Μεταλλίδης Συμεών Παθολόγος Λοιμωξιολόγος Επίκουρος Καθηγητής ΑΠΘ Τμήμα Λοιμώξεων Α Παθολογικής Κλινικής Διευθυντής: Καθηγητής Δανιηλίδης Μιχαήλ
Ας δούμε πως φτάσαμε ως εδώ
Οι ίδιοι προβληματισμοί 12 χρόνια τώρα
Κλινικές μελέτες vs κλινικής εμπειρίας και πεποίθησης NNRTIs vs PΙs
Πρώτης γενιάς NNRTIs: Efavirenz September 1998 Nevirapine June 1996
Efavirenz: 14 χρόνια first line therapy Το μόνο φάρμακο με έγκριση πριν από το 2000 που παραμένει στις θεραπείες πρώτης γραμμής
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
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 (%) 100 90 80 70 60 50 40 30 20 10 0 89 74 Combined EFV arms Triple-NRTI arm 83 61 < 200 copies/ml < 50 copies/ml Level of Virologic Suppression Gulick RM, et al. N Engl J Med. 2004;350:1850-1861. clinicaloptions.com/hiv
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) 100,000-299,999 30,000-99,999 < 30,000 0.35 Overall effect P =.63 0.66 1.00 1.75 2.85 Ribaudo H, et al. IAC 2006. Abstract THLB0211. Decreased Increased Risk Risk clinicaloptions.com/hiv
Efavirenz: 14 χρόνια first line therapy Προβληματισμοί για την διάρκεια θεραπείας και την ανεκτικότητα στο σχήμα
Proportion With VL < 400 c/ml (%) NNRTIs in Clinical Practice DP-006: Long-term Durability of NNRTI-Based Therapy 100 80 60 40 20 0 B/L P <.0001 EFV vs IDV triple-drug arms at Week 168 12 24 36 48 60 72 84 96 108 120 132 144 156 168 Weeks ITT, M = F analysis: proportion of subjects with response according to TLOVR definition of treatment success. Tashima K, et al. IAC 2004. Abstract TuPeB4547. EFV + ZDV + 3TC (n = 422) EFV + IDV (n = 429) IDV + ZDV + 3TC (n = 415) 48% 40% 30% clinicaloptions.com/hiv
NNRTIs in Clinical Practice ACTG 384: Trend Favoring Initiation With ZDV + 3TC When EFV Used Hazard Ratio for ddi + d4t vs ZDV + 3TC 3.0 2.5 2.0 1.5 1.0 0.5 2nd 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;349:2293-2303. clinicaloptions.com/hiv
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
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 2006. Abstract THLB0204. clinicaloptions.com/hiv
NNRTIs in Clinical Practice ACTG 5142: Outcomes at Week 96 (ITT) Patients (%) 100 80 60 40 20 0 67 No VF LPV/RTV + 2 NRTIs EFV + 2 NRTIs LPV/RTV + EFV 76 73 54 60 61 No Regimen Completion P =.041 93 92 86 VL < 200 P =.003 89 83 77 VL < 50 P =.01 P =.01 285 241 268 Median CD4+ Change 300 200 100 0 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 2006. Abstract THLB0204. clinicaloptions.com/hiv
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
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;361:2230-2240. Daar ES, et al. Ann Intern Med. 2011;154:445-456.
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) 0.8 0.6 0.4 0.2 0 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 0 24 48 72 96 120 144 168 192 216 Wks From Randomization 265 266 265 264 246 247 245 242 229 223 233 223 Sax PE, et al. J Infect Dis. 2011:204;1191-1201. 220 211 220 214 205 195 212 205 163 151 164 158 120 104 123 110 78 65 80 69 26 21 26 22
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 (%) 100 80 60 40 20 HR: 2.33 (95% CI: 1.46-3.72; P <.001, log-rank test) TDF/FTC (26 events) ABC/3TC (57 events) 0 0 12 24 36 48 60 72 84 96 108 Pts at Risk, n ABC/3TC 398 363 313 267 222 188 137 87 49 20 TDF/FTC 399 361 321 284 236 204 160 104 65 23 Sax PE, et al. N Engl J Med. 2009;361:2230-2240. Wks Since Randomization
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 (%) 100 80 60 40 20 86 82 ITT, NC = F 81 79 75 69 76 67 71 61 CD4+ gain: +374 +312 Pts at Risk, n RAL 400 mg BID EFV 600 mg QHS 0 0 12 24 48 72 96 120 144 168 192 216 240 Wks 281 278 279 280 281 281 277 280 281 281 277 279 282 282 282 281 282 282 281 281 282 282 282 279 Rockstroh JK, et al. J Acquir Immune Dis Syndr. 2013;63:77-85.
