Boosted Protease Inhibitors: Παρόν και µέλλον στην θεραπεία της HIV-νόσου

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1 Boosted Protease Inhibitors: Παρόν και µέλλον στην θεραπεία της HIV-νόσου

2 Boosted Regimens: Εισαγωγή

3 AIDS-σχετιζόµενη θνητότητα και επίδραση των PIs 80,000 Deaths (n) 70,000 60,000 50,000 40,000 30,000 20,000 10, Yr of Death Introduction of PI-containing triple ART

4 Χρονολογική εξέλιξη της τάξης των PIs Πολλά χάπια ανά ηµέρα Πολλαπλές δόσεις Υψηλή τοξικότητα SQV RTV IDV Καλύτερη ανοχή boosted SQV/RTV IDV/RTV APV NFV ATV ATV/RTV DRV/RTV 1 χάπι την ηµέρα (+ RTV & NRTIs) Boosting για όλα Αντιµετωπίσιµη τοξικότητα Single-tablet regimens ATV/COBI Σχήµατα µια φορά την ηµέρα DRV/COBI Coformulation DRV/COBI/TAF/FTC PAST FPV/RTV LPV/RTV PRESENT (Not-too-distant) FUTURE

5 Ritonavir-Boosted PIs Οι PIs παραδοσιακά συγχορηγούνται µε RTV ( mg QD) που δρα σαν φαρµακολογικός ενισχυτής Η RTV αναστέλλει το CYP3A4 στο ήπαρ, αυξάνοντας την συγκέντρωση και τον χρόνο ηµίσειας ζωής των PI [1] Η ενίσχυση επιτρέπει την λιγότερη συχνή χορήγηση και την χορήγηση µικρότερων δόσεων Η χρήση της RTV σχετίζεται µε διάρροια, ναυτία, αυξηµένα λιπίδια και αλληλεπιδράσεις φαρµάκων [2] Mean Plasma Concentration (SD) at Steady State (ng/ml) [3] Pharmacologic Boosting of ATV by RTV 10, Hrs ATV/RTV 300/100 mg QD ATV 400 mg QD Median wild-type EC 90 = 14 ng/ml 1. Merry C, et al. AIDS 1997;11:F29-F Ritonavir [package insert]. 3. Atazanavir [package insert].

6 Κύριες αλληλεπιδράσεις µε RTV Αύξηση επιπέδων µε RTV Μείωση επιπέδων µε RTV Maraviroc Anticonvulsants (some) Antiarrythmics Antidepressants (some) Anticancer agents Bupropion Anticonvulsants (some) Ethinyl estradiol Antidepressants (some) Methadone Beta-blockers Theophylline Calcium channel blockers Rifampin Colchicine Digoxin Erectile dysfunction drugs Glucocorticoids Methamphetamine Rifabutin Sedatives/hypnotics Statins (some)

7 Cobicistat: ένας νέος ενισχυτής Μικρό µόριο χωρίς δραστικότητα έναντι του HIV Παρόµοια από το BL της TC και TGs σε σχέση µε την RTV όταν ενισχύουν τον ίδιο παράγοντα [1] Είναι αναστολέας και µεταβολίζεται από CYP3A4; Πολλές αλληλεπιδράσεις [2,3] Ήπια αύξηση της Cr εξαιτίας αναστολής της σωληναριακής έκκρισης [3] Δεν σχετίζεται µε αλλαγές του GFR 1. Gallant JE, et al. J Infect Dis. 2013;208: DHHS Guidelines. May TDF/FTC/EVG/COBI [package insert]. 4. Rilpivirine [package insert]. 5. Dolutegravir [package insert].

8 DRV/COBI FDC Bioequivalent to DRV + RTV and to DRV + COBI PK analyses in healthy subjects Plasma Concentration of DRV (ng/ml; Mean ± SD) DRV Concentration When Administered as DRV + RTV or as DRV/COBI Coformulation [1] DRV/RTV 800/100 mg QD as single agents (n = 32) DRV/COBI 800/150 mg QD as FDC (n = 33) DRV/COBI 800/150 mg QD as FDC (n = 33) Hrs 1. Kakuda TN, et al. Clin Pharmacol Abstract O_ Kakuda TN, et al. IAS Abstract MOPE DRV Concentration When DRV and COBI Administered as Single Agents or as Coformulation [2] Single agents; fed (n = 38) FDC; fed (n = 40) Single agents; fasted (n = 72) FDC; fasted (n = 74) Hrs

9 Key Drug Drug Interactions With COBI Αύξηση επιπέδων µε COBI Antacids Αύξηση επιπέδων του COBI Azole antifungals Antiarrythmics Clarithromycin Benzodiazepines Beta-blockers Calcium channel blockers Erectile dysfunction drugs Inhaled/injectable corticosteroids Μείωση επιπέδων του COBI Rifabutin Carbamazepine Phenytoin OCPs (norgestimate) Statins DHHS Adult Guidelines. May No interaction between COBI and methadone

10 Μεταβολές στην κρεατινίνη µε Cobicistat και Ritonavir Change in Creatinine Level, Median mg/dl (IQR) COBI RTV BL Wks Interpretation of changes in renal function may be problematic when using coformulations of COBI and TDF [1] Coformulated drugs containing COBI should not be initiated in patients with estimated CrCl < 70 ml/min or used with other nephrotoxic drugs [2,3] 1. Gallant J, et al. J Infect Dis. 2013;208: TDF/FTC/EVG/COBI [package insert]. 3. DHHS Guidelines. May 2014.

11 Boosted PIs στην θεραπεία των Naive ασθενών

12 DHHS Guidelines: Boosted PIs in Recommended Regimens NNRTI Boosted PI INSTI For All Pts, Regardless of BL VL or CD4+ Count EFV/TDF/FTC ATV/RTV + TDF/FTC DRV/RTV + TDF/FTC RAL + TDF/FTC EVG/COBI/TDF/FTC DTG + ABC/3TC* DTG + TDF/FTC Only for Pts With Pre-ART VL < 100,000 c/ml EFV + ABC/3TC* RPV/TDF/FTC ATV/RTV + ABC/3TC* *Only for pts who are HLA-B*5701 negative. Only for those with CD4+ cell counts > 200 cells/mm 3. If initiating ART in a pt with acute/early HIV before resistance test results are available, use a boosted PI plus NRTIs due to slow emergence of PI resistance and uncommon transmitted resistance DHHS Guidelines. May 2014.

13 Βασικά δεδοµένα για Atazanavir/ Ritonavir και Darunavir/Ritonavir σε Naive Ασθενείς

14 Atazanavir/Ritonavir Comparative Studies in Treatment-Naive Pts Randomized, noninferiority phase III studies Primary endpoint: HIV-1 RNA < 50 c/ml at Wk 48 CASTLE [1] (open label) ART-naive pts VL 5000 c/ml (N = 883) ATV/RTV + TDF/FTC (n = 440) LPV/RTV BID* + TDF/FTC (n = 443) ACTG 5202 [2] (third agent, open label; NRTIs prematurely unblinded) ART-naive pts VL 1000 c/ml (N = 1857) ATV/RTV + TDF/FTC (n = 465) ATV/RTV + ABC/3TC (n = 463) EFV + TDF/FTC (n = 464) EFV + ABC/3TC (n = 465) GS-103 [3] (placebo controlled) *SGC until Wk 48. ART-naive pts VL 5000 c/ml egfr 70 ml/min (N = 708) ATV/RTV + TDF/FTC (n = 355) EVG/COBI/TDF/FTC (n = 353) 1. Molina JM, et al. Lancet. 2008;372: Daar E, et al. Ann Intern Med. 2011;154: De Jesus E, et al. Lancet. 2012;379:

