แนวทางการดูแลรักษาเด็กและวัยรุ่ นติดเชื้อเอช ไอ วี
พ. ศ. 2556
รศ พญ ธันยวีร ์ ภูธนกิจ
หน่ วยโรคติดเชื้ อ ภาควิชากุมารเวชศาสตร์ คณะแพทยศาสตร์ จุฬาลงกรณ์มหาวิทยาลัย
HIVNAT, ศูนย์วจิ ยั โรคเอดส์ สภากาชาดไทย
thanyawee.p@hivnat.org
02-256-4930
Pediatric HIV and co-infection 25-26 July, 2013
แนวทางการดูแลเด็กและวัยรุ่นติดเชื้ อเอชไอวี 2013




สถานการณ์ การรักษาผูต้ ิดเชื้ อเอชไอวีทวั ่ โลก
การเริ่มยาต้านไวรัส (When to start?) ในทารก-เด็ก-วัยรุ่น
สูตรยาต้านไวรัส (What to start?) ในทารก-เด็ก-วัยรุน่
การติดตามหลังเริ่มยาต้านไวรัส (Treatment monitoring)
People receiving ART: 2003-2012
WHO 2015 Target
15 million on Treatment
WHO 3 by 5 campaign
9.7 million by 2012
630,000 children
4.2 million AIDS death
averted from ART
0.3 million at 2002
WHO Global update on HIV treatment 2013
Children (0-14 yr) receiving ART by 2012
WHO Global update on HIV treatment 2013
New Pediatric HIV case: 1996-2012
2015 Target
Elimination of HIV PMTCT
> 90% of pregnant women received ART
800,000 new pediatric HIV
has been averted during
2005-2012
2015
WHO Global update on HIV treatment 2013
PMTCT coverage by WHO region
WHO Global update on HIV treatment 2013
Framework of HIV treatment and care
ENTRY
POINT
S
PED
ARV
CLINICS
UNDERSTAND
DYNAMICS
WHO Global update on HIV treatment 2013
When to start ?
•
•
•
•
Early infant diagnosis
HIV functional cure: Mississippi Baby
Update WHO treatment guideline 2013
Thai MOPH treatment guideline 2013
HIV diagnosis: 1st step of linkage to care

Entry Points: Infant born from HIV +ve mother
Mother: 2 HIV tests at 1st, 3rd trimester
 Statistics
2012: Prevalence of HIV in pregnant
ANC = 0.6% no ANC = 3.1%
Father: couple counseling
 Statistics

2012: only 20% of father was tested
Other entry points:
 severe
infection, TB clinic, malnutrition, immunization clinic
การวินิจฉัยการติดเชื้อเอชไอวีในทารก

Laboratory for Early Infant Diagnosis
HIV DNA PCR (ตรวจหาเชื้ อไวรัสจากเม็ดเลือดขาว) +/ HIV RNA PCR (ตรวจหาปริมาณไวรัสในพลาสมา) copies/ml


ควรเริม่ ตรวจเมื่อไหร่
 ความเสี่ยงสูง (มารดาได้รบ
ั ยาต้าน < 4 สัปดาห์ หรือ HIV VL > 1000 c/ml)

แนะนาเจาะเลือด 3 ครั้ง 1,2,4 เดือน (หากผลเลือดบวก จะได้ไม่ตอ้ งหยุด ART)
 ความเสี่ยงต ่า
 แนะนาเจาะเลือด

2 ครั้ง ครั้งแรกอายุ 1-2 เดือน และซ้าเมื่ออายุ ตั้งแต่ 4 เดือน
ควรเจาะเลือดซ้าเมื่อไหร่ (ต้องการผลยืนยัน 2 ครัง้ )
หากผลPCR เมื่ออายุ 1-2 เดือนเป็ นบวก ควรรี บตรวจซ้ าทันที
 หากผล PCR เมื่ออายุ 1-2 เดือนเป็ นลบ ควรตรวจซ้ าเมื่ออายุ 4 เดือน

