Μεταλλίδης Συμεών Παθολόγος Λοιμωξιολόγος Επίκουρος Καθηγητής ΑΠΘ Τμήμα Λοιμώξεων Α Παθολογικής Κλινικής Διευθυντής: Καθηγητής Δανιηλίδης Μιχαήλ

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1 Μεταλλίδης Συμεών Παθολόγος Λοιμωξιολόγος Επίκουρος Καθηγητής ΑΠΘ Τμήμα Λοιμώξεων Α Παθολογικής Κλινικής Διευθυντής: Καθηγητής Δανιηλίδης Μιχαήλ

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3 Ας δούμε πως φτάσαμε ως εδώ

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5 Οι ίδιοι προβληματισμοί 12 χρόνια τώρα

6 Κλινικές μελέτες vs κλινικής εμπειρίας και πεποίθησης NNRTIs vs PΙs

7 Πρώτης γενιάς NNRTIs: Efavirenz September 1998 Nevirapine June 1996

8 Efavirenz: 14 χρόνια first line therapy Το μόνο φάρμακο με έγκριση πριν από το 2000 που παραμένει στις θεραπείες πρώτης γραμμής

9 Efavirenz: 14 χρόνια first line therapy Για πολλά χρόνια υπήρχε η κλινική πεποίθηση ότι οι ασθενείς με υψηλά ιικά φορτία και χαμηλά CD4 θα έπρεπε να θεραπεύονται με PIs

10 NNRTIs in Clinical Practice ACTG 5095: Efficacy N = 1147 antiretroviral-naive patients randomized to ZDV/3TC/ABC ZDV/3TC + EFV ZDV/3TC/ABC + EFV 167 patients developed virologic failure 21% in the triple-nrti arm 11% in the combined EFV arms (P <.001) Time to virologic failure shorter for triple NRTI regardless of baseline VL 10 5 copies/ml: P <.001 < 10 5 copies/ml: P =.001 Similar CD4+ cell count changes Subjects With VL Suppression at Week 48 (%) Combined EFV arms Triple-NRTI arm < 200 copies/ml < 50 copies/ml Level of Virologic Suppression Gulick RM, et al. N Engl J Med. 2004;350: clinicaloptions.com/hiv

11 NNRTIs in Clinical Practice ACTG 5095: Effect of EFV Similar Across All Viral Loads Risk of VF By Baseline VL Initial therapy of treatmentnaive patients ACTG 5095 regimens (N = 765) ZDV/3TC + EFV ZDV/3TC/ABC + EFV Effect of EFV similar across all viral loads and CD4+ count levels No difference between 3 vs 4 antiretrovirals 300,000 (ref) 100, ,999 30,000-99,999 < 30, Overall effect P = Ribaudo H, et al. IAC Abstract THLB0211. Decreased Increased Risk Risk clinicaloptions.com/hiv

12 Efavirenz: 14 χρόνια first line therapy Προβληματισμοί για την διάρκεια θεραπείας και την ανεκτικότητα στο σχήμα

13 Proportion With VL < 400 c/ml (%) NNRTIs in Clinical Practice DP-006: Long-term Durability of NNRTI-Based Therapy B/L P <.0001 EFV vs IDV triple-drug arms at Week Weeks ITT, M = F analysis: proportion of subjects with response according to TLOVR definition of treatment success. Tashima K, et al. IAC Abstract TuPeB4547. EFV + ZDV + 3TC (n = 422) EFV + IDV (n = 429) IDV + ZDV + 3TC (n = 415) 48% 40% 30% clinicaloptions.com/hiv

14 NNRTIs in Clinical Practice ACTG 384: Trend Favoring Initiation With ZDV + 3TC When EFV Used Hazard Ratio for ddi + d4t vs ZDV + 3TC nd regimen failure 2nd virologic failure 1st regimen failure 1st virologic failure 95% confidence interval Favors initiation with ddi + d4t Favors initiation with ZDV + 3TC 0 EFV NFV Robbins GK, et al. N Engl J Med. 2003;349: clinicaloptions.com/hiv

15 Efavirenz: 14 χρόνια first line therapy Οι κλινικοί γιατροί επιμένουν όμως γιατί καμιά μελέτη δεν έχει γίνει vs Lopinavir/ritonavir τον καλύτερο μέχρι τώρα PI

16 NNRTIs in Clinical Practice ACTG 5142: LPV/RTV vs EFV vs LPV/RTV + EFV Stratified for VL or > 100,000, hepatitis coinfection, and selection of NRTI Week 96 Antiretroviral-naive patients, VL > 2000 copies/ml, any CD4+ cell count (N = 753) LPV/RTV SGC 533/133 mg twice daily + EFV 600 mg once daily (n = 250) LPV/RTV SGC 400/100 mg twice daily + 2 NRTIs* (n = 253) EFV 600 mg once daily + 2 NRTIs* (n = 250) *3TC plus either ZDV, d4t XR, or TDF, selected by investigator before randomization. Riddler S, et al. IAC Abstract THLB0204. clinicaloptions.com/hiv

17 NNRTIs in Clinical Practice ACTG 5142: Outcomes at Week 96 (ITT) Patients (%) No VF LPV/RTV + 2 NRTIs EFV + 2 NRTIs LPV/RTV + EFV No Regimen Completion P = VL < 200 P = VL < 50 P =.01 P = Median CD4+ Change CD4+ Cell Count (cells/mm 3 ) EFV + 2 NRTIs superior to LPV/RTV + 2 NRTIs in coprimary endpoint of time to virologic failure (P =.006) EFV + 2 NRTIs not significantly different to LPV/RTV + 2 NRTIs in coprimary endpoint of time to regimen completion (P =.02) LPV/RTV + 2 NRTIs superior to EFV + 2 NRTIs in CD4+ cell count change Riddler S, et al. IAC Abstract THLB0204. clinicaloptions.com/hiv

18 Efavirenz: 14 χρόνια first line therapy Ενώ μέχρι τώρα όλα τα φάρμακα ήθελαν να συγκριθούν με το Lopinavir/ritonavir τώρα όλοι θέλουν να συγκριθούν με το efavirenz

19 Evolving Options for First-line Antiretroviral Therapy clinicaloptions.com/hiv ACTG 5202: First-line Therapy With ABC/3TC vs TDF/FTC + EFV vs ATV/RTV Stratified by HIV-1 RNA < or 100,000 copies/ml Wk 96 TDF/FTC* 300/200 mg QD + EFV 600 mg QD (n = 464) Antiretroviral-naive patients with HIV-1 RNA 1000 copies/ml and any CD4+ cell count (N = 1857) *Double blind. Open label. ABC/3TC* 600/300 mg QD + EFV 600 mg QD (n = 465) TDF/FTC* 300/200 QD + ATV/RTV 300/100 mg QD (n = 465) ABC/3TC* 600/300 mg QD + ATV/RTV 300/100 mg QD (n = 463) Sax PE, et al. N Engl J Med. 2009;361: Daar ES, et al. Ann Intern Med. 2011;154:

20 Evolving Options for First-line Antiretroviral Therapy clinicaloptions.com/hiv A5202: Time to Virologic Failure in Patients With HIV-1 RNA < 100,000 c/ml 1.0 Probability (Remaining Free of Virologic Failure) EFV + TDF/FTC (33 events) EFV + ABC/3TC (39 events) ATV/RTV + TDF/FTC (29 events) ATV/RTV + ABC/3TC (35 events) Pts at Risk, n EFV + TDF/FTC EFV + ABC/3TC ATV/RTV + TDF/FTC ATV/RTV + ABC/3TC Wks From Randomization Sax PE, et al. J Infect Dis. 2011:204;

21 Evolving Options for First-line Antiretroviral Therapy clinicaloptions.com/hiv A5202: Time to Virologic Failure in Patients With HIV-1 RNA 100,000 c/ml Probability of No Virologic Failure (%) HR: 2.33 (95% CI: ; P <.001, log-rank test) TDF/FTC (26 events) ABC/3TC (57 events) Pts at Risk, n ABC/3TC TDF/FTC Sax PE, et al. N Engl J Med. 2009;361: Wks Since Randomization

22 Evolving Options for First-line Antiretroviral Therapy clinicaloptions.com/hiv STARTMRK: Efficacy of RAL vs EFV RAL is BID vs QD (EFV) but fewer adverse events (52% vs 80%) HIV-1 RNA < 50 c/ml (%) ITT, NC = F CD4+ gain: Pts at Risk, n RAL 400 mg BID EFV 600 mg QHS Wks Rockstroh JK, et al. J Acquir Immune Dis Syndr. 2013;63:77-85.

