Paediatric HIV: update

EACS Advanced HIV course

Montpellier, 3-5th Sept 2008

Carlo Giaquinto

Department of Paediatrics,

Padova, Italy

Presentation overview

• Children & HIV in developed countries

• Women pregnancy & HIV

• PMTCT / MTCT in developing countries

• Children & HIV in developing countries

Two Pediatric Epidemics

High-resource countries

New perinatal infections are rare

Effective treatment available

Aging cohort of infected children

Concerns long-term complications of treatment

Low-resource countries

1,000 infants are newly infected each day

Diagnosis of infection in infants problematic

Problems with drug access

Treatment when available is started late.

Pediatric HIV Infection in the West: A success story

1. Lee GM et al. Pediatrics 2006;117:273-832. 219 study summary July 23 2007

• With effective prevention of most new perinatal HIV infection, it is estimated that <250 newly infected infants are born annually in the U.S and about 500 in Europe.

• Effective therapies for HIV in children have prolonged life and quality of life1.

• The median age of over 3,500 HIV-infected children followed at US pediatric clinical trials sites is 14.8 years2 .

In the USA, the Majority of HIV-Infected Children Are Receiving ARTPediatric Spectrum of Disease Project, 1994-2001

McConnell M et al. JAIDS 2005;38:488-94 – PSD includes over 2,000 children from 6 areas US

In 2001, 78% of HIV-infected children were on ARV and 66% were receiving 3-drug HAART

0

20

40

60

80

100

Per

cen

tag

e o

f ch

ild

ren

1994n=2196

1995n=2235

1996n=2235

1997n=2210

1998n=2218

1999n=2218

2000n=2155

2001n=2040

MonotherapyNo TherapyUnclassified

Triple TherapyDual Therapy

HAART era

Decrease in AIDS, Death, and Hospital Admissions in HIV+ Children in the HAART Era, United Kingdom

Judd A et al. Clin Infect Dis 2007;45:918-24

Same asUS ratein 2006

Mean age at death 2006:

18.2 years

Age at Death (1994-2006) in HIV-Infected Children Enrolled in PACTG 219 Long-Term Follow-Up Study

Mean age at death 1994:

8.9 years

3,553 childrenMedian f/u 5.3 yrs

298 deaths

HAART EraCourtesy Mike Brady, Paige Williams

0

2

4

6

8

10

12

14

16

18

20

22

Age at Death by Year of Deathfor Infected Children

1994 1996 1998 2000 2002 2004 2006Year

Med

ian

Ag

e at

Dea

th (

IQR

)

Primary Causes of Death (1994-2006) in HIV-Infected Children Enrolled in PACTG 219

N = 3,553 children Median f/u 5.3 yrs 298 deathsCourtesy Mike Brady, Paige Williams

AIDS OICardiomyopathyStroke

End Stage AIDSCNS diseaseHepatitis

PheumoniaMalignancyAccident / other

SepsisRenal failure

0%

10%

20%

30%

40%

1994–1996 1997–2000 2001–2006

Increase 1994–2006: End stage AidsSepsisRenal Failure

Encephalopathy in Pediatric HIV Infection

Van Rie A et al. Eur J Pediatr Neurol 2007;11:1-9

• Prior to ART, 13-25% of children with HIV infection and 35-50% with AIDS were diagnosed with encephalopathy.

• Highest incidence 1st 2 years of life: incidence rate 9.9% in 1st year, 4.2% in 2nd year, and <1% thereafter.

• Reported risk factors for neuroAIDS include: – Maternal advanced disease

– Low CD4 count in child

– Elevated plasma and CSF viral load

– Perinatal route of transmission

– Lack of ARV treatment

Decline in Progressive and Static Encephalopathy Children with Perinatal Infection in HAART Era

Shabhag MC et al. Arch Pediatr Adolesc Med 2008;159:651-6

29.6%

12.1%

49.7%

18.2%

0%

20%

40%

60%

80%

% w

ith

En

cep

hal

op

ath

y

Progressive Encephalopathy Progressive + Static Encephalopathy

Pre-HAART era (born before 1996) HAART era (born after 1996)

P=0.049 P=0.02

146 children with perinatal infection followed between 1990 and 2003 at Children’s Hospital Philadelphia

Encephalopathy in Pediatric HIV Infection

• However, ART does not eliminate HIV-related CNS disease.

