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
Eficacia en Ensayos Clínicos pivotales en naïves RPV 102 2 EVG/C=EFV Echo/Thrive 1 RPV=EFV STAR 10 RPV=EFV EFV Startmrk 3 RAL>EFV Single 4 DTG>EFV EVG/c ACTG5202 5 ATV/r=EFV RAL Spring-2 6 DTG=RAL DTG 103 7 EVG/C=ATV/r ACTG 5257 9 RAL>ATV/r RAL>DRV/r Flamingo 8 DTG>DRV/r ATV/r ACTG 5257 9 DRV/r>ATV/r DRV/r 1. Cohen CJ et al. JAIDS 2012; 60 (1): 33-42 ; 2. Sax PE et al. Lancet 2012; 379: 2439 48; Rockstroh JK et al. JAIDS 2013; 63 (1); 4. Walmsley SL et al. N Engl J Med 2013; 369:1807-1818; 5. Daar ES, et al. Ann Intern Med 2011;154:445 56; 6. Raffi F et al. Lancet. 2013 Mar 2;381(9868):735-43; 7. DeJesus E, et al. Lancet 2012;379:2429 38; 8. Feinberg J et al. 52 ICAAC, September 9-12, 2012, H-1464a; 9. Landovitz RJ et al. CROI 2014. Abstract 85. 10. Cohen C. AIDS 2014, 28:989 997.
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
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
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
Cumulative Incidence of Virologic Failure Difference in 96 wk cumulative incidence (97.5% CI) -20-10 0 10 20 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%)
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%) -20-10 0 10 20 Favors DRV/r ATV/r vs DRV/r 9.2% (5.5%, 13%)
Cumulative Incidence of Virologic or Tolerability Failure Difference in 96 wk cumulative incidence (97.5% CI) Favors RAL -20-10 0 10 20 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
Proportion VL 50 copies/ml ITT, regardless of ART change ITT, off-art=failure (SNAPSHOT) 24 48 96 144 ATV/r 83% 90% 88% 90% RAL 90% 92% 94% 94% DRV/r 83% 88% 89% 90% 24 48 96 144 ATV/r 70% 73% 63% 62% RAL 84% 83% 80% 76% DRV/r 77% 77% 73% 71%
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.
Orkin C et al HIV Med 2012; 14:49 59.
PI Resistance Rare at VF in First-line Studies of Boosted PIs Study n PI Wk Genotypes Major PI Mutations CASTLE [1] 440 443 ATV/RTV LPV/RTV 96 26 26 1 0 ACTG 5202 [2] 463 465 ATV/RTV 96 83 57 1 0 Study 103 [3] 355 ATV/RTV 144 NR 0 ARTEMIS [4] 343 346 DRV/RTV LPV/RTV 96 31 46 0 0 FLAMINGO [5] 242 DRV/RTV 48 NR 0 ACTG 5257 [6] 605 601 ATV/RTV DRV/RTV 96 75 99 0 0 Among 4303 pts in these trials, only 2 pts developed major PI mutations at initial VF 1. Molina JM, et al. Lancet. 2008;372:646-655. 2. Daar ES, et al. Ann Intern Med. 2011;154:445-456. 3. Clumeck N, et al. EACS 2013. Abstract LBPS7/2. 4. Mills A, et al. AIDS. 2009;23:1679-1688. 5. Clotet B, et al. Lancet. 2014;[Epub ahead of print]. 6. Landovitz R, et al. CROI 2014. Abstract 85.
Patient with bad adherence
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 : # NCT01237444 Pedro Cahn on behalf of the GARDEL study group
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
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
100% 90% 80% 70% 60% 50% 40% 30% 20% 10% Viral load <50 copies/ml at week 48 (ITTe), baseline VL > 100.000 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
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
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
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] 8000 6000 4000 2000 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) 0 0 6 12 18 Hrs 1. Kakuda TN, et al. Clin Pharmacol. 2012. Abstract O_20. 2. Kakuda TN, et al. IAS 2013. Abstract MOPE029. 24 8000 6000 4000 2000 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) 0 0 4 8 12 16 20 24 Hrs
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. NCT01440569. 2. ClinicalTrials.gov. NCT01565850.
EIMC. En prensa
Lennox JL et al. Annals of internal medicine 2014
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
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 1 +0 15 (2.1%) +2 (+0.3%) 3 (0.9%) +1 (+0.3%) 0 +2 (+0.6%) M184V/I 15 +2 M184V/I 3 +1 M184V/I 0 +2 K65R 5 0 K65R 3 +0 K65R 0 0