Allegato 1 Analisi delle prove

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1 Ato 1 Ans prov I pro vutzon prov snt ontnut n qusto to sono stt rzzt ppno pproo mtoooo GRADE worn roup pr trmnr qutà prov snt n rzon qust post. Utror normzon su qusto pproo sono ontnut n Szon 2. A1.1 I mton è n trttmnto pnnz opp? Amto L Dt: 23 osto 200 Pr pnnz opp I trttmnto on mton è pù trttmnto sntossnt o nssun trttmnto? Sttn: Rvson sstmt: Mtt RP t. (n prss) Mton mntnn trpy vrsus no opo rpmnt trpy or opo pnn (CLIB 3, 2003) [10] ; Br AM t. (200) A systmt rvw o osrvton s on trtmnt o opo pnn. [19] (Pr tutto qusto to 1 st nr punto è stto rotto uno us mt rtv qu r). Dsno o o Trttmnto on mton Assnz trttmnto Uso opp [,188,189] (oow-up sottvo: 1 ms - 2 nn) 3 Stu n rnomzzt Aun ( 1) 28/104 (2,9%) 110/12 (8,3%) RR ( 0,23 0,44) AR mno 30/1000 ( mno 830 mno 430) Comportmnto rmnoso [,188,189] (oow-up ottvo: 1 ms - 2 nn) 3 Stu n rnomzzt Aun ( 1) /18 (2,8%) 18/18 (9,%) RR 0,393 ( 0,12 1,2) AR mno 20/1000 ( mno 00 pù 19) Morttà ontrot rnomzzt [188,10,189] (RCT) (oow-up ottvo: 2-3 nn) Nssun mt 3 Stu n rnomzzt o sprs ( 2) 3/21 (1,4%) /219 (3,2%) RR 0,493 (0,0 to 4,23) AR mno 1/1000 ( mno 100 pù 30) 9 Morttà (quss us) ossrvzon [190,191,192,193,194] (oow-up ottvo: 2, nn-21 nn) Nssun mt Stu ossrvzon nonsstny 2/19421 (1,3%) 103/2314 (4,%) RR 0,3 ( 0,29 0,48) AR mno 20/1000 ( mno 30 mno 10) 9 Morttà (ovros) ossrvzon [190,191,19,193,19] (oow-up ottvo: 2, nn-12 nn) Nssun mt Rsutt Stu ossrvzon nonrunt tr ( 1)10 Etto strmmnt ort (+2) 0/31 (0,2%) 41/3244 (1,3%) RR 0,1 ( 0,0 0,3) AR mno 10/1000 ( mno 20 0,00) 9 Rtnzon n trttmnto [10,108,10] (oow-up ottvo: 1 ms-2 nn) Nssun mt 3 Stu n rnomzzt 13/24 (8,1%) 3/21 (2,1%) RR 3,03 ( 1,,3) AR pù 40/1000 ( pù 20 pù 0) Tr n sttn mutor; u onott n Stt Unt uno n Svz Tr ontrot rnomzzt (RCT): n uno oton onmnt uto; n uno non ro n uno nuto Rnom t mo Tr RCT, uno onotto n Stt Unt, uno n Svz uno n Cn In uno oton onmnt ut n u non r Cnqu n sttn mutor; onott n It, Austr, Svz, Stt Unt Spn (uno pr suno stto) Qutà st su S Nwst-Ottw: szon, u sst 3 tr sst 2; omprtà, uno o ssto 3, tr sst 1 uno o ssto 0; sto, u sst 2 tr sst 1 Cnqu n sttn mutor: u onott n On, uno n It, uno n Stt Unt uno n Spn Qutà st su S Nwst-Ottw: szon, quttro sst 3 uno o 2; omprtà, u stmt 2 tr stmt 1; sto, uno o stmto 2 quttro stmt 1 Evt trontà sttst p<0,00001, m tutt rsutt ornt Tr n sttn mutor, onott n Hon Kon, Tn Stt Unt (uno n suno stto) Tr RCT, tutt on oton onmnt non r At

