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Tobacco addiction and HIV infection: toward the implementation of cessation programs. ANRS CO3 Aquitaine Cohort.

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(1)Tobacco addiction and HIV infection: toward the implementation of cessation programs. ANRS CO3 Aquitaine Cohort. Antoine Bénard, Fabrice Bonnet, Jean-François Tessier, Hélène Fossoux, Michel Dupon, Patrick Mercié, Jean-Marie Ragnaud, Jean-François Viallard, François Dabis, Geneviève Chêne, et al.. To cite this version: Antoine Bénard, Fabrice Bonnet, Jean-François Tessier, Hélène Fossoux, Michel Dupon, et al.. Tobacco addiction and HIV infection: toward the implementation of cessation programs. ANRS CO3 Aquitaine Cohort.. AIDS Patient Care and STDs, Mary Ann Liebert, 2007, 21 (7), pp.458-68. �10.1089/apc.2006.0142�. �inserm-00168599�. HAL Id: inserm-00168599 https://www.hal.inserm.fr/inserm-00168599 Submitted on 21 Oct 2011. HAL is a multi-disciplinary open access archive for the deposit and dissemination of scientific research documents, whether they are published or not. The documents may come from teaching and research institutions in France or abroad, or from public or private research centers.. L’archive ouverte pluridisciplinaire HAL, est destinée au dépôt et à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d’enseignement et de recherche français ou étrangers, des laboratoires publics ou privés..

(2) HAL author manuscript AIDS PATIENT CARE and STDs 21, 7 (2007) 458-68.  

