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![Page 1: Antiretroviral Therapy in Children With Drug Resistance Virus By Kulkanya Chokephaibulkit, MD Department of Pediatrics Faculty of Medicine Siriraj Hospital.](https://reader031.fdocuments.in/reader031/viewer/2022013011/56649ef65503460f94c0a507/html5/thumbnails/1.jpg)
Antiretroviral Therapy
in Children With Drug
Resistance Virus
Antiretroviral Therapy
in Children With Drug
Resistance Virus
By
Kulkanya Chokephaibulkit, MD
Department of Pediatrics
Faculty of Medicine Siriraj Hospital
Mahidol University
By
Kulkanya Chokephaibulkit, MD
Department of Pediatrics
Faculty of Medicine Siriraj Hospital
Mahidol University
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Recommended Drug Regimen to StartRecommended Drug Regimen to Start
Preferred Options
AZT/ABC/d4T+3TC+
NVP/EFV
For infants exposed to
SD-NVP consider
AZT/d4T/ABC+3TC+
LPV/r
THAILAND (2007)
AZT/d4T+3TC+
NVP / EFV (in > 3yo)
First choice
2NRTIs+ LPV/r or NFV
or
2NRTIs+EFV or NVP
Preferred
2NRTIs+ LPV/r or ATV/r
2NRTI + EFV (or NVP
in < 3Y)
Choices of 2NRTI
AZT+3TC/FTC
ABC+3TC/FTC
ddI+FTC
TDF+3TC/FTC (>18yo)
May use AZT+ABC,
AZT+ddI
WHO (2008)EU (2004)USA (2008)
AIDSinfo.nih.gov Sharland M. HIV Med 2004 www.who.intAIDSinfo.nih.gov Sharland M. HIV Med 2004 www.who.int
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Children Do Not Response to HAART As Well
As Adults VL and CD4 At 12 Months After Initiation of HAART
Children Do Not Response to HAART As Well
As Adults VL and CD4 At 12 Months After Initiation of HAART
Judd A. CID 2007;45:918-24.
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In Usual Practice in UK
By 6 Years of Treatment
In Usual Practice in UK
By 6 Years of Treatment
N=4306
• Virological failure 38%
• >1 major mutation 27%
• Mutation > 2 drug classes 20%
>>PI with RTV had lower risk of resistance
The UK Collaborative Group on HIV Drug
Resistance, UK CHIC Study Group
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Survival of children who started HAART in Takeo and Siem Reap.
Janssens B. Pediatrics 2008;120:e1134-1140.
Effectiveness of HAART in HIV-Positive Children: Evaluation at 12 Months in a Routine Program
in Cambodia
Effectiveness of HAART in HIV-Positive Children: Evaluation at 12 Months in a Routine Program
in Cambodia
Factors associated with VL>400 after 12 M of HAART is being orphans
Factors associated with VL>400 after 12 M of HAART is being orphans
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Predictors of Long-Term Viral Failure Among Ugandan
Children and Adults Treated With Antiretroviral Therapy
Predictors of Long-Term Viral Failure Among Ugandan
Children and Adults Treated With Antiretroviral Therapy
Kamya MR. JAIDS 2007;46:187-93.
