open¢access kidneytransplantoutcomesinhiv -positive
TRANSCRIPT
Zheng et al. AIDS Res Ther (2019) 16:37 https://doi.org/10.1186/s12981-019-0253-z
RESEARCH
Kidney transplant outcomes in HIV-positive patients: a systematic review and meta-analysisXin Zheng1,2, Lian Gong1,2, Wenrui Xue3, Song Zeng1,2, Yue Xu1,2, Yu Zhang3 and Xiaopeng Hu1,2*
Abstract
Background: Kidney transplantation is now a viable alternative to dialysis in HIV-positive patients who achieve good immunovirological control with the currently available antiretroviral therapy regimens. This systematic review and meta-analysis investigate the published evidence of outcome and risk of kidney transplantation in HIV-positive patients following the PRISMA guidelines.
Methods: Searches of PubMed, the Cochrane Library and EMBASE identified 27 cohort studies and 1670 case series evaluating the survival of HIV-positive kidney transplant patients published between July 2003 and May 2018. The regimens for induction, maintenance therapy and highly active antiretroviral therapy, acute rejection, patient and graft survival, CD4 count and infectious complications were recorded. We evaluated the patient survival and graft survival at 1 and 3 years respectively, acute rejection rate and also other infectious complications by using a random-effects analysis.
Results: At 1 year, patient survival was 0.97 (95% CI 0.95; 0.98), graft survival was 0.91 (95% CI 0.88; 0.94), acute rejec-tion was 0.33 (95% CI 0.28; 0.38), and infectious complications was 0.41 (95% CI 0.34; 0.50), and at 3 years, patient survival was 0.94 (95% CI 0.90; 0.97) and graft survival was 0.81 (95% CI 0.74; 0.87).
Conclusions: With careful selection and evaluation, kidney transplantation can be performed with good outcomes in HIV-positive patients.
© The Author(s) 2019. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
BackgroundTraditionally, human immunodeficiency virus (HIV)-positive patients (HIV+) has not been considered to be good candidates for solid-organ transplantation for the poor prognosis of HIV patients. However, with the intro-duction of antiretroviral combination therapy (cART), the survival of HIV+ patients have been great improved. While the frequency of Acquired Immune Deficiency Syndrome (AIDS)-related events has consequently decreased, mortality due to organ failure has become a significant concern.
The initial attempts at kidney transplantation (KT) in HIV+ patients led to poor outcomes, but better results occurred with the availability of highly active antiretrovi-ral therapy (HAART) [1, 2].
In this scenario, KT started to be proposed as a treat-ment even as “standard-of-care” for end-stage renal dis-ease (ESRD) in selected HIV+ patients [3].
A multicentre study in the USA found that the survival rates for HIV+ recipients fall between those reported for older KT recipients and for all recipients in the American national database [4].
Despite these encouraging results, many issues still need to be addressed. Among the more relevant are the elevated incidence of acute rejection (AR), lower patient survival (PS) and graft survival (GS), and the hurdles caused by the interaction of immunosuppressive and antiretroviral (ARV) drugs. We conducted a systemic review and meta-analysis to determine the effectiveness of KT in the presence of HIV. Specifically, we examined PS and GS, AR and infectious complications in HIV+ patients who have undergone KT.
Open Access
AIDS Research and Therapy
*Correspondence: [email protected] Department of Urology, Beijing Chaoyang Hospital, Capital Medical University, 8 Gongti Nanlu, Chaoyang District, Beijing, ChinaFull list of author information is available at the end of the article
Page 2 of 32Zheng et al. AIDS Res Ther (2019) 16:37
MethodsStudy designThe study design of a systematic review and meta-analysis was chosen to define the published evidence of the effectiveness of KT in HIV+ patients. The study followed the Preferred Reporting Items for System-atic Reviews and Meta-Analysis (PRISMA) statement standards [5]. Our review was registered at the Inter-national Prospective Register of Systematic Reviews (PROSPERO CRD42018109178).
Search strategyWe searched the Medline (1966 to June 2018), EMBASE (1974 to June 2018), and Cochrane Controlled Trials Reg-ister databases to identify studies that referred to KT in HIV+ patients; we also searched the reference lists of the retrieved studies. The following search terms were used: KT, HIV+, AIDS. A combination of subject headings and keywords for KT, HAART, HIV+ recipient, allograft sur-vival, antiretroviral therapy, donor selection, ESRD and immunosuppression was used for the literature search.
Eligibility criteriaCohort studies and case–control studies were all eli-gible for inclusion if they reported outcomes of KT in HIV+ patients. Studies reporting outcomes shorter than 12 months post transplantation and transplanta-tion occurring before HAART were introduced were excluded. Articles were independently assessed by 2 reviewers (X Z and WR X) according to the predeter-mined eligibility criteria. Any disagreement between reviewers was resolved by discussion with a third reviewer (XP H).
Data extractionAll data were extracted independently by 2 reviewers (X Z and WR X) onto a Microsoft Excel spreadsheet (XP Professional Edition; Microsoft Corp, Redmond, WA), and any discrepancies were resolved by consensus. The following information was collected for each study: the study country, sample size, inclusion criteria, exclusion criteria, induction and maintenance immunosuppres-sion, HAART regimen, mean CD4 T-cell counts (CD4 counts) pre-transplant and post-transplant, infectious complications, post-transplant neoplasia, PS and GS at 1 and 3 years, and AR rate. In order to analyse data of Infectious complications (IC), all infections requiring hospitalization were registered.
Quality grading of studiesThe quality of each study used for the meta-analysis was assessed based on the Newcastle–Ottawa-Scale (NOS)
for cohort studies [6]. The evaluation of study quality included the following three categories: (i) selection (4 items), (ii) comparability (2 items), and (iii) the assess-ment of outcome (3 items). The NOS ranges from zero to a maximum of 9 points. Five authors (X Z, W X, S Z, Y X and Y Z) independently assessed the articles. The overall NOS score was determined as the median of all 5 individual NOS assessments. Study quality was graded as good (≥ 8 points), fair (6 or 7 points), and poor (≤ 5 points) [6].
Data analysisWe undertook the descriptive analyses to identify the number of studies with relevant data, the countries where the studies were conducted, and other popula-tion attributes. The transplant outcome data were pooled using different transformations according to their differ-ent normal distribution conditions.
The data for PS, GS, AR, IC at 1 year and PS at 3 years were analysed using log transformation.
The data for GS at 3 years were analysed using arcsine transformation.
The transformed data were combined to estimate the pooled percentages with 95% confidence intervals using a random-effects model.
The transformed data were combined to estimate the pooled percentages with 95% confidence intervals using a random effects model [7] and presented as for-est plots. We assessed the heterogeneity among studies using the Cochran Q test ( χ2
n−1 ; p < 0.05 to denote sta-
tistical significance) and estimated the amount of vari-ation by I2 [8]. Statistical sources of heterogeneity were explored by examining the relationship between one or more study-level characteristics and the effect sizes that were observed in the studies using weighted least squares meta-regression. A rank correlation test of funnel plot asymmetry (z) was used to assess the presence of publi-cation bias. Statistical analysis was performed using the R statistical software package (R Development Core Team, Vienna, Austria; URL: http://www.R-proje ct.org; ver-sion 2.9.0), using the software libraries ‘meta’ and ‘meta-for’, for the meta-analysis and meta-regression models, respectively.
ResultsSystematic study reviewThe search strategy identified 86 citations (Fig. 1), and among these, we identified 53 studies that appeared to bge relevant to our study. Finally, 27 of these studies, con-taining 1670 cases, met the inclusion criteria. Agreement between reviewers for assessment of study eligibility was 100%.
Page 3 of 32Zheng et al. AIDS Res Ther (2019) 16:37
Detailed characteristics of all included studies are provided in Table 1. A majority of the studies were con-ducted in the US or Europe. All these details are summa-rized in Tables 2 and 3.
Regarding immunosuppression and rejection, most of the patients received antibody induction therapy with different regimens containing basiliximab, daclizumab,
antithymocyte globulin (ATG) or methylprednisolone. The maintenance regimens were mainly composed of cyclosporin A (CSA), mycophenolate mofetil (MMF), tacrolimus (TAC) and steroids, which were the same as the maintenance regimens for HIV-negative patients.
Mean CD4 counts were steady in most of the patients. As we observed, in all the cohorts with available data
Fig. 1 PRISMA flow chart of literature research
Page 4 of 32Zheng et al. AIDS Res Ther (2019) 16:37
Tabl
e 1
Iden
tifie
d st
udie
s fo
r sys
tem
atic
revi
ew a
ccor
ding
to P
RISM
A g
uide
lines
Stud
yCo
untr
ySa
mpl
e si
zeIn
clus
ion
crite
ria
Excl
usio
n cr
iteri
aTh
e du
ratio
n of
dia
lysi
sD
urat
ion
of H
IV in
fect
ion
Stud
y tip
e
Rola
nd (2
008)
USA
18U
ndet
ecta
ble
HIV
for 3
mon
ths,
CD
4 T-
cell
coun
ts ≥
200
/μL,
N
o hi
stor
y of
OI
Patie
nts
with
pre
viou
sly
trea
ted
oppo
rtun
istic
com
plic
atio
ns
(exc
ept p
rogr
essi
ve m
ultif
ocal
le
ukoe
ncep
halo
path
y, c
hron
ic
cryp
tosp
orid
iosi
s, ly
mph
oma
and
visc
eral
Kap
osi’s
sar
com
a [K
S]) w
ere
elig
ible
Not
spe
cifie
dN
ot s
peci
fied
Pros
pect
ive
stud
y
Touz
ot (2
010)
Paris
27N
ot s
peci
fied
Not
spe
cifie
dN
ot s
peci
fied
Not
spe
cifie
dRe
tros
pect
ive
coho
rt s
tudy
Maz
ueco
s (2
006)
Spai
n10
CD
4 T-
cell
coun
ts ≥
200
/μL
for
mor
e th
an 6
mon
ths,
Und
e-te
ctab
le H
IV fo
r 3 m
onth
s, st
a-bl
e A
RT (i
n ca
se o
f ind
icat
ed)
for l
onge
r tha
n 3
mon
ths,
and
no p
rese
nce
of d
efini
te A
IDS
com
plic
atio
ns
His
tory
of A
IDS-
defin
ing
infe
c-tio
n7.
