J Wen

J Marteau

S Bouvier

M Risbet

F Cristofari

P Secordel

Comparison of microstructure changes induced in two pearlitic rail steels subjected to a fullscale wheel/rail contact rig test

Keywords: Steel, rail-wheel tribology, electron microscopy, wear testing

This study focused on the comparison of the microstructure changes induced in two pearlitic rail steels subjected to full-scale wheel-rail contact rig tests (DB Systemtechnik, Germany): a conventional R260 steel grade and a heat-treated premium R370CrHT rail grade (also known as MHH400). The total loading of the wheel/rail contact rig test was computed to be 2.4 million gross tons but aimed at reproducing large deformations caused by loadings around 100 million gross tons into the materials.

The description of the microstructure showed the ability of the rig to reproduce large loadings.

Through the coupling of optical and SEM observations, EBSD measurements and hardness tests along the depths of the tested rails, it was shown that the plastic deformation was much more confined in R370CrHT than in R260. This thorough comparison of the microstructure changes will help the building of wear scenarios.

Introduction

Surface damage of rail steels and related costs of inspection and maintenance are important issues for modern railway infrastructures. Moreover, the constant rise of loadings, frequency and speed of trains only intensifies this issue with the increase of the stresses borne by the railways. To limit contact 2/24 fatigue and wear, new steel grades have been searched for several years. In the fifties, hypoeutectoid steels (bi-phased ferrite/pearlite steels) were preferred (e.g. R220). Then, in the seventies, hardness increase was looked for to limit fatigue contact and wear. This resulted in the increase of carbon content and thus the development of eutectoid steels such as R260. From the eighties, the mechanical properties of rail steels were further improved with the development of thermal treatments (e.g. R350HT) and the use of selective alloying (e.g. R370CrHT). These developments were conducted concurrently with the examination of the resistance of these materials to wear and fatigue. Currently, the main known metallurgical factors contributing to the wear and fatigue resistance of pearlitic steels are: solid solution hardening, the size of pearlite colonies [START_REF] Elwazri | The effect of microstructural characteristics of pearlite on the mechanical properties of hypereutectoid steel[END_REF], the interlamellar spacing [START_REF] Clayton | Effect of interlamellar spacing on the wear resistance of eutectoid steels under rolling-sliding conditions[END_REF] and the size of prior austenite grains [START_REF] Das | Effects of microstructural parameters on the mechanical properties of eutectoid rail steels[END_REF].

To investigate the behavior of rails subjected to rolling contact, microstructural analysis is often performed before and after their loading using optical microscope observations coupled with hardness tests [START_REF] Alwahdi | Subsurface microstructural analysis and mechanical properties of pearlitic rail steels in service[END_REF][START_REF] Zhao | Effects of decarburization on the wear resistance and damage mechanisms of rail steels subject to contact fatigue[END_REF]. Scanning Electron Microscopy (SEM) is an increasingly favored method of observation [START_REF] Zhou | Field and laboratory investigation of the relationship between rail head check and wear in a heavy-haul railway[END_REF][START_REF] Lee | Wear of conventional pearlitic and improved bainitic rail steels[END_REF]. However, the microstructure descriptions tend to remain qualitative rather than quantitative (e.g. the description of colony orientation [START_REF] Larijani | The effect of anisotropy on crack propagation in pearlitic rail steel[END_REF][START_REF] Wetscher | Changes in the mechanical properties of a pearlitic steel due to large shear deformation[END_REF]), with the exception of the interlamellar spacing [START_REF] Athukorala | Characterisation of head-hardened rail steel in terms of cyclic plasticity response and microstructure for improved material modelling[END_REF]. A quantitative description of the microstructure of pearlitic steels remains little addressed due to its complexity and its large cost in terms of analysis and measuring time. The use of the Electron BackScattering Diffraction (EBSD) technique is slowly growing for the characterization of the microstructure of pearlitic steels [START_REF] Takahashi | Investigation of Orientation Gradients in Pearlite in Hypoeutectoid Steel by use of Orientation Imaging Microscopy[END_REF][START_REF] Debehets | Analysis of the variation in nanohardness of pearlitic steel: Influence of the interplay between ferrite crystal orientation and cementite morphology[END_REF]. More recently, Linz et al. [START_REF] Linz | EBSD study of early-damaging phenomena in wheel-rail model test[END_REF] investigated the early damage phenomena taking place in R260 steel by coupling SEM, EBSD and hardness results. Similarly, Dylewski et al. [START_REF] Dylewski | Multiscale characterization of head check initiation on rails under rolling contact fatigue: Mechanical and microstructure analysis[END_REF] used a multiscale analysis to examine head check initiation in R260 steel.

As underlined by Pointner [START_REF] Pointner | High strength rail steels-The importance of material properties in contact mechanics problems[END_REF], despite the numerous studies, the relationship between the features of the microstructure of grade steels and mechanical contact or more particularly the resistance to wear and fatigue is not clearly established yet.

Based on these observations, the study presented hereafter focused on the comparison of the microstructure changes induced in two pearlitic rail steels subjected to full-scale wheel-rail contact rig tests (DB Systemtechnik, Germany). The coupling of optical and SEM observations, EBSD measurements and hardness tests along the depths of the tested rails were used to investigate the 3/24 plastic deformation differences between a conventional R260 steel grade and a heat-treated premium R370CrHT rail grade (also known as MHH400) at the scale of the microstructure. 1: Composition of the discussed grade rails (weight %), according to [START_REF]European Norm EN 13674-1+A1. Railway applications -track -rail -Part 1: Vignole railway rails 46 kg/m and above[END_REF]. The steels examined in this paper are indicated using a mark ( * ).

Materials and methods

Rail material and test rig conditions

Two pearlitic steel grades were tested: R260 and R370CrHT improved to achieve 400 HB on the surface (also known as MHH400). Their chemical compositions are presented in Table 1. One rail made from each pearlitic steel grade was tested. Both rails had a 60E2 profile (thus a section of 76.48 cm²) and a total length of 3.2 m. The rail segments were subjected to 100,000 load cycles using a full scale linear test rig (DB Systemtechnik, Germany) with a static contact force of 120 kN, a lateral force of 10 kN and a rolling contact length of 2 m. Each test lasted approximately 4 days. The forces were only applied during forward motion. The wheel was completely raised from the rail during the reverse motion so that the testing scenario corresponded to a rolling in a single direction. An angle of attack of 3 mrad was used to simulate the testing conditions of curve negotiation. Monoblock wheels made of ER8 steel with a S1002 profile were used for the tests, in accordance with [START_REF]NF EN 13715+A1 -January 2011 -Railway applications -Wheelsets and bogies -Wheels -Tread profile[END_REF]. The total load of the rail was approximately equal to 2.4 million gross tons (MGT) but it aimed at simulating an equivalent on-track loading of 100 MGT.

