Th ee-decade neu ological
and neu ocogni i e ollow-up
o HIV-1-in ec ed pa ien s
on bes -a ailable an i e o i al
he apy in Finland
T Heikinheimo,
1
E Pou iainen,
1,2
O Salonen,
3
I Elo aa a,
4
M Ris ola
5
To ci e: Heikinheimo T,
Pou iainen E, Salonen O,
e al. Th ee-decade
neu ological
and neu ocogni i e ollow-up
o HIV-1-in ec ed pa ien s
on bes -a ailable an i e o i al
he apy in Finland. BMJ Open
2015;5:e007986.
doi:10.1136/bmjopen-2015-
007986
▸P epublica ion his o y o
his pape is a ailable online.
To iew hese iles please
isi he jou nal online
(h p://dx.doi.o g/10.1136/
bmjopen-2015-007986).
Recei ed 16 Feb ua y 2015
Re ised 19 Sep embe 2015
Accep ed 30 Sep embe 2015
Fo numbe ed a ilia ions see
end o a icle.
Co espondence o
D T Heikinheimo;
e u.heikinheimo-connell@
hus. i
ABSTRACT
Objec i es: Is i possible o li e wi hou
neu ocogni i e o neu ological symp oms a e being
in ec ed wi h HIV o a e y long ime? These
s udy pa ien s wi h decades-long HIV in ec ion in
Finland we e obse ed in his ollow-up s udy
du ing h ee ime pe iods: 1986–1990, in 1997 and
in 2013.
Se ing: Pa ien s om g ea e Helsinki a ea we e
selec ed om ou pa ien ’s uni o in ec ious diseases.
Pa icipan s: The s udy included 80 HIV pa ien s.
Pa ien s wi h hea y alcohol consump ion, cen al
ne ous sys em diso de o psychia ic disease we e
excluded.
P ima y and seconda y ou come measu es: The
pa ien s unde wen neu ological and neu opsychological
examina ions, MRI o he b ain and labo a o y es s,
including blood CD4 cells and plasma HIV-1 RNA.
Neu opsychological examina ion included se e al
measu es: sub es s o Wechsle Adul In elligence Scale,
Wechsle Memo y Scale-Re ised, lis lea ning, S oop
and T ail-Making-B es . The Beck Dep ession In en o y
and Fa igue Se e i y Scale we e also ca ied ou . The
ob ained da a om he h ee ime pe iods we e
compa ed wi h each o he .
Resul s: Owing o high mo ali y among he o iginal
80 pa ien s, e en ually, 17 pa icipa ed in all h ee
examina ions pe o med be ween 1986 and 2013. The
ime om he HIV diagnosis was 27 (23–30) yea s.
Blood CD4 cells a he diagnosis we e 610 (29–870)
cells/mm
3
, and he nadi CD4 168 (4–408) cells/mm
3
.
The ime on combined an i e o i al ea men was 13
(5–17) yea s. 9 pa ien s su e ed om a igue, 5 had
polyneu opa hy and 3 had lacuna ce eb al in a c s.
The e was a sub le inc ease o b ain a ophy in 2
pa ien s. Mild dep essi e symp oms we e common.
The neu opsychological ollow-up showed ypical age-
ela ed cogni i e changes. No HIV-associa ed demen ia
ea u es we e de ec ed.
Conclusions: Polyneu opa hy, a igue and mild
dep ession we e common, bu mo e se e e neu ological
abno mali ies we e absen . These long- e m su i ing
HIV-se oposi i e pa ien s, while on bes -a ailable
ea men , showed no e idence o HIV-associa ed
neu ocogni i e diso de in neu opsychological and
neu o adiological e alua ions.
INTRODUCTION
HIV has been challenging mankind o mo e
han 30 yea s. The i us c osses he blood–
b ain ba ie (BBB) and en e s he cen al
ne ous sys em (CNS) a an ea ly s age o he
in ec ion—and ne e lea es i . Wi hou ea -
men , HIV g adually causes a a ie y o neu o-
logical complica ions including HIV-associa ed
neu ocogni i e diso de (HAND). This can
a y om a clinically asymp oma ic o
mild neu ocogni i e diso de o se e e
HIV-associa ed demen ia (HAD). Wi h he
de elopmen o combined an i e o i al
he apy (cART), pa ien s wi h good adhe ence
can li e a long symp om- ee li e, and HAD
has become a e.
1
Howe e , cART does no
elimina e he i us, and i is claimed ha a
subs an ial po ion o pa ien s s ill de elop
neu ocogni i e impai men s.
2–5
A low le el
o cell- o-cell i al eplica ion also occu s
du ing he mos success ul cART egimens.
