The new

england journal

of

medicine

o r i g in a l a r t i c l e

Primary Isoniazid Prophylaxis against Tuberculosis in HIV-Exposed Children

Shabir A. Madhi, M.D., Ph.D., Sharon Nachman, M.D., Avy Violari, M.D., Soyeon Kim, Sc.D., Mark F. Cotton, M.D., Ph.D., Raziya Bobat, M.D., Patrick Jean-Philippe, M.D., George McSherry, M.D, and Charle Mitchell, M.D., for the P1041 Study Team

Abstract
B a c k g r o un d

T h e d u al e p i d e m i c o f h u m a n i m m u n o d e f i c i e n cFy vi trhu I tV) rc udl ro m es D e(pH ar mea n tnod f St cu i eb ne ce an ef cr hi nc oa l o gW y /e N ac t io on nad l R rcha Fo u du ao s e i so a m ak jo cs a ius f s ic n res s a n d d e a t h i n s u b- S a h a r a n TA ue cetaed dno ti on : V ac ci ne Pr ev e nt a b le Di ea e a nd ed -b in de , d , p l a c e b o -c o n t r o l l e d t r i a l o f p r e ex pos rb al n ol m iz u re i s o n i a z i d p r o p h y l a x i sthe M e di c a l R e e a rc h Co u n c i l: R e p i r a t o au ga in t be rs ct u l o s i s in H I V - inf e c te d c hi l dr e n a n d u ninf e cr te dn dcM hei nl in dr nl Pe ogs y a ge ea a xp tho ee nd Re t eo a rc H h U ni t ( S . A . M . ) , a n d t h e P e r i n a t a l H I V Re I V d ur in g t h e p e r i n a t a l pe r i od
Methods

re in 5cu 2 rc hd ild r e n ( 1 9 0 % ) i n t h e i s o n i az i d g r o u p a n d 5 3 ( 1 9 3 % ) i n t h e p l a c e b o g oo un pg ( HI P = 9 inf 3 ) e c te d c h i l dr e n , t h e r e w a s n o sDi rg Ar m V -0 un ca n ct S h deif f ye nMi ct ec hin hne . ni Mafdih i,M rr ,r ae nd ellt co r ie b as ute ly o tt h hi b ar ic le cn oc m be inn ece d o f t u be r cu l os i s i n f e c t i o n , t u b e r cu l os is d it s i id ed, e q ou r a ld e ta et t w e. e ina z ti hd e g isr on o u p ( 3 9 c h i l d r e n , 1 0 % ) a n d t h e p l a c e bo g rNoEu (M 4e 5d 2 c0 h1i1;365 l d r :e , 1. 1 np gl J 2n 1 -3 1 ; P T% he ra = t e0 4 o4 f )t u b e r c u l o s i s w a s 1 2 1 c a s e s p e r 1 000 c hCopyright ild-y a rs (95% c oSociety. nf i e 2011 Massachusetts Medical d e I] nc i n to ter [C , e9 5 1v5a3l ) am o n g H I V - i n f e c t e d c h il d r e n a s c o m p ar e d wi t h 4 1 p e r 1 09 05 0% c C h il ( I ,d 3y 1e ar t os 5 2 ) a m o n g HI V - u n i n f e c t e d c h i l d r e n T h e r e w e r e n o s i g n i f cc ae nst id fl ei rn- i c a l o r s e v e r e l a b o r a t o r y t o x i c e f f ec t s b e t w e e n t r e a t m e n t e in ni f c groups
Conclusions

e a rc h U ni t ( A . V . ) , U ni v e r i t y o f t h e W i tw a t e r r a n d , J o h a n n e b u r g ; St e ll e n b o c h U ni v e r i t y , C a p e T o w n ( M . F . C . ) ; a n d t h e e r a n do m W l y a s s i g n e d 54 8 H I V - i n f e c t e d a n d 80 H iI tV u naZ fe ea dta il n a rb na tn s ((R9 1 . )t U n4 i v er y -o fn Kiw u lc ut N , f Du .B n i Sloo ug th r i co af ; t bo he d De a rei tm nt t o o 1 2 0 d ay s o f a ge ) t o iso n i a z i d ( 1 0 t o 2 0 m g pa e llr i k rA a fm yp w geh pf P e di a t r i c , St a t e U n i v e r i t y o f N e w Y o r k er d a y ) o r m a t c h i n g p l a c e b o f o r 9 6 w e e ks A l l p a t i e n t s a t rS e tc ivBe do kb ac il er o C a (l S m e. t oe ny ro , St on y lB ok .N ) ;t te h e G na( Cn G) vu a cr c iin tB io a g a in s t t u b e r c u l o s i s w i t h in 3 0 da Ce ys a rf fte Vce t aerc dh , nte o rr B ib o ir t att h i t i HI c in A inf IDS e Re D ee p am rtm or f e Bi tw ar te v i a ti r c d, t cc hi dr ha a d n t i r e t r o v i ra l t h e ra p y T h e p r i m a r y o u t c o m a c le se s nt o ee an st u so Ha r e School of Public Health, Boton (S.K.); u b e r c u l o s i s d is e as e a n d d e a t h i n H I V - i n f ect ed c h i l d r e n a n d H e la nctk otnuFo ber n ct n rtyeJa u nc du a tli os o n is , D ii v i ife on o if o nl ,ostis u be r -e as e , a n d d e a t h i n H I V - u n i n f ect ed c h cu d is ld nh ew i, th in 0y 8 l vw A IiDS , r Be et da MD (P9 .J6 .- P .t) o ; P1 e nn ani a St a t e U ni v e r i t y C o ll e g e o f M e d i c in e , eeks aft en r d o m i za t i o n ra H e r h e y (G . M . ) ; a n d t h e U ni v e r i t y o f Mi a m i , Mia m i (C . M . ) . A d d r e r e p r in t r e Results q u e t t o D r . Ma d h i a t t h e R e p ir a t o r y A n t i r e t r o vi r al t h e r a p y w a s i n i t i a t e d i n 9 8 9 %a no I Vg-ei a nl f P eac to egd h il drc rh eU nni t d, d f MH e nin th e nc Re ea Oe . B 7e 53 , B th a mo , r G au en 2 0 13 uA rim ng he t -ui d o ntg H IsV ny f e ct e d c h i l d re n , p r o t oc o l - d e fPi . n do xt 9 u0b rcu le ors is dte ag th oc, S o u t h A f r i c a , o r a t m a d h i @r m p r u .co. z a .

P r i m a r y is o n i a z i d p r o p h yl a x is d i d n o t i m p r o v e t u b e r cu l os is - d is e as e f r e e s ur l I V - i n f e c te d c h il d r e n o r t u b e r c ul o s i s - i n f e c t i o n f r e e s ur vi v al am o n am ov niv g aH g Ie Vd - uc nh in feH ct i l-dr e n im m u n i ze d w i t h B C G v a c c i n e D e s p i t e a c c e s s t o a n t i r e t r oy v, i ra t hb eu ra - e n o f t u b e r c u l o s i s r e m a i n e d h i gh a m o n g HI V - i nf e c t e d c h i l dr p tl he rd en (h Fu da e tdi o n a l I n s t i t u te s o f H ea l t h an d S e c ur e t h e F u t ur e ; C lini ca l T ria l s g b y t e nN o v n um b N er C,T0 00 8 0 1 1 9 )

n engl j med 365;1 nejm.org july 7, 2011

21

The New England Journal of Medicine Downloaded from nejm.org on February 14, 2013. For personal use only. No other uses without permission. Copyright 2011 Massachusetts Medical Society. All rights reserved.

