Liver Enzyme Elevation After Hepatitis C Virus Cure: Is There a Sex Effect? (ANRS CO13 HEPAVIH Cohort)

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We read with great interest Zhang et al.'s work on liver enzyme elevation (LEE) after hepatitis C virus (HCV) cure [1]. While the authors found no evidence of an effect of HIV status on post-cure LEE, they showed that female sex, pretreatment alanine aminotransferase (ALT) and pretreatment cirrhosis were positively associated with this outcome. Their study limitations included its single-centre nature, the lack of data on alcohol use and the relatively small number of HIV-HCV co-infected individuals. We thus further explored the potential impact of HIV-related markers and alcohol use on post-HCV cure LEE in a larger sample of HIV-HCV co-infected adults enrolled in the French, prospective, multicentre cohort ANRS CO13 HEPAVIH [2]. Participants provided written informed consent. We selected participants cured from HCV thanks to direct-acting antiviral treatment (DAA), who had completed at least one clinical follow-up visit after HCV cure, and with available pretreatment data on age, sex, place of birth, body mass index, ALT and aspartate transaminase (AST) levels, CD4 cell count, HIV viral load, history or current cirrhosis or hepatocellular carcinoma and alcohol use (AUDIT-C [3]). We conducted a multivariable mixed-effects logistic regression model over the post-HCV cure follow-up period, with LEE as the outcome. As in Zhang et al., we defined LEE as ALT or AST above the upper normal limit (35 and 25 IU/L for males and females, respectively). Our study population comprised 160 participants, of whom 78.1% were male. The median (interquartile range [IQR]) follow-up time was 207 [139–254] weeks. A total of 100 patients (62.5%) had at least one LEE after the end of treatment (EOT). Post-cure LEE was positively associated with female sex and pretreatment ALT level. Neither HIV-related markers nor unhealthy alcohol use was associated with post-cure LEE (Table 1). There were more participants with LEE before treatment initiation (89.4%) than after EOT (McNemar test, p < 0.001). Among the 143 individuals who had a LEE before treatment initiation, 30.8% had no LEE after EOT. In this study, restricted to the specific population of HIV-HCV co-infected individuals, we found a high percentage of individuals with a post-cure LEE, in accordance with the findings from Zhang et al.'s work [1]. However, we also observed a significant decrease in this percentage, which highlights the positive impact of HCV cure. In line with Zhang et al.'s results, we found no evidence of any impact of HIV-related markers on post-cure LEE. However, we confirmed the surprising finding that male sex was identified as a protective factor for post-cure LEE. In a previous study, no such relationship between sex and persistent alteration of liver tests was found after DAA-related HCV cure [4]. Further studies should be conducted to confirm and investigate this seemingly protective effect of male sex on LEE in the DAA era. We thank all study participants. ANRS CO13 HEPAVIH Study Group: Scientific Committee of the ANRS CO13 HEPAVIH Study Group: D. Salmon—co-principal investigator; L. Wittkop—co-principal investigator and methodologist; P. Sogni—co-principal investigator; P. Carrieri, B. Spire and K. Ory—project managers; P. Trimoulet, J. Izopet, L. Serfaty, L. Alric, M.A. Valantin, G. Pialoux, J. Chas, K. Barange, A. Naqvi, E. Rosenthal, A. Bicart-See, O. Bouchaud, A. Gervais, C. Lascoux-Combe, C. Goujard, K. Lacombe, C. Duvivier, D. Neau, P. Morlat, F. Bani-Sadr, F. Boufassa, C. Solas, H. Fontaine, L. Piroth, A. Simon, D. Zucman, F. Boué, P. Miailhes, E. Billaud, H. Aumaître, D. Rey, G. Peytavin and O. Zaeglel-Faucher—representative members of the sponsor (clinical research and pharmacovigilance department) and representative members of patient organisation including TRT5. Clinical Centres (ward/participating physicians): APHP, Hôpitaux Universitaires Paris Centre, Paris (Médecine Interne et Maladies Infectieuses: