Chemoprophylaxis in the prevention of tberculosis
NORMA I SOZA PINEDA, SUSAN M. PEREIRA, ELIANA DIAS MATOS, MAURICIO L BARRETO
Tu b ercu lo sis ch em o p ro p h yla xis is a t h era p eu t ic m ea su re fo r t h e p reven t io n o f in fect io n b y Myco b a ct eriu m t u b ercu lo sis o r t o a vo id d evelo p m en t o f t h e d isea se in in d ivid u a ls a lrea d y in fect ed wit h it . Iso n ia zid is t h e m o st co m m o n ly u sed t h era p y; h o wever, t h e u se o f rifa m p icin a n d p yra zin a m id e h a s recen t ly b een in t ro d u ced . Th e o b ject ives o f t h is st u d y were t o review t h e resu lt s o f t h e p rin cip a l st u d ies eva lu a t in g t h e in d ica t io n s fo r ch em o p ro p h yla xis wit h iso n ia zid a lo n e a n d in a sso cia t io n wit h o t h er d ru g s, it s effica cy in t h e p reven t io n o f t u b ercu lo sis wit h resp ect t o t h e d ifferen t risk g ro u p s a n d t h e a lt ern a t ive reg im en s a va ila b le. A syst em a t ic re visio n o f t h e m e d ica l lit e ra t u re wa s ca rrie d o u t wit h p a rt icu la r e m p h a sis o n clin ica l t ria ls a n d m e t a -a n -a lyses. Offici-a l reco rd s were -a lso co n su lt ed . Th o se st u d ies in vo lvin g r-a n d o m ized clin ic-a l t ri-a ls o n t h e u se o f iso n ia zid , rifa m p icin o r p yra zin a m id e in HIV- p o sit ive o r n eg a t ive p a t ien t s were select ed . Iso n ia zid co n t in u es t o b e effect ive fo r t h e p reven t io n o f t u b ercu lo sis in p o p u la t io n s o f b o t h HIV- n eg a t ive a n d HIV- p o sit ive in d ivid u a ls. Th e st a n d a rd d o se o f 5 - 1 5 m g / kg / d a y h a s sh o wn sim ila r p ro t ect io n o ver t rea t m en t p erio d s ra n g in g fro m six t o t welve m o n t h s. Th e risk o f d evelo p in g h ep a t it is wa s less t h a n 1 % ; h o wever m o n it o rin g d u rin g t rea t m en t is reco m m en d ed in p a t ien t s o ver 3 5 yea rs o f a g e a n d in u sers o f a lco h o l. St u d ies in vo lvin g t rea t m en t reg im en s wit h o t h er fo rm s o f m ed ica t io n were in co n clu sive a n d n ew st u d ies wo u ld h a ve t o b e p erfo rm ed t o eva lu a t e t h e effica cy o f t h ese reg im en s in p o p u la t io n s a t h ig h risk o f d evelo p in g t u b ercu lo sis.
Abbre viatio ns use d in this pape r:
9 5 % CI – 9 5 % co n fid en ce in t erva l
AIDS – Acq u ired im m u n o d eficien cy syn d ro m e ATS – Am erica n Th o ra cic So ciet y
BCG – Ba cillu s Ca lm et t e- Gu érin BTS – Brit ish Th o ra cic So ciet y EMB – Et h a m b u t o l
HIV – Hu m a n im m u n o d eficien cy viru s INH – Iso n ia zid
Mt b – Myco b a ct eriu m t u b ercu lo sis
PAS – Pa ra - a m in o sa licylic a cid PPD – Pu rified p ro t ein d eriva t ive PZA – Pyra zin a m id e
RFB – Rifa b u t in RIF – Rifa m p in RR – Rela t ive risk TB – Tu b ercu lo sisM
INTRODUCTION
Tu bercu losis (TB) chemoprophylaxis con sist s of t he admin ist rat ion of ison iazid (INH) t o in dividu als u n in fect ed wit h Mycobact eriu m t u bercu losis (Mt b) i n o r d e r t o p r e v e n t i n f e c t i o n (p r i m a r y ch em o p ro p h yla xis) o r t o in fect ed in d ivid u a ls in o rd er t o a vo id t h e d evelo p m en t o f t h e d isea se (seco n d a ry p ro p h yla xis). Ho wever, o t h er d ru gs, su ch a s rifa m p in (RIF) a n d p yra zin a m id e (PZA), h ave recen t ly b een in t ro d u ced .(1 )
Sin ce 1952, INH has been u sed for TB t reat men t in t he USA an d in Brazil. Sin ce 1965, t he Am erican Th o ra cic So ciet y (ATS) h a s reco m m en d ed t h e u se of INH for TB prophylaxis in in dividu als presen t in g p o sit ive react io n s in t u b ercu lin t est s (t u b ercu lin rea ct o rs). In t h e ea rly 1 9 7 0 s, t h e u se o f INH wa s a sso cia t ed wit h severe h ep a t o t oxicit y, wh ich ca n b e fat al. Fro m 1 9 7 4 o n , t h e ATS rest rict ed t h e u se of INH t o t u bercu lin react ors you n ger t han 35 an d t h o se o ld er t h a n 3 5 wh o p resen t ed a h ig h risk fo r TB rea ct iva t io n , p ro vid in g t h a t t h ey h a d n o t b een d iag n o sed wit h liver d isease. Lat er, in 1 9 8 3 , it was su ggest ed t hat pat ien t s in cert ain age bracket s who were receivin g INH be clin ically mon it ored t hrou gh p erio d ic a ssessm en t o f liver fu n ct io n . Th e u se o f INH sh o u ld b e d isco n t in u ed if a m in o t ra n sfera se le ve ls re a ch t h re e t o f ive t im e s h ig h e r t h a n n ormal.(2 - 4 )
Th e o b ject ive o f t h is st u d y wa s t o a n a lyze a n d r e vie w t h e p r in c ip a l s t u d ie s o n s e c o n d a r y ch em o p ro p h yla xis wit h INH a n d it s effect iven ess in TB p reven t io n . We sp ecifica lly in t en d ed t o review q u est io n s reg a rd in g p reven t ive t rea t m en t fo r TB, id en t ifyin g t h e effect iven ess o f INH in t h e va rio u s risk g ro u p s, in clu d in g t h o se in fect ed wit h h u m a n im m u n o d eficien cy viru s (HIV), a s well a s id e n t ifyin g a lt e rn a t ive re g im e n s, d e t e rm in in g d u ra t io n o f t re a t m e n t , e va lu a t in g su p p o rt in g evid en ce, a n d a ssessin g a d verse effect s.
