ͷ
ǤǣȋͰͱͲͳʹ͵Ȍ
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Vi ological ou come among HIV
in ec ed pa ien s ans e ed
om pedia ic ca e o adul uni s
ǡȋͷͿͿͽȂͶͷͽȌ
Ca olina Bel án-Pa ezͷ, Miguel Gu ié ez-Lópezͷ, Ma ina Rubio-Ga idoͷ,
Ana Valadés-Alca azͷ, Luis P ie o, José Tomás Ramos, San iago Jiménez De O yͺ,
Ma isa Na a oͺ, C is ina Díez-Rome oͻ, Fede ico Pulidoͼ, Eulalia Valenciaͽ,
Á ica Holguínͷ* & The Mad id Coho o HIV-In ec ed Child en in eg a ed in he Pedia ic
ȋȌ
The aim o his ans e sal s udy was o desc ibe he i ological and immunological ea u es o
ǦͷͿͿͽǤǦ
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subjec s wi h a ailable esis ance polȀƤǤ
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ǦȋͽͷǤ;άǤͺͺάǢγͶǤͶͶͶͿȌǡ
ȋͽǤ;άǤͷǤͷάǢζͶǤͶͶͶͷȌȋͿǤͷάǤͷάǢγͶǤͶͼȌǤǦͷǦ
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Globally, an es ima ed 1.7 million child en below 15yea s old we e li ing wi h human immunode iciency i us
(HIV) by he end o 20181. Young people (10–24yea s), including adolescen s (10–19yea s), a e ulne able o
HIV in ec ion, mainly o adolescen s who li e in se ings wi h a gene alized HIV epidemic. In 2018, he e we e
app oxima ely 1.6 million adolescen people li ing wi h HIV2. The Wo ld Heal h O ganiza ion (WHO) es ima es
ha one-se en h o all new HIV in ec ions occu du ing adolescence.
Since 2005, HIV in ec ion has become a ch onic disease o childhood. Pe ina ally in ec ed popula ion li e
o adul hood and a e ansi ioning om pedia ic o adul ca e in an inc easing numbe 3. Pe ina ally in ec ed
child en who each adolescence ha e been exposed o a ious an i e o i al (ARV) d ug egimens du ing hei
li e ime and ha e a highe isk o de eloping ARV esis ance, comp omising he success o p esen and u u e
ea men s op ions4. Indeed, adolescen s li ing wi h pe ina ally acqui ed HIV and ans e ed o adul ca e
OPEN
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uni s, ha e highe mo ali y5 and i ological ailu e a es compa ed o younge child en and adul s6, 7. Thus, i
is especially necessa y o check clinical and i ological s a us o his popula ion, including pe iodic su eillance
s udies moni o ing he d ug esis ance mu a ions (DRM) p e alence o he main ARV amilies in clinical use
in o de o ensu e p ope ea men 8.
To da e, ew s udies ha e in es iga ed he clinical s a us and epidemiological da a o ans e ed pa ien s
om pedia ic o adul ca e. Among high-income coun ies, Spain has one o he mos s udied and well epo ed
pe ina al HIV coho , wi h 1,335 HIV-in ec ed child en, adolescen s and you hs egis e ed since 19959,10. The
p esen s udy upda es he demog aphic, epidemiological and i ological ea u es by Decembe 2017 in HIV-1
in ec ed adolescen s/you hs ans e ed o adul uni s in Mad id wi h a ailable esis ance geno ypes s. pa ien s
unde pedia ic ca e.
Resul s
Ǥ By he end
o Decembe 2017, 290 pa ien s o he Mad id Coho o HIV-in ec ed child en and adolescen s we e unde
clinical ollow-up in 17 public hospi als in Mad id, Spain. A signi ican highe numbe o hem we e bo n in
Spain s. o eigne s coun ies (84.1%, s. 15.9%; p < 0.0001). A o al o 279 had da a ela ed ansmission ou e
and 199 ela ed o i al load, CD4 and CD8 coun s. Among subjec s wi h a ailable da a, a signi ican highe
a e acqui ed he in ec ion by e ical ou e (95.3%) s. ans usion (2.9%) o sexual in e cou se (1.8%). In he
las a ailable epo , mos p esen ed ≤ 500 s. > 500 HIV-1-RNA copies/ml (84.4% s. 16.6%; p < 0.0001), > 350
s. ≤ 350 CD4cells/mm3 (89.4% s. 10.6%; p < 0.0001). Mos showed < 15% s. ≥ 15% nadi CD4% (60.8% s.
39.2%; p < 0.0001), < 200 s. ≥ 200 nadi CD4 coun s (41.2% s. 58.8%; p < 0.0001), and ≥ 25% s. < 25% CD8 a e
(92.5% s. 7.5%; p < 0.0001). Majo i y p esen ed CD4/CD8 a io < 1 s. ≥ 1 (58.3% s. 41.7%; p < 0.001).
Among hem, 106 emained in pedia ics ca e uni s and 184 we e ans e ed o adul ca e uni s om 1997
o Decembe 2017. Table1 summa izes hei demog aphic cha ac e is ics. Bo h g oups we e mainly pe ina ally
HIV-in ec ed and 57% o hem we e emale. By Decembe o 2017 he mean age o he coho was 27 (SD 4.2)
yea s old o ans e ed and 15.6 (SD5.7) yea s old o non- ans e ed pa ien s. The median age a diagnosis was
1.3 (IQR 0.4–4.6) yea s o ans e ed and 0.6 (IQR 0.2–4.6) yea s o non- ans e ed pa ien s. Mos (90.7%) o
ans e ed we e diagnosed be o e he yea 2000 and 74.4% in he 1990s. The ansi ion o pa ien s om pedia ic
uni s o adul heal h ca e occu ed a median age o 18.7 (IQR 17.6–20.8) yea s old, and mainly (91.8%) a e
yea 2002. The a e o ans e ed subjec s wi h na i e Spania d o igin was signi ican ly highe han in he non-
ans e ed (92.9% s. 68.9%; p < 0.0001). Only 6% o ans e ed you hs we e bo n in A ica o La in Ame ica
s. 29.2% o non- ans e ed pa ien s (Table1). Conside ing he whole s udy coho wi h a ailable esis ance da a
(n = 208), he a e o ea ed pa ien s was signi ican ly highe han hose ARV-naï e (81.1% s. 18.9%; p < 0.0001),
as well as hose wi h mono-dual s. iple ARV class expe ience (52.3% s. 25.9%; p < 0.0001).