• Differential penetration of antiretroviral drugs into CNS (Mitchell C. Mental Retard Develop Disabil 2006;12:216-22; Caparelli E. AIDS 2005;19:949-52; Antinori A. CID 2005;41:1787-93)).

– AZT>d4T>ABC>3TC>ddI

– NVP>EFV

– IDV>LPV>SQV=NFV=RTV=APV (very low)

In the HAART era there was a 10-fold decrease in the incidence of HIV encephalopathy

Patel et al WAIDS 2008

0

5

10

15

20

25

1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006

Year

Inc

ide

nc

e p

er

10

00

pe

rso

n-y

ea

rs

0

10

20

30

40

50

60

70

80

90

100

Pe

rce

nt

on

HA

AR

T

Incidence rate

% on HAART

Decline in mortality with HAART sustained over 10 years, but there has not been further decrease since about 2000.

Mortality in HIV-infected children is still >30 fold higher than similarly aged children (0.49 per 100 infected children vs 0.02 per 100 children aged 5-14 years in US, p<0.001).

As in adults, there has been evolution in causes of death over time, with decrease in AIDS OI and increase in “end stage AIDS” multi-organ failure, sepsis and renal disease.

Comments on Mortality of HIV in Children Today

Challenges in the Treatment of Pediatric HIV Infection in High Resource Settings

Drug resistance: primary, acquired

Pharmacokinetics

Lack salvage drugs for children

Complications of therapy

Adherence

Mental health

Adolescence - transition to adult care.

Effective Therapy is Prolonging Life Spectrum of Disease Changed

Prevalence of Transmitted Primary ARVDrug Resistance in New perinatal HIV Infection

Type of ResistanceNY*

98-991 (N=91)

NY*

01-022 (N=42)

US

02-053 (N=21)

Any resistance 12.1% 19.1% 23.8%

NRTI 7.7% 7.1% 14.3%

NNRTI 3.3% 11.9% 19.0%

PI 3.3% 2.4% 0%

>2 classes 2.2% 2.4% 9.5%

1 Parker MM, et al. JAIDS 2003;32:292-7.

2 Karchava M, et al. JAIDS 2006;42:614-9.

3 Persaud D, et al. J Infect Dis 2007;195:1402–10.

58%increase

* Non-subtype B virus found in 4.4% of infants born 1998-9 &16.7% of infants born 2001-02.

Acquired Drug Resistance

Leads to the development of multi-drug resistant virus

However Newer drugs used for salvage in adults often not available in childrenLag in development of pediatric formulations

Many older children had sequential mono & dual therapy prior to starting HAART & may have had periods of

inadequate adherence

Necessitates more complex regimens

Limits choices for effective therapy

Acquired drug resistance

After first line failure 88% of ART treated children have at least 1 significant resistance mutation (RM)

- 88% NRTI RM- 52% NNRTI RM- 8% PI RM

Sunpath H et al CROI 2008 Abs 587

After first line NNRTI failure 52% of children have at least 1 significant resistance mutation (RM)

- 52% NRTI RM- 43% NNRTI RM

Sungaknuparph S et al CROI 2008 Abs 588

Antiretroviral Drugs Approved in Adults

N(t)RTI NNRTI PIsEntry/Fusion

InhibitorsIntegrase Inhibitors

ABC EFV ATV Enfurvirtide RAL

ddI NVP DRV MVC

FTC Etravirine FosAMP

3TC IDV

d4T LPV/r

TDF NFV

Ritonavir

SQV

TPV

but Not Yet Approved in Children

LPV/r exposure is initially low in infants < 6 weeks of age but increases dramatically during the first year of life

Week 2 1 year P value

LPV Dose (mg/m2) 267 (246-296) 331 (305-331) 0.047

Cpre (mcg/mL) 1.81 (1.54-2.67) 8.19 (4.79-10.8) 0.031

Cmax (mcg/mL) 4.76 (3.30-7.06) 14.2 (10.6-15.6) 0.031

AUC (mcg*h/mL) 36.6 (28.6-62.0) 134 (87.9-13.6) 0.016

CL/F (L/h/m²) 5.64 (4.30-9.98) 2.44 (2.44-3.47) 0.016

Despite the low initial LPV exposure, viral suppression was achieved by most infants at 48 weeks

