6.

7 Use of PIs in initial therapy

The efficacy of PIs in ARV-nave children has been demonstrated b!t in order to preserve a potent ne" class for second-line re#imens PIs !s!ally are not !sed in first-line therapy. $o"ever for infants and children %&' months "ho have been e(posed to )VP or other ))RTIs either directly or via maternal treatment before labo!r d!rin# delivery or "hen breastfeedin# the PI *PV+r is no" recom-mended as part of a first-line re#imen. PIs prevent viral replication by inhibitin# the activity of an en,yme called protease that is !sed by $IV to cleave proteins re-!ired in the assembly of ne" vir!s particles. The PIs in !se for children incl!de *PV RTV nelfinavir .)/V0 ata,anavir .ATV0 fos-amprenavir ./PV0 dar!navir .1RV0 2374 and addi-tional ne" PIs that are c!rrently available to treat ad!lts. RTV is e(ceptional as it inhibits the liver en,yme that normally metaboli,es PIs. It is not !sed for its o"n antiviral activity b!t remains "idely !sed in lo" doses to boost the effects of other PIs. *PV+r is the only PI available to date in a co-for-m!lation and has been !sed e(tensively in children. /!rther more detailed information on c!rrently available PIs is available in in 5hapter 6&. Anne( 7 details ARV dosin# information. This information may be !pdated bet"een p!blications. Readers are advised to cons!lt the "ebsite for the most !p-to-date information. http8++"""."ho.int+hiv+topics+paediatric+en+inde(.html

6.9 :!mmary of 5hapter 6 ; /irst *ine ARV Re#imens

Table 6<8 :!mmary of preferred first-line ARV re#imens for infants and children

Patient #ro!p I)/A)T: Infant or child %&' months not e(posed to ARVs Infant or child %&' months e(posed to ))RTI Infant or child %&' months "ith !n>no"n ARV e(pos!re 5$I*1R7) 5hildren &' months to ? years 5hildren @? years

:tandard first-line re#imen

)VP = & )RTI *PV+r = & )RTI )VP = & )RTI )VP = & )RTI )VP or 7/V = & )RTI

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Do( E8 )evirapine-based re#imens

)evirapine = AFT+?T5 .preferred0 AR )evirapine = AD5+?T5 AR )evirapine = d'T+?T5

Do( 68 7faviren,-based re#imens

7faviren, = AFT+?T5 .preferred0 AR 7faviren, = AD5+?T5 AR 7faviren, = d'T+?T5

Do( 78 Protease inhibitor-based re#imens

*opinavir+ritonavir = AFT+?T5 .preferred0 AR *opinavir+ritonavir = AD5+?T5 AR *opinavir+ritonavir = d'T+?T5

Table 668 Preferred first-line re#imens for specific sit!ations

:it!ation 5A)5AGITA)T 5A)1ITIA):

Preferred first-line re#imen

5hild or adolescent "ith severe anaemia 5hild %? years "ith TD treatment

)VP = & )RTIs .avoid AFT0 )VP = & )RTIs AR ? )RTIs8 AFT or d'T = .?T5 = AD50 7/V = & )RTIs AR ? )RTIs8 AFT or d'T = .?T5 = AD50 T1/ = /T5 or ?T5 = ))RTIH

5hild @? years or adolescent "ith TD treatment

Adolescent "ith hepatitis D

1*

7/V sho!ld not be initiated in the first trimester of pre#nancy or prescribed to "omen "ith the potential to become

pre#nant !nless effective contraceptive !se is ass!red.

? 7

CLINICAL AND LABORATORY MONITORING n, very low quality of evidence)

5.
7.6 Recommendatio ns

Chere

capacity

for

51'

7.1.1 1.

51' monitorin# 7.6.& Viral load monitorin#

meas!rement is limited tar#et the !se of 51' monitorin# to assess the si#nificance of clinical events. (Conditional recommendation, very low quality of evidence)

51' sho!ld be 6. V* determination is desirable

meas!red at the ART. time of dia#nosis (Strong recommendation, of $IV infection moderate quality of evidence) and every 6 7. V* sho!ld be assessed to months confirm clinical or thereafter. imm!nolo#ical fail!re "here Gonitor "ith possible prior to s"itchin# increasin# treatment re#imen. fre-!ency as (Conditional recommendation, 51' co!nt very low quality of evidence) approaches threshold for 7.6.? Ro!tine clinical and startin# ART. laboratory monitorin#

b!t not essential prior to initiatin#

(Strong recommendatio 8. n, very low quality of evidence)

Daseline

haemo#lobin

level

2.