Ǥ Fo
he p esen ans e sal s udy we included only 133 (72.3%) o 184 ans e ed and 75 (70.7%) o 106 non- ans-
e ed pa ien s o he s udy coho wi h a ailable pol sequence o geno ypic esis ance p o iles in hei clinical
epo s. By Decembe 2017 all pa ien s we e on ART and mos (70.7% o non- ans e ed and 65.4% o ans-
e ed) we e i ologically supp essed (< 50 RNA cp/ml). Non- ans e ed pa ien s p esen ed highe median
nadi CD4 cells han ans e ed in pe cen age (15% s. 11%; p < 0.0001) and coun s (379 [IQR 206–500] s.
187 [IQR 41.2–345.5]; p < 0.0001), and simila median CD4 pe cen ages (33.3% s. 31.6%) and CD4 cells coun s
(781 [IQR 561–962] s. 725 [IQR 498–901] cells/mm3). In bo h coho s, a ound 70% o pa ien s had 25–50%
o CD4+ T cells pe cen age a sampling, and o e 70% o hem eached > 500 cells/mm3 (Table1). Howe e ,
s a is ical di e ences we e obse ed in CD8 cells measu es be ween bo h coho s. T ans e ed you hs showed
highe median CD8 pe cen ages (39.6% [IQR 34–53] s. 36% [IQR 28–42]; p = 0.0004) and coun s (873 [IQR
701–1,210] s. 795 [IQR 552–1,077] cells/mm3; p = 0.0232). Nea ly hal (44%) o pedia ic pa ien s achie ed
CD4/CD8 a io ≥ 1, whe eas a signi ican ly highe numbe o he ans e ed coho had CD4/CD8 a io < 1
(61.6% s. 45.3%; p = 0.0291).
A sampling ime, mos ans e ed (88%) and non- ans e ed (66.7%) had p e ious ARV expe ience, wi h
highe median age a i s ART expe ience among ans e ed s. non- ans e ed (3.4 [IQR 0.9–6.4] s. 0.8
[IQR 0.3–4.3] yea s; p = 0.0023) (Table2). Thus, ART s a occu ed signi ican ly ea lie a e HIV diagnosis
in non- ans e ed han in ans e ed: 4.5weeks [IQR 0.4–24.8] s. 1.5yea s [IQR 0.2–4.6] (p < 0.0001). The
mos common ARV expe ience among bo h ans e ed (43.6%) and non- ans e ed pa ien s (60%) we e mono
o dual NRTI-based egimens (Table2). Double NRTI/NNRTI egimens we e signi ican ly less equen in
ans e ed compa ed o non- ans e ed pa ien s (0.9% s. 8%; p = 0.0285) and iple-class expe ience includ-
ing NRTI/NNRTI/PI mo e equen (33.3% s. 18%; p = 0.0612) (Table2). Expe ience wi h o he d ug amilies
( usion, in eg ase, o CCR5 inhibi o ) was sca ce in bo h g oups. Rega ding speci ic ARVs, s a udina (d4T)
exposu e was signi ican ly mo e equen in ans e ed (43.6% s. 20%; p = 0.004) as didanosine (ddI, 44.4% s.
20%; p = 0.0029) and i ona i (RTV, 34.2% s. 6%; p < 0.0001) and abaca i (ABC) we e less equen (12.8%
s. 28%; p = 0.025, da a non-shown).
ǤǦǤ Among 208 pa ien s
wi h a ailable esis ance p o ile, 16 (12%) ans e ed and 23 (31%) non- ans e ed pa ien s we e ART naï e a
sampling. Among hem, TDR we e ound in 4 (17.4%) non- ans e ed and 2 (12.5%) ans e ed pa ien s based
on WHO 2009 SDRM lis (Table2). TDR o NNRTI was mo e equen in non- ans e ed and TDR o NRTI in
ans e ed. TDR mu a ions ound in non- ans e ed we e M41L, D67N, M184V, L210W, T215Y/S in RT and
L24I, D30N, V32I, I54V, V82A and N88D in PR. In ans e ed only M41L in RT.