6 +
6.6
(1–2
2) y
ears
10.6
+ 6
.9 (2
–19)
yea
rsRe
tros
pect
ive
coho
rt s
tudy
Stoc
k (2
003)
USA
10U
ndet
ecta
ble
HIV
for 3
mon
ths;
CD
4 T-
cell
coun
ts ≥
200
/μL;
no
hist
ory
of o
ppor
tuni
stic
infe
c-tio
ns; a
nd to
lera
ting
a st
able
A
RV re
gim
en fo
r 3 m
onth
s be
fore
tran
spla
nt
AID
S-de
finin
g op
port
unis
tic
infe
ctio
n; h
isto
ry o
f can
cer
or o
ppor
tuni
stic
neo
plas
m
(exc
ept f
or tr
eate
d ba
sal
cell
carc
inom
a or
in s
itu
anog
enita
l can
cer),
and
HC
V po
sitiv
ity in
kid
ney
patie
nts
with
find
ings
of c
irrho
sis
on
liver
bio
psy
Not
spe
cifie
dN
ot s
peci
fied
Pros
pect
ive
stud
y
Stoc
k (2
010)
USA
150
CD
4 T-
cell
coun
ts ≥
200
/μL
and
Und
etec
tabl
e H
IV fo
r whi
le
rece
ivin
g st
able
ART
in th
e 16
wee
ks b
efor
e tr
ansp
lant
a-tio
n
Patie
nts
with
pre
viou
sly
trea
ted
oppo
rtun
istic
com
plic
atio
ns,
with
the
exce
ptio
n of
pro
gres
-si
ve m
ultif
ocal
leuk
oenc
epha
-lo
path
y, c
hron
ic in
test
inal
cr
ypto
spor
idio
sis,
prim
ary
cent
ral n
ervo
us s
yste
m ly
m-
phom
a, a
nd v
isce
ral K
apos
i’s
sarc
oma
Not
spe
cifie
dN
ot s
peci
fied
Pros
pect
ive
stud
y
Kum
ar (2
004)
USA
40Pa
tient
s be
adh
eren
t to
dial
ysis
tr
eatm
ent a
nd H
AA
RT, h
ave
plas
ma
HIV
-1 R
NA
< 4
00
copi
es/m
L, a
nd a
bsol
ute
CD
4 T-
cell
coun
ts ≥
200
/μL
Not
spe
cifie
dN
ot s
peci
fied
Not
spe
cifie
dRe
tros
pect
ive
coho
rt s
tudy
Qiu
(200
6)U
SA38
Not
spe
cifie
dN
ot s
peci
fied
Not
spe
cifie
dN
ot s
peci
fied
Regi
stry
stu
dy
Tan
(200
4)U
SA7
Und
etec
tabl
e H
IV fo
r 3 m
onth
s, C
D4
T-ce
ll co
unts
≥ 2
00/μ
LN
ot s
peci
fied
Not
spe
cifie
dN
ot s
peci
fied
Retr
ospe
ctiv
e co
hort
stu
dy
Page 5 of 32Zheng et al. AIDS Res Ther (2019) 16:37
Tabl
e 1
(con
tinu
ed)
Stud
yCo
untr
ySa
mpl
e si
zeIn
clus
ion
crite
ria
Excl
usio
n cr
iteri
aTh
e du
ratio
n of
dia
lysi
sD
urat
ion
of H
IV in
fect
ion
Stud
y tip
e
Cart
er (2
006)
USA
20Fi
rst,
cand
idat
es m
et s
tand
ard
crite
ria fo
r pla
cem
ent o
n th
e ki
dney
tran
spla
nt w
aitin
g lis
t. Se
cond
, can
dida
tes
had
unde
-te
ctab
le H
IV fo
r 3 m
onth
s, C
D4
T-ce
ll co
unts
≥ 2
00/μ
L fo
r 6
mon
ths
His
tory
of c
ance
r or o
ppor
tun-
istic
neo
plas
m (e
xcep
t for
tr
eate
d ba
sal c
ell c
arci
nom
a,
cuta
neou
s Ka
posi
’s sa
rcom
a or
in s
itu a
noge
nita
l can
cer),
pr
ior t
rans
plan
t, pr
egna
ncy,
si
gnifi
cant
HIV
-rel
ated
was
t-in
g (>
5%
wei
ght l
oss
over
3
mon
ths)
, coi
nfec
tion
with
he
patit
is C
with
evi
denc
e of
cirr
hosi
s on
live
r bio
psy,
hi
stor
y of
chr
onic
inte
stin
al
cryp
tosp
orid
iosi
s of
> 1
mon
th
dura
tion,
his
tory
of p
rogr
es-
sive
mul
tifoc
al le
ukoe
n-ce
phal
opat
hy o
r doc
umen
ted
resi
stan
t fun
gal i
nfec
tions
Not
spe
cifie
dN
ot s
peci
fied
Pros
pect
ive
stud
y
Gru
ber (
2008
)U
SA8
(1) C
D4
T-ce
ll co
unts
≥ 2
00/μ
L an
d ul
tras
ensi
tive
vira
l loa
d (U
SVL)
less
than
50
RNA
cop
-ie
s/m
L fo
r mor
e th
an o
r equ
al
to 6
mon
ths
and
(2) n
o hi
stor
y of
sig
nific
ant A
IDS-
asso
ciat
ed
oppo
rtun
istic
infe
ctio
ns o
r ne
opla
sms,
both
whi
le o
n hi
ghly
act
ive
antir
etro
vira
l th
erap
y (H
AA
RT)
Not
spe
cifie
dN
ot s
peci
fied
Not
spe
cifie
dRe
tros
pect
ive
coho
rt s
tudy
Gom
ez (2
013)
Spai
n7
Patie
nts
do n
ot s
uffer
from
an
y co
nditi
on; C
D4
T-ce
ll co
unts
≥ 2
00/μ
L; U
ndet
ecta
-bl
e vi
ral l
oad
(< 5
0 co
pies
/mL)
; So
cial
sta
bilit
y; A
dher
ence
to
trea
tmen
tIn
dru
g ab
user
s: pe
riod
of a
bsti-
nenc
e of
at l
east
2 y
ears
Not
spe
cifie
dN
ot s
peci
fied
Not
spe
cifie
dRe
tros
pect
ive
coho
rt s
tudy
Izzo
(201
7)Ita
ly28
CD
4 T-
cell
coun
ts ≥
200
/μL,
un
dete
ctab
le H
IV R
NA
(if t
he
patie
nt w
as o
n cA
RT) a
nd
pres
umab
le g
ood
com
plia
nce
to fo
llow
up
and
ther
apy
Not
spe
cifie
dN
ot s
peci
fied
Not
spe
cifie
dRe
tros
pect
ive
coho
rt s
tudy
Page 6 of 32Zheng et al. AIDS Res Ther (2019) 16:37
Tabl
e 1
(con
tinu
ed)
Stud
yCo
untr
ySa
mpl
e si
zeIn
clus
ion
crite
ria
Excl
usio
n cr
iteri
aTh
e du
ratio
n of
dia
lysi
sD
urat
ion
of H
IV in
fect
ion
Stud
y tip
e
Rola
nd (2
004)
USA
26C
D4
T-ce
ll co
unts
≥ 2
00/μ
L;
unde
tect
able
HIV
RN
AEl
evat
ed H
IV R
NA
Lev
el, L
ow
CD
4 T-
Cell
Coun
t, H
isto
ry O
f O
ppor
tuni
stic
Infe
ctio
n O
r N
eopl
asm
, Or I
ncom
plet
ely
Eval
uate
d A
ltere
d M
enta
l St
atus
Not
spe
cifie
dN
ot s
peci
fied
Retr
ospe
ctiv
e co
hort
stu
dy
Gas
ser (
2009
)U
SA27
Und
etec
tabl
e pl
asm
a H
IV
RNA
for 6
mon
ths
befo
re
tran
spla
ntat
ion,
CD
4 T-
cell
coun
ts ≥
200
/μL
and
no
use
of IL
-2 o
r GM
-CSF
in th
e 6
mon
ths
prio
r to
tran
spla
nta-
tion
Preg
nanc
y an
d si
gnifi
cant
was
t-in
g or
wei
ght l
oss
Not
spe
cifie
dN
ot s
peci
fied
Pros
pect
ive
stud
y
Gat
hogo
(201
4)U
K35
CD
4 T-
cell
coun
ts ≥
200
/μL
and
unde
tect
able
HIV
RN
A le
vels
fo
r a m
inim
um o
f 6 m
onth
s
Not
spe
cifie
d4.
2 ye
ars
7.2
year
sRe
tros
pect
ive
coho
rt s
tudy
Bais
i (20
16)
Italy
18Pa
tient
s ne
ver t
reat
ed w
ith A
RVs
with
CD
4 T-
cell
coun
ts ≥
200
/μL
Patie
nts
on A
RVs
with
CD
4 T-
cell
coun
ts ≥
200
/μL
stab
le fo
r at
leas
t 12
mon
ths
and
plas
ma
HIV
-RN
A u
ndet
ecta
ble
at th
e tim
e of
incl
usio
n on
wai
ting
list
Com
plia
nce
to/w
illin
gnes
s to
co
ntin
ue A
RVs
and
prop
hy-
laxi
s of
opp
ortu
nist
ic in
fec-
tions
, if i
ndic
ated
If fe
mal
e, p
regn
ancy
test
(b
-HCG
) neg
ativ
e (m
onth
ly
mon
itorin
g)
His
tory
of A
IDS-
defin
ing
oppo
rtun
istic
infe
ctio
ns in
the
prev
ious
2 y
ears
His
tory
of n
eopl
asm
(with
the
exce
ptio
n of
in s
itu c
ervi
cal
neop
lasi
a an
d ba
so-c
ellu
lar
carc
inom
a w
ith a
doc
u-m
ente
d di
seas
e-fre
e pe
riod
of m
ore
than
5 y
ears
; rec
over
y fro
m m
alig
nant
dis
ease
mus
t be
cer
tified
by
an o
ncol
ogis
t)D
etec
tabl
e pe
riphe
ral b
lood
H
HV
DN
A V
LBr
east
-feed
ing
unde
rway
Not
spe
cifie
dN
ot s
peci
fied
retr
ospe
ctiv
e co
hort
stu
dy
Xia
(201
4)U
SA24
3N
ot s
peci
fied
Excl
usio
ns w
ere
mul
ti-or
gan
tran
spla
nts
and
reci
pien
ts
that
wer
e pe
diat
ric, h
epat
itis
B su
rfac
e an
tigen
pos
itive
, ha
d m
issi
ng o
r unk
now
n H
IV
or H
CV
sero
stat
us o
r rec
eive
d a
prev
ious
live
r tra
nspl
ant.
Add
ition
al e
xclu
sion
s w
ere
reci
pien
t HIV
-ser
opos
itivi
ty
and
dono
r hep
atiti
s C
ser
o-po
sitiv
ity
83.5
% o
f pat
ient
s Pr
etra
nspl
ant d
ialy
-si
s > 3
yea
rs
Not
spe
cifie
dRe
gist
ry s
tudy
Lock
e (2
015)
USA
481
Not
spe
cifie
dN
ot s
peci
fied
Not
spe
cifie
dN
ot s
peci
fied
Regi
stry
stu
dy
Page 7 of 32Zheng et al. AIDS Res Ther (2019) 16:37
Tabl
e 1
(con
tinu
ed)
Stud
yCo
untr
ySa
mpl
e si
zeIn
clus
ion
crite
ria
Excl
usio
n cr
iteri
aTh
e du
ratio
n of
dia
lysi
sD
urat
ion
of H
IV in
fect
ion
Stud
y tip
e
Abb
ott (
2004
)U
SA47
Not
spe
cifie
dN
ot s
peci
fied
4.8 ±
5.0
yea
rsN
ot s
peci
fied
Cris
telli
(201
7) B
razi
lBr
azil
39N
ot s
peci
fied
Not
spe
cifie
d42
mon
ths
96 m
onth
sRe
tros
pect
ive
coho
rt s
tudy
Cris
telli
(201
7) S
pain
Braz
il15
Not
spe
cifie
dN
ot s
peci
fied
84 m
onth
s12
0 m
onth
sRe
tros
pect
ive
coho
rt s
tudy
Maz
ueco
s (2
013)
Spai
n36
a. C
D4
T-ce
ll co
unts
≥ 2
00/μ
L fo
r > 6
mon
ths
b. H
IV-1
RN
A u
ndet
ecta
ble
c. O
n st
able
ant
i-ret
rovi
ral
ther
apy >
3 m
onth
sd.
No
othe
r com
plic
atio
ns
from
AID
S (e
.g.,
oppo
rtun
istic
in
fect
ion,
incl
udin
g as
perg
il-lu
s, tu
berc
ulos
is, c
occi
dioi
de-
myc
osis
, res
ista
nt fu
ngal
in
fect
ions
, Kap
osi’s
sar
com
a or
ot
her n
eopl
asm
)e.
Mee
ting
all o
ther
crit
eria
for
kidn
ey tr
ansp
lant
atio
n
1. M
etas
tatic
can
cer
2. O
ngoi
ng o
r rec
urrin
g in
fec-
tions
that
are
not
effe
ctiv
ely
trea
ted
3. S
erio
us c
ardi
ac o
r oth
er
ongo
ing
insu
ffici
enci
es th
at
crea
te a
n in
abili
ty to
tole
rate
tr
ansp
lant
sur
gery
4. S
erio
us c
ondi
tions
that
are
un
likel
y to
be
impr
oved
by
tran
spla
ntat
ion
as li
fe
expe
ctan
cy c
an b
e fin
itely
m
easu
red
5. D
emon
stra
ted
patie
nt n
on-
com
plia
nce,
whi
ch p
lace
s th
e or
gan
at ri
sk b
y no
t adh
erin
g to
med
ical
reco
mm
enda
tions
6. P
oten
tial c
ompl
icat
ions
from
im
mun
osup
pres
sive
med
ica-
tions
are
una
ccep
tabl
e to
the
patie
nt (e
.g.,
the
bene
fits
of
stay
ing
on d
ialy
sis
outw
eigh
th
e ris
ks a
ssoc
iate
d w
ith
tran
spla
ntat
ion)
7. A
IDS
(dia
gnos
is b
ased
on
CD
C d
efini
tion
of C
D4
T-ce
ll co
unt <
200
/μL)
49.5
mon
ths
Not
spe
cifie
dRe
tros
pect
ive
coho
rt s
tudy
Rosa
(201
6)U
SA58
Not
spe
cifie
dN
ot s
peci
fied
Not
spe
cifie
dN
ot s
peci
fied
Vica
ri (2
016)
Braz
il53
Bein
g cl
inic
ally
sta
ble
unde
r H
AA
RT, h
avin
g at
leas
t a
6-m
onth
per
iod
of s
tabl
e C
D4
T-ce
ll co
unts
≥ 2
00/μ
L, a
nd
unde
tect
able
vira
l loa
d
Not
spe
cifie
dN
ot s
peci
fied
Not
spe
cifie
dPr
ospe
ctiv
e st
udy
Page 8 of 32Zheng et al. AIDS Res Ther (2019) 16:37
Tabl
e 1
(con
tinu
ed)
Stud
yCo
untr
ySa
mpl
e si
zeIn
clus
ion
crite
ria
Excl
usio
n cr
iteri
aTh
e du
ratio
n of
dia
lysi
sD
urat
ion
of H
IV in
fect
ion
Stud
y tip
e
Boss
ini (
2014
)Ita
ly13
CD
4 T-
cell
coun
ts ≥
200
/μL
and
unde
tect
able
pla
sma
HIV
ty
pe-1
RN
A le
vels
bas
ed o
n an
ultr
asen
sitiv
e po
lym
eras
e ch
ain
reac
tion
assa
y w
hile
re
ceiv
ing
stab
le H
AA
RT d
urin
g th
e 3
mon
ths
befo
re tr
ans-
plan
tatio
n
His
tory
of p
rogr
essi
ve m
ultif
ocal
le
ukoe
ncep
halo
path
y, c
hron
ic
inte
stin
al c
rypt
ospo
ridio
sis,
lym
phom
a, o
r vis
cera
l Kap
osi’s
sa
rcom
a
5.0 ±
3.1
yea
rsN
ot s
peci
fied
Regi
stry
stu
dy
Maz
ueco
s (2
011)
Spai
n20
a. C
D4
T-ce
ll co
unts
≥ 2
00/μ
L fo
r > 6
mon
ths
b. H
IV-1
RN
A u
ndet
ecta
ble
c. O
n st
able
ant
i-ret
rovi
ral
ther
apy >
3 m
onth
sd.
