Paediatric HIV: Stateofthe ART in 2006

1
Paediatric HIV State-of-the ART in 2006

• IDS ARV TRAINING
• Croatia, 3 -5 November 2006
• Franklyn Eseme MD

2
PATHOGENESIS OF HIV INFECTION Similar to that of
adults

• The reverse transcriptase, an enzyme that
  transform the viral RNA genome in a linear
  double-stranded DNA, is the the essential tool
  for integration of viral genome in the DNA of
  human cells.
• The major target of HIV infection is the CD4 T
  lymphocyte, although HIV can also infect other
  white blood cell types such as macrophages.
• Productive infection of lymphocytes (both in the
  blood and in other tissue compartment) results in
  the destruction of the human cell and in the
  release of new copies of viruses that can further
  infects other human lymphocytes.
• As a consequence, an high amount of HIV RNA in
  the blood and a progressive decline in CD4 T
  cells develops, which are responsible of impaired
  immune defense of the infected patients and
  clinical features of AIDS.

3
Pediatric HIV

• Considerations unique to infants, children, and
• young adults

4
Special Considerations in Pediatric ARV
Therapy

• Diagnostic issues
• Pharmacokinetic changes
• Availability of pediatric formulations
• Natural history differences in virologic and
  immunologic markers
• Adherence issues

5
Children are not small adults !

• Differences
• Different Immunology
• - Developing immune system
• - Functioning thymus
• Different patterns of HIV RNA
• - natural decline of HIV- RNA up to 5 yrs
• Different Pharmacokinetics
• - Developing metabolic pathways

Age as a major variable
6
Children are not small adults !

• Differences
• Different Immunology
• - Developing immune system
• - Functioning thymus
• Different patterns of HIV RNA
• - natural decline of HIV- RNA up to 5 yrs
• Different Pharmacokinetics
• - Developing metabolic pathways

Age as a major variable
Different response to ART in adults and children
7
Changing Pharmacokinetics

• Age-related differences between children adults
• Body composition
• Renal excretion
• Liver metabolism
• Gastrointestinal function
• Enzyme maturation
• Drug distribution, metabolism and clearance
• Drug dosing and toxicities

Lead to potential differences in
8
Schaks et al NEJM 2003
9
Naive T cells increase only marginally and after
prolonged periods of therapy
Mario (Mago) Clerici, Chair of Immunology,
University of Milano School of Medicine
10
Diagnostic Issues

• Early identification all pregnant women must be
  offered HIV counseling and testing
• Perinatal infection primary infection
• Early diagnosis starting therapy during
  primary/early infection

11
Diagnostic Issues in Infants

• HIV is diagnosed by 2 positive HIV virologic
  tests performed on blood samples 2 separate dates
• Use DNA PCR or HIV culture for diagnosing at
• Birth (lt48 hours)
• 14 days (optimal)
• 12 months
• 36 months

12
Diagnostic Issues in Infants

• HIV is reasonably excluded with
• 2 or more negative virologic tests
• One at age gt1 month
• One at age gt4 months
• 2 or more negative HIV antibody tests at gt6
  months (in the absence of breast feeding)

13
Pediatric HIV ClassificationAge-Specific CD4
Immunologic Categories
14
Pediatric HIV Classification Clinical
Categories

• Category E Perinatally Exposed
• Category N Not Symptomatic
• Category A Mildly Symptomatic
• Category B Moderately Symptomatic
• Category C Severely Symptomatic

15
Immunologic Parameters in Children

• Absolute CD4 counts in healthy children are much
  higher than in adults
• Normal absolute CD4 counts slowly decline to
  adult levels by age 6
• If using CD4 count for ARV decision, use
  appropriate levels
• CD4 percent varies less with age and may be a
  better immunologic parameter to follow in
  children lt6 years

16
DISTINCT FEATURES IN RESPONSE TO ANTIRETROVIRAL
THERAPY BETWEEN ADULTS AND CHILDREN

• CD4 cell count at baseline are more predictive of
  immunologic response in adults than in children
• High HIV-1 RNA levels are predictors of virologic
  failure in adults, less so in children
• In children, immune reconstitution is mainly
  contributed by naive CD4 cells in adults is a
  byfasic process

17
Normal CD4 count in uninfected children are
consistently higher than those observed in adults
and slowly decline to adult value by age 5
yrs (ECS PIDJ, 1992, 11 1018.1026, Shearer et al
J All Clin Immunol 2003, 112 973-980)
18
HIV RNA and ChildrenClinical Considerations