The new

england journal

of

medicine

ubercu sl io t es s i sh a is d h ex ig is ht li yn g e np dreom g ir c am in s for the prevention of s u b- S a h a m r ao nt h Ae fr rit co a -, c a an t isom ni s as gi g eI dV C hi l dr e n in hi lsdi t tura or na v oa f tH b y fte hcet e od ng p iw der m m im u -r a l t r e a t m e n t , woi it n h g He IV ei cg iovf e h n ua na tn ire t rm o vi 1 rT n od e f i c i e n c r us t y e 1 (e H as Ic Ve d 1d ) e d s t a v u d i n e , l a m iv u d i n e , wy h iv c ih p ih mp ae ri in lc yr i n l -u burden o t ul b or si r s i taom de ur l tc s o in af nd oe pr ic nu a lvi no an vig r ,ap u na t r ea y - s pw e ict ih f i c g ui d e a h i g h p re v a ln en c, e o orf z Hi IdV nd f ec i s iva si on e as oc - l o p i n a v i r li es ovi u i nt ei,o n lam ul d , sa n id a te d w i t h hi g h r a te s o f t ran rsi mi o inr o f t os nsai v rium tuberculosis yJysayuanb uamryo o hbyftry -5 S tb ue dy En lm nt and Participants o t h e r co2n tTahce tr s e f o r e , i t h as en prro olpo se ed t h a t i n a r eE as ch as Sc oc uur th ct aw , e te un b eD rcu om s ib se - r 2 0 0 4 an d nr s ou llm en t o r eA df rbi e e cl e p r ev e n t i o nn s giE en s r wi is i az m of pe hc yt-e d c o h o rt Ju et r 2a 0te 08 o ltl h me no t no f i td h ec h He IV -o up nr in laxis, which so faor mh ed o n2 l 00 y h en ht osl db o r n t o HI V wa s c pa lv ee t et da rg i ne t Ju ne 6 o Ius nfa c o n t a c t s io ac dtu t sww th i v ie sn pt ui tf um m sg f nff e el d oi m e np o ws ei rt e de i e dst h ea r oru ho r p r o gr am s M T B a c i d -f fo ar s tt h be a cpi r l ev li , eb ed in ucdhil e do t e r s mi s s i o n ne tie o xp n an o f dm o t thoe r -c tol th r an h i gh - r i s k g r oo ufp s H I V T h e H I V - i n f e c t i o n s t a t u s o f i n f an t s w a s Among othe m om pn es t eo nf t H c Ihil d1 r eD nN , A po l y m e r as edr e wi t esre m ii m ne du n bo y cm ea VM T B i nf e c t i o n c in t ihne- re f irs t i2 aC rs l if s H a IsV s -oucn ii - n fe ct ed i n ha a ct o ny e (P R )o ft es te i n ig ated with a 4 rih sk h ie pem s e tnat t us o f co t unbf e rm - ed b y a f3 a% nts a do f t ht e r d ne ev ge a lt o iv ir c u l o s i s d urin gs e t co h en 6d nA en lx s to th e nsN tk h e g,1 a2 ivm e ori D As P C R as s a y 2 4 w ee k s a f t e r o f cu l t u r e - c on nd f ior m m ie dt i to un b ear n cu i se g is as d nb ra za dl o as n a ti in vc er e HI Ve e zy y m e - li n k e d a f a c t o ri m om f u mn oo rs eo r th 0s s aa myo n gLH IA V) -in c8 t em d ocn htih lba e n t 2a (E IS af t e1 s of age 7 ,8 d re n u n d e rPa 2r ty a u ra s rt h e m ge o erre e ,e n po ie cF ip no tf s ra w rs ot ll e d be t w e e n t h e 9 1 s t a n d m o r te m s t1 u2 di e o id if i E e ld lo sr i aa s ia 0e ts h h da av ys f el n i ft e i gti u bb i lei r tc yuc r isti e n c l u d e d r el ea din g cca up ste oo i n vH ec c hi dr ei ff td h ea e tBhC G a IcVc-i inf ne bte y d3 0 dl a ye s n o in f age; no hisAfr i c a , a cto co u not fi nt g fe or rc1 t ios 1 8% tt h ,s ki n no t hn es ry ub ul2 os in t ho ef id ne fa an w ee xposure 10 c h i l d9r, e In son dih as wg ni ceaf lf le vn efn e se s di n toi aaz im cr o bsi h oo lo yc t c io i rm ca s e o f t u b e r c u p r e v e n t in g p rl o e ,s o si nc tt io tu c ub u l er os sl o di inmen t i n t h e og sr is r oa ve ab ne tr it c iu ss i ea s tsr e e at c h i l d r e n w h o h a d km no ow nec ntt a t he pe r sto th r oa tc h te w tim of hn es i n a fan nd t s no birth; 1 3 ut w i t h i n f ee cv tio t1 ub er t lo s ls r io s l,e t ion t h ri v e , r e c ur r e n t p n e um o n ia , du es nc e- 1b o fc u fi a i ur e p r e e x p o s ur e p r ch op y il c ax ae s an bm em en eo vs au lp ua rh on d ii s a rh rh ,o o tr i un ptre ed ss ii n ve condiH I V - i n f e c t ed i n fa n t s o r u n itn dt h ce h ri l t dha r enn HI ex if oe nct s eo V- i nf e c t i o n po s e d t o H I IV g w th ean rina ta pe bo n fd aurin nts ee r e pr do ml l y ari so sd i gn ed tt oh r e c e i v e d ai l y g r o u p s a t i isn r is oo r st cu oc nri e a as z ie dd , a t k a fd eu be o fr 1 0l ot s oi s2 0 m g pe r k i l o g r a m Ou r s t u dy u aw te ed th e o sa e lta yc e ab no d O ef cr ac y po o f ebvoadl y i gh t, r fp t fhi e as efc t s o f t h e i r isoniazid ve o rt rpi r ee po os e psru ol p hm yc rasrus e, p il na ccl e u bo d i nf g m ex th pu rr im fa ethoxazole l a x i s a g a i np s rt o t rc is HtI a Vi -l iendf ei c d ec h dp rl ee nm e n t a r y pu hb ye la x ul i so , sa r ei n de nt e th Si ul p and uninfe ed c ihxi ,l dar v ea ni l e o sw ei dt h t ot h HeIV f u d lul r t in Acpt pe nd ax bp le eg x tt h oe f this arpe r i n a t a l pe r i od , w h e n t r e a t t wN as to a rg rted at tt im c le en a E Js M 3 t o 4 m o n t h s o f a g e a n d c o n t i n u e d f o r 9 6 w e e ks
S t u dy O b j e c t i v e s a n d E n d P o in t s

M e t h oT dh s e c o p r i m a r y o bje c t i v e s w er e t o c o m p a r e t h e i s o n i a z i d a n d p l a c e b o g r o u p s w i t h r es pe c t t o t u S t u dy S i t be es r c ul o s i s - d i s e a s e f r e e s u r vi v al ( h e r e af t e r r e f e rr e d T hi s m u l t i c e t no te as r, p e e2 r3e, e r an z le , m do on ug b lH eI - V - i n f e c t ed dh is a es as -f s ud ro v mi iv a ) da blind, place bi ol -dcro ed rie al ol fo s is o -ni az id - s u r v iv a l ch en nt raonlld t utb rcu is in fe ct w i oa ns fur n ee dertaken in Afr ic ent ef re s c (t C hn ri ( ht eh rr ee ae f tS eo r ur tehf e r re da n t o c as in io -s frH eea n s iu r v iv a l ) B a r a g w aa nm at Ho pit Jo ae nd n es b iu rgr;e n T y9 g6 e rw be ee rg oh ng HsIV ua n li ,n f eh ct ch ld k s a ft e r r a n H os p i t a l ,d o U mi n iv it te , r Cd a ipe Ts ow nf; r e e s u r vi v al ze ar ts io ny Tohf e S e nl dl epnobo i nst c h fo sea eand King E d e VfI iI r s Ht os p cu ita l ,e n Dc uer b ) ea no em a n y c a u s e wdw as a tr h oc rr oa f nd an td h o fr c e n t e ro r i nt u Bb oe tr sw an (P r se M n at h H t ap l ,o i n t f o r i n f e c c ul oa sis di in sc ees as , a ar ni d eosepni d G a b o r o nt e ) nE- n oe llm er nv ti v aa t l tw he oh te s wf a nt a o sc ic te be en - c e o f d ea t h io fre su a sB t irs ur r ga n s h o r t l y f r bo em f o re ea s tu wb as t el rom t iesd A lel , o r M T B i n ant yh c us e dy , tu e rcu sin s ad e as
22
n engl j med 365;1 nejm.org july 7, 2011

The New England Journal of Medicine Downloaded from nejm.org on February 14, 2013. For personal use only. No other uses without permission. Copyright 2011 Massachusetts Medical Society. All rights reserved.

I s o n i a z i d P r o p h y l a xiE s xi p no H se I d Children

T ab le 1. Feature

Algorithm Used to Screen for and Diagnose Clinical Tuberculosis.* Score 0 1 24 6080% <60% or a drop of 2 percentile Sputum-confirmed Reactive (5 or 10 mm) Ye Ye 2 3 >4 4

Week of illne

(including cough) <2

Nutritional tatu (% weight for age) >80% Family hi tory of tuberculo i Tuberculin kin te t None Negative

Reported by family

Fever not re ponding to treatment No for >2 wk Confirmed or u pected EPTB No

* The algorithm i from the tuberculo i guideline for14 South Africa. Study participant with a core of 4 or more (excluding the tuberculin kin te t) during creening at their routine vi it every 3 month were creened further by mean of a tuberculin kin te t and a che t radiograph. Ev alu a ti o n fo r m a lnu t ri ti on w a p e rf or m e d ac co rd i ng to Wo15 rl o d nHe thalt e hb a Oi rg of an izz a c ti or on e g u i de li ne and clinical and laboratory evaluation . A reactive kin te t wa defined a an induration of at lea t 5 mm in horizontal diameter in HIV-infected children and an induration of at lea t 10 mm in HIV-uninfected children. Extrapulmonary tuberculo i (EPTB) included extrathoracic lymphadenopathy, joint or bone involvement, abdominal ma , meningiti , and tuberculo i of the pine, diagno ed according to criteria that were pre pecified in the protocol.

