned 84 days (Days 295 to 379) Virologic Non-Suppression (4%) 1)Virologic failure* #1 VL of 330,000 (W48), 1,890 (W51), and 991 c/mL (W54) W48: No detectable RPV concentrations Pan-sensitive virus at W48 & W51 2)Virologic failure #2 VL of 63 (W36) and 95 c/mL (W48) W48: Switched back to EFV/FTC/TDF W51: VL <50 c/mL No Week 48 Data † (2%) 3)Lost to follow-up due to incarceration 4

Secondary Endpoint: RPV PK after Switching from EFV GS Weeks Post-Switch (EFV/FTC/TDF to RPV/FTC/TDF) Mean (95% CI) Rilpivirine (C trough ) or Efavirenz Concentrations (anytime) * Protein-binding adjusted; Corbett JW, et al. J Med. Chem 2000:43; EFV IC 90 (~10ng/mL) EFV Concentrations (ng/ml) EFV Concentration RPV C trough (ng/ml) RPV C trough RPV mean C trough in ECHO/THRIVE RPV IC 90 (~12 ng/mL) Mills A, et al. HIV Clinical Trials 2013;14(5):216–223 EFV mean C trough above IC 90 (~10 ng/ml*) up to ~4 weeks RPV mean C trough within reference range by 2 weeks No subject had RPV below quantifiable levels at any visit except for 1 non- adherent subject at W48 5

6 Metabolism of EFV produces a highly neurotoxic metabolite (8-OH-EFV) that is capable of damaging neurites at very low concentrations. Thus, cognitive impairments associated with EFV may involve synaptic damage mediated by its major metabolite, 8-OH-EFV

UK Study - ATR to EPA Switch due to CNS Toxicity Changes in CNS Adverse Events and Sleep ACTG CNS Toxicity ScoreSleep Questionnaire Score Open-label, multicenter, 24-week study of 40 virologically suppressed subjects with ongoing CNS toxicity at least 12 wks of ATR (median 40 mos) 2 switching to EPA 1.Rowlands J, et al. ICAAC Washington, DC. #H Rowlands J, et al. BHIVA Liverpool. Oral #O4 3.Nelson M, et al. ICAAC Denver, CO. #H-672b Baseline Week 4 3 Week 12 Total CNS score (%) p<0.001 Baseline Week 4 3 Week 24 Median total sleep score (%) p< EPA = RPV/FTC/TDF; ATR = EFV/FTC/TDF Switching ATR to EPA led to significant improvement in CNS toxicity and sleep quality with 100% maintenance of virologic suppression Identification of individuals with efavirenz toxicity is essential as alternative agents lead to improvements in tolerability and toxicity 7

CNS Adverse Events  Overall Grade 2-4 CNS adverse events significantly decreased at Week 4, 12 and 24 (p<0.001) UK Study - ATR to EPA Switch due to CNS Toxicity Rowlands J, et al. ICAAC Washington, DC. #H1005 Rowlands J, et al. BHIVA Liverpool. Oral #O4 Eight of 10 CNS adverse events showed statistically significant improvement (P<0.05) Impaired Concentration Abnormal dreams Aggressive mood Anxiety Depression Insomnia Headache Confusion Any symptom Dizziness Somnolence Proportions (%) Grade 2-4 CNS Adverse Events P<0.001 P=0.103 P=0.004 P=0.021 P=0.012 P=0.020 P=0.999 P<0.001 P=0.001 P<0.001 Week 4 Baseline Week 12 Week 24 8

Switching to STR of Eviplera due to Regimen Intolerance  Reasons for switch: CNS (66%), GI (16%), metabolic (13%), other reasons (8%)  Efficacy: 84% patients remained suppressed (<50 c/mL) at Week 16  Patient-reported outcomes: Quality of life, number of symptoms, degree of discomfort, treatment satisfaction (ease and flexibility) were all significantly improved 4 wks post-switch  After 4 weeks, >80% of patients felt EPA was slightly to much better than their previous ART Podzamczer D, et al. HIV Glasgow, UK. Poster #282 PRO-STR - Spanish STR Cohort Prospective, multicenter study of HIV-infected patients on stable ART for ≥ 3 months who switched to EPA from NNRTI (75%) and PI (25%) due to intolerance of previous regimen (n=122) Switching to an STR of RPV/FTC/TDF resulted in significant improvements of symptoms of prior ART intolerance, quality of life, and treatment satisfaction Baseline Week 4 Week 16 ACTG Symptom Index Satisfaction with Treatment Health Related Quality of Life (EQ-5D) X = P ≤ for paired data vs. baseline Baseline