Predictors of Virologic Failure at 12 Months
454 Adults Started on First-Line Therapy
222 Children and Adolescents Started on
First-Line Therapy
Multivariate Analysis Multivariate Analysis
OR (95% CI) P OR (95% CI) P
Male gender 1.48 (0.77to 2.83) 0.24 2.44 (1.20 to 4.93) 0.01
WHO stage-Stage III vs. stage I-II-Stage IV vs. stage I-II
0.93 (0.35 to 2.45)
1.19 (0.041 to 3.43)
0.88
0.75
2.68 (0.71 to 10.2)
1.04 (0.16 to 6.72)
0.15
0.96
d4T-3TC-NVP vs. ZDV-3TC-EFV
2.59 (1.20 to 5.59) 0.02 2.46 (1.23 to 4.90) 0.01
Baseline CD4 <5% or <100 cell/mm3 (adults)
1.34 (0.74 to 2.40) 0.33 2.69 (1.28 to 5.63) 0.009
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Clinical Criteria
for Treatment Failure
Clinical Criteria
for Treatment Failure• US and Thai
– Progressive neuroldevelopmental deterioration
– Growth failure
– Severe / recurrent infection / illness
• WHO
– New stage 4 condition (very same to AIDS)
– May consider in new stage 3 condition
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Immunologic Criteria for
Treatment Failure
Immunologic Criteria for
Treatment Failure• US
– For severe immunologic stage, CD4 response <5% (or < 50
cells) after 1 yr of Rx
– CD4 decline >5% or to less than baseline
• Thai
– Change in immunologic classification
– In those with CD4 <15%, persistent decline >5%
– Rapid decline (30% in 6 mo)
• WHO
– CD4 decline to <15% in 1-3 yo., <10% in 3-5 yo.,
<100 cells in < 5 yo.
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Failure Rate of NVP-Based VS EFV-Based regimens in Thai
children (Siriraj Hospital): Median F/U = 3 yr
Failure Rate of NVP-Based VS EFV-Based regimens in Thai
children (Siriraj Hospital): Median F/U = 3 yr
10/449/232/341/38- No. of failure needed to
EFVNVPEFVNVP
ExperienceNaive
18242424- Median duration of Rx
before switching (mo.)
(22.7%)(39%)(5.8%)(2.6%)switch from NNRTI
All were switched to boosted PI or double boosted PI
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Virologic Criteria for Treatment FailureVirologic Criteria for Treatment Failure
• US
– Incomplete response to RX (VL decline < 1 log after 3 mo of
Rx (>6 mo in experienced cases) or VL still > 400 after 6 mo
– Viral rebound (Increase >0.5log (3-fold) in >2 yo or
>0.7 log (5-fold) in <2 yo)
• Thai
– Same as US
• WHO – No criteria. However, if CD4 and clinical criteria are
conflicting, then use HIV-RNA >100,00 copies/mL as
consideration to change treatment
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Some FactsSome Facts• Some patients who were on HAART may
maintain clinical and immunological benefit up
to 3 years despite detectable virus
>> Patients who have persistent
improvement of CD4 despite persistent viremia,
should be considered to continue ART.
However, if appropriate regimen is available, it
is preferred to change before more resistance
developed
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Treatment Failure Defined by
Immunologic Markers Alone May
Result in Unnecessary Regimen
Change in Resource-Limited Settings
Treatment Failure Defined by
Immunologic Markers Alone May
Result in Unnecessary Regimen
Change in Resource-Limited Settings
• In 54 adherent, clinically stable patients with immunologic failure (category 3)
– HIV-1 RNA >400 copies in 30 (56%) cases
• Median HIV-1 RNA: 93,686 copies/mL (range: 2611-694,993)
– HIV-1 RNA <400 copies in 24 (44%) cases
Basenero A, Castelnuovo B, Birabwa E, et al. 4th IAS, July 22-25, 2007; Sydney, Australia. Abstract WEAB102.
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Number of Children Taking ART Under NHSO Was 7,908
(September 2008)
Number of Children Taking ART Under NHSO Was 7,908
(September 2008)
0
100
200
300
400
500
600
700
800
900
1000
คน
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 ปี�
จำ�� แนกต�มช่ วงอ�ยุ�
รั�บยา รัวม
www.nhso.go.thwww.nhso.go.th
No.No.