23 Evolving Options for First-line Antiretroviral Therapy clinicaloptions.com/hiv Efficacy of EVG/COBI/TDF/FTC vs EFV/TDF/FTC HIV-1 RNA < 50 copies/ml (%) Diff: 3.6%, 95% CI (-1.6% to +8.8%) CD4+ change: +239 vs +206 cells/mm 3 (P =.009) No difference by baseline characteristics EVG/COBI/TDF/FTC EFV/TDF/FTC 9 0 Virologic Success Virologic Nonsuppression No Wk 48 Data Sax P, et al. Lancet. 2012;379: Sax P, et al. IAS Abstract TUPE028.

24 Evolving Options for First-line Antiretroviral Therapy clinicaloptions.com/hiv SINGLE: Dolutegravir + ABC/3TC vs Efavirenz/TDF/FTC in Tx-Naive Pts 100 DTG + ABC/3TC EFV/TDF/FTC Proportion of Patients (%) CD4 from BL Wk 96 adjusted difference in response (95% CI): +8.0% (+2.3% to +13.8%); P =.006 Treatment Wk 96 From BL Adjusted Mean SE DTG: 80% EFV: 72% Difference in Response (95% CI) DTG + ABC/3TC QD (n = 414) (14.3, 73.6) EFV/TDF/FTC QD (n = 419) P = Wk DTG superior to EFV at Wk 48 [1] and Wk 96 [2] Treatment-related study d/c: 3% in DTG vs 11% in EFV arm at Wk 96; comparable rates of virologic failure (6% in each arm at Wk 96) No resistance in DTG arm through Wk 9 1. Walmsley S, et al. N Engl J Med. 2013;369: Walmsley S, et al. CROI Abstract 543.

25 NNRTIs: συμμόρφωση

26 Evolving Options for First-line Antiretroviral Therapy clinicaloptions.com/hiv Adherence Inversely Related to Number of Doses per Day 100 P =.008 P <.001 P =.001 Mean Dose-Taking Adherence (%) Overall QD BID TID QID Studies of Electronic Monitoring of Adherence Claxton AJ, et al. Clin Ther. 2001;23:

27 Evolving Options for First-line Antiretroviral Therapy clinicaloptions.com/hiv Fixed-Dose Antiretrovirals: Μελλοντικός σχεδιασμός Tenofovir/emtricitabine/efavirenz Ο πρώτος συνδυασμός σταθερής δόσης που συνδυάζει 2 διαφορετικές κατηγορίες αντιρετροϊκών φαρμάκων Θα είναι η πρώτη θεραπεία με ένα χάπι μια φορά την ημέρα Αναμένεται το 2006

28 Atripla: κι όλα άλλαξαν

29 Tenofovir + Emtricitabine + Efavirenz (Atripla) (2) nrti + (1) nnrti Δόση: 1 δισκίο qd - Tenofovir 300 mg - Emtricitabine 200 mg - Efavirenz: 600 mg Atripla Λήψη χωρίς φαγητό Study 934 Ανεπιθύμητες ενέργεις: CNS (efavirenz) DHS/PP

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34 Μελέτη ADONE Συμμόρφωση στην αγωγή και ποιότητα ζωής με ένα χάπι την ημέρα (Atripla) Η πρώτη μελέτη που αξιολόγησε την αλλαγή σε Atripla από TDF/FTC + EFV ή TDF + FTC + EFV Την μεταβολή από 3 ή 2 χάπια σε 1 με τις ίδιες ουσίες Jules Levin EACS Nov Cologne Germany

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36 NNRTIs: τα νεώτερα φάρμακα

37 NNRTIs: etravirine

38 Clinical Strategies for Optimizing Outcomes With Next-Generation Agents HIV-infected patients with VF on current HAART regimen, history of 1 NNRTI resistance mutations, 3 primary PI mutations, HIV-1 RNA > 5000 copies/ml (DUET-1: N = 612; DUET-2: N = 591) Etravirine 200 mg BID + DRV/RTV-containing OBR (n = 599) Placebo + DRV/RTV-containing OBR (n = 604) *Planned Week 24 analysis: primary endpoint HIV-1 RNA < 50 copies/ml (TLOVR). Investigator-selected OBR to consist of DRV/RTV (600/100 mg/ml) + 2 NRTIs ± Week 48 ENF. clinicaloptions.com/hiv DUET-1 and -2: Etravirine + DRV/RTV- Containing OBR Phase III Trials Week 24* Madruga JV, et al. Lancet. 2007;370: Lazzarin A, et al. Lancet. 2007;370: Mills A, et al. IAS Abstract WESS Katlama C, et al. IAS Abstract WESS Cahn P, et al. ICAAC Abstract H-717.

39 Clinical Strategies for Optimizing Outcomes With Next-Generation Agents DUET-1 and -2: Patients With VL < 50 c/ml at Week 24 (ITT TLOVR) Responders ± 95% CI (%) DUET-1 and -2 Pooled Analysis P < % 41% ETR + OBR (n = 599) Placebo + OBR (n = 604) Time (Weeks) Cahn P, et al. ICAAC Abstract H-717. clinicaloptions.com/hiv

40 Clinical Strategies for Optimizing Outcomes With Next-Generation Agents DUET-1 and -2: Response (< 50 c/ml) According to BL DRV Fold Change Patients With HIV-1 RNA < 50 c/ml at Week 24 (%) / 345 DRV FC < 10 DUET-1 and -2 Pooled Analysis ETR + OBR Placebo + OBR / /129 39/132 31/71 2 1/67 DRV FC DRV FC > 40 Cahn P, et al. ICAAC Abstract H-717. clinicaloptions.com/hiv

41 Clinical Strategies for Optimizing Outcomes With Next-Generation Agents DUET-1 and -2: Any Grade Adverse Events at Week 24 Adverse Events Through Week 24, % Etravirine (n = 599) Placebo (n = 604) Adverse event of any grade Rash (all types) 17* 9 Diarrhea Nausea Headache 9 12 Neurologic disorders Psychiatric disorders Hepatic adverse events 5 5 *P =.0001 vs placebo. Cahn P, et al. ICAAC Abstract H-717. clinicaloptions.com/hiv

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44 NNRTIs: riplivirine

45 Clinical Strategies for Optimizing Outcomes With Next-Generation Agents ECHO/THRIVE: Rilpivirine Noninferior to Efavirenz Through Wk 96 HIV-1 RNA < 50 c/ml at Wk 96 (ITT-TLOVR) n = 686 RPV 682 EFV Pooled Data Cohen CJ, et al. AIDS. 2013;27: More virologic failures with RPV vs EFV: 14% vs 8% Difference due to more failures between Wks 0-48; failures comparable between arms from Wks Development of NRTI mutations more common with RPV vs EFV E138K mutation with RPV cross-resistance with ETR Discontinuation for AEs more common with EFV vs RPV: 9% vs 4% clinicaloptions.com/hiv

46 Clinical Strategies for Optimizing Outcomes With Next-Generation Agents ECHO/THRIVE Post Hoc Analysis: Wk 96 Efficacy by Baseline VL and CD4+ Count HIV-1 RNA < 50 copies/ml (%) Rilpivirine Efavirenz Cohen CJ, et al. AIDS. 2013;27: n = n = k > 100k - > 500k < k < 200 < 350 By Baseline HIV-1 RNA (copies/ml) By Baseline CD4+ Count (cells/mm 3 ) 79 clinicaloptions.com/hiv

