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Improved Growth and Anemia in HIV-Infected African Children Taking Cotrimoxazole Prophylaxi
Andrew Prendergast, A Sarah Walker, Veronica 2 2 1 Mulenga, Chifumbe Chintu, and Diana M !ibb
1 M"C 2 1 1

a ociated with mortality /&1- 6e aimed to determine whether CT" prophylaxi ha any effect on growth and anemia in HIV-infected African childrenM1#*.DS 7(r t(dy wa an o, ervational analy i of children recr(ited to the CHAP trial- CHAP wa a do(,le-,lind) randomized) place,o-controlled trial) cond(cted d(ring 0..'*0..3) that enrolled HIV-infected +am,ian children aged '*'& year at 8niver ity Teaching Ho pital) 9( aka /'1- After informed conent wa received from caregiver ) children were randomized to receive daily CT" !0&. mg for children ,% year of age: &;.mg for children % year of age# or matching place,oAntiretroviral therapy !A<T# wa not p(,licly availa,le for children in +am,ia d(ring the trial: A<T wa received for ,'= of child-timeChildren were followed (p every month for the fir t '> week ) then every 0 month thereafter ,lood ample were o,tained for f(ll ,lood co(nt) malarial film) and !from ?(ly 0..'# C2& cell co(nt mea (rement - 6eight and height were mea (red at all clinic vi it and were expre ed a weight-forage + core !6A+# and height-for-age + core !HA+# /%1- The trial primary o(t-come were mortality and adver e event po i,ly related to t(dy dr(g- In 7cto,er 0..3) in accordance with advice from the 2ata and 5afety @onitoring Committee) the trial wa topped premat(rely ,eca( e of (, tantial and ( tained ,enefit in the CT" gro(p /'1<andom effect model were ( ed to e timate trend in 6A+) HA+) C2& cell percentage) and hematological parameter ) ( ing child-level random effect for ,a eline !intercept# and trend ! lope# and fixed-effect lope varying ,y randomized arm- Aor ne(trophil co(nt) a 0- lope model wa fitted in the CT" gro(p to e timate known early toxicity- A Boint log-normal model for (rvival wa ( ed to adB( t for informative cen oring from death />1) which wa higher in the place,o gro(p- Analy e were (ndertaken ( ing 5tata) ver ion ''-' !5tata#-

Clinical #rials $nit, %ondon, $nited &ingdom' and $ni(ersit) #eaching *os+ital, %usaka, ,ambia

The impact of cotrimoxazole !CT"# on growth and$or anemia wa inve tigated in %&' h(man imm(nodeficiency vir( -infected) antiretroviral therapy*naive +am,ian children enrolled in the Children with HIV Anti,iotic Prophylaxi trialCompared with children randomized to receive place,o) children randomized to receive CT" had lower decrea e in weight-for-age !P - -.&# and height-for-age !P - -.'#) and greater increa e in hemoglo,in level ! P - -.'#- The e finding arg(e for expanded early CT" ( eCotrimoxazole !CT"# i an inexpen ive) ,road- pectr(m anti,iotic that red(ce mor,idity and mortality among h(man imm(nodeficiency vir( !HIV#-infected children /') 01 when taken daily a prophylaxi - CT" ha activity again t malaria and common ,acterial pathogen ca( ing diarrhea and pne(monia) even in area of high re i tance /') 01- In the Children with HIV Anti,iotic Prophylaxi !CHAP# trial) the impact of CT" ap-peared to ,e principally attri,(ta,le to red(ction in lower re- piratory tract infection /') 01) with ,enefit acro all age and C2& cell co(nt However) the preci e mechani m ,y which CT" red(ce mor,idity and mortality remain incompletely (nder tood) and CT" may have activity ,eyond imply red(cing interc(rrent illne e /31- 4eca( e of the increa ing appreciation of the ,enefit of CT" in HIV-infected individ(al ) we decided to f(rther explore the impact of CT" on mor,idity in the CHAP trial- In partic(lar) maln(trition and anemia are common among HIVinfected children in 5(,-5aharan Africa and are independently

