MultilingualMultiDomain/MultiDomain/cross_domain_outputs/Health/encoded/test.bpe.en

▁Conduct ▁an ▁objective ▁assessment ▁of ▁the ▁existing ▁services ▁in ▁relation ▁to ▁family ▁planning .
▁As ▁a ▁collabor ative ▁effort ▁of ▁Sri ▁Lanka ▁College ▁of ▁Obstetric ians ▁& ▁G y na ec ologists ▁and ▁Family ▁Health ▁Bureau ▁National ▁guidelines ▁on ▁post ▁ab ort ion ▁care ▁were ▁final ised , ▁pr inted ▁and ▁launched ▁in ▁2015.
▁management ▁of ▁women ▁present ing ▁with ▁an ▁ab ort ion , ▁in ▁order ▁to ▁provide ▁comprehensive ▁high ▁quality ▁post ▁ab ort ion ▁care ▁services ▁to ▁them , ▁which ▁include ▁management ▁of ▁ab ort ion ▁and ▁its ▁life ▁threat ening ▁complications , ▁providing ▁emot ional ▁support , ▁family ▁planning ▁counsel ing ▁and ▁services , ▁and ▁there after ▁ensuring ▁appropriate ▁refer ral .
▁One ▁1 day ▁programme ▁for ▁PH NS S ▁was ▁conducted ▁and ▁total ▁number ▁trained ▁was ▁21 .
▁This ▁is ▁to ▁be ▁achieved ▁by ▁providing ▁safe ▁and ▁effective ▁family ▁planning ▁services .
▁The ▁Family ▁Planning ▁Unit ▁introduced ▁a ▁3 - day , ▁in - s erv ice , ▁training ▁of ▁trainers ▁( T o T ) ▁programme ▁for ▁service ▁providers ▁in ▁2015 ▁with ▁the ▁aim ▁of ▁improving ▁their ▁knowledge , ▁at itudes ▁and ▁skills ▁in ▁all ▁aspects ▁of ▁family ▁planning ▁service ▁provision , ▁including ▁coun se lling ▁and ▁emergency ▁management .
▁The ▁total ▁number ▁trained ▁was ▁22 3.
▁N ecess ary ▁equipment ▁are ▁an ▁essential ▁pre - re qu is ite ▁for ▁family ▁planning ▁clinics ▁to ▁provide ▁a ▁quality ▁service ▁to ▁cl ients .
▁Family ▁Planning ▁Unit ▁compiled ▁a ▁comprehensive ▁d at ab ase ▁on ▁family ▁planning ▁clinics , ▁both ▁in ▁the ▁preventive ▁and ▁cur ative ▁sectors , ▁so ▁that ▁gaps ▁can ▁be ▁identified ▁and ▁address ed .
▁To ▁mon itor ▁complications ▁for ▁family ▁planning ▁methods ▁the ▁form ats ▁for ▁not ification ▁and ▁investigation ▁of ▁adverse ▁events ▁and ▁fail ures ▁to ▁family ▁planning ▁methods ▁were ▁rev ised ▁and ▁introduced ▁island ▁wide .
▁So ▁each ▁year , ▁a ▁number ▁of ▁new ▁family ▁planning ▁clinics ▁are ▁established ▁with ▁modern ▁equipment ▁and ▁registered ▁to ▁achieve ▁access ibility ▁and ▁equity ▁for ▁all ▁Sri ▁Lankans .
▁Director ▁General ▁of ▁Health ▁Services ▁issued ▁instructions ▁on ▁the ▁necess ity ▁of ▁having ▁dedicated ▁family ▁planning ▁clinics ▁in ▁all ▁hospitals ▁to ▁ensure ▁access ibility ▁and ▁equity .
▁In ▁2015, ▁FHB ▁has ▁given ▁registration ▁to ▁18 ▁new ▁family ▁planning ▁clinics ▁in ▁MOH ▁areas ▁island ▁wide .
▁For ▁sm o oth ▁function ▁of ▁these ▁clinics , ▁FHB ▁has ▁provided ▁all ▁necessary ▁equipment .
▁FHB ▁is ▁the ▁foc al ▁point ▁for ▁School ▁Health ▁Programme ▁in ▁Sri ▁Lanka .
▁The ▁services ▁are ▁delivered ▁through ▁primary ▁health care ▁staff ▁in ▁collaboration ▁with ▁provincial ▁health ▁and ▁educational ▁ministries .
▁Des ign ated ▁officers ▁are ▁being ▁assign ed ▁as ▁School ▁Medical ▁Officers ▁( S M O ) ▁in ▁Kandy , ▁Galle , ▁Jaffna ▁and ▁Colombo ▁to ▁conduct ▁school ▁health ▁activities ▁in ▁urban ▁areas .
▁School ▁medical ▁services ▁include ▁School ▁Medical ▁Inspect ion ▁( S MI ) ▁of ▁children ▁and ▁making ▁relevant ▁refer r als .
▁In ▁addition , ▁MOHs ▁are ▁supp osed ▁to ▁organ ize ▁Be h aviour ▁Ch ange ▁Com mun ication ▁programmes ▁aimed ▁at ▁children ▁with ▁a ▁view ▁to ▁promote ▁their ▁health ▁with ▁special ▁re ference ▁to ▁sexual ▁and ▁reproductive ▁health ▁concerns , ▁reduction ▁of ▁risk ▁beh avi ours ▁for ▁to b acc o , ▁alcohol , ▁drugs ▁abuse ▁and ▁HIV / A I DS .
▁Family ▁Health ▁Programme ▁includes ▁preventive ▁health care ▁needs ▁of ▁school ▁children ▁and ▁adolescents .
▁The ▁target ▁group ▁of ▁the ▁School ▁Health ▁Programme ▁is ▁children ▁and ▁adolescents ▁attending ▁government ▁schools .
▁Family ▁Health ▁Bureau , ▁being ▁the ▁foc al ▁point ▁of ▁the ▁school ▁health ▁programme , ▁is ▁involved ▁in ▁planning , ▁providing ▁technical ▁guidance , ▁monitoring , ▁evalu ating ▁the ▁programme ▁activities , ▁conducting ▁research ▁and ▁management ▁of ▁log istics ▁relevant ▁to ▁school ▁health ▁activities .
▁A part ▁from ▁the ▁S MI , ▁the ▁PHIs ▁conduct ▁school ▁sanitation ▁survey ▁in ▁the ▁schools ▁annually , ▁findings ▁of ▁which ▁are ▁used ▁for ▁making ▁the ▁school ▁environment ▁safe ▁and ▁health y .
▁Ministry ▁and ▁other ▁Government ▁and ▁Non - Go vernment al ▁Organ izations ▁to ▁provide ▁services ▁such ▁as ▁safe ▁water , ▁san itary ▁facilities ▁and ▁ref use ▁disp osal ▁in ▁school ▁premises .
▁In ▁2015, ▁only ▁33 2 ▁out ▁of ▁337 ▁MOH ▁areas ▁( 97 .6 %) ▁submitted ▁Qu ar ter ly ▁School ▁Health ▁Return s ▁( H ▁79 7) ▁for ▁all ▁four ▁quarters .
▁In ▁addition , ▁B ody ▁Mass ▁Ind ex ▁( B MI ) ▁of ▁all ▁students ▁in ▁grade ▁10 ▁is ▁assessed ▁and ▁necessary ▁nutritional ▁interventions ▁are ▁done ▁during ▁the ▁nutrition ▁month ▁each ▁year .
▁During ▁year ▁2015, ▁9 7, 2 7 9 ▁(8 9 .4 %) ▁grade ▁10 ▁students ▁were ▁assessed ▁for ▁their ▁nutritional ▁status ▁and ▁trends ▁of ▁prevalence ▁of ▁low ▁BMI ▁and ▁over weight ▁among ▁male ▁and ▁female ▁students ▁were ▁given ▁in ▁figure ▁12 ▁and ▁13.
▁Low ▁BMI ▁among ▁grade ▁10 ▁students ▁in ▁2015 ▁was ▁23 .9% , ▁whereas ▁over weight ▁among ▁grade ▁10 ▁students ▁in ▁2015 ▁was ▁4.2 %.
▁Following ▁up ▁of ▁children ▁with ▁special ▁needs , ▁suspected ▁heart ▁disease ▁, ▁visual ▁def ects ▁& ▁hearing ▁def ects ▁has ▁been ▁strengthened .
▁According ▁to ▁the ▁study ▁done ▁on ▁coverage ▁of ▁interventions ▁and ▁the ▁feasibility ▁of ▁method ology ▁done ▁by ▁Family ▁Health ▁Bureau ▁in ▁2015, ▁90% ▁of ▁schools ▁have ▁started ▁the ▁W IF S ▁programme , ▁while ▁61 % ▁of ▁schools ▁have ▁completed ▁24 ▁weeks ▁therapy .
▁Le af let ▁for ▁W IF S ▁programme ▁target t ng ▁primary ▁school ▁children ▁was ▁prepared , ▁pr inted ▁and ▁distributed ▁throughout ▁the ▁country .
▁Ministry ▁of ▁Education ▁together ▁with ▁Family ▁Health ▁Bureau ▁designed ▁a ▁training ▁programme ▁for ▁teachers ▁on ▁“ he alth ▁and ▁physical ▁education ” ▁and ▁developed ▁a ▁resource ▁guide .
▁Two ▁thousand ▁and ▁thirty ▁teachers ▁have ▁already ▁been ▁trained ▁in ▁the ▁above ▁training ▁programme , ▁working ▁in ▁con j unction ▁with ▁National ▁Institute ▁of ▁Education .
▁National ▁Coordin ating ▁Committee ▁( NC C ) ▁on ▁School ▁Health ▁of ▁the ▁Ministry ▁of ▁Health ▁is ▁ch aired ▁by ▁the ▁Director ▁General ▁of ▁Health ▁Services ▁and ▁function ▁as ▁the ▁main ▁exec utive ▁body ▁taking ▁decisions ▁with ▁regard ▁to ▁the ▁school ▁health ▁activities ▁providing ▁policy , ▁guideline ▁and ▁technical ▁direct ives ▁to ▁be ▁taken ▁up ▁at ▁the ▁Ste ering ▁committee ▁of ▁Ministry ▁of ▁Education .
▁This ▁programme ▁was ▁launched ▁in ▁2007 ▁and ▁apprec iable ▁level ▁of ▁effort ▁had ▁to ▁be ▁made ▁to ▁implement ▁the ▁programme ▁at ▁schools .
▁The ▁necessary ▁technical ▁guidance ▁was ▁provided ▁by ▁the ▁School ▁Health ▁Unit ▁of ▁the ▁Family ▁Health ▁Bureau ▁for ▁implementation .
▁H PS ▁were ▁categor ized ▁as ▁follows ; ▁School ▁is ▁a ▁place ▁where ▁health y ▁practices ▁can ▁be ▁root ed ▁into ▁adolescent ▁beh av ior .
▁Five ▁new ▁“ Y ov un ▁Piyasa ” ▁centers ▁will ▁be ▁established ▁in ▁the ▁Southern ▁Province ▁in ▁2016 .
▁Field - t est ing ▁of ▁these ▁tools ▁and ▁the ▁development ▁of ▁service ▁implementation ▁guideline ▁on ▁AYFHS ▁is ▁planned ▁to ▁be ▁carried ▁out ▁in ▁2016 .
▁For ▁provision ▁of ▁services ▁to ▁adolescents ▁and ▁youth , ▁Adolescent ▁Youth ▁F riend ly ▁Health ▁Service ▁( AY FHS ) ▁Cent ers ▁under ▁the ▁name ▁of ▁“ Y ow un ▁Piyasa ” ▁were ▁being ▁established ▁in ▁government ▁hospitals .
▁Guideline ▁for ▁public ▁health ▁staff ▁on ▁adolescent ▁sexual ▁and ▁reproductive ▁health ▁service ▁provision ▁has ▁been ▁dra f ted , ▁target t ng ▁the ▁reduction ▁of ▁teenage ▁pregnancies ▁which ▁was ▁5.3 ▁% ▁in ▁2014.
▁Adv oc acy ▁programme ▁for ▁hon ou rab le ▁jud icial ▁members ▁was ▁conducted ▁on ▁the ▁importance ▁the ▁provision ▁of ▁adolescent ▁sexual ▁reproductive ▁health ▁services ▁for ▁the ▁need y ▁groups ▁with ▁the ▁participation ▁of ▁Director ▁General ▁of ▁Health ▁Services .
▁Se x ual ▁and ▁reproductive ▁health ▁package ▁for ▁public ▁health ▁mid wives , ▁as ▁an ▁aid ▁on ▁provision ▁of ▁adolescent ▁sexual ▁reproductive ▁health ▁education ▁for ▁young ▁persons ▁in ▁the ▁field ▁was ▁developed .
▁Development ▁of ▁youth ▁health ▁web ▁site ▁for ▁15 -24 ▁years ▁age ▁group ▁was ▁initiated ▁which ▁includes ▁youth ▁friendly ▁content ▁in ▁all ▁three ▁languages .
▁Near ly ▁20 -2 5 % ▁of ▁youth ▁experienced ▁acute ▁illness es ▁preventing ▁them ▁from ▁attending ▁product ive ▁work ▁during ▁the ▁preced ing ▁month .
▁The ▁common est ▁cause ▁of ▁acute ▁illness ▁was ▁fever ▁with ▁or ▁without ▁a ▁c ough ▁and ▁cold ▁(1 7 .9 %).
▁You ng ▁mal es ▁experienced ▁inj uries ▁/ acc idents ▁as ▁one ▁of ▁the ▁leading ▁ca uses ▁for ▁abs ent ee ism .
▁L if est y les ▁H alf ▁of ▁the ▁mal es ▁and ▁three ▁quarter ▁of ▁fem ales ▁had ▁not ▁done ▁man ual ▁work ▁in ▁the ▁preced ing ▁week .
▁Appro xim ately ▁44 % ▁of ▁total ▁youth ▁were ▁spending ▁five ▁or ▁more ▁days ▁in ▁the ▁preced ing ▁week ▁as ▁“ sc re ent ime ” ▁with ▁a ▁higher ▁female ▁prep o nder ance .
▁M ale ▁youth ▁were ▁prom in ently ▁engaged ▁in ▁formal ▁exerc ise ▁(1 7 %) ▁compared ▁to ▁4 .5% ▁of ▁fem ales .
▁An alysis ▁of ▁the ▁National ▁Youth ▁Health ▁Survey ▁2012 -201 3 ▁was ▁completed ▁in ▁2015.
▁The ▁table ▁shows ▁characteristics ▁of ▁the ▁R and om ized ▁Con t rolled ▁T ri als ▁( R CT s ).
▁For ▁patients ▁with ▁severe ▁COVID -19, ▁the ▁table ▁shows ▁the ▁grade ▁summary ▁of ▁findings ▁with ▁relative ▁and ▁absolute ▁effects ▁of ▁Rem desivir ▁compared ▁with ▁standard ▁care ▁for ▁the ▁outcomes ▁of ▁interest , ▁with ▁certainty ▁r at ings , ▁informed ▁by ▁the ▁L M NA ▁.
▁The ▁planned ▁subgroup ▁analyses ▁were ▁limited ▁by ▁available ▁data ▁but ▁demonst rated ▁low ▁to ▁moderate ▁cred ibility ▁of ▁a ▁subgroup ▁effect , ▁based ▁on ▁severe ▁versus ▁critical ▁disease ▁and ▁therefore ▁these ▁are ▁presented ▁separ ately ▁and ▁with ▁separate ▁recommendations .
▁We ▁were ▁unable ▁to ▁perform ▁subgroup ▁analysis ▁by ▁age ▁given ▁the ▁sp ars ity ▁of ▁data .
▁There ▁is ▁only ▁low - to - mod erate ▁cred ibility ▁of ▁a ▁subgroup ▁effect ▁between ▁severe ▁and ▁critical ▁disease .
▁If ▁there ▁is ▁no ▁effect ▁mod ification , ▁then ▁it ▁is ▁more ▁likely ▁that ▁there ▁is ▁no ▁difference .
▁Cred ible ▁interval ▁includes ▁no ▁important ▁difference .
▁Cred ible ▁interval ▁includes ▁important ▁benefits .
▁For ▁patients ▁with ▁critical ▁COVID -19, ▁we ▁suggest ▁not ▁to ▁use ▁Rem desivir ▁( ag ain st ▁conditional ▁recommendation ) ▁.
▁See ▁practical ▁information ▁for ▁use ▁of ▁Rem de vis ir ▁in ▁patients ▁with ▁non - severe ▁or ▁severe ▁COVID -19 ▁if ▁needed .
▁Evidence ▁to ▁benefits ▁and ▁harms ▁In ▁patients ▁with ▁critical ▁COVID -19, ▁Rem desivir ▁possibly ▁has ▁little ▁or ▁no ▁effect ▁on ▁mortality , ▁but ▁need ▁for ▁mechanical ▁ventilation ▁and ▁has ▁an ▁uncertain ▁effect ▁on ▁time ▁to ▁sympt om ▁improvement .
▁The ▁GDG ▁considered ▁the ▁potential ▁of ▁small ▁subgroup ▁effects ▁in ▁immun o - comp rom ised ▁patients ▁and ▁crit ically ▁ill ▁patients ▁with ▁pro l ong ed ▁det ection ▁of ▁SARS - CoV -2 ▁R NA ▁in ▁blood ▁spec imens ; ▁however , ▁given ▁the ▁p au c ity ▁of ▁data ▁and ▁concerns ▁for ▁harm , ▁it ▁was ▁felt ▁that ▁a ▁conditional ▁recommendation ▁against ▁the ▁use ▁of ▁Rem desivir ▁was ▁appropriate .
▁Rem desivir ▁is ▁administered ▁as ▁one ▁intra ven ous ▁inf usion ▁daily ▁over ▁10 ▁consec utive ▁days , ▁and ▁rather ▁than ▁in ▁an ▁out p ati ent ▁setting , ▁this ▁is ▁more ▁easily ▁oper ational ized ▁in ▁hospital ized ▁patients ▁with ▁critical ▁disease .
▁When ▁moving ▁from ▁evidence ▁to ▁the ▁conditional ▁recommendation ▁against ▁remdesivir ▁in ▁patients ▁with ▁critical ▁COVID -19, ▁the ▁GDG ▁emphasized ▁the ▁lack ▁of ▁benefit ▁on ▁surv ival ▁or ▁other ▁patient ▁important ▁outcomes .
▁The ▁GDG ▁recognized ▁there ▁is ▁ongoing ▁uncertainty , ▁and ▁there ▁may ▁still ▁be ▁a ▁sub set ▁of ▁patients ▁that ▁would ▁benefit ▁( e . g . ▁immun oc om p rom ised , ▁pers ist ent ▁vir aemia ) ▁but ▁there ▁is ▁insufficient ▁evidence ▁to ▁make ▁recommendations ▁specific ▁to ▁these ▁sub se ts ▁of ▁critical ▁patients .
▁When ▁patients ▁with ▁severe ▁and ▁critical ▁COVID -19 ▁were ▁considered ▁together , ▁po ol ed ▁analysis ▁demonst rated ▁that ▁Rem desivir ▁probably ▁had ▁little ▁or ▁no ▁impact ▁on ▁mortality ▁( ▁O R ▁0.9 5, ▁95% ▁CI ▁0.8 4 –1 .07 ).
▁When ▁considered ▁separ ately , ▁Rem desivir ▁possibly ▁has ▁an ▁important ▁reduction ▁on ▁mortality ▁( OR ▁0.8 9, ▁95% ▁CI ▁0.7 8 –1 .0 2) ▁in ▁those ▁with ▁severe ▁COVID -19, ▁while ▁having ▁no ▁impact ▁on ▁mortality ▁in ▁those ▁with ▁critical ▁C ▁O VID -19 ▁( OR ▁1.1 5, ▁95% ▁CI ▁0.8 9 –1 .5 1 ).
▁However , ▁now ▁that ▁our ▁understanding ▁of ▁COVID -19 ▁disease ▁course ▁has ▁improved , ▁it ▁f its ▁that ▁those ▁earlier ▁in ▁their ▁disease ▁tra ject ory ▁( severe , ▁but ▁not ▁yet ▁critical ) ▁may ▁have ▁more ▁viral ▁rep lication ▁and ▁therefore ▁benefit ▁more ▁from ▁ant ivir al ▁therapy .
▁U lt im ately , ▁the ▁GDG ▁decided ▁that ▁the ▁direction ▁of ▁effect ▁mod ification ▁was ▁probably ▁correctly ▁hypot hes ized , ▁which ▁increased ▁the ▁cred ibility ▁of ▁subgroup ▁finding .
▁B ased ▁on ▁this , ▁the ▁GDG ▁considered ▁a ▁likely ▁chance ▁or ▁unclear ▁expl anation ▁of ▁the ▁apparent ▁effect ▁mod ification .
▁None ▁of ▁the ▁included ▁R and om ized ▁Con t rolled ▁T ri als ▁( R CT s ) ▁enrolled ▁children ▁or ▁pregnant ▁woman , ▁and ▁therefore ▁the ▁applic ability ▁of ▁this ▁recommendation ▁to ▁children ▁remains ▁uncertain .
▁As ▁the ▁pandemic ▁ev ol ves ▁and ▁similar ▁to ▁other ▁COVID -19 ▁interventions , ▁there ▁is ▁ongoing ▁uncertainty ▁related ▁to ▁the ▁effect ▁of ▁Rem desivir ▁based ▁on ▁variants ▁and ▁individual ▁imm une ▁status .
▁The ▁table ▁shows ▁the ▁relative ▁and ▁absolute ▁effects ▁of ▁Rem desivir ▁in ▁patients ▁with ▁severe ▁and ▁critical ▁COVID -19 ▁compared ▁with ▁standard ▁care ▁for ▁the ▁outcomes ▁of ▁interest , ▁with ▁certainty ▁r at ings , ▁informed ▁by ▁the ▁L N MA ▁that ▁included ▁five ▁RCTs ▁which ▁enrolled ▁76 43 ▁participants ▁.
▁The ▁planned ▁subgroup ▁analyses ▁were ▁limited ▁by ▁available ▁data ▁but ▁did ▁demonst rate ▁sufficient ▁cred ibility ▁of ▁a ▁subgroup ▁effect ▁to ▁inform ▁specific ▁recommendations ▁for ▁severe ▁versus ▁critical ▁disease .
▁Therefore ▁these ▁tables ▁on ▁summary ▁of ▁findings ▁are ▁presented ▁separ ately .
▁The ▁largest ▁trial ▁( s olid ar ity ) ▁was ▁not ▁blind ed .
▁The ▁L N MA ▁for ▁Rem desivir ▁in ▁critical ▁COVID -19 ▁was ▁informed ▁by ▁three ▁R and om ized ▁Control ▁T ri als ▁( R CT s ) ▁which ▁enrolled ▁10 12 ▁patients .
▁Rem desivir ▁was ▁developed ▁for ▁treatment ▁of ▁He p at it is ▁C ▁virus ▁infection , ▁and ▁was ▁also ▁studied ▁in ▁E b ola ▁and ▁Mar burg ▁virus ▁infections ▁before ▁being ▁rep ur p osed ▁for ▁SARS - CoV -2 .
▁Rem desivir ▁is ▁a ▁nucle os ide ▁drug .
▁It ' s ▁mechanism ▁of ▁action ▁invol ves ▁ch ain ▁term ination , ▁which ▁is ▁different ▁to ▁le th al ▁mut ag enes is : ▁the ▁drug ▁is ▁incor por ated ▁pre fe rent ially ▁to ▁the ▁end og enous ▁ad en os ine ▁nucle os ide ▁by ▁the ▁SARS - CoV -2 ▁poly mer ase ▁during ▁rep lication ▁of ▁the ▁R NA ▁g en ome .
▁Un l ike ▁many ▁other ▁ch ain - ter min ating ▁nucle os ide ▁drugs ▁used ▁for ▁other ▁virus es , ▁Rem desivir ▁e lic its ▁delay ed ▁ch ain ▁term ination ▁because ▁R NA ▁synt hesis ▁is ▁term inated ▁after ▁the ▁addition ▁of ▁three ▁more ▁nucle ot ides , ▁rather ▁than ▁at ▁the ▁point ▁of ▁Rem desivir ▁incor por ation ▁.
▁Em erg ence ▁of ▁ant ivir al ▁resistance :
▁Under ▁a ▁select ive ▁pressure ▁in ▁v it ro , ▁SA R - CoV -2 ▁resistance ▁to ▁Rem desivir ▁emer ged ▁and ▁was ▁associated ▁with ▁mut ations ▁( e . g . ▁E 80 2 D ▁and ▁V 7 92 I ) ▁within ▁the ▁sequ ence ▁c od ing ▁for ▁the ▁poly mer ase ▁.
▁The ▁E 80 2 D ▁mut ation ▁was ▁reported ▁in ▁a ▁case ▁study ▁describ ing ▁an ▁immun oc om p rom ised ▁patient ▁receiving ▁Rem desivir ▁who ▁experienced ▁rec r udes c ence ▁of ▁high - gr ade ▁viral ▁s hed d ing ▁following ▁a ▁trans ient ▁vi rolog ical ▁response ▁to ▁the ▁drug ▁.
▁Moreover , ▁the ▁V 7 92 I ▁mut ation ▁has ▁also ▁been ▁document ed ▁in ▁two ▁trans pl ant ▁rec ip ients ▁with ▁pers istant ▁SARS - CoV -2 ▁infection ▁.
▁If ▁Rem desivir ▁is ▁widely ▁used ▁in ▁an ▁out p ati ent ▁setting , ▁the ▁clinical ▁sign ific ance ▁of ▁these ▁observations ▁is ▁unclear .
▁The ▁initial ▁strong ▁recommendation ▁concerning ▁Bar ic it inib ▁for ▁patients ▁with ▁severe ▁or ▁critical ▁COVID -19, ▁was ▁updated ▁in ▁the ▁12 th ▁version ▁of ▁the ▁guideline .
▁It ▁followed ▁the ▁availability ▁of ▁new ▁evidence ▁demonst r ating ▁that ▁the ▁increment al ▁surv ival ▁benefit ▁aff ord ed ▁by ▁Bar ic it inib ▁ex ists ▁even ▁among ▁patients ▁also ▁tre ated ▁with ▁corticosteroids ▁and ▁I L -6 ▁recept or ▁block ers .
▁We ▁recommend ▁treatment ▁with ▁Bar ic it inib , ▁for ▁patients ▁with ▁severe ▁or ▁critical ▁COVID -19.
▁C orticostero ids ▁and ▁I L -6 ▁recept or ▁block ers ▁( T oc il iz um ab ▁and ▁Sar il um ab ) ▁are ▁also ▁recommended , ▁and ▁may ▁be ▁administered ▁in ▁combination ▁with ▁Bar ic it inib ▁to ▁patients ▁with ▁severe ▁or ▁critical ▁COVID -19 ▁( see ▁Section ▁6 .11 ▁and ▁6.1 5 ).
▁The ▁panel ▁ac know led ged ▁that ▁given ▁clinical ▁trials ▁were ▁not ▁represent ative ▁of ▁the ▁global ▁population ▁and ▁that ▁the ▁risk ▁benefit ▁may ▁be ▁less ▁advant age ous , ▁particularly ▁in ▁areas ▁where ▁certain ▁infect ious ▁diseases ▁such ▁as ▁HIV ▁infections , ▁t u ber c ul osis ▁and ▁certain ▁fun gal ▁infections ▁that ▁are ▁endemic ▁or ▁in ▁patients ▁with ▁an ▁increased ▁risk ▁of ▁opport un istic ▁infections .
▁The ▁panel ▁ant icip ated ▁that ▁there ▁would ▁be ▁situations ▁where ▁clinic ians ▁may ▁opt ▁for ▁less ▁ag gress ive ▁immun os u pp ressive ▁therapy ▁and / ▁or ▁to ▁comb ine ▁medic ations ▁in ▁a ▁step wise ▁f ash ion ▁in ▁patients ▁who ▁are ▁det er ior ating .
▁None ▁of ▁the ▁included ▁RCTs ▁enrolled ▁children , ▁and ▁therefore ▁the ▁applic ability ▁of ▁this ▁recommendation ▁to ▁children ▁remains ▁uncertain .
▁Additional ▁considerations ▁are ▁available ▁in ▁a ▁summary ▁of ▁practical ▁issues .
▁Use ful ▁information ▁can ▁also ▁be ▁found ▁in ▁the ▁United ▁States ▁F ood ▁and ▁D rug ▁Administration ▁( F DA ) ▁fact ▁she et ▁for ▁health ▁care ▁providers , ▁based ▁on ▁the ▁emergency ▁use ▁auth or ization ▁( E U A ) ▁of ▁Bar ic it inib ▁.
▁R ou te , ▁d os age ▁and ▁duration :
▁The ▁recommended ▁dose ▁is ▁4 ▁mg ▁daily ▁or ally ▁in ▁adults ▁with ▁e ▁G F R ▁ ≥ ▁60 ▁m ▁L / min /1 .7 3 ▁m ▁2
▁A ▁duration ▁of ▁14 ▁days ▁of ▁total ▁treatment ▁or ▁until ▁hospital ▁dis charge , ▁wh ic he ver ▁is ▁first .
▁The ▁opt imal ▁duration ▁of ▁treatment ▁is ▁unknown , ▁and ▁the ▁proposed ▁duration ▁reflect s ▁what ▁was ▁used ▁in ▁the ▁trials ▁providing ▁evidence ▁on ▁treatment ▁effects ▁of ▁Bar ic it inib .
▁D ose ▁reg imen ▁adjust ment ▁level :
▁Patients ▁with ▁le uk op en ia , ▁re nal ▁imp air ment ▁or ▁he p atic ▁imp air ment ▁( not e : ▁these ▁par am eters ▁should ▁be ▁monitored ▁during ▁treatment ); P ati ents ▁taking ▁strong ▁organ ic ▁an ion ▁trans por ter ▁3 ▁( O AT 3) ▁in hib itors ▁( e . g . ▁Pro b en ec id ), ▁there ▁are ▁drug ▁inter act ions ▁which ▁war rant ▁dose ▁redu ctions .
▁Bar ic it inib ▁( l ike ▁I L -6 ▁recept or ▁block ers ) ▁should ▁be ▁initiated ▁at ▁the ▁same ▁time ▁as ▁system ic ▁corticosteroids ; ▁specific ▁t im ing ▁during ▁hospitalization ▁or ▁the ▁course ▁of ▁illness ▁is ▁not ▁spec ified .
▁Consider ing ▁benefits ▁and ▁harms ▁in ▁patients ▁with ▁severe ▁or ▁critical ▁illness , ▁Bar ic it inib ▁reduces ▁mortality ▁and ▁probably ▁reduces ▁duration ▁of ▁mechanical ▁ventilation ▁and ▁hospital ▁length ▁of ▁stay .
▁It ▁probably ▁results ▁in ▁little ▁or ▁no ▁increase ▁in ▁serious ▁adverse ▁events .
▁Sub group ▁analyses ▁were ▁undert aken ▁for ▁J A K ▁in hib itors ▁as ▁a ▁class ▁( r ather ▁than ▁on ▁individual ▁drugs ) ▁and ▁revealed ▁no ▁evidence ▁of ▁a ▁subgroup ▁effect ▁on ▁relative ▁risk ▁in ▁younger ▁( < ▁70 ▁years ) ▁versus ▁older ▁patients ; ▁those ▁with ▁critical ▁versus ▁severe ▁COVID -19 ; ▁those ▁receiving ▁and ▁not ▁receiving ▁corticosteroids ▁at ▁bas eline ; ▁and ▁those ▁receiving ▁and ▁not ▁receiving ▁Rem desivir ▁or ▁I L -6 ▁block ers ▁at ▁bas eline .
▁Certainty ▁of ▁evidence ▁was ▁r ated ▁as : ▁high ▁for ▁decreased ▁mortality ▁( alth ough ▁the ▁panel ▁ac know led ged ▁that ▁the ▁relatively ▁short ▁follow - up ▁period ▁close ▁to ▁28 ▁days ▁is ▁possibly ▁insufficient ▁to ▁capture ▁all ▁relevant ▁events ); ▁moderate ▁for ▁reduction ▁in ▁hospital ▁length ▁of ▁stay , ▁mechanical ▁ventilation ▁and ▁serious ▁adverse ▁events , ▁all ▁r ated ▁down ▁for ▁serious ▁imprecision ; ▁and ▁low ▁for ▁time ▁to ▁clinical ▁st ability , ▁r ated ▁down ▁for ▁very ▁serious ▁imprecision .
▁The ▁GDG ▁noted ▁in ▁particular ▁that ▁the ▁risk ▁of ▁serious ▁infections ▁( b acter ial ▁and ▁fun gal ) ▁may ▁vary ▁consider ably ▁in ▁different ▁parts ▁of ▁the ▁world ▁according ▁to ▁the ▁back ground ▁prevalence ▁of ▁infections ▁( s uch ▁as ▁t u ber c ul osis ).
▁This ▁may ▁not ▁be ▁so ▁important ▁given ▁the ▁short ▁course ▁of ▁Bar ic it inib ▁used ▁for ▁treatment ▁of ▁COVID -19, ▁but ▁evidence ▁is ▁limited ▁given ▁the ▁limited ▁geograph ic ▁spread ▁of ▁the ▁included ▁trials ▁and ▁short ▁follow - up ▁periods .
▁Val ue ▁and ▁preferences ▁of ▁patients :
▁App lying ▁the ▁agreed ▁upon ▁values ▁and ▁preferences ▁( see ▁Section ▁7 ), ▁the ▁GDG ▁inf er red ▁that ▁almost ▁all ▁well - in formed ▁patients ▁with ▁severe ▁or ▁critical ▁COVID -19 ▁would ▁want ▁to ▁receive ▁Bar ic it inib ▁due ▁to ▁the ▁likely ▁reduction ▁in ▁mortality , ▁and ▁moderate ▁certainty ▁evidence ▁of ▁little ▁or ▁no ▁increase ▁in ▁serious ▁adverse ▁events .
▁The ▁benefit ▁of ▁Bar ic it inib ▁on ▁mortality ▁was ▁de em ed ▁of ▁critical ▁importance ▁to ▁patients ▁and ▁the ▁GDG ▁was ▁re ass ured ▁by ▁the ▁moderate ▁certainty ▁evidence ▁of ▁little ▁or ▁no ▁increase ▁in ▁serious ▁adverse ▁events .
▁Res ource ▁imp lications , ▁equity ▁and ▁human ▁rights :
▁Comp ared ▁with ▁some ▁other ▁candidate ▁treat ments ▁for ▁COVID -19, ▁Bar ic it inib ▁is ▁exp ensive .
▁A ccess ▁to ▁these ▁drugs ▁is ▁challeng ing ▁in ▁many ▁parts ▁of ▁the ▁world ▁and , ▁without ▁conc er ted ▁effort , ▁is ▁likely ▁to ▁remain ▁so , ▁especially ▁in ▁resource - p oor ▁areas .
▁It ▁is ▁therefore ▁possible ▁that ▁this ▁strong ▁recommendation ▁could ▁ex acer b ate ▁health ▁inequ ity .
▁The ▁GDG ▁was ▁also ▁sens itive ▁to ▁the ▁fact ▁that ▁allow ing ▁the ▁combined ▁use ▁of ▁the ▁J A K ▁in hib itor ▁Bar ic it inib ▁and ▁I L -6 ▁recept or ▁block ers ▁would ▁likely ▁further ▁reduce ▁the ▁availability ▁of ▁these ▁medic ations .
▁The ▁GDG ▁strongly ▁reinfor ces ▁the ▁need ▁to ▁improve ▁drug ▁availability , ▁particularly ▁in ▁resource - con st rained ▁areas .
▁On ▁the ▁other ▁hand , ▁given ▁the ▁demonst rated ▁benefits ▁for ▁patients , ▁it ▁should ▁also ▁provide ▁a ▁st im ul us ▁to ▁eng age ▁all ▁possible ▁mechanism s ▁to ▁improve ▁global ▁access ▁to ▁these ▁treat ments .
▁On ▁17 ▁December ▁202 1, ▁WHO ▁published ▁the ▁7 th ▁In v itation ▁to ▁Man ufact ure rs ▁of ▁The rapeut ics ▁against ▁COVID -19 ▁to ▁submit ▁an ▁Exp ression ▁of ▁Inte rest ▁( E O I ) ▁for ▁Produ ct ▁Evaluation ▁to ▁the ▁WHO ▁Pre qu al ification ▁Unit , ▁which ▁includes ▁Bar ic it inib .
▁At ▁a ▁time ▁of ▁drug ▁short age , ▁it ▁may ▁be ▁necessary ▁to ▁prior it ize ▁use ▁of ▁Bar ic it inib ▁through ▁clinical ▁tri age ▁such ▁as ▁prior it izing ▁patients ▁with ▁the ▁highest ▁bas eline ▁risk ▁for ▁mortality ▁( e . g . ▁those ▁with ▁critical ▁disease ▁over ▁those ▁with ▁severe ▁disease ), ▁in ▁whom ▁the ▁absolute ▁benefit ▁of ▁treatment ▁is ▁therefore ▁greatest .
▁Other ▁suggest ions ▁for ▁prior it ization , ▁which ▁lack ▁direct ▁evidence , ▁include ▁focus ing ▁on ▁patients ▁with ▁an ▁act ively ▁det er ior ating ▁clinical ▁course , ▁and ▁av o iding ▁Bar ic it inib ▁in ▁those ▁with ▁established ▁mult ior gan ▁failure ▁( in ▁whom ▁the ▁benefit ▁is ▁likely ▁to ▁be ▁smaller ).
▁Ac cept ability ▁and ▁feasibility ▁of ▁study :
▁As ▁Bar ic it inib ▁is ▁administered ▁or ally ▁once ▁daily , ▁hospital ized ▁patients ▁should ▁find ▁it ▁easy ▁to ▁accept ▁this ▁treatment
▁In ▁patients ▁who ▁cannot ▁sw all ow ▁table ts , ▁Bar ic it inib ▁can ▁be ▁crushed , ▁disp ers ed ▁in ▁water , ▁and ▁given ▁via ▁a ▁n as og ast ric ▁t ub e ▁( see ▁Practical ▁information ).
▁In ▁the ▁12 th ▁it eration ▁of ▁the ▁guideline , ▁the ▁GDG ▁confirmed ▁the ▁existing ▁strong ▁recommendation ▁to ▁use ▁Bar ic it inib ▁in ▁patients ▁with ▁severe ▁or ▁critical ▁COVID -19.
▁The ▁upd ate ▁was ▁based ▁on ▁additional ▁data ▁from ▁8 15 6 ▁patients ▁enrolled ▁in ▁the ▁rec overy ▁trial , ▁which ▁confirmed ▁the ▁surv ival ▁( now ▁high ▁certainty ▁evidence ) ▁and ▁other ▁benefits , ▁with ▁little ▁or ▁no ▁serious ▁adverse ▁events , ▁of ▁a ▁drug ▁that ▁may ▁be ▁administered ▁easily ▁.
▁The ▁GDG ▁ac know led ged ▁that ▁some ▁serious ▁adverse ▁events , ▁such ▁as ▁fun gal ▁infections , ▁may ▁not ▁have ▁been ▁accur ately ▁captured ▁during ▁the ▁relatively ▁short ▁follow - up ▁period ▁in ▁the ▁included ▁trials .
▁Because ▁of ▁different ▁mechanism s ▁of ▁action , ▁the ▁GDG ▁considered ▁Bar ic it inib ▁separ ately ▁from ▁other ▁J A K ▁in hib itors ▁( as ▁out l ined ▁below ).
▁Cost s ▁and ▁access ▁remain ▁important ▁considerations ▁and ▁the ▁GDG ▁recogn izes ▁that ▁this ▁recommendation ▁could ▁ex acer b ate ▁health ▁inequ ities .