47 Clinical Strategies for Optimizing Outcomes With Next-Generation Agents Summary of Results From Phase III Studies of RPV vs EFV More virologic failures, especially with HIV-1 RNA > 100k [1,2] Difference reduced in open-label study, suggesting importance of adherence, food effect [2] DHHS: RPV is not recommended in patients with pretreatment HIV-1 RNA > 100,000 copies/ml; higher rate of virologic failures reported in patients with pre-art CD4+ count < 200 cells/mm 3 who were treated with RPV + 2 NRTIs [3] RPV resistance mutation (E138K) causes cross-resistance with ETR [1,2] Fewer drug discontinuations with RPV than EFV [1,2] Fewer rash, CNS events; better lipids [1,2] 1. Cohen CJ, et al. AIDS. 2013;27: Cohen C, et al. Glasgow Abstract O DHHS Guidelines. February clinicaloptions.com/hiv

48 NNRTIs: ανάπτυξη αντοχής μετά από αποτυχία του πρώτου σχήματος

49 Clinical Strategies for Optimizing Outcomes With Next-Generation Agents Emergence of Resistance After Failure of EFV + NRTIs at Week 144 (ITT) EFV-Containing Regimens 100 NNRTI M184V TAM K65R GS 934 [1] GS 903 [2] Patients failing therapy with resistance (%) TDF + FTC (n = 244) ZDV/3TC (n = 243) TDF + 3TC (n = 299) 1. Arribas JR, et al. IAS Abstract WEPEB Gallant JE, et al. JAMA. 2004;292: n = 13/19 2/19 21/29 10/29 2/29 26/47 18/47 8/ clinicaloptions.com/hiv

50 Clinical Strategies for Optimizing Outcomes With Next-Generation Agents ACTG 5142: ARV Resistance Mutations After Virologic Failure (ITT) LPV/RTV + 2 NRTIs *P =.002 for EFV + NRTIs vs LPV/RTV + NRTIs comparison. P <.001 for EFV + NRTIs vs LPV/RTV + NRTIs comparison. EFV + 2 NRTIs LPV + EFV VF, n (%) 94 (37) 60 (24) 73 (29) Genotypic assays, n Any mutations, n (%) 16 (21)* 22 (48)* 39 (70) Major PI mutations, n (%) 0 (0) 0 (0) 2 (4) NNRTI mutations, n (%) 2 (3) 20 (44) 37 (66) NRTI mutations, n (%) 15 (19) 14 (30) 6 (11) Mutations in 2 classes, n (%) 1 (1) 12 (26) 4 (7) Haubrich RH, et al. HIV Resistance Workshop Abstract 57. clinicaloptions.com/hiv

51 Clinical Strategies for Optimizing Outcomes With Next-Generation Agents clinicaloptions.com/hiv

52 Clinical Strategies for Optimizing Outcomes With Next-Generation Agents Genetic barrier A simplified overview Class ARVs Genetic barrier ZDV/3TC, d4t/3tc ++ NRTIs ABC/3TC, TDF/3TC + TDF/FTC ++ NNRTIs EFV, NVP, ETV, RPV + ETV, RPV +/++ PIs Boosted +++/++++ Fusion inhibitors T20 + CCR5 antagonists MVC Integrase inhibitors ++ (for R5 virus) RAL, ELV + clinicaloptions.com/hiv

53 Dr Michelle Gordon October 2009 NNRTIs και αντοχή Οι μη νουκλεοσιδικοί αναστολείς της RT (NNRTIs) συνδέονται σε μια υδροφοβική θήκη (called the NNRTI-binding pocket) Οι NNRTIs αναστέλλουν την μεταγραφή αποδεσμεύοντας το ενεργό σημείο του ενζύμου που σχετίζεται με την πολυμεράση Μία και μόνο μετάλλαξη στην NNRTI-binding pocket μπορεί να οδηγήσει σε υψηλού βαθμού αντοχή σε ένα ή περισσότερα NNRTIs (low genetic barrier).

54 Mutations Selected by NNRTIs Efavirenz Etravirine Nevirapine The International AIDS Society USA Johnson et al. Topics HIV Med. December Updates available at

55 Pooled ECHO and THRIVE Week 96 Full Dataset Virologic Failure* & Genotypic Analysis RPV N=686 EFV N=682 Time of failure Up to Week 48 Week 48 to 96* Up to Week 48 Week 48 to 96 VF, n (%) 73 (11) 22 (3) 36 (5) 16 (2) - Rebounder, n (%) 29 (4) 21 (3) 18 (3) 15 (2) - Never Suppressed, n (%) 44 (6) 1 (0.1) 18 (3) 1 (0.1) VF with resistance data, n Any emergent NNRTI RAMs, n (%) 39 (58) 6 (33) 16 (57) 4 (29) - Most frequent NNRTI RAM, n (%) E138K 27 (40) E138K 3 (17) K103N 11 (39) K103N 3 (21) Any emergent NRTI RAMs, n (%) 41 (61) 6 (33) 9 (32) 2 (14) - Most frequent NRTI RAM, n (%) M184I 27 (40) M184I 4 (22) M184V 6 (21) M184I 2 (14) *VF was defined as follows: a) first achiev ed 2 consecutive VL v alues < 50 c/ml, followed by 2 consecutiv e VL of 50 c/ml (also called a rebounder ), or b) first achiev ed 2 consecutive VL < 50 c/ml and stopped treatment, with a last observ ed VL on treatment of 50 c/ml (also called a stopped treatment while not suppressed ), or c) nev er achieved 2 consecutive VL v alues of < 50 c/ml and had an increase in VL of at least 0.5 log c/ml abov e the nadir (also called a never suppressed ) ; At least one emergent NNRTI RAM (from the NNRTI RAM list) or IAS-USA N(t)RTI RAM Cohen C, et al. IAS 2011; Rome. #TULBPE032 55

56 Χρόνος μέχρι την εμφάνιση ιολογικής αποτυχίας ασθενών με HIV-1 λοίμωξη που λαμβάνουν θεραπεία πρώτης γραμμής και το προφίλ της αντοχής στην διάρκεια της δεκαετίας Τσαχουρίδου Όλγα 1, Σκούρα Λεμονιά 2, Νικοπούλου Άννα 1, Χατζηδημητρίου Δημήτριος 2, Παπαδημητρίου Ευαγγελία 2, Χριστάκη Ειρήνη 1, Βαλαγκούτη Δέσποινα 1, Ρενάσκο Ινδιάνα 1, Τερζή Ειρήνη 1, Χρυσανθίδης Θεόφιλος 1, Ζεμπεκάκης Παντελής 1 Τσούκρα Παρασκευή 1, Φοροζίδου Ευρώπη 1, Κολλάρας Παναγιώτης 1, Μαλισιόβας Νικόλαος, Δανιηλίδης Μιχαήλ 1, Μεταλλίδης Συμεών 1. Α Παθολογική Κλινική, Τμήμα Λοιμωξιολογίας, ΠΓΝΘ ΑΧΕΠΑ, Ιατρικό Τμήμα, ΑΠΘ 1 Εργαστήριο Μικροβιολογίας, Ιατρικό Τμήμα ΑΠΘ 2 Ασθενείς με αρχικό σχήμα με NNRTIs Ασθενείς με αρχικό σχήμα με PIs Σύνολο ασθενών Ρ Ασθενείς 179 (39,5%) 274 (60,5%) 453 (100%) 0,001 Ασθενείς με VF 18 (10%) 26 (9.4%) 44 (9.7%) 0,54 Άνδρες 149 (83,2 %) 220 (80,3 %) 369 (81,5 %) 0,254 Άνδρες με VF 14 (7.8%) 20 (7.2%) 34 (7.6%) 0.32 Ηλικία 35,9 ± 11,7 41,5 ± 12 39,3 ± 12,2 0,001 Ασθενείς με VF 34.8 ± ± ± Ηλικία >50 στην διάγνωση 24 (13,4%) 68 (24,8%) 92 (20,3%) 0,002 Ασθενείς με VF 2 (1.1%) 7 (2.5%) 9 (1.9%) 0.34 AIDS στην διάγνωση 14 (7,8%) 70 ( 25,5%) 84 (18,5 %) 0,001 Ασθενείς με VF Διάρκεια θεραπείας σε μήνες Ασθενείς που έκαναν αλλαγή για οποιαδήποτε αιτία 17,9 ± 23 (110) 19,3 ± 20 (132) 18,7 ± 21,3 (242) 0,56 Ασθενείς που έκαναν αλλαγή λόγω ιολογικής αποτυχίας 21,1 ± 16,4 (18) 19,3 ± 16,4 (26) 20 ± 16,2 (44) 0,45 Αγωγή με 2 ης γραμμής NRTIs 10 (55.5%) 15 (57.6%) 25 (56.8%) 0.45