67
E en du ing e ec i e cART he e is a la en
ese oi o blood CD4 cells ca ying he
HIV genome, which is compe en o eplica-
ion.
89
Low nadi CD4 seems o p edic , a
S eng hs and limi a ions o his s udy
▪The s udy was a e y long- e m, me iculous
ollow-up o HIV-in ec ed pa ien s.
▪The s udy e alua ed almos hal o he Finnish
HIV popula ion du ing 1986–1990.
▪A sys ema ic neu opsychological and neu o-
logical, neu oimaging and HIV in ec ion assess-
men is included.
▪The s udy sample is small.
▪Su i al bias.
Heikinheimo T, e al.BMJ Open 2015;5:e007986. doi:10.1136/bmjopen-2015-007986 1
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leas pa ially, e e sible HAND.
2
Ve y long- e m
ollow-up s udies on he e olu ion o neu ocogni i e
unc ion among HIV-in ec ed pa ien s a e lacking. To
he bes o ou knowledge, his is he fi s s udy desc ib-
ing a g oup o pa ien s ollowed up o as many as
30 yea s.
Public heal hca e p o ides HIV ea men in Finland.
In he Helsinki a ea, he in ec ious disease uni a
Au o a Hospi al has p o ided medical ea men o
HIV in ec ion since 1983.
10
The fi s an i e o i al agen ,
zido udine, became a ailable a Au o a Hospi al in
1987. A coho s udy was s a ed in 1986, las ing 5 yea s,
o examine he CNS symp oms associa ed wi h HIV
in ec ion.
11
The HIV-in ec ed pa ien s we e hen ein es-
iga ed in 1997.
12
Fo his s udy, we e-in i ed he
pa ien s in 2013, o ob ain a longi udinal e alua ion o
hei neu ocogni ion, and o examine he neu ological
and neu oimaging findings o his g oup o people who
became in ec ed wi h HIV-1 mo e han 25 yea s ago,
and who ha e been ea ed wi h op imal he apy. In
Finland, an i i al HIV medica ion is ee o pa ien s
h ough he Finnish communicable disease legisla ion.
METHODS
Cen e and pa ien s
This is an obse a ional ollow-up s udy o HIV-in ec ed
pa ien s who we e fi s en olled in a neu ological and
neu opsychological examina ion du ing 1986–1990.
13 14
HIV in ec ion and AIDS a e epo able diseases in
Finland. The fi s pa ien wi h an HIV in ec ion was
diagnosed in 1983.
10
The in ec ious disease uni a
Au o a Hospi al in Helsinki akes ca e o HIV-in ec ed
indi iduals wi hin he g ea e Helsinki a ea. The hospi al
managed a o al o 98 HIV-in ec ed pa ien s in 1986.
The numbe o pa ien s inc eased e e y yea o 248 by
he yea 1991. A ound hal o hese pa ien s (n=106)
we e fi s e alua ed o his s udy du ing 1986–1990. The
exclusion c i e ia we e: his o y o CNS disease o p esen
HIV- ela ed CNS disease (no HAD), se e e demen ia,
ma ked lea ning disabili y, p ominen alcohol consump-
ion (scale 4, see below) and e usal o pa icipa ion.
Thus, 85 pa ien s pa icipa ed in he ini ial s udy.
13 15
La e , a u he fi e pa ien s wi h p e iously diagnosed
psychia ic p oblems we e excluded. Thus he s udy
coho a ailable o he ollow-up o alled 80 pe sons.
We included hose pa ien s who we e e-in i ed and who
ag eed o pa icipa e in all h ee s udy in e en ions in
1986–1990,
11
1997
12
and 2013, in his analysis.
S udy in e en ions
Du ing all h ee examina ion pe iods, de ailed medical
his o y was aken oge he wi h in o ma ion on pa ien s’
educa ional backg ound, p o ession and occupa ion.
F om each pa ien ’s medical eco ds and p e ious
esea ch eco ds, he ollowing da a we e eco ded:
da es o acquisi ion and diagnosis o HIV in ec ion,
his o y o ART, and he da e o ini ia ion o cART and
possible in e up ions o he he apy. Vi ologically sup-
p essi e he apy was defined as ha ing mos plasma HIV
i al loads below he limi o de ec ion be o e he yea
2000 and below 50 copies/mL he ea e . Blood CD4
cells (cells/mm
3
) wi hin he yea o diagnosis and nadi
CD4 ( he lowes blood CD4 cells alue measu ed since
pa ien ’s HIV diagnosis), he da e o plasma HIV-1 RNA
le el being below 400 copies and below 50 copies, and
any AIDS e en s, we e eco ded. Pa ien s we e u he
di ided in o wo g oups depending on whe he hey had
used cART o mo e han 10 yea s con inuously e sus
pa ien s wi h <10 yea s o cART use, o ea men in e -
up ions. Pa ien s we e also di ided in o hose wi h low
nadi CD4 (<200 cells/mm
3
) and hose wi h highe
nadi CD4 alues, and compa ed.