15 CASTLE: ATV/RTV vs LPV/RTV in Naive Pts Through 96 Wks ATV/RTV + TDF/FTC (n = 440) LPV/RTV = TDF/FTC (n = 443) ATV/RTV noninferior to LPV/RTV at Wk 48 [1] ; superior at Wk 96 [2] HIV-1 RNA < 50 c/ml (%) n/n = / 440 Δ 1.7% (-3.8 to 7.1) P = NS Wk / 443 Δ 6.1% (0.3 to 12.0) P < / 440 Wk / 443 Results consistent across BL HIV-1 RNA, CD4+ cell count, subgroups VF in 7% of each arm by Wk 96 1 pt in ATV/RTV arm with major PI mutation at Wk 96 vs 0 in LPV/RTV arm; NRTI resistance in 7 vs 10, respectively Similar CD4+ cell count increase: +268 (ATV/RTV) vs +290 (LPV/RTV) at Wk Molina JM, et al. Lancet. 2008;372: Molina JM, et al. J Acquir Immune Defic Syndr. 2010;53:

16 A5202: Efficacy With ATV/RTV vs EFV Cumulative Probability of VF EFV + TDF/FTC (57 events) ATV/RTV + TDF/FTC (57 events) EFV + ABC/3TC (72 events) ATV/RTV + ABC/3TC (83 events) *Interim analysis showed time to VF shorter with ABC/3TC in pts with BL VL > 100,000 c/ml Pts With Resistance, n Wks From Randomization Resistance at Wk 96 EFV Arms ATV/RTV Arms NRTI NNRTI 68 1 Similar time to VF with ATV/RTV vs EFV, whether with TDF/FTC or ABC/3TC Time to safety (P =.048) and tolerability (P <.001) endpoints shorter with EFV when paired with ABC/3TC but not when with TDF/ FTC Similar CD4+ count increase with ATV/RTV vs EFV when paired with ABC/3TC (+250 vs +251) but greater when paired with TDF/FTC (+252 vs +221) NRTI + NNRTI 36 0 PI resistance 0 1 Less resistance at VF with ATV/ RTV vs EFV Daar ES, et al. Ann Intern Med. 2011;154: Sax PE, et al. J Infect Dis. 2011;204:

17 EVG/COBI/TDF/FTC Noninferior to ATV/RTV + TDF/FTC Through Wk 144 HIV-1 RNA < 50 c/ml (%) EVG/COBI/TDF/FTC (n = 353) ATV/RTV + TDF/FTC (n = 355) Δ 3.0% (-1.9 to 7.8) Δ 1.1% (-4.5 to 6.7) Δ 3.1% (-3.2 to 9.4) EVG/COBI arm noninferior to ATV/ RTV arm at Wk 48 primary endpoint [1] and through Wk 144 [2,3] Results consistent across subgroups: BL HIV-1 RNA, CD4+ count, adherence, age, sex, race VF: 8% in EVG/COBI arm vs 7% in ATV/RTV arm at Wk pts with resistance (NRTI + INSTI) in EVG/COBI arm vs 2 (PI only) in ATV/ RTV arm at Wk 144 Similar CD4+ count increase at Wk 144: +280 (EVG/COBI) vs +293 (ATV/RTV) 0 Wk 48 Wk 96 Wk DeJesus E, et al. Lancet. 2012;379: Rockstroh J, et al. J Acquir Immune Defic Syndr. 2013;62: Clumeck N, et al. EACS Abstract LBPS7/2.

18 Lipid Changes From BL to Wk 48 Median Change (mg/dl) Median Change (mg/dl) P < CASTLE [1] ATV/RTV LPV/RTV P <.0001 TC LDL HDL TG 58 Median Change (mg/dl) Study 103 [3] 11 EVG/COBI ATV/RTV P =.006 TC LDL HDL TG 70 ACTG 5202 [2] 60 P <.001 EFV + TDF/FTC EFV + ABC/3TC ATV/RTV + TDF/FTC ATV/RTV + ABC/3TC 40 P < P < P < P = P < TC LDL HDL TG This slide is an illustration only and not meant to be a cross-study comparison. 1. Molina JM, et al. Lancet. 2008;372: Daar E, et al. Ann Intern Med. 2011;154: De Jesus E, et al. Lancet. 2012;379:

19 ACTG 5202 Substudy: Loss of Bone With EFV vs ATV/RTV Initiation Change in Spine BMD EFV ATV/RTV Change in Hip BMD Change From BL (%) P = Change From BL (%) P = Visit Wk From Randomization Visit Wk From Randomization EFV ATV/RTV EFV ATV/RTV McComsey G, et al. J Infect Dis. 2011;203:

20 ATV/RTV Ανεπιθύµητες ενέργειες ATV/RTV vs LPV/RTV [1,2] : Περισσότερο εξάνθηµα ATV/RTV vs EFV [3] : Ελάττωση της CrCl (with TDF/FTC) vs αύξησης µε EFV; Λιγότερα γεγονότα ΚΝΣ Substudy [4] : µεγαλύτερη απώλεια οστικής µάζας (not hip) BMD Όλες οι µελέτες : Περισσότερος ίκτερος Ποσοστό 5% µε 9% [5] 1. Molina JM, et al. Lancet. 2008;372: Molina JM, et al. J Acquir Immune Defic Syndr. 2010;53: Daar ES, et al. Ann Intern Med. 2011;154: McComsey G, et al. J Infect Dis. 2011;203: Atazanavir [package insert].

21 DRV/RTV Comparative Studies in Treatment-Naive Pts Randomized, noninferiority phase III studies Primary endpoint: HIV-1 RNA < 50 c/ml at Wk 48 ARTEMIS [1,2] (open label) ART-naive pts VL 5000 c/ml (N = 689) DRV/RTV + TDF/FTC (n = 343) LPV/RTV QD or BID + TDF/FTC (n = 346) No phase III clinical trial comparison with EFV FLAMINGO [3] (open label) ART-naive pts VL 1000 c/ml (N = 484) DRV/RTV + 2 NRTIs* (n = 242) DTG + 2 NRTIs* (n = 242) *Investigator-selected NRTI backbone: either TDF/FTC or ABC/3TC. 1. Ortiz R, et al. AIDS. 2008;22: Mills A, et al. AIDS. 2009;23: Clotet B, et al. Lancet. 2014;[Epub ahead of print].

22 ARTEMIS: DRV/RTV vs LPV/RTV in Naive Pts Through 96 Weeks HIV-1 RNA < 50 c/ml (%) DRV/RTV + TDF/FTC (n = 343) Δ 5.6% (-0.1 to 11.0) P <.001 noninferiority LPV/RTV + TDF/FTC (n = 346) Δ 8.4% ( ) P <.001 noninferiority P <.012 superiority Wk 48 [1] Wk 96 [2] DRV/RTV noninferior to LPV/RTV at Wk 48; superior at Wk 96 Efficacy results better in DRV/RTV arm among those with BL VL > 100K (P =.023) c/ml and CD4+ < 200 (P =.009) VF in 1% of DRV/RTV arm vs 2% of LPV/RTV by Wk 96 No major PI mutations in either arm at Wk 96; NRTI mutations in 2 pts in DRV/RTV arm vs 5 in LPV/RTV arm CD4+ count increase at Wk 96: +171 (DRV/RTV) vs +188 (LPV/RTV) Significantly smaller mean change in TC and TG at Wk 48 with DRV/RTV 1. Ortiz R, et al. AIDS. 2008;22: Mills A, et al. AIDS. 2009;23:

23 FLAMINGO: DTG vs DRV/RTV + 2 NRTIs in Naive Patients at Wk 48 HIV-1 RNA < 50 c/ml at Wk 48 (%) / 242 DTG 50 mg QD + NRTIs Δ +7.1% ( ; P =.025) / 242 DRV/RTV 800/100 mg QD + NRTIs Clotet B, et al. Lancet. 2014;[Epub ahead of print]. DTG superior to DRV/RTV at Wk 48 primary efficacy endpoint Efficacy results better in DTG arm among pts with BL VL > 100K VF < 1% (n = 2) in each arm at Wk 48 No pts with resistance in either arm at Wk 48 Treatment-related study d/c: 2% in DTG arm vs 4% in DRV/RTV arm Same CD4+ cell count increase at Wk 48: +210 cells/mm³ in each arm Mean increase in fasting LDL-C at Wk 48 significantly lower in DTG arm than DRV/RTV arm (P <.0001)

24 DRV/RTV ανεπιθύµητες ενέργειες DRV/RTV vs LPV/RTV [1] Την Wk 96, περισσότερη διάρροια µε LPV/RTV; Περισσότερο εξάνθηµα µε DRV/RTV arm (3% vs 1%, not significant) DRV/RTV vs DTG [2] Περισσότερη διάρροια µε DRV/RTV; Περισσότερος πονοκέφαλος µε DTG Μικρή οξεία αύξηση κρεατινίνης τις πρώτες 4 wks στη θεραπεία µε DTG 1. Mills A, et al. AIDS. 2009;23: Clotet B, et al. Lancet. 2014;[Epub ahead of print].