57 Στον πίνακα που ακολουθεί φαίνονται οι μεταλλάξεις που αναπτύχθηκαν στους ασθενείς που παρουσίασαν ιολογική αποτυχία Ασθενείς με αρχικό σχήμα με ΝΝRTIs 18 ασθενείς με VF, 3 χωρίς καμία μετάλλαξη Ν Μεταλλάξεις RT Ν Μεταλλάξεις Πρωτεάσης Ασθενείς με αρχικό σχήμα με ΡΙs 26 ασθενείς, με VF, 13 χωρίς καμία μετάλλαξη Ν Μεταλλάξεις RT Ν Μεταλλάξεις Πρωτεάσης 6 K103N 4 L10I, M36I 4 M184V 7 M36I 5 M184V 3 I13V 2 D67N, K70R, K103N 4 L89M, I13V, L10I 3 Y181C 2 L63P, I62V, I93L 1 V106I, E138A, L74V, Y75I, V75T, Y75A, Y188L, T69N, G190A, K219Q 3 H69K, L63P 2 E44D 1 K20I, L19I, A71T, I54V, H69K, L89M 2 L90M 1 V179D, M41L, L210W, T215Y,K101Q, G190A, G190S, P225H, D67N, K70R, K219Q, K219E, V118I, A62V, V75I, K101I, Y115F, G190S 1 G16E, L33V, E35G, I54M, A71T, K20M, I62V, A71I, V77I, I93L

58 NNRTIs: μεταδιδόμενη αντοχή και η κλινική της σημασία

59 Επιλογή του πρώτου σχήματος First shot is your best shot Μεταλλάξεις - μεταδιδόμενη αντοχή

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61 Μεταδιδόμενη Αντοχή Επιπολασμός σε νεοδιαγνωσθέντες naïve HIV ασθενείς στην Ευρώπη: 8.4 % (5.6% έως 12.4% σε ορισμένους πληθυσμούς) Frentz D, Boucher CA, van de Vijver DA. AIDS Rev 2012 Υψηλά ποσοστά μεταδιδόμενης αντοχής στη Βόρεια Ελλάδα 12.5% ( ) Skoura L, Metallidis S, Buckton AJ et al. J Antimicrob Chemother % ( ) Tenth European Meeting on HIV & Hepatitis, Barcelona, Spain, ο Συνέδριο AIDS

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64 NNRTIs και συννοσηρότητα

65 Medical comorbidities among 66,840 HIV- and 33,420 HIV+ veterans 100 Prevalence (%) ,1 Hypertension Diabetes Vascular Pulmonary Liver Renal <40 HIV- <40 HIV HIV HIV HIV HIV+ 60+ HIV- 60+ HIV+ (Goulet, CID 2007)

66 Αλληλεπίδραση HIV-Φυματίωσης

67 Επιλογή αγωγής για ασθενή με HIV και TBC EACS Guidelines 2014 Προτεινόμενη 1 ης γραμμής αντιρετροϊκή θεραπεία σε συνδυασμό με αντιφυματική αγωγή Tenofovir/Emtricitabine/Efavirenz Abacavir/Lamivudine/Efavirenz

68 Ριφαμπικίνη και NNRTI Curran A et al, Management of TB/HIV co-infection, AIDS Rev 2012

69 Ριφαμπικίνη και δόση Efavirenz BHIVA 2011 >60kg EFV 800mg < 60 kg EFV 600mg EACS 2014 Standard dose (some recommend 800mg if not black African) CDC 2013 Therefore, because of its potency, simplicity, and proven clinical efficacy, use of efavirenz 600mg with 2 NRTIs, along with rifampin-based tuberculosis treatment is the preferred strategy for co-treatment of HIV and tuberculosis Some clinicians may increase the dose of efavirenz to 800mg in persons weighing >50kg. We consider that data are insufficient to support a definitive statement in this regard.

70 Αλληλεπίδραση HIV-HCV

71 First and Foremost: Choosing and Using First-line Antiretroviral Therapy clinicaloptions.com/hiv Drug Drug Interactions With BOC and TVR Antiretroviral Interactions With Boceprevir Interactions With Telaprevir RPV [1,2] No clinically relevant interactions No clinically relevant interactions EVG/COBI No data No clinically relevant interactions TDF/FTC [3] DTG [4] No clinically relevant interactions No clinically relevant interactions ATV/RTV [5] DRV/RTV [5] EFV [5] Coadministration not recommended Coadministration not recommended Coadministration not recommended Coadministration not recommended Coadministration not recommended Increase TVR dose to 1125 mg q8h RAL [5] No clinically relevant interactions No clinically relevant interactions 1. Rhee E, et al. CROI Abstract Rilpivirine [package insert]. 3. Custodio J, et al. ICAAC Abstract A Dolutegravir [package insert]. 5. DHHS Adult Guidelines. February 2013.

72 Evolving Switch Strategies for Virologically Suppressed HIV-Infected Patients clinicaloptions.com/hiv Simeprevir and Rilpivirine: Day 7 PK Alone and in Combination Simeprevir Rilpivirine Plasma Concentration of SIM (ng/ml), Day Plasma Concentration of RPV (ng/ml), Day urs SIM 150 mg QD for 11 days (n = 21) Hrs RPV 25 mg QD for 11 days (n = 23) SIM 150 mg QD + RPV 25 mg QD for 11 days (n = 21) No clinically relevant interactions observed between RPV and SIM No relevant differences in incidence of AEs observed with SIM alone vs coadministration of SIM and RPV Ouwerkerk-Mahadevan S, et al. IDWeek Abstract

73 Evolving Switch Strategies for Virologically Suppressed HIV-Infected Patients clinicaloptions.com/hiv Simeprevir and Darunavir/Ritonavir: Day 7 PK Alone and in Combination Plasma Concentration of SIM (ng/ml), Day Simeprevir Darunavir Ritonavir Hrs Plasma Concentration of DRV (ng/ml), Day 7 SIM 150 mg QD for 7 days (n = 21) SIM 50 mg QD + DRV/RTV 800/100 mg QD for 7 days (n = 25) Hrs DRV/RTV 800/100 mg QD for 7 days (n = 23) DRV/RTV 800/100 mg QD + SIM 50 mg QD for 7 days (n = 25) Plasma Concentration of RTV (ng/ml), Day Hrs DRV/RTV 800/100 mg QD for 7 days (n = 23) DRV/RTV 800/100 mg QD + SIM 50 mg QD for 7 days (n = 25) SIM exposure 2.6-fold higher when coadministered with DRV/RTV vs SIM alone When coadministered with SIM, DRV exposure increased 18% and RTV exposure increased 32% Ouwerkerk-Mahadevan S, et al. IDWeek Abstract

74 HIV και νεφρική λειτουργία

75

76 Evolving Switch Strategies for Virologically Suppressed HIV-Infected Patients clinicaloptions.com/hiv EVG/COBI/TDF/FTC vs EFV or ATV/RTV: Creatinine Changes Change From BL in Serum Creatinine (mg/dl; IQR) BL EVG/COBI/TDF/FTC EFV/TDF/FTC Wks BL EVG/COBI/TDF/FTC ATV/RTV + TDF/FTC Wks Cobicistat is associated with reduced active secretion of creatinine in the renal tubules leading to initial rises in creatinine levels Sax P, et al. Lancet. 2012;379: DeJesus E, et al. Lancet. 2012;379:

77 HIV και κύηση

78 Evolving Switch Strategies for Virologically Suppressed HIV-Infected Patients clinicaloptions.com/hiv Changes in Perinatal Guidelines 2012 The Panel recommends that EFV be continued in pregnant women receiving EFV-based ART who present for antenatal care in the first trimester, provided the regimen is resulting in virologic suppression (CIII) Pregnant women receiving and tolerating NVP-containing regimens who are virologically suppressed should continue the regimen, regardless of CD4+ cell count (AIII) DHHS Perinatal Guidelines. July 2012.