Age in YrAge in Yr
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Result of HIV-RNA Tests (N= 5,925 specimens)
(September 2008)
Result of HIV-RNA Tests (N= 5,925 specimens)
(September 2008)
VL<2,000; 4,422; 75%
VL=>2,000; 1,503; 25%
VL<2,000 VL=>2,000www.nhso.go.thwww.nhso.go.th
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Resistance is probably
the cause of failure if the
patient takes medicine
Resistance is probably
the cause of failure if the
patient takes medicine
Fact:
Imperfect adherence hasten the
time to failure
Fact:
Imperfect adherence hasten the
time to failure
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Resistance Development While on 2NRTI+NNRTI Regimens
Resistance Development While on 2NRTI+NNRTI Regimens
Very early failure: 3TC-R: M184V
Early failure:
3TC-R: M184V
NNRTI-R: e.g.K103N, Y181C/I, Y188L, G190A/S
Other NRTI-R: minimal or none
Late failure:
3TC-R: M184V
NNRTI-R: e.g.K103N, Y181C/I, Y188L, G190A/S
TAMs: M41L, D67N, K70R, L210W, T215Y, K219Q/E
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Drug Resistance Mutations in Adults Who
Failed FDC of d4T/3TC/NVP
Drug Resistance Mutations in Adults Who
Failed FDC of d4T/3TC/NVP
Sungkanuparph S. CID 2007;44:447-52.Sungkanuparph S. CID 2007;44:447-52.
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Predictors of Long-Term Viral Failure Among Ugandan
Children and Adults Treated With Antiretroviral Therapy
Predictors of Long-Term Viral Failure Among Ugandan
Children and Adults Treated With Antiretroviral Therapy
Kamya MR. JAIDS 2007;46:187-93..
Genotype Mutations CD4 Count
Patient No. (Age in Years)
Regimen At 6-12 Months
1 (27) NVP, 3TC, d4T M184V, K103N
2 (31) NVP, 3TC, d4T M184V, K103N, T215Y
3 (26) NVP, 3TC, d4T M184V, K103N, G190A
4 (32) NVP, 3TC, d4T V751, M184V, Y181C, T69N, V751, T215Y
5 (41) NVP, 3TC, d4T M184V, K103N
6 (13) NVP, 3TC, d4T M184V, L210D, G190A
7 (16) NVP, 3TC, d4T M184V, K103N
8 (10) EFV, 3TC, d4T T69S, M184V, Y188L
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Class-Sparing Regimens for Initial
Treatment of HIV-1 Infection
Class-Sparing Regimens for Initial
Treatment of HIV-1 Infection
Riddler SA. NEJM 2008;358:2095—2106.
+2NRTIP <0.003
@wk 96 +2NRTI
EFV + 2NRTI has
lower chance of
virologic failure than
LPV/r + 2NRTI.
EFV+LPV/r was equal
to EFV+2NRTI, but
more likely
associated with drug
resistance.
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Gupta R. CID 2008;47:712-22.
Emergence of Drug
Resistance After Receipt of
First-Line HAART
A Systematic Review of Clinical Trials at 48
wks by ITT
Emergence of Drug
Resistance After Receipt of
First-Line HAART
A Systematic Review of Clinical Trials at 48
wks by ITT
Virologic Failure @ 48 wk
NNRTI = 4.9% (3.9-6.1%)
bPI = 5.3% (4.4-6.4%)
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Prevalence of NRTI Resistance Among 95 HIV-infected
Children Who Had Received Dual NRTI For > 6 Months
NAMs, 60% had <4 NAMs, and 40% had NAMs.
Prevalence of NRTI Resistance Among 95 HIV-infected
Children Who Had Received Dual NRTI For > 6 Months
NAMs, 60% had <4 NAMs, and 40% had NAMs.
Lolekha R. CID 2005;40:309-12.
