Inibitori delle proteasi: la versatilità della classe Diego Ripamonti - Malattie Infettive - Bergamo XIV CONGRESSO NAZIONALE SIMIT novembre 2015

Disclosures Diego Ripamonti received advisory fees, speaker fees, travel and education from: - BMS - ViiV - Janssen - Merk - Gilead 2

60,000 Mortalità AIDS-correlata e PI-based HAART HAART (= PI-based regimens) 80,000 70,000 50,000 40,000 30,000 20,000 10,000 0 Deaths (n) Yr of Death CDC.gov. Epidemiology of HIV infection.

L’evoluzione dei PIs PASSATOPRESENTEFUTURO Many pills per day Multiple doses necessary Improved tolerability Some boosted 1 pill per day (+ RTV & NRTIs) Boosting gold standard Manageable toxicity More coformulations Single-tablet regimens High toxicity Once-daily dosing Coformulation Some treatment-limiting toxicity SQV RTV IDV APV NFV FPV/RTV LPV/RTV ATV ATV/RTV DRV/RTV ATV/COBI DRV/COBI DRV/COBI/TAF/FTC SQV/RTV IDV/RTV

No resistance at failure High genetic barrier Metabolic profile MDR viruses HAART Backbone protection Versatility of boosted PIs in anti-HIV therapy Special populations: -- Pregnancy -- Cirrhosis -- HIV encephalopathy -- children Once daily option Different dosages by setting De-intensification Coformulation PI/r

Resistance mutations at failure in naive patients on boosted PI Drug class ACTG (1809 pts, 96 wks) ACTG (1857 pts, 96 wks) NEAT-01 3 (805 pts, 96 wks) Flamingo 4 (484 pts, 96 wks) Study (708 pts, 96 wks) TDF/FTC+ DRV/r TDF/FTC+ ATV/r TDF/FTC+ RAL TDF/FTC+ ATV/r TDF/FTC+ EFV ABC/3TC+ ATV/r ABC/3TC+ EFV DRV/r+ TDF/FTC DRV/r+ RAL TDF/FTC + DTG TDF/FTC + DRV/r TDF/FTC+ EVG/c TDF/FTC+ ATV/r NRTI 3 (DRV arm) 8 (ATV arm) 17 (RAL arm) 16 (PI arms) 36 (EFV arm) 0 (TDF arm) 1 (RAL arm) (PI arm) 4 (EVG arm) PI 0 (DRV) 0 (ATV) 1 (ATV)0 (TDF arm) 0 (RAL arm) 00 (ATV arm) NNRTI II 1 (DRV arm) 1 (ATV arm) 11 (RAL arm) (EVG arm) 4. Molina JM et al. J Int AIDS Soc. 2014;17: Landovitz RJ et al. CROI Daar E et al. Ann Intern Med Raffi F et al. CROI Abstract 84LB.5. Rockstroh J et al. JAIDS. 2013;62:

Monotherapy in switch strategies

Antinori A et al. Glasgow 2014 PROTEA study - DRV/r + 2NRTI (136 pts) - DRV/r mono (137 pts) MonoTriple Switching to monotherapy in treatment maintenance week 48 analysis, HIV RNA < 50 c/ml % 1.Switch strategy 2.nadir CD4 > 200 cells 3.no previous failure 4.no HIV encephalopathy 5.no HBV 6.no HCV (?) Patient’s selection

Study (N of pts) Follow-up Primary PI mutations secondary PI mutations mutations in gag gene mean CD4 increase Efficacy of reinduction OK04 1 (100 vs 98) 96 weeks 2 vs 23.0 vs 3.5 (in 15 patients) No difference+71 vs +41 § 83% (10/12) MONOI 2 (112 vs 113) 96 weeks 1° vs 01/9 patientsNo difference+70 vs +39 § 100% (5/5) MONET 3 (127 vs 126) 144 weeks 1 vs 1No differenceNot done+95 vs +9985% (6/7) §non statisticamente significativo; °mutazione V11I, già presente 7 anni prima; For all comparisons: mono vs triple arm Risks of monotherapy compared to HAART 1. Arribas J. JAIDS 2009; 2. Valantin M. JAC 2012; 3. Arribas J. HIV Med 2012 Resistance mutations at failure Immune recovery salvage

Moltò J et al. JAC 2015 DRV/r 800 mg DRV/r 600 mg 2NRTI 50 pts 48 weeks 90% 94% Mean time on < 50 c/ml: 106 weeks

DUET: Virological response at Week 48 (TLOVR) with fully active ETR and fully active DRV Fully active ETR = patients with ETR FC  3; DRV = patients with DRV FC  10; ETR and DRV were not included in the PSS calculation; Analysis excludes patients who discontinued for reasons other than VF; *Logistic regression; ‡ According to Antivirogram ® Placebo + BR (n=236) ETR + BR (n=227) Patients with viral load <50 copies/mL at Week 48 (%) Number of active NRTIs in the BR (PSS) ‡ Total number of active agents used (including ETR + DRV) 80/10857/10762/7555/7833/4128/443/36/7 74% 53% 83% 71% 80% 64% 100% 86% p=0.0011* p=0.0177* p=0.0283* p=N/A ≥3 234≥5 N.Clumeck, ET AL.

