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

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

 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.

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

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

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

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

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.

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

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

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

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.

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

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

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

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

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.

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

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.

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%)

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.

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

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

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

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

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)

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

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

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

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

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

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

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

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

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.

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

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

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

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

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.

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.

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

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)

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

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

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)

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.)

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.

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)

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

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

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

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

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)

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)

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%

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

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

Treatment • Supportive• Specific• Palliative

Care Givers & Family

Care Provider

Team

YOU

YOU