51' sho!ld be meas!red prior to initiatin# ART. 9. (Strong recommendatio n, very low quality of evidence)

.and "hite cell co!nt if available0 sho!ld be assessed at initiation of ART. (Conditional recommendation low quality evidence) /or infants and children meas!re haemo#lobin at "ee> 9 after initiation of AFTcontainin# re#i-mens or more fre-!ently if symptoms indicate. (Conditional recommendation, very low quality of evidence)

3.

51' sho!ld be meas!red every 6 months after10. Iro"th development and initiatin# ART. n!trition sho!ld be monitored (Conditional monthly. recommendatio (Strong recommendation, low n, very low quality of evidence) quality of evidence) 11. *aboratory monitorin# for Geas!re 51' if ne" clinical i sta#in# events develop incl!din# #ro"th falterin# and ne!rodevelopmental delay. (Strong recommendatio to(icity sho!ld be symptom directed. (Strong recommendation, very low quality of evidence)

4.

(1) :ta#in#
chan#es

events are in health

stat!s that res!lt in a chan#e in the childJs sta#e of $IV as per C$A #!idelines. :ee Anne(es 5 and 1.

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7.& Principle
The inability to perform laboratory monitorin# notably for 51' or viral load sho!ld not prevent chil-dren from receivin# ART.

7.? Dac>#ro!nd
5linical and laboratory assessments sho!ld be performed at baseline .i.e. at entry into $IV care0 for children "ho have entered care b!t are not yet eli#ible for ART and at initiation of and "hile on ART.

In reso!rce-limited settin#s C$A recommends that clinical parameters be !sed in conK!nction "ith laboratory assessment "here available for monitorin# of children "ith $IV "ho are on ART. The in-ability to perform laboratory monitorin# notably for 51' or viral load sho!ld not prevent children from receivin# ART. It is hi#hly desirable that each co!ntry establish a laboratory monitorin# protocol in order to improve the efficacy of therape!tic interventions and to ens!re the ma(im!m level of safety "hen deliverin# ARV dr!#s 239-6<<4.

7.' Daseline clinical and laboratory assessments

The baseline eval!ation of $IV-infected infants and children incl!des clinical assessment and basic laboratory tests "here available. Ane of the obKectives of this initial assessment is eval!ation for the presence of active opport!nistic infections .AIs0. This visit to the clinic also serves as an opport!nity to provide co!nsellin# and s!pport for children and+or care#ivers re#ardin# disclos!re of their $IV stat!s to others n!trition and secondary prevention as "ell as for identifyin# any other specific needs.

Do( 98 Daseline clinical assessment for children

/ollo"in# confirmation of $IV infection stat!s the baseline clinical assessment for children sho!ld incl!de8

1 2 3 4 5 6 7 8

"ei#ht hei#ht head circ!mference and other meas!res of #ro"th clinical sta#in# of $IV disease .Anne( 50 developmental stat!s screenin# for malaria TD disease and e(pos!re to TD

identification of concomitant medical conditions .e.#. hepatitis D or 5 infection TD other coinfections or AIs pre#nancy in adolescent #irls0 details of concomitant medications incl!din# co-trimo(a,ole and traditional or herbal therapies n!tritional stat!s incl!din# assessment of the -!ality and -!antity of inta>e for those eli#ible for ART assessment of the childJs and care#iverJs preparedness for therapy.