25 Κύριες αλληλεπιδράσεις µε ATV/ RTV και DRV/RTV

26 Drug Drug Interactions With First-line Boosted PIs and Lipid-Lowering Therapy Antiretroviral Contraindicated Titrate Dose No Dose Adjustment ATV/RTV DRV/RTV Lovastatin Simvastatin Lovastatin Simvastatin Atorvastatin Rosuvastatin Atorvastatin Pravastatin Rosuvastatin Pitavastatin Pitavastatin DHHS Adult Guidelines. May 2014.

27 First-line Boosted PI Drug Drug Interactions With OCPs Antiretroviral Effect on OCP Dosing Recommendation ATV/RTV [1,2] Ethinyl estradiol AUC 19% Norgestimate AUC 85% DRV/RTV [1,2] Ethinyl estradiol AUC 44% Norethindrone AUC 14% OCP should contain 35 mcg ethinyl estradiol Additional methods of contraception recommended 1. DHHS Adult Guidelines. May DHHS Perinatal Guidelines. March 2014.

28 First-line Boosted PI Drug Drug Interactions With Acid-Reducing Agents ARV Antacids H2-Receptor Antagonists ATV/RTV DRV/RTV Give ATV 2 hrs before or 1 hr after antacids or buffered medications No clinically relevant interactions Give ATV/RTV simultaneously with and/or 10 hrs after the H2-receptor antagonist If using TDF and H2-receptor antagonist in ARTexperienced pts, use ATV/ RTV 400/100 mg Use dose equivalent of famotidine 40 mg BID in ART-naive pts or 20 mg BID in ART-experienced pts No clinically relevant interactions Proton Pump Inhibitors PPIs should be administered at least 12 hrs before ATV/ RTV PPIs not recommended in PI-experienced pts Use dose equivalent of omeprazole 20 mg daily in PI-naive pts No clinically relevant interactions

29 Boosted PIs στην κύηση

30 Antiretroviral Agents and Pregnancy Guideline Categorization NRTI NNRTI PI Entry Inhibitor INSTI Fusion Inhibitor Preferred ABC/3TC* TDF/FTC or 3TC EFV LPV/RTV ZDV/3TC ATV/RTV Alternative NVP DRV/RTV SQV/RTV** RAL Insufficient data RPV FPV/RTV MVC DTG EVG/COBI Not recommended ABC/3TC/ZDV d4t ddl ETR IDV/RTV NFV RTV TPV T20 *Should not be used in pts who are HLA-B*5701 positive. TDF combinations should be used with caution in pts with renal insufficiency. Most experience for use in pregnancy but potential for hematologic toxicity. After first 8 wks of pregnancy. Preferred when potential for drug drug interactions with PI a problem. Once-daily administration not recommended for pregnant pts. ǁ Use with caution in pts with CD4+ counts > 250 cells/mm 3 due to potential for liver toxicity; use with caution with ABC since both associated with potential for HSR. **Baseline EKG recommended; contraindicated in pts with preexisting cardiac condition. Limited data on use in pregnancy, but may be considered when drug drug interactions with PI regimens are a concern. Because of toxicity, lower rates of virologic suppression or lack of data in naive pts. DHHS Perinatal Guidelines. March 2014.

31 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 ( )

32 New Coformulations

33 Ongoing Studies of COBI-Boosted DRV Plus 2 NRTIs Phase IIIb study in tx-naive tx-exp d pts with no DRV RAMs [1] Randomized, double-blind phase II trial [2] Primary endpoint: grade 3 or grade 4 AEs by Wk 24 Primary endpoint: HIV-1 RNA < 50 copies/ml at Wk 24 Secondary endpoints: HIV-1 RNA at Wk 24 and Wk 48 Wk 24 Wk 48 Pts with HIV-1 RNA 500; naive or on stable ART for 12 wks and sensitive to 2 NRTIs with no DRV RAMS (N = 300) Wk 24 DRV + COBI + 2 NRTIs Wk 48 ART-naive pts, HIV-1 RNA 5000 c/ml, egfr 70 ml/min (N = 150) DRV/COBI/TAF/FTC QD (n = 75) DRV/COBI + TDF/FTC (n = 75) Coformulation of DRV and COBI being considered for approval by FDA 1. ClinicalTrials.gov. NCT ClinicalTrials.gov. NCT

34 ATV/COBI + TDF/FTC Noninferior to ATV/RTV + TDF/FTC Through Wk 48 Randomized, double-blind, phase III trial in ART-naive patients Primary endpoint: HIV-1 RNA < 50 copies/ml at Wk 48 Wk 24 Wk Δ -2.2% (-7.4 to 3.0) ATV/COBI ATV/RTV ART-naive pts, HIV-1 RNA 5000 c/ml, egfr 70 ml/ min (N = 692) TDF/FTC + ATV/COBI (n = 344) TDF/FTC + ATV/RTV (n = 348) Coformulation of ATV and COBI being considered for approval by FDA Gallant JE, et al. J Infect Dis. 2013;208: Patients (%) Virologic Success* Virologic Failure n = No 6 Data *HIV-1 RNA < 50 c/ml as defined by FDA Snapshot algorithm Discontinued for AE, death, or missing data.

35 Boosted Atazanavir: Πλεονεκτήµατα και Μειονεκτήµατα Πλεονεκτήµατα Παρόµοια αποτελεσµατικότητα µε EFV at Wk 96 [1] Ευνοϊκό λιπιδαιµικό προφίλ [2,3] Μικρή πιθανότητα αντοχής [1-3] Παρόµοιο φορτίο χαπιών µε DRV/RTV Μπορεί να δωθεί unboosted Το σχήµα µια φορά την ηµέρα απαιτεί RTV 100 mg/day Θα κυκλοφορήσει µε cobicistat σε ένα χάπι [4] Μειονεκτήµατα Υψηλότερα ποσοστά αποτυχίας σε σχέση DRV/RTV and RAL in ACTG 5257 λόγω ανεπιθύµητων ενεργειών [5] Αύξηση χολερυθρίνης σε 4% µε 9% των ασθενών [6] Αλληλεπίδραση µε acid-reducing agents [6] Απαιτείται φαγητό [6] Δεν υπάρχουν πλάνα για STR 1. Daar ES, et al. Ann Intern Med. 2011;154: Molina JM, et al. Lancet. 2008;372: Molina JM, et al. J Acquir Immune Defic Syndr. 2010;53: Gallant JE, et al. J Infect Dis. 2013;208: Landovitz R, et al. CROI Abstract Atazanavir [package insert].

36 Boosted Darunavir: Πλεονεκτήµατα και Μειονεκτήµατα Πλεονεκτήµατα Ευνοϊκό λιπιδαιµικό προφίλ [1,2] Μικρή πιθανότητα αντοχής [1,2] Παρόµοιο φορτίο χαπιών µε ATV/RTV Μειονεκτήµατα Εξάνθηµα σε ~ 6% των ασθενών ; Χρήση µε προσοχή σε ασθενείς µε sulfa allergy [4] Μικρότερος κίνδυνος αποτυχίας σε σχέση µε ATV/RTV in ACTG 5257 [3] Το σχήµα µια φορά την ηµέρα απαιτεί RTV 100 mg/day Κατώτερο του DTG in Flamingo study [5] Δεν µπορεί να δοθεί unboosted Θα κυκλοφορήσει µε cobicistat σε ένα χάπι 1 Ortiz R, et al. AIDS. 2008;22: Mills AM, et al. AIDS. 2009;23: Landovitz R, et al. CROI Abstract Darunavir [package insert]. 5. Clotet B, et al. Lancet. 2014;[Epub ahead of print].

