Terapia del paciente naive con un régimen de Inhibidor de la proteasa Dr. Jose R Arribas IX Curso de avances en Infección VIH y hepatitis virales

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1 Terapia del paciente naive con un régimen de Inhibidor de la proteasa Dr. Jose R Arribas IX Curso de avances en Infección VIH y hepatitis virales clinicaloptions.com/hiv

2 Eficacia en Ensayos Clínicos pivotales en naïves RPV EVG/C=EFV Echo/Thrive 1 RPV=EFV STAR 10 RPV=EFV EFV Startmrk 3 RAL>EFV Single 4 DTG>EFV EVG/c ACTG ATV/r=EFV RAL Spring-2 6 DTG=RAL DTG EVG/C=ATV/r ACTG RAL>ATV/r RAL>DRV/r Flamingo 8 DTG>DRV/r ATV/r ACTG DRV/r>ATV/r DRV/r 1. Cohen CJ et al. JAIDS 2012; 60 (1): ; 2. Sax PE et al. Lancet 2012; 379: ; Rockstroh JK et al. JAIDS 2013; 63 (1); 4. Walmsley SL et al. N Engl J Med 2013; 369: ; 5. Daar ES, et al. Ann Intern Med 2011;154:445 56; 6. Raffi F et al. Lancet Mar 2;381(9868):735-43; 7. DeJesus E, et al. Lancet 2012;379: ; 8. Feinberg J et al. 52 ICAAC, September 9-12, 2012, H-1464a; 9. Landovitz RJ et al. CROI Abstract Cohen C. AIDS 2014, 28:

3 Study Design Study 103 Randomized, double-blind, double dummy, active-controlled, international study Treatment Naïve HIV-1 RNA 5000 c/ml Any CD4 cell count egfr 70 ml/min 1:1 * (n=350) STB QD ATV/r+TVD Placebo QD (n=350) ATV+RTV+TVD QD STB Placebo QD * Randomization stratified by screening HIV-1 RNA ( vs >100,000 c/ml) Week 48 Primary Endpoint Week 144 Secondary Endpoint HIV-1 RNA < 50 c/ml by snapshot analysis (ITT) Non-inferiority margin (Wk48): 12% Conducted in parallel with Study 102 comparing STB to ATR

4 Efficacy Endpoint: HIV-1 RNA <50 c/ml Study 103 Primary (Wk 48) and Secondary (Wk 96 and 144) Percentage of subjects (%) STB (n=353) ATV+RTV+TVD (n=355) Virologic Success * Virologic Failure * No data * Favors ATV+RTV+TVD -12% W48 W96 W144 95% CI for Difference 0 Favors STB 2.7% -2.1% 7.5% 1.1% 1-4.5% 6.7% 3.1% 1-3.2% 9.4% 12% * Virologic outcome as defined by FDA Snapshot algorithm

5 A5257 Study Design* HIV-infected patients, 18 yr, with no previous ART, VL 1000 c/ml at US Sites Randomized 1:1:1 to Open Label Therapy Stratified by screening HIV-1 RNA level ( vs < 100,000 c/ml), A5260s metabolic substudy participation, cardiovascular risk ATV 300 mg QD + RTV 100mg QD + FTC/TDF 200/300 mg QD RAL 400 mg BID + FTC/TDF 200/300 mg QD DRV 800 mg QD + RTV 100 mg QD + FTC/TDF 200/300 mg QD Study Conclusion 96 weeks after final participant enrolled Follow-up continued for 96 weeks after randomization of last subject (range 2-4 years) regardless of status on randomized ART *With the exception of RTV, all ART drugs were provided by the study

6 Cumulative Incidence of Virologic Failure Difference in 96 wk cumulative incidence (97.5% CI) ATV/r vs RAL 3.4% (-0.7%, 7.4%) DRV/r vs RAL 5.6% (1.3%, 9.9%) ATV/r vs DRV/r -2.2%(-6.7%, 2.3%)

