Draft WHO Pediatric ARV Guidelines Revision Summary

10/23/05

Lynne M. Mofenson, M.D.

Pediatric, Adolescent and Maternal AIDS Branch

National Institute of Child Health and Human Development

National Institutes of Health

Department of Health and Human Services

Considerations in Revision• Stand-alone guidelines for children (in 2003,

children incorporated into adult guidelines).• Guidelines evidence-based but public health

oriented: simple, standardized.• Any revisions should enable treatment of a

child before they develop severe disease.• To better identify risk of severe disease, may

need to increase the number of age-related CD4 risk thresholds.

• Use of new WHO pediatric staging to guide starting therapy, monitoring treatment.

• Need advocacy for early infant diagnosis; advocacy for pediatric formulations; simplified weight-band based dosing tables.

When to Start Antiretroviral Therapy? • In adults: defer for as long as possible

without clinical deterioration or compromising immunological response…

• For children, considerations include that:– Highest mortality in children <18 mo/o.– Inability to diagnose infection <18 mo/o is

major problem for treatment.• Need to start ARV in exposed child <18

mo (need verify infection status at 18 mo).– Response to ART– ART availability for different ages– Family, social, adherence aspects

• No randomized evidence

Changes to Pediatric Guidelines: When to Start• Changed age-related CD4/TLC values from two

to four age categories (based on HPPCMS data).• Incorporated new ped HIV staging system into

decisions:– Staging and recommendations for ART:

• Stage 4: treat all regardless of lab • Stage 3: treat all regardless of lab (except if

child >18 mos and CD4 available, use CD4 guided decision for TB, LIP, OHL, low plts)

• Stage 2: CD4 or TLC guided decision• Stage 1: treat only if CD4 available for

decision

When to Start ARVs in Children<18 mos >18 mos

Stage 4* CD4 All All

No CD4 All All

Stage 3* CD4 All All (except TB**, OHL, LIP, thrombocytopenia, where do CD4 guided)

No CD4 All All**

Stage 2 CD4 CD4 guided CD4 guided

No CD4 TLC guided TLC guided

Stage 1 CD4 CD4 guided CD4 guided

No CD4 Do not rx Do not rx* Stabilize any OI before initiate ARV** Pulmonary TB: Eval CD4 (if avail)/clinical status after several wks TB rx to decide if need ARV and if so, when ARV start in relation to TB rx

Draft WHO Age-Related CD4 and TLC values for Antiretroviral Treatment Decisions in Children

Start ARV When CD4% or Count is+:

<11 mo 1 yr - <3 yr 3 yr - <5 yr >5 yr

CD4%* <25% <20% <15% <15%

CD4 count* <1,500 <750 <350 <200

*CD4% preferred in children <5 years; CD4 count preferred in children >5 years.

If CD4 Assay Not Available, Start ARV When TLC Is+:

<11 mos 1yr - <3yr 3yr - <5 yr >5 yr

TLC <4,000 <3,000 <2,500 <1,500

+ART should be started at these levels regardless clinical stage

12-Month Risk of Death By Age and TLC or CD4%HIV Pediatric Prognostic Marker Collaborative Study

0

20

40

60

80

100

0 1000 2000 3000 4000 5000 6000 7000 8000

Prob

abilit

y (%)

3-5 yr2,500

1-3 yr3,000

<1 yr4,000

>5 yr1,500

5%

Total Lymphocyte Count CD4%

0

20

40

60

80

100

0 5 10 15 20 25 30 35 40 45 50

Prob

abilit

y (%

)

6 months

1 year

2 years

5 years

10 years

5%

<1 yr25%

1-3 yr20%

>3 yr15%

Age (yrs) 5% Risk of Death

  CD4% CD4 count

0.5 36 1748

1 23 1162

1.5 18 808

2 16 572

2.5 14 409

3 13 294

4 11 153

5 9 143

6 8 134

7 8 125

8 7 117

9 7 110

10 6 103

1,500

750

350

200

Age-Related CD4 Absolute Count Associated With 5% Risk of Death Within 12 Months

0

5

10

15

20

25

30

Pro

bab

ility

of

dea

th (

%)

0 1 2 3 4 5 6 7 8 9 10Age (years)

12-Month Mortality Risk, Selected CD4%/Count and TLC Age ThresholdsHIV Pediatric Prognostic Marker Collaborative Study (Dunn et al)

CD4%<25 (<1yr), <20% (1 to <3 yrs), <15% (3 to <5 yrs), <15% (≥ 5 yrs)

TLC<4000 (<1yr), <3000 (1 to <3 yrs), <2500 (3 to <5 yrs), <1500 (≥ 5 yrs)

CD4<1500 (<1yr), <750 (1 to <3 yrs), <350 (3 to <5 yrs), <200 (≥ 5 yrs)

Changes to Pediatric Guidelines: What to Start • ARV choice problem is lack pediatric formulations

and lack of dose information for some ARV/ages.– Excludes TFV 1st line therapy for children (no

formulation, dose not defined, safety unclear) as opposed to adult recs.

