Decreased darunavir concentrations during once-daily co-administration with maraviroc and raltegravir: OPTIPRIM-ANRS 147 trial

Decreased darunavir concentrations during once-daily co-administration with maraviroc and... Abstract Background The OPTIPRIM-ANRS 147 trial compared intensive combination ART (darunavir/ritonavir, tenofovir disoproxil fumarate/emtricitabine, raltegravir and maraviroc) started early during primary HIV-1 infection with standard tritherapy with darunavir/ritonavir, tenofovir disoproxil fumarate and emtricitabine. From month 6 to 18, the percentage of viral load values <50 copies/mL was lower in the pentatherapy arm than in the tritherapy arm. Here we compared antiretroviral drug concentrations between the two arms. Methods Plasma samples were collected from 50 patients at various times after drug administration. A Bayesian approach based on published population pharmacokinetic models was used to estimate residual drug concentrations (Ctrough) and exposures (AUC) in each patient. A mixed linear regression model was then used to compare the AUC and Ctrough values of each drug used in both groups. Results Published models adequately described our data and could be used to predict Ctrough and AUC. No significant difference in tenofovir disoproxil fumarate, emtricitabine and ritonavir parameters was found between the two arms. However, darunavir Ctrough and AUC were significantly lower in the pentatherapy arm than in the tritherapy arm (P = 0.03 and P = 0.04, respectively). Conclusions Adding maraviroc and raltegravir to darunavir-based tritherapy decreased darunavir concentrations. Compliance issues, maraviroc–darunavir interaction and raltegravir–darunavir interaction were suspected and may affect the kinetics of viral decay during pentatherapy. A specific pharmacokinetic interaction study is needed to explore the interactions between darunavir and maraviroc and raltegravir. Introduction The OPTIPRIM-ANRS 147 trial was designed to establish whether intensive combination ART (darunavir, ritonavir, tenofovir disoproxil fumarate/emtricitabine, raltegravir and maraviroc) started early during primary HIV-1 infection had a greater effect on the HIV reservoir than the recommended triple-drug regimen (darunavir/ritonavir, tenofovir disoproxil fumarate and emtricitabine). This trial showed no additional benefit of pentatherapy on HIV-DNA levels.1 On the contrary, although 60% of patients in the pentatherapy arm and only 31% of patients in the tritherapy arm had a viral load <50 copies/mL at 3 months (P = 0.01), the situation was reversed at 6 months (71% versus 89%), 12 months (78% versus 96%) and 18 months (82% versus 96%) (P < 0.05). This paradoxical result may have been due to lower antiretroviral exposure in the pentatherapy arm, because of pharmacological interactions or adherence issues. The aim of the present study was thus to compare darunavir, ritonavir, emtricitabine and tenofovir concentrations and exposures between the tritherapy and pentatherapy arms of the OPTIPRIM-ANRS 147 trial. Methods Patients OPTIPRIM-ANRS 147 was a randomized, open-label, Phase 3 trial involving 90 patients in 33 French hospitals. Complete details of the study protocol have been published elsewhere.1 The study was approved by the Sud-Méditerranée-1 Ethics Committee and the French Health Products Safety Agency, and complied with the Helsinki Declaration. All participants gave written informed consent. Treatment Patients allocated to the standard regimen took four pills per day, consisting of 300 mg of tenofovir disoproxil fumarate plus 200 mg of emtricitabine (once daily), 800 mg of darunavir (two pills once daily), and 100 mg of ritonavir (once daily). Patients allocated to the intensive regimen took four additional pills: 400 mg of raltegravir (twice daily) and 150 mg of maraviroc (twice daily). Sampling Blood was sampled for pharmacokinetic analyses at 3, 6 and 24 months, at various intervals after drug administration. Age, body weight, serum creatinine and CD4+ cell counts were recorded. Analytical methods Plasma concentrations of darunavir, ritonavir, emtricitabine, tenofovir, raltegravir and maraviroc were determined at the Clinical Pharmacology Laboratory of Cochin Hospital, Paris, using validated LC-tandem MS methods. The lower limit of quantification was 10 ng/mL for emtricitabine, maraviroc, raltegravir, ritonavir and tenofovir, and 40 ng/mL for darunavir. Pharmacokinetic analyses Owing to sparse sampling and variable delays between sampling and drug intake, concentrations could not be compared directly between groups. A Bayesian approach, using models from the literature, was thus used to estimate the residual concentration and exposure for each drug in each patient. The choice was made after comparison of all population pharmacokinetic models available in the literature, in terms of the study population and the robustness of the model. To check that the chosen model was applicable to our data, OPTIPRIM-measured concentrations were superimposed on a visual predictive check (VPC) of the literature models. When there was no VPC in published models, we compared our data with published targets. From the selected applied model, individual predicted parameters were determined for each patient in the OPTIPRIM dataset for the available sampling times, given the dosage history and the body weight, age and serum creatinine covariate values. The trough concentration (Ctrough) and area under the curve from 0 to 12 or 24 h after last drug intake (AUC0–12 or AUC0–24) were derived for each patient. For each drug used in both arms, exposures and Ctrough were compared between tritherapy and pentatherapy by means of a mixed linear regression model (random effect/patient). The darunavir Ctrough was compared with a concentration of 550 ng/mL (10 times the IC50). This