Preventive use of isoniazid in risk g roups
Ba sed o n t h e sen sit ivit y a n d sp ecificit y o f p u rified p ro t ein d eriva t ive (PPD) t u b ercu lin t est s a n d TB p reva len ce in t h e va rio u s risk g ro u p s, several cu t o ff p o in t s h ave b een reco m m en d ed . An in d u ra t io n 5 m m is co n sid ered p o sit ive in Mt b -in fe ct e d -in d ivid u a ls wh o a re a t h ig h risk fo r d evelo p in g act ive TB.(5 ) An in d u rat io n 1 0 m m is
co n sid ered p o sit ive in t h o se wh o are likely t o h ave h a d a recen t in fect io n o r in t h o se wh o p resen t
a n y t yp e o f clin ica l co n d it io n t h a t in crea ses t h eir risk o f d evelo p in g t h e d isea se. In in d ivid u a ls a t lo w risk, fo r wh o m t u b ercu lin t est s are n o t u su ally reco m m en d ed , a n in d u ra t io n 1 5 m m sh o u ld b e co n sid ered p o sit ive.(4 ,5 )
Chemoprophylaxis in non- infected
individuals (primary)
In Bra z il, t h e Min ist é rio d a Sa ú d e (He a lt h Min ist ry) reco m m en d s t h a t n ewb o rn s co h a b it in g wit h a ct ive TB in d ivid u a ls b e t rea t ed wit h INH d u r in g t h e f ir s t t h r e e m o n t h s o f lif e a n d su b seq u en t ly b e su b m it t ed t o t u b ercu lin t est in g . If t h e resu lt s a re p o sit ive (in d u ra t io n 1 0 m m ), ch em o p ro p h yla xis sh o u ld b e co n t in u ed fo r a n addit ion al t hree mon t hs. If t he resu lt s are n egat ive, a d m in ist ra t io n o f t h e d ru g sh o u ld b e in t erru p t ed a n d t h e ch ild ren va ccin a t ed wit h t h e b a cillu s Ca l m e t t e - Gu é r i n (BCG) v a c c i n e .( 6 ) Th e s e
recom m en dat ion s are sim ilar t o t hose m ade by t he ATS an d BTS (Brit ish Thoracic Societ y).(4 ,7 ) However,
Am erica n p u b lic h ea lt h o fficia ls reco m m en d t h a t ch ild ren b o rn t o m o t h ers in fect ed wit h HIV b e su b m it t ed t o an n u al t u b ercu lin t est s.(8 )
Chemoprophylaxis in infected
individuals (secondary)
accordan ce wit h t he fin din gs of a con t rolled clin ical st u dy on con t act wit h TB pat ien t s in t he hom e, in which it was dem on st rat ed t hat TB in ciden ce was highest am on g children less t han 5 years of age (12.9/ 1000). The occu rren ce of TB in t his age grou p is always con sidered a recen t in fect ion , an d INH has demon st rat ed high efficacy (87%) again st su ch in fect ion s.(9)
The gen eral con sen su s in t he lit erat u re is t hat children you n ger t han 5, t een agers an d you n g adu lt t u bercu lin react ors con st it u t e high- risk grou ps an d shou ld be advised t o accept chemoprophylaxis.(5,7,10)
In a n o b serva t io n a l st u d y co m p risin g 2 4 9 4 ch ild ren , t h e in cid en ce o f TB a m o n g ch ild ren r e c e ivin g a 1 2 - m o n t h c o u r s e o f INH ch em o p ro p h ylaxis was 3 .2 / 10 0 0 / year, co m p ared w it h 3 0 . 2 / 1 0 0 0 / ye a r in t h e p la c e b o g r o u p . Admin istration of INH provided 90% protection an d n o d e a t h s w e re re p o rt e d a m o n g t h o se w it h pu lm on ary TB. In addit ion , n o disease react ivat ion was observed du rin g adolescen ce, which su ggest s that the treatmen t provided lon g- term protection .(11)
Individuals who have recently (within the past 12 months) undergone tuberculin conversion (to 10 mm of induration) are also considered a high- risk group. Children younger than 4 who have positive reactions (10 mm) should be considered recent reactors.(4)
There is a high prevalen ce of act ive TB am on g in d ig e n o u s p o p u la t io n s. Fo r e xa m p le , a m o n g m em bers of t he Yan om am i t ribe, t he rat e is 6.4% of 625 individuals, which is approximately 100 times higher t han t he prevalen ce in t he st at e of Amazon as in gen eral (68/ 100,000).(1 2 ,1 3 ) This calls for specific
preven t ion m easu res. In t he USA, in dividu als from variou s et hn ic grou ps (African American s, Hispan ic American s, an d Nat ive American s) t hat have limit ed access t o healt h care services are con sidered high-risk grou ps, an d preven t ive t herapy is t herefore recom m en ded when ever t hese in dividu als becom e t u bercu lin react ors, even if t here are n o ot her risk fact ors for TB.(4 )
Ch e m o p r o p h yla x is , u n d e r s t r ic t m e d ic a l su pervision , is also recom m en ded for t hose who m ay n ot have act ive TB bu t have severe react ion s t o t u bercu lin t est s, as well as for t hose have n ot previou sly u n dergon e chemot herapy an d t hose who presen t ot her ext ran eou s con dit ion s t hat m ay be co n d u cive t o TB d evelo p m en t . Su ch co n d it io n s in clu d e a lco h o lism , in su lin - d ep en d en t d ia b et es mellit u s, silicosis, severe kidn ey disease, sarcoidosis,
