Supplementary webappendix
Supplement to: Gatell JM, Assoumou L, Moyle G et al. Switching from a ritonavir- boosted protease inhibitor to a dolutegravir- based regimen for maintenance of HIV viral suppression in patients with high cardiovascular risk: 48 weeks results from the NEAT022, randomized non-inferiority trial.
APPENDIX
Switching from a ritonavir- boosted protease inhibitor to a dolutegravir- based regimen for maintenance of HIV viral suppression in patients with high cardiovascular risk: 48 weeks results from the NEAT022, randomized non-inferiority trial.
José M Gatell (1), Lambert Assoumou (2), Graeme Moyle (3), Laura Waters (4), Margaret Johnson (5), Pere Domingo (6), Julie Fox (7), Esteban Martinez (1), Hans–Jürgen Stellbrink (8), Giovanni Guaraldi (9), Mar Masia (10), Mark Gompels (11), Stephane De Wit (12), Eric Florence (13), Stefan Esser (14), François Raffi (15), Anton L Pozniak (3), NEAT022 Study Group*.
(1) Hospital Clinic/IDIBAPS. University of Barcelona. Barcelona. Spain, (2) Sorbonne Universités, INSERM, UPMC Univ Paris 06, Institut Pierre Louis d’épidémiologie et de Santé Publique (IPLESP UMRS 1136), Paris, France, (3) Chelsea & Westminster Hospital and St Stephens AIDS Trust. London. UK, (4) Mortimer Market Center. London. UK, (5) Royal Free Hospital. London. UK. (6) Hospital de Sant Pau. Barcelona. Spain. (7) Guys and St. Thomas Hospital. London. UK. (8) ICH Study Center. Hamburg. Germany, (9) University of Modena and Reggio Emilia. Modena. Italy, (10) Hospital de Elche. Elche. Spain. (11) Southmead Hospital. Bristol. UK, (12) Saint Pierre Hospital. Université Libre de Bruxelles. Brussels. Belgium, (13) Institute of Tropical Medicine. Antwerp. Belgium, (14) Universitatsklinikum. Essen AoR. Germany, (15) University Hospital of Nantes. Nantes. France. France.
Supplementary Table 1. Number of sites and participants per country
Country / Number of sites / Total number of participantsUnited Kingdom / 8 / 164
Spain / 8 / 99
Germany / 5 / 62
Belgium / 3 / 25
France / 4 / 28
Italy / 4 / 37
Total / 32 / 415
Supplementary table 2: Inclusion/exclusion criteria
Inclusion Criteria:
Patient volunteers who meet all of the following criteria are eligible for this trial:
1. Is male or female aged over 50, OR aged over 18 years with a Framingham risk score above 10% (see appendix 6 for method of calculation)
2. Has documented HIV-1 infection
3. Has signed the Informed Consent Form voluntarily
4. Is willing to comply with the protocol requirements
5. Has been receiving an ARV regimen containing a boosted PI (darunavir, atazanavir, lopinavir, saquinavir or fosamprenavir) plus 2NRTIs for >24 weeks
6. Has stable virological suppression (plasma HIV-RNA <50 copies/mL for >24 weeks)
7. If female and of childbearing potential, is using effective birth control methods (see appendix 4) and is willing to continue practising these birth control methods during the trial and for at least 2 weeks after the last dose of study medication. Note: Non-childbearing potential is defined as either post-menopausal (12 months of spontaneous amenorrhoea and ≥45 years) or physically incapable of becoming pregnant with documented tubal ligation, hysterectomy or bilateral oophorectomy
8. If a heterosexually active male, he is using effective birth control methods and is willing to continue practising these birth control methods during the trial and until follow-up visit
Exclusion Criteria
Patients meeting 1 or more of the following criteria cannot be selected:
1. Infected with HIV-2
2. Using any concomitant therapy disallowed as per the reference safety information and product labelling for the study drugs
3. Has acute viral hepatitis including, but not limited to, A, B, or C
4. Has chronic hepatitis B and/or C with AST and/or ALT >5 x ULN
Note: Subjects can enter trial with chronic HBV if HBV-DNA undetectable at screen (and no detectable result in last 6 months) and with chronic HCV if not expected to require treatment during the trial period.