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Demog aphic cha ac e is ics Non- ans e eda (N = 106) T ans e edb (N = 184) P alue
Female, No. (%) 61 (57.5) 106 (57.6) 1.0000
Rou e o in ec ion, No. (%)
Pe ina ally 93 (87.7) 173 (94) 0.0766
T ans usion 2 (1.9) 6 (3.3) 0.7148
Sexual 2 (1.9) 3 (1.6) 1.0000
Unknown 9 (8.5) 2 (1.1) 0.0024
Age, yea s, mean [SD], No. (%) 15.6 [5.7] 27 [4.2] < 0.0001
0 o < 6 7 (6.6) 0 0.0008
6 o < 12 22 (20.8) 0 < 0.0001
12 o < 18 40 (37.7) 3 (1.6) < 0.0001
18 o < 24 31 (29.2) 44 (23.9) 0.3187
24 o ≤ 30 6 (5.7) 93 (50.6) < 0.0001
> 30 0 44 (23.9) < 0.0001
Pe iod o HIV diagnosis, No. (%)
1985–1989 0 30 (16.3) < 0.0001
1990–1994 4 (3.8) 88 (47.8) < 0.0001
1995–1999 23 (21.7) 49 (26.6) 0.3491
2000–2004 28 (26.4) 12 (6.5) < 0.0001
2005–2009 20 (18.9) 1 (0.6) < 0.0001
2010–2014 20 (18.9) 3 (1.6) < 0.0001
2015–2016 10 (9.4) 1 (0.6) < 0.0001
Unknown 1 (0.9) 0 0.3655
Age a diagnosis, yea s, median [IQR], No. (%) 0.6 [0.2–4.6] 1.3 [0.4–4.6] 0.0742
0 o < 6 86 (81.2) 149 (81.0) 1.0000
6 o < 12 14 (13.2) 27 (14.7) 0.8614
12 o ≤ 18 5 (4.7) 8 (4.3) 1.0000
Unknown 1 (0.9) 0 0.3655
Calenda yea o ans e , No. (%)
1997–1999 – 4 (2.2)
2000–2002 – 9 (4.9)
2003–2005 – 21 (11.4)
2006–2008 – 29 (15.8)
2009–2011 – 47 (25.5)
2012–2014 – 42 (22.8)
2015–2017 – 30 (16.3)
Unknown – 2 (1.1)
Age a ans e , yea s, median [IQR] – 18.7 [17.6–20.8]
O igin o bi hc, No. (%)
Spain (Wes Eu ope) 73 (68.9) 171 (92.9) < 0.0001
Po ugal (Wes Eu ope) 0 1 (0.5) 1.0000
Eas Eu ope 0 1 (0.5) 1.0000
No h A ica 2 (1.9) 2 (1.1) 0.6249
Sub-Saha an A ica 19 (17.9) 2 (1.1) < 0.0001
Sou h and Cen al Ame ica 10 (9.4) 7 (3.8) < 0.0001
Asia 2 (1.9) 0 0.1328
Vi ological ea u esd No. (%)
Non- ans e ed
N = 75 (70.7)
T ans e ed
N = 133 (72.3) P alue
Vi al load, median [IQR], No. (%) 35 [20–37] 37 [20–71] 0.0441
≤ 20 28 (37.3) 43 (32.3) 0.5427
21–50 25 (33.4) 44 (33.1) 1.0000
51–200 4 (5.3) 18 (13.5) 0.0983
201–500 1 (1.3) 5 (3.7) 0.4220
501–1,000 3 (4.0) 2 (1.5) 0.3536
1,001–10,000 3 (4.0) 9 (6.8) 0.5429
> 10,000 3 (4.0) 11 (8.3) 0.3876
Unknown 8 (10.7) 1 (0.8) 0.0014
Con inued
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Ǧͷ
Ǥ To assess he acqui ed d ug esis ance (ADR) p e alence acco ding o d ug amily, we analyzed he las
a ailable esis ance in o ma ion (pol sequence and esis ance p o ile) closes o he end o Decembe 2017 in
50 pedia ic and 117 ART-expe ienced ans e ed you hs (Table2, Fig.1a). ADR p e alence was signi ican ly
highe in p e ea ed ans e ed han non- ans e ed pa ien s (71.8% s. 44%; p = 0.0009), mainly o NRTI
(72.8% s. 31.1%; p < 0.0001) and PI (29.1% s. 12%; p = 0.0262), p esen ing simila NNRTI esis ance (32%
s. 22.2%; p = 0.2453). The p esence o iple-class esis an i uses was simila in bo h g oups (15.2% s. 6.8%;
Table 1. Demog aphic and i ological-immunological ea u es o non- ans e ed and ans e ed pa ien s
in he Mad id coho a he end o Decembe 2017. a Pa ien s om Mad id Coho o HIV-1 in ec ed child en
and adolescen s unde ollow-up in pedia ic uni s. b T ans e ed om pedia ic o adul uni s. c Bi h o igin o
pa ien s by coun y: Po ugal (n = 1), Romania (n = 1), Mo occo (n = 4), Came oon (n = 1), Equa o ial Guinea
(n = 15), Mozambique (n = 1), Nige ia (n = 4), A gen ina (n = 1), Boli ia (n = 2), Colombia (n = 2), Ecuado
(n = 4), Gua emala (n = 1), Hai i (n = 1), Hondu as (n = 3), Mexico (n = 1), Pe u (n = 1), Dominican Republic
(n = 1), China (n = 1), and India (n = 1). d Vi ological ea u es in pa ien s wi h esis ance in o ma ion. Vi al
Load: HIV-1 RNA-copies/ml. In bold, signi ican p alues (< 0.05).