lym p h o m a , lo n g - t e r m c o r t ic o s t e r o id u s e (im m u n osu ppression dose), can cer chem ot herapy, u se o f im m u n o su p p re ssa n t s, a n d p re se n t in g ra d io g ra p h s co m p a t ib le wit h la t e n t TB. Th is recom m en dat ion is based on t he fact t hat chron ic diseases su ch as diabet es, lym phom a, an d severe k id n e y d is e a s e a ll r e s u lt in s o m e le ve l o f im m u n o s u p p r e s s io n o r r e q u ir e t h e u s e o f cort icost eroids as part of t he t reat m en t , t hereby in creasin g t he risk of developin g react ivat ion TB. Ne ve rt h e le ss, t h is risk h a s n o t b e e n p re cise ly d e t e r m in e d . It is k n o w n t h a t , d u e t o it s im m u n osu ppression effect , a cou rse of predn ison e at doses higher t han 15 m g for 2 or m ore weeks su bst an t ially redu ces t u bercu lin react ion , in creasin g t he risk for t he developm en t of TB. There is n o eviden ce t hat chem oprophylaxis is recom m en ded fo r in d ivid u a ls re ce ivin g le ss t h a n 1 5 m g o f predn ison e or it s equ ivalen t s. It is n ecessary t o evalu at e pat ien t risk for liver in ju ry.(3 - 5 )
In developed countries, immigrants from regions where there is high prevalence of TB are also considered a high- risk group. In the USA, the incidence of TB in t h is p o p u la t io n in crea sed b et ween 1 9 8 6 (2 7 .1 / 100,000) an d 1993 (33.6/ 100,000), represen t in g 21.6% of all TB cases in 1986 and 29.6% of all cases in 1993. At the end of an 8- year study, incidence a m o n g im m ig ra n t s (3 0 .6 / 1 0 0 ,0 0 0 / ye a r) w a s determined to be 4 times higher than among non-immigrants (8.1/100,000/year).(14) The Pan American
Health Organization and the BTS also recommend that this group receive preventive therapy.(15,16)
Treat men t for lat en t in fect ion wit h Mt b du rin g pregnancy should be delayed until after delivery and should be administered with extreme caution in high-risk cases.(16) The ATS recommends its implementation
in pregn an t women in fect ed wit h HIV an d recen t ly exposed t o act ive TB or havin g previou sly been tuberculin reactors.(4) National health care officials in
t he USA recommen d t he admin ist rat ion of INH aft er t he first t hree mon t hs of pregn an cy for women who are HIV- positive tuberculin reactors and have contact with active- TB patients.(8)
Clinical evaluation of the use of isoniazid
in chemoprophylaxis
Th e effect iven ess o f INH u se (a t a d o se o f 5 m g / k g , m a x i m u m 3 0 0 m g / d a y ) i n chem oprophylaxis has been est ablished in dou ble-blin d, placebo- con t rolled, ran domized clin ical t rials ca rried o u t sin ce t h e 1 9 6 0 s. In a st u d y co n d u ct ed in Ala ska , est im a t ed effect iven ess fo r o n e- yea r t rea t m en t wa s 7 5 % in t h e first 4 yea rs o f fo llo w-u p, an d a lon g- last in g prot ect ive effect was shown : 7 0 % a ft er 1 5 yea rs a n d 5 0 % a ft er 1 9 yea rs.(1 0 ,1 7 ,1 8 )
In t he USA, a clin ical t rial showed a decrease in TB in cid en ce a m o n g in d ivid u a ls h a vin g co n t a ct wit h TB in t h e h o m e a n d t rea t ed wit h INH, wh ich p r e v e n t e d p r i m a r y p u l m o n a r y TB a n d ext ra p u lm o n a ry TB in u n in fect ed ch ild ren . Th e sa m e st u d y sh o wed a d ecrea se in t h e n u m b er o f p u lm o n ary TB cases am o n g ad u lt s.(1 9 ) Th e au t h o rs
o f t h ese st u d ies rep o rt ed n eit h er INH resist a n ce n o r sig n ifican t sid e effect s. An o t h er st u d y sh o wed t h a t , in a p o p u la t io n o f wa r ve t e ra n s in Sa n Fra n cisco , USA, 6 0 % were p ro t ect ed a g a in st TB react ivat ion .(2 0 ) A recen t met a- an alysis amon g
HIV-n egat ive iHIV-n dividu als, iHIV-n clu diHIV-n g 11 coHIV-n t rolled cliHIV-n ical t rials, fo u n d a relat ive risk (RR) o f 0 .4 0 an d a 9 5 % co n fid en ce in t erva l (9 5 % CI) o f 0 .31 - 0 .5 2 . Th is co rresp o n d s t o 6 0 % p ro t ect io n in va rio u s kn o wn h ig h - risk g ro u p s. Su ch g ro u p s in clu d e t h o se h avin g h ad co n t act wit h act ive- TB p at ien t s, t h o se livin g in a rea s wit h a h ig h TB p reva len ce, t h o se in st it u t io n alized fo r ch ro n ic p sych iat ric d iso rd ers, t h o se recen t ly co n vert ed t o t u b ercu lin rea ct o rs, t h o se wit h n o p revio u s h ist o ry o f ch em o t h era p y wh o se X- rays are co m p at ib le wit h lat en t TB, t h o se wit h p n eu m o co n io sis d u e t o silica exp o su re a n d t hose havin g had a kidn ey t ran splan t . This fin din g is in a cco rd a n ce wit h t h o se in t h e lit era t u re if we co n sid er t h a t t h e level o f p ro t ect io n is a d eq u a t e fo r p o p u lat io n s at lo w risk fo r TB. In t h o se at h ig h risk, co n sid erin g t h e d u ra t io n o f t rea t m en t , t h is prot ect ion wou ld have on ly a m in or im pact on t he p reven t io n o f n ew ca ses.