"ecei(ed 1- .ctober 2/1/' acce+ted 22 December 2/1/ Corres+ondence0 Andrew Prendergast, MD, M"C Clinical #rials $nit, 222 1uston "oad, %ondon 2W1 2DA, $nited &ingdom 3a4+5ctu mrc ac uk6 Clinical 7nfectious Diseases 2/11'-238609-:;9-< #he Author 2/11 Published b) .=ford $ni(ersit) Press on behalf of the 7nfectious Diseases Societ) of America All rights reser(ed >or Permissions, +lease e?mail0 4ournals +ermissions5ou+ com
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Aive h(ndred forty-one children !median age) &-& year : interC(artile range /ID<1) 0-'*;-3 year # were enrolled: 0>; were randomized to receive CT" and 0E3 to receive place,o- Half the children were male- Three-C(arter !E&=# had pre-vio( ly ,een ho pitalized- @edian follow-(p time wa ';-F month !ID<) '3->*0&-. month #G 'F-& month !ID<) '&-E*0&-'

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month # in the CT" gro(p and 'E-E month !ID<) '0-F*03-F month # in the place,o gro(p- 7verall) E& children !0;=# taking CT") compared with ''0 !&0=# taking place,o) died !P - -...0# /'1C2& cell percentage mea (rement were availa,le for %.& children !F3= of cohort: median of 0 mea (rement per child#- @ean C2& cell percentage at ,a eline wa '0-3= ! tandard de-viation /521) E-.=#- @ean ann(al change in C2& cell percentage wa 1.-'&= !F%= confidence interval /CI1) 2-%% to -;3# for the CT" gro(p and -.-3E= !F%= CI) 2'-'; to -&&# for place,o !heterogeneity) P - -33#: Ta,le '6eight and height mea (rement were availa,le for all %&' children !median of '' and F time per child in the CT" and place,o gro(p ) re pectively#- There wa high ,a eline prevalence of (nderweight and t(nting) with mean 6A+ and HA+ of -0-;& !52) '->3# and -3-0% !52) '-&;#) re pectively5(, eC(ently) there wa a tati tically ignificant difference ,etween children randomized to receive CT" or place,o in ann(al change in 6A+ !mean) 2.-'% /F%= CI) 2-0; to 2-.31 v 2-3% /F%= CI) 2-&F to 2-0'1: heterogeneity) P - -.&# and HA+ !mean) 2.-.E /F%= CI) 2-'% to -.'1 v 2-00 /F%= CI) 2-3. to 2-'3: het-erogeneity) P - -.'#- Taken together) children taking T@P-5@" had ignificantly lower decrea e in 6A+ and HA+ than did children taking place,oHemoglo,in level and platelet co(nt mea (rement were availa,le for %3; children !FF= of cohort# and ne(trophil co(nt for %3E children !FF= of cohort#) with a median of % mea (rement in ,oth gro(p - @ean ,a eline hemoglo,in level wa F-&& g$d9 !52) '-0E g$d9#: &F= of children had mild anemia !F*'.-F g$d9#) 3>= had moderate anemia !,F g$d9#) and '= had evere anemia !,>g$d9#- Children taking CT" had a ignificantly greater (, eC(ent ann(al increa e in hemoglo,in level than did children taking place,o !mean) -33 g$d9 /F%= CI) -0.*-&E1 v -.; g$d9 /F%= CI) 2-.; to -0&1: heterogeneity) P - -.'#- @ean ,a eline ne(trophil co(nt wa 3-0' : '. cell $9 !52) '->0
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: '. cell $9#) decrea ing ,y a mean of -%. !F%= CI) 2-E&*-0># d(ring the fir t & week in the T@P-5@" gro(p only- 5(,eC(ently) ne(trophil co(nt increa ed imilarly in children taking T@P-5@" and place,o !mean ann(al increa e) -&E : '. cell $9 /F%= CI) -0%*->F : '. cell $91 v -&> : '. cell $9 /F%= CI)
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-0%*->E : '. cell $91: heterogeneity) P - -FE#- @ean ,a eline platelet co(nt wa 0F> :'. cell $9 !52) ''> :'. cell $9#: the ann(al decrea e wa imilar in children taking CT" and F F place,o !mean) '3 :'. cell $9 /F%= CI) 0%*' :'. cell $91 v '& :'. cell $9 /F%= CI) 0;*' :'. cell $91: heterogeneity) P - -;F#- Taken together) children taking CT" had a ignificantly greater increa e in hemoglo,in level ,(t a greater initial decrea e in ne(trophil co(nt: the decrea e in platelet co(nt wa imilar ,e-tween gro(p D7SC$SS7.2 The CHAP trial demon trated that daily CT" prophylaxi red(ce mor,idity and mortality among HIV-infected children in 5(,-5aharan Africa /') 01- Here) we pre ent new data from thi trial) howing that CT" ( e in (ntreated HIV-infected children i a ociated with lower decrea e in weight- and height-for-age and improvement in anemiaHIV-infected children in 5(,-5aharan Africa are freC(ently (nderweight and t(nted /&1- 4eca( e of the impact of n(tri-tional tat( on mortality /&1) improving weight i a critical goal of HIV program - A<T-naive children taking CT" had at lea t a 0-fold red(ction in weight-for-age decrea e and 3-fold re-d(ction in height-for-age decrea e) compared with tho e taking place,o- 6e were (na,le to inve tigate the impact of CT" together with A<T) ,eca( e A<T wa not p(,licly availa,le in +am,ia d(ring 0..'* 0..3- Children in CHAP) therefore) had progre ive deterioration in 6A+ and HA+ ,eca( e of ongoing HIV di ea e progre ionHowever) f(t(re t(die ho(ld inve tigate whether CT" and A<T have an additive impact on growthF F F F