▁This ▁strong ▁recommendation ▁further ▁streng t hens ▁the ▁imp et us ▁to ▁address ▁these ▁concerns ▁and ▁maxim ize ▁access ▁across ▁regions ▁and ▁countries .
▁The ▁GDG ▁did ▁not ▁ant icip ate ▁important ▁variability ▁in ▁patient ▁values ▁and ▁preferences , ▁and ▁judged ▁that ▁other ▁contextual ▁factors ▁would ▁not ▁al ter ▁the ▁recommendation ▁( see ▁Evidence ▁to ▁Dec ision ).
▁The ▁role ▁of ▁I L -6 ▁recept or ▁block ers ▁and ▁Bar ic it inib :
▁The ▁GDG ▁had ▁previously ▁made ▁a ▁strong ▁recommendation ▁for ▁the ▁use ▁of ▁I L -6 ▁recept or ▁block ers ▁( T oc il iz um ab ▁and ▁Sar il um ab ) ▁or ▁Bar ic it inib ▁as ▁alternative ▁ag ents ▁administered ▁in ▁addition ▁to ▁corticosteroids ▁for ▁patients ▁with ▁severe ▁or ▁critical ▁COVID -19.
▁The ▁GDG ▁had ▁e lected ▁to ▁ref rain ▁from ▁recommend ing ▁comb ining ▁these ▁three ▁immun os u pp ressive ▁drugs ▁until ▁clear ▁evidence ▁of ▁increment al ▁benefit ▁emer ged .
▁The ▁rec overy ▁trial ▁has ▁now ▁provided ▁evidence ▁that ▁comb ining ▁corticosteroids , ▁I L -6 ▁recept or ▁block ers ▁and ▁Bar ic it inib ▁provides ▁increment al ▁surv ival ▁benefit ▁.
▁Spe c if ically , ▁in ▁rec overy , ▁26 59 ▁patients ▁received ▁Bar ic it inib ▁along ▁with ▁corticosteroids ▁and ▁I L -6 ▁recept or ▁block ers .
▁The ▁effect ▁of ▁bar ic it inib ▁in ▁this ▁subgroup ▁was ▁consist ent ▁with ▁the ▁b ene ▁f icial ▁effect ▁of ▁bar ic it inib ▁in ▁patients ▁who ▁were ▁not ▁tre ated ▁with ▁I L -6 ▁recept or ▁block ers ▁.
▁Although ▁these ▁three ▁immun os u pp ressive ▁drugs ▁are ▁recommended ▁and ▁may ▁be ▁administered ▁joint ly , ▁the ▁panel ▁ant icip ated ▁that ▁there ▁would ▁be ▁situations ▁where ▁clinic ians ▁may ▁opt ▁for ▁less ▁ag gress ive ▁immun os u pp ressive ▁therapy ▁and / or ▁to ▁comb ine ▁medic ations ▁in ▁a ▁step wise ▁f ash ion ▁in ▁patients ▁who ▁are ▁det er ior ating .
▁However , ▁since ▁the ▁drugs ▁have ▁not ▁under g one ▁direct ▁compar isons , ▁if ▁this ▁situation ▁ar ises , ▁the ▁GDG ▁felt ▁that ▁clinic ians ▁should ▁choose ▁be ▁tw een ▁Bar ic it inib ▁and ▁I L -6 ▁recept or ▁block ers ▁on ▁the ▁basis ▁of ▁experience ▁and ▁comfort ▁using ▁the ▁drugs ; ▁local ▁institution al ▁policies ; ▁route ▁of ▁administration ▁( B aric it inib ▁is ▁oral ; ▁I L -6 ▁recept or ▁block ers ▁are ▁intra ven ous ); ▁and ▁cost .
▁However , ▁since ▁the ▁drugs ▁have ▁not ▁under g one ▁direct ▁compar isons , ▁if ▁this ▁situation ▁ar ises , ▁the ▁GDG ▁felt ▁that ▁clinic ians ▁should ▁choose ▁be ▁tw een ▁Bar ic it inib ▁and ▁I L -6 ▁recept or ▁block ers ▁on ▁the ▁basis ▁of ▁experience ▁and ▁comfort ▁using ▁the ▁drugs ; ▁local ▁institution al ▁policies ; ▁route ▁of ▁administration ▁( B aric it inib ▁is ▁oral ; ▁I L -6 ▁recept or ▁block ers ▁are ▁intra ven ous ); ▁and ▁cost .
▁Un certainty ▁also ▁remains ▁with ▁regard ▁to ▁administration ▁of ▁Bar ic it inib ▁to ▁pregnant ▁or ▁lactating ▁women .
▁The ▁decision ▁regarding ▁use ▁of ▁this ▁therapeutic ▁should ▁be ▁made ▁be ▁tw een ▁the ▁pregnant ▁individual ▁and ▁their ▁health ▁care ▁prov ider ▁while ▁discuss ing ▁whether ▁the ▁potential ▁benefit ▁just ifies ▁the ▁potential ▁risk ▁to ▁the ▁mother ▁and ▁f et us ▁( see ▁Research ▁evidence ▁and ▁Practical ▁information ▁tab s ).
▁All ▁RCTs ▁enrolled ▁patients ▁in ▁in - p ati ent ▁settings .
▁For ▁patients ▁with ▁severe ▁or ▁critical ▁COVID -19, ▁the ▁grade ▁summary ▁of ▁findings ▁table ▁shows ▁the ▁relative ▁and ▁absolute ▁effects ▁of ▁Bar ic it inib ▁compared ▁with ▁standard ▁care ▁for ▁the ▁outcomes ▁of ▁interest , ▁with ▁certainty ▁r at ings , ▁informed ▁by ▁the ▁L N MA ▁.
▁Bas eline ▁risk ▁estimate ▁summary
▁For ▁severe ▁and ▁critical ▁illness es , ▁for ▁the ▁critical ▁outcome ▁of ▁mortality , ▁the ▁applied ▁bas eline ▁risk ▁estimate ▁was ▁13% ▁(1 30 ▁in 1 000 ).
▁As ▁for ▁other ▁related ▁recommendations ▁in ▁this ▁guideline , ▁the ▁estimate ▁is ▁der ived ▁from ▁the ▁sol id ar ity ▁trial ▁for ▁severe ▁and ▁critical ▁patients ▁adjusted ▁for ▁treatment ▁effects ▁of ▁corticosteroids .
▁For ▁other ▁outcomes , ▁we ▁used ▁the ▁med ian ▁of ▁the ▁control ▁arm ▁of ▁the ▁R and om ized ▁Con t rolled ▁T ri als ▁( R CT s ) ▁that ▁contrib uted ▁to ▁the ▁evidence ▁( see ▁Section ▁7 ).
▁Four ▁pre - spec ified ▁subgroup ▁analyses ▁were ▁undert aken ▁for ▁J A K ▁in hib itors ▁as ▁a ▁class ▁rather ▁than ▁for ▁individual ▁drugs :
▁Age : ▁younger ▁adults ▁( < ▁70 ▁years ) ▁versus ▁older ▁adults ▁( ≥ ▁70 ▁years ).
▁Sever ity ▁of ▁illness ▁at ▁time ▁of ▁treatment ▁init iation :
▁non - severe ▁versus ▁severe ▁versus ▁critical .
▁Con com it ant ▁use ▁of ▁corticosteroids ▁at ▁bas eline .
▁No ▁evidence ▁of ▁subgroup ▁effects ▁was ▁identified ▁on ▁the ▁relative ▁risk ▁of ▁critical ▁outcomes ▁across ▁all ▁pre - spec ified ▁effect ▁mod if iers .
▁Conf idence ▁interval ▁includes ▁no ▁important ▁difference .
▁Cond itional ▁recommendation ▁against ▁Ru x ol it inib ▁and ▁To f ac it inib :
▁We ▁suggest ▁not ▁to ▁use ▁Ru x ol it inib ▁or ▁To f ac it inib ▁for ▁patients ▁with ▁severe ▁or ▁critical ▁COVID -19 ▁( c ond itional ▁recommendations ).
▁Clin icians ▁should ▁consider ▁using ▁these ▁drugs ▁only ▁if ▁neither ▁Bar ic it inib ▁nor ▁I L ▁- 6 ▁recept or ▁block ers ▁( T oc il iz um ab ▁or ▁Sar il um ab ) ▁are ▁available .
▁The ▁GDG ▁emphasized ▁the ▁need ▁for ▁more ▁trial ▁evidence ▁to ▁better ▁inform ▁the ▁recommendations .
▁Practical ▁information , ▁route , ▁d os age ▁and ▁duration :
▁We ▁refer ▁to ▁the ▁table ▁of ▁trial ▁characteristics ▁( R ux ol it inib ▁and ▁To f ac it inib ) ▁to ▁guide ▁the ▁administration ▁of ▁these ▁ag ents , ▁in ▁the ▁absence ▁of ▁other ▁available ▁information .
▁Ru x ol it inib ▁or ▁To f ac it inib ▁( l ike ▁I L -6 ▁recept or ▁block ers ) ▁should ▁be ▁initiated ▁with ▁system ic ▁corticosteroids ;
▁specific ▁t im ing ▁during ▁hospitalization ▁or ▁the ▁course ▁of ▁illness ▁is ▁not ▁spec ified .
▁Evidence ▁to ▁decisions , ▁benefits ▁and ▁harms :
▁The ▁effects ▁of ▁Ru x ol it inib ▁or ▁To f ac it inib ▁on ▁mortality , ▁need ▁for ▁mechanical ▁ventilation ▁and ▁hospital ▁length ▁of ▁stay ▁remain ▁uncertain .
▁To f ac inib ▁may ▁increase ▁adverse ▁events ▁leading ▁to ▁drug ▁discontin uation .
▁Sub group ▁analyses ▁were ▁undert aken ▁for ▁J A K ▁in hib itors ▁as ▁a ▁class ▁( r ather ▁than ▁on ▁individual ▁drugs ) ▁and ▁revealed ▁no ▁evidence ▁of ▁a ▁subgroup ▁effect ▁on ▁relative ▁risk ▁in ▁younger ▁( < ▁70 ▁years ) ▁versus ▁older ▁patients ; ▁those ▁receiving ▁and ▁not ▁receiving ▁corticosteroids ; ▁those ▁with ▁severe ▁versus ▁critical ▁COVID -19 ; ▁and ▁those ▁receiving ▁and ▁not ▁receiving ▁Rem desivir .
▁Due ▁to ▁serious ▁imprecision ▁in ▁small ▁co h orts ▁( R ux ol it inib : ▁two ▁RCTs , ▁475 ▁patients ; ▁To f ac it inib : ▁one ▁RCT , ▁289 ▁patients ) ▁with ▁few ▁events ▁and ▁serious ▁indirect ness ▁( per tain ing ▁to ▁RCTs ▁for ▁Ru x ol it inib , ▁most ▁patients ▁did ▁not ▁receive ▁corticosteroids ), ▁certainty ▁of ▁evidence ▁was ▁r ated ▁as ▁low ▁or ▁very ▁low ▁for ▁all ▁prior it ized ▁outcomes ▁for ▁both ▁drugs .
▁App lying ▁the ▁agreed ▁values ▁and ▁preferences ▁( see ▁Section ▁7 ), ▁the ▁GDG ▁inf er red ▁that , ▁given ▁the ▁low ▁or ▁very ▁low ▁certainty ▁evidence ▁on ▁mortality ▁and ▁the ▁other ▁prior it ized ▁benefit ▁outcomes ▁and ▁the ▁remaining ▁possibility ▁of ▁serious ▁adverse ▁effects , ▁the ▁majority ▁of ▁well - in formed ▁patients ▁would ▁not ▁want ▁to ▁receive ▁Ru x ol it inib ▁or ▁To f ac it inib .
▁The ▁GDG ▁ant icip ated , ▁however , ▁that ▁because ▁benefit ▁has ▁not ▁been ▁exclud ed , ▁and ▁because ▁a ▁class ▁effect ▁of ▁J A K ▁in hib itors ▁might ▁exist ▁( s uch ▁that ▁Bar ic it inib ▁provides ▁indirect ▁evidence ▁of ▁benefit ▁for ▁the ▁other ▁J A K ▁in hib itors ), ▁a ▁min ority ▁of ▁well - in formed ▁patients ▁would ▁choose ▁to ▁receive ▁one ▁or ▁other ▁drug ▁in ▁circum st ances ▁in ▁which ▁neither ▁Bar ic it inib ▁nor ▁I L ▁- 6 ▁recept or ▁block ers ▁( T oc il iz um ab ▁or ▁Sar il um ab ) ▁were ▁available .
▁The ▁GDG ▁noted ▁that , ▁given ▁the ▁recommendation ▁against ▁use ▁of ▁Ru x ol it inib ▁or ▁To f ac it inib , ▁efforts ▁to ▁ensure ▁access ▁to ▁drugs ▁should ▁focus ▁on ▁those ▁that ▁are ▁currently ▁recommended .
▁As ▁Ru x ol it inib ▁and ▁To f ac it inib ▁are ▁administered ▁or ally ▁twice ▁daily , ▁this ▁treatment ▁should ▁be ▁easy ▁to ▁accept ▁for ▁hospital ized ▁patients ▁with ▁severe ▁and ▁critical ▁COVID -19.
▁When ▁moving ▁from ▁evidence ▁to ▁the ▁conditional ▁recommendation ▁not ▁to ▁use ▁Ru x ol it inib ▁or ▁To f ac it inib ▁in ▁patients ▁with ▁severe ▁or ▁critical ▁COVID -19, ▁the ▁GDG ▁emphasized ▁the ▁low ▁to ▁very ▁low ▁certainty ▁evidence ▁for ▁mortality , ▁duration ▁of ▁mechanical ▁ventilation ▁and ▁possible ▁increase ▁in ▁serious ▁adverse ▁events ▁( part ic ular ly ▁for ▁To f ac it inib ).
▁The ▁GDG ▁emphasized ▁the ▁need ▁for ▁more ▁trial ▁evidence ▁to ▁better ▁inform ▁the ▁recommendations ; ▁this ▁is ▁ant icip ated ▁through ▁ongoing ▁trials ▁for ▁these ▁J A K ▁in hib itors .
▁Un certainty ▁also ▁remains ▁with ▁regard ▁to ▁the ▁administration ▁of ▁Ru x ol it inib ▁or ▁To f ac it inib ▁to ▁pregnant ▁or ▁lactating ▁women .
▁The ▁L N MA ▁on ▁Ru x ol it inib ▁was ▁informed ▁by ▁two ▁RCTs ▁that ▁enrolled ▁475 ▁patients ▁across ▁non - severe , ▁severe ▁and ▁critical ▁illness ▁subgroup s ▁.
▁For ▁patients ▁with ▁severe ▁and ▁critical ▁COVID -19, ▁the ▁grade ▁summary ▁of ▁findings ▁table ▁for ▁Ru x ol it inib ▁shows ▁the ▁relative ▁and ▁absolute ▁effects ▁compared ▁with ▁usual ▁care ▁for ▁the ▁outcomes ▁of ▁interest , ▁with ▁certainty ▁r at ings .
▁See ▁Section ▁7 ▁for ▁sources ▁of ▁bas eline ▁risk ▁estimates ▁inform ing ▁absolute ▁estimates ▁of ▁effect .
▁The ▁GDG ▁pre - spec ified ▁several ▁subgroup ▁analyses ▁of ▁interest ▁across ▁all ▁J A K ▁in hib itors ▁of ▁interest ; ▁of ▁these , ▁no ▁significant ▁relative ▁subgroup ▁effects ▁were ▁found .
▁Please ▁see ▁the ▁summary ▁accomp any ing ▁the ▁recommendation ▁for ▁Bar ic it inib ▁for ▁more ▁det ails .
▁Most ▁patients ▁probably ▁did ▁not ▁receive ▁corticosteroids ▁at ▁bas eline .
▁Con com it ant ▁use ▁of ▁corticosteroids ▁pot ent i ates ▁the ▁benef icial ▁effect ▁of ▁inter le uk in -6 ▁recept or ▁block ers .
▁Inter le uk in -6 ▁is ▁downstream ▁in ▁the ▁Jan us ▁k in ase ▁pathway .
▁Therefore , ▁the ▁effect ▁of ▁Ru x ol it inib ▁may ▁have ▁been ▁larger ▁in ▁most ▁patients ▁who ▁had ▁received ▁st ero ids .
▁Further , ▁the ▁Ru x ol it inib ▁trial ▁probably ▁included ▁many ▁patients ▁with ▁non - severe ▁disease .
▁A ▁benef icial ▁effect ▁of ▁Jan us ▁k in ase ▁in hib itors ▁may ▁be ▁limited ▁to ▁patients ▁with ▁severe ▁or ▁critical ▁disease .
▁The ▁cred ible ▁interval ▁includes ▁important ▁harm ▁and ▁important ▁benefit .
▁There ▁was ▁only ▁one ▁event ▁in ▁the ▁single ▁trial ▁that ▁reported ▁this ▁outcome , ▁of ▁4 24 ▁patients ▁enrolled ▁in ▁the ▁study .
▁The ▁cred ible ▁interval ▁includes ▁important ▁benefit ▁and ▁important ▁harm .
▁Cred ible ▁interval ▁includes ▁important ▁harm ▁and ▁important ▁benefit ▁( using ▁a ▁min imal ▁important ▁difference ▁th res hold ▁of ▁1 ▁day ).
▁The ▁L N MA ▁for ▁To f ac it inib ▁was ▁informed ▁by ▁one ▁RCT ▁that ▁enrolled ▁289 ▁patients ▁across ▁non - severe , ▁severe ▁and ▁critical ▁illness ▁subgroup s ▁.
▁The ▁trial ▁was ▁registered ▁and ▁published ▁in ▁a ▁pe er - re view ed ▁journal ; ▁it ▁exclud ed ▁children ▁and ▁pregnant ▁women .
▁The ▁table ▁shows ▁the ▁characteristics ▁of ▁the ▁RCT .
▁V ery ▁few ▁events : ▁only ▁21 ▁in ▁total ▁(16 / 14 2 ▁in ▁To f ac it inib ▁arm ▁and ▁5 / 14 2 ▁in ▁place bo ▁arm ).
▁Me chan ism ▁of ▁reported ▁action ▁: 1
▁T y pe ▁I ▁and ▁T y pe ▁II ▁Cy t ok ine ▁Re cept ors ▁are ▁a ▁family ▁of ▁recept ors ▁employ ed ▁by ▁over ▁50 ▁Inter le uk ins , ▁Inter fer ons , ▁col ony ▁st im ul ating ▁factors , ▁and ▁h orm ones ▁.
▁The ▁int race ll ular ▁sign all ing ▁tr ig ge red ▁by ▁these ▁recept ors ▁is ▁med iated ▁by ▁Jan us ▁k in ases ▁( J A K s ), ▁a ▁small ▁family ▁of ▁k in ases ▁including ▁J A K 1, ▁J A K 2, ▁J A K 3, ▁and ▁T y ro s ine ▁k in ase ▁2 ▁( T Y K 2).
▁T y pe ▁I ▁Cy t ok ines ▁include ▁I L ▁- 2, ▁I F N - γ , ▁I L -1 2, ▁and ▁T N F b , ▁and ▁T y pe ▁II ▁Cy t ok ines ▁include ▁I L ▁- 4, ▁I L - 5, ▁I L - 6, ▁I L -1 0, ▁and ▁I L -1 3.
▁J A K ▁in hib itors ▁are ▁a ▁class ▁of ▁drugs ▁which ▁in hib it ▁int race ll ular ▁sign all ing ▁through ▁mult if act or ial ▁effects ▁on ▁Cy t ok ine ▁sign all ing .
▁As ▁a ▁consequ ence , ▁they ▁inter fe re ▁with ▁many ▁cell ular ▁respons es , ▁including ▁ant ivir al ▁respons es , ▁An gi ot ens in - Con ver ting ▁En zy me ▁2 ▁( AC E 2) ▁expression , ▁T ▁cell ▁function ▁and ▁different iation ▁and ▁m ac ro ph age ▁activ ation ▁.
▁Bar ic it inib , ▁Ru x ol it inib , ▁and ▁To f ac it inib ▁are ▁at ▁least ▁three ▁of ▁nine ▁J A K ▁in hib itors
▁These ▁three ▁drugs ▁are ▁all ▁generally ▁considered ▁to ▁be ▁non - specific ▁J A K ▁in hib itors , ▁but ▁differences ▁in ▁the ▁specific ity ▁and ▁pot ency ▁for ▁different ▁J A K s ▁are ▁evident .
▁Bar ic it inib ▁has ▁been ▁described ▁as ▁a ▁J A K 1 / J A K 2 ▁in hib itor , ▁Ru x ol it inib ▁as ▁J A K 1 / J A K 2 ▁> ▁T Y K 2, ▁and ▁to ▁To f ac it inib ▁as ▁J A K 3 / J A K 1 ▁> ▁J A K 2/ T Y K 2; ▁other ▁differences ▁have ▁also ▁been ▁previously ▁described ▁.
▁Stud ies ▁evalu ating ▁J A K ▁in hib itors ▁for ▁the ▁treatment ▁of ▁COVID -19 ▁have ▁been ▁conducted ▁at ▁doses ▁that ▁are ▁as ▁high ▁or ▁higher ▁than ▁those ▁approved ▁for ▁other ▁indic ations , ▁such ▁as ▁R he um at oid ▁ar th rit is , ▁My el of ib ro s is , ▁and ▁U l cer ative ▁col it is .
▁Therefore , ▁pl a us ibility ▁is ▁cont ing ent ▁upon ▁the ▁role ▁of ▁Cy t ok ine ▁sign all ing ▁in ▁COVID -19, ▁and ▁not ▁on ▁whether ▁the ▁pharmac ok inet ics ▁at ▁the ▁studied ▁dose ▁is ▁sufficient ▁to ▁in hib it ▁the ▁target ▁pro te ins .
▁There ▁are ▁notable ▁differences ▁in ▁the ▁approved ▁doses , ▁sched ules , ▁pharmac ok inet ics , ▁cont ra ind ic ations , ▁and ▁indic ations ▁of ▁these ▁drugs ▁for ▁other ▁indic ations .
▁Col lect ively , ▁these ▁differences ▁limit ▁the ▁confidence ▁to ▁consider ▁a ▁class - w ide ▁recommendation ▁with ▁currently ▁available ▁data .
▁S ot ro v imab ▁( up d ated ▁13 ▁January ▁2023 ) ▁Information ▁Box
▁Up d ated ▁evidence ▁supporting ▁the ▁initial ▁strong ▁recommendation ▁against ▁use ▁of ▁S ot ro v imab ▁for ▁patients ▁with ▁non - severe ▁COVID -19 ▁was ▁published ▁in ▁this ▁13 th ▁it eration ▁of ▁the ▁guideline , ▁following ▁the ▁availability ▁of ▁data ▁showing ▁in ▁v it ro ▁ne ut ral ization ▁activity ▁is ▁d imin ished ▁with ▁S ot ro v imab ▁with ▁currently ▁circul ating ▁SARS - CoV -2 ▁variants ▁and ▁sub v ari ants ▁( e . g . ▁O m ic ron ).
▁For ▁patients ▁with ▁non - severe ▁COVID -19 ▁strong ▁recommendation ▁against ▁updated ▁evidence .
▁We ▁recommend ▁against ▁treatment ▁with ▁S ot ro v imab ▁( st r ong ▁recommendation ▁against ).
▁See ▁decision ▁support ▁tool ▁that ▁dis pl ays ▁benefits ▁and ▁harms ▁of ▁N irmatrelvir , ▁R it onavir , ▁M olnupiravir , ▁and ▁Rem desivir .
▁The ▁GDG ▁considered ▁in ▁v it ro ▁data ▁demonst r ating ▁that ▁ne ut ral ization ▁of ▁currently ▁circul ating ▁variants ▁of ▁SARS - CoV -2 ▁and ▁their ▁sub v ari ants ▁with ▁S ot ro v imab ▁is ▁d imin ished .
▁There ▁was ▁cons ensus ▁among ▁the ▁panel ▁that ▁the ▁meaning ful ▁reduction ▁of ▁in ▁v it ro ▁ne ut ral ization ▁activity ▁strongly ▁suggests ▁absence ▁of ▁clinical ▁effectiveness ▁of ▁mon ocl on al ▁antib odies ▁such ▁as ▁S ot ro v imab .
▁There ▁was ▁also ▁cons ensus ▁regarding ▁the ▁need ▁for ▁clinical ▁trial ▁evidence ▁in ▁order ▁to ▁confirm ▁clinical ▁effectiveness ▁of ▁new ▁mon ocl on al ▁antib odies ▁that ▁rel i ably ▁ne ut ral ize ▁circul ating ▁st rain s ▁in ▁v it ro .
▁Given ▁the ▁strong ▁recommendation ▁against ▁using ▁S ot ro v imab ▁for ▁patients ▁with ▁non - severe ▁COVID -19, ▁practical ▁considerations ▁were ▁felt ▁to ▁be ▁less ▁relevant ▁here .
▁Evidence ▁to ▁decision ▁benefits ▁and ▁harms :
▁On ▁the ▁basis ▁of ▁clinical ▁trial ▁evidence ▁that ▁remains ▁available ▁via ▁the ▁L N MA , ▁in ▁the ▁8 th ▁version ▁of ▁this ▁guideline , ▁GDG ▁had ▁previously ▁made ▁a ▁conditional ▁recommendation ▁for ▁use ▁of ▁S ot ro v imab ▁to ▁patients ▁with ▁non - severe ▁COVID -19 ▁at ▁highest ▁risk ▁of ▁hospitalization .
▁At ▁the ▁time , ▁the ▁panel ▁ac know led ged ▁that ▁the ▁emergence ▁of ▁future ▁variants ▁could ▁reduce ▁the ▁clinical ▁effectiveness ▁of ▁S ot ro v imab .
▁In ▁the ▁12 th ▁version ▁of ▁this ▁guideline , ▁rather ▁than ▁new ▁clinical ▁trial ▁evidence , ▁the ▁change ▁in ▁recommendation ▁was ▁tr ig ge red ▁by ▁new ▁in ▁v it ro ▁evidence ▁demonst r ating ▁that ▁S ot ro v imab ▁has ▁very ▁d imin ished ▁in ▁v it ro ▁ne ut ral ization ▁activity ▁to ▁currently ▁circul ating ▁sub v ari ants ▁of ▁SARS - CoV -2 .
▁There ▁was ▁cons ensus ▁among ▁the ▁panel ▁that ▁it ▁is ▁highly ▁unl ike ly ▁that ▁the ▁clinical ▁effectiveness ▁of ▁S ot ro v imab ▁would ▁pers ist ▁in ▁the ▁absence ▁of ▁adequate ▁in ▁v it ro ▁ne ut ral ization ▁of ▁the ▁circul ating ▁variants .
▁Accordingly , ▁the ▁panel ▁concluded ▁that ▁the ▁evidence ▁upon ▁which ▁the ▁previous ▁recommendation ▁h ing ed ▁was ▁no ▁longer ▁applic able .
▁For ▁this ▁13 th ▁version ▁of ▁the ▁guideline , ▁the ▁GDG ▁reviewed ▁additional ▁in ▁v it ro ▁ne ut ral ization ▁data ▁that ▁emer ged ▁after ▁the ▁change ▁in ▁the ▁guideline ▁for ▁S ot ro v imab ▁and ▁C as ir iv imab - I m de v imab , ▁and ▁that ▁included ▁information ▁on ▁new ▁variants .
▁This ▁increment al ▁evidence ▁support s ▁the ▁change ▁in ▁recommendation ▁and ▁streng t hens ▁the ▁GDG ’ ▁s ▁confidence ▁that ▁the ▁strong ▁recommendation ▁not ▁to ▁use ▁S ot ro v imab ▁( and ▁C as ir iv imab - I m de v imab ) ▁is ▁applic able ▁to ▁the ▁current ▁SARS - CoV 2 ▁e c ology .
▁More ▁information ▁on ▁the ▁interpret ation ▁of ▁the ▁results ▁of ▁in ▁v it ro ▁ne ut ral ization ▁data ▁can ▁be ▁found ▁in ▁Section ▁6 .6 .1 ▁( me chan ism ▁of ▁action ) ▁and ▁in ▁correspond ence ▁published ▁in ▁The ▁L ance t ▁.
▁Certainty ▁of ▁the ▁Evidence ▁in ▁light ▁of ▁the ▁recent ▁in ▁v it ro ▁evidence , ▁the ▁GDG ▁concluded ▁that ▁the ▁clinical ▁effects ▁of ▁S ot ro v imab ▁for ▁COVID -19 ▁caused ▁by ▁the ▁currently ▁circul ating ▁variants ▁and ▁sub v ari ants ▁of ▁SARS - CoV -2 ▁are ▁highly ▁uncertain .
▁The ▁existing ▁trial ▁evidence ▁identified ▁in ▁the ▁L N MA ▁was ▁judged ▁to ▁be ▁at ▁moderate ▁certainty ▁for ▁reduced ▁hospitalization ▁and ▁high ▁certainty ▁for ▁absence ▁of ▁inf usion ▁re act ions , ▁with ▁no ▁or ▁small ▁differences ▁in ▁mortality ▁or ▁mechanical ▁ventilation .
▁With ▁the ▁new ▁circul ating ▁SARS - CoV -2 ▁variants , ▁this ▁trial ▁evidence ▁would ▁be ▁r ated ▁as ▁very ▁low , ▁meaning ▁that ▁the ▁benefits ▁of ▁S ot ro v imab ▁cannot ▁be ▁determined ▁by ▁trials ▁performed ▁before ▁the ▁new ▁variants ▁occurred .
▁App lying ▁the ▁agreed ▁upon ▁values ▁and ▁preferences ▁( see ▁Section ▁7 ), ▁the ▁GDG ▁inf er red ▁that , ▁in ▁the ▁absence ▁of ▁com pe lling ▁evidence ▁of ▁clinical ▁effectiveness ▁for ▁the ▁currently ▁circul ating ▁SARS - CoV -2 ▁variants , ▁almost ▁all ▁well - in formed ▁patients ▁would ▁choose ▁not ▁to ▁receive ▁S ot ro v imab
▁The ▁strong ▁recommendation ▁against ▁the ▁use ▁of ▁S ot ro v imab ▁is ▁further ▁supported ▁by ▁the ▁challeng es ▁with ▁availability ▁and ▁feasibility , ▁such ▁as ▁limited ▁production , ▁intra ven ous ▁administration ▁and ▁require ment ▁for ▁expert ise ▁to ▁offer ▁such ▁treatment ▁while ▁oral ▁ant ivir al ▁the rap ies ▁are ▁also ▁available .
▁Although ▁previous ▁clinical ▁trial ▁evidence ▁available ▁via ▁the ▁L N MA ▁remains ▁accur ate , ▁the ▁panel ▁concluded ▁that ▁it ▁is ▁no ▁longer ▁applic able ▁to ▁COVID -19 ▁caused ▁by ▁the ▁SARS - CoV -2 ▁variants ▁that ▁are ▁currently ▁circul ating ▁g lob ally .
▁The ▁panel ▁summer ised ▁that ▁the ▁lik eli hood ▁of ▁COVID -19 ▁caused ▁by ▁former ▁variants ▁was ▁extremely ▁low ▁and ▁that ▁according ly , ▁evidence ▁of ▁S ot ro v imab ' s ▁clinical ▁effectiveness ▁for ▁COVID -19 ▁was ▁none x ist ent .
▁The ▁panel ▁applied ▁the ▁same ▁rational e ▁to ▁the ▁recommendation ▁for ▁C as ir iv imab - I m de v imab .
▁Rel iance ▁on ▁in ▁v it ro ▁evidence :
▁The ▁GDG ▁agreed ▁that ▁large ▁high - qu ality ▁clinical ▁trials ▁generally ▁provide ▁the ▁best ▁evidence ▁of ▁clinical ▁effectiveness ▁for ▁therapeutic ▁interventions .
▁The ▁GDG ▁also ▁contin ues ▁to ▁base ▁its ▁recommendations ▁st rict ly ▁on ▁crit ically ▁important ▁outcomes .
▁From ▁the ▁pers pective ▁of ▁clinical ▁guidelines , ▁mechan istic ▁studies ▁and ▁sur rog ate ▁outcomes ▁are ▁useful ▁to ▁identify ▁candidate ▁the rap ies ▁for ▁clinical ▁trials , ▁but ▁are ▁of ▁no ▁use ▁in ▁confirm ing ▁clinical ▁effectiveness .
▁The ▁panel ▁concluded ▁that ▁the ▁emerging ▁evidence ▁demonst r ating ▁the ▁reduced ▁ne ut ral ization ▁of ▁current ▁variants ▁by ▁S ot ro v imab ▁in ▁v it ro ▁would ▁likely ▁have ▁just ified ▁not ▁laun ching ▁clinical ▁trials ▁and ▁now ▁rend ers ▁the ▁results ▁of ▁previous ▁trials ▁in app lic able .
▁In ▁v it ro ▁ass ays ▁were ▁de em ed ▁sufficient ▁to ▁rule ▁out ▁a ▁clinical ▁effect .
▁Not with standing , ▁pro of ▁of ▁pot ent ▁in ▁v it ro ▁ne ut ral ization ▁would ▁not ▁be ▁sufficient ▁to ▁confirm ▁clinical ▁effectiveness .
▁Therefore , ▁the ▁GDG ▁will ▁only ▁consider ▁making ▁recommendations ▁for ▁new ▁mon ocl on al ▁antib odies ▁once ▁they ▁have ▁been ▁rig or ously ▁evaluated ▁in ▁clinical ▁trials .
▁S ot ro v imab ▁( VI R - 78 3 1; ▁G S K 4 18 21 36 ) ▁is ▁a ▁single ▁human ▁mon ocl on al ▁antib ody ▁that ▁b ind s ▁to ▁a ▁cons erv ed ▁ep it ope ▁of ▁the ▁SARS - CoV -2 ▁sp ike ▁pro te in , ▁preventing ▁the ▁virus ▁from ▁ent ering ▁cell s .
▁Ne ut ral ization ▁of ▁SARS - CoV -2 ▁( U S A ▁W A 1 / 20 20 ) ▁was ▁achieved ▁in ▁V ero ▁E 6 ▁cell s ▁with ▁an ▁E ▁C 90 ▁value ▁of ▁0 .19 ▁ μ g / m ▁L ▁.
▁S ot ro v imab ▁ser um ▁concent r ations ▁in ▁CO ME T - IC E ▁( s ing le ▁500 ▁mg ▁IV ▁inf usion ) ▁provided ▁geomet ric ▁mean ▁C m ax ▁( at ▁the ▁end ▁of ▁a ▁1 ▁h r ▁IV ▁inf usion ) ▁of ▁11 7 .6 ▁ μ g / m ▁L ▁( N = 12 9, ▁C V % ▁40 ) ▁and ▁a ▁geomet ric ▁mean ▁day ▁29 ▁ser um ▁concent ration ▁of ▁24 .5 ▁ μ g / m ▁L ▁.
▁P op ulation ▁mean ▁ser um ▁concent r ations ▁are ▁therefore ▁expected ▁to ▁be ▁12 9 - f old ▁higher ▁after ▁29 ▁days ▁than ▁the ▁concent r ations ▁needed ▁in ▁v it ro ▁to ▁ne ut ral ize ▁the ▁original ▁st rain ▁of ▁SARS - CoV -2 .
▁Information ▁in ▁the ▁F DA ▁Em erg ency ▁Use ▁Auth or ization ▁states ▁“ n o ▁change ” ▁in ▁activity ▁of ▁S ot ro v imab ▁against ▁Al ph a , ▁Bet a , ▁G am ma , ▁E ps il on , ▁L ota , ▁K app a , ▁D elt a ▁( inc lud ing ▁with ▁K 4 17 N ), ▁L amb d a ▁and ▁M u .
▁S ot ro v imab ▁has ▁been ▁reported ▁to ▁re tain ▁activity ▁against ▁B A .1 ▁O m ic ron ▁in ▁p se ud o ▁virus ▁ass ays ▁but ▁with ▁higher ▁concent r ations ▁being ▁required ▁for ▁ne ut ral ization ▁compared ▁with ▁the ▁wild - ty pe ▁virus ▁.
▁The ▁F DA ▁summar ized ▁the ▁reported ▁in ▁v it ro ▁ne ut ral ization ▁data ▁( EC 90 ) ▁available ▁for ▁B A .2 ▁O m ic ron ▁and ▁its ▁interpret ation ▁in ▁the ▁context ▁of ▁the ▁pharmac ok inet ics ▁of ▁s ot ro v imab ▁in ▁hum ans ▁.
▁The ▁presented ▁data ▁shows ▁the ▁E C ▁90 ▁to ▁be ▁between ▁25 .3 ▁and ▁4 8, ▁1 - f old ▁higher ▁for ▁B A .2 ▁O m ic ron ▁than ▁for ▁pre - O m ic ron ▁variants .
▁In ▁the ▁associated ▁analysis , ▁assum ing ▁a ▁6 .5% ▁or ▁12 % ▁pen et ration ▁of ▁antib ody ▁from ▁ser um ▁into ▁the ▁l ung ▁( ▁as ▁described ▁for ▁other ▁mon ocl on al ▁antib odies ), ▁it ▁was ▁shown ▁that ▁concent r ations ▁required ▁for ▁rob ust ▁ne ut ral ization ▁were ▁unl ike ly ▁to ▁be ▁achieved ▁in ▁the ▁l ung .
▁Furthermore , ▁the ▁independent ▁safety ▁monitoring ▁committee ▁for ▁the ▁CO ME T - T A I L ▁trial ▁recommended ▁early ▁term ination ▁of ▁the ▁250 ▁mg ▁int ram us c ular ▁( I M ) ▁S ot ro v imab ▁arm ▁due ▁to ▁a ▁higher ▁rate ▁of ▁hospitalization ▁than ▁either ▁500 ▁mg ▁I M ▁or ▁500 ▁mg ▁intra ven ous ▁( IV ) ▁arms .
▁Since ▁the ▁ser um ▁ne ut ral ization ▁of ▁500 ▁mg ▁IV ▁S ot ro v imab ▁against ▁the ▁O m ic ron ▁B A .2 ▁vari ant ▁( s er um ▁concent ration ▁divided ▁by ▁the ▁inv it ro ▁E C 90 ) ▁is ▁expected ▁to ▁be ▁lower ▁than ▁that ▁observed ▁with ▁250 ▁mg ▁I M ▁S ot ro v imab ▁against ▁the ▁D elt a ▁vari ant , ▁it ▁is ▁unl ike ly to ▁be ▁effective ▁in ▁treat ing ▁patients ▁with ▁the ▁O m ic ron ▁B A .2 ▁vari ant .
▁The ▁GDG ▁members ▁summer ise ▁that ▁mon ocl on al ▁antib odies ▁most ▁likely ▁need ▁to ▁pen et rate ▁the ▁respiratory ▁tract ▁to ▁achieve ▁clinical ▁effectiveness .
▁Consider ing ▁all ▁available ▁in ▁v it ro ▁ne ut ral ization ▁exper im ents , ▁when ▁ser um ▁concent r ations ▁are ▁corre cted ▁for ▁pen et ration ▁into ▁the ▁l ung , ▁the ▁target ▁concent r ations ▁( de f ined ▁by ▁the ▁effective ▁concent ration ▁required ▁for ▁90% ▁ne ut ral ization ▁[ EC 90 ] ▁of ▁viral ▁partic les ) ▁are ▁unl ike ly ▁to ▁be ▁achieved .
▁The ▁GDG ▁has ▁considered ▁but ▁rejected ▁the ▁suggest ion ▁that ▁target ▁concent r ations ▁ne ut ral izing ▁50% ▁of ▁viral ▁partic les ▁in ▁ser um ▁can ▁rel i ably ▁pred ict ▁clinical ▁effectiveness ▁.
▁E C 90 ▁is ▁at ▁least ▁nine ▁times ▁higher ▁than ▁E C 50.