Vi ological ea u esd No. (%)
Non- ans e ed
N = 75 (70.7)
T ans e ed
N = 133 (72.3) P alue
CD4 pe cen age, mean [SD], No. (%) 33.3% [9.2] 31.6% [11.4] 0.2715
< 25% 11 (14.7) 35 (26.3) 0.0571
25–50% 55 (73.3) 90 (67.7) 0.4346
> 50% 1 (1.3) 7 (5.3) 0.2631
Unknown 8 (10.7) 1 (0.8) 0.2715
CD4 cells/mm3, median [IQR], No. (%) 781 [561–962] 725 [498–901] 0.279
≤ 200 2 (2.6) 7 (5.3) 0.4934
201–350 4 (5.3) 8 (6.0) 1.0000
351–500 8 (10.7) 19 (14.3) 0.5244
501–1,000 39 (52.0) 74 (55.7) 0.6646
1,001–1,500 11 (14.7) 22 (16.5) 0.8440
> 1,500 3 (4.0) 2 (1.5) 0.3536
Unknown 8 (10.7) 1 (0.8) 0.0014
Nadi CD4 pe cen age, median [IQR], No. (%) 15% [11–22.7] 11% [3–16.7] 0.0001
< 15% 33 (44.0) 88 (66.2) 0.0022
15–24% 22 (29.3) 36 (27.0) 0.7492
≥ 25% 12 (16.0) 8 (6.0) 0.0265
Unknown 8 (10.7) 1 (0.8) 0.0014
Nadi CD4 (cells/mm3), median [IQR], No. (%) 379 [206–500] 187 [41.2–345.5] < 0.0001
< 200 15 (20.0) 67 (50.4) < 0.0001
200–499 35 (46.6) 57 (42.8) 0.6632
≥ 500 17 (22.7) 8 (6.0) 0.0007
Unknown 8 (10.7) 1 (0.8) 0.0014
CD8 pe cen age, median [IQR], No. (%) 36% [28–42] 39.6% [34–53] 0.0004
< 25% 11 (14.6) 4 (3.0) 0.0036
25–50% 48 (64.0) 92 (69.2) 0.4466
> 50% 8 (10.7) 36 (27.0) 0.0049
Unknown 8 (10.7) 1 (0.8) 0.0014
CD8 cells/mm3, median [IQR], No. (%) 795 [552–1077] 873 [701–1210] 0.0232
≤ 200 1 (1.3) 1 (0.8) 1.0000
201–350 3 (4.0) 3 (2.2) 0.6694
351–500 7 (9.3) 7 (5.2) 0.2651
501–1,000 37 (49.4) 69 (51.9) 0.7735
1,001–1,500 16 (21.3) 37 (27.8) 0.3251
> 1,500 3 (4.0) 15 (11.3) 0.1208
Unknown 8 (10.7) 1 (0.8) 0.0014
CD4/CD8 a io [IQR], No. (%) 0.9 [0.6–2.3] 0.8 [0.4–1.2] 0.0205
< 1 34 (45.3) 82 (61.6) 0.0291
≥ 1 33 (44.0) 50 (37.6) 0.0849
Unknown 8 (10.7) 1 (0.8) 0.0014
ͻ
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p = 0.2735). Among p e ea ed pa ien s, we iden i ied hese speci ic ADR p esen o e 5% o ea ed pa ien s.
Se en ou en p e alen ADR o NRTIs in he s udy popula ion (M41L, D67N, T69D, K70R, L210W, T215Y and
K219Q) we e signi ican ly mo e equen in he ans e ed s. he non- ans e ed coho , mainly D67N, M41L
Table 2. Vi ological ea u es and HIV d ug esis ance mu a ions in HIV-in ec ed child en and ans e ed
wi h a ailable pol sequence o esis ance p o ile a sampling ime. ART an i e o i al he apy, NRTI nucleoside
e e se- ansc ip ase inhibi o , NNRTI non-nucleoside e e se- ansc ip ase inhibi o , PI p o ease inhibi o ,
INI in eg aseinhibi o , T20 en u i ide, TDR ansmi ed d ug esis ance, DRM d ug esis ance mu a ion,
SD s anda d de ia ion, IQR in e qua ile ange, CRF ci cula ing ecombinan o m, URF unique ecombinan
o m; Sub ype in o ma ion was a ailable in 205 o he 208 pa ien s unde s udy. They included 203 subjec s
wi h pol sequence and wo pa ien s (1 non- ans e ed and 1 ans e ed you h) wi h no a ailable pol sequence
bu a ailable HIV-1 a ian in o ma ion in hei clinical epo .In bold, signi ican p alues (< 0.05). *Bo h
ans e ed adolescen and child had INI, T20 and CXCR5 inhibi o expe ience. a Pa ien s om Mad id Coho
o HIV-1 in ec ed child en and adolescen s unde ollow-up in pedia ic uni s. b T ans e ed om pedia ic o
adul uni s.
Va iable Non- ans e eda (N = 75) T ans e edb (N = 133) P alue
ART exposu e, No. (%)
Naï e 23 (30.6) 16 (12.0) 0.0015
T ea ed 50 (66.7) 117 (88.0) 0.0004
Unknown 2 (2.7) 0 0.1289
ART expe ience, No. (%) 50 117
Mono/dual NRTI 30 (60.0) 51 (43.6) 0.8825
NRTI + NNRTI 4 (8.0) 1 (0.9) 0.0285
NRTI + PI 3 (6.0) 12 (10.2) 0.5566
T iple (NRTI + NNRTI + PI) 9 (18.0) 39 (33.3) 0.0612
Wi h ≥ 3 amily d ugs* 1 (2.0) 1 (0.9) 0.5104
Unknown da a 3 (6.0) 13 (11.1) 0.3972
Age a i s ART expe ience, yea s, median [IQR] 0.8 [0.3–4.3] 3.4 [0.9–6.4] 0.0023
Time om diagnosis o ART s a , median [IQR] 4.5weeks [0.4–24.8] 1.5yea s [0.2–4.6] < 0.0001
ART exposu e ime, yea s, median [IQR] 15.2 [10.5–19.4] 22.7 [20.8–24.4] < 0.0001
Yea o las a ailable sequence, No. (%)
1993–1997 4 (5.3) 15 (11.3) 0.2112
1998–2002 6 (8.0) 21 (15.8) 0.1342
2003–2007 15 (20.0) 38 (28.6) 0.1888
2008–2012 30 (40.0) 32 (24.1) 0.0184
2013–2017 18 (24.0) 27 (20.2) 0.5996
Unknown 2 (2.7) 0 0.1289
Nº o naï e pa ien s pol wi h sequence, No. 23 16
Nº o naï e pa ien s wi h TDR, No. (%) 4 (17.4) 2 (12.5) 1.0000
To NRTI 3 (13.0) 2 (12.5) 1.0000
To NNRTI 0 0
To PI 3 (13.0) 0 0.2550
Double esis ance (NRTI + PI) 2 (8.7) 0 0.5033
T iple esis ance (NRTI + NNRTI + PI) 0 0
Only
To NRTI 1 (4.3) 2 (12.5) 0.5570
To NNRTI 0 0
To PI 1 (4.3) 0 1.0000
Nº o p e ea ed pa ien s, No.
