Chapter+7: Discussion+
7.1 Clinical+study+
7.1.1 Clinical+outcomes+of+HIVSexposed,+uninfected+infants.+
We!found!that!HIVDexposed,!uninfected!infants!had!increased!rates!of!illness,!in!keeping!
with!a!number!of!other!studies.11,19,24,36,38!HIVDexposed,!uninfected!infants!had!significantly!
more!attendances!to!primary!health!clinics!and!there!was!a!trend!towards!increased!
admissions!to!hospital!for!infectious!morbidity.!!A!study!enrolling!over!14,000!infants,!of!
which!nearly!3,000!were!uninfected!HIVDexposed!infants,!in!Zimbabwe!found!that!up!to!the!
age!of!2!years,!HIVDexposed,!uninfected!infants!were!1.2!times!more!likely!to!attend!primary!
healthcare!for!illness.24!We!detected!a!similar!increase!in!attendance!at!any!primary!health!
clinic!(30%!increased),!however!since!our!study!cohort!was!significantly!smaller!this!did!not!
reach!statistical!significance.!The!rate!of!hospital!admission!for!serious!infectious!morbidity!
was!also!higher!amongst!HIVDexposed,!uninfected!infants!in!our!study.!The!Zimbabwe!study!
also!found!that!HIVDexposed,!uninfected!infants!were!hospitalised!up!to!50%!more!often!in!
the!neonatal!period.!Later!in!infancy!rates!of!hospital!admission!were!similar!to!HIVD unexposed!infants.!When!only!considering!LRTI!as!the!cause!of!admission,!neonates!were!
2.7!times!more!likely!to!be!admitted!to!hospital.24!The!trends!observed!in!our!study!were!in!
keeping!with!these!results.!Other!smaller!studies!have!not!observed!a!difference.16,43!!
!
A!number!of!factors!may!intersect!to!explain!the!reasons!for!increased!morbidity!and!
mortality!in!uninfected!HIVDexposed!infants!and!children,!not!least!powerful!socioDeconomic!
forces.!In!our!study!HIVDinfected!women!were!more!likely!to!live!in!an!informal!housing!
structure!with!no!household!running!water!or!toilet.!Marinda!found!that!lower!household!
wealth!was!associated!with!an!increased!risk!of!death!in!HIVDexposed,!uninfected!infants.10! We!found!that!women!living!with!HIV!were!older!and!more!likely!to!have!had!more!than!one!
child!compared!to!HIVDuninfected!mothers.!Other!studies!have!consistently!observed!these!
differences.!10,45,62,203!The!number!of!children!in!the!household!may!impact!household!
resources!and!also!transmission!of!pathogens.!!
!
Another!factor!that!has!been!considered!to!impact!morbidity!and!mortality!is!replacement!
feeding!of!HIVDexposed,!uninfected!infants.!In!this!study!all!HIVDexposed!infants!received!
exclusive!replacement!feeding,!whereas!all!HIVDunexposed!infants!were!breastDfed!at!birth!
and!the!majority!were!still!receiving!breast!milk!at!4!months!of!age.!!!
!
In!our!study!there!was!no!difference!in!birth!weight!or!subsequent!growth!of!infants.!Some!
studies!have!observed!a!difference!in!birth!weight,!whilst!others!have!not!found!any!
difference.10,44D46,204,205!However,!subsequent!growth!has!been!consistently!found!to!be!
similar!in!HIVDexposed,!uninfected!infants!compared!to!unexposed!infants.43D46!In!large!
studies!the!absolute!difference!in!birth!weight!was!minor.!We!deliberately!excluded!preterm!
infants!and!low!birth!weight!infants!(LBW,!<2.5kg),!therefore!it!is!not!altogether!surprising!
that!we!failed!to!detect!a!significant!difference.10On!a!population!level,!an!increase!in!the!
number!of!LBW!infants!might!have!a!significant!impact!since!this!is!a!risk!factor!for!increased!
mortality!rates.61!!
!
7.1.2 The+effect+of+HIV+infection+on+haematological+parameters+
HIVDinfected!mothers!tended!to!have!lower!haemoglobin!levels!and!had!significantly!
reduced!RBC!counts!compared!to!uninfected!mothers.!This!is!commonly!observed!in!studies!
of!HIVDinfected!individuals!and!is!thought!to!be!due!to!reduced!erythropoiesis!caused!by!
inflammatory!cytokines.206,207!Maternal!anaemia!is!associated!with!HIV!progression!and!
mortality.206!We!did!not!observe!difference!in!haemoglobin!at!birth!or!16!weeks!amongst!
any!groups!of!infants.!!
!