79 Evolving Switch Strategies for Virologically Suppressed HIV-Infected Patients clinicaloptions.com/hiv Antiretroviral Pregnancy Registry: Birth Defects With First Trimester Exposure Enrolls ~ 1300 women exposed to ART each yr (80% US) 18,488 live births with follow-up data through July with first trimester exposure Overall birth defect prevalence comparable to CDC population based surveillance data: 2.9 per 100 live births vs 2.7 Commonly used PIs not associated with increased birth defect rate Antiretroviral Pregnancy Registry. Interim Report. December Drug NRTIs ABC ddi FTC 3TC d4t TDF ZDV PIs ATV DRV IDV LPV NFV RTV NNRTIs EFV NVP RPV INSTIs Defects/Live Births, n ( > 200 First Trimester Exposures) 27/905 20/416 34/ / /805 46/ / /878 5/212 7/289 26/ / / /766 31/1061 Insufficient data Insufficient data Prevalence, % (95% CI) 3.0 ( ) 4.8 ( ) 2.4 ( ) 3.1 ( ) 2.6 ( ) 2.3 ( ) 3.2 ( ) 2.2 ( ) 2.4 ( ) 2.4 ( ) 2.3 ( ) 3.9 ( ) 2.3 ( ) 2.3 ( ) 2.9 ( )

80 HIV και λιπίδια

81 Factors associated with mortality in HIV infected patients with metabolic syndrome

82 Treatment Trade-Offs: Weighing the Benefits and Risks of First-Line ART clinicaloptions.com/hiv Effects of HAART on Lipids EFV associated with greater lipid change than RAL in STARTMRK [1] EFV associated with greater cholesterol changes than ATV/RTV in ACTG 5202 [2] 1. Lennox J, et al. Lancet. 2009;374: Daar ES, et al. Ann Intern Med. 2011;154: Molina JM, et al. Lancet. 2008;372: Ortiz R, et al. AIDS. 2008;22:

83 LIPID CHANGES WITH ARV TREATMENT A RV class Dru g Effect T otal cholesterol T riglycerides HDL-C LDL-C Nev irapine Efa v irenz NNRT Is Etr avirine 2 No ch ange Rilpivirine 3 No ch a nge No ch a nge No ch a nge No ch a nge Stavudine Zidov udine No ch ange La mivudine No ch ange A bacavir No ch a nge No ch a nge No ch a nge NRT Is A bacavir/lamivudine No ch ange A bacavir/lamivudine/zidovudine No ch ange Dida nosine No ch ange No ch ange Em tricitabine No ch ange T enofovir No ch a nge No ch a nge No ch a nge No ch a nge IIs Ra ltegravir No ch a nge No ch a nge No ch a nge No ch a nge In dinavir* No ch ange Nelfinavir No ch ange No ch ange Sa quinavir* PIs Lopinavir/ritonavir No ch ange Fosa mprenavir* No ch ange A tazanavir* No ch a nge No ch a nge No ch a nge No ch a nge Da runavir/ritonavir 4 No ch a nge Ritonavir (full dose) No ch ange No ch ange Fu sion/ent En furvitide No ch a nge No ch a nge No ch a nge No ch a nge ry in hibitors Ma raviroc No ch a nge No ch a nge No ch a nge No ch a nge *Effects shown are for ritonavir-boosted drugs Atazanavir not licensed for unboosted use in the UK or EU Adapted from: 1. Martin A and Emery S. Exp Rev Clin Pharmacol 2009;2: ; 2. Fautkenheuer G, et al. J Antimicrob Chemother 2012;67: ; 3. Cohen C, et al. Lancet 2011;378: ; 4. Mills AM, et al. AIDS 2009;23:

84 Switch Pis to NNRTIs vs lipid lowering agents Colesterol total a los 12 meses

85 Treatment Trade-Offs: Weighing the Benefits and Risks of First-Line ART clinicaloptions.com/hiv SPIRIT: Change in Fasting Lipids From Baseline at Wks 24 and 48 Significant reductions in TC, LDL, TG, HDL, TC:HDL ratio at Wk 24 among RPV/TDF/FTC switch pts Mean Changes From Baseline (mmol/l) TC LDL TG HDL Palella F, et al. AIDS. 2014;28: Mean Change TC:HDL ratio RPV/TDF/FTC (immediate, Day 1 - Wk 24) RPV/TDF/FTC (delayed, Wk 24 - Wk 48) brtv + 2 NRTIs (Days 1 - Wk 24) RPV/TDF/FTC (immediate, Day 1 - Wk 48)

86 HIV και οστική νόσος

87 Treatment Trade-Offs: Weighing the Benefits and Risks of First-Line ART clinicaloptions.com/hiv Antiretroviral Exposure and Risk of Osteoporotic Fractures: HAART Era 1,3 1,2 Hazard Ratio 1,1 1,0 0,9 0,8 MV Model 1: Controlling for CKD, age, race, tobacco use, diabetes and BMI; MV Model 2: Controlling for Model 1 variables + concomitant exposure to other ARVs.

88 NNRTIs ανεπιθύμητες ενέργειες

89

90 First and Foremost: Choosing and Using First-line Antiretroviral Therapy clinicaloptions.com/hiv Low Discontinuation for AEs in Clinical Trials With Preferred and Newer Agents Agent EFV (ACTG 5202) [1] Discontinuation Rate for AEs by Wk 48 in Major Clinical Trials, % 9 (TDF/FTC arm) ATV/RTV (CASTLE) [2] 2 DRV/RTV (ARTEMIS) [3] 3 RAL (STARTMRK) [4] 3 RPV (ECHO) [5] 2 EVG/COBI (GS102) [6] 4 DTG (SINGLE) [7] 2 1. Daar E, et al. Ann Intern Med. 2011;154: Molina JM, et al. Lancet. 2008;372: Ortiz R, et al. AIDS. 2008;22: Lennox J, et al. Lancet. 2009;374: Molina JM, et al. Lancet. 2011;378: Sax P, et al. Lancet. 2012;379: Walmsley S, et al. ICAAC Abstract H-556b.

91 First and Foremost: Choosing and Using First-line Antiretroviral Therapy clinicaloptions.com/hiv CNS Adverse Effects of EFV Neuropsychiatric symptoms typically develop within first 4 weeks, resolve within 2-4 weeks [1] In ACTG 384, EFV CNS adverse effects predictable, self-limited [2] In CLASS study, sleep disorders and vivid dreams more common with EFV [3] Adverse Effect, % EFV-Containing Regimens Other Regimens Sleep disorders 7 < 1 Vivid dreams 5 < 1 1. Fortin C, et al. Expert Rev Anti Infect Ther. 2004;2: Shafer R, et al. N Engl J Med. 2003;349: Bartlett J, et al. J Acquir Immune Defic Syndr. 2006;43:

92 First and Foremost: Choosing and Using First-line Antiretroviral Therapy clinicaloptions.com/hiv TMC278-C204: Any Cause CNS AEs and Metabolic Parameters Patient Outcome at Week 48 Rilpivirine EFV 600 mg (n = 89) 25 mg (n = 93) 75 mg (n = 95) 150 mg (n = 91) AE, regardless of causality, % [1] Any CNS disorder Vertigo Dizziness Somnolence Abnormal dreams/nightmares Mean lipid change from baseline [2] TC, mg/dl LDL, mg/dl HDL, mg/dl TC-to-HDL ratio TG, mg/dl Yeni P, et al. EACS Abstract P7.2/07.

93 First and Foremost: Choosing and Using First-line Antiretroviral Therapy clinicaloptions.com/hiv Pooled ECHO and THRIVE: Wk 12 Full Dataset Ανεπιθύμητες ενέργειες Επίπτωση των ΑΕ όλων των βαθμών RPV EFV Κεφαλαλγία 5.2% 5.1% Ναυτία 9.6% 10.4% Εφιάλτες 6.7% 10.4% Ζάλη 7.7% 25.2% Εξάνθημα 2.0% 8.4% Αυπνια 2.9% 6.5% Proportion of Subjects (%) Any Grade AEs of Interest Week 0-4 Week > 4-8 Week > RPV EFV RPV EFV Total (%) Psychiatric Neurological Rashbaum B, et al. ICAAC Chicago. #H

94 First and Foremost: Choosing and Using First-line Antiretroviral Therapy clinicaloptions.com/hiv Frequency of Serious Psychiatric Events Among EFV-Treated Patients Psychiatric Event, % Severe depression EFV (n = 1008) Control (n = 635) Suicide ideation Nonfatal suicide attempts Aggressive behavior Paranoid reactions Manic reactions Factors Associated With Increased Occurrence of Psychiatric Symptoms* Use of EFV History of injection drug use Psychiatric history Receipt of psychiatric medication at study entry *Similar associations in the EFV and control group.