2 A1.2 I trttmnto on onst opp ru uson HIV? Amto L, Mnozz S Dt: 22 mo 200 I trttmnto on onst v ssr usto pr prvnzon nzon HIV o pr ruzon omportmnt to rso? pr v nttv Sttn: Rvson sstmt: Gown L t. (2004) Susttuton trtmnt o ntn opo usrs or prvnton o HIV nton (CLIB 4, 2004) [203]. Dsno o o Trttmnto on onst Assnz trttmnto (RR) (IC 9%) Comportmnto nttvo: prvnz omportmnto nttvo, o oort [198] (oow-up sottvo: 18 ms) Nssun mt 1 Stuo ossrvzon 12/12 (82,2%) 9/103 (94,2%) RR 0,8 ( 0,80 0,9) AR mno 120/1000 ( mno 200 mno 40) Comportmnto nttvo: prvnz omportmnto nttvo [199] (oow-up sottvo: 4 ms) Nssun mt 1 Stuo no rnomzzto Un rto ro ( 1) 44/129 (34,1%) 93/124 (,0%) RR 0,4 ( 0,3 0,9) AR mno 410/1000 ( mno 20 mno 300) Comportmnto nttvo: prntu pznt onv mtr utzzto pr uso novnoso, ossrvzon [198,200,201] (oow-up sottvo: 0-18 ms) Nssun mt 3 Stu ossrvzon 83/301 (2,%) 424/1020 (41,%) RR 0,4 ( 0,3 0,9) AR mno 230/1000 ( mno 400 mno 0) Comportmnto sssu: ssso pmnto [198] (oow-up: 18 ms) Nssun mt 1 Stuo ossrvzon 43/12 (28,3%) 4/103 (4,%) RR 0.2 ( ) AR mno 10/1000 ( mno 290 mno 0) Comportmnto sssu: ssso non prottto [198,200] (oow-up: 3- ms) Nssun mt 2 Stu ossrvzon 14/213 (81,%) 4/4 (84,%) RR 0,94 ( 0,8 1,02) AR mno 0/1000 ( mno 130 pù 10) Sroonvrson HIV [198,200] (oow-up vr: no nn) 2 Stu ossrvzon Nssun mt 1/9 (2,8%) 24/29 (8,1%) RR 0,3 ( 0,19 0,) AR mno 0/ Uno o n sttn mutor, onotto n Stt Unt (Mtzr, 1993) [198] Uno o srttvo n u Autor ssto qutà o o su s punt (srzon popozon, srzon rtr tà, ustmnto pr ttor ontrzon, mno 20% prso oow-up, prsnz o-ntrvnto, nornz n rot t tr rupp), sst 0 1, ov 0 = no s. Su s qusto sstm sszon, o o è stto ssto 1 Rnom t mo Uno o onotto n Austr, n un sttn rsnz (n rr) Lo o è stto ssto 1 Dtnut pnnt opp Tutt tr sono stt onott n sttn mutor, u n Stt Unt uno n Grmn Tr oort, u sst 1 uno 2 Uno o oort ssto 1 Entrm n sttn mutor, uno onotto n Stt Unt uno n Grmn Entrm sst 1 Du oort: Mtzr (1993) [198] un ruppo ontroo snz trttmnto szonto ruppo mton, Moss (1994) [202] un ruppo ontroo szonto ontmporno nrsso prormm stnnz opp Ln u pr trttmnto rmooo psoso pnnz opp

3 A1.3 L uprnorn è n trttmnto pnnz opp? Amto L, Mnozz S Dt: 23 mo 200 Pr pnnz opp trttmnto on uprnorn è pù po? Rm: rovro Rvson sstmt: Mtt RP t. Buprnorpn mntnn vrsus po or mton mntnn or opo pnn (2008, n prss) [118]. Dsno o o Buprnorn Po Rtnzon n trttmnto: 2-4 m uprnorn vrso po o 1 m uprnorn [184,204,109,110] (oow-up ottvo: 2-1 sttmn ) Nssun mt 2 Stu n rnomzzt Uno o n sttn rovro ( 1) 141/242 (8%) 114/24 (4%) RR 1,24 ( 1,0 1,4) AR pù 100/1000 ( pù 30 pù 210) Urn postv morn: 2-4 m uprnorn vrso po o 1 m uprnorn Nssun mt Rsutt 2 Stu n rnomzzt nonrunt tr ( 1) Uno o n sttn rovro ( 1) SMD 0.10 ( 0,8 1,01) Rtnzon n trttmnto: 8 m uprnorn vrso po o 1 m uprnorn [184,204,109,110] (oow-up ottvo: 2-1 sttmn ) Nssun mt 2 Stu n rnomzzt Uno o n sttn rovro ( 1) 119/218 (4%) 114/24 (4%) RR 1,21 ( 1,02 1,44) pù 80/1000 ( pù 9 pù 191) Urn postv morn: 8 m uprnorn vrso po o 1 m uprnorn Nssun mt Rsutt 2 Stu n rnomzzt nonrunt tr ( 1) Uno o n sttn rovro ( 1) SMD 0,28 ( 0,4 0,10) Rtnzon n trttmnto: 1 m uprnorn vrso 1 m uprnorn [184,204,109,110] (oow-up ottvo: 2-1 sttmn ) Nssun mt 1 Stuo no rnomzzto 110/181 (1%) 4/18 (40%) RR 1,2 ( 1,23 1,88) pù 210/1000 ( pù 90 pù 30) Urn postv morn: 1 m uprnorn vrso po o 1 m uprnorn Nssun mt 1 Stuo no rnomzzto SMD 0, ( 0,44 0,8) Du RCT: uno n sttn rovro, uno n sttn mutor, ntrm onott n Stt Unt Entrm on oton onmnt poo r Rnom t mo Durt trttmnto Po o 1 m uprnorn orno At