model was applied to all the data (3, 6 and 24 months) and then, assuming that adherence would worsen over time, we constructed the same model with 3 month data only. Results Population characteristics Only data with known times between sampling and drug intake were used for pharmacokinetic analysis. For this reason, data from 50 patients (92 concentrations) were used for the pharmacokinetic analysis, 22 in the tritherapy group and 28 in the pentatherapy group. At the time of the pharmacokinetic evaluation, the median age was 35.5 years (from 20 to 62 years) and the median body weight was 73.5 kg (from 42 to 119 kg) and comparable between groups. The median time after intake was 14.9 h (20 min to 29.7 h). Bayesian approach One population pharmacokinetic model was selected for each molecule: Moltó et al.2 for darunavir, Baheti et al.3 for tenofovir, Valade et al.4 for emtricitabine, Chan et al.5 for maraviroc and Arab-Alameddine et al.6 for raltegravir. The concentrations measured in the OPTIPRIM trial were well described by VPC models in the literature (Figure 1), indicating these models were applicable to our data. Thus, a maximum a posteriori probability (Bayesian estimation) could be derived from these models to predict individual pharmacokinetic parameters for the six drugs. Exposures and Ctrough of darunavir, ritonavir, emtricitabine, tenofovir, raltegravir and maraviroc are shown in Table 1. No significant differences between the two arms were found with respect to the AUC and Ctrough of tenofovir, emtricitabine and ritonavir. The only significant differences concerned the AUC and Ctrough of darunavir (P = 0.03 and P = 0.04, respectively). Only one patient in the tritherapy group (4.5%) and two patients in the pentatherapy group (7.1%) had a Ctrough <550 ng/mL. To identify low adherence issues, exposures and Ctrough were compared between 3, 6 and 24 months, but no significant difference was found. Table 1. Bayesian estimates (AUC and Ctrough) of darunavir, ritonavir, emtricitabine, tenofovir, raltegravir and maraviroc   Total population  Tritherapy group  Pentatherapy group  P  AUC (ng·mL−1·h), median (min–max)   darunavir  63 651 (28 264–157 030)  74 481 (37 882–157 030)  57 635 (28 264–139 400)  0.03*   ritonavir  6099 (417–46 815)  5873 (417–46 815)  6376 (726–43 599)  0.72   emtricitabine  17 000 (7599–73 140)  16 006 (7599–73 140)  17 880 (8669–53 604)  0.55   tenofovir  4008 (1435–8739)  4026 (1435–8739)  3923 (1976–7060)  0.81   raltegravir  4123 (1216–58 865)  –  4123 (1216–58 865)  –   maraviroc  1736 (768–7532)  –  1736 (768–7532)  –  Ctrough (ng/mL), median (min–max)           darunavir  1599 (274–5182)  1989 (274–5182)  1388 (466–4496)  0.04*   ritonavir  39 (2–1220)  37.8 (2–1220)  42 (3–1093)  0.83   emtricitabine  154 (26–1995)  135 (26–1995)  171 (35–1262)  0.76   tenofovir  50 (5–223)  50 (7–223)  50 (5–147)  0.82   raltegravir  93 (11–4439)  –  93 (11–4439)  –   maraviroc  91 (20–472)  –  91 (20–472)  –    Total population  Tritherapy group  Pentatherapy group  P  AUC (ng·mL−1·h), median (min–max)   darunavir  63 651 (28 264–157 030)  74 481 (37 882–157 030)  57 635 (28 264–139 400)  0.03*   ritonavir  6099 (417–46 815)  5873 (417–46 815)  6376 (726–43 599)  0.72   emtricitabine  17 000 (7599–73 140)  16 006 (7599–73 140)  17 880 (8669–53 604)  0.55   tenofovir  4008 (1435–8739)  4026 (1435–8739)  3923 (1976–7060)  0.81   raltegravir  4123 (1216–58 865)  –  4123 (1216–58 865)  –   maraviroc  1736 (768–7532)  –  1736 (768–7532)  –  Ctrough (ng/mL), median (min–max)           darunavir  1599 (274–5182)  1989 (274–5182)  1388 (466–4496)  0.04*   ritonavir  39 (2–1220)  37.8 (2–1220)  42 (3–1093)  0.83   emtricitabine  154 (26–1995)  135 (26–1995)  171 (35–1262)  0.76   tenofovir  50 (5–223)  50 (7–223)  50 (5–147)  0.82   raltegravir  93 (11–4439)  –  93 (11–4439)  –   maraviroc  91 (20–472)  –  91 (20–472)  –  Asterisks indicate statistical significance (P < 0.05). Figure 1. View largeDownload slide Visual inspection check (VPC) of darunavir, tenofovir, emtricitabine and raltegravir (as examples). Crosses, pentatherapy arm; circles, tritherapy arm. Figure 1. View largeDownload slide Visual inspection check (VPC) of darunavir, tenofovir, emtricitabine and raltegravir (as examples). Crosses, pentatherapy arm; circles, tritherapy arm. Discussion In the OPTIPRIM trial, virological efficacy was, surprisingly, lower in the pentatherapy arm than in the tritherapy arm at 6, 12 and 18 months (P < 0.05). One possible additional explanation was lower antiretroviral concentrations in the pentatherapy group, due to poorer adherence or to pharmacological interactions. Regarding treatment adherence issues, the number of pills in the pentatherapy arm was greater (8 pills twice daily) than in the tritherapy arms (4 pills once daily). Concentrations measured in both groups corresponded to those reported in the literature, with no very low concentrations, and drug levels were not significant between 3, 6 and 24 months, arguing against an adherence problem. The proportion of patients in the PP population who stated that they had not missed a dose on the previous weekend was at least 90% at all visits except in the intensive combination ART group at month 18 (P = 0.02) and month 24 (P = 0.18) (data not shown).1 However, concentrations were only determined in half the patients, and the measured concentrations only reflect adherence at the time of sampling. There were no significant differences for AUC or Ctrough of tenofovir, emtricitabine or ritonavir between the tritherapy and pentatherapy arms. However, the AUC and Ctrough of darunavir differed significantly (P = 0.03 and P = 0.04, respectively). Few patients had a Ctrough <550 ng/mL. This target concentration, which is used by default, corresponds to 10 times the IC50 and is not a real