Supplementary appendix - TheLancet.com Homepage Hernando Knobel, Manuel Marquez, Martin Pilar...
Transcript of Supplementary appendix - TheLancet.com Homepage Hernando Knobel, Manuel Marquez, Martin Pilar...
Supplementary appendixThis appendix formed part of the original submission and has been peer reviewed. We post it as supplied by the authors.
Supplement to: Bernardino JI, Mocroft A, Mallon PW, et al. Bone mineral density and inflammatory and bone biomarkers after darunavir–ritonavir combined with either raltegravir or tenofovir–emtricitabine in antiretroviral-naive adults with HIV-1: a substudy of the NEAT001/ANRS143 randomised trial. Lancet HIV 2015; published online Sept 30. http://dx.doi.org/10.1016/S2352-3018(15)00181-2.
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NEAT 001/ANRS 143 Study Group
Asterisk (*) indicates staff who left during the trial. Trial Development Team (TDT):
Belgium: Nikos Dedes (Brussels) France: Genevieve Chene, Laura Richert (Bordeaux), Clotilde Allavena, Francois Raffi (Nantes) and Brigitte Autran (Paris) Italy: Andrea Antinori, Raff aella Bucciardini and Stefano Vella (Rome) Poland: Andrzej Horban (Warsaw) Spain: Jose Arribas (Madrid) UK: Abdel G Babiker, Marta Boffito, Deenan Pillay and Anton Pozniak (London)
Trial Steering Committee (TSC):
Belgium: Xavier Franquet* and Siegfried Schwarze (Brussels) Denmark: Jesper Grarup (Copenhagen) France: Genevieve Chene, Aurelie Fischer*, Laura Richert, Cedrick Wallet (Bordeaux), Francois Raffi (Nantes), Alpha Diallo, Jean-
Michel Molina, and Juliette Saillard (Paris) Germany: Christiane Moecklinghoff (Janssen Pharmaceuticals; Freiburg) and
Hans-Jurgen Stellbrink (Hamburg) Italy: Stefano Vella (Rome) Netherlands: Remko Van Leeuwen (Amsterdam) Spain: Jose Gatell (Barcelona) Sweden: Eric Sandstrom (Stockholm) Switzerland: Markus Flepp (Zurich) UK: Abdel G Babiker, Fiona Ewings*, Elizabeth C George, Fleur Hudson, and Anton Pozniak (London) USA: Gillian Pearce*, Romina Quercia*, Felipe Rogatto (Gilead Sciences; Foster City, CA), Randi Leavitt, and Bach-Yen Nguyen*
(Merck Laboratories; Whitehouse Station, NJ). Independent Data Monitoring Committee (IDMC):
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Germany: Frank Goebel (Munich) Italy: Simone Marcotullio (Rome) UK: Abdel Babiker, Fiona Ewings*, Elizabeth C George, Fleur Hudson*, Navrup Kaur, Peter Sasieni, Christina Spencer-Drake*
(London) and Tim Peto (Oxford) USA: Veronica Miller (Washington DC).