4 A1.4 Mton vrso uprnorn Amto L, Mnozz S Dt: 22 mrzo 200 Pr trttmnto pnnz opp vono ssr ust os ss uprnorn o os ss mton? Sttns: Rvson sstmt: Mtt RP t. Buprnorpn mntnn vrsus po or mton mntnn or opo pnn (2008, n prss) [10]. Dsno o o Dos ss uprnorn Dos ss mton Rtnzon n trttmnto: os ss uprnorn vrso os ss mton [20,20,8,20,12,208,209] (oow-up ottvo: -48 sttmn ) Stu n rnomzzt Nssun mt 2/484 (2,%) 310/492 (3,0%) RR 0,82 0,2 0,94) 130/1000 ( mno 220 mno 40) Uso opp urnt trttmnto [210,20,20,12,208,209] (mo nto : punt pù ss) Stu n rnomzzt Nssun mt SMD 0,12 ( 0,2 +0,02) Uso on urnt trttmnto [210,20,20,208,209] (mo nto : punt pù ss) Stu n rnomzzt Nssun mt SMD 0,11 ( 0,03 +0,2) Uso nzozpn urnt trttmnto [210,20,208,209] (mo nto : punt pù ss) 4 Stu n rnomzzt Nssun mt SMD 0,11 ( 0,04 +0,2) 4 Comportmnto rmn [20] (mo nto : punt pù ss) 1 Stuo no rnomzzto Nssun mt m 9 11 SMD 0,14 n ( 0,41 +0,14) Tutt n sttn mutor, Ps orn: tr Stt Unt, uno Austr, uno Svzzr, uno Austr, uno Rno Unto Du on oton onmnt uto, pr tr nqu non srtto; / n oppo o Rnom t mo Durt trttmnto Tutt n sttn mutor, Ps orn: tr Stt Unt, uno Austr, uno Austr, uno Svzzr / n oppo o; uno on oton onmnt uto, pr nqu non rto Dt st su ns urn Tutt n sttn mutor, Ps orn: tr Stt Unt, uno Austr, uno Austr 4/ n oppo o; uno on oton onmnt uto, pr nqu non rto Tutt n sttn mutor, Ps orn: u Stt Unt, uno Austr, uno Austr 3/4 n oppo o; uno on oton onmnt uto, pr nqu non rto sttn mutor, onotto n Austr m Doppo o, oton onmnt uto n Soo uno o on rsutt non sttstmnt sntv 8 Ln u pr trttmnto rmooo psoso pnnz opp

5 Amto L, Mnozz S Dt: 23 mrzo 200 Pr trttmnto pnnz opp sono pù os mort uprnorn (-12 m/) o os mort mton (0-80 m/)? Sttns: Rvson sstmt: Mtt RP t. Buprnorpn mntnn vrsus po or mton mntnn or opo pnn (2008, n prss) [10]. Dsno o o At os uprnorn (-12 m/) At os mton (0-80 m/) Rtnzon n trttmnto [20,20,8,20,12,208,209] (oow-up: 1-2 sttmn ) Stu n rnomzzt Nssun mt Inonsstny ( 1) 18/3 (44,4%) 199/32 (,%) RR 0,9 ( 0,4 0,99) 120/1000 ( mno 230 mno 10) Uso opp [210,20,20,12,208,209] (mo nto : punt pù ss) 3 Stu n rnomzzt Nssun mt 1 1 SMD 0,2 ( 0,0 0,0) Us o on (ttr nt y: owr sors) 1 Stu n rnomzzt Nssun mt Dt moto mprs o sprs ( 2) SMD 0,22 ( 0,30 0,4) Tutt n sttn mutor, s onott n Stt Unt, uno n It Tutt n oppo o, uno on oton onmnt uto, pr tr non srtto Etrontà vt p=0,04 Dsno o o tt su Durt trttmnto Tutt n sttn mutor tutt onott n Stt Unt Dt st su ns urn Tr n oppo o, uno on oton onmnt uto, pr tr non rto In sttn mutor, onotto n Stt Unt Doppo o, oton onmnt non rto Soo uno o, po pznt, rsutto non sttstmnt sntvo At 9

6 A1. Qu os mton vono ssr utzzt? Amto L, Mnozz S Dt: 24 mrzo 200 Pr trttmnto pnnz opp sono pù os mton 40-9 m/ o os 1-39 m/? Sttns: Rvson sstmt: Fno F t. Mton mntnn t rnt oss or ron pnn (CLIB 3, 2003) [140]. Dsno o o Dos ntrm mton (40-9 m/) Bss os mton (1-39 m/) Rso ssouto (AR) (IC 9%) Rtnzon n trttmnto [108] (oow-up ottvo: 20 sttmn) 1 Stuo no rnomzzto Nssun mt 44/84 (2,4%) 34/82 (41,%) RR 1,2 ( 0,91 1,) pù 110/1000 ( mno 40 pù 20) Morttà [19] (oow-up ottvo: nn) Nssun mt 1 Stuo ossrvzon 1/32 (0,3%) 4/822 (0,%) RR 0, ( 0,0,0) mno 2/1000 ( mno 20 pù ) Moto ss 9 Sttn mutor, onotto n Stt Unt Doppo o, oton onmnt non ro Soo uno o Fx t mo Uno o prosptto oort (CPS), n sttn mutor, onotto n On; pr os ntrm n CPS = -0 m/; ss os = - m/ Un CPS qutà mort Ampo ntrvo onnz CPS Amto L, Mnozz S Dt: 24 mrzo 200 Pr trttmnto pnnz opp sono pù os mton m/ oos 1-39 m/? Sttns: Rvson sstmt: Fno F t. Mton mntnn t rnt oss or ron pnn (CLIB 3, 2003) [140]. Dsno o o Mntnmnto mtono (0-120 m/) Mntnmnto mtono (1-39 m/) Rso rtvo (RR) (IC 9%) Rso ssouto (AR) (IC 9%) Rtnzon n trttmnto -2 sttmn (oow-up ottvo: -2 sttmn) Stu n rnomzzt Nssun mt 138/24 (,9%) 102/249 (41,0%) RR 1.3 ( 1,13 1,3) pu 10/1000 ( 0 20) Astnnz opp (prntu mpon urn ntv pr 12 sttmn) 1 Stuo no rnomzzto Nssun mt Dt moto mprs o sprs ( 2) WMD -2,0 ( -4,8-0,8) Astnnz opp 3-4 sttmn (ns urn) 3 Stu n rnomzzt Nssun mt Rsutt nonrunt ( 1) /118 34/119 RR 1,9 ( 1,1 2,18) Astnnz on 3-4 sttmn (ns urn) 2 Stu n rnomzzt Nssun mt 3/83 20/8 RR 1,81 ( 1,1 2,8) Etrontà sntv 0 Ln u pr trttmnto rmooo psoso pnnz opp