The diagnosis o o he condi ions was eco ded om
he medical eco ds and using in o ma ion om he
pa ien : medica ion o die used o diabe es melli us,
hype ension ( ea ed, o a his o y o hype ension as
sys olic blood p essu e ≥140 mm Hg o dias olic blood
p essu e ≥90 mm Hg, o bo h), hype choles e olaemia
( ea ed o o al choles e ol le el ≥5.0 mmol/L,
low-densi y lipop o ein (LDL) le el ≥3.0 mmol/L, o
high-densi y lipop o ein (HDL) le el <1.0 mmol/L)
and ca dio ascula disease (p io diagnosis o co ona y
hea disease o myoca dial in a c ion). Diagnosis o
neph opa hy o signs o p o ein in u ine we e eco ded.
Any his o y o dep ession o bipola diso de , and diag-
nosis o epilepsy o demen ia, we e asce ained. Pa ien s
we e also ques ioned abou hei smoking habi s, and
whe he hey used any illegi ima e d ugs. Alcohol con-
sump ion was es ima ed (scale 0–4) in he fi s and las
e alua ions.
15
In he scale, 0=in equen use (0–100 g
alcohol pe week), 1=social d inke (101–250 g), 2=mod-
e a e use (251–350 g), 3=hea y d inke (351–500 g)
and 4=alcohol abuse (>500 g). The body mass index
was calcula ed o all pa ien s, o es ima e hei nu i-
ional s a us (unde weigh body mass index (BMI)
≤18.5 kg/m
2
) and obesi y (BMI ≥30 kg/m
2
).
Neu ological in es iga ions
In 2013, all he pa icipan s comple ed a a igue se e i y
scale (FSS) o m ansla ed in o Finnish, o de e mine
he le el o a igue pa ien s we e expe iencing.
16
The
FSS has nine s a emen s wi h a sco e ange 1–7. The
pa ien acco ds a alue based on how well he s a emen
eflec s his condi ion du ing he p e ious week. A o al
sco e ≥36 (max 63) in he FSS sugges s he pa ien is
su e ing om a igue.
16
In he yea 2013 assessmen , he diagnosis o polyneu -
opa hy o ea men o neu opa hic pain was eco ded.
Each pa icipan unde wen a neu ological e alua ion
pe o med by a neu ologis in all h ee ime pe iods. In
2013, we used a neu os a us sco ing sys em and he
expanded disabili y scale s a us (EDSS).
17
The neu os a-
us is di ided in o he domains o isual, b ains em,
py amidal, ce ebella , senso y and bowel/bladde .
We excluded he ce eb al domain, because we
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unde ook neu opsychological in es iga ions wi h mo e
de ailed in o ma ion. Each domain gi es he pa ien a
unc ional sys em sco e (FS) whe e 0–1=no symp oms,
signs only; 2–3=mild symp oms and signs; 3=mode a e
symp oms and signs; 4–6=se e e symp oms and signs.
The domains a e used o de e mine pa ien s’EDSS
oge he wi h pa ien ’s abili y o walk (ambula o y).
Bo h he neu os a us and EDSS a e used widely o es i-
ma e he unc ional disabili y o pa ien s wi h mul iple
scle osis. Fo his s udy, hey we e adap ed wi h he
pu pose o s anda dising he neu ological s a us and
making he clinical neu ological examina ion easie o
analyse quan i a i ely.
Neu opsychological in es iga ion
The neu opsychological examina ion included measu es
o memo y: he Logical Memo y I o he Wechsle
Memo y Scale–Re ised (Wechsle ’s memo y scale
(WMS)–R),
18
and a lis lea ning ask.
19
The easoning
was assessed using Simila i ies and Block Design sub es s
o he Wechsle Adul In elligence Scale (WAIS).
20
The
execu i e unc ions we e assessed wi h he T ail Making
B
21
and he In e e ence sub ask o he S oop colou
wo d es .
22
The speed o pe o mance was measu ed
wi h he Digi Symbol sub es o he WAIS and a naming
sub es o he S oop colou wo d es . Dep ession was
e alua ed wi h a sho o m o he Beck Dep ession
In en o y (BDI).