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 (%) 100 80 60 40 20 88 84 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 7 7 5 EVG/COBI/TDF/FTC EFV/TDF/FTC 9 0 Virologic Success Virologic Nonsuppression No Wk 48 Data Sax P, et al. Lancet. 2012;379:2439-2448. Sax P, et al. IAS 2012. Abstract TUPE028.
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 (%) 80 60 40 20 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) 325.3 10.5 44.0 (14.3, 73.6) EFV/TDF/FTC QD (n = 419) 281.4 10.9 P =.004 0 0 4 8 1216 24 32 40 48 60 72 84 96 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;369:1807-1818. 2. Walmsley S, et al. CROI 2014. Abstract 543.
NNRTIs: συμμόρφωση
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 (%) 80 60 40 20 71 79 69 65 51 0 Overall QD BID TID QID Studies of Electronic Monitoring of Adherence Claxton AJ, et al. Clin Ther. 2001;23:1296-1310.
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
Atripla: κι όλα άλλαξαν
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
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 13 2009 Cologne Germany
NNRTIs: τα νεώτερα φάρμακα
NNRTIs: etravirine
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;370:29-38. Lazzarin A, et al. Lancet. 2007;370:39-48. Mills A, et al. IAS 2007. Abstract WESS204.1. Katlama C, et al. IAS 2007. Abstract WESS204.2. Cahn P, et al. ICAAC 2007. Abstract H-717.
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 (%) 100 75 50 25 DUET-1 and -2 Pooled Analysis P <.0001 59% 41% ETR + OBR (n = 599) Placebo + OBR (n = 604) 0 0 4 8 12 16 20 24 Time (Weeks) Cahn P, et al. ICAAC 2007. Abstract H-717. clinicaloptions.com/hiv
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 (%) 100 75 50 25 0 71 246/ 345 DRV FC < 10 DUET-1 and -2 Pooled Analysis ETR + OBR 56 57 Placebo + OBR 30 44 200/ 358 73/129 39/132 31/71 2 1/67 DRV FC 10-40 DRV FC > 40 Cahn P, et al. ICAAC 2007. Abstract H-717. clinicaloptions.com/hiv
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 93 93 Rash (all types) 17* 9 Diarrhea 15 20 Nausea 14 11 Headache 9 12 Neurologic disorders 15 19 Psychiatric disorders 13 15 Hepatic adverse events 5 5 *P =.0001 vs placebo. Cahn P, et al. ICAAC 2007. Abstract H-717. clinicaloptions.com/hiv
NNRTIs: riplivirine
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) 100 80 78 78 60 40 20 0 n = 686 RPV 682 EFV Pooled Data Cohen CJ, et al. AIDS. 2013;27:939-950. 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 48-96 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
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 (%) 100 80 60 40 20 0 84 Rilpivirine Efavirenz 80 71 76 Cohen CJ, et al. AIDS. 2013;27:939-950. 65 73 100 80 60 40 20 56 69 71 75 81 79 85 n = 368 329 249 270 69 83 n = 34 36 194 175 313 307 144 164 0 100k > 100k - > 500k < 50 50-200 - 350 500k < 200 < 350 By Baseline HIV-1 RNA (copies/ml) By Baseline CD4+ Count (cells/mm 3 ) 79 clinicaloptions.com/hiv
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;27:939-950. 2. Cohen C, et al. Glasgow 2012. Abstract O425. 3. DHHS Guidelines. February 2013. clinicaloptions.com/hiv
NNRTIs: ανάπτυξη αντοχής μετά από αποτυχία του πρώτου σχήματος
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 (%) 80 60 40 20 0 68 11 0 0 TDF + FTC (n = 244) ZDV/3TC (n = 243) TDF + 3TC (n = 299) 1. Arribas JR, et al. IAS 2007. Abstract WEPEB029. 2. Gallant JE, et al. JAMA. 2004;292:191-201. 72 34 n = 13/19 2/19 21/29 10/29 2/29 26/47 18/47 8/47 7 0 55 38 0 17 clinicaloptions.com/hiv
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 78 46 56 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 2007. Abstract 57. clinicaloptions.com/hiv
Clinical Strategies for Optimizing Outcomes With Next-Generation Agents clinicaloptions.com/hiv
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
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).