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Interpretation of Genotypic ResistanceInterpretation of Genotypic Resistance
• NRTIs:– Any TAM: resist to AZT
– TAM I pathway: More resistance; TAM II: still can use ddI, TDF
– M41L + T215F/Y: resist d4T
– 2-3 TAMS may be able to use ddI, TDF, ABC
– >3 TAMs: resist all NRTI
– M41L, L210W, T215Y pathway is more resistant than D67N, K70R, K219Q/E
– 69 insertion+ T215Y+ 2 of M41L, A62V, K70R, L210W : resist to all NRTI
– Q151M complex: Q151M+F77L+(A62V, V75I, F116Y): resist to all NRTI except TDF
– L74V, K65R: resist to ABC and ddI
– K65R: resist to TDF, but still susceptible to AZT
TAM I: M41L, L210W, T215YTAM II: D67N, K70R, K219Q, K219E
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Drug Options for Salvage Regimens
Drug Options for Salvage Regimens
• NRTI– AZT if no bad TAMs– ddI, TDF, ABC if < 4 TAMs, and no K65R– (TDF should not be used for <18 yo, and ABC is
expensive)– 3TC may still use with M184V to reduce fitness
• NNRTI: once resist, no option left• PI:
– LPV/r is excellent esp. for PI naïve– ATV/r is expensive, use with dyslipidemia– SQV is expensive, and only pill available– IDV/r is less potent and renal toxic
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Interpretation of Genotypic ResistanceInterpretation of Genotypic Resistance
• NNRT: Any single mutation cause high level resistance
• PI: need more than 3-4 mutations to confer resistance– 2 UPAM (universal PI-asso mutation) at 82, 84,
and 90 position will resist to RTV, IDV, SQV, APV
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Options for a Second-Line Regimen For Adults
Who Failed FDC of d4T/3TC/NVP
Options for a Second-Line Regimen For Adults
Who Failed FDC of d4T/3TC/NVP
Sungkanuparph S. CID 2007;44:447-52.Sungkanuparph S. CID 2007;44:447-52.
NRTI resistance pattern Options for the second-line ART regimen
PI-based regimen Backbone NRTIs in settings without NRTI limitation
M184V alone (Boosted) PI AZT plus ddI or TDF
M184V plus TAMs Boosted PI ddI plus ABC or TDF
M184 plus K65R Boosted PI AZT plus ABC or d4T plus ABC
M184V plus Q151M (Double) boosted PI TDF plus?
Q151M alone (Double) boosted PI TDF plus?
K65R alone (Boosted) PI 3TC plus either AZT, ABC, or d4T
No NRTI resistance (Boosted) PI 3TC plus either TDF, ddI, AZT, ABC, or d4T
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What Regimen to Change To (US)What Regimen to Change To (US)
Guideline for the Use of Antiretroviral Agents in Pediatric HIV Infection Oct26, 2006
Initial Regimen Recommended Change
2 NRTIs+NNRTI - 2 NRTIs (based on resistance testing) plus PI
2 NRTIs+PI - 2 NRTIs (based on resistance testing) plus NNRTI
- 2 NRTIs (based on resistance testing) plus alternative PI (with low-dose ritonavir boosting If possible, based on resistance testing)-NRTI(s) (based on resistance testing) plus NNRTI plus alternative PI (with low-dose ritonavir boosting if possible, based on resistnace testing)
3 NRTIs (recommended only in special circumstances)
- 2 NRTIs (based on resistance testing) plus NNRTI or PI- NRTI(s) (based on resistance testing) plus NNRTI plus PI
Failed regimens including NRTI, NNRTI, PI (recommended only in special circumstances)
- >1 NRTI (based on resistance testing) plus a newer PI (with low-dose ritonavir, based on resistance testing)
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RECOMMENDED SECOND-LINE REGIMENS IN
INFANTS AND CHILDREN IN THE EVENT OF
TREATMENT FAILURE OF FIRST-LINE REGIMENS
RECOMMENDED SECOND-LINE REGIMENS IN
INFANTS AND CHILDREN IN THE EVENT OF
TREATMENT FAILURE OF FIRST-LINE REGIMENS
First-line regimen at
failure
Preferred second-line regimen
(A(II))
RTI components
(NRTI/NNRTI)
PI component
2 NRTI + 1 NNRTI
AZT- or d4T- containing
ABC + containing
ddI + ABC
ddI + AZT
plus
LPV/r
Or
SQV/r
Or
NFV
Triple NRTI ddI + EFV or NVP WHO Guideline 2006
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NelfinavirNelfinavirContamination with
a carcinogen, ethyl
methane sulfonate
(EMS) during the
production.
Do Not Use
Contamination with
a carcinogen, ethyl
methane sulfonate
(EMS) during the
production.
Do Not Use
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Problems of Drugs for Salvage Regimens for Children in Thailand
• ddI available in giant generic tablet to dissolve in water, unfriendly taste. ddI-EC is not available by NHSO, and not for young children.
