Antiretroviral resistance at virological failure in the NEAT 001/ANRS 143 trial: raltegravir plus darunavir/ritonavir or tenofovir/emtricitabine plus darunavir/ritonavir as first-line ART

Abstract

Introduction

In Europe, a combination of two NRTIs or nucleotide analogue reverse transcriptase inhibitors (NtRTIs) and an NNRTI, a ritonavir-boosted PI or an integrase strand transfer inhibitor (ISTI) is recommended for initial therapy for HIV-1-infected patients.¹ The tolerability and toxicity profile of NtRTIs, in particular the cardiovascular risk with abacavir and bone and renal toxicity with tenofovir, has led to the investigation of NtRTI-sparing alternative antiretroviral combinations.^2–6 NEAT 001/ANRS 143 was a European open-label, non-inferiority, Phase III randomized trial that evaluated the efficacy of the NtRTI-sparing regimen of raltegravir plus darunavir/ritonavir versus a standard-of-care regimen of tenofovir/emtricitabine plus darunavir/ritonavir in treatment-naive adults. This study showed the non-inferiority of the NtRTI-sparing strategy (raltegravir plus darunavir/ritonavir arm) versus the standard regimen, but only in participants with baseline CD4 cell counts >200 cells/mm³.⁷ As described in the main study report, genotypic analysis was done at screening and at all visits from 32 weeks onwards for participants who had an HIV-1 RNA load ≥500 copies/mL. Among participants who underwent genotypic testing to assess emerging resistance at the time of virological failure, treatment-emergent resistance was seen in no participant in the standard of-care group and in 6 of 29 (21%) in the NtRTI-sparing group, 5 of whom had resistance to ISTI and 1 to NtRTI.⁷ While IN-associated resistance frequency and profile are somewhat well characterized with raltegravir used in combination with tenofovir/emtricitabine,^8,9 there is little information available for raltegravir combined with darunavir/ritonavir in a randomized study. Therefore, the objectives of the present study were to describe the full resistance profile at virological failure and to determine factors associated with the development of IN resistance mutations.

Methods

Study design

NEAT 001/ANRS 143 was a European open-label, non-inferiority, Phase III randomized trial conducted in 15 European countries. Eight hundred and five participants were randomized in a 1/1 ratio to receive 400 mg of raltegravir twice daily plus 800 mg of darunavir and 100 mg of ritonavir once daily (n = 401) or tenofovir/emtricitabine in a 245 and 200 mg fixed-dose combination once daily plus 800 mg of darunavir and 100 mg of ritonavir once daily (n = 404). Eligible individuals had a baseline plasma viral load (VL) of >1000 copies/mL and no evidence of major IAS-USA-resistance mutations¹⁰ on genotypic testing, historically or at screening. The primary endpoint was the time to virological or clinical failure, with preplanned sub-group analyses of the primary endpoint by baseline CD4 cell count and HIV-1 RNA concentration. Ethics committee approval was obtained from all participating centres, in accordance with the principles of the Declaration of Helsinki. All trial participants gave written informed consent.

Genotypic resistance analyses and interpretation

The criteria for genotypic testing was a confirmed VL >50 copies/mL or any single VL >500 copies/mL at or after W32. In addition, insufficient virological response was defined as either a decrease of <1 log₁₀ copies/mL in HIV-1 RNA concentration at week 18 or an HIV-1 RNA concentration ≥400 copies/per mL at week 24. In this situation of insufficient virological response before week 32, the decision to perform genotypic testing and/or change in treatment was optional and left to the clinician.⁷ Although protocol-defined virological failure was considered to occur during or after week 32, genotypes that were tested before because of insufficient virological response were included in the resistance analysis. In patients with multiple virological failures, we analysed all available resistance tests, except that resistance developed on second-line therapy was not considered in the analysis. Bulk sequences of the reverse transcriptase (RT), protease and IN genes on RNA were determined using the ANRS consensus technique primer sequences described at http://www.hivfrenchresistance.org. In the main results paper,⁷ resistance mutations were interpreted according to the 2009 IAS-USA list of mutations (reference list used at time of inclusion), and in the present study, with the 2014 IAS-USA version.¹¹ A genotypic test was performed at baseline for RT and protease genes, at each site's local laboratory, and for RT, protease and IN genes at virological failure, mainly in the Pitié-Salpêtrière Virology Laboratory. Only data from participants with a successful genotypic test were available for the analyses. To assess potential factors associated with resistance development in participants treated with darunavir/ritonavir plus raltegravir, the baseline characteristics of VL and CD4 plus T cell count were evaluated.