5. Any investigational drug within 30 days prior to the trial drug administration
6. Any prior evidence of primary viral resistance (if a resistance test is available) based on the presence of any major resistance-associated mutation to backbone NRTI
7. History of prior virological failure, eg 2 consecutive HIV-1 RNA >50 c/ml -at or after week 32 following first ART initiation or confirmed rebound viraemia >200 copies/ml after having a VL of <50 copies/ml without resistance test (NOTE: Switch for toxicity or tolerability with wild type virus does not count as virological failure)
8. Dialysis or renal insufficiency (creatinine clearance < 50ml/min)
9. History of decompensated liver disease (AST or ALT≥5x the upper limit of normal (ULN) or ALT ≥ )3 x ULN and bilirubin ≥ 1.5 x ULN with > 35% direct bilirubin.
10. Unstable liver disease (as defined by the presence of ascities, encephalopathy, coagulopathy, hypoalbuminemia, esophagael or gastic varices, or persistent jaundice), know biliary abnormalities (with the exception of Gilbert’s syndrome or asymptomatic gallstones))
11. Subjects with severe hepatic impairment (Class C) as determined by Child-Pugh classification (see appendix 5)
12. If female, currently pregnant or breastfeeding
13. Opportunistic infection within 4 weeks prior to first dose of DTG
14. Clinical decision that a switch of antiretroviral therapy should be immediate
15. Screening blood result with any grade 3/4 toxicity according to Division of AIDS (DAIDS) grading scale, except: asymptomatic grade 3 glucose, amylase or lipid elevation or asymptomatic grade 4 triglyceride elevation (re-test allowed).
16. Any condition (including illicit drug use or alcohol abuse) or laboratory results which, in the investigator’s opinion, interfere with assessments or completion of the trial.
17. History or presence of allergy to the study drug or their components
Supplementary figure 1. Time to virological failure. The Kaplan Meier method was used to to estimate the probability of virological success censoring at week 48 or last follow-up date if not seen at week 48. Time to loss virological success was defined as the time between the date of study treatment initiation (baseline, week 0) and the date of virological failure. For patient who did not receive allocated intervention we used the randomization date as baseline
Supplementary Fig. 2. Patients with protocol defined virological failures (n=5; solid symbols) or blips (21 episodes in 19 patients; empty symbols).
DTG=Dolutegravir, PI/r=ritonavir boosted protease inhibitors, VF= Protocol defined virological failure
Supplementary Fig 3. Subgroup analysis for the primary efficacy end point
Supplementary Figure 4. Subgroup analysis for the percentage changes in lipid fractions
4a) Subgroup analysis for the changes in total cholesterol
4b) Subgroup analysis for the changes in non-HDL cholesterol
4c) Subgroup analysis for the changes in LDL cholesterol
4d) Subgroup analysis for the changes in triglycerides
4e) Subgroup analysis for the changes in total cholesterol/HDL cholesterol ratio
Supplementary figure 5: Change in eGFR from baseline (CKD-EPI estimates). P values <0.001 at all time points.
Trial Management team at SSAT & in participating countries:
UK; Richard Haslop Senior 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.
Statistical Unit:
Lambert Assoumou, Head of the monitoring and statistical data analysis centre for ANRS, Pierre Louis Institute of Epidemiology and Public Health, UMR-S 1136, INSERM and Sorbonne Universités UPMC Paris Univ 06, France and Dominique Costagliola, Head of the Pierre Louis Institute of Epidemiology and Public Health, UMR-S 1136, INSERM and Sorbonne Universités UPMC Paris Univ 06, France
Endpoint Review Committee:
Anton L Pozniak NEAT ID President (Committee Chair), London, UK. Robert F Miller University College, London, UK. Nicole Pagani, London, UK. and John Watson, Birmingham UK.
Main investigators of sub studies:
Biomarkers sub study:
Esteban Martinez (co-chair), Jose M Gatell (co-chair), Lambert Assoumou, MA Muñoz, Graeme Moyle, Laura Waters, Margaret Johnson, Pere Domingo, Julie Fox, Hans–Jurgen Stellbrink, Giovanni Guaraldi, Mar Masia, Mark Gompels, Stephane De Wit, Eric Florence, Stefan Esser, François Raffi and Anton Pozniak.
Carotid intima-media thickness and arterial stiffness sub studies:
Miguel Camafort (co-chair), Monica Domenech (co-chair), Jose M Gatell, Lambert Assoumou, Esteban Martinez, Giovanni Guaraldi, Pere Domingo, Stefano Rusconi, Mar Massia, Christine Katlama, Daniel Podzamczer, François Raffi, Jose Luis Casado, Georg Behrens and Anton Pozniak.