No
othe
r com
plic
atio
ns
from
AID
S (e
.g.,
oppo
rtun
istic
in
fect
ion,
incl
udin
g as
perg
il-lu
s, tu
berc
ulos
is, c
occi
dioi
de-
myc
osis
, res
ista
nt fu
ngal
in
fect
ions
, Kap
osi’s
sar
com
a or
ot
her n
eopl
asm
)e.
Mee
ting
all o
ther
crit
eria
for
kidn
ey tr
ansp
lant
atio
n
1. M
etas
tatic
can
cer
2. O
ngoi
ng o
r rec
urrin
g in
fec-
tions
that
are
not
effe
ctiv
ely
trea
ted
3. S
erio
us c
ardi
ac o
r oth
er
ongo
ing
insu
ffici
enci
es th
at
crea
te a
n in
abili
ty to
tole
rate
tr
ansp
lant
sur
gery
4. S
erio
us c
ondi
tions
that
are
un
likel
y to
be
impr
oved
by
tran
spla
ntat
ion
as li
fe
expe
ctan
cy c
an b
e fin
itely
m
easu
red
5. D
emon
stra
ted
patie
nt n
on-
com
plia
nce,
whi
ch p
lace
s th
e or
gan
at ri
sk b
y no
t adh
erin
g to
med
ical
reco
mm
enda
tions
6. P
oten
tial c
ompl
icat
ions
from
im
mun
osup
pres
sive
med
ica-
tions
are
una
ccep
tabl
e to
the
patie
nt (e
.g.,
the
bene
fits
of
stay
ing
on d
ialy
sis
outw
eigh
th
e ris
ks a
ssoc
iate
d w
ith
tran
spla
ntat
ion)
7. A
IDS
(dia
gnos
is b
ased
on
CD
C d
efini
tion
of C
D4
coun
t < 2
00 c
ells
/mm
3 )
6.53
± 5
.62
year
s8.
45 ±
5.0
1 ye
ars
Pros
pect
ive
stud
y
Gat
hogo
(201
6)U
K76
Not
spe
cifie
dN
ot s
peci
fied
4.9
year
sN
ot s
peci
fied
Regi
stry
stu
dy
Mal
at (2
018)
USA
120
An
unde
tect
able
vira
l loa
d, C
D4
T-ce
ll co
unts
≥ 2
00/μ
L, a
nd b
e on
an
ART
regi
men
for a
t lea
st
6 m
onth
s
Not
spe
cifie
d16
yea
rsN
ot s
peci
fied
Retr
ospe
ctiv
e co
hort
stu
dy
The
pape
r by
Cris
telli
et a
l. co
ntai
ns tw
o co
hort
s fr
om B
razi
l and
Spa
in s
epar
atel
y, s
o w
e tr
eat i
t as
two
inde
pend
ent c
ohor
ts
Page 9 of 32Zheng et al. AIDS Res Ther (2019) 16:37
Tabl
e 2
Imm
unos
uppr
essi
on a
nd re
ject
ion
Stud
yFo
llow
-up
days
[mea
n ±
SD
or
med
ian
(ran
ge)]
Indu
ctio
nM
aint
enan
ceTy
pe o
f rej
ectio
nTr
eatm
ent o
f rej
ectio
n
Rola
nd 2
008)
1520
± 5
93 d
ays
Ant
i-CD
25C
SA, S
tero
ids ±
MM
FA
cute
cel
lula
r 14
(78%
)A
cute
vas
cula
r 1 (6
%)
Acu
te c
ellu
lar a
nd v
ascu
lar 2
(1
1%)
Not
spe
cifie
d
Touz
ot (2
010)
29 m
onth
s (ra
nge
12–4
8 m
onth
s)A
ntiin
terle
ukin
2 re
cept
or
antib
ody
(Bas
ilixi
mab
, Nov
artis
, 20
mg
at d
ay 0
and
day
4) (
26)
and
poly
clon
al a
ntith
ymoc
yte
glob
ulin
s (1
) (Th
ymog
lobu
line,
G
enzy
me,
1.5
mg/
kg/d
ay d
ur-
ing
4 da
ys)
CSA
or D
29, S
tero
ids ±
MM
F. M
MF
was
giv
en a
t 100
0 m
g tw
ice
a da
y. M
ethy
lpre
dnis
o-lo
ne w
as g
iven
as
follo
wed
: 50
0 m
g in
trav
enou
sly
at d
ay 0
an
d 12
5 m
g at
day
1. F
rom
day
2,
20
mg/
day
of o
ral p
red-
niso
ne w
as g
iven
and
tape
red
prog
ress
ivel
y to
10
mg/
day
at 6
mon
ths
and
5 m
g/da
y at
9
mon
ths
Acu
te c
ellu
lar r
ejec
tion
Ster
oid
puls
es
Maz
ueco
s (2
006)
489 ±
468
day
sAT
G(1
); A
nti-C
D25
(3)
TAC
, MM
F an
d st
eroi
dsN
ot s
peci
fied
Mpr
ed (2
50 m
g) R
ituxi
mab
(for
A
MR)
Stoc
k (2
003)
480 ±
300
day
sN
ot u
sed
CSA
, MM
F an
d st
eroi
dsN
ot s
peci
fied
Mild
reje
ctio
n w
as tr
eate
d w
ith
bolu
s st
eroi
ds a
nd a
sw
itch
in
mai
nten
ance
imm
unos
uppr
es-
sion
from
CSA
to ta
crol
imus
. Va
scul
ar (t
ype
II) re
ject
ion
was
tr
eate
d w
ith th
e po
lycl
onal
an
ti-T-
cell
agen
t Thy
mog
lobu
lin,
bolu
s st
eroi
ds, a
nd a
sw
itch
in
mai
nten
ance
imm
unos
uppr
es-
sion
from
+ D
15 to
tacr
olim
us
Stoc
k (2
010)
1.7
year
sA
n in
duct
ion
ther
apy
by a
m
onoc
lona
l ant
iinte
rleuk
in 2
re
cept
or a
ntib
ody,
ant
ithym
o-cy
te g
lobu
lin (A
TG),
or b
oth
was
pe
rmitt
ed
Initi
al im
mun
osup
pres
sive
ther
-ap
y in
clud
ed g
luco
cort
icoi
ds,
CSA
or T
AC
, and
MM
F. Si
rolim
us
was
use
d in
pat
ient
s w
ith
calc
ineu
rin-in
hibi
tor-
asso
ciat
ed
neph
roto
xici
ty
Acu
te c
ellu
lar r
ejec
tion
epi-
sode
s(42
)A
cute
vas
cula
r rej
ectio
n ep
i-so
des(
4)A
cute
cel
lula
r and
vas
cula
r rej
ec-
tion
epis
odes
com
bine
d(7)
Chr
onic
and
acu
te re
ject
ion
epis
odes
(4)
Not
spe
cifie
d
Kum
ar (2
004)
730
days
Ant
iinte
rleuk
in 2
rece
ptor
an
tibod
yCy
clos
porin
e, s
irolim
us, a
nd
Ster
oids
.Ce
ll an
d an
tibod
y m
edia
ted
reje
ctio
n (2
/9)
Met
hylp
redn
isol
one(
9)In
trav
enou
s im
mun
e gl
obul
in a
nd
ritux
imab
(2)
Qiu
(200
6)18
25 d
ays
Ant
i-CD
25 (2
3)C
SA(2
0); T
ac(1
3); S
ir(14
); St
eroi
d-sp
arin
g(1)
Not
spe
cifie
dN
ot s
peci
fied
Page 10 of 32Zheng et al. AIDS Res Ther (2019) 16:37
Tabl
e 2
(con
tinu
ed)
Stud
yFo
llow
-up
days
[mea
n ±
SD
or
med
ian
(ran
ge)]
Indu
ctio
nM
aint
enan
ceTy
pe o
f rej
ectio
nTr
eatm
ent o
f rej
ectio
n
Tan
(200
4)14
85 ±
425
day
s; 24
6 ±
87
days
Non
e (4
2%) (
dece
ased
don
or)
Ale
mtu
zum
ab (5
7%) (
livin
g-re
late
d do
nor)
TAC
, MM
F an
d St
eroi
dsN
ot s
peci
fied
Not
spe
cifie
d
Cart
er (2
006)
854
days
Indu
ctio
n th
erap
y w
ith ly
mph
o-cy
te-d
eple
ting
agen
ts w
as
avoi
ded.
IL-2
rece
ptor
inhi
bito
r in
duct
ion
was
use
d
All
patie
nts
rece
ived
per
iope
ra-
tive
ster
oids
, MM
F (2
–3 g
/day
), a
calc
ineu
rin in
hibi
tor (
eith
er
cycl
ospo
rine
or TA
C),
and/
or
siro
limus
Trea
tmen
t for
acu
te re
ject
ion
cons
iste
d of
3 d
ays
of h
igh-
dose
m
ethy
lpre
dnis
olon
e, fo
llow
ed
by a
pre
dnis
one
tape
r, an
d in
crea
sed
mai
nten
ance
imm
u-no
supp
ress
ion,
whi
ch fr
eque
ntly
m
eant
sw
itchi
ng th
e re
cipi
ent
from
cyc
losp
orin
e to
tacr
olim
us.
Add
ition
ally
, mod
erat
e-to
-sev
ere
case
s of
reje
ctio
n w
ere
trea
ted
with
thym
oglo
bulin
on
an in
di-
vidu
aliz
ed b
asis
Gru
ber (
2008
)15
mon
ths
All
patie
nts
rece
ived
indu
ctio
n th
erap
y w
ith a
ntiin
terle
ukin
2
rece
ptor
ant
ibod
y (b
asili
xim
ab
20 m
g on
pos
tope
rativ
e da
ys 0
an
d 4)
or d
acliz
umab
(1.5
mg/
kg o
n da
ys 0
and
7)
CSA
, MM
F an
d St
eroi
dsN
ot s
peci
fied
Bord
erlin
e or
gra
de I
reje
ctio
n ep
isod
es w
ere
trea
ted
with
m
ethy
lpre
dnis
olon
e 50
0 m
g IV
fo
r 3 d
ays,
follo
wed
by
a st
eroi
d ta
per.
Ster
oid-
resi
stan
t gra
de
I, an
d gr
ade
II re
ject
ions
wer
e tr
eate
d w
ith 5
to 7
dai
ly d
oses
of
Thy
mog
lobu
lin w
ith ta
rget
ab
solu
te C
D3
coun
ts le
ss th
an o
r eq
ual t
o 10
Góm
ez (2
013)
16.0
mon
ths
(rang
e 3.
0 to
96
.6 m
onth
s)Iin
duct
ion
ther
apy
used
ant
i-in
terle
ukin
2 re
cept
or a
ntib
ody
(bax
ilixi
mab
) (3/
7)
TAC
, MM
F an
d St
eroi
dsN
ot s
peci
fied
Patie
nts
wer
e tr
eate
d w
ith s
tero
id
puls
es, w
hich
reve
rsed
acu
te
reje
ctio
n an
d im
prov
ed re
nal
func
tion
Izzo
(201
7)12
6.1
wee
ksTh
e pa
tient
s re
ceiv
ed a
n in
duc-
tion
ther
apy
with
ant
iinte
rleu-
kin
2 re
cept
or a
ntib
ody
(bas
ilixi
-m
ab) i
n tw
o do
ses.
Intr
aven
ous
met
hylp
redn
isol
one
was
gi
ven
in ta
perin
g do
ses
and
disc
ontin
ued
on d
ay 5
aft
er
tran
spla
ntat
ion,
or re
ceiv
ed
basi
lixim
ab, m
ethy
lpre
dni-
solo
ne a
nd a
ntily
mph
ocyt
e se
rum
as
indu
ctio
n th
erap
y
TAC
, MM
F an
d St
eroi
dsN
ot s
peci
fied
Not
spe
cifie
d
Rola
nd (2
004)
314
days
(3–1
696)
Not
spe
cifie
dC
SA, M
MF
and
Ster
oids
Not
spe
cifie
dN
ot s
peci
fied
Page 11 of 32Zheng et al. AIDS Res Ther (2019) 16:37
Tabl
e 2
(con
tinu
ed)
Stud
yFo
llow
-up
days
[mea
n ±
SD
or
med
ian
(ran
ge)]
Indu
ctio
nM
aint
enan
ceTy
pe o
f rej
ectio
nTr
eatm
ent o
f rej
ectio
n
Gas
ser (
2009
)N
ot s
peci
fied
Ten
of th
e 27
tran
spla
nt re
cipi
-en
ts re
ceiv
ed a
ntith
ymoc
yte
glob
ulin
(ATG
) per
iope
rativ
ely
(i.e.
imm
edia
tely
prio
r to
tran
s-pl
anta
tion
[n =
9],
or w
ithin
the
first
12
wee
ks p
ostt
rans
plan
ta-
tion
[n =
1])
Twen
ty-fi
ve o
f the
27
[92.