• ABC is expensive and not available by NHSO• TDF is available but can use only in adolescents
and adults• LPV/r available only in adult generic tablet
(200/50), children need to cut the pill• IDV is available, but the TDM is not feasible in
routine• SQV is expensive and not available by NHSO• ATV is limited available, and only in adult tablet
formulation
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Lopinavir/ritonavir (Cap133/33, Tab 200/50, Tab 100/25)
Lopinavir/ritonavir (Cap133/33, Tab 200/50, Tab 100/25)
• Heat stable tablet is easier
• Recommended dose using 200/50 mg tab:– 15-25 kg 1 tab– 25-35 kg 1.5 tab– > 35 kg 2 tab
Study in 33 children (14 used 1.5 tab) at Siriraj, QSNICH, HIVNATMean Ctrough (SD) = 8.2 (5.7) using Abbott
= 8.2 (5.4) mg/L using Matrix
Abbott133/33 mg
Matrix200/50 mg
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Recommendation of Salvage Regimen in Thai Children
Recommendation of Salvage Regimen in Thai Children
Failing Regimens Salvage Regimens
AZT/d4T+3TC
+EFV/NVP
- GPOvir S
- GPOvir Z
Preferred
- ddI+3TC or ddI+ABC Plus LPV/r
Use TDF(+AZT/3TC) if Tanner stage 4 or > 18 yo
Alternative if > 3 (bad) TAMs esp. with high VL
-Double boosted PI (e.g. LPV/r+SQV, LPV/r+IDV) +/-3TC
Need good adherence, and close monitoring
* TAM mutation = 41L, 215Y, 210W, 67N, 70R, 219Q/E
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Salvage Regimen for The Patients
Who Fail dual NRTIs Regimens
Salvage Regimen for The Patients
Who Fail dual NRTIs Regimens
• If < 3 TAMs or good TAMs:
– New 2NRTI + boosted PI
• If > 3 TAMs (esp” bad TAMs 41L, 210W, 215Y) :
– NNRTI + boosted PI + 1-2NRTI
• Careful if to salvage with NRTIs + NNRTI
• Always check genotype if to continue NRTI
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Advantages vs Drawbacks of Each PI
Advantages vs Drawbacks of Each PIAdvantages Drawbacks
LPV/
r
Highly effectiveHigh resistancethresholdLiquid formulation available
Need refrigeratorBig size pillExpensiveGI side effects, and dyslipidemia
SQV/r
Good efficacyNo dyslipidemia
Dose only for >25 kgBig size, and many pillsExpensiveGI side effects
IDV/r EffectiveSmall and Less pill
Kidney toxicityNeed hydrationNeed blood level monitoring
ATV/r
Highly effectiveNo dyslipidemia
ExpensiveMay cause hyperbilirubinemiaUse only for > 6 year-old
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Efficacy of 2NRTI+lopinavir/ritonavir
In 21 PI-
naïve Children Who Failed 2NRTI+NNRTI
Efficacy of 2NRTI+lopinavir/ritonavir
In 21 PI-
naïve Children Who Failed 2NRTI+NNRTI
0
10
20
30
40
50
60
70
80
90
100
6 months 12 months
Viral load <400
Viral load <50
Delaugerre, et al. J Acquir Immune Defic Syndr 2004;37 :1269-1275.
86
71
10092
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Factors Influencing Virologic Response (VL<400 copies/mL) In Children
Receiving LPV/r Salvage Regimens ( Response in 56/67; 66%)
Factors Influencing Virologic Response (VL<400 copies/mL) In Children
Receiving LPV/r Salvage Regimens ( Response in 56/67; 66%)
Resino S. JAC2004;54:921-31.
a Beginning of HAART protocol with LPV and other new drugs.
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FDA Approved ATV In Children March 2008FDA Approved ATV In Children March 2008
• ATV capsule can be used from >6 yo.
• It should be used with RTV
• It should not be used in <3 mo.