Mutations Selected by NNRTIs Efavirenz Etravirine Nevirapine 2010. The International AIDS Society USA Johnson et al. Topics HIV Med. December 2009. Updates available at www.iasusa.org.
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 67 18 28 14 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
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 2000-2010. 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 ± 8.7 43.1 ± 10.4 39.7 ± 10.4 0.001 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 3 2 5 0.35 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
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
NNRTIs: μεταδιδόμενη αντοχή και η κλινική της σημασία
Επιλογή του πρώτου σχήματος First shot is your best shot Μεταλλάξεις - μεταδιδόμενη αντοχή
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% (2000-2007) Skoura L, Metallidis S, Buckton AJ et al. J Antimicrob Chemother. 2011 21.8% (2009-2011) Tenth European Meeting on HIV & Hepatitis, Barcelona, Spain, 2012 24 ο Συνέδριο AIDS
NNRTIs και συννοσηρότητα
Medical comorbidities among 66,840 HIV- and 33,420 HIV+ veterans 100 Prevalence (%) 10 1 0,1 Hypertension Diabetes Vascular Pulmonary Liver Renal <40 HIV- <40 HIV+ 40-49 HIV- 40-49 HIV+ 50-59 HIV- 50-59 HIV+ 60+ HIV- 60+ HIV+ (Goulet, CID 2007)
Αλληλεπίδραση HIV-Φυματίωσης
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
Ριφαμπικίνη και NNRTI Curran A et al, Management of TB/HIV co-infection, AIDS Rev 2012
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.
Αλληλεπίδραση HIV-HCV
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 2013. Abstract 537. 2. Rilpivirine [package insert]. 3. Custodio J, et al. ICAAC 2013. Abstract A-1576. 4. Dolutegravir [package insert]. 5. DHHS Adult Guidelines. February 2013.
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 7 4000 3000 2000 1000 0 0 4 8 12 16 20 24 Plasma Concentration of RPV (ng/ml), Day 7 250 200 150 100 50 0 0 4 8 12 16 20 24 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 2012. Abstract 36620.
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 7 6000 5000 4000 3000 2000 1000 0 Simeprevir Darunavir Ritonavir 0 4 8 12 16 20 24 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) 10000 8000 6000 4000 2000 0 0 4 8 12 16 20 24 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 7 10000 8000 6000 4000 2000 0 0 4 8 12 16 20 24 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 2012. Abstract 36620.
HIV και νεφρική λειτουργία
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) 0.35 0.30 0.25 0.20 0.15 0.10 0.05 0-0.05-0.10 BL EVG/COBI/TDF/FTC EFV/TDF/FTC 2 4 8 12 16 24 32 40 48 Wks 0.28 0.24 0.20 0.16 0.12 0.08 0.04 0-0.04 BL EVG/COBI/TDF/FTC ATV/RTV + TDF/FTC 2 4 8 12 16 24 32 40 48 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;379:2439-2448. DeJesus E, et al. Lancet. 2012;379:2429-2438.
HIV και κύηση
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.
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 2013 7790 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 2013. 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 34/1400 136/4360 21/805 46/1982 129/4000 19/878 5/212 7/289 26/1125 47/1211 52/2260 18/766 31/1061 Insufficient data Insufficient data Prevalence, % (95% CI) 3.0 (2.0-4.3) 4.8 (3.0-7.3) 2.4 (1.7-3.4) 3.1 (2.6-3.7) 2.6 (1.6-4.0) 2.3 (1.7-3.1) 3.2 (2.7-3.8) 2.2 (1.3-3.4) 2.4 (0.8-5.4) 2.4 (1.0-4.9) 2.3 (1.5-3.4) 3.9 (2.9-5.1) 2.3 (1.7-3.0) 2.3 (1.4-3.7) 2.9 (2.0-4.1)
HIV και λιπίδια
Factors associated with mortality in HIV infected patients with metabolic syndrome
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;374:796-806 2. Daar ES, et al. Ann Intern Med. 2011;154:445-456. 3. Molina JM, et al. Lancet. 2008;372:646-655. 4. Ortiz R, et al. AIDS. 2008;22:1389-1397.