• Add ABC to 1st line NRTIs as virologically superior to AZT/3TC (PENTA), and to begin to get away from d4T (did not want to completely change recs as countries just starting roll-out).

• Drugs:– Dual NRTI: combination of AZT or d4T or 3TC or ABC

(do not use AZT/d4T; possible combos AZT/3TC, d4T/3TC, AZT/ABC, 3TC/ABC, d4T/ABC).

– plus NNRTI – prefer NVP if <3 yrs, EFV if >3 yrs.• 2nd line: Continue 3TC re: decreased viral fitness?• Weight-band based dosing tables (underway).

Changes to Pediatric Guidelines: What to Start• Issue of infant PMTCT exposure and resistance:

– Resistance develops in mom pre- or during pregnancy, IP, PP while BF; transmits to infant.

– Resistance developing infant during infant prophylaxis component.

• Important to note that not all failures of PMTCT are due to resistance (majority not resistant).

• Current rec: Children with prior NVP or 3TC prophylaxis should be eligible for HAART, including NNRTI regimen and not denied access to life-saving therapy.

• Studies ongoing/to start in kids to address response to NNRTI therapy post SD NVP exposure.

• Since no new data and studies pending, no change recommended to current language.

ARV REGIMENS for Pediatric Patients1st Line ARV Considerations 2nd Line ARV

Dual NRTI (choose 2, except do not use AZT/d4T)

3TCor

AZT

[d4T]

Minimal toxicity

Anemia

Lipodystrophy/lactic acidosis/

peripheral neuropathy

ddI (+ 3TC?)

ABC (+ 3TC?)

or

ABC Hypersensitivity reaction AZT (+ 3TC?)

PLUS

NNRTI (choose 1, see age preference)

NVPor

Prefer <3 yr (<10kg) LPV/r or SQV/r or SQV/NFV or NFV

EFV Prefer >3 yr (>10 kg) LPV/r or SQV/r or

SQV/NFV or NFV

Alternative ARV Choices for Pediatric Patients1st Line ARV Considerations 2nd Line ARV

3 NRTI Combo (choose 3 except do not use AZT/d4T): NRTI:

3TCor

AZT

[d4T]

Minimal toxicity

Anemia

Lipodystrophy/lactic acidosis/

peripheral neuropathy

ddI (+ 3TC?)

or

ABC Hypersensitivity reaction

PLUS a PI:

LPV/r or SQV/r or

SQV/NFV or NFV*

PLUS an NNRTI:

NVP or EFV

Summary: 1st and 2nd Line ARV Regimens in Children

ddI + EFV* or NVP AZT or d4T + 3TC + ABC

PI

Component

RTI

Component * +

2nd Line Regimen

1st Line Regimen *

ddI + AZTABC + 3TC + NVP or EFV**

LPV/r or

SQV/r# or

SQV#/NFV or

NFV%

ddI + ABCAZT or d4T + 3TC + NVP or EFV**

Comments:

* TDF not currently approved for clinical use in children.

+ May consider continuing 3TC because of possible decreased viral fitness

** EFV approved only in children with more than 3 years old.

# SQV-boosted regimen only in children with body weight> 25 kg (only capsules available).

% NFV in places without cold chain; non-boosted PI less optimal.

Example of Weight-Based Dosing Table for Children Including Pediatric and Adult Formulations

Weight (kg)

Nevirapine syrup Nevirapine tablets

Lead-in dose Weeks 1 & 2

syrup(10mg/ml)

Full Dose syrup

(10mg/ml)

Lead-in doseWeeks 1 & 2

200mg tablets

Full Dose

200mg tablets

5-6.9 2 4.5

7-9.9 3.5 7

10-11.9 4 8

12-14.9 5 10 ½ am only ½ am and pm

15-19.9 7 14 1 am or ½ am or pm 1 am and ½ pm

20-29.9 ½ am and pm 1 am and pm

30-34.9 1 am and pm

Changes to Ped Guideline: Monitoring Before and While On ARVs

• Monitoring:

– Primarily clinical-based.

– Importance of weight gain/maintenance in clinical evaluation.

– Encourage increased use CD4.

– Do not use TLC to monitor therapy (only for start).

– AZT – baseline Hb suggested and recheck at ~8 weeks.

– Symptom-directed for other lab tests.

Baseline and Monitoring Pediatric ARV

Baseline On ARVConfirm dx N/A

Clinical stage Clinical stage

Readiness Adherence

Concom conditions/meds Concom conditions/meds

Wt, ht, develop Wt, Ht, growth, development

Nutritional status Nutritional status

CD4 (desirable not required) CD4 q 6-12 mos (or clinical indic)

Hb (esp if on AZT) Hb (WBC) 1-3 mos post start ARV, then Sx directed

Other lab Sx-directed, eg ALT, lipid, glucose

VL if available VL if indicated (to confirm CD4 drop?)

Changes to Ped Guidelines: Toxicity Management • Improve description of toxicity in children.

• Outline temporal issues (early vs late).

• Immediate, life-threatening: Stop all drugs. Once resolves, restart with substitute for offending drug.

– Staggered stopping if NNRTI?

• Non-life threatening:

– Continue ARV if can, if mild or moderate.