• Safety: Cough 21% Jaundice 13%
Fever 19% Diarrhea 8%
Headache 7% Running nose 6%
Increase bilirubin 49%
• Efficacy at 24 wk, VL <50
Rx-naïve : 59%
Rx-exp : 24%
Increase CD4 : 171 cell/mm3
http://www.aidsmap.com/en/news/80F577BE-9DFE-4796-B4A7-BC9E0CB33149.asp
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Indinavir Plasma Levels at Different DosageIDV can be used safely at 220-300 mg/M2 plus RTV 100 mg
Indinavir Plasma Levels at Different DosageIDV can be used safely at 220-300 mg/M2 plus RTV 100 mg
Cmax
Cmin
IDV
co
nce
ntr
atio
n,
mg
/L
A B C D E
100
10
1
.1
0.01
Dosage Children Adults Adults Children IDV 220-300 mg/M2 600mg 400mg 400 mg/M2
RTV 100mg 400mg/M2 100mg 100mg 125 mg/m2 Level associate with toxicity
Minimum target trough
Cressey TR, et al. JAC 2005;55:1041-4.,
Bergshoeff AS. AAC 2004;48: 1904-7.
Plipat N, et al. PIDJ 2007;26:86-8
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National Access Program to ART
(NHSO) (September 2008)
National Access Program to ART
(NHSO) (September 2008)E
3%
A85%
B 2%
C1% D 9%
A B C D E
www.nhso.go.thwww.nhso.go.th
A= AZT/d4T+3TC+NVP/EFV B= AZT/d4T+3TC+IDV/r intolerance to AC= ddI/TDF+3TC+IDV/r or NNRTI D= 2NRTI + LPV/rD = others
A= AZT/d4T+3TC+NVP/EFV B= AZT/d4T+3TC+IDV/r intolerance to AC= ddI/TDF+3TC+IDV/r or NNRTI D= 2NRTI + LPV/rD = others
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At least half of the infants exposed to perinatal single-dose NVP developed NVP
resistance.
Infants may need SECOND-LINE regimen from the start!
At least half of the infants exposed to perinatal single-dose NVP developed NVP
resistance.
Infants may need SECOND-LINE regimen from the start!
Check genotype for NVP-R to all infants exposed to SD-NVP
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Frequency of Development of NVP Resistance in Infants
Frequency of Development of NVP Resistance in Infants
Rate (%)
0
10
20
30
40
50
60
70
80
90
100
NVP- R
A1= NVP - NVP
A2= NVP - NVP/AZT
B1= NO - NVP
B2= NO - NVP/AZT
87
57
74
27
Mom - Baby
NVP-R reduced by eliminate maternal
NVP and use of neonatal NVP+AZT
Eshleman SH. JID 2006;193:479-81.
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0
20
40
60
80
100
120
<6 mo > 6mo Infants
NVP (N=112)
Pla (N=106)
P<0.001 P= 0.39 VL
<40
0 at
6 m
o R
x
N = 60 N = 158
Time from SD-NVP/Pla
58
10088 92
23
90
Response to NVP-based HAART After
Exposure to Peripartum SD-NVP (MASHI)
Response to NVP-based HAART After
Exposure to Peripartum SD-NVP (MASHI)
Lockman S. NEJM 2007;356;11:135-47.
Mean age of Rx initiation = 8 mo.