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(21) D `> E s 3?12+. ≥. ­+*(!;+ª7"4+ 12 +B/ 3› 1(!@£!</!+§+#9;+!4+!S /6;’0" P :­12+ O=P ˆ12+m. 3 P 53/(Q P /ˆ€+Y/12+|/7"+!=l! =3d+ 4*  ;|¨327"x;!@ +=33? !„•12!@¬/Š/6+Y`512+!=6 P +:<W!;+3hC \(\ HAL author manuscript. D 3212+. inserm-00168599, version 1. 53?+.!+}* + 912+=332ˆ€+—3;7"9 7B3hC=& !":W:=/6+ 1=32+•3dS=/6+ I ‡ H iRs¢32 1?+®0 =3!432+ 12+7k3w32!@5C. ≥. “)*/1g7 +.! !. ≥. T L */1§0 7+!)žk6+ I ‡ H iks. 3?:8+œ+.* W!;+| /6+ 912+3?+.!+¡4*. +#912+•3w32ˆ€+379 7ž32S>12!@§R§˜23’ 9 /!R /6+%`-12+!6ž9;9 P : !]C>\ D 7";!@ž/6+NT]U ˜ +7ž34*]/6+ I ‡ H iRsc3?:+K0"˜ 6—€;: P +3*k1247ƒU—/ L S=0 +}#6]32+KR7"9 P  +}+#6"7"k332W!@"€;: P +} L C &(*/S}*8 +#1ž7"9 P  /!SK/6+g12+=3 P :Q*M/6+y3?12+a0 =3 P !+#1"/6+a/6A12+=3264:SK0 +ª!: P ;+yRy/6+ {6+}7" ˆ€; !— 3kR9ž327"x4!A@ 0=3°+|€: P  + P 328!@«€;k3 P .:! P 7+#12N32:<+S@12 P  +|*k1247ƒU ‹ 324: P  +.:  ! 7"/ˆ€ +yR 3kR9 3 7"x4!@ Œ  cU ‹ + p /12+#7+:  7"(ˆ€ +yR 3//9 3(7 x;!@ Œ S 12 P /ˆ!;+:  P 32+   ;:@k3/23C _  `>1 )€;: P +. ≥. ”S§/6+c9;/‰+.!•23¡0"+ 12+ !;32<+#12+ =3. 32ˆ@;!8*(<!•(: ¢7" ˆ€; +| Ro3›R9 327"xW!A@ !o3? 6#€+  ¦+ 1(+!• +  ¢œ0 #12 R +=3d32 !N912@12#7žC ‡ p +=332ˆ€+"!43 P 7"9 !;*=/6+#1’1 P @]3/6#!B ;|0 +#12+"+#*/!;+§|12!A@ B/6+N*k12+ O=P +!  * /6+ˆ1Y!;3 P 7"9(!]C­‡ p +3w32ˆ€+¬:<64:œ!;3 P 7%9(!¬0"3¢+*›!;+•¨•3 :64: /*/10"47 +.! !. ≥. ≥. T @4:<3w3?+3¢4*. L */1F7"+!]C _\ ‡ p |+3d32ˆ€+N•.!!#;R3®!]3 P 79 !0 =3F;+*›!;+=3’. : !]3 P 7%9(!]C§‡ p •+=3d32ˆ€+ !;3 P 7"9(!„*l7"1 96W!;+|Sg;#1(;˜ P 12 +=32Sg+.!•;•+#9;W!;+3?S 7N9;6+ 7"!;+3?SF+=3› •3©1": ]32+ 1(@4<m|.<©<+/6;:<.7<+ ‹ ¯ H s Œ 0"=3 +*(!;+©3"M:<+=3/%m!+ i(!43 P 7"9(‰!C.‡ p +=332ˆ€+}!]3 P 7"9/!*{6+#1?!+}1;!+K0=3 +.* W!;+|B=3°v:+=3/{}!•+ 0 ++#x;i(!43 P 7"9/!­!­+ p |+3d32ˆ€+ž!;3 P 7"9(!¥4*’#12#x0"3[4+*/W!;+|g•3Mž!43 P 7"9(‰!¥4*’ :<+3›>!|+}«7"!=/6C G +=3 P :˜23°4*{!</ˆ!;+M+#9;+!+!;S+#912+=332;!B!B7B=/ˆ€(‰!N 3//9§3 7"x;!@"0"+#1?+ 3//12/*›<+4! #@;+ ‹ 6R7"k32+ž˜23°7+<! Œ S-@;+ !+#12S5+ p +3w32ˆ€-+N1 P @ !;3 P 79 !ž#!6k3/ 1 *   +=3d32 !£k +#7N9F/6M#12+žx!0%!§/g+§=3d32; +m0"˜/6m/;| 3(7"x;W!A@ª;+6#€; P 12S !ª! =/6+ 1N#6; 12 +#1 R3//<=3B3 P .6 =3—$%&(' /12 !4327Bk332;!ª• + @1(+=3?S P 12 ! 32!;+m*›1w3/$%&(' 9;]32˜(ˆ€+ “.