95 24th Annual CCO HIV and Hepatitis C Symposium clinicaloptions.com Increased Risk of Suicidality Associated With EFV 5% Efavirenz Efavirenz-free HR (95% CI) 2.28 ( ), P =.006 Probability events/5817 PY* (8.08/1000 PY).01 As-treated HR 2.16 ( ) 0 *Person-years, sum of at-risk follow-up. Mollan K, et al. IDWeek Abstract Wks to Suicidality 15 events/4099 PY* (3.66/1000 PY)

96 24th Annual CCO HIV and Hepatitis C Symposium clinicaloptions.com Increased Risk of Suicidality Associated With EFV as First-Line ART Randomization to EFV-based initial ART associated with 2-fold increase in hazard of suicidality* vs EFV-free ART among patients in 4 ACTG studies (A5095, A5142, A5175, A5202) Overall Events/PYs (IR per 1000 PYs) EFV EFV Free HR (95% CI) P Value 47/5817 (8.08) 15/4099 (3.66) 2.28 ( ).006* Study A5095 A5142 A5175 A5202 6/739 8/ / /2315 (8.12) (7.99) (7.38) (8.64) 1/364 2/510 2/889 10/2336 (2.75) (3.92) (2.25) (4.28) 3.00 ( ) 2.04 ( ) 3.28 ( ) 2.02 ( ).94 Region US Multinational 39/4346 8/1471 (8.97) (5.44) 13/3354 2/745 (3.88) (2.68) 2.32 ( ) 2.02 ( ) Increased Suicidality With EFV-Free Increased Suicidality With EFV *Composite of suicide, suicide attempt, and suicidal ideation. Mollan K, et al. Ann Intern Med. 2014;161:1-10.

97 NNRTIs αλληλεπιδράσεις φαρμάκων

98 First and Foremost: Choosing and Using First-line Antiretroviral Therapy clinicaloptions.com/hiv Drug Drug Interactions With First-line ART and Lipid-Lowering Therapy Antiretroviral Contraindicated Titrate Dose No Dose Adjustment RPV [1] EVG/COBI/TDF/ FTC [1] DTG [2] ATV/RTV [1] DRV/RTV [1] EFV [1] RAL [1] Lovastatin Simvastatin Lovastatin Simvastatin Lovastatin Simvastatin Atorvastatin Rosuvastatin Atorvastatin Rosuvastatin Atorvastatin Pravastatin Rosuvastatin Atorvastatin Simvastatin Pravastatin Rosuvastatin 1. DHHS Adult Guidelines. February Dolutegravir [package insert]. Atorvastatin Pitavastatin Pitavastatin

99 First and Foremost: Choosing and Using First-line Antiretroviral Therapy clinicaloptions.com/hiv Drug Drug Interactions With OCPs Antiretroviral Effect on OCP Dosing Recommendation RPV [1,2] Ethinyl estradiol AUC 14% Norethindrone: no significant change EVG/COBI Ethinyl estradiol AUC 25% TDF/FTC [1,3] Norgestimate No dose adjustment Weigh the risks and benefits of norgestimate and consider alternative contraceptive DTG [4] No clinically relevant interaction No dose adjustment ATV/RTV [1,2] Ethinyl estradiol AUC Norgestimate DRV/RTV [1,2] Ethinyl estradiol AUC 44% Norethindrone AUC 14% EFV [1,2] No effect on ethinyl estradiol Active metabolites of norgestimate OCP should contain 35 mcg ethinyl estradiol Additional methods of contraception recommended A reliable method of barrier contraception must be used in addition to hormonal contraceptives RAL [1,2] No clinically relevant interaction No dose adjustment 1. DHHS Adult Guidelines. February DHHS Perinatal Guidelines. July TDF/FTC/EVG/COBI [package insert]. 4. Dolutegravir [package insert].

100 First and Foremost: Choosing and Using First-line Antiretroviral Therapy clinicaloptions.com/hiv Drug Drug Interactions With Acid- Reducing Medications and Newer ARVs ARV Antacids H2-Receptor Antagonists RPV [1] EVG/COBI TDF/FTC [1] DTG [2] Give antacids at least 2 hrs before or at least 4 hrs after RPV Separate EVG/COBI/ FTC/TDF and antacid administration by > 2 hrs DTG should be given 2 hrs before or 6 hrs after taking medications containing polyvalent cations Give H2-receptor antagonists at least 12 hrs before or at least 4 hrs after RPV No clinically relevant interactions Proton Pump Inhibitors Contraindicated No clinically relevant interactions No clinically relevant interactions 1. DHHS Adult Guidelines. February Dolutegravir [package insert].

101 NNRTIs και μελέτες αλλαγής Ας τις δούμε πέρα από τον αρχικό τους στόχο

102 Evolving Switch Strategies for Virologically Suppressed HIV-Infected Patients clinicaloptions.com/hiv STRATEGY-NNRTI: Switch to EVG/COBI/TDF/FTC in Suppressed Pts Randomized, open-label switch study in pts virologically suppressed on an NNRTI + TDF/FTC regimen for 6 mos Primary endpoint: HIV-1 RNA < 50 copies/ml at Wk 48 HIV-1 RNA < 50 c/ml, 2 previous regimens, no resistance to FTC or TDF and CrCl 70 ml/min (N = 434) Switch to EVG/COBI/TDF/FTC QD (n = 291) Remain on NNRTI + TDF/FTC (n = 143) *Pts with previous VF ineligible. Pozniak A, et al. CROI Abstract 553LB.

103 Evolving Switch Strategies for Virologically Suppressed HIV-Infected Patients clinicaloptions.com/hiv STRATEGY-NNRTI: Change to EVG/COBI Noninferior to Stable NNRTIs at Wk 48 Patients (%) Δ +5.3% (95% CI: -0.5 to +12) EVG/COBI/TDF/FTC (n = 290) Stable NNRTIs (n = 143) Regimens: EFV, 78%; NVP, 17%; RPV, 4%; ETR, < 1%; 74% on EFV/TDF/FTC; 91% on first regimen Results similar across all baseline virologic and demographic subgroups 3 pts with VF in EVG/COBI arm and 1 in NNRTI arm n = < Virologic Success* Virologic Nonresponse 6 11 No Data *HIV-1 RNA < 50 c/ml as defined by FDA Snapshot algorithm Discontinued for AE, death, or missing data. Pozniak A, et al. CROI Abstract 553LB. Reproduced with permission. No pts with resistance in either arm 5 in the switch arm and 1 in the NNRTI arm discontinued due to adverse event

104 Evolving Switch Strategies for Virologically Suppressed HIV-Infected Patients clinicaloptions.com/hiv Subject Reporting Symptoms (%) STRATEGY-NNRTI: Outcomes in Patients Switching from EFV-based Therapy HIV Symptom Index Vivid Dreams Insomnia Anxiety Dizziness * Baseline EVG/COBI/TDF/FTC NNRTI + TDF/FTC BL W48 BL W48 BL W48 BL W48 BL W48 BL W48 BL W48 BL W48 *P <.001, P <.01 (comparison with baseline within treatment group). Decreases noted at Wk 4 & sustained through Wk 48. P <.001, vivid dreams & P <.01, dizziness (comparison of changes from baseline at Wk 48 between treatment group). HIV Treatment Satisfaction questionnaire, score range: -30 to 30. Pozniak A, et al. Lancet Infect Dis. 2014;14: Wk 48 EVG/COBI/TDF/FTC NNRTI + TDF/FTC Subjects who switched to EVG/COBI/TDF/FTC from EFV + TDF/FTC had Lower rates of neuropsychiatric symptoms at Wk 48 compared with baseline Higher treatment satisfaction scores at Wk 24 (mean: 21 vs 14; P <.001) *

