Transcript Draft WHO Pediatric ARV Guidelines

Draft WHO Pediatric ARV Guidelines
Revision Summary
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
10/23/05
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
All
All
All
All
All
All (except TB**, OHL,
LIP, thrombocytopenia,
where do CD4 guided)
No CD4
CD4
All
CD4 guided
All**
CD4 guided
No CD4
TLC guided
TLC guided
CD4
CD4 guided
CD4 guided
Do not rx
Do not rx
Stage 4* CD4
No CD4
Stage 3* CD4
Stage 2
Stage 1
No CD4
* 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
CD4%*
<25%
CD4 count* <1,500
<20%
<750
<15%
<350
>5 yr
<15%
<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
<1 yr
4,000
100
3-5 yr
2,500
60
>5 yr
1,500
40
40
20
5%
0
5%
0
1000 2000 3000 4000 5000 6000 7000 8000
Total Lymphocyte Count
>3 yr
15%
60
20
0
6 months
1 year
2 years
5 years
10 years
1-3 yr
20%
80
Probability (%)
Probability (%)
100
1-3 yr
3,000
80
<1 yr
25%
0
5
10
15
20
25
30
CD4%
35
40
45
50
Age-Related CD4 Absolute Count Associated With
5% Risk of Death Within 12 Months
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
12-Month Mortality Risk, Selected CD4%/Count and TLC Age Thresholds
HIV Pediatric Prognostic Marker Collaborative Study (Dunn et al)
30
CD4%<25 (<1yr), <20% (1 to <3 yrs), <15% (3 to <5 yrs), <15% (≥ 5 yrs)
CD4<1500 (<1yr), <750 (1 to <3 yrs), <350 (3 to <5 yrs), <200 (≥ 5 yrs)
25
Probability of death (%)
TLC<4000 (<1yr), <3000 (1 to <3 yrs), <2500 (3 to <5 yrs), <1500 (≥ 5 yrs)
20
15
10
5
0
0
1
2
3
4
5
Age (years)
6
7
8
9
10
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 Patients
1st Line ARV
Considerations
2nd Line ARV
Dual NRTI (choose 2, except do not use AZT/d4T)
3TC
Minimal toxicity
ddI (+ 3TC?)
Anemia
Lipodystrophy/lactic acidosis/
peripheral neuropathy
ABC (+ 3TC?)
Hypersensitivity reaction
AZT (+ 3TC?)
or
AZT
[d4T]
or
ABC
PLUS
NNRTI (choose 1, see age preference)
NVP
Prefer <3 yr (<10kg)
LPV/r or SQV/r or
SQV/NFV or NFV
Prefer >3 yr (>10 kg)
LPV/r or SQV/r or
SQV/NFV or NFV
or
EFV
Alternative ARV Choices for Pediatric Patients
1st Line ARV
Considerations
3 NRTI Combo (choose 3 except do not use AZT/d4T):
3TC
Minimal toxicity
2nd Line ARV
NRTI:
ddI (+ 3TC?)
or
AZT
[d4T]
Anemia
Lipodystrophy/lactic acidosis/
peripheral neuropathy
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
2nd Line Regimen
1st Line Regimen *
RTI
Component * +
PI
Component
AZT or d4T + 3TC + NVP or EFV**
ddI + ABC
ABC + 3TC + NVP or EFV**
ddI + AZT
AZT or d4T + 3TC + ABC
ddI + EFV* or NVP
LPV/r or
SQV/r# or
SQV#/NFV or
NFV%
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
Nevirapine syrup
Weight
(kg)
Lead-in dose
Full
Weeks 1 & 2
Dose
syrup
syrup
(10mg/ml)
(10mg/ml)
Nevirapine tablets
Lead-in dose
Weeks 1 & 2
Full
Dose
200mg tablets
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
½ am and pm
1 am and pm
20-29.9
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 ARV
Confirm 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 Failure
Clinical stage
Considerations
1
2 new or
recurrent
No switch
Consider adherence
Monitor closely clinical
Check adherence
Rx/manage coinfection/OI (eg, TB #)
Nutritional issues if growth criteria
Consider regimen switch
Check adherence
Rx/manage coinfection/OI (eg, TB)
Nutritional issues if growth criteria
Switch regimen
3 new or
recurrent
4 new or
recurrent
# 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 NVPbased 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?