1. 25th October 2016
Switching from a boosted protease inhibitor (PI/r) based regimen to a Dolutegravir (DTG) regimen in virologically suppressed patients with high cardiovascular risk (Framingham score >10% or age > 50 years) is non-inferior and decreases lipids: The NEAT 022 study
J.M. Gatell1, L. Assoumou2, G. Moyle3, L. Waters4, E. Martinez5, H.-J. Stellbrink6, G. Guaraldi7, S. de Wit8, F. Raffi9, A. Pozniak10 on behalf of NEAT022 Study Group
1Hospital Clinic/IDIBAPS. University of Barcelona, Infectious Diseases, Barcelona, Spain, 2Sorbone Universites, INSERM, UPMC Univ Paris 06. IPLESP UMRS 1136, Paris, France, 3Chelsea and Westminster Hospital, London, United Kingdom, 4Mortimer Market Center, London, United Kingdom, 5Hospital Clinic/IDIBAPS. University of Barcelona, Barcelona, Spain, 6Infectiologisches Centrum, Hamburg, Germany, 7University of Modena and Reggio Emilia, Modena, Italy, 8Saint Pierre University Hospital, Université Libre de Bruxelles, Brussels, Belgium, 9CHU Hotel-Dieu Nantes, Nantes, France, 10Chelsea & Westminster Hospital, London, United Kingdom
NEAT22/SSAT060 week 48 data

2. Acknowledgements / Conflicts of interest
25th October 2016
Acknowledgements / Conflicts of interest
Acknowledgements
NEATid Foundation is a not for profit private foundation to promote research and education projects in the HIV field. NEAT022/SSAT060 trial was also supported by SSAT and ViiV Healthcare. We thank the European AIDS Treatment Group for collaboration. Spanish centers and Spanish investigators were partially supported by project RD12/0017 integrated in the Plan Nacional I+D+i and co-funded by ISCIII- Subdirección General de Evaluación and European Regional Development Fund (ERDF).
Conflicts of interest
Dr. Josep M Gatell has received honoraria for AB, lectures or travel support and research grants (his institution) from ViiV, MSD, Gilead, Janssen and Abbvie. Conflicts of interest for the rest of co-authors will be disclosed in the manuscript
NEAT22/SSAT060 week 48 data

3. Introduction NEAT022 study hypothesis:
25th October 2016
Introduction
A substantial proportion of clinically stable and virologically suppressed HIV-infected patients receive triple antiretroviral therapy including two nucleos(t)ides analogues plus a PI/r/c
These patients, particularly those with high cardiovascular risk (older than 50 years or with a Framingham risk score >10%), may benefit from switching the PI/r/c to an INSTI
The STRIIVING study (1) demonstrated the efficacy and safety of this strategy in a broad, non-selected population.
NEAT022 study hypothesis:
By switching to a DTG regimen, in a targeted population with high cardiovascular risk, plasma lipid profile will improve and cardiovascular risk may decrease while virological suppression will be maintained and tolerance will not be compromised
NEAT22/SSAT060 week 48 data

4. Patients and methods (I): Study design
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Patients and methods (I): Study design
96-weeks European (6 countries), multicenter (32 sites) , prospective, randomized, open-label, non-inferiority trial (-10%)
Eligibility criteria
HIV-infected patients with plasma HIV-1 RNA < 50 copies/ml for ≥ 6 months on triple therapy PI/r + 2NRTI’ s
Age >50 years and/or Framingham risk score >10% at 10 years
No documented resistance mutations and no previous episodes of confirmed virological failure whilst receiving ART unless documented lack of resistance mutations
Randomization 1:1
stratified by country
DTG + 2NRTI’s (DTG)
PI/r + 2NRT´’s (PI/r)
DTG + 2NRTI’s (DTG)
Week
Primary endpoint
Immediate switching
Deferred switching
NEAT22/SSAT060 week 48 data

5. Patients and methods (II)
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Patients and methods (II)
Co-primary endpoints
Proportion of patients free of therapeutic failure at 48 weeks, in the ITT population
Percent change in fasting total cholesterol in plasma at 48 weeks
Secondary endpoints:
Proportion of patients free of therapeutic failure at 48 weeks, in the per protocol population
Proportion of patients free of therapeutic failure at 48 weeks stratified by baseline Framingham score (15%)
Changes from baseline in CD4+ values at 48 weeks
Percent changes from baseline in other lipid fractions (triglycerides, LDL, non-HDL, HDL cholesterol and TC/HDL ratio) at 48 weeks
Changes from baseline in plasma eGFR levels at 48 weeks
Incidence of adverse events and treatment discontinuation due to toxicity or tolerability problems
Sub studies (changes at 48 weeks in)
Biomarkers (n=300+)
CIMT (n=100)
AS (n=56)
ECG analysis (n=300+)
Special lipid fractions
NEAT22/SSAT060 week 48 data