Measurements

Microstructure analysis

4/24

Specimens of 10 x 10 mm² were cut from the tested rails. The specimens were taken from the area located 5 mm from the symmetrical axis of the rail head either in the worn part or in the non-deformed part of the rail. Microstructures were characterized using a field emission gun-scanning electron microscope (Σigma TM , Zeiss, Germany) equipped with a EBSD detector (OptiPlex 7040, Nordif, Norway). EBSD measurements were performed with an accelerating voltage of 25 kV, a tilt of 70° and a working distance of 20 mm. Different measurement step sizes were chosen depending on the required resolutions for the investigations: 500 nm for nodule characterization and 100 nm for assessing local plastic deformation. Orientation maps were calculated with TSL OIM data collection TM software [START_REF]OIM analysis 5.3 software user manual[END_REF].

The specimens cut from the rails were polished using successive abrasive SiC papers (P300, P500, P1000, P2000 and P4000) to remove the oxidized and contaminated layers. Then, the samples were polished with 3 µm, 1 µm diamond solution and OPS solution respectively for 10 min, 8 min and 5 min. For EBSD measurements, the specimens were polished with 10% oxide polishing suspension solution and 90% of H2O in Buehler VibroMet TM 2 vibratory polisher for three days. For Optical Microscopy (OM) observation, chemical attack in 1% Nital solution for 5 seconds was employed.

Wear and microhardness

After the wheel/rail tests, measurements of the rail profiles using a MiniProf profilometer were performed to determine the transverse profile and the corresponding wear depths. Micro-hardness measurements were performed with a Vickers indenter using a LECO M-400 micro-hardness tester with a load of 300 gf (HV0.3). The indentation tests were achieved on the cross-section of the specimens with a distance between two indents equal to four times the mean indentation length. Three lines of tests were completed on each examined cross-section.

Results and discussion

Macroscopic observations

The cyclic stresses caused by the contact between wheel and rail entailed significant changes in the rail profiles. Figure 1a presents the average values of rail profiles for R260 and R370CrHT after the rolling contact wheel/rail test with a total load approximately equal to 2.4 MGT, as well as a 60E2 reference profile. The loss of transverse rail profile was more severe in R260 than in R370CrHT.

5/24

Based on the profile shapes, the wear depth was estimated to be around 0.8 mm for R260 while it was equal to 0.2 mm for R370CrHT.

It is worth noting that a series of OM observations along the rail profiles (Figure 1b, c andd) also

showed that headchecks took place in the R260 rail while no headchecks were detected in the R370CrHT rail. This piece of information underlines the bench ability of reproducing effects caused by curve negotiation.

Microscopic observations

Hereafter, the presented results will focus on the wear zone schematically depicted in Figure 1a. The evolution of the microstructure of this area will be compared to the area called 'symmetrical zone' underlined in Figure 1a. The symmetrical area was chosen as reference for the microstructure characterization because it does not undergo any deformation during the test. A closer examination of Figure 1a shows a slight loss of profile in the symmetrical zone compared to the reference line but it 6/24 was caused by grinding prior to the rolling contact test. It should be noted that the field corner of rails is often chosen as the reference instead of the symmetrical zone. However, such a choice would not be relevant for this study because the examined R370CrHT steel underwent thermal treatment that led to the development of different microstructure characteristics in the field corner and symmetrical zone.

Initial state

Both materials had a pearlite microstructure composed of alternating lamellae of ferrite and cementite phases (as underlined in Figure 2a). As the interlamellar spacing Sp is known to play a crucial role in the yield strength and hardness of pearlite steel, it was quantified in both materials. Two hundred fifty measurements were performed across straight lamellae groups, as illustrated in Figure 2a andb. These measurements were performed at different depths to get an average value of Sp for the undeformed areas. The average interlamellar spacing of R260 was identified to be equal to 310 ± 20 nm while it was equal to 73 ± 5 nm for R370CrHT. Thus, the average interlamellar spacing was approximately four times larger in R260 than in R370CrHT. Then, microstructure characterization of the unloaded area of the rails was performed using SEM-EBSD measurements. First, large EBSD maps with a step size of 500 nm were performed in the symmetrical zone, near the surface, to quantify the nodule size. Nodules were defined as regions separated by misorientation angles larger than 10°. Figure 3a and b shows the Inverse Pole Figures (IPF) obtained in the symmetrical area of the worn rail samples, near the surface, for R260 and R370CrHT, respectively. The nodule size was found to be around 37 µm ± 29 µm for R260 and 25 ± 14 µm for R370CrHT. Despite the large standard deviations, these computations showed that R260 had larger nodule sizes than R370CrHT and that the nodule sizes were more spread (the coefficient of variation was equal to 0.78 for R260 and 0.56 for R370CrHT). Based on these large EBSD maps, pole figures were also drawn. For the sake of brevity these figures were not included but no preferential orientation of pearlite was observed for both R260 and R370CrHT with respect to the rolling direction.

7/24

Thus, no texture developed in the near surface of the railheads during the production of the rails.

Figure 4 shows the results of finer EBSD scans with a step size of 100 nm in the same region. IPF maps were superimposed with Image Quality (IQ) results and IQ map with the values of the rotation angles. For R260, as the interlamellar spacing is larger than the EBSD step size, the lamellar microstructure clearly appeared on the combined IPF and IQ maps. On the opposite, for R370CrHT, the interlamellar spacing is too small compared to the EBSD step to give a clear definition of the lamellae. For the selected areas, a total length of boundaries of 1.2 mm was measured for R260 with 64% of Low Angle Boundaries (LAB) i.e. boundaries with rotation angles comprised between 2 and 10 degrees and 36% of High Angle Boundaries (HAB) i.e. boundaries with rotation angles comprised between 10 and 65 degrees. For R370CrHT, a total length of boundaries of 2.3 mm was measured for an equal size of zone, composed of 60 % of LAB and 40% for HAB. These computations were repeated on several areas. The difference of total length of boundaries between R260 and R370CrHT was significant and can be explained by the finer nodule and colony structure of R370CrHT compared to R260.

8/24

Worn state

First, the evolution of interlamellar spacing Sp and hardness was determined as a function of the rail depth (Figure 5). The interlamellar spacing was quantified with a statistical analysis of SEM images for both materials. Near the material surface, Sp fell by around 50% for R260 if compared to the value found in the symmetrical area while Sp only fell by around 20 % for R370CrHT. Furthermore, for R260, Sp gradually increased from the surface of the material down to a depth of approximately 1500 µm, while for R370CrHT there was a steep increase until a depth of only 350 µm. It should be noted that after these brutal variations caused by the material deformation, both materials showed a slight 10/24 increase of Sp with depth, instead of reaching a plateau. This slight increase results from the different cooling rates of the material during the steelmaking process. Microindentation tests were also performed on the cross-section of both materials. Figure 5b presents the variation of the microhardness divided by the microhardness determined before loading, as a function of depth. An increase of the microhardness of 60% at the surface of the material was observed for R260 while this increase was only of 30% for R370CrHT. The microhardness of R260 gradually decreased until a depth of approximately 600 µm while the microhardness of R370CrHT quickly decreased over a depth of around 350 µm. It should be noted that the interlamellar spacing and the microhardness varied over similar depths for R370CrHT. On the opposite, for R260, the variation depth of the interlamellar spacing took place over around twice the distance determined for the microhardness. Figure 6 shows the SEM-EBSD characterization of the microstructure directly below the worn surface for the rail sample R260. The SEM images showed that there were no visible lamellar structures retained in the subsurface of the wear zone of R260 in the first 60 µm below the surface (Zoom A).