LPV/r pharmacokinetics in HIV-infected infants < 6 weeks

Capparelli, E Poster 573, CROI 2008

Recommended dose of LPV/r is sub-optimal in PI-experienced children

47 paediatric patients on 52 weeks of study follow up.• 51% achieved VL<400 copies/mL

• LPV trough <5.7 mg/L (p=0.05) and baseline LPV resistance (p=0.005) were independently and significantly associated with failure to achieve VL<400 copies/mL

Pharmacokinetic modelling and simulation• Data from 33 patients was used to create a model, and this model was used to

simulate 1000 children to determine the % with trough LPV concentration <5.7mg/L after standard dosing.

• Data from this model showed that in children given standard LPV dose (230 mg/m2), 49.3% would fail to reach the target trough.

In PI pre-treated children, LPV plasma levels should be optimized in order to achieve maximal virologic

suppressionRahkmanina, N, Poster 574, CROI 2008

DELPHI: Darunavir Evaluation in Paediatric HIV-1-Infected Treatment-Experienced Patients

Spinosa-Guzman S, Oral Abstract 78LB, CROI 2008

• Target treatment-experienced adult DRV exposures were achieved in children across weight bands and age groups

• Trough concentrations (C0h) were well above the protein-binding corrected EC50 value of 550 ng/mL† in all children

Pharmacokinetics of DRV, median (range)*

DELPHI (paediatric patients)

N = 80

Pooled POWER 1 and 2‡

(adult patients)N = 119

AUC24hr, nghr/mL 127,340(67,054 – 230,720)

123,336(67,714 – 212,980)

C0h, ng/mL 3888(1836 – 7821)

3539(1255 – 7368)

* Estimated using populations pharmacokinetic analysis; † For wild-type virus‡ Primary 24-week analysis of integrated data from POWER 1 and 2 trials, Sekar V, et al., 13 th CROI 2006 Abs J-121

In treatment-experienced HIV-1-infected children and adolescents at week 24, DRV/r showed:

• good virologic response rates• positive clinical outcomes• favourable safety and tolerability• comparable exposure to adults and confirmed appropriate dose-selection in this

paediatric population

Long-term Complications of HIV Infection & of ART in Children

• Metabolic complications

• Abnormal fat accumulation & wasting• Abnormal lipid profiles• Insulin resistance• Osteopenia/ bone disease

• Mitochondrial toxicity

• Liver disease

• Renal disease

• Adolescent obesity

Metabolic Complications of ART in ChildrenMetabolic disorders reported in HIV-infected children on ART

Lipodystrophy 6 - 47%

Hyperlipidaemia 13 - 67%

Insulin resistance 0 - 13%

hyper-insulinaemia 60%

Tassiopoulos K et al. JAIDS. 2008; in pressVigano A et al. Antivir Ther. 2007;12:297-302Ene L et al. Eur J Pediatr. 2007;166:13-21Ergun-Longmire B et al. Endocr Prac. 2006;12:514-21Dzwonek AB et al. JAIDS. 2006;43:121-3

Carter RJ et al. JAIDS. 2006;41:453-60Farley J et al. JAIDS. 2005;38:480-7Beregszaszi M et al. JAIDS. 2005;40:161-8European Paediatric Lipdystrophy Group. AIDS. 2004;18:1443-1451McComsey G et al. Pediatrics. 2003;111:e275-81

Puberty is the time when children are most likely to develop metabolic complications.

Cholesterol >220:

Entry: 13% of 2123 children

Follow-up: additional 13%

(median f/u 50.4 mos)

Incidence 3.4/100 pt-yr

Development of hypercholesterolaemia is more frequent in children on pi-based HAART tassiopoulos K et al. JAIDS 2008 in press

0.7

0.8

0.9

1.0

Pro

p. h

yper

cho

l fre

e

0 6 12 18 24 30 36 42 48 54 60Months to consecutive CHOL 220+ or censoring

Median––––

Total82

378250

1413

Count4

4213

219

Censor78

336237

1194

Baseline ART use

no ARTART, no HAARTHAART, no PIHAART + PI

NO ARTIncidence 1.3/100 pt/yr

HAART, no PIIncidence 1.4/100 pt/yr

ART but not HAARTIncidence 2.8/100 pt-yr

HAART including PIIncidence 4.1/100 pt-yr

Probability of Developing Lipodystrophy in HIV-Infected Children Increases with Tanner StageTaylor P et al. Pediatrics 2004;114:e235-42