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We Should Test for Drug Resistance in All Infants Exposed to SD-NVP
We Should Test for Drug Resistance in All Infants Exposed to SD-NVP
• More incidence of NVP-R in adults recently
• High rate of NVP-R in infected infants (50%) after
single dose perinatal exposure
What if Genotyping is not available• May try NVP regimen with close VL monitoring• Infants who have a very rapid disease progression should not try NVP regimen, but should get LPV/r
What if Genotyping is not available• May try NVP regimen with close VL monitoring• Infants who have a very rapid disease progression should not try NVP regimen, but should get LPV/r
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A Cases ScenarioA Cases Scenario• A 3 week old infant, healthy, came for F/U
• The mother received AZT from 34 week and SD-NVP at labour
• The infant received AZT+3TC+SD-NVP
• The PCR at birth was positive
• Need to start HAART ASAP, and check if there is NVP-R
• Don’t forget to give AZT+3TC plus NVP (SD or 2 wks) in
high risk cases (late Rx, poor compliance)
• Need to start HAART ASAP, and check if there is NVP-R
• Don’t forget to give AZT+3TC plus NVP (SD or 2 wks) in
high risk cases (late Rx, poor compliance)
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Antiretroviral Drugs for Neonates Exposed to HIVAntiretroviral Drugs for
Neonates Exposed to HIV Drugs Dose
Duration •Syr. AZT 2 mg/kg Q 6 hr
1-6 wks or 4 mg/kg Q 12 hr
1-6 wks•SD-NVP 2 mg/kg @ 48-72 hr-old
once (or twice)•NVP 2 mg/kg Q 24 hr x 7 d
total 2 wk then 4 mg/kg Q24 hr x 7 d•Syr 3TC 2 mg/kg Q 12 hr
1-4 wk
Thai-MOPH SD-NVP 2 mg/kg @ birth or 48-72 hr. +
Syr. AZT 2 mg/kg Q 6 hr x1 wk if maternal AZT >4 wks OR x 6
wks if maternal AZT <4 wks
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LPV/r in Infants Younger than 6 MonthLPV/r in Infants Younger than 6 Month
• Slightly higher clearance than older children
• At 24 weeks, 53% had VL < 400 cp/mL
• Poor adherence is the problem of virologic failure
• Suggested dose in < 6 mo = 300/75 mg/M2 (vs 230/57.5 mg/m@ in > 6 mo)
• PACTG 1030: After 24 wks of LPV/r-HAART initiate before 6 mo, 70% had VL<50 cp/mL
Chadwick EG. AIDS 2008; 11;22(2):249-55
Persaud D. JID 2007;195:1402-10
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LPV/r-Based Versus NVP-Based
HAART For Infants
LPV/r-Based Versus NVP-Based
HAART For InfantsLPV/r
• Advantages: – Highly effective
– Better immunologic response
– Liquid formulation available
– No pre-existing resistance
– High resistance barrier
• Disadvantages: – Expensive
– Not good taste
– Should be refrigerated
– Less experience in < 6 mo. (not approved)
NVP
• Advantages:– Cheap, affordable in all
settings
– Better taste
– Liquid formulation available
– May be less effective
– FDC available
• Disadvantages: – May have pre-existing
resistance esp. from perinatal NVP use
– Low resistance barrier
– Potential A/E in 15-20% (hepatitis, rash)
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Management of Some Adverse
Events From ARV
Management of Some Adverse
Events From ARV• Switch ARV:
– Anemia -> change AZT– Lipodystrophy -> change d4T – Rash, hepatitis-> change NVP (sometimes EFV)
• Dyslipidemia: start intervention when• Cholesterol > 200 mg%• LDL > 130 mg%• Triglyceride > 200 mg%
– Start with diet control, exercise– If not improve, consider switch to ATV (now
approve from 5 yo.)
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Prevalence of Dyslipidemia from the Data
Collection on Adverse Events of Anti-HIV
Drugs (D:A:D)
Prevalence of Dyslipidemia from the Data
Collection on Adverse Events of Anti-HIV
Drugs (D:A:D)
Fontas E. JID 2004;189:1056-74.
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Rash fromNevirapine Rash fromNevirapine
• Found in 15-20% mostly within 2-4 wks (up to 12 wks)• may associated with hepatitis• Can’t be prevented by steroid• Rx: stop NVP, antihistamine (+steroid)
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Lipodystrophy Associated with Stavudine Mostly found in older children getting into puberty
1/3 improved after stopping d4T and with growth spurt
Lipodystrophy Associated with Stavudine Mostly found in older children getting into puberty
1/3 improved after stopping d4T and with growth spurt
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Phillips AN. The Lancet 2007;370:1923-8.
Cumulative risk of
extensive triple-class
virological failure
Cumulative risk of
virological failure of for
individual drug classes according to years from start of that
class PI/r=ritonavir-boosted protease inhibitor.