f e ct i o n S e co n d a r y s t sy u dy m po tb o jms ec t a ivnes d s fo ig r ntsh e s ucgoghes or tt iv e o f M TB i n f e c o f H I V - in f e c te d c t ihi o lnd, r e an n in wt erra ed e to rm da eltetru m b in er ec u w lin hes th kin te s t w i t h t h e e r i s o n i a z i d pu rs oe ph oy fl a Rx T i2 s3 d2 ec Tr Ue as ( Se td a te th ne s i Sn ecr ium den In ce stitut), a chest o f t u b e r cu l o s i s irn afdi eo ct giroanp h a ,t an 96 d w m ei e ck ro s ba in od log w ih ce o th r ehi r s t o p a t h o l o gi i t r e d u c e d t h e ca ri s l ke o vf a lH u IaVt i di on s ea ass e c lp in ro ic ga r lel s ys i n od ni , cd ae te - d I n c h i l d re n f in e d as t h e f i r s su t s oc pe cu cr te rd e no ce f h oa f vw ino gr s peunl im no gn o af r yt h te uberculosis, two Centers for D gi asse t as rie c w Co an sh tr io nl gs a,n d t w Pr o ei v ne dn u tci e od n- s (p Cu D tCu) m s a m p l e s , o r clinical categor bi o zt ah tiw on e ro e f tH es IV t ed i nb f ec y t m io en a no sr odf e a u th ramine staining A s e co n d a r y o b j e a ctniv de af o m ryt co hb e ac ct oe hroi r atl o cu f lH tu IV re - uw n as i n - t es t ed w i t h t h e f e ct e d c h i l d r e u ns w e as o f tt oh e d eB ta ec rm te icn e me wth he otd he a rt is no an t ii o an - a l l y a c c r e di te d z i d p r o p h yl a x is i lm ap br oo ra v to ed ri e dsi sM ey as ce o -bf a rc ee te ri su ar l v iiv so a l a te s w e r e ana l yz e d f o r d r u g r es is t a n c e w i t h t h e us e o f t h e B A C T E C T u b e r c u l o s i s In v e s t i g a t i o n 4a u tte cm o m( e 6n 0d sO ys B ec t o n D i c k i n s o n ) Categorization O n t h e b as i s o f p os i t iv e res u l t s o f t h es e e v a l u P ar t i c i p an t s w e a rt e i os nc sr, e c e hi ne l dr d ef n o rr e sc ye mi p vt eo dma s dia o f gtn uo bsei r s - o f d e f ini te , culosis at each s tpur dy oba vi bsl iet , an od r as pos s es ss ib e ld e f utru tb he e rcu r i lfo s i s ( T ab l e 2 ) t h e y h a d a sC co hr i led r oe f n 4 wohr o m s eo rhee a o ln t ht h ce a rcel i p nr ic oa v li da el r gso initiated anr i t h m s c a l e1 4(ex T ab c tl l iue td u 1ib ) n, e gr c su c loors ii nsg t o re n a tt h m ee n t b u t w h o d i d n o t f u l f i l l t u be r cu l i n s k i p nrt oes t ot c o C lh- id le df r ien ne d we c rr e ita el rs ia o f as os r ess a e dd i a g n o s i s o f t u be r f o r p u l m o na r y t u cu b le os r cu islo ws ei rse w ch l as e ns ip fr ied s e as n t ihnagv iw n ig t h n o n - a l g o r i t h m c l i n i c a l o r ra d i o g ratp uh be i cr cu ev l os i d ie sn c L eao te f npt n t eu ub m eo rn cu ia l os o is r i n f e ct i o n w as at the discretion d o if a t gh ne os a e tdt e on nd i tn hg e p bh as ys is i co ia f na Fpo o rs i t iv e t u be r cu l i n children with Ms Tk Bi n ex tp es os t u(ri e n ,d u th ra et i so tn u dy 5 dr m um g w in as h o r i z o n t a l d i a m d i s c o n t i n u ed a n d e o te pe r nin -la Hbe I Vl - in i sfo en c ite az di d c hi wl as dr ea nd an d 1 0 mm in H I V m i n is t e r e d a c c u on rd in in f ec g tte od t c hh e i lgdur ie dn e)l ,i n i es n t ih ne Sa ob ust e hn c e o f e v i d e n c e A f r i 1c4a o f a c t i v e t u b e r c u l o s i s di s ea s e , 9 6 w e e k s a f te r r an I n v es t i ga t i o n s f o r d tou mi be za rcu t il o on s iA s ni n ecnl d udpo edi n cto l r -e v i e w co m m i t t e e o f l ec t i o n o f i n f o r m s a tt u io dn y -o te n a tm h ec lsi t na it c us ian osf w sp hu ot u wm e re u n a w a re o f t h e s m e a r s i n t h e s it n ud d ex y-g c ras ou ep , a a shsi isgt nm ory e ntta sk i rn eg vif eo w r e d a l l d ea t h s a n d
23

n engl j med 365;1 nejm.org july 7, 2011

The New England Journal of Medicine Downloaded from nejm.org on February 14, 2013. For personal use only. No other uses without permission. Copyright 2011 Massachusetts Medical Society. All rights reserved.

The new

england journal

of

medicine

T ab le 2.

Protocol-Defined Criteria for Categorization of Tuberculosis Disease and Infection. Microbiologic, adiographic, Histologic, and Clinical Criteria

Tuberculosis Category

M y c o b a c t e r i u m t Definite u b e r c tuberculo u l o s i s ig c S V i . g i M u g p a d g r V . 2 g M i g % M r V r e . g p i p u r a . g V p r a r a g M pinal fluid pecimen gpgc.i.yiM( The preence of a Probable t l e a ttuberculo tw o c l ii n i c a l c r i t e r i a i n t h e a l g o r i th m h o w n i n T a b l e 1 poitive auramine taining of an induced-putum or gatric-wahing mear h i t o l o g i c f i n d i n g ( c a e a t i n g g r a n u l o m a ) ; o r p o i ti v e a u r a m i n e t a i n i n g wahing or induced-putum mear and a chet radiograph uggetive of Po ible tuberculo i , p or of tu lu either uggetive a gatricberculoi*

An algorithm core 6 and a radiograph ugge tive of tuberculo i , or a po itive tuberculin kin te t (induration 5 mm in horizontal diameter) and a che t radiograph ugge tive of tuberculo i A po itive tuberculin kin te t at week 96 after randomization in the ab ence of active tuberculo i (definite, probable, or po ible)

Latent infection

* Ra di o gr ap h i c f i nd i ng th at w er e c on i de r ed t o be u g ge ti v e of p u l m ona r y tu b er c u lo i i nc lu d ed h i l ar l y m p ha de no p ath y , alveolar con olidation, a miliary pattern of le ion , and cavitation in the lung parenchyma.

po t e n t i a l l y tsa ub fe e try cu m l os on is i-tro erl ia ntg ed bo pa rr im d a isr yp r ao nvdi dse ed c -i n t h e S u po n d a r y e n d po i n t s plementary Appendix S c r ee n i n g f o r sa K faep t lan y w M ase iu en rde es r t ima ake te n s aw t esr c eh e ud se - d t o s umma u l ed v is i t s rie zv ee r th y e3 di m so t ri nt bh us tiw on h io le f t im h ee pa to r te ic fi fp i ca an cy t s an d s af e t y w e r e r e c e i vein ng d tpo he i ns ts t uD da ytd a ro un g e Sn cd r e po e nin i ng t s inw ce lu re d ecde n s o r ed a t s e r u m l iv ew r ee en kz 9 y6 m,e wt ies th t sa ,ll cow om ap n lce et e f ob r l ood t h e c io nu cn lu ts s ,i o n o f e n d an d c lini ca l n po e iur nt os l o fgi oc r 1 e2 v aa l ua d dti ito in os n af lo r w ee p ekri sp ( hu ep r atl o 1 0 8 w ee k s neuropathy w afite th r t ran he do us mi ezo af t ia o nm ) od Loi g fi -e r ank d De tensv te srw ere us ed to Developmen cto am l p Sa c rr e ee t nin h es ge Td e isst, t rw ib iu th tio se nv s eb rie tt yw g er ea nd the study i n g b a se d on gro cr u ip ts er i Cao f xr om r e gtrhe e sD siv oi ns iw on as of u Ac se - d f o r h a zar d ra t i o s q u i r e d I m m u no de f i c ienc y a Sn yd nda rn ome a l ys ates t he ad Nj a u -s t ed f o r c ov a r i a t es t i o n a l I n s t i t u t e o fA n Aa l ll e y rse gy s fa on ll do w In efd ec at ni o in u tsen D t ii s oe na -s to es t r e at a p 1 6) ( NI A ID p r oa c h u n l ess o t h e r w i s e s pe c i f i e d D a t a o n c h i l d r en wh o se g u a r d i a n s de c l i n e d f u r t h er s t ud y S t u dy O v e r sf io gl h t - u p be f o r e m e e t i n g a s t u dy e n d po i n t w e r e l ow The study w ce as ns ao prp erd ova etd t b hy e t dhaet ei nosft itth ue til oas na t lf o r el l o w - u p v is i t v i e w bo a r d o A f le l a t es c ht i p na gr t w i as cip ta w toi -nsg i dceedn a te t r t, he th 5e %M se ig dn - ificance i c i n es C o n le tv ro e ll C T o um nc a ii ln t in ain S otu hte h sA if grn ii cfa i, ca an ncde t lh ee vel for each D i v i s i o n o f A IDc So h ao t r tt h a e t NI 5A %, ID nT oh m ei n sa tu l d Py v w aa lu s es c oonf - 0 04 9 2 a n d d u c te d i n a c c 0 o0 rd 4a 9n 3 ce for wb it eh tw Geood e n -C g lri o nu ic p adl if P fe ra re cn c e s in t h e H I V t i ces g u i d e inl f ie nc es te a d na dn t dh e H I De V -c unin lar fa et cite on d o cf oh Hoer ltssi ,n k re i spectively, Wr i t t e n i n f o wre m r e dr e cq ou n ir se en d t in w as the ob ft in aa il ne ad na f lr y os m isto hf e t h e p rimar y l e ga l g u a r d i ea nn ds po o fi nt thse Acl h l iP l dv re an l ube es f o pr re es t eh ne ty e du n w -e r e n o m i n a l d e r w e n t rD an ad ta om wiz ea rt ei o ana n l Ayz l le a d uw th it oh r st h ve ou ucsh e fo ofr S tA hS e software, a c cu r a c y a n d c o m p l e t e n es s ve orf s i to hn e 9 a1 n a(lS ys AS es I p nr se t i- t u t e ) s e n t ed a n d t h e a d h e r e n ce o f t h e s t u d y a n d t h i s r e po r t t o t h e p r o t oco l , a v a i l a b l e a t NE M R eJ s uol rg ts
Statistical Analysis Characteristics of the Participants

T h e s t u dy w asA d tes ot ig an l e od f a 5n 4d 8 pow H I Ve - re i nd f ec to t ee dv a n lu da t 8e 06 HIV-unins t u d y o u tc foem cteesd in in df ea pn etn sd w en et r ley ein n rto hl e l ed H;I V thin efe mcate jo dr i t y ( 6 5 % ) and HIV-uninw fe ect re e de n cr oo h lo le rt ds i A n d Jo eh tai nl n e es d b du es rg c rFi ipg u r e 1 A s h o ws t i o n o f t h e sa th me p ld eissp i os z ei tc ia ol ncuol f a tt ih oe n 2 (7 w4 itH h Ia V - ti a n rg f ee ct t e d i n fa n t s sa m p l e o f e 5 n 00 r o lH l ed I V - ii n n fe ec at ce hd s a tu n d y8 g 0r 0o u Hp IV ; - tuhnei ns-t u d y d r u g w as f e ct e d c h ii ni l dt ri e an te ) da n wi dt hi on f ov 4 e dra sy ig s haf t tb ey r t rh an ed d oa miz t aa t ai n od n, except
24

n engl j med 365;1 nejm.org july 7, 2011

The New England Journal of Medicine Downloaded from nejm.org on February 14, 2013. For personal use only. No other uses without permission. Copyright 2011 Massachusetts Medical Society. All rights reserved.