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;2:381 389; 2. Fautkenheuer G, et al. J Antimicrob Chemother 2012;67:685 690; 3. Cohen C, et al. Lancet 2011;378:229 237; 4. Mills AM, et al. AIDS 2009;23:1679 1688
Switch Pis to NNRTIs vs lipid lowering agents Colesterol total a los 12 meses
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) 0-0.2-0.4-0.6-0.8-1.0-0.65 TC LDL TG HDL -0.03-0.62-0.65-0.41 Palella F, et al. AIDS. 2014;28:335-344. 0-36 -0.41-0.60 0.03-0.90-0.72-0.03-0.05-0.05-0.1 Mean Change 0.1 0-0.1-0.2-0.3-0.4-0.5 TC:HDL ratio 0.08-0.27-0.43-0.35 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)
HIV και οστική νόσος
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.
NNRTIs ανεπιθύμητες ενέργειες
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;154:445-456. 2. Molina JM, et al. Lancet. 2008;372:646-655. 3. Ortiz R, et al. AIDS. 2008;22:1389-1397. 4. Lennox J, et al. Lancet. 2009;374:796-806. 5. Molina JM, et al. Lancet. 2011;378:238-246. 6. Sax P, et al. Lancet. 2012;379:2439-2448. 7. Walmsley S, et al. ICAAC 2012. Abstract H-556b.
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;2:671-684. 2. Shafer R, et al. N Engl J Med. 2003;349:2304-2315. 3. Bartlett J, et al. J Acquir Immune Defic Syndr. 2006;43:284-92.
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 34 35 31 53 Vertigo 1 2 0 11 Dizziness 11 7 8 30 Somnolence 3 3 4 11 Abnormal dreams/nightmares 1 6 0 10 Mean lipid change from baseline [2] TC, mg/dl 8 3 5 31 LDL, mg/dl 3 1-1 15 HDL, mg/dl 5 6 5 12 TC-to-HDL ratio -0.4-0.6-0.4-0.3 TG, mg/dl -5-19 -5 18 Yeni P, et al. EACS 2007. Abstract P7.2/07.
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 (%) 40 35 30 25 20 15 10 5 Any Grade AEs of Interest Week 0-4 Week > 4-8 Week > 8-12 1.2 1 9.5 0.9 2 17.7 0.3 0.6 14.7 0.9 1.4 35 0 RPV EFV RPV EFV Total (%) 11.7 20.6 15.6 37.3 Psychiatric Neurological Rashbaum B, et al. ICAAC 2011. Chicago. #H2-805 93
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) 2.4 0.9 Suicide ideation 0.7 0.3 Nonfatal suicide attempts Aggressive behavior Paranoid reactions 0.5 0 0.4 0.5 0.4 0.3 Manic reactions 0.2 0.3 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.
24th Annual CCO HIV and Hepatitis C Symposium clinicaloptions.com Increased Risk of Suicidality Associated With EFV 5%.05.04 Efavirenz Efavirenz-free HR (95% CI) 2.28 (1.27-4.10), P =.006 Probability.03.02 47 events/5817 PY* (8.08/1000 PY).01 As-treated HR 2.16 (1.16-4.00) 0 *Person-years, sum of at-risk follow-up. Mollan K, et al. IDWeek 2013. Abstract 40032. 0 24 48 72 96 120 144 168 192 Wks to Suicidality 15 events/4099 PY* (3.66/1000 PY)
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 (1.27-4.10).006* Study A5095 A5142 A5175 A5202 6/739 8/1001 13/1763 20/2315 (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 (0.36-24.88) 2.04 (0.43-9.62) 3.28 (0.74-14.52) 2.02 (0.94-4.31).94 Region US Multinational 39/4346 8/1471 (8.97) (5.44) 13/3354 2/745 (3.88) (2.68) 2.32 (1.23-4.38) 2.02 (0.43-9.53).87 0.02 1.00 50.00 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.