0 1 2 3 4 5

Tanner Stage

0

10

20

30

40

50

60

70

80

90

100

Per

cen

t w

ith

ou

t li

po

dys

tro

ph

y

Impaired glucose homeostasis

Impaired glucose tolerance was present in 20% of adolescents and young adults infected perinatally on ART from a mean of 13 years, suggesting an increased risk of Type 2 diabetes and cardiovascular diseases

Hadigan C CROI 2008 Abs 591

Puberty is the primary determinant of reduced insulin sensitivity in ART experienced children and adolescents

Vigano’ et al CROI 2008 Abs 592

Mental Health in HIV-Infected Children and YouthScharko AM. AIDS Care 2006;18:441-5

Review of 8 studies including 328 HIV-infected children age 4-21 years; data were compared to prevalence in overall population.

Mental health disorder

Prevalence (%)

Increased Risk-Ratio

Attention deficit disorder 24% 6 - fold

Anxiety disorder 29% 3.8 - fold

Depression 25% 7.1 - fold

HIV-Infected Children Have Higher Rates of Psychotropic or Behavioral Treatments Compared to Uninfected Similarly Socioeconomic Controls: P1055

Data provided by Sharon Nachman MD

45%

HIV-uninfectedHIV-infected

Treatment, by HIV Status

40%

35%

30%

25%

20%

15%

10%

5%

0%Med orBehav

Tx

BehavTx

MedTx

Stimulant SSRI Neuro-leptic

Anti-Hypert

Other

Challenges in Adolescent HIV Care

Knowledge of HIV infection.

Linking to (and retaining in) health care.

Accepting (and adhering to) therapy.

Mental health issues.

Complexities of transition to adult care.

High risk population for HIV transmission.

Rice E et al. Prospect Sex Repro Health 2006;38:162-7 Murphy DA et al . J Adol Health 2001;29S:57-63Sturdevant MS et al. J Adol Health 2001;29S:64-71

Kadivar H et al. AIDS Care 2006;18:544-9 Rotheram-Borus M et al. J Adoles 2001;24:791-802Lightfoot M et al. Am J Health Behav 2005;29:162-71.

40-60% of HIV-infected adolescents continue to engage in unprotected sex.

High rate substance use, smoking

Short-cycle therapy in adolescents following continuous therapy with established viral suppression: The effect on

viral load suppression

32 subjects with viral suppression aged 12-24 switched from continuous HAART to short-cycle therapy (SCT) with a schedule of 4 days on (mon-thurs) and 3 days off (fri-sun) HAART.

Viral suppression was maintained in 62.5% of participants.

Significantly more subjects infected before age 9 discontinued SCT (p=0.0155).

No significant losses of CD4+ T cells were noted in those with or without VL breakthrough. Adherence by self report was high for both groups ,with no difference in those with viral rebound.

Of 12 patients with viral load rebound, 9 re-suppressed after re-initiating continuous HAART.

Rudy, B Poster 580, CROI 2008

Total < 9 years > 9 years p-value

Discontinued SCT: n (%) 18 (56.3) 12 (80.0) 6 (35.3) 0.0155

Viral load rebound: n (%) 12 (37.5) 7 (46.7) 5 (29.4) 0.4670

Cumulative Incidence of First Pregnancy in 174 Perinatally HIV-Infected Sexually Active Girls Age >13 Years, PACTG 219CBrogly SB et al. Am J Public Health 2007;97:1047–1052

By age 19 years, 24.2% of sexually active girls had been pregnant at least once(6 had 2nd pregnancy, 1 had 3rd)

0

5

10

15

20

25

30

35

40

45

Cu

mu

lati

ve In

cid

ence

of

Fir

st P

reg

nan

cy (

%)

0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 95 100 105 110 115 120 125 130 135

Months Since 13th Birthday

#1 Challenge in Low Resource Countries:

Continued HIV Transmission to Women &

Poor Implementation of PMTCT

Challenges in Management of Pediatric HIV Infection in Low Resource Countries

Caribbean

0

10

20

30

40

50

60

70

Per

cent

fem

ale

(%)

Sub-Saharan Africa

GLOBAL

Asia

E Europe & C Asia

Latin America

1990‘91 ‘92 ‘93 ‘94 ‘95 ‘96 ‘97 ‘98 ‘99 ‘00 ‘01 ‘02 ‘03 ‘04 ‘05 ‘06 2007

Year

5

% of Female HIV-Infected Adults By Geographic Location, 1990-2007

Source: UNAIDS/WHO Dec 2007

Incidence of pregnancy and desire for children

Months after ART Initiation

Baseline 3 6 9 12 15 18 21 24

2

0

4

6

8

10

12

0

10

20

30

40

50

60

70

80

90

100

27

p < 0.04

% W

om

en

Inci

den

ce o

f p

reg

nan

cy p

er 1

00 W

Y

p < 0.001

Wants more children

Partner wants more children

Sexually active

Weidle, P Oral Abstract 74, CROI 2008

Effectiveness of NNRTI-containing ART in women previously exposed to a single dose of nevirapine: A multi-country

cohort study

Suc

cess

(%

)

Time since NVP exposure (months)

*P < 0.001 vs unexposed

*91

7687

92

0

25

50

75

100

Unexposed 1 to 6 7 to 12 > 12

Weidle, P Oral Abstract 48, CROI 2008

• A high proportion of women in this cohort responded to NNRTI-based HAART at 24 weeks whether previously exposed to SD-NVP or not.

• Increased risk of failure among women with exposure to SD-NVP within 6 months and perhaps 12 months before initiation on NNRTI-based HAART.

• Women exposed to SD-NVP more than 12 months prior to initiation of NNRTI-based HAART did as well as women who were not exposed to SD-NVP.

Despite Effective Regimens to Prevent MTCT, Globally Only 11% of Women Receive ARV Prophylaxis

Interagency Task Team on PMTCT Report Card Feb 2007 UNICEF/WHO/UNAIDS

8%12%

28%

16%

3%

14% 15%

37%

95%

2%

29%

77%

0

25

50

75

100

India West &CentralAfrica

East &SouthAfrica

EasternAsia &Pacific

Central &South

America

Central &EasternEurope

%HIV+ women identified 2005 %HIV+ women given ARV 2005

Per

cen

tag

e (%

)

Regions with95% of all MTCT

Very low risk of MTCT in women on HAART who achieve viral suppression: the UK and Ireland, 2000 to 2006

MTCT rate 95% CI n infected total

Overall 1.2 (0.9 – 1.5) 61 5151

2000 – 2002 1.6 (1.0 – 2.4) 23 1456

2003 – 2006 1.0 (0.7 – 1.4) 38 3695

At least 14 days of ART 0.8 (0.6 – 1.1) 40 4864

ART and mode of delivery

HAART + elective CS 0.7 (0.4 – 1.2) 17 2337

HAART + planned vaginal 0.7 (0.2 – 1.8) 4 565

HAART + emergency CS 1.7 (1.0 – 2.8) 15 877

AZT mono + elective CS 0.0 (0.0 – 0.8) 0 467

HAART 1.0 (0.7 – 1.3) 40 4120

HAART from conception 0.1 (0.0 – 0.6) 1 928

HAART + VL<50 copies/ml 0.1 (0.0 – 0.4) 3 2117

There was no difference in MTCT rates according to BHIVA guidelines: HAART with elective CS, HAART with planned vaginal delivery and AZT with elective CS

Townsent, C Poster 653, CROI 2008

Prevention of postnatal infection

Extended infant post exposure prophylaxis significantly reduces postnatal HIV transmission

NVP or NVP/ZDV for 14 weeks in infants(7.2%vs 13% MTCT at 9 mo) Taha T et al CROI 2008 Abs 42LB

NVP for 6 weeks in infants(8.0 vs 11% MTCT at 6 mo) Sastry J et al CROI 2008 Abs 43

HAART in women for 6 mo (uncontrolled)(5.9% MTCT at 12 mo) Thomas T et al CROI 2008 Abs 45aLB

HAART in women for 12 mo (uncontrolled)(2.9% MTCT at 12 mo) Marazzi M et al CROI 2008 Abs 239

Emergence of HIV drug resistance among breastfeeding infants born to HIV infected mother taking ART

Zeh C et al CROI 2008 Abs 84LB

The Challenge of Pediatric HIV Infection in Resource-Poor Countries

While high rates of HIV infection in women, few women know they are infected and there is poor access to ARV to prevent MTCT.