pharmacokinetic–pharmacodynamic relationship. This substudy was too small to highlight a possible pharmacodynamic relationship between viral load and AUC or Ctrough. Compared with the tritherapy arm, the pentatherapy group received in addition raltegravir and maraviroc. Both drugs may be responsible for an interaction with darunavir. Some findings supported the existence of raltegravir–darunavir interactions. Cattaneo et al.7 showed that co-administration of raltegravir was associated with a 40% reduction in darunavir Cmax and estimated AUC, but had no effect on Ctrough. Taiwo et al.8 provided clinical evidence that combined raltegravir/darunavir-based antiretroviral regimens may be less effective than other regimens. As raltegravir is two-thirds metabolized by UDP-glucuronosyltransferase, whereas darunavir is metabolized by cytochrome P450, this interaction was believed to be driven by induction of a drug transporter. Goldwirt et al.9 found a small but significant decrease in darunavir concentrations in 10 patients following a switch from enfuvirtide to raltegravir. Fabbiani et al.10 also reported a potential interaction between darunavir and raltegravir. Finally, in formal drug–drug interaction studies in healthy volunteers, raltegravir was also shown to decrease the pharmacokinetics of atazanavir (decreasing AUC and Ctrough by 17% and 29%)11 or amprenavir (decreasing AUC and Ctrough by 19% and 33%).12 Other arguments support the existence of maraviroc–darunavir interactions. Firstly, both of them are mostly metabolized by CYP450 enzymes in the liver, and particularly by CYP3A4. The interaction is known to lead to a decrease in maraviroc dosage by 4-fold when coadministered with boosted PI. Kakuda et al.13 studied interactions between darunavir/ritonavir, maraviroc and etravirine in healthy volunteers and showed that darunavir exposure and Ctrough decreased by 15% and 25%, respectively, in the presence of maraviroc co-administration. In the OPTIPRIM study, the effect of maraviroc on darunavir Ctrough could have been more pronounced because of a once-daily rather than twice-daily administration. In other studies without pharmacokinetic data, the virological efficacy of maraviroc plus darunavir/ritonavir was inferior to darunavir/ritonavir plus tenofovir/emtricitabine.14 Finally, the slight difference in the darunavir AUCs in the pentatherapy group could contribute to explaining the different virological results in the OPTIPRIM study as due to less efficient diffusion in the HIV reservoir caused by a lower plasma concentration, limiting tissue diffusion and hence reducing the impact on residual viral replication in the pentatherapy arm.15,16  A different hypothesis could explain this difference: lower compliance in the pentatherapy group; interaction between darunavir and raltegravir; or interaction between darunavir and maraviroc. A combined regimen with these drugs could be an option in particular situations at the chronic stage. Therefore it would be relevant to evaluate, in a specific pharmacokinetic interaction study, the interactions between darunavir, maraviroc and raltegravir. Acknowledgements Members of the OPTIPRIM ANRS-147 Study Group CHRU Saint-Jacques (Besançon), Service de Médecine Interne: B. Hoen, C. Bourdeaux. Hôpital de Bicêtre (Paris), Service de Médecine Interne et Maladies Infectieuses: J. F. Delfraissy, C. Goujard, I. Amri, E. Fourn, Y. Quertainmont, M. Môle. Hôpital Lariboisiére (Paris), Service de Médecine Interne: A. Rami, A. Durel, M. Diemer, M. Parrinello. CHR Aix en Provence, Service d'Hématologie Oncologie: T. Allégre. Hôpital Font-Pré (Toulon), Service d'Infectiologie: A. Lafeuillade, G. Hittinger, V. Lambry, M. Carrerre, G. Philip. Institut Pasteur, Centre Médical: C. Duvivier, P. H. Consigny, C. Charlier, M. Shoai, F. Touam. Hôpital Tenon (Paris), Service des Maladies Infectieuses: G. Pialoux, L. Slama, T. L'Yavanc, P. Mathurin, A. Adda, V. Berrebi. Hôpital Cochin (Paris), Département de Médecine Interne: D. Salmon, E. Chakvetadze, T. Tassadit, E. Ousseima, M. P. Pietri. Hôpital Henri Mondor (Paris), Service d'Immunologie Clinique: Y. Levy, A. S. Lascaux, J. D. Lelievre, M. Giovanna, S. Dominguez, C. Dumont. Hôpital Pitié Salpétriére (Paris), Service des Maladies Infectieuses et Tropicales: C. Katlama, M. A. Valentin, S. Seang, L. Schneider, N. Kiorza, A. Chermak, S. Ben Abdallah. Hôpital Pitié Salpétriére (Paris), Service de Médecine Interne: A. Simon, F. Pichon, M. Pauchard. Hôpital Saint-Louis (Paris), Service des Maladies Infectieuses: J. M. Molina, C. Lascoux, D. Ponscarme, N. Colin De Verdiere, A. Scemla, N. De Castro, A. Rachline, V. Garrait, W. Rozenbaum, S. Ferret, S. Balkan, F. Clavel, M. Tourdjman, M. Lafaurie, A. Aslan, J. Goguel, S. M. Thierry, V. De Lastours, S. Gallien, J. Pavie, J. Delgado, C. Mededji, R. Veron. Hôpital P. Zobda Quitman (Fort de France), Service des Maladies Infectieuses et Tropicales: S. Abel, S. Pierre-Franéois, C. Baringhton. CHU Angers, Service des Maladies Infectieuses et Tropicales: J. M. Chennebault, Y. M. Vandamme, P. Fialaire, S. Rehaiem, V. Rabier, P. Abgueguen. Hépital Saint André (Bordeaux), Service de Médecine Interne et Maladies Infectieuses: P. Morlat, M. A. Vandenhende, N. Bernard, D. Lacoste, C. Michaux, F. Paccalin, M. C. Receveur, S. Caldato, J. Delaune. Hôpital Pellegrin (Bordeaux), Service des Maladies Infectieuses et Tropicales: J. M. Ragnaud, D. Neau, L. Lacaze-Buzy. Hôpital Edouard Herriot (Lyon), Service d'Immunologie Clinique: J. M. Livrozet, F. Jeanblanc, D. Makhloufi, F. Brunel Dalmas, J. J. Jourdain, P. Chiarello. Hôpital Bichat Claude Bernard (Paris), Service des Maladies Infectieuses et Tropicales: P. Yeni, B. Phung, C. Rioux, C. Godard, F. Louni, N. El Alami Talbi, G. Catalano, F. Guiroy. Hôpital Gui de Chauliac (Montpellier), Service des Maladies Infectieuses