6%]
indi
vidu
als
wer
e in
itiat
ed o
n a
stan
dard
trip
le IS
regi
men
co
nsis
ting
of s
tero
ids
(Pre
d-ni
sone
), a
calc
ineu
rin in
hibi
tor
(Cyc
losp
orin
e A
or T
AC
) and
a
nucl
eotid
e/D
NA
syn
thes
is
inhi
bito
r (M
MF
or A
zath
iopr
ine)
Not
spe
cifie
dN
ot s
peci
fied
Gat
hogo
(201
4)N
ot s
peci
fied
Of t
he 3
2 pa
tient
s w
ith a
vail-
able
dat
a, 3
0 (8
8%) r
ecei
ved
indu
ctio
n im
mun
osup
pres
sive
th
erap
y co
nsis
ting
of b
asi-
lixim
ab (7
3%) o
r dac
lizum
ab
(27%
) with
met
hylp
redn
isol
one,
an
d tw
o pa
tient
s re
ceiv
ed
met
hylp
redn
isol
one
only
. 30
(88%
) rec
eive
d in
duct
ion
imm
unos
uppr
essi
ve th
erap
y co
nsis
ting
of b
asili
xim
ab (7
3%)
or d
acliz
umab
(27%
) with
m
ethy
lpre
dnis
olon
e, a
nd tw
o pa
tient
s re
ceiv
ed m
ethy
lpre
d-ni
solo
ne o
nly
All
patie
nts
rece
ived
trip
le
mai
nten
ance
imm
unos
uppr
es-
sive
ther
apy
cons
istin
g of
a C
NI,
myc
ophe
nola
te o
r aza
thio
-pr
ine,
and
Ste
roid
s
Not
spe
cifie
dSi
x pa
tient
s re
spon
ded
to p
ulse
d co
rtic
oste
roid
; oth
er o
r add
i-tio
nal t
reat
men
t int
erve
ntio
ns to
co
mba
t AR
incl
uded
intr
aven
ous
imm
unog
lobu
lin (I
VIG
, 1⁄4
4),
plas
ma
exch
ange
(1/4
1), A
TG
(1/4
1), r
ituxi
mab
(1/4
2) a
nd a
ug-
men
tatio
n of
bas
elin
e im
mun
o-su
ppre
ssio
n (1
/48)
Bais
i (20
16)
3.1
year
sTw
o re
cipi
ents
rece
ived
indu
c-tio
n th
erap
y w
ith a
sta
ndar
d do
se o
f bas
ilixi
mab
; 500
mg
intr
aven
ous
(IV) m
ethy
lpre
d-ni
solo
ne (M
P) w
as g
iven
in
tra-
oper
ativ
ely,
follo
wed
by
oral
pre
dnis
olon
e pr
ogre
s-si
vely
tape
red
from
16
mg
to
com
plet
e w
ithdr
awal
with
in
the
3rd
mon
th
Imm
unos
uppr
essi
on p
roto
-co
l inc
lude
d a
dela
yed
CSA
(2
.5 m
g/kg
bid
whe
n cr
eatin
ine
was
< 3
.0 m
g/dL
) tar
gete
d to
mai
ntai
n C
SA (C
2 le
vel)
at
initi
al v
alue
of 1
000
ng/m
L.
At p
ost-
oper
ativ
e da
y (p
od)
21, e
vero
limus
(EVL
) 0.7
5 m
g bi
d w
as in
trod
uced
(EVL
0.
75 m
g bi
d; ta
rget
EVL
trou
gh
bloo
d le
vels
[TLC
]: 8e
10 n
g/m
L an
d C
sAC
2: 4
00e5
00 n
g/m
L); s
tero
id w
as ta
pere
d to
4
mg/
day
with
in 4
5 da
ys. A
fter
6
mon
ths,
EVL
and
CsA
blo
od
leve
ls w
ere
targ
eted
to E
VLTL
C
6 to
8 n
g/m
L an
d C
sAC
2, 2
50
to 3
50 n
g/m
L. A
fter
the
first
6
case
, myc
ophe
nolic
aci
d (M
PA)
720
mg
bid
was
add
ed u
ntil
pod
21
Not
spe
cifie
dN
ot s
peci
fied
Page 12 of 32Zheng et al. AIDS Res Ther (2019) 16:37
Tabl
e 2
(con
tinu
ed)
Stud
yFo
llow
-up
days
[mea
n ±
SD
or
med
ian
(ran
ge)]
Indu
ctio
nM
aint
enan
ceTy
pe o
f rej
ectio
nTr
eatm
ent o
f rej
ectio
n
Xia
(201
4)N
ot s
peci
fied
Not
spe
cifie
dN
ot s
peci
fied
Not
spe
cifie
dN
ot s
peci
fied
Lock
e (2
015)
3.8
year
sN
ot s
peci
fied
Not
spe
cifie
dN
ot s
peci
fied
Not
spe
cifie
d
Abb
ott (
2004
)2.
62 ±
1.3
2 ye
ars
Indu
ctio
n an
tibod
y us
e(22
)Cy
clos
porin
e(30
)TA
C(1
9)M
MF(
38)
AZA
(7)
Not
spe
cifie
dN
ot s
peci
fied
Cris
telli
(201
7) B
razi
l2.
8 ye
ars ±
2.5
1N
o in
duct
ion(
17)
ATG
(11)
Ant
iinte
rleuk
in 2
rece
ptor
ant
i-bo
dy (b
asili
xim
ab)(1
1)
TAC
, MM
F an
d St
eroi
ds(2
3)C
SA, M
MF
and
Ster
oids
(2)
TAC
, AZA
and
Ste
roid
s(12
)O
ther
(2)
Bord
erlin
e ch
ange
s(5)
, IA
(6),
IB(7
), IIA
(1),
IIB(3
)N
ot s
peci
fied
Cris
telli
(201
7) S
pain
4.6
year
s ± 2
.85
No
indu
ctio
n(2)
ATG
(6)
antii
nter
leuk
in 2
rece
ptor
ant
i-bo
dy (b
asili
xim
ab)(7
)
TAC
, MM
F an
d St
eroi
ds(1
2)M
TOR,
MM
F an
d St
eroi
dsF(
3)Bo
rder
line
chan
ges(
2), I
A(1
), IB
(0),
IIA(1
)N
ot s
peci
fied
Maz
ueco
s (2
013)
33.6
mon
ths
Not
spe
cifie
dN
ot s
peci
fied
Bord
erlin
e/IA
(3),
IB(2
), IIA
(4),
Ant
ibod
y-m
edia
ted(
2)N
ot s
peci
fied
Rosa
(201
6)10
28 ±
813
day
sA
ll of
the
patie
nts
rece
ived
ant
i–th
ymoc
yte
glob
ulin
, bas
ilixi
-m
ab a
nd m
ethy
lpre
dnis
olon
e fo
r ind
uctio
n.
Pred
niso
ne(5
2), I
VIG
(5),
Ritu
xim
ab(7
), TA
C(5
7), M
MF(
57),
Siro
limus
(3),
Cycl
ospo
rine(
2)
Not
spe
cifie
dN
ot s
peci
fied
Vica
ri (2
016)
Not
spe
cifie
dN
o in
duct
ion(
26)
ATG
(5)
antii
nter
leuk
in 2
rece
ptor
ant
i-bo
dy (b
asili
xim
ab)(2
2)
Ster
oids
(53)
, TA
C(4
0), C
yclo
-sp
orin
e(10
), M
MF(
41),
AZA
(9),
mTO
R in
hibi
tors
(1)
Ant
ibod
y-m
edia
ted
AR(
2)A
ntib
ody-
med
iate
d A
R(3)
Not
spe
cifie
d
Boss
ini (
2014
)50
± 2
2.0
mon
ths
Ant
iinte
rleuk
in 2
rece
ptor
an
tibod
y (b
asili
xim
ab) a
nd
met
hylp
redn
isol
one
TAC
or c
yclo
spor
ine
and
MM
FC
MR(
4), A
MR(
4), a
nd b
oth
CM
R an
d A
MR
(mix
ed)(4
). O
vera
ll,
indi
cato
rs o
f AM
R w
ere
pres
ent
in e
ight
of 1
2 ep
isod
es (6
6.6%
)
Acu
te c
ellu
lar-
med
iate
d re
jec-
tions
(CM
R) w
ere
trea
ted
with
m
ethy
lpre
dnis
olon
e (M
P) a
t hig
h do
ses
(800
–100
0 m
g di
vide
d in
to 4
day
s) a
nd s
ubse
quen
tly
tape
red
to a
dai
ly d
ose
betw
een
8 an
d 4
mg/
day
to b
e m
ain-
tain
ed in
defin
itely
. Tre
atm
ent
of a
ntib
ody-
med
iate
d re
ject
ion
(AM
R) in
volv
ed a
com
bina
-tio
n of
mul
tiple
mod
aliti
es,
incl
udin
g hi
gh d
oses
of s
tero
ids,
plas
ma
exch
ange
, int
rave
nous
im
mun
oglo
bulin
s (IV
Ig),
and
thym
oglo
bulin
Page 13 of 32Zheng et al. AIDS Res Ther (2019) 16:37
Tabl
e 2
(con
tinu
ed)
Stud
yFo
llow
-up
days
[mea
n ±
SD
or
med
ian
(ran
ge)]
Indu
ctio
nM
aint
enan
ceTy
pe o
f rej
ectio
nTr
eatm
ent o
f rej
ectio
n
Maz
ueco
s (2
011)
39.9
8 ±
36.
51 m
onth
sA
nti-C
D25
(6),
Thym
oglo
bulin
(1)
TAC
(18)
MM
F(2)
Myc
ophe
nola
te(2
0)
Ant
ibod
y m
edia
ted
acut
e re
jec-
tion
Gat
hogo
(201
6)N
ot s
peci
fied
Ant
iinte
rleuk
in 2
rece
ptor
ant
i-bo
dy (b
asili
xim
ab)(6
8)A
lem
tuzu
mab
(2)
Ritu
xim
ab +
pla
sma
exch
ange
(1)
Puls
ed c
ortic
oste
roid
s on
ly(2
)
Calc
ineu
rin in
hibi
tor +
MM
F or
A
ZA +
Ster
oids
(76)
TAC
mon
othe
rapy
(2)
Not
spe
cifie
dN
ot s
peci
fied
Mal
at (2
018)
16 y
ears
Ant
iinte
rleuk
in 2
rece
ptor
ant
i-bo
dy (b
asili
xim
ab)
Calc
ineu
rin in
hibi
tors
(CN
Is),
siro
limus
, and
Ste
roid
sTA
C, M
MF,
and
low
-dos
e St
erio
dsBe
lata
cept
(3)
Not
spe
cifie
dN
ot s
peci
fied
Page 14 of 32Zheng et al. AIDS Res Ther (2019) 16:37
Tabl
e 3
HIV
and
rela
ted
com
plic
atio
ns
Stud
yH
AA
RT re
gim
enPh
arm
acok
inet
ic
chan
ges
Mea
n CD
4 T-
cell
coun
ts p
re-T
X (c
ells
/μL
)
Mea
n CD
4 T-
cell
coun
ts p
ost-T
XPr
ophy
laxi
s ag
ains
t opp
ortu
nist
ic
infe
ctio
n
Infe
ctio
us
com
plic
atio
nsPo
st-t
rans
plan
t ne
opla
sia
Rola
nd (2
008)
Varie
d (z
idov
udin
e an
d st
avud
ine
avoi
ded)
Not
spe
cifie
d43
9 (2
93–6
13)
Not
spe
cifie
dO
I pro
phyl
axis
incl
uded
lif
e-lo
ng tr
imet
h-op
rim-s
ulfa
met
h-ox
azol
e, d
apso
ne
or a
tova
quon
e to
pr
even
t Pne
umoc
ystis
ca
rinii
pneu
mon
ia
(PC
P), b
rief a
ntifu
ngal
pr
ophy
laxi
s us
ing
fluco
nazo
le, a
nd
Cyto
meg
alov
irus
(CM
V) p
roph
ylax
is
with
eith
er a
cycl
ovir
or v
alcy
te, d
epen
ding
up
on th
e re
cipi
ent
and
dono
r CM
V st
atus
Cand
ida
esop
hagi
tis(1
); C
MV(
1)N
ot s
peci
fied
Touz
ot (2
010)
Not
spe
cifie
dBe
caus
e of
per
sist
ent
high
trou
gh le
vel
of C
NI,
prot
ease
in
hibi
tor t
reat
men
t w
as s
topp
ed in
nin
e pa
tient
s du
ring
the
first
wee
k of
pos
t-tr
ansp
lant
atio
n an
d in
five
oth
ers
durin
g th
e fo
llow
-up
386
545
(3 m
onth
s)53
4 (6
mon
ths)
460
(12
mon
ths)
569
(24
mon
ths)
Patie
nts
rece
ived
ga
ncic
lovi
r or
valg
angy
clov
ir fo
r cy
tom
egal
oviru
s an
d tr
imet
hopr
im/
sulfa
met
hoxa
zole
for
Pneu
moc
ystis
jiro
veci
i, fo
r at l
east
6 m
onth
s. Fo
r pat
ient
s w
ith a
pa
st h
isto
ry o
f tub
er-
culo
sis,
Ison
iazi
d w
as
adde
d fo
r 9 m
onth
s
Pyel
onep
hriti
s(18
)Pn
eum
onia
(5)
Sept
ic s
hock
(1)
Oth
ers(
4)C
MV(
2)BK
viru
s(1)
Lym
phom
a(1)
Maz
ueco
s (2
006)
Varie
dN
ot s
peci
fied
≥ 2
0067
0 ±
481
Not
spe
cifie
dPn
eum
onia
(3)
VZV(
1)N
ot s
peci
fied
Stoc
k (2
003)
Varie
dN
ot s
peci
fied
423 ±
93
419 ±
287
Stan
dard
pro
phyl
axis
fo
r Pne
umoc
ystis
, cy
tom
egal
oviru
s (C
MV
), an
d fu
ngal
in
fect
ions
wer
e us
ed
acco
rdin
g to
sta
ndar
d tr
ansp
lant
pro
toco
ls
Stap
hylo
cocc
us a
ureu
s w
ound
infe
ctio
n(2)
Hae
mop
hilu
s in
fluen
za
bact
eria
l pne
umo-
nia(
1)S.
