What is the virological support for reduced drug...
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What is the virological support for reduced drug regimens?
Pr Anne-Genevieve MarcelinPitié-Salpêtrière Hospital
UMR 1136University Pierre et Marie Curie
Paris, France
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Disclosure of Personal and Commercial Support
& Handling of Bias
• AG Marcelin has no commercial interests.
• AG Marcelin has received travel grants, honoraria, and study
grants from various pharmaceutical companies including
Gilead Sciences, Merck-Sharp & Dohme-Chibret, Janssen-
Cilag and ViiV Healthcare.
• AG Marcelin prepared the content of this presentation using
his own material with no commercial input.
• AG Marcelin may discuss cases and circumstance when
drugs are used off label; this is his own personal clinical
experience. For the proper use of medications, please review
the Product Monographs.
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Current recommendations
• HIV infection is deleterious starting in the very first days followinginfection
• No current strategy for HIV cure
• HIV has to be controlled with life long ART
• 3-drugs combination is still recommended for all patients startingtreatment
• Recent guidelines provide some recommendations for simplification in virologically suppressed patients
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1987AZT monotherapy
1994-1995NRTI dual therapy
1996-19972 NRTI + PI
B.A Larder et al ; Science 1989
B.A Larder et al ; Nature 1993
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• Prob. 1 virus resistant to drug A 1/10 000 to 100 000 (10-4 to 10-5)• Prob. 1 virus resistant to drug B 1/10 000 to 100 000 (10-4 to 10-5)
• Prob. 1 virus resistant to drugs A+B 10-4 /10-5 x 10-4 /10-5 = 10-8 to 10-10
• Prob. 1 virus resistant to drug C 1/10 000 to 100 000 (10-4 to 10-5)
Probability 1 virus resistant to drugs A + B + C = 1/10-12 to 10-15
<<< 109 to 1010 of new viruses/day
WT virus
virus resistant to drug A
virus resistant to drugs A + B
virus resistant to drug Bvirus resistant to drug C
Pressure Drug A
PressureDrugs A + B
Drugs. A + B + C
= 0
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Do we still need 3 ARV to achieve viral suppression? • Patients are initiated at much earlier stages (2010-2013): shift in
• CD4: 200 to 405 cells/mm3
• HIV VL: 5 to 4.58 log10 cps/ml
• Need for evaluation of “lighter” antiretroviral regimens, i.e. dual or single ARV combinations with potential benefits
• reduced toxicity• better tolerability• less resistance• class-sparing• lower costs
Rather than triple therapy for all, the new dogma should become ART and lifelong viral suppression for all
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Ideal candidates
• High antiviral potency
• High robustness in term of genetic barrier to resistance
• Favorable pharmacokinetics properties (minimal inter and intra variability)
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Ideal candidates
• High antiviral potency
• High robustness in term of genetic barrier to resistance
• Favorable pharmacokinetics properties (minimal inter and intra variability)
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(1)
these immature virions produced in the presence of PIs are incapable of efficiently completing entry (1), reverse transcription
(2), and post–reverse transcription steps (3)
S.Alireza Rabi et al; J.Clin. Invest. 2013
Multi-step inhibition explains HIV-1 protease inhibitorpharmacodynamics and resistance
(3)(2)
At clinical concentrations, the entry inhibition by PIs is a majorcomponent of their overall inhibitory potential
… PIs act like multiple drugs in one
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** Approved dose for etravirine is 200mg BID1. Min S. AIDS 2011.
2. DeJesus E. J Acquir Immune Defic Syndr 2006 ; 43:1-5.
3. Markowitz et al. JAIDS Volume 43(5) 15 December 2006 pp 509-515.
4. Gallant JE et al. JAIDS 2017
5. Goebel et al. AIDS 2006, 20:1721–1726.
6. Sankatsing et al. AIDS 2003, 17:2623–2627.
7. Fätkenheuer G, et al. IAS 2007. Abstract WESS202.
8. Adkins et al. Drugs 1998, 56( 6): 1055-1064
9. Kilby JM. AIDS Res Hum Retroviruses 2002; 18:685-694.
10. Murphy RL. AIDS 2001;15:F1-F9.
11. Fätkenheuer G et al. Nat Med 2005 Nov; 11:1170-1172.
12. Eron JJ, N Engl J Med 1995, 333:1662-1669.
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POTENCY: ARTs in MONOTHERAPY
INSTI PI
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Clinical trials in naive patients :
INI vs EFV and INI vs IP/r
INI vs EFV ATV/r DRV/r
RALSTARTMRK
RAL ≈ EFV
ACTG A5257
RAL > ATV/r & DRV/r
EVG/coGS-US-236-0102
EVG/co ≈ EFV
GS-US-236-0103
EVG/co ≈ ATV/r
WAVES
EVG/co > ATV/r
DTGSINGLE
DTG > EFV*
ARIA
DTG > ATV/r
FLAMINGO
DTG > DRV/r
≈ : Non-inferiority ; > : Superiority ; * DTG/ABC/3TC > EFV/TDF/FTC
Références en fin de présentation
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Ideal candidates
• High antiviral potency
• High robustness in terms of genetic barrier to resistance
• Favorable pharmacokinetics properties (minimal inter and intra variability)
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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/RTV96
26
26
1
0
ACTG 5202[2] 463
465ATV/RTV 96
83
57
1
0
Study 103[3] 355 ATV/RTV 144 NR 0
ARTEMIS[4] 343
346
DRV/RTV
LPV/RTV96
31
46
0
0
FLAMINGO[5] 242 DRV/RTV 48 NR 0
ACTG 5257[6] 605
601
ATV/RTV
DRV/RTV96
75
99
0
0
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.