7 Amto L, Mnozz S Dt: 24 mrzo 200 Pr trttmnto pnnz opp sono pù os mton m/ o os 40-9 m/? Sttns: Rvson sstmt: Fno F t. Mton mntnn t rnt oss or ron pnn (CLIB 3, 2003) [140]. Dsno o o Mntnmnto mtono (0-120 m/) Mntnmnto mtono (40-9 m/) Rtnzon n trttmnto -13 sttmn [211,212] (oow-up ottvo: -13 sttmn) 2 Stu n rnomzzt Nssun mt 2 138/13 (9,8%) 13/14 (8,%) RR 1,01 ( 0,91 1,12) pù 10/1000 ( mno 80 pù 90) Rtnzon n trttmnto 2-40 sttmn [213,211,214] (oow-up ottvo: 2-40 sttmn) 3 Stu n rnomzzt Nssun mt 1/2 (,%) 130/283 (4,9%) RR 1,23 ( 1,0 1,4) pù 100/1000 ( pù 30 pù 190) Astnnz opp [212] (oow-up ottvo : 3-4 sttmn ) 1 Stuo no rnomzzto Nssun mt Dt moto mprs o sprs ( 2) 10/31 (32,3%) /28 (21,4%) RR 1,1 ( 0,3 3,1) pù 110/1000 ( mno 120 pù 330) Attvtà rmn [212] (ottvo sottvo Intrvo:. Mo nto : punt pù ss) 1 Stuo no rnomzzto Nssun mt Dt moto mprs o sprs ( 2) WMD 0,0 ( -0,03 0,13) Morttà [19] (oow-up ottvo: nn) Nssun mt n 1 m Stuo ossrvzon n Dt moto mprs o sprs ( 2) o 0/31 (0%) 1/32 (0,3%) RR 0,38 ( 0,02 9,34) 0/1000 ( mno 10 pù 10) Moto ss 9 Entrm n sttn mutor ntrm onott n Stt Unt Entrm n oppo o, oton onmnt non ro Fx t mo Tutt n sttn mutor tutt onott n Stt Unt Aoton onmnt uto, n 2 non ro; 2 n oppo o, 1 n snoo o Sttn mutor, onotto n Stt Unt Dt st su ns urn Doppo o, oton onmnt non ro Soo uno o, po prtpnt Durnt trttmnto Sttn mutor, onotto n Stt Unt Numro mo/sttmn ttvtà rmn m 1 CPS, sttn mutor, onotto n On. Pr t os n CPS = > m/, os ntrm = -0 m/ n o 1 CPS qutà mort Po vnt Amto L, Mnozz S Dt: 24 mrzo 200 Pr trttmnto pnnz opp sono pù os moto vt mton (>120 m/) o os vt (0-120 m/)? Sttns: Rvson sstmt: Fno F t. Mton mntnn t rnt oss or ron pnn (CLIB 3, 2003) [140]. Dsno o o Rtnzon n trttmnto [213] (oow-up ottvo: 2 sttmn) 1 Stuo no rnomzzto Nssun mt 2/40 o sprs ( 2) (2,%) Dos moto vt mton (>109 m/) Dos vt mton (0-109 m/) 2/40 (%) Rso rtvo (RR) (IC 9%) RR 0,9 ( 0,9 1,34) (AR) (IC 9%) mno 30/1000 ( mno 240 pù 190) 1 Sttn mutor, onotto n Stt Unt Sn n oton onmnt uto 1 o, po prtpnt Fx t mo At 1

8 A1. Mton os sr vrso onst -2-rnr pr stnnz opp Amto L Dt: 2 ro 200 Pr trttmnto stnnz opp I mton os sr è pù onst -2-rnr? Pznt o popozon: Quss pznt pnnt opp sr sottopors trttmnto sntossnt opp Sttns: o rovro Rvson sstmt: Gown L; Ap-2 rnr onsts or t mnmnt o opo wtrw (CLIB 4, 2004) [222] ; Amto t.; Mton t tpr oss or t mnmnt o opo wtrw (CLIB 3, 200) [222]. Dsno o o Tpr mton Ap2 rnr onsts Rtv rs (RR) (9% CI) Asout rs (AR) (9% CI) Comptmnto trttmnto [21,21,21,218, 219,220,221] (oow-up ottvo: mssmo 30 orn ) Stu n rnomzzt Nssun mt Inonsstny ( 1) 18/21 (,9%) 192/32 (8,9%) RR 1,09 ( 0,90 1,32) pù 0/1000 ( mno 0 pù 180) Rut ssto ms oow-up (ns ntnton to trt [ITT]) [21] (oow-up ottvo: ms) 1 Stuo no rnomzzto Nssun mt 11/2 o sprs ( 2) (44%) 10/24 (41,%) RR 1,0 ( 0, 2,02) pù 20/1000 ( mno 20 pù 300) / sono stt onott n sttn rovro, 2 n sttn mutor; Ps orn: USA (3), Rno Unto (2), Spn (2). Atr u nno onsrto qusto sto, m s trtt ossrvzon; qust è ron pr u sono stt sus mt-ns 2/ on oton onmnt uto; n / mtoo non ro; tutt n oppo o Etrontà sntv: p=0,004 rsutt non sttstmnt sntv Rnom t mo Durt trttmnto L qutà t rportt r moto povr pr qusto rsutto. I moo n u sono stt rportt rsutt r moto trono non prmsso ntrr rsutt n mt-ns. Quttro stt nno mostrto onst -2-rnr srtno un tto potnsvo mor mton Lo o è stto onotto n Stt Unt, n sttn mutor Doppo o, oton onmnt non ro Soo 1 o on po prtpnt (49) Fx t mo 2 Ln u pr trttmnto rmooo psoso pnnz opp