I s o n i a z i d P r o p h y l a xiE s xi p no H se I d Children

A HIV-Infected
548 Children underwent randomization 359 Were from Johannesburg 132 Were from Cape Town 53 Were from Durban 4 Were from Botswana

B HIV-Uninfected
806 Children underwent randomization 519 Were from Johannesburg 280 Were from Cape Town 7 Were from Durban

274 Were assigned to receive 274 Were assigned to receive IH placebo 273 Received I H 274 Received placebo 1 ever received I H, failed to return

403 Were assigned to receive 403 Were assigned to receive IH placebo 403 Received I H 401 Received placebo 2 Did not receive placebo 1 Mother was HIVuninfected 1 Had randomization error

75 Completed intervention 81 Completed intervention 34 Were lost to follow-up 21 Were lost to follow-up 7 Were unable to get to 1 Was unable to get to the clinic the clinic 4 Withdrew consent 6 Withdrew consent 5 Were unwilling to adhere 1 Was unwilling to adhere to study requirements to study requirements 18 Could not be contacted 13 Could not be contacted 34 Discontinued intervention 31 Discontinued intervention 11 Had exposure to TB case 11 Had exposure to TB case 1 Had laboratory toxicity 11 Did not meet protocol 12 Did not meet protocol definition of clinical TB definition of clinical TB 2 Disallowed concomitant 1 Had peripheral neuropathy medication 9 Did not adhere to regimen 1 Discontinued following 130 Did not complete interhospitalization vention because of study 6 Did not adhere to regimen closure 141 Did not complete intervention because of study closure

246 Completed intervention 261 Completed intervention 56 Were lost to follow-up 60 Were lost to follow-up 24 Were unable to get to 23 Were unable to get to the clinic the clinic 13 Withdrew consent 16 Withdrew consent 3 Were unwilling to adhere 2 Were unwilling to adhere to study requirements to study requirements 16 Could not be contacted 19 Could not be contacted 101 Discontinued intervention 80 Discontinued intervention 34 Had exposure to TB case 26 Had exposure to TB case 9 Did not meet protocol 8 Did not meet protocol definition of clinical TB definition of clinical TB 1 Had peripheral neuropathy 46 Did not adhere to regimen 57 Did not adhere to regimen

273 Were included in analysis 274 Were included in analysis 1 Was excluded from analysis

403 Were included in analysis

401 Were included in analysis 2 Were excluded from analysis

an d omiz Figur at eio 1n .,E an nrd oF l lm o le l ow nt ,- up o f t h e HIV - Inf e c t e d an d HIV - Uni n f e c t e d S t u d y C oh o r t s . F o ur H I V - in f e c t e d c hil d r e n ( o n e in t h e i o n ia z i d g r o up an d t hr e e in t h e p l a c e b o g ro up ) w h o w e r e p o ie t ive fo ee lin ee re que nr t lHI yV coant f b ir a m de towb HI ub V --u nin f e c t e d . S i x HI V - unin f e c t e d c hil dr e n (t w o in t h e i o nia z i d g ro up a n de fr oe urn in h tei ve pla cr eb ho w e gt a fo HIoV garo t up b a) ew l in e w e r e ub e q u e n t l y co n f ir m e d t o b e HI V - inf e c t e d . T h e n umb e r o f p a irco t in ct ip an o t fe or ll ow - io up d inu e td lto hte t in ve nt n odr ew nh oo t e t h o e w h o w e r e l o t t o f o ll o w - up o r d i co n t inu e d t h e in t e r ve n t i o n b ed fo r im an r yf o er n d ip on inttinuin o c -g t h e in t e r ve n t i o n ar e e num e r a t e d o n l y f o r t h o e n o t l o t t o f o l l o c ur re . r Te ha e p re a o co w - up . I N H d e e e ir oc nia zid Tn B ot tub ul o . , and

i n 1 c h i l d w h oc e n iv ev ee d r BrC ec Ge v iva ed c c ii t na a tni d o nw b as y ex 30 c ld ua d ys ed o f a g e , b e f o r e f r o m t h e a n a l ys th is e iT r hp eo s d ii t s ipos v ei t Hi IV o n so ta f t tuhse w HaI s V -d e t e rm i n e d T h e m a u n i n f ec t e d i n fa jn otrsi ,t yi nocfl u infa ding t s 2w c eh ri el d in rd ei ng e wn ho ou d s iA dfricans (970%) n o t r e c e i v e t h e Bsyt ucd hy an dr cu eg , ian n dt h w ee r He I Ve- x in cf lu ed cte ed d fcr o oh m ort, a higher t h e a n a l ys is , is s h o pe wr nc e in n tF ai g ge u ro ef 1c Bh i l d re n o f m i x ed a n c es t r y w e re The baseline chara ec n tr e o rl il s et di ci s n w th ee r e isg oe nn ia ez ra id lly g rw oe ul pl - A h i s t o r y o f balanced betwee m na t e hr en a tw l o t ug bre orcu u pl s os (T is ab w l as e 3r ) e ip no r t e d f o r 7 1 % a n d b o t h co h o r t s I n fa 7 n2 ts % uonf d HI e rV w -e i nf nt ec rt ae nd do am nd iza HIt V io -u nn i n f e c t e d p a r t i c i at a median age pa on ft9 s, 6 rd es a pec ys t Aiv l le l iy n fF ao nu ts r p har dt ire c i- p a n t s i n t h e H I V n engl j med 365;1 nejm.org july 7, 2011

25

The New England Journal of Medicine Downloaded from nejm.org on February 14, 2013. For personal use only. No other uses without permission. Copyright 2011 Massachusetts Medical Society. All rights reserved.

The new

england journal

of

medicine

i n f ec t e d tco ub he or rc t, ul w oh si os i n dii e t ida, l lan y d h ao dnl ay po tu s ibt e iv re cu H lI o Vs i s e n d p o i n t s PCR test, w weer ree si u nb cs lu ed qe ud e ni t nl yt h fe o ue nf d fic to a cb ye aH n IV a l-ys ne is g -f o r t h es e ative on P pC aR r t as i c sa i py an A ts t s Et iu th de y r ep nrto rt yo , c6 o5 l -3d% e fo inf e H dIV tu -berculosis in f e c te d in f an otrs dw ee a rt e h a oc s cu ym rr pe td o ma i n t i5 c2 ( c Ch Di C l dc re lini n ca (1 l 90%) in the c a t e g o r y N ) ai n sd o n2 i6 a2 z i% d w ge ro re up mi as ldc ly om sypa m rpet d om wa ith ic53 children ( ca te g o r y A ) ( (T 19 a3 b )l ei n3 ) t hA em p o ln ag ce c bhi old gr e on u pw ( hh oa z wa errd e ratio, 098; c o n f i r m e d 9t5 o% b co e n H fI iV d-e inc fe e cti e nd te , rtv hael m [C ed I ]i ,a n 0 6C 7D4 to + 144) (Fig 1 l y m p h oc y ti e n pe t h receS nu tp ap g lee m an ed n tH a Ir V y- 1 A pvp ie ra n ld il x o) ad Tu w be ere rculosis ac28% and 6 c2 o5 u, n0 t0 e0 d c fo or p i3 es 1 pe ( 5 r9 6 m% i l) l i o li ft e th r, e rp es r ipec ma -r y e n d p o i n t s tively, at s in t ut dh ye ei n st orn yi ,a z a in dd g1 r7 o1 u pc hi an l dr d ef n o r( 3 31 85 ( % 7)1 7 h% ad ) in the a lr ea d y s t ar p tel d a cto e bo r eg cr eo iv ue p a (Pn = t ir0 e4 t0 ro ) ;v ir da e la t th r ea at cm coeunnt t e d f o r 2 1 ( T a b l e 3 ) ( 4 0 4 % ) a n d 1 5 ( 2 8 3 % ) o f t h e p r i m a r y e n d po i n t s i n t h e t w o g r o u p s , r es pec t iv e l y (P = 0 12 ) T h e re E f f i c a c y s u l t s w e r e s i m i l a r w h e n t h e a n a l ys i s w a s a d j us t e d HIV-Infected Cohort f o r s t a t us w i t h r es pe ct t o a n t i re t r ov i r a l t r e a t m e n t P rim ar y e n d ap tob inas t se lar in ee da en td ai lm ed a t ien r nTaal b h le is t4o r Py ar o ti fct iu b e r cu l os is p an t s w h o r e Oa vc eh ra ed ll , m 9o 8r9 e% t h oa f nH o IV n -einfeencd te po d icn hi tld w reere n w e r e ini t i categorized a te ad c co on r da in ng t irteot rto hv eir a f il r s tt r ea en tm d epo nt i nd t urin me gt t h e s t u d y E i gh t p Ta hr et ircei s pu a ln tt s s ow f ia th n apl r ye sv e iso us of p tr ho e t oc s eocl o -d ne df ai rnye d e n d p o in t s
Table 3. Baseline Demographic and Clinical Characteristics of Children andomly Assigned to Isoniazid or Placebo.* HIV-Infected Children Total (N = 547) Age day Median Range Weight-for-age z core Median Range Male ex no. (%) Race or ethnic group no. (%) Indigenou African Mixed ance try or other Biologic mother a primary caregiver no. (%) Hou ing type no. (%) Brick hou e Shack or wooden tructure Ho tel Hou ehold ize no. of member Median Range Brea t-feeding no. (%) Ever brea t-fed Brea t-fed at ba eline 73 (13.3) 29 (5.3) 37 (13.6) 15 (5.5) 36 (13.1) 14 (5.1) 48 (6.0) 7 (0.9) 24 (6.0) 3 (0.7) 24 (6.0) 4 (1.0) 4 2 to 15 4 2 to 15 5 2 to 15 5 2 to 21 5 2 to 21 4 2 to 16 345 (63.3) 162 (59.3) 183 (67.3) 198 (36.3) 109 (39.9) 2 (0.4) 2 (0.7) 89 (32.7) 0 468 (58.2) 235 (58.3) 233 (58.1) 336 (41.8) 168 (41.7) 168 (41.9) 0 0 0 536 (98.0) 264 (96.7) 272 (99.3) 11 (2.0) 9 (3.3) 2 (0.7) 504 (92.1) 254 (93.0) 250 (91.2) 775 (96.4) 389 (96.5) 386 (96.3) 29 (3.6) 14 (3.5) 15 (3.7) 792 (98.5) 394 (97.8) 398 (99.3) 0.58 0.61 0.54 0.35 0.37 0.34 4.29 to 3.07 3.44 to 3.07 4.29 to 3.032.83 to 3.95 2.14 to 3.95 2.83 to 3.64 237 (43.3) 114 (41.8) 123 (44.9) 411 (51.1) 200 (49.6) 211 (52.6) 96 97 95 96 96 96 91 to 120 91 to 120 91 to 120 91 to 120 91 to 120 91 to 120 I oniazid Group (N = 273) Placebo Group (N = 274) HIV-Uninfected Children Total (N = 804) I oniazid Group (N = 403) Placebo Group (N = 401)