Statistical analyses

The Kaplan–Meier method was used to estimate the cumulative proportion of patients with IN resistance in the NtRTI-sparing strategy arm, assuming that patients who did not experience virological failure did not develop resistance. Rank-sum tests, χ² tests and tests for trend were used to compare characteristics at baseline and failure between participants who developed at least one IN resistance mutation and those who did not.

Results

Overall, 127 participants (69/401 in the raltegravir plus darunavir/ritonavir arm and 58/404 in the tenofovir/emtricitabine plus darunavir/ritonavir arm) met the criteria for genotypic testing with, at or after week 32, either a confirmed VL of >50 copies/mL or at least one VL of >500 copies/mL. Baseline characteristics of participants are reported in Table 1. At least one resistance test was obtained for 110 participants (61 in the raltegravir plus darunavir/ritonavir arm and 49 in the tenofovir/emtricitabine plus darunavir/ritonavir arm), although not all tests were successful in all genes. The median HIV RNA at the time of genotype testing was significantly different in participants who failed between the two arms: 373 copies/mL (IQR: 110–1064 copies/mL) in the raltegravir plus darunavir/ritonavir arm versus 133 copies/mL (IQR: 67–56 copies/mL) in the tenofovir/emtricitabine plus darunavir/ritonavir arm; P = 0.02. In the tenofovir/emtricitabine plus darunavir/ritonavir arm, among the 49 participants who met criteria for genotypic testing and had a successful genotypic resistance test, no major IAS-USA resistance mutation was observed; thus, all further analyses are limited to the raltegravir  plus darunavir/ritonavir arm. Of the 61 genotypes tested in the raltegravir  plus darunavir/ritonavir arm, we obtained 55, 53 and 57 sequences for IN, RT and protease genes, respectively. At baseline, none had a major IAS RT or protease resistance mutation detected by Sanger sequencing. In those with at least one successful genotypic test, 15/55 (27.3%) in the raltegravir darunavir/ritonavir arm had viruses with IN resistance mutations (12 N155H alone, 1 N155H + Q148R, 1 F121Y and 1 Y143C), 2/53 (3.8%) with NtRTI resistance mutations (K65R, M41L), and 1/57 (1.8%) with a primary protease mutation (L76V) (Table 2). Three patients presented minor IN resistance mutations (L74M or T97A) that could be interpreted as polymorphisms. The cumulative risk in patients in the darunavir/ritonavir plus raltegravir arm to experience virological failure and emergent IN resistance-associated mutations (RAMs) was 2.1% (95% CI 1.0%–4.1%) at week 48 and 3.9% (95% CI 2.4%–6.4%) at week 96. HIV-1 RNA values at failure were not significantly different in those who failed with or without an IN mutation [median 731 copies/mL (IQR: 192–14 864 copies/mL) versus 351 copies/mL (IQR: 134–904 copies/mL); P = 0.17]. The proportion of patients in the raltegravir arm who achieved full virological success when switched to a different regimen (mostly raltegravir changed to tenofovir/emtricitabine) was impressive in those who switched after failure with resistance (13/15 participants; 86.7%). The frequency of IN mutations at failure was significantly associated with baseline VL: 7.1% (1/14) for participants harbouring a baseline VL of <100 000 copies/mL, 25.0% (7/28) for a baseline VL of ≥100 000 copies/mL and <500 000 copies/mL and 53.8% (7/13) for a baseline VL of ≥500 000 copies/mL (P_TREND = 0.007). Although a prespecified sub-group analysis showed that the NtRTI-sparing regimen was inferior to the standard regimen in patients with a baseline CD4 count of <200 cells/mm³, there was no statistically significant difference in the proportion of IN resistance between patients with a baseline CD4 count <200 cells/mm³ and those with a baseline CD4 count of ≥200 cells/mm³ (36.8% versus 22.2%, P  = 0.25).⁷ Of note, 4/15 participants with IN resistance mutations had a VL of < 200 copies/mL at the time of testing. Figure 1 shows the time to detection of IN resistance mutations on raltegravir plus darunavir/ritonavir (based on all participants in this arm), which tended to emerge early (between 19 and 96 weeks).