▁Not ▁fully ▁ne ut ral izing ▁the ▁virus ▁population ▁not ▁only ▁car ries ▁the ▁risk ▁of ▁in e ffic acy ▁but ▁also ▁increases ▁the ▁lik eli hood ▁of ▁emergence ▁of ▁selected ▁resistance .
▁Em erg ence ▁of ▁selected ▁resistance ▁has ▁already ▁been ▁widely ▁document ed ▁with ▁S ot ro v imab ▁use ▁against ▁sus cept ible ▁variants , ▁particularly ▁in ▁the ▁context ▁of ▁immun oc om p rom ised ▁patients ▁.
▁C as ir iv imab - I m de v imab ▁( up d ated ▁13 ▁January ▁2023 ) ▁Information ▁Box ▁updated ▁evidence ▁supporting ▁the ▁initial ▁strong ▁recommendation ▁against ▁the ▁use ▁of ▁the ▁ne ut ral izing ▁antib odies ▁C as ir iv imab ▁- ▁Im de v imab ▁for ▁patients ▁with ▁COVID -19 ▁was ▁published ▁in ▁this ▁13 th ▁version ▁of ▁the ▁WHO ▁living ▁guideline .
▁Pre vious ly , ▁a ▁conditional ▁recommendation ▁was ▁provided ▁for ▁patients ▁with ▁non - severe ▁COVID -19 ▁at ▁highest ▁risk ▁of ▁hospitalization ▁and ▁for ▁patients ▁with ▁severe ▁and ▁critical ▁illness ▁with ▁ser o ▁negative ▁status .
▁Following ▁the ▁emergence ▁of ▁the ▁currently ▁circul ating ▁SARS - CoV -2 ▁variants ▁and ▁sub v ari ants ▁( s uch ▁as ▁O m ic ron ) ▁now ▁domin ating ▁world w ide , ▁and ▁availability ▁of ▁in ▁v it ro ▁data ▁showing ▁lack ▁of ▁or ▁d imin ished ▁ne ut ral ization ▁activity , ▁the ▁GDG ▁made ▁a ▁strong ▁recommendation ▁against ▁the ▁use ▁of ▁C as ir iv imab - I m de v imab ▁for ▁all ▁patients ▁with ▁COVID -19.
▁New ▁evidence ▁further ▁aff irm s ▁this ▁recommendation .
▁For ▁all ▁patients ▁with ▁COVID -19 ▁strong ▁recommendation ▁against ▁updated ▁evidence ▁is ▁no ▁change ▁in ▁recommendation .
▁We ▁recommend ▁against ▁treatment ▁with ▁C as ir iv imab - I m de v imab ▁( st r ong ▁recommendation ▁against ).
▁Several ▁other ▁therapeutic ▁options ▁exist ▁for ▁patients ▁with ▁COVID -19 ▁across ▁the ▁severity ▁sp ect r um : ▁see ▁decision ▁support ▁tool ▁that ▁dis pl ays ▁benefits ▁and ▁harms ▁of ▁N irmatrelvir - R It onavir , ▁M olnupiravir ▁and ▁Rem desivir .
▁The ▁GDG ▁considered ▁in ▁v it ro ▁data ▁demonst r ating ▁that ▁C as ir iv imab - I m de v imab ▁does ▁not ▁ne ut ral ize ▁the ▁currently ▁circul ating ▁variants ▁of ▁SARS - CoV -2 ▁and ▁their ▁sub ▁variants .
▁Given ▁the ▁strong ▁recommendation ▁against ▁using ▁C as ir iv imab - I m de v imab ▁for ▁all ▁patients ▁with ▁COVID -19, ▁practical ▁considerations ▁were ▁felt ▁to ▁be ▁less ▁relevant ▁here .
▁Accordingly , ▁the ▁panel ▁concluded ▁that ▁the ▁evidence ▁upon ▁which ▁the ▁previous ▁recommendations ▁h ing ed ▁was ▁no ▁longer ▁applic able .
▁The ▁GDG ▁reviewed ▁additional ▁in ▁v it ro ▁ne ut ral ization ▁data ▁that ▁emer ged ▁after ▁the ▁change ▁in ▁the ▁guideline ▁for ▁S ot ro v imab ▁and ▁C as ir iv imab - I m de v imab ▁and ▁that ▁included ▁information ▁on ▁new ▁variants .
▁In ▁light ▁of ▁the ▁recent ▁in ▁v it ro ▁evidence , ▁the ▁GDG ▁concluded ▁that ▁the ▁clinical ▁effects ▁of ▁C as ir iv imab - I m de v imab ▁for ▁COVID -19 ▁caused ▁by ▁the ▁currently ▁circul ating ▁variants ▁and ▁sub v ari ants ▁of ▁SARS - CoV -2 ▁are ▁highly ▁uncertain .
▁T ri als ▁performed ▁before ▁these ▁variants ▁occurred ▁provided ▁overall ▁moderate ▁certainty ▁evidence ▁for ▁mod est ▁benefits ▁and ▁neg l igible ▁harms , ▁as ▁demonst rated ▁in ▁grade ▁summary ▁of ▁findings ▁tables ▁available ▁in ▁previous ▁vers ions ▁of ▁this ▁living ▁guideline .
▁The ▁GDG ▁also ▁contin ues ▁to ▁base ▁its ▁recommendations ▁st rict ly ▁on ▁pred e f ined ▁patient - im port ant ▁outcomes .
▁C as ir iv imab ▁and ▁Im de v imab ▁are ▁two ▁fully ▁human ▁antib odies ▁( R E G N 10 93 3 ▁and ▁R E G N 10 98 7 ).
▁Their ▁mechanism ▁of ▁action ▁is ▁very ▁pl a us ible :
▁They ▁b ind ▁to ▁the ▁SARS - CoV -2 ▁sp ike ▁pro te in ▁and ▁have ▁demonst rated ▁ant ivir al ▁activity ▁in ▁r hes us ▁m ac a qu es ▁and ▁Sy rian ▁gold en ▁h am st ers ▁.
▁Ph armac ok inet ic ▁data ▁in ▁patients ▁with ▁non - severe ▁COVID -19 ▁show ▁that ▁ant ivir al ▁concent r ations ▁of ▁both ▁antib odies ▁against ▁pre - O m ic ron ▁variants ▁are ▁achieved ▁and ▁maintained ▁for ▁at ▁least ▁28 ▁days ▁after ▁intra ven ous ▁administration ▁of ▁the ▁combination ▁at ▁a ▁total ▁dose ▁of ▁1200 ▁mg ▁( 600 ▁mg ▁each ▁antib ody ) ▁or ▁above ▁.
▁Pre - O m ic ron ▁ant ivir al ▁concent r ations ▁are ▁also ▁achieved ▁and ▁maintained ▁using ▁a ▁sub cut ane ous ▁total ▁dose ▁of ▁1200 ▁mg ▁( 600 ▁mg ▁of ▁each ▁antib ody ) ▁in ▁un inf ected ▁individuals ▁for ▁pro phylaxis ▁.
▁H alf - l ives ▁range ▁from ▁25 ▁to ▁37 ▁days ▁for ▁both ▁antib odies .
▁It ▁was ▁post ulated ▁that ▁administration ▁might ▁have ▁different ial ▁effects ▁in ▁patients ▁who ▁have ▁produced ▁their ▁own ▁anti - S A RS - CoV -2 ▁sp ike ▁pro te in ▁antib odies ▁( here after ▁ser op os itive ) ▁compared ▁with ▁those ▁who ▁have ▁not ▁( here after ▁ser one g ative ).
▁It ▁was ▁hypot hes ized ▁that ▁effects ▁might ▁be ▁larger , ▁or ▁rest ric ted ▁to , ▁ser one g ative ▁individuals ▁who ▁have ▁not ▁yet ▁mount ed ▁an ▁effective ▁antib ody ▁response .
▁Data ▁describ ing ▁the ▁in ▁v it ro ▁ne ut ral ization ▁of ▁different ▁variants ▁by ▁mon oc ol on al ▁antib odies ▁are ▁coll ated ▁on ▁the ▁N I H NC AT S ▁Op en ▁Data ▁Port al .
▁Several ▁reports ▁have ▁demonst rated ▁that ▁in ▁v it ro ▁ne ut ral ization ▁of ▁p se ud o vir us ▁containing ▁the ▁B A .1 ▁O m ic ron ▁sp ike ▁pro te in ▁and ▁in ▁v it ro ▁ne ut ral ization ▁of ▁aut he nt ic ▁B A .1 ▁O m ic ron ▁virus ▁is ▁d ram at ically ▁reduced ▁or ▁lost ▁for ▁C as ir iv imab ▁and ▁Im de v imab .
▁Furthermore , ▁the ▁combination ▁of ▁C as ir iv imab ▁and ▁Im de v imab ▁had ▁no ▁impact ▁upon ▁sub gen omic ▁viral ▁R NA ▁in ▁the ▁l ung s ▁or ▁n as al ▁tur b in ate ▁of ▁K 18 ▁human ▁A ▁CE 2 ▁trans gen ic ▁m ice ▁infected ▁with ▁B ▁A .1 ▁O m ic ron ▁.
▁Red u ctions ▁for ▁in ▁v it ro ▁ne ut ral izing ▁activity ▁have ▁been ▁reported ▁for ▁C as ir iv imab ▁and / or ▁Im de v imab ▁against ▁B A .2 , ▁B A .4 ▁and ▁B ▁A .5 ▁O m ic ron ▁sub line ages ▁and ▁ser um ▁from ▁patients ▁that ▁received ▁the ▁combination ▁also ▁does ▁not ▁ne ut ral ize ▁B A .2 , ▁B A .4 ▁and ▁B A .5 ▁sub line ages .
▁For ▁patients ▁with ▁non - severe ▁COVID -19, ▁we ▁recommend ▁not ▁to ▁use ▁F l uv ox am ine , ▁except ▁in ▁the ▁context ▁of ▁a ▁clinical ▁trial ▁( rec ommend ed ▁only ▁in ▁research ▁settings ).
▁Several ▁therapeutic ▁options ▁are ▁recommended ▁for ▁patients ▁with ▁non - severe ▁COVID -19 ▁including ▁N irmatrelvir , ▁R it onavir , ▁M olnupiravir , ▁and ▁Rem desivir .
▁For ▁cho osing ▁between ▁the ▁therapeutic ▁options , ▁see ▁Section ▁6.1 ▁and ▁the ▁decision ▁support ▁tool , ▁which ▁dis pl ays ▁benefits ▁and ▁harms ▁of ▁the ▁options .
▁The ▁GDG ▁made ▁a ▁recommendation ▁against ▁using ▁F l uv ox am ine ▁for ▁treatment ▁of ▁patients ▁with ▁COVID -19 ▁outside ▁the ▁setting ▁of ▁a ▁clinical ▁trial ▁and ▁therefore ▁practical ▁considerations ▁are ▁less ▁relevant ▁for ▁this ▁drug .
▁In ▁patients ▁with ▁non - severe ▁COVID -19, ▁F l uv ox am ine ▁probably ▁has ▁little ▁or ▁no ▁effect ▁on ▁mortality ▁and ▁may ▁have ▁little ▁or ▁no ▁effect ▁on ▁mechanical ▁ventilation ▁and ▁hospitalization , ▁with ▁no ▁data ▁reported ▁for ▁time ▁to ▁sympt om ▁resolution ▁and ▁adverse ▁effects ▁leading ▁to ▁drug ▁discontin uation .
▁The ▁GDG ▁concluded ▁that ▁the ▁balance ▁between ▁benefits ▁and ▁potential ▁harms ▁does ▁not ▁favour ▁treatment .
▁The ▁planned ▁subgroup ▁analyses ▁for ▁F l uv ox am ine ▁versus ▁standard ▁care ▁for ▁age ▁and ▁time ▁of ▁sympt om ▁onset ▁did ▁not ▁support ▁any ▁differences ▁in ▁relative ▁effects , ▁whereas ▁disease ▁severity ▁could ▁not ▁be ▁performed ▁since ▁trials ▁only ▁enrolled ▁patients ▁with ▁non - severe ▁COVID -19.
▁The ▁evidence ▁summary ▁was ▁informed ▁by ▁3 ▁trials ▁with ▁22 25 ▁participants ▁included ▁in ▁the ▁L N MA .
▁The ▁largest ▁trial ▁( n = 14 80 ) ▁excl us ively ▁enrolled ▁patients ▁in ▁Brazil ▁.
▁The ▁panel ▁also ▁raised ▁concerns ▁regarding ▁the ▁uncertain ▁applic ability ▁of ▁this ▁trial ▁conducted ▁in ▁a ▁single ▁country .
▁Given ▁the ▁agreed ▁upon ▁values ▁and ▁preferences ▁statement ▁( see ▁Section ▁7 ), ▁the ▁GDG ▁inf er red ▁that ▁almost ▁all ▁well - in formed ▁patients ▁would ▁choose ▁not ▁to ▁receive ▁F l uv ox am ine ▁therapy ▁for ▁COVID -19 ▁based ▁on ▁the ▁available ▁evidence .
▁The ▁GDG ▁did ▁not ▁believe ▁that ▁other ▁considerations , ▁such ▁as ▁feasibility , ▁acceptability , ▁equity ▁and ▁cost , ▁would ▁impact ▁this ▁specific ▁recommendation .
▁Spe c if ically , ▁the ▁GDG ▁did ▁not ▁consider ▁the ▁potential ▁role ▁of ▁F l uv ox am ine ▁as ▁an ▁ant ide p ress ant ▁for ▁this ▁guideline ▁of ▁medic ations ▁for ▁COVID -19.
▁The ▁panel ▁ac know led ged ▁that ▁effective ▁therapeutic ▁alternatives ▁for ▁non - severe ▁COVID -19 ▁were ▁exp ensive , ▁which ▁could ▁limit ▁their ▁availability ▁in ▁resource - con st rained ▁areas .
▁However , ▁although ▁F l uv ox am ine ▁is ▁relatively ▁in exp ensive , ▁compared ▁with ▁other ▁drugs ▁used ▁for ▁COVID -19, ▁and ▁widely ▁available , ▁including ▁in ▁low - in come ▁settings , ▁the ▁evidence ▁does ▁not ▁just ify ▁the ▁use ▁of ▁F l uv ox am ine ▁for ▁non - severe ▁COVID -19 ▁any where .
▁Although ▁the ▁cost ▁of ▁F l uv ox am ine ▁may ▁be ▁low , ▁the ▁GDG ▁panel ▁raised ▁concerns ▁regarding ▁the ▁risk ▁of ▁d iver ting ▁attention ▁and ▁resources ▁away ▁from ▁interventions ▁that ▁are ▁more ▁likely ▁to ▁provide ▁a ▁benefit .
▁To ▁avoid ▁the ▁risk ▁of ▁writing ▁recommendations ▁that ▁would ▁risk ▁per p et u ating ▁and ▁leg it im izing ▁un equ al ▁access ▁to ▁more ▁effective ▁drugs , ▁the ▁panel ▁believed ▁that ▁it ▁would ▁be ▁prefer able ▁to ▁emphasize ▁the ▁need ▁for ▁more ▁equ itable ▁access ▁to ▁effective ▁therapeutic ▁options .
▁The ▁panel ▁noted ▁that ▁in ▁the ▁largest ▁trial ▁more ▁patients ▁discontin ued ▁the ▁investig ational ▁product ▁in ▁the ▁F l uv ox am ine ▁group ▁than ▁in ▁the ▁place bo ▁group .
▁Not ing ▁that ▁effective ▁therapeutic ▁alternatives ▁exist ▁for ▁non - severe ▁COVID -19, ▁the ▁GDG ▁did ▁not ▁ant icip ate ▁important ▁variability ▁in ▁patient ▁values ▁and ▁preferences .
▁The ▁panel ▁also ▁did ▁not ▁believe ▁that ▁other ▁considerations , ▁such ▁as ▁resource ▁considerations , ▁access ibility , ▁feasibility , ▁and ▁equity ▁( ▁see ▁summary ▁of ▁these ▁factors ▁under ▁evidence ▁to ▁decision ) ▁impact ed ▁this ▁specific ▁recommendation .
▁None ▁of ▁the ▁included ▁studies ▁enrolled ▁children , ▁and ▁therefore ▁the ▁applic ability ▁of ▁this ▁recommendation ▁to ▁children ▁is ▁currently ▁uncertain .
▁However , ▁the ▁panel ▁did ▁not ▁see ▁a ▁reason ▁to ▁assume ▁that ▁children ▁with ▁COVID -19 ▁would ▁respond ▁any ▁differently ▁to ▁treatment ▁with ▁F l uv ox am ine .
▁The ▁L N MA ▁for ▁F l uv ox am ine ▁was ▁informed ▁by ▁three ▁RCTs ▁which ▁enrolled ▁22 25 ▁patients ▁with ▁non - severe ▁illness ▁in ▁out p ati ent ▁settings .
▁All ▁three ▁RCTs ▁were ▁registered , ▁and ▁two ▁were ▁published ▁in ▁a ▁pe er - re view ed ▁journal .
▁All ▁three ▁studies ▁were ▁conducted ▁in ▁out p ati ents .
▁None ▁of ▁the ▁included ▁studies ▁enrolled ▁children .
▁For ▁patients ▁with ▁non - severe ▁COVID -19, ▁the ▁grade ▁summary ▁of ▁findings ▁table ▁shows ▁the ▁relative ▁and ▁absolute ▁effects ▁of ▁F l uv ox am ine ▁compared ▁with ▁standard ▁care ▁for ▁the ▁outcomes ▁of ▁interest , ▁with ▁certainty ▁r at ings , ▁informed ▁by ▁the ▁L N MA ▁.
▁B ased ▁on ▁data ▁from ▁the ▁together ▁trial ▁, ▁no ▁cred ible ▁subgroup ▁effects ▁were ▁observed ▁on ▁the ▁primary ▁outcome ▁by ▁age ▁( child ren ▁vs ▁adults ▁vs ▁older ▁adults ) ▁and ▁time ▁from ▁sympt om ▁onset ▁(0 –3 ▁days ▁vs ▁4 – 7 ▁d a ▁y s ).
▁Plan ned ▁subgroup ▁analyses ▁for ▁disease ▁severity , ▁age ▁and ▁chronic ▁conditions ▁( abs olute ▁effects ), ▁ser ological ▁status ▁and ▁vaccination ▁status ▁were ▁prec lud ed ▁by ▁lack ▁of ▁available ▁data .
▁The ▁bas eline ▁risk ▁across ▁the ▁entire ▁population ▁is ▁very ▁low , ▁meaning ▁that ▁any ▁impact ▁on ▁mortality ▁will ▁be ▁very ▁small .
▁There ▁are ▁some ▁people ▁with ▁much ▁higher ▁bas eline ▁risk , ▁which ▁are ▁not ▁easily ▁ident if iable .
▁For ▁these ▁patients , ▁it ▁is ▁pl a us ible ▁that ▁F l uv ox am ine ▁may ▁have ▁an ▁important ▁impact ▁on ▁mortality .
▁The ▁cred ible ▁interval ▁includes ▁both ▁important ▁harm ▁and ▁important ▁benefit .
▁F l uv ox am ine ▁is ▁a ▁select ive ▁ser ot on in ▁re u pt ake ▁in hib itor ▁( S S RI ) ▁approved ▁as ▁an ▁ant ide p ress ant .
▁The ▁ant ide p ress ant ▁effects ▁of ▁F l uv ox am ine ▁are ▁related ▁to ▁in hib ition ▁of ▁the ▁ser ot on in ▁trans por ter ▁in ▁the ▁brain , ▁which ▁serv es ▁to ▁increase ▁the ▁concent r ations ▁of ▁ser ot on in ▁in ▁the ▁sy n apt ic ▁cle ft .
▁In ▁COVID -19, ▁several ▁put ative ▁anti - inf lam m atory ▁or ▁ant ivir al ▁mechanism s ▁of ▁action ▁have ▁been ▁proposed ▁.
▁First , ▁anti - inf lam m atory ▁properties ▁have ▁been ▁post ulated ▁as ▁a ▁result ▁of ▁ser ot on in ▁trans por ter ▁in hib ition ▁in ▁pl ate lets ▁and / or ▁l ung s , ▁but ▁this ▁is ▁based ▁upon ▁indirect ▁evidence ▁from ▁non - CO VID -19 ▁disease ▁models .
▁Second ly , ▁host - d ire cted ▁ant ivir al ▁properties ▁have ▁been ▁proposed ▁via ▁ag on ism ▁of ▁the ▁s ig ma -1 ▁recept or , ▁for ▁which ▁some ▁evidence ▁ex ists ▁from ▁other ▁virus es ▁for ▁an ▁involve ment ▁in ▁R NA ▁rep lication , ▁but ▁there ▁are ▁currently ▁no ▁published ▁pre cl in ical ▁studies ▁that ▁directly ▁demonst rate ▁or ▁ref ute ▁a ▁mechanism ▁in ▁COVID -19.
▁Therefore , ▁pl a us ibility ▁requ ires ▁interpret ation ▁of ▁indirect ▁evidence ▁for ▁anti - inf lam m atory ▁or ▁ant ivir al ▁mechanism s , ▁which ▁are ▁currently ▁un pro ven ▁pre cl in ically ▁and ▁not ▁directly ▁related ▁to ▁the ▁mechanism ▁and ▁site ▁of ▁action ▁in ▁dep ression .
▁Col ch ic ine ▁( published ▁14 ▁July ▁202 2) ▁Information ▁Box :
▁The ▁recommendation ▁concerning ▁Col ch ic ine ▁for ▁patients ▁with ▁non - severe ▁COVID -19 ▁was ▁published ▁on ▁14 ▁July ▁202 2, ▁in ▁the ▁ele vent h ▁version ▁of ▁the ▁WHO ▁living ▁guideline ▁and ▁in ▁the ▁B M J ▁as ▁rapid ▁recommendations .
▁It ▁followed ▁the ▁availability ▁of ▁13 ▁RCTs ▁that ▁enrolled ▁18 , 1 72 ▁patients , ▁as ▁per ▁the ▁L N MA ▁on ▁drug ▁the rap ies ▁.
▁We ▁recommend ▁against ▁treatment ▁with ▁Col ch ic ine ▁( st r ong ▁recommendation ▁against ) ▁for ▁patients ▁with ▁non - severe ▁COVID -19.
▁Practical ▁Information : ▁The ▁GDG ▁made ▁a ▁strong ▁recommendation ▁against ▁using ▁Col ch ic ine ▁for ▁treatment ▁of ▁patients ▁with ▁non - se ▁ vere ▁COVID -19 ▁and ▁therefore ▁practical ▁considerations ▁are ▁less ▁relevant .
▁In ▁patients ▁with ▁non - severe ▁COVID -19, ▁Col ch ic ine ▁probably ▁has ▁little ▁or ▁no ▁impact ▁on ▁mortality ▁and ▁mechanical ▁ventilation , ▁may ▁have ▁little ▁or ▁no ▁impact ▁on ▁hospital izations , ▁and ▁may ▁increase ▁the ▁lik eli hood ▁of ▁adverse ▁effects ▁leading ▁to ▁drug ▁discontin uation .
▁The ▁panel ▁discussed ▁the ▁risk ▁of ▁drug ▁inter act ions ▁and ▁Col ch ic ine ' s ▁nar row ▁therapeutic ▁window , ▁particularly ▁in ▁patients ▁with ▁or ▁at ▁risk ▁of ▁he p atic ▁and ▁re nal ▁failure .
▁Col ch ic ine ▁to xic ity ▁can ▁be ▁severe ▁and ▁some ▁times ▁f atal .
▁The ▁planned ▁subgroup ▁analyses ▁for ▁Col ch ic ine ▁versus ▁standard ▁care ▁did ▁not ▁show ▁different ▁relative ▁effects ▁for ▁disease ▁severity , ▁and ▁age ▁( child ren , ▁adults , ▁older ) ▁with ▁no ▁data ▁reported ▁from ▁illness ▁onset .
▁The ▁evidence ▁summary ▁on ▁Col ch ic ine ▁was ▁informed ▁by ▁a ▁systematic ▁review ▁including ▁13 ▁trials ▁with ▁18 , 1 72 ▁participants .
▁The ▁evidence ▁was ▁most ▁ab und ant ▁for ▁mortality ▁with ▁inc om ple te ▁reporting ▁for ▁other ▁outcomes ▁( e . g . ▁five ▁trials ▁with ▁5 98 ▁participants ▁for ▁adverse ▁effects ).
▁A ▁single ▁trial ▁of ▁44 8 8 ▁participants ▁, ▁which ▁contrib uted ▁almost ▁all ▁of ▁the ▁evidence ▁on ▁hospital izations , ▁was ▁stopped ▁prem ature ly .
▁Certainty ▁of ▁evidence ▁was ▁r ated ▁as : ▁moderate ▁for ▁mortality ▁and ▁mechanical ▁ventilation ▁( rated ▁down ▁for ▁indirect ness ); ▁low ▁for ▁admission ▁to ▁hospital ▁( rated ▁down ▁for ▁imprecision ▁and ▁risk ▁of ▁bias ); ▁and ▁low ▁for ▁adverse ▁effects ▁leading ▁to ▁drug ▁discontin uation ▁( rated ▁down ▁for ▁imprecision ▁and ▁risk ▁of ▁bias ).
▁Values ▁and ▁preferences ▁: ▁Given ▁the ▁agreed ▁upon ▁values ▁and ▁preferences ▁statement ▁( see ▁Section ▁7 ), ▁the ▁GDG ▁inf er red ▁that ▁almost ▁all ▁well - in formed ▁patients ▁would ▁choose ▁not ▁to ▁receive ▁Col ch ic ine ▁based ▁on ▁a ▁v ail able ▁evidence ▁regarding ▁relative ▁benefits ▁and ▁harms .
▁The ▁GDG ▁did ▁not ▁believe ▁that ▁other ▁considerations , ▁such ▁as ▁feasibility , ▁acceptability , ▁equity , ▁and ▁cost , ▁impact ed ▁this ▁specific ▁recommendation .
▁However , ▁although ▁Col ch ic ine ▁is ▁relatively ▁in exp ensive , ▁compared ▁with ▁other ▁drugs ▁used ▁for ▁COVID -19, ▁and ▁widely ▁available , ▁including ▁in ▁low - in come ▁settings , ▁the ▁evidence ▁does ▁not ▁just ify ▁the ▁use ▁of ▁Col ch ic ine ▁for ▁non - severe ▁COVID -19 ▁any where .
▁Although ▁the ▁cost ▁of ▁Col ch ic ine ▁may ▁be ▁low , ▁the ▁GDG ▁raised ▁concerns ▁regarding ▁the ▁risk ▁of ▁d iver ting ▁attention ▁and ▁resources ▁away ▁from ▁interventions ▁that ▁are ▁more ▁likely ▁to ▁provide ▁a ▁benefit .
▁To ▁avoid ▁writing ▁recommendations ▁that ▁would ▁risk ▁per p et u ating ▁and ▁leg it im izing ▁un equ al ▁access ▁to ▁more ▁effective ▁drugs , ▁the ▁panel ▁believed ▁that ▁it ▁would ▁be ▁prefer able ▁to ▁emphasize ▁the ▁need ▁for ▁more ▁equ itable ▁access ▁to ▁effective ▁therapeutic ▁options .
▁Justification : ▁When ▁moving ▁from ▁evidence ▁to ▁the ▁strong ▁recommendation ▁against ▁the ▁use ▁of ▁Col ch ic ine ▁for ▁patients ▁with ▁non - severe ▁COVID -19, ▁the ▁GDG ▁emphasized ▁the ▁moderate ▁certainty ▁evidence ▁of ▁no ▁effect ▁on ▁mortality ▁and ▁mechanical ▁ventilation , ▁and ▁the ▁low ▁certainty ▁evidence ▁of ▁no ▁effect ▁on ▁hospital izations , ▁but ▁possible ▁harm ▁associated ▁with ▁treatment .
▁Spe c if ically , ▁the ▁panel ▁recognized ▁the ▁risks ▁of ▁di arr ho e a , ▁cy t op en ia , ▁and ▁other ▁to xic ities , ▁particularly ▁among ▁patients ▁with , ▁or ▁at ▁risk ▁of ▁re nal ▁failure , ▁as ▁potential ly ▁important ▁to ▁patients ▁with ▁non - severe ▁COVID -19.
▁However , ▁the ▁panel ▁did ▁not ▁see ▁a ▁reason ▁to ▁assume ▁that ▁children ▁with ▁COVID -19 ▁would ▁respond ▁any ▁differently ▁to ▁treatment ▁with ▁Col ch ic ine .
▁Summary : ▁The ▁systematic ▁review ▁for ▁Col ch ic ine ▁included ▁13 ▁trials ▁that ▁enrolled ▁18 , 1 72 ▁patients .
▁All ▁but ▁three ▁trials ▁were ▁registered .
▁None ▁of ▁the ▁studies ▁enrolled ▁children .
▁For ▁patients ▁with ▁non - severe ▁COVID -19, ▁the ▁grade ▁summary ▁of ▁findings ▁table ▁shows ▁the ▁relative ▁and ▁absolute ▁effects ▁of ▁Col ch ic ine ▁compared ▁with ▁standard ▁care ▁for ▁the ▁outcomes ▁of ▁interest , ▁with ▁certainty ▁r at ings , ▁informed ▁by ▁the ▁L N MA ▁.
▁B ased ▁on ▁data ▁from ▁the ▁CO L C OR ON A ▁trial , ▁no ▁cred ible ▁subgroup ▁effects ▁were ▁observed ▁on ▁the ▁primary ▁outcome ▁by ▁age ▁( child ren ▁vs ▁adults ▁vs ▁older ▁adults ) ▁and ▁disease ▁severity ▁( non - severe ▁vs ▁severe ).
▁Plan ned ▁subgroup ▁analyses ▁for ▁time ▁from ▁sympt om ▁onset , ▁age ▁and ▁chronic ▁conditions ▁( abs olute ▁effects ), ▁ser ological ▁status ▁and ▁vaccination ▁status ▁were ▁prec lud ed ▁by ▁lack ▁of ▁available ▁data .
▁Col ch ic ine ▁is ▁an ▁anti - inf lam m atory ▁drug ▁used ▁to ▁treat ▁g out , ▁rec urrent ▁per ic ard it is , ▁famil ial ▁med iter r ane an ▁fever , ▁and ▁other ▁infl amm atory ▁indic ations .
▁There ▁are ▁several ▁proposed ▁mechanism s ▁of ▁action ▁that ▁are ▁the or ized ▁to ▁ob vi ate ▁infl amm ation ▁associated ▁path ology ▁seen ▁in ▁COVID -19 ▁, ▁which ▁include ▁a ▁reduction ▁in ▁chem ot axis ▁of ▁ne ut ro ph il s , ▁in hib ition ▁of ▁infl amm ation ▁sign all ing ▁and ▁decreased ▁production ▁of ▁cy t ok ines ▁such ▁as ▁Inter le uk in -1 b ▁( I L -1 b ).
▁There ▁are ▁no ▁published ▁data ▁at ▁the ▁time ▁of ▁public ation ▁from ▁animal ▁models ▁of ▁SARS - CoV -2 ▁infection ▁to ▁support ▁or ▁ref ute ▁pre - cl in ical ▁efficacy ▁or ▁harm ▁of ▁Col ch ic ine ▁in ▁associated ▁disease ▁path ology .
▁There ▁are ▁marked ▁differences ▁between ▁trials , ▁in ▁terms ▁of ▁the ▁doses ▁and ▁sched ules , ▁that ▁have ▁been ▁investigated ▁in ▁COVID -19.
▁In ▁addition , ▁some ▁studies ▁used ▁d osing ▁sched ules ▁which ▁changed ▁throughout ▁the ▁course , ▁starting ▁with ▁one ▁dose ▁or ▁sched ule ▁and ▁then ▁changing ▁to ▁a ▁different ▁dose ▁or ▁sched ule , ▁after ▁a ▁pred et erm ined ▁interval .
▁The ▁pharmac ok inet ics ▁of ▁col ch ic ine ▁are ▁dose ▁linear ▁between ▁0.5 m g ▁and ▁1.5 m g , ▁but ▁the ▁substant ive ▁vari ation ▁between ▁studies ▁included ▁in ▁the ▁N MA ▁prec lud es ▁a ▁rob ust ▁interpret ation ▁of ▁differences ▁in ▁outcome ▁associated ▁with ▁dose ▁and ▁sched ule .
▁It ▁followed ▁the ▁availability ▁of ▁six ▁RCTs , ▁as ▁per ▁the ▁L N MA ▁on ▁drug ▁the rap ies .
▁No ▁changes ▁were ▁made ▁to ▁the ▁molnupiravir ▁recommendation ▁in ▁this ▁13 th ▁version ▁of ▁the ▁guideline .
▁See ▁Section ▁6.1 ▁for ▁help , ▁to ▁identify ▁patients ▁at ▁the ▁highest ▁risk ▁for ▁hospitalization .
▁The ▁conditional ▁recommendation ▁reflect s ▁the ▁concern ▁for ▁w ides p read ▁treatment ▁with ▁molnupiravir , ▁before ▁more ▁safety ▁data ▁become ▁available .
▁The ▁use ▁of ▁molnupiravir ▁should ▁be ▁accomp an ied ▁by ▁m it igation ▁strategies ▁such ▁as ▁av o iding ▁the ▁drug ▁in ▁younger ▁adults , ▁active ▁pharmac ov ig il ance ▁programmes , ▁and ▁monitoring ▁viral ▁poly mer ase ▁and ▁sp ike ▁sequ ences ▁( see ▁Justification ).
▁Practical ▁info ▁route , ▁d os age , ▁and ▁duration : ▁Additional ▁considerations ▁are ▁available ▁in ▁three ▁summ aries ▁of ▁practical ▁issues : ▁molnupiravir ▁for ▁COVID -19, ▁administration ▁of ▁molnupiravir ▁for ▁COVID -19, ▁safety ▁and ▁monitoring ▁for ▁patients ▁receiving ▁molnupiravir ▁for ▁COVID -19 ; ▁here ▁follows ▁a ▁brief ▁summary ▁of ▁the ▁key ▁points : ▁the ▁recommended ▁dose ▁for ▁molnupiravir ▁is ▁800 ▁mg ▁table t ▁every ▁12 ▁hours ▁daily ▁for ▁5 ▁days , ▁as ▁per ▁the ▁reg imen ▁evaluated ▁in ▁large ▁trials ▁inform ing ▁the ▁recommendation .
▁In ▁the ▁included ▁studies , ▁molnupiravir ▁was ▁administered ▁within ▁5 ▁days ▁of ▁disease ▁onset .
▁Evidence ▁to ▁decision ▁benefits ▁and ▁harms ▁in ▁patients ▁with ▁non - severe ▁COVID -19, ▁molnupiravir ▁probably ▁reduces ▁admission ▁to ▁the ▁hospital ▁and ▁time ▁to ▁sympt om ▁resolution , ▁and ▁may ▁reduce ▁mortality .
▁The ▁effect ▁of ▁molnupiravir ▁on ▁mechanical ▁ventilation ▁is ▁very ▁uncertain .
▁T reat ment ▁does ▁not ▁increase ▁the ▁lik eli hood ▁of ▁adverse ▁effects , ▁leading ▁to ▁drug ▁discontin uation .
▁These ▁deli ber ations ▁( see ▁Justification ▁section ) ▁were ▁based ▁on ▁molnupiravir ' s ▁mechanism ▁of ▁action ▁and ▁available ▁pre - cl in ical ▁data ▁( see ▁Me chan ism ▁of ▁action ▁section ).
▁The ▁balance ▁between ▁benefits ▁and ▁potential ▁harms ▁was ▁close ▁but ▁fav ored ▁treatment ▁in ▁the ▁highest ▁risk ▁group ▁if ▁implemented ▁with ▁other ▁m it igation ▁strategies ▁to ▁avoid ▁harm ▁at ▁individual ▁and ▁population ▁level ▁( see ▁M it igation ▁St r ateg ies ▁section ).
▁There ▁is ▁a ▁risk ▁that ▁mon other ap y ▁with ▁molnupiravir ▁( as ▁for ▁other ▁ant ivir al ▁mon other ap ies ) ▁may ▁be ▁associated ▁with ▁emergence ▁of ▁drug ▁resistance , ▁as ▁has ▁been ▁seen ▁with ▁other ▁ant ivir als ▁( see ▁Me chan ism ▁of ▁action ▁section ).
▁The ▁absolute ▁benefits ▁of ▁molnupiravir ▁on ▁hospital ▁admission ▁depend ▁on ▁the ▁pro gn osis .
▁M olnupiravir ▁would ▁ex ert ▁such ▁a ▁benefit ▁in ▁patients ▁at ▁the ▁highest ▁risk ▁of ▁hospitalization ▁( ab ove ▁10% ▁bas eline ▁risk ), ▁such ▁as ▁those ▁who ▁lack ▁COVID -19 ▁vaccination , ▁older ▁people , ▁or ▁those ▁with ▁immun ode fic i encies ▁and / or ▁chronic ▁diseases .
▁The ▁conditional ▁recommendation ▁for ▁the ▁use ▁of ▁molnupiravir ▁in ▁those ▁at ▁the ▁highest ▁risk , ▁reflect s ▁this ▁th res hold : ▁60 ▁fewer ▁hospital izations ▁per ▁1,000 ▁patients , ▁and ▁a ▁greater ▁ant icip ated ▁absolute ▁surv ival ▁benefit , ▁although ▁this ▁was ▁not ▁possible ▁to ▁quant ify , ▁in ▁the ▁absence ▁of ▁data .
▁The ▁planned ▁subgroup ▁analyses ▁could ▁not ▁be ▁performed ▁in ▁the ▁absence ▁of ▁subgroup ▁data , ▁reported ▁public ly ▁or ▁provided ▁by ▁investig ators .
▁Certainty ▁of ▁the ▁Evidence : ▁The ▁evidence ▁summary ▁was ▁informed ▁by ▁six ▁trials ▁with ▁4, 7 96 ▁participants , ▁included ▁in ▁the ▁L N MA , ▁including ▁the ▁M O ▁Ve - O U T ▁study .
▁In ▁addition , ▁the ▁GDG ▁felt ▁that ▁there ▁was ▁some ▁indirect ness ▁because ▁of ▁the ▁possible ▁emergence ▁of ▁variants ▁( inc lud ing ▁O m ic ron ) ▁for ▁which ▁the ▁effectiveness ▁of ▁currently ▁available ▁mon ocl on al ▁antib odies ▁may ▁be ▁reduced .
▁This ▁reinfor ces ▁that ▁molnupiravir ▁should ▁be ▁reserv ed ▁for ▁those ▁at ▁highest ▁risk .
▁Ch all eng es ▁in ▁shared ▁decision - m aking ▁and ▁in ▁communic ating ▁the ▁harms ▁versus ▁benefits ▁of ▁molnupiravir , ▁may ▁also ▁be ▁increased ▁in ▁L MI C s .
▁Ind ividual ▁countries ▁may ▁form ulate ▁their ▁guidelines ▁considering ▁available ▁resources ▁and ▁prior it ize ▁treatment ▁options ▁according ly .
▁A ccess ▁to ▁SARS - CoV -2 ▁diagn ost ics : ▁Since ▁this ▁recommendation ▁emphas izes ▁the ▁need ▁to ▁admin ister ▁treatment ▁with ▁molnupiravir ▁within ▁5 ▁days ▁of ▁sympt om ▁onset ; ▁increasing ▁access ▁and ▁ensuring ▁appropriate ▁use ▁of ▁diagn ost ic ▁tests ▁is ▁essential .
▁Thus , ▁the ▁availability ▁and ▁use ▁of ▁rel iable ▁and ▁timely ▁COVID -19 ▁diagn ost ic ▁tests ▁( inc lud ing ▁the ▁use ▁of ▁N A AT ▁and ▁Ag - R D T s ) ▁are ▁needed ▁to ▁improve ▁access ▁to ▁drugs , ▁especially ▁those ▁target ing ▁the ▁early ▁phase ▁of ▁the ▁disease .