Risk of Extensive Virological Failure to The Three Antiretroviral Drug Classes An Observational cohort study
Risk of Extensive Virological Failure to The Three Antiretroviral Drug Classes An Observational cohort study
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Lower Risk of AIDS If Stay On Failing RegimensFrench cohort 2000-2005 in patients
with CD4 <200 for > 6 months
Lower Risk of AIDS If Stay On Failing RegimensFrench cohort 2000-2005 in patients
with CD4 <200 for > 6 months
Stay on Falling Regimen (> 1 drug)
VL >500
Interrupt Rx VL
>500
On HAART VL <50
N = 8783 N = 2399 N =4351
New AIDS event
(per pt-yr.)
14.5 18.5 4.5
- New AIDS event associated with CD4 <50, VL >30,000
- Interrupt Rx had highest risk of AIDS
Kousignian I. CID 2007;46:296-304
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What need to investigate next in children?
What need to investigate next in children?
• Double boosted vs single boosted PI in PI-naïve patients – From initiation of salvage
– After successful viral suppression
• What to use after first-line PI resistance– New PI: Darunavir
– New class: Integrase inhibitor, receptor antagonist
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Second-line regimen in childrenRetrospective cohort: 8 centers from Thailand
241 children failed NNRTI-based regimen
Second-line regimen in childrenRetrospective cohort: 8 centers from Thailand
241 children failed NNRTI-based regimen
Puthanakit and Ananworanich, et al.-in preparationPuthanakit and Ananworanich, et al.-in preparation
Single-boosted (n=104)
Double boosted PI (n=137)
Age 8.9(6.1-11.1) 9.4 (7.6-11.2)
CD4% 17 (7-24) 6 (2-12)
Plasma HIV RNA 4.5 (3.9-5.1) 4.9 (4.5-5.4)
Multi NRTI resistance 11/89 (12.4) 69/114 (60.5)
HIV RNA <400 copies ml
49/59 (83.1) 42/50 (84.0)
CD4% gain (n=147) 7 (2-12) 10 (6-15)
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Changes in Risk of Death After HIV Seroconversion Compared
With Mortality in the General Population
Changes in Risk of Death After HIV Seroconversion Compared
With Mortality in the General Population
Bhaskaran K. JAMA 2008;300:51-9.
0
5
10
15
20
25
30
35
40
45
Pre-1996 1996-1997
1998-1999
2000-2001
2002-2003
2004-2006
40.8
31.4
11.9 9.5 8.56.1
Excess Mortality (/1000 person year)
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Adjusted Life Expectancy On CART
In High-Income CountriesAn analysis of 14 cohort studies by year of F/U and baseline CD4
Adjusted Life Expectancy On CART
In High-Income CountriesAn analysis of 14 cohort studies by year of F/U and baseline CD4
The average number of years remaining to be lived at age 20 years
was about 2/3 of that in the general population in these countries.
The Lancet 2008;372:293-9.
1996-9 2000-2 2003-5 1996-2005 CD4 <100 CD4100-199 CD4 >200
At exact age
20 years
36.1 41.2 49.4 43.1 32.4 42.0 50.4
At exact age
35 years
25.0 30.1 37.3 31.7 27.0 30.4 37.2
% surviving
from 20- 44 yr
75.5% 79.5% 85.7% 81.1% 59.8% 80.6% 89.9%
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Age Group Distribution of HIV-Infected Children at Siriraj Hospital (Feb 08)
26
85
104
19
0
20
40
60
80
100
120
Below 5 Yrs 5-9 Yrs 10-14 Yrs 15-18 Yrs
Age Group
Nu
mb
er
of
Pati
en
ts
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Next Challenging Issues For The
Grown-Up HIV-Infected Children
Next Challenging Issues For The
Grown-Up HIV-Infected Children• Disclosure: children need to know their
diagnosis and get positive attitude before becoming adolescent
• Lifelong adherence
• Being a teenager
– Sex issues
– Peer’s acceptance
– High risk behaviors
• Future education and career
• Making own family
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Treatment • Supportive• Specific• Palliative
Care Givers & Family
Care Provider
Team
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YOU
YOU