Characteristic

26

n engl j med 365;1 nejm.org july 7, 2011

The New England Journal of Medicine Downloaded from nejm.org on February 14, 2013. For personal use only. No other uses without permission. Copyright 2011 Massachusetts Medical Society. All rights reserved.

I s o n i a z i d P r o p h y l a xiE s xi p no H se I d Children

Table

3.

(Continued.) HIV-Infected Children Total (N = 547) I oniazid Group (N = 273) Placebo Group (N = 274) HIV-Uninfected Children Total (N = 804) I oniazid Group (N = 403) Placebo Group (N = 401)

Characteristic

Maternal hi tory of tuberculo i no. (%) During index pregnancy Before index pregnancy Any hi tory of tuberculo i BCG vaccination no. (%) Within 7 day after birth 8 to 29 day after birth CDC clinical HIV category no. (%) N A B C HIV-uninfected Mi ing data CD4+ cell % Median Range CD4+ category no. (%) <20% 2024% 2534% 35% Mi ing data or HIV-uninfected Pla ma HIV-1 RNA copie /ml Median Interquartile range Antiretroviral treatment at or before tudy entry no. (%) 625,000 46,000 to 750,000 171 (31.5) 710,000 482,000 97,905 to 258,000 to 750,000 750,000 78 (28.7) 93 (34.3) 111 (21.5) 86 (16.7) 187 (36.2) 132 (25.6) 31 56 (21.7) 40 (15.5) 90 (34.9) 72 (27.9) 15 55 (21.3) 46 (17.8) 97 (37.6) 60 (23.3) 16 28 6 to 58 29 6 to 53 28 6 to 58 354 (65.3) 178 (65.7) 176 (64.9) 142 (26.2) 37 (6.8) 5 (0.9) 4 (0.7) 5 74 (27.3) 16 (5.9) 2 (0.7) 1 (0.4) 2 68 (25.1) 21 (7.7) 3 (1.1) 3 (1.1) 3 513 (93.8) 255 (93.4) 258 (94.2) 34 (6.2) 18 (6.6) 16 (5.8) 787 (97.9) 395 (98.0) 392 (97.8) 17 (2.1) 8 (2.0) 9 (2.2) 2 (0.4) 37 (6.8) 39 (7.1) 0 14 (5.1) 14 (5.1) 2 (0.7) 23 (8.4) 25 (9.1) 6 (0.7) 51 (6.3) 57 (7.1) 4 (1.0) 29 (7.2) 33 (8.2) 2 (0.5) 22 (5.5) 24 (6.0)

* Percentage may not add to 100 becau e of rounding. BCG denote bacille CalmetteGurin, CDC Center for Di ea e Control and Prevention, HIV human immunodeficiency viru , and HIV-1 human immunodeficiency viru type 1. Hou ing type wa not provided for two HIV-infected participant in the placebo group. Category N denote a ymptomatic, A mildly ymptomatic, B moderately ymptomatic, and C everely ymptomatic. Participant with mi ing data and HIV-uninfected participant were excluded from the percentage . E x cl u de d inw g ed r at e ae v fre om n a th nd e ii x o nH ia I Vz ii d n faencd te p d lap ca erb tioc g ip ra on ut p,w re i tphe c m tii v e l y . HI V - u n i n f e c te d participant were excluded from the percentage . The range wa 400 to 750,000 for both tudy group . HIV-uninfected participant were excluded from the percentage .

w e r e c o n s i s ti e sn ot n iw a iztih d lg a rco ku p o f(e 1f 0f ip ca a rt cy ici Ip n aa nd tsd, i t3i 7 o% n ,) a n d t h e p l a a pos t h oc a n a l ys is c o ef bot h ge r oco up m po ( 1s 1i tp ea r e tni d cip po ain ntts , o4 f 0% ; P = 0 8 3 ) T h e probable o ov r er d ae l lf i in n icti e d en tu ce b eo r fcutl u os b is e rs ch uo lo wse id s w no a s 1 2 1 ca s e s p e r s i g n i f i c a n t d i f f e re n c e i n i n 1c 0 i0d0 en c ce h i lb de -y tw ea ee rn s ( t9 h5 e% C I , 9 5 t o 1 5 3 )
27

n engl j med 365;1 nejm.org july 7, 2011

The New England Journal of Medicine Downloaded from nejm.org on February 14, 2013. For personal use only. No other uses without permission. Copyright 2011 Massachusetts Medical Society. All rights reserved.

The new

england journal

of

medicine

T ab le 4. Summary of First End Point Met toward Primary Outcome Measures in Children andomly Assigned to Isoniazid or Placebo.* End Point HIV-Infected Children HIV-Uninfected Children I oniazid Placebo I oniazid Placebo Total Group Group Total Group Group (N = 547) (N = 273) (N = 274) P Value (N = 804) (N = 403) (N = 401)P Value no. (%) Primary end point: tuberculo i di ea e or death Specific end point Protocol-defined tuberculo i Definite PTB Probable PTB Po ible PTB Definite EPTB 69 (12.6) 31 (11.4) 38 (13.9) 0.40 8 (1.5) 8 (1.5) 48 (8.8) 3 (0.5) 5 (1.8) 5 (1.8) 21 (7.7) 0 0 21 (7.7) 3 (1.1) 3 (1.1) 27 (9.9) 3 (1.1) 2 (0.7) 15 (5.5) 59 (7.3) 14 (1.7) 9 (1.1) 36 (4.5) 0 0 4 (0.5) 21 (2.6) 28 (6.9) 31 (7.7) 8 (2.0) 3 (0.7) 0 0 2 (0.5) 6 (1.5) 6 (1.5) 0 0 2 (0.5) 105 (19.2) 52 (19.0) 53 (19.3) 0.93 no. (%) 84 (10.4) 39 (9.7) 45 (11.2) 0.44

17 (4.2) 19 (4.7)

Probable EPTB and po ible PTB 2 (0.4) Death without prior tuberculo i36 (6.6) Latent tuberculo i

9 (2.2) 12 (3.0)

* Percentage for pecific outcome may not add to the total percentage becau e of rounding. P value are for the log-rank te t. P = 0.85 in an analy i adju ted for tatu with re pect to antiretroviral treatment at ba eline and maternal hi tory of tuberculo i . Protocol-defined tuberculo i included any epi ode that fulfilled the protocol- pecified criteria for po ible, probable, or definite i , a confirmed by the end-point review committee. EPTB denote extrapulmonary tuberculo i , and PTB pulmonary tuberculo i . tuberculo One HIV-infected participant with po ible pulmonary tuberculo i later fulfilled the criteria for probable pulmonary tuberculo i . Latent tuberculo i wa evaluated at 96 week of age by mean of a tuberculin kin te t (with an induration 10 mm in con idered to be reactive). horizontal diameter The outcome wa not evaluated for HIV-infected children becau e mo t children had not completed 96 week in the tudy when the tudy ended.