Linkage into HIV care: Thailand
Number of infant positive at first PCR
Total infant received CD4 count test
Total infant initiated ART
118
108
104
94
92
81
65
63
57
44
37
32
Mean age (days)
at first CD4
Mean age (days)
at ART
81
78
2007
2008
2009
2010
2011
517
429
379
269
176
535
425
398
268
156
35
NAP database: 30 Jun 2012
Functional cure: a Mississippi baby
HIV RNA
30 hours
HIV DNA+
AZT/3TC/NVP
started on day 1
Loss to follow up
and stop ART
at age 18 months
AZT/3TC/LPV/r
from day 7
Persaud D, 2013 Oral late breaker, Abstract 48LB
When to start: WHO guideline 2013
AGE
GROUP
<1 YEARS
1-2 YEARS
2-5 YEARS
≥5 YEARS
2010 RECOMMENDATIONS
AGE
GROUP
2013 RECOMMENDATIONS
Treat ALL
Strong recommendation,
moderate-quality evidence
Treat ALL
Conditional recommendation,
very-low-quality evidence
Initiate ART with CD4 count ≤750
cells/mm3 or <25%, irrespective
of WHO clinical stage
< 1 YEAR
Treat ALL
Strong recommendation, moderate-quality
evidence
1-5 YEARS
Treat ALL
Conditional recommendation, very-lowquality evidence
Priority: children < 2 years or WHO stage 3-4
or CD4 count ≤ 750 cells/mm3 or < 25%
Initiate ART with CD4 count ≤350
cells/mm3 (As in adults),
irrespective of WHO clinical stage
AND
WHO clinical stage 3 or 4
≥5 YEARS
CD4 ≤ 500 cells/mm3
Conditional recommendation, very-lowquality evidence
CD4 ≤350 cells/mm³ as a priority (As in
Adults)
Strong recommendation, moderate-quality
evidence
When to start: Thai guideline: 2013
US 2012
PENTA 2009
Thai 2013
< 1 year
All
All
All
1-3 year
CDC cat B, C or
CD4 < 25%, < 1000
cell/mm3
CDC cat B, C or
CD4 < 25%, < 1000
cell/mm3
CDC cat B, C or
CD4 < 25% or < 1000
cell/mm3
3-5 year
CDC cat B, C or
CD4 < 25%, < 750
cell/mm3
CDC cat B, C or
CD4 < 25%, < 500
cell/mm3
CDC cat B, C or
CD4 < 25% or < 500
cell/mm3
5- 15 year
CDC cat B, C or
CDC cat B, C or
CDC cat B, C or
CD4 < 500 cell/mm3 CD4 < 350 cell/mm3 CD4 < 500 cell/mm3
< 350 cell (AI)
350-500 cell (BII)
Infant < 3 mo: Early treatment lower AIDS/Death
Death: 4% versus 16% (HR = 0.24, p <0.001)
Cat C: 6.3% versus 25.6% ( HR = 0.25, p<0.001)
CHER trial CIPRA South Africa; Violari A. NEJM 2008;359:2233-44.
Children: when to start ?
• PREDICT trial1 (1-12 years, RCT n=300)
AIDS-free survival did not differ between deferred
(CD4 <15%) and early treatment (CD4 15-24%)
144 week survival = 98.7% vs 97.9%
• IeDea SA2 (2-5 years, cohort n = 5,732)
3-year mortality rate was not difference in Rx all and
using CD4 threshold
All vs CD4 < 25% vs CD4 < 15%  4.5% vs 4.5% vs 5.3%
1 Puthanakit T. Lancet Infect Dis 2012:933-941.
2 Schomaker M. IeDEA Southern Africa Collaboration 2012
Children: Effect of ART

Growth outcomes
 South
African cohort (N= 2,399)
2 year of HAART: only 81%, 64% achieved normal weight, height
Risk factors of poor recovery: age > 3 year, baseline severe growth failure
 PREDICT
study
 Early treatment