et Tropicales: J. Reynes, J. M. Jacquet, V. Fauchere, C. Merle, V. Lemoine, M. Loriette, D. Morquin, A. Makinson, N. Atoui, C. Tramoni. Hôtel Dieu (Nantes), Service d'Infectiologie: F. Raffi, C. Allavena, B. Bonnet, S. Bouchez, N. Feuillebois, C. Brunet-Franéois, V. Reliquet, O. Mounoury, P. Morineau-Le-Houssine, E. Billaud, D. Brosseau, H. Hüe. Hôpital de l'ARCHET 1 (Nice), Service des Maladies Infectieuses et Tropicales: P. Dellamonica, M. Vassallo, A. Leplatois, J. Durant, A. Naqvi, A. Joulié. Hôpital Pontchaillou (Rennes), Service des Maladies Infectieuses: F. Souala, C. Michelet, C. Arvieux, P. Tattevin, H. Leroy, M. Revest, F. Fily, J. M. Chapplain, C. M. Ratajczak. Hôpital Bretonneau (Tours), Service de Médecine Interne et Maladies Infectieuses: G. Gras, L. Bernard, J. F. Dailloux, V. Laplantine. Hôpital Purpan (Toulouse), Service des Maladies Infectieuses et Tropicales: L. Cuzin, B. Marchou, S. Larrigue, M. Chauveau, F. Balsarin, M. Obadia. Hôpital G. Dron (Tourcoing), Service Universitaire régional des Maladies Infectieuses et du Voyageur: A. Chéret, S. Bonne, T. Huleux, F. Ajana, I. Alcaraz, V. Baclet, H. Melliez, N. Viget, X. De La Tribonniere, E. Aissi, J. Poissy. Hôpital de la Conception (Marseille), Service des Maladies Infectieuses: I. Ravaux, A. Vallon, M. Varan. Hôpital de Brabois (Nancy), Service des Maladies Infectieuses et Tropicales: T. May, L. Letranchant, C. Burty, A. Briaud, S. Wassoumbou, M. Stenzel, M. P. Bouillon. CHU Charles Nicolle (Rouen), Hôpital de Jour Maladies Infectieuses et Tropicales: Y. Debab, F. Caron, I. Gueit, C. Chapuzet, F. Borsa Lebas, M. Etienne. Hôpital de la Croix Rousse (Lyon), Service des Maladies Infectieuses: P. Miailhes, T. Perpoint, A. Senechal, I. Schlienger, L. Cotte, C. Augustin Normand, A. Boibieux, T. Ferry, N. Corsini, E. Braun, J. Lippran, F. Biron, C. Chidiac, S. Pailhes, J. Lipman, E. Braun, J. Koffi, V. Thoirain, C. Brochier. Hôpital Mignot (Le Chesnay), Service des Maladies Infectieuses et Tropicales: A. Greder Belan, A. Therby, S. Monnier, M. Ruquet. Centre Hospitalier Intercommunal (Créteil), Service de Médecine Interne: V. Garrait, L. Richier. Hôpital La Grave (Toulouse), Service de Dermatologie et Médecines Sociale: F. Prevoteau Du Clary. Funding The study was funded by ANRS. ViiV Healthcare, Gilead, Janssen and Merck Sharp & Dohme acted as co-funders through an ANRS contract. The funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. All the authors accept responsibility for the veracity and completeness of the data reported. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication. Transparency declarations V. A.-F. reports grants from Agence Nationale de Recherche sur le Sida (ANRS) and conference fees from Gilead. C. R. reports grants from ANRS and has received conference fees from ViiV and AbbVie. A. C. reports grants from Merck and personal fees from Gilead, ViiV and Janssen. All other authors: none to declare. References 1 Chéret A, Nembot G, Mélard A et al.   Intensive five-drug antiretroviral therapy regimen versus standard triple-drug therapy during primary HIV-1 infection (OPTIPRIM-ANRS 147): a randomised, open-label, phase 3 trial. Lancet Infect Dis  2015; 15: 387– 96. Google Scholar CrossRef Search ADS PubMed  2 Moltó J, Xinarianos G, Miranda C et al.   Simultaneous pharmacogenetics-based population pharmacokinetic analysis of darunavir and ritonavir in HIV-infected patients. Clin Pharmacokinet  2013; 52: 543– 53. Google Scholar CrossRef Search ADS PubMed  3 Baheti G, Kiser JJ, Havens PL et al.   Plasma and intracellular population pharmacokinetic analysis of tenofovir in HIV-1-infected patients. Antimicrob Agents Chemother  2011; 55: 5294– 9. 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Pharmacol Res  2012; 65: 198– 203. Google Scholar CrossRef Search ADS PubMed  8 Taiwo B, Zheng L, Gallien S et al.   Efficacy of a nucleoside-sparing regimen of darunavir/ritonavir plus raltegravir in treatment-naive HIV-1-infected patients (ACTG A5262). AIDS  2011; 25: 2113– 22. Google Scholar CrossRef Search ADS PubMed  9 Goldwirt L, Braun J, de Castro N et al.   Switch from enfuvirtide to raltegravir lowers plasma concentrations of darunavir and tipranavir: a pharmacokinetic substudy of the EASIER-ANRS 138 trial. Antimicrob Agents Chemother  2011; 55: 3613– 5. Google Scholar CrossRef Search ADS PubMed  10 Fabbiani M, Di Giambenedetto S, Ragazzoni E et al.   Darunavir/ritonavir and raltegravir coadministered in routine clinical practice: potential role for an unexpected drug interaction. Pharmacol Res  2011; 63: 249– 53. Google Scholar CrossRef Search ADS PubMed  11 Zhu L, Butterton J, Persson A et al.   Pharmacokinetics and safety of twice-daily atazanavir 300 mg and raltegravir 400 mg in healthy individuals. Antivir Ther  2010; 15: 1107– 14. Google Scholar CrossRef Search ADS PubMed  12 Luber D, Slowinski A, Acosta DP et al.   Steady-state pharmacokinetics (PK) of fosamprenavir (FPV) and raltegravir (RAL) alone and combined with unboosted and ritonavir-boosted FPV in fasted healthy volunteers. Abstract. 2009 ACCP Annual Meeting, Anaheim, California, USA. 13 Kakuda TN, Abel S, Davis J et al.   Pharmacokinetic interactions of maraviroc with darunavir-ritonavir, etravirine, and etravirine-darunavir-ritonavir in healthy volunteers: results of two drug interaction trials. Antimicrob Agents Chemother  2011; 55: 2290– 6. Google Scholar CrossRef Search ADS PubMed  14 Stellbrink H-J, Le Fevre E, Carr A et al.   Once-daily maraviroc versus tenofovir/emtricitabine each combined with darunavir/ritonavir for initial HIV-1 treatment. AIDS  2016; 30: 1229– 38. Google Scholar CrossRef Search ADS PubMed  15 Massanella M, Fromentin R, Chomont N. Residual inflammation and viral reservoirs: alliance against an HIV cure. Curr Opin HIV AIDS  2016; 11: 234– 41. Google Scholar CrossRef Search ADS PubMed  16 Fletcher CV, Staskus K, Wietgrefe SW et al.   Persistent HIV-1 replication is associated with lower antiretroviral drug concentrations in lymphatic tissues. Proc Natl Acad Sci USA  2014; 111: 2307– 12. Google Scholar CrossRef Search ADS PubMed  © The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. 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Abstract