▁National ▁programs ▁should ▁opt im ize ▁their ▁testing ▁systems ▁to ▁reflect ▁local ▁epidemi ology , ▁response ▁objectives , ▁available ▁resources ▁and ▁needs ▁of ▁their ▁populations .
▁Only ▁a ▁min ority ▁of ▁patients ▁who ▁are ▁at ▁the ▁highest ▁risk ▁are ▁likely ▁to ▁achieve ▁sufficient ▁benefits ▁to ▁comp ens ate ▁for ▁the ▁risks ▁and ▁other ▁limitations ▁and ▁dis ad vant ages ▁of ▁therapy .
▁These ▁include ▁a ▁lack ▁of ▁rel iable ▁tools ▁to ▁identify ▁high - risk ▁patients , ▁limited ▁availability ▁of ▁the ▁drug , ▁and ▁the ▁safety ▁concerns ▁summar ized ▁below :
▁The ▁GDG ▁had ▁concerns ▁about ▁the ▁risk ▁of ▁emerg ent ▁resistance ▁with ▁a ▁new ▁ant ivir al ▁deployed ▁as ▁mon other ap y ▁( see ▁Me chan ism ▁of ▁Action ▁section ▁ ).
▁M olnupiravir ▁is ▁mut ag en ic ▁in ▁m amm alian ▁cell s ▁in ▁v it ro , ▁but ▁there ▁is ▁no ▁evidence ▁of ▁mut ag en ic ity ▁in ▁animal ▁models ▁or ▁hum ans .
▁The ▁GDG , ▁therefore , ▁ac know led ged ▁uncertainty ▁regarding ▁longer - term ▁g en etic ▁to xic ity ▁and ▁potential ▁for ▁mal ign ancy ▁associated ▁with ▁molnupiravir .
▁Similarly , ▁since ▁molnupiravir ▁e lic ited ▁emb ry o - f etal ▁le th ality ▁and ▁ter at og en ic ity ▁in ▁off s pr ing ▁when ▁given ▁to ▁pregnant ▁animals , ▁it ▁should ▁not ▁be ▁used ▁in ▁pregnant ▁or ▁breastfeeding ▁women .
▁The ▁GDG ▁ac know led ged ▁that ▁sp erm at og enes is ▁may ▁also ▁be ▁especially ▁pr one ▁to ▁the ▁mut ag en ic ▁effects ▁of ▁molnupiravir , ▁but ▁that ▁there ▁was ▁uncertainty ▁regarding ▁the ▁consequences ▁to ▁children ▁con ceived ▁by ▁fathers ▁receiving ▁or ▁having ▁recently ▁received ▁molnupiravir .
▁App lic ability : ▁The ▁applic ability ▁of ▁this ▁recommendation ▁to ▁children , ▁breastfeeding ▁and ▁pregnant ▁women , ▁is ▁currently ▁uncertain , ▁as ▁the ▁included ▁RCTs ▁enrolled ▁only ▁non - pre gn ant ▁adults .
▁However , ▁the ▁GDG ▁concluded ▁that ▁molnupiravir ▁should ▁not ▁be ▁offered ▁to ▁children , ▁breastfeeding ▁or ▁pregnant ▁women ▁with ▁COVID -19.
▁In ▁addition , ▁men ▁planning ▁to ▁con ceive ▁should ▁be ▁o ri ent ed ▁on ▁the ▁potential ▁for ▁temporary ▁g en ot ox ic ▁effect ▁on ▁sp erm ▁cell ▁production ▁( see ▁M it igation ▁St r ateg ies ▁section ).
▁The ▁GDG ▁also ▁had ▁concerns ▁about ▁whether ▁the ▁drug ▁would ▁re tain ▁efficacy ▁against ▁emerging ▁variants ▁of ▁concern , ▁such ▁as ▁O m ic ron .
▁While ▁there ▁is ▁no ▁mole c ular ▁basis ▁for ▁a ▁loss ▁of ▁efficacy , ▁the ▁GDG ▁noted ▁that ▁the ▁higher ▁viral ▁lo ads ▁and ▁associated ▁disease ▁severity ▁may ▁impact ▁the ▁effectiveness ▁of ▁molnupiravir .
▁Summary ▁- ▁Evidence ▁Summary : ▁the ▁L N MA ▁for ▁molnupiravir ▁was ▁informed ▁by ▁six ▁RCTs ▁which ▁enrolled ▁4, 82 7 ▁patients ▁with ▁non - severe ▁illness ▁in ▁out p ati ent ▁settings ; ▁the ▁L N MA ▁team ▁had ▁access ▁to ▁data ▁for ▁4, 7 96 ▁patients .
▁For ▁patients ▁with ▁non - severe ▁COVID -19, ▁the ▁GRADE ▁Summary ▁of ▁F ind ings ▁table ▁shows ▁the ▁relative ▁and ▁absolute ▁effects ▁of ▁molnupiravir ▁compared ▁with ▁standard ▁care ▁for ▁the ▁outcomes ▁of ▁interest , ▁with ▁certainty ▁r at ings , ▁informed ▁by ▁the ▁L N MA .
▁Ser ological ▁Stat us ▁( s er op os itive ▁versus ▁ser one g ative )
▁V acc ination ▁status ▁( un v acc inated ▁versus ▁vacc inated )
▁All ▁studies ▁enrolled ▁un v acc inated ▁individuals ▁with ▁time ▁from ▁sympt om ▁onset ▁< 5 ▁days .
▁Data ▁regarding ▁ser ological ▁status ▁were ▁not ▁reported .
▁There ▁are ▁some ▁people ▁with ▁much ▁higher ▁bas eline ▁risk , ▁who ▁are ▁not ▁easily ▁ident if iable .
▁For ▁these ▁patients , ▁molnupiravir ▁may ▁have ▁an ▁important ▁impact ▁on ▁mortality .
▁The ▁single ▁trial ▁reporting ▁mechanical ▁ventilation , ▁was ▁not ▁blind ed .
▁V ery ▁few ▁events ▁result ed ▁in ▁very ▁large ▁cred ible ▁intervals ▁that ▁include ▁important ▁and ▁un im port ant ▁effects .
▁The ▁u pper ▁cred ible ▁interval ▁includes ▁a ▁small ▁and ▁un im port ant ▁effect ▁on ▁hospitalization ▁(4 ▁fewer ▁per ▁1000 ).
▁All ▁three ▁trials ▁were ▁at ▁high ▁risk ▁of ▁bias ▁for ▁dev i ations ▁from ▁intended ▁intervention ▁( l ack ▁of ▁blind ing ).
▁One ▁trial ▁was ▁at ▁high ▁risk ▁of ▁bias ▁for ▁possible ▁in ade qu ate ▁random ization ▁con ce al ment .
▁M it igation ▁strategies ▁to ▁address ▁safety ▁concerns : ▁Inf o ▁Box ▁with ▁the ▁safety ▁concerns ▁related ▁to ▁molnupiravir ▁( see ▁Me chan ism ▁of ▁Action ▁section ): ▁The ▁WHO ▁recogn izes ▁the ▁need ▁to ▁m it ig ate ▁risks , ▁both ▁for ▁individual ▁patients ▁and ▁at ▁the ▁population ▁level .
▁The ▁conditional ▁recommendation ▁takes ▁into ▁account ▁one ▁such ▁strategy : ▁limit ing ▁the ▁intervention ▁to ▁patients ▁that ▁are ▁at ▁higher ▁risk ▁of ▁hospitalization ▁or ▁death .
▁T yp ical ▁characteristics ▁of ▁people ▁at ▁highest ▁risk ▁include ▁those ▁with ▁older ▁age , ▁immun ode fic i encies ▁and / or ▁chronic ▁diseases ▁( e . g . ▁di abetes ) ▁and ▁lack ▁of ▁COVID -19 ▁vaccination .
▁See ▁WHO ▁recommendations ▁for ▁further ▁information ▁on ▁COVID -19 ▁vaccination : ▁St r ateg ic ▁Adv is ory ▁Group ▁of ▁Ex per ts ▁on ▁Im mun ization .
▁Other ▁m it igation ▁strategies ▁include : ▁Dec isions ▁around ▁treatment ▁with ▁molnupiravir ▁must ▁be ▁done ▁using ▁a ▁shared ▁decision - m aking ▁model , ▁ensuring ▁the ▁clinic ian ▁is ▁well ▁educated ▁on ▁the ▁potential ▁benefits ▁and ▁harms ▁of ▁therapy ▁and ▁able ▁to ▁explain ▁these ▁to ▁the ▁patient ▁in ▁order ▁to ▁make ▁well - in formed ▁decisions .
▁M olnupiravir ▁should ▁not ▁be ▁given ▁to ▁pregnant ▁or ▁breastfeeding ▁women ▁or ▁to ▁children .
▁In ▁case ▁of ▁doubt ▁about ▁pregnancy , ▁a ▁pregnancy ▁test ▁should ▁be ▁performed ▁prior ▁to ▁treatment ▁init iation .
▁If ▁a ▁woman ▁of ▁child ▁bearing ▁age ▁is ▁considered ▁for ▁treatment , ▁coun se lling ▁regarding ▁birth ▁control ▁during ▁treatment ▁and ▁for ▁4 ▁days ▁after ▁the ▁last ▁dose ▁of ▁molnupiravir ▁should ▁be ▁facilit ated .
▁Men ▁planning ▁to ▁con ceive ▁should ▁be ▁o ri ent ed ▁on ▁the ▁potential ▁for ▁temporary ▁g en ot ox ic ▁effect ▁on ▁sp erm ▁cell ▁production , ▁and ▁those ▁who ▁are ▁sex ually ▁active ▁with ▁fem ales ▁should ▁be ▁coun se lled ▁to ▁use ▁birth ▁control ▁during ▁treatment ▁and ▁for ▁at ▁least ▁3 ▁months ▁after ▁the ▁last ▁dose ▁of ▁molnupiravir ▁.
▁Ph armac ov ig il ance : ▁The ▁use ▁of ▁molnupiravir ▁should ▁be ▁accomp an ied ▁by ▁a ▁rob ust , ▁active ▁pharmac ov ig il ance ▁program .
▁Me chan ism ▁of ▁Action : ▁M olnupiravir ▁is ▁an ▁or ally ▁available ▁ant ivir al , ▁which ▁was ▁origin ally ▁designed ▁as ▁an ▁in ▁flu en za ▁treatment , ▁although ▁not ▁approved .
▁The ▁drug ▁in hib its ▁rep lication ▁of ▁SARS - CoV -2 ▁with ▁an ▁in ▁v it ro ▁pot ency ▁broad ly , ▁similar ▁to ▁remdesivir , ▁and ▁was ▁re - p ur p osed ▁early ▁in ▁development ▁as ▁an ▁ant ivir al ▁for ▁SARS - CoV -2 .
▁M olnupiravir ▁is ▁an ▁or ally ▁available ▁pro d rug ▁of ▁ ß - D - N 4 - h y dro x y cy t id ine ▁( N H C ).
▁It ▁is ▁a ▁nucle os ide ▁drug , ▁but ▁the ▁mechanism ▁of ▁action ▁invol ves ▁le th al ▁mut ag enes is ▁of ▁the ▁virus .
▁The ▁result ant ▁N H C , ▁containing ▁R NA s ▁are ▁then ▁themselves ▁used ▁as ▁a ▁tem pl ate ▁for ▁production ▁of ▁subsequent ▁R NA s , ▁which ▁are ▁pred ic ted ▁to ▁be ▁mut ated , ▁and ▁therefore , ▁not ▁believed ▁to ▁form ▁function al ▁virus es .
▁M olnupiravir ▁is ▁given ▁or ally ▁twice ▁daily ▁unl ike ▁remdesivir , ▁which ▁is ▁given ▁by ▁intra ven ous ▁inf usion ▁once ▁daily .
▁In ▁health y ▁vol unt e ers , ▁molnupiravir ▁(8 00 m g ) ▁ach ie ves ▁maximum ▁pl as ma ▁concent r ations ▁of ▁its ▁active ▁met ab ol ite ▁at ▁3, 600 ▁n g / m L .
▁This ▁is ▁higher ▁than ▁that ▁of ▁remdesivir ▁(2 200 ▁n g / m ▁L ).
▁However , ▁the ▁int race ll ular ▁half - life ▁of ▁molnupiravir ▁active ▁met ab ol ite ▁is ▁sh or ter ▁in ▁human ▁cell ▁lines ▁(3 h ) ▁compared ▁with ▁that ▁of ▁remdesivir ' s ▁active ▁met ab ol ite ▁( 35 h ).
▁High ▁doses ▁of ▁molnupiravir ▁(2 50 ▁mg / kg ▁twice ▁daily ) ▁have ▁been ▁shown ▁to ▁be ▁effective ▁in ▁SARS - CoV -2 - inf ected ▁Sy rian ▁gold en ▁h am st ers ; ▁however , ▁the ▁animal ▁pl as ma ▁pharmac ok inet ics ▁were ▁not ▁reported ▁to ▁bench m ark ▁against ▁those ▁seen ▁in ▁hum ans .
▁Evidence ▁of ▁ant ivir al ▁activity ▁is ▁also ▁available ▁from ▁a ▁study ▁in ▁SARS - CoV -2 ▁infected ▁f er re ts ▁at ▁lower ▁doses .
▁When ▁molnupiravir ▁was ▁combined ▁with ▁fav ip ir avir ▁in ▁infected ▁Sy rian ▁gold en ▁h am st ers , ▁the ▁efficacy ▁was ▁greater ▁than ▁when ▁either ▁drug ▁was ▁given ▁alone .
▁M olnupiravir ▁re tain s ▁activity ▁against ▁Al ph a ▁and ▁Bet a ▁variants ▁in ▁v iv o ▁, ▁and ▁the ▁D elt a ▁and ▁O m ic ron ▁variants ▁in ▁v it ro .
▁No ▁data ▁are ▁currently ▁available ▁demonst r ating ▁activity ▁against ▁the ▁D elt a ▁or ▁O m ic ron ▁variants ▁in ▁v iv o , ▁and ▁while ▁there ▁appears ▁to ▁be ▁no ▁mole c ular ▁basis ▁for ▁a ▁loss ▁of ▁activity , ▁there ▁is ▁res idual ▁uncertainty ▁around ▁whether ▁a ▁higher ▁rep lication ▁or ▁transmission ▁rate ▁may ▁impact ▁efficacy ▁of ▁the ▁drug .
▁Em erg ence ▁of ▁resistance : ▁The ▁emergence ▁of ▁resistance ▁to ▁drugs ▁used ▁for ▁other ▁virus es ▁is ▁var ied ; ▁with ▁some ▁resistance ▁emerg es ▁read ily , ▁and ▁with ▁others ▁emerging ▁more ▁slowly .
▁The ▁bar ri er ▁to ▁resistance ▁for ▁a ▁given ▁drug ▁with ▁a ▁given ▁virus ▁is ▁generally ▁considered ▁to ▁increase ▁with ▁the ▁number ▁of ▁mut ations ▁that ▁are ▁required ▁to ▁emer ge .
▁In su fficient ▁data ▁are ▁currently ▁available ▁to ▁as c ertain ▁how ▁high ▁the ▁bar ri er ▁of ▁resistance ▁is ▁with ▁SARS - CoV -2 ▁for ▁molnupiravir .
▁B ased ▁on ▁experi ences ▁with ▁other ▁nucle os ide ▁ant ivir al ▁drugs ▁( s ome ▁have ▁a ▁high ▁bar ri er ▁to ▁resistance ▁and ▁some ▁have ▁a ▁low ▁bar ri er ▁to ▁resistance ), ▁molnupiravir ▁will ▁place ▁a ▁select ive ▁pressure ▁for ▁viral ▁resistance ▁mut ations ▁within ▁an ▁individual , ▁with ▁the ▁potential ▁to ▁spread ▁at ▁a ▁population ▁level .
▁Non cl in ical ▁and / or ▁clinical ▁data ▁are ▁therefore ▁needed , ▁but ▁are ▁not ▁currently ▁available ▁for ▁molnupiravir .
▁Res istance ▁occur s ▁through ▁in he rent ▁variability ▁in ▁viral ▁sequ ences ▁that ▁happen ▁sp on t ane ously ▁as ▁the ▁virus ▁rep lic ates .
▁Ch ance ▁vari ations ▁become ▁selected , ▁known ▁as ▁select ive ▁pressure , ▁when ▁they ▁conf er ▁a ▁surv ival ▁advant age ▁in ▁the ▁presence ▁of ▁the ▁drug .
▁Sometimes , ▁there ▁is ▁a ▁fit ness ▁cost ▁to ▁the ▁virus ▁and ▁secondary ▁mut ations ▁can ▁subsequ ently ▁be ▁selected , ▁to ▁restore ▁fit ness .
▁The ▁major ▁uncertainty ▁rel ates ▁to ▁how ▁quickly ▁resistance ▁will ▁emer ge , ▁rather ▁than ▁whether ▁it ▁will ▁emer ge .
▁There ▁may ▁be ▁a ▁higher ▁risk ▁of ▁resistance ▁in ▁immun oc om p rom is d ▁patients ▁because ▁of ▁a ▁longer ▁tail ▁of ▁rep lication ▁in ▁this ▁group .
▁There ▁may ▁also ▁be ▁a ▁higher ▁risk ▁of ▁resistance ▁in ▁patients ▁with ▁poor ▁adherence ▁where ▁the ▁virus ▁is ▁exp osed ▁to ▁sub op t imal ▁drug ▁concent r ations .
▁The ▁rate ▁at ▁which ▁resistance ▁emerg es ▁will ▁be ▁slow er ▁if ▁drugs ▁are ▁given ▁in ▁combination ▁because ▁more ▁mut ations ▁will ▁be ▁required ▁to ▁conf er ▁resistance ▁to ▁multiple ▁drugs ▁than ▁will ▁be ▁required ▁for ▁one ▁drug .
▁Of ▁note , ▁animal ▁studies ▁have ▁also ▁demonst rated ▁drug ▁comb inations ▁to ▁be ▁more ▁effective .
▁The ▁risk ▁of ▁resistance ▁to ▁individual ▁patients ▁is ▁drug ▁failure ▁due ▁to ▁comp rom ised ▁efficacy .
▁The ▁g en etic ▁bar ri er ▁to ▁resistance ▁cannot ▁be ▁estimated ▁without ▁data .
▁Em erg ence ▁of ▁new ▁variants : ▁It ▁has ▁been ▁proposed ▁that ▁random ▁mut ag enes is ▁ar ising ▁from ▁the ▁molnupiravir ▁mechanism ▁of ▁action ▁might ▁increase ▁d iversity ▁in ▁the ▁viral ▁sequ ences ▁that ▁may ▁result ▁in ▁more ▁rapid ▁emergence ▁of ▁new ▁variants .
▁There ▁is ▁no ▁direct ▁evidence ▁to ▁support ▁or ▁ref ute ▁the ▁variants ▁hypot hesis ▁and ▁as ▁such ▁the ▁risk ▁is ▁currently ▁un qu ant if iable .
▁The ▁rate ▁of ▁resistance ▁emergence ▁and ▁the ▁risk ▁of ▁additional ▁d iversity ▁in ▁the ▁viral ▁g en ome ▁leading ▁to ▁new ▁variants ▁were ▁ac know led ged ▁to ▁be ▁higher , ▁with ▁a ▁higher ▁number ▁of ▁patients ▁receiving ▁the ▁intervention .
▁Non - cl in ical ▁Saf ety : ▁The ▁GDG ▁reviewed ▁the ▁pub l ically ▁available ▁data ▁on ▁non - cl in ical ▁safety ▁of ▁molnupiravir ▁from ▁the ▁F DA ▁meeting ▁documents , ▁for ▁molnupiravir ▁Em erg ence ▁Use ▁Auth or ization ▁( 30 ▁November ▁2021 ).
▁The ▁following ▁safety ▁concerns ▁were ▁highlight ed : ▁G en etic ▁to xic ology ▁data ▁demonst rated ▁that ▁molnupiravir ▁is ▁mut ag en ic ▁in ▁v it ro , ▁but ▁there ▁was ▁no ▁evidence ▁of ▁mut ag en ic ity ▁in ▁animal ▁models .
▁The ▁GDG ▁ac know led ged ▁uncertain ties ▁in ▁the ▁available ▁data ▁and ▁concluded ▁that ▁based ▁upon ▁the ▁available ▁information ▁molnupiravir ▁may ▁or ▁may ▁not ▁be ▁car c in og en ic ▁in ▁hum ans .
▁The ▁GDG ▁determined ▁that ▁molnupiravir ▁should ▁not , ▁therefore , ▁be ▁administered ▁to ▁pa ed i at ric ▁patients .
▁Im port ant ly , ▁low ▁concent r ations ▁of ▁N H C ▁(0 .09 % ▁maternal ▁exp os ures ) ▁were ▁det ect able ▁in ▁10 - day - old ▁r at ▁p up s ▁suggesting ▁that ▁N H C ▁is ▁present ▁in ▁breast ▁milk .
▁The ▁GDG ▁determined ▁molnupiravir ▁should ▁not ▁be ▁administered ▁to ▁breastfeeding ▁women .
▁In ▁developmental ▁and ▁reproductive ▁to xic ology ▁assess ments , ▁reduced ▁f o etal ▁body ▁weights ▁were ▁observed ▁in ▁r ats ▁and ▁ra bb its , ▁with ▁higher ▁exp os ures ▁also ▁being ▁associated ▁with ▁emb ry o - f o etal ▁le th ality ▁and ▁ter at og en ic ity ▁in ▁r ats .
▁Accordingly , ▁molnupiravir ▁should ▁not ▁be ▁administered ▁during ▁pregnancy .
▁There ▁was ▁an ▁absence ▁of ▁available ▁data ▁relating ▁to ▁sp erm at og enes is , ▁which ▁may ▁be ▁particularly ▁pr one ▁to ▁the ▁effect ▁of ▁a ▁mut ag en ▁in ▁adult ▁mal es .
▁No ▁data ▁are ▁available ▁to ▁quant ify ▁the ▁consequences ▁of ▁this ▁for ▁emb ry o / f o et us ▁con ceived ▁by ▁fathers ▁who ▁were ▁receiving ▁or ▁had ▁recently ▁received ▁molnupiravir .
▁Con val es cent ▁pl as ma ▁( published ▁7 ▁December ▁202 1) ▁Inf o ▁Box ▁- ▁recommendations ▁concerning ▁con val es cent ▁pl as ma ▁for ▁patients ▁with ▁non - severe , ▁severe ▁and ▁critical ▁COVID -19 ▁were ▁published ▁on ▁7 ▁December ▁2021 ▁as ▁the ▁seventh ▁version ▁of ▁the ▁WHO ▁living ▁guideline ▁and ▁in ▁the ▁B M J ▁as ▁R ap id ▁Recommend ations .
▁No ▁changes ▁were ▁made ▁to ▁the ▁con val es cent ▁pl as ma ▁recommendations ▁in ▁this ▁13 th ▁version ▁of ▁the ▁guideline .
▁Practical ▁info : ▁The ▁GDG ▁made ▁a ▁strong ▁recommendation ▁against ▁using ▁con val es cent ▁pl as ma ▁for ▁the ▁treatment ▁of ▁patients ▁with ▁non - severe ▁COVID -19 ▁and ▁a ▁recommendation ▁against ▁using ▁con val es cent ▁pl as ma ▁in ▁those ▁with ▁severe ▁or ▁critical ▁COVID -19, ▁outside ▁the ▁context ▁of ▁a ▁clinical ▁trial .
▁Given ▁this , ▁we ▁will ▁not ▁go ▁into ▁det ail ▁regarding ▁the ▁many ▁practical ▁issues ▁related ▁to ▁con val es cent ▁pl as ma ▁including ▁but ▁not ▁limited ▁to : ▁identification ▁and ▁rec ruitment ▁of ▁potential ▁don ors , ▁collection ▁of ▁pl as ma , ▁st or age ▁and ▁distribution ▁of ▁pl as ma , ▁and ▁inf usion ▁of ▁con val es cent ▁pl as ma ▁into ▁rec ip ients .
▁Con val es cent ▁pl as ma ▁probably ▁does ▁not ▁impact ▁mechanical ▁ventilation .
▁There ▁were ▁no ▁data ▁evalu ating ▁the ▁risk ▁of ▁hospitalization ▁with ▁con val es cent ▁pl as ma ▁and ▁therefore , ▁the ▁impact ▁is ▁very ▁uncertain .
▁Con val es cent ▁pl as ma ▁probably ▁does ▁not ▁result ▁in ▁important ▁increases ▁in ▁risks ▁of ▁transf usion - rel ated ▁acute ▁l ung ▁inj ury ▁( T RA L I ), ▁transf usion - ass oci ated ▁circul atory ▁over lo ad ▁( T AC O ), ▁or ▁all erg ic ▁re act ions .
▁Certainty ▁of ▁the ▁evidence , ▁The ▁certainty ▁in ▁mortality ▁was ▁high , ▁whereas ▁mechanical ▁ventilation ▁was ▁moderate ▁due ▁to ▁serious ▁risk ▁of ▁bias .
▁Certainty ▁was ▁r ated ▁as ▁moderate ▁for ▁T RA L I ▁and ▁T AC O ▁due ▁to ▁serious ▁risk ▁of ▁bias , ▁and ▁for ▁all erg ic ▁re act ions ▁due ▁to ▁concerns ▁regarding ▁risk ▁of ▁bias ▁and ▁imprecision .
▁Values ▁and ▁Pre ferences : ▁The ▁GDG ▁inf er red ▁that , ▁in ▁addition ▁to ▁the ▁agreed ▁upon ▁values ▁and ▁preferences , ▁almost ▁all ▁well - in formed ▁patients ▁would ▁choose ▁against ▁receiving ▁con val es cent ▁pl as ma , ▁based ▁on ▁available ▁evidence ▁regarding ▁relative ▁benefits ▁and ▁harms .
▁From ▁a ▁population ▁pers pective , ▁feasibility , ▁acceptability , ▁equity ▁and ▁cost ▁are ▁other ▁important ▁elements ▁to ▁take ▁into ▁account .
▁For ▁patients ▁with ▁non - severe ▁illness , ▁the ▁GDG ▁considered ▁that ▁resource ▁and ▁feasibility ▁issues ▁may ▁be ▁am pl ified ▁in ▁the ▁out p ati ent ▁setting , ▁and ▁mob il izing ▁the ▁use ▁of ▁con val es cent ▁pl as ma ▁on ▁a ▁large ▁scale ▁would ▁likely ▁be ▁of ▁question able ▁feasibility .
▁These ▁resources ▁and ▁feasibility ▁issues ▁are ▁comp ounded ▁for ▁those ▁with ▁non - severe ▁diseases ▁who ▁are ▁most ▁often ▁out p ati ents .
▁Also , ▁this ▁process ▁is ▁cost ly ▁and ▁time - c ons um ing .
▁Given ▁the ▁number ▁of ▁patients ▁with ▁non - severe ▁disease ▁and ▁the ▁low ▁event ▁rate ▁in ▁this ▁subgroup ▁of ▁patients , ▁mob il izing ▁the ▁use ▁of ▁con val es cent ▁pl as ma ▁on ▁a ▁large ▁scale ▁would ▁be ▁of ▁question able ▁feasibility .
▁Although ▁blood ▁transf usion ▁is ▁accept able ▁to ▁most , ▁there ▁is ▁a ▁sub set ▁of ▁the ▁population ▁that ▁will ▁not ▁accept ▁all og en ic ▁blood ▁transf usion .
▁There ▁are ▁also ▁reg ul atory ▁challeng es ▁in ▁most ▁j ur is d ict ions ▁related ▁to ▁blood ▁product ▁transf usion .
▁Justification : ▁A ▁combination ▁of ▁the ▁evidence , ▁values ▁and ▁preferences , ▁and ▁feasibility ▁contrib uted ▁to ▁the ▁strong ▁recommendation ▁against ▁con val es cent ▁pl as ma ▁in ▁patients ▁with ▁non - severe ▁COVID -19.
▁Most ▁important ly , ▁given ▁there ▁was ▁no ▁benefit ▁demonst rated ▁in ▁any ▁of ▁the ▁critical ▁or ▁important ▁outcomes ▁for ▁either ▁non - severe ▁or ▁severe ▁or ▁critical ▁COVID -19, ▁the ▁GDG ▁did ▁not ▁see ▁any ▁just ification ▁for ▁the ▁resources ▁( inc lud ing ▁time ▁and ▁cost ) ▁that ▁would ▁be ▁associated ▁with ▁the ▁administration ▁of ▁con val es cent ▁pl as ma .
▁The ▁recommendation ▁also ▁took ▁into ▁account ▁possible ▁associated ▁harms ▁( alth ough ▁not ▁demonst rated ▁in ▁the ▁evidence ▁summary , ▁there ▁is ▁always ▁a ▁potential ▁for ▁harm ▁with ▁blood ▁product ▁transf usion ), ▁the ▁low ▁bas eline ▁risk ▁of ▁mortality , ▁mechanical ▁ventilation , ▁and ▁hospitalization ▁in ▁non - severe ▁illness , ▁and ▁feasibility ▁challeng es ▁with ▁the ▁administration ▁of ▁con val es cent ▁pl as ma .
▁Tit ers ▁of ▁ne ut ral izing ▁antib odies ▁var ied ▁substant ially ▁between ▁included ▁trials , ▁with ▁over ▁half ▁of ▁the ▁trials , ▁not ▁reporting ▁or ▁considering ▁rec ip ient ▁tit res ▁at ▁all .
▁In ▁fact , ▁the ▁largest ▁trial ▁( R EC O V ER Y ) ▁did ▁not ▁report ▁on ▁don or ▁antib ody ▁tit res ▁at ▁all .
▁Even ▁when ▁tit res ▁were ▁reported , ▁the ▁method ▁for ▁testing ▁and ▁the ▁volume ▁of ▁pl as ma ▁inf used ▁var ied .
▁This ▁made ▁it ▁impossible ▁to ▁provide ▁any ▁analysis ▁based ▁on ▁don or ▁tit re ▁levels ▁or ▁assess ▁for ▁cred ible ▁subgroup ▁effects .
▁App lic ability : ▁The ▁applic ability ▁of ▁this ▁recommendation ▁to ▁children ▁or ▁pregnant ▁women ▁is ▁currently ▁uncertain , ▁as ▁the ▁included ▁RCTs ▁enrolled ▁non - pre gn ant ▁adults .
▁However , ▁the ▁risk ▁of ▁hospitalization ▁in ▁children ▁is ▁generally ▁extremely ▁low , ▁and ▁the ▁GDG ▁inf er red ▁that ▁in ▁the ▁absence ▁of ▁immun os u pp ression ▁or ▁another ▁significant ▁risk ▁factor , ▁children ▁should ▁not ▁receive ▁the ▁intervention .
▁All ▁RCTs ▁were ▁registered , ▁and ▁80% ▁were ▁published ▁in ▁pe er - re view ed ▁jour n als ; ▁20% ▁were ▁prep r int s .
▁1% ▁of ▁patients ▁were ▁enrolled ▁in ▁out p ati ent ▁settings .
▁The ▁table ▁shows ▁characteristics ▁of ▁the ▁RCTs , ▁of ▁which ▁two ▁trials ▁used ▁compar isons ▁to ▁pl as ma ▁as ▁a ▁place bo ▁and ▁were ▁not ▁included ▁in ▁the ▁evidence ▁summ aries .
▁We ▁are ▁aware ▁of ▁two ▁additional ▁published ▁RCTs ▁comparing ▁con val es cent ▁pl as ma ▁to ▁standard ▁care ▁or ▁place bo .
▁These ▁trials ▁were ▁not ▁incor por ated ▁in ▁the ▁latest ▁analysis ▁presented ▁to ▁the ▁GDG , ▁based ▁on ▁which ▁recommendations ▁were ▁made .
▁For ▁patients ▁with ▁non - severe ▁COVID -19, ▁the ▁GRADE ▁Summary ▁of ▁F ind ings ▁table ▁shows ▁the ▁relative ▁and ▁absolute ▁effects ▁of ▁con val es cent ▁pl as ma ▁compared ▁with ▁usual ▁care ▁for ▁the ▁outcomes ▁of ▁interest , ▁with ▁certainty ▁r at ings .
▁This ▁evidence ▁summary ▁was ▁informed ▁by ▁the ▁L N MA ▁po ol ing ▁data ▁from ▁1, 60 2 ▁patients ▁in ▁4 ▁RCTs , ▁for ▁the ▁outcome ▁of ▁mortality ▁and ▁less ▁data ▁available ▁for ▁other ▁outcomes , ▁except ▁for ▁all erg ic ▁re act ions ▁(8 ▁RCTs , ▁243 ▁patients ).
▁Sub group ▁analysis : ▁We ▁pre - spec ified ▁the ▁following ▁subgroup ▁analyses ▁of ▁interest : ▁Age : ▁younger ▁adults ▁( < ▁70 ▁years ) ▁versus ▁older ▁adults ▁( > ▁70 ▁years ).
▁Sever ity ▁of ▁illness ▁( at ▁time ▁of ▁treatment ▁init iation ): ▁non - severe ▁versus ▁severe ▁and ▁critical .
▁T reat ment ▁dose : ▁higher ▁tit re ▁versus ▁lower ▁tit re ▁pl as ma .
▁The ▁subgroup ▁analyses ▁were ▁performed ▁on ▁patients ▁across ▁all ▁disease ▁sever ities .
▁The ▁majority ▁of ▁subgroup s ▁did ▁not ▁have ▁sufficient ▁data ▁across ▁outcomes ▁of ▁interest ▁to ▁purs ue ▁subgroup ▁analyses .
▁Of ▁those ▁that ▁did , ▁we ▁found ▁no ▁significant ▁subgroup ▁effects ▁for ▁the ▁severity ▁of ▁illness ▁( p =0 .8 0) ▁and ▁age ▁( p =0 .8 4) ▁on ▁mortality , ▁and ▁of ▁severity ▁of ▁illness ▁( p =0 .1 7) ▁on ▁mechanical ▁ventilation .
▁GDG ▁agreed ▁the ▁cred ible ▁interval ▁includes ▁some ▁concern ▁regarding ▁all erg ic ▁re act ions , ▁though ▁ac know led ges ▁that ▁the ▁bas eline ▁risk ▁is ▁low .
▁For ▁patients ▁with ▁severe ▁or ▁critical ▁COVID -19, ▁only ▁in ▁research ▁settings , ▁we ▁recommend ▁not ▁to ▁use ▁con val es cent ▁pl as ma ▁for ▁treatment ▁of ▁COVID -19, ▁except ▁in ▁the ▁context ▁of ▁a ▁clinical ▁trial ▁( rec ommend ed ▁only ▁in ▁research ▁settings ).
▁Evidence ▁to ▁decision ▁benefits ▁and ▁harms ▁in ▁severe ▁or ▁critical ▁patients : ▁Con val es cent ▁pl as ma ▁may ▁not ▁result ▁in ▁an ▁important ▁impact ▁on ▁mortality , ▁mechanical ▁ventilation , ▁time ▁to ▁sympt om ▁improvement , ▁length ▁of ▁hospital ▁stay ▁or ▁vent il ator - f ree ▁days .
▁However , ▁there ▁is ▁always ▁potential ▁for ▁harm ▁with ▁blood ▁product ▁transf usion ▁although ▁not ▁demonst rated ▁in ▁the ▁evidence ▁summary .
▁Certainty ▁of ▁the ▁Evidence : ▁The ▁certainty ▁in ▁mortality ▁was ▁low ▁due ▁to ▁concerns ▁with ▁indirect ness , ▁risk ▁of ▁bias ▁and ▁imprecision .
▁The ▁GDG ▁r ated ▁down ▁certainty ▁to ▁low ▁for ▁mechanical ▁ventilation , ▁length ▁of ▁hospital ▁stay ▁and ▁vent il ator - f ree ▁days ▁for ▁serious ▁risk ▁of ▁bias ▁and ▁serious ▁imprecision , ▁and ▁to ▁low ▁for ▁time ▁to ▁sympt om ▁improvement ▁due ▁to ▁very ▁serious ▁imprecision .
▁Justification : ▁After ▁substant ial ▁discussion , ▁the ▁GDG ▁decided ▁to ▁make ▁a ▁recommendation ▁against ▁con val es cent ▁pl as ma ▁in ▁patients ▁with ▁severe ▁or ▁critical ▁COVID -19, ▁except ▁in ▁the ▁context ▁of ▁clinical ▁trials .
▁Given ▁the ▁low ▁certainty ▁evidence ▁suggesting ▁a ▁small ▁or ▁no ▁effect ▁on ▁mortality , ▁mechanical ▁ventilation , ▁and ▁time ▁to ▁sympt om ▁improvement , ▁with ▁possible ▁associ ate ▁harms ▁( alth ough ▁not ▁demonst rated in ▁the ▁evidence ▁summary , ▁there ▁is ▁always ▁a ▁potential ▁for ▁harm ▁with ▁blood ▁product ▁transf usion ) ▁the ▁panel ▁agreed ▁further ▁research ▁address ing ▁these ▁patient - im port ant ▁outcomes ▁would ▁be ▁valuable .
▁This ▁research ▁focus es ▁on ▁severe ▁or ▁critical ▁COVID -19 ▁and ▁was ▁also ▁informed ▁by ▁the ▁feasibility ▁( p ati ents ▁are ▁already ▁hospital ized ) ▁and ▁bas eline ▁risk ▁of ▁mortality ▁and ▁requ iring ▁life ▁support ▁interventions ▁( h ig her ▁in ▁severe ▁or ▁critical ▁COVID -19 ).
▁The ▁panel ▁identified ▁high - t it re ▁products ▁as ▁the ▁highest ▁priority ▁for ▁future ▁research ▁as ▁well ▁as ▁the ▁need ▁to ▁report ▁on ▁don or ▁tit re ▁and ▁volume ▁inf used ▁which ▁can ▁give ▁an ▁idea ▁of ▁the ▁dil ution ▁of ▁tit res ▁in ▁the ▁rec ip ient .
▁Similarly , ▁the ▁panel ▁identified ▁ser one g ative ▁COVID -19 ▁patients ▁as ▁the ▁highest ▁priority ▁for ▁future ▁con val es cent ▁pl as ma ▁research .
▁A ▁recommendation ▁to ▁only ▁use ▁a ▁drug ▁in ▁the ▁setting ▁of ▁clinical ▁trials ▁is ▁appropriate ▁when ▁there ▁is ▁low ▁certainty ▁evidence , ▁and ▁future ▁research ▁has ▁a ▁potential ▁for ▁reducing ▁uncertainty ▁about ▁the ▁effects ▁of ▁the ▁intervention ▁and ▁for ▁doing ▁so ▁at ▁a ▁reason able ▁cost .
▁Summary ▁evidence - ▁summary ▁for ▁con val es cent ▁pl as ma ▁- ▁please ▁see ▁summary ▁for ▁patients ▁with ▁non - severe ▁COVID -19 ▁above .
▁It ▁provides ▁det ails ▁about ▁the ▁L N MA ▁and ▁16 ▁included ▁trials ▁across ▁disease ▁sever ities , ▁as ▁well ▁as ▁subgroup ▁analyses ▁that ▁did ▁not ▁det ect ▁cred ible ▁effects ▁based ▁on ▁age , ▁the ▁severity ▁of ▁illness , ▁or ▁d os age ▁of ▁con val es cent ▁pl as ma .
▁The ▁GRADE ▁summary ▁of ▁findings ▁table ▁shows ▁the ▁relative ▁and ▁absolute ▁effects ▁of ▁con val es cent ▁pl as ma ▁compared ▁with ▁usual ▁care ▁for ▁the ▁outcomes ▁of ▁interest ▁for ▁patients ▁with ▁severe ▁and ▁critical ▁COVID -19, ▁with ▁certainty ▁r at ings .