Figure 1.

Time to detection of IN resistance mutations, raltegravir plus darunavir/ritonavir arm, NEAT 001/ANRS 143 trial.

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Discussion

NEAT 001/ANRS 143 was a Phase III trial of an NtRTI-sparing regimen that compared an ISTI (raltegravir) with an NtRTI standard backbone (tenofovir/emtricitabine) in first-line therapy with a boosted PI (darunavir/ritonavir). This trial showed that a regimen of raltegravir plus darunavir/ritonavir was overall non-inferior to a standard treatment for antiretroviral-naive participants, but it was inferior for those with a CD4 count of <200 cells/mm³. Through week 96, a high proportion of participants treated with either regimen had VL suppression (HIV-1 RNA load <50 copies/mL in 78.6%  of participants in the NtRTI-sparing group and 82.2% in the standard group).⁷ However, the NtRTI-sparing regimen of raltegravir plus darunavir/ritonavir was associated with higher rates of virological failure in those with baseline CD4 counts of <200 cells/mm³ and was associated with the selection of resistance mutations at virological failure, especially those mutations conferring resistance to ISTI. Whereas no resistance mutation was found in the genotype of participants with virological failure from the standard arm, IN mutation resistance was observed in more than one-quarter of samples collected at failure in the raltegravir plus darunavir/ritonavir arm. Our results confirm very well-established data on the almost complete absence of development of protease RAMs at virological failure in patients on a first-line ritonavir-boosted PI combined with two NtRTIs,^12,13 whereas such resistance mutations are more likely when a ritonavir-boosted PI is combined with an NNRTI,¹⁴ or, to a lesser extent, with an ISTI.¹⁵ These data suggest a mutual bidirectional protection of NtRTI and PI/ritonavir when combined, with regards to resistance selection,¹⁶ as illustrated by the total absence of selection of RT or protease RAMs in the 49 virological failures on ritonavir-boosted darunavir plus tenofovir/emtricitabine.

However, we cannot rule out that resistance mutations are selected outside the protease genes such as gag-pol cleavage sites and gp41,^16–18 and this question should be examined in future studies. In NEAT 001, the cumulative risk of IN resistance at virological failure in patients treated with darunavir/ritonavir plus raltegravir at week 48 was 2.1%, which is higher than the risk of resistance development reported in other studies with raltegravir plus tenofovir/emtricitabine given as first-line therapy, which ranged from 0.2%¹⁹ to 1.4%²⁰ at week 48. A higher rate of integrase resistance has been reported in previous studies of raltegravir plus ritonavir-boosted PI. In the SPARTAN study, a randomized controlled multicentre pilot study in 94 naive HIV-infected participants received atazanavir plus raltegravir or ritonavir-boosted atazanavir plus tenofovir/emtricitabine, after 24 weeks of follow-up, 4 (6.3%) participants in the NRTI-sparing arm failed with development of IN resistance mutations, while no resistance mutations were observed in the control arm. Three of the four participants with resistance at failure had baseline HIV-1 RNA >500 000 copies/mL.²¹