Then, there was the co-existence of curved and fragmented cementite lamellae, as underlined with Zoom B. Numerous porosities can be observed and seem to be residual marks of precipitates. EBSD measurements performed in the same area as the SEM images showed a significant loss of Kikuchi patterns for the first 30 µm below the surface. For a depth larger than 30 µm, the nodule structure was completely lost but very small clusters of crystallites sharing similar orientations were perceived: these clusters tended to be very thin (around 1 µm) along ND and elongated (around 5 µm) along the TD.

11/24

Figure 7 presents the SEM-EBSD characterization of the microstructure below the worn surface for the rail sample R370CrHT. In the SEM images, contrary to R260, the flattened microstructure was clearly discernible directly below the surface as well as further down the cross-section. A clear tilt of the microstructure was observed: the microstructure realigned itself with the direction of deformation caused by the shearing. As for the EBSD measurements, the loss of Kikuchi patterns occurred at a smaller depth than for R260 (around 5 to 10 µm). A steep gradient of microstructure was perceived: in the first 15 µm, small clusters of crystallites sharing similar orientations were observed, with an increase of these cluster sizes with the increase of the depth of the observation.

12/24 The plastic deformation of the materials caused by the contact between wheel and rail can also be apprehended by visualizing local misorientations. Figure 8 presents the Kernel Average Misorientations (KAM) obtained for R260 and R370CrHT, for the selected zones in the IPF maps of 14/24 Figure 6 and Figure 7. Below the worn surface, there was a striking difference in KAM evolutions between the rail sample R260 and R370CrHT. In R260, excluding the non-indexed Kikuchi patterns in the subsurface, KAM between 10° and 65° represented a fraction of 39% of the surface and were distributed all along the examined area. Thus, a considerable number of high-angle boundaries were produced in the near surface. On the opposite, for the same depth, KAM between 10° and 65° represented a fraction of 22% of the surface for R370CrHT. Moreover, a clear gradient was observed in the R370CrHT sample with a decrease of the KAM angles along the depth of the cross-section.

Thus, R370CrHT showed a steeper gradient confined to the near surface of the railhead.

These results were checked with the computation of the misorientation angle for the near-surface wear zone in R260 and R370CrHT and were compared with the misorientation angle computed for the nearsurface symmetrical areas i.e. the unloaded state (Figure 9). The Mackenzie distribution [START_REF] Mackenzie | Second Paper on the Statistics Associated with the Random Disorientation of Cubes[END_REF] was also drawn as a reference for a cubic sample with a random texture. The distribution of misorientation angle in the symmetrical zone was found to be different from the shown random distribution for both steel grades. It can be explained by the rail production method as well as by the pearlite structure (colony, lamellae) that led to have much LAB than HAB in the considered measurements (as can be observed in Figure 4) and thus caused a distribution that differed from 'standard' grain definition.

Then, plastic deformation led to the creation of HAB through the subdivision and rotation of the lamellae and the changes of shape and size of the ferrite grains. More specifically, based on Figure 9, it can be seen that in R260, the number fraction of high misorientation angle was nearly twice higher below the surface in the loaded state compared to the unloaded state. For R370CrHT, the results were completely different: low and high misorientation angles tended to have similar values of number fraction but there was an increase of medium misorientation angles (between 20 and 30 degrees).

15/24 The microstructure evolution of R260 and R370CrHT was then investigated at different depths below the worn surface using EBSD measurements. Figure 10 and Figure 11 are representative of the EBSD characterizations performed at 150, 500 and 3500 µm in R260 and R370CrHT, respectively. A quick look at the superimposed IQ and rotation angle maps already emphasized the difference of behaviors between R260 and R370CrHT. The red color standing for rotation angles larger than 10° clearly prevailed in the R260 map. More specifically, for R260, the maps combining IPF and IQ suggested a larger interlamellar spacing with the increase of depth, which confirmed the results shown in Figure 5.

Contrary to the observations made immediately below the worn surface (Figure 6), larger substructures recalling prior-nodules and colonies were observed. However, the disorientations remained too large to try to identify and quantify these substructures. On the combined IQ and rotation angle map, a total length of boundaries equal to 13.7 mm was calculated for the examined depth of 150 µm, composed of 30% of LAB and 70% of HAB. This total length of boundaries progressively decreased along the depth of the sample R260 with a total length of 12.2 mm at 500 µm, with 39% of LAB and 61% of HAB. This decreasing was even larger at a depth of 3500 µm with a total length of 9.9 mm, with 53% of LAB and 47% of HAB. However, the total length of boundaries as well as the fraction of HAB remained much larger than the reference (Figure 4). A non-deformed microstructure was only identified from a depth of 5 mm for R260.

17/24

On the opposite, R370CrHT quickly retrieved a microstructure devoid of any plastic markers (at the scale of the EBSD). The EBSD characterizations performed at a depth of 150 µm below the worn surface showed structures very similar to nodules with elongated shapes titled relative to the loading axis (ND). These structures contained some HAB but LAB were dominant. A total length of boundaries equal to 8.7 mm was identified at a depth of 150 µm, with 63% of LAB and 37% of HAB.

Then, this total length quickly dropped at a value of 4.1 mm for a depth of 500 µm, with 56% of LAB and 44% of HAB. Finally, the total length of boundaries was equal to 2.7 mm for a depth of 3500 µm, with 64% of LAB and 35% of HAB. It is worth noting that in R370CrHT, even if the total length of boundaries was different along the investigated depths, the ratio of LAB and HAB remained globally unchanged. For R370CrHT, the performed analyses showed that the indicators of plastic activity were confined to a depth of around 700 µm, which is seven times smaller than the value identified for R260.

Figure 10 and Figure 11 also showed that in R260, the nodule and colony structures were quickly lost and there were important rotations of lamellae. On the other side, in R370CrHT, colony and nodule structures were largely kept, even when undergoing large deformations. Thus, it seems that in R370CrHT, small interlamellar spacing, combined with small colony and nodule structures, led to the formation of strong cell structures that are more resistant to plastic deformation.

18/24 It should be noted that even if the total load of the rig-tested rails was estimated to be around 2.4 MGT, the large plastic deformations were characteristics of much larger tonnages. The microstructure 20/24 characteristics of the examined R260 after deformation were closer to the observations performed by Dylewski et al. on a R260 that had supported 350 MGT in real traffic conditions [START_REF] Dylewski | The tridimensional gradient of microstructure in worn rails -Experimental characterization of plastic deformation accumulated by RCF[END_REF] than the observations made on a R260 at the early stages of deformation (1.3 to 16 MGT) [START_REF] Dylewski | Multiscale characterization of head check initiation on rails under rolling contact fatigue: Mechanical and microstructure analysis[END_REF].

The previous results showed that the deformation behavior of R260 and R370CrHT at the microstructure scale was strikingly different. Figure 12 schematically summarizes the microstructure evolution differences between both steel grades. For R260, directly below the worn surface, there was a complete loss of the microstructure: no colonies, nodules or lamellae were observed. Then, some fragmented and curved lamellae were observed as well as some clusters of crystallites showing similar orientations. In R260, the HAB were so numerous and predominant that the nodule structure could not be identified. Signatures of plastic deformations were found until a depth of approximately 5000 µm.