NNRTIs αλληλεπιδράσεις φαρμάκων
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 2013. 2. Dolutegravir [package insert]. Atorvastatin Pitavastatin Pitavastatin
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 2013. 2. DHHS Perinatal Guidelines. July 2012. 3. TDF/FTC/EVG/COBI [package insert]. 4. Dolutegravir [package insert].
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 2013. 2. Dolutegravir [package insert].
NNRTIs και μελέτες αλλαγής Ας τις δούμε πέρα από τον αρχικό τους στόχο
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 2014. Abstract 553LB.
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 (%) 100 80 60 40 Δ +5.3% (95% CI: -0.5 to +12) 93 88 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 = 20 0 1 < 1 271 126 3 1 16 16 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 2014. 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
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 100 70 60 50 40 30 20 10 0 61 HIV Symptom Index Vivid Dreams Insomnia Anxiety Dizziness * 35 136 224 75 212 64 64 65 101 56 87 40 119 84 224209 48 100 41 87 Baseline EVG/COBI/TDF/FTC NNRTI + TDF/FTC 103 222 71 208 40 100 34 87 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;14:590-599. 53 48 47 46 34 Wk 48 EVG/COBI/TDF/FTC NNRTI + TDF/FTC 40 39 40 37 37 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) 90 225 * 23 49 211 37 99 32 87
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;28:335-344.
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 (%) 100 80 60 40 20 0 93.7 89.9 92.1 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) 0.9 5 1.3 5.4 5 6.6 Virologic Failure No Data 100 80 60 40 20 0 89.3 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;28:335-344.
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, (%) 100 80 60 40 20 0 RPV/TDF/FTC PI/RTV + 2 NRTIs 95.0 95.5 89.2 92.3 152/160 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 -4.8 3.2 11.3-1.4 5.8 12.9-12 0 +12 Palella F, et al. IAC 2012. Abstract TUAB0104.
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) 0-0.2-0.4-0.6-0.8-1.0-0.65 TC LDL TG HDL -0.03-0.62-0.65-0.41 Palella F, et al. AIDS. 2014;28:335-344. 0-36 -0.41-0.60 0.03-0.90-0.72-0.03-0.05-0.05-0.1 Mean Change 0.1 0-0.1-0.2-0.3-0.4-0.5 TC:HDL ratio 0.08-0.27-0.43-0.35 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)
NNRTIs: το μέλλον
Lersivirine Νέος NNRTI από την Pfizer
Lersivirine vs Efavirenz σε μη θεραπευμένους ασθενείς που λαμβάνουν TDF/FTC: Εβδομάδα 48 HIV-1 RNA < 50 copies/ml Through Wk 48 (%) 100 80 60 40 20 54/63 (86%) 51/65 (79%) 51/65 (79%) LRV 500 mg LRV 750 0 0 mg n = 45 44 41 20 21 22 0 2 4 8 16 24 32 40 48 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 (%) 100 80 60 40 20 80 86 88 75 62 82 LRV 500 mg LRV 750 mg EFV 600 mg Vernazza P, et al. IAS 2011. Abstract TUAB0101. Pfizer NNRTI.
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 2011. Abstract TUAB0101.
Doravirine (MK-1439): Investigational NNRTI PART 1 Dose-ranging ~ 200 patients (~ 40/group) MK-1439 25 mg* Wk 24 Primary time point for dose selection Wk 96 End of study treatment for part 1 MK-1439 50 mg* MK-1439 100 mg* MK-1439 selected dose MK-1439 200 mg* Efavirenz* Efavirenz *All with TDF/FTC Morales-Ramirez J, et al. CROI 2014. Abstract 92LB.
Doravirine vs EFV Phase II: 24-Wk Results HIV-1 RNA < 40 Copies/mL (%) 100 80 60 40 20 0 MK-1439 all doses combined: 76.4% 80.0 32/40 32/42 30/40 32/41 27/42 MK-1439 25 mg 76.2 MK-1439 50 mg 71.4 MK-1439 100 mg 78.0 MK-1439 200 mg 64.3 Efavirenz 600 mg Morales-Ramirez J, et al. CROI 2014. Abstract 92LB.