Wi h pol sequences 49 113 1.0000
Wi h esis ance p o ile 1 4 1.0000
HIV-1 a ian s p e alence, No. (%) N = 75 N = 130
B sub ype 51 (68.0) 121 (93.1) < 0.0001
Non-B a ian s 24 (32.0) 9 (6.9) < 0.0001
Pu e non-B sub ypes 8 (10.7) 4 (3.1) 0.0329
CRF 15 (20.0) 4 (3.1) 0.0001
URF 1 (1.3) 1 (0.8) 1.0000
Unknown 0 3 (2.3) 0.3005
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and T215Y (41.7% s. 6.7%, p < 0.0001; 38.9% s. 13.3%, p = 0.0019; 30.1% s. 6.7%, p = 0.0013, espec i ely). No
signi ican di e ences we e ound in ADR o NNRTI and in ADR o PI L90M, change mo e equen in ans-
e ed you h (22.6% s. 8%; p = 0.0405) (Fig.1b).
Figu e2 shows he p edic ed esis ance le el o 20 ARV o he mos used d ug amilies (NRTI, NNRTI, PI)
among he 162 p e ea ed subjec s unde s udy ca ying ADR (49 non- ans e ed and 113 ans e ed) wi h
a ailable pol sequences. The ans e ed coho epo ed a signi ican ly highe a e o pa ien s wi h high esis -
ance le el o a NRTI amily d ugs han non- ans e ed (60.1% s. 27.2%; p = 0.0081), mainly o d4T (38.2% s.
11.4%; p = 0.001), AZT (37.3% s. 11.4%; p = 0.002), ddI (33.3% s. 11.4%; p = 0.006) and ABC (32.4% s. 11.4%;
p = 0.008). The a e o non- ans e ed and ans e ed pa ien s wi h p edic ed high esis ance le el o NNRTI
and PI did no show signi ican di e ences, excep o nel ina i (NFV), wi h highe a es o esis ance among
ans e ed you hs.
Figu e1. Acqui ed d ug esis an p e alence and he mos ep esen a i e mu a ions in he s udy p e ea ed
popula ion om he Mad id Coho o HIV-1 in ec ed child en and adolescen s. (A) ADR p e alence acco ding
o d ug class in 167 p e ea ed pa ien s wi h pol sequence o esis ance da a. (B) ADR p e alence o e 5% in 167
p e ea ed pa ien s. T iple-class: ADR o NNRTI + NRTI + PI. ADR o NNRTI + PI was no ound. E o ba s
indica e exac hyb id Wilson/B own 95% CIs. S a is ical di e ences: ****p < 0.0001; **p < 0.01; *p < 0.05 Chi-
squa e es . Resul s we e calcula ed in 49 PR and 45 RT sequences o esis ance p o iles om non- ans e ed
pa ien s and in 110 PR and 103 RT sequences o esis ance p o iles om ans e ed indi iduals a sampling.
ADR acqui ed HIV d ug esis ance mu a ions, NTP non- ans e ed pa ien s, TP ans e ed pa ien s.
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By con as , a signi ican highes a e o non- ans e ed pa ien s we e suscep ible o all NRTI, NNRTI and
PI d ugs compa e o ans e ed you hs (70.4% s. 28.4%, p < 0.0001; 61.4% s. 32.3%, p = 0.0011 and 83.3% s.
58.4%, p = 0.0011, espec i ely). Addi ional complemen a y da a ela ing o low and in e media e d ug esis -
ance le els o each d ug in he s udy popula ion a e epo ed in Supplemen a y Fig.S1. We iden i ied he spe-
ci ic d ugs wi h he highes suscep ibili y in bo h coho s, ep esen ing in e es ing al e na i es o escue ART
egimens i equi ed. Mos PI and he new NNRTI (DOR, RPV, and ETR) we e he d ugs showing he highes
suscep ibili ies in ans e ed you hs.
ǦͷǤ HIV-1 a ian was known in 205 (98.6%) o he
208 pa ien s wi h a ailable pol sequence (n = 203) geno ypic esis ance p o ile (n = 5). Among hem, 203 (97.6%)
could be success ully sub yped by phy. O e all, 172 (83.9%) o he 205 HIV-1 subjec s we e in ec ed wi h HIV-1
sub ype Bpol, being he p edominan a ian , as p e iously epo ed9,10. HIV-1 sub ype B in ec ions we e mo e
equen han by non-B a ian s (83.9% s. 16.1%; p < 0.0001) in he whole coho .
Ne e heless, sub ype Bpol p e alence was signi ican ly highe among ans e ed s. pedia ic coho (93.1%
s. 68%; p < 0.0001). Non- ans e ed pa ien s p esen ed a highe p e alence o pu e non-B a ian s a pol (10.7%
s. 3.1%; p = 0.033) and in e -sub ype ecombinan (CRF and URF) a ian s han ans e ed (21.3% s. 3.9%;
p = 0.0001).
Among he 33 pa ien s (24 non- ans e ed and 9 ans e ed) in ec ed by HIV-1 non-B a ian s a pol, all
bu 5 cases we e bo n ab oad o a leas one o hei pa en s we e immig an s coming om Sub-Saha an A ica,
Eas e n Eu ope o La in Ame ica (Supplemen a y TableS1). Among he 24 non- ans e ed pa ien s ca ying
non-B a ian s, 6 (25%) we e pu e non-B sub ypes (3C, 1A, 1A6, 1F1), 17 (70.8%) we e CRF, mainly CRF02_AG
(8 cases, 33.3%) and CRF01_AE (2 cases, 8.3%), he mos globally dis ibu ed CRFs. We also ound URF (1 case,
4.2%) om Equa o ial Guinea. Among he 9 ans e ed you hs ca ying non-B a ian s a pol, 3 (33.3%) we e
in ec ed by pu e non-B a ian s (1A, 1A2, 1H), 4 (44.4%) we e CRF (1 CRF01_AE, 1 CRF02_AG, 1 CRF12_BF,
and 1 CRF28_BF) and bo n in Spain, and he emaining 2 ca ied URF including sub ype C o G sequences,
espec i ely (Supplemen a y TableS1).