6. Patients and methods (III)
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Patients and methods (III)
Sample size
420 Participants (210 per group)
Efficacy: 90% success rate and a non-inferiority margin of -10%
Expected a between treatment difference in total cholesterol of 12%
Analysis population
ITT population: all patients who underwent randomization
Per-protocol: all randomized patients except those who did not fulfil the eligibility criteria, withdrew consent, lost to follow-up or discontinued study medication for any reasons other than virological failure or adverse events
Safety population: all randomized patients who received at least 1 dose any study treatment
Method
Kaplan-Meir method to estimate percentage of patients with treatment success , censoring at week 48 or last follow-up date if missing value at week 48.
Treatment success was defined by the absence of two consecutive HIV-1 RNA >50 copies/mL with no study treatment discontinuation for any reason (eg. Death, toxicity, lost to follow-up, consent withdrawal)
NEAT22/SSAT060 week 48 data

7. 25th October 2016
Study disposition
and eligible to continue DTG based regimen up to week 96
and eligible to deferred switching to DTG up to week 96
NEAT22/SSAT060 week 48 data

8. Baseline characteristics (I): n(%) or median (IQR)
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Baseline characteristics (I): n(%) or median (IQR)
DTG (n=205)
PI/r (n=210)
Total (n=415)
Age > 50 years
179(87.3)
184(87.6)
363(87.5)
Framingham score > 10% at 10 years
155(75.6)
151(71.9)
306(73.7)
Male gender
181(88.3)
189(90.0)
370(89.2)
White race
173(84.4)
180(85.7)
353(85.1)
Mode of HIV transmission
Male homosexual sexual intercourse
130(63.4)
131(62.4)
261(62.9)
Heterosexual sexual intercourse
43(23.9)
48(22.9)
97(23.4)
Other
26(12.7)
31(14.8)
57(13.7)
CD4 count; cells per µL
635( )
585( )
617( )
HIV RNA >50 copies/ml
7(3.4)
1(0.5)
8(2)
Hepatitis C IgG antibodies
27(13.4)
24(11.6)
51(12.5)
Time since undetectable viral load (< 50 copies per ml); years
4.9( )
5.3( )
5( )
Current Smokers
78(38)
79(37.8)
157(37.9)
Diabetes
11(5.5)
13(6.3)
24(5.9)
Family history of cardiovascular disease
87(43.3)
89(43.4)
176(43.3)
>= 1 CVD risk factor
151(73.7)
154(73.3)
305(73.5)
Receiving lipid lowering agents
63(30.7)
60(28.6)
123(29.6)
Daily exercise
64(32.5)
59(28.9)
123(30.5)
Fasting plasma lipids
Total cholesterol; mmol/L
5.2( )
5.1( )
5.1( )
Triglycerides; mmol/L
1.6( )
1.6( )
NEAT22/SSAT060 week 48 data

9. Baseline characteristics (II): n (%)
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Baseline characteristics (II): n (%)
DTG (n=205)
PI/r (n=210)
Total (n=415)
Backbone nucleos(t)ides
TDF / FTC
134 (65.4)
135 (64.3)
269 (64.8)
Abacavir/ 3TC
63 (30.7)
67 (31.9)
130 (31.3)
Other
8 (3.9)
8 (3.8)
16 (3.9)
PI/r at baseline
Darunavir/r
105 (51.5)
107 (51.0)
212 (51.2)
Atazanavir/r
77 (37.7)
74 (35.2)
151 (36.5)
22(10.7)
29(13.8)
51(12.3)
NEAT22/SSAT060 week 48 data

10. Results (I): Co-primary efficacy endpoint
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Results (I): Co-primary efficacy endpoint
ITT population
ITT
NEAT22/SSAT060 week 48 data

11. Results (II): Co-primary efficacy endpoint
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Results (II): Co-primary efficacy endpoint
ITT population
NEAT22/SSAT060 week 48 data

12. Results (III): Sensitivity analysis
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Results (III): Sensitivity analysis
Per protocol population
NEAT22/SSAT060 week 48 data