9 A1. Frm pr stnnz opp Amto L Dt: 2 ro Pr trttmnto stnnz opp mton os sr è pù uprnorn ovr ssr utzzto n tutt pznt? Sttns: o rovro Rvson sstmt: Gown t.; Buprnorpn or t mnmnt o opo wtrw (CLIB 2, 200) [19] ; Amto t.; Mton t tpr oss or t mnmnt o opo wtrw (CLIB 3, 200) [224]. Dsno o o Mton os sr Buprnorn os sr Comptmnto trttmnto [223,220] (oow-up ottvo: orn ) 2 Stu n rnomzzt Nssun mt 21/30 o sprs ( 2) (0%) 2/33 (8,8%) RR 0,88 ( 0, 1,1) mno 100/1000 ( mno 290 pù 100) Ett nsrt [223] (vrzon n prsson ssto Intrvo:. Mo nto : punt pù ss) 1 Stu n rnomzzt Nssun mt WMD -,1 o sprs ( 2) ( -14,3) Entrm sono stt onott n sttn rovro; Ps orn: Grmn (1), USA (1) 2/2 on oton onmnt non ro; ntrm n oppo o Rnom t mo Po pznt (3) Lo o è stto onotto n USA n sttn rovro In oppo o, oton onmnt non ro Soo 1 o, on po prtpnt (39) Durt trttmnto Amto L Dt: 13 sttmr 200 Pr trttmnto stnnz opp uprnorn os sr è pù onst -2-rnr? Sttns: rovro Rvson sstmt: Gown L t.; Buprnorpn or t mnmnt o opo wtrw (CLIB 2, 200) [19]. Dsno o o Buprnorn Aonst - 2-rnr (AR) (IC 9%) Comptmnto trttmnto [13,22,22,228,229,230,231] (oow-up ottvo) 8 Stu n rnomzzt Nssun mt Inonsstny ( 1) 31/0 (2,%) 1/38 (41,0%) RR 1, ( 1,24 2,2) pù 300/1000 ( ) Ett vvrs (oow-up ottvo) Nssun mt 2 Stu n rnomzzt 0/292 (20,%) 1/1 (30,%) RR 0.9 ( 0, 1,1) mno 100/1000 ( mno 0 pù 0) 3 Punt stnnz (punto stnnz ottvo po) 3 Stu n rnomzzt Nssun mt SMD -0,1 ( -0,8-0,3) Punt stnnz (punto omptto tutt prtpnt) 2 Stu n rnomzzt Nssun mt 28 1 SMD -0,9 8 ( -0,9-0,39) 10, tutt n sttn mutor, onott n USA, 1 n Austr, 1 n In 1 n It Pr oton onmnt, 3 sst om, 1 3, 1 onott n Austr 2 n USA 2 RCT, 1 ssto 1 Rnom t mo Etrontà sntv 2, uno onotto n USA, uno n Austr Fx t mo At 3

10 A1.8 G ntonst sotto szon v vono ssr ust pr stnnz opp? Dvo M, Amto L Dt: 2 ro 200 G ntonst opp sotto szon v vono ssr utzzt pr stnnz opp? sottopost stnnz ontrot Sttns: D rovro Rvson sstmt: Gown L t.; Opo ntonsts wt mnm ston or opo wtrw (CLIB 1, 200) [10]. Dsno o o Antonst opp sotto v szon Controo Rso ssouto (AR) (IC 9%) Comptmnto trttmnto [232,233,234,231] (oow-up ottvo: 3- orn ) Nssun mt Inonsstny 4 Stu n rnomzzt ( 1) 198/231 (8,%) 118/13 (2,4%) RR 1,2 ( 0,80 2,00) 0/1000 ( mno 40 pù 180) Grvtà urt sntom stnnz [23,23,23,231] (oow-up sottvo ottvo) 4 Stu n rnomzzt Sr mt ( 1), protà s ( 1) Non è stto poss onrontr s Ett nsrt [23,23] (oow-up sottvo: 3 orn ) Nssun mt 2 Stu ossrvzon n protà s ( 1), /94 (,4%) 1/80 (1,2%) RR 3,1 ( 0, 21,32) pù 0/1000 ( mno 10 pù 110) Moto ss 8 Pznt on rut oow-up [234] (oow-up sottvo: ms) 1 Stuo no rnomzzto Nssun mt Un rto ro ( 1) m 1/32 m (4,9%) 18/32 (,2%) RR 0,83 ( 0,2 1,3) mno 100/1000 ( mno 200 pù 100) Ps orn : It (2), Rno Unto (1) USA (1); 3 sono stt onott n sttn mutor, 1 n rm rovro. In 3/4 oton onmnt non ro n 1/4 nuto; 2 n oppo o, pr 2 nssun normzon su tà. Etrontà sttstmnt sntv Rnom t mo Durt trttmnto V sono mportnt rnz, notr, n t trttmnto n tpo trp untv 2 prosptt ontrot, ntrm onott n USA n sttn mutor Aoton onmnt non ro n 1 o nuto n un tro L RR è supror 3. Lo o è stto onotto n It n sttn mutor Aoton onmnt non ro, nssun normzon su tà o o m Soo 1 o, po prtpnt (98) onotto n sttn mutor n Stu ossrvzon 4 Ln u pr trttmnto rmooo psoso pnnz opp