37 Transmitted HIV Drug Resistance in MSM in 11 Jurisdictions, Genotypic analysis of pol sequences of samples from 10,894 newly diagnosed MSM pts in CDC National HIV-1 Surveillance System All cases with sequences Cases classified as recent infections (n = 3083) Cases classified as long-standing infections (n = 7810) Cases (%) or more NNRTI NRTI PI Transmitted Drug Resistance Mutations Bañez Ocfemia MC, et al. CROI Abstract 579.

38 Υπέρ και κατά στην επιλογή σχήµατος µε RTV-Boosted PIs ως πρώτη γραµµή θεραπείας Πλεονεκτήµατα Ισχυρή δραστικότητα; Μικρά ποσοστά µεταδιδόµενης αντοχής Αύξηση των CD4+ cell γενικά µεγαλύτερη από ότι µε EFV Αντοχή σε PI γενικά σπάνια σε ιολογική αποτυχία Μικρή πιθανότητα για αντοχή σε NRTI σε boosted PI αποτυχία Οι επιλογές είναι ευρύτερες επί αποτυχίας συµπεριλαµβανοµένων και των PIs Μειονεκτήµατα Μεταβολικές επιπλοκές κύρια σε ορισµένους PIs και ή low-dose RTV Γαστρεντερική δυσανεξία σε PIs και ή low-dose RTV Αλληλεπιδράσεις (CYP450) LPV/RTV ο µόνος PI σε ένα χάπι Τουλάχιστον 2 χάπια την ηµέρα No STR *Current as of July 2014

39 Αποτυγχάνοντας από ένα σχήµα µε PI

40 Ενδιαφέρουσα περίπτωση n Ο ΒΛΔΗ (MSM) παρουσίασε ιολογική αποτυχία µετά από ένα αρχικό σχήµα µε TDF/FTC + ATV/RTV n Τωρινά CD4+ cell είναι 320 cells/mm³ n Τωρινό HIV-1 RNA είναι 10,500 copies/ml (αρχικά 18,000) µετά από µια περίοδο που ήταν µη ανιχνεύσιµος για 3 χρόνια n Η αρχική αντοχή Κ103Ν n Ιολογική αποτυχία λόγω µη συµµόρφωσης n Τον ενοχλεί ο ίκτερος n Ο γονοτυπικός έλεγχος δείχνει n M184V

41 Ενδιαφέρουσα περίπτωση n Τι αγωγή θα δίνατε: 1. TFV/FTC + boosted DRV 2. TFV/FTC + ETR 3. TFV/FTC + RAL 4. TFV/FTC + boosted DRV+ RAL 5. 3TC + boosted PI + RAL 6. TFV/FTC + ETR + RAL

42

43 De Meyer, Antimicrob Agents Chemother 2005; De Meyer, IHDRW 2006 The genetic barrier of PIs in vitro Increase in PI selection concentration DRV (R41T, K70E) TPV (L33V, M46L, V82T) ATV (L10F, V32I, M46I, I62V, A71V, I84V, N88S) LPV (L10F, L23I, M46I, I50V, I54V, L63P, V82A) APV (L10F, V32I, L33F, M46I, I47V, I50V) NFV (L10F, D30N, R41K, K45I, M46I, V77I, I84V, N88D) SQV (G48V, A71V, G73S, I84V, L90M) RTV (G16E, M46I, V82F, I84V) Time (days)

44 Applying Best Practices for HIV-Infected Patients With Initial Regimen Failure clinicaloptions.com/hiv Πολλές απορίες σχετικά µε την αντοχή σε PI δεν έχουν ικανοποιητική απάντηση Σε ένα ασθενή που αποτυγχάνει σε σχήµα µε boosted PI χωρίς ανάπτυξη αντοχής παραµένει ο PI πλήρως ενεργός? Δεν υπάρχει τυχαιοποιηµένη µελέτη Ποια είναι η επίπτωση ενός µικρού αριθµού µεταλλάξεων σε PI? Εξαρτάται από το είδος του PI και το είδος των µεταλλάξεων Π.χ. µία µόνο µετάλλαξη δεν θα επηρεάσει την ευαισθησία σε LPV/RTV

45 In Pts With Isolated M184V, (3TC or FTC) + NRTI + bpi Sufficient for Suppression Retrospective analysis of pts with M184V mutation in British Columbia HIV Drug Treatment Program, Pts categorized by regimen after identification of M184V 3TC or FTC + NRTI + bpi (n = 48) 3TC or FTC + NRTI + bpi + another ART agent (n = 25) 3TC/FTC-sparing: 2 NRTIs + bpi ± another ART agent (n = 44) Neither failed regimen nor subsequent regimen associated with time to HIV-1 RNA suppression Hull M, et al. ICAAC Abstract H-916. Factor Associated With Virologic Suppression HR (95% CI) IDU history 0.37 ( ) Regimen failed at M184V detection NNRTI based Reference bpi based 0.77 ( ) Other 1.37 ( ) Subsequent regimen (3TC or FTC) + NRTI + bpi (3TC or FTC) + NRTI + bpi + additional active agent(s) (3TC or FTC)-sparing: 2 NRTIs + bpi ± additional agents 95% adherence 6 mos after study start, % Reference 1.09 ( ) 0.61 ( ) 2.40 ( )

46 Newer protease mutation score Daruavir is a newer PI with activity against resistant HIV, approved June 2006 POWER studies showed patients treated with darunavir and optimized background meds had VL < 50 copies/ml greater than for comparator Pis Response to darunavir was found to be dependent on 11 PI mutations at baseline The International AIDS Society USA Johnson et al. Topics HIV Med. December Updates available at

47 Darunavir response by DRV score Patients (%) with HIV-1 RNA <50 copies/ml at Week 24 50% A wrinkle: The common PI mutation at 82A may actually have a positive effect on viral response to darunavir 22% 10% 0-2 mutations 3 mutations 4 mutations Number of Darunavir mutations at baseline The International AIDS Society USA Johnson et al. Topics HIV Med. December Updates available at

48 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.

49 Applying Best Practices for HIV-Infected Patients With Initial Regimen Failure clinicaloptions.com/hiv ODIN: QD vs BID DRV/RTV + OBR in Treatment-Experienced Patients Stratified by baseline HIV-1 RNA and > 50,000 copies/ml Wk 48 Treatment-experienced adults with stable HAART for 12 wks, HIV-1 RNA > 1000 copies/ml, CD4+ > 50 cells/mm 3, no DRV RAMs (N = 590) QD DRV/RTV 800/100 mg + OBR* (n = 294) BID DRV/RTV 600/100 mg + OBR* (n = 296) *OBR included 2 active NRTIs. Primary PI mutations in < 2% of patients in either arm Cahn P, et al. CROI Abstract 57.

50 Applying Best Practices for HIV-Infected Patients With Initial Regimen Failure clinicaloptions.com/hiv ODIN: HIV-1 RNA < 50 copies/ml at Wk 48 Overall and by Screening HIV-1 RNA HIV-1 RNA < 50 copies/ml (%) Difference in response, QD vs BID: ITT = 1.2% (95% CI: -6.1%, 8.5%) Wks QD DRV/RTV 800/100 mg BID DRV/RTV 600/100 mg CD HIV-1 RNA < 50 copies/ml, Wk 48 (%) n = ,000 > 50,000 Screening HIV-1 RNA (copies/ml) Similar rates of virologic failure: 22% (QD) vs 18% (BID) Higher rate of lipid abnormalities with BID vs QD arm TC 21% vs 10% (P <.007) LDL-C: 17% vs 10% (P =.019) TG 11% vs 5% (P =.014) Cahn P, et al. CROI Abstract 57. Reproduced with permission.