In the PROGRESS pilot study, which compared the NtRTI-sparing regimen of lopinavir/ritonavir plus raltegravir with the standard-of-care regimen of lopinavir/ritonavir plus tenofovir/emtricitabine in treatment-naive HIV-infected patients, therapy failed in eight subjects in the lopinavir/ritonavir plus raltegravir arm, three of whom had IN resistance mutations (3.7%). One of them had also an emergent major protease mutation; conversely, in the tenofovir/emtricitabine arm, only one of five patients whose treatment failed had an M184V mutation.¹⁵ Whether these differences are related to the different backbones, two NtRTIs or ritonavir-boosted protease, in combination with raltegravir, or to differences in resistance testing and analysis is unknown. One could hypothesize that, similar to what is observed with PI/ritonavir therapy, tenofovir/emtricitabine confers some protection against the risk of resistance emergence at virological failure with raltegravir therapy. The mechanism of this NtRTI protection could be an undiscovered molecular interaction within the HIV replication cycle or more probably a consequence of the very long t_1/2 of intracellular tenofovir and emtricitabine, providing forgiveness to the great variability of raltegravir exposure. In contrast, despite its high genetic barrier to resistance, darunavir/ritonavir, with a relatively short t_1/2, might confer less forgiveness to raltegravir, especially in situations of partial or intermittent non-adherence. Further analyses will assess adherence and raltegravir plasma concentrations in NEAT 001 to elucidate reasons for the high rate of resistance emergence, especially in patients with high baseline VL. Many studies have consistently shown that the first cause of failure is non-adherence leading to suboptimal drug concentrations. We do not expect to have different findings in our study, and whatever the results of adherence and pharmacokinetic analyses, the message from our resistance results, which is very important from a clinical standpoint, is that when raltegravir plus darunavir/ritonavir first-line therapy fails, there is a high rate of emergence of resistance to ISTIs, even at a low level of failure, whereas resistance was absent in both RT and protease genes at the failure of tenofovir/emtricitabine plus darunavir/ritonavir.

On the other hand, differences in assays used for resistance testing in the various studies should be considered, and more importantly, different timepoints of analysis (first confirmed virological failure sample) and level of VL at the time of genotyping, which might greatly influence genotype results.²² This renders cross-study comparisons hazardous with regards to the prevalence of resistance at virological failure. Indeed, in NEAT 001, the resistance analysis population differed from those of previous studies of raltegravir plus tenofovir/emtricitabine^19,20 and from a pilot uncontrolled study of raltegravir plus darunavir/ritonavir.²³ In the latter study, ACTG 5262, the rate of IN resistance at virological failure was 4.5%; 5 out of 25 patients with virological failure and genotype testing had IN resistance mutations at virological failure and a baseline VL of >100 000 copies/mL. In NEAT 001, the proportion of participants in the darunavir/ritonavir plus raltegravir group with a baseline VL of >100 000 copies/mL who experienced virological failure and emergent IN RAMs was 9.6%, versus 10.4% in ACTG 5262.²³ Initiating ART with the combination of ritonavir-boosted darunavir plus raltegravir in patients with high baseline VL is associated with an unacceptably high risk of raltegravir resistance on treatment, particularly in those with an HIV-1 RNA load of >500 000 copies/mL; 27.3% developed resistance on treatment in our study. The main selected IN mutation in our study was the N155H raltegravir signature mutation alone, so most viruses at virological failure remained, in theory, susceptible to dolutegravir, except for the one harbouring the F121Y mutation that confers phenotypic resistance to dolutegravir as well.²⁴ The uncontrolled pilot VIKING 3 study has shown the efficacy of dolutegravir twice a day in raltegravir failure with the mutation N155H alone.²⁵ However, great caution and more clinical studies are needed, as recent data suggest that dolutegravir might also select for N155H and that viruses harbouring such a mutation might have diminished susceptibility to dolutegravir when used once daily.²⁶ One limitation of our study is the absence of genotypic information, due to either the absence of an available sample or the failure to obtain a sequence in 12% of participants qualifying for resistance testing in the raltegravir plus darunavir/ritonavir arm. This proportion was 16% in the tenofovir/emtricitabine plus darunavir/ritonavir arm. Another limitation of our study is that the protocol did not ask for IN gene sequence at baseline, as at the time of recruitment there was little clinical use of IN inhibitors, and the risk of transmitted drug resistance was very low for the IN class (1.7% for IN resistance mutation in the PRIMO cohort of recently infected patients).²⁷ Although we cannot formally rule out that some participants might have had IN resistance before the initiation of therapy, this is highly unlikely, as N155H mutation confers high-level phenotypic resistance to raltegravir. In such a circumstance, virological failure would have occurred much more rapidly, without the early virological suppression seen in 9 of 13 patients with N155H mutation. Although none of the RT (n = 2) and protease (n = 1) resistance mutations evidenced at failure were detected at baseline using Sanger sequencing, ultradeep sequencing on those baseline samples could help to determine whether these emergent RT (M41L, K65R) and protease (L76V) mutations are due to selection or re-emergence of transmitted minority resistant variants. Of clinical relevance, IN resistance was seen in patients (4/15) with very low-level viraemia (HIV RNA load between 50 and 200 copies/mL), a phenomenon already described in the ACTG 5262 study.²³ In another study of risk factors for raltegravir resistance development in clinical practice, we showed that 7.7% (6/78) of patients with HIV RNA load between 50 and 200 copies/mL had IN resistance mutations.²⁸ Thus, viral rebound with two consecutive HIV RNA values >50 copies/mL should be considered a marker of definite virological failure in patients receiving darunavir/ritonavir plus raltegravir, and genotypic resistance testing should be performed without delay in these patients.