23
All pa icipan s we e in es iga ed
wi h he same neu opsychological es s in all h ee s udy
pe iods.
Neu o adiological in es iga ion
MRI was pe o med on 16 pa ien s bo h in 1997 and
2013. The fi s b ain MRI was pe o med using a 1.5 T
uni (Siemens, Vision). The MRI p o ocol included con-
en ional T2, fluid-a enua ed in e sion eco e y, T2
co onal and T1 mul iplana econs uc ion (MPR) sagi -
al images. The second imaging, in 2013, was pe o med
using a 3 T uni (Philips, Achie a). The MRI p o ocol
also included T2*, suscep ibili y weigh ed imaging
(SWI) and di usion weigh ed imaging (DWI) axial
sequences.
All b ain abno mali ies including in a c s and bleed-
ings we e eco ded. Whi e ma e hype in ensi ies
(WMHIs) we e classified as pe i en icula WMHIs o
deep WMHIs, and g aded 0 h ough 3. The se e i y o
whi e ma e lesions (WMLs) was a ed wi h he Fazekas
scale.
24
The bicauda e a ios and he wid h on he hi d
en icle we e measu ed o es ima e b ain a ophy.
Labo a o y in es iga ions
Apa om he HIV labo a o y wo k up a o emen ioned,
he ollowing labo a o y assessmen s we e made: a com-
ple e blood coun , li e unc ion (aspa a e amino ans-
e ase, alanine amino ans e ase, alkaline phospha ase,
o al bili ubin), kidney unc ion (c ea inine, p o ein in
u ine), plasma glucose and lipids ( o al choles e ol, high
HDL, LDL and iglyce ides), i al hepa i is se ology
(hepa i is B an igens (HBsAg, HBcAb), hepa i is C
an igen (HCVAb), syphilis se ology ( eponema palli-
dum haemagglu ina ion and ca diolipin an igen
(Vene eal Disease Resea ch Labo a o y) es s).
A cu en ce eb ospinal fluid (CSF) sample was a ail-
able o ou ine analysis om nine pa ien s.
S a is ics
S a is ical analyses we e compu ed using IBM s a is ics
so wa e SPSS V.22.00. Neu opsychological pa ame e s
we e analysed wi h mul i a ia e analyses o a iance
(Mano as) con olling he e ec o age in all analyses.
In he analysis o o he pa ame e s, simple pa ame ic
and non-pa ame ic es s along wi h simple desc ip i e
s a is ics, we e used, as app op ia e.
All pa ien s ga e hei w i en in o med consen o
pa icipa e in he s udy.
RESULTS
A e exclusions, he o iginal s udy g oup consis ed o 80
pa ien s du ing he pe iod 1986–1990. By he 1997
e alua ion, 47 pa ien s had passed away, 7 had been los
o ollow-up and 3 pa ien s e used he ollow-up e alu-
a ion; consequen ly, 23 pa ien s we e e alua ed in 1997.
Be ween 1997 and he cu en e alua ion, a u he fi e
pa ien s had passed away, wo om AIDS- ela ed compli-
ca ions a e 1997, and h ee om non-AIDS- ela ed
causes ou o mo e yea s a e 1997. Fo he la es e alu-
a ion, we we e able o con ac 18 HIV-in ec ed pa ien s
o pa icipa e in he neu ological, neu opsychological,
adiological and labo a o y wo k up. The pa ien s we e
all men. They had a sexually acqui ed HIV in ec ion, 16
h ough homosexual o bisexual con ac and wo
h ough he e osexual con ac s. All 18 pa ien s ga e hei
consen o pa icipa e in he s udy. One was oo ill o
pa icipa e in ex ended in es iga ions and was only
isi ed by he neu ologis s. His EDSS was 9.0. Du ing he
in e en ion in 2013, he died. No signs o
HIV-associa ed b ain damage we e obse ed in pos
mo em au opsy. The esul s o he emaining 17
pa ien s a e epo ed he e.
The demog aphic and clinical cha ac e is ics a e p e-
sen ed in able 1. O he 17 pa ien s, 11 (65%) had low
nadi CD4 o <200 cells/mm
3
, and 3 (18%) had had
AIDS e en s (one pa ien wi h oesophageal candida, one
wi h pneumocys is pneumonia, and one wi h Kaposi’s
sa coma and pneumocys is pneumonia. The pa ien wi h
wo AIDS illnesses had con ulsions wice while ecei ing
ea men o pneumocys is pneumonia). The e we e no
eli e con olle s o HIV-1 i aemia among he pa ien s,
whose median o he maximal HIV-1 i al load in
plasma was 145 000 copies/mL ( ange 10 900–9 360 000
copies/mL). The median yea o fi s s a ing ART was
1992 ( ange 1989–2002). Nine pa ien s had unde gone
con inuously i ologically supp essi e ART o 10 yea s
o longe . The emaining eigh pa ien s had had in e -
up ions o supp essi e ART o had aken con inuously
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supp essi e ART o <10 yea s. The cu en an i e o i al
combina ions a e shown in able 2.