aur
eus e
ndoc
ardi
-tis
(1)
Not
spe
cifie
d
Page 15 of 32Zheng et al. AIDS Res Ther (2019) 16:37
Tabl
e 3
(con
tinu
ed)
Stud
yH
AA
RT re
gim
enPh
arm
acok
inet
ic
chan
ges
Mea
n CD
4 T-
cell
coun
ts p
re-T
X (c
ells
/μL
)
Mea
n CD
4 T-
cell
coun
ts p
ost-T
XPr
ophy
laxi
s ag
ains
t opp
ortu
nist
ic
infe
ctio
n
Infe
ctio
us
com
plic
atio
nsPo
st-t
rans
plan
t ne
opla
sia
Stoc
k (2
010)
Prot
ease
-inhi
bito
r–ba
sed(
63)
NN
RTI-b
ased
(59)
Prot
ease
-inhi
bito
r-ba
sed
and
NN
RTI-
base
d(15
)N
ucle
osid
e an
alog
ues
only
(5)
Nuc
leos
ide
anal
ogue
s on
ly(6
)N
one(
2)
Not
spe
cifie
d52
4N
ot s
peci
fied
Prop
hyla
xis
agai
nst
oppo
rtun
istic
in
fect
ion
incl
uded
lif
elon
g th
erap
y to
pr
even
t Pne
umoc
ystis
jir
ovec
ii pn
eum
onia
, flu
cona
zole
for a
nti-
fung
al p
roph
ylax
is,
and
valg
anci
clov
ir or
ga
ncic
lovi
r to
prev
ent
cyto
meg
alov
irus
infe
ctio
n. M
acro
lide
prop
hyla
xis
agai
nst
Myc
obac
teriu
m
aviu
m c
ompl
ex w
as
requ
ired
whe
n th
e C
D4+
T-ce
ll co
unt
drop
ped
belo
w 7
5 ce
lls p
er c
ubic
mil-
limet
er
Pseu
dom
onas
aer
ugi-
nosa
sep
sis(
1)Re
nal-c
ell c
arci
nom
a(2)
Kapo
si’s
sarc
oma(
2)O
ral s
quam
ous-
cell
carc
inom
a(2)
Squa
mou
s-ce
ll sk
in
canc
er(1
)Ba
sal-c
ell s
kin
canc
er(1
)Th
yroi
d gl
and
canc
er(1
)
Kum
ar (2
004)
Varie
dA
ll pa
tient
s co
ntin
-ue
d th
eir H
AA
RT
regi
men
s.
≥ 2
00≥
400
Infe
ctio
n pr
ophy
laxi
s w
as g
anci
clov
ir or
va
lgan
cycl
ovir
for
cyto
meg
alov
irus,
trim
etho
prim
/su
lfam
etho
xazo
le
or d
apso
ne fo
r Pne
u-m
ocys
tis c
arin
ii, a
nd
nyst
atin
for o
ral a
nd
esop
hage
al th
rush
fo
r 200
day
s af
ter
tran
spla
ntat
ion
Seps
is(1
)C
hest
infe
ctio
n(2)
Nec
rotiz
ing
fasc
iitis
(1)
Infe
ctio
n of
lym
phoc
-oe
le(1
)A
dmitt
ed u
rinar
y tr
act
infe
ctio
n(9)
Not
spe
cifie
d
Qiu
(200
6)N
ot s
peci
fied
Not
spe
cifie
dN
ot s
peci
fied
Not
spe
cifie
dN
ot s
peci
fied
Bact
eria
l pne
umon
ia(1
)N
ot s
peci
fied
Tan
(200
4)Va
ried
Not
spe
cifie
d58
9 ±
313
946 ±
800
424 ±
384
Not
spe
cifie
dPl
anta
r fas
ciiti
s(1)
Basa
l cel
l car
cino
ma
Page 16 of 32Zheng et al. AIDS Res Ther (2019) 16:37
Tabl
e 3
(con
tinu
ed)
Stud
yH
AA
RT re
gim
enPh
arm
acok
inet
ic
chan
ges
Mea
n CD
4 T-
cell
coun
ts p
re-T
X (c
ells
/μL
)
Mea
n CD
4 T-
cell
coun
ts p
ost-T
XPr
ophy
laxi
s ag
ains
t opp
ortu
nist
ic
infe
ctio
n
Infe
ctio
us
com
plic
atio
nsPo
st-t
rans
plan
t ne
opla
sia
Cart
er (2
006)
Not
spe
cifie
dPa
tient
s re
sum
ed th
eir
pre-
tran
spla
nt H
AA
RT
ther
apy
whe
n an
ora
l di
et w
as s
tart
ed, t
ypi-
cally
1 o
r 2 d
ays
afte
r tr
ansp
lant
.
Not
spe
cifie
dN
ot s
peci
fied
Varie
dCa
ndid
a oe
soph
agi-
tis(1
)S.
aur
eus e
ndoc
ardi
tis
with
sep
tic e
mbo
liza-
tion(
1)St
rept
ococ
cus v
irida
ns
bact
erae
mia
(1)
Pseu
dom
onas
pne
umo-
nia
with
mul
ti-or
gan
failu
re(1
)Es
cher
ichi
a co
li ur
osep
-si
s(1)
Cultu
re-n
egat
ive
uros
epsi
s(1)
Ente
roco
ccus
bac
tera
e-m
ia(1
)Po
lym
icro
bial
pne
umo-
nia
seps
is(1
)Cl
ostr
idiu
m d
iffici
le
colit
is(1
)D
iver
ticul
itis
and
seco
ndar
y ba
cter
ial
perit
oniti
s(1)
Influ
enza
, bac
teria
l pn
eum
onia
(1)
Pseu
dom
onas
pne
umo-
nia(
1)
Not
spe
cifie
d
Page 17 of 32Zheng et al. AIDS Res Ther (2019) 16:37
Tabl
e 3
(con
tinu
ed)
Stud
yH
AA
RT re
gim
enPh
arm
acok
inet
ic
chan
ges
Mea
n CD
4 T-
cell
coun
ts p
re-T
X (c
ells
/μL
)
Mea
n CD
4 T-
cell
coun
ts p
ost-T
XPr
ophy
laxi
s ag
ains
t opp
ortu
nist
ic
infe
ctio
n
Infe
ctio
us
com
plic
atio
nsPo
st-t
rans
plan
t ne
opla
sia
Gru
ber (
2008
)A
ll re
cipi
ents
wer
e m
aint
aine
d on
at
leas
t tw
o nu
cleo
side
re
vers
e tr
ansc
ripta
se
inhi
bito
rs, t
hree
in
com
bina
tion
with
a
riton
avir-
boos
ted
prot
ease
inhi
bito
r (PI
), tw
o in
com
bina
tion
with
a n
on-b
oost
ed
PI, a
nd tw
o in
com
bi-
natio
n w
ith n
evira
p-in
e (a
non
nucl
eosi
de
reve
rse
tran
scrip
tase
in
hibi
tor)
Not
spe
cifie
d≥
200
≥ 2
00A
ntim
icro
bial
pro
phy-
laxi
s w
as in
itiat
ed
with
in th
e fir
st 2
4 to
48
h a
fter
sur
gery
. A
ll pa
tient
s re
ceiv
ed
trim
etho
prim
/sul
-fa
met
hoxa
zole
one
si
ngle
-str
engt
h da
ily
for 6
mon
ths
and
nyst
atin
5 m
L fo
ur
times
per
day
for
1 m
onth
. Cyt
omeg
-al
oviru
s pr
ophy
laxi
s w
as a
dmin
iste
red
depe
ndin
g on
the
patie
nt’s
risk-
stra
tified
pr
ofile
CM
V(1)
Pneu
mon
ia(1
)U
rinar
y tr
act i
nfec
-tio
n(3)
Not
spe
cifie
d
Gom
ez (2
013)
Not
spe
cifie
dPr
otea
se in
hibi
tor t
reat
-m
ent w
as s
topp
ed
with
sub
stitu
tion
of
the
inte
gras
e in
hibi
-to
r Ral
tegr
avir
504
373.
5 (3
mon
ths)
488
(6 m
onth
s)Pa
tient
s re
ceiv
ed
trim
etho
prim
–sul
-fa
met
hoxa
zole
for
Pneu
moc
ystis
jiro
vecc
ii
Not
spe
cifie
dEp
stei
n–Ba
rr v
irus
high
gr
ade-
rela
ted
B-ce
ll ly
mph
oma(
1)
Izzo
(201
7)N
ot s
peci
fied
To a
void
PK
inte
rac-
tions
, cA
RT w
as
mod
ified
from
a P
I/ N
NRT
I-bas
ed to
an
InST
I-bas
ed re
gim
en
in 1
1/20
pat
ient
s al
ive
with
func
tioni
ng
graf
t (65
%);
7/11
wer
e sw
itche
d to
ralte
-gr
avir
and
4/11
wer
e sw
itche
d to
dol
ute-
grav
ir. 7
/20
(35%
) w
ere
on tr
eatm
ent
with
a c
ART
regi
men
in
clud
ing
both
InST
I an
d PI
/rito
navi
r (RT
V)
or e
favi
renz
(EFV
) at
the
end
of fo
llow
-up
337
400
Not
spe
cifie
dPn
eum
onia
and
urin
ary
trac
t inf
ectio
ns w
ere
the
mos
t com
mon
di
agno
sis
Skin
Kap
osi’s
sar
com
a(2)
Colo
rect
al c
ance
r(1)
Page 18 of 32Zheng et al. AIDS Res Ther (2019) 16:37
Tabl
e 3
(con
tinu
ed)
Stud
yH
AA
RT re
gim
enPh
arm
acok
inet
ic
chan
ges
Mea
n CD
4 T-
cell
coun
ts p
re-T
X (c
ells
/μL
)
Mea
n CD
4 T-
cell
coun
ts p
ost-T
XPr
ophy
laxi
s ag
ains
t opp
ortu
nist
ic
infe
ctio
n
Infe
ctio
us
com
plic
atio
nsPo
st-t
rans
plan
t ne
opla
sia
Rola
nd (2
004)
441
(200
–105
4)43
6 (3
–975
)N
ot s
peci
fied
Cand
ida
esop
hagi
tis(1
); St
aphy
loco
ccal
se
psis(
1)
Not
spe
cifie
d
Gas
ser (
2009
)A
RT c
onsi
sted
of n
ucle
-os
ide/
nucl
eotid
e re
vers
e tr
ansc
ripta
se
inhi
bito
rs (R
TI) a
nd/
or n
on-n
ucle
osid
e RT
I and
/or p
rote
ase
inhi
bito
rs, m
ostly
co
mbi
ned
as a
thre
e-cl
ass
ther
apy
Not
spe
cifie
d48
3N
ot s
peci
fied
Not
spe
cifie
dN
ot s
peci
fied
Not
spe
cifie
d
Gat
hogo
(201
4)A
ntire
trov
iral t
hera
py
was
str
atifi
ed a
s co
ntai
ning
rito
navi
r-bo
oste
d pr
otea
se
inhi
bito
rs, n
on-
nucl
eosi
de re
vers
e tr
ansc
ripta
se in
hibi
-to
rs (N
NRT
I) or
oth
er
(regi
men
s co
ntai
n-in
g nu
cleo
side
/nu
cleo
tide
reve
rse
tran
scrip
tase
with
or
with
out i
nteg
rase
in
hibi
tors
)
Not
spe
cifie
d36
6N
ot s
peci
fied
Rega
rdin
g th
e m
anag
e-m
ent a
nd p
reve
ntio
n of
cyt
omeg
alov
irus
(CM
V) i
nfec
tion,
so
me
cent
res
rou-
tinel
y ad
min
iste
red
valg
anci
clov
ir pr
oph-
ylax
is fo
r 3 m
onth
s po
sttr
ansp
lant
atio
n (ir
resp
ectiv
e of
do
nor/
reci
pien
t CM
V Ig
G s
tatu
s), w
hile
oth
-er
s pr
escr
ibed
CM
V pr
ophy
laxi
s to
reci
pi-
ents
of g
raft
s fro
m
CM
V Ig
G-p
ositi
ve
dono
rs o
r com
bine
d re
gula
r pos
ttra
ns-
plan
t CM
V su
rvei
l-la
nce
with
pre
emp-
tive
valg
anci
clov
ir tr
eatm
ent i
f the
CM
V vi
ral l
oad
exce
eded
3–
4000
cop
ies/
mL
Urin
ary
trac
t inf
ec-
tion(
10)
Pneu
mon
ia(5
)Ce
llulit
is(2
)Py
rexi
a of
unk
now
n or
igin
(1)
Her
pes
sim
plex
vira
l en
ceph
aliti
s(1)
Not
spe
cifie
d
Page 19 of 32Zheng et al. AIDS Res Ther (2019) 16:37
Tabl
e 3
(con
tinu
ed)
Stud
yH
AA
RT re
gim
enPh
arm
acok
inet
ic
chan
ges
Mea
n CD
4 T-
cell
coun
ts p
re-T
X (c
ells
/μL
)
Mea
n CD
4 T-
cell