Trial Management Team (TMT):
France: Clotilde Allavena and François Raffi (Nantes) Italy: Stefano Vella (Rome) UK: Anton Pozniak (London)
CMG-EC, INSERM U897 Coordinating Unit, Bordeaux, France:
Geneviève Chêne, Head of coordinating CTU, Member, Bordeaux, France Fabien Arnault*, Coordinating CTU representative, Member, Bordeaux, France Céline Boucherie*, Bordeaux CTU representative, Observer, Bordeaux, France Aurélie Fischer*, Coordinating CTU representative, Member, Bordeaux, France Delphine Jean*, Bordeaux CTU representative, Observer, Bordeaux, France Virginie Paniego*, Coordinating CTU representative, Member, Bordeaux, France Felasoa Paraina, Bordeaux CTU representative, Observer, Bordeaux, France Laura Richert, Coordinating CTU representative, Member, Bordeaux, France Elodie Rouch*, Bordeaux CTU representative, Observer, Bordeaux, France Christine Schwimmer, Coordinating CTU representative, Member, Bordeaux, France Malika Soussi*, Bordeaux CTU representative, Observer, Bordeaux, France Audrey Taieb*, Bordeaux CTU representative, Observer, Bordeaux, France Monique Termote, Coordinating CTU representative, Member, Bordeaux, France Guillaume Touzeau*, Coordinating CTU representative, Member, Bordeaux, France Cédrick Wallet, Bordeaux CTU representative, Member, Bordeaux, France
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MRC Clinical Trials Coordinating Unit, London, UK:
Abdel G Babiker, Trial Statistician, Member, London, UK Adam Cursley, MRC CTU representative, Observer, London, UK Wendy Dodds*, MRC CTU representative, Member, London, UK Fiona Ewings*, Trial Statistician, Member, London, UK Elizabeth C George, Trial Statistician, Member, London, UK Anne Hoppe*, MRC CTU representative, Observer, London, UK Fleur Hudson, MRC CTU representative, Member, London, UK Ischa Kummeling*, MRC CTU representative, Observer, London, UK Filippo Pacciarini*, MRC CTU representative, Observer, London, UK Nick Paton*, MRC CTU representative, Observer, London, UK Charlotte Russell, MRC CTU representative, Observer, London, UK Kay Taylor*, MRC CTU representative, Observer, London, UK Denise Ward, MRC CTU representative, Observer, London, UK
CHIP Coordinating Unit, Copenhagen, Denmark:
Bitten Aagaard*, CHIP CTU representative, Observer, Copenhagen, Denmark Marius Eid, CHIP CTU representative, Observer, Copenhagen, Denmark Daniela Gey*, CHIP CTU representative, Member, Copenhagen, Denmark Birgitte Gram Jensen*, CHIP CTU representative, Observer, Copenhagen, Denmark Jesper Grarup, CHIP CTU representative, Member, Copenhagen, Denmark Marie-Louise Jakobsen*, CHIP CTU representative, Observer, Copenhagen, Denmark Per O. Jansson, CHIP CTU representative, Member, Copenhagen, Denmark Karoline Jensen*, CHIP CTU representative, Member, Copenhagen, Denmark Zillah Maria Joensen, CHIP CTU representative, Observer, Copenhagen, Denmark Ellen Moseholm Larsen*, CHIP CTU representative, Observer, Copenhagen, Denmark Christiane Pahl*, CHIP CTU representative, Observer, Copenhagen, Denmark
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Mary Pearson*, CHIP CTU representative, Member, Copenhagen, Denmark Birgit Riis Nielsen, CHIP CTU representative, Observer, Copenhagen, Denmark Søren Stentoft Reilev*, CHIP CTU representative, Observer, Copenhagen, Denmark
Amsterdam Medical Center Coordinating Unit, Amsterdam, The Netherlands:
Ilse Christ, AMC CTU representative, Observer, Amsterdam, The Netherlands Desiree Lathouwers*, AMC CTU representative, Member, Amsterdam, The Netherlands Corry Manting, AMC CTU representative, Member, Amsterdam, The Netherlands Remko Van Leeuwen, AMC CTU representative, Member, Amsterdam, The Netherlands
ANRS, Paris, France: Alpha Diallo, Pharmacovigilance representative, Member, Paris, France Bienvenu Yves Mendy*, Pharmacovigilance representative, Member, Paris, France Annie Metro*, Pharmacovigilance representative, Member, Paris, France Juliette Saillard, Sponsor representative, Member, Paris, France Sandrine Couffin-Cadiergues, Sponsor representative, Observer, Paris, France
ISS, Rome, Italy: Anne-Laure Knellwolf*, NEAT management representative, Observer, Rome, ltaly Lucia Palmisiano, NEAT management representative, Member, Rome, ltaly Local CTUs:
GESIDA, Madrid, Spain:
Esther Aznar, Cristina Barea*, Manuel Cotarelo*, Herminia Esteban, Iciar Girbau*, Beatriz Moyano, Miriam Ramirez*, Carmen Saiz, Isabel Sanchez, Maria Yllescas
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ISS, Rome, Italy:
Andrea Binelli, Valentina Colasanti, Maurizio Massella, Lucia Palmisiano.