• HIV RNA and CD4 assays are independently
  predictive of risk of disease progression
• Both help determine when to start and when to
  change ARV therapy
• A 5-fold change in HIV RNA copies/mL in infants
  or 3-fold change in children is biologically and
  clinically significant

19
PENTA 5 Immunology sub-studies

• - Increased thymic output after initiation of
  ART (n33)
• (De Rossi et al JID 2002 186312-20)
• - T cell receptor gene rearragement excision
  circles (TREC)

20
Immunological response is better in younger
children whereas younger children have poorer
virological response (CHIPS cohort) (Walker AS
et al AIDS 2004, 18 1915 -1924)
gt4 years
gt4 years
21
Changing spectrum of HIV disease with HAART

• Marked decrease in deaths/ hospital admissions
  since 1997
• HIV becoming a chronic disease
• Issues of drug adherence, acceptability and
  toxicity dominate
• About 35 of HIV infected children in US/Europe
  are teenagers
• Social aspects of HIV remain key
• Lack of access to therapy for the vast majority
  of infected individuals.

22
Uptake of HAART and decreasing risk of death in
CASCADE adult cohort
HAART
1600000
Dual
1400000
Mono
1200000
Exp
Naïve
1000000
800000
600000
400000
200000
0
1985
1986
1987
1988
1989
1990
1991
1992
1993
1994
1995
1996
1997
1998
1999
2000/01
23
Estimated progression to serious disease (CDC
stage C) by calendar period of birth
After
After 1996
Children born 1995-1999, cohort 3
Children born 1989-1994, cohort 2
Children born 1985-1988, cohort 1
Progression to AIDS at one year gt25 in cohort
1, 15 in cohort 2 and 5 in cohort 3
ECS, Pediatrics 2001
24
Risk of disease progression (The Lancet 2003
3621605-1611).
lt1 risk
1-2
25
Antiviral efficacy of HAART in naive adult
patientsHIV RNA lt 50 copies at week 24, ITT
switch failure analysis
91
STACCATO
SQV/r 2 NRTIs
0
20
40
60
80
100
Subjects with HIV RNA lt 50 copies/mL ()
26
In children When to start Treatment What
to start with When to switch
27
When to start ?

• Primary infection - soon after birth?
• Based on HIV RNA Viral load/CD4?
• (or their rate of change with age)?
• Based on clinical symptoms/signs?
• Balance costs benefits of HAART

28
Issues to consider when starting therapy in
Children

• Parents wishes, state of health, ART experience
• Likelihood of good longterm adherence
• What formulations could this child take?
• What PK data are available for infants?
• What drugs are other family members on?

29
Issues to consider when starting therapy in
Children
STARTING IS RARELY AN EMERGENCY. TIME TAKING
IN PREPARING THE FAMILY IS NEVER WASTED !

• Parents wishes, state of health, ART experience
• Likelihood of good longterm adherence
• What formulations could this child take?
• What PK data are available for infants?
• What drugs are other family members on?

30
Indications for Initiation of ARV Therapy in
Children lt12 Months of Age
31
Indications for Initiation of ARV Therapy in
Children Age gt1 Year
32
PENTA Guidelines When to start treatment
When risk of progression to AIDS/death in 12 mo
is gt 10
33
12-month mortality risk at selected thresholds
for CD4, CD4 count and TLC, by age
CD4lt25 (lt1yr), lt20 (1 to lt3 yrs), lt15 (3 to lt5
yrs), lt15 ( 5 yrs)
CD4lt1500 (lt1yr), lt750 (1 to lt3 yrs), lt350 (3 to
lt5 yrs), lt200 ( 5 yrs)
TLClt4000 (lt1yr), lt3000 (1 to lt3 yrs), lt2500 (3 to
lt5 yrs), lt1500 ( 5 yrs)
0
1
2
3
4
5
6
7
8
9
10
Age (years)
34
WHO Guidelines. When to Start ARVs in Children
Stabilize any OI before initiate ARV
Pulmonary TB Eval CD4 (if avail)/clinical status
after 1-2 mos TB rx to decide when ARV start in
relation to TB rx if need ARV (see TB section)
35
WHO Age-Related CD4 and TLC Values for ARV
Treatment Decisions in Children
CD4 preferred in children lt5 yrs CD4 count
preferred in children gt5 yrs.
36
In children When to start Treatment What
to start with When to switch
37
Considerations

• - adherence (number of pills, number of
  doses
• - managment toxicities
• - drug dosing chart
• - compatibility with food
• - side effects