In d ivid u a ls w it h se ve re re a c t io n s t o P P D (in d u ra t io n 1 0 m m ), ra n g in g fro m 2 8 t o 6 5 ca ses p er 1 0 0 ,0 0 0 in h a b it a n t s, a re kn o wn t o b e a t h ig h risk fo r co n t ra ct in g a ct ive TB. Ho wever, t h is risk d ecrea ses wit h t h e p a ssa g e o f t im e.(1 8 )
Ran domized con t rolled clin ical t rials in volvin g pat ien t s wit h pu lmon ary fibrot ic lesion s have been u sed t o compare t he effect iven ess of INH regimen s
ran gin g from 3 mon t hs t o 2 years. These st u dies have shown that, after a follow- up period of 5 years, a 3- mon th regimen decreased TB in ciden ce by 21%, a 6- month regimen by 65% and a 12- month regimen by 75%. In comparison t o pat ien t s in t he placebo group, the ratio between benefit and risk was 1.2 for t he first regimen , 2.6 for t he secon d an d 2.1 for t he t hird. In 2003, Smieja et al.,(2 1 ) in t he previou sly
men t ion ed met a- an alysis, report ed n o sign ifican t differen ces bet ween 6- mon t h an d 12- mon t h INH regimes (RR = 0.44 an d RR = 0.38, respect ively; p = 0.08). However, t his differen ce may be sign ifican t , depen din g on t he risk of developin g act ive TB. For example, it has been est imat ed t hat it wou ld be n ecessary t o t reat 179 in dividu als for 6 mon t hs in order to prevent 1 TB case under low- risk conditions (in adu lt t u bercu lin react ors wit h n ormal chest X-rays and risk of developing hepatitis lower than 0.5%). Using the 12- month regimen, 161 individuals would have t o be t reat ed in order t o preven t 1 case. In pat ien t s at high risk for TB in fect ion (20%), it has been est imat ed t hat 1 case is preven t ed for every 8 o r 9 p a t ien t s t rea t ed .(2 1 ) An o t h er a sp ect t o b e
co n sid ered is t h a t t h e sh o rt er t h e d u ra t io n o f t reat men t , t he higher t he complian ce, t hat is, more people will complete the treatment (78% in 6- month regimen s an d 68% in 12- mon t h regimen s).(22)
In a clin ical t rial in Can ada, t he effect iven ess of INH alone and in combination with para-aminosalicylic acid (PAS) in t he preven t ion of TB react ivat ion was est imat ed in in dividu als diagn osed wit h lat en t TB. Aft er 18 mon t hs of t reat men t , t he au t hors observed n o ben efit s provided by t he u se of INH alon e or in combination if the period of treatment was less than 6 months, with reactivation rates similar to those seen in t he con t rol grou p. The u se of INH combin ed wit h PAS effected a 90% decrease in the reactivation rate, in comparison wit h a 70% decrease from t he u se of INH alone. They also reported an increase (from 30% to 60%) in the incidence of mild adverse effects with t he combin at ion of INH an d PAS. These side effect s cau sed n on complian ce wit h t reat men t t o in crease from 19% t o 42%, t hereby limit in g INH u se.(23)
Chemoprophylaxis with other treatment
regimens
TB was lower t han expect ed, an d m ort alit y du e t o liver failu re began t o be relat ed t o t he u se of INH. Moreover, poor complian ce wit h t he t reat men t (du e t o it s lon g du rat ion ) an d t he occu rren ce of co-in fect ion wit h HIV/ AIDS has m ot ivat ed st u dies on t he effect iven ess of chem oprophylaxis u sin g ot her drugs, which, of necessity, requires the study of their im plem en t at ion . In 2000, t he ATS released a series o f r e c o m m e n d a t io n s o n c h e m o p r o p h yla x is , su ggest in g t hat a 2- mon t h cou rse of RIF or PZA be u sed as a su bst it u t e for INH. These fin din gs were based on clin ical trials an d experimen ts in an imals.(5)
In 1 9 9 8 , t h e BTS re c o m m e n d e d t h a t TB ch em o p ro p h yla xis co n sist o f t h e u se o f INH fo r 6 m o n t h s o r t h e co m b in a t io n o f INH a n d RIF fo r 3 m on t hs. Based on con t rolled clin ical t rials, t he u se o f b o t h d ru g s co m b in ed h as sh o wn sim ilar effect s t o t h e u se o f INH a lo n e, wit h n o in crea se in t h e n u m b er o f a d verse effect s.(1 5 ) In 2 0 0 0 , it wa s
s u g g e s t e d t h a t , w h e n u s in g b o t h d r u g s in co m b in at io n , t h e d u rat io n o f t reat m en t sh o u ld b e red u ced t o 2 m o n t h s, a n d t h a t INH a lo n e sh o u ld n o lo n g e r b e u se d fo r p re ve n t io n sin ce b o t h reg im en s h a d p ro ven t o b e sim ila rly b en eficia l. Treat men t of high- risk, HIV- n egat ive pat ien t s wit h t h e INH a n d RIF reg im en fo r 3 m o n t h s p ro ved t o b e a s effect ive a s t h e INH reg im en fo r 6 m o n t h s. Th e RIF an d PZA reg im en fo r 2 m o n t h s is less well t o lera t ed t h a n reg im en s u sin g INH o r RIF a lo n e. Th e co m b in a t io n o f INH a n d RIF is well t o lera t ed b y ch ild ren fo r p erio d s eq u a l t o o r g rea t er t h a n 3 m o n t hs. Ho wever, t h e BTS st ill reco m m en d s t h e u se o f RIF co m b in ed wit h INH fo r 3 m o n t h s a s a n a lt ern a t ive t o t h e 6 - m o n t h INH reg im en .(7 )
In a n exp erim en t a l st u d y u sin g g u in ea p ig s va ccin a t ed wit h BCG, t h e effica cy o f a 6 - m o n t h co u rse o f INH wa s co m p a red t o t h a t o f 2 - m o n t h co u rses o f RIF alo n e, RIF + PZA, an d RIF + PZA + INH. Do se s, in re la t io n t o se ru m le ve ls, we re eq u iva len t t o t h o se u sed in h u m a n p o p u la t io n s. Trea t m en t st a rt ed 2 weeks a ft er in fect io n . Aft er 2 m on t hs of t herapy u sin g t he variou s regim en s, t he st u d y sh o wed t h a t t h e n u m b er o f p o sit ive resu lt s in sp leen cu lt u re was 1 0 0 % in sp ecim en s fro m g u in ea p ig s t rea t ed wit h t h e first reg im en , 5 0 % wit h t h e seco n d reg im en , 0 % wit h t h e t h ird , a n d 80% with the last. After the use of INH for 6 months, t he percen t age of posit ive spleen cu lt u res was 38%. Th e st u d y also t est ed t h e ext rem e effect iven ess o f t h e RIF + PZA re g im e n co m p a re d t o t h e RIF