 All patients maintained virologic suppression (< 50 c/mL)  Significantly improved quality of life 4 months after switch (EQ5D); p =  Majority (28/32) of patient-reported symptoms improved at Month 4 Switch from ATR to EPA Reduces Patient-Reported Symptoms with Improved Quality of Life and Lipids “Switching from ATR to EPA is a safe, well tolerated strategy that improves the overall health status of HIV-treated patients in terms of QoL and self- reported patient oriented outcomes.” Maggiolo, F. Glasgow, UK 2014, #P266 Total Cholesterol EPA in Switch (Italy) ATR - EFV/FTC/TDF, EPA - RPV/FTC/TDF Randomized, single centre study evaluating virologically suppressed patients on stable ATR switching from ATR to EPA immediately (n=44) or after 4 months (n=20) <200 mg/dL (Grade 1) 200 to 239 mg/dL (Grade 2) ≥240 mg/dL (Grade 3) 16% % of Subjects ‡

Author’s Last Name, Conference Name, Year, Presentation # 11

Median Changes in Fasting Lipids from Baseline Study 102 1,2 Study Change From BL at Week 144 (mg/dL ) STB (n=701) ATR (n=352) ATV+RTV+TVD (n=355) P =0.007 P =0.021  No difference in change in TC to HDL ratio in either treatment groups TC: total cholesterol; LDL: low density lipoprotein; HDL: high density lipoprotein; TG: triglycerides Study 102 and 103 (STB vs. ATR and ATV+RTV+TVD) – Week 144 Study Study 102 1, Wohl D, et al. JAIDS 2014; 65 (3):e Wohl D, et al. ICAAC Denver, CO. #H-672a 3. Clumeck N, et al. JAIDS 2014;65 (3):e Data on file. Gilead Sciences, Inc.

Median Change in Fasting Lipids from Baseline to Wk 48 Study 111 Baseline (Q1, Q3) † : TC* LDL* HDL TG* 177 (159, 210) 113 (93, 132) 49 (41,58) 114 (86, 147) Median Change in Fasting Lipid Values, mg/dL * P < 0.05 from Wilcoxon Signed-Rank test † (Q1, Q3) = 25 th percentile, 75 th percentile TC:HDL ratio decreased by 0.17 (p=0.14) Mills A, et al. HIV Clinical Trials 2013;14(5):216–223 13

Retrospective, multicentre, cohort study switching from PI or NNRTI (n=508) Switching to EPA in Virologically Suppressed Patients Improves Lipid Profile Pinnetti C, et al. Glasgow 2014, #P280 At 6 months, 1.1% VF and 5.5% had discontinued for any reason Only the number of pre-switch regimens was associated with VF (HR 1.13, p=0.001) Type of pre-switch regimen was not associated with discontinuation or failure; with no VFs observed with switching off ATR or RAL regimens Total CholesterolTriglycerides “Switching to EPA in virologically suppressed patients could be a good strategy with low risk of virological failure or treatment discontinuation…with significant improvement in lipid profile.” EPA in Switch (Italy) ‡

Switching NVP to EPA: Efficacy, Safety, Lipids and Cardiovascular Risk Rokx C, et al. HIV Glasgow, UK. Poster 257 NVP to EPA Switch - Netherlands Proportion of Subjects, % Virologic Efficacy (ITT)  Significant  in subjects achieving TC and LDL goals (+26% & +15%) and ↓ in HDL goal (-19%)*  Median Framingham risk score did not change over 24 weeks (-7%, p = 0.029)  The systolic blood-pressure decreased 6.0 mmHg (P=.007) Prospective, open-label, controlled trial in virologically suppressed HIV-1 patients on NVP+FTC/TDF switched EPA (n=50) or continuing NVP regimen (n=139) Week 48  Low VF rate: 6% EPA vs. 8% NVP  Low discontinuation due to AEs at Week 48 (n=2)  1 subject discontinued due to non- adherence A NVP to EPA switch “could be used in HIV-1 patients at risk for CV diseases” Total Cholesterol at Week 24 <200 mg/dL (Grade 1) 200 to 239 mg/dL (Grade 2) ≥240 mg/dL (Grade 3) 19% 6% *National Cholesterol Education Project, ATP III Classification W12 W48 % of Subjects ‡

100%, of subjects switching from NVP+FTC/TDF to the CPA maintained virologic suppression through 12 weeks Allavena C, et al. ICAAC Denver, CO. #H-657 Meal Questionnaire –No impact on virologic outcome was observed despite 17% of cases (33% with breakfast) meal intake below 399 kcal RPV and NVP mean plasma concentration after switching from NVP RPV plasma concentration (μg/L) NVP plasma concentration (μg/L) Weeks Post Switch Lower limit of RPV phase 3 mean trough level (50µg/L) NVP had only a short and limited inductive effect on RPV metabolism, which is not clinically significant CPA = RPV/FTC/TDF Virologic Outcomes Switching NVP+FTC/TDF to CPA Open-label single center study evaluating efficacy after switching virologically suppressed patients from NVP+FTC/TDF to Complera ® (N=32) 16