Children often present to health system with advanced disease.

Rapid progression and high mortality due to HIV in children, yet few receive treatment.

Early treatment would prevent many deaths but infant diagnosis not available.

Data from African perinatal prevention trials from breastfeeding HIV transmission study meta-analysis: mortality in infected children was 53% at 2 years of ageNewell et al. Lancet 2004;364:1236–43

0

0.1

0.2

0.3

0.4

0.5

0.6

0 100 200 300 400 500 600 700 800 900

Age at last visit or at death (days)

Cu

mu

lati

ve p

rob

abil

ity

of

dea

th

InfectedOverallUnknown HIV statusNot infected

Mean survival 1.6 years

By age 2.5 years, 60% mortality

Estimated Number of HIV-Infected Children Needing and Number Receiving Antiretroviral Treatment

By Region as of December 2006

Source: World Health Organization, April 2007

ARV Coverage 13% 67% 21% 20% <1%

0

200,000

400,000

600,000

800,000

Sub-Saharan Africa

Latin America/Caribbean

E/S/SE Asia Europe/Central Asia

N Africa/Middle East

# Needing ART # Receiving ART

Virologic Suppression in Children on HAART from 17 Studies in Sub-Saharan Africa

Sutdiffe CG et al. Lancet Infect Dis 2008;8:447-89

%<50 copies/mL %<250 or <400 copies/mL or unk %<1,000 copies/mL

Median viral load decrease approximately2.0 log within 1 year of starting ART.

Viral Suppression After 1 Year Was 49-81% 17 Studies in Sub-Saharan Africa

Sutdiffe CG et al. Lancet Infect Dis 2008;8:447-89

%<50 copies/mL %<250 or <400 copies/mL or unk %<1,000 copies/mL

CD4% Increase in Children on HAART from 14 Studies in Sub-Saharan Africa

Sutdiffe CG et al. Lancet Infect Dis 2008;8:447-89

CD4% increased in 1st year of treatment, seeming to plateau after 12-18 months

However, Normalization of CD4 Percentageto >25% with HAART was Uncommon

However, children in low-resource countries who receive ART are starting at older ages than high resource countries

Baseline Median Age

% RNA undetectable on HAART

Janssens/Cambodia 2007 N=212 6.0 yrs 74% <400 (17 mos)

George/Haiti 2007 N=100 6.3 yrs 56% <50 (12 mos)

Wamawala/Kenya 2007 N=67 4.4 yrs 67% <400 (6 mos)

Reddi/S Africa 2007 N=151 5.7 yrs 80% <50 (12 mos)

Puthanakit/Thailand 2007 N=107 7.7 yrs 70% <50 (3.7 yrs)

Kamya/Uganda 2007 N=250 9.2 yrs 74% <400 (12 mos)

Kekitiinwa/Uganda 2008 Abs 584 N=876 7.6 yr 70% <400 (6 mos)

Children in low-resource countries who receive ART are starting treatment when already severely immune deficient

Baseline Median Age

Baseline Median CD4

% RNA undetectable on HAART

Janssens/Cambodia 2007 N=212 6.0 yrs 6% 74% <400 (17 mos)

George/Haiti 2007 N=100 6.3 yrs 12% 56% <50 (12 mos)

Wamawala/Kenya 2007 N=67 4.4 yrs 6% 67% <400 (6 mos)

Reddi/S Africa 2007 N=151 5.7 yrs 8% 80% <50 (12 mos)

Puthanakit/Thailand 2007 N=107 7.7 yrs 5% 70% <50 (3.7 yrs)

Kamya/Uganda 2007 N=250 9.2 yrs 8.6% 74% <400 (12 mos)

Kekitiinwa/Uganda 2008 Abs 584 N=876 7.6 yr 8% 70% <400 (6 mos)

00

Years since HAART initiation

5

10

15

20

25

30

35

40

Mea

n C

D4

%

1 2 3 4 5 6

Recovery of immune status with HAART is dependent on CD4% at time HAART is initiated

Patel K et al. Clin infect dis 2008; 46: 507-515

1,236 children enrolled in PACTG 219 not on HAART at study initiation

CD4 <15%CD4 15–24%CD4 >25%

Notimmunedeficient

Immunedeficient

Immune reconstitution syndrome in HIV-infected children started on HAART

Most commonly reported from low resource countries, likely because they are starting treatment at lower CD4 levels than in US.