reg im en fo r 3 m o n t h s. Usin g sim ila r p ro ced u res, sp leen cu lt u res were 1 0 0 % p o sit ive u sin g t h e INH reg im en fo r 6 m o n t h s, co m p a red t o 2 0 % u sin g RIF fo r 3 m o n t h s, 0 % u sin g RIF + PZA fo r 2 m o n t h s, a n d 8 0 % u sin g t h e co m b in a t io n o f t h e 3 d ru g s fo r 2 m o n t h s. Six m o n t h s a ft er t h e en d o f t h e t rea t m en t , t h e p ro p o rt io n o f p o sit ive resu lt s were 100%, 60%, 56%, an d 95%, respect ively. The 2 - m o n t h RIF + PZA reg im en an d t h e 3 - m o n t h RIF reg im en p ro ved t o b e m o re effect ive t h a n t h e 6 -m o n t h INH reg i-m en .(2 4 )
In an ot her experim en t al st u dy, t he efficacy of RIF in variou s t reat men t regimen s (RIF alon e, RIF + PZA an d RIF + INH + PZA) was evalu at ed. In fect ed gu in ea pigs were in it ially t reat ed wit h INH + PZA for 7 weeks. Lat er, 4 grou ps com prisin g 47 gu in ea pigs each, received t he variou s t reat m en t regim en s for 6 weeks. A fift h grou p con sist in g of 10 gu in ea pigs was t he con t rol grou p an d received INH + PZA for 13 weeks. Aft er a period of bet ween 26 an d 35 weeks, t he an im als were sacrificed so t hat spleen cu lt u re resu lt s cou ld be evalu at ed. The percen t age of posit ive resu lt s were 74% in t he RIF- on ly grou p, 63% in t he RIF + INH grou p, an d 53% in t he RIF + PZA + INH g ro u p . Th ese d ifferen ces were n o t st at ist ically sign ifican t , so efficacy of t he variou s regim ens was det erm in ed t o be qu it e sim ilar.(2 5 )
A placebo- con t rolled, dou ble- blin d clin ical t rial co n d u ct e d in Ho n g Ko n g a n d in vo lvin g m a le p a t ien t s d ia g n o sed wit h silico sis co m p a red fo u r t rea t m en t reg im en s (RIF fo r 3 m o n t h s = 1 4 2 p a t ien t s; INH + RIF fo r 3 m o n t hs = 1 61 p a t ien t s; INH fo r 6 m o n t h s = 1 2 3 p a t ien t s; p la ceb o = 1 3 3 p a t ien t s) o ver a fo llo w- u p p erio d o f 5 yea rs. Th e p ro b a b ilit y o f d evelo p in g TB wa s 1 0 % wh en RIF wa s u sed , 1 6 % wh en t h e co m b in a t io n o f INH a n d RIF was u sed , 1 7 % wh en INH alo n e was u sed , an d 27% when a placebo was u sed. Regimen s in clu din g RIF p ro ved less likely t o ca u se h ep a t o t o xicit y. Reg im en s u sin g INH a lo n e o r in co m b in a t io n showed higher am in ot ran sferase con cen t rat ion s in t h e se ru m o f p a t ie n t s d u rin g t h e p e rio d o f t rea t m en t (p < 0 .0 01 ). Th e au t h o rs reco m m en d ed t h a t o t h er st u d ies b e p erfo rm ed so t h a t m o re effect ive an d safer t reat men t regimen s for pat ien t s d iag n o sed wit h silico sis co u ld b e fo u n d .(2 6 )
su b ject s received eit h er 6 0 0 m g o f RIF a lo n e o r 4 0 0 m g o f INH co m b in ed wit h 1 2 5 0 m g o f PZA, t he INH an d PZA in accordan ce wit h recommen ded d o ses. Aft er a fo llo w- u p p erio d o f 4 years, TB was d i a g n o s e d i n 11 m a l e s w h o h a d r e c e i ve d m ed ica t io n (a n n u a l in cid en ce o f 1 4 8 0 / 1 0 0 ,0 0 0 ) a n d in 1 5 m a les o f t h e p la ceb o g ro u p (p = 0 .4 0 ). The au t hors det erm in ed t hat t he lack of t reat m en t reg im en effica cy wa s co rrela t ed wit h silico sis a s well a s wit h a h ig h risk o f rein fect io n d u e t o t h e h ig h in cid en ce o f TB in t h a t co m m u n it y.(2 7 )
Recen t ly, t he American en t it ies t he ATS an d t he CDC recommen ded t hat t he combin at ion of RIF an d PZA n ot be u sed in an y preven t ive TB t reat m en t regim en s. Accordin g t o dat a from pat ien t cohort st u dies con du ct ed in t he USA, high rat es of severe liver im pairm en t an d m ort alit y resu lt from t he u se of the two drugs. Other treatment alternatives should be con sidered for TB preven t ion .(2 8 )
Prevention of drug - resistant TB
In cases of INH resist an ce, t he ATS recommen ds t h e u se o f RIF (1 0 m g / kg ). Th ey a lso reco m m en d t h e u se o f et h a m b u t o l (EMB, 1 5 m g / kg ) wh en t h e st rain is proven t o be su scept ible. For bot h regimes, 6 - m o n t h co u rses are reco m m en d ed fo r ad u lt s an d 9 - m o n t h co u rses fo r ch ild ren . If t h ere is evid en ce of con t act wit h mu lt idru g- resist an t TB, daily doses o f t h e EMB + PZA co m b in at io n (2 0 m g / kg an d 2 5 m g / k g , r e s p e c t i v e l y ) f o r 6 m o n t h s a r e reco m m en d ed . Alt h o u g h t h ere are lim it ed d at a o n t he u se of qu in olon es as t herapeu t ic agen t s again st TB wh en t h ere is resist a n ce t o EMB, t h e u se o f PZA co m b in ed wit h a q u in o lo n e (4 0 0 m g / d a y o flo xa cin o r 7 5 0 m g / d a y cip ro flo xa cin ) fo r 6 mon t hs has been recommen ded. It is recommen ded t h a t 6 - t o 9 - m o n t h co u rses o f RIF, a lo n e o r in co m b in a t io n wit h EMB, b e g iven t o ch ild ren a n d im m u n o su p p ressed a d u lt s wh o h a ve h a d co n t a ct wit h pat ien t s in fect ed wit h INH- resist an t TB st rain s wh en st ra in s a re su scep t ib le t o t h e la t t er d ru g(4 ,7 )