11 A1.9 G ntonst opp sotto szon proon o nsts vono ssr mpt pr stnnz opp? Dvo M, Amto L Dt: 2 ro 200 G ntonst opp sotto szon proon vono ssr mpt pr stnnz opp? sottopost trttmnto stnnz Sttns: D rovro Rvson sstmt: Gown L t.; Opo ntonsts unr vy ston or nsts or opo wtrw (CLIB 2, 200) [11]. Dsno o o Antonst opp sotto szon proon Astnnz opp stnr Comptmnto trttmnto (onronto on onn) (oow-up ottvo: 1-3 orn ) 2 Stu n rnomzzt Nssun mt 4/8 (8%) 9/121 (8,%) RR 1,1 ( 0,9 1,8) pù 10/1000 ( mno 140 pù 30) Comptmnto trttmnto (onronto on uprnorn) (oow-up ottvo: 1-3 orn ) 1 Stuo no rnomzzto Nssun mt o sprs ( 2) /3 (20%) 9/3 (24,3%) RR 0,82 ( 0,34 1,9) mno 0/1000 ( mno 230 pù 10) Inzo ntrxon (onronto on onn) 2 Stu n rnomzzt Nssun mt 3/8 (8%) 21/84 (2%) RR 3,4 ( 2,32 4,98) Inzo ntrxon (onronto on uprnorn) 1 Stuo no rnomzzto Nssun mt o sprs ( 2) 33/3 (94%) 3/3 (9%) RR 0,9 ( 0,88 1,0) Grvtà urt stnnz [13] (oow-up sottvo on s sszon: ) 1 Stuo no rnomzzto Nssun mt protà s ( 1) Non è stto poss onrontr s Evnt vvrs (oow-up ottvo: 1-4 orn ) 2 Stu n rnomzzt Nssun mt 14/28 (%) 4/28 (1,4%) RR 3,41 ( 1,13 9,12) Evnt vvrs potnzmnt t [13] (oow-up ottvo: 1-4 orn ) 1 Stuo no rnomzzto Nssun mt 3/3 o sprs ( 2) (8,%) 0/1 (0%) RR 14 ( 0,4 23,8) 90/1000 ( mno 10 pù 180) 9 Rut oow-up (ns ITT) [13,12] (oow-up ottvo [ns urn]: 12 ms) 2 Stu n rnomzzt Nssun mt m 4/8 (8%) 109/121 (90,1%) RR 0,9 3 ( 0,88 1,08) mno 30/1000 ( mno 110 pù 0) Rtnzon 12 ms [13,12] (oow-up ottvo: 12 ms) 2 Stu n rnomzzt Nssun mt 3/8 (40,%) 43/121 (3,%) RR 0,9 ( 0,9 1,30) mno 20/1000 ( mno 110 pù 110) I Ps n u 2 sono stt onott sono: USA (1), Austr (1), ntrm n sttn rovro In ntrm mtoo oton onmnt non è stto rto, 1 o è stto onotto n sn n (soo pznt norvno qu trttmnto rno sottopost), tro è stto onotto snz nssun tà Fx t mo Durt trttmnto L sto non è n qusto ontsto Lo o è stto onotto n USA n rm rovro Mtoo oton onmnt non rto, o non o Soo uno o t uto-rrt Bsto su t uto-rrt nssun tto os-rspost mostrto tr 2 RCT pr sntom stnnz urt Soo uno o po prtpnt (10) Qusto è un sto Etto os-rspost mostrto tr 2 RCT onronto tr os rnt m Dt st su uno o on t prntu pznt prs oow-up n Soo u, po prtpnt (8) At

12 A1.10 I trttmnto sntossnt opp v ssr onotto n sttn mutor o rovro? Amto L Dt: 2 ro 200 Pr sntosszon opp trttmnto sntosszon v ssr onotto n sttn rovro o n sttn mutor? Sttns: vrso rovro Rvson sstmt: : Dy E. t.; Inptnt vrsus otr sttns or toxton or opo pnn (CLIB 2, 200) [18]. Dsno o o Trttmnto sntosszon n Sttn rovro Trttmnto sntosszon n Sttn mutor Comptmnto trttmnto [238] (oow-up ottvo: 10 orn ) 1 Stuo no rnomzzto Sr mt ( 1) /10 o sprs ( 2) (0%) 11/30 (3,%) RR 1,91 ( 1,03 3,) pù 330/1000 ( 0 pù 0) Moto ss Rut oow-up [238] (oow-up ottvo: 10 orn) 1 Stuo no rnomzzto Sr mt ( 1) 10/10 o sprs ( 2) (100%) 28/30 (93,3%) RR 1,0 ( 0,9 1,18) pù 0/1000 ( mno 90 pù 220) Moto ss Lo o è stto onotto n USA V sono stt sr prom rurnt mtoo rnomzzzon Fx t mo Durt trttmnto Po prtpnt (40) Ln u pr trttmnto rmooo psoso pnnz opp