19% of 153 children started on HAART had IRIS, median onset 4 weeks; 10% died.

Thailand (Puthanakit T et al. PIDJ 2006;25:53-8)

17% of 148 children started on HAART had IRIS, median onset 2 weeks; most common BCG-related IRIS disease.

South Africa (Smith K et al. CROI 2008 Abs 75)

Implications for when to start antiretroviral therapy in children

Children <1 year are at high risk of death; aggressive treatment seems warranted.

However:

Need to build capacity for early diagnosis

Viral suppression with ART less in infants

Limited pediatric formulations

Minimal data on dosing in children

Limited data on efficacy of early treatment

Studies early HAART at age <3-12 months show viral suppression in 18%-73%

Study NAge Start

HAART (MONTHS)Viral response

Belgium

Van der Linden PIDJ 2007 17 <2.5<50

71% at 4.7 yrs

PACTG 356

Luzuriaga NEJM 2004 25<3

(median 2)

<400

60% at 4 yrs

PENTA 7

PENTA AIDS 2004 20<5

(median 2.5)

<400

44% at 1.5 yrs

Italian Register

Chiappini AIDS 2006 30<6

(median 3.6)

Undetectable

73% at 4 yrs

PACTG 1030

Chadwick AIDS 2008 21<6

(median 3.7)

<400

53% at 6 mos

French Perinatal

Faye PIDJ 2002 31<12

(median 3.7)

<500

18% at 2 yrs

Early HAART at age <3-12 months is associated with no AIDS progression and maintenance of immune reconstitution

Study NAge Start

HAART (MONTHS)

Viral response

Other

Belgium

Van der Linden PIDJ 2007

17 <2.5<50

71% at 4.7 yrs

No AIDS

82% CD4 >25%

PACTG 356

Luzuriaga NEJM 2004 25<3

(median 2)

<400

60% at 4 yrsNo AIDS, 4 yr

PENTA 7

PENTA AIDS 2004 20<5

(median 2.5)

<400

44% at 1.5 yrs

No AIDS, 1.5 yr

90% CD4 >25%

Italian Register

Chiappini AIDS 2006 30<6

(median 3.6)

Undetectable

73% at 4 yrs

No AIDS, 4 yr

97% CD4 >25%

PACTG 1030

Chadwick AIDS 2008 21<6

(median 3.7)

<400

53% at 6 mos

French Perinatal

Faye PIDJ 2002 31<12

(median 3.7)

<500

18% at 2 yrs

No AIDS, 2 yr

88% CD4 >25%

CHER: 76% reduction in the risk of death with immediate (arms 2 & 3) compared to deferred (arm 1) HAART

CROI 2008 Abs 76, Abs 600

0

0.20

0.40

0.60

0.80

1F

ailu

re p

rob

abil

ity

DeferredImmediate p = 0.0002

0 3 6 9 12

Time to death (months)

125252

104213

72145

4499

2252

Patients at riskArm 1Arm 2 & Arm 3

4%

16%

Most deaths occurred withinfirst 6 months (ie. before age 10 months)

WHO 2008 Revised Guidelines: When to Start Antiretroviral Therapy in HIV-Infected

Children <

12 months

Confirmed HIV

< 12 months

Presumptive Severe HIV*

1- 4 yrs

> 5yrs

All regardless of CD4/clinical

All regardless of CD4/clinical

Clinical or immunecriteria

Clinical or immune criteria

<20% or

12-35 mos: <750/uL36-59 mos: <350/uL

<15% or

<200/uL

*If lack ability for viral test, use WHO presumptive diagnosis of severe HIV (thrush, severe pneumonia or sepsis) in infants with + HIV antibody test and with clinical symptoms of severe HIV – need to confirm infection status as soon as possible.