Our!data!show!that!HIVDinfected!women!had!lower!WBC!than!uninfected!mothers,!however!
their!infants!also!had!similar!WBC!at!birth!compared!to!unexposed!infants.!Multiple!
haematological!abnormalities!have!been!observed!in!HIVDexposed,!uninfected!infants!
exposed!to!antiDretroviral!drugs!in#utero!or!postpartum,!particularly!Zidovudine,!in!many!
studies!and!in!diverse!locations.208!Anaemia!is!transient!in!most!studies,!however!
neutropenia!and!lymphopenia!may!be!more!prolonged.!Anaemia!is!more!pronounced!in!
infants!born!to!mothers!receiving!combination!antiretroviral!treatment.!!
!
7.1.3 Assessment+of+Mtb+sensitization+in+pregnancy+
Discordant!results!were!common!between!TST!and!QFN!tests,!however,!the!agreement!
between!tests!was!similar!amongst!HIVDinfected!(73%)!and!uninfected!women!(76%).!Until!
recently!there!were!no!studies!examining!the!performance!of!IGRAs!in!pregnancy,!however!
very!recently!two!studies!have!been!published!that!show!fair!agreement!between!TST!and!
IGRA!in!pregnancy,!κ=!0.26!–!0.45,!in!line!with!the!concordance!found!in!our!study,!κ=!
0.49.209,210!To!our!knowledge,!there!are!no!published!studies!examining!the!concordance!of!
IGRAs!and!TST!in!pregnant!women!living!with!HIV.!
!
Although!TST!reactivity!and!interpretation!are!unaltered!in!pregnancy,!both!tests!are!well!
know!to!be!affected!by!HIV!infection,!particularly!with!increasing!immunosuppression.211! There!is!little!data!to!inform!the!use!of!IGRAs!in!pregnancy!with!one!study!concluding!that!
the!performance!of!IGRAs!are!comparable!in!pregnant!and!nonDpregnant!women.209!Recent!
data!suggests!that!pregnant!women!with!latent!TB!are!not!more!likely!to!progress!to!active!
disease!than!nonDpregnant!women,!even!in!the!presence!of!HIV!infection.212!However,!active!
TB!in!pregnancy,!in!particular,!extrapulmonary!TB!is!associated!with!considerable!maternal!
morbidity!and!mortality,!intrauterine!growth!restriction,!premature!delivery!and!infant!
mortality.213!Accurate!identification!of!maternal!Mtb!sensitisation!and!appropriate!use!of!
isoniazid!preventative!therapy!(IPT)!to!prevent!progression!to!disease!is!therefore!critical.!
IPT!can!be!used!safely!in!pregnancy!and!is!effective!in!preventing!active!disease.214!IGRAs!
may!be!a!useful!tool!in!identifying!women!at!increased!risk!of!active!TB!who!would!benefit!
from!IPT.!In!one!study,!a!positive!IGRA!was!associated!with!a!4.5!fold!increased!risk!of!TB!in!
the!2!years!postpartum.!For!women!with!a!CD4!count!of!less!than!250!cells/μl,!a!positive!
IGRA!was!also!associated!with!an!increased!risk!of!mortality!and!with!infant!TB!and!
mortality.215!In!this!study!the!indeterminate!rate!was!significantly!higher!(15%)!than!the!rate!
observed!in!our!study!(1%).!!
!
7.1.4 Clinical+correlates+of+BCG+vaccination+
All!infants!had!evidence!of!a!BCG!scar!at!4!months!of!age,!but!HIVDexposed!infants!tended!to!
have!smaller!scars.!The!actual!difference!was!small!and!did!not!reach!statistical!significance,!
p=!.05.!In!a!study!in!The!Gambia,!Ota!et#al!observed!a!tendency!for!HIVDexposed,!uninfected!
children!to!fail!to!develop!a!BCG!scar,!however!they!examined!the!response!at!18!months!of!
age!compared!to!just!4!months!in!our!study.216!Other!studies!have!not!found!any!difference!
in!the!proportion!of!HIVDexposed,!uninfected!infants!who!develop!a!scar!at!3!D!4!months!of!
age!compared!to!unexposed!infants.73!Whilst!a!BCG!scar!is!a!indicator!of!vaccination,!there!is!
no!clinical!evidence!that!the!size!of!the!BCG!scar!is!associated!with!protection!against!
TB.200,217!Scar!size!has!however!been!correlated!with!immune!responses!to!BCG.!Djuardi!and!
colleagues!found!that!BCG!scar!size!at!4!years!of!age!was!moderately!correlated!with!Th2!
responses!to!PPD!at!5!months!postDBCG!vaccination.!This!response!diminished!with!
increasing!time!post!BCG!vaccination.85!Elliott!also!observed!a!moderate!positive!correlation!
between!BCG!scar!size!and!ILD5!response!to!mycobacterial!antigens.218!!
!