DUAL strategies IP/r +MRV +NNRTI +RAL +3TC Two-drug regimens ETR NVP MRV +RAL DTG3TC? ATV/r + 3TC DRV/r + 3TC LOP/r + 3TC DTGRPV? ATV/r + MRV DRV/r + MRV

StudyDual armTriple armF-up NaiveNEATRAL+ DRV/rTDF/FTC + DRV96 Gardel3TC+ LOP/r2NRTIs + LOP/r96 MODERNMRV+DRV/rTDF/FTC+DRV/r48 SwitchSALT3TC+ ATV/r2NRTIs+ ATV/r96 OLE3TC+ LOP/r2NRTIs+ LOP/r48 ATLAS-M3TC+ ATV/r2NRTIs+ ATV/r48 MARCHMRV+ DRV/r2NRTIs+ DRV/r48 GUSTAMRV+ DRV/r2NRTIs+ DRV/r48 PI-based dual strategies: randomized trials

ATV/r2NRTIs ATV/r 143 pts 48 weeks 3TC SALT - Switch study - on first line regimen - no previous failure - from PI regimen: 65% - from TDF: (82%) - nadir CD4: 212 ( ) - baseline CD4: 582 ( ) - < 50 c/ml: 28 (15-53) months - HCV RNA pos: 20% - on TDF after random: 71% - on ABC after random: 23% Perez-Molina JA et al. Lancet Infect Dis 2015 Data are median (IQR) Non-inferiority trial (-12%), < 50 copies/ml SALT Trial HAART

Arribas JR et al. Lancet Infect Dis 2015 OLE OLE Trial 121 pts 118 pts 48 weeks - switch study - no previous failure - from LOP-based rx: 100% - from TDF: (61%) - nadir CD4: 176 (72-266) - baseline CD4: 610 ( ) - < 50 c/ml: 47 (28-73) months Data are median (IQR) Non-inferiority trial (-12%), < 50 copies/ml, ITT LOP/r2NRTIs LOP/r3TC od LOP/r based Rx

Treatment arm CD4 count increase Viral blips*Virological 1 blip2 blipsFailure ITT Resistance mutations Triple-1117%4%3%1 (184V) Dual cells (-35 to 80) 15%3%4% Viral blips and immune response Treatment arm CD4 count increase Viral blips*Virological Failure ITT Resistance mutations Triple (121)40 (SD 254)9.9%2.4%- Dual (118)+29 (SD 182 ) p= %2.5%1 (184V, 103A) SALT Trial OLE Trial

ATLAS-M Trial Di Giambenedetto S et al. EACS 2015 ATLAS-M Trial Data are medians in dual vs triple - switch study - no previous failure - from TDF: 78 vs 83% - nadir CD4: 274 vs 257 cells - baseline CD4: 622 vs 616 cells - < 50 c/ml: 23 vs 20 months Non-inferiority trial (-12%), < 50 copies/ml

Di Giambenedetto S et al. EACS 2015 ATLAS-M Trial

Di Giambenedetto S et al. EACS 2015 ATLAS-M Trial

PI/r + MRV

DRV/rMRV 300mg od 165 pts 48 weeks HAART - Switch study - no previous failure - R5 tropic virus - from PI regimen: 64 vs 54% - nadir CD4: 201 vs 222 cells - baseline CD4: 659 vs 686 cells - < 50 c/ml: 55 vs 58 mos - HCV RNA pos: 14 vs 11.5 % Non-inferiority trial (-10%), < 50 copies/ml HAART GUSTA Rossetti B et al. EACS 2015 Gusta Trial Data are median in dual vs triple

Rossetti B et al. EACS 2015 Gusta Trial

Pett SL et al. EACS 2015 MARCH Trial MARCH - Switch study (< 200 cp/ml) - no previous failure - R5 tropic virus (genotipic) - mean CD4 (SD): 617 (251) - ARV duration: 6.1 years - from PI regimen: 100%

Pett SL et al. EACS 2015 MARCH Trial

Pett SL et al. EACS 2015 MARCH Trial Switching to MRV+PI/r was associated to a significantly lower virological control Emergence of resistance at failure

No resistance at failure High genetic barrier Metabolic profile MDR viruses HAART Backbone protection Versatility of boosted PIs in anti-HIV therapy special populations: -- Pregnancy -- Cirrhosis -- HIV encephalopathy -- children Once daily option different dosages by setting deintensification Coformulation PI/r Nessuna altra classe di farmaci antiretrovirali ha dimostrato in 20 anni una simile versatilità di impiego

From HAART to STR regimens TDF/FTC/EFV TAF/FTC/EGV-c TAF/FTC/RPV ABC/3TC/DTG Mills A et al. JAIDS Apr 10 (Phase 2 study, 48 weeks) TAF/FTC/DRV/cobi PI

Thanks

Barriera genetica, sviluppo di resistenze e farmaci antivirali Llibre JM et al. AIDS Rev, 2015