University of Athens Medical School, Greece:
Olga Anagnostou, Vicky Gioukari, Giota Touloumi. Study Investigators:
Austria: Brigitte Schmied (National Coordinating Investigator), Armin Rieger, Norbert Vetter
Belgium: Stephane De Wit (National Coordinating Investigator), Eric Florence, Linos Vandekerckhove
Denmark: Jan Gerstoft (National Coordinating Investigator), Lars Mathiesen
France: Christine Katlama (National Coordinating Investigator), Andre Cabie, Antoine Cheret, Michel Dupon, Jade Ghosn*, Pierre-Marie Girard, Cécile Goujard, Yves Lévy, Jean-Michel Molina, Philippe Morlat, Didier Neau, Martine Obadia, Philippe Perre, Lionel Piroth, Jacques Reynes, Pierre Tattevin, Francois Raffi, Jean Marie Ragnaud*, Laurence Weiss, Yazdanpanah Yazdan*, Patrick Yeni, David Zucman
Germany: Georg Behrens (National Coordinating Investigator), Stefan Esser, Gerd Fätkenheuer, Christian Hoffmann, Heiko Jessen, Jürgen Rockstroh, Reinhold Schmidt, Christoph Stephan, Stefan Unger
Greece: Angelos Hatzakis (National Coordinating Investigator), George L Daikos, Antonios Papadopoulos, Athamasios Skoutelis
Hungary: Denes Banhegyi (National Coordinating Investigator)
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Ireland: Paddy Mallon (National Coordinating Investigator), Fiona Mulcahy
Italy: Andrea Antinori (National Coordinating Investigator), Massimo Andreoni, Stefano Bonora, Francesco Castelli, Antonella D’Arminio Monforte, Giovanni Di Perri, Massimo Galli, Adriano Lazzarin, Francesco Mazzotta, Torti Carlo*, Vincenzo Vullo
The Netherlands: Jan Prins (National Coordinating Investigator), Clemens Richter, Dominique Verhagen, Arne Van Eeden*
Poland: Andrzej Horban (National Coordinating Investigator)
Portugal: Manuela Doroana (National Coordinating Investigator), Francisco Antunes*, Fernando Maltez, Rui Sarmento-Castro,
Spain: Juan Gonzalez Garcia (National Coordinating Investigator), José López Aldeguer, Bonaventura Clotet, Pere Domingo, Jose M Gatell, Hernando Knobel, Manuel Marquez, Martin Pilar Miralles, Joaquin Portilla, Vicente Soriano, Maria-Jesus Tellez
Sweden: Anders Thalme (National Coordinating Investigator), Anders Blaxhult, Magnus Gisslen
UK: Alan Winston (National Coordinating Investigator), Julie Fox, Mark Gompels, Elbushra Herieka, Margaret Johnson, Clifford Leen, Anton Pozniak, Alastair Teague, Ian Williams
Endpoint Review Committee (ERC):
Australia: Mark Alastair Boyd, (Sydney) Denmark: Jesper Grarup, Per O Jansson, Nina Friis Møller, and Ellen Frøsig
Moseholm Larsen (Copenhagen) France: Philippe Morlat (Bordeaux), Lionel Piroth (Dijon), and Vincent Le Moing (Montpellier) Netherlands: Ferdinand W N M Wit, chair (Amsterdam) Poland: Justyna Kowalska (Warsaw) Spain: Juan Berenguer and Santiago Moreno (Madrid) Switzerland: Nicolas J Müller (Zurich)
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UK: Estée Török (Cambridge), Frank Post (London), and Brian Angus (Oxford) Sub-study working groups:
Virology working group: Vincent Calvez (coordinator), Charles Boucher, Simon Collins, David Dunn (statistician), Sidonie Lambert, Anne-Geneviève Marcelin, Carlo Federico Perno, Deenan Pillay, Ellen White (statistician)
Pharmacology and adherence working group: Marta Boffito (coordinator), Adriana Ammassari, Andrea Antinori, Wolgang Stoehr (statistician)
Immunology working group: Brigitte Autran (coordinator), Reinhold Ernst Schmidt, Michal Odermarsky, Colette Smith, Rodolphe Thiébaut (statistician)