▁This ▁evidence ▁summary ▁was ▁informed ▁by ▁the ▁L N MA , ▁po ol ing ▁data ▁from ▁14 36 6 ▁patients ▁in ▁10 ▁studies ▁for ▁the ▁outcome ▁of ▁mortality , ▁with ▁less ▁data ▁available ▁for ▁other ▁outcomes .
▁Cred ible ▁interval ▁does ▁not ▁exclud e ▁important ▁benefit .
▁Me chan ism ▁of ▁action ▁- ▁The ▁proposed ▁primary ▁mechanism ▁of ▁action ▁for ▁con val es cent ▁pl as ma ▁invol ves ▁the ▁transfer ▁of ▁end og enous ly ▁produced ▁ne ut ral izing ▁antib odies ▁present ▁within ▁the ▁pl as ma ▁from ▁previously ▁infected ▁and ▁rec overed ▁patients ▁into ▁patients ▁with ▁active ▁infection ▁.
▁Therefore , ▁the ▁under lying ▁pl a us ibility ▁for ▁this ▁mechanism ▁of ▁action ▁depends ▁upon ▁whether ▁sufficient ▁antib ody ▁concent r ations ▁remain ▁following ▁the ▁dil ution ▁from ▁don or ▁to ▁rec ip ient .
▁As ▁such , ▁the ▁ne ut ral izing ▁antib ody ▁tit re ▁within ▁the ▁don or ▁pl as ma ▁as ▁well ▁as ▁the ▁volume ▁administered ▁are ▁likely ▁to ▁be ▁important .
▁Data ▁gener ated ▁in ▁Sy rian ▁gold en ▁h am st ers ▁have ▁demonst rated ▁the ▁efficacy ▁of ▁con val es cent ▁pl as ma ▁against ▁SARS - CoV -2 ▁at ▁a ▁tit re ▁of ▁1: 25 6 0, ▁but ▁not ▁at ▁a ▁tit re ▁of ▁1: 3 20, ▁when ▁given ▁at ▁a ▁volume ▁of ▁1 m l , ▁which ▁ext rap ol ates ▁based ▁on ▁average ▁blood ▁volume ▁to ▁a ▁human ▁d osing ▁volume ▁of ▁300 m l ▁.
▁It ▁should ▁be ▁further ▁recognized ▁that ▁the ▁concent r ations ▁( t it re ) ▁of ▁ne ut ral izing ▁antib odies ▁present ▁within ▁con val es cent ▁pl as ma ▁are ▁highly ▁variable ▁between ▁don ors ▁and ▁that ▁there ▁are ▁different ▁method olog ies ▁available ▁to ▁measure ▁it .
▁Ant ib ody ▁tit re , ▁method ology ▁employ ed , ▁and ▁the ▁volume ▁of ▁con val es cent ▁pl as ma ▁administered ▁all ▁vary ▁widely ▁across ▁the ▁studies ▁that ▁have ▁investigated ▁this ▁approach ▁in ▁COVID -19.
▁Ant ib ody ▁tit re ▁of ▁the ▁don or ▁pl as ma ▁was ▁not ▁recorded ▁in ▁12 / 16 ▁trials , ▁meaning ▁the ▁tit re ▁may ▁have ▁been ▁high ▁or ▁may ▁have ▁been ▁low .
▁However , ▁in ▁3 ▁of ▁the ▁trials ▁in ▁which ▁don or ▁tit re ▁was ▁not ▁recorded , ▁a ▁lower ▁cut - off ▁was ▁applied ▁at ▁a ▁tit re ▁of ▁either ▁1: 1 60 ▁( for ▁2 ▁trials ) ▁or ▁1: 4 00.
▁The ▁largest ▁trial ▁( R EC O V ER Y ) ▁did ▁not ▁report ▁don or ▁antib ody ▁tit res ▁although ▁only ▁don ors ▁with ▁a ▁tit re ▁above ▁1: 100 ▁were ▁eligible . ▁One ▁(1 / 16 ) ▁trial ▁did ▁not ▁provide ▁information ▁on ▁what ▁volume ▁of ▁pl as ma ▁was ▁administered ▁meaning ▁volume ▁could ▁have ▁been ▁high ▁or ▁could ▁have ▁been ▁low .
▁Both ▁volume ▁and ▁don or ▁tit re ▁were ▁only ▁known ▁for ▁6 / 16 ▁trials .
▁For ▁trials ▁in ▁non - severe ▁patients : ▁Only ▁three ▁trials ▁were ▁conducted ▁in ▁non - severe ▁patients ▁using ▁antib ody ▁tit res ▁of ▁1: 4 0, ▁1: 2 9 2, ▁and ▁1: 3 200 ▁with ▁vol um es ▁administered ▁of ▁250 –3 00 ▁ml , ▁400 ▁ml ▁and ▁250 ▁ml , ▁respectively ▁( est im ated ▁dose ▁range ▁of ▁100 - f old ).
▁Two ▁trials ▁studied ▁both ▁non - severe ▁and ▁severe / c rit ical ▁patients , ▁one ▁of ▁which ▁didn ’ t ▁record ▁antib ody ▁tit re , ▁and ▁the ▁other ▁which ▁used ▁200 – 250 ▁+ /- ▁75 ▁ml ▁of ▁pl as ma ▁with ▁a ▁tit re ▁of ▁1: 1 60.
▁Inter le uk in -6 ▁recept or ▁block ers ▁( published ▁6 ▁July ▁202 1) ▁Inf o ▁Box ▁- ▁The ▁recommendation ▁concerning ▁I L -6 ▁recept or ▁block ers ▁( t oc il iz um ab ▁or ▁s ar il um ab ) ▁was ▁published ▁on ▁6 ▁July ▁2021 ▁as ▁the ▁fifth ▁version ▁of ▁the ▁WHO ▁living ▁guideline .
▁It ▁followed ▁the ▁public ation ▁of ▁R EC O V ER Y ▁and ▁R E M AP - C AP ▁trial ▁public ations ▁in ▁February ▁202 1, ▁and ▁new ▁trial ▁data ▁from ▁10 20 ▁patients ▁randomized ▁head - to - head ▁to ▁either ▁to cil iz um ab ▁or ▁s ar il um ab ▁in ▁R E M AP - C AP ▁being ▁made ▁available ▁to ▁the ▁WHO ▁on ▁1 ▁June ▁2021 .
▁No ▁changes ▁were ▁made ▁to ▁the ▁recommendations ▁in ▁this ▁13 th ▁version ▁of ▁the ▁guideline .
▁C orticostero ids ▁have ▁previously ▁been ▁strongly ▁recommended ▁in ▁patients ▁with ▁severe ▁and ▁critical ▁COVID -19 ▁and ▁we ▁recommend ▁patients ▁meeting ▁these ▁severity ▁criteria ▁should ▁receive ▁both ▁corticosteroids ▁and ▁I L -6 ▁recept or ▁block ers .
▁The ▁J A K ▁in hib itor ▁bar ic it inib ▁is ▁now ▁recommended ▁for ▁the ▁treatment ▁of ▁patients ▁with ▁severe ▁and ▁critical ▁COVID -19, ▁I L -6 ▁recept or ▁block ers ▁and ▁bar ic it inib ▁may ▁be ▁given ▁together .
▁Practical ▁Inf o ▁- ▁R ou te : ▁I L -6 ▁recept or ▁block ers ▁are ▁administered ▁intra ven ously ▁for ▁the ▁treatment ▁of ▁patients ▁with ▁severe ▁or ▁critical ▁COVID -19 ; ▁sub cut ane ous ▁administration ▁is ▁not ▁used ▁in ▁this ▁case .
▁I L ▁- 6 ▁recept or ▁block er ▁therapy ▁should ▁be ▁administered ▁in ▁combination ▁with ▁system ic ▁corticosteroids , ▁which ▁may ▁be ▁administered ▁both ▁or ally ▁and ▁intra ven ously , ▁with ▁due ▁consideration ▁to ▁their ▁high ▁b io av ail ability ▁but ▁possible ▁mal abs or ption ▁in ▁the ▁case ▁of ▁int est inal ▁d ys f unction ▁with ▁critical ▁illness .
▁D uration : ▁T oc il iz um ab ▁and ▁s ar il um ab ▁are ▁administered ▁as ▁single ▁intra ven ous ▁doses , ▁typically ▁over ▁1 ▁hour .
▁A ▁second ▁dose ▁may ▁be ▁administered ▁12 ▁to ▁48 ▁hours ▁after ▁the ▁first ▁dose ; ▁this ▁was ▁offered ▁vari ably ▁in ▁major ▁clinical ▁trials ▁at ▁the ▁disc ret ion ▁of ▁treat ing ▁clinic ians ▁if ▁a ▁clinical ▁response ▁was ▁felt ▁to ▁be ▁in ade qu ate .
▁D uration ▁of ▁conc urrent ▁system ic ▁corticosteroids ▁is ▁typically ▁u pt o ▁10 ▁days , ▁though ▁may ▁vary ▁between ▁5 ▁and ▁14 ▁days .
▁D ose : ▁T oc il iz um ab ▁is ▁d osed ▁at ▁8 m g ▁per ▁kil ogram ▁of ▁actual ▁body ▁weight , ▁u pt o ▁a ▁maximum ▁of ▁800 m g .
▁Sar il um ab ▁is ▁most ▁common ly ▁d osed ▁at ▁400 m g , ▁consist ent ▁with ▁what ▁was ▁used ▁in ▁R E M AP - C AP .
▁R en al ▁dose ▁adjust ment ▁is ▁not ▁currently ▁war r anted ▁for ▁either ▁drug .
▁Monitoring : ▁R out ine ▁blood ▁work ▁including ▁ne ut ro ph il ▁count , ▁pl ate lets , ▁trans amin ases , ▁and ▁total ▁b il ir ub in ▁should ▁be ▁che cked ▁prior ▁to ▁init iation ▁of ▁therapy .
▁All ▁patients ▁should ▁be ▁monitored ▁for ▁signs ▁and ▁symptoms ▁of ▁infection , ▁given ▁the ▁increased ▁risk ▁with ▁immun os u pp ression ▁in ▁addition ▁to ▁system ic ▁corticosteroids .
▁Patients ▁on ▁longer ▁term ▁I L -6 ▁recept or ▁block er ▁therapy ▁are ▁at ▁risk ▁of ▁active ▁t u ber c ul osis , ▁invas ive ▁fun gal ▁infections ▁and ▁opport un istic ▁path og ens .
▁R is ks ▁and ▁benefits ▁of ▁therapy ▁should ▁be ▁considered ▁care fully ▁in ▁patients ▁with ▁any ▁active , ▁severe ▁infection ▁other ▁than ▁COVID -19 ; ▁ca ution ▁is ▁adv ised ▁when ▁considering ▁the ▁use ▁of ▁to cil iz um ab ▁in ▁patients ▁with ▁a ▁history ▁of ▁rec ur ring ▁or ▁chronic ▁infections ▁or ▁with ▁under lying ▁conditions ▁which ▁may ▁pred is p ose ▁them ▁to ▁infections .
▁T im ing : ▁I L -6 ▁recept or ▁block ers ▁should ▁be ▁initiated ▁with ▁system ic ▁corticosteroids ; ▁specific ▁t im ing ▁during ▁hospitalization ▁or ▁the ▁course ▁of ▁illness ▁is ▁not ▁spec ified .
▁That ▁being ▁said , ▁I L -6 ▁recept or ▁block ers ▁have ▁been ▁administered ▁early ▁in ▁the ▁course ▁of ▁hospitalization ▁in ▁the ▁included ▁trials ▁and ▁clinic ians ▁may ▁consider ▁this ▁approach ▁if ▁possible .
▁The ▁R EC O V ER Y ▁trial ▁demonst rated ▁reduced ▁risk ▁of ▁death ▁also ▁in ▁patients ▁already ▁receiving ▁corticosteroids ▁and ▁I L -6 ▁recept or ▁block ers , ▁resulting ▁in ▁an ▁updated ▁recommendation ▁to ▁allow ▁the ▁combination ▁of ▁I L -6 ▁recept or ▁block ers ▁and ▁bar ic it inib ▁in ▁the ▁12 th ▁it eration ▁of ▁this ▁WHO ▁guideline .
▁The ▁evidence ▁regarding ▁the ▁risk ▁of ▁serious ▁adverse ▁events ▁( S A Es ) ▁is ▁uncertain .
▁Low ▁certainty ▁evidence ▁suggested ▁that ▁the ▁risk ▁of ▁b acter ial ▁infections ▁in ▁the ▁context ▁of ▁immun os u pp ression ▁treatment ▁with ▁I L -6 ▁recept or ▁block ers ▁may ▁be ▁similar ▁to ▁usual ▁care ▁.
▁However ▁the ▁GDG ▁had ▁some ▁concerns ▁that , ▁given ▁the ▁short - term ▁follow - up ▁of ▁most ▁trials ▁and ▁the ▁challeng es ▁associated ▁with ▁accur ately ▁capturing ▁adverse ▁events ▁such ▁as ▁b acter ial ▁or ▁fun gal ▁infection , ▁the ▁evidence ▁summary ▁may ▁under rep resent ▁the ▁risks ▁of ▁treatment ▁with ▁I L -6 ▁recept or ▁block ers .
▁Furthermore , ▁the ▁trials ▁of ▁I L -6 ▁recept or ▁block ers ▁that ▁inform ▁this ▁recommendation ▁were ▁most ly ▁performed ▁in ▁high - in come ▁countries ▁where ▁the ▁risk ▁of ▁certain ▁infect ious ▁complications ▁may ▁be ▁less ▁than ▁in ▁some ▁other ▁parts ▁of ▁the ▁world , ▁and ▁so ▁the ▁general iz ability ▁of ▁the ▁data ▁on ▁adverse ▁events ▁is ▁unclear .
▁We ▁did ▁not ▁have ▁any ▁data ▁exam ining ▁different ial ▁risk ▁of ▁harm ▁based ▁on ▁whether ▁patients ▁received ▁one ▁or ▁two ▁doses ▁of ▁I L -6 ▁recept or ▁block er .
▁Sub group ▁analyses ▁indicated ▁no ▁effect ▁mod ification ▁based ▁on ▁I L -6 ▁recept or ▁block er ▁drug ▁( s ar il um ab ▁or ▁to cil iz um ab ) ▁or ▁disease ▁severity ▁( c rit ical ▁vs ▁severe ) ▁and ▁therefore ▁this ▁recommendation ▁app lies ▁to ▁all ▁adult ▁patients ▁with ▁either ▁severe ▁or ▁critical ▁COVID -19 ▁.
▁We ▁were ▁unable ▁to ▁exam ine ▁subgroup s ▁based ▁on ▁ele v ation ▁of ▁infl amm atory ▁mark ers ▁or ▁age ▁due ▁to ▁insufficient ▁trial ▁data ▁( see ▁Research ▁evidence ).
▁Sub group ▁analyses ▁evalu ating ▁bas eline ▁st ero id ▁use ▁found ▁greater ▁benefit ▁of ▁I L -6 ▁recept or ▁block ers ▁in ▁patients ▁receiving ▁st ero ids ▁compared ▁with ▁those ▁who ▁were ▁not ▁( p =0 .02 6 ), ▁demonst r ating ▁that ▁st ero id ▁use ▁does ▁not ▁abol ish ▁and ▁might ▁enhance ▁the ▁benef icial ▁effect ▁of ▁I L -6 ▁recept or ▁block ers .
▁Since ▁st ero ids ▁are ▁already ▁strongly ▁recommended ▁in ▁patients ▁with ▁severe ▁and ▁critical ▁COVID -19, ▁we ▁did ▁not ▁form ally ▁evalu ate ▁the ▁cred ibility ▁of ▁this ▁subgroup ▁analysis ▁as ▁there ▁would ▁be ▁no ▁rational e ▁for ▁a ▁subgroup ▁recommendation ▁for ▁patients ▁not ▁receiving ▁corticosteroids .
▁Certainty ▁of ▁the ▁evidence ▁- ▁certainty ▁of ▁evidence ▁was ▁r ated ▁as ▁high ▁for ▁mortality ▁and ▁need ▁for ▁mechanical ▁ventilation .
▁Certainty ▁in ▁the ▁duration ▁of ▁mechanical ▁ventilation ▁was ▁r ated ▁as ▁low ▁due ▁to ▁serious ▁risk ▁of ▁bias ▁due ▁to ▁concerns ▁regarding ▁lack ▁of ▁blind ing ▁in ▁included ▁trials , ▁and ▁for ▁imprecision ▁as ▁the ▁lower ▁limit ▁of ▁the ▁confidence ▁interval ▁suggested ▁no ▁effect .
▁Certainty ▁in ▁the ▁duration ▁of ▁hospitalization ▁was ▁r ated ▁as ▁low ▁due ▁to ▁a ▁serious ▁risk ▁of ▁bias ▁from ▁lack ▁of ▁blind ing ▁in ▁included ▁trials ▁and ▁for ▁inc ons ist ency ▁related ▁to ▁differences ▁in ▁point ▁estimates ▁and ▁lack ▁of ▁over l ap ▁in ▁confidence ▁intervals .
▁Certainty ▁in ▁serious ▁adverse ▁events ▁was ▁r ated ▁as ▁very ▁low ▁due ▁to ▁the ▁risk ▁of ▁bias ▁related ▁to ▁lack ▁of ▁blind ing ▁and ▁as c ertain ment ▁bias , ▁and ▁very ▁serious ▁imprecision ▁due ▁to ▁very ▁wide ▁confidence ▁intervals ▁which ▁did ▁not ▁rule ▁out ▁important ▁benefit ▁or ▁harm ; ▁certainty ▁in ▁risk ▁of ▁b acter ial ▁or ▁fun gal ▁infections ▁was ▁r ated ▁as ▁low ▁due ▁to ▁similar ▁concerns ▁regarding ▁serious ▁risk ▁of ▁bias ▁and ▁serious ▁imprecision .
▁Certainty ▁in ▁evidence ▁was ▁r ated ▁as ▁moderate ▁when ▁comparing ▁the ▁effect ▁on ▁mortality ▁between ▁to cil iz um ab ▁and ▁s ar il um ab ▁due ▁to ▁issues ▁with ▁imprecision .
▁Values ▁and ▁preferences ▁- ▁App lying ▁the ▁agreed ▁values ▁and ▁preferences , ▁the ▁majority ▁of ▁the ▁GDG ▁inf er red ▁that ▁almost ▁all ▁well - in formed ▁patients ▁would ▁want ▁to ▁receive ▁I L -6 ▁recept or ▁block ers .
▁The ▁benefit ▁of ▁I L -6 ▁recept or ▁block ers ▁on ▁mortality ▁was ▁de em ed ▁of ▁critical ▁importance ▁to ▁patients , ▁despite ▁the ▁very ▁low ▁certainty ▁around ▁serious ▁adverse ▁events .
▁C urrent ly , ▁access ▁to ▁these ▁drugs ▁is ▁challeng ing ▁in ▁many ▁parts ▁of ▁the ▁world , ▁and ▁without ▁conc er ted ▁effort ▁is ▁likely ▁to ▁remain ▁so , ▁especially ▁in ▁resource - p oor ▁areas .
▁It ▁is ▁therefore ▁possible ▁that ▁this ▁strong ▁recommendation ▁for ▁I L -6 ▁recept or ▁block ers ▁could ▁ex acer b ate ▁health ▁inequ ity .
▁At ▁a ▁time ▁of ▁drug ▁short age , ▁it ▁may ▁be ▁necessary ▁to ▁prior it ize ▁use ▁of ▁I L -6 ▁recept or ▁block ade ▁through ▁clinical ▁tri age .
▁Many ▁j ur is d ict ions ▁have ▁suggested ▁mechanism s ▁for ▁tri aging ▁the ▁use ▁of ▁these ▁treat ments .
▁These ▁include ▁prior it izing ▁patients ▁with ▁the ▁highest ▁bas eline ▁risk ▁for ▁mortality ▁( e . g . ▁those ▁with ▁critical ▁disease ▁over ▁those ▁with ▁severe ▁disease ), ▁in ▁whom ▁the ▁absolute ▁benefit ▁of ▁treatment ▁is ▁therefore ▁greatest .
▁I L -6 ▁recept or ▁block ers ▁are ▁relatively ▁easy ▁to ▁admin ister ▁and ▁only ▁require ▁one , ▁or ▁at ▁most , ▁two ▁doses .
▁Justification ▁- ▁When ▁moving ▁from ▁evidence ▁to ▁the ▁strong ▁recommendation ▁to ▁use ▁I L -6 ▁recept or ▁block ers ▁( t oc il iz um ab ▁or ▁s ar il um ab ) ▁in ▁patients ▁with ▁severe ▁or ▁critical ▁COVID -19, ▁the ▁GDG ▁emphasized ▁the ▁high ▁certainty ▁evidence ▁of ▁improved ▁surv ival ▁and ▁reduction ▁in ▁need ▁for ▁mechanical ▁ventilation .
▁Additional ▁trial ▁data ▁from ▁R E M AP - C AP ▁( see ▁Research ▁evidence ▁section ) ▁provided ▁more ▁conc l usive ▁evidence ▁regarding ▁the ▁equival ence ▁of ▁to cil iz um ab ▁and ▁s ar il um ab .
▁The ▁GDG ▁ac know led ged ▁the ▁uncertain ▁data ▁regarding ▁SA Es ▁and ▁b acter ial ▁infections , ▁but ▁felt ▁that ▁the ▁evidence ▁of ▁benefit ▁for ▁the ▁two ▁most ▁important ▁patient ▁outcomes ▁war r anted ▁a ▁strong ▁recommendation .
▁Cost s ▁and ▁access ▁were ▁important ▁considerations ▁and ▁it ▁was ▁recognized ▁that ▁this ▁recommendation ▁could ▁ex acer b ate ▁health ▁inequ ities .
▁H ope fully ▁this ▁strong ▁recommendation ▁will ▁provide ▁imp et us ▁to ▁address ▁these ▁concerns ▁and ▁ensure ▁access ▁across ▁regions ▁and ▁countries .
▁Sub group ▁analyses ▁- ▁The ▁GDG ▁did ▁not ▁find ▁any ▁evidence ▁of ▁a ▁subgroup ▁effect ▁across ▁patients ▁with ▁different ▁levels ▁of ▁disease ▁severity ▁( severe ▁vs ▁critical ), ▁or ▁by ▁I L -6 ▁recept or ▁block er ▁drug ▁( t oc il iz um ab ▁vs ▁s ar il um ab ).
▁There ▁was ▁insufficient ▁data ▁to ▁assess ▁subgroup ▁effect ▁by ▁ele v ation ▁of ▁infl amm atory ▁mark ers ▁or ▁age .
▁Although ▁the ▁GDG ▁considered ▁a ▁subgroup ▁analysis ▁of ▁patients ▁receiving ▁corticosteroids ▁at ▁bas eline ▁as ▁compared ▁with ▁those ▁that ▁were ▁not , ▁the ▁panel ▁did ▁not ▁see ▁a ▁need ▁to ▁consider ▁subgroup ▁recommendations ▁for ▁I L -6 ▁recept or ▁block ers ▁in ▁those ▁not ▁receiving ▁corticosteroids ▁as ▁all ▁severe ▁and ▁critical ▁COVID -19 ▁patients ▁should ▁be ▁receiving ▁corticosteroids ▁( see ▁previous ▁strong ▁recommendation ▁below ).
▁T aken ▁together , ▁the ▁GDG ▁felt ▁that ▁the ▁recommendation ▁app lies ▁to ▁both ▁to cil iz um ab ▁and ▁s ar il um ab ▁and ▁all ▁adult ▁patients ▁with ▁severe ▁or ▁critical ▁COVID -19.
▁The ▁role ▁of ▁I L -6 ▁recept or ▁block ers ▁and ▁bar ic it inib ▁the ▁GDG ▁had ▁previously ▁made ▁a ▁strong ▁recommendation ▁for ▁use ▁of ▁bar ic it inib ▁or ▁I L -6 ▁recept or ▁block ers ▁( t oc il iz um ab ▁and ▁s ar il um ab ) ▁or ▁bar ic it inib ▁as ▁alternative ▁ag ents ▁administered ▁in ▁addition ▁to ▁corticosteroids ▁for ▁patients ▁with ▁severe ▁or ▁critical ▁COVID -19.
▁The ▁R EC O V ER Y ▁trial ▁has ▁now ▁provided ▁this ▁evidence ▁that ▁comb ining ▁corticosteroids , ▁I L -6 ▁recept or ▁block ers ▁and ▁bar ic it inib ▁provides ▁increment al ▁surv ival ▁benefit ▁.
▁However , ▁since ▁the ▁drugs ▁have ▁not ▁under g one ▁direct ▁compar isons , ▁if ▁this ▁situation ▁ar ises , ▁the ▁GDG ▁felt ▁that ▁clinic ians ▁should ▁choose ▁between ▁bar ic it inib ▁and ▁I L -6 ▁recept or ▁block ers ▁on ▁the ▁basis ▁of ▁experience ▁and ▁comfort ▁using ▁the ▁drugs ; ▁local ▁institution al ▁policies ; ▁route ▁of ▁administration ▁( bar ic it inib ▁is ▁oral ; ▁I L -6 ▁recept or ▁block ers ▁are ▁intra ven ous ); ▁and ▁cost .
▁However , ▁since ▁the ▁drugs ▁have ▁not ▁under g one ▁direct ▁compar isons , ▁if ▁this ▁situation ▁ar ises , ▁the ▁GDG ▁felt ▁that ▁clinic ians ▁should ▁choose ▁between ▁bar ic it inib ▁and ▁I L -6 ▁recept or ▁block ers ▁on ▁the ▁basis ▁of ▁experience ▁and ▁comfort ▁using ▁the ▁drugs ; ▁local ▁institution al ▁policies ; ▁route ▁of ▁administration ▁( bar ic it inib ▁is ▁oral ; ▁I L -6 ▁recept or ▁block ers ▁are ▁intra ven ous ); ▁and ▁cost .
▁App lic ability : ▁None ▁of ▁the ▁included ▁RCTs ▁enrolled ▁children , ▁and ▁therefore ▁the ▁applic ability ▁of ▁this ▁recommendation ▁to ▁children ▁is ▁currently ▁uncertain .
▁However , ▁the ▁GDG ▁had ▁no ▁reason ▁to ▁think ▁that ▁children ▁with ▁COVID -19 ▁would ▁respond ▁any ▁differently ▁to ▁treatment ▁with ▁I L -6 ▁recept or ▁block ers .
▁Sar il um ab ▁is ▁not ▁approved ▁in ▁children , ▁so ▁if ▁an ▁I L ▁- 6 ▁recept or ▁block er ▁is ▁used ▁in ▁this ▁population , ▁to cil iz um ab ▁is ▁prefer red .
▁The ▁GDG ▁also ▁recognized ▁that ▁in ▁many ▁settings ▁children ▁are ▁common ly ▁admitted ▁to ▁hospital ▁with ▁acute ▁respiratory ▁illness es ▁caused ▁by ▁other ▁path og ens ; ▁as ▁a ▁result , ▁it ▁may ▁be ▁challeng ing ▁to ▁determine ▁who ▁is ▁ill ▁with ▁severe ▁COVID -19, ▁even ▁with ▁a ▁positive ▁test , ▁and ▁therefore ▁likely ▁to ▁benefit ▁from ▁I L -6 ▁recept or ▁block ade .
▁There ▁were ▁similar ▁considerations ▁in ▁regard ▁to ▁pregnant ▁women , ▁with ▁no ▁data ▁directly ▁exam ining ▁this ▁population , ▁but ▁no ▁rational e ▁to ▁suggest ▁they ▁would ▁respond ▁differently ▁than ▁other ▁adults .
▁The ▁drug ▁may , ▁however , ▁cross ▁the ▁pl ac ental ▁mem br ane , ▁although ▁it ▁is ▁uncertain ▁what ▁effect ▁trans ient ▁immun os u pp ression ▁in ▁the ▁f et us ▁may ▁have ▁and ▁this ▁should ▁be ▁we ighed ▁against ▁the ▁potential ▁benefit ▁for ▁the ▁mother .
▁Most ▁of ▁the ▁data ▁on ▁inter le uk in -6 ▁recept or ▁block ers ▁comes ▁from ▁trials ▁that ▁were ▁un b l ind ed .
▁The ▁cred ible ▁interval ▁includes ▁small ▁but ▁important ▁harm .
▁The ▁trials ▁that ▁studied ▁inter le uk in -6 ▁recept or ▁block ers ▁had ▁disc rep ant ▁results : ▁some ▁increased ▁length ▁of ▁stay , ▁and ▁others ▁reduced ▁length ▁of ▁stay .
▁The ▁L N MA ▁on ▁I L -6 ▁recept or ▁block ers ▁was ▁informed ▁by ▁30 ▁RCTs ▁with ▁10 ▁6 18 ▁participants ▁and ▁provided ▁relative ▁estimates ▁of ▁effect ▁for ▁all ▁patient - im port ant ▁outcomes ▁except ▁mortality , ▁which ▁came ▁from ▁the ▁prospect ive ▁met a - an alysis ▁( P MA ).
▁Of ▁the ▁trials ▁included ▁in ▁the ▁L N MA , ▁all ▁were ▁registered ▁and ▁examined ▁patients ▁with ▁severe ▁or ▁critical ▁illness ▁related ▁to ▁COVID -19 ▁( t rial ▁characteristics ▁table ▁available ▁upon ▁request ).
▁Of ▁the ▁trials , ▁37 % ▁were ▁published ▁in ▁pe er ▁reviewed ▁jour n als , ▁3 % ▁were ▁available ▁as ▁prep r int s ▁and ▁60 % ▁were ▁completed ▁but ▁unpublished .
▁The ▁evidence ▁summary ▁for ▁mortality ▁was ▁based ▁on ▁27 ▁RCTs ▁and ▁10 ▁9 30 ▁participants ▁from ▁the ▁P MA ▁.
▁We ▁used ▁the ▁P MA ▁for ▁mortality ▁as ▁it ▁included ▁some ▁additional ▁unpublished ▁data ▁that ▁reported ▁on ▁this ▁outcome .
▁The ▁GDG ▁recognized ▁that ▁usual ▁care ▁is ▁likely ▁variable ▁between ▁centres ▁and ▁regions , ▁and ▁has ▁ev olved ▁over ▁time .
▁However , ▁given ▁all ▁of ▁the ▁data ▁come ▁from ▁RCTs , ▁use ▁of ▁these ▁co - inter ventions ▁that ▁comp r ise ▁usual ▁care ▁would ▁be ▁expected ▁to ▁be ▁bal anced ▁between ▁study ▁patients ▁randomized ▁to ▁either ▁the ▁intervention ▁or ▁usual ▁care ▁arms .
▁The ▁GRADE ▁Summary ▁of ▁F ind ings ▁table ▁shows ▁the ▁relative ▁and ▁absolute ▁effects ▁of ▁I L -6 ▁recept or ▁block ers ▁compared ▁with ▁usual ▁care ▁for ▁the ▁outcomes ▁of ▁interest ▁in ▁patients ▁with ▁severe ▁and ▁critical ▁COVID -19, ▁with ▁certainty ▁r at ings .
▁The ▁GDG ▁requested ▁subgroup ▁analyses ▁based ▁on ▁age ▁( < ▁70 ▁years ▁versus ▁older ), ▁disease ▁severity ▁( severe ▁versus ▁critical ), ▁levels ▁of ▁infl amm atory ▁mark ers ▁and ▁bas eline ▁corticostero id ▁use ▁for ▁the ▁following ▁outcomes : ▁mortality , ne ed ▁for ▁and ▁duration ▁of ▁mechanical ▁ventilation , ▁duration ▁of ▁hospitalization , ▁and ▁risks ▁of ▁SA Es ▁and ▁b acter ial ▁infections .
▁B ased ▁on ▁subgroup ▁analyses , ▁the ▁GDG ▁determined ▁that ▁there ▁was ▁no ▁subgroup ▁effect ▁across ▁any ▁pre - spec ified ▁outcomes ▁of ▁interest ▁based ▁on ▁disease ▁severity .
▁The ▁GDG ▁considered ▁the ▁results ▁of ▁a ▁subgroup ▁analysis ▁of ▁all ▁included ▁RCTs ▁based ▁on ▁system ic ▁corticostero id ▁use ▁for ▁the ▁outcome ▁of ▁mortality .
▁The ▁analysis ▁suggested ▁that ▁the ▁relative ▁effects ▁of ▁I L -6 ▁recept or ▁block ers ▁var ied ▁as ▁a ▁function ▁of ▁the ▁use ▁of ▁system ic ▁corticosteroids ▁at ▁bas eline .
▁C ru cial ly , ▁st ero ids ▁did ▁not ▁abol ish ▁and ▁may ▁even ▁enhance ▁the ▁benef icial ▁effect ▁of ▁I L -6 ▁recept or ▁block ers ▁on ▁mortality .
▁For ▁reasons ▁described ▁below , ▁the ▁GDG ▁did ▁not ▁form ally ▁evalu ate ▁the ▁cred ibility ▁of ▁this ▁subgroup ▁analysis .
▁When ▁comparing ▁to cil iz um ab ▁and ▁s ar il um ab , ▁based ▁on ▁the ▁P MA , ▁there ▁was ▁no ▁evidence ▁of ▁a ▁subgroup ▁effect ▁.
▁However , ▁there ▁were ▁more ▁data , ▁and ▁therefore ▁greater ▁prec ision , ▁for ▁to cil iz um ab + st ero ids ▁versus ▁st ero ids ▁alone ▁( OR 7 7, ▁95% ▁CI ▁0.6 8 ▁– 0 .8 7) ▁as ▁compared ▁with ▁s ar il um ab + st ero ids ▁versus ▁st ero ids ▁alone ▁( OR ▁0.9 2, ▁95% ▁CI ▁0.6 1 ▁– 1 .3 8 ).
▁In ▁addition ▁to ▁these ▁subgroup ▁data , ▁the ▁GDG ▁reviewed ▁head - to - head ▁data ▁from ▁R E M AP - C AP ▁investig ators ▁which ▁demonst rated ▁no ▁difference ▁between ▁to cil iz um ab ▁as ▁compared ▁with ▁s ar il um ab ▁in ▁a ▁population ▁of ▁patients ▁all ▁receiving ▁corticosteroids ▁( 36 .5% ▁mortality ▁with ▁to cil iz um ab , ▁33 .9% ▁mortality ▁with ▁s ar il um ab ).
▁Bas eline ▁risk ▁for ▁mortality ▁and ▁mechanical ▁ventilation ▁were ▁der ived ▁from ▁the ▁WHO ▁S OL I DA RI T Y ▁trial ▁for ▁patients ▁with ▁severe ▁and ▁critical ▁COVID -19, ▁adjusted ▁for ▁corticosteroids ▁as ▁part ▁of ▁standard ▁of ▁care ▁(16 % ▁bas eline ▁risk ▁x ▁R R ▁0.7 9 ▁for ▁corticosteroids ▁= ▁13 %).
▁The ▁control ▁arm ▁of ▁the ▁WHO ▁S OL I DA RI T Y ▁trial , ▁performed ▁across ▁a ▁wide ▁vari ety ▁of ▁countries ▁and ▁geograph ical ▁regions , ▁was ▁identified ▁by ▁the ▁GDG ▁panel ▁as ▁generally ▁representing ▁the ▁most ▁relevant ▁source ▁of ▁evidence ▁for ▁bas eline ▁risk ▁estimates ▁for ▁mortality ▁and ▁mechanical ▁ventilation ▁for ▁severe ly ▁and ▁crit ically ▁ill ▁patients ▁with ▁COVID -19.
▁We ▁d ow ng r aded ▁for ▁some ▁concerns ▁regarding ▁risk ▁of ▁bias ▁due ▁to ▁lack ▁of ▁blind ing ▁and ▁as c ertain ment ▁bias .
▁We ▁d ow ng r aded ▁due ▁to ▁very ▁wide ▁confidence ▁intervals ▁cross ing ▁the ▁n ull .
▁We ▁d ow ng r aded ▁for ▁some ▁concerns ▁regarding ▁risk ▁of ▁bias ▁due ▁to ▁lack ▁of ▁blind ing .
▁We ▁d ow ng r aded ▁as ▁the ▁lower ▁limit ▁of ▁the ▁confidence ▁interval ▁was ▁close ▁to ▁the ▁n ull .
▁D ow ng r aded ▁due ▁to ▁differences ▁in ▁point ▁estimates ▁and ▁lack ▁of ▁over l ap ▁in ▁confidence ▁intervals .
▁Me chan ism ▁of ▁action ▁I L -6 ▁is ▁a ▁ple iot ro pic ▁cy t ok ine ▁which ▁activ ates ▁and ▁reg ul ates ▁the ▁imm une ▁response ▁to ▁infections .
▁Ele v ated ▁I L -6 ▁concent r ations ▁are ▁associated ▁with ▁severe ▁outcomes ▁in ▁COVID -19, ▁including ▁respiratory ▁failure ▁and ▁death , ▁although ▁the ▁role ▁of ▁I L -6 ▁in ▁disease ▁path og enes is ▁is ▁unclear .
▁T oc il iz um ab ▁and ▁s ar il um ab ▁are ▁mon ocl on al ▁antib odies ▁approved ▁for ▁use ▁in ▁r he um at oid ▁ar th rit is .
▁They ▁ant ag on ize ▁the ▁mem br ane ▁bound ▁and ▁sol ub le ▁forms ▁of ▁the ▁I L -6 ▁recept or ▁( I L -6 R / s I L -6 R ).
▁T oc il iz um ab ▁is ▁approved ▁for ▁intra ven ous ▁use ▁in ▁r he um at oid ▁ar th rit is ▁and ▁s ar il um ab ▁for ▁sub cut ane ous ▁use , ▁although ▁in ▁COVID -19 ▁both ▁have ▁been ▁studied ▁intra ven ously .
▁At ▁the ▁studied ▁doses ▁in ▁COVID -19, ▁both ▁medicines ▁are ▁expected ▁to ▁achieve ▁very ▁high ▁levels ▁of ▁recept or ▁occup ancy ▁based ▁upon ▁studies ▁in ▁r he um at oid ▁ar th rit is .
▁I L -6 ▁recept or ▁block ers ▁are ▁being ▁rep ur p osed ▁in ▁terms ▁of ▁indic ation ▁but ▁not ▁in ▁terms ▁of ▁the ▁primary ▁pharmac ological ▁mechanism ▁of ▁action .
▁E ffic acy ▁in ▁COVID -19 ▁depends ▁upon ▁the ▁importance ▁of ▁I L -6 ▁sign all ing ▁in ▁the ▁path oph ys i ology ▁of ▁the ▁disease , ▁rather ▁than ▁upon ▁whether ▁the ▁doses ▁used ▁achieve ▁target ▁concent r ations .
▁It ▁followed ▁the ▁increased ▁international ▁attention ▁on ▁ivermectin ▁as ▁a ▁potential ▁therapeutic ▁option .
▁No ▁changes ▁were ▁made ▁to ▁the ▁ivermectin ▁recommendation ▁in ▁this ▁13 th ▁version ▁of ▁the ▁guideline .
▁We ▁are ▁aware ▁of ▁a ▁few ▁relatively ▁small ▁trials ▁published ▁since ▁our ▁recommendation ▁was ▁made ▁and ▁that ▁one ▁key ▁trial ▁has ▁since ▁been ▁ret ra cted ▁given ▁concerns ▁about ▁research ▁fraud .
▁However , ▁the ▁updated ▁evidence ▁summary ▁from ▁the ▁L N MA ▁is ▁consist ent ▁with ▁our ▁previously ▁made ▁recommendation .
▁Rem ark : ▁This ▁recommendation ▁app lies ▁to ▁patients ▁with ▁any ▁disease ▁severity ▁and ▁any ▁duration ▁of ▁symptoms .