38
Choice of Initial ARV Therapy

• Consideration of resistance testing before
  initiation of therapy in newly diagnosed infants
  lt12 months
• Particularly if mother has known or suspected
  drug-resistant virus

39
Adherence Issues in Children

• Availability of drugs in palatable, liquid or
  mixable formulations
• Difficulty of giving drugs that have food
  restrictions, because of childrens (particularly
  infant) eating schedules
• Childrens dependence on caregivers for
  administration

40
Adherence Issues in Children

• Timing issues, e.g., during school hours
• Families reluctance to disclose HIV diagnosis
  may limit medication administration at
  daycare/school
• Childrens developmental level influences ability
  and willingness to take medications

41
Adherence Issues in Adolescents

• Lack of belief in the effectiveness of ARV
• Low self-esteem
• Unstructured and chaotic lifestyle
• Lack of familial and social support

• Denial and fear of their HIV infection
• Misinformation
• Distrust of the medical establishment
• Fear of ARV

42

• Issues around specific drugs
• Pharmacokinetics
• - with age
• - once daily dosing
• - problems with what plasma levels mean for NRTI
  but intracellular levels require large amount of
  bloods
• Formulations tablets, powder, liquid (volumes,
  taste) comparison across these
• Combined formulations (as in adults)
• Calculation and measurement of doses
• Design of trials/studies of news drugs
• Timing of producing data

43
PENTA guidelines Which ART regimens to start

• Infants
• either
• 2 NRTI 1 NNRTI (NVP)
• or
• 2 NRTI 1 PI (lopinavir or NFV)

Children either 2 NRTI 1 NNRTI (EFV or
NVP) or 2 NRTI 1 PI (lopinavir or PI boosted
or NFV)
44
3TC can be considered to be maintained in 2nd
line regimens to reduce the viral fitness.
Non-boosted PI (NFV alone) is less optimal than
boosted PI.
45
WHO WHAT TO START WITH ? First Line ARV Drugs in
children and young adolescents
EFV
AZT or d4T
3TC or FTC
ABC
NVP
Triple NRTI alternative approach
Triple NRTI regimen can be considered where
NNRTI options are complicated (e.g. viral
hepatitis co-infection, TB co infection, pregnant
adolescents or if CD4 count gt 250 cells /mm3
severe reactions to NVP or EFV and HIV-2
infection).
46
Initial ARV TherapyRecommended (NNRTI-Based)
47
NNRTI-Based Regimens

• Disadvantages
• Cross resistance among NNRTIs
• Rare, but serious life-threatening skin rashes
• Hepatic toxicity
• Multiple drug interactions

• Advantages
• Effective
• Palatable
• Less dyslipidemia/fat maldistribution
• PI-sparing
• Lower pill burden

48
Initial ARV TherapyRecommended (PI-Based)
49
PI-Based Regimens

• Advantages
• Potent
• NNRTI-sparing
• Targets HIV at 2 steps
• Resistance requires multiple mutations

• Disadvantages
• High pill burden
• Multiple drug interactions
• Metabolic complications
• Poor palatability
• Few pediatric formulations

50
Initial ARV TherapyRecommended (NRTI-Based)
51
NRTI-Based Regimens

• Advantages
• Spares other classes of drugs
• Minimal drug-drug interactions
• Limited NRTI cross resistance
• Palatable
• Lower pill burden

• Disadvantages
• May be less potent than other regimens
• Rare, but serious lactic acidosis/hepatic
  steatosis
• Potential for ABC hypersensitivity

52
Initial ARV Therapy Not Recommended

• Monotherapyexcept ZDV prophylaxis for HIV
  exposed infants during the first 6 weeks of life
• Certain 2 NRTI combinations
• Antagonistic ZDV/d4T
• Overlapping toxicities d4T/ddC, ddI/ddC, 3TC/ddC
• Similiar structure and identical resistance
  3TC/FTC
• Saquinavir requires RTV boosting to achieve
  adequate drug level pediatric dose unknown

53
Recommendations on ART for infants and children
exposed to ARV B(IV)
Infants who were exposed to ARVs for PMTCT either
the maternal or infant component and/or Breastfeed
ing infants who are exposed to ARV because of
maternal ART
Should be considered eligible for the standard
2NRTI 1NNRTI first line ARV regimen using the
same doses and criteria as unexposed children
54
In children When to start Treatment What
to start with When to switch
55
Changing ARV Therapy