Discussion
T ansi ion o adul ca e is c ucial o HIV-in ec ed adolescen s. This popula ion aces wi h impo an challenges
o ensu e long- e m i ological supp ession when eaching adul hood. Howe e , li le is known abou hei
cu en heal h s a us in each coun y, despi e an expec ed inc ease in he numbe o child en being ans e ed
in o adul uni s in he coming yea s. Se e al s udies ha e assessed he cu en s a e o adolescen su i o s o
pe ina ally o ea ly acqui ed HIV9, 11–17. Table3 shows all ela ed s udies on HIV-1 pa ien s ans e ed om
paedia ic o adul uni s wo ldwide.
Du ing he ea ly nine ies, Spain had he highes incidence o mo he - o-child ansmission in Wes e n Eu ope
among he oin use s HIV-in ec ed women, leading o high HIV ansmissions in child en bo n be ween 1980
and 199018. The Mad id coho is one o he bes cha ac e ized pe ina al coho in Eu ope and wo ldwide, along
wi h he UK/I eland11, he Ne he lands13 and New Yo k Ci y15 coho s (Table3). Fu u e ansi ioning p og ams
Figu e2. P edic ed high esis ance le el o an i e o i al d ugs in p e ea ed pa ien s om he Mad id Coho
o HIV-1 in ec ed child en and adolescen s. Suscep ibili y le el was es ima ed in he 162 p e ea ed pa ien s
wi h a ailable pol sequence acco ding o he S an o d HIVdb In e p e a ion Algo i hm. E o ba s indica e exac
hyb id Wilson/B own 95% CIs. S a is ical di e ences: **p < 0.01 Chi-squa e es . Resul s we e calcula ed in 48
PR and 44 RT sequences om non- ans e ed pa ien s and in 109 PR and 102 RT sequences om ans e ed
indi iduals a sampling. ABC abaca i , AZT zido udine, d4T s a udine, ddI didanosine, FTC em ici abine,
TDF eno o i disop oxil uma a e, 3TC lami udine, DOR do a i ine, EFV e a i enz, ETR e a i ine, NVP
ne i apine, RPV ilpi i ine, ATV a azana i , DRV da una i , FPV osamp ena i , IDV indina i , LPV lopina i ,
NFV nel ina i , SQV saquina i , TPV ip ana i , NRTI nucleoside e e se- ansc ip ase inhibi o , NNRTI non-
nucleoside e e se- ansc ip ase inhibi o , PI p o ease inhibi o .
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will ep esen a challenge mainly in low-income coun ies28,29 whe e mos HIV-in ec ed-child en and adoles-
cen s li e19,31.
By he end o Decembe 2017, wo- hi ds o he pe ina ally in ec ed pa ien s in ou coho in Mad id (Spain)
had eached adolescence and ansi ioned o adul ca e. He e, despi e simila median age a ans e , ans e ed
you hs in he p esen s udy we e younge a HIV diagnosis (1.3 s. 2yea s old) and a i s ART expe ience (3.4 s.
5.6yea s old) han he same coho 6yea s be o e9. Addi ionally, o e six yea s, ou pe ina al coho had imp o ed
hei immunological s a us signi ican ly ega ding he a e o ans e ed achie ing CD4 T cells > 500cells/mm3
coun s (74% s. 55.3% epo ed in 2011; p = 0.0031), eaching a es highe han in compa able s udies in UK/
I eland11 (42%), New Yo k15 (38.9%) and A gen ina17 (36.3%). The good eco e y o CD4 coun s in he Mad id
coho could be due o an ea ly diagnosis and ea men and imp o ed ART egimens, in ag eemen wi h o he
s udies epo ing ha be e ini ial s a us is associa ed wi h imp o ed immune eco e y20–22.
Rega ding i ological ou come, ou upda ed da a showed a 27% inc ease in ans e ed you hs wi h a ail-
able sequence wi h unde ec able i al load (UVL) in ou Spanish coho om 2011 o 2017 (38.4% s. 65.4%;
p < 0.0001) (Table3). Swedish and I alian coho s p esen ed highe a es o ans e ed pa ien s achie ing UVL12,14
and Canadian and A gen ina ans e ed coho s he lowes 16,17 (42.2% s. 45%, espec i ely), despi e being
conside ed high-income coun ies. Ne e heless, in some high-income coun ies, ans e ed young people
s ill ha e high a es o i ological ailu e immedia ely be o e, du ing, and sho ly a e ansi ion (36% in he
Ne he lands)13, as well as a loss o ollow-up a e ansi ion (nea ly 14% in Spain23 and in he Ne he lands13),
mainly in he i s yea a e ans e .
By he end o Decembe 2017, a hi d o ans e ed you hs s ill had incomple e i al supp ession, and lowe
median CD4/CD8 a io han non- ans e ed pa ien s, a p edic o o inc eased immunoac i a ion and immu-
nosenescence despi e ART
24. The incomple e i aemia supp ession could be explained by pa ial adhe ence o
ea men , a key p oblem in adolescence. Mo eo e , mos ans e ed you hs o he s udy coho was in ec ed in
he mono and bi- he apy e a, ecei ing se e al subop imal ea men s and selec ing a high a e o his o ic DRM,
one o he majo obs acles o an e ec i e ART
25. The complex clinical managemen in pe ina ally-in ec ed you hs
impac s in he cu en immune- i ological con ol o HIV in ec ion compa ed o adul s and o pa ien s unde
pedia ic ca e, who p obably ha e ecei ed op imal ART egimens. Thus, be e immune- i ological si ua ion
du ing ansi ion o adul uni s is expec ed in u u e ans e ed coho s.