▁A ▁recommendation ▁to ▁only ▁use ▁a ▁drug ▁in ▁the ▁setting ▁of ▁clinical ▁trials ▁is ▁appropriate ▁when ▁there ▁is ▁very ▁low ▁certainty ▁evidence ▁and ▁future ▁research ▁has ▁a ▁large ▁potential ▁for ▁reducing ▁uncertainty ▁about ▁the ▁effects ▁of ▁the ▁intervention ▁and ▁for ▁doing ▁so ▁at ▁a ▁reason able ▁cost .
▁Practical ▁Inf o ▁- ▁The ▁GDG ▁made ▁a ▁recommendation ▁against ▁using ▁ivermectin ▁for ▁treatment ▁of ▁patients ▁with ▁COVID -19 ▁outside ▁the ▁setting ▁of ▁a ▁clinical ▁trial ▁and ▁therefore ▁practical ▁considerations ▁are ▁less ▁relevant ▁for ▁this ▁drug .
▁Evidence ▁To ▁Dec ision ▁- ▁Benef its ▁and ▁harms : ▁The ▁effects ▁of ▁ivermectin ▁on ▁mortality , ▁mechanical ▁ventilation , ▁hospital ▁admission , ▁duration ▁of ▁hospitalization ▁and ▁viral ▁clear ance ▁remain ▁uncertain ▁because ▁of ▁very ▁low ▁certainty ▁of ▁evidence ▁address ing ▁each ▁of ▁these ▁outcomes .
▁I ver mectin ▁may ▁have ▁little ▁or ▁no ▁effect ▁on ▁time ▁to ▁clinical ▁improvement ▁( low ▁certainty ▁evidence ).
▁I ver mectin ▁may ▁increase ▁the ▁risk ▁of ▁SA Es ▁leading ▁to ▁drug ▁discontin uation ▁( low ▁certainty ▁evidence ).
▁Sub group ▁analyses ▁indicated ▁no ▁effect ▁mod ification ▁based ▁on ▁dose .
▁We ▁were ▁unable ▁to ▁exam ine ▁subgroup s ▁based ▁on ▁patient ▁age ▁or ▁severity ▁of ▁illness ▁due ▁to ▁insufficient ▁trial ▁data ▁( see ▁Research ▁evidence ).
▁Therefore , ▁we ▁assum ed ▁similar ▁effects ▁in ▁all ▁subgroup s .
▁Certainty ▁of ▁the ▁evidence ▁for ▁most ▁key ▁outcomes , ▁including ▁mortality , ▁mechanical ▁ventilation , ▁hospital ▁admission , ▁duration ▁of ▁hospitalization ▁and ▁viral ▁clear ance , ▁the ▁GDG ▁considered ▁the ▁evidence ▁of ▁very ▁low ▁certainty .
▁Evidence ▁was ▁r ated ▁as ▁very ▁low ▁certainty ▁primarily ▁because ▁of ▁very ▁serious ▁imprecision ▁for ▁most ▁outcomes : ▁the ▁ag g reg ate ▁data ▁had ▁wide ▁confidence ▁intervals ▁and / or ▁very ▁few ▁events .
▁There ▁were ▁also ▁serious ▁concerns ▁related ▁to ▁the ▁risk ▁of ▁bias ▁for ▁some ▁outcomes , ▁spec if ically ▁lack ▁of ▁blind ing , ▁lack ▁of ▁trial ▁pre - reg istr ation , ▁and ▁lack ▁of ▁outcome ▁reporting ▁for ▁one ▁trial ▁that ▁did ▁not ▁report ▁mechanical ▁ventilation ▁despite ▁pre - spec ifying ▁it ▁in ▁their ▁protoc ol ▁( p ublic ation ▁bias ).
▁For ▁more ▁det ails , ▁see ▁the ▁Justification ▁section ▁for ▁this ▁recommendation .
▁For ▁other ▁outcomes , ▁including ▁SA Es ▁and ▁time ▁to ▁clinical ▁improvement , ▁the ▁certainty ▁of ▁the ▁evidence ▁was ▁low .
▁The ▁panel ▁ant icip ated ▁little ▁vari ation ▁in ▁values ▁and ▁preferences ▁between ▁patients , ▁when ▁it ▁came ▁to ▁this ▁intervention .
▁Resources ▁and ▁Other ▁Consider ations : ▁I ver mectin ▁is ▁a ▁relatively ▁in exp ensive ▁drug ▁and ▁is ▁widely ▁available , ▁including ▁in ▁low - in come ▁settings .
▁The ▁low ▁cost ▁and ▁wide ▁availability ▁do ▁not , ▁in ▁the ▁GDG ' s ▁view , ▁mand ate ▁the ▁use ▁of ▁a ▁drug ▁in ▁which , ▁any ▁benefit ▁remains ▁very ▁uncertain ▁and ▁ongoing ▁concerns ▁regarding ▁harms ▁remain .
▁Although ▁the ▁cost ▁may ▁be ▁low ▁per ▁patient , ▁the ▁GDG ▁raised ▁concerns ▁about ▁d iver ting ▁attention ▁and ▁resources ▁away ▁from ▁care , ▁likely ▁to ▁provide ▁a ▁benefit ▁such ▁as ▁corticosteroids ▁in ▁patients ▁with ▁severe ▁COVID -19 ▁and ▁other ▁support ive ▁care ▁interventions .
▁Also , ▁the ▁use ▁of ▁ivermectin ▁for ▁COVID -19 ▁would ▁d iver t ▁drug ▁supply ▁away ▁from ▁path olog ies ▁for ▁which ▁it ▁is ▁clearly ▁indicated , ▁potential ly ▁contrib uting ▁to ▁drug ▁short ages , ▁especially ▁for ▁hel min th ▁control ▁and ▁el imination ▁programmes .
▁Other ▁endemic ▁infections ▁that ▁may ▁wor s en ▁with ▁corticosteroids ▁should ▁be ▁considered .
▁If ▁st ero ids ▁are ▁used ▁in ▁the ▁treatment ▁of ▁COVID -19, ▁emp ir ic ▁treatment ▁with ▁ivermectin ▁may ▁still ▁be ▁considered ▁in ▁St r ong y lo id ias is ▁endemic ▁areas , ▁at ▁the ▁disc ret ion ▁of ▁clinic ians ▁over see ing ▁treatment , ▁al be it ▁not ▁for ▁treatment ▁of ▁COVID -19 ▁itself .
▁Justification : ▁When ▁moving ▁from ▁evidence ▁to ▁a ▁recommendation ▁on ▁the ▁use ▁of ▁ivermectin ▁in ▁patients ▁with ▁COVID -19, ▁only ▁in ▁the ▁context ▁of ▁a ▁clinical ▁trial , ▁the ▁GDG ▁emphasized ▁the ▁high ▁degree ▁of ▁uncertainty ▁in ▁the ▁most ▁critical ▁outcomes ▁such ▁as ▁mortality ▁and ▁the ▁need ▁for ▁mechanical ▁ventilation .
▁It ▁also ▁noted ▁the ▁evidence ▁suggesting ▁possible ▁harm ▁associated ▁with ▁treatment , ▁with ▁increased ▁adverse ▁events .
▁The ▁GDG ▁did ▁not ▁ant icip ate ▁important ▁variability ▁in ▁patient ▁values ▁and ▁preferences .
▁Comp ared ▁with ▁previous ▁drugs ▁evaluated ▁as ▁part ▁of ▁the ▁WHO ▁The rapeut ics ▁and ▁COVID -19 : ▁living ▁guideline , ▁currently , ▁there ▁are ▁far ▁fewer ▁RCT ▁data ▁available ▁for ▁ivermectin .
▁The ▁existing ▁data ▁on ▁ivermectin ▁also ▁have ▁a ▁substant ially ▁higher ▁degree ▁of ▁uncertainty , ▁with ▁included ▁trials ▁having ▁enrolled ▁substant ially ▁fewer ▁patients ▁with ▁far ▁fewer ▁events .
▁Although ▁16 ▁RCTs ▁contrib uted ▁to ▁the ▁evidence ▁summary ▁inform ing ▁this ▁drug , ▁only ▁five ▁directly ▁compared ▁ivermectin ▁with ▁the ▁standard ▁of ▁care ▁and ▁reported ▁mortality .
▁Of ▁these ▁five ▁RCTs , ▁two ▁were ▁at ▁high ▁risk ▁of ▁bias , ▁due ▁to ▁in ade qu ate ▁blind ing .
▁One ▁of ▁these ▁two ▁trials ▁also ▁started ▁en ro lling ▁and ▁random izing ▁patients ▁prior ▁to ▁the ▁protoc ol ▁being ▁public ly ▁post ed , ▁another ▁factor ▁that ▁contrib utes ▁to ▁an ▁increased ▁risk ▁of ▁bias .
▁The ▁potential ▁impact ▁of ▁risk ▁of ▁bias ▁is ▁ex em pl ified ▁by ▁subgroup ▁analyses ▁for ▁mortality ▁based ▁on ▁trial ▁risk ▁of ▁bias .
▁As ▁demonst rated ▁in ▁the ▁forest ▁plot , ▁the ▁po ol ed ▁estimate ▁across ▁all ▁five ▁RCTs ▁that ▁directly ▁compare ▁ivermectin ▁with ▁standard ▁care ▁suggests ▁a ▁reduction ▁in ▁mortality ▁with ▁ivermectin , ▁but ▁this ▁effect ▁is ▁not ▁apparent ▁if ▁we ▁only ▁consider ▁the ▁trials ▁at ▁low ▁risk ▁of ▁bias ▁( which ▁together ▁contrib ute ▁nearly ▁two - th ird s ▁of ▁the ▁evidence ).
▁This ▁finding ▁increases ▁the ▁degree ▁of ▁uncertainty ▁regarding ▁the ▁true ▁effect ▁of ▁ivermectin ▁on ▁mortality .
▁Cons ist ent ▁with ▁the ▁direct ▁evidence , ▁a ▁similar ▁p hen omen on ▁is ▁observed ▁with ▁the ▁indirect ▁evidence ▁comparing ▁ivermectin ▁to ▁the ▁standard ▁of ▁care ▁( v ia ▁compar isons ▁against ▁hy dro x y ch lor o qu ine ▁and ▁l op in avir / ritonavir ).
▁The ▁indirect ▁evidence ▁suggesting ▁a ▁reduction ▁in ▁mortality ▁with ▁ivermectin ▁is ▁dri ven ▁almost ▁entire ly ▁by ▁one ▁study ▁which ▁is ▁at ▁high ▁risk ▁of ▁bias ▁due ▁to ▁a ▁lack ▁of ▁detailed ▁des cript ion ▁of ▁blind ing ▁or ▁random ization ▁and ▁the ▁lack ▁of ▁a ▁public ly ▁available ▁study ▁protoc ol .
▁Fore st ▁plot ▁demonst r ating ▁a ▁direct ▁comparison ▁of ▁ivermectin ▁versus ▁standard ▁of ▁care ▁for ▁mortality ▁with ▁subgroup ▁analysis ▁by ▁risk ▁of ▁bias ▁IV : ▁in verse ▁vari ance .
▁In ▁addition ▁to ▁concerns ▁related ▁to ▁the ▁risk ▁of ▁bias , ▁for ▁the ▁outcome ▁of ▁mortality , ▁there ▁are ▁very ▁serious ▁concerns ▁related ▁to ▁imprecision .
▁According ▁to ▁GRADE , ▁imprecision ▁is ▁evaluated ▁based ▁on ▁both ▁a ▁confidence ▁interval ▁approach ▁and ▁an ▁evaluation ▁of ▁information ▁size ▁( e vent ▁number ), ▁ensuring ▁there ▁is ▁adequate ▁information ▁on ▁which ▁to ▁make ▁informed ▁judgments .
▁In ▁this ▁case , ▁despite ▁confidence ▁intervals ▁that ▁suggest ▁benefit ▁with ▁ivermectin , ▁the ▁information ▁size ▁is ▁very ▁low .
▁For ▁mortality ▁( and ▁ign oring ▁the ▁concerns ▁related ▁to ▁risk ▁of ▁bias ▁discussed ▁above ), ▁there ▁were ▁nine ▁deaths ▁across ▁all ▁5 11 ▁patients ▁randomized ▁to ivermectin ▁(1 .76 %) ▁and ▁22 ▁deaths ▁across ▁all ▁40 4 ▁patients ▁randomized ▁to ▁standard ▁of ▁care ▁(5 .4 5 %).
▁This ▁is ▁an ▁extremely ▁small ▁number ▁of ▁events ▁on ▁which ▁to ▁base ▁conc l usions , ▁and ▁far ▁below ▁the ▁opt imal ▁information ▁size .
▁In ▁fact , ▁perform ing ▁a ▁the ore tical ▁exerc ise ▁in ▁which ▁a ▁change ▁of ▁three ▁events ▁( de ath s ) ▁is ▁made ▁from ▁those ▁randomized ▁to ▁standard ▁of ▁care ▁to ▁those ▁randomized ▁to ▁ivermectin ▁elimin ates ▁any ▁stat istical ▁sign ific ance , ▁a ▁finding ▁that ▁suggests ▁that ▁results ▁could ▁reason ably ▁be ▁due ▁to ▁chance ▁alone .
▁Furthermore , ▁the ▁evidence ▁inform ing ▁this ▁comparison ▁is ▁from ▁multiple ▁small ▁trials , ▁adding ▁to ▁the ▁risk ▁of ▁un rec ogn ized ▁im bal ances ▁in ▁study ▁arms .
▁Given ▁the ▁strong ▁lik eli hood ▁that ▁chance ▁may ▁be ▁playing ▁a ▁role ▁in ▁the ▁observed ▁findings , ▁the ▁panel ▁believed ▁there ▁was ▁very ▁serious ▁imprecision ▁further ▁lower ing ▁the ▁overall ▁certainty ▁in ▁findings .
▁This ▁combination ▁of ▁serious ▁risk ▁of ▁bias ▁and ▁very ▁serious ▁imprecision ▁contrib uted ▁to ▁very ▁low ▁certainty ▁of ▁the ▁evidence ▁for ▁mortality ▁despite ▁a ▁point ▁estimate ▁and ▁confidence ▁interval ▁that ▁appear ▁to ▁suggest ▁benefit ▁with ▁ivermectin .
▁As ▁a ▁result , ▁the ▁panel ▁concluded ▁that ▁the ▁effect ▁of ▁ivermectin ▁on ▁mortality ▁is ▁uncertain .
▁Sim ilar ▁considerations ▁were ▁applied ▁to ▁the ▁other ▁critical ▁outcomes ▁including ▁mechanical ▁ventilation , ▁hospital ▁admission , ▁and ▁duration ▁of ▁hospitalization ▁and ▁result ed ▁in ▁very ▁low ▁certainty ▁for ▁these ▁outcomes ▁as ▁well .
▁Sub group ▁An alys es : ▁We ▁conducted ▁subgroup ▁analysis ▁only ▁for ▁the ▁effect ▁of ▁the ▁ivermectin ▁dose ▁and ▁the ▁panel ▁did ▁not ▁find ▁any ▁evidence ▁of ▁a ▁subgroup ▁effect ▁( see ▁Research ▁Evidence ).
▁A ▁lack ▁of ▁within - t rial ▁compar isons ▁prevent ed ▁subgroup ▁analyses , ▁by ▁age ▁or ▁disease ▁severity .
▁Therefore , ▁the ▁panel ▁did ▁not ▁make ▁any ▁subgroup ▁recommendation ▁for ▁this ▁drug .
▁In ▁other ▁words , ▁the ▁recommendation ▁against ▁ivermectin , ▁except ▁in ▁the ▁context ▁of ▁clinical ▁trials , ▁is ▁applic able ▁across ▁disease ▁severity , ▁age ▁groups , ▁and ▁all ▁dose ▁reg imens ▁of ▁ivermectin .
▁App lic ability : ▁None ▁of ▁the ▁included ▁RCTs ▁enrolled ▁children ▁under ▁15, ▁and ▁therefore , ▁the ▁applic ability ▁of ▁this ▁recommendation ▁to ▁children ▁is ▁currently ▁uncertain .
▁However , ▁the ▁panel ▁had ▁no ▁reason ▁to ▁think ▁that ▁children ▁with ▁COVID -19 ▁would ▁respond ▁any ▁differently ▁to ▁treatment ▁with ▁ivermectin .
▁There ▁were ▁similar ▁considerations ▁for ▁pregnant ▁women , ▁with ▁no ▁data ▁directly ▁exam ining ▁this ▁population , ▁but ▁no ▁rational e ▁to ▁suggest ▁they ▁would ▁respond ▁differently ▁to ▁other ▁adults .
▁Summary : ▁Evidence ▁Summary : ▁The ▁L N MA ▁on ▁ivermectin ▁was ▁based ▁on ▁16 ▁RCTs ▁and ▁2, 40 7 ▁participants .
▁Of ▁the ▁included ▁studies , ▁75 % ▁examined ▁patients ▁with ▁non ▁severe ▁disease ▁and ▁25% ▁included ▁both ▁severe ▁and ▁non - severe ▁patients .
▁A ▁number ▁of ▁the ▁included ▁studies ▁did ▁not ▁report ▁on ▁our ▁outcomes ▁of ▁interest .
▁Of ▁the ▁studies , ▁25% ▁were ▁published ▁in ▁pe er - re view ed ▁jour n als , ▁44 % ▁were ▁available ▁as ▁prep r int s ▁and ▁31 % ▁were ▁completed ▁but ▁unpublished ▁( see ▁Table ▁on ▁T rial ▁Char acter istics ).
▁We ▁exclud ed ▁a ▁number ▁of ▁qu as i - R CT s .
▁The ▁GRADE ▁Summary ▁of ▁F ind ings ▁table ▁shows ▁the ▁relative ▁and ▁absolute ▁effects ▁of ▁ivermectin ▁compared ▁to ▁usual ▁care ▁for ▁the ▁outcomes ▁of ▁interest ▁in ▁patients ▁with ▁COVID -19, ▁with ▁certainty ▁r at ings .
▁Sub group ▁analysis : ▁The ▁N MA ▁team ▁performed ▁subgroup ▁analyses ▁which ▁could ▁result ▁in ▁distinct ▁recommendations ▁by ▁subgroup s .
▁The ▁ivermectin ▁dose ▁subgroup ▁analyses ▁were ▁performed ▁from ▁the ▁direct ▁comparison ▁of ▁ivermectin ▁versus ▁usual ▁care .
▁For ▁these ▁analyses , ▁met a - re gress ion ▁was ▁used ▁to ▁evalu ate ▁the ▁effect ▁of ▁c um ul ative ▁dose ▁as ▁a ▁continuous ▁variable , ▁and ▁further ▁add ▁a ▁co v ari ate ▁for ▁single ▁vs ▁multiple ▁d osing ▁reg imens .
▁This ▁approach ▁was ▁based ▁on ▁in p ut ▁from ▁the ▁pharmac ology ▁experts ▁( led ▁by ▁Professor ▁And rew ▁O w en ) ▁who ▁performed ▁pharmac ok inet ic ▁sim ulations ▁across ▁trial ▁doses , ▁and ▁found ▁that ▁c um ul ative ▁ivermectin ▁dose ▁was ▁expected ▁to ▁cor rel ate ▁with ▁key ▁pharmac ok inet ic ▁par am eters ▁when ▁single - ▁and ▁multiple - d ose ▁studies ▁were ▁se g reg ated .
▁It ▁should ▁be ▁noted ▁that ▁the ▁included ▁trials ▁did ▁not ▁directly ▁assess ▁the ▁pharmac ok inet ics ▁of ▁ivermectin , ▁and ▁our ▁approach ▁was ▁based ▁upon ▁sim ulations ▁val id ated , ▁where ▁possible ▁against ▁published ▁pharmac ok inet ics ▁in ▁hum ans .
▁The ▁panel ▁used ▁a ▁pre - spec ified ▁frame work ▁incor por ating ▁the ▁I C E MA N ▁tool ▁to ▁assess ▁the ▁cred ibility ▁of ▁subgroup ▁findings .
▁The ▁GDG ▁panel ▁requested ▁subgroup ▁analyses ▁based ▁on : ▁age ▁( c ons ider ing ▁children ▁vs ▁younger ▁adults ▁vs ▁older ▁adults ▁[ 70 year s ▁or ▁older ] ); ▁illness ▁severity ▁( non - severe ▁vs ▁severe ▁vs ▁critical ▁COVID -19 ); ▁time ▁from ▁onset ▁of ▁symptoms ; ▁and ▁use ▁of ▁con com it ant ▁medic ations .
▁However , ▁there ▁was ▁insufficient ▁within - t rial ▁data ▁to ▁perform ▁any ▁of ▁these ▁subgroup ▁analyses , ▁based ▁on ▁our ▁pre - spec ified ▁protoc ol .
▁The ▁panel ▁recognized ▁that ▁usual ▁care ▁is ▁likely ▁variable ▁between ▁centres ▁and ▁regions , ▁and ▁has ▁ev olved ▁over ▁time .
▁However , ▁given ▁all ▁of ▁the ▁data ▁come ▁from ▁RCTs , ▁use ▁of ▁these ▁co - inter ventions ▁that ▁comp r ise ▁usual ▁care ▁should ▁be ▁bal anced ▁between ▁study ▁patients ▁randomized ▁to ▁either ▁the ▁intervention ▁or ▁usual ▁care ▁arms .
▁Me chan ism ▁of ▁Action : ▁I ver mectin ▁is ▁an ▁ant ip aras it ic ▁agent ▁that ▁inter fe res ▁with ▁n erve ▁and ▁mus cle ▁function ▁of ▁hel min th s , ▁through ▁b ind ing ▁gl ut am ate - g ated ▁ch lor ide ▁ch ann els .
▁B ased ▁on ▁in ▁v it ro ▁exper im ents , ▁some ▁have ▁post ulated ▁that ▁ivermectin ▁may ▁have ▁a ▁direct ▁ant ivir al ▁effect ▁against ▁SARS - CoV -2 .
▁However , ▁in ▁hum ans , ▁the ▁concent r ations ▁needed ▁for ▁in ▁v it ro ▁in hib ition ▁are ▁unl ike ly ▁to ▁be ▁achieved ▁by ▁the ▁doses ▁proposed ▁for ▁COVID -19.
▁I ver mectin ▁had ▁no ▁impact ▁on ▁SARS - CoV -2 ▁viral ▁R NA ▁in ▁the ▁Sy rian ▁gold en ▁h am ster ▁model ▁of ▁SARS - CoV -2 ▁infection .
▁No ▁direct ▁evidence ▁for ▁any ▁mechanism ▁of ▁ant ivir al ▁action ▁against ▁SARS - CoV -2 ▁currently ▁ex ists .
▁Some ▁have ▁proposed , ▁based ▁pred omin ant ly ▁upon ▁research ▁in ▁other ▁indic ations , ▁that ▁ivermectin ▁has ▁an ▁immun om od ul atory ▁effect , ▁but ▁again , ▁the ▁mechanism ▁remains ▁unclear .
▁H ist or ical ▁data ▁showed ▁that ▁ivermectin ▁improved ▁surv ival ▁in ▁m ice , ▁given ▁a ▁le th al ▁dose ▁of ▁l ip op oly s ac ch ar ide , and ▁has ▁benefits ▁in ▁mur ine ▁models ▁of ▁at op ic ▁d erm at it is ▁and ▁all erg ic ▁ast h ma .
▁For ▁SARS CoV -2 , ▁one ▁hypot hesis ▁suggests ▁immun om od ulation ▁med iated ▁by ▁all ost eric ▁mod ulation ▁of ▁the ▁al ph a -7 ▁n ic ot in ic ▁a ce ty l chol ine ▁recept or ▁( ind irect ly ▁by ▁mod ul ating ▁the ▁activity ▁of ▁l ig and s ▁of ▁the ▁recept or ).
▁Although ▁investig ators ▁have ▁demonst rated ▁this ▁action ▁in ▁v it ro , ▁concent r ations ▁used ▁in ▁these ▁exper im ents ▁have ▁been ▁even ▁higher ▁than ▁those ▁required ▁for ▁an ▁ant ivir al ▁effect , ▁and ▁therefore , ▁very ▁unl ike ly ▁to ▁be ▁achieved ▁in ▁hum ans .
▁In ▁the ▁Sy rian ▁gold en ▁h am ster ▁model ▁of ▁SARS - CoV -2 ▁infection , ▁ivermectin ▁result ed ▁in ▁some ▁changes ▁in ▁p ul mon ary ▁imm une ▁p hen o ▁type , ▁consist ent ▁with ▁all ost eric ▁mod ulation ▁of ▁the ▁al ph a -7 ▁n ic ot in ic ▁a ce ty l chol ine ▁recept or .
▁However , ▁ivermectin ▁did ▁not ▁appear ▁to ▁res c ue ▁body ▁weight ▁loss , ▁which ▁is ▁a ▁hall m ark ▁of ▁disease ▁in ▁this ▁model , ▁and ▁drug ▁concent r ations ▁were ▁not ▁meas ured ▁to ▁ext rap olate ▁to ▁those ▁achieved ▁in ▁hum ans .
▁T aken ▁together , ▁there ▁remains ▁great ▁uncertainty ▁regarding ▁the ▁relevance ▁of ▁any ▁immun om od ul atory ▁or ▁anti - inf lam m atory ▁action ▁of ▁ivermectin .
▁Hy dro x y ch lor o qu ine ▁( published ▁17 ▁December ▁2020 ) ▁Inf o ▁Box ▁The ▁recommendation ▁concerning ▁hy dro x y ch lor o qu ine ▁was ▁published ▁17 ▁December ▁2020 ▁as ▁the ▁third ▁version ▁of ▁the ▁WHO ▁living ▁guideline ▁and ▁in ▁the ▁B M J ▁as ▁R ap id ▁Recommend ations .
▁It ▁followed ▁the ▁pre - pr int ▁public ation ▁of ▁the ▁WHO ▁S OL I DA RI T Y ▁trial ▁on ▁15 ▁October ▁2020 , ▁reporting ▁results ▁on ▁treatment ▁with ▁hy dro x y ch lor o qu ine , ▁remdesivir ▁and ▁l op in avir / ritonavir ▁in ▁hospital ized ▁patients ▁with ▁COVID -19.
▁No ▁changes ▁were ▁made ▁to ▁the ▁hy dro x y ch lor o qu ine ▁recommendation ▁in ▁this ▁13 th ▁version ▁of ▁the ▁guideline .
▁Practical ▁Inf o , ▁The ▁GDG ▁made ▁a ▁strong ▁recommendation ▁against ▁using ▁hy dro x y ch lor o qu ine ▁or ▁ch lor o qu ine ▁for ▁treatment ▁of ▁patients ▁with ▁COVID -19.
▁The ▁use ▁of ▁hy dro x y ch lor o qu ine ▁may ▁prec lud e ▁the ▁use ▁of ▁other ▁important ▁drugs ▁that ▁also ▁pro l ong ▁the ▁Q ▁T ▁interval , ▁such ▁as ▁a z ith rom y c in ▁and ▁flu or o qu in ol ones .
▁Con com it ant ▁use ▁of ▁drugs ▁that ▁pro l ong ▁the ▁Q ▁T ▁interval ▁should ▁be ▁done ▁with ▁ext reme ▁ca ution .
▁Evidence ▁To ▁Dec ision ▁Benef its ▁and ▁harms : ▁Hy dro x y ch lor o qu ine ▁and ▁ch lor o qu ine ▁probably ▁do ▁not ▁reduce ▁mortality ▁or ▁mechanical ▁ventilation ▁and ▁may ▁not ▁reduce ▁duration ▁of ▁hospitalization .
▁The ▁evidence ▁does ▁not ▁exclud e ▁the ▁potential ▁for ▁a ▁small ▁increased ▁risk ▁of ▁death ▁and ▁mechanical ▁ventilation ▁with ▁hy dro x y ch lor o qu ine .
▁The ▁effect ▁on ▁other ▁less ▁important ▁outcomes , ▁including ▁time ▁to ▁sympt om ▁resolution , ▁admission ▁to ▁hospital , ▁and ▁duration ▁of ▁mechanical ▁ventilation , ▁remains ▁uncertain .
▁Hy dro x y ch lor o qu ine ▁may ▁increase ▁the ▁risk ▁of ▁di arr ho e a ▁and ▁n ause a / v om iting ; ▁a ▁finding ▁consist ent ▁with ▁evidence ▁from ▁its ▁use ▁in ▁other ▁conditions .
▁D i arr ho e a ▁and ▁v om iting ▁may ▁increase ▁the ▁risk ▁of ▁hyp ov ola em ia , ▁hypot ension ▁and ▁acute ▁kid ney ▁inj ury , ▁especially ▁in ▁settings ▁where ▁health ▁care ▁resources ▁are ▁limited .
▁Whether ▁or ▁not ▁and ▁to ▁what ▁degree ▁hy dro x y ch lor o qu ine ▁increases ▁the ▁risk ▁of ▁card i ac ▁to xic ity , ▁including ▁life - th reat ening ▁arr h y th m ias , ▁is ▁uncertain .
▁Sub group ▁analyses ▁indicated ▁no ▁effect ▁mod ification ▁based ▁on ▁severity ▁of ▁illness ▁( comp aring ▁either ▁critical ▁vs ▁severe / non - severe ▁or ▁non - severe ▁vs ▁critical / severe ) ▁or ▁age ▁( comp aring ▁those ▁aged ▁< ▁70 ▁years ▁vs ▁older ).
▁Further , ▁the ▁c um ul ative ▁dose ▁and ▁pred ic ted ▁day ▁3 ▁ser um ▁t rough ▁concent r ations ▁did ▁not ▁mod ify ▁the ▁effect ▁for ▁any ▁outcome .
▁We ▁also ▁reviewed ▁evidence ▁comparing ▁the ▁use ▁of ▁hy dro x y ch lor o qu ine ▁plus ▁a z ith rom y c in ▁vs ▁hy dro x y ch lor o qu ine ▁alone .
▁There ▁was ▁no ▁evidence ▁that ▁the ▁addition ▁of ▁a z ith rom y c in ▁mod ified ▁the ▁effect ▁of ▁hy dro x y ch lor o qu ine ▁for ▁any ▁outcome ▁( very ▁low ▁certainty ).
▁Certainty ▁of ▁the ▁evidence ▁for ▁the ▁key ▁outcomes ▁of ▁mortality ▁and ▁mechanical ▁ventilation , ▁the ▁panel ▁considered ▁the ▁evidence ▁to ▁be ▁of ▁moderate ▁certainty .
▁For ▁example , ▁the ▁cred ible ▁interval ▁around ▁the ▁po ol ed ▁effect , ▁leaves ▁open ▁the ▁possibility ▁of ▁a ▁very ▁small ▁reduction ▁in ▁mortality .
▁The ▁quality ▁of ▁evidence ▁was ▁low ▁for ▁di arr ho e a ▁and ▁n ause a / v om iting ▁because ▁of ▁lack ▁of ▁blind ing ▁in ▁many ▁of ▁the ▁trials ▁and ▁because ▁the ▁total ▁number ▁of ▁patients ▁enrolled ▁in ▁trials ▁reporting ▁these ▁outcomes ▁was ▁smaller ▁than ▁the ▁opt imal ▁information ▁size ▁( alth ough ▁the ▁cred ible ▁interval ▁laid ▁entire ly ▁on ▁the ▁side ▁of ▁harm ▁for ▁both ▁outcomes ), ▁for ▁all ▁other ▁outcomes , ▁the ▁certainty ▁of ▁the ▁evidence ▁was ▁low ▁or ▁very ▁low .
▁The ▁primary ▁concerns ▁with ▁the ▁data ▁were ▁imprecision ▁( c red ible ▁intervals ▁included ▁both ▁important ▁benefit ▁and ▁important ▁harm ) ▁as ▁well ▁as ▁risk ▁of ▁bias ▁( l ack ▁of ▁blind ing ).
▁Values ▁and ▁Pre ferences : ▁App lying ▁the ▁agreed ▁values ▁and ▁preferences , ▁the ▁GDG ▁inf er red ▁that ▁almost ▁all ▁well - in formed ▁patients ▁would ▁not ▁want ▁to ▁receive ▁hy dro x y ch lor o qu ine , ▁given ▁the ▁evidence ▁suggesting ▁there ▁was ▁probably ▁no ▁effect ▁on ▁mortality ▁or ▁need ▁for ▁mechanical ▁ventilation ▁and ▁there ▁was ▁a ▁risk ▁of ▁adverse ▁events , ▁including ▁di arr ho e a ▁and ▁n ause a ▁and ▁v om iting .
▁Resources ▁and ▁Other ▁Consider ations : ▁Hy dro x y ch lor o qu ine ▁and ▁ch lor o qu ine ▁are ▁relatively ▁in exp ensive ▁compared ▁with ▁other ▁drugs ▁used ▁for ▁COVID -19 ▁and ▁are ▁already ▁widely ▁available , ▁including ▁in ▁low - in come ▁settings .
▁Despite ▁this , ▁the ▁panel ▁felt ▁that ▁almost ▁all ▁patients ▁would ▁choose ▁not ▁to ▁use ▁hy dro x y ch lor o qu ine ▁or ▁ch lor o qu ine ▁because ▁the ▁harms ▁outwe igh ▁the ▁b ene ▁f its .
▁Justification : ▁When ▁moving ▁from ▁evidence ▁to ▁the ▁strong ▁recommendation ▁against ▁the ▁use ▁of ▁hy dro x y ch lor o qu ine ▁or ▁ch lor o qu ine ▁for ▁patients ▁with ▁COVID -19, ▁the ▁panel ▁emphasized ▁the ▁moderate ▁certainty ▁evidence ▁of ▁probably ▁no ▁reduction ▁in ▁mortality ▁or ▁need ▁for ▁mechanical ▁ventilation .
▁It ▁also ▁noted ▁the ▁evidence ▁suggesting ▁possible ▁harm ▁associated ▁with ▁treatment , ▁with ▁increased ▁n ause a ▁and ▁di arr ho e a .
▁In ▁other ▁words , ▁the ▁strong ▁recommendation ▁is ▁applic able ▁across ▁disease ▁severity , ▁age ▁groups , ▁and ▁all ▁doses ▁and ▁dose ▁sched ules ▁of ▁hy dro x y ch lor o qu ine .
▁The ▁trials ▁included ▁patients ▁from ▁around ▁the ▁world , ▁with ▁all ▁disease ▁sever ities , ▁and ▁tre ated ▁in ▁different ▁settings ▁( out p ati ent ▁and ▁in p ati ent ). ▁Although ▁the ▁trials ▁did ▁not ▁report ▁subgroup ▁effects ▁by ▁time ▁from ▁sympt om ▁onset , ▁many ▁of ▁the ▁trials ▁enrolled ▁patients ▁early ▁in ▁the ▁disease ▁course .
▁The ▁GDG ▁panel ▁therefore ▁felt ▁that ▁the ▁evidence ▁app lies ▁to ▁all ▁patients ▁with ▁COVID -19.
▁App lic ability : ▁Special ▁P op ulations : ▁None ▁of ▁the ▁included ▁RCTs ▁enrolled ▁children , ▁and ▁therefore , ▁the ▁applic ability ▁of ▁this ▁recommendation ▁to ▁children ▁is ▁currently ▁uncertain .
▁However , ▁the ▁panel ▁had ▁no ▁reason ▁to ▁think ▁that ▁children ▁with ▁COVID -19 ▁would ▁respond ▁any ▁differently ▁to ▁treatment ▁with ▁hy dro x y ch lor o qu ine .
▁Hy dro x y ch lor o qu ine ▁cross es ▁the ▁pl ac ental ▁bar ri er ▁and ▁there ▁are ▁concerns ▁that ▁it ▁may ▁lead ▁to ▁ret inal ▁damage ▁in ▁ne on ates .
▁Although ▁hy dro x y ch lor o qu ine ▁has ▁been ▁used ▁in ▁pregnant ▁women ▁with ▁system ic ▁aut o im m une ▁diseases , ▁such ▁as ▁system ic ▁l up us ▁er y t hem at os us , ▁pregnant ▁women ▁may ▁have ▁even ▁more ▁reasons ▁than ▁other ▁patients ▁to ▁be ▁rel uct ant ▁to ▁use ▁hy dro x y ch lor o qu ine ▁for ▁COVID -19.
▁In ▁combination ▁with ▁a z ith rom y c in , ▁there ▁was ▁no ▁evidence ▁from ▁the ▁N MA ▁that ▁the ▁addition ▁of ▁a z ith rom y c in ▁mod ified ▁the ▁effect ▁of ▁hy dro x y ch lor o qu ine ▁for ▁any ▁outcome .
▁As ▁there ▁were ▁no ▁trial ▁data ▁suggesting ▁that ▁a z ith rom y c in ▁fav ou rab ly ▁mod ifies ▁the ▁effect ▁of ▁hy dro x y ch lor o qu ine , ▁the ▁recommendation ▁against ▁hy dro x y ch lor o qu ine ▁and ▁ch lor o qu ine ▁app lies ▁to ▁patients ▁whether ▁or ▁not ▁they ▁are ▁con com it ant ly ▁receiving ▁a z ith rom y c in .
▁The ▁GDG ▁panel ▁felt ▁that ▁it ▁was ▁unl ike ly ▁future ▁studies ▁would ▁identify ▁a ▁subgroup ▁of ▁patients ▁that ▁are ▁likely ▁to ▁benefit ▁from ▁hy dro x y ch lor o qu ine ▁or ▁ch lor o qu ine .
▁The ▁L N MA ▁on ▁hy dro x y ch lor o qu ine ▁was ▁based ▁on ▁30 ▁RCTs ▁with ▁10, 92 1 ▁participants , ▁providing ▁relative ▁estimates ▁of ▁the ▁effect ▁on ▁patient - im port ant ▁outcomes .
▁Five ▁of ▁the ▁trials ▁(4 14 ▁total ▁participants ) ▁randomized ▁some ▁patients ▁to ▁ch lor o qu ine .
▁The ▁GRADE ▁Summary ▁of ▁findings ▁table ▁shows ▁the ▁relative ▁and ▁absolute ▁effects ▁of ▁hy dro x y ch lor o qu ine ▁compared ▁with ▁usual ▁care ▁for ▁the ▁outcomes ▁of ▁interest ▁in ▁patients ▁with ▁COVID -19, ▁with ▁certainty ▁r at ings .
▁Sub group ▁An alysis : ▁For ▁hy dro x y ch lor o qu ine , ▁the ▁GDG ▁panel ▁requested ▁subgroup ▁analyses ▁based ▁on ▁age ▁( c ons ider ing ▁children ▁vs ▁younger ▁adults ▁[ e . g . ▁< ▁70 ▁years ] ▁vs ▁older ▁adults ▁[ e . g . ▁70 ▁years ▁or ▁older ] ), ▁illness ▁severity ▁( non - severe ▁vs ▁severe ▁vs ▁critical ▁COVID -19 ) ▁and ▁based ▁on ▁whether ▁or ▁not ▁it ▁was ▁co - ad min istered ▁with ▁a z ith rom y c in ; ▁the ▁panel ▁also ▁requested ▁a ▁subgroup ▁analysis ▁based ▁on ▁high ▁dose ▁vs ▁low - d ose ▁hy dro x y ch lor o qu ine .
▁A ▁categor ical ▁approach ▁to ▁hy dro x y ch lor o qu ine ▁d osing ▁proved ▁impossible ▁because ▁the ▁trials ▁used ▁vary ing ▁lo ading ▁doses , ▁contin uation ▁doses ▁and ▁dur ations .
▁Therefore , ▁in ▁collaboration ▁with ▁a ▁pharmac ology ▁expert ▁( Pro f essor ▁And rew ▁O w en ), ▁we ▁model ed ▁the ▁expected ▁ser um ▁concent r ations ▁over ▁time .
▁We ▁hypot hes ized ▁that ▁higher ▁t rough ▁concent r ations ▁early ▁in ▁the ▁treatment ▁course ▁( e . g . ▁t rough ▁concent ration ▁on ▁Day ▁3) ▁might ▁be ▁more ▁effective ▁than ▁lower ▁early ▁t rough ▁concent r ations .