? 3

Do( 38 Daseline laboratory assessment for children

1 2 3 4 5 6 7

confirmation of $IV infection !sin# virolo#ical or antibody testin#

meas!rement of L51'= .preferable for children %E years0 or absol!te 51' cell co!nt "here available haemo#lobin meas!rement "here AFT-containin# first-line re#imens are bein# !sed "hite blood cell co!nt .CD50 if available pre#nancy test if indicated from the history for se(!ally active adolescent #irls hepatitis D and 5 stat!s "here available V* "here available

7.E Ro!tine monitorin# of children "ho are not yet eli#ible for ART
Deca!se of the rapid rate of disease pro#ression in infants and yo!n# children more fre-!ent clinical and laboratory monitorin# is indicated for them than for ad!lts. The clinical eval!ation of $IV-infected children "ho are not yet eli#ible for ART sho!ld be performed every three to si( months at a mini-m!m and sho!ld incl!de the same parameters as are !sed in the baseline eval!ation. 51' monitor-in# sho!ld be performed every si( monthsM the res!lts of 51' meas!rement are !sef!l in determinin# "hether the child has become eli#ible for treatment and+or co-trimo(a,ole prophyla(is. 5linical eval!ation and 51' meas!rements sho!ld be obtained more fre-!ently as the clinical or imm!nolo#ical threshold for initiatin# ART approaches and at initiation of ART .see Table 6&0. Ro!tine monitorin# of viral load is not essential "here capacity and reso!rces are constrained and C$A does not recommend specific virolo#ical thresholds for initiatin# treatment.

Percent 51' is preferred for children less than E years of a#e rather than absol!te 51' co!nt. $o"-ever the inability to perform laboratory monitorin# notably for 51' or viral load sho!ld not prevent children from receivin# ART.

7.6 Ro!tine monitorin# of children on ART

Ance an infant or child is on ART the fre-!ency of clinical monitorin# "ill depend on their response to ART. At a minim!m after startin# ART follo"-!p visits sho!ld occ!r8

1 2

for infants at "ee>s & ' 9 and then every ' "ee>s for the first year for children at "ee>s & ' 9 6& and then every & to ? months once the child has

stabili,ed on therapy.
:ee Anne( N /i#!re 7 for a description of the ro!tine follo"-!p visits for infants and children on ART.

Ro!tine clinical assessment sho!ld incl!de addressin# the childJs and+or care#iverJs !nderstandin# of and adherence to therapy alon# "ith their need for additional s!pport. Oey si#ns of an infantJs and childJs response to ART incl!de8

1 2 3

improvement in #ro"th in infants and children "ho have been failin# to #ro" improvement in ne!rolo#ical symptoms and development in children "ith

encephalopathy or those "ho have demonstrated delay in the achievement of developmental milestones decreased fre-!ency of infections .bacterial infections oral thr!sh and+or other AIs0.

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Abservation of the childJs responses to therapy sho!ld incl!de vi#ilance for symptoms of potential dr!# to(icities or treatment fail!re .i.e. reassessment of C$A clinical sta#e0.
*aboratory assessment of 51' val!es is desirable at a minim!m of si( months after the initiation of ART and every si( months thereafter. Gore fre-!ent 51' monitorin# is indicated in cases of ne" or rec!rrent clinical sta#in# events #ro"th falterin# or ne!rodevelopmental delay. Chere capacity for meas!rin# 51' is limited monitorin# sho!ld be tar#eted to the assessment of clinical events. Ro!-tine monitorin# for viral load is not essential "here capacity and reso!rces are constrainedM ho"ever viral load sho!ld be !sed "henever possible to confirm s!spected clinical or imm!nolo#ical fail!re. Chere available viral load sho!ld be assessed at si( months after initiation of ART for infants on ))RTI-based re#imens "ho are >no"n to have been e(posed to ))RTIs intrapart!m or thro!#h breastfeedin#. /ail!re to s!ppress the viral load to belo" E <<< copies+ml in an adherent child at this time "arrants s"itchin# to a PI-based re#imen .see 5hapter 660.