Dep ession was diagnosed and ea ed in 4 (24%)
pa ien s. In he esul s o BDI be ween he h ee s udy
ime pe iods no significan changes appea ed: BDI
mean sco es we e 4.65, 5.53 and 5.00, espec i ely
(F iedman, χ
2
=0.5, p=0.779) indica ing mild dep essi e
symp oms. The BDI esul did no a y be ween he
g oups o low nadi CD4 o pa ien s wi h cART o mo e
han 10 yea s. Hype ension was medica ed and ea ed
in 5 (29%) pa ien s. Diabe es was diagnosed in wo
pa ien s. Neph opa hy was diagnosed in wo pa ien s,
one caused by diabe es and he o he by p os a ic hype -
plasia, while wo o he pa ien s had p o ein in u ine.
Dyslipidaemia was diagnosed in 11 (65%) pa ien s. One
pa ien was unde weigh (BMI 17.5 kg/m
2
) and one
obese (BMI 34.3 kg/m
2
). Alcohol consump ion had
been mode a e and was educed significan ly be ween
he fi s and las examina ion (mean sco e±SD: 0.82
±.0.64 s 0.35±0.79, Wilcoxon, Z=−2.3, p=0.021).
Tobacco smoking was no ed in 7 (41%) pa ien s. One
pa ien admi ed o occasionally using ma ihuana. None
o he pa ien s used in a enous o o he illegi ima e
d ugs.
Fou o he pa ien s had a diagnosis o neu opa hy.
On clinical neu ological examina ion, an addi ional
pa ien had signs o neu opa hy (Senso y FS 3.0–4.0).
Fou o fi e pa ien s wi h neu opa hy had been ea ed
wi h deoxynucleosides, ou wi h s a udine om 3 o
10 yea s and 3 wi h didanosine om 3 o 4.5 yea s. Only
one pa ien wi h neu opa hy had no been ea ed wi h
deoxynucleosides. Al oge he , six pa ien s had EDSS
be ween 3.0 and 4.0 (mean=3.4), indica ing mode a e
disabili y. In fi e, his was due o neu opa hy. One
pa ien had mild ex apy amidal findings and bladde
dys unc ion, which inc eased his EDSS. None o he
pa ien s had p ominen loss o ision, ce ebella a axia,
ma ked py amidal symp oms o o he clea signs o CNS
abno mali ies. They we e all ully ambula o y. Mos o
he pa ien s (16) had in ac sensa ion o smell.
The neu opsychological examina ion showed a mild
decline in aw sco es, pa icula ly be ween he second
and las examina ion, bu no significan changes we e
ound when age was con olled o in s a is ical analyses
( epea ed measu es Manco a) ( able 3). No e ec on
cogni ion was aced on pa ien s du ing he ollow-up
whe he hey we e on cART o a leas 10 yea s con inu-
ously, o <10 yea s, had an in e up ion o cART, o low
nadi CD4.
The neu o adiological ollow-up showed only a
minimal age- ela ed inc ease in a ophic changes. The
mean bicauda e a io was 0.12 in 1997 and 0.13 in 2013,
and he mean wid h o he hi d en icle was 0.57 and
0.68 cm, espec i ely. Two o he pa ien s showed a
sligh ly mo e p ominen inc ease in a ophy. Fou
pa ien s had new WMHIs. Th ee o he pa ien s had new
lacuna in a c s, one o which had al eady been seen in
1997. One o he h ee pa ien s also had mic ohaemo -
hages no seen in 1997. One o hese pa en s wi h
s oke was he eldes (75 yea s) o ou s udy g oup and
had some decline in neu opsychological pe o mance.
Howe e , he o he pa ien s wi h mild b ain a ophy o
s oke seen in he MRI had no de ec able decline in cog-
ni i e pe o mance.
A CSF sample was aken om nine pa ien s in 2013.
HIV-1 in CSF was below 20 copies/mL in eigh pa ien s.
The amplifica ion es ailed echnically on one sample.
Abou hal o he pa ien s had ele a ed p o ein o
immunoglobulin in CSF ( able 4). The leucocy e coun
and immunoglobulin–albumin a io we e wi hin no mal
ange in mos pa ien s s udied ( able 4).