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Background In patients treated with tenofovir-disoproxil fumarate renal tubular toxicity have been reported. Among risk factors, a role has been recognized for:  High TFV plasma concentrations;  Boosted PIs use (associated with higher TFV exposure trough intestinal CYP3A4 and p-glycoprotein and tubular MRP4 inhibition) Impairment in kidney tubular function in patients receiving tenofovir is associated with higher tenofovir plasma concentrations Rodríguez-Nóvoa et al. AIDS 2010; 24: 1064–1066

Background The suggested mechanism is TFV reduced urinary excretion, followed by “entrapment” in proximal tubular cells with consequent mitochondrial toxicity Reduced TFV urinary output (low urinary-to-plasma concentration ratio) is associated with signs of tubular damage (Marinaro, ICAR 2014) u/p TFV ratio X PI/R

Background Data on tenofovir plasma exposure when associated with rilpivirine are scarced but it has been reported to be higher than with other NNRTIs Ramanathan CROI 2013 No study has so far investigated tenofovir pharmacokinetics and tubular safety are unknown in patients switching to tenofovir/emtricitabine/rilpivirine.

MATERIALI E METODI  Studio prospettico di coorte non interventistico presso la Clinica Universitaria Amedeo di Savoia.  Pazienti adulti HIV positivi che passavano sia da regimi contenenti tenofovir che tenofovir- free al STR rilpivirina, tenofovir, emtrcitabina con HIV RNA < 50 copie/mL  Sono state analizzate le resistenze genotipiche cumulative in quei pazienti che avevano eseguito un test del genotipo virale.  Alle settimane 0,12 e 48 abbiamo valutato: – HIV RNA – [TFV] urinarie e plasmatiche a 12 ore dalla somministrazione – Esame completo urine 24 h e creatinina plasmatica – [RBP] U/creatininuria su campione spot ( alle settimane 0 e 12) – Predittori indiretti di danno tubulare (PTH, vitamina D, bALP) (alle settimane 0 e 12)  Abbiamo suddiviso i risultati in sottogruppi sulla base del regime assunto prima dello switch

VARIABILE N assoluto (%) NUMERO DI PAZIENTI ARRUOLATI per EFFICACIA 153 (100) NUMERO DI PAZIENTI ARRUOLATI per SICUREZZA RENALE 92 (100) SESSO M 123 (80,4) F 30 (19,6) RAZZA Caucasica 143 (93,5) Africana 6 (3,9) Latina 4 (2,6) Coinfezione HCV 28 (18,3) Precedente HAART con NNRTI 81 (52,9) Precedente HAART con PI 63 (41,2) Precedente HAART con altre classi 9 (5,9) Resistenze maggiori 11 (7,2) VARIABILEMediana (IQR) Età47 (40,4-52,4) BMI 23,44 (20,82- 25,82) Linfociti CD4560 ( ) CARATTERISTICHE DELLA POPOLAZIONE 49% da ATRIPLA

RISULTATI TDF_plasma da NNRTI 56 vs.77 ng/mL p= Ratio U/pl da NNRTI 419 vs. 234 p= P>0.05 Ratio Urine/plasma [TFV urine] [TFV plasma]

RISULTATI  Nel sottogruppo dei pazienti da NN non sono state riscontrate variazioni significative nei valori delle urine nelle 24 ore (p> 0.05).  Escrezione frazionata di acido urico e frazione riassorbita di fosfato entro i range di normalità alla settimana 48 ( 0.82)

RISULTATI 25 Non variazioni significative di Retinol Binding Protein (RBP)/creatinina su urine nei pazienti provenienti da Atripla

DISCUSSIONE RPV rispetto a EFV aumenta l’assorbimento intestinale di TFV attraverso la glicoproteina-P, ma non agisce sui trasportatori del tubulo renale deputati alla clearance del farmaco. u/p TFV ratio RPV = =

CONCLUSIONI - Lo switch da ATRIPLA ® a EVIPLERA ® 27 Mantenimento della soppressione virologica Miglioramento del profilo di tollerabilità neuropsichico Miglioramento dei patient-reported outcomes (soddisfazione, quality of life) Miglioramento del profilo lipidico Non impatto significativo sul profilo di tollerabilità renale (tubulopatia) malgrado incremento delle concentrazioni plasmatiche di TFV

Andrea Calcagno Letizia Marinaro Laura Trentini MCristina Tettoni Chiara Alcantarini Micol Ferrara Francesca Patti Chiara Montrucchio Ilaria Motta Filippo Lipani Prof Giovanni Di Perri Antonio D’Avolio Jessica Cusato Marco Simiele Lorena Baietto Alessandra Arialdo Amedeo De Nicolò Sarah Allegra Debora Pensi Mauro Sciandra Tiziano Allice Maria Grazia Milia Valeria Ghisetti ID Unit Viro lab PK lab