(22) 32+ 12:‰@ ‹ <6/7k3?+c­Q23ª7"+|<! Œ !=/12:ž*ž$N&(' !* +=/! ‹ I s%Vc+:<:ž P != !.  L AU /7"7"e Œ .! != ˆ12+/12€; 12:—/12+w/7"+!=/6 P :< 9; +#!=/:<: + 3w3?4 +|Ÿ0"˜ 6¡  327"x4!A@;+6|€;‰ P 1C HAL author manuscript. Ÿ+m12+0„!© P /:!;+§4*N3 9;+8*(<§!• +#1(€;+!= !43 P 32<!@ 53?+#1(€;+£4 !ª7"/ˆ€; !S+ p +=332ˆ€+ 1 P @¢!43 P 7N9 !SB+ 912+=332ˆ€+¦379 7ž3£! ! =/!+ 4+ 9;+.!+!5C}r /‰€ !S 0"6<6ƒ›3 !432<+#12+|•3 /6+[32R3*/1327"x4!@•+=332 !S0"•3 /6+«*/1w3›3/ +#9*]/6+} P /:!;+C.‡ p +=332ˆ€+}1 P @ !43 P 7"9/!SK0"6<6 !+•+=332˜  +=3Ry;+m #x;+#!¡!  6#1(@;+g+*/12+©327"x4!@Ÿ+3w3d/!SK0 =3"/6+. inserm-00168599, version 1. 32+|! 3› +#95CNs"+ 912+=3w32ˆ€+ 3;79 7B3?S 0"6<6 ;+=3©!   P !• +#1ª!< + 327"x;W!A@ +3w32(! != +#1(€+.!•(‰!N P v!+•+43{ ;+k1?+ +—/ž+ !6!+[/6+N+*›* + ˆ€;+!+•33*{!= +#1(€+.!•(‰!S0"•3 /6+[/6 1w 3› + 9;S4#!N!/W!+}+#9;+!+!N0 3 /6+*/ P 1›/6B3/ +#9]C.  %& *  * H 7N94:<+—32 •+}:< P :<(‰! Ÿ+!•(9; +/6 /6+—91291R/‰! 4*{12+#@ P :<#1327"4x;+ 1w3™0"Q/6%`š E s 3?12+. ≥. N0  P :B+—V;U ©C. #x4!A@§!= | P !• /6+N*/+32ˆW:<˜ 4* /6+—12+#1 P ˜ 7ž+ != S40"+%:8 P :< +/6 /6+NW!: P 32‰4!ž4*”UU  P /9;w/+!=23!"/6+N7"4!•/6: 9;+#12;B4*5/6+3 P 1?€+0 P :ž::0 */1}912+k324! *:<+=33{/6!. ±. ” C.  A9;+M!+N+#1(121{0"=3°*› p + ‹ k0%§32+| Œ !/6+«91?91k/!B;* 12+#@ P :<#1F327"x;+ 1w3F7"4!A@/6;+ €;+#12::5327"94:<+}AU £C H  h/<3› :]!.:]32k3 u>12+€.:<+!|+m+=3› 7 +=3#1?+ª12+#9;1› + =3M91291k/!]3ž0"Q/6Ÿ/6+ˆ1m‘4 !*›<+!;+©!= +#1(€;: ‹ I & Œ C s"*/*(+#1?+.!•+=3F*{912+#€;:<+!•+N|12!A@B žW* *(+#1?+.!•9/‰+.!•23F#6; 12 +#1 R3//<=3™0 +#12+N|47N9;#12+| P 32W!@ uv+#1w3?!¤ 3. χ. .  +•3RdC5 0%g7 P :˜ ˆ€#12< +:‰@;83› B12+ @12+=332k!­7";+.:<3«0 +#12+ž|!;3›/1 P  +|/­+!= W* . €;#12 +=3%*’!8|/!++#9;+!;+! #!ª7  ˆ€; !aR 3k/9 3(7 x;!@5C H  w/83› :>!:32R3 P 32+. .

(23) HD"H 32*8k0" 12+S-€+#1w32;! ;C T ‹ HD"H & !43› ˜ P  +—& !CQS I #1S E 1R/6 I #12:!S]Ž H;D}Œ C D  iR€;: P + >U]C˜U4 0 =3!432<+#12+|•33› /<3› :8:ž32@4!*(<•!=dC HAL author manuscript. ±M  M  ’ .     (  . H  p 6 P !12+"!—k0 +#!= "!+} P /9;w/+!=23{6"}.:<!4 K€;R32Q{!!+}*]/6+}*/‰€+9; 1›(‰.9; !@N0 #1243  P 12!@N/6+—3/ P  %9;+#12;]C D 7 4!@N/6+7"S]•V"12++ˆ€+"—3?+.:<*/i(7B!;R3/ +#12+ O=P +=3/(‰!!.12+}! AU‘. inserm-00168599, version 1. 7N9;:8+ +˜ S <+.:<!@B!"+ p 6 P 3› ˆ€;˜ 4*•T ‹ */@5C Œ C r +|.! #@;+}*]/6+12+=3(9;!+!•23 0"•3{VV +•#1w3!“V 0 +#12+7 +.!C 0 6 P !12+"#!!!;+9; +!=23 ‹ V{ Œ 0 +#12+©W!* + +|Ÿ/61? P @6 67")1;<3d+ pAP :B|!• h S ”U ‹ L Œ /61  P @6 6;+ + 1(]32+ pAP =: != +#1? P 1d32+S}‘V ‹ ‘ Œ /61  P @6¡!

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