13 A1.11 L trp rmoo on ntonst ntrxon v ssr ust pr trttmnto pnnz opp? Mnozz S, Amto L Dt: 23 mrzo 200 I ntrxon or v ssr usto pr pnnz opp? Pznt o popozon: Pznt pnnt opp Sttns: Rvson sstmt: Mnozz t.; Or ntrxon trtmnt or opo pnn (CLIB 1, 200) [10]. Dsno o o Ntrxon or Po Rso rtvo (RR) (IC 9%) (AR) (IC 9%) Rtnzon n trttmnto [239,240,241,242,243] (oow-up ottvo: 2-9 ms ) Stu n rnomzzt Nssun mt 3/10 (33,3%) 31/98 (31,%) RR 1.08 ( 0,4 1,) pù 20/1000 ( mno 90 pù 140) Uso opp [239,244,240,241,242,243] (oow-up ottvo : 2-9 ms ) Stu n rnomzzt Sr mt ( 1) 8/139 (48,9%) 9/110 (2,%) RR 0.2 ( 0,8 0,90) mno 180/1000 ( mno 290 mno 0) Rut oow-up [241,242] (oow-up: ms-1 nno) 2 Stu n rnomzzt Nssun mt 2/43 o sprs ( 2) (0,%) 24/38 (3,2%) RR 0.94 ( 0, 1,34) mno 40/1000 ( mno 20 pù 180) Comportmnto rmn [24,24] (oow-up ottvop: -10 ms ) 2 n Stu n rnomzzt Nssun mt p Popozon sp (rso rr) ( 1) o sprs ( 2) 13/4 (24,1%) 1/32 (4,9%) RR 0.0 ( 0,2 0,91) mno 240/1000 ( mno 440 mno 30) Moto ss Sttn mutor. Ps orn: Isr 2, USA 1, Russ 1, Spn 1 In 2 oton onmnt uto, pr tro non ro; tutt n oppo o Fx t mo Durt trttmnto Tutt n sttn mutor. Ps orn: Isr 2, USA 1, Cn 1, Russ 1, Spn 1 Su s ns urn 2 on oton onmnt uto, pr tro non ro; tutt n oppo o. Ans ITT non ust Entrm n sttn mutor, uno onotto n Isr, tro n Spn 1 on oton onmnt uto, pr uno non ro, ntrm n oppo o Po pznt, rsutt non sttstmnt sntv Tutt n sttn mutor, onott n USA, Cn Russ, uno pr suno stto 1 on oton onmnt uto, n 2 non ro,tutt n oppo o m Numro sott on mno un vnto vvrso n Entrm n sttn mutor ntrm onott n USA o Numro sott rnvt n rr p Entrm on oton onmnt non ro prto non q 2, po pznt At

14 A1.12 I trttmnt psoso vono ssr ssot trttmnt rmoo? Amto L, Mnozz S Dt: 23 mrzo 200 I trttmnt psoso ssot trttmnt rmoo sono pu trttmnt rmoo so? Pznt o popozon: Pznt pnnt opp Sttns: Rvson sstmt: Amto t.; Psyoso omn wt onst mntnn trtmnts vrsus onst mntnn trtmnts on or trtmnt o opo pnn (CLIB 4, 2004) [2]. Dsno o o Trttmnt psoso on trttmnt rmoo Trttmnt rmoo so Rso rtvo (RR) (IC 9%) Rso ssouto (AR) (IC 9%) Rtnzon n trttmnto [24,248,249,212,20,21,22,23] (oow-up ottvo: -24 sttmn ) 8 Stu n rnomzzt Nssun mt 228/29 (%) 10/214 (9,4%) RR 0,94, ( 0,8 1,02) mno 0/1000 ( mno 120 pù 20) Uso opp [24,1,21,22,23] (oow-up ottvo 9 : -32 sttmn ) Stu n rnomzzt Nssun mt 0/18 (3,4%) 10/201 (2,2%) RR 0,9 ( 0,3 0,91) mno 190/1000 ( mno 320 mno 0) Rtnzon n trttmnto trmn oow-up [2,248,2] (oow-up ottvo: 4-48 sttmn) 3 Stu n rnomzzt Nssun mt 10/13 (4,4%) 2/8 (1,3%) RR 0,90 ( 0, 1,0) mno 0/1000 ( mno 190 pù 0) Astnnt trmn oow-up [248,2] (oow-up: 1-12 ms) 2 Stu n rnomzzt Nssun mt m Inonsstny (-1) n 44/0 n (2,9%) 2/38 (1,1%) RR 0,88 ( 0, 1,1) mno 90/1000 ( mno 20 pù 90) Tutt n Sttn mutor tutt onott n USA Tutt trnn 1 on oton onmnt non ro, n 1 nuto; 2 n oppo o Fx t mo Durt trttmnto Esuno o o on oton onmnt nuto, rsutto non m Tutt n sttn mutor tutt onott n USA Su s ns urn Tutt on oton onmnt non ro, 1 n oppo o Rnom t mo Tutt n sttn mutor tutt onott n USA Tutt on oton onmnt non ro, 1 n oppo o Entrm n sttn mutor onott n USA m 1 n oppo o, 2 on oton onmnt non ro n Du on rsutt ontrstnt 8 Ln u pr trttmnto rmooo psoso pnnz opp