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Growth impairment i m(ltifactorial) relating to increa ed freC(ency of infection ) poor oral intake) mala, orption) and per i tent diarrhea /E1- The effect of CT" on growth may ,e primarily attri,(ta,le to a red(ction in evere interc(rrent infection : red(ced diarrhea among children receiving CT" i likely to ,e e pecially important- A trial in HIV-(n creened children admitted with mea le in G(inea-4i a( fo(nd le pne(monia and ignificantly greater '-month weight gain with E day of CT") compared with place,o /;1- However) CT" co(ld al o theoretically lower imm(ne activation in HIV-infected children- A maBor driver of imm(ne activation i micro,ial tran location) where,y g(t ,acteria and micro,ial-a ociated prod(ct cro the inte tinal m(co a to enter the y temic cir-c(lation /F1- CT" may lower inte tinal ,acterial ,(rden and) there,y) red(ce micro,ial tran location /31- @icro,ial tran -location i ,elieved to (nderlie t(nting maln(trition) even in HIV-(ninfected children) thro(gh the growth-inhi,iting effect of imm(ne activation /'.1- If f(t(re t(die confirm that CT" impact micro,ial tran location and$or imm(ne activation) it might imilarly improve growth in HIV(ninfected children- 8nfort(nately) tored pla ma ample from CHAP were not availa,le to inve tigate thi f(rther in HIVinfected childrenAnemia i common in HIV-infected children and i a oci-ated with poor progno i /&1- In the pre ent t(dy) the va t maBority of children had ,a eline anemia- However) children taking CT" had &-fold greater increa e in hemoglo,in level than did tho e taking place,o- Anemia in HIV infection i m(ltifac-torial) ,(t the mo t important mechani m i fail(re of eryth-ropoie i - CT" may pla( i,ly red(ce level of cytokine that impair erythropoie i /''1) ,oth directly) ,y red(cing imm(ne activation) and indirectly) ,y preventing infection - There wa no clear impact of CT" on C2& cell co(nt decrea e) con i tent with finding from A<Ttreated ad(lt in the 2evelopment of Antiretroviral Therapy in Africa trial /31- However) children only had a median of 0 C2& cell co(nt mea (rement ) and the finding of no difference ,etween gro(p co(ld alternatively re-flect low power- Children taking CT" had a ignificant initial decrea e in ne(trophil co(nt) likely ,eca( e of toxicity- 5(,- eC(ently) ne(trophil co(nt increa ed at a imilar rate in the place,o gro(p) altho(gh the rea on for the ne(trophil co(nt increa e in ,oth gro(p i (nclear7ne po i,le explanation i ongoing expo (re and re pon e to infection in ,oth gro(p of A<T-naive children- Tho e receiving CT" had lower mortality ,(t till had nonfatal infection driving the ne(trophil re pon e- Ainally) CT" had no ignificant impact on platelet co(nt) which decrea ed in ,oth gro(p ) reflecting ongoing (ntreated HIV infectionThere are everal important implication from thi t(dy- CT" improve growth and anemia) even witho(t A<T: however) CT" roll-o(t in 5(,-5aharan Africa remain poor- Altho(gh mo t co(ntrie have policie for CT" ( e) only &= of eligi,le children