▁We ▁also ▁hypot hes ized ▁that ▁higher ▁maximum ▁ser um ▁concent r ations ▁( e . g . ▁pe ak ▁concent ration ▁on ▁the ▁last ▁day ) ▁might ▁result ▁in ▁higher ▁risk ▁of ▁adverse ▁effects ▁than ▁lower ▁maximum ▁ser um ▁concent r ations .
▁In ▁our ▁pharmac ok inet ic ▁model , ▁the ▁c um ul ative ▁dose ▁was ▁highly ▁cor rel ated ▁with ▁all ▁measures ▁of ▁ser um ▁concent r ations ▁on ▁Day ▁3 ▁and ▁the ▁final ▁day ▁of ▁treatment , ▁and ▁therefore ▁we ▁decided ▁to ▁use ▁c um ul ative ▁dose ▁as ▁the ▁primary ▁analysis .
▁Day ▁3 ▁t rough ▁concent ration ▁was ▁least ▁strongly ▁cor rel ated ▁with ▁total ▁c um ul ative ▁dose ▁( R 2 ▁= ▁0 .3 76 ), ▁and ▁therefore , ▁we ▁performed ▁a ▁sens it ivity ▁subgroup ▁analysis ▁with ▁pred ic ted ▁Day ▁3 ▁t rough ▁concent r ations ▁for ▁efficacy ▁outcomes .
▁L op in avir - ritonavir ▁( published ▁17 ▁December ▁2020 ) ▁Inf o ▁Box ▁The ▁recommendation ▁concerning ▁l op in avir - ritonavir ▁was ▁published ▁17 ▁December ▁2020 ▁as ▁the ▁third ▁version ▁of ▁the ▁WHO ▁living ▁guideline ▁and ▁in ▁the ▁B M J ▁as ▁R ap id ▁Recommend ations .
▁It ▁followed ▁the ▁prep r int ▁public ation ▁of ▁the ▁WHO ▁S OL I DA RI T Y ▁trial ▁on ▁15 ▁October ▁2020 , ▁reporting ▁results ▁on ▁treatment ▁with ▁l op in avir - ritonavir , ▁remdesivir , ▁and ▁hy dro x y ch lor o qu ine ▁in ▁hospital ized ▁patients ▁with ▁COVID -19 ▁.
▁No ▁changes ▁were ▁made ▁to ▁the ▁l op in avir - ritonavir ▁recommendation ▁in ▁this ▁13 th ▁version ▁of ▁the ▁guideline .
▁Evidence ▁To ▁Dec ision ▁Benef its ▁and ▁H arm s : ▁The ▁GDG ▁panel ▁found ▁a ▁lack ▁of ▁evidence ▁that ▁l op in avir - ritonavir ▁improved ▁outcomes ▁that ▁matter ▁to ▁patients ▁such ▁as ▁reduced ▁mortality , ▁need ▁for ▁mechanical ▁ventilation , ▁time ▁to ▁clinical ▁improvement , ▁and ▁others .
▁For ▁mortality ▁and ▁need ▁for ▁mechanical ▁ventilation , ▁this ▁was ▁based ▁on ▁moderate ▁certainty ▁evidence , ▁for ▁the ▁other ▁outcomes ▁low ▁or ▁very ▁low ▁certainty ▁evidence .
▁There ▁was ▁low ▁certainty ▁evidence ▁that ▁l op in avir - ritonavir ▁may ▁increase ▁the ▁risk ▁of ▁di arr ho e a , ▁n ause a , ▁and ▁v om iting , ▁a ▁finding ▁consist ent ▁with ▁the ▁indirect ▁evidence ▁evalu ating ▁its ▁use ▁in ▁patients ▁with ▁HIV .
▁There ▁was ▁an ▁uncertain ▁effect ▁on ▁viral ▁clear ance ▁and ▁acute ▁kid ney ▁inj ury .
▁As ▁there ▁was ▁no ▁evidence ▁of ▁a ▁stat istical ▁subgroup ▁effect , ▁we ▁did ▁not ▁form ally ▁evalu ate ▁using ▁the ▁I C E MA N ▁tool .
▁Certainty ▁of ▁the ▁Evidence : ▁The ▁evidence ▁is ▁based ▁on ▁a ▁link ed ▁systematic ▁review ▁and ▁N MA ▁of ▁seven ▁RCTs ; ▁po ol ing ▁data ▁from ▁7, 42 9 ▁patients ▁hospital ized ▁with ▁various ▁sever ities ▁of ▁COVID -19 ▁and ▁vari ably ▁reporting ▁the ▁outcomes ▁of ▁interest ▁to ▁the ▁guideline ▁panel .
▁The ▁panel ▁agreed ▁that ▁there ▁was ▁moderate ▁certainty ▁for ▁mortality ▁and ▁need ▁for ▁mechanical ▁ventilation , ▁low ▁certainty ▁for ▁di arr ho e a , ▁n ause a , ▁and ▁duration ▁of ▁hospitalization , ▁and ▁very ▁low ▁certainty ▁in ▁the ▁estimates ▁of ▁effect ▁for ▁viral ▁clear ance , ▁acute ▁kid ney ▁inj ury ▁and ▁time ▁to ▁clinical ▁improvement .
▁Resources ▁and ▁other ▁considerations : ▁Although ▁the ▁cost ▁of ▁l op in avir - ritonavir ▁is ▁not ▁as ▁high ▁as ▁some ▁other ▁investig ational ▁drugs ▁for ▁COVID -19, ▁and ▁the ▁drug ▁is ▁generally ▁available ▁in ▁most ▁health care ▁settings , ▁the ▁GDG ▁raised ▁concerns ▁about ▁opportunity ▁costs ▁and ▁the ▁importance ▁of ▁not ▁drawing ▁attention ▁and ▁resources ▁away ▁from ▁best ▁support ive ▁care ▁or ▁the ▁use ▁of ▁corticosteroids ▁in ▁severe ▁COVID -19.
▁Although ▁the ▁trials ▁did ▁not ▁report ▁subgroup ▁effects ▁by ▁time ▁from ▁sympt om ▁onset , ▁many ▁of ▁the ▁trials ▁enrolled ▁patients ▁early ▁in ▁the ▁disease ▁course .
▁The ▁strong ▁recommendation ▁is ▁applic able ▁across ▁disease ▁severity ▁and ▁age ▁groups .
▁However , ▁the ▁panel ▁had ▁no ▁reason ▁to ▁think ▁that ▁children ▁with ▁COVID -19 ▁would ▁respond ▁any ▁differently ▁to ▁treatment ▁with ▁l op in avir - ritonavir .
▁In ▁patients ▁using ▁l op in avir - ritonavir ▁for ▁HIV ▁infection , ▁it ▁should ▁generally ▁be ▁continued ▁while ▁receiving ▁care ▁for ▁COVID -19.
▁Additional ▁considerations ▁in ▁patients ▁who ▁have ▁und ia gn osed ▁or ▁unt reated ▁HIV , ▁use ▁of ▁l op in avir - ritonavir ▁alone ▁may ▁promote ▁HIV ▁resistance ▁to ▁important ▁ant ire t ro vir als .
▁W ides p read ▁use ▁of ▁l op in avir - ritonavir ▁for ▁COVID -19 ▁may ▁cause ▁drug ▁short ages ▁for ▁people ▁living ▁with ▁HIV .
▁Of ▁note , ▁none ▁of ▁the ▁included ▁studies ▁enrolled ▁children ▁or ▁adolescents ▁under ▁the ▁age ▁of ▁19 ▁years ▁old .
▁The ▁GRADE ▁Summary ▁of ▁F ind ings ▁table ▁shows ▁the ▁relative ▁and ▁absolute ▁effects ▁of ▁l op in avir - ritonavir ▁compared ▁with ▁usual ▁care ▁for ▁the ▁outcomes ▁of ▁interest ▁in ▁patients ▁with ▁COVID -19 ▁across ▁all ▁disease ▁sever ities , ▁with ▁certainty ▁r at ings .
▁No ▁changes ▁were ▁made ▁to ▁the ▁corticostero id ▁recommendations , ▁in ▁this ▁13 th ▁version ▁of ▁the ▁guideline .
▁Where as ▁the ▁recommendations ▁remain ▁unch anged , ▁the ▁evidence ▁summary ▁for ▁corticosteroids ▁in ▁patients ▁with ▁COVID -19 ▁was ▁updated , ▁before ▁the ▁6 th ▁it eration ▁of ▁this ▁living ▁guideline .
▁The ▁bas eline ▁risk ▁estimates ▁for ▁mortality ▁are ▁now ▁based ▁on ▁the ▁WHO ▁Sol id ar ity ▁T rial ▁( as ▁for ▁other ▁drugs ▁in ▁this ▁guideline ), ▁rather ▁than ▁the ▁initial ▁I S AR IC ▁co h ort ▁study ▁that ▁likely ▁o ve rest im ates ▁current ▁mortality ▁risks ▁at ▁the ▁global ▁level .
▁The ▁upd ate ▁was ▁also ▁needed ▁to ▁inform ▁the ▁bas eline ▁risk ▁for ▁mortality , ▁in ▁the ▁evidence ▁summary ▁inform ing ▁the ▁strong ▁recommendation ▁for ▁I L -6 ▁recept or ▁block ers , ▁in ▁addition ▁to ▁standard ▁of ▁care ▁for ▁patients ▁with ▁severe ▁or ▁critical ▁COVID -19, ▁where ▁corticosteroids ▁provide ▁a ▁relative ▁reduction ▁in ▁mortality ▁by ▁21 %.
▁Practical ▁Inf o ▁- ▁R ou te : ▁System ic ▁corticosteroids ▁may ▁be ▁administered ▁both ▁or ally ▁and ▁intra ven ously .
▁Of ▁note , ▁while ▁the ▁b io av ail ability ▁of ▁de x am eth as one ▁is ▁very ▁high ▁( that ▁is , ▁similar ▁concent r ations ▁are ▁achieved ▁in ▁pl as ma ▁after ▁oral ▁and ▁intra ven ous ▁int ake ), ▁crit ically ▁ill ▁patients ▁may ▁be ▁unable ▁to ▁absor b ▁any ▁nut ri ents ▁or ▁medic ations ▁due ▁to ▁int est inal ▁d ys f unction .
▁Clin icians , ▁therefore , ▁may ▁consider ▁admin ister ing ▁system ic ▁corticosteroids ▁intra ven ously , ▁rather ▁than ▁or ally , ▁if ▁int est inal ▁d ys f unction ▁is ▁suspected .
▁D uration : ▁While ▁more ▁patients ▁received ▁corticosteroids ▁in ▁the ▁form ▁of ▁de x am eth as one ▁6 m g ▁daily ▁for ▁up ▁to ▁10 ▁days , ▁the ▁total ▁duration ▁of ▁reg imens ▁evaluated ▁in ▁the ▁seven ▁trials ▁var ied ▁between ▁5 ▁and ▁14 ▁days , ▁and ▁treatment ▁was ▁generally ▁discontin ued ▁at ▁hospital ▁dis charge ▁( that ▁is , ▁the ▁duration ▁of ▁treatment ▁could ▁be ▁less ▁than ▁the ▁duration ▁st ip ulated ▁in ▁the ▁protoc ols ).
▁D ose : ▁The ▁once - d aily ▁de x am eth as one ▁form ulation ▁may ▁increase ▁adherence .
▁A ▁dose ▁of ▁6 m g ▁of ▁de x am eth as one ▁is ▁equivalent ▁( in ▁terms ▁of ▁gl uc oc ort ic oid ▁effect ) ▁to ▁150 ▁mg ▁of ▁hy dro c ort is one ▁( that ▁is , ▁50 m g ▁every ▁8 ▁hours ), ▁40 m g ▁of ▁pred n is one , ▁or ▁32 m g ▁of ▁m eth yl p red n is ol one ▁(8 m g ▁every ▁6 ▁hours ▁or ▁16 m g ▁every ▁12 ▁hours ).
▁Monitoring : ▁It ▁would ▁be ▁pr ud ent ▁to ▁mon itor ▁gl uc ose ▁levels ▁in ▁patients ▁with ▁severe ▁and ▁critical ▁COVID -19, ▁regard less ▁of ▁whether ▁the ▁patient ▁is ▁known ▁to ▁have ▁di abetes .
▁T im ing : ▁The ▁t im ing ▁of ▁therapy , ▁from ▁the ▁onset ▁of ▁symptoms ▁was ▁discussed ▁by ▁the ▁panel .
▁I MR ▁reporting ▁was ▁system at ically ▁higher ▁than ▁that ▁reported ▁from ▁R H - M IS .
▁This ▁coverage ▁r anged ▁from ▁1 .4% ▁in ▁Colombo ▁M C ▁to ▁55 .2% ▁in ▁Ampara ▁district .
▁The ▁maternal ▁component ▁is ▁further ▁sub - d iv ided ▁into ▁areas ▁such ▁as ; ▁Ant en atal , ▁The ▁diagram ▁also ▁depic ts ▁the ▁refer ral ▁and ▁back ▁refer ral ▁path ways ▁available ▁for ▁people ▁conf ron ted ▁by ▁health ▁conditions ▁related ▁to ▁family ▁health ▁( child ▁birth , ▁childhood ▁illness ▁etc .) ▁in ▁p ink ▁lines .
▁Un av ail ability ▁was ▁c ited ▁as ▁the ▁main ▁reason ▁for ▁non - use , ▁by ▁the ▁un mar ▁13.
▁FHB ▁is ▁the ▁technical ▁unit ▁techn ically ▁gu iding ▁the ▁RMNCAYH ▁Programme .
▁S et ting ▁bar ri ers ▁on ▁relationships ; ▁bl am ing ▁/ sc old ing ▁and ▁physical ▁violence ▁by ▁the ▁part ner ▁were ▁reported ▁as ▁experi ences ▁of ▁int imate ▁part ner ▁violence .
▁MOH ▁is ▁the ▁Man ager ▁of ▁the ▁MOH ▁team , ▁tr ative ▁supervision ▁of ▁the ▁MOH ▁team ▁becomes ▁the ▁main ▁responsibility ▁of ▁the ▁MOH .
▁In ▁addition , ▁Family ▁Health ▁Programme ▁includes ▁an ▁oral ▁health ▁component ▁which ▁focus es ▁on ▁maternal ▁and ▁child ▁oral ▁health ▁care .
▁Values ▁and ▁preferences ▁App lying ▁the ▁agreed ▁upon ▁v ▁al ues ▁and ▁preferences ▁( see ▁Section ▁7 ), ▁the ▁GDG ▁in ▁f er red ▁that ▁the ▁majority ▁of ▁well - in formed ▁patients ▁with ▁severe ▁COVID -19 ▁would ▁want ▁to ▁receive ▁remdesivir ▁due ▁to ▁the ▁possible ▁r ▁ed uction ▁in ▁mortality ▁and ▁need ▁f ▁or ▁invas ive ▁mechanical ▁ventilation .
▁It ▁forms ▁of ▁a ▁well - or gan ized ▁health ▁care ▁system , ▁implementing ▁services ▁through ▁33 8 ▁division al ▁health ▁units ▁called ▁Medical ▁Officer ▁of ▁Health ▁( MOH ) ▁areas .
▁As ▁described ▁in ▁section ▁6.1 .5 .4 ▁this ▁could ▁be ▁an ▁under ▁reporting ▁and ▁Month ly ▁Ex pected ▁Mother s ▁Reg ister ▁( H ▁5 15 ).
▁The ▁trend ▁had ▁re vers ed ▁since ▁that ▁year ▁and ▁both ▁sources ▁however , ▁demonst rate ▁a ▁clear ▁decl ining ▁trend .
▁Family ▁Planning ▁Qu ater ly ▁Return ▁( H ▁1200 ▁B ) ▁3.
▁The ▁Figure ▁46 ▁comp ares ▁the ▁National ▁Inf ant ▁Mortality ▁R ate ▁( I MR ), ▁calculated ▁from ▁the ▁R HMIS ▁with ▁the ▁I MR ▁reported ▁by ▁the ▁Registrar ▁General .
▁Reproductive ▁Health ▁cent re ▁services ▁provided ▁by ▁a ▁team ▁lead ▁by ▁a ▁Vis iting ▁Obstetric ian ▁G y na ec ologist .
▁Table ▁15 ▁pres ents ▁the ▁infant ▁and ▁children ▁under ▁five ▁mortality ▁rates ▁and ▁the ▁proportion ▁of ▁reported ▁infant ▁deaths ▁investigated ▁by ▁PH NS s ▁( or ▁SP HM s ▁when ▁P N HS s ▁are ▁not ▁available ).
▁Only ▁40 .7% ▁of ▁married ▁and ▁sex ually ▁active ▁youth ▁were ▁pract ic ing ▁a ▁family ▁planning ▁method .
▁In ▁serv ing ▁this ▁mission ▁the ▁programme ▁rel ies ▁on ▁a ▁ble nd ▁of ▁d omiciliary ▁and ▁institution al ized ▁interventions ▁delivered ▁by ▁multi ▁discip lin ary ▁team ▁of ▁health ▁professionals .
▁On ▁average ▁around ▁1/ 5 th ▁of ▁total ▁pregnancies ▁registered ▁were ▁not ▁reported ▁as ▁deliveries .
▁Certainty ▁of ▁evidence ▁was ▁r ated ▁as : ▁moderate ▁for ▁decreased ▁hospitalization ▁( rated ▁down ▁due ▁to ▁concerns ▁regarding ▁serious im p rec ision ▁and ▁risk ▁of ▁bias ), ▁low ▁for ▁mortality ▁( rated ▁down ▁due ▁to ▁serious ▁imprecision ▁and ▁indirect ness ), ▁and ▁high ▁for ▁adverse effect s ▁leading ▁to ▁drug ▁discontin uation .
▁This ▁was ▁successfully ▁conducted ▁in ▁18 ▁Dist ricts ▁with ▁over ▁95% ▁attendance .
▁Table ▁6 ▁pres ents ▁the ▁percent ages ▁of ▁pregnant ▁mothers , ▁who ▁were ▁visited ▁at ▁least ▁once ▁and ▁average ▁number ▁of ▁field ▁visits ▁paid ▁to ▁them ▁by ▁PHM .
▁However , ▁Sri ▁Lanka ▁is ▁well - pl aced ▁with ▁regard ▁to ▁maternal ▁mortality ▁on ▁par ▁with ▁high ▁income ▁countries . ▁‘ D e ath ▁of ▁a ▁woman ▁while ▁pregnant ▁or ▁within ▁42 ▁days ▁of ▁term ination ▁of ▁pregnancy , ▁ir res pective ▁of ▁the ▁duration ▁and ▁the ▁site ▁of ▁the ▁pregnancy ▁- from ▁any ▁cause ▁related ▁to ▁or ▁ag g rav ated ▁by ▁the ▁pregnancy ▁or ▁its ▁management ▁but ▁not ▁from ▁accident al ▁or ▁incident al ▁ca uses ’ ▁is ▁considered ▁as ▁a ▁maternal ▁death .
▁The ▁GDG ▁ac k n o ▁w led ged ▁that ▁there ▁was ▁a ▁p au c ity ▁o ▁f ▁information ▁relating ▁to ▁emergence ▁of ▁resistance ▁and ▁much ▁mor ▁e ▁data ▁were ▁needed ▁to ▁in ▁form ▁the ▁recommendation .
▁In ▁promoting ▁access , ▁WHO ▁has ▁pr ▁equal ified ▁gener ic ▁vers ions ▁of ▁molnupiravir ▁and ▁one ▁g ▁en eric ▁version ▁of ▁nirmatrelvir - ritonavir .
▁Per cent age ▁of ▁target ▁children ▁scre ened ▁in ▁each ▁district ▁is ▁given ▁in ▁Figure ▁6 5.
▁Table ▁13 ▁shows ▁the ▁average ▁number ▁of ▁clinic ▁visits ▁by ▁an ▁infant ▁is ▁around ▁5 ▁during ▁past ▁5 ▁years .
▁Al most ▁all ▁mothers ▁delivering ▁knew ▁their ▁blood ▁group ▁and ▁Rh ▁status ▁while ▁25 .9 ▁% ▁of ▁clinic ▁attending ▁mothers ▁get ▁the ▁testing ▁done ▁at ▁field ▁clinics .
▁Medical ▁officer ▁had ▁examined ▁only ▁5 9 .1% ▁of ▁mothers ▁after ▁the ▁hospital ▁dis charge .
▁Act ive ▁sequ ence ▁monitoring ▁of ▁SARS - CoV -2 ▁det ected ▁in ▁clinical ▁respiratory ▁samples ▁( i . e . ▁may ▁include ▁poly mer ase ▁and ▁sp ike ) ▁should ▁be ▁arr anged ▁for ▁patients ▁receiving ▁therapy , ▁including ▁higher - risk ▁individuals ▁( im mun oc om p rom ised ).
▁The ▁latter ▁is ▁a ▁platform ▁used ▁by ▁the ▁WHO ▁Ph armac ▁o v ig il ance ▁team ▁to ▁le ▁ver age ▁machine ▁learning ▁and ▁ar ▁t ific ial ▁intelligence ▁to ▁support ▁sa ▁f ety ▁prepared ness ▁and ▁sign al ▁de ▁t ection ▁functions .
▁In ▁order ▁to ▁improve ▁the ▁quality ▁the ▁intervention , ▁pro curement ▁of ▁iron / f olate ▁combined ▁table ts ▁in ▁bl ister ▁pack s ▁was ▁initiated ▁in ▁2015.
▁Although ▁this ▁system ▁capt ures ▁a ▁lot ▁of ▁no ise , ▁it ▁allow s ▁to ▁identify ▁adverse ▁events , ▁provided ▁confirm ation .
▁Of ▁the ▁23 ▁vot ing ▁panel ▁members , ▁19 ▁( 83 %) ▁vot ed ▁in ▁favor ▁of ▁a ▁strong ▁recommendation , ▁and ▁4 ▁(1 7 %) ▁vot ed ▁in ▁favor ▁of ▁a ▁conditional ▁recommendation .
▁Figure ▁3 .10 : ▁Distribution ▁of ▁Special ▁Care ▁Bab y ▁Un its ▁Figure ▁3 .11 : ▁N ur se ▁perform ing ▁the ▁he al ▁p ric k ▁test ▁for ▁and ▁Ne on atal ▁Int ensive ▁Care ▁Un its ▁in ▁the ▁country ▁newborn ▁screening ▁for ▁congenital ▁hyp oth y roid ism ▁at ▁D G H ▁Vavuniya ▁3.4 .3 ▁Int rodu ction ▁of ▁Newborn ▁Guid elines ▁to ▁all ▁the ▁districts ▁3.4 .5 ▁Sc aling ▁up ▁of ▁Newborn ▁Sc reening ▁for ▁C rit ical ▁Cong en ital ▁Hear t ▁D ise ases ▁As ▁part ▁of ▁the ▁road ▁m ap ▁to ▁improve ▁quality ▁of ▁ne on atal ▁care , ▁Clin ical ▁Guid elines ▁on ▁Newborn ▁Care ▁were ▁developed ▁by ▁an ▁expert ▁panel .
▁Only ▁39 .4% ▁of ▁women ▁attending ▁belong ▁to ▁35 ▁year ▁age ▁co h ort .
▁Figure ▁18 ▁indicates ▁that ▁a ▁consider able ▁percentage ▁of ▁mothers ▁may ▁not ▁receive ▁their ▁first ▁postpartum ▁visit ▁during ▁the ▁first ▁10 ▁days ▁following ▁delivery .
▁Child ▁Health ▁Child ▁Development ▁and ▁Special ▁Ne eds .
▁However , ▁there ▁was ▁not ▁an ▁established ▁ca usal ▁link ▁to ▁pr ▁o ve ▁that ▁nirmatrelvir - ritonavir ▁caused ▁the ▁out c ▁o me ▁and ▁important ▁information ▁was ▁missing .
▁In ▁this ▁pers pective , ▁attention ▁is ▁paid ▁to ▁the ▁opportunity ▁cost ▁associated ▁with ▁the ▁w ides p read ▁provision ▁of ▁the rap ies ▁for ▁COVID -19.
▁Community ▁Dental ▁Clin ics ▁( CD C ) ▁are ▁located ▁in ▁highly ▁pop ulated ▁met ro p ol it an ▁areas ▁and ▁d ental ▁sur ge ons ▁working ▁in ▁these ▁clinics ▁focus ing ▁on ▁preventive ▁care ▁to ▁specialized ▁groups ▁like ▁pregnant ▁mothers ▁and ▁children ▁below ▁3 ▁years ▁of ▁age .
▁Ampara ▁(7 3 .7 %) ▁and ▁Badulla ▁( 72 .0 %) ▁districts ▁reported ▁the ▁highest ▁C P R ▁( over ▁70 %) ▁in ▁the ▁country .
▁All ▁m aps ▁show ▁bound aries ▁of ▁26 ▁RDHS ▁area .
▁In ▁2010 ▁M R ▁vaccines ▁was ▁replaced ▁by ▁MMR ▁( M um ps , ▁Me as les , ▁Rub ella ) ▁vaccine ▁and ▁at ▁present ▁2 ▁doses ▁of ▁MMR ▁vaccine ▁are ▁given ▁to ▁all ▁children ▁at ▁1 ▁and ▁3 ▁years ▁of ▁age .
▁This ▁strategy ▁used ▁for ▁screening ▁for ▁O P M D ▁and ▁refer ring ▁all ▁those ▁people ▁who ▁score ▁more ▁than ▁12 ▁in ▁the ▁risk ▁factor ▁model , ▁to ▁a ▁d ental ▁sur ge on ▁at ▁the ▁ne arest ▁hospital .
▁F o et o - inf ant ▁mortality ▁sur veillance ▁mechanism ▁was ▁form ulated ▁and ▁f et o inf ant ▁death ▁reviews ▁were ▁introduced ▁in ▁12 ▁districts .
▁N irmatrelvir - ritonavir ▁probably ▁has ▁little ▁or ▁no ▁impact ▁on ▁mortality .
▁Co ver ing ▁all ▁the ▁centres ▁in ▁the ▁country ▁04 ▁training ▁were ▁held ▁in ▁Colombo , ▁Kandy , ▁Batticaloa ▁and ▁Anuradhapura .
▁It ▁could ▁be ▁considered ▁as ▁one ▁of ▁the ▁most ▁comprehensive ▁community ▁based ▁register s ▁of ▁the ▁country , ▁which ▁records ▁det ails ▁of ▁all ▁children ▁perman ently ▁res iding ▁in ▁the ▁PHM ▁area , ▁it ▁should ▁approxim ate ▁the ▁total ▁number ▁of ▁estimated ▁births ▁of ▁the ▁country .
▁T w enty ▁nine ▁School ▁Dental ▁Therap ist ▁were ▁recruited ▁during ▁the ▁year ▁2015 ▁to ▁the ▁government ▁sector .
▁Figure ▁3 .3 : ▁No . ▁of ▁teenage ▁pregnant ▁mothers ▁reported ▁Figure ▁3.6 : ▁Per cent age ▁of ▁teenage ▁pregn encies ▁by ▁district ▁in ▁2014 ▁and ▁2015 ▁• ▁( P ublished ▁standards ▁of ▁maternal ▁care ▁Stand ards ▁of ▁maternal ▁care ▁document ▁was ▁published ▁to ▁ensure ▁the ▁sustain ability ▁of ▁current ▁achieve ments ▁and ▁move ▁towards ▁the ▁future ▁targets ▁in ▁maternal ▁care ).
▁However , ▁it ▁should ▁be ▁noted ▁that ▁percentage ▁of ▁deliveries ▁reported ▁out ▁of ▁registered ▁pregnancies ▁for ▁2011 ▁was ▁only ▁81 .6% ▁( Table ▁9 ).
▁Near ly ▁one ▁fifth ▁of ▁youth ▁were ▁feeling ▁sad ▁or ▁help less ness ▁and ▁had ▁stopped ▁their ▁routine ▁work ▁for ▁a ▁while ▁and ▁6 .4% ▁felt ▁like ▁the ▁above ▁for ▁two ▁weeks ▁or ▁more .
▁Ab out ▁45 ▁Consultant ▁P a ed i at ric ians ▁/ ▁Ne on at ologists ▁were ▁trained ▁as ▁trainers ▁in ▁Bab y ▁F riend ly ▁Hospital ▁Init i ative .
▁T yp ical ▁characteristics ▁of ▁people ▁at ▁the ▁highest ▁risk ▁include ▁those ▁who ▁are ▁un v acc inated , ▁older ▁people , ▁or ▁those ▁with ▁immun ode fic i encies ▁and / or ▁chronic ▁diseases ▁( e . g . ▁di abetes ).
▁Figure ▁13 ▁shows ▁the ▁number ▁of ▁different ▁types ▁of ▁antenatal ▁morbid ities ▁that ▁occurred ▁during ▁antenatal ▁period ▁and ▁correspond ing ▁cases ▁per ▁10,000 ▁pregnancies .
▁St ill b irth ▁and ▁early ▁ne on atal ▁mortality ▁rates ▁were ▁5.3 ▁per ▁1000 ▁total ▁births ▁and ▁4.8 ▁per ▁1000 ▁live ▁births ▁respectively .
▁One ▁fifth ▁consum ed ▁pre - co oked ▁food ▁like ▁sa us ages ▁while ▁one ▁fourth ▁had ▁taken ▁food ▁with ▁high ▁s alt .
▁These ▁include : ▁information ▁on ▁target ▁population , ▁perform ances ▁of ▁maternal ▁care , ▁child ▁care , ▁well ▁woman ▁clinic ▁and ▁family ▁planning ▁services ▁provided ▁both ▁at ▁field ▁and ▁clinic ▁sett ng s .
▁Pre - pre gn ancy ▁f olic ▁ac id ▁was ▁reported ▁by ▁61 .5% ▁while ▁92 .8% ▁and ▁90 .3% ▁of ▁mothers ▁reported ▁taking ▁iron ▁and ▁calc ium ▁table ts ▁during ▁the ▁previous ▁one ▁week .
▁6 .5 .1 ▁Maternal ▁Mortality ▁in ▁Sri ▁Lanka ▁Mannar ▁Trincomalee ▁Vavuniya ▁Sri ▁Lanka , ▁being ▁an ▁indust ri ally - de velop ing ▁country , ▁has ▁shown ▁a ▁remark able ▁success ▁in ▁reducing ▁maternal ▁deaths ▁over ▁the ▁years .
▁The ▁Table ▁shows ▁the ▁characteristics ▁of ▁the ▁RCTs .
▁SA AR C ▁Development ▁Fund ▁Project ▁on ▁Maternal ▁and ▁Child ▁Health ▁was ▁initiated ▁to ▁strengthen ▁newborn ▁care ▁services ▁across ▁the ▁country .
▁The ▁balance ▁between ▁benefits ▁and ▁potential ▁harms ▁fav ours ▁treatment , ▁but ▁only ▁in ▁the ▁highest ▁risk ▁gr ▁o up .
▁Primary ▁school ▁comple tion ▁rate ▁of ▁these ▁children ▁re aches ▁97 % , ▁while ▁only ▁89 % ▁comple t es ▁up ▁to ▁grade ▁9 ▁and ▁adolescents ▁(10 -19 ▁years ) ▁comp r ise ▁19 % ▁of ▁total ▁population ▁in ▁Sri ▁Lanka ▁and ▁of ▁them ▁70% ▁attend ▁schools .
▁The ▁document ary ▁on ▁GBV “ S am an ala ▁Pal ama ” ▁was ▁launched .
▁Public ▁Health ▁Inspect ors ▁carry ▁out ▁the ▁initial ▁screening ▁of ▁children ▁and ▁MOHs ▁then ▁conduct ▁Medical ▁examination .
▁According ▁to ▁R H - M IS , ▁around ▁12 .6 ▁% ▁newborns ▁in ▁2011 ▁we ighed ▁less ▁than ▁2500 ▁grams ▁and ▁hence ▁became ▁Low ▁B irth ▁Weight ▁( L BW ) ▁babies .
▁The ▁GDG ▁decided ▁against ▁r ating ▁certainty ▁down ▁for ▁imprecision ▁for ▁outcomes ▁where ▁low ▁event ▁rates ▁ref lected ▁very ▁low ▁bas eline ▁risks ▁( e . g . ▁mortality ).
▁Cl ose ▁monitoring ▁of ▁Sri ▁Lanka ▁Code ▁for ▁the ▁Promotion , ▁Protection ▁and ▁Supp ort ▁of ▁Bre ast ▁feeding ▁and ▁Mar ket ing ▁of ▁Des ign ated ▁Produ cts ▁was ▁ens ured ▁with ▁regular ▁meetings ▁with ▁Secretary ▁Health .
▁MOH ▁staff ▁includes ▁School ▁Dental ▁Therapists ▁( SD T ) ▁who ▁are ▁responsible ▁for ▁providing ▁routine ▁d ental ▁care ▁for ▁school ▁children .
▁H ▁o we ver , ▁in ▁lo ▁w - risk ▁patients , ▁the ▁absolute ▁b ene ▁fit ▁is ▁very ▁small ▁and ▁unl ike ly ▁to ▁be ▁import an ▁t ▁to ▁most ▁pa ▁t ients .
▁For ▁patients ▁with ▁non - severe ▁COVID -19 ▁strong ▁recommendation ▁against ▁we ▁recommend ▁against ▁treatment ▁with ▁con val es cent ▁pl as ma ▁( st r ong ▁recommendation ▁against ).
▁Res p onse ▁rate ▁was ▁ ........ The ▁key ▁findings ▁include ; ▁Health ▁promotion ▁commit te es ▁were ▁established ▁only ▁in ▁87 .8% ▁of ▁which ▁83 % ▁had ▁completed ▁the ▁self ▁– ▁assessment .
▁This ▁cont rast s ▁with ▁ch ain - ter min ation ▁seen ▁with ▁other ▁ant ivir al ▁nucle os ide ▁anal og ues ▁( e . g . ▁remdesivir ▁and ▁those ▁used ▁in ▁HIV ▁or ▁H C V .
▁The ▁official ▁mission ▁of ▁the ▁Family ▁Health ▁Programme ▁is ▁“ to ▁contrib ute ▁to ▁the ▁attain ment ▁of ▁highest ▁possible ▁levels ▁of ▁health ▁of ▁all ▁women , ▁children ▁and ▁families ▁through ▁provision ▁of ▁comprehensive , ▁sustain able , ▁equ itable ▁and ▁quality ▁maternal ▁and ▁child ▁health ▁services ▁in ▁a ▁support ive , ▁cult urally ▁accept able ▁and ▁family ▁friendly ▁setting .”
▁Ne on atal ▁examination ▁was ▁performed ▁among ▁98 .8% ▁of ▁babies ▁before ▁the ▁dis charge .
▁Prov isions ▁are ▁included ▁in ▁Family ▁Health ▁Programme ▁to ▁deliver ▁preventive ▁health ▁care ▁services ▁to ▁school ▁children ▁and ▁adolescents .
▁T ▁he ▁lack ▁of ▁data ▁regarding ▁the ▁e ▁f f ect ▁in ▁immun oc om p rom ised ▁patients ▁was ▁also ▁highlight ed .
▁Resources ▁and ▁other ▁considerations ▁Ac cept ability ▁and ▁feasibility ▁Rem desivir ▁is ▁administered ▁as ▁one ▁in ▁tra ven ous ▁inf usion ▁daily ▁over ▁10 ▁consec utive ▁days , ▁and ▁rather ▁than ▁in ▁an ▁out p a ▁t ient ▁setting , ▁this ▁is ▁more ▁easily ▁oper ational ized ▁in ▁hospital ized ▁patients ▁with ▁severe ▁disease .
▁On ▁average , ▁a ▁mother ▁made ▁7 ▁field ▁clinic ▁visits ▁during ▁her ▁pregnancy ▁( Table ▁4 ).
▁Three ▁vol um es ▁of ▁Clin ical ▁Guid elines ▁on ▁Newborn ▁Care ▁were ▁introduced ▁to ▁hospitals ▁in ▁all ▁the ▁districts ▁in ▁the ▁country ▁during ▁the ▁year ▁2015.
▁However , ▁the ▁screening ▁was ▁not ▁rest ric ted ▁to ▁this ▁co h ort , ▁attended ▁the ▁clinic ▁for ▁the ▁above ▁conditions .
▁Only ▁half ▁of ▁the ▁youth , ▁have ▁heard ▁about ▁the ▁BMI ▁concept .
▁The ▁R EC O V ER Y ▁investig ators ▁reported ▁a ▁subgroup ▁analysis ▁suggesting ▁that ▁the ▁init iation ▁of ▁therapy ▁7 ▁days ▁or ▁more ▁after ▁sympt om ▁onset ▁may ▁be ▁more ▁benef icial ▁than ▁treatment ▁initiated ▁within ▁7 ▁days ▁of ▁sympt om ▁onset .
▁All ▁MOHs ▁are ▁required ▁to ▁send ▁a ▁return ▁on ▁the ▁summary ▁of ▁the ▁activities ▁done ▁during ▁the ▁month ▁which ▁is ▁introduced ▁to ▁the ▁Public ▁Health ▁Staff ▁during ▁a ▁technical ▁upd ate ▁for ▁them ▁at ▁the ▁FHB .
▁Table ▁1: ▁Distribution ▁of ▁different ▁types ▁of ▁staff ▁person nel ▁in ▁the ▁MOH ▁teams ▁around ▁the ▁country , ▁2011 ▁C ateg ory ▁of ▁staff ▁Figure ▁3 ▁shows ▁3 ▁human ▁resource ▁availability ▁indicators ▁of ▁Family ▁Health ▁Programme .
▁Therefore , ▁if ▁pa ▁t ients ▁at ▁higher ▁risk ▁receive ▁the ▁intervention , ▁this ▁may ▁ex acer b ate ▁health ▁inequ ity .
▁Of ▁them ▁3 .7% ▁( n =3 23 7) ▁were ▁identified ▁as ▁un s at isf act ory ▁sm ears ▁while ▁0.6 6 % ▁had ▁a ▁diagnosis ▁( L S I L ( n =2 77 ), ▁H S I L ▁( n = 66 ), ▁G land ular ( n =3 1 ), ▁AS C U S ▁(1 3 1 ), ▁Mal ign ancies ▁( N =5 7) ).
▁One ▁should ▁use ▁ca ution ▁when ▁admin ister ing ▁r ▁em desivir ▁to ▁patients ▁with ▁significant ▁l iver ▁or ▁kid ney ▁disease .
▁At ▁the ▁district ▁level , ▁MOMCH ▁is ▁supported ▁by ▁Regional ▁Superv ising ▁Public ▁Health ▁Nurs ing ▁S ister ▁( RS PH NO ) ▁and ▁District ▁Superv ising ▁Public ▁Health ▁Inspector ▁( SP HI D ) ▁in ▁h ier arch ical ▁administrative ▁relationship ▁where ▁PH NS ▁is ▁also ▁supp osed ▁to ▁superv ise ▁SP HM .
▁Del i very ▁reporting ▁for ▁estimated ▁deliveries ▁var ied ▁from ▁90 .2 ▁% ▁( K il in ochchi ) ▁to ▁50 .8 ▁% ▁( C ol ombo )
▁Reg ular ▁Maternal ▁and ▁Child ▁Nutrition ▁Sub com mittee ▁meetings .
▁years ▁in ▁schools ▁with ▁less ▁than ▁200 ▁students .
▁The ▁following ▁table ▁pres ents ▁the ▁overall ▁staff ▁position ▁of ▁the ▁MOH ▁areas ▁around ▁the ▁country . ▁lack ▁public ▁health ▁staff ▁according ▁to ▁norm s ▁to ▁implement ▁the ▁programme .
▁Dist ricts ▁of ▁Ampara , ▁Kegalle , ▁Matale , ▁Monaragala , ▁Colombo , ▁Hamb an th ota , ▁Polonnaruwa ▁and ▁Kalutara ▁had ▁an ▁overall ▁coverage ▁of ▁over ▁50 %.