coun
ts p
ost-T
XPr
ophy
laxi
s ag
ains
t opp
ortu
nist
ic
infe
ctio
n
Infe
ctio
us
com
plic
atio
nsPo
st-t
rans
plan
t ne
opla
sia
Bais
i (20
16)
To a
void
dru
g in
tera
c-tio
ns b
etw
een
prot
ease
inhi
bito
rs
and
IS, A
RV w
as g
iven
in
the
imm
edia
te
post
-ope
rativ
e pe
riod
with
enf
uvirt
ide
in
com
bina
tion
with
2
nucl
eosi
de a
nalo
gues
or
1 n
ucle
osid
e an
a-lo
gue
and
ralte
grav
ir (R
AL)
, whi
ch w
as
adm
inis
tere
d w
ithin
48
h
Onc
e st
eady
sta
te o
f IS
was
ach
ieve
d (o
n av
erag
e, p
od 3
0), T
20
was
sto
pped
and
H
AA
RT w
as m
odi-
fied
on th
e ba
sis
of
HIV
pre
-tra
nspl
ant
geno
type
pro
file,
in
divi
dual
dru
g to
ler-
abili
ty, a
nd c
linic
al
cond
ition
s
441
Not
spe
cifie
dFo
r Pne
umoc
ystis
jir
ovec
ii pr
ophy
laxi
s, w
e us
ed a
6 m
onth
co
urse
of t
rimet
ho-
prim
–sul
fam
etox
azol
. Fo
r CM
V pr
ophy
laxi
s, al
l pat
ient
s re
ceiv
ed
IV g
anci
clov
ir or
ora
l va
lgan
cicl
ovir
for a
3-
mon
th tr
eatm
ent;
in th
e ca
se o
f don
or/
reci
pien
t CM
V st
atus
, sp
ecifi
c an
ti-C
MV
imm
unog
lobu
lins
wer
e ad
ded
Not
spe
cifie
dN
o ne
opla
sms
wer
e re
port
ed
Xia
(201
4)N
ot s
peci
fied
Not
spe
cifie
dN
ot s
peci
fied
Not
spe
cifie
dN
ot s
peci
fied
Not
spe
cifie
dN
ot s
peci
fied
Lock
e (2
015)
Not
spe
cifie
dN
ot s
peci
fied
Not
spe
cifie
dN
ot s
peci
fied
Not
spe
cifie
dN
ot s
peci
fied
Not
spe
cifie
d
Abb
ott (
2004
)N
ot s
peci
fied
Not
spe
cifie
dN
ot s
peci
fied
Not
spe
cifie
dN
ot s
peci
fied
Not
spe
cifie
dN
ot s
peci
fied
Cris
telli
(201
7) B
razi
lN
on-b
oost
ed p
rote
ase-
inhi
bito
r(2)
Boos
ted
prot
ease
in
hibi
tor(1
6)N
NRT
I(20)
Nuc
leos
ide
anal
ogs
only
(2)
Nee
d fo
r ant
iretr
ovira
l ch
ange
s(14
)D
rug
inte
ract
ions
with
C
NI/m
TORi
(3)
Ther
apeu
tic fa
ilure
(5)
Adv
erse
eve
nts(
4)U
nava
ilabl
e dr
ug(1
)U
ncle
ar re
ason
(1)
> 2
0035
6 (3
mon
ths)
502
(1 y
ear)
556
(3 y
ears
)
All
patie
nts
rece
ived
pr
ophy
lact
ic
trim
etho
prim
/sul
fa-
met
hoxa
zole
aga
inst
Pn
eum
ocys
tis ji
rove
cii
and
toxo
plas
mos
is fo
r at
leas
t 6 m
onth
s
Surg
ical
site
(5)
Urin
ary
trac
t(13
)Re
spira
tory
trac
t(15
)Cy
tom
egal
oviru
s(7)
Varic
ella
-zos
ter v
irus(
6)Es
opha
geal
can
didi
-as
is(5
)
Non
-ski
n ca
ncer
(1)
Cris
telli
(201
7) S
pain
Non
-boo
sted
pro
teas
e-in
hibi
tor(2
)Bo
oste
d pr
otea
se
inhi
bito
r(5)
NN
RTI(4
)In
tegr
ase
inhi
bito
r(4)
Nee
d fo
r ant
iretr
ovira
l ch
ange
s(9)
; Dru
g in
tera
ctio
ns w
ith C
NI/
mTO
Ri(8
); U
ncle
ar
reas
on(1
)
> 2
0040
3 (3
mon
ths)
491
(1 y
ear)
456(
3 ye
ars)
All
patie
nts
rece
ived
pr
ophy
lact
ic tr
imet
h-op
rim/s
ulfa
met
h-ox
azol
e ag
ains
t Pn
eum
ocys
tis ji
rove
cii
and
toxo
plas
mos
is fo
r at
leas
t 6 m
onth
s
Surg
ical
site
(1)
Urin
ary
trac
t(5)
Resp
irato
ry tr
act(
3)Cy
tom
egal
oviru
s(1)
Non
-ski
n ca
ncer
(2)
Page 20 of 32Zheng et al. AIDS Res Ther (2019) 16:37
Tabl
e 3
(con
tinu
ed)
Stud
yH
AA
RT re
gim
enPh
arm
acok
inet
ic
chan
ges
Mea
n CD
4 T-
cell
coun
ts p
re-T
X (c
ells
/μL
)
Mea
n CD
4 T-
cell
coun
ts p
ost-T
XPr
ophy
laxi
s ag
ains
t opp
ortu
nist
ic
infe
ctio
n
Infe
ctio
us
com
plic
atio
nsPo
st-t
rans
plan
t ne
opla
sia
Maz
ueco
s (2
013)
Not
spe
cifie
dA
tren
d w
as o
bser
ved
to in
crea
se n
on-
nucl
eosi
de re
vers
e tr
ansc
ripta
se in
hibi
-to
rs u
se, a
lthou
gh
with
out s
igni
fican
t di
ffere
nces
at t
he e
nd
of th
e st
udy.
Pro
teas
e in
hibi
tors
con
tinue
d to
be
adm
inis
tere
d af
ter K
T, b
ut th
eir u
se
drop
ped
sign
ifica
ntly
at
the
end.
On
the
cont
rary
, the
use
of
inte
gras
e in
hibi
tor
(ralte
grav
ir) in
crea
sed
mos
t sig
nific
antly
af
ter K
T, a
nd th
at
incr
ease
was
mai
n-ta
ined
at t
he e
nd o
f th
e st
udy,
sug
gest
ing
a go
od to
lera
nce
to
the
drug
420
413
(1 m
onth
)49
7 (3
mon
ths)
570
(1 y
ear)
627
(2 y
ears
)61
8 (3
yea
rs)
The
mai
n pr
ophy
-la
ctic
ther
apie
s fo
r in
fect
ions
incl
uded
tr
imet
hopr
im–s
ul-
fam
etho
xazo
le fo
r Pn
eum
ocys
tis (a
t le
ast 6
mon
ths)
, gan
-ci
clov
ir/va
lgan
cicl
ovir
for c
ytom
egal
oviru
s (a
t lea
st 3
mon
ths)
an
d is
onia
zid
for
patie
nts
with
a p
ast
hist
ory
of tu
berc
ulo-
sis
(9 m
onth
s)
Bact
eria
l inf
ectio
n(41
)Fu
ngal
infe
ctio
n(2)
Vira
l inf
ectio
n(6)
Skin
car
cino
ma(
3)Ka
posi
’s sa
rcom
a(1)
Ly
mph
opro
lifer
ativ
e di
sord
er(1
)
Rosa
(201
6)Th
e th
ree
mos
t co
mm
on re
gim
ens
post
-tra
nspl
ant w
ere
nucl
eosi
de re
vers
e tr
ansc
ripta
se in
hibi
-to
rs (N
RTI)
plus
PI,
NRT
I plu
s IN
STI,
and
NRT
I plu
s N
NRT
I
A to
tal o
f 30
(52%
) pa
tient
s un
derw
ent
ART
mod
ifica
tions
af
ter t
rans
plan
546.
07 ±
271
.04
318.
54 ±
240
.73
(12
mon
ths)
374.
14 ±
235
.68
(26
mon
ths)
401.
57 ±
283
.71
(52
mon
ths)
Not
spe
cifie
dC
MV(
11)
Oth
ers
not s
peci
fied
Not
spe
cifie
d
Vica
ri(20
16)
Reve
rse
tran
scrip
tase
in
hibi
tors
wer
e us
ed fo
r all
patie
nts,
Non
-nuc
leos
ide
reve
rse
tran
scrip
tase
in
hibi
tors
wer
e us
ed
by 2
9 pa
tient
s, an
d pr
otea
se in
hibi
tors
w
ere
used
by
21
patie
nts
Not
spe
cifie
d57
7.3 ±
333
.561
0.3 ±
318
.5N
ot s
peci
fied
Bact
eria
l inf
ectio
n(55
)Cy
tom
egal
oviru
s in
fec-
tion(
39)
Poly
oma
viru
s in
fec-
tion(
7)O
ther
vira
l inf
ectio
ns(8
) (In
clud
e he
rpes
si
mpl
ex, v
aric
ella
zo
ster
, ade
novi
rus,
and
deng
ue)
Not
spe
cifie
d
Page 21 of 32Zheng et al. AIDS Res Ther (2019) 16:37
Tabl
e 3
(con
tinu
ed)
Stud
yH
AA
RT re
gim
enPh
arm
acok
inet
ic
chan
ges
Mea
n CD
4 T-
cell
coun
ts p
re-T
X (c
ells
/μL
)
Mea
n CD
4 T-
cell
coun
ts p
ost-T
XPr
ophy
laxi
s ag
ains
t opp
ortu
nist
ic
infe
ctio
n
Infe
ctio
us
com
plic
atio
nsPo
st-t
rans
plan
t ne
opla
sia
Boss
ini (
2014
)Th
e H
AA
RT re
gi-
men
was
pro
teas
e in
hibi
tor (
PI)-b
ased
in
10
case
s an
d no
n-nu
cleo
side
reve
rse
tran
scrip
tase
inhi
bito
r (N
NRT
I)-ba
sed
in th
e la
st tw
o pa
tient
s
Ant
iretr
ovira
l the
rapy
w
as te
mpo
raril
y in
terr
upte
d on
the
day
of tr
ansp
lant
atio
n an
d re
star
ted
with
in
4 da
ys. O
nly
two
patie
nts
rem
aine
d w
ithou
t HA
ART
af
ter t
rans
plan
tatio
n be
caus
e th
ey m
ain-
tain
ed a
n ad
equa
te
imm
unol
ogic
al a
nd
viro
logi
cal c
ontr
ol
352 ±
174
352 ±
174
(1 y
ear)
Trim
etho
prim
–sul
-fa
met
hoxa
zole
for
6 m
onth
s
Pneu
mon
ia(5
)H
SV 2
gen
italis
(1)
Mal
aria
(1)
CM
V in
fect
ious
(3)
UTI
(3)
Epid
idym
itis(
2)Es
opha
geal
can
didi
-as
is(1
)BK
VN(1
)
Kapo
si’s
sarc
oma(
1)
Maz
ueco
s (2
011)
Not
spe
cifie
dTw
o pa
tient
s re
mai
ned
with
out H
AA
RT
afte
r tra
nspl
anta
tion
beca
use
they
mai
n-ta
ined
an
adeq
uate
im
mun
olog
ical
and
vi-
rolo
gica
l con
trol
> 2
00>
200
Not
spe
cifie
dBa
cter
ial(1
0)M
ycot
ic(1
)C
MV(
1)O
ther
viru
s(2)
Lym
phom
a(1)
Gat
hogo
(201
6)PI
/r c
onta
inin
g(30
)N
NRT
I con
tain
ing(
40)
Inte
gras
e in
hibi
tor c
on-
tain
ing
Ralte
grav
ir(23
)
Not
spe
cifie
d36
6N
ot s
peci
fied
Not
spe
cifie
dN
ot s
peci
fied
Not
spe
cifie
d
Mal
at (2
018)
Varie
dN
ot s
peci
fied
≥ 2
00N
ot s
peci
fied
Not
spe
cifie
dN
ot s
peci
fied
Not
spe
cifie
d
Page 22 of 32Zheng et al. AIDS Res Ther (2019) 16:37
(22/27 cohorts), mean CD4 counts pre-TX and post-TX were greater than 200 cells/μL, and even elevated post transplantation.
Prophylaxis against opportunistic infection was com-mon in most studies as follows: patients received gan-ciclovir or valganciclovir for cytomegalovirus and trimethoprim/sulfamethoxazole, dapsone or atovaquone for Pneumocystis jirovecii for at least 6 months.