51 Applying Best Practices for HIV-Infected Patients With Initial Regimen Failure clinicaloptions.com/hiv NRTI + 3TC/FTC + Boosted PI Effective Second-Line Regimen in Pts With M184V British Columbia HIV Drug Treatment Program, Pts with M184V ± NNRTI RAMs but no PI or other NRTI RAMs (N = 117) No significant difference in likelihood of HIV-1 RNA suppression between 3 types of second-line regimen No advantage from including an additional active agent or sparing 3TC/FTC Second-Line Regimen 3TC/FTC + NRTI + boosted PI HR, Time to Virologic Suppression (95% CI) 3TC/FTC + NRTI + boosted PI + additional active agent(s) 1.09 ( ) 3TC/FTC-sparing NRTIs + boosted PI ± additional active agent(s) 0.61 ( ) Hull M, et al. ICAAC Abstract H-916. Ref

52 Applying Best Practices for HIV-Infected Patients With Initial Regimen Failure clinicaloptions.com/hiv Συστάσεις για ασθενείς που αποτυγχάνουν σε αρχικό σχήµα µε PI Αναζητήστε την αιτία αποτυχίας Η αντοχή σε PI είναι σπάνια σε αρχικό σχήµα µε boosted PI [1-4] Άλλοι boosted PI θα είναι πλήρως ενεργοί αλλά πρέπει να εξετάσετε τα προβλήµατα του αρχικού σχήµατος πχ ανεκτικότητα Η αντοχή σε NRTI είναι επίσης σπάνια σε αρχική θεραπεία µε boosted PI [1-4] Η παρουσία περιορισµένων µεταλλάξεων δεν αναµένεται να επηρεάσει την αποτελεσµατικότητα του επακόλουθου σχήµατος µε ΝRTIs + boosted PI Τα δεδοµένα υποστηρίζουν την χρήση QD δοσολογίας του DRV/RTV ή του LPV/RTV στους θεραπευµένους ασθενείς µε λίγη ή καθόλου αντοχή σε PI [5,6] Δεν υπάρχουν ξεκάθαρα δεδοµένα αν η προσθήκη ενός τρίτου παράγοντα διαφορετικής κατηγορίας θα έχει όφελος 1. Molina JM, et al. Lancet. 2008; 372: Daar E, et al. CROI Abstract 59LB. 3. Ortiz R, et al. AIDS. 2008; 22: Eron J Jr, et al. Lancet. 2006;368: Cahn P, et al. CROI Abstract Zadjenverg R, et al. J Acquir Immune Defic Syndr. 2010;[Epub ahead of print].

53

54 Ενδιαφέρουσα περίπτωση n Τι αγωγή θα δίνατε: 1. TFV/FTC + boosted DRV 2. TFV/FTC + ETR 3. TFV/FTC + RAL 4. TFV/FTC + boosted DRV+ RAL 5. 3TC + boosted PI + RAL 6. TFV/FTC + ETR + RAL

55 Ενδιαφέρουσα περίπτωση n Ο ΒΛΔΗ (MSM) παρουσίασε ιολογική αποτυχία µετά από ένα αρχικό σχήµα µε TDF/FTC + ATV/RTV n Τωρινά CD4+ cell είναι 320 cells/mm³ n Τωρινό HIV-1 RNA είναι 10,500 copies/ml (αρχικά 18,000) µετά από µια περίοδο που ήταν µη ανιχνεύσιµος για 3 χρόνια n Η αρχική αντοχή αρνητική n Ιολογική αποτυχία λόγω µη συµµόρφωσης n Τον ενοχλεί ο ίκτερος n Ο γονοτυπικός έλεγχος δείχνει n Καµία ανάπτυξη αντοχής

56 Ενδιαφέρουσα περίπτωση n Τι αγωγή θα δίνατε: 1. TFV/FTC + boosted DRV 2. TFV/FTC + Efavirenz 3. TFV/FTC + Riplivirine 4. TFV/FTC + ELV + combisistat (stribild) 5. TFV/FTC + RAL

57 Δεν ξέρω πια είναι η σωστή απάντηση

58 Ο ανερχόµενος ρόλος των αναστολέων ιντεργκράσης στην θεραπεία της HIV λοίµωξης

59 Ο βιολογικός κύκλος του ιού και ο µηχανισµός δράσης

60 HIV Viral Life Cycle Maturation Attachment fusion Uncoating Integration Budding Reverse transcription Transcription, translation Assembly

61 HIV Viral Life Cycle Currently available integrase inhibitors Raltegravir (approved 10/07) Elvitegravir* (approved 8/12) Dolutegravir (approved 8/13) *Currently available only as part of a coformulated single-tablet regimen. Maturation Attachment fusion Uncoating Integrase inhibitors Budding Reverse transcription Transcription, translation Assembly

62 Crystal Structure of Retroviral Integrase with INSTIs RAL and EVG Bind the Same Integrase Active Site IN with No Inhibitor IN with RAL (MK0518) IN with EVG (GS9137) Y143 Y143 Y143 EVG and RAL bind to the same IN active site MK0518=RAL=raltegravir; GS9137=EVG=elvitegravir Images colored by atoms (light grey, C; red, O; and blue, N). Grey spheres are Mn 2+ or Mg 2+ ions. RESEARCH Hare et al, 2008, Nature, 464:232-6

63 Integrase Inhibitors in DHHS Guidelines NNRTI Boosted PI INSTI Preferred Regimens EFV/TDF/FTC ATV/RTV + TDF/FTC DRV/RTV + TDF/FTC RAL + TDF/FTC EVG/COBI/TDF/FTC DTG + ABC/3TC DTG + TDF/FTC Alternative Regimens EFV + ABC/3TC RPV/TDF/FTC or RPV + ABC/3TC ATV/RTV + ABC/3TC DRV/RTV + ABC/3TC FPV/RTV + (TDF/FTC or ABC/3TC) LPV/RTV + (TDF/FTC or ABC/3TC) RAL + ABC/3TC Όλοι οι αναστολείς ιντεργκράσης είναι πλέον στα προτεινόµενα σχήµατα πρώτης γραµµής DHHS Guidelines. February DHHS Recommendation on INSTIs. October 2013.

64 Η χρήση των αναστολέων ιντεργκράσης σε Naive ασθενείς

65 STARTMRK: Raltegravir vs Efavirenz in Treatment-Naive Patients Randomized, double-blind (through 5 yrs), placebo-controlled, phase III trial Primary endpoint: HIV-1 RNA < 50 copies/ml at Wk 48 Stratified by HIV-1 RNA (> vs 50,000 copies/ml) and viral hepatitis status HIV-infected, treatment-naive patients with HIV-1 RNA > 5000 copies/ml and no resistance to EFV, TDF, or FTC (N = 563) Raltegravir 400 mg BID + TDF/FTC (n = 281) Efavirenz 600 mg QHS + TDF/FTC (n = 282) Lennox J, et al. Lancet. 2009;374:

66 STARTMRK: RAL vs EFV in Treatment- Naive Patients: 5-Yr Final Report RAL noninferior to EFV in HIV-1 RNA < 50 c/ml at Wk 48 (primary endpoint; ITT, NC = F analysis); superior from Wk 192 HIV-1 RNA < 50 c/ml (%) Pts at Risk, n RAL 281 EFV Wks Rockstroh J, et al. J Acquir Immune Defic Syndr. 2013;63: : +9.5% (95% CI: 1.7% to 17.3%; noninferiority P <.001)

67 STARTMRK: RAL vs EFV in Treatment- Naive Patients: 5-Yr Final Report Δραστικότητα το ίδιο και καλύτερη σε σχέση µε EFV CD4+ cell count at Wk 240: +374 (RAL) vs +312 (EFV) RAL σχετίστηκε µε Λιγότερες επιπλοκές από το ΚΝΣ (39.1% vs 64.2%; P <. 001) Λιγότερες αλληλεπιδράσεις (52.0% vs 80.1%; P <.001) VF and Resistance at Wk 240 RAL (n = 281) EFV (n = 282) VF, n (%) 55 (19.6) 59 (20.9) Resistance data available, n INSTI or NNRTI mutations only, n NRTI mutations only, n 3 2 NRTI + (RAL or EFV) resistance mutations, n 3 3 Λιγότερες διακοπές λόγω ανεπιθύµητων ενεργειών (5% vs 9%) Rockstroh J, et al. J Acquir Immune Defic Syndr. 2013;63:77-85 plus Supplemental Digital Content.