13. Results (IV): Subgroup analysis for efficacy
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Results (IV): Subgroup analysis for efficacy
NEAT22/SSAT060 week 48 data

14. Results: Protocol defined episodes of VF
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Results: Protocol defined episodes of VF NA
Documented
bad adherence
NRM
NRM= No resistance mutations
NA = Could not be amplified
NRM NA NA
NEAT22/SSAT060 week 48 data

15. Results (VI): Co-primary lipids endpoint
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Results (VI): Co-primary lipids endpoint
No changes in the utilization of lipid lowering agents . Around 30% in each arm and both at baseline and week 48.
NEAT22/SSAT060 week 48 data

16. Results (VII): Subgroup analysis for total cholesterol
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Results (VII): Subgroup analysis for total cholesterol
NEAT22/SSAT060 week 48 data

17. Results (VIII): Subgroup analysis for LDL-cholesterol
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Results (VIII): Subgroup analysis for LDL-cholesterol
NEAT22/SSAT060 week 48 data

18. Results: Co-primary lipids endpoint
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Results: Co-primary lipids endpoint
NEAT22/SSAT060 week 48 data

19. Results (IX): Changes in CD4´s
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Results (IX): Changes in CD4´s
NEAT22/SSAT060 week 48 data

20. Results (X): Summary of Adverse Events
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Results (X): Summary of Adverse Events
DTG (n=204)
PI/r (n=208)
P value
Patients n (%)
Adverse events (n)
Any adverse event
153 (75.0)
395
132 (63.5)
352
0.01
Grade 3 or 4 adverse events
12(5.9) 17
19(9.1) 32
0.26
Serious adverse events 14
16(7.7) 27
0.56
Any AE related with ART
26(12.8)
41^
15(7.2)
21^^
0.07
Discontinuation due to adverse events
7(3.4) 7*
3(1.4)
3**
0.22
Death
1(0.5)&
1.00
^ episodes of mood or sleep or CNS disorders
^^ episodes of mood or sleep or CNS disorders
* case of acute Hep C and 6 cases of mood and/or sleep disorders.
** 1 case of Hep C, 1 of dyspepsia and 1 of declining renal function
& accidental fall with skull fracture
NEAT22/SSAT060 week 48 data

21. Results (XI): Change in GFR (CKD-EPI estimates)
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Results (XI): Change in GFR (CKD-EPI estimates)
P<0.001 at all time points
NEAT22/SSAT060 week 48 data

22. 25th October 2016
Conclusions
Over 48 weeks, in virologically suppressed patients with high cardiovascular risk (older than 50 years or with a Framingham score >10%) and receiving triple therapy with PI/r + 2NRTI’s
Switching to a DTG regimen was non-inferior. Sensitivity and subgroup analysis support this conclusion
Improved total cholesterol and other lipid fractions in the overall population and in several subgroups
Very few episodes of VF and no resistance mutations selected.
Overall tolerance was good and similar in both arms.
Sub studies focusing on changes in biological markers, CIMT, AS are ongoing.
Switching to a DTG regimen has the potential benefit of reducing risk of CVD
NEAT22/SSAT060 week 48 data

23. Acknowledgements The Neat 22 study team End Point Review Committee
25th October 2016
Acknowledgements
Thanks to all the study participants and their partners, families, care givers and the staff of all sites
The Neat 22 study team
Trial Steering Committee:
Anton Pozniak Chairman NEAT ID / Steering committee vice Chair; Jose Gatell Overall Chief Investigator / Steering committee Chair; Jose Ramon Arribas NEAT ID Representative; Stephane de Wit NEAT ID Representative; Stefano Vella NEAT ID Representative; Georg Behrens Chief Investigator Germany; Giovanni Guaraldi Chief Investigator Italy; Esteban Martinez Chief Investigator / Sub study Chairman Spain; Graeme Moyle Chief Investigator UK; Francois Raffi Chief Investigator France; Linos Vandekerkhove Chief Investigator Belgium; Lambert Assoumou Statistician; Dominique Costagliola Statistician; Jose- Emilio Martin ViiV representative.
Independent Data Safety Monitoring Board:
Tim Peto DSMB Chair Oxford UK; Adrian Palfreeman University of Leicester NHS Trust UK; Ed Wilkins North Manchester General Hospital UK
End Point Review Committee
Dr Anton Pozniak NEAT ID President, Professor Rob Miller HIV Physician, Dr Nicole Pagani HIV Physician and Dr John Watson Consultant Physician.
Management team at SSAT & in participating countries:
UK; Richard Haslop Snr Project Manager, Charlotte Allcock Project Manager, Katy Burdett, Snr CRA Jamie Oyenowo CRA & Saru Anthonipillai CTA. Germany; Christian Riegel & Kai Oliver Kypke. Spain; Maria Joyera & Maria Montserrat Vizcaya Perich. France; Julie Jaulin. France/Belgium; Florence Renard. Italy; Silvia Cacciaguerra & Chiara Zanone.
NEAT22/SSAT060 week 48 data