On the contrary, for R370CrHT, the microstructure was still observed directly below the worn surface, even if it was very deformed. Thin and elongated structures tilted relative to the loading direction (ND)

were present until a depth of 50 µm. Then, the nodules, even if flattened and tilted, were clearly observed. They quickly regained their round shape with the increase of depth. Signatures of plastic deformations were found until a depth of only 700 µm. Based on these characterizations, it seems that the smaller interlamellar spacing in R370CrHT, combined with smaller structuration (colony, nodule) led to the formation of strong cell structures that are more resistant to plastic deformation, thus slowing down material wear.

21/24

Figure 12: Schematic illustration of microstructure evolution below the worn surface of two rail grades R260 and R370CrHT after rolling contact wheel/rail rig testing.

Conclusion

The purpose of this investigation was to examine rail wear in two pearlitic steel: a standard grade (R260) and a heat-treated premium grade (R370CrHT improved to 400 HB). To do so, a full-scale wheel/rail contact rig test was used to reproduce large deformations (loadings around 100 MGT) in a short period of time (computed loadings were equal to 2.4 MGT). Macroscopic observations of worn rails showed that the loss of transverse rail profile caused by the test was more severe in R260 as the wear depth was at least four times larger than the one identified for R370CrHT.

The combination of optical, SEM observations, microhardness tests and EBSD characterization enabled us to explain this difference of wear behavior. The main results of this study are:

-plastic deformation was much more confined in R370CrHT than in R260. The examination of the misorientation angles and rotation angles led to identify microscopic plastic deformation activity until a depth of 5 mm for R260 while this depth was only equal to 700 µm for R370CrHT.

-Stronger strain-hardening was noticed for R260 with an increase of the microhardness at the surface of the material of 60% while it was only 30% for R370CrHT. Moreover, the microhardness varied over a depth of 600 µm for R260 while it decreased over a depth of only 350 µm for R370CrHT.

-The R260 steel rail completely lost its microstructure below the worn surface (absence of colonies, nodules, lamellae) contrary to the R370CrHT steel that kept visible lamellae and had elongated sheared structures tilted relative to the loading axis.

-High angle boundaries were predominant in R260 and prevented any recognition of nodule structuration. On the contrary, nodule structuration was quickly retrieved below the surface in R370CrHT.

-The smaller interlamellar spacing in R370CrHT, compared to R260, combined with smaller structuration (colony, nodule) led to the formation of strong cell structures that are more resistant to plastic deformation, thus slowing down material wear.

22/24

This through comparison of the microstructure changes induced in two pearlitic rail steels subjected to a wheel/rail contact rig test will help the building of wear scenarios. Future work will focus on smaller scale to improve the understanding of lamellae deformation.

Figure 1 :

 1 Figure 1: (a) Profiles of rails after rolling contact wheel/rail rig testing and reference profile for 60E2; (b) OM observations of the wear and head check zones in the cross section of two rails, (c) magnified OM figure for R370CrHT and (d) magnified OM figure for R260.

Figure 2 :

 2 Figure 2: SEM images of typical pearlite microstructure for the undeformed (a) R260 and (b) R370CrHT rail grades with examples of determination of interlamellar spacing (SP) and the computed distribution of interlamellar spacing for (c) R260 and (d) R370CrHT. Cementite and ferrite lamellae are indicated by green and blue arrow in (a).

Figure 3 : 24 Figure 4 :

 3244 Figure 3: EBSD characterization of the undeformed zone (symmetrical area) in the worn rail samples with a step of 500 nm: IPF of (a) R260 and (b) R370CrHT.

Figure 5 :

 5 Figure 5: Variation of interlamellar spacing Sp (a) and microhardness HV/HV(undeformed) (b) with the distance from the worn surface in R260 and R370CrHT after rolling contact tests.

Figure 6 :

 6 Figure 6: SEM-EBSD observations of the near surface of rail R260 after rig-testing, taken from the cross-section (ND-TD plane), (a) SEM observation and (b) IPF map of the same area.

Figure 7 :

 7 Figure 7: SEM-EBSD observations of the near surface of rail R370CrHT after rig-testing taken from the cross-section (ND-TD plane).

Figure 8 : 24 Figure 9 :

 8249 Figure 8: KAM maps corresponding to the selected rectangle in Figure 6 and Figure 7, R260 (a) and R370CrHT (b).

Figure 10 : 24 Figure 11 :

 102411 Figure 10: EBSD characterization performed at depths of 150, 500 and 3500 µm in R260: (a), (c), (e) IPF maps superimposed with image quality; (b), (d), (f) IQ map with grain boundaries (2-5° in blue, 5-10° in green, 15-65° in red).

Acknowledgements

The authors would like to thank France Rail Industry, IRT Railenium for their support for this project.


Dr Nicolas Golse
email: nicolasgolse@me.com

MD Pablo Duarte

MD Andrea Fontana

MD Cristiane Bündchen

Vincent Karam

PhD Marc-Antoine Allard

MD PhD Gabriella Pittau

MD Oriana Ciacio

J.-C Duclos-Vallée

PhD Antonio Sa Cunha

MD Jean-Charles Duclos-Vallee

MD Denis Castaing

MD Daniel Cherqui

PhD René Adam

PhD Didier Samuel

MD PhD Eric Vibert

Comparative analysis of outcomes after liver resection and liver transplantation for early stages hepatocellular carcinoma in HIV-infected patients. An intention-to-treat analysis

niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

INTRODUCTION

The use of combined antiretroviral therapy has enabled improved control of the human immunodeficiency virus (HIV) [START_REF] Samji | Closing the gap: increases in life expectancy among treated HIV-positive individuals in the United States and Canada[END_REF]. However, a higher risk of mortality of HIV/hepatitis C (HCV) co-infected patients persists because of extra-hepatic conditions [START_REF] Salmon-Céron | HIV/HCV co-infected cirrhotic patients are no longer at higher risk for HCC or end-stage liver disease as compared to HCV mono-infected patients[END_REF]. Indeed, there is a close association between HIV, HCV and hepatitis B virus (HBV), and the presence of HIV used to shorten the time to the onset of fibrosis (3) so that liver transplantation (LT) is now a well validated indication in the event of end-stage liver disease (ESLD) in HIV+ patients [START_REF] Feray | Survival and recurrence of hepatitis C after liver transplantation in patients coinfected with human immunodeficiency virus and hepatitis C virus[END_REF][START_REF] Tateo | Long-term follow-up of liver transplanted HIV/hepatitis B virus coinfected patients: perfect control of hepatitis B virus replication and absence of mitochondrial toxicity[END_REF][START_REF] Terrault | International Liver Transplantation Society Consensus Statement on Hepatitis C Management in Liver Transplant Recipients[END_REF]. Nevertheless, the recent introduction of new direct-acting antiviral agents (DAA) means that ESLD as a major indication for LT is diminishing in this co-infected population [START_REF] Gadiparthi | Use of direct-acting antiviral agents in hepatitis C virus-infected liver transplant candidates[END_REF].