Fi e pa ien s had posi i e HBcAb, indica ing an ea lie
hepa i is B in ec ion. None, howe e , we e HBsAg posi-
i e; hence none o he pa ien s we e ch onically
Table 1 Demog aphic and clinical cha ac e is ics o he
s udy popula ion
Cha ac e is ic (uni ) Median Range
Age (yea s) 57.0 46–75
Educa ion (yea s) 12.0 9–23
HIV in ec ion* (yea s) n=16 28 23–31
HIV diagnosis†(yea s) 27 23–30
CD4 a diagnosis‡(cells/mm
3
) n=15 610 29–870
nadi CD4 (cells/mm
3
) 168 4–408
ARV (yea s) 19 9–24
cART (yea s) 13 5–17
BMI (kg/m
2
) 23.4 17.5–34.3
EDSS 2.0 1.0–4.0
FSS 32 9–63
The numbe o pa ien s (n) is 17 unless men ioned o he wise.
*Pa ien s’own es ima ions abou ime om HIV in ec ion.
†Time om HIV diagnosis.
‡The i s blood CD4 cells, wi hin a yea o he diagnosis.
ARV, use o any an i e o i al he apy; BMI, body mass index;
cART, an i e o i al he apy consis ing o a leas 3 agen s; EDSS,
expanded disabili y scale s a us; FSS, a igue s a us scale.
Table 2 Cu en cART egimens o 17 HIV-in ec ed
pa ien s
cART egime
Numbe o
pa ien s Rema ks
2NRTI+boos ed PI 7
2NRTI+NNRTI 3
2NRTI+INSTI 1
1NRTI+boos ed PI
+INSTI
1 In ole ance o NRTIs
1NRTI+boos ed PI
+NNRTI
1 1 class ART esis ance
NNRTI+boos ed PI
+INSTI
2 2 class ART esis ance
in bo h pa ien s
2NRTI+boos ed PI
+NNRTI+INSTI
2 3 class ART esis ance
in bo h pa ien s
2NRTI, wo nucleoside e e se ansc ip ase inhibi o s; ART,
an i e o i al he apy; INSTI, in eg ase s and ans e inhibi o ;
NNRTI, non-NRTI; PI, p o ease inhibi o .
4Heikinheimo T, e al.BMJ Open 2015;5:e007986. doi:10.1136/bmjopen-2015-007986
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in ec ed wi h hepa i is B. One pa ien had a posi i e
syphilis se ology wi h his o y, and a se ological ollow-up
o an adequa e ea men o syphilis. All pa ien s we e
HCVAb nega i e.
DISCUSSION
This s udy shows, o he fi s ime, ha Finnish
HIV-1-in ec ed pa ien s who ecei e adequa e an i-HIV
he apy may p ese e hei neu ological and neu ocog-
ni i e unc ion well despi e o a his o y o HIV in ec ion
o up o 30 yea s.
All cART-medica ion egimes a e educing he isk o
he se e es o ms o HAND. Ne e heless, milde o ms
ha e been epo ed as becoming mo e common.
25 26
HIV is anspo ed om he pe iphe y h ough he BBB
in he CNS wi h bo h monocy es and CD4 cells.
27 28
In
he CNS, he monocy es ans e HIV in o mac ophages
and mic oglial cells, bo h o which can p oduce HIV
i ions. HIV in ec ion may ei he be haema ogenous o
‘au onomous’, when i al eplica ion akes place in he
CNS, o a mix u e o bo h.
27
As ocy es also become
in ec ed wi h HIV, bu HIV does no eplica e in as o-
cy es. The in ec ed mac ophages and mic oglial cells
elici an inflamma o y eac ion, which leads o ec ui -
men o mo e in ec ed immune cells in he b ain.
28
Fu he as ocy es con ibu e o he damage o he b ain
by p oducing neu o oxic ac o s, such as glu ama e.
26
The only known he apy educing CNS damage by HIV
is ART. E en a mono he apy wi h zido udine dec eases
he amoun o inflamma o y eac ion in he CSF.
29
The
mode n cART egimens inhibi he eplica ion o HIV
almos comple ely in he pe iphe y. These egimens
ha e been shown o educe he HIV load o an unde ec -
able le el in he CNS in mos pa ien s.
30
The inflamma-
ion ma ke s in he CSF may pe sis a an ele a ed le el
e en a e 4 yea s o i ologically success ul cART.
31
Ou
esul s indica e ha cogni i e unc ion can be p ese ed
in HIV-in ec ed pa ien s o a couple o decades, despi e
he p obable inflamma o y ac i i y in he CNS.