Table 6&8 *aboratory parameters for monitorin# infants and children at baseline before and d!rin# ART

*aboratory tests for dia#nosis and monitorin#

Daseline .at entry into care0

At initiation of first-line or second-line ART re#imen

7very si( months

As re-!ired or symptomdirected

$IV dia#nostic testin# $aemo#lobin

a

CD5 and differential co!nt L51'= or absol!te 51' cell co!nt

b

Pre#nancy testin# in adolescent #irls /!ll chemistry .incl!din# b!t not restricted to liver en,ymes renal f!nction #l!cose lipids amylase lipase and ser!m e electrolytes0 $IV V* meas!rement AI screenin# ."here possible0
f #

1 2 3 4 5 6 7

$aemo#lobin monitorin# at "ee> 9 after initiation of ART is recommended if AFT is !sed. $IV-infected children not yet eli#ible for ART sho!ld be monitored "ith 51' co!nt every si( months. /or infants and children "ho develop ne" or rec!rrent C$A sta#e & or ? events or "hose 51' co!nt approaches threshold val!es the fre-!ency of 51' meas!rement can be increased.L51'= is preferred in children %E years of a#e. Pre#nancy testin# may be needed for adolescent #irls prior to initiatin# a re#imen containin# 7/V. /or pre#nant adolescent #irls provide prophyla(is or combination ART to those "ho are in need of it for their o"n health and+ or to prevent vertical transmission. .:ee C$A PGT5T I!idelines &<6<0 26<&4 Ro!tine monitorin# .every si( months0 of f!ll chemistry partic!larly lipid levels liver en,ymes and renal f!nction sho!ld be considered for infants and children on second-line dr!#s. At present V* meas!rement is not a prere-!isite for initiation or re#!lar monitorin# of ART in reso!rce-limited settin#s. V* can be !sed to dia#nose $IV infection and to confirm clinical or imm!nolo#ical fail!re prior to s"itchin# treatment re#imen. V* sho!ld be assessed in infants on ))RTI-based re#imens "ho are >no"n to have been e(posed to ))RTIs intrapart!m or thro!#h breastfeedin#.

' 6

*aboratory assessment of the childJs response to treatment and monitorin# of adverse reactions sho!ld be directed by clinical symptoms .see Anne(es / and I0 tho!#h. some ro!tine monitorin# tests are advisable in accordance "ith the !se of specific dr!#s. In infants and children initiated on AFTcontainin# re#imens haemo#lobin sho!ld be meas!red 9 "ee>s after startin# ART or more fre-!ently if symptoms indicate. *iver f!nction tests .*/T i.e. liver en,ymes0 are recommended d!rin# the first fe" months of treatment in infants and children receivin# )VP "ho have any si#ns of hepa-titis or hepatoto(icity "ho are coinfected "ith hepatitis vir!ses or "ho are on hepatoto(ic medica-tions. Dased on data in ad!lts on ART ro!tine monitorin# of */Ts is !nli>ely to be cost-effective 26<64.

7.7 *aboratory capacity for ro!tine monitorin#

*aboratory protocols for monitorin# the safety and efficacy of ART are important. $o"ever C$A reco#ni,es that the same laboratory infrastr!ct!res may not be available at all levels of the healthcare system. Therefore C$A has tiered its laboratory monitorin# recommendations to primary health-care centres .level 60 district hospitals .level &0 and re#ional referral centres .level ?0 in order to facilitate $IV care and treatment in a variety of settin#s. :tandard -!ality assessment of laboratories at all levels is important for ens!rin# reliability. 7(istin# tools for addressin# laboratory capacity and -!ality incl!de the follo"in#8

1 2

C$A laboratory recommendations by level are #iven in Anne(

I and at

http8++"""."ho.int+hiv+ amds+C$A*abRecommendationDylevel/inal.pdf C$A cons!ltation on technical and operational recommendations for scale-!p of

laboratory ser-vices and monitorin# $IV antiretroviral therapy in reso!rce-limited settin#s http8++"""."ho.int+hiv+ p!b+meetin#reports+scale!p+en+

1ia#nostics

and

laboratory

technolo#y

.1*T0

"ebsite

http8++"""."ho.int+dia#nosticsPlaboratory+ en+

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8. WHAT TO EXPECT IN THE FIRST SIX MONTHS OF THERAPY

TD0 may occ!r res!ltin# in apparent clinical deterioration. This is not attrib!table to fail!re of therapy b!t rather to its s!ccess and the res!ltin# imm!ne reconstit!tion. It is important to allo" s!fficient time on therapy before K!d#in# the 9.6 Principles effectiveness of a re#imen and to consider the Q In most children 51' cell co!nts rise "ith the possibility of IRI: in children "ith "orsenin# initiation of ART and imm!ne recovery. disease in the first fe" months of ART. :!pportin# Q 5omplications observed in the first fe" "ee>s adherence d!rin# this period is critical and in s!ch follo"in# the initiation of ART are more cases s"itchin# of ARV re#imen "o!ld be common in children "ith severeinappropriate.

imm!nodeficiency.