Toxicity, including co-infection working group: Jose Arribas (coordinator), Jose Ignacio Bernardino De La Serna, Antonella Castagna, Stephane De Wit, Xavier Franquet, Hans-Jackob Furrer, Christine Katlama, Amanda Mocroft (statistician), Peter Reiss
Quality of life working group: Raffaella Bucciardini (coordinator), Nikos Dedes, Vincenzo Fragola, Elizabeth C George (statistician), Marco Lauriola, Rita Murri, Pythia Nieuwkerk, Bruno Spire, Alain Volny-Anne, Brian West
Neurocognitive function working group: Hélène Amieva (coordinator), Andrea Antinori, Josep Maria Llibre Codina, Laura Richert, Wolgang Stoehr (statistician), Alan Winston
Pharmaco-economics working group: Francesco Castelli (coordinator), Marco Braggion (statistician), Emanuele Focà
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Additional information about bone and inflammatory biomarkers The following markers were measured by automated chemiluminescence immunoassay
(CLIA): bone specific alkaline phosphatase (reference ranges 5.7-32.9 µg/L for men
and 4.7-27 µg/L for premenopausal women, intra-assay coefficient of variation (CV)
1.5%), c-terminal collagen crosslinks (CTX-1) (reference ranges 0.15-0.75 ng/mL for
men and 0.11-0.74 ng/mL for post-menopausal women, intra-assay CV 3.2%), intact N-
terminal pro-peptide of type 1 procollagen (P1NP) reference ranges 27.7-127.6 ng/mL,
intra-assay CV 3%) osteocalcin (OC) (reference ranges 10.4-45.6 ng/mL, intra-assay
CV 2.2%), and 25-OH-vitamin D (intra-assay CV 5.5%; intact PTH intra-assay CV
2.6%). RANKL was measured by enzyme-immunoanalysis with an intra-assay CV 8%.
The following markers were analysed by Multiplex enzyme-immunoanalysis
(HBNMAG-51K): osteoprotegerin (OPG) (reference ranges 130-350 pg/mL, intra-assay
CV 3%), osteopontin (OPN) (reference ranges 2008-20631 pg/mL, intra-assay CV 3%),
IL-6 (reference ranges 5-7 pg/mL, intra-assay CV 5%), IL-1 (reference ranges 5-10
pg/mL, intra-assay CV 6%) and TNF- (reference ranges 1-3 pg/mL, intra-assay CV
4%).
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Table 1. Bone Mineral Density and DEXA parameters at randomisation in the three anatomical sites DRV/r + RAL
(N = 65) DRV/r + TDF/FTC
(N = 68) Total
(N = 133) P value*
Lumbar spine
BMD (g/cm2): median (IQR) 1.10 (1.0 - 1.22) 1.16 (1.02 - 1.23) 1.13 (1.01 - 1.23) 0.26
Z-score: median (IQR) -0.4 (-1.1 - 0.3) -0.2 (-0.9 - 0.3) -0.2 (-1.0 - 0.3) 0.43
T-score: median (IQR) -0.5 (-1.2 - 0.3) -0.2 (-0.9 - 0.4) -0.3 (-1.1 - 0.4) 0.31
Osteoporosis: n (%) 4 (6.6) 1 (1.5) 5 (3.9) 0.14
Osteopenia: n (%) 14 (23) 13 (19.1) 27 (20.9) 0.59
Z score < -2: n (%) 6 (9.8) 3 (4.4) 9 (7.0) 0.23
Femoral neck
BMD (g/cm2): median (IQR) 0.93 (0.86 - 1.06) 0.98 (0.89 - 1.11) 0.96 (0.87 - 1.08) 0.13
Z-score: median (IQR) -0.2 (-0.8 - 0.6) 0.2 (-0.3 - 0.7) 0 (-0.6 - 0.6) 0.05
T-score: median (IQR) -0.6 (-0.9 - 0.4) -0.1 (-0.8 - 0.6) -0.2 (-0.8 - 0.5) 0.16
Osteoporosis: n (%) 0 (0) 1 (1.5) 1 (0.8) 0.35
Osteopenia: n (%) 10 (16.7) 11 (15.9) 21 (16.3) 0.91
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Z score < -2: n (%) 0(0) 0(0) 0(0) -
Total hip
BMD (g/cm2): median (IQR) 1.01 (0.93 - 1.11) 1.07 (0.97 - 1.16) 1.04 (1.00 - 1.10) 0.032
Z-score: median (IQR) -0.1 (-0.7 - 0.7) 0.3 (-0.3 - 0.8) 0.1 (-0.4 - 0.7) 0.05
T-score: median (IQR) -0.2 (-0.9 - 0.5) 0.2 (-0.5 - 0.8) 0 (-0.7 - 0.6) 0.048
Osteoporosis: n (%) 0 (0) 1 (1.5) 1 (0.8) 0.35
Osteopenia: n (%) 12 (19.7) 9 (13) 21 (16.2) 0.31
Z score < -2: n (%) 0 (0) 1 (1.5) 1 (0.8) 0.34
*P value from Kruskall-Wallis test for continuous variables and chi-squared test for categorical variables Bone mineral density data was not available for all patients at baseline.