Kaposi’s sarcoma and skin cancer were the most observed post-transplant neoplasia. As we showed in Table 3, in all the cohorts with available data (11/27 cohorts, 360 cases in total), there are 6 cases of Kaposi’s sarcoma, 6 cases of skin cancer, 4 cases of lymphoma and 9 cases of other neoplasia.
Quality of studies included in the meta-analysisEach of the 27 studies included in the meta-analysis was assessed by the NOS to investigate the risk of bias within the studies. Table 4 shows the results of the qual-ity assessment. None of the studies had less than three points in the category selection. Two studies controlled for age and gender, and 9 controlled for other factors, such as the HAART regimen and/or immunosuppression therapy. Finally, 5 studies were graded as good quality and 22 as fair quality.
Patient survival post KTTwenty-seven studies reporting PS at 1-year post KT included PS estimate to post KT for 1429 patients; how-ever, only nine studies including 509 patients reported PS at 3 years. The results of the analysis are shown in Figs. 2 and 3. At 1 year, 97% (95% CI 0.95; 0.98, I2 = 36%) of patients survived, while 94% (95% CI 0.90; 0.97, I2 = 44%) of patients survived at 3 years.
Graft survival post KTTwenty-six studies including 1391 patients reported GS at 1-year post KT, and nine studies including 509 patients reported GS at 3 years. The results of the analysis are shown in Figs. 4 and 5. At 1 year, 91% (95% CI 0.88; 0.94, I2 = 69%) of grafts had survived, and GS subsequently declined to 0.81 (95% CI 0.74; 0.87, I2 = 69%) at 3 years.
Acute rejection post KTTwenty-five studies including 1051 patients reported AR post KT at 1 year, and the results of the analysis are shown in Fig. 6. At 1 year, 33% (95% CI 0.28; 0.38, I2 = 60%) of patients had AR.
Infectious complications post KTNineteen studies including 584 patients reported IC post KT at 1 year; the results of the analysis are shown
in Fig. 7. At 1 year, 41% (95% CI 0.34; 0.50, I2 = 59%) of patients had IC.
DiscussionTo our knowledge, this is the first systematic review and meta-analysis of such a large scale to report the outcomes of KT in HIV+ patients. We review and meta-analysis the outcomes in HIV+ KT patients, and looks at the 1- and 3-year GS/PS and AR rate.
The availability of cART has made KT a feasible treat-ment for selected HIV+ patients with ESRD, with out-comes somewhat inferior to those observed among the overall population of KT recipients [4, 9–11].
Outcomes of KTKT is now a viable treatment for select patients with HIV and ESRD. Moreover, the high incidence of mor-bidity and mortality resulting from cardiovascular issues in HIV+ patients [12, 13], as well as the negative effects of prolonged steroid use on conditions associated with cardiovascular risk, such as diabetes, dyslipidaemia, and hypertension, are well known [14, 15].
However, data regarding long-term outcomes and com-parisons with appropriately matched HIV− patients are still lacking.
Locke et al. analysed 510 adult KT recipients with HIV matched 1:10 with HIV− controls. They found that HIV− and HIV mono-infected KT recipients had similar GS and PS, whereas HIV/HCV co-infected recipients had worse outcomes [16].
Izzo et al. found that the survival rate of patients was 82.1% and functioning grafts was 71.4% [17], and a recent report from the Italian national transplantation registry showed a PS rate of 95% and a GS rate of 85% between 2006 and 2014 [18].
Stock et al. [4] reported a survival rate of 94.6% 1 year after transplantation (88.2% after 3 years) in a multicen-tric trial (150 patients), and in a published review with a small number of patients, the survival rate was 93% within the first year of transplantation (254 patients) [19]. What’s more, as the high incidence of co-infection with HCV in HIV+ patients, co-infection is likely a driver of poor outcomes [20].
In our analyses, at 1 year, PS was 0.97 (95% CI 0.95; 0.98), GS was 0.91 (95% CI 0.88; 0.94), and at 3 years, PS was 0.94 (95% CI 0.90; 0.97), GS was 0.81 (95% CI 0.74; 0.87).
Immunosuppression therapyOne of the most challenging goals in solid-organ trans-plantation is to tailor the immunosuppressive regimen for each individual patient to minimize immunosuppres-sion while still preventing AR. Opportunistic infections
Page 23 of 32Zheng et al. AIDS Res Ther (2019) 16:37
Tabl
e 4
NO
S sc
ore
Aut
hor
(ref
s.)
Repr
esen
tativ
enes
s of
the
expo
sed
coho
rt
Sele
ctio
n of
the
non-
expo
sed
coho
rt
Asc
erta
inm
ent
of e
xpos
ure
Out
com
e of
inte
rest
no
t pre
sent
at
sta
rt
Com
para
bilit
y:
age
and
sex
Com
para
bilit
y:
othe
r fac
tors
Ass
essm
ent
of o
utco
me
Follo
w-u
p lo
ng
enou
gh
Ade
quac
y of
follo
w-u
pTo
tal N
OS
scor
eSt
udy
qual
ity
Rola
nd [4
8]1 ●
0 ○
1 ●
1 ●
0 ○
0 ○
1 ●
1 ●
1 ●
6Fa
ir
Touz
ot [3
1]1 ●
0 ○
1 ●
1 ●
0 ○
0 ○
1 ●
1 ●
1 ●
6Fa
ir
Maz
ueco
s [4
9]1 ●
0 ○
1 ●
1 ●
0 ○
0 ○
1 ●
1 ●
1 ●
6Fa
ir
Stoc
k [5
0]1 ●
0 ○
1 ●
1 ●
0 ○
0 ○
1 ●
1 ●
1 ●
6Fa
ir
Stoc
k [4
]1 ●
0 ○
1 ●
1 ●
0 ○
0 ○
1 ●
1 ●
1 ●
6Fa
ir
Kum
ar [5
1]1 ●
0 ○
1 ●
1 ●
0 ○
0 ○
1 ●
1 ●
1 ●
6Fa
ir
Qiu
[52]
1 ●
1 ●
1 ●
1 ●
0 ○
0 ○
1 ●
1 ●
1 ●
7Fa
ir
Tan
[53]
1 ●
0 ○
1 ●
1 ●
0 ○
0 ○
1 ●
1 ●
1 ●
6Fa
ir
Cart
er [5
4]1 ●
0 ○
1 ●
1 ●
0 ○
0 ○
1 ●
1 ●
1 ●
6Fa
ir
Gru
ber [
55]
1 ●
0 ○
1 ●
1 ●
0 ○
0 ○
1 ●
1 ●
1 ●
6Fa
ir
Góm
ez [5
6]1 ●
0 ○
1 ●
1 ●
0 ○
0 ○
1 ●
1 ●
1 ●
6Fa
ir
Izzo
[17]
1 ●
0 ○
1 ●
1 ●
0 ○
0 ○
1 ●
1 ●
1 ●
6Fa
ir
Rola
nd [5
7]1 ●
0 ○
1 ●
1 ●
0 ○
0 ○
1 ●
1 ●
1 ●
6Fa
ir
Gas
ser [
58]
1 ●
0 ○
1 ●
1 ●
0 ○
0 ○
1 ●
1 ●
1 ●
6Fa
ir
Gat
hogo
[1
0]1 ●
1 ●
1 ●
1 ●
0 ○
1 ●
1 ●
1 ●
1 ●
8G
ood
Bais
i [59
]1 ●
0 ○
1 ●
1 ●
0 ○
0 ○
1 ●
1 ●
1 ●
6Fa
ir
Xia
[20]
1 ●
1 ●
1 ●
1 ●
1 ●
1 ●
1 ●
1 ●
1 ●
9G
ood
Lock
e [1
1]1 ●
0 ○
1 ●
1 ●
1 ●
1 ●
1 ●
1 ●
1 ●
8G
ood
Abb
ott [
2]1 ●
1 ●
1 ●
1 ●
0 ○
0 ○
1 ●
1 ●
1 ●
7Fa
ir
Cris
telli
Bra
zil
[60]
1 ●
0 ○
1 ●
1 ●
0 ○
0 ○
1 ●
1 ●
1 ●
6Fa
ir
Cris
telli
Sp
ain
[60]
1 ●
0 ○
1 ●
1 ●
0 ○
0 ○
1 ●
1 ●
1 ●
6Fa
ir
Maz
ueco
s [6
1]1 ●
1 ●
1 ●
1 ●
0 ○
1 ●
1 ●
1 ●
1 ●
8G
ood
Rosa
[40]
1 ●
0 ○
1 ●
1 ●
0 ○
1 ●
1 ●
1 ●
1 ●
7Fa
ir
Vica
ri [3
0]1 ●
1 ●
1 ●
1 ●
0 ○
0 ○
1 ●
1 ●
1 ●
7Fa
ir
Boss
ini [
27]
1 ●
0 ○
1 ●
1 ●
0 ○
0 ○
1 ●
1 ●
1 ●
6Fa
ir
Maz
ueco
s [9
]1 ●
1 ●
1 ●
1 ●
0 ○
1 ●
1 ●
1 ●
1 ●
8G
ood
Gat
hogo
[3
4]1 ●
0 ○
1 ●
1 ●
0 ○
1 ●
1 ●
1 ●
1 ●
7Fa
ir
Page 24 of 32Zheng et al. AIDS Res Ther (2019) 16:37
Stan
dard
ized
ass
essm
ent o
f stu
dy q
ualit
y ba
sed
on th
e N
ewca
stle
–Ott
awa-
Scal
e fo
r coh
ort s
tudi
es. E
ach
of th
e 29
stu
dies
was
ass
esse
d fo
r the
cat
egor
y’s
sele
ctio
n (4
item
s), c
ompa
rabi
lity
(2 it
ems)
, and
out
com
e (3
ite
ms)
. Ful
fille
d an
d un
fulfi
lled
crite
ria a
re p
rese
nted
by
of th
e so
lid rh
ombo
id (●
) and
ope
n ci
rcle
(○),
resp
ectiv
ely.
Stu
dy q
ualit
y w
as g
rade
d as
goo
d (≥
8 p
oint
s), f
air (
6 or
7 p
oint
s), a
nd p
oor (≤
5 p
oint
s)
Tabl
e 4
(con
tinu
ed)
Aut
hor
(ref
s.)
Repr
esen
tativ
enes
s of
the
expo
sed
coho
rt
Sele
ctio
n of
the
non-
expo
sed
coho
rt
Asc
erta
inm
ent
of e
xpos
ure
Out
com
e of
inte
rest
no
t pre
sent
at
sta
rt
Com
para
bilit
y:
age
and
sex
Com
para
bilit
y:
othe
r fac
tors
Ass
essm
ent
of o
utco
me
Follo
w-u
p lo
ng
enou
gh
Ade
quac
y of
follo
w-u
pTo
tal N
OS
scor
eSt
udy
qual
ity
Mal
at [6
2]1 ●
0 ○
1 ●
1 ●
0 ○
1 ●
1 ●
1 ●
1 ●
7Fa
ir
Sum
●29
829
293
929
2929
Sum
○0
210
026
200
00
Per
cent
●10
028
100
100
1031
100
100
100
Page 25 of 32Zheng et al. AIDS Res Ther (2019) 16:37
and malignancies often attributed to immunosuppression itself remain a significant cause of death after transplan-tation. In the field of HIV+ organ transplantation, find-ing a balanced approach to immunosuppression is even more critical.
Currently, the vast majority of KT patients receive induction immunosuppression, which has been shown to greatly reduce the risk of rejection and improve PS and GS [21]. As shown in our analyses, most of the HIV+ KT patients received induction therapy. The two most com-monly used induction agents are ATG and IL-2 receptor blocker (anti-IL2R) [22].
Guidelines from the Kidney Disease: Improving Global Outcomes transplant working group recommended anti-IL2R as the first-line treatment for patients at low risk for rejection and ATG for those at high risk [23].
Despite being the standard of care for most HIV patients, the use of induction immunosuppres-sion for HIV+ patients, particularly ATG, remains controversial.
On the one hand, HIV+ patients have high rates of rejec-tion and thus stand to benefit significantly from induction. On the other hand, the risks posed from prolonged lym-phocyte depletion are of major concern given that HIV+ patients are perceived to already threaten T cell popula-tions and reduced immunity, both states that are associ-ated with an increased risk of opportunistic infections.
A recent study showed that ATG induction was asso-ciated with long-term impairment of T cell function and related infections, even after the patients had normal-ized CD4 counts [24]. This finding is also a reminder that the CD4 counts incompletely assesses the recovery of an immunocompetent CD4 T cell pool.
The incidence and severity of IC following transplan-tation are largely dictated by the recipient’s capacity for immune reconstitution. A study by Suarez et al. indicate that ATG-induced CD4 lymphopenia can be prolonged, and even at 1 year post transplant, a substantial proportion of patients has CD4 counts < 200/μL [25]. The baseline CD4 counts did not influence the risk of death, graft loss or AR.
Fig. 2 Pooled estimated proportion of patients surviving the first year, analyzed using a random effects model
Page 26 of 32Zheng et al. AIDS Res Ther (2019) 16:37
Fig. 3 Pooled estimated proportion of patients surviving the third year, analyzed using a random effects model
Fig. 4 Pooled estimated proportion of graft surviving the first year, analyzed using a random effects model
Page 27 of 32Zheng et al. AIDS Res Ther (2019) 16:37
These findings suggest that although in current practice, HIV+ candidates with pre-transplant CD4 counts between 200 and 349/μL are eligible for KT [26] and are likely to
have outcomes similar to those with higher counts, this group of patients carries a substantial risk of lymphopenia and associated infections following ATG induction.