Beyond the risk of ESLD, HIV+ patients are exposed to the other complications of chronic liver disease and particularly hepatocellular carcinoma (HCC). Classically, there was an increased incidence of HCC among HIV carriers, with HCC being diagnosed at an advanced stage and involving more infiltrative-type lesions and portal vein thrombosis [START_REF] Lewin | Imaging Features and Prognosis of Hepatocellular Carcinoma in Patients with Cirrhosis Who Are Coinfected with Human Immunodeficiency Virus and Hepatitis C Virus[END_REF][START_REF] Gelu-Simeon | Prognostic factors of survival in HIV/HCV co-infected patients with hepatocellular carcinoma: The CARCINOVIC Cohort[END_REF], causing almost half of liver-related deaths [START_REF] Rosenthal | Liver-related deaths in HIV-infected patients between 1995 and 2010 in France: the Mortavic 2010 study in collaboration with the Agence Nationale de Recherche sur le SIDA (ANRS) EN 20 Mortalité 2010 survey[END_REF]. The risk of HCC has been reported as being seven-fold higher in HIV+ patients than in the general population [START_REF] Berretta | Clinical presentation and outcome of non-AIDS defining cancers, in HIVinfected patients in the ART-era: the Italian Cooperative Group on AIDS and tumors activity[END_REF]. However, thanks to the better efficacy and safety of DAA and highly active antiretroviral therapy (HAART), recent studies in the literature have suggested that this higher risk of HCC in co-infected populations no longer exists [START_REF] Salmon-Céron | HIV/HCV co-infected cirrhotic patients are no longer at higher risk for HCC or end-stage liver disease as compared to HCV mono-infected patients[END_REF][START_REF] Vaziri | Liver transplant listing for hepatitis C-associated cirrhosis and hepatocellular carcinoma has fallen in the United Kingdom since the introduction of directacting antiviral therapy[END_REF].

In HIV+ patients, HCC may have a more aggressive course [START_REF] Bourcier | Primary liver cancer is more aggressive in HIV-HCV coinfection than in HCV infection. A prospective study (ANRS CO13 Hepavih and CO12 Cirvir)[END_REF], and little data has been published on resection in this setting. Conversely, the evolving role of LT for HCC in HIV+ patients has been widely reported. Most teams initially contraindicated LT [START_REF] Puoti | Hepatocellular carcinoma in HIV-infected patients: epidemiological features, clinical presentation and outcome[END_REF][START_REF] García-Samaniego | Hepatocellular carcinoma in HIV-infected patients with chronic hepatitis C[END_REF] because of theoretically poorer outcomes due to the progression of HIV and HCV [START_REF] Benedetto | Hepatocellular carcinoma in HIV patients treated by liver transplantation[END_REF]. More recently, numerous publications have demonstrated that LT is a safe procedure with outcomes comparable to those seen in the HIV-population [START_REF] Vibert | Liver transplantation for hepatocellular carcinoma: the impact of human immunodeficiency virus infection[END_REF][START_REF] Agüero | Human immunodeficiency virus infection does not worsen prognosis of liver transplantation for hepatocellular carcinoma[END_REF][START_REF] Benedetto | Multicenter italian experience in liver transplantation for hepatocellular carcinoma in HIV-infected patients[END_REF], so that LT is becoming a standard of care in HIV+ patients [START_REF] Baccarani | Pros and cons of liver transplantation in human immunodeficiency virus infected recipients[END_REF][START_REF] Miro | Outcome and management of HCV/HIV coinfection pre-and post-liver transplantation. A 2015 update[END_REF]. However, the high incidence of drop-outs remains a frequent issue and, even if there is no consensual recommendation regarding the management of HCC in HIV+ patients [START_REF] Study | European Association For The Study Of The Liver. EASL Clinical Practice Guidelines: Management of hepatocellular carcinoma[END_REF], one might wonder whether resection could also be a valuable option in highly selected HIV+ patients.

The aim of this study was therefore to consider the results of resection for HCC in HIV+ patients in a single tertiary centre and to compare the outcomes under intentionto-treat with those who were listed for transplantation. Our specific aim was to determine whether in HIV+ patients, BCLC stages 0-A HCC should be preferentially resected or transplanted.

PATIENTS AND METHODS

Study design and patients

The records of all patients with HIV and HCC listed for primary LT (liver transplant candidates = LTc+) or treated with liver resection (LR+) between January 2000 and December 2017 at the Centre Hepato-Biliaire, Paul Brousse Hospital (Villejuif, France) were evaluated retrospectively from our prospective database. Those listed for LT because of ESLD without HCC and those with incidental HCC (native liver) were not included in this analysis. The study population thus comprised 58 patients, of whom 32 were transplanted (LT+) and 15 were resected (LR+). The cut-off point for follow-up was June 2018.

The criteria used to indicate LT for HCC could be seen to change over the years: between 2000 and 2013, the Milan criteria were applied [START_REF] Mazzaferro | Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis[END_REF] but the AFP score was subsequently deployed [START_REF] Duvoux | Liver transplantation for hepatocellular carcinoma: a model including αfetoprotein improves the performance of Milan criteria[END_REF].

The diagnosis of HCC was based on preoperative imaging and tumour marker levels;

if necessary, biopsies of liver nodules were performed [START_REF] Study | European Association For The Study Of The Liver. EASL Clinical Practice Guidelines: Management of hepatocellular carcinoma[END_REF][START_REF]European Association For The Study Of The Liver, European Organisation For Research And Treatment Of Cancer[END_REF]. Fibrosis was scored according to the METAVIR classification [START_REF] Bedossa | An algorithm for the grading of activity in chronic hepatitis C. The METAVIR Cooperative Study Group[END_REF].

Before listing for any type of treatment, all patients had received HAART and both virological and immunological characteristics had been evaluated [START_REF] Miro | Outcome and management of HCV/HIV coinfection pre-and post-liver transplantation. A 2015 update[END_REF]. HIV was staged according to the 1993 Centers for Disease Control and Prevention classification criteria [START_REF] From The Centers For | revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults[END_REF]. In all patients, antiviral therapies were administered according to current practices [START_REF] Coilly | Optimum timing of treatment for hepatitis C infection relative to liver transplantation[END_REF][START_REF] Shaffer | Solid Organ Transplantation for HIV-Infected Individuals[END_REF].

Before LT and during the waiting time on list, locoregional treatments for HCC were implemented if required: local destruction using radiofrequency ablation (RFA), and/or transarterial chemoembolization (TACE). In the case of LT for an HCC recurrence after resection (performed during the study period in a curative intent), the patient was placed in the LR+ group (intention-to-treat analysis).

The first part of the study included an intention-to-treat analysis that evaluated all patients as from the time of listing for transplant (LTc+) or resection (LR+). We specifically focused on patients who had initially been either transplantable or resectable using current criteria (AFP score ≤2, Model for End-Stage Liver Disease

[MELD] <12, platelet level >100.10 9 /L, without macrovascular invasion, age <70), in order to compare the strategies in the event of BCLC stages 0-A HCC.