has better growth parameter at 3 years of F/U
Cognitive function outcomes
 No
different in cognitive function at 3 years of F/U between
early and deferred treatment in the PREDICT study
Feinstien L et al. J Acquir Immune Defic Syndr 2012;61:235–242
Puthanakit T et al. Ped Infect Dis J 2013:32:501-8.
Adult: Treatment as Prevention (TasP)
HAART initiation when CD4 350-550 cell/mm3 versus CD4 < 350 cell
96% reduction in HIV transmission to uninfected partners
Early
N =886
Defer
N = 877
Criteria to Rx: CD4 cell
350-550 cell
< 250 , < 350 cell
No. of infected partner
1
27
Morbidity/mortality
40
65
Death
10
13
Extrapulmonary TB
3
7
< 0.0001
0.001
Cohen M et al. N Eng J Med 2011; 365:493-505.
What to start- 1st line HAART ?
Infant < 3 year : LPV/r is better than NVP
: Switch strategies
Children 3-10 year : EFV > NVP
Adolescent > 10 year: TDF-based once daily regimen
Approved antiretroviral drugs in children
NRTI
NNRTI
Protease
Inhibitor
Integrase
Inhibitor
Entry
inhibitor
Zidovudine
Nevirapine
Lopinavir/r
( > 2 week)
Raltegravir
(> 2 years)
Enfuvirtide
(> 6 years)
Stavudine
Efavirenz
(> 3 mo)
Atazanavir/r
(> 6 years)
Elvitegravir
Maraviroc
> 16 years
Lamivudine
Emtricitabine
Etravirine
(> 6 years)
Darunavir/r
(> 3 years)
Dolutegravir
Didanosine
> 2 weeks
Rilpivirine
> 12 years
Fosamprenavir
(> 6 months)
Abacavir
> 3 months
Tenofovir
> 2 years
Tipranavir/r
(> 2 years)
DHHS pediatric HIV treatment guideline Nov 1, 2012
What to start ? WHO 2013
2013 recommendations
Age group
< 3 years
3-10 years
PI
LPV/r is preferrred NVP as alternative
2 NRTIs
ABC+ 3TC or AZT +3TC
NNRTI
EFV is preferred NVP as alternative
2NRTIs
In preferential order:
ABC + 3TC or
AZT + 3TC or TDF + FTC (3TC)
NNRTI
2NRTIs
EFV is preferred NVP as alternative
In preferential order:
TDF + FTC or 3TC
ABC + 3TC
AZT + 3TC
10-19 years
(weighing ≥35 kg)
What to start: Thai guideline 2013 (draft)
< 1 year
Preferred
Alternative
1-3 years
3-12 years
> 12 years
AZT+ 3TC+ LPV/r
AZT+3TC+LPV/r ABC+ 3TC+ LPV/r AZT+ 3TC + EFV
ABC+3TC+LPV/r AZT+ 3TC+ NVP ABC+ 3TC + EFV
ABC+ 3TC+NVP
TDF + 3TC + EFV
AZT+3TC +NVP
AZT+3TC +NVP d4T +3TC +LPV/r
TDF +3TC + EFV
d4T +3TC +NVP d4T +3TC+NVP
AZT +3TC +EFV
AZT +3TC +NVP
Efficacy of LPV/r-based HAART in infants 6 mo-3 yr(P1060)
Cohort I: Exposed to SD-NVP (N =164)
Palumbo P et al. N Eng J Med 2010;363:1511-20.
Efficacy of LPV/r-based HAART in infants 6 mo-3 yr(P1060)
Cohort II: Not exposed to SD-NVP (N =288)
Violari A et al. N Eng J Med 2012;366:2380-9.
Treatment switch to NVP-based after initial VL
suppression with LPV/r-based ART (NEVEREST)
Cumulative probability of
VL rebound > 1000 c/ml
At week 72 = 10% vs 24%
Continue LPV/r-based
Switch to NPV-based
Can switch from LPV/r to
NVP after VL < 50 copies/ml.
Must perform at 24-48week
after switch to detect one
with VL rebound
Kuhn L. Lancet Infect Dis 2012:12:521-30.
HAART in children: EFV, NVP, PI
-
Efficacy of EFV versus NVP, EFV versus boosted PI
Dosage of EFV in children 3 month to 3 years
Dosage in adult 400 mg versus 600 mg (ENCORE study)
Metaanalysis on risk of congenital malformation when use in
women with child bearing age
Children: EFV versus NVP-based ART
Botswana-Baylor retrospective cohort HIV-infected children 3-16 years (N= 804)
Median age 8 years, CD4 = 13%, Plasma HIV RNA = 5.3 log10 copies/ml
NRTI backbone: AZT/3TC 92% F/U time 69 months
VL failure at 5 year
EFV = 12.8%
NVP = 25.1%
Lowenthal ED. JAMA 2013;309:1803-9.
Children: PI and NNRTI-based similar VL outcome
NRTI RAM
1-2
>3
6%
2%
22%
5%
The PENPACT-1 Study Team. Lancet Infect Dis. 2011;11:273-83.
Efavirenz:FDA approved for > 3 mo

