1. 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

2. 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

3. 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< 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 ?

4. Antiretroviral Therapy Goals
Test a maximum of high risk individuals
10 6
10 5
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 cp/mL
MACHA : 454 CD4 ; VL : cp/mL
CYRIL : CD4 ; VL : cp/mL
JOHN CD4 VL< 50 cp/mL since 12 years
Maximal Viral suppression for all
Below level of detection

5. 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

6. 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 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

7. Single drug regimen in initiation MONARK mono LPV/r vs AZT/3TC/LPV/rPI
Monark :LPV mono
> 400 c/mL
100%
< 50 c/mL
80%
60%
40%
Responders
Lower viral load
W4 VL < 400 cp/mL
Lower HIV DNA= log10cp/106 PBMC
Non-Responders HIV
Higher BL VL
Higher DNA 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.

8. 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 < 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 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

9. 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

10. 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:

11. 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 %
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
P. Cahn IAS MoAB0106LB

12. 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 : )
DRV/r + TDF/FTC, 93.3% (95% CI : )
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:

13. 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 < 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
W patients
No VF; one SAE unrelated ART
Figueroa IAS Poster MOPEB0287

14. 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, N=37
≤ 100, 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

15. GEMINI 1 &2 Phase IIII DTG/3TC vs DTG/TDF/FTC in naive patients
Naive HIV patients
HIV RNA
then up to
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

16. Impact of mono/dual strategy on reservoir and genital compartment
Viral reservoir HIV DNA
MONARK : Similar decrease in mono vs TRI : (mono) vs (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 ( )
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

17. 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 Gunthard H et al JAMA 2016

18. 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%)

19. 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

20. 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

21. 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