The second part compared survival rates in both groups (LT+ vs LR+) as from treatment in terms of overall survival (OS), time-to-recurrence (TTR) [START_REF] Llovet | Design and endpoints of clinical trials in hepatocellular carcinoma[END_REF], disease-free survival (DFS) and their predictors.

Following their discharge, transplanted patients visited our outpatient clinic every 2 weeks for the first 2 months, and then once every 3 months, undergoing systematic Doppler sonography and AFP assays. A CT-scan was performed in the event of a rising AFP level or lower arterial index resistances and/or abnormal hepatic test findings.

Resected patients underwent an initial CT-scan at postoperative day (POD) 30 and then once every 3 or 4 months (+AFP assay) during the first 2 years. Biological and imaging follow-up was subsequently scheduled every six months.

Statistical analysis

Continuous variables are described as medians and ranges, and categorical variables as a percentage. Categorical data were compared using the X2 test or Fisher's exact test, whereas continuous variables were compared using a T-test or the Mann-Whitney U test, as appropriate.

Survival was analysed using the Kaplan-Meier method, and the results were compared using the log-rank test. Overall survival was calculated from the date of inclusion or surgery until death or the last follow-up examination. DFS was defined as the period between surgery and the first postoperative recurrence or death. Baseline and tumour characteristics, as peri-and post-surgery variables, were assessed as predictors of outcome using Cox proportional hazards models. Variables associated with a P value <0.10 under univariate analysis were considered for multivariate analysis. The hazard ratio (HR) estimates and associated 95% confidence intervals (CI) were calculated, and a P-value ≤0.05 in the Cox model was considered to be statistically significant.

Intention-to-treat survival was calculated from the day of inclusion on the waiting list (LTc+ group) or the indication of surgery (LR+ group). Death was considered as postoperative mortality in the case of events occurring during hospitalisation for the first surgery, or before POD 90.

RESULTS

General characteristics of HIV+ patients in our centre

During the study period, 714 HIV+ patients were evaluated, including 136 (19%) patients who suffered from HCC. Among these, 58 were listed for transplantation or resection and are described below while the 78 others were not candidates for surgery.

Characteristics of LTc+ and LR+ patients at diagnosis (Table 1)

Liver transplantation was indicated in 43 patients with HCC and resection was proposed to 15 others. Almost all the patients presented with controlled HIV infection.

The LTc+ group presented poorer general status, but a lower tumour burden with a lower median AFP score (not significant) and a lower "outside-Milan" frequency (5% vs 27%, p=0.04). The "extra-criteria" LTc+ patients (n=4 according to the rules at that time) were nonetheless listed because of their Milan scores (before the era of AFP scores).

Early course after listing

In the LTc+ group, there were 11 (26%) drop-outs, with a median time before delisting of 159 days (range = 27-753 days). Among these patients, most were receiving RFA (n=3) and/or TACE (n=9) while waiting for LT. The principal reasons for drop-outs were tumour progression with the occurrence of macrovascular invasion (n=4), extrahepatic metastasis (n=3), multiple liver nodules out of the transplant criteria (n=2) and death from sepsis (n=1) or unknown causes (n=1).

In the LT+ group (n=32), treatments on the waiting list included surgical resection (n=2), RFA (n=8) or TACE (n=19). The median waiting time before LT was 126 days (range = 24-990 days).

The only differences highlighted among LTc+ patients who dropped out versus those who did not were the initial AFP level (median: 37 vs 7 [2-1700], p=0.01), and the AFP score (median: 1 [0-3] vs 0 [0-4], p=0.06), higher in the drop-out group.

In the LR+ group, all listed patients were resected (no progression before surgery), the median waiting time being 24 days (range= 9-75 days). Two resected patients developed a recurrence after resection in curative-intent and then underwent salvage transplantation.

Under intention-to-treat, the survival rates at 1, 3 and 5 years after listing were (Fig. 1) 81%, 60% and 44% versus 86%, 58% and 58% in the LTc+ and LR+ groups, respectively (p=0.75).

Comparison of transplantable and resectable patients (intention-to-treat)

In order to compare the two strategies (transplantation vs resection) when both treatments were potentially applicable, we used intention-to-treat OS to compare patients with transplantable and resectable HCC. We thus compared nine patients in the LTc+ subgroup against nine patients in the LR+ subgroup. There were no differences regarding epidemiological and virological features between the two groups, and particularly no difference relative to HBV or HCV co-infection. As expected, liver function was poorer in the transplant group, with a median MELD score of 9.3 ± 1.5 vs 7.8 ± 1.5 (p=0.05). There was no significant difference regarding platelet levels (p=0.83), AFP levels (p=0.69), the median number of lesions (p=0.08) and maximal HCC size (p=0. [START_REF] Yopp | Presentation, treatment, and clinical outcomes of patients with hepatocellular carcinoma, with and without human immunodeficiency virus infection[END_REF]. No postoperative deaths occurred after resection and only one after LT (cardiogenic shock at POD 70). The median OS values after listing in the transplant and resection subgroups were 66.8 months and 39.4 months, respectively. One-, 3-and 5-years survival rates were 89%, 78% and 67% vs 100%, 73% and 49% in the LTc+ and LR+ groups, respectively (p=0.82).

Characteristics of patients at transplantation or resection (Table 2)

There were no statistically significant differences between the groups regarding epidemiological features. The most prevalent cause of cirrhosis was HCV, involved in 81% and 87% of LT+ and LR+ cases, respectively. Among co-infected HIV/HCV patients, 15% and 38% of them had a history of co-infection with HBV in the LT+ and LR+ groups, respectively (p=0.13), but only three patients (LR+ group only) presented with a persistently positive HBV viral load at the time of surgery (p=0.17). Portal hypertension was more severe in the LT+ group, as evidenced by the platelets count, lower in this group (68 vs 158 [57-239], p=0.001).

HIV infection was better controlled in the LR+ group, as reflected by higher levels of CD4 lymphocytes. Moreover, using the CDC classification, 50% of patients in group LT and 13% in group LR were classified as having AIDS-indicator conditions (p=0.04).

In the resected group, tumours were larger on preoperative imaging but all patients presented a single lesion, unlike the LT group where 11 patients (34%) had multiple lesions (p=0.009). In the resection group, tumours also displayed a more aggressive pattern; four of them (27%) were considered to have advanced tumours (BCLC C) because of macrovascular invasion. Twelve patients (80%) underwent minor hepatectomy (<3 segments).

Early postoperative outcomes in the LT+ and LR+ groups (Table 2)

In the transplant cohort, major complications (Dindo-Clavien III-IV) were recorded in 12 recipients (37.5%). Two developed primary non-function and were re- In the resected group, three major postoperative complications occurred (n=3; 20%): two patients required an urgent exploratory laparotomy for bleeding and biliary leak, and another developed post-hepatectomy liver failure (grade C), which was treated medically. There were no postoperative death.

Overall survival at six months reached 87.5% (four deaths) and 86% (two deaths) in the LT+ and LR+ groups, respectively.