Some HIV-in ec ed pa ien s ha e been desc ibed as
ha ing a i al escape o HIV in he CNS in spi e o suc-
cess ul cART in he pe iphe y.
32
The phenomenon is
ai ly a e, a ec ing a mino i y o pa ien s ecei ing suc-
cess ul cART. Taking in o accoun he labo a o y in es i-
ga ions, clinical examina ions and b ain MRI
pe o med, i appea s ou coho did no include such
pa ien s. The ac o s con ibu ing o he good cogni i e
s a e in ou pa ien s p obably include long- e m ART,
which, on a e age, had been 19 yea s, o which, on
a e age, 13 yea s had been on cART. Second, he lack o
d ug abuse, which is pe haps syne gis ic wi h HIV o
cause HAND. The CHARTER s udy ec ui ed 1555
HIV-in ec ed pa ien s ac oss he USA and ound ha
52% had a leas mild neu opsychological impai men .
2
In ha s udy sample, abou one- hi d (28%) we e using
some ec ea ional d ug. Thi d, he good neu ocogni i e
ou come is caused mos likely by biological a ia ion in
ou pa ien s’p ope ies o esis HIV in ec ion, and hei
willingness o s a ART. Fou h, lack o hepa i is C in ec-
ion may con ibu e o he good neu ocogni i e
ou come o ou pa ien s.
33 34
Table 3 Cogni i e unc ioning o he 17 HIV-in ec ed pa ien s a h ee ollow-up examina ions
Yea o examina ion
Follow-up ime/yea s
1986–1990
0
1997
7–11
2013
23–27 Mano a/Ano a* E ec size
Mean (SD)†Mean (SD) Mean (SD) F p Value η
2
Cogni i e unc ion
Memo y 1.920 0.172 0.390
WMS logical memo y 11.9 (2.1) 13.8 (2.5) 10.0 (2.6) –– –
Lis lea ning 57.9 (6.2) 61.9 (5.4) 57.3 (7.4) –– –
Reasoning 0.895 0.496 0.230
WAIS simila i ies 21.9 (1.7) 21.3 (1.8) 20.9 (2.0) –– –
WAIS block design 40.9 (6.5) 41.5 (5.3) 37.9 (6.1) –– –
Execu i e unc ion 0.330 0.953 0.099
T ail-making B 85.3 (21.5) 99.4 (29.8) 105.9 (27.2) –– –
S oop in e e ence es ( ime) 104.2 (24.8) 99.2 (22.6) 115.5 (34.8) –– –
Speed o pe o mance 1.221 0.353 0.289
WAIS digi symbol 59.3 (11.0) 55.4 (16.8) 48.9 (12.7) –– –
S oop naming ( ime) 55.4 (11.6) 57.0 (11.4) 67.4 (15.7) –– –
*Age is used as a co a ia e.
†Raw sco es.
WAIS, Wechsle Adul In elligence Scale.
Table 4 Ce eb ospinal luid o nine pa ien s in 2013
Median Range
O e uppe
limi o no mal
P o ein, mg/L 451 268–675 5/9
Leucocy es 1 0–4 1/9
Immunoglobulin 31 10–82 4/9
Ig index 0.60 0.55–0.70 4/9
Ig/Alb index 0.16 0.09–0.22 1/9
Heikinheimo T, e al.BMJ Open 2015;5:e007986. doi:10.1136/bmjopen-2015-007986 5
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The only significan neu ological impai men de ec ed
in ou s udy popula ion was pe iphe al neu opa hy.
Apa om one pa ien wi h ex apy amidal signs, no
signs o o he CNS impai men we e ound on clinical
examina ion. The ea lie ART p obably con ibu ed o
he de elopmen o neu opa hy, because many pa ien s
had used deoxynucleoside analogues, which a e known
o cause oxic neu opa hy, as a pa o hei ART.
A g ea p opo ion o ou pa ien s had diseases ha
cons i u e isks o ce eb o ascula diseases. Howe e , he
only isk ac o ha was significan ly highe han in he
gene al popula ion o Finland, was, expec edly, he p e a-
lence o hype choles e olaemia. This is a well-known side
e ec o cART, especially he g oup o p o ease inhibi-
o s.
35 36
Diabe es, hype ension and hype choles e ol-
aemia we e ea ed app op ia ely, which also dec eased
he isks o neu ological and neu ocogni i e de ec s.
Al hough he neu opsychological aw sco es declined,
especially be ween he second and las examina ion, no
significan di e ences we e ound when he e ec o age
was con olled o . Thus, he decline may be explained
by he no mal ageing e ec s, as he ollow-up pe iod was
almos 30 yea s, wi h he pa ien s being, on a e age,
57 yea s o age a he ime o he las examina ion.
