Treatment Initiation: What to Expect from Dual or Mono-therapy ? Do we need triple therapy for everyone .. for life ? Treatment Initiation: What to Expect from Dual or Mono-therapy ? Pr Christine Katlama Sorbonne Université Paris VI Pitié-Salpêtriere Hospital, Paris

Disclosure Pr C Katlama has served as a speaker and scientific board consultant for MSD , Janssen , ViiV , BMS Research grant : Janssen ----- Notes de la réunion (22/07/17 11:21) ----- here are my disclosure

Reasons for individualizing ART Using mono/dual strategies Context Earlier ART initiation Pitié Salpétriere 2016 57% start ART with > 350 CD4 and 41% with VL< 30 000 cp/mL Recent / New drugs more potent and robust Decades of suppressive ART needed with prolonged drug exposure Preserve drug options Challenges Maintain long life viral suppression Keep ART simple Minimize toxicity Avoid drug-drug interactions Maintain non infectious status Optimize ART Cost ----- Notes de la réunion (22/07/17 11:21) ----- Why should we think NOW to move from the all "triple therapy concept that have been the only rule for 20 years ?

Antiretroviral Therapy Goals Test a maximum of high risk individuals 10 6 1 000 000 10 5 100 000 10 4 10 000 10 3 1 000 10 2 100 20 Treat all HIV infected patients and maintain in care Do we have to give triple ART for all? ADAM : 57 CD4 ; VL 354 000 cp/mL MACHA : 454 CD4 ; VL : 74 000 cp/mL CYRIL : 678 CD4 ; VL : 6890 cp/mL JOHN 956 CD4 VL< 50 cp/mL since 12 years Maximal Viral suppression for all Below level of detection

Drug Mono/Dual ART : Which drugs to rely on ? What is needed Potency Once daily dosing High tolerability Favorable PK /long half life Virologic robustness Low primary resistance rates Potential drugs NRTI TDF/TAF - FTC PI Darunavir/r NNRTI Rilpivirine Integrase inhibitors RAL QD Dolutegravir Future drugs ? Doravirine MK-8591

Mono/Dual ART Initiation Regimen Mono PI Monark LPV 2 NRTI TDF 3TC FTC INI + IP XTG/3TC ACTG 5353 PADDLE PI/NNRTI LPV/EFV ACTG 5142 Protease Inhibitors /3TC LOPI/3TC GARDEL DRV /3TC ANDES Maraviroc/PI Modern MVC/ DRV/r VEMAN MVC /LPV/r A 4001078 MVC/ATV/r All MVC based strategies were non enough potent INI+PI NEAT-01 DTG/3TC PADDLE ACTG 5353 Amit Achra , Mwasakifwa,Amin, Boyd LANCET HIV 2016

Single drug regimen in initiation MONARK mono LPV/r vs AZT/3TC/LPV/r PI Monark :LPV mono > 400 c/mL 100% 50 - 400 < 50 c/mL 80% 60% 40% Responders Lower viral load W4 VL < 400 cp/mL Lower HIV DNA= 2.86 log10cp/106 PBMC Non-Responders HIV Higher BL VL Higher DNA 3.16 log10 cp/106 PBMC P = 0.05 20% 0% 16 32 48 Weeks Flandre P Antiviral therapy 2009 Avettand-Fenoel et al J Antimicrob Chemother 2010; 65: 1005–1007 Delfraissy JF, AIDS 2008; 22: 385 – 93.

Two drug regimen as initiation ART : A concept started..20 years ago ANRS TRILEGE Naïve patients Induction 12 weeks induction phase with AZT+3TC+IDV Then de-escalation for AZT+3TC vs AZT+IDV vs 3-DR Superiority of 3-DR But in those with baseline HIV-RNA < 30 000 copies/ml, no significant difference between the 3 study arms Pialoux G, NEJM 1998 ACTG 343 Naïve patients Ind 24 sem AZT/3TC/IDV Then de-escalation for AZT+3TC vs IDV vs 3-DR MT : CV 11 800 cp/ml Superiority of 3-DR But if high CD4 and VS > 200 cp/mL difference NS Although the results of this trial are somewhat disappointing, they should not discourage future at- tempts to simplify therapies for HIV Havlir DV, NEJM 1998