Recurrence and survival after transplantation or resection (Fig. 1 and2, Table 3)

The median follow-up after LT and resection was 45 [0-135] months and 22 months, respectively. LR+ patients developed a higher recurrence rate than transplanted patients (n=8, 53% vs n=5, 16%; p=0.02), and earlier recurrence (4.2 months [2. 3-32.4 months] vs 11.7 months [3.1-46.1 months], p=0.62). The OS at 1, 3 and 5 years reached 81%, 68% and 59% in the LT+ group versus 86%, 58% and 58% in the LR+ group (p=0.84). There was a trend towards longer DFS in the LT+ group as this reached 78%, 68% and 56% at 1, 3 and 5 years, versus 53%, 33% and 33% in the LR+ group (p=0.06). The mean time-to-recurrence was significantly shorter in the resected group (35 months vs 112 months, p=0.001).

In the LT+ group, there were three (60%) initial extrahepatic recurrences, one (20%) intra-hepatic recurrence only, and one (20%) both intra and extrahepatic localisation.

The median survival after recurrence was 5.2 months and none of these patients were alive at the last follow-up. One recipient received RFA for post-LT recurrence.

At the end of follow-up, 17 patients (53%) in the LT+ group were alive without a recurrence and 15 recipients died (47%). Three of them clearly died from liverassociated complications (cirrhosis after reinfection from HCV, fibrosing cholestatic hepatitis, severe rejection after treatment with INF-based therapy for HCV reinfection).

All eight recurrences in the LR+ group were solely intrahepatic. Two patients were managed with a combination of TACE and salvage LT, and they were still alive (without a recurrence) 12 and 20 months later. One patient underwent a repeat resection and died from a recurrence after 17 months. Other patients received TACE (n=4) and best supportive care (n=1). The median survival after a recurrence was 8.3 months. At the last follow-up, 10 patients (67%) in the LR+ group were alive, six without disease and four with a recurrence; four patients died after a recurrence and one died from liver failure (after discharge).

In the LT+ group, mean survival was better in recipients who achieved SVR compared to those who did not, at respectively 123 and 36 months (p<0.001). In the LR+ group, there was no difference between groups as a function of SVR status (mean OS: 53 months if SVR+ vs 28 months if SVR-; p=0.74).

DISCUSSION

Statement of principal findings

This study reports on the largest cohort of HIV-carrier patients resected for HCC (n=15). We observed that hepatectomy for HCC procured the same OS as LT for HCC in HIV+ patients, when either inclusion at surgery or at diagnosis were considered. However, we observed a longer TTR survival in the LT+ group that could partly be explained by the more advanced stage of HCC in the LR+ group.

Even in the subgroup of patients who were potentially transplantable and resectable at diagnosis, the two strategies did not differ in terms of OS (p=0.82).

Our aim was not to demonstrate the superiority of a strategy, but rather to highlight the feasibility and reliability of hepatectomy in this context. Obviously, the LTc+ and LR+ groups were not strictly comparable, and only a few LTc+ patients could initially have been resected (9/43; 21%).

As previously reported, we confirm the high rate of drop-outs among LT candidates (11/43; 26%) [START_REF] Vibert | Liver transplantation for hepatocellular carcinoma: the impact of human immunodeficiency virus infection[END_REF][START_REF] Benedetto | Multicenter italian experience in liver transplantation for hepatocellular carcinoma in HIV-infected patients[END_REF]. Interestingly, two patients who dropped-out had been resectable at diagnosis. We also confirmed the negative impact of high AFP level at diagnosis, and as a predictor of a higher risk of drop-out.

Strengths and weaknesses of the study

The main strength of this study was its sample size which, though limited, is the largest cohort of hepatic resections to have been reported in this setting. This series also reflects current management in a western, tertiary high-volume centre (>150 LT/year) with particular easy access to HAART and DAA. Indeed, most studies available in the literature reported "historical" series without DAA and their transposition to current practices remains limited. Finally, the intention-to-treat design, completing the posttreatment analysis, strengthened the clinical relevance of the study.

The study was however affected by a series of limitations. The most important was its retrospective design which reduced the scope of its conclusions because of potential bias. Finally, the short follow-up period in the LR+ group prevented us from drawing definitive conclusions regarding long-term events in this group.

One important remark is that 75% of our transplanted cohort was managed before the era of new anti-HCV therapies. Although not statistically significant, the resected cohort was more recent. This is of great importance because it has now been clearly demonstrated that new DAA display considerable efficacy after LT, with high SVR rates and excellent tolerability [START_REF] Antonini | Sofosbuvir-Based Regimens in HIV/HCV Coinfected Patients After Liver Transplantation: Results From the ANRS CO23 CUPILT Study[END_REF][START_REF] Antonini | Therapy with boceprevir or telaprevir in HIV/hepatitis C virus co-infected patients to treat recurrence of hepatitis C virus infection after liver transplantation[END_REF], without causing a negative impact on the incidence of de novo HCC (as was initially suspected) [START_REF] Nahon | Incidence of Hepatocellular Carcinoma After Direct Antiviral Therapy for HCV in Patients With Cirrhosis Included in Surveillance Programs[END_REF][START_REF] Kinoshita | Impact of direct-acting antivirals on early recurrence of HCV-related HCC: Comparison with interferon-based therapy[END_REF][START_REF] Waziry | Hepatocellular carcinoma risk following direct-acting antiviral HCV therapy: A systematic review, meta-analyses, and meta-regression[END_REF]. These good results have been confirmed in a recent multicentric study in HCV/HIV-coinfected patients [START_REF] Manzardo | Direct-acting antivirals are effective and safe in HCV/HIV-coinfected liver transplant recipients who experience recurrence of hepatitis C: A prospective nationwide cohort study[END_REF].

Using these drugs, we could expect even better long-term survival rates for HIV/HCV co-infected recipients than those demonstrated by our present series, and a comparison of survival versus resected patients could become more clearly in favour of LT.

Interpretation with reference to other studies

Rightly, the place for LT in HIV+ patients is now well established in a context of either ESLD or HCC. However, due to recent rises in the incidence of HCC in these patients and the shortage of liver grafts, alternatives to LT are now needed to avoid unacceptable waiting on the list or even higher rates of drop-outs [START_REF] Pinato | Hepatocellular carcinoma: an evolving challenge in viral hepatitis and HIV coinfection[END_REF].

Despite its consensual acceptance, LT for HCC in HIV-carriers raises many questions. First, Miro et al. recently updated the data, showing that survival in HCV/HIV co-infected patients was poorer than in HCV mono-infected patients (no long-term effects of DAA were reported) because of more aggressive HCV recurrences leading to graft loss and death (5-year survival: 50-55%) [START_REF] Miro | Outcome and management of HCV/HIV coinfection pre-and post-liver transplantation. A 2015 update[END_REF]. In most series, as in ours, almost all HIV+ LT candidates are HCV-carriers so their expected survival is not as good as in the HIV-population. In the present series, 5-year survival in the LTc+ group under intention-to-treat only reached 44%.

Moreover, LT is a difficult procedure in this setting, as confirmed by intra-and postoperative data revealing more complex interventions than resections. After LT, there is also a high risk of opportunistic infections in HIV+ recipients. In a recent French series that included patients in whom adapted preventive measures had been implemented (vaccination, antibacterial/antiviral/antifungal prophylaxis), Teicher et al. reported up to 7% of post-LT deaths related to infection, and a MELD score >17 was associated with a 2-fold higher risk of developing infectious complications [START_REF] Teicher | Infectious complications after liver transplantation in human immunodeficiency virus-infected recipients[END_REF].