▪ Among 4303 pts in these trials, only 2 pts developed major PI mutations at initial VF
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• Long dissociative half life from integrase (71h)
• High inhibitory quotient (x19)
• High virologic potency (-2,46 log in monotherapy)
• No resistance mutations (INTI and INSTI) in any randomised clinical trials in naive or suppressed patients treated by triple combination
Hightower KE, et al. Antimicrob Agents Chemother 2011;5:4552–9 − Song I, et al. IWCP 2012. Résumé O07 − Elliot E, et al. IWCPHIV 2015. Abstract 13 − Min S, et al. AIDS 2011;25:1737–45 − Raffi F et al. Lancet Infect Dis 2013;13:927–935 − Walmsley S et al. J Acquir Immune Defic Syndr 2015 − ViiV data on file (SINGLE 144-week clinical study report) − Clotet B et al. Lancet 2014;383:2222–2231 − MolinaJM et al. Lancet 2015 − Orrell et al. AIDS 2016; Durban, South Africa. Slides THAB0205LB. − Trottier B, et al. ICAAC 2015. Oral presentation − Llibre et al. CROI 2017; Seattle, WA. Abstract 2421.
Virologic robustness of DTG
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Monotherapy
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Virologically suppressed patients
• PI/r monotherapy:
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PI/r monotherapy is possible if…• Clinical criteria:
- High adherence- No previous CNS disorders- Nadir CD4 > 200/mm3
• Virological parameters: - Previous long term virologic suppression
- > at least 12 months (Guiguet et al ; AIDS 2012)
- Low residual viremia- USVL < 1 cp/ml associated with low risk of VF (S Lambert-Niclot et al ; JID 2011)
- Low viral DNA before switch- French guidelines: HIV DNA < 200 copies/10⁶ PBMCs and not > 1000 copies/10⁶ PBMCs
- No previous failure or resistance- No HBV chronic infection
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PI/r monotherapy is possible if…• Clinical criteria
- High adherence- No previous CNS disorders- Nadir CD4 > 200/mm3
• Virological- Previous long term virologic suppression
> at least 12 months (Guiguet et al ; AIDS 2012)
- Low residual viremiaUSVL < 1 cp/ml associated with low risk of VF (S Lambert-Niclot et al ; JID 2011)
- Low viral DNA before switchFrench guidelines: HIV DNA < 200 copies/10⁶ PBMCs and not > 1000 copies/10⁶ PBMCs
- No previous failure or resistance- No HBV chronic infection
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Virologically suppressed patients
• DTG monotherapy:• DOMONO: Switch to DTG Monotherapy in Virologically Suppressed Pts Not
Sufficient
▪ Randomized comparison of switch to DTG 50 mg QD monotherapy vs continued baseline ART for 24 wks in virologically suppressed pts with no previous VF
▪ At Wk 24, DTG monotherapy non inferior to continued baseline ART for maintained HIV-1 RNA < 200 c/mL
▪ Study d/c early because of high VF rate after 48 wks of DTG monotherapy
– VF in 8/77 pts with DTG monotherapy vs 3/152 pts on combination ART in concurrent control group (P = .03)
– Among 6 VF cases with resistance data in DTG monotherapy group, 3/6 developed INSTI resistance (N155H, R263K, S230R, n = 1 each)
Wijting I, et al. CROI 2017. Abstract 451LB.
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Virologically suppressed patients
• DTG monotherapy:
– DOMONO: Switch to DTG Monotherapy in Virologically Suppressed Pts Not Sufficient
▪ Randomized comparison of switch to DTG 50 mg QD monotherapy vs continued baseline ART for 24 wks in virologically suppressed pts with no previous VF
▪ At Wk 24, DTG monotherapy non inferior to continued baseline ART for maintained HIV-1 RNA < 200 c/mL
▪ Study d/c early because of high VF rate after 48 wks of DTG monotherapy
– VF in 8/77 pts with DTG monotherapy vs 3/152 pts on combination ART in concurrent control group (P = .03)
– Among 6 VF cases with resistance data in DTG monotherapy group, 3/6 developed INSTI resistance (N155H, R263K, S230R, n = 1 each)
Wijting I, et al. CROI 2017. Abstract 451LB.