68 QDMRK: RAL QD Inferior to RAL BID at Wk 48 in Treatment-Naive Patients HIV-1 RNA < 50 c/ml (NC = F) Randomized, noninferiority phase III trial of RAL 800 mg QD (n = 382) vs RAL 400 mg BID (n = 389), both with TDF/FTC [1] RAL QD inferior to RAL BID at Wk 48 in ITT (NC = F) analysis Lower RAL trough levels associated with higher risk of failure in QD arm but not in BID arm / 382 Wk / 389 : -5.7 (95% CI: to -0.83; P for noninferiority =.044) RAL 800 mg QD (n = 382) RAL 400 mg BID (n = 389) More resistance at failure in QD arm Parameter, n Pts with VF* and HIV-1 RNA > 400 c/ml RAL QD (n = 382) RAL BID (n = 388) Resistance data available FTC resistance only 11 2 Integrase inhibitor and FTC resistance 9 2 No evidence of resistance 7 7 *Failure included both failure to suppress and rebounders. Most patients with VF and RAL resistance had 2 mutations associated with resistance to RAL. PK studies of 2 new RAL formulations administered as 1200-mg once daily showed promise in healthy patients [2] 1. Eron J, et al. Lancet Infect Dis. 2011;11: Krishna R, et al. EACS 2013, Abstract PE10/17.

69 ACTG 5257: Comparison of ATV/RTV vs RAL vs DRV/RTV in First-line Therapy

70 ACTG 5257: Open-Label ATV/RTV vs RAL vs DRV/RTV in First-line ART Stratified by HIV-1 RNA < or 100,000 c/ml, participation in metabolic substudy, CV risk Wk 96 after last patient enrolled ATV/RTV 300/100 mg QD + TDF/FTC (n = 605) ART-naive patients with HIV-1 RNA 1000 c/ml (N = 1809) RAL 400 mg BID + TDF/FTC (n = 603) Primary endpoints VF: time to HIV-1 RNA > 1000 c/ml (at Wk 16 or before Wk 24) or > 200 c/ml (at or after Wk 24) TF: time to discontinuation of randomized component for toxicity Composite endpoint: the earlier occurrence of either VF or TF in a given participant Switch of regimens allowed for tolerability Landovitz R, et al. CROI Abstract 85. DRV/RTV 800/100 mg QD + TDF/FTC (n = 601)

71 ACTG 5257: Primary Endpoint Analyses at Wk 96 Virologic Failure Tolerability Failure Composite Endpoint Regimens equivalent in time to VF Significantly greater incidence of treatment failure with ATV/RTV vs RAL or DRV/RTV In part due to high proportion of pts with hyperbilirubinemia Considering both efficacy and tolerability, RAL superior to either boosted PI DRV/RTV superior to ATV/RTV ATV/RTV vs RAL 3.4% (-0.7 to 7.4) DRV/RTV vs RAL 5.6% ( ) ATV/RTV vs DRV/RTV -2.2% (-6.7 to 2.3) Favors RAL ATV/RTV vs RAL 13% ( ) DRV/RTV vs RAL 3.6% ( ) Favors DRV/RTV ATV/RTV vs DRV/RTV 9.2% ( ) Favors RAL ATV/RTV vs RAL 15% (10-20) Favors RAL DRV/RTV vs RAL 7.5% ( ) Favors DRV/RTV ATV/RTV vs DRV/RTV 7.5% ( ) Difference in 96-Wk Cumulative Incidence (97.5% CI) Landovitz R, et al. CROI Abstract 85. Reproduced with permission.

72 Elvitegravir/Cobicistat vs EFV or ATV/RTV + TDF/FTC in Treatment-Naive Pts Randomized, double-blind, active-controlled phase III studies Primary endpoint: HIV-1 RNA < 50 copies/ml at Wk 48 Study 102 [1] (N = 700) Treatment naive; HIV-1 RNA 5000 copies/ml; any CD4+ cell count; susceptible to TDF, FTC, and EFV, or ATV; egfr 70 ml/min Study 103 [2] (N = 708) EVG/COBI/TDF/FTC QD (n = 348) EFV/FTC/TDF QD (n = 352) EVG/COBI/TDF/FTC QD (n = 353) ATV/RTV + TDF/FTC QD (n = 355) 1. Sax P, et al. Lancet. 2012;379: DeJesus E, et al. Lancet. 2012;379:

73 EVG/COBI/TDF/FTC Noninferior to EFV/ TDF/FTC Through Wk 144 HIV-1 RNA < 50 copies/ml (%) EVG/COBI/TDF/FTC (n = 348) Δ: 3.6% (-1.6 to 8.8) Δ: 2.7% (-2.9 to 8.3) EFV/TDF/FTC (n = 352) Δ: 4.9% (1.3 to 11.1) Wk 48 Wk 96 Wk 144 EVG/COBI arm noninferior to EFV arm at Wk 48 primary endpoint [1] and through Wk 144 [2,3] Results consistent across subgroups: BL HIV-1 RNA, CD4+ cell count, age, sex, race Treatment-related study d/c: 6% in EVG/COBI arm vs 7% in EFV arm at Wk 144 VF: 7% in EVG/COBI arm and 10% in EFV arm at Wk 144 Similar CD4+ cell count increase at Wk 144: +321 cells/mm 3 (EVG/COBI) vs +300 cells/mm 3 (EFV) 1. Sax PE, et al. Lancet. 2012;379: Zolopa A, et al. J Acquir Immune Defic Syndr. 2013;63: Wohl D, et al. ICAAC Abstract H-672a.

74 EVG/COBI/TDF/FTC Noninferior to ATV/RTV + TDF/FTC Through Wk 144 HIV-1 RNA < 50 copies/ml (%) EVG/COBI/TDF/FTC (n = 353) ATV/RTV + TDF/FTC (n = 355) Δ: 3.0% (-1.9 to 7.8) Δ: 1.1% (-4.5 to 6.7) Δ: 3.1% (-3.2 to 9.4) Wk 48 Wk 96 Wk 144 EVG/COBI arm noninferior to ATV/ RTV arm at Wk 48 primary endpoint [1] and through Wk 144 [2,3] Results consistent across subgroups: BL HIV-1 RNA, CD4+ count, adherence, age, sex, race Treatment-related study d/c: 6% in EVG/COBI arm vs 9% in ATV/RTV arm at Wk 144 VF: 8% in EVG/COBI arm vs 7% in ATV/RTV arm at Wk 144 Similar CD4+ cell count increase at Wk 144: +280 cells/mm 3 (EVG/ COBI) vs +293 cells/mm 3 (ATV/ RTV) 1. De Jesus E, et al. Lancet. 2012;379: Rockstroh J, et al. J Acquir Immune Defic Syndr. 2013;62: Clumeck N, et al. EACS Abstract LBPS7/2.

75 EVG/COBI/TDF/FTC ανεπιθύµητες ενέργειες EVG/COBI vs EFV: Λιγότερες επιπλοκές από ΚΝΣ, λιγότερο εξάνθηµα, λιγότερη αύξηση σε TC, HDL-C, and LDL-C περισσότερη ναυτία [1] EVG/COBI vs ATV/RTV: Λιγότερος ίκτερος, παρόµοια αύξηση σε TC, HDL-C, and LDL-C; Μικρότερη αύξηση TG [2] Μικρή οξεία αύξηση κρεατινίνης εξαιτείας του COBI 0.14 ± 0.13 mg/dl at Wk 48; most change occurs by Wk 2 [3] 1. Sax P, et al. Lancet. 2012;379: DeJesus E, et al. Lancet. 2012;379: TDF/FTC/EVG/COBI [package insert].