D e t a i lT sho eno c vo em ra p l ll i ianncce ide wn it ch e s o tf u t dy u bfe orl c l ow ulo -u si ps, w a s 4 1 c a s e s HIV-AIDS disep as ee r 1 p000 r o gr ch ei s lsdi oyne, a an rs d ( 9m 5% o rC ta I ,l i3 t1 y t ro at 5e 2s) S i x HI V a n d c a us es o fu n di en aftect h ed a r ec h p irl o dv re id n ed (th in ree t heea c Sh up ip nle th - e is o n i a z i d mentary a An pd pep nl d a ic xe b So elg f -r re ou po p rst)e d i e co dm op f l ieai n th ce e ra t gas t r oe n t e r i t i s s c h e d u l e d v iosri t u s n(k dn eo fw in n ed r ea as s on no s (mi Ta sb se le d 1 do in s et s he s in Sc ue pplement h e l as t v t is ar iy t ) Ar p ap ne gn e di d xf)r o Sm ur7 vi4 va t lo d9i 2 d% no a tc rdoi s ff se v r is s ii tgn s i f i can t l y and did not d bet if f w e ee r s ni g tn h if eic sa tu n dy t l yg b ro eu tw pse e (P n> t 0h 9e 9 )s tSuedl y f - r e po r t ed groups co m p l i a n ce a t s c h ed u l ed v is i t s r a n g ed f r o m 6 2 t o 8 2 % a c r o s s v i s i ts a n d w a s s i m i l a r i n t h e t w o g r o u p s
HIV-Uninfected Cohort
Dp r ua gt- S b iw l ia ts y 1 T4 e4 s% t ing T h e r a t e o f l o s s to f o ll o w - u 9u 6s c we ep etki s ( 9 5 % C IO , v1 e2 ra 0 l l t, o i s 1o 7n 0 i)a z in i dt h re es c is oth ao nrt c eo f wa cs h ii ld e re nn tif w ie i td h -i n 5 o f o u t H I V i n f e ct i o 1n 9 , cw h ii tl h d rn eo n s ( i2g6n3i % f i ;c a 9n 5t% d C i fI f, e 9 re 2n t co e 512) with b e t w e e n t h e icu so lt nu ia re zid co a nn fd irp ml e ad c etb uo bg ero cu ul p os s is ( Pw= ho 0 5w 8e ) r e t es t e d Eighty-fou fr o rc h s il us dc re ep n t i( b 1 i0 li 4t% y ) Orfe a th c es he ed 5a cp hri i lm da re ry n ,e 2 n dc h i l d r e n point, a com (1 p os H Ii V te - inof fe c t te u be d rc an ud l os 1 is H d IV is -e unin a sf ee , c lte ad te ) nw t e r e in t h e t u b e r c u l o s i iss o in nf ie ac zt id iog nr , oo urp da en ad t h3 T(h ae l l eH s It V im - uan t ie nd f ehct ae zd - ) w e re a r d r a t i o f o r t h e i s o n i a z i di ng r to hu e pp a la scc eo bm o pgar roeudp w i t h t h e p l a c e b o g r o u p w as 0 8 5 ( 9 5 % C I , 0 5 5 t o 1 3 0 ) au fe ( T a b l e 4 , a n d F i g 1 i n t h e SS pt py l e m e n t a r y A p pe n d i x ) T h e r eR w at as es no of sgi r ga nd ie fic 3a n ot r d hif gh fe erre n cl ce ini bceat lw o ee r nl a b o r a t o r y study gr ao bu np os rm(P al = i t i0e4s4 w ) e (T re a bsl ie m4 i l)arA i nn a ltys he es t o w fo asl t l u d y gr o u p s , s ec o n d a r y set n rd a t po i f ii ed n t sa c sc ho o rw de in d gl a tc o k Ho If V e s ft fa it c us acy ( To a fb l e 2 i n t h e isoniazid pr So up ph py l la em x iesn a ts ar cy om A p pe a rn e d iw x) ith Wp i tla hct eh be o ex c e p t i o n o f

28

n engl j med 365;1 nejm.org july 7, 2011

The New England Journal of Medicine Downloaded from nejm.org on February 14, 2013. For personal use only. No other uses without permission. Copyright 2011 Massachusetts Medical Society. All rights reserved.

I s o n i a z i d P r o p h y l a xiE s xi p no H se I d Children

g r a d e 3 p e ri p h e vs ra l 0 n % e)ur , o wpear teh y mo inr e on li ek e H lI y V -tin o f be e c te se d v e re l y i m m u n o child in the ison ci oa m zp id r og mi ro su ep d , (a C lD l C g rca ad tee go 3r y o rB h o ig r hC e,r 8 8 % v s 8 % ) , toxic effects w res re oll ve esds, lik a ll eo ly w in tog bf e o rr e th ceiv re insgum ap nt t iir oe nt r o v ir a l t r ea t of treatmentm wei n th t a th t es tru ad ny do em nt ly r y as (s 9 i% g nved s 3 s1 tu %dy ), had lower CD4+ d r u g A l l r e p o r t ab l e pe ser r icou en s ta ad gv es er s (e 20 e% v en vs t s2a 8r% e ) , a n d w e r e m o r e s es h o w n i n Tv ae b rl e el y 3 m i nal t nh oe u rSi u sh pe pd lem a te n stu ad ry y A ep np tr ey nd (i m xe d i a n z s c o r e , 1 5 6 v s 0 5 8 ) I n a d di t i o n , 9 % o f c h i l d r e n in t h e s t u d y b y Z a r e t a l h a d a r e a ct iv e t u b e rcu l i n s k i n Discussion t es t a t s t u d y e n t r y , po s s i b l y i n d i c a t i n g p r e v i o us T h e p r e v e n t i o n o f t u b e rcu l M os TB isin in f epe ct r io in na t a l l y e x p o s e d H I V - in f e c te d Co an nd trH ar Iy V -t unin o tfh ee c te f id nd in if nan gs t so f in t h e m e t a - a n a l ys i s ar e a s wi t h h i g h i n oc fi d ae nn ti cte usbeorfcut lu ob se is r cp ulr o os pi h s y an l ad xiH s I iV n H I V - i n f e ct e d in f e c t i o n , s u c h a s asdouul t th s ew rn ith A fa ri ca no , ni r se a ct ma iv e jot r up bu eb r cu - 17 l i n s k i n t es t , li c h e a l t h c h a l l e n tghee T s h teu dy o n lbyy cu Z rar re n et t a a ll t e sh rn oa wte iv de a 4 9 % r e d u ct i o n t o B C G v a c c i n ain tio m no r ft oa r li p ty r e an v edn tai n6g8 % tub re ed r cu u cl tos io is n i in s t h e in c i d e n c e chemoprophyla ox f it su , bes er pc ec ul io asl i ls y am wit oh ng is o cn hil id ar ze id n O wu it rh a n o n r e a c t i v e 8 s t u d y s h ow e d n o b e n e f i t o t f u is be o rncu ia lz in i d1 s A as k icn lpi r n te es ic ex ta po lly - re l e v a n t as pe c t s u r e p r o p h y l a x io sfin t h iemf p in ro d vi i nn gg s d bi y s eZaasre eftr e ae l is su t rh via vta l t h e c a us es o f a mo n g H I V - i n f e c t de ea d tch h i in ldr ben o to hr g in ro fe uc p tsi ow ne -r fe r ep e rim a ri l y a t t ri b u te d t o s ur v i v a l am o n g H I Vs- e unin psf ise c ( te 44 d%c ) hi , lp dn re eu n mSoimi n i laa r ( -2 2 % ) , a n d gas t r oe n l y , a p o s t h o c tearint a is l y( s9 is %) t, han t o in t c dir l uedce td lytt ho e tcu ob m ep rc ou si l te osis However, o u t c o m e o f p r o t toco u be l -d r cu e fl ios ne is d c to uu be ld r cu hl aovsei sp , rd ee da is tpo h ,s ed t h e c h i l d r e n o r n o n - a l g o ri t h m t u b e r c u l o ts oi s ba sc hto ew ri ea d1 l 9n I in of a e sd c ig d ti nif io tn io - n , t h e g r e a t es t ca n t dif f e r e n d ci ef s f ein r eo nu c tc e oi m n e su bre vi tv wal e eo nb s th ee r v iesd o nia b ezt iw de e n t h e g r o u p s g r o u p ( 2 4 2 % ) a n oc d cu t hre r ed pla pc re im bo a rg i lry ou wpi t ( h2 i4 n 13 %, 0 d a ys a f t e r r a n d o m P = 0 9 3 ) a m o n g H iI z Va -t in io fn e, c tw ed ith c hm i la d rg re in n a l d i f f e r e n c es be t w e e n t h e A m e t a - ana l y gs r iosu p os f t t ria h el rse a o ft f e tr ub Te hre cu s lto usdi y s al pr so o- e n r o l l e d 4 4 8 % o f phylaxis in HIV th -i en f ce h ct i le dd r ea nd d uu l trsi nsg h ow t h ed e co th ua rt s ei so of- h o s p i t a l i z a t i o n niazid reduced the inciden fo cr e a on f t au cu be t20 e r cu i ll lonsess is (by 6 2 % ) i n t h os e w i t h a B po e csa it us ive e tth ue be p rcu rog l i rness sk io in t f es r o tm M T B i n f ec t i o n 7s b u t w a s in e f f e c t i v e in t ot h a1o c te iv e wi dt ih s eaasn ee g ta ak ti es v e1 te ts o t,3 m o n t h s t o be 21 s u g g e s t in g t h a t p r o p h y l a x m i sa d nto ih fe e es s t m n ed e o, c t hp arn ev i sem n tb p y riw - h i c h is o n i a z i d mar y t u be r cu l o s ip sr o In p haydl d a ixtiis on p ,r e tv he e nm te ed t at -u abe na rl cu ysl ios s i s a n d i m p r ov e d s h o w e d n o s i g n is f iucra vn ivt a o l vi e nr a th l le r s etd uu dy ct i b oy n Z in a r meot r -a l r e m a i n s u n ex t a li1t7y These da pt l a in ar ee d c It o ri rso b por sa s te i bd l eb , yh o w ur e s vt eu rd , yt ,h a t t h e r e d u c t i o n in which isoniai zn i dt h pe r o ip nh cy id la ex ni c se f a oi fl e tu d b teorcu p lro es vi e s no tbserved in the t u b e r c ul o s i iss o am n io an zg i d Hg IV ro -i un pf e bcyt e Zd a rc h e itl d arl e w n aw si t th ho eur te s u l t o f t r e a t a history of MTB me ex n pos t ou fru e n r e co g n i z e d u n d e r l y i n g p r i m a r y t u b e r T h e o t h e r m a jcu or l os p iusb l i is n ht e hd e s etn urd oy lle od f ic sh o in ld ia rz e in d, as w as o b s e r v e d 2s 2 p r o p h y l a x i s i n H I V - i n f e c t ed i n ce ha ir ld ly r esnt u w das ie ur n a od t fe hir e s-r on ti ha azni dt ,h e r e t a k e n i n C a p e sT uo lw t n o ,f S po ru ot ph hy Al f ari xca i s Ia sg oa ni i az n si td M pT rB o - i n f ec t i o n a n d i t s p h y l a x i s w as as psr oc og ia re te ss di o wn i, t hw a hi c 5h 4% w ar s ed tu hc et o io bn j eic nt i v e in o ur s t u d y a l l -c a u s e m o r t a lP io ty s sa ib nd l e ar e 7a 2s % o nr s ed wuhct yi o is no i nn i az th id e prophylaxis was i n c i d e n ce o f t u b ienr e cu ff le os cis t iv , e p ri o nmc pht ii ln dg r eena r w ly ith tr o iu atl k n o w n M T B e xp otermination by s ur th e e ind a ot ur a s atn ud dy sa in fe ctl y ud m eo a nis to ur bi o np gt im a l d o s e o f t h e 1d 8T h e r e w b oa r der rueg , m iasro kn ei d az d id iff re er se is nt ca es n cb ee ,tl w aee ck n o f c o m p l i a n c e wi t h the HIV-infected t hc eh m ild e re di ca n t ei n o rno lr le egim d ie nn o , u arn d sti usd sy u e s r e g ar din g t h e a n d t h os e i n t h e C s pe a pe cif Ti o cw i tn y s otfu t dy h, e ls im t ui dy t i ne gn a d po i n t s A d is cus s i o n d i r e ct c o m p a rois f otn h es o fe t fa he c t foi r nsd ii n s ga sv f ari o la mb lt e he i nt w th oe S u p p l e m e n t a r y s t u d i e s T h e c h il d r e n e n r o l A le pd pe b ny d iZ x ar e t al a s c o m p a r e d w i t h o u r coFh io nr a tl l w y, e re a loi lm d iet r a t( im o ed n i oa f no a ug r es, t u dy i s r e l a t e d t o 2 4 7 m o n t h s v s p9 o6 s sd ib ay le s )c , hh an ag d eb s e in e nt h tr ee a et pe i d e fm oi ro t lo ug - y of tubercub e rcu l o s i s i n s lo os m is e a cn as desi nbem fo or rt eal e it ny r oal m lm oe nn gt H ( IV 16 -i % nfected children
n engl j med 365;1 nejm.org july 7, 2011