7 Cumulative Incidence of Tolerability Failure Difference in 96 wk cumulative incidence (97.5% CI) Favors RAL ATV/r vs RAL 13% (9.4%, 16%) DRV/r vs RAL 3.6% (1.4%, 5.8%) Favors DRV/r ATV/r vs DRV/r 9.2% (5.5%, 13%)

8 Cumulative Incidence of Virologic or Tolerability Failure Difference in 96 wk cumulative incidence (97.5% CI) Favors RAL Favors RAL Favors DRV/r ATV/r vs RAL 15% (10%, 20%) DRV/r vs RAL 7.5% (3.2%, 12%) ATV/r vs DRV/r 7.5% (2.3%, 13%) *Consistent results seen with TLOVR at a 200 copies/ml threshold

9 Proportion VL 50 copies/ml ITT, regardless of ART change ITT, off-art=failure (SNAPSHOT) ATV/r 83% 90% 88% 90% RAL 90% 92% 94% 94% DRV/r 83% 88% 89% 90% ATV/r 70% 73% 63% 62% RAL 84% 83% 80% 76% DRV/r 77% 77% 73% 71%

10 FLAMINGO (ING114915) Study Design HIV+ ART-naive VL 1,000 c/ml Stratified by screening plasma HIV-1 RNA ( vs >100,000 c/ml) and background dual NRTI (ABC/3TC or TDF/FTC*) Open-label randomized phase DTG 50 mg QD + 2 NRTIs DRV/r 800 mg/100 mg QD + 2 NRTIs Extension phase DTG + ART Randomization Week 48 analysis Week 96 analysis Primary endpoint: proportion with HIV-1 RNA <50 c/ml at Week 48, FDA Snapshot analysis, -12% non-inferiority (NI) margin Secondary endpoints: antiviral activity, safety, tolerability, health outcomes and viral resistance *Investigator selected backbone of choice 14th European AIDS Conference; October 16-19, 2013; Brussels, Belgium Clotet et al. EACS 2013; Brussels, Belgium. Abstract LBPS4/6.

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12 Orkin C et al HIV Med 2012; 14:49 59.

13 PI Resistance Rare at VF in First-line Studies of Boosted PIs Study n PI Wk Genotypes Major PI Mutations CASTLE [1] ATV/RTV LPV/RTV ACTG 5202 [2] ATV/RTV Study 103 [3] 355 ATV/RTV 144 NR 0 ARTEMIS [4] DRV/RTV LPV/RTV FLAMINGO [5] 242 DRV/RTV 48 NR 0 ACTG 5257 [6] ATV/RTV DRV/RTV Among 4303 pts in these trials, only 2 pts developed major PI mutations at initial VF 1. Molina JM, et al. Lancet. 2008;372: Daar ES, et al. Ann Intern Med. 2011;154: Clumeck N, et al. EACS Abstract LBPS7/2. 4. Mills A, et al. AIDS. 2009;23: Clotet B, et al. Lancet. 2014;[Epub ahead of print]. 6. Landovitz R, et al. CROI Abstract 85.

14 Patient with bad adherence

15 Dual therapy with Lopinavir/ Ritonavir (LPV/r) and Lamivudine (3TC) is non-inferior to standard triple drug therapy in Naïve HIV-1 infected subjects : 48-week results of the GARDEL Study. ClinicalTrials.gov : # NCT Pedro Cahn on behalf of the GARDEL study group

16 Study design Phase III, randomized, international, controlled, open-label study Study included adult patients from Argentina, Chile, Mexico, Peru, Spain, US. Stratified by screening HIV-1 RNA ( or > 100,000 copies/ml) Wk 24 interim analysis Wk 48 primary endpoint ARV-naive patients, 18 years HIV-1 RNA >1000 copies/ml No IAS-USA defined NRTI or PI resistance at screening* HB(s)Ag negative (N = 426) DT: LPV/r 400/100mg BID + 3TC 150 mg BID (n=217) TT: LPV/r 400/100mg BID + 3TC or FTC and a third investigator-selected NRTI in fixed-dose combination (n=209) *Defined as > 1 major or > 2 minor LPV/r mutations) LPV major mutations include the following mutations: V32I; I47V/A; L76V; V82A/F/T/S