In summary, during 96 weeks of follow-up, resistance to ISTI was detected in 15 of 401 participants randomized to darunavir/ritonavir plus raltegravir (3.7%). Approximately one-quarter (27%) of samples at failure had IN resistance mutations, with risk of resistance related to baseline HIV RNA load. Most patients with resistance mutations achieved complete suppression when switched to other regimens, most often tenofovir/emtricitabine instead of raltegravir, with continuation of ritonavir-boosted darunavir.

It would be interesting to investigate other NtRTI-sparing strategies combining an ISTI with a higher genetic barrier to resistance and a longer t_1/2, such as dolutegravir, in combination with a boosted PI. Based on these results on resistance, initiation of ART with the alternative regimen of ritonavir-boosted darunavir and raltegravir in patients with CD4 >200 cells/mm³ should be limited to patients with an HIV RNA load of <500 000 copies/mL and should be discussed for patients with HIV RNA loads between 100 000 and 500 000 copies/mL.

Funding

The French National Institute for Health and Medical Research—France Recherche Nord&Sud Sida-HIV Hépatites (INSERM-ANRS) is the sponsor and a funder of the trial. NEAT is a project funded by the Instituto Superiore di Sanità—Rome, by the EU under the Sixth Framework programme, project number LSHP-CT-2006-037570. The trial was also supported by Gilead Sciences, Janssen Pharmaceuticals and Merck Laboratories.

Transparency declarations

F. R. has received honoraria for advisories or invited talks or conferences and research grants from Abbvie Labs, Bristol-Myers Squibb, Gilead Sciences, Merck Laboratories, MSD, Janssen Pharmaceuticals and ViiV Healthcare. A. Pozniak has been an advisor and invited speaker and received honoraria, research grant, travel and education from Abbvie, GlaxoSmithKline, ViiV, Bristol-Myers Squibb, Gilead Sciences, Janssen Pharmaceuticals, Merck & Company and Tobira. A. G. M. has received honoraria for advisories or invited talks or conferences and research grants from Abbvie Labs, Bristol-Myers Squibb, Gilead Sciences, Merck Laboratories, MSD, Janssen Pharmaceuticals and ViiV Healthcare. V. C. has received honoraria for advisories or invited talks or conferences and research grants from Abbvie Labs, Bristol-Myers Squibb, Gilead Sciences, Merck Laboratories, MSD, Janssen Pharmaceuticals and ViiV Healthcare. The institution of C. S. and L. W. has received support from Gilead, Tibotec, Roche, MSD, Janssen Pharmaceuticals, Boehringer Ingelheim, Bristol-Myers Squibb, GlaxoSmithKline, ViiV Healthcare, Abbott and Pfizer for the organization of an annual academic workshop and for ongoing clinical trials of INSERM-ANRS. The other authors have none to declare.

Acknowledgements

We acknowledge the initial contribution of Professor Deenan Pillay, for the set-up of the virology sub-group of the trial. We thank the NEAT 001/ANRS 143 study participants and their partners, families and caregivers for participation in the study. We also thank the staff from all the centres participating in the trial. We are grateful for the collaboration with the European AIDS Treatment Group (EATG).