Abstract Background The OPTIPRIM-ANRS 147 trial compared intensive combination ART (darunavir/ritonavir, tenofovir disoproxil fumarate/emtricitabine, raltegravir and maraviroc) started early during primary HIV-1 infection with standard tritherapy with darunavir/ritonavir, tenofovir disoproxil fumarate and emtricitabine. From month 6 to 18, the percentage of viral load values <50 copies/mL was lower in the pentatherapy arm than in the tritherapy arm. Here we compared antiretroviral drug concentrations between the two arms. Methods Plasma samples were collected from 50 patients at various times after drug administration. A Bayesian approach based on published population pharmacokinetic models was used to estimate residual drug concentrations (Ctrough) and exposures (AUC) in each patient. A mixed linear regression model was then used to compare the AUC and Ctrough values of each drug used in both groups. Results Published models adequately described our data and could be used to predict Ctrough and AUC. No significant difference in tenofovir disoproxil fumarate, emtricitabine and ritonavir parameters was found between the two arms. However, darunavir Ctrough and AUC were significantly lower in the pentatherapy arm than in the tritherapy arm (P = 0.03 and P = 0.04, respectively). Conclusions Adding maraviroc and raltegravir to darunavir-based tritherapy decreased darunavir concentrations. Compliance issues, maraviroc–darunavir interaction and raltegravir–darunavir interaction were suspected and may affect the kinetics of viral decay during pentatherapy. A specific pharmacokinetic interaction study is needed to explore the interactions between darunavir and maraviroc and raltegravir. Introduction The OPTIPRIM-ANRS 147 trial was designed to establish whether intensive combination ART (darunavir, ritonavir, tenofovir disoproxil fumarate/emtricitabine, raltegravir and maraviroc) started early during primary HIV-1 infection had a greater effect on the HIV reservoir than the recommended triple-drug regimen (darunavir/ritonavir, tenofovir disoproxil fumarate and emtricitabine). This trial showed no additional benefit of pentatherapy on HIV-DNA levels.1 On the contrary, although 60% of patients in the pentatherapy arm and only 31% of patients in the tritherapy arm had a viral load <50 copies/mL at 3 months (P = 0.01), the situation was reversed at 6 months (71% versus 89%), 12 months (78% versus 96%) and 18 months (82% versus 96%) (P < 0.05). This paradoxical result may have been due to lower antiretroviral exposure in the pentatherapy arm, because of pharmacological interactions or adherence issues. The aim of the present study was thus to compare darunavir, ritonavir, emtricitabine and tenofovir concentrations and exposures between the tritherapy and pentatherapy arms of the OPTIPRIM-ANRS 147 trial. Methods Patients OPTIPRIM-ANRS 147 was a randomized, open-label, Phase 3 trial involving 90 patients in 33 French hospitals. Complete details of the study protocol have been published elsewhere.1 The study was approved by the Sud-Méditerranée-1 Ethics Committee and the French Health Products Safety Agency, and complied with the Helsinki Declaration. All participants gave written informed consent. Treatment Patients allocated to the standard regimen took four pills per day, consisting of 300 mg of tenofovir disoproxil fumarate plus 200 mg of emtricitabine (once daily), 800 mg of darunavir (two pills once daily), and 100 mg of ritonavir (once daily). Patients allocated to the intensive regimen took four additional pills: 400 mg of raltegravir (twice daily) and 150 mg of maraviroc (twice daily). Sampling Blood was sampled for pharmacokinetic analyses at 3, 6 and 24 months, at various intervals after drug administration. Age, body weight, serum creatinine and CD4+ cell counts were recorded. Analytical methods Plasma concentrations of darunavir, ritonavir, emtricitabine, tenofovir, raltegravir and maraviroc were determined at the Clinical Pharmacology Laboratory of Cochin Hospital, Paris, using validated LC-tandem MS methods. The lower limit of quantification was 10 ng/mL for emtricitabine, maraviroc, raltegravir, ritonavir and tenofovir, and 40 ng/mL for darunavir. Pharmacokinetic analyses Owing to sparse sampling and variable delays between sampling and drug intake, concentrations could not be compared directly between groups. A Bayesian approach, using models from the literature, was thus used to estimate the residual concentration and exposure for each drug in each patient. The choice was made after comparison of all population pharmacokinetic models available in the literature, in terms of the study population and the robustness of the model. To check that the chosen model was applicable to our data, OPTIPRIM-measured concentrations were superimposed on a visual predictive check (VPC) of the literature models. When there was no VPC in published models, we compared our data with published targets. From the selected applied model, individual predicted parameters were determined for each patient in the OPTIPRIM dataset for the available sampling times, given the dosage history and the body weight, age and serum creatinine covariate values. The trough concentration (Ctrough) and area under the curve from 0 to 12 or 24 h after last drug intake (AUC0–12 or AUC0–24) were derived for each patient. For each drug used in both arms, exposures and Ctrough were compared between tritherapy and pentatherapy