24. All NEAT 022 investigators (32 sites from 6 European countries):
Belgium; Linos Vandekerckhove (Universitaire Ziekenhuis Gent), Stephanie De Wit, Nathan Clumeck, Kabamba Kabeya, and Coca Necsoi (Brussels CHU Saint-Pierre), Eric Florence, and Maartje Van Frankenhuijsen (Institute Of Tropical Medicine Antwerp). France; Francois Raffi, and Clothilde Allavena (Service des Maladies Infectieuses et Tropicales du CHU de Nantes), Jean-Michel Molina (Hospital Saint Louis), Yazdan Yazdanpanah, and Bao-Chau Phung (Hospital Bichat Claude-Bernard), Christine Katlama, and Luminita Schneider (La Pitié-Salpêtrière Hospital). Germany; Christoph Stephan, Timo Wolf, Gundolf Schüttfort, Philipp De Leuw, Siri Göpel, and Annette Haberl (Klinikum der Goethe-Universitat Frankfurt), Juergen Rockstroh, Jan-Christian Wasmuth, Carolynne Schwarze-Zander, and Christoph Boesecke (Medizinische Klinik und Poliklinik Bonn), Hans-Jurgen Stellbrink, Axel Adam, Thomas Buhk, Stefan Fenske, Stefan Hansen, Christian Hoffmann, Michael Sabranski, and Knud Schewe (ICH Infektiologisches Centrum Hamburg), Stephan Esser, Isabel Hermes, and Robert Jablonka (Universitatsklinikum Essen AoR), Georg Behrens, Matthias Stoll, Gerrit Ahrenstorf, and Reinhold Schmidt (Medizinische Hochschule Hannover MHH). Italy; Giovanni Guraraldi, Cristina Mussini, Vanni Borghi, Chiara Stentarelli, Federica Carli, Gabriella Orlando, and Antonella Lattanzi (University of Modena), Antonella D'Arminio Montforte (Hospital San Paolo), Massimo Di Pietro, and Francesco Maria Fusco (Hospital SMAnnunziata), Massimo Galli (Hospital L. Sacco). Spain; Esteban Martinez PI at Hospital Clinic Villarroel (Barcelona), Mª Gracia Mateo Garcia, Maria de Mar Gutiérrez Macia, Maria Karuna Lamarca Soria, and Ana Garcia Sarasola (Hospital de la Santa Creu i Sant Pau), Joaquin Portilla at Hospital General Uni. Alicante, Mar Masia, Félix Gutiérrez Rodero, and Sergio Padilla Urrea (Hospital General Uni. De Elche), Bonaventura Clotet, Eugenia Negredo, Patricia Echeverría, and Anna Bonjoch (Hospital Germans Trias i Pujol), José L. Casado (Hospital Ramon y Cajal), Daniel Podzamczer PI at Hospital de Bellvitge (Barcelona), Juan Gonzalez, José Ignacio Bernardino, José Ramón Arribas, Maria Luisa Montes, Ignacio Perez, and Victor Hontañón (Unidad VIH Hospital Uni. La Paz). UK; Graeme Moyle, Maddalena Cerrone, Nicole Pagani, Gurmit Jagjit Singh, Manisha Yapa, Akil Jackson, Alessia Dalla Pria, Emilie Elliot, David Hawkins, Marta Boffito, and Margherita Bracchi (Chelsea and Westminster). Jaime Vera, Amanda Clarke, Professor Rajkumar, Sarah Cavilla, Catherine Kirby, Larissa Mulka, Sonia Raffe, Sarah Stockwell, Nisha Mool, and Fiona Cresaru (Elton John Centre), Alan Winston (St Mary’s, Imperial). Laura Waters, Pierre Pellegrino, Lewis Haddow, Sarah Pett, Alesandro Arenas-Pinto , and Collins Iwaji (Mortimer Market Centre). Julie Fox, Julianne Lwanga, Juan Tiraboschi, Naomi Fitzgerald, Rebecca Simons, and Barry Peters (St Thomas’). Margaret Johnson, M. Tyrer, Sara Madge, Mike Foule, Fiona Burns, Gabrielle Murphy, D. R. Mair, and Anjly Jain (Royal Free). Chloe Orkin and Philip Bright (Bart’s). Dr. Gompels, Jane Nicholls and Sarah Johnston (Southmead).