were receiving CT" in 0..E /'01: implementation i freC(ently impeded ,y lack of availa,ility /'31- The c(rrent t(dy arg(e for earlier identification of HIV-infected children and more widepread CT" ( e) to red(ce mor,idity and mortality and to improve growth and anemia) even where A<T i (navaila,le- 6here A<T i availa,le) T@P-5@" may have additive effect on n(trition and anemia- 4eca( e of the recent finding that T@P-5@" prophylaxi at A<T initiation red(ce mortality among HIVinfected ad(lt /31) clinician ho(ld trongly con ider tarting or contin(ing CT" therapy in children entering A<T program 6hether CT" can (, eC(ently ,e topped i ,eing inve tigated in the Antiretroviral <e earch for 6atoto trial) c(rrently (nderway in 8ganda and +im,a,we-

Acknowledgments
6e thank the familie and children enrolled in CHAP and 2r Hiko Pantazi !8niver ity of Athen # for a i tance with the implementation of the Boint modelC*AP Stud) 7n(estigators 8niver ity Teaching Ho pital) 9( aka) +am,iaG C Chint() G? 4hat) V @(lenga) < Chile he) C Ialengo) A @( we( @(yawa) ? Ial(waBi) @@ @(tengo) V 4walya) P Chitam,ala) @ Choongo) 9 Hamak(,e) 5 @(tam,o) ? @wan a) 2 @wenya) I @(tela) G @(l(nd() A Ia olo) @ J(m,e) 4 @andanda) @ @(tengo) V @(denda) 9 4anda) T Chipoya) and 4 Chanda- @<C Clinical Trial 8nit) 9ondon) 8I: 2@ Gi,,) A H(nn) H Iagan on) P Ielleher) and A5 6alker- 2ata and 5afety @onitoring CommitteeG T Peto !Chairman#) @ 5harland) @ D(igley) and

E 4iem,a>inancial Su++ort The CHAP trial wa f(nded ,y the 2epartment for

International 2evelopment) 8nited IingdomPotential conflicts of interest A-P- ha received payment for the development of ed(cational material for Paediatric K(ropean Hetwork for Treatment of AI25 training co(r e and i a recipient of a cholar hip from the Conference of <etrovir( e and 7pport(ni tic Infection !C<7I# to attend the 0.'' C<7I meeting- A-5-6- ha ,een a ,oard mem,er for Ti,otec and ?I2: ha received grant (pport form 8I @edical <e earch Co(ncil) the 8I Hational In tit(te for Health <e earch) 8I 2epartment of International 2evelopment) K8 K(ropean-2eveloping Co(ntrie Clinical Trial Partner hip) G5I) and Gilead: and ha received payment for a lect(re from Gilead 5cience - V-@- ha received grant (pport from K(ropean and 2eveloping Co(ntrie Trial Partner hip for clincial trial on paediatric A2C antiretroviral and travel) accommodation ) and meeting expen e from K2CTP- 2-@-4- ha ,een a ,oard mem,er for Ti,otec: ha erved a the trial teering committee chair for a trial of T@P-5@" prophylaxi f(nded ,y 6ellcome Tr( t: ha received grant (pport from the 8I @edical <e earch Co(ncil) 8I 2epartment of International 2evelopment) K8 K(ropean-2eveloping Co(ntrie Clini-cal Trial Partner hip) K8 K(rocord Programme) Health Technology A e ment) and 8I Hational In tit(te of Health: and ha received grant from G5I) A,,ott) and Gilead) for additional (, t(die in pecific trial - C-C- no conflict -

"eferences

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prophylaxi again t opport(ni tic infection in HIV-infected +am,ian children !CHAP#G a do(,le-,lind randomi ed place,o-controlled trial- 9ancet 0..&: 3>&G';>%*E'cotrimoxazole on ca( e of death) ho pital admi ion and anti,iotic ( e in HIVinfected children- AI25 0..E: 0'GEE*;&-

0- @(lenga V) Aord 2) 6alker A5) et al- Kffect of

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