NNRTIs: Κόστος
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%) 0,002 15 ± 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 ± 9855,3 17749,5 ± 14656,3 14874,4 ± 13441,3 0,001 Μηνιαίο κόστος θεραπείας δεύτερης γραμμής 606,7 ± 117,1 (110) NNRTIs (68) 576.2 ± 83.5 578 ± 127,2 (132) NNRTIs (30) 532.7 ± 11.5 590,9 ± 122,8 (242) NNRTIs (98) 563.41 ± 94.1 0,08 PIs (42) 643.9 ±117.4 PIs (102) 591.7 ± 129.1 PIs (144) 607.3 ± 127.6 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)
Ποσοστό ασθενών ανά χρονικό διάστημα έναρξης θεραπεία μετά την διάγνωση στους ασθενείς με HIV στη Βόρειο Ελλάδα μεταξύ 2000-2010 Σύνολο 76.1% Μέσος όρος CD4 60 <250 50 40 55,3 Σύνολο 23.9% Μέσος όρος CD4 > 400 30 20 10 20,8 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
Ετήσιες αλλαγές θεραπείας
Ετήσιο κόστος αντιρετροικής αγωγής για έναρξη σε 130 naïve ασθενείς 1200000 1000000 800000 773.760 1.035.840 600000 400000 200000 118.560 13 10% 104 80% 143.520 13 10% 0 PI NNRTI Ιντεργκράση Σύνολο
Ετήσιο κόστος αντιρετροικής αγωγής για έναρξη σε 130 naïve ασθενείς 1200000 1000000 800000 600000 Αύξηση από 118.560 σε 410.400 Μείωση από 773.760 σε 491.400 Αύξηση από 143.520 σε 220.800 410.400 491.400 220.800 1.122.600 Αύξηση από 1.035.840 σε 1.122.600 400000 200000 0 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 86.760
Ετήσιο κόστος αντιρετροικής αγωγής για έναρξη σε 130 naïve ασθενείς 1400000 1200000 1000000 800000 Καμία μεταβολή Μείωση από 773.760 σε 386.680 Αύξηση από 143.520 σε 717.600 717600 1222840 Αύξηση από 1.035.840 σε 1.222.840 600000 400000 200000 0 118560 13 10% Καμία μεταβολή 386680 52 40% Μείωση από 80% σε 40% 65 50% Αύξηση από 10% σε 50% PI NNRTI Ιντεργκράση Σύνολο Αύξηση 187.000 Αντιστοιχούν σε 25 ασθενείς με NNRTIs
Φανταστείτε στο μέλλον ένα κλειστό προϋπολογισμό για τα αντιρετροϊκά
NNRTIs: Συμπεράσματα
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 (%) 100 80 60 40 20 0 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] 85.3 89.0 89.8 TDF/FTC ATV/RTV EFV 1. Lennox JL, et al. Lancet. 2009;374:796-806. 2. Daar ES, et al. Ann Intern Med. 2011;154:445-456. 3. Efavirenz/tenofovir/emtricitabine [package insert]. September 2011. 4. Johnson VA, et al. Top HIV Med. 2010;18:156-163. 5. Riddler SA, et al. N Engl J Med. 2008;358:2095-2106. 6. Efavirenz [package insert]. September 2011.
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
Σας ευχαριστώ πολύ για την προσοχή σας
Επιλέγοντας σχήμα μετά από αποτυχία με NNRTI
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 25000 Γονοτυπική αντοχή Y181C Μ184V
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
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 52 51 1 NNRTI 76 77 0 PI 32 31 1 PI 36 39 2 PIs 32 30 3-class experienced 46 46 Madruga JV, et al. Lancet. 2007;370:49-58.
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 (%) 100 80 60 40 20 0 71 P =.005 60 Overall (n = 595) DRV/RTV LPV/RTV 1. Madruga JV, et al. Lancet. 2007;370:49-58. 2. De Meyer S, et al. Glasgow 2008. Abstract O424.