76 Dolutegravir vs Currently Preferred Regimens in Treatment-Naive Pts Randomized, noninferiority phase III studies Primary endpoint: HIV-1 RNA < 50 copies/ml at Wk 48 SPRING-2 [1] (active controlled) ART-naive pts VL 1000 c/ml (N = 822) DTG 50 mg QD + 2 NRTIs* (n = 411) RAL 400 mg BID + 2 NRTIs* (n = 411) SINGLE [2] (placebo controlled) FLAMINGO [3] (open label) ART-naive pts VL 1000 c/ml HLA-B*5701-neg CrCL > 50 ml/min (N = 833) ART-naive pts VL 1000 c/ml (N = 484) DTG 50 mg QD + ABC/3TC QD (n = 414) EFV/TDF/FTC QD (n = 419) DTG 50 mg QD + 2 NRTIs* (n = 242) DRV/RTV 800/100 mg QD + 2 NRTIs* (n = 242) *Investigator-selected NRTI backbone: either TDF/FTC or ABC/3TC. 1. Raffi F, et al. Lancet. 2013;381: Walmsley S, et al. N Engl J Med. 2013;369: Feinberg J, et al. ICAAC Abstract H1464a.

77 SPRING-2: DTG vs RAL + 2 NRTIs in Naive Patients HIV-1 RNA < 50 copies/ml (%) DTG 50 mg QD (n = 411) Δ: 2.5% (-2.2% to 7.1%) / / 411 RAL 400 mg BID (n = 411) Δ: 4.4% (-1.1% to 10.0%) / 411 Wk 48 Wk / 411 DTG noninferior to RAL at both Wk 48 primary endpoint [1] and Wk 96 [2] Treatment-related study d/c: 2% in each arm at Wk 96 VF at Wk 96 [2] : 5% (22/411) in DTG arm and 7% (29/411) in RAL arm Similar CD4+ cell count increase at Wk 96: +276 cells/mm 3 (DTG) vs +264 cells/mm 3 (RAL) 1. Raffi F, et al. Lancet. 2013;381: Raffi F, et al. IAS Abstract TULBPE17.

78 HIV-1 RNA < 50 c/ml at Wk 48 (%) SINGLE: DTG + ABC/3TC vs EFV/TDF/ FTC in Naive Patients at Wk Δ +7.4% (95% CI +2.5% to +12.3%; P =.003) / 414 DTG 50 mg + ABC/3TC QD / 419 EFV/TDF/ FTC QD Walmsley S, et al. N Engl J Med. 2013;369: DTG superior to EFV at Wk 48 primary efficacy endpoint Treatment-related study d/c: 2% in DTG arm vs 10% in EFV arm VF at Wk 48: 4% (18/414) in DTG arm and 4% (17/419) in EFV arm CD4+ cell count increase at Wk 48 greater with DTG: +267 cells/mm 3 (DTG) vs +208 cells/mm 3 (EFV) (P <.001)

79 FLAMINGO: DTG vs DRV/RTV + 2 NRTIs in Naive Patients at Wk 48 HIV-1 RNA < 50 c/ml at Wk 48 (%) Δ +7.1% (95% CI: +0.9% to +13.2%; P =.025) / 242 DTG 50 mg QD + NRTIs / 242 DRV/RTV 800/100 mg QD + NRTIs Feinberg J, et al. ICAAC Abstract H1464a. DTG superior to DRV/RTV at Wk 48 primary efficacy endpoint Treatment-related study d/c: 2% in DTG arm vs 4% in DRV/RTV arm VF at Wk 48: < 1% (n = 2) in each arm Similar CD4+ cell count increase at Wk 48: +210 cells/mm³ in each arm

80 Similar Efficacy of INSTIs (RAL or DTG) + ABC/3TC or TDF/FTC, Even for High BL VL In SPRING-2, similar efficacy with ABC/3TC or TDF/FTC + RAL or DTG, including with high BL HIV-1 RNA* HIV-1 RNA < 50 c/ml at Wk 48 by FDA Snapshot Analysis (%) n/ N = / 257 *Pooled data from both INSTIs / / 42 Eron J, et al. Glasgow Abstract P / 88 < 100k 100K - < 250K 250K - 500K > 500K 81 13/ / 38 Baseline HIV-1 RNA (c/ml) 72 13/ 18 ABC/3TC TDF/FTC 64 18/ 28

81 Αναστολείς ιντεργκράσης για αρχική θεραπεία Σε µια εποχή µε πολλαπλές επιλογές οι αναστολείς ιντεργκράσης έχουν αρκετά πλεονεκτήµατα Καλή δραστικότητα, ανεκτικότητα και καλό µεταβολικό προφίλ Η µεταδιδόµενη αντοχή είναι µικρή και δεν απαιτείται αρχικός έλεγχος αντοχής Λίγες αλληλεπιδράσεις (RAL, DTG) Σπάνια η αντοχή µε το DTG STR (EVG)

82 Μελέτες αλλαγής θεραπείας µε αναστολείς ιντεργκράσης

83 Switching Virologically Suppressed Patients to RAL SWITCHMRK-1 and -2 [1] Switching to RAL inferior to remaining on LPV/RTV-based regimen in pts with HIV-1 RNA < 50 c/ml for > 3 mos, particularly among those with previous VF TC, non HDL-C, and TG improved in switch pts SPIRAL [2] Switching from to RAL noninferior to remaining on boosted PI-based regimens through Wk 48 in pts with HIV-1 RNA < 50 c/ml for 6 mos Switching to RAL significantly improved lipids and TC:HDL-C ratio EASIER/ANRS 138 [3] Switch from ENF to RAL regimens maintained virologic suppression through Wk 48 in patients with multidrug resistance and HIV-1 RNA < 400 c/ml for 3 mos 1. Eron J, et al. Lancet. 2010;375: Martinez E, et al. AIDS. 2010;24: Gallien S, et al. J Antimicrob Chemother. 2011;66:

84 Virologic Suppression in SWITCHMRK in Patients With and Without Previous VF HIV-1 RNA < 50 copies/ml (%) at Wk 24 (NC = F) RAL LPV/RTV 0 n = Prev VF No VF Eron J, et al. Lancet. 2010;375:

85 Study 123: Switch From RAL + TDF/FTC to EVG/COBI/TDF/FTC Open-label, multicenter, 48-wk pilot study of switch from RAL + TDF/FTC to EVG/COBI/TDF/FTC in pts with HIV-1 RNA < 50 c/ml for 6 mos (N = 48) Primary endpoint: HIV-1 RNA < 50 c/ml at Wk 12 postswitch Secondary endpoints: Safety and tolerability by Wk 24 and Wk 48 HIV-1 RNA < 50 c/ml at Wk 24 and Wk 48 postswitch All subjects maintained virologic suppression at Wks 12 and 24 38/38 subjects who reached Wk 48 at time of report also suppressed TC and LDL-C improved; no renal AEs Crofoot G, et al. IAS Abstract TUPE283. HIV-1 RNA < 50 c/ml (%) /48 48/48 38/38* Wk 12 Wk 24 Wk 48

86 Drug Drug Interactions With Integrase Inhibitors and Key Drugs RAL [1,2] EVG/COBI [1] DTG [3] Rifampin Aluminum- or magnesiumcontaining antacids Antacids Benzodiazepines Beta blockers Calcium channel blockers Erectile dysfunction drugs Inhaled/injectable corticosteroids MVC OCPs (norgestimate) Rifampin Statins EFV ETR FPV/RTV Medications containing polyvalent cations (Ca++, Mg++), including laxatives, antacids Metformin Rifampin TPV/RTV 1. DHHS Adult Guidelines. February Raltegravir [package insert]. 3. Dolutegravir [package insert].