▁This ▁indicates ▁a ▁delay ▁in ▁examination ▁and ▁55 ▁Annual ▁Report ▁Family ▁Health ▁Programme ▁201 1, ▁O ral ▁Health ▁Since ▁200 7, ▁an ▁O ral ▁Health ▁component ▁was ▁integr ated ▁into ▁the ▁Family ▁Health ▁Programme ▁and ▁the ▁services ▁are ▁delivered ▁through ▁Maternal ▁and ▁Child ▁Health ▁and ▁School ▁Health ▁Programmes .
▁In ▁addition , ▁there ▁are ▁additional ▁app lications ▁under ▁review ▁for ▁both ▁products .
▁Ministry ▁of ▁health ▁with ▁the ▁collaboration ▁of ▁National ▁C ancer ▁Control ▁Programme ▁has ▁commenced ▁early ▁det ection ▁and ▁prevention ▁of ▁O P M D ▁and ▁O ral ▁C ancer ▁to ▁strengthen ▁the ▁primary ▁oral ▁health ▁care ▁in ▁Sri ▁Lanka .
▁However , ▁88 .8% ▁of ▁all ▁mothers ▁tested ▁for ▁H b ▁before ▁12 ▁weeks ▁of ▁pregnancy ▁and ▁among ▁them ▁20 .9% ▁were ▁having ▁H b ▁% ▁below ▁11 g / d l .
▁Other ▁Regional ▁Cent res ▁are ; ▁TH ▁Per adeniya ; ▁Central ▁Province , ▁P G H ▁Badulla ; ▁Uva ▁Province , ▁P G H ▁Ratnapura ; ▁Sab arag amuwa ▁Province , ▁P G H ▁Kurunegala ; ▁North ▁Western ▁Province , ▁TH ▁Anuradhapura ; ▁North ▁Central ▁Province , ▁TH ▁Jaffna ; ▁Northern ▁Province ▁and ▁TH ▁Batticaloa ; ▁Eastern ▁Province ▁will ▁be ▁done ▁in ▁2016 .
▁CH D R ▁Al most ▁all ▁mothers ▁were ▁delivered ▁in ▁health ▁institutions ▁while ▁only ▁very ▁few ▁cases ▁delivered ▁at ▁home .
▁Women ▁who ▁were ▁identified ▁with ▁problems ▁were ▁referred ▁to ▁appropriate ▁centres ▁for ▁further ▁management ▁and ▁they ▁were ▁followed ▁up ▁in ▁the ▁field ▁by ▁the ▁area ▁PHM .
▁Training ▁conducted ▁for ▁Health ▁and ▁Education ▁officers ▁in ▁Monaragala , ▁Kalutara , ▁Gampaha , ▁Hambantota , ▁Jaffna , ▁Anuradhapura , ▁Colombo , ▁Matara , ▁K il in ochchi , ▁Kandy , ▁Kegalle , ▁Mannar , ▁Jaffna ▁districts ▁on ▁L ife ▁sk ill ▁development ▁and ▁Adolescent ▁Health .
▁L ah ug ala ▁( 90 .4 %), ▁Na ula ▁(8 7 .6% ), ▁B iy agama ▁(8 7 .1 %), ▁R amb uk k ana ▁(8 6 .9 %), ▁K are ith iv u ▁(7 9 .2 %), ▁D er an iy agala ▁(7 9 .1 %), ▁U hana ▁(7 9 .1 %), ▁De hi ow ita ▁( 78 .7 %), ▁H ing ur ak g oda ▁( 78 .5% ), ▁Ampara ▁( 78 .5 %) ▁and ▁P alle p ola ▁( 78 .5 %) ▁MOH ▁areas ▁were ▁award ed ▁a ▁place ▁from ▁first ▁to ▁t enth ▁for ▁the ▁highest ▁coverage ▁of ▁attendance ▁of ▁35 ▁year ▁co h ort ▁of ▁women ▁for ▁W WC ▁services .
▁Care ▁includes ▁creating ▁awareness , ▁health ▁promotion , ▁screening ▁and ▁appropriate ▁interventions ▁to ▁reduce ▁risk ▁factors ▁that ▁might ▁affect ▁future ▁pregnancies ▁of ▁the ▁reproductive ▁aged ▁women .
▁( S um m ery ▁of ▁H 7 97 ▁not ▁received ▁is ▁attached ▁with ▁An ne xt ure ) ▁There ▁were ▁10 14 4 ▁schools ▁and ▁1, 72 9, 2 68 ▁children ▁to ▁be ▁examined ▁out ▁of ▁the ▁enrolled ▁4, 0 4 1, 55 9 ▁children . The ▁S MI s ▁were ▁conducted ▁in ▁9, 80 2 ▁schools ▁resulting ▁in ▁overall ▁school ▁coverage ▁96 .7 %.
▁The ▁lowest ▁rank ing ▁areas ▁( C P R ▁less ▁than ▁50 ) ▁are ▁mainly ▁from ▁Northern ▁and ▁Eastern ▁Prov inces .
▁They ▁need ▁family ▁planning ▁and ▁other ▁reproductive ▁health ▁services ▁and ▁psych ological ▁support .
▁More ▁than ▁90 ▁% ▁of ▁women ▁attending ▁W WC s ▁were ▁scre ened ▁for ▁Hy per t ension , ▁D i abetes ▁and ▁breast ▁problems .
▁Figure ▁3.1 3 : ▁Ne on atal ▁Ret rie val ▁Te am ▁– ▁Lady ▁R idge way ▁Hospital ▁following ▁the ▁training ▁programme ▁3.4 .7 ▁Training ▁on ▁E ss ential ▁Newborn ▁Care ▁and ▁Bre ast feeding ▁C oun sel ing ▁For ▁the ▁third ▁success ive ▁year ▁all ▁the ▁Medical ▁Officers ▁pass ing ▁M D ▁P a ed i at ric s ▁Part ▁I ▁were ▁trained ▁as ▁trainers ▁in ▁E ss ential ▁Newborn ▁Care ▁and ▁Bre ast feeding ▁C oun sel ing ▁Cour se .
▁Such ▁patients ▁will ▁experience ▁tri v ial ▁benefits ▁from ▁the ▁use ▁of ▁nirmatrelvir - ritonavir .
▁Qu ar ter ly ▁MCH ▁Return ▁( H ▁50 9) ▁provides ▁a ▁comprehensive ▁set ▁of ▁data ▁on ▁the ▁performance ▁of ▁RMNCAYH ▁programme ▁at ▁the ▁MOH ▁level .
▁R out ine ▁activities ▁Figure ▁45 : ▁Ge ograph ical ▁vari ations ▁in ▁Inf ant ▁Mortality ▁R ate ▁( RH - M IS ) ▁Jaffna ▁More ▁than ▁15, ▁10 ▁to ▁15, ▁L ess ▁than ▁10, ▁K il in ochchi , ▁M ull at iv u , ▁Mannar , ▁Trincomalee , ▁Vavuniya , ▁Anuradhapura , ▁Puttalam , ▁Polonnaruwa , ▁Batticaloa , ▁Kurunegala ▁During ▁2011 ▁92 .6% ▁of ▁the ▁MOHs ▁have ▁sent ▁their ▁returns ▁on ▁nutrition ▁month ▁activities .
▁Their ▁target ▁group ▁includes ▁students ▁of ▁gr ades ▁1, ▁4, ▁and ▁7, ▁and ▁in ▁schools ▁with ▁more ▁than ▁200 ▁students ▁in ▁the ▁base ▁school , ▁all ▁children ▁below ▁the ▁age ▁of ▁13 ▁years , ▁with ▁less ▁than ▁200 ▁students ▁at ▁the ▁base ▁school , ▁and ▁500 ▁pres chool ▁children . ▁During ▁the ▁year ▁2015, ▁there ▁were ▁48 8 ▁S D C s ▁man ned ▁by ▁3 83 ▁S D T s .
▁Main ▁Activities ▁The ▁intra ▁ut er ine ▁cont ra cept ive ▁dev ice ▁has ▁been ▁in ▁use ▁for ▁re vers ible ▁cont ra ception ▁for ▁over ▁five ▁decades ▁as ▁a ▁method ▁of ▁interval ▁family ▁planning .
▁Given ▁the ▁evidence ▁from ▁r at ▁p up s ▁of ▁an ▁impact ▁on ▁growth ▁pl ate ▁th ick ness , ▁molnupiravir ▁should ▁not ▁be ▁used ▁in ▁children .
▁Therefore ▁since ▁1995 ▁to ▁200 1, ▁girls ▁in ▁11 ▁to ▁16 ▁years ▁were ▁immun ized ▁at ▁schools ▁while ▁other ▁women ▁in ▁child ▁bearing ▁Rub ella ▁coverage ▁has ▁been ▁very ▁high ▁over ▁the ▁time ▁and ▁in ▁201 1, ▁over ▁96 % ▁mothers ▁were ▁protected ▁for ▁Rub ella ▁by ▁the ▁time ▁they ▁get ▁pregnant .
▁P rel imin ary ▁work ▁on ▁I Y C F ▁strategy ▁development
▁In ▁assessment ▁of ▁re action ▁to ▁an ▁inv itation ▁from ▁an ▁unknown ▁person ▁who ▁made ▁contact ▁through ▁a ▁missed ▁call , ▁nearly ▁10% ▁reported ▁that ▁they ▁would ▁go ▁and ▁meet ▁that ▁person ▁with ▁or ▁without ▁a ▁friend ▁and ▁only ▁3 .0 % ▁sought ▁some ▁help .
▁A ▁W WC ▁off ers ▁a ▁general ▁physical ▁examination , ▁meas uring ▁height , ▁weight ▁and ▁blood ▁pressure , ▁breast ▁and ▁cervical ▁examination ▁( inc lud ing ▁taking ▁of ▁a ▁pap ▁sm ear ) ▁and ▁basic ▁investigations ▁like ▁check ing ▁for ▁blood ▁sugar .
▁N irmatrelvir ▁is ▁co ad min istered ▁with ▁rit onavir , ▁an ▁HIV ▁pr ▁o te ase ▁in hib itor , ▁used ▁in ▁this ▁c ▁on te xt ▁to ▁bo ost ▁the ▁pharmac ▁o k inet ics ▁of ▁nirmatrelvir ▁but ▁without ▁ex er ting ▁any ▁direct ▁ant ivir al ▁activity ▁itself ▁.
▁This ▁survey ▁compris ed ▁of ▁facility ▁assessment , ▁morbidity ▁estim ation ▁and ▁assessment ▁of ▁knowledge ▁of ▁relevant ▁health ▁workers .
▁Add ress ▁the ▁issue ▁of ▁over weight ▁among ▁pregnant ▁mothers . ▁In ▁order ▁to ▁assess ▁that , ▁pregnant ▁mothers ▁should ▁be ▁identified ▁before ▁12 ▁weeks ▁of ▁pregnancy .
▁Table ▁3 .7 ▁reflect s ▁the ▁live ▁births ▁reported ▁by ▁PHMs ▁as ▁a ▁proportion ▁of ▁the ▁live ▁births ▁reported ▁through ▁the ▁vital ▁registration ▁system .
▁Further ▁it ▁indicates ▁the ▁tre mend ous ▁potential ▁that ▁it ▁creat es ▁to ▁ensure ▁the ▁The ▁clinic ▁care ▁given ▁to ▁antenatal ▁mothers ▁is ▁expected ▁to ▁be ▁comp lim ent ed ▁by ▁d omiciliary ▁care ▁offered ▁by ▁PHMs .
▁A ccess ▁to ▁SARS - CoV -2 ▁diagn ost ics : ▁Since ▁this ▁recommendation ▁emphas izes ▁the ▁need ▁to ▁admin ister ▁tr ▁eat ment ▁with ▁remdesivir ▁within ▁7 ▁days ▁of ▁sympt om ▁onset , ▁increasing ▁access ▁and ▁ensuring ▁appropriate ▁use ▁o ▁f ▁diagn ost ic ▁tests ▁is ▁ess en ▁t ial .
▁3 ▁M A IN ▁A CT I VI T I ES ▁CO ND U CT ED ▁B Y ▁FA MI L Y ▁P L AN N ING ▁UNI T ▁2015 :
▁Those ▁were , ▁di abetes , ▁hy per t ension , ▁mal n utrition , ▁breast ▁and ▁cervical ▁mal ign ancies .
▁Sub group ▁analysis ▁all ▁included ▁RCTs ▁evaluated ▁I L -6 ▁recept or ▁block ers ▁excl us ively ▁in ▁severe ly ▁or ▁crit ically ▁ill ▁adults ▁with ▁COVID -19 ▁requ iring ▁hospitalization .
▁The ▁table ▁10 ▁exam ines ▁the ▁efficiency ▁of ▁these ▁activities .
▁With ▁regard ▁to ▁knowledge ▁on ▁sex ually ▁trans mitted ▁infections ▁( ST I ), ▁more ▁than ▁half ▁of ▁the ▁youth ▁correctly ▁identified ▁the ▁risk ▁of ▁S T I ▁even ▁after ▁a ▁single ▁sexual ▁inter c our se ▁and ▁48 % ▁knew ▁that ▁g en ital ▁u l c ers ▁could ▁be ▁a ▁sympt om ▁of ▁S T I .
▁3, 55 3, 2 95 ▁eligible ▁families ▁(10 2 %) ▁during ▁the ▁same ▁year ▁indic ating ▁that ▁reaching ▁the ▁target ▁population ▁has ▁been ▁almost ▁univers al .
▁L ess ons ▁lear nt ▁were ▁transl ated ▁into ▁action ▁at ▁hospital , ▁district ▁and ▁national ▁levels .
▁These ▁included ▁breast ▁and ▁cervical ▁mal ign ancies ▁and ▁non - com mun ic able ▁diseases ; ▁di abetes , ▁hy per t ension .
▁The rapeut ics ▁and ▁COVID -19 : ▁living ▁guideline ▁- ▁W ▁or ld ▁Health ▁Organization ▁( W HO ) ▁For ▁patients ▁with ▁non - severe ▁COVID -19 ▁at ▁highest ▁risk ▁of ▁hospitalization ▁Up d ated ▁St r ong ▁recommendation ▁for ▁We ▁recommend ▁treatment ▁with ▁nirmatrelvir - ritonavir ▁( st r ong ▁recommendation ▁f ▁or ).
▁However ▁C S M MR ▁for ▁se pt ic ▁ab ort ion ▁remains ▁more ▁or ▁less ▁st ag n ant ▁over ▁the ▁years .
▁Cap acity ▁building ▁of ▁medical ▁under gr at u ates ▁on ▁the ▁respons ib ilities ▁of ▁a ▁medical ▁professional ▁in ▁respond ing ▁to ▁GBV ▁is ▁considered ▁as ▁vital ▁in ▁order ▁to ▁strengthen ▁the ▁health ▁sector ▁response ▁to ▁GBV .
▁It ▁was ▁felt ▁that ▁remdesivir ▁would ▁have ▁an ▁important ▁effect ▁in ▁the ▁se ▁ vere ▁subgroup ▁and ▁a ▁conditional ▁recommendation ▁could ▁be ▁made ▁f ▁or ▁this ▁group .
▁Summary ▁Evidence , ▁summary ▁the ▁L N MA ▁on ▁con val es cent ▁pl as ma ▁included ▁16 ▁RCTs ▁that ▁enrolled ▁16 ▁23 6 ▁patients ▁across ▁non - severe , ▁severe , ▁and ▁critical ▁illness ▁subgroup s .
▁U lt im ately , ▁the ▁panel ▁made ▁its ▁recommendation ▁on ▁the ▁basis ▁of ▁the ▁moderate ▁certainty ▁evidence ▁of ▁a ▁28 - day ▁mortality ▁reduction ▁of ▁8 .7% ▁in ▁the ▁crit ically ▁ill ▁and ▁6 .7% ▁in ▁patients ▁with ▁severe ▁COVID -19 ▁who ▁were ▁not ▁crit ically ▁ill , ▁respectively .
▁Health ▁Administration ▁of ▁Sri ▁Lanka , ▁Sri ▁Lanka ▁has ▁a ▁dev olved ▁health ▁system ▁resulting ▁in ▁Ministry ▁of ▁Health ▁at ▁central ▁level ▁and ▁separate ▁provincial ▁ministries ▁of ▁Health .
▁Sri ▁Lanka ▁reported ▁a ▁MMR ▁of ▁16 94 ▁per ▁100 ,000 ▁live ▁births ▁in ▁the ▁year ▁19 47 ▁and ▁gradually ▁reduced ▁the ▁same ▁over ▁the ▁last ▁few ▁decades ▁to ▁achieve ▁the ▁best ▁in ▁the ▁South ▁Asian ▁Reg ion .
▁Each ▁MOH ▁is ▁supp osed ▁to ▁comp ile ▁H ▁50 9 ▁in ▁3 ▁cop ies ▁and ▁send ▁one ▁to ▁FHB , ▁2 nd ▁copy ▁to ▁RDHS ▁Office ▁before ▁the ▁25 th ▁of ▁the ▁month ▁following ▁each ▁quarter ▁( Figure ▁5 ).
▁Ob st ac les ▁to ▁access ing ▁L MI C s ▁due ▁to ▁cost ▁and ▁availability ▁are ▁of ▁concern .
▁Report ing ▁of ▁sub f ert ility ▁is ▁low ▁and ▁in ▁2015 ▁it ▁was ▁only ▁2 .7 %.
▁The ▁information ▁on ▁clinic ▁visits ▁to ▁specialist ▁units ▁and ▁private ▁sector ▁is ▁not ▁reported ▁in ▁R H - M IS .
▁A ▁rapid ▁communication ▁system ▁to ▁save ▁pregnant ▁mothers ▁to ▁facilit ate ▁contract ibility ▁between ▁hospital ▁and ▁field ▁health care ▁workers ▁was ▁introduced ▁and ▁established ▁in ▁13 ▁districts .
▁There ▁may ▁be ▁an ▁important ▁difference ▁in ▁mortality ▁in ▁these ▁patients .
▁Mic ron ut ri ent ▁supp lementation ▁in ▁field ▁care ▁is ▁one ▁of ▁the ▁interventions ▁in ▁maternal ▁care ▁programme ▁for ▁prevention ▁and ▁control ▁of ▁anaemia ▁and ▁other ▁m ic ron ut ri ent ▁defic i encies .
▁Ass essment ▁of ▁nutritional ▁status , ▁det ection ▁and ▁corre ction ▁of ▁health ▁problems , ▁providing ▁immun ization ▁and ▁wor m ▁treatment , ▁provision ▁of ▁m ic ron ut ri ent ▁supp lement ations ▁to ▁children ▁are ▁foc used ▁during ▁the ▁School ▁Medical ▁Inspect ions .
▁In ▁the ▁10 th ▁it eration ▁of ▁the ▁guideline , ▁a ▁ne ▁w ▁recommendation ▁was ▁made ▁f ▁or ▁the ▁use ▁o ▁f ▁remdesivir ▁for ▁patients ▁with ▁non - se ▁ vere ▁illness .
▁However , ▁out ▁of ▁antenatal ▁mothers ▁attending ▁field ▁clinics , ▁only ▁75 .1% ▁were ▁tested ▁for ▁VDRL ▁at ▁the ▁field ▁clinic ▁where ▁as ▁only ▁58 .8% ▁of ▁HIV ▁test ▁were ▁done ▁.
▁N irmatrelvir ▁exhib ited ▁ant ivir al ▁activity ▁against ▁SARS - CoV -2 ▁in ▁different iated ▁normal ▁human ▁b ron ch ial ▁ep it hel ial ▁cell s ▁with ▁an ▁E C 50 ▁of ▁0 .06 ▁m ic r ▁o mol ar ▁and ▁an ▁E ▁C 90 ▁of ▁0 .1 8 ▁m ic rom ol ar ▁.
▁As ▁a ▁whole , ▁RMNCAYH ▁programme ▁focus es ▁on ▁a ▁s iz able ▁proportion ▁( ar ound ▁54 %) ▁of ▁the ▁population , ▁which ▁includes ▁children , ▁adolescents , ▁youth ▁and ▁those ▁in ▁the ▁reproductive ▁ages .
▁The ▁reasons ▁for ▁the ▁four ▁ca ution ary ▁votes , ▁which ▁w ▁ere ▁shared ▁by ▁some ▁panel ▁members ▁who ▁vot ed ▁in ▁favour ▁of ▁a ▁strong ▁recommendation , ▁are ▁summar ized ▁below .
▁Pre ference ▁to ▁different ▁methods ▁of ▁cont ra cept ives ▁var ied ▁and ▁the ▁vari ation ▁seems ▁to ▁be ▁consist ent .
▁96 ▁% ▁of ▁mothers ▁had ▁visited ▁a ▁field ▁antenatal ▁clinics ▁which ▁are ▁conducted ▁at ▁field ▁clinics ▁or ▁non - s pecial ists ▁institutions ▁at ▁least ▁once ▁during ▁2011 .
▁Child ▁Health ▁Development ▁Record ▁( CH D R ) ▁is ▁being ▁updated ▁every ▁year , ▁and ▁in ▁2015 ▁new ▁add itions ▁were ▁made ▁to ▁include ▁the ▁new ▁fields ▁added ▁to ▁the ▁programme .
▁At ▁the ▁National ▁Maternal ▁Mortality ▁Review s ▁conducted ▁at ▁district ▁level ▁by ▁Family ▁Health ▁Bureau ▁in ▁collaboration ▁with ▁technical ▁experts ▁from ▁the ▁Sri ▁Lanka ▁College ▁of ▁Obstetric ians ▁and ▁G y na ec ologists ▁and ▁other ▁relevant ▁professional ▁bodies , ▁the ▁cause ▁of ▁death ▁is ▁confirmed ▁and ▁the ▁associated ▁factors ▁that ▁may ▁have ▁contrib uted ▁to ▁the ▁death ▁are ▁discussed ▁to ▁prevent ▁such ▁death ▁in ▁the ▁future .
▁It ▁could ▁also ▁be ▁a ▁reflection ▁of ▁sound ▁health ▁care ▁network ▁of ▁the ▁country ▁which ▁facilit ates ▁the ▁service ▁prov ider – rec ip ient ▁contact s .
▁The ▁new ▁package ▁of ▁intervention ▁on ▁pre ▁pregnancy ▁care ▁has ▁been ▁introduced ▁to ▁c ater ▁for ▁the ▁needs ▁of ▁newly ▁married ▁couples .
▁School ▁health ▁programme ▁targets ▁children ▁and ▁adolescents ▁attending ▁schools , ▁ministries ▁over lo ok s ▁the ▁sal ient ▁issues ▁related ▁to ▁the ▁School ▁Health ▁Programme .
▁Int ra - N atal ▁and ▁Newborn ▁Care ▁Al most ▁all ▁the ▁deliveries ▁around ▁the ▁country ▁occur ▁in ▁institutions .
▁Certainty ▁of ▁the ▁Evidence ▁Certainty ▁of ▁evidence ▁was ▁r ated ▁as : ▁low ▁for ▁decreased ▁mortality ▁( rated ▁down ▁from ▁high ▁for ▁imprecision ▁and ▁inc ▁on s ist ency g iven ▁the ▁ongoing ▁uncertainty ▁regarding ▁cred ibility ▁of ▁the ▁severity ▁of ▁illness ▁subgroup ▁effect ▁mod ification ); ▁moderate ▁for red uction ▁in ▁need ▁for ▁invas ive ▁mechanical ▁ventilation ; ▁and ▁moderate ▁for ▁little ▁or ▁no ▁impact ▁on ▁time ▁to ▁sympt om ▁improvement .
▁Ste ps ▁were ▁taken ▁to ▁strengthen ▁the ▁field ▁health ▁component ▁of ▁AY F H ▁service ▁provision ▁through ▁training ▁of ▁the ▁trainers ▁from ▁the ▁district ▁level .
▁Give ▁the ▁P P ▁morbid ities ▁reported ▁by ▁number ▁and ▁rate ▁( per ▁1000 ▁P M ) ▁Out ▁of ▁total ▁pregnancies ▁registered , ▁4 .2% ▁were ▁not ▁reported ▁as ▁outcomes .
▁3 .3 ▁Low ▁B irth ▁Weight ▁Low ▁birth ▁weight ▁among ▁newborns ▁is ▁still ▁a ▁problem ▁enc ount ered ▁even ▁though ▁the ▁percentage ▁has ▁gone ▁down ▁slight ly ▁during ▁last ▁three ▁years .
▁The ▁leading ▁ca uses ▁of ▁maternal ▁deaths ▁were ▁heart ▁disease , ▁respiratory ▁diseases ▁and ▁ob stetric ▁ha emor r h age ▁( Figure ▁5.3 ).
▁The ▁system ▁was ▁continu ously ▁res h aped ▁to ▁maintain ▁the ▁t im el iness , ▁data ▁quality ▁and ▁coverage .
▁However , ▁the ▁potential ▁long - term ▁harms ▁of ▁molnupiravir ▁remain ▁uncertain ▁and ▁a ▁matter ▁of ▁concern , ▁in ▁the ▁absence ▁of ▁clinical ▁data .
▁Figure ▁x ▁and ▁x ▁show ▁the ▁number ▁of ▁maternal ▁deaths ▁(2 001 ▁– ▁200 5) ▁and ▁the ▁Maternal ▁Mortality ▁R ati o ▁(1 9 95 ▁to ▁2015 ) ▁respectively .
▁As ph y x ia ▁happened ▁to ▁be ▁the ▁next ▁common ▁cause ▁of ▁infant ▁deaths .
▁Rev ision ▁of ▁standards ▁for ▁AYFHS ▁was ▁initiated ▁with ▁the ▁participation ▁of ▁the ▁international ▁expert ▁with ▁the ▁support ▁from ▁World ▁Health ▁Organization .
▁Short ▁dur ations ▁of ▁therapy ▁needed ▁in ▁C ▁O VID -19 ▁may ▁make ▁drug ▁inter act ions ▁eas ier ▁to ▁manag ▁e ▁than ▁they ▁are ▁for ▁HIV , ▁but ▁tw ic ▁e ▁daily ▁administration ▁means ▁that ▁the ▁rit onavir ▁dose ▁is ▁double ▁th a ▁t ▁used ▁in ▁most ▁modern ▁an ▁t ire t ro vir al ▁reg imens .
▁( Table ▁6 .2 ) ▁of ▁eligible ▁couples ▁over time ▁is ▁given ▁in ▁figures ▁6 .2 .1 ▁New ▁Ac cept ors ▁by ▁method ▁Table ▁6 .2 : ▁Con t re ace pt ive ▁methods ▁new ▁accept ors ▁by ▁method ▁from ▁2012 ▁2015 ▁It em ▁2012 ▁2013 ▁2014 ▁2015 ▁New ▁Ac cept ors ▁23 8, 0 16 ▁18 1, 6 45 ▁12 7, 1 30 ▁15 3, 90 1 ▁( No .)
▁Ge ograph ic ▁vari ations ▁are ▁often ▁prominent ▁in ▁nutritional ▁indicators ▁where ▁the ▁RDHS s ▁Rath napura ▁and ▁Ampara ▁were ▁pers ist ent ▁to ▁have ▁more ▁than ▁30% ▁of ▁mothers ▁with ▁low ▁BMI ▁at ▁the ▁beginning ▁of ▁their ▁pregnancy ▁for ▁last ▁two ▁years ▁( f igure ▁15 ).
▁The ▁GDG ▁no ▁t ed ▁with ▁c ▁on c ern ▁the ▁dear th ▁of ▁p ed i at ric ▁data ▁and ▁a ▁strong ▁call ▁f ▁or ▁research ▁in ▁this ▁area ▁was ▁made .
▁Report ing ▁of ▁infant ▁births ▁and ▁deaths ▁are ▁low ▁through ▁R H - M IS ▁compared ▁to ▁Registrar ▁General ' s ▁Department ▁reporting .
▁App lic ability ▁Only ▁one ▁o ▁f ▁the ▁included ▁trials ▁included ▁child r ▁en ▁(1 2 ▁years ▁of ▁age ▁and ▁older ), ▁and ▁the ▁numbers ▁w ▁ere ▁extremely ▁small ; ▁therefore ▁the ▁applic ability ▁of ▁this ▁recommendation ▁to ▁children ▁remains ▁uncertain .
▁Six ty ▁two ▁AD C ’ s ▁which ▁are ▁located ▁in ▁school ▁premises ▁were ▁man ned ▁by ▁Dental ▁Sur ge ons ▁c ater ing ▁to ▁the ▁children ▁above ▁13 ▁years ▁of ▁age ▁and ▁special ▁groups .
▁This ▁high ▁coverage ▁has ▁been ▁presented ▁throughout ▁the ▁period ▁since ▁2007 .
▁The ▁GDG ▁used ▁the ▁I C E MA N ▁tool ▁to ▁assess ▁the ▁cr ▁ed ibility ▁of ▁this ▁subgroup ▁finding ▁as ▁this ▁w ▁as ▁cru cial ▁to ▁inform ing ▁the ▁direction ▁of ▁the ▁recommendation .
▁K il in ochchi , ▁M ull at iv u , ▁Mannar , ▁Trincomalee , ▁Vavuniya , ▁Anuradhapura , ▁Puttalam , ▁Polonnaruwa , ▁Batticaloa , ▁Kurunegala , ▁Matale , ▁Ampara , ▁Kal m une i , ▁k andy ▁9 .2 ▁New ▁Ac cept or ▁R ate ▁Gampaha , ▁Kegalle , ▁Badulla , ▁Nuwara - E li ya , ▁Colombo , ▁and ▁Monaragala ▁R H - M IS ▁has ▁a ▁special ▁registration ▁system ▁to ▁record ▁the ▁pattern ▁of ▁accept ance ▁of ▁cont ra cept ive ▁methods ▁by ▁couples .
▁Cond u cted ▁two ▁B i - ann ual ▁Review ▁Worksh ops ▁for ▁Medical ▁Officers ▁of ▁Maternal ▁and ▁Child ▁Health ▁and ▁annual ▁Review ▁Worksh ops ▁for ▁Regional ▁Superv ising ▁Public ▁Health ▁Nurs ing ▁Officers ▁and ▁Survey ▁Stat istical ▁Officers ▁at ▁District ▁level .
▁The ▁figure ▁38 ▁pres ents ▁the ▁percentage ▁of ▁total ▁estimated ▁children ▁who ▁were ▁registered ▁by ▁PHMs , ▁since ▁2007 ▁to ▁2011 .
▁The ▁administrative ▁and ▁technical ▁guidance ▁relevant ▁to ▁the ▁Family ▁Health ▁Programme ▁is ▁integr ated ▁into ▁the ▁usual ▁multi - t ier ▁organ iz ational ▁arrange ment ▁of ▁the ▁Ministry ▁of ▁Health .
▁One ▁main ▁component ▁of ▁this ▁package ▁is ▁sens it ization ▁of ▁the ▁new ▁couples ▁Health ▁system ▁and ▁its ▁providers ▁are ▁strateg ically ▁placed ▁and ▁are ▁very ▁likely ▁to ▁come ▁across ▁these ▁surviv ors ▁and ▁have ▁a ▁unique ▁on ▁some ▁important ▁top ics ▁which ▁would ▁enable ▁them ▁to ▁have ▁a ▁good ▁mar ital ▁life .
▁Short age ▁and ▁mal - d ist ribution ▁of ▁S D T s , ▁transportation ▁problems ▁for ▁condu ction ▁of ▁out ▁reach ▁clinics , ▁inc ons ist encies ▁in ▁work lo ad ▁of ▁S D T s ▁and ▁problems ▁in ▁class ification ▁of ▁oral ▁diseases ▁by ▁the ▁S D T s ▁are ▁some ▁of ▁the ▁main ▁challeng es ▁fac ed ▁by ▁the ▁School ▁Dental ▁Services .
▁T ▁his ▁subgroup ▁analysis ▁was ▁based ▁en ▁t ire ly ▁on ▁within - t rial ▁compar isons ▁rather ▁than ▁between - t rial ▁compar isons ▁which ▁increased ▁the ▁cred ibility .
▁St ated ▁below ▁is ▁the ▁summary ▁of ▁annual ▁statistics ▁of ▁School ▁Dental ▁Services ▁submitted ▁by ▁S D TT ▁for ▁the ▁year ▁2015.
▁Hy per t ension ▁was ▁found ▁among ▁4 .0 ▁% ▁of ▁women ▁while ▁1.8 ▁% ▁of ▁them ▁were ▁D i abet ics ▁reporting ▁of ▁pap ▁sm ears .
▁Recommend ations ▁from ▁the ▁B ot tle ▁N ec k ▁An alysis ▁will ▁be ▁used ▁in ▁the ▁development ▁of ▁the ▁Sri ▁Lanka ▁Every ▁Newborn ▁Action ▁Plan ▁2017 -20 20 .
▁Figure ▁3.1 4 : ▁Medical ▁Officers ▁pass ing ▁M D ▁P a ed i at ric s ▁Part ▁I ▁in ▁June ▁2015 ▁following ▁E NC C ▁and ▁B F ▁C oun sel ing ▁3.4 .8 ▁Technical ▁Adv is ory ▁Committee ▁on ▁Newborn ▁and ▁Child ▁Health ▁The ▁T AC NC H ▁was ▁con ven ed ▁once ▁in ▁two ▁months ▁during ▁the ▁year ▁2015 ▁under ▁the ▁ch air m ans hip ▁of ▁D DG ▁PHS
▁The ▁School ▁Health ▁Unit ▁of ▁the ▁Family ▁Health ▁Bureau ▁assisted ▁Ministry ▁of ▁Education ▁to ▁advoc ate ▁health y ▁c ant een ▁policy ▁and ▁iss uing ▁a ▁circular ▁describ ing ▁the ▁health y ▁food ▁items ▁that ▁should ▁be ▁available ▁in ▁a ▁school ▁c ant een ▁has ▁been ▁issued .
▁Resources ▁and ▁other ▁considerations ▁Ac cept ability ▁and ▁feasibility ▁Rem desivir ▁is ▁administered ▁as ▁one ▁in ▁tra ven ous ▁inf usion ▁daily ▁over ▁3 ▁consec utive ▁days , ▁representing ▁a ▁f ▁eas ibility ▁challenge ▁in ▁out p ati ents ▁aim ing ▁to ▁a ▁v oid ▁hospital ▁admission .
▁A ▁stakehold er ▁workshop ▁was ▁conducted ▁and ▁study ▁instruments ▁were ▁pret ested ▁and ▁final ised ▁in ▁2015.
▁A ▁series ▁of ▁well - des ign ed ▁pack ages ▁are ▁available ▁to ▁deliver ▁these ▁interventions ▁to ▁target ▁groups .
▁With out ▁direct ▁data ▁and ▁low ▁certainty ▁confidence ▁in ▁indirect ▁compar isons ▁the ▁GDG ▁ch ose ▁no ▁t ▁to ▁make ▁compar ative ▁recommendations ▁between ▁drugs , ▁but ▁r ▁at her ▁remark ▁that ▁nirmatrelvir - ritonavir ▁may ▁be ▁super ior ▁based ▁on ▁its ▁e ▁f fic acy ▁compared ▁with ▁standard ▁of ▁care ▁and ▁that ▁ult im ately , ▁choice ▁of ▁therapeutic ▁may ▁be ▁based ▁on ▁practical ▁issues ▁such ▁as ▁administr ▁at ion ▁and ▁po ▁t ential ▁drug - d rug ▁inter act ions .
▁PH NS ▁and ▁SP HM ▁have ▁a ▁h ier arch ical ▁administrative ▁relationship ▁where ▁PH NS ▁has ▁to ▁superv ise ▁SP HM .
▁There ▁are ▁four ▁main ▁ongoing ▁special ▁community ▁oral ▁health ▁programmes ▁conducting ▁successfully ▁Is land ▁wide .
▁Not ▁count ing ▁pregnancies ▁that ▁had ▁ended ▁up ▁as ▁ab ort ion ▁as ▁delivery ▁and ▁gaps ▁in ▁post ▁n atal ▁registration ▁may ▁be ▁possible ▁reasons ▁for ▁this .
▁1.1 ▁School ▁Health ▁Sur ve ys ▁It ▁is ▁a ▁responsibility ▁of ▁range ▁PHI ▁to ▁complete ▁the ▁school ▁health ▁survey ▁annually .
▁This ▁reinfor ces ▁that ▁remdesivir ▁should ▁be ▁reserv ed ▁for ▁those ▁at ▁highest ▁risk .
▁The ▁main ▁strategy ▁used ▁to ▁fulf ill ▁this ▁is ▁by ▁ensuring ▁women ▁of ▁child ▁bearing ▁age ▁and ▁their ▁partners ▁receiving ▁a ▁comprehensive ▁package ▁of ▁pre - conception ▁care .
▁Finally , ▁11 3 ▁maternal ▁deaths ▁were ▁identified ▁to ▁calculate ▁the ▁national ▁maternal ▁mortality ▁ratio ▁of ▁33 .7 ▁per ▁100 ,000 ▁live ▁births .
▁However , ▁now ▁that ▁our ▁understanding ▁of ▁COVID -19 ▁disease ▁c ▁our se ▁has ▁improved , ▁it ▁f its ▁th a ▁t ▁those ▁earlier ▁in ▁their ▁disease ▁tra ject ory ▁( severe , ▁but ▁no ▁t ▁yet c rit ical ) ▁may ▁have ▁more ▁viral ▁rep lication ▁and ▁therefore ▁benefit ▁more ▁from ▁an ▁an ▁t i - vir al ▁therapy . U lt im ately , ▁the ▁GDG ▁decided ▁th a ▁t ▁the ▁direction ▁of ▁effect ▁mod ification ▁was ▁probably ▁correctly ▁hypot hes ized , ▁which ▁inc r ▁e ased ▁the ▁cred ibility ▁of ▁the ▁subgroup ▁finding .
▁Se ven ▁(07) ▁awareness ▁programmes ▁on ▁family ▁planning ▁were ▁conducted ▁in ▁seven ▁districts ▁in ▁seven ▁provinces ▁( C ent ral , ▁North ▁Central , ▁Eastern , ▁Northern , ▁Southern , ▁North ▁Western , ▁and ▁Uva ) ▁in ▁2015.
▁Con tra cept ive ▁failure ▁rate ▁and ▁complications , ▁Services ▁for ▁sub f ert ile ▁couples ▁Con tra cept ive ▁method ▁fail ures ▁are ▁supp osed ▁to ▁be ▁reported ▁through ▁R H - M IS .
▁Other ▁contextual ▁factors , ▁such ▁as ▁resource ▁considerations , ▁access ibility , ▁feasibility , ▁and ▁impact ▁on ▁health ▁equity ▁did ▁not ▁al ter ▁the ▁recommendation .
▁The ▁per inatal ▁mortality ▁rate ▁was ▁10 .1 ▁per ▁1000 ▁total ▁births .
▁Family ▁Health ▁Programme ▁promot es ▁early ▁and ▁regular ▁antenatal ▁care .
▁F ail ure ▁rates ▁for ▁different ▁methods ▁are ▁given ▁in ▁Table ▁6 .. 2.
▁In ▁2016, ▁Family ▁Health ▁Bureau ▁will ▁use ▁a ▁dedicated ▁soft w are ▁programme ▁to ▁stream line ▁the ▁log istics ▁and ▁supply ▁ch ain ▁management ▁of ▁all ▁W WC ▁items . t ied ▁having ▁di abetes ▁me ll it us .
▁The ▁graph ▁draw s ▁the ▁attention ▁for ▁need ▁for ▁cause - specific ▁preventive ▁strategies ▁to ▁reduce ▁maternal ▁deaths ▁further ▁in ▁the ▁country .
▁Un certainty ▁also ▁remains ▁with ▁regard ▁to ▁administration ▁of ▁remdesivir ▁to ▁pregnant ▁or ▁lactating ▁women .