We obse ed a high TDR a e in he s udy coho , mainly in he ans e ed g oup. The highe p e alence o
esis ance ound in ans e ed s. non ans e ed indi iduals could be due o he olde age and longe he apy
expe ience wi h less e icacious an i e o i al ea men s and many egimen swi ches s. non- ans e ed. The
ans e ed adolescen s had o ace he mono he apy and dual he apy egimens a ailable a he ime, hus
inc easing he isk o i ological ailu es and unsupp essed i aemia due o esis ance de elopmen . In ou
s udy, he 4 ans e ed wi h TDR we e e ically HIV-1 in ec ed adolescen s, collec i e ound o ha e highe
isk o ea men ailu e han newly HIV in ec ed you h, p obably as a esul o hei li elong in ec ion and hei
Table 3. Compa ison o published s udies om HIV-1 pa ien s ans e ed om pedia ic ca e o adul uni s
wo ldwide. HIV human immunode iciency i us, e e e ence, No. numbe o ans e ed pa icipan s in each
s udy, DX diagnosis, cART combina ion an i e o i al he apy, ART an i e o i al he apy, seq sequences, DRM
d ug esis ance mu a ion, NRTI nucleoside e e se- ansc ip ase inhibi o , NNRTI non-nucleoside e e se-
ansc ip ase inhibi o , PI p o ease inhibi o , UVL unde ec able i al load ≤ 50 RNA copies/ml a las a ailable
i aemia, excep om USA s udy23 (< 400 cp/ml), cp copies; dash: no p o ided da a. HIV non-B a ian s
include HIV-1 sub ypes di e en han sub ype B and ecombinan s. a DRM ound o NRTI + NNRTI, NRTI + PI
and NNRTI + PI d ug class amilies. b DRM ound o NRTI + NNRTI + PI d ug class amilies.
Coun y( e ) No. Da e
Pe ina al
in ec ion
Median age (yea s) ART
expe ience
(mean,
yea )
Ra e o DRM in p e- ea ed pa ien s
Mos equen
DRM
TDR in
naï e
pa ien s
HIV
non-B
a ian s
Clinical s a us
A ans e
HIV
DX
Fi s
cART
No o
polseq To any
Only o
NRTI
Only o
NNRTI
Only
o PI Duala/T ipleb
CD4 > 500
cells/mm3UVL
P esen s udy 184 1997–
2017 94% 18.7 1.3 3.5 22.7 113 75.2% 23.1% 2.6% 7% 28.2%/15.4%
NRTI: D67N
NNRTI:K103N
PI: L90M
19% 6.9% 74% 65.4%
Spain9112 1997–
2011 93.7% 18.9 2 5.6 11.5 58 81% 28.5% 7.1% 14.6% 31%/17.3%
NRTI:M41L
NNRTI:K103N
PI: L90M
0% 1.9% 55.3% 38.4%
UK/I eland11 644 1996–
2016 91% 17.4 6.4 9.6 7.8 381 82% 9.3% 16.2% 0.7% 44%/12%
NRTI:M184V
NNRTI:K103N
PI: L90M
6% – 42% 60%
Sweden12 34 2013–
2015 91% 19 – 9 – 32 – – – – 25%/– – – – – 96%
The
Ne he lands13 54 1996–
2014 78% 18.8 8.4 10.4 – – – – – – – – – – – –
I aly14 24 2004–
2006 100% 18 – – 14 13 69.2% – – – 46.2%/– NRTI:M41L – – – 75%
USA15 735 2006–
2015 100% 22 – – – – – – – – – – – – 38.9% 51.8%
Canada16 45 1999–
2011 71% 18.1 – – – 38 73.7% 21% 55.3% 50% –/31.6% – – 20%
28.9%
< 200 cells/
ml
42.2%
A gen ina17 37 2011 100% 18 – – 15 – – – – – –/45%
NRTI: D67N
NNRTI:K103N
PI: V82A
– – 36.3% 45%
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hea ily ART exposi ion6. Mo eo e , HIV in ec ed pa ien s du ing childhood in ou ans e ed coho we e
mainly in ec ed du ing he ea ly 1990s, when Spain had one o he highes a es o AIDS in Eu ope. The inad-
equa e ART egimens in hei HIV-in ec ed mo he s could also con ibu e o he high esis an le el ound in
pe ina ally in ec ed ans e ed g oup.
The ART expansion in low-income coun ies whe e mos pedia ic in ec ions occu and he insu icien
adhe ence suppo , equen subop imal ART egimens in HIV-in ec ed mo he s and child en, lack o ou ine
i al load (VL) and esis ance moni o ing in mos o hese se ings, can lead o he sp eading o esis an i uses
among new in ec ions in naï e and ea ed child en. In ac , nea ly 85% o naï e non- ans e ed pa ien s in ou
s udy we e bo n ab oad o om HIV-in ec ed pa en s coming om low-income coun ies, whe e ART has been
expanding in he las yea s, wi hou he implemen a ion o a ailabili y o op imal ART egimens26. TDR a e in
pe ina ally HIV-1 in ec ed pa ien s in Mad id was highe han in pe ina al coho s om UK/I eland (6%)11, 27,
and in mos pedia ic coho s wo ldwide28, as well as in adul s om Eu ope (8.3%)29 and in he Spanish AIDS
Resea ch Ne wo k o adul s (7.9%)30. The p esence o TDR has impo an clinical consequences due o he
in luence o baseline d ug esis ance pa e ns in he ou come o i s -line ART in child en31 and adul s29 and is
a s ong p edic o o ea men ailu e.