17 Viral load <50 copies/ml at week 48 (ITTe) 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% DT TT (p= 0.171, difference +4.6% [CI 95% :-2.2% to +11.8%]) 88.3% 83.7% 0% BSL W4 W8 W12 W24 W36 W48

18 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% Viral load <50 copies/ml at week 48 (ITTe), baseline VL > copies/ml DT TT (p= 0.145, difference +9.3% [CI 95% :-2.8% to +21.5%]) 87.2% 77.9% 0% BSL W4 W8 W12 W24 W36 W48

19 Number of patients, n (%) Protocol-Defined Virologic Failure and Emergent Resistance Mutations PDVF: 2 measurements of HIV-1 RNA at least 1 week apart >400 copies/ml at week 24 > 50 copies/ml at week 48 Emergent resistance mutations, in samples successfully amplified: DT: 2 out of 5 both M184V TT: 0 out of 8 DT (N=214) TT (N=202) Confirmed virological failures 10 (4.6 %) 12 (5.9 %)* HIV-1 RNA at failure (copies/ml) IQR) (median- 236 (183-17,687) 1027 (123-4,880) Never suppressed 2 8 Rebounders 8 4 Primary PI RAMs 0 0 NRTI RAMs (M184V) 2 0 *p=0.72

20 Milestones in the Evolution of the PI Class Many pills per day Multiple doses necessary High toxicity PAST SQV RTV IDV Improved tolerability Some boosted SQV/RTV IDV/RTV APV NFV ATV ATV/RTV DRV/RTV 1 pill per day (+ RTV & NRTIs) Boosting gold standard Manageable toxicity More coformulations Singletablet regimens ATV/COBI Once-daily dosing DRV/COBI Coformulation DRV/COBI/TAF/FTC Some treatment-limiting toxicity FPV/RTV LPV/RTV PRESENT (Not-too-distant) FUTURE

21 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

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25 Ongoing Studies of COBI-Boosted DRV Plus 2 NRTIs Phase IIIb study in tx-naive tx-exp d pts with no DRV RAMs [1] Primary endpoint: grade 3 or grade 4 AEs by Wk 24 Randomized, double-blind phase II trial [2] 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

26 EIMC. En prensa

27 Lennox JL et al. Annals of internal medicine 2014

28 Conclusiones Los IPs potenciados son apropiados para muchos pacientes naïve Gran experiencia clínica Prácticamente no hay resistencia primara Alto grado de supresión virológico en terapia de inicio. No selección de resistencias tras fracaso. Buen perfil metabólico (ATV y DRV) Cobicistat puede ofrecer una nueva oportunida de coformulación FLEXIBILIDAD Terapias duales

29 Emergent Resistance Through Week 144 Study 102/103 Week 144 STB (n=701) EFV/TVD (n=352) ATV/r + TVD (n=355) n (%) W96 W144 W96 W144 W96 W144 Population Analyzed 36 (5.1%) +6 (0.9%) 23 (6.5%) +5 (1.4%) 16 (4.5%) +3 (0.8%) Emergent Resistance 16 (1.9%) +2 (+0.3%) 10 (2.8%) +4 (+1.1%) 0 +2 (+0.6%) Primary INSTI-R 14 (2.0%) +1 (+0.1%) 10 (2.8%) +4 (+1.1%) 0 0 or NNRTI-R E92Q 9 0 K103N 9 +4 I50L 0 0 or PI-R N155H 5 0 K101E 3 +2 I84V 0 0 Primary NRTI-R Q148R 3 0 V108I 2 +2 N88S 0 0 T66I 2 0 Y188F/H/L 2 +1 T97A 0 +1 M230L 2 +0 V90I 1 +0 G190A/S 1 +0 P225H (2.1%) +2 (+0.3%) 3 (0.9%) +1 (+0.3%) 0 +2 (+0.6%) M184V/I M184V/I 3 +1 M184V/I 0 +2 K65R 5 0 K65R 3 +0 K65R 0 0

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