Binuke 20 naive patients VL < 30 000 cp/ml Med : 10.395 cp/ml CD4 > 350/mm3 med : 592 Initiation with 2 NRTI TDF/FTC : 19 ABC/3TC : 1 1 Stop ART Time to VL < 50 cp/mL : 4 weeks [4-12] 2017 : all remained VS median FU : 47 months n=20 Seang S et al. J Antimicrob Chemother. 2014

PI 3TC GARDEL: Dual ART LPV/r +3TC Non inferior to Triple ART in ART naïve patients Phase III, randomized, controlled, open-label study Argentina, Chile, Mexico, Peru, Spain, US. HIV-1 RNA < 50 W48 ITT exposed -Snapshot W96 ITT Snapshot 88.3 % 90.3% 83. 7 % 84.4 % LPV/r 400/100mg BID + 3TC 150 mg BID n=217 426 ART- naive pts VL: 4.87 log CD4: 320/mm3 No PI resistance The main inclusion criteria are described in the box. Randomization was stratified by viral load at screening. LPV/r 400/100mg BID + 3TC /FTC + NRTI n=209 Grade 2-3 adverse events more frequent in triple-ART arm (88 vs 65 events) Hyperlipidemia more common in dual-ART arm (23 vs 16 pts) Limited resistance ( 2 with M184V in LPV/3TC ) Cahn P, et al. Lancet Infect Dis. 2014;14:572-580.

Dual DRV/r 800/100 +3TC vs TDF+FTC+DRV/r in naïve patients PI 3TC Dual DRV/r 800/100 +3TC vs TDF+FTC+DRV/r in naïve patients Phase 4, randomized, multicentric, open label study , Wk 48 Primary endpoint Stratified at screening by HIV-1 RNA (≤ or > 100,000 copies/mL) % HIV RNA < 400 cp/mL Wk 24 Interim analysis 145 ARV- naive patients 5 sites in Argentina 18 years 4.5 log HIV copies/ml 24% >5 log CD4 : 383 /mm3 No IAS-USA defined NRTI or PI resistance at screening* HB(s)Ag negative ITT snapshot 95% On Treatment 100% Discontinuations 4 Withdraw consent (1) ,SAE (1), LTFU (1) , RASH (1) Dual therapy DRV/r 800/100mg QD + 3TC 300 mg QD n= 75 Triple therapy : DRV/r 800/100mg QD + 3TC /TDF 300/300mg QD n=70 ITT snapshot 97% On Treatment 99 % Discontinuations 1 PDVF 1 P. Cahn IAS 2017 MoAB0106LB

NEAT 001/ANRS 143 DRV/r + RAL vs DRV/r + TDF/FTC PI/Ral NEAT 001/ANRS 143 DRV/r + RAL vs DRV/r + TDF/FTC 20 40 100 60 % 80 4 8 12 18 24 32 48 64 96 DRV/r + RAL, 89.4% (95% CI : 85.7-92.4) DRV/r + TDF/FTC, 93.3% (95% CI : 90.3-95.6) HIV RNA < 50 c/mL 805 ART naive patients CD4 : 345/mm3 CV : 4.76 log > 105cp/ml : 35% When CD4 are low or VL high prefer triple ART Raffi F. Lancet 2014;384:1942-51

Dual Therapy with Dolutegravir in HIV-infected ART-naive Patients DTG/3TC Dual Therapy with Dolutegravir in HIV-infected ART-naive Patients PADDLE Pilot Antiretroviral Design with Dolutegravir (50mg) Lamivudine (300mg) 20 patients, ART naive > 5000 < 100.000 c/mL, because of differences of screening to baseline values, 4 patients had VL > 100‘000 c/mL From Week 8 onwards all patients had VL < 50 c/mL 18/20 pts achieved VL < 50 c/mL at Wk 48 1 suicide 1 PDVF at Wk 36 Figueroa MI, et al., et al, AIDS 2016 W96 18 patients No VF; one SAE unrelated ART Figueroa IAS 2017 Poster MOPEB0287