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Dual therapy
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Virologically suppressed patients
• PI/r + 3TC– DUAL-GESIDA 8014: DRV/r + 3TC Dual ART was non inferior to triple ART (TDF/FTC or
ABC/3TC + DRV/r) at Wk 48
» No resistance mutations in the 2 dual-therapy patients who experienced virologicfailure
– ANRS 12286/MOBIDIP: after viral suppression with boosted PI plus NRTI in second-line ART, maintenance therapy with boosted PI plus 3TC was associated with a higher rate of success than PI monotherapy, despite the presence of M184V (96%) at first-line treatment failure
Pulido F, et al. HIV Glasgow 2016. Abstract O331Ciaffi L, Lancet HIV 2017, May 28, 2017 (Epub ahead of print)
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M184V: reduced replicative capacity=> residual activiral effect of 3TC prevents relapse of viral replication in combination with PI/r in patients
already suppressed
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Virologically suppressed patients
• INSTI based regimen• NNRTI
– ANRS 163 ETRAL: switch to RAL + ETR was effective in maintaining viral suppression at Wk 48 in 165 patients
» 1 pt with VF, VL = 11 607 c/ml confirmed at 18 472 c/ml, RAL S and ETR R : K101E, Y181C and G190A/S (see EACS PS6/4 from Soulie et al.)
– SWORD: switch from suppressive ART to DTG + RPV was non inferior to continued baseline ART at Wk 48
» 1 pt with confirmed criteria for virologic withdrawal at Wk 36 in DTG + RPV arm had K101K/E, no INSTI resistance
• 3TC– LAMIDOL: switch to DTG + 3TC was effective in maintaining viral suppression at Wk 48
» no INSTI resistance in 3 pts with virologic failureLlibre JM, et al. CROI 2017. Abstract 44LB.
Joly V, et al. CROI 2017. Abstract 458.
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ACTG A5353: DTG + 3TC for Treatment-Naive Pts
▪ Single-arm phase II study
▪ Baseline: 31% HIV-1 RNA > 100,000 c/mL
1. Taiwo BO, et al. IAS 2017. Abstract MOAB0107LB.
2. ClinicalTrials.gov. NCT02831673. 3. ClinicalTrials.gov. NCT02831764.
Virologic
Outcome at
Wk 24, n (%)
Baseline HIV-1 RNA, copies/mLTotal
(N = 120)> 100,000
(n = 37)
≤ 100,000
(n = 83)
Success* 33 (89) 75 (90) 108 (90)
Nonsuccess 3 (8) 2 (2) 5 (4)
No data 1 (3) 6 (7) 7 (6)
▪ n = 3 with PDVF; n = 1 with emergent M184V and R263R/K mixture
– All 3 pts had DTG levels reflective of suboptimal adherence
*HIV-1 RNA < 50 copies/mL.
ART-naive pts with
HIV-1 RNA ≥ 1000 and < 500,000 copies/mL;
no RT, INSTI, major PI resistance mutations
(N = 120)
DTG 50 mg + 3TC 300 mg
Primary Endpoint
Wk 24
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Conclusions (1)
• Triple therapy: remains the gold standard for virologists- No resistance in case of first line VF with PI/r or DTG
• Drugs with high potency and high genetic barrier to resistance
• HIV treatment is currently evolving towards individualized therapy- To adjust chronic therapies to each individual
• 20% of patients are receiving dual therapies in our clinical center
- We need to evaluate these strategies
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Conclusions (2)
• Monotherapy
- With DTG not recommended- Unacceptable risk of resistance in case of VF
- Possible in virologically suppressed patients• With PI/r
• Mainly DRV/r• Despite LLV, no emergence of resistance• Clinical and virological tools to identify good candidates (UsVL < 1 cp/ml, HIV DNA <
2.3 log and no resistance)• Represents only 4% of patients in our clinical center
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Conclusions (3)
• Dual therapy• In virologically suppressed:
• Several options: with PI/r or DTG• RT inhibitors are still needed: 3TC or NNRTI (RPV, ETR)• 3TC can be substitute to 2 NRTIs even when it shouldn’t work• Need for more resistance data in case of VF in routine care: risk of resistance higher than with
triple therapy?
• In naïve: • Waiting for large clinical trials results: GEMINI 1 & 2 Phase IIII, DTG/3TC vs DTG/TDF/FTC
(results expected in 2018)
• Risk of reactivation when removing 3TC/FTC/TDF in patients with chronic HBV infection
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VirologyPitié-Salpêtrière
Pr Vincent Calvez
Dr Marc Wirden
Dr Eve Todesco
Dr Cathia Soulie
Dr Thuy Nguyen
Isabelle Malet
Nathalie Desire
Saint AntoinePr L Morand Joubert
Dr Sidonie Lambert-Niclot
Dr Djeneba Fofana
Infectious Diseases
Pr Christine Katlama
Dr Roland Tubiana
Dr Marc-Antoine Valantin
Rachid Agher
Biostatistics
Dr Philippe Flandre
Pr Dominique Costagliola
Dr Lambert Assoumou
Maxime Grude