What to start with

Implications of resistance following Single-dose NVP prophylaxis

Given 1st line recommendation forNNRTI-based therapy

In low resource settings

36%42%

33%27%

20%13%

8%

17%

46%53%

87%

0%

20%

40%

60%

80%

100%

Thai S Africa (NOm om NVP)

Cote d'Ivorie Thai Malaw i(NVAZ NO

m om NVP)

Thai S Africa(w ith m om

NVP)

S Africa HIVNET 012 SAINT Malaw i(NVAZ w ithm om NVP)

Single-dose NVP prophylaxis is associated with NVP resistance acquisition in infants failing prophylaxis

Clade: E,B C A E,B C E,B C C A,D C C CRF01, 06

AZT + SD NVP

SD NVP

SD NVP, no maternal SD NVP

AZT + SD NVP, no maternal SD NVP

% w

ith r

esis

tanc

e

Infants who become HIV-infected despite single-dose NVP prophylaxis may be more likely to have viral failure with later nvp-based HAARTLockman S, et al. Nejm 2007;356:135–47

Analysis after 6 months of HAART: 10/13 in SD NVP group and 1/12 placebo group

had HIV RNA >400 copies/mL

Median ageat start HAART

8.5 months

0

20

40

60

80

0 6 12 18 24 30 36

Months since the Start of ART

% w

ith

RN

A >

400

c/m

L Single dose of NVP

Placebo

Optimal initial ART trials for infants with SD NVP exposure

Study Age start HAART Strategy Endpoint

OPH612Kenya

(N=186)

6-12 mosNVP Resistance Screening

If sensitive, randomise to NVP vs non-NVP HAART

% viral suppression after 24 mos

NEVERESTS Africa

(N=100)

<24 mos

Suppress then switch Start with LPV/r, if in 1st year suppress to <400 for >3 mos:

Randomize switch to NVP or stay on LPV

% RNA <50

at 6 mos post randomisation

Strategy obs study

S Africa

(N=63)

Immediate, <2 mos

Deferred, median 5 mos

4-drug strategyAZT/3TC/NVP/NFV immediate

vs deferred, all exposed to single-dose NVP

% suppressed at 1 year

P1060Multicountry

(N=576)

6-36 mos

Direct Comparison NVP vs PI

Infants with/without NVP exp

Randomize LPV/r vs NVP HAART

% RNA<50

at 6 mos post randomisation

What to start (WHO Paediatric HIV/ART working group, Geneva April 2008)

For HIV infected infants with no exposure to NNRTIs, or with unknown exposure to maternal or infant ARVs, standard NVP-containing triple therapy should be started

Strong recommendation

For HIV infected infants with a history of exposure to single dose nevirapine or NNRTI containing maternal ART or preventive antiretroviral regimens, a protease inhibitor based triple ART regimen should be started. Where protease inhibitors are not available, nevirapine based therapy should be used

Strong recommendation

Challenges in Treatment of HIV-Infected Children in Low Resource Settings

Pediatric formulations

Fewer ARV approved in children

More costly than adult preparations

FDC just becoming available

Dosing weight/size based, change as child grows, problems for busy health clinic.

Liquid drugs transport/storage problems.

Complexity of therapy in context multiple co-moribidities (TB, malaria, malnutrition…)

Improved therapeutic exposure of NVP using WHO pediatric weight band dosing

WHO weight band dosing of NVP:• results in therapeutic concentrations in 80% of subjects without

incurring a high freq of excessive NVP exposure.• achieves target exposure in a greater proportion of subjects than the

FDA dose of 4-7mg/kg.

The 50-mg tablet strength maximises the therapeutic index.

WHO weight band dosing should be used in resource-limited settings.

Capparelli, E Poster 576, CROI 2008

Projected Subject NVP doses and exposure

WHO Weight Band Dosing

Median / IQR

FDA Dosing (4 or 7 mg/kg)

Median / IQR

Dose (mg/m²) every 12h 174 (162-187) 153 (112-172)

Cmin (mcg/mL) 5.7 (3.80-8.0) 4.6 (3.0-6.9)

AUC (mcg*h/mL) 77.7 (55.8-107.2) 62.2 (45.1-90.8)

Thank you for your attention …

Courtesy Peter Havens MD