29

The New England Journal of Medicine Downloaded from nejm.org on February 14, 2013. For personal use only. No other uses without permission. Copyright 2011 Massachusetts Medical Society. All rights reserved.

The new

england journal

of

medicine

b e ca u s e o f in b cr u ea rg s , ebde faocre c e tsh s e to i nan t rt od ir e ut cr to io vn ir aol f t a r ea n tt iretroviral m e n t T h e ot v re r aa tl m l er n a tt ,e w oas f a3 0 p2 ri 8m pe a rry 1e0n0d, 00 po0i na t n d 1 0 , 0 1 6 pe r a m o n g H1 IV 0-0 i, n0 f0 e0 ct , erd es cp he i lcd tr iv ee nl y in , in o uc r hi s ltd urd ey n w un ad s e2 r 25 % y ea r s o f 8 o v e r a p e ri o d o f 9 6 w Te he ek b s, u ar g w d e hi ec n ho i fs t b ue be lo r cu w lt oh se i s4a 0m %o n g H I V r a t e t h a t in w f e co te rd igi cn hi al ld ly r e es n t( i1 m 2a 1t ed cas W ee s t ph ee rr e 1f 0o0r 0 e c hi l d - y ea r s ) continued en inr o o lur l i nsg t ucd hyil d rr ee ma n in ae ft de r hi g th h e d ie nsi p t ii a tel a t ar cc geests to a n e n ro l l m e n tt i ro ef t r5 o0 vi0r a pa l rt tr ie ca i pa t mnet n s t hA ad h ibe gh en bu re ra dc eh n ed o f t u b e r c ul o The futility as n iasly w s is as, a n le sv oe i rd th ee n lt es ifs ie , di nad m ic oa n tgedH I tV h -ex a t po s e d u n even with it nh fe ec t m e os d tc h oi pl t di r m e is nt( ic 4 1esc t as im es a t pe es r , i 1t00 w0a s child-years) un l ik e l y tT ha he t ste he fis nt du id ny g swu an s da ed rs ec qo u raet et lh ye pn oe w ee dr e td o t eo x p l o r e al s h o w s i g nti e f irn cat n itv e d io f fer p t en i oc ne ssf o in r the pri em ve an ry t i en on d and managep o i n t s b e t w e en tm hen tt w o fg r to uu b ps e r cu Ou l os r s ist u in d yHwa I Vs - ex pos e d c h i l d r e n a d e q ua te l y p o w e r e d ( 9 1 7 % ) t o d e te c t a 5 0 % r e la T h e c o n t en t o f t h i s a r t ic l e i s s o l e l y t he re s po n s ib i l i t y o f t he t i v e r e d u c t iao rd ima peo m g t HI un t h oin rs p an do r ey s ne on t d nec s in s at rs i l y are po re n s en t hV e - o f f ic i a l v ie w s o f he l n I n se t it em s o th i n f e c t e d c h i l d r e n o n t h e bt a s iN sat io on f aa s ut ti a ft H eea t lh at O ve r a lt l h sup t fc or he nu at ao l M ernalPediatric 2 5 % o f t h e c h i l dr e n in ep o pr la etb o I nt ge r ro pi on w u al td A d o l e sc en t A I DS C l i n ic a l T r i a l s ( I M P A A C T ) G r o u p wa s p rov id e d r e a c h a p r i m a r by y e pf o nt e e1 A 9I 6 - 86 we e) k pee E ru in oic de, K e n n e d y g rn ad nts roim tho e v NI Ar I D t( h U0 06 32 , th Se h ri v ta i tt u te d eH lt h o anu d r H uman Dy ev e l o p m e n t an incidenc se i rmNi a l tai o rna t lo I n t sh oo bfs C ehi r lv dea i n stud (N D,) , i a Nt au tid on I ns t ii ta u tz ei d of p Mr eo nt ah l y He a l t h ( A I 0 68 6 3 2 ) In conclu s Ii C oHn nn do t uhre s ya l is on p T h is w o r k w as s u p p o r t ed b y t h e S t a t is t i c a l a n d Da t a A n a lys i s l a x i s a s c o m p ar i t th ce oc hw al so fs P aub fe t l tin - er N I A I D c oC ee nd t e r wat he p H laa r va rdb S oo l ic b Hu ea h, eufnd ope t ie vx e p ao gr er me e np t sr o wi th th Pe di aa t ri ID s S t C lti u ni b ca l rTc riu als Group fective as p rrae seu p hy le ax is gca A in e I 4d 1 1a 10 dI t MP A e AC Gd rou Ue 01 l o s i s in HI V -( i5n U f0 e1c A te n) da n H Vh-eu Ininf cT te cphi( l1dr n AI068616) Supp o r t o f t h e s it e s wa s p ro v i de d by N I A I D a n d t he N I C H D I n t er n a However, the r en sa ul l a tn sd o o ur td ui d ed s cnif ic t io Dfo me st ic sPe at y r ic ar an Mp ate er al H It V oC la i n ic a l T r i a l s Ns et w rku (tN I CA HD ntr ac Nh 0 1d -D - 9 -b 00 HHSN2672 00setting such a Soo h fri c coa wi t th n u ambe hr ig uKal u1r/ he st ud y V wa i s nf a le sc o tf iuo nn de dMby d e n o f t u b e r80 c0 u0 l0 o1 sCi )s T a nd HI u ca h g ri a nn-t f ro m t h e S e c u re t h e Fu t u r e Fu n d , a p h i l a n t h ro py p rog r a m s po n s o re d by B r i st o l s i g h t ha s b e e n g a in e d in t o Mtyer he e id s S qp u ib b e mi o l o g y o f Diu sctlos rm si p e ra t u b e r cu l os i s i n s o hu e rren f oA fr c ro a v ii de n d t by h et he aut h oofr sa a nre - a v a i l ab le w it h et f ud l l yt ec xo t n of is ar M o rg t i r e t r o v i r al t r e a t m e n t I n at hs u dt uhc te dt ici le n at CN aE pJ e e t h a n k t h e pa W re n t s a n d l eg a l g u a rd i a n s fo r a l lo w i n g t hei r Town from 2 0i0 0 0ic7, t eh ie d f l ; c tu ur e l -t h c a re w o rk ch ld 4 re nt o to 2 pa rt i pat n in thc e ic l ie nn ic c a le t ro ia hl et h ea r o p ro vs id i w n ga c to the pas rt ts ot0 her mbe c o n f i rm e d t u ber esr f coul si sa re 15 96 ca eic si pa pne r; 1 0 ,m 0e0 0 rs of the P1 4n 1t m si st nc g i id n et n hec c 7 I n H I V - i n f e c t ed in a f0 a d d i ts teiao n fo , rt a hse i in eo n d uc t o f t h e s t udy ; Pe t e r R D o n a l d , M D , a nd H S i mo n S ch a a f , M D , f o r t h ei r c r it ic a l r e o f h os p i t a l i z a t i v oie nw foo l tau e -c ot n an ael lli n g , M D , f o r h e r f rt hcu e m nr u sc rip ; fainrdm Aed n neke Hd ess ne t rr ibc ut io o n st i os d r so us ep ib e i ls i t-y t e st i n g c a t e g o r i e s o f p u l m o n a r y tc uob ul i ug n -J hc a nt n
References
1.Nunn