Q In a child "ith advanced $IV disease the lac> 9.? 51' recovery of initial improvement does not necessarily reflect a poor response to ART. In most children 51' cell co!nts rise "ith the
initiation of therapy and imm!ne recovery.

9.& Dac>#ro!nd

Ienerally 51' levels increase over the co!rse of

the first year of treatment reach a platea! and then The first si( months on ART are critical. 5linical contin!e to rise f!rther over the second year 2'74. and imm!nolo#ical improvement is e(pected b!t$o"ever in some children severe dr!# to(icities and+or imm!ne reconstit!tionimm!nos!ppression may persist. The lo"er the inflammatory syndrome .IRI:0 may emer#e. :ome 51' levels at the start of ART the slo"er the chil-dren fail to respond as e(pected or may even recovery. At the same time per-sistent fail!re to e(hibit clinical deterioration d!rin# this time.see a 51' response sho!ld alert the clinician to 5omplica-tions in the first fe" "ee>s follo"in# the potential adherence problems or non-response to initiation of ART are seen most commonly "henART. In this case viral load determination can be therapy is started in children "ith severe !sef!l. imm!nodeficiency. Apparent fail!re to improve in a child "ith ad-vanced $IV disease does not9.' 7arly ARV to(icity necessarily reflect a poor response to ARTM it ta>es time for $IV viral replication to be controlled by/irst-line dr!# to(icities fall into t"o cate#ories8 ART and for the childJs imm!ne system to recover. early to(icity !s!ally presentin# in the first fe" It also ta>es time for the catabolism associated"ee>s to months of therapy and late to(icity. "ith $IV infection to be reversed partic!larly in $ypersensitivity reactions may be diffic!lt to children "ith si#nificant $IV-associated "astin#. distin#!ish from ac!te clinical events s!ch as Additionally as a child "ith advanced diseasemalaria and from the many manifestations of recovers imm!ne f!nction e(acerbation ofIRI:. 5hapters 3 and 6< provide more detail on previo!sly s!bclinical coe(istin# infections .e.#.identifyin# and mana#in# to(icity. ' ?

9.E Gortality on ART

Chile ART si#nificantly decreases mortality overall death rates are hi#h in the first si( months after initiation of ART partic!larly "hen children start ART "ith sta#e ' clinical events severe imm!nos!p-pression severe maln!trition or very lo" haemo#lobin 2? 6<?4.

9.6 Imm!ne reconstit!tion inflammatory syndrome

Imm!ne reconstit!tion inflammatory syndrome .IRI:0 is a spectr!m of clinical si#ns and symptoms tho!#ht to be associated "ith imm!ne recovery bro!#ht abo!t by a response to antiretroviral treat-ment 26<' 6<E4. Chile most $IV-infected children e(perience rapid benefit from ART some !nder#o clinical deterioration. This is the res!lt of either the !nmas>in# of latent or s!bclincial infection or the reactivation of previo!sly dia#nosed and often treated conditions .infectio!s or non-infectio!s0 sometimes termed Rparado(icalS IRI: 26<' 6<6-6<94. There are limited data on IRI: in infants and children and the ca!ses are not clearly !nderstood. The onset of IRI: in children most often occ!rs "ithin the first "ee>s to months follo"in# the initiation of ART and is seen most often in children "ho initiate ART "ith very lo" L51'= levels .%6EL0 26<6 6<34. The most common AI associated "ith IRI: in children is TD b!t those on treatment for Pne!mocys-tis pne!monia .P5P0 or cryptosporidiosis or "ho have herpes simple( vir!s .$:V0 f!n#al parasitic or other infections may also develop IRI: 266< 6664. Chere D5I imm!ni,ation of infants and children is ro!tine D5I-associated IRI: .locali,ed and systemic0 is fre-!ently observed 26<3 66&4 .see 5hap-ter 6?0. Gost cases of parado(ical IRI: resolve spontaneo!sly or can be mana#ed "ith non-steroidal anti-inflammatory dr!#s altho!#h some episodes of IRI: can be severe and even lead to death 266?4. Unmas>in# IRI: #enerally re-!ires treatment of the AI and concomitant anti-inflammatory therapy. In clinical settin#s "here IRI: is s!spected it is often diffic!lt to e(cl!de other ac!te infectio!s illnesses and it may be necessary to start empiric antiinfective therapy in addition to specific treatment for IRI:. Accasionally IRI: becomes pro#ressively "orse and may re-!ire a short co!rse of treatment "ith corticosteroids and rarely a temporary discontin!ation of ART 26<64. The same ART re#imen sho!ld be restarted once IRI: has improved.