25. All NEAT 022 investigators (continuation):
UK; Graeme Moyle, Maddalena Cerrone, Nicole Pagani, Gurmit Jagjit Singh, Manisha Yapa, Akil Jackson, Alessia Dalla Pria, Emilie Elliot, David Hawkins, Marta Boffito, and Margherita Bracchi (Chelsea and Westminster). Jaime Vera, Amanda Clarke, Professor Rajkumar, Sarah Cavilla, Catherine Kirby, Larissa Mulka, Sonia Raffe, Sarah Stockwell, Nisha Mool, and Fiona Cresaru (Elton John Centre), Alan Winston (St Mary’s, Imperial). Laura Waters, Pierre Pellegrino, Lewis Haddow, Sarah Pett, Alesandro Arenas-Pinto , and Collins Iwaji (Mortimer Market Centre). Julie Fox, Julianne Lwanga, Juan Tiraboschi, Naomi Fitzgerald, Rebecca Simons, and Barry Peters (St Thomas’). Margaret Johnson, M. Tyrer, Sara Madge, Mike Foule, Fiona Burns, Gabrielle Murphy, D. R. Mair, and Anjly Jain (Royal Free). Chloe Orkin and Philip Bright (Bart’s). Dr. Gompels, Jane Nicholls and Sarah Johnston (Southmead).

26. Backup slides

27. Results: Protocol defined VF and blips
25th October 2016
Results: Protocol defined VF and blips
NEAT22/SSAT060 week 48 data

28. Results: Subgroup analysis for non-HDL cholesterol
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Results: Subgroup analysis for non-HDL cholesterol
NEAT22/SSAT060 week 48 data

29. Results: Subgroup analysis for triglycerides
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Results: Subgroup analysis for triglycerides
NEAT22/SSAT060 week 48 data

30. Results: Subgroup analysis for HDL-cholesterol
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Results: Subgroup analysis for HDL-cholesterol
NEAT22/SSAT060 week 48 data

31. Results: Subgroup analysis for TC:HDL
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Results: Subgroup analysis for TC:HDL
NEAT22/SSAT060 week 48 data

32. Results: Summary of Adverse Events
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Results: Summary of Adverse Events
DTG (n=204)
PI/r (n=208)
P value
Patients n(%)
Adverse events (n)
AE’s , any grade, >= 5% patients
Digestive
42 (20.6) 52
38 (18.3) 54
0.62
Muscular or skeletal
51 (25.0) 66
39 (18.8) 56
0.15
Cardiovascular
11 (5.4) 13
21 (10.1) 23
0.10
Respiratory
64 (31.4) 94
49 (23.6)
0.08
Dermatological
36 (17.6) 43
27 (13.0) 38
0.22
Genitourinary
28 (13.7) 33
14 (6.7) 26
0.02
Systemic
27 (13.2) 28
31 (14.9)
0.67
Neuropsyquiatric
44 (21.6) 64
36 (17.3) 47
0.32
Grade 3/4laboratory adverse events
Any grade 3 or 4 laboratory adverse event
5(2.5) 8
29(13.9) 46
 <0.01
Alanine aminotransferase concentration >5xULN
1(0.5) 1
1 (0.5)
 1.00
Bilirubin >2.5xULN
2 (1.0) 4
16(7.7)
LDL cholesterol >4.9 mmol/L
0 (0.0)
10 (4.8)
<0.01
NEAT22/SSAT060 week 48 data

33. 25th October 2016
Literature cited
(1) Trottier B, Lake J, Logue K, et al. Switching to Abacavir/Dolutegravir/Lamivudine Fixed Dose Combination (ABC/DTG/3TC FDC) from a PI, INI or NNRTI Based Regimen Maintains HIV Suppression. 55th Interscience Conference on Antimicrobials Agents and Chemotherapy. San Diego, CA. USA; September 17-21, 2015.
NEAT22/SSAT060 week 48 data

34. DTG
PI/r

35. DTG
PI/r