P , R eid A , D e Co c KM od T R ub , Jer oh n s tc oa neus Ri o nb g erse ts vo er ne Sc , oU m ym s u n it y - ac q u i re d low er 5k . Wo c u lo s i s a n d H I V i n f e c t io P n ,: e tt he ag l lo Tb ua bl e rse cutre l- ossp is i rt at ra on rs y mt irsac s ito i nn f te o cy t io ou ns n gi n h u m a n i m t i n g J I n f e c t Di s 20 0 7 ; 1 9 ch 6i :ld S ren u p pi ln 1a: SS5o- ut m S1 h u4 nA ofd r ef ic a ic nien cc oy mm v iu rn u it s yt: y pe 1 - i n f e c t ed ch i l id o de d le kl o in og p h K,o u s e h o l d a d n ren d coC mm l i nu ni I ntfy ec i nf t e Dc is - 20 0 0; 3 1 : 1 7 0 - 6 2 . L a w n S D , Bek ker L G , M m M yer L , W o od R I m pac t o f t iH oIn V ri in s fkesc t Cio l inn I n f e c tC h Di9 is n u0 1 C0 , ;M 5 uden 1:40 d1 a- 8 V , Luc a s S , et a l . t2 o n t h e ep i dem io lo g y o f t ub M au r losi a i ss B in J, a G ie Lu n Rg P ,dS is ce ha as ae f s H at S , ne etc ro a l ps y i n A f r ic a n c h i l 6 . erc p e r i - u r b a n co m m u n i t y i T n hS e o na u tt hu ra A fl r ihci a s: t otd rhy ren e o fd y c ihni g l dh f ro oo m d re i nstp ra ir - at o r y i l l n e s s e s : a n e e d fo r ag e - s p e c i f ic i n t er ho vra en c ti io c ns t ub Cerc lin u lo s d ies s :cr a i pc tr iviteic n ae l cr re ov p ie sy w sot fu dy L a n ce t 20 0 2 ; I n f e c t Di s 2 0 0 6 ; 4 2 : 1 0 4 0 l it -7 er at u re f ro m t h e p re - chem 360 ot: h 98 e5 r apy - 9 0 er a n ,t M J y Ter ub er L , c Lu n g Di s 2 A0 ns 0 4 r; i8 : N 3A 9, 2 K -4 o0 mbe 2 A H , K enyo n T A , e t 3 . M i dd e l koo p K , Bek k e r L IG 1a 0. D a w s o n R , W oo d R R at e s H f et ss ub e erc l i nuglo A si C, sa C l oP t at t oh no lo Mg F, y Ja en nd nin ca gu s se Ts , o f de at h i n a s e 7 .o t r a nsm i s s i o n t o ch i l d ren et a na d l ad Ho ig leh sc ien ncti s den c e r ie os f o t ub f h erc um u lo as ni s i m m u n o def ic ien c y v i r u s i n a c o m m u n it y w i t h a h a im gh o np greHI va Vl enc i nfe e ct of ep dos i it nfa i vnet sa: nd e v- in deg en at c ie ve f rp oe md i at r i c re f er r a l H I V i n f e c t io n a mo n g ad ua ltS s oC ut l ihn AI f nrfic ea cn t p oh p os u lp at it ioanl - ba ad s mei d s ss io t ns udy i n Bot s wa n a Pe d i at r Di s 2 0 0 8 ; 4 7 : 34 9 - 5 5 h ig h l ig h t s t h e n e e d f o r Ii n m fp e ro c tv e Dids tJ ub 20 erc 03 u; - 2 2 : 4 3- 7 D iose dens c o n tL ro , l st r at eg ie Hs s u Cl K i1 n H nh fe i rctty Di ye s a r s a f t er i s o n i a z i d : 4 . M ad h i S A , H u eb n er R E, los 1 . IT A d uc T , W e sl e y D , C oo p er 2 0P 0A 9 ;H 4 I8 V: -110 8co 1-4i t s i m p ac t o n t ub erc u l o s i s i n c h i ld re n a n d i nfe ct i o n i n c h i l d r e n h o s M t ad alh is iedS A w,i tPe h t ter u sen K, a Mdo ad le hs i cA en , t s J A M A 1 98 4 ; 25 1 : 1 28 3 - 5 8p .i b e r c u l os is i n S o u t h A f r ic Ka ho In ot s aJ l T M ub , erc K l u g ma n K P S1 m In ie c. r je a aM se J ,d M da is rceas h ee t t i CA , C o o k D J , 2 Lu n g Di s 2 0 0 0; 4 : 4 4 8- 5 4 b u r d e n a n d a n t i b i o St m i ca ir les l is FM tan Ic so en i oa fzb ida ct f oer r ipare ven t i n g t u -

30

n engl j med 365;1 nejm.org july 7, 2011

The New England Journal of Medicine Downloaded from nejm.org on February 14, 2013. For personal use only. No other uses without permission. Copyright 2011 Massachusetts Medical Society. All rights reserved.

Copyright 2011 Massachusetts Medical

I s o n i a z i d P r o p h y l a xiE s xi p no H se I d Children

Society. All rights reserved

b erc u l o s i s i n n o n - H I V i nw fe wc w tu ec ddp mer c so u cn dsa v i s e du / c Co l i nt itc oa M nlt Fr, i Wa a ls ss / er mE a,nS m i J t, Co c h r a n e D at ab a se Sy st R de ov cu 2men 0 0 0; ts 2/ :D A I D S _ A E _ G r Wh adit in elg aT wabA le , Z a r H J H i g h i n c i den c e o f a n CD001363 _FinalDec2004pdf) t i m ic ro b i a l re s i s t a n t o rg a n i sm s i n c l ud i n g e 7A p reovl en o t Cio , nA d e t ifa I , S h e ex p tp ee nrd de S d ,s p Ve oc l mink trum beta-lactamase pro1 3Hs . u K H I so n i a z id i n t h 1 .k a n d t re at men t o f t ub erc u lo J sTi r s ea : a t m20 en -y t eoaf r la te n t t u b de ur cc i ng ulo Ent s ie s r in ob fe acti eo rn iaceae and methis t udy o f t he e f f e c t i ven e si s n iH n IVchin i ld fe ren c te d p e r s o n s c C i lol c in h -r ran es ei s Dt a a tnt ab St aa s ph e y l o c o c c u s au r e u s i n J A M A 1 9 7 4 ; 2 2 9 : 5 28- 3 3 S y s t R ev 2 0 1 0 ; 1 : C D 0 00 1 n7 a1 s o ph a r y n g e a l a n d b l o o d i s o l a t e s o f io8 n Z a lr T Hub J , er Cot c ut-o n M F , S t rH a Iu Vs- s i nS f, ec ette d a l ch i l d ren f ro m Ca p e T o w n, 1 4T . h e S o u t h A f r ic a n N at 1 .a l o s is C o n t r o l Pr o g ra m m e E Pr f fa e ct c ti co af l i g so un id ia ez - id p ro p hy So la ux th i s Ao fn r icmo a r BtM aC l - I n fe c t Di s 2 0 0 8 ; 8 : 4 0 l i n es , 2 0 04 ( h t t p : / / w w w k i tznh y a en ad lth in gc o id vz en a/c e o f t ub 2 erc M ua lorsai iss i B n J ,c h Gi ie l - R P , S ch a a f H S , Be yer s 0. ch r p / doc u men t s / G u i del i n e d s ren / G uw id it eh lin He IV s : randomisN ed , D cont a ro ld l lPeR d, S t a rke J R C h i ld h o o d p u l % 20 N at io n a l /T ube rc u lo s i s /tS rA ia % l 20 BTB MJ %2 2 0 0 7 ; 3 3 4 : 1 3 6 m o n a r y t ub erc u lo s i s : o ld w i s d o m a n d G u id e l i n e s% 20 20 0 4 pd f ) , eM w ad ch ha i lS l en A ge s A m J Re s p i r C r i t Ca re 1 9M . oo r e D P , K l ug m a n K Pn Ra o ll n eu o tr f itS io tn re : p at o coc c us p n Meu ed mo 20 n0 ia 6e ; 1 i7 n3 : h1 o0 s7 - 8- 9 0 1 5M . a n ag emen t o f se v ere m m a n u a l f o r p hy s ic i a ns a n pd ita o lt ih z er a t iso en n io fo r r ac ut e c o2 m m uu nn it ty -Fac Wq , uFi e rere d b e e S H P re v en t i v e e f 1M . o h e a l t h w o rker s Gene va: W o p rld neu Hmo e an lt ia h a s s o c i a t e df e w ci tt s h o cfu l it su o re n i-a cz oi n d - i n t h e t re at men t o f pr i Or ga n i z a t i o n , 1 99 9 ( h t t p f: i/ rm /w ew d wM wyhco oi b na t/ c t e ri u m t u mb ae rr yc u t ub l o erc s i su lo in s c is h i il n - c h i l d ren N E n g l J nutrition/publications/s de ren ve :ra em pa nle nu umoc trit oi c oc na/ l c o M nj e ud g at 1e 9 6v 1a ;c 2c 6 i5 n:e 7 1 3- 2 1 e n / m a na g e _ s e v e r e _ ma l n p u ro t rb it ei o st nud _ eyn g Pe pd d ifat ) r I n f e cCopyright t Di s J 2011 20 1 Massachusetts 0; 29 : Medical Society. D A ID S / RS C T o x i c i t y t a b 1l 0 e9 s9 , -2 00 40 4 ( h t t p : / / 1 6.

journal

archive at nejm.org

Every article published by the is now available at , beginning with the first a r t i c l e p u b l i s h e d i n J a n u a r y 1 8 1 2 T h e e n t i r e a r c h i v e i s f u l l y s e a r c h a b l e , and browsing of titles and tables of contents is easy and available to all Ind i v i d u a l s u b s c r i b e r s a r e e n t i t l e d t o f r e e 2 4 - h o u r a c c e s s t o 5 0 a r c h i v e a r t i c l e s p e r y e a r Access to content in the archive is available on a per-article basis and is also being provided through many institutional subscriptions

n engl j med 365;1 nejm.org july 7, 2011

31

The New England Journal of Medicine Downloaded from nejm.org on February 14, 2013. For personal use only. No other uses without permission.