What is the virological support for reduced drug regimens?

Pr Anne-Genevieve MarcelinPitié-Salpêtrière Hospital

UMR 1136University Pierre et Marie Curie

Paris, France

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.

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

1987AZT monotherapy

1994-1995NRTI dual therapy

1996-19972 NRTI + PI

B.A Larder et al ; Science 1989

B.A Larder et al ; Nature 1993

• 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

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

Ideal candidates

• High antiviral potency

• High robustness in term of genetic barrier to resistance

• Favorable pharmacokinetics properties (minimal inter and intra variability)

Ideal candidates

• High antiviral potency

• High robustness in term of genetic barrier to resistance

• Favorable pharmacokinetics properties (minimal inter and intra variability)

(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

** 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

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

Ideal candidates

• High antiviral potency

• High robustness in terms of genetic barrier to resistance

• Favorable pharmacokinetics properties (minimal inter and intra variability)

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

• 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

Monotherapy

Virologically suppressed patients

• PI/r monotherapy:

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

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

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.

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.

Dual therapy

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)

M184V: reduced replicative capacity=> residual activiral effect of 3TC prevents relapse of viral replication in combination with PI/r in patients

already suppressed

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.

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

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

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

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

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