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9. ARV DRUG TOXICITY

not discontin!ation ART. re-!ire of all life-

3.6 threatenin# to(icity Principle re-!ires discontin!ation s

:evere

of all ARV dr!#s and the G initiation of ap-propriate s!pportive therapy !ntil ore attentio the child is stabili,ed n and the to(icity is sho!ld be paid resolved.

to 5 Re#ardless of pharma their severity adverse covi#ila reactions may affect nce s!rveill adherence to therapyM ance in the child and care#ivers paediat sho!ld be familiar "ith ric side-effects pop!lati potential and "ith si#ns of ons. to(icities that are serio!s 2 T and re-!ire immediate o(icities contact "ith the can be provider. monitor ed 3.& Dac>#ro!nd clinicall y. Antiretroviral a#ents can be Ro!tine responsible for a "ide ran#e laborat of to(icities from lo"-#rade ory intolerance that may be selfmonitori limitin# to life-threatenin# n# side-effects. 1ifferentiatin# altho!# bet"een complications of h $IV disease and ART desirabl to(icity .also >no"n as e is not adverse reactions0 is essometimes diffic!lt. sential. Alternative e(pla-nations for

an observed to(icity co!ld G

a conc!rrent oderate incl!de infectio!s process .e.#. or common child-hood severe to(icitie illnesses incl!din# hepatitis A in a child "ith symptoms s may of hepatitis or malaria in a re-!ire child "ith severe anaemia0 s!bstit! or a reaction to medications tion of a other than ARVs .e.#. dr!# isonia,id-ind!ced hepatitis b!t do in a child on treatment for

TD or rash

a .e.#. )VP-related symptomatic hepatoto(icity

ind!ced is rare in children0 "hile by co- others are more commonly trimo(a,ol reported in children than e0. )on ad!lts .e.#. 7/V-related dr!#related rash or T1/-related loss of bone density0. Gost children

clinical on ART are from middle- or events or lo"-income settin#s "here adverse pharma-covi#ilance systems reactions may not be developed and that not are adverse reactions may be !nderreported. Gore atten-

ca!sed by tion sho!ld be paid to an ARV pharmacovi#ilance and dr!# do post-mar>etin# s!rveillance not re-!ire in paediatric pop!lations. ARV dr!#s

1r!#-related adverse reactions "hile on ART be can occ!r immediately chan#ed. .soon after a dr!# has Altho!#h been administered0 early there are ."ithin the first days or fe"er data "ee>s of treatment0 or late on ARV .after months or more of dr!# treat-ment0. Adverse to(icity in reactions can vary in children severity from mild to than in severe to life-threatenin# ad!lts the and may be specific to the f!ll dr!# or #eneric to the spectr!m class of dr!#s in !se. .:ee of ARV Do( 6< for #!idin# to(icities principles in the observed mana#ement of ARV dr!# in ad!lts to(icity.0
to has also been 3.? reported in children 266'4.

To(icities

$o"ever some Haematological: dr!#to(icities ind!ced bone-marro" are less s!ppression most common commonly seen "ith AFT in children .anaemia ne!tropenia than ad!lts in and

The most common to(icities incl!de the follo"in#8

more rarely thrombocytopenia0.

' E