by means of a mixed linear regression model (random effect/patient). The darunavir Ctrough was compared with a concentration of 550 ng/mL (10 times the IC50). This model was applied to all the data (3, 6 and 24 months) and then, assuming that adherence would worsen over time, we constructed the same model with 3 month data only. Results Population characteristics Only data with known times between sampling and drug intake were used for pharmacokinetic analysis. For this reason, data from 50 patients (92 concentrations) were used for the pharmacokinetic analysis, 22 in the tritherapy group and 28 in the pentatherapy group. At the time of the pharmacokinetic evaluation, the median age was 35.5 years (from 20 to 62 years) and the median body weight was 73.5 kg (from 42 to 119 kg) and comparable between groups. The median time after intake was 14.9 h (20 min to 29.7 h). Bayesian approach One population pharmacokinetic model was selected for each molecule: Moltó et al.2 for darunavir, Baheti et al.3 for tenofovir, Valade et al.4 for emtricitabine, Chan et al.5 for maraviroc and Arab-Alameddine et al.6 for raltegravir. The concentrations measured in the OPTIPRIM trial were well described by VPC models in the literature (Figure 1), indicating these models were applicable to our data. Thus, a maximum a posteriori probability (Bayesian estimation) could be derived from these models to predict individual pharmacokinetic parameters for the six drugs. Exposures and Ctrough of darunavir, ritonavir, emtricitabine, tenofovir, raltegravir and maraviroc are shown in Table 1. No significant differences between the two arms were found with respect to the AUC and Ctrough of tenofovir, emtricitabine and ritonavir. The only significant differences concerned the AUC and Ctrough of darunavir (P = 0.03 and P = 0.04, respectively). Only one patient in the tritherapy group (4.5%) and two patients in the pentatherapy group (7.1%) had a Ctrough <550 ng/mL. To identify low adherence issues, exposures and Ctrough were compared between 3, 6 and 24 months, but no significant difference was found. Table 1. Bayesian estimates (AUC and Ctrough) of darunavir, ritonavir, emtricitabine, tenofovir, raltegravir and maraviroc   Total population  Tritherapy group  Pentatherapy group  P  AUC (ng·mL−1·h), median (min–max)   darunavir  63 651 (28 264–157 030)  74 481 (37 882–157 030)  57 635 (28 264–139 400)  0.03*   ritonavir  6099 (417–46 815)  5873 (417–46 815)  6376 (726–43 599)  0.72   emtricitabine  17 000 (7599–73 140)  16 006 (7599–73 140)  17 880 (8669–53 604)  0.55   tenofovir  4008 (1435–8739)  4026 (1435–8739)  3923 (1976–7060)  0.81   raltegravir  4123 (1216–58 865)  –  4123 (1216–58 865)  –   maraviroc  1736 (768–7532)  –  1736 (768–7532)  –  Ctrough (ng/mL), median (min–max)           darunavir  1599 (274–5182)  1989 (274–5182)  1388 (466–4496)  0.04*   ritonavir  39 (2–1220)  37.8 (2–1220)  42 (3–1093)  0.83   emtricitabine  154 (26–1995)  135 (26–1995)  171 (35–1262)  0.76   tenofovir  50 (5–223)  50 (7–223)  50 (5–147)  0.82   raltegravir  93 (11–4439)  –  93 (11–4439)  –   maraviroc  91 (20–472)  –  91 (20–472)  –    Total population  Tritherapy group  Pentatherapy group  P  AUC (ng·mL−1·h), median (min–max)   darunavir  63 651 (28 264–157 030)  74 481 (37 882–157 030)  57 635 (28 264–139 400)  0.03*   ritonavir  6099 (417–46 815)  5873 (417–46 815)  6376 (726–43 599)  0.72   emtricitabine  17 000 (7599–73 140)  16 006 (7599–73 140)  17 880 (8669–53 604)  0.55   tenofovir  4008 (1435–8739)  4026 (1435–8739)  3923 (1976–7060)  0.81   raltegravir  4123 (1216–58 865)  –  4123 (1216–58 865)  –   maraviroc  1736 (768–7532)  –  1736 (768–7532)  –  Ctrough (ng/mL), median (min–max)           darunavir  1599 (274–5182)  1989 (274–5182)  1388 (466–4496)  0.04*   ritonavir  39 (2–1220)  37.8 (2–1220)  42 (3–1093)  0.83   emtricitabine  154 (26–1995)  135 (26–1995)  171 (35–1262)  0.76   tenofovir  50 (5–223)  50 (7–223)  50 (5–147)  0.82   raltegravir  93 (11–4439)  –  93 (11–4439)  –   maraviroc  91 (20–472)  –  91 (20–472)  –  Asterisks indicate statistical significance (P < 0.05). Figure 1. View largeDownload slide Visual inspection check (VPC) of darunavir, tenofovir, emtricitabine and raltegravir (as examples). Crosses, pentatherapy arm; circles, tritherapy arm. Figure 1. View largeDownload slide Visual inspection check (VPC) of darunavir, tenofovir, emtricitabine and raltegravir (as examples). Crosses, pentatherapy arm; circles, tritherapy arm. Discussion In the OPTIPRIM trial, virological efficacy was, surprisingly, lower in the pentatherapy arm than in the tritherapy arm at 6, 12 and 18 months (P < 0.05). One possible additional explanation was lower antiretroviral concentrations in the pentatherapy group, due to poorer adherence or to pharmacological interactions. Regarding treatment adherence issues, the number of pills in the pentatherapy arm was greater (8 pills twice daily) than in the tritherapy arms (4 pills once daily). Concentrations measured in both groups corresponded to those reported in the literature, with no very low concentrations, and drug levels were not significant between 3, 6 and 24 months, arguing against an adherence problem. The proportion of patients in the PP population who stated that they had not missed a dose on the previous weekend was at least 90% at all visits except in the intensive combination ART group at month 18 (P = 0.02) and month 24 (P = 0.18) (data not shown).1 However, concentrations were only determined in half the patients, and the measured concentrations only reflect adherence at the time of sampling. There were no significant differences for AUC or Ctrough of tenofovir, emtricitabine or ritonavir between the tritherapy and pentatherapy arms. However, the AUC and Ctrough of darunavir differed significantly (P = 0.03 and P = 