Fig. 5 Pooled estimated proportion of graft surviving the third year, analyzed using a random effects model
Fig. 6 Pooled estimated proportion of acute rejection at the first year, analyzed using a random effects model
Page 28 of 32Zheng et al. AIDS Res Ther (2019) 16:37
A study by Bossini et al. showed that in HIV+ KT recipients treated with basiliximab and maintained on a calcineurin inhibitor (CNI)-mycophenolic acid (MPA)-based regimen, early corticosteroid withdrawal was asso-ciated with a very high incidence of AR and that kidney function was worse in patients with rejection [27].
However, in contrast to the studies above, in a large national cohort of 830 HIV+ KT recipients, Kucirka found wide variation in the use of induction immuno-suppression, with > 30% of HIV+ patients receiving no induction compared with only 20% of their HIV coun-terparts. Therefore, the study indicated that the use of induction, including the lymphocyte-depleting agent ATG, was not associated with an increased risk of infec-tions. Despite the fact that induction recipients were at higher risk for AR, the researchers observed lower rates of delayed graft function (DGF), AR, graft loss and days spent hospitalized in the first year after KT as well as a trend towards lower mortality. They suggested that the benefits of induction immunosuppression to prevent graft rejection in HIV+ KT recipients far outweigh the perceived risk of increased infections. Because the study had the largest sample size to date and the cohort was nationally representative rather than a select study population, this study claims to be more credible. Fur-thermore, the authors accounted for confounding and treatment selection bias, which previous studies did not
do, and they did this using inverse probability of treat-ment weighting (IPTW), a method that allowed them to adjust for many clinical and demographic factors even when modelling relatively rare outcomes such as graft loss and death [28].
Acute rejectionA high risk of AR is a well-known concern in HIV-infected kidney graft recipients. With regard to rejec-tion, most studies observed a higher number of events in HIV+ patients than in HIV− patients. AR may occur as a result of immune dysregulation and the continuous inflammatory state of HIV+ recipients, in whom immu-nogenicity is increased following allograft implantation [4, 29].
Vicari et al. [30] evaluated the outcomes of KT in recip-ients with HIV infection under HAART in Brazil. The main results showed that HIV+ recipients presented a higher incidence of DGF, rejection, and bacterial infec-tions and had lower PS and GS rates in comparison with a paired control group.
In the study, the incidence of treated AR was higher in the HIV+ group, and the incidence of biopsy-confirmed AR was numerically higher in this group. Additionally, even though an identical incidence of antibody-mediated AR occurred, the incidence of steroid-resistant rejection was numerically higher in the HIV group. Many reports
Fig. 7 Pooled estimated proportion of infectious complication at the first year, analyzed using a random effects model
Page 29 of 32Zheng et al. AIDS Res Ther (2019) 16:37
have revealed an elevated incidence of AR in HIV+ recipients, varying between 31% and 55% [4, 9, 10], although a significantly lower incidence was reported in one study [31]. Stock et al. [4] reported that a significant proportion of acute cellular rejections were steroid resist-ant and that no episodes of antibody-mediated AR were observed in their cohort.
However, Malat et al. [32] described an elevated inci-dence of mixed cellular and antibody-mediated rejec-tions. Furthermore, Locke et al. [33] reported that HIV+ patients who received ATG induction therapy had a much lower risk of rejection compared to patients with-out induction and that the risk was similar to uninfected controls.
Gathogo et al. [34] reported that TAC has an impact in reducing the incidence of AR in HIV+ recipients com-pared to cyclosporin A (CSA). The reasons for such an elevated incidence and severity of AR in HIV+ KT recip-ients are not clear. Dysregulation of the immune system along with a continuous inflammatory state caused by HIV infection, perhaps in association with a variability in drug exposure, has been hypothesized to explain these almost uniformly elevated incidences of rejection [4, 10, 35].
In addition, the elevated incidence of acute cellular rejection has been recently hypothesized to partially occur a result of an infiltration of inflammatory cells that occurs in response to tubular cell infection by HIV [36].
A study by Malat showed a relatively higher incidence of mixed rejection in HIV+ recipients compared with that reported for non-HIV transplant recipients. A donor terminal serum creatinine greater than 2.5 mg/dL pre-dicted mixed rejection and was associated with poor outcomes. Donor selection and optimization of immu-nosuppression may be critical in these patients [36]. Even if rejection was controlled successfully with steroid ther-apy, these results, as previously reported, suggest a possi-ble scenario where the immune system, damaged by HIV infection, has a worse response to immunosuppressive treatment with respect to the general population, even in patients without a severe immunological dysfunction at the time of transplantation. In our analyses, AR at 1 year was 0.33 (95% CI 0.28; 0.38).
Infectious complicationsDuring the first decades of the renal transplantation era, a serious IC developed in up to 70% of patients following transplantation, resulting in fatal outcomes in as many as 11% to 40% of cases [37]. In a recent case–control study with a median follow-up of 5 years, Ailioaie et al. [38] found a similar incidence of post-transplant IC in HIV+ KT recipients compared with matched KT HIV− controls. An IC incidence of 29% after transplantation
was previously reported [19], and the incidence of post-transplant neoplasms has been described as similar to the incidence in HIV− patients. In our analyses, the incidence of IC observed at 1 year was 42% (95% CI 0.34; 0.50, I2 = 59%), and the rate of incidence of IC observed in this study in HIV+ KT patients is in line with the fre-quencies reported in a study by Stock et al. [4] where 38% of 150 HIV− KT recipients had at least one infection that required hospitalization.
However, the long-term patient and graft outcome of the whole cohort were not influenced by HIV status but were adversely influenced by infections, as survival was diminished in patients having at least one infection.
Furthermore, one-third of HIV+ KT recipients in a study by Ailioaie et al. did not have any episodes of infec-tion, and repeated infections were not frequent. More importantly, the rate of incident infections was not differ-ent between the HIV+ and HIV− matched groups.
Drug interactionAs experience with transplantation in HIV+ patients grow, significant drug–drug interactions between ART and maintenance immunosuppression have been identi-fied as a major clinical challenge.
Post-transplant management of HIV infection with protease inhibitor (PI) and nonnucleoside reverse tran-scriptase inhibitor (NNRTI)-based ART is complicated by reciprocal drug interactions with immunosuppressive therapy, especially CNI, because of inhibition or induc-tion of P450 cytochrome enzymes. Co-administration of PIs with CNIs requires significantly decreased CNI doses and prolonged dosing intervals to avoid supratherapeutic trough levels.
Despite appropriate CNI dose adjustments, variations of drug serum levels are difficult to control and have been linked to increased graft rejection in HIV+ KT recipients [34, 39].
In a study of 150 HIV+ KT patients, the largest to date, higher-than-expected rates of rejection were reported (31% and 41% at 1 and 3 years, respectively) [4]. The authors speculated that increased rates of rejection may have been secondary to altered CNI levels since only one-third of patients on PI- or NNRTI-based regimens underwent CNI dose adjustments.
In a study by Rosa et al., patients receiving PI-contain-ing regimens had lower PS at 1 and 3 years than patients receiving PI-sparing regimens—85% vs. 100% (p = 0.06) and 82% vs. 100% (p = 0.03), respectively [40].
The increased risk of AR in HIV+ individuals has been largely attributed to reduced exposure to immuno-suppressive agents due to drug–drug interactions with ART [4, 41, 42]. Other factors, such as infection of the
Page 30 of 32Zheng et al. AIDS Res Ther (2019) 16:37
allograft, previous alloimmunization and immune activa-tion, might also play roles in predisposition to rejection [43].
This observation might be due to the effects of PI on tacrolimus levels, considering that the overwhelming majority of these patients were on a PI-containing regi-men and that more than half had tacrolimus levels above target at the time of infection. PI could also influence the net state of immunosuppression by increasing the level or effect of other immunosuppressants, such as prednisone and mycophenolate.
The most important finding in the present study is the association between PI use and adverse outcomes, namely, reduced 3-year PS and GS, and increased risk of serious non-opportunistic infections. These observations remained true in analyses restricted to patients receiving nucleoside reverse transcriptase inhibitor (NRTI) “back-bone”; thus, even after excluding the potential influence of other agents included in the ART regimen, PI contin-ued to be associated with poor outcomes.
However, the use of NNRTI or tenofovir disoproxil fumarate (TDF) did not influence GS. Tenofovir alafena-mide (TAF) is a new formulation of tenofovir associated with less kidney (and bone) toxicity [44]. Whether TAF has added clinical benefit over TDF in KT recipients remains to be established.
In a large single-centre study of HIV+ KT recipients conducted by Boyle et al. [45], treatment with TDF at the time of transplant was not associated with 36-month death-censored primary allograft loss after adjustment for DGF and a propensity score for TDF exposure.
Given that specific recipient characteristics, such as hepatitis B co-infection and certain HIV mutations, continue to make TDF-based regimens the most likely to provide adequate viral suppression post-transplant, despite observational data for nephrotoxicity in the non-transplant population.
However, given the limitations of this study, TDF should be reserved for patients who have limited ART options and should be used very cautiously in the KT population, with appropriate dose adjustment and sur-veillance of kidney function, including kidney biopsy when indicated. Substituting TAF for TDF in KT patients is reasonable, but it should be noted that no data are yet available on long-term kidney outcomes with TAF in KT and non-KT recipients in the setting of both preserved and reduced glomerular filtration rate (GFR).
Since their introduction in 2007, integrase strand transfer inhibitors (INSTIs) have been proposed as preferred post-transplant ART because of a favour-able pharmacologic profile with decreased potential for drug interactions [3, 4, 42, 46]. In a study by Stock et al. [4] the majority of patients were on PIs or NNRTIs with
only 4% of participants receiving INSTIs; these patients were also receiving PI, NNRTI or maraviroc, making it impossible to draw conclusions about INSTI-based therapy. In a series of 27 HIV+ KT patients in France predominantly on PI or NNRTI-based regimens (93%), 70% required post-transplant ART modification due to drug interactions with CNIs [32].
Recently, Alfano et al., reported that preferred drug included raltegravir and dolutegravir for INSTI class, maraviroc for CCR5 receptor antagonist, lamivudine for NRTI, and rilpivirine for NNRTI, which offered advantage of having no drug interactions [47].
In summary, we believe that INSTI or CCR5-based therapy should be the preferred ART in patients with HIV who undergo KT, primarily because of decreased drug–drug interactions with immunosuppressive medi-cations such as CNIs, enabling easier monitoring of immunosuppressive medications and superior graft outcomes. However, larger and more controlled trials are needed to better assess the long-term outcomes of INSTI-based therapy to elucidate factors related to GS other than direct reciprocal drug interactions.
ConclusionsIn conclusion, this systematic review and meta-analy-sis demonstrated that with careful selection of patients and multidisciplinary evaluation, KT can be performed with good outcome in HIV+ patients. Moreover, with the advent of INSTI-based cART regimens, drug–drug interactions between cART and immunosuppressants have been dramatically reduced. Nevertheless, fur-ther studies are needed to optimize immunosuppres-sive therapy regimens for HIV+ patients, with the aim of reducing the high rate of AR after transplantation. Furthermore, this review still has its limitations, such as lack of sufficient studies, possibility of some overlap-ping patient cohorts, short of comparator. And we are also looking forward to other novel papers as more and more studies regarding KT of HIV+ patients.
AbbreviationsHIV: human immunodeficiency virus; AIDS: Acquired Immune Deficiency Syndrome; HAART : highly active antiretroviral therapy; KT: kidney transplanta-tion; cART : antiretroviral combination therapy; ESRD: end-stage renal disease; CD4 counts: CD4 T cell counts; AR: acute rejection; PS: patient survival; GS: graft survival; IC: infectious complications; PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-Analysis; NOS: Newcastle–Ottawa-Scale; ATG : antithymocyte globulin; CSA: cyclosporin A; MMF: mycophenolate mofetil; TAC : tacrolimus; MPA: mycophenolic acid; PI: protease inhibitor; DGF: delayed graft function; IPTW: inverse probability of treatment weighting; NNRTI: non-nucleoside reverse transcriptase inhibitor.
AcknowledgementsHao Tang assisted with the development of the search strategy.
Page 31 of 32Zheng et al. AIDS Res Ther (2019) 16:37
Authors’ contributionsXZ was a main contributor in the design, implementation and writing of the manuscript. XPH guided the study design and implementation. WRX independently assessed articles and extracted data independently. SZ, YX and YZ reviewed the articles. LG contributed much in the revised version of our manuscript for updating the literature and revising the paper. So, LG was added as co-first author. All authors read and approved the final manuscript.
FundingNot applicable.
Availability of data and materialsThe datasets during and/or analysed during the current study available from the corresponding author on reasonable request.
Ethics approval and consent to participateNot applicable.
Consent for publicationNot applicable.
Competing interestsThe authors declare that they have no competing interests.
Author details1 Urology Institute, Capital Medical University, Beijing, China. 2 Department of Urology, Beijing Chaoyang Hospital, Capital Medical University, 8 Gongti Nanlu, Chaoyang District, Beijing, China. 3 Department of Urology, Beijing You-An Hospital, Capital Medical University, Beijing, China.
Received: 24 June 2019 Accepted: 9 November 2019
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