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Table 2. New cases of osteoporosis, osteopenia and Z score < -2 during the trial
RAL + DRV/r TDF/FTC + DRV/r OR (95% CI)*
Week 48 Osteoporosis Osteopenia Z < -2.0 Osteoporosis Osteopenia Z < -2.0
Lumbar spine 0 4 1 1 7 2 1.42 (0.39-5.26)
Femoral neck 0 6 0 0 3 0 0.37 (0.087-1.57)
Total hip 1 2 1 0 5 0 2.03 (0.38-10.98)
Week 96
Lumbar spine 0 4 1 2 4 2 0.81 (0.19-3.47)
Femoral neck 1 8 0 1 7 1 0.67 (0.22-2.04)
Total hip 1 2 1 0 2 0 0.79 (0.11-5.88)
* OR for Osteopenia (TDF/FTC + DRV/r vs. RAL + DRV/r)
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Table 3. Absolute values for bone and inflammatory biomarkers at randomisation.
Biomarker N DRV/r + RAL N DRV/r + TDF/FTC P-value Osteocalcin ng/mL 48 11.6 (10.2, 13) 56 11.7 (10.3, 13.1) 0.88 BSAP µg/L 48 12.5 (11.7, 13.3) 55 13.5 (12.5, 14.5) 0.17 P1NP ng/mL 48 44.3 (38.4, 50.6) 56 45.1 (40, 50.2) 0.83 Osteoprotegerin pg/mL 47 299 (265.9, 352.1) 56 338 (289.2, 386.8) 0.22 Serum CTX-1 ng/mL 48 0.4 (0.35, 0.5) 55 0.4 (0.3, 0.5) 0.4 RANKL pmol/L 20 0.59 (0.22, 0.96) 31 0.52 (0.28, 0.76) 0.72 Osteopontin pg/mL 47 5421 (4317, 6526) 56 5425 (4145, 6705) 0.99 Urine CTX-1 /creatinine ratio 65 195.4 (163.5, 227.3) 68 206.8 (180.6, 232) 0.6 25-vit D ng/mL 47 19.2 (16.5, 21.9) 53 20.6 (17.5, 23.5) 0.49 iPTH pg/mL 47 31.9 (27.2, 36.6) 56 32.2 (28.5, 35.9) 0.91 IL-1 pg/mL 46 0.4 (0.3, 0.5) 55 0.4 (0.3, 0.5) 0.22 IL-6 pg/mL 47 1.2 (0.0, 2.4) 56 1.4 (0.6, 2.2) 0.80
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TNF- pg/mL 44 4.1 (2.7, 5.5) 56 4 (3.6, 4.4) 0.77
Note: BSAP: Bone specific Alkaline Phosphatase. P1NP: Pro-collagen type 1 N-pro-peptide. CTX-1: Type 1 C terminal collagen crosslinks. RANKL: Receptor activator of NF- ligand. CRLP: C-terminal collagen crosslinks. iPTH: intact-parathyroid hormone.
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Figure2.Boxplotofboneandinflammatorybiomarkersbytreatment2a.Formationmarkers
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