15 A1.13 L ssstnz psoso ssot trp rmoo pr stnnz opp è pù ut ssstnz rmoo so? H S, Dvo M, Amto L Dt: 2 ro 200 Quss trttmnto rmooo pr stnnz ssoto un trttmnto psoso è pù trttmnto rmooo soo? Pznt o popozon: Assuntor opp Sttns: Rvson sstmt: Amto t.; Psyoso n prmoo trtmnts vrsus prmoo trtmnts or opo toxton (CLIB 2, 2004) [19]. Dsno o o Trttmnto stnnz rmoo on trttmnto psoso Astnnz rmoo so (AR) (IC 9%) Comptmnto trttmnto [28,29,20,21,22] (oow-up ottvo: mmnt 18 sttmn, ntrvo 2-2 ) Stu n rnomzzt Nssun mt 3/89 (41,%) 24/9 (2,3%) RR 1.8, ( 1,11 2,) pù 10/1000 ( pù 40 pù 300) Uso sostnz prmr urnt trttmnto [28,20,21] (mpon urn) (oow-up: mmnt 18 sttmn, ntrvo 2-2 ) 3 Stu n rnomzzt Nssun mt 40/ (2.%) 30/4 (.%) RR 1.30 ( 0,99 1,0) pù 10/1000 ( mno 10 pù 330) Rut oow-up [28,21,23] (ottvo: ns urn. Foow-up: 1 nno) 3 Stu n rnomzzt Nssun mt 2/123 (20.3%) 38/8 (44.%) RR 0.41,m ( 0,2 0,2) mno 280/1000 ( mno 400 mno 10) Sott nno uso tr sostnz: rtur [28] (ottvo: mpon urn. Foow-up: 1 sttmn ) 1 Stuo no rnomzzto Nssun mt Dt moto mprs o sprs ( 2) 9/19 (4,4%) /20 (30%) RR 1.8 ( 0,0 3,9) pù 10/1000 ( mno 130 pù 40) Moto ss 4 Sott nno uso tr sostnz: nzozpn [28] (ottvo: mpon urn. Foow-up: 1 sttmn ) 1 Stuo no rnomzzto Nssun mt Dt moto mprs o sprs ( 2) 1/19 (%) 1/20 (89.%) RR 0.84 ( 0,2 1,13) mno 140/1000 ( mno 380 pù 90) Moto ss 4 Sott nno uso tr sostnz: on [28] (ns urn. Foow-up: 1 sttmn ) 1 Stuo no rnomzzto Nssun mt Dt moto mprs o sprs ( 2) 11/19 (%) 12/20 (3.2%) RR 0.8 ( 0,2 1,4) mno 80/1000 ( mno 390 pù 230) Moto ss Tutt sono stt onott n USA n sttn mutor Quttro on oton onmnt non ro uno nuto; 2 n o snoo (prtpnt n o soo pr ntrvnt rmoo) pr 3 non sono stt rportt t su tà Fx t mo Svot un ns snstà suno o o on oton onmnt nuto (ss C) mt-ns (Ros 2002, 48 prtpnt) [22]. I rsutto non m, rmnno sntvmnt vor trttmnt ssot (RR 0,4 [IC 9% 0,2 0,9]) Durt trttmnto Tutt on oton onmnt non ro, 2 n oppo o 1 no. Po pznt (109) Lo o è stto onotto n USA, n sttn mutor (B 199) [28] Aoton onmnt non ro, n sn n Soo uno o, po prtpnt mpo ntrvo onnz Srs posstà nrzzzon trttmnt ort Soo uno o, po prtpnt m Svot un ns snstà suno o o on oton onmnt nuto (ss C) mt-ns (Yno 2002, 119 prtpnt) [23]. I rsutto è vntto non sttstmnt sntvo (RR 0,84 [9% IC 0,8 1,04]) n Aoton onmnt nuto, n prto o Po prtpnt mpo ntrvo onnz p Lo o è stto onotto n USA, n sttn mutor (Yno 2002) [23] LEGENDA Consstny: L Consstny vut somnz stm tto tr. S v è un mportnt non sp nonsstnz n rsutt, u n tto stmto pr qu sto mnus. Drnz n rzon tto, rnzz qust rnz oro sntvtà sttst u son r mportnz. Drtnss: L Drtnss vut onronttà tr popozon, ntrvnt msur sto n o qu ntrss. Esmpo: v può ssr su rtnss s popozon ntrss è pù nzn, pù mt qu n o. o sprs: mportnz mprs or sprs t pn tpo sto onsrto: sprs t rtv un sto onsr morttà om vnto vvrso, vrnno un pso mor rsptto tr st mno mportnt. Esmpo pr r s t sono mprs o sprs : un soo o, on po prtpnt, un mpo ntrvo onnz. : S rrmnto mt suzon o o. Pr RCT son onsrr utzz oton onmnt, tà oow-up. I msrmnto ozon o oton onmnt vut prsnz o mno rnz sstmt n rtr n s qu prtpnt vnono ssnt rupp n o; tà vut tà o mno prtpnt, prson sntro ooro vono vutr vrs msur sto. At 9