It h a s b een reco m m en d ed t h a t HIV- p o sit ive p at ien t s wh o h ave h ad co n t act wit h INH- resist an t act ive- TB p at ien t s b e evalu at ed o n a case- b y- case b a sis. Fo r su ch p a t ien t s, t h e d ecisio n t o u se o t h er d r u g s s h o u l d b e b a s e d o n t h e r e s u l t s o f su scep t ib ilit y t est in g o f t h e Mt b st rain iso lat ed , as we ll a s o n t h e g u id e lin e s e st a b lish e d b y t h e resp ect ive h ea lt h ca re a u t h o rit ies.(1 ,5 )
Tuberculosis prevention in HIV- positive
patients
In d ivid u a ls wh o a re HIV p o sit ive a re a t h ig h risk fo r b eco m in g in fect ed wit h TB. Two sp ecific co n d it io n s sh o u ld b e t a ken in t o co n sid era t io n fo r t h is g ro u p : react io n t o t u b ercu lin t est s is p o o r in in d ivid u a ls wit h severe im m u n o d eficien cy, a n d chest X- rays of in dividu als wit h coin fect ion presen t at yp ical ch aract erist ics. Th ese t wo asp ect s m ake it m o re d if f icu lt t o d ist in g u ish b e t w e e n la t e n t in f e c t io n a n d a c t ive d is e a s e . Ho w e ve r, t h e In t ern at ion al Un ion Again st Tu bercu losis an d Lu n g Dise a se a n d t h e Wo rld He a lt h Org a n iz a t io n reco m m en d p reven t ive t h era p y fo r p a t ien t s wit h co in fect io n .(2 9 )
It is reco m m en d ed t h a t HIV- p o sit ive p a t ien t s, reg a rd less o f a g e, wit h n o evid en ce o f a ct ive TB or previou s hist ory of TB t reat men t whose react ion t o t u b ercu lin t est is eq u al t o o r g reat er t h an 5 m m a n d wh o se ch est X- ra ys a re n o rm a l sh o u ld b e t re a t e d fo r la t e n t Mt b in fe ct io n . Am o n g t h is p o p u la t io n , t h e risk o f a cq u irin g TB h a s b een est im a t ed a t b et ween 1 .7 a n d 7 .9 / 1 0 0 p eo p le/ ye a r(3 0 ), w h ic h is w h y t h e id e n t if ic a t io n o f
co in fect io n a n d t h e a d m in ist ra t io n o f p reven t ive t rea t m en t a re h ig h ly releva n t . Effica cy o f t h is t herapy has n ot been con firmed in in dividu als wit h n e g a t i v e t u b e r c u l i n t e s t r e s u l t s (a n e r g i c in dividu als). Some clin ical trials in volvin g this grou p h ave sh o wn t h at p at ien t s d o n o t m arked ly b en efit from preven t ive t reat men t wit h INH. Problems wit h d ru g a b so rp t io n a n d severe im m u n o su p p ressio n are likely to in terfere with therapy efficacy. However, t h e u se o f INH fo r 1 2 m o n t h s is reco m m en d ed fo r HIV- p o sit ive p a t ien t s, even fo r t h o se wh o se PPD resu lt s are n egat ive, if t hey have had recen t con t act w it h in d ivid u a ls d ia g n o s e d w it h in f e c t io u s pu lmon ary TB. For t his grou p of pat ien t s, decision s o n t h e u s e o f c h e m o p ro p h yla xis s h o u ld b e co n sid ered o n a ca se- b y- ca se b a sis.(4 ,6 ,8 ,2 9 )
Isoniazid and tuberculosis prevention in
HIV- positive patients
In Brazil, the TB chemoprophylaxis treatment of choice for HIV- positive patients is 5 to 10 mg/kg/day of INH (maximum dose: 300 mg/day) for 6 consecutive months.(6) In the USA, the drug of choice is also INH
recommends that adults should continue therapy for 12 months.(5,8) Nevertheless, the American Academy
of Pediat rics recommen ds t hat , for children , t he duration of such treatment be less than 9 months.(4)
Various controlled, randomized clinical trials have shown t he effect iven ess of INH in adu lt popu lat ion s coin fect ed wit h HIV an d TB. In five of t hese st u dies, t he effect iven ess of INH was assessed by comparin g pat ien t s receivin g INH t o t hose receivin g a placebo an d t o t hose receivin g n o t reat men t . Bet ween 1986 an d 1992, t he in ciden ce of TB in Hait i decreased 83% in t u bercu lin t est react ors receivin g daily doses of INH for 12 mon t hs. This prot ect ion con t in u ed t hrou ghou t a fou r- year period of follow- u p.(31)
A 6 - m o n t h co u rse o f d a ily a d m in ist ra t io n o f INH in t u b ercu lin rea ct o rs a n d n o n rea ct o rs h a s b een eva lu a t ed in va rio u s st u d ies, wit h va ryin g resu lt s. In a st u d y ca rried o u t in Ug a n d a , t h e au t h o rs rep o rt ed 6 8 % p ro t ect io n .(3 0 ) In Ken ya, t h e
rat e o f p ro t ect io n was lo wer (4 0 %; 9 5 % CI = 0 .2 3 – 1 .6 0 ).(3 3 ) In Za m b ia , p ro t ect io n p ro vid ed b y t h e
u se o f INH t w ice a w e e k f o r 6 m o n t h s w a s co n sid ered lo w (3 8 % ; 9 5 % CI = 0 .3 8 – 0 .9 9 ). Prot ect ion was higher (70%) in t u bercu lin react ors, b u t resu lt s were n o t st at ist ically sig n ifican t d u e t o t h e sm all n u m b er o f in d ivid u als in t h is g ro u p .(3 4 )
Wh alem et al., in 1 9 9 7 , an d Go rd in et al., in 2 0 0 0 , a lso rep o rt ed lit t le p ro t ect io n p ro vid ed b y INH in an erg ic in d ivid u als.(3 2 ,3 5 )
In a m et a- an alysis en com passin g seven st u dies t hat com prised a t ot al of 2367 people t reat ed wit h INH an d 2162 con t rols, t he RR of developin g TB was 0.58 in t he t reat ed grou p (95% CI = 0.43 – 0 .8 0 ), co rresp o n d in g t o 4 2 % effica cy. Th e RR amon g t u bercu lin react ors was 0.40 (95% CI = 0.24 – 0.65; 60% efficacy), com pared wit h 0.84 am on g t u bercu lin n on react ors (95% CI = 0.54 – 1.30; 16% efficacy). Est imat ed RR for mort alit y preven t ion was 0.94 (95% CI = 0.83 – 1.07), correspon din g t o 6% prot ect ion . Am on g t u bercu lin react ors, t he RR for m ort alit y preven t ion was 0.79 (95% CI = 0.37 – 1.70) versu s 1.0 for t u bercu lin n on react ors (95% CI = 0 .9 0 – 1 .1 7 ). Th e a u t h o rs o f t h is st u d y con clu ded t hat admin ist rat ion of INH for 6 mon t hs in HIV- posit ive pat ien t s who are t u bercu lin react ors redu ced TB in ciden ce by 60%.(3 6 )