May 2013; EFV was approved for children 3-36 month
Body weight
Dosage
3.5 to 5 kg
100 mg
5 to 7.5 kg
150 mg
7.5 to 15 kg
200 mg
15 to 20 kg
250 mg
20 to 25 kg
300 mg
25 to 32.5 kg
350 mg
32.5 to 40 kg
400 mg
> 40 kg
600 mg
• Open capsule mixed with food
• Use within 30 min after mixing
• Avoid food 2 hours after
http://www.fda.gov/ForConsumers/ByAudience/ForPatientAd
vocates/HIVandAIDSActivities/ucm350744.htm
EFV: adult dose 400 mg vs 600 mg
EFV 400 mg
(N=321)
EFV 600 mg
( N=309)
Mean age (years)
36 (10)
36 (10)
Mean CD4 cell
273(97)
271(101)
4.76 (0.84)
4.73(0.90)
HIV RNA < 200 copies/ml
94.1%
92.2%
EFV-related adverse events
36.8%
47.2%
% Discontinuation due to EFV- AE
1.9%
5.8%
Baseline characteristics
Median HIV RNA (log10)
At week 48
EFV 400 mg has non-inferior virological efficacy compare to EFV 600 mg
and has lower rate of discontinuation due to adverse events
Puls R, ENCORE1 Study Group: IAS 2013 WELBB01
HAART in children: NRTIs backbone
-
Start with non-thymidine analogue
Once daily regimen
Abacavir, Tenofovir
ART Regimen Sequences
Current practice
AZT(d4T) + 3TC +
EFV(NVP)
New approach
TDF (ABC) + 3TC + EFV (NVP)
NRTIs + LPV/r or ATV/r
TDF+ 3TC + Boosted PI
Abacavir use in children
CON
PRO

Use as a once daily

Cost, availablity

Combination tablet: ABC/3TC (Kivexa)


Low risk of metabolic complication

Resistance mutation:
Risk of ABC hypersensitivity,
recommend for HLA-B*5701
screening prior to start Rx

% HLA-B*5701 among Thais
K65R, M184V, L74V, Y115F

= 4.0% (95% CI: 1.6-8.0%)
Dosage (8 mg/kg/day)
14 to 21 kg
300 mg/day
>21 to < 30 kg
450 mg/day
> 30 kg
600 mg/day

Few data in large scale program in
children compare to AZT, d4T
Puthanakit T. Ped Infect Dis J 2013;32:252-3.
Abacabir in children; ARROW trial
VL < 400 copies/ml
A: ABC/3TC/NNRTI
B: ABC/AZT/3TC/NNRTI  ABC/3TC/NNRTI
C: ABC/AZT/3TC/NNRTI  ABC/AZT/3TC
week 24 week 144
77%
84%
88%
(p= 0.009)
65% (p =0.009)
ARROW Trial
Lancet 2013; 381:
1391-1403
Poorer VL outcome: ABC vs d4T
Johannesburg observational cohort
VL < 400 c/ml
100%
91%
LPV-based
90%
80%
77%
71%
67%
70%
60%
50%
40%
EFV-based
88%
51%
ABC
d4T
51%
40%
30%
20%
10%
0%
N
Mo 6
88
351
Mo 12
106 480
Mo6
Mo12
81 398
117 659
Technau KG, et al.Ped Infect Dis J 2013; 32:851-5.
Tenofovir disoproxil fumarate (TDF)in children
Jan 18, 2012: US FDA approved tenofovir for
treatment of HIV-infected children > 2 years
Body weight TDF daily dose
17 - < 22 kg
150 mg
22-<28 kg
200 mg
28-<35 kg
250 mg
> 35 kg
300 mg
LPV/r decrease tenofovir clearance
Population PK among 93 children from
5-18 years of age with 283 samples
Without
LPV/r
With LPV/r
TDF daily
dosage
20 to 30 kg
20-40 kg
150 mg
>30-40 kg
>40-55 kg
225 mg
> 40 kg
> 55 kg
300 mg
2012 DHHS guideline recommend TDF for children with Tanner stage 4-5 and
consider in stage 3 and use as alternative in stage 1-2
2013: WHO guideline recommend TDF for age > 10 years and BW > 35 kg
Bouazza N, et al. JAIDS 2011; 58: 283-8.
Tenofovir use in children: Monitoring for toxicity