D. Salmon, R. Usubillaga; Hépato-gastro-entérologie: P. Sogni, B. Bienvenu, O. Launay-Puybasset, C. Bernasconi, A. Brunet, B. Silbermann, H. Boucher, F. Rollot, O. Zak Dit Zbar, S. Pol, C. Le Jeunne-Ballif, P. Louergue, H. Mehawej, L. Merine-Belardi, F. Almasi, N. Benammar, L. Alagna, S. Chaussade, L. Guillevin; Anatomo-pathologie: B. Terris; Virologie: C. Norgeux); APHP Pitié-Salpétrière, Paris (Maladies Infectieuses et Tropicales: C. Katlama, M.A. Valantin, H. Stitou, F. Caby, L. Paris, L. Schneider, R. Tubiana; Médecine Interne: A. Simon, L. Roudière, O. Benveniste, G. Breton, M. Bonmarchand, M. Kirstetter; Anatomo-pathologie: F. Charlotte, F. Capron; Virologie: V. Calvez, V. Thibaut, C. Soulie, B. Abdi, S. Lambert-Niclot); APHM Sainte-Marguerite, Marseille (Immuno-Hématologie Clinique: S. Bregigeon-Ronot, O. Zaegel-Faucher, H. Laroche, A. Menard, E. Gaubert-Marechal; Virologie: S. Thirée, C. Tamalet, C. Hakimi; Anatomo-pathologie: J.C. Poluzzi; Pharmacologie: C. Solas); APHP Tenon, Paris (Maladies Infectieuses et Tropicales: G. Pialoux, J. Chas, L. Lassel, T. Lyavanc, S. Le Nagat, L. Slama, A. Canesti; Anatomo-pathologie: P. Callard; Virologie: B. Bachour); CHU Purpan, Toulouse (Médecine interne: L. Alric, N. Sigur, D. Bonnet, M. Guivarch; Hépato-gastro-entérologie: K. Barange, J.M. Peron, P. Massip, L. Cuzin, M. Obada, E. Bonnet, M. Alvarez, E. Labau, M. Mularczyk, N. Bourdoncle, J. Penecy, L. Porte, F. Busato, S. Khatibi, J. Bernard; Anatomo-pathologie: J. Selves; Virologie: F. Larroquette, V. Ferrer, J. Chiabrandon); CHU Archet, Nice (Médecine Interne: E. Rosenthal, C. Pradier, V. Mondain, P. Dellamonica, P.M. Roger, S. Ferrando, C. Ceppi; Infectiologie: A. Naqvi, V. Rio, B. Dunais, B. Prouvost, F. De Salvadore-Guillouet, I. Prebost, J. Durant, P. Pugliese; Anatomo-pathologie: J.F. Michels, M.C. Saint-Paul; Virologie: C. Partouche, K. Nerini); APHP Avicenne, Bobigny (Médecine Interne, Unité VIH: O. Bouchaud, S. Abgrall, I. Zamord, F. Bidegain, M. Azghay, C. Rouyer, M. Tatay, F. Mechai; Anatomo-pathologie: A. Martin; Virologie: Y. Baazia, V. Iwaka-Bande, A. Gerber); Hôpital Joseph Ducuing, Toulouse (Médecine Interne: A. Bicart-See, D. Garipuy, M.J. Ferro-Collados, F. Gaches; Virologie: F. Abravanel, F. Larroquette, J. Chiabrandon); APHP Bichat—Claude-Bernard, Paris (Maladies Infectieuses: A. Gervais, Y. Yazdanpanah; Anatomo-pathologie: D. Henin; Virologie: M. Bertine, M. Onambele; Pharmacologie: G. Peytavin); APHP Saint-Louis, Paris (Maladies infectieuses: C. Lascoux-Combe, T. Kandel, C. Pintado, J.M. Molina, C. Gatey, S. Gallien, W. Rozenbaum, M. Lafaurie, A.L. Munier, D. Ponscarme, M. Previllon, N. Colin De Verdière, M.G. Tateo; Virologie: P. Palmer, A. Gabassi, R. Amarsy, MC. Mazeron); APHP Saint-Antoine (Maladies Infectieuses et Tropicales: K. Lacombe, J. Krause, P. Ingiliz, P.M. Girard, B. Lefebvre, N. Valin, M.C. Mehoyas, S. Fournier, J.L. Meynard, Z. Ouazene, H. Guyon, P. Roussard, F. Lallemand, G. Raguin, D. Bollens, M. Tourneur, H. Bideault, L. Fonquernie, J. Pacanowski; Anatomo-pathologie: D. Wendum; Virologie: D. Fofana, T. Thithuthuon); APHP, Hôpitaux Paris Sud, Bicêtre/Paul Brousse (Médecine Interne: C. Goujard, Y. Quertainmont, E. Teicher, L. Escaut, O. Derradji; Virologie: C. Pallier, F. Veillet, L. Mouna); APHP Necker, Paris (Maladies Infectieuses et Tropicales: O. Lortholary, C. Duvivier, C. Rouzaud, M. Shoai Tehrani, S. Boucly, G. Obenga, J.P. Viard; Virologie: E. Gardiennet, A. Mélard); CHU Bordeaux Hôpital Pellegrin, Bordeaux (Maladies Infectieuses et Tropicales: D. Neau, A. Ochoa, E. Blanchard, C. Cazanave, M. Dupon, H. Dutronc, F. Dauchy, H. Wille; Anatomo-pathologie: P. Bioulac-Sage; Virologie: P. Trimoulet); CHU Bordeaux Hôpital Saint-André, Bordeaux (Médecine Interne et Maladies Infectieuses: P. Morlat, D. Lacoste, F. Bonnet, N. Bernard, M. Hessamfar, F. Paccalin, C. Martell, M. C. Pertusa, M. Vandenhende, P. Mercié, T. Pistone, M.C. Receveur, M. Méchain, P. Duffau, C. Rivoisy, I. Faure D. Malvy, J. Roger-Schmeltz, D. Dondia; Anatomo-pathologie: P. Bi

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