In t h e USA, a st u d y o f t h e p ro t ect ive effect o f a 2 4 - m o n t h co u rse o f INH ch em o t h era p y o n t h e in cid en ce o f d isea ses ca u sed b y m yco b a ct eria in HIV- p o sit ive, in ject io n d ru g u sers sh o wed t h at TB
risk d ecrea sed in 8 3 % o f t h ese in d ivid u a ls wit h t h e u se o f in t erm it t en t , t wice- weekly d o ses.(3 5 )
Use of other drug s for preventing active
tuberculosis in HIV- positive individuals
Severa l co n t ro lled ra n d o m ized clin ica l t ria ls h a ve b een ca rried o u t in o rd er t o eva lu a t e p ro p er du rat ion of t reat men t an d t he effect s of combin in g o t h er d ru g s wit h INH. Th e co m b in ed u se o f INH an d RIF for 3 mon t hs in daily doses has been shown t o provide 59% prot ect ion . It has also been shown t h a t d a ily a d m in is t r a t io n o f a t h r e e - d r u g co m b in a t io n o f INH, RIF a n d PZA p ro vid es 5 7 % p ro t ect io n . Th ese resu lt s were sim ila r t o t h o se fo u n d fo r t h e u se o f INH a lo n e fo r 6 m o n t h s.(5 ,3 2 )
The levels of protection provided by twice- weekly, 3 - m o n t h t rea t m en t reg im en s u sin g t wo d ru g s combin ed (INH + RIF) or t hree dru gs combin ed (INH + RIF + PZA) were 59% and 57%, respectively. These resu lt s were similar t o t hat regimen u sin g INH t wice a week for 6 mon t hs.(32) The combin ed u se of RIF
an d PZA for 3 mon t hs provided 42% prot ect ion , similar t o t hat provided by t he u se of INH alon e, t wice a week, for 6 mon t hs.(34) In Hait i, t he level of
prot ect ion provided by t wo regimen s (2 mon t hs of RIF + PZA an d 6 mon t hs of INH t wice a week) was similar aft er a follow- u p period of 12 mon t hs.(38) In
an ot her st u dy carried ou t in t he USA, Hait i, Brazil a n d Me xico , t h e a u t h o rs re p o rt e d t h a t d a ily adm in ist rat ion of RIF com bin ed wit h PZA for 2 months provided the same level of protection against TB as the daily u se of INH for 12 mon ths.(35) In Hong
Kon g, a st u dy wit h pat ien t s su fferin g from silicosis showed that daily administration of RIF for 3 months provided prot ect ion (90%) similar t o t hat of t he INH regimen for 6 mon t hs (86%).(26)
A st u d y in vo lvin g a co h o rt o f HIV- p o sit ive t u b ercu lin rea ct o rs wa s ca rried o u t in o rd er t o d et erm in e t h e co n t rib u t io n o f ch em o p ro p h yla xis u sin g INH a lo n e fo r 1 2 m o n t h s t o t h e su rviva l o f t h ese p a t ien t s. Th e a u t h o rs rep o rt ed t h a t t h is c h e m o p r o p h yla x is r e g im e n w a s r e la t e d t o d ecrea sed risk fo r a ct ive TB – a n n u a l in cid en ce o f 2 % in t h e st u d y g ro u p a n d 4 .8 % in t h e p la ceb o grou p. These resu lt s su ggest t hat chemoprophylaxis con t ribu t es t o t he su rvival of HIV- posit ive pat ien t s in a rea s wh ere t h ere is h ig h TB p reva len ce.(3 9 )
t o lera n ce, a s well a s t h e effica cy o f a 1 2 - m o n t h co u rse o f ch em o p ro p h yla xis wit h INH a lo n e in co m p ariso n t o a 3 - m o n t h co u rse o f RIF co m b in ed wit h INH. Th e au t h o rs rep o rt ed t h at t h e in cid en ce of act ive TB was 4.23/ 100 people/ year in t he INH-o n ly g rINH-o u p , a n d 2 .0 8 / 1 0 0 p eINH-o p le/ yea r in t h e RIF + INH g ro u p . Th e RR o f a cq u irin g a ct ive TB wit h t h e RIF + INH reg im en wa s 0 .51 (9 5 % CI = 0 .0 9 – 2 .0 8 ) wh en co m p a red t o t h e u se o f INH a lo n e.(4 0 )
It is recommen ded t hat regimen s t arget in g HIV-p o sit ive HIV-p a t ien t s n o t in clu d e PZA. Severe liver damage report ed in relat ion t o daily admin ist rat ion o f t h e RIF- PZA co m b in a t io n t o HIV- n e g a t ive pat ien t s. In devisin g t reat men t st rat egies for lat en t TB in fect io n in HIV- p o sit ive p a t ien t s exp o sed t o st rain s resist an t t o INH o r RIF, t h e RR o f exp o su re t o r e s i s t a n t s t r a i n s m u s t b e t a k e n i n t o co n sid e ra t io n . Th e re f o re , e a ch ca se m u st b e eva lu a t ed in co n su lt a t io n wit h lo ca l h ea lt h ca re au t horit ies.(4 ,8 )
In t h e USA, o t h er d ru g s h ave b een u sed . On e su ch d ru g is rifab u t in (RFB), wh ich h as b een u sed t o p reven t t h e d issem in a t io n o f in fect io n wit h Myco b act eriu m aviu m . Fo r HIV- p o sit ive p at ien t s, American healt h care officials cu rren t ly recommen d t h e u se o f RFB fo r a p erio d o f 4 m o n t h s o r RFB co m b in ed wit h PZA fo r 2 m o n t h s. If t h ere is resist a n ce t o INH o r RIF, t h e use o f RFB m u st b e b a sed o n t h e risk o f exp o su re t o resist a n t st ra in s, so each case m ust b e co n sid ered sep arat ely. Sin ce RFB in t era ct s wit h p ro t ea se in h ib it o rs a n d wit h n o n - n u cleo sid e reverse t ran scrip t ase an alo g s, it is recom m en ded t hat doses be redu ced by half (from 3 0 0 m g / d ay t o 1 5 0 m g / d ay). Pro p h ylaxis wit h RIF sh o u ld n o t b e u se d a s a ro u t in e p re ve n t ive t rea t m en t sin ce resist a n ce m a y o ccu r.(8 )
Toxic effects of isoniazid
No a d verse effect s, su ch a s h ep a t it is, were rep o rt ed in t h e first st u d ies o f INH.(9 ) In 1 9 7 2 , t h e