Renal toxicity





Risk for acute renal failure or eGFR < 60 /ml/min:0.2-1.7%
Proximal tubular dysfunction – hypophosphatemia: 2-4%
Longer exposure – increase risk
More risk of toxicity when combine with boosted PI > NNRTI
Bone mineral density
Decline in BMD from baseline, usually occur
during first 6-12 months of treatment, stable thereafter
 Adult: risk of osetoporotic fracture 1.12 compare to
non-tenofovir regimen
 Children: clinical significance of low BMD is unknown

GS-7340 (TAF)specific uptakes in the lymphoid cells; 25 mg compare to 300 mg TDF
Single tablet regimens for children
Tenofovir 300/emtricitabine 200 /efavirenz
600(Atripla)
Age > 12 years and BW > 40 kg
Tenofovir 300 /emtricitabine 200 /rilpivirine
25(Complera)
Age > 18 years
Tenofovir/emtricitabine/elvitegravir/cobicistat
(Quad 1/ Stribild)
Age > 18 years
Cobicistat = a pharmacoenhancer, inhibitor P450 3A enzymes,
= boosts intestinal absorption of atazanavir, darunavir, GS7340
Drug development: monthly injectable ART

GSK 744
 HIV
integrase inhibitor/ dolutegravir analogue
 Injectable nanosuspension; IM SC
 Achieve plasma concentration > 4 times IC90 in healthy adults

TMC-278 LA
 Long-acting
nanosuspension of rilpivirine (NNRTI)
 IM loading 1200 mg then maintenance 600 mg q 4 week
 Plasma level comparable to oral rilpivirine 25 mg/day
Spreen W. IAS 2013 WEAB0103
Treatment monitoring
Point of care testing CD4
Point of care testing plasma HIV RNA
“International drug purchasing facility” established in 2006
To improve access to treatment and diagnositics for HIV TB
Malaria in low-income countries.
Laboratory monitoring: CD4

CD4 test
 Point
of care testing will help for linkage to HIV treatment
25 ul of whole blood CD4
cell count report in 20 min
AlereTM Prima CD4
/
http://alerehiv.com/hiv-monitoring/alere-pima-cd4
CD4
Product Pipeline
Alere
Pima
CD4
HumaCount
BD
Zyomyx
mBio
Partec Mini
2009
Omega
Diagnostics
Daktari
2010
2011
2012
2013
Instruments
*Estimated - timeline and sequence may change
Murtagh slide collection
2014
Disposable
CD4 monitoring

Less important after immune recovery to threshold
level and have HIV virological suppression
Adult patient who had CD4 > 300 cell/mm3
and HIV RNA < 200 copies/ml are
unlikely to have CD4 drop < 200 cell/mm3,
Only 3% in 4 years of follow-up
How to break the habit ?
Gale et al.Clin Infect Dis 2013; 56:1340-3.
Laboratory monitoring: Viral load

Plasma HIV Viral load
 Recommended
 Base
for treatment monitoring
on NHSO data; only 60% of children have annual VL testing
 WHO
threshold for switching regimen: VL > 1000 copies/ml
 Point of care testing for HIV Viral load
Liat Platform
200 Ul plasma or
50 ul fingerstick blood
Turn around time 30-55 min
Pipeline: HIV Viral Load and Early Infant diagnosis (EID)
Micronics
Liat
Alere Q
WAVE 80
EOSCAPE
ALL
Cavidi
AMP
Lynx EID
Biohelix
SAMBA EID
SAMBA VL
NWGHF VL
Gene
XPert
Lumora
2012
2013
2014
2015
Murtagh slide collection
2016
Recommend further readings
http://www.jiasociety.org/index.php/jias/pages
/view/thematicadolescents
http://www.who.int/hiv/pub/guid
elines/arv2013/en/index.html
Thank you for your attention