5353 Dolutegravir/3TC in naive pts % VL<50 cp/mL snapshot W24 DTG/3TC 5353 Dolutegravir/3TC in naive pts % VL<50 cp/mL snapshot W24 Phase II, single-arm, 52-week, pilot study DTG 50mg + 3TC 300 mg/d in naïve patients CD4: 350/mm3 with VL ≥1000 and <500,000 cpm Primary outcome Success VL < 50 cpm at W24 Non success VL>400 W16 or W20 VL>200 after W24 Baseline HIV-1 RNA    > 100,000 N=37 ≤ 100,000 N=83 Total N=120 Virologic success 33 (89%) 75 (90%) 108 HIV-1 RNA < 50 cpm [95% CI] [75-97%] [82%,96%] [83%,95%] Virologic non-success 3 (8%) 2 (2%) 5 (4%) HIV-1 RNA ≥ 50 cpm Discontinued study Rx while HIV RNA ≥ 50* No virologic data in window 1 (3%) 6 (7%) 7 (6%) Discontinued study treatment for other reasons # On study but missing data in window * Poor adherence; # Lost to follow-up, pregnancy B.Taiwo et al IAS 2017 Mo [95% Confidence intervals] for proportion of participants with virologic success at Week 24

GEMINI 1 &2 Phase IIII DTG/3TC vs DTG/TDF/FTC in naive patients Naive HIV patients HIV RNA 1000-100 000 then up to 500 000 CD4 > 200 PrEP ou PEP allowed if >1 month no HBV infection Naive patients DTG/3TC DTG+TDF/FTC Primary End point proportion patients with HIV RNA <50 cp/mL 700 patients enrolled Results expected in 2018

Impact of mono/dual strategy on reservoir and genital compartment Viral reservoir HIV DNA MONARK : Similar decrease in mono vs TRI : - 0.79 (mono) vs -0.68 (tri) log HIV DNA /106 PBMC Avettand-Fenoel et al JAC 2010; 65: 1005–1007 MONOI: Similar decline in HIV DNA from BL to W96 ( - 0.51) Lambert-Niclos Plos one 2012 BINUKE : decrease -0.4 log from 464 copies/106 PBMCs at baseline to 206 copies/106 PBMCs (IQR 65–340 copies) at W24 Seang S et al. J Antimicrob Chemother. 2014 Viral replication in genital compartment MONARK : 10 pts ; no viral production in sperm Ghosn J et al JAC 2008 ; 61: 1344

Guidelines are introducing dual ART EACS1 Alternative RAL 400 mg, 1 tablet bid + DRV/c 800/150 mg, 1 tablet qd or + DRV 800 mg, 1 tablet qd + RTV 100 mg, 1 tablet qd Only if CD4 count > 200 cells/µL and HIV-VL < 100,000 copies/mL DHSS2 Altenative when TAF, TDF, or ABC Cannot be Used: • DRV/r plus RAL (BID) (CI) —if HIV RNA <100,000 copies/mL and CD4 >200 cells/mm3 • LPV/r plus 3TCa (BID) (CI) IAS 3 When TDF/TAF or ABC cannot be taken DRV/c or DRV/r + RAL or DTG or 3TC 1 EACS 2017 2 https://aidsinfo.nih.gov/guidelines 3 Gunthard H et al JAMA 2016

Mono or dual Strategies in Real Life Pitié Salpétrière Experience 2016 Initiation n=150 Suppressive ART n=4283 3-DR n=125 83% n= 3161 73.8% 2-DR n=14 9.3% n= 855 20 % 1-DR n=7 4.6% n = 195 4.5 % Mono or dual STRATEGIES : PSL (25%)

Comparaison of - 3DR-DTG - Ind Maintenance with 3-DR then DTG-3TC - DTG-3TC Results : Similar 5-year survival rate (90% efficacy ) NAIVE patients 2-DR prefered strategy if VS > 90% If 50% uptake Ind Maint DTG+3TC : saving 550 millions USD in 5 years 2-DR DTG+3TC : saving 800 millions USD SWITCH if 25% of all suppressed patients swicth to DTG/3TC : saving > 3 billion USD

Final Thoughts Individualization of ART is a key challenge for lifelong HIV infection with currently no option for stopping treatment Dual ART with potent and robust drugs is a realistic ART option for treatment-naive patients with low to moderate viral load and good immune status. Robust options such as Darunavir or Dolutegravir combined with 3TC are very promising ; more data will be forthcoming in 2018 New NRTIs , NNRTIs, INIs and other classes of drugs with high potency and robust genetic barrier to resistance should be investigated as part of dual ART

Acknowledgement Pitie Salpétriere Team et al outside R.Tubiana, MA Valantin, F.Caby, L Schneider, S.Seang, R.Palich, J.Ghosn V Calve,z AG Marcelin, G Peytavin, B.Autran, D.Costagliola, L.Assoumou International drug reduced strategies aficionados Pedro Cahn, Babafemi Taiwo, E Martinez, R.Murphy