first evid en ce o f a d verse effect s wa s rep o rt ed in pat ien t s su bm it t ed t o t herapy wit h INH in t he USA – in creased t ran sam in ase levels an d fat al hepat it is. Du rin g t h era py, 1 9 o f t h e 2 3 2 1 p a t ien t s t rea t ed (8 .2 cases/ 1 0 0 0 p eo p le/ 9 m o n t h s) sh o wed clin ical sign s of liver disease an d t he deat hs of t wo pat ien t s were at t ribu t ed t o t he medicat ion .(4 1 ) A clin ical t rial
ca rried o u t b y p u b lic h ea lt h ca re a g en cies in t h e USA sh o wed t h a t , in a g ro u p o f 1 3 ,8 31 p a t ien t s receivin g INH, 1 % d evelo p ed h ep a t it is, a n d t h e
in cid en ce wa s h ig h er (2 .3 %) in p a t ien t s o ver t h e ag e o f 5 0 . In ad d it io n t o ag e, alco h o lism h as b een sh o wn t o co rrela t e sig n ifica n t ly wit h a h ig h er risk o f d evelo p in g h ep a t it is.(4 2 ) In a st u d y co n d u ct ed
in Ho n g Ko n g , sim ila r resu lt s were fo u n d fo r a g ro u p co m p risin g 6 7 9 silico sis p a t ien t s, 1 % o f wh ich d evelo p ed liver d a m a g e. Of t h e 9 p a t ien t s diagn osed wit h liver in ju ry, 4 had received t he INH reg im en , a n d 5 h a d b een g iven a p la ceb o . On ly o n e p a t ien t receivin g t h e INH reg im en d evelo p ed sig n s o f h ep a t it is.(2 6 ) Ot h er a u t h o rs h a ve rep o rt ed
ra t es o f risk fo r a cq u irin g h ep a t it is fro m INH u se ra n g in g f ro m 2 % t o 1 0 % , w it h 5 % t o 1 0 % est im at ed m o rt alit y rat es. Clin ical m o n it o rin g an d c a u t i o u s u s e o f c h e m o p r o p h y l a x i s a r e reco m m en d ed fo r p a t ien t s wh o freq u en t ly u se alco h o l, h ave p re- exist in g liver o r kid n ey in ju ry, o r a re sim u lt a n eo u sly receivin g o t h er d ru g s t h a t a re t o xic t o t h e liver o r p a n crea s.(4 3 )
A st u d y carried o u t in Sp ain in vo lvin g HIV-posit ive pat ien t s compared t wo differen t t reat men t regim en s (a 3- m on t h cou rse of 300 m g/ day of INH + 6 0 0 m g / d ay o f RIF versu s a 1 2 - m o n t h co u rse o f 3 0 0 m g / d a y o f INH). Th e a u t h o rs d em o n st ra t ed t h a t o n ly 1 8 % o f p a t ien t s receivin g INH + RIF sh o wed sig ns o f h ep at o t oxicit y, co m p ared t o 41 % o f p a t ien t s receivin g INH a lo n e (RR = 2 .2 2 ; 9 5 % CI = 1 .2 3 – 4 .01 ).(3 8 )
Th e fa ct t h a t t h e p o p u la t io n u n d e r st u d y p resen t ed a h ig h p reva len ce o f h ep a t it is C m a y exp lain t h e h ig h levels o f t ran sam in ases. Ho wever, b et ween p a t ien t s wh o p resen t ed a n t i- h ep a t it is C a n t ib o d ies a n d t h o se wh o d id n o t , t h ere were n o sig n ifican t d ifferen ces in relat io n t o t h e in cid en ce o f a d verse effect s a n d h ep a t o t o xicit y wit h t h e regimen adopt ed. Du rat ion of t reat men t correlat ed wit h t he appearan ce of t oxic effect s, in depen den t ly o f t h e t yp e o f d ru g em p lo yed .(4 0 )
A st u d y co m p risin g 2 8 ,0 0 0 p u lm o n a ry fib ro sis p a t ien t s p resen t in g p o sit ive t u b ercu lin resu lt s, select ed from 115 dispensaries in various cou n t ries, sh o wed t h a t t h e in cid en ce o f h ep a t it is in t h o se su b m it t ed t o ch em o p ro p h yla xis wit h INH fo r 1 2 , 2 4 o r 5 2 weeks wa s 0 .5 %, co m p a red wit h 0 .1 % in t h o se receivin g a p la ceb o . Red u cin g t h e d u ra t io n o f t rea t m en t h a s b een fo u n d t o red u ce t h e risk o f a cq u irin g h ep a t it is in 1 .6 / 1 0 0 0 p eo p le su b m it t ed t o t h e 6 - m o n t h reg im en a n d in 2 .7 / 1 0 0 0 p eo p le su b m it t ed t o t h e 3 - m o n t h reg im en .(2 2 ) In 1 9 7 9 ,
probable an d 82 possible cases of hepat it is am on g 1 3 ,8 3 8 p eo p le u sin g INH.(4 2 ) In 1 9 9 7 , Sa lp et er et
a l.(4 4 ) id en t ified t wo d ea t h s a t t rib u t a b le t o t h e u se
o f INH wit h in a g ro u p o f a p p ro xim a t ely 2 0 0 ,0 0 0 pat ien t s t reat ed for 6 m on t hs, con clu din g t hat t he in cid en ce o f INH- relat ed m o rt alit y is lo w.
CONCLUSIONS AND RECOMMENDATIONS
Th e va rio u s st u d ies reviewed h a ve sh o wn t h a t INH co n t in u es t o b e effect ive in t h e p reven t io n o f a ct ive TB in b o t h HIV- n eg a t ive a n d HIV- p o sit ive popu lat ion s. Ou r resu lt s are st at ist ically sign ifican t an d clin ically relevan t .
In t h e m a jo rit y o f st u d ies, t rea t m en t reg im es in volvin g INH are t ypically 6 m on t hs or 12 m on t hs in d u ra t io n , a n d t h e d o sa g es u sed a re 5 – 1 5 m g / kg/ day (maximu m, 300 mg/ day). Similar prot ect ion h as b een ach ieved wit h b o t h t reat m en t d u rat io n s. Pro t ect io n is sig n ifica n t ly less wh en reg im en s sh o rt er t h a n 6 m o n t h s a re em p lo yed , b u t t h ere is n o sig n ifican t in crease in p ro t ect io n if reg im en s lo n g er t h a n 1 2 m o n t h s a re u sed . Th e 1 2 - m o n t h reg im en sh o u ld b e reco m m en d ed fo r very h ig h -risk g ro u p s.
In u sin g INH fo r TB ch em o p ro p h ylaxis, t h e risk o f t o xic effect s, esp ecia lly h ep a t it is, a p p ea rin g , alt hou gh sign ifican t , is ou t weighed by t he ben efit s o f it s u se. Ag e (o ver 3 5 ) a n d a lco h o l u se h a ve b een a sso cia t ed wit h h ig h er risks o f d evelo p in g h ep a t it is t h a n t h a t p resen t ed b y INH u se.
Fu rt h e r st u d ie s a re n e ce ssa ry in o rd e r t o eva lu a t e t h e effect iven ess o f t h ese, a n d o t h er, reg im en s t h a t in clu d e INH wh en em p lo yed in p o p u la t io n s a t h ig h risk o f d evelo p in g a ct ive TB.
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