In he MRI, he signs o silen s okes suppo he
esea ch, which shows an inc ease o he incidence o
s oke in he ageing HIV popula ion.
37 38
Only wo o
ou pa ien s had de eloped b ain issue a ophy ha was
mo e significan han in gene ally heal hy ageing men
(annually 0.1–0.3%).
39 40
The limi a ions o he s udy include he su i al benefi
and small sample size. I may well be ha ou popula ion
o su i o s om he e a when an i-HIV medica ion was
no a ailable o did no gi e long- e m supp ession o
HIV-1 eplica ion ep esen a subg oup o HIV-in ec ed
pa ien s who ole a e he in ec ion be e han men on
a e age. On he o he hand, he ec ui ed s udy g oup
ep esen s almos a hal o HIV-in ec ed pa ien s ea ed
in Au o a Hospi al du ing he 1980s.
In conclusion ou esul s gi e c edence o he iew
ha HIV-1-in ec ed pa ien s may well p ese e hei neu-
ocogni i e unc ion when cART is s a ed in ime and
deli e ed well, and when o he condi ions ha could
h ea en he b ain a e ea ed app op ia ely. Apa om
polyneu opa hy, no significan neu ological o neu o-
psychological end o impai men was ound in ou
s udy g oup. I is possible ha he p e alence o neu o-
cogni i e impai men in he CHARTER s udy may no
apply o all HIV-1-in ec ed pa ien s.
Au ho a ilia ions
1
Depa men o Neu ology, Helsinki Uni e si y Cen al Hospi al, Helsinki,
Finland
2
Rehabili a ion Founda ion, Helsinki, Finland
3
Depa men o Radiology, Helsinki Uni e si y Cen al Hospi al, Helsinki,
Finland
4
Neu oimmunology Uni , Medical School, Uni e si y o Tampe e, Tampe e,
Finland
5
Depa men o In ec ious Diseases a Au o a Hospi al, Helsinki Uni e si y
Cen al Hospi al, Helsinki, Finland
Acknowledgemen s The au ho s hank Ms Ou i Debnam, RN, o p ac ical
assis ance in conduc ing his s udy. They also hank Tim Connell o
p oo eading he a icle.
Con ibu o s TH d a ed he i s e sions o he a icle. EP and IE collec ed
he o iginal da a and he e alua ions du ing 1986–1990 and 1997. EP and TH
p oduced he s a is ical da a, and OS analysed he MRIs om 1997 and 2013.
MR e alua ed he HIV in ec ion in 1997 and 2013, and o ganised he
e alua ion o he coho in 2013. EP ca ied ou he neu opsychological
assessmen and TH pe o med he neu ological assessmen .
Funding This wo k was suppo ed by an un es ic ed esea ch g an o he
in e en ion in 2013 h ough he Clinical Resea ch Ins i u e o HUCH by
AbbVie. TH ecei ed suppo om Helsinki Uni e si y Hospi al esea ch unds,
Mai e Taponen Founda ion and O ion esea ch unds.
Compe ing in e es s TH ecei ed a el expenses om AbbVie, Baye and
O ion. EP ecei ed a el expenses and consul a ions om AbbVie. MR
ecei ed Hono a ia, consul a ions o a el expenses om Abb ie, BMS,
Gilead, GSK, Janssen and Me ck.
E hics app o al The Medical E hical commi ee o he Hospi al Dis ic o
Helsinki and Uusimaa.
P o enance and pee e iew No commissioned; ex e nally pee e iewed.
Da a sha ing s a emen Addi ional da a is a ailable by emailing: Te u.
[email p o ec ed]
Open Access This is an Open Access a icle dis ibu ed in acco dance wi h
he C ea i e Commons A ibu ion Non Comme cial (CC BY-NC 4.0) license,
which pe mi s o he s o dis ibu e, emix, adap , build upon his wo k non-
comme cially, and license hei de i a i e wo ks on di e en e ms, p o ided
he o iginal wo k is p ope ly ci ed and he use is non-comme cial. See: h p://
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Heikinheimo T, e al.BMJ Open 2015;5:e007986. doi:10.1136/bmjopen-2015-007986 7
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he apy in Finland
pa ien s on bes -a ailable an i e o i al
neu ocogni i e ollow-up o HIV-1-in ec ed
Th ee-decade neu ological and
T Heikinheimo, E Pou iainen, O Salonen, I Elo aa a and M Ris ola
doi: 10.1136/bmjopen-2015-007986
2015 5: BMJ Open
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