Members of the NEAT 001/ANRS 143 Study Group

Trial Development Team (TDT)

Belgium: Nikos Dedes (Brussels); France: Geneviève Chêne, Laura Richert (Bordeaux), Clotilde Allavena, François 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: Geneviève Chêne, Aurélie Fischer*, Laura Richert, Cédrick Wallet (Bordeaux), François Raffi (Nantes), Alpha Diallo, Jean-Michel Molina, and Juliette Saillard (Paris); Germany: Christiane Moecklinghoff (Janssen Pharmaceuticals; Freiburg) andHans-Jürgen 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)

Germany: Frank Goebel (Munich); Italy: Simone Marcotullio (Rome); UK: Abdel G. 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; Fabien Arnault*, Coordinating CTU representative, Member; Céline Boucherie*, Bordeaux CTU representative, Observer; Aurélie Fischer*, Coordinating CTU representative, Member; Delphine Jean*, Bordeaux CTU representative, Observer Virginie Paniego*, Coordinating CTU representative, Member; Felasoa Paraina, Bordeaux CTU representative, Observer; Laura Richert, Coordinating CTU representative, Member; Elodie Rouch*, Bordeaux CTU representative, Observer; Christine Schwimmer, Coordinating CTU representative, Member; Malika Soussi*, Bordeaux CTU representative, Observer; Audrey Taieb*, Bordeaux CTU representative, Observer; Monique Termote, Coordinating CTU representative, Member; Guillaume Touzeau*, Coordinating CTU representative, Member; Cédrick Wallet, Bordeaux CTU representative, Member.

MRC Clinical Trials Coordinating Unit, London, UK

Abdel G. Babiker, Trial Statistician, Member; Adam Cursley, MRC CTU representative, Observer; Wendy Dodds*, MRC CTU representative, Member; Fiona Ewings*, Trial Statistician, Member; Elizabeth C. George, Trial Statistician, Member; Anne Hoppe*, MRC CTU representative, Observer; Fleur Hudson, MRC CTU representative, Member; Ischa Kummeling*, MRC CTU representative, Observer; Filippo Pacciarini*, MRC CTU representative, Observer; Nick Paton*, MRC CTU representative, Observer; Charlotte Russell, MRC CTU representative, Observer; Kay Taylor*, MRC CTU representative, Observer; Denise Ward, MRC CTU representative, Observer.

Centre for Health and Infectious Disease Research (CHIP)Coordinating Unit, Copenhagen, Denmark

Bitten Aagaard*, CHIP CTU representative, Observer; Marius Eid, CHIP CTU representative, Observer; Daniela Gey*, CHIP CTU representative, Member; Birgitte Gram Jensen*, CHIP CTU representative, Observer; Jesper Grarup, CHIP CTU representative, Member; Marie-Louise Jakobsen*, CHIP CTU representative, Observer; Per O. Jansson, CHIP CTU representative, Member; Karoline Jensen*, CHIP CTU representative, Member; Zillah Maria Joensen, CHIP CTU representative, Observer; Ellen Moseholm Larsen*, CHIP CTU representative, Observer; Christiane Pahl*, CHIP CTU representative, Observer; Mary Pearson*, CHIP CTU representative, Member; Birgit Riis Nielsen, CHIP CTU representative; Søren Stentoft Reilev*, CHIP CTU representative, Observer.

Amsterdam Medical Center Coordinating Unit, Amsterdam, The Netherlands

Ilse Christ, AMC CTU representative, Observer; Desiree Lathouwers*, AMC CTU representative, Member; Corry Manting, AMC CTU representative, Member; Remko Van Leeuwen, AMC CTU representative, Member.

ANRS, Paris, France

Alpha Diallo, Pharmacovigilance representative, Member; Bienvenu Yves Mendy*, Pharmacovigilance representative, Member; Annie Metro*, Pharmacovigilance representative, Member; Juliette Saillard, Sponsor representative, Member; Sandrine Couffin-Cadiergues, Sponsor representative, Observer.

ISS, Rome, Italy

Anne-Laure Knellwolf*, NEAT management representative, Observer; Lucia Palmisiano, NEAT management representative, Member.

Local Clinical Trials Units (CTUs)

GESIDA, Madrid, Spain: Esther Aznar, Cristina Barea*, Manuel Cotarelo*, Herminia Esteban, Iciar Girbau*, Beatriz Moyano, Miriam Ramirez*, Carmen Saiz, Isabel Sanchez, Maria Yllescas; 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, François 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); 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); 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 coinfection, 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.

Pharmacoeconomics working group. Francesco Castelli (coordinator), Marco Braggion (statistician), Emanuele Focà.

Asterisk (*) indicates staff members who left during the trial.

References

Author notes