105 Evolving Switch Strategies for Virologically Suppressed HIV-Infected Patients clinicaloptions.com/hiv SPIRIT: Switch to RPV/TDF/FTC From Boosted PI Regimens in Suppressed Pts Multicenter, randomized, open-label switch study Primary endpoint: maintenance of HIV-1 RNA < 50 copies/ml at Wk 24 (FDA Snapshot algorithm) Wk 24 Primary endpoint Wk 48 Pts with HIV-1 RNA < 50 copies/ml on stable RTV-boosted PI + 2 NRTIs for 6 mos, no previous NNRTI use (N = 476) Switch to RPV/TDF/FTC (n = 317) Continue RTV-Boosted PI* + 2 NRTIs (n = 159) Continue RPV/TDF/FTC (n = 317) Switch to RPV/TDF/FTC (n = 159) *PIs: ATV/RTV, 37%; LPV/RTV, 33%; DRV/RTV, 20%; FPV/RTV, 8%; SQV/RTV, 2%. Palella F, et al. AIDS. 2014;28:

106 Evolving Switch Strategies for Virologically Suppressed HIV-Infected Patients clinicaloptions.com/hiv SPIRIT: Virologic Suppression at Wk 24 and Wk 48 Switch to RPV/TDF/FTC noninferior to continuing boosted-pi regimen at Wk 24 23/24 pts with preexisting K103N maintained virologic suppression at Wk 24 FDA Snapshot at Wk 24 FDA Snapshot at Wk 48 Subjects (%) Virologic Suppression RPV/TDF/FTC (immediate sw itch, Day 1 - Wk 24) bpi + 2 NRTIs (delayed, Day 1 - Wk 24) RPV/TDF/FTC (delayed sw itch, Wk 24 - Wk 48) Virologic Failure No Data RPV/TDF/FTC (immediate sw itch, Day 1 - Wk 48) 2.5 Virologic Virologic Suppression Failure 8.2 No Data Palella F, et al. AIDS. 2014;28:

107 Evolving Switch Strategies for Virologically Suppressed HIV-Infected Patients clinicaloptions.com/hiv SPIRIT: Pretreatment HIV-1 RNA and Outcomes HIV-1 RNA < 50 c/ml at Wk 24, (%) RPV/TDF/FTC PI/RTV + 2 NRTIs /160 83/93 128/134 48/52 < 100K 100K Pretreatment HIV-1 RNA, copies/ml 95% CI for Difference Favors PI/RTV + 2 NRTIs 100K < 100K Favors RPV/TDF/FTC Palella F, et al. IAC Abstract TUAB0104.

108 Evolving Switch Strategies for Virologically Suppressed HIV-Infected Patients clinicaloptions.com/hiv SPIRIT: Change in Fasting Lipids From Baseline at Wks 24 and 48 Significant reductions in TC, LDL, TG, HDL, TC:HDL ratio at Wk 24 among RPV/TDF/FTC switch pts Mean Changes From Baseline (mmol/l) TC LDL TG HDL Palella F, et al. AIDS. 2014;28: Mean Change TC:HDL ratio RPV/TDF/FTC (immediate, Day 1 - Wk 24) RPV/TDF/FTC (delayed, Wk 24 - Wk 48) brtv + 2 NRTIs (Days 1 - Wk 24) RPV/TDF/FTC (immediate, Day 1 - Wk 48)

109 NNRTIs: το μέλλον

110 Lersivirine Νέος NNRTI από την Pfizer

111 Lersivirine vs Efavirenz σε μη θεραπευμένους ασθενείς που λαμβάνουν TDF/FTC: Εβδομάδα 48 HIV-1 RNA < 50 copies/ml Through Wk 48 (%) /63 (86%) 51/65 (79%) 51/65 (79%) LRV 500 mg LRV mg n = EFV 600 VL < 100,000 VL 100,000 mg HIV-1 RNA < 50 copies/ml at Wk 48, % (n) LRV 500 mg LRV 750 mg EFV Participants at South African sites 72 (18) 68 (22) 83 (24) BL HIV-1 RNA < 100,000 copies/ml 79 (14) 86 (14) 87 (15) BL HIV-1 RNA 100,000 copies/ml 50 (4) 38 (8) 78 (9) Participants recruited elsewhere 81 (47) 84 (43) 87 (39) BL HIV-1 RNA < 100,000 copies/ml 81 (31) 87 (30) 89 (26) BL HIV-1 RNA 100,000 copies/ml 81 (16) 77 (13) 85 (13) HIV-1RNA < 50 copies/ml Through Wk 48 (%) LRV 500 mg LRV 750 mg EFV 600 mg Vernazza P, et al. IAS Abstract TUAB0101. Pfizer NNRTI.

112 LRV vs EFV: Ανάλυση αντοχής και ασφάλειας Οι μεταλλάξεις που ανευρέθηκαν 3/4 ασθενείς που απέτυχαν λαμβάνοντας LRV 500 mg (all clade B)* 1) M184M/I/V, K101E, V108I, H221H/Y; 2) M184M/I/V, Y188Y/H, F227F/L, L234L/I; 3) M184V, V90I, F227C (V90I detected at screening, BL, and failure). 1/5 ασθενείς που απέτυχε λαμβάνοντας LRV 750 mg (clade C) M184V, V106M, F227L 1/3 που απέτυχε λαμβάνοντας EFV (clade B) K103N. Ο ολικός κίνδυνος ΑΕ ήταν παραπλήσιος στις δύο ομάδες Υψηλότερη συχνότητα βαθμού 3/4 ΑΕ στην ομάδα της EFV vs LRV Η LRV συσχετίστηκε με υψηλότερο ποσοστό ναυτίας (23% in 500-mg arm; 42% in 750-mg arm) και κεφαλαλγίας EFV συσχετίστηκε με υψηλότερα ποσοστά ΑΕ από το ΚΝΣ και εξάνθημα Vernazza P, et al. IAS Abstract TUAB0101.

113 Doravirine (MK-1439): Investigational NNRTI PART 1 Dose-ranging ~ 200 patients (~ 40/group) MK mg* Wk 24 Primary time point for dose selection Wk 96 End of study treatment for part 1 MK mg* MK mg* MK-1439 selected dose MK mg* Efavirenz* Efavirenz *All with TDF/FTC Morales-Ramirez J, et al. CROI Abstract 92LB.

114 Doravirine vs EFV Phase II: 24-Wk Results HIV-1 RNA < 40 Copies/mL (%) MK-1439 all doses combined: 76.4% /40 32/42 30/40 32/41 27/42 MK mg 76.2 MK mg 71.4 MK mg 78.0 MK mg 64.3 Efavirenz 600 mg Morales-Ramirez J, et al. CROI Abstract 92LB.