0.04, respectively). Few patients had a Ctrough <550 ng/mL. This target concentration, which is used by default, corresponds to 10 times the IC50 and is not a real pharmacokinetic–pharmacodynamic relationship. This substudy was too small to highlight a possible pharmacodynamic relationship between viral load and AUC or Ctrough. Compared with the tritherapy arm, the pentatherapy group received in addition raltegravir and maraviroc. Both drugs may be responsible for an interaction with darunavir. Some findings supported the existence of raltegravir–darunavir interactions. Cattaneo et al.7 showed that co-administration of raltegravir was associated with a 40% reduction in darunavir Cmax and estimated AUC, but had no effect on Ctrough. Taiwo et al.8 provided clinical evidence that combined raltegravir/darunavir-based antiretroviral regimens may be less effective than other regimens. As raltegravir is two-thirds metabolized by UDP-glucuronosyltransferase, whereas darunavir is metabolized by cytochrome P450, this interaction was believed to be driven by induction of a drug transporter. Goldwirt et al.9 found a small but significant decrease in darunavir concentrations in 10 patients following a switch from enfuvirtide to raltegravir. Fabbiani et al.10 also reported a potential interaction between darunavir and raltegravir. Finally, in formal drug–drug interaction studies in healthy volunteers, raltegravir was also shown to decrease the pharmacokinetics of atazanavir (decreasing AUC and Ctrough by 17% and 29%)11 or amprenavir (decreasing AUC and Ctrough by 19% and 33%).12 Other arguments support the existence of maraviroc–darunavir interactions. Firstly, both of them are mostly metabolized by CYP450 enzymes in the liver, and particularly by CYP3A4. The interaction is known to lead to a decrease in maraviroc dosage by 4-fold when coadministered with boosted PI. Kakuda et al.13 studied interactions between darunavir/ritonavir, maraviroc and etravirine in healthy volunteers and showed that darunavir exposure and Ctrough decreased by 15% and 25%, respectively, in the presence of maraviroc co-administration. In the OPTIPRIM study, the effect of maraviroc on darunavir Ctrough could have been more pronounced because of a once-daily rather than twice-daily administration. In other studies without pharmacokinetic data, the virological efficacy of maraviroc plus darunavir/ritonavir was inferior to darunavir/ritonavir plus tenofovir/emtricitabine.14 Finally, the slight difference in the darunavir AUCs in the pentatherapy group could contribute to explaining the different virological results in the OPTIPRIM study as due to less efficient diffusion in the HIV reservoir caused by a lower plasma concentration, limiting tissue diffusion and hence reducing the impact on residual viral replication in the pentatherapy arm.15,16  A different hypothesis could explain this difference: lower compliance in the pentatherapy group; interaction between darunavir and raltegravir; or interaction between darunavir and maraviroc. A combined regimen with these drugs could be an option in particular situations at the chronic stage. Therefore it would be relevant to evaluate, in a specific pharmacokinetic interaction study, the interactions between darunavir, maraviroc and raltegravir. Acknowledgements Members of the OPTIPRIM ANRS-147 Study Group CHRU Saint-Jacques (Besançon), Service de Médecine Interne: B. Hoen, C. Bourdeaux. Hôpital de Bicêtre (Paris), Service de Médecine Interne et Maladies Infectieuses: J. F. Delfraissy, C. Goujard, I. Amri, E. Fourn, Y. Quertainmont, M. Môle. Hôpital Lariboisiére (Paris), Service de Médecine Interne: A. Rami, A. Durel, M. Diemer, M. Parrinello. CHR Aix en Provence, Service d'Hématologie Oncologie: T. Allégre. Hôpital Font-Pré (Toulon), Service d'Infectiologie: A. Lafeuillade, G. Hittinger, V. Lambry, M. Carrerre, G. Philip. Institut Pasteur, Centre Médical: C. Duvivier, P. H. Consigny, C. Charlier, M. Shoai, F. Touam. Hôpital Tenon (Paris), Service des Maladies Infectieuses: G. Pialoux, L. Slama, T. L'Yavanc, P. Mathurin, A. Adda, V. Berrebi. Hôpital Cochin (Paris), Département de Médecine Interne: D. Salmon, E. Chakvetadze, T. Tassadit, E. Ousseima, M. P. Pietri. Hôpital Henri Mondor (Paris), Service d'Immunologie Clinique: Y. Levy, A. S. Lascaux, J. D. Lelievre, M. Giovanna, S. Dominguez, C. Dumont. Hôpital Pitié Salpétriére (Paris), Service des Maladies Infectieuses et Tropicales: C. Katlama, M. A. Valentin, S. Seang, L. Schneider, N. Kiorza, A. Chermak, S. Ben Abdallah. Hôpital Pitié Salpétriére (Paris), Service de Médecine Interne: A. Simon, F. Pichon, M. Pauchard. Hôpital Saint-Louis (Paris), Service des Maladies Infectieuses: J. M. Molina, C. Lascoux, D. Ponscarme, N. Colin De Verdiere, A. Scemla, N. De Castro, A. Rachline, V. Garrait, W. Rozenbaum, S. Ferret, S. Balkan, F. Clavel, M. Tourdjman, M. Lafaurie, A. Aslan, J. Goguel, S. M. Thierry, V. De Lastours, S. Gallien, J. Pavie, J. Delgado, C. Mededji, R. Veron. Hôpital P. Zobda Quitman (Fort de France), Service des Maladies Infectieuses et Tropicales: S. Abel, S. Pierre-Franéois, C. Baringhton. CHU Angers, Service des Maladies Infectieuses et Tropicales: J. M. Chennebault, Y. M. Vandamme, P. Fialaire, S. Rehaiem, V. Rabier, P. Abgueguen. Hépital Saint André (Bordeaux), Service de Médecine Interne et Maladies Infectieuses: P. Morlat, M. A. Vandenhende, N. Bernard, D. Lacoste, C. Michaux, F. Paccalin, M. C. Receveur, S. Caldato, J. Delaune. Hôpital Pellegrin (Bordeaux), Service des Maladies Infectieuses et Tropicales: J. M. Ragnaud, D. Neau, L. Lacaze-Buzy. Hôpital Edouard Herriot (Lyon), Service d'Immunologie Clinique: J. M. Livrozet, F. Jeanblanc, D. Makhloufi, F. Brunel Dalmas, J. J. Jourdain, P. Chiarello. Hôpital Bichat Claude Bernard (Paris), Service des Maladies Infectieuses et Tropicales: P. Yeni, B. Phung, C. Rioux, C. Godard, F. Louni, N. El Alami Talbi, G. Catalano, F. Guiroy. Hôpital Gui de Chauliac (Montpellier), Service des Maladies Infectieuses et Tropicales: J. Reynes, J. M. Jacquet, V. Fauchere, C. Merle, V. Lemoine, M. Loriette, D. Morquin, A. Makinson, N. Atoui, C. Tramoni. Hôtel Dieu (Nantes), Service d'Infectiologie: F. Raffi, C. Allavena, B. Bonnet, S. Bouchez, N. Feuillebois, C. Brunet-Franéois, V. Reliquet, O. Mounoury, P. Morineau-Le-Houssine, E. Billaud, D. Brosseau, H. Hüe. Hôpital de l'ARCHET 1 (Nice), Service des Maladies Infectieuses et Tropicales: P. Dellamonica, M. Vassallo, A. Leplatois, J. Durant, A. Naqvi, A. Joulié. Hôpital Pontchaillou (Rennes), Service des Maladies Infectieuses: F. Souala, C. Michelet, C. Arvieux, P. Tattevin, H. Leroy, M. Revest, F. Fily, J. M. Chapplain, C. M. Ratajczak. Hôpital Bretonneau (Tours), Service de Médecine Interne et Maladies Infectieuses: G. Gras, L. Bernard, J. F. Dailloux, V. Laplantine. Hôpital Purpan (Toulouse), Service des Maladies Infectieuses et Tropicales: L. Cuzin, B. Marchou, S. Larrigue, M. Chauveau, F. Balsarin, M. Obadia. Hôpital G. Dron (Tourcoing), Service Universitaire régional des Maladies Infectieuses et du Voyageur: A. Chéret, S. Bonne, T. Huleux, F. Ajana, I. Alcaraz, V. Baclet, H. Melliez, N. Viget, X. De La Tribonniere, E. Aissi, J. Poissy. Hôpital de la Conception (Marseille), Service des Maladies Infectieuses: I. Ravaux, A. Vallon, M. Varan. Hôpital de Brabois (Nancy), Service des Maladies Infectieuses et Tropicales: T. May, L. Letranchant, C. Burty, A. Briaud, S. Wassoumbou, M. Stenzel, M. P. Bouillon. CHU Charles Nicolle (Rouen), Hôpital de Jour Maladies Infectieuses et Tropicales: Y. Debab, F. Caron, I. Gueit, C. Chapuzet, F. Borsa Lebas, M. Etienne. Hôpital de la Croix Rousse (Lyon), Service des Maladies Infectieuses: P. Miailhes, T. Perpoint, A. Senechal, I. Schlienger, L. Cotte, C. Augustin Normand, A. Boibieux, T. Ferry, N. Corsini, E. Braun, J. Lippran, F. Biron, C. Chidiac, S. Pailhes, J. Lipman, E. Braun, J. Koffi, V. Thoirain, C. Brochier. Hôpital Mignot (Le Chesnay), Service des Maladies Infectieuses et Tropicales: A. Greder Belan, A. Therby, S. Monnier, M. Ruquet. Centre Hospitalier Intercommunal (Créteil), Service de Médecine Interne: V. Garrait, L. Richier. Hôpital La Grave (Toulouse), Service de Dermatologie et Médecines Sociale: F. Prevoteau Du Clary. Funding The study was funded by ANRS. ViiV Healthcare, Gilead, Janssen and Merck Sharp & Dohme acted as co-funders through an ANRS contract. The funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. All the authors accept responsibility for the veracity and completeness of the data reported. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication. Transparency declarations V. A.-F. reports grants from Agence Nationale de Recherche sur le Sida (ANRS) and conference fees from Gilead. C. R. reports grants from ANRS and has received conference fees from ViiV and AbbVie. A. C. reports grants from Merck and personal fees from Gilead, ViiV and Janssen. All other authors: none to declare. References 1 Chéret A, Nembot G, Mélard A et al.   Intensive five-drug antiretroviral therapy regimen versus standard triple-drug therapy during primary HIV-1 infection (OPTIPRIM-ANRS 147): a randomised, open-label, phase 3 trial. Lancet Infect Dis  2015; 15: 387– 96. Google Scholar CrossRef Search ADS PubMed  2 Moltó J, Xinarianos G, Miranda C et al.   Simultaneous pharmacogenetics-based population pharmacokinetic analysis of darunavir and ritonavir in HIV-infected patients. Clin Pharmacokinet  2013; 52: 543– 53. Google Scholar CrossRef Search ADS PubMed  3 Baheti G, Kiser JJ, Havens PL et al.   Plasma and intracellular population pharmacokinetic analysis of tenofovir in HIV-1-infected patients. Antimicrob Agents Chemother  2011; 55: 5294– 9. Google Scholar CrossRef Search ADS PubMed  4 Valade E, Tréluyer J-M, Bouazza N et al.   Population pharmacokinetics of emtricitabine in HIV-1-infected adult patients. Antimicrob Agents Chemother  2014; 58: 2256– 61. Google Scholar CrossRef Search ADS PubMed  5 Chan PLS, Jacqmin P, Lavielle M et al.   The use of the SAEM algorithm in MONOLIX software for estimation of population pharmacokinetic-pharmacodynamic-viral dynamics parameters of maraviroc in asymptomatic HIV subjects. J Pharmacokinet Pharmacodyn  2011; 38: 41– 61. Google Scholar CrossRef Search ADS PubMed  6 Arab-Alameddine M, Fayet-Mello A, Lubomirov R et al.   Population pharmacokinetic analysis and pharmacogenetics of raltegravir in HIV-positive and healthy individuals. Antimicrob Agents Chemother  2012; 56: 2959– 66. Google Scholar CrossRef Search ADS PubMed  7 Cattaneo D, Gervasoni C, Cozzi V et al.   Co-administration of raltegravir reduces daily darunavir exposure in HIV-1 infected patients. 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Google Scholar CrossRef Search ADS PubMed  14 Stellbrink H-J, Le Fevre E, Carr A et al.   Once-daily maraviroc versus tenofovir/emtricitabine each combined with darunavir/ritonavir for initial HIV-1 treatment. AIDS  2016; 30: 1229– 38. Google Scholar CrossRef Search ADS PubMed  15 Massanella M, Fromentin R, Chomont N. Residual inflammation and viral reservoirs: alliance against an HIV cure. Curr Opin HIV AIDS  2016; 11: 234– 41. Google Scholar CrossRef Search ADS PubMed  16 Fletcher CV, Staskus K, Wietgrefe SW et al.   Persistent HIV-1 replication is associated with lower antiretroviral drug concentrations in lymphatic tissues. Proc Natl Acad Sci USA  2014; 111: 2307– 12. Google Scholar CrossRef Search ADS PubMed  © The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

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Journal of Antimicrobial ChemotherapyOxford University Press

Published: Apr 1, 2018

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