– If severe, switch one offending drug (within class substitution usually) without stop.

• Late toxicity, such as lipodystrophy:

– Management – could change d4T to AZT.

• Include more details on management/algorithm?

Changes to Ped Guidelines: When to Switch for Treatment Failure

• Important to check adherence before change.• Must have adequate trial ARVs (eg, >6 mos).• Before change for growth failure, need assure

adequate nutrition, treatment OIs (esp, TB).• Algorithm development?

– Before change, must check adherence, nutrition, resolution TB/acute OI.

• Use new clinical staging for decisions?– New or recurrent Stage 3 or 4: change.– New or recurrent Stage 3 (selected

conditions?): consider change?• If use CD4 criteria, need repeat value before

change (also clinical status important in decision).

Changes to Ped Guidelines: When to Switch

• When Switch for Treatment Failure:– Clinical criteria (if keep selected selected

clinical criteria vs use of pediatric clinical staging):• Lack/decline in growth

–Weight most important

–Must be sure unexplained (eg, in presence of adequate nutrition, treated TB, etc).

• Loss developmental milestones/ encephalopathy

• New or recurrent OI

–Must differentiate from IRS

Changes to Ped Guidelines: When to Switch• When Switch for Treatment Failure:

– CD4 criteria:• If only CD4 and no symptoms, may decide

not to change.• Viral load monitoring may be useful in this

situation (confirm significance).• If after reasonable trial of therapy (eg, after 6

months of therapy), switch if CD4 not above or if declines to age-related threshold for initiation of therapy (considering clinical status).

• Include a % change from peak? Does baseline value matter?

• Absence of any concurrent conditions that can be associated with lowered CD4.

Potential Proposal to Use Clinical Staging to Decide on Switch Due to Treatment FailureClinical stage Considerations

1 No switch

2 new or recurrent

Consider adherence

Monitor closely clinical

3 new or recurrent

Check adherence

Rx/manage coinfection/OI (eg, TB #)

Nutritional issues if growth criteria

Consider regimen switch

4 new or recurrent

Check adherence

Rx/manage coinfection/OI (eg, TB)

Nutritional issues if growth criteria

Switch regimen # TB may not indicate treatment failure

Changes to Ped Guidelines: TB and ARV• TB and ARV:

– Drug interactions especially problem in kids due to lack pediatric ARV formulation/drug dosing younger kids, so not many choices.

– Need emphasize case detection (child with TB may reflect TB in household not necessarily immune suppression).

– TB diagnosis difficulty in kids, most often empiric therapy issue (dx TB if respond to TB treatment).

– All kids with pulmonary TB should be CONSIDERED for ARV (stage III).

– CD4 thresholds used to determine overall need for start ARV in child with pulmonary TB are as per “when to start” thresholds.

Changes to Ped Guidelines: TB and ARV• TB and ARV:

– Importance of clinical response to TB rx in determining when ARV start in relation to TB rx (or whether to start ARV if no CD4 available).

– When start ARV if pulmonary TB in child?• Stabilize TB before make decisions ARV

(response first few weeks of TB rx):– If respond well to TB rx, defer ARV until

complete TB rx.– If not respond after initial TB rx, start ARV.

– Where does CD4 fit in this determination? Adult group will have CD4 gradation to determine when to start ARV in pt with TB (<200 start ARV 2wk-2 mos of TB rx; 200-350 defer till complete TB rx). Should we have this for children and, if so, what thresholds?

Changes to Ped Guidelines: TB and ARV• TB and ARV:

– What ARV to start (or to change if on 1st line) if on rifampin:• If <3 yrs:

–Triple NRTI (eg, AZT/3TC/ABC) (TFV role?)

vs–NVP-based ARV:

»Adult group may say continue NVP-based therapy if no other options are available.

• If >3 yrs:–EFV-based (no dose increase)

Changes to Ped Guidelines: TB and ARV• TB and ARV:

– If on 2nd line therapy:• If have failed NNRTI, then is now receiving

boosted PI, which is “contraindicated” with rifampin.

• Stop PI and use triple NRTI including TFV if age-appropriate (dose/formulation issues; can’t give with concurrent ddI).

• Adult group says could still use boosted PI (LPV/r or SQV/r; SQV/NFV?) but with increased monitoring (LFT) who concurrent boosted PI and rifampin rx.

• Adult group to advocate for availability of rifabutin (then can give boosted PI or NNRTI).

Changes to Ped Guidelines: Adherence• Adherence:

– Two types problems• Program level (cost, formulations, supply)

–Reduce cost/free drug–Reliable supply – forecasting needs–Pediatric formulation needs

• Individual level–Discuss challenges in children, how to

maximize»Education, pro-active approach»Reduce pill burden»Disclosure»DOT/outreach/community»Family focused care

Other suggested changes to Ped Guidelines:• Treatment interruptions:

– Not enough information to make recommendations on this

• Adolescent section:– Discuss EFV issues in adolescent girls,

contraception– Deal with transition to adult care

• Salvage:– Not enough info ped drugs, needs

individualization• HBV/HCV coinfection:

– Will be some discussion in adult guidelines; should ped cover as well?