115 NNRTIs: Κόστος

116 Κόστος αντιρετροϊκής θεραπείας και νοσηλείες ασθενών με HIV-1 λοίμωξη σε σχέση με το αρχικό θεραπευτικό σχήμα. Τσαχουρίδου Όλγα 1, Ζεμπεκάκης Παντελής 1, Βαλαγκούτη Δέσποινα 1, Ρενάσκο Ινδιάνα 1, Τερζή Ειρήνη 1, Χρυσανθίδης Θεόφιλος 1, Ντζιοβάρα Άννα-Μαρία 1, Βασδέκη Δήμητρα 1, Κολλάρας Παναγιώτης 1, Δανιηλίδης Μιχαήλ 1, Μεταλλίδης Συμεών 1. Α Παθολογική Κλινική, Τμήμα Λοιμωξιολογίας, ΠΓΝΘ ΑΧΕΠΑ, Ιατρικό Τμήμα, ΑΠΘ 1 Ασθενείς με αρχικό σχήμα με NNRTIs Ασθενείς με αρχικό σχήμα με PIs Σύνολο ασθενών Ασθενείς 179 (39,5%) 274 (60,5%) 453 (100%) 0,001 Άνδρες 149 (83,2 %) 220 (80,3 %) 369 (81,5 %) 0,254 Ηλικία 35,9 ± 11,7 41,5 ± 12 39,3 ± 12,2 0,001 Ηλικία >50 στην διάγνωση Χρόνος μέχρι την έναρξη της πρώτης θεραπείας σε μήνες 24 (13,4%) 68 (24,8%) 92 (20,3%) 0, ± 18,5 8 ± 14,4 10,8 ± 16,5 0,001 AIDS στην διάγνωση 14 (7,8%) 70 ( 25,5%) 84 (18,5 %) 0,001 AIDS στην πορεία 17 (10,4%) 45 (22,1%) 62 (16,8%) 0,002 Μηνιαίο κόστος 502,7 ± 128,6 593,8 ± 122,8 557,8 ± 132,7 0,001 θεραπείας σε ευρώ Διάρκεια πρώτης γραμμής θεραπείας σε μήνες 23,4 ±25,8 30,1 ± 25,5 27,5 ± 25,8 Ρ 0,007 Ασθενείς που δεν έκαναν αλλαγή 36,2 ± 27,5 (54) 47,3 ±23,8 (106) 43,6 ± 25,6 (160) 0,002 Ασθενείς που έκαναν αλλαγή 17,9 ± 23 (110) 19,3 ± 20 (132) 18,7 ± 21,3 (242) 0,56 Συνολικό κόστος πρώτης γραμμής θεραπείας σε ευρώ 10473,4 ± 9855, ,5 ± 14656, ,4 ± 13441,3 0,001 Μηνιαίο κόστος θεραπείας δεύτερης γραμμής 606,7 ± 117,1 (110) NNRTIs (68) ± ± 127,2 (132) NNRTIs (30) ± ,9 ± 122,8 (242) NNRTIs (98) ± ,08 PIs (42) ±117.4 PIs (102) ± PIs (144) ± Νοσηλεία 82 (45,8%) 186 (67,9%) 268 (59,2%) 0,001 Αριθμός νοσηλειών 1. (49) 1 (79) 1 (128) 2 (14) 2 (62) 2 (76) >3 (18) >3 (41) >3 (59)

117 Ποσοστό ασθενών ανά χρονικό διάστημα έναρξης θεραπεία μετά την διάγνωση στους ασθενείς με HIV στη Βόρειο Ελλάδα μεταξύ Σύνολο 76.1% Μέσος όρος CD4 60 < ,3 Σύνολο 23.9% Μέσος όρος CD4 > ,8 8,7 8,2 2,8 2,6 1,5 0 < 30 ημέρες 1ος χρόνος 2ος χρόνος 3ος χρόνος 4ος χρόνος 5ος χρόνος > 5 έτη

118 Ετήσιες αλλαγές θεραπείας

119 Ετήσιο κόστος αντιρετροικής αγωγής για έναρξη σε 130 naïve ασθενείς % % % 0 PI NNRTI Ιντεργκράση Σύνολο

120 Ετήσιο κόστος αντιρετροικής αγωγής για έναρξη σε 130 naïve ασθενείς Αύξηση από σε Μείωση από σε Αύξηση από σε Αύξηση από σε Αύξηση 45 35% 33 από 10% 25% σε 35% 65 50% Μείωση από 80% σε 50% 20 15% Αύξηση από 10% σε 15% PI NNRTI Ιντεργκράση Σύνολο Αύξηση

121 Ετήσιο κόστος αντιρετροικής αγωγής για έναρξη σε 130 naïve ασθενείς Καμία μεταβολή Μείωση από σε Αύξηση από σε Αύξηση από σε % Καμία μεταβολή % Μείωση από 80% σε 40% 65 50% Αύξηση από 10% σε 50% PI NNRTI Ιντεργκράση Σύνολο Αύξηση Αντιστοιχούν σε 25 ασθενείς με NNRTIs

122 Φανταστείτε στο μέλλον ένα κλειστό προϋπολογισμό για τα αντιρετροϊκά

123 NNRTIs: Συμπεράσματα

124 Treatment Trade-Offs: Weighing the Benefits and Risks of First-Line ART clinicaloptions.com/hiv Efavirenz-Προσέγγιση με βάση τον ασθενή Πλεονεκτήματα Πολλά χρόνια χρήσης πολλά κλινικά δεδομένα Επί της παρούσης gold standard σαν θεραπεία πρώτης γραμμής Το ίδιο ή περισσότερο αποτελεσματικό σε σχέση με άλλα σχήματα σε συγκριτικές μελέτες [1,2] 1 pill QD coformulation of EFV/TDF/FTC [3] Μεγάλος χρόνος ημίσειας ζωής Θεραπεία εκλογής για ασθενείς με TB Patients Without Virologic Failure (%) ACTG 5202: 96-Wk Results [2] 83.4 ABC/3TC Μειονεκτήματα Χαμηλός γενετικός φραγμός μια μετάλλαξη προσδίδει αντοχή [4] Υψηλότερος κίνδυνος ανάπτυξης αντοχής σε NRTI σε αποτυχία σε σχέση με boosted PIs [2,5] Επιπλοκές από το ΚΝΣ [6] Τερατογένεση [6] Πιθανές αλληλεπιδράσεις (CYP450) [6] TDF/FTC ATV/RTV EFV 1. Lennox JL, et al. Lancet. 2009;374: Daar ES, et al. Ann Intern Med. 2011;154: Efavirenz/tenofovir/emtricitabine [package insert]. September Johnson VA, et al. Top HIV Med. 2010;18: Riddler SA, et al. N Engl J Med. 2008;358: Efavirenz [package insert]. September 2011.

125 Treatment Trade-Offs: Weighing the Benefits and Risks of First-Line ART clinicaloptions.com/hiv Riplivirine Προσέγγιση με βάση τον ασθενή Agent Πιο φιλικό σε ασθενή: RPV Που επιθυμεί θεραπεία με ένα χάπι την ημέρα Που δεν θέλει να αντιμετωπίσει επιπλοκές από το ΚΝΣ Ανησυχεί για τα λιπίδια Λιγότερο φιλικό σε ασθενή: Με πιθανά κακή συμμόρφωση Ανάγκη για φάρμακα που ελαττώνουν την οξύτητα του στομάχου Υψηλό baseline VL Baseline VL < 100,000 copies/ml

126 Σας ευχαριστώ πολύ για την προσοχή σας

127

128 Επιλέγοντας σχήμα μετά από αποτυχία με NNRTI

129 Ενδιαφέρουσα περίπτωση Ασθενής με διάγνωση το 2000 με 100 CD4 και έναρξη αγωγής με NVP + AZT/3TC Σταθερός και μη ανιχνεύσιμος για χρόνια Το 2005 αλλαγή σε NVP + ABC/3TC Ένα χρόνο αργότερα λόγω ψυχολογικών προβλημάτων και κακής συμμόρφωσης παρουσιάζει ιικό φορτίο Γονοτυπική αντοχή Y181C Μ184V

130 Ενδιαφέρουσα περίπτωση Τι αγωγή θα δίνατε: 1. TFV/FTC + boosted PI 2. TFV/FTC + ETR 3. TFV/FTC + RAL 4. TFV/FTC + boosted PI + RAL 5. 3TC + boosted PI + RAL

131 Applying Best Practices for HIV-Infected Patients With Initial Regimen Failure clinicaloptions.com/hiv TITAN: DRV/RTV vs LPV/RTV in Treatment-Experienced Patients DRV- and LPV-naive patients with HIV-1 RNA > 1000 c/ml and on current regimen for 12 wks randomized to DRV/RTV 600/100 mg BID plus OBR or LPV/RTV 400/100 mg BID plus OBR Previous ARV Experience, % DRV/RTV (n = 440) LPV/RTV (n = 443) 4 NRTIs NNRTI PI PI PIs class experienced Madruga JV, et al. Lancet. 2007;370:49-58.

132 Applying Best Practices for HIV-Infected Patients With Initial Regimen Failure clinicaloptions.com/hiv TITAN: Virologic Outcomes With DRV/RTV vs LPV/RTV in Tx-Experienced Patients DRV/RTV superior to LPV/RTV in rates of HIV-1 RNA < 400 copies/ml at Wk 48 (primary endpoint) [1] HIV-1 RNA < 50 copies/ml at Wk 48 [1] HIV-1 RNA < 400 copies/ml at Wk 96 [2] All analyses ITT-TLOVR HIV-1 RNA < 50 copies/ml at Wk 48 (%) P = Overall (n = 595) DRV/RTV LPV/RTV 1. Madruga JV, et al. Lancet. 2007;370: De Meyer S, et al. Glasgow Abstract O424.