On the other hand, the role of liver resection in HIV+ patients needed to be specified because very few reports are available. To the best of our knowledge, only eight papers have been published on resection in HIV+ patients [START_REF] Manzardo | Direct-acting antivirals are effective and safe in HCV/HIV-coinfected liver transplant recipients who experience recurrence of hepatitis C: A prospective nationwide cohort study[END_REF] 117 ng/ml), which explains why their observed OS was lower than ours (1-, 3-, 5-year OS: 100%, 50%, 33%, respectively) [START_REF] D'amico | Liver Resection for HCC in HIV-infected patients: A single center experience[END_REF].

More interesting is a comparison of our results in the LR+ group with data published in HIV-populations. Our 1-, 3-and 5-year OS and DFS rates after resection were 86%/ 58%/58% and 53%/33%/33%, respectively. In HCV+ HIV-populations, Hanazaki et al. reported 3-and 5-year OS of 63% and 52%, and DFS of 33% and 20%, rates that were lower than ours [START_REF] Hanazaki | Hepatic resection for large hepatocellular carcinoma[END_REF]. Yeh et al. found 1-, 3-, and 5-year OS rates of 63%, 42%, and 32%, and their DFS were 51%, 34%, and 27%, once again lower than ours [START_REF] Yeh | Prognostic factors of hepatic resection for hepatocellular carcinoma with cirrhosis: univariate and multivariate analysis[END_REF]. These results, showing no additional mortality in HIV-infected patients, justify the place of HCC resection in HIV+ patients with results that are (at least) equivalent to those obtained in the general population.

Finally, although it is now accepted that LT can offer several advantages over resection under an intention-to-treat analysis in the general population [START_REF] Menahem | Liver transplantation versus liver resection for hepatocellular carcinoma in intention to treat: An attempt to perform an ideal meta-analysis[END_REF][START_REF] Adam | Resection or transplantation for early hepatocellular carcinoma in a cirrhotic liver: does size define the best oncological strategy?[END_REF], we probably need to apply the same decisional algorithm in both HIV+ and HIV-patients, in view of current graft shortages and the immediate availability of resection.

CONCLUSION

Liver transplantation and liver resection in HIV+ carriers procure comparable DFS and OS rates, either under intention-to-treat or after treatment, but targeting different populations. Indeed, in our study, the two groups differed quite markedly, with LTc+ patients displaying a more impaired liver function while LR+ patients were suffering from more advanced HCC. However, in rare situations when both treatments are potentially feasible at diagnosis, there is no clear argument in favour of LT because the DFS benefit seems to be counterbalanced by a higher drop-out rate. Whichever strategy is chosen, it should perhaps only be proposed to selected young patients, particularly those with a controlled viral load through the use of HAART and DAA in the event of HCV co-infection, and to ensure a strict monitoring after treatment.

FIGURES LEGENDS Fig 1

Figure 1a: OS after listing for transplantation or resection (p=0.75) Figure 1b: OS after transplantation or resection (p=0.84)

  transplanted, but died during the post-transplant period from multiple septic complications. A third recipient died at POD 10 due to massive abdominal haemorrhage and one patient died after discharge from hospital, at POD 70 days due to unexpected cardiogenic shock. The other eight patients developed one or more of the following complications: sepsis (pulmonary origin [n=3], acute appendicitis [n=1]), abdominal bleeding (n=3), acute renal failure (n=3) biliary leak (n=1), haemorrhagic shock (n=1), and pulmonary embolism (n=1).

  cases; median number of cases/report = 3) (14,39-45). Regarding the two largest cohorts published by Berretta et al. (n=13) (41) and Yopp et al. (n=7) (45), they did not provide any data on the resection subgroup. D'Amico et al. detailed tumour characteristics (n=6): they resected more advanced tumours than our group (mean size: 4.45cm; mean preoperative AFP level:

Fig 2 :Fig 3 :

 23 Fig 2: DFS after transplantation or resection (p=0.06)

Figure 1a .Figure 2 .

 1a2 Figure 1a. OS after listing for transplantation and resection (p=0.75)

Table 2 . Perioperative and pathological data of transplanted and resected patients.

 2

	Characteristics	LT+ (n=32)	LR+ (n=15)	p-value
	Preoperative data
	Age, years	50.4 (36.6 -64.8)	53.6 (37.9 -71.9)	0.24
	Male gender, n (%)	23 (71.9)	11 (69.2)	>0.99
	Diabetes, n (%)	8 (25.0)	2 (13.3)	0.46
	Alcohol consumption, n (%)	9 (28.1)	6 (40.0)	0.51
	Liver disease
	HCV	22 (68.8)	8 (53.3)
	HBV	5 (15.6)	2 (13.3)	0.36
	HCV + HBV	4 (12.5)	5 (33.3)
	Other	1 (3.1)	0 (0.0)
	HCV viral load (undetectable ≤1.6 log	11 (42.36)	8 (61.5)	0.43
	10/ml)
	Presence of HCV SVR, n (%)	14 (53.8)	10 (76.9)	0.29
	Prior treatment
	Surgery or RFA	11 (34.4)	3 (20.0)
	TACE	14 (43.8)	4 (26.7)	0.09
	None	7 (21.9)	8 (53.3)
	MELD score, median (Min-Max)	14.0 (7.0 -40.0)	8.0 (6.0 -16.0)	<0.001
	HCC within Milan criteria, n (%)	30 (93.8)	11 (73.3)	0.07
	Child-Pugh A/B/C, n (%)	15 (46.9) /11 (34.4) /6	13 (86.7) /2 (13.3)
				0.03
		(18.8)	/0
	AFP score, median (Min-Max)	0.0 (0.0 -4.0)	1.0 (0.0 -4.0)	0.15
	AFP level, µg/L, median (Min-Max)	7.5 (1 -1772)	19.2 (2.3 -1000)	0.16
	Undetectable HIV (≤1.6 log 10/ml), n (%)	31 (96.9)	12 (80.0)	0.09
	CD4 count, median (Min-Max)	292 (54 -840)	500 (231 -950)	0.003
	BCLC stage 0/A/B/C, n (%)	1 (3.1) / 29 (90.6) / 2	2 (13.3) /9 (60.0) /
				0.006
		(6.3) / 0	0 / 4 (26.7)
	Number of lesions at imaging, median	1 (1 -3)	1 (1 -1)	0.01
	(Min-Max)
	Lesion size at imaging (max diameter, cm),	1.9 (1.0 -7.0)	2.8 (1.5 -12.0)	0.02
	median (Min-Max)
	Treatment before 2014, n (%)	24 (75.0)	8 (53.3)	0.18

AFP: alpha-fetoprotein, AIDS: acquired immunodeficiency syndrome, CCI: Comprehensive Complication Index RFA: radiofrequency ablation, SVR: sustained virological response, TACE: transarterial chemoembolization

Characteristics

Listed for LT (LTc) n=43

Listed for resection (LR) n=15 p-value