• Failure based on virologic, immunologic, or
  clinical parameters
• Toxicity or intolerance on the current therapy
• Consider change if there is new data
  demonstrating that another regimen is superior to
  the current regimen

56
Clinical Considerations for Changing ARV Therapy

• Progressive neurodevelopmental deterioration
• Growth failure despite adequate nutritional
  support
• Disease progression

57
Immunologic Considerations for Changing ARV
Therapy

• Change in immune classification
• For children with lt15 CD4, persistent decline
  of 5
• Rapid and substantive decrease in CD4 count (ie,
  gt30 decline in lt6 months)

58
Virologic Considerations for Changing ARV Therapy

• Less than 1.0 log10 decrease in HIV RNA from
  baseline 8-12 weeks after start of ARV therapy
• HIV RNA not suppressed to undetectable levels
  after 4-6 months
• Repeated detection in HIV RNA levels after
  undetectable levels on ARVs
• A reproducible increase in HIV RNA after
  substantial response

59
Changing ARVs for Toxicity/Intolerance

• Choose drugs from same class with different
  toxicity/side effect profiles
• Change of a single drug is permissible if a
  single drug can be identified as a cause of
  toxicity
• Do not reduce dose below lower end of therapeutic
  dose range for the particular drug

60
Changing ARVs for Treatment Failure/Disease
Progression

• Assess and review adherence
• Review patient medications
• Perform resistance testing
• Consider overlap in resistance
• Change ARVs to contain at least 2 or 3 new ARVs
• Consider clinical trials of investigational ARVs
• Discuss quality of life issues

61
WHEN TO SWITCH ? Switching to second line
therapy for treatment failure based on WHO
paediatric clinical staging
62
Determinants of treatment failure

• Drug toxicity

Ease of dosing
Suboptimal PK
Socio/cultural aspects (i.e age)
Regimen tolerability
Suboptimal potency
Incomplete ADHERENCE
Treatment failure Virologic/immunoogic/clinical
failure
Mod from Carr, Lancet, 2002
63
Determinants of treatment failure

• Drug toxicity

Ease of dosing
Suboptimal PK
Socio/cultural aspects (i.e age)
Regimen tolerability
Suboptimal potency
Incomplete ADHERENCE
Treatment failure Virologic/immunoogic/clinical
failure
Mod from Carr, Lancet, 2002
64
Determinants of treatment failure

• Drug toxicity

Ease of dosing
Suboptimal PK
Socio/cultural aspects (i.e age)
Regimen tolerability
Suboptimal potency
development of lipodistrophy.
Incomplete ADHERENCE
care givers, adolescents, knowledge of diagnosis
Treatment failure Virologic/immunoogic/clinical
failure
Mod from Carr, Lancet, 2002
65
Nelfinavir
trough level
vs
daily dose
Penta 7 PK -
(mg/Kg/d). (Litalien C et al PIDJ 2003)
/ml)
ng
trough level (
Nelfinavir
Nelfinavir
daily dose (mg/kg/d)
66
What to switch to ? Choice of the second line
regimen
Second-line
Preferred first-line
ddI ABC PI/r

ZDV or (d4T)
NVP or EFV
3TC or FTC


ABC
NVP or EFV
3TC or FTC


ddI ZDV PI/r
Triple NRTI alternative
ZDV or d4T
ABC
3TC or FTC


NVP or EFV PI/r
3TC can be maintained in a second line regimen
67
Laboratory parameters for routine monitoring of
infants and children during ART
68
ART IN FIXED DOSE COMBINATIONS ADULT AND
PAEDIATRIC FORMULATIONS
Adult Tablet
Junior Baby
d4T 3TC NVP
FORMULATIONS
Adult d4T (30 mg or 40mg), 3TC 150mg, NVP
200 mg)
"Junior" d4T 12mg, 3TC 60mg, NVP 100 mg
Children
Adult Tablet
Junior Baby
"Baby" d4T 6mg, 3TC 30mg, NVP 50mg
69
Fat Redistribution and Metabolic Abnormalities in
HIV-Infected Children and Adolescents in Europe

• The Italian Register on HIV infection in
  Children
• The European Collaborative Study
• Universities of Milan, Turin and Florence,
  Italy
• Institute of Child Health, London, UK

70
Fat redistribution
Types of fat redistribution in the 117 cases

• Overall Prevalence
• 29.0 (117/403) for any fat redistribution
• 10.1 for central lipohypertrophy alone
• 7.9 for peripheral lipoatrophy alone
• 10.9 for mixed type