ADR p e alence among ART-expe ienced pa ien s has dec eased o e ime in he Mad id coho o all
d ug amilies (Supplemen a y TableS2). The signi ican educ ion in he a e o non- ans e ed pa ien s wi h
ADR o NRTI class ( om 62.1% in 2011 o 28% in 2017; p < 0.0001) could likely be due o he implemen a ion
o LPV/ as a i s -line combined an i e o i al ea men (cART) in Spain since 2008, and he wi hd awal o
NFV in 200732. The signi ican dec ease o ADR o PI in pa ien s unde pedia ic ca e and ans e ed you hs in
Spain could e lec he imp o emen s in ART due o a ailabili y o new d ug classes in he las yea s. Ne e he-
less, in 2017 ans e ed pa ien s s ill main ained he highes ADR p e alence o NRTI (64.1%), since i was he
i s a ailable d ug class o clinical use, ABC and AZT being he mos comp omised d ugs, along wi h ddI and
d4T no-longe -used ARV compa ing o non- ans e ed pa ien s (Fig.2). This was due o he highe p esence o
D67N, M41L and T215Y esis ance mu a ions in RT in 42.7%, 38.8% and 30.1% o ans e ed you h, espec i ely.
T iple-class esis ance was de ec ed in 15.2% o ans e ed you hs, a lowe a e han he one p e iously
epo ed in he same s udy coho (17.3%), as in o he ans e ed coho s in Canada (31.6%)16 and A gen ina
(45%)17, and highe han in UK (12%)11. All pa ien s ca ying iple-class esis ance in ou coho we e bo n
be ween 1987 and 1996, and 43.9% o hem had expe ienced mono/dual NRTI he apies be o e cART imple-
men a ion, which may ha e led o ea men ailu e and subsequen ADRM selec ion due o he incomple e
i al supp ession33. I is impo an o highligh ha he compa ison be ween ans e ed and non- ans e ed
pa ien s was comple ely ela ed wi h he ime-pe iod when hey we e in ec ed and ea ed, sugges ing ha a
di ec compa ison may no be accu a e in his s udy.
Despi e high ADR a e o he h ee main ARV amilies among ans e ed, ou da a showed ha some NNRTI
(DOR, ETR, and RPV) and PI (DRV and TPV) emained good op ions o escue he highly p e ea ed pa ien s
in he s udy coho . Mo eo e , nowadays young people could bene i om newly licensed d ugs o ea HIV-1
in adul s, like cell-en y and in eg ase inhibi o s34. Su eillance o TDR and ADR p e alence among HIV-1
in ec ed child en and adolescen s is c i ically impo an in de e mining i changes o empi ic i s , second and
hi d-line ART egimens a e equi ed35.
Rega ding HIV in ec ing a ian s, in ec ions wi h non-B a ian s in non- ans e ed pa ien s inc eased sig-
ni ican ly om 2011 o 2017 (11.5% o32%; p = 0.0004), mos ly due o he inc emen o child en in ec ed by CRF
(6.9% s. 20%; p = 0.0065). Despi e ha ac ha sub ype B was he p e alen a ian in he ans e ed coho ,
non-B in ec ions also inc eased among ans e ed om 1.9% (2011) o 6.9% (2017) (Table3). Ine i ably, his
i al he e ogenei y could a ec he e icacy o HIV-1 moni o ing, a ec ing he clinical managemen o HIV-1
in ec ion o disease p og ession36,37.
The main limi a ion o he s udy is ha esis ance esul s de i ed om a ailable pol sequence o esis ance
p o iles closes o Decembe 2017, anging om 1993 o 2017 bu mainly da ing om 2005 o 2010 (Table2).
The e o e, esis ance pa e ns may no p ecisely e lec ea u es in Decembe 2017. Mo eo e , we only used da a
om pa ien s wi h a ailable esis ance es ing, excluding o he i ological s udy pa ien s wi hou pol sequences.
VL quan i ica ion assays wi h di e en limi o de ec ions di e ed ac oss pa ien s and yea s du ing he clinical
ollow-up o he s udy coho .
The wo ld is home o mo e young people (ages 10–24yea s old) now han a any o he ime in his o y, and
we need o ocus and ca e o his collec i e i we wan o end he AIDS epidemic by 2030. Ou s udy demon-
s a ed ha good clinical managemen could achie e he goal ha mos HIV-1-in ec ed pa ien s ans e ed
om pedia ic ca e o adul uni s may main ain i ological supp ession and high CD4 coun s, dec easing ADR
p e alence and imp o ing hei clinical s a us. This highligh s he impo ance o VL and d ug esis ance moni-
o ing wo ldwide in all HIV-in ec ed-pedia ic and young popula ion o ART op imiza ion i equi ed du ing
he ch onic clinical ollow-up o in ec ion.
Me hods
Ǥ In his mul icen e obse a ional e ospec i e and ans e sal s udy, we iden i ied 290
pa ien s en olled in he Mad id Coho o HIV In ec ed Child en and Adolescen s including all you hs ans-
e ed om pedia ic ca e o adul uni s and all non- ans e ed pa ien s by Decembe 2017. Among hem, 208
(133 ans e ed and 75 non- ans e ed pa ien s) had a leas one a ailable HIV-1 polime ase (pol) sequence
o geno ypic esis ance p o iles in hei clinical epo s, p esen ing simila demog aphical and clinical ea u es
o he o e all popula ion. Fo esis ance es ing and HIV-1 a ian cha ac e iza ion we selec ed he sequence/
p o ile closes o Decembe 2017 pe pa ien , de ining as sampling ime he yea o collec ion o sequenced
samples, which anged om 1993 o 2017. Mos sequences we e p e iously epo ed by ou g oup9,10, excep 20