87 Raltegravir : Πλεονεκτήµατα και Μειονεκτήµατα Πλεονεκτήµατα INSTI µε τα περισσότερα δεδοµένα ασφάλειας και αποτελεσµατικότητας approved in 2007 Noninferior to EFV in initial therapy at Wk 48 superior from Wk 192 through Yr 5 final analysis Λιγότερες επιπλοκές από ΚΝΣ, λιγότερο εξάνθηµα και καλύτερο λιπιδαιµικό προφίλ σε σχέση µε EFV Λιγότερες αλληλεπιδράσεις Όχι επίδραση φαγητού Πολλά δεδοµένα σε πολυθεραπευµένους ασθενείς Μειονεκτήµατα Δοσολογία 2 φορές την ηµέρα No FDC available or planned Κατώτερο του DTG σε πολυθεραπευµένους ασθενείς Κίνδυνος αντοχής σε ιολογική αποτυχία Με ιολογική αποτυχία συνήθως 2- class resistance

88 Elvitegravir : Πλεονεκτήµατα και Μειονεκτήµατα Πλεονεκτήµατα Το µόνο STR Noninferior to EFV and ATV/RTV in initial therapy Λιγότερες επιπλοκές από ΚΝΣ, λιγότερο εξάνθηµα και καλύτερο λιπιδαιµικό προφίλ σε σχέση µε EFV Λιγότερος ίκτερος σε σχέση µε ATV/RTV Ασφαλής αλλαγή από first-line RAL Noninferior to RAL σε πολυθεραπευµένους ασθενείς Μειονεκτήµατα Όχι σε ασθενείς µε egfr < 70 ml/ min Πρέπει να λαµβάνεται µε φαγητό Cobicistat αναστέλλει την σωληναριακή έκκριση της κρεατινίνης Περισσότερη ναυτία σε σχέση µε EFV Κίνδυνος αντοχής σε ιολογική αποτυχία Με ιολογική αποτυχία συνήθως 2- class resistance Το COBI έχει αρκετές αλληλεπιδράσεις Μόνο σε STR

89 Dolutegravir : Πλεονεκτήµατα και Μειονεκτήµατα Πλεονεκτήµατα Δοσολογία µια φορά την ηµέρα Μικρό χάπι Noninferior to RAL and superior to EFV and DRV/RTV Διατηρεί ίδια ή καλύτερη δραστικότητα σε σχέση µε EFV, RAL, DRV/RTV σε χαµηλά και υψηλά HIV-1 RNA φορτία Fewer CNS and rash events vs EFV Σε ιολογική αποτυχία δεν αναπτύχθηκε αντοχή Λίγες αλληλεπιδράσεις Με ή χωρίς φαγητό Μειονεκτήµατα Not yet available as part of FDC Αναστέλλει την σωληναριακή έκκριση της κρεατινίνης Λιγότερα δεδοµένα

90 Η χρήση των αναστολέων ιντεργκράσης σε πολυθεραπευµένους ασθενείς

91 Study 145: Elvitegravir vs Raltegravir in Treatment-Experienced Patients Randomized, placebo-controlled phase III study Wk 48 Wk 96 HIV-infected pts, HIV-1 RNA 1000 copies/ ml, resistance or 6 mos of exposure to 2 antiretroviral classes (N = 702) Elvitegravir 150 mg (or 85 mg) QD* + Boosted PI + Third Agent (n = 351) Raltegravir 400 mg BID + Boosted PI + Third Agent (n = 351) *EVG currently unavailable as single agent. EVG dose reduced to 85 mg QD for pts receiving ATV/RTV or LPV/RTV as part of background regimen. Background regimen to include fully active RTV-boosted PI, selected using resistance testing. Selected from ENF, ETR, MVC, or NRTI. Option of also adding FTC or 3TC for pts with M184V/I. Molina J, et al. Lancet Infect Dis. 2012;12:27-35.

92 Study 145: EVG Noninferior to RAL at Wks 48 and 96 Subjects (%) Wk 48 Wk 96 Wk 48 Wk 96 Wk 48 Wk 96 Virologic Response Virologic Failure* EVG (n = 351) RAL (n = 351) Other *VF includes never suppressed, rebound, switch of BR, and d/c due to lack of efficacy. Others include death, discontinuation due to AE, investigator s discretion, lost to follow-up, pregnancy, protocol violation, subject noncompliance, withdrawal of consent. Similar incidence of resistance at VF with EVG vs RAL Integrase resistance: 6.6% vs 7.4% OBR resistance: 7.4% vs 7.1% Both regimens well tolerated Higher rates of diarrhea with EVG at Wks 48 and 96 Discontinuations: 3% vs 4% Elion R, et al. J Acquir Immune Defic Syndr. 2013;63:

93 SAILING: Dolutegravir vs Raltegravir in ART-Exp d, Integrase Inhibitor Naive Pts Randomized, double-blind, noninferiority, phase III study Stratified by number of fully active background agents, use of DRV, screening HIV-1 RNA ( vs > 50,000 copies/ml) Wk 48 Treatment-experienced, integrase inhibitor naive patients with HIV-1 RNA > 400 copies/ml and 2 class resistance (N = 715) Dolutegravir 50 mg QD + Raltegravir placebo + OBR* (n = 354) Raltegravir 400 mg BID + Dolutegravir placebo + OBR* (n = 361) *OBR comprising at least 1 and no more than 2 active agents. Cahn P, et al. Lancet. 2013;382:

94 SAILING: Superior Rate of Virologic Suppression With DTG vs RAL at Wk 48 Subjects (%) Δ: 7.4% (95% CI: ; P =.03) 64 Virologic Success Virologic Nonresponse Cahn P, et al. Lancet. 2013;382: DTG + OBR (n = 354) RAL + OBR (n = 361) 9 9 No Wk 48 Data Lower incidence of resistance at VF with DTG vs RAL Integrase resistance: 1% (4/354) vs 5% (17/361); P =.003 OBR resistance: 1% (4/354) vs 3% (12/361) Both regimens well tolerated with similar AE profiles Grades 2-4: 8% vs 9% Discontinuations: 3% vs 4% No difference in outcome between study arms when combined with fully active DRV/RTV

95 VIKING-3: Dolutegravir After Failure of Integrase Inhibitor Based Regimen Phase III single-arm trial Day 8 Wk 24 Wk 48 Pts with HIV-1 RNA 500 c/ml, RAL and/or EVG resistance, and resistance to 2 other antiretroviral classes* (N = 183) Mean HIV-1 RNA change from baseline to Day 8 Overall: -1.4 log 10 copies/ml (P <.001) No primary integrase resistance mutations at BL: -1.6 log 10 copies/ml Q secondary integrase resistance mutation: -1.1 log 10 copies/ml Q secondary integrase resistance mutations: -1.0 log 10 copies/ml Nichols G, et al. Glasgow Abstract O232. Dolutegravir 50 mg BID + Continue Failing Regimen Functional Monotherapy *Detected at screening or based on historical evidence. Dolutegravir 50 mg BID + Optimized Background Regimen With Overall Susceptibility Score 1 (ie, 1 active drug) Optimized Therapy

96 VIKING-3: Efficacy of DTG in INSTI-Experienced Pts at Wk wk data on full cohort (N = 183) and 48-wk data on first 114 pts Response rates affected by baseline INSTI resistance but not overall susceptibility score of background regimen Outcome, n (%) Wk 24 (n = 183) HIV-1 RNA < 50 c/ml at Wk 24 (snapshot, ITT-E) Wk 48 (n = 114) 126 (69) 64 (56) Virologic nonresponse 50 (27) 44 (39) d/c due to AE or death 5 (3) 5 (4) HIV-1 RNA < 50 c/ml at Wk 24 by INSTI Mutation(s), n/n (%) Overall Susceptibility Score Total No Q148 4/4 (100) 35/40 (83) 57/70 (76) 96/114 (79) Q /2 (100) 8/12 (67) 10/17 (59) 20/31 (65) Q /2 (50) 2/11 (18) 1/3 (33) 4/16 (25) Nichols G, et al. IAS Abstract TULBPE19.

97 Αποτυγχάνοντας σε ένα αρχικό σχήµα µε αναστολέα ιντεργκράσης δεν υπάρχει σωστή και λάθος απάντηση µόνο η πραγµατικότητα.. RESEARCH

98 Primary Drug Resistance Mutations for INSTIs EVG vs RAL EVG Primary INSTI-RAMs T E T* S Q N raltegravir elvitegravir 66 I A K 92 Q G 97* A* 147 G 148 R H K 155 H S IN RAL Primary INSTI-RAMs E Y Q N raltegravir Q R R H H H C K IN EVG=elvitegravir; RAL: raltegravir; INSTI-RAMs=integrase strand-transfer inhibitor resistance-associated mutations; *: T97A may require RESEARCH additional mutations for resistance