Module 3:

Management of Patients on
Antiretroviral Therapy

Unit 4: HIV Infection and Use of

Antiretroviral Treatment in
Children
GOAL
 To impart knowledge on HIV infection
and the use of ARV drugs in Children
OBJECTIVES
 Describe the epidemiology and natural
history of HIV in children
 Describe the diagnosis and staging of HIV
infection in children
 Describe when and how to initiate, change
and stop ART
 Describe ARV monitoring in children
 Describe drug related side effects and
interactions
 Describe adherence problems and support
 Epidemiology
 1 million live births in Kenya annually
 10% born to HIV infected mothers
 Without PMTCT 30% of these become infected
 About 20-30,000 neonates acquire HIV annually
 About 10,000 (50%) die within first 2 years
 HIV has made a huge impact on infant mortality
 Children form ~10% of all HIV infected population
in Kenya (150,000)
Epidemiology: Transmission
 Over 90%of HIV infection in infants
and young children is from HIV
positive mothers (Mother to Child
Transmission -MTCT)
Epidemiology: Transmission
Other routes
 Sexual

 Contaminated needles and instruments

 Transfusions of contaminated blood and

blood products
 Special risk – sicklers and haemophiliacs
 Factors Facilitating MCT
Increased by:
 Maternal
 Recent maternal HIV infection
 High viral loads
 Low CD4 cell counts
 AIDS/late stage disease
 Obstetric factors
 Delivery practices (including episiotomy)
 PROM; membrane rupture >4 hours pre-delivery
 Instrumented delivery
 Vaginal delivery vs pre-labor c/section
 Factors Facilitating MCT
 Infant prematurity (<34 weeks)
 Breast feeding
 Prolonged breastfeeding
 Mixed feeding – breast and bottle
 Sore nipples
 Oral thrush in baby
 Natural History
Background
 CD4 counts high in children.

 Decline to adult levels by 6 yrs.

 CD4% does not change with age.

 Natural History
Age-related Decrease in CD4+ Number

6000
CD+ Number/mm3

4000
5th percentile
95th percentile
2000

0
0 4 9 12 24 60
Age in Months
 Natural History
Age-related Decrease in CD4+
Percentage

80
60
CD4+ %

5th percentile
40
95th percentile
20
0 0 4 9 12 24 60
Age in Months
 Natural History of Pediatric HIV
Infection
 In HIV infected children
 Low viral load at birth, rise to several million
copies within the first 1-2 months of life
 Very slow decline over several years to reach “set
point”

 Very high HIV RNA levels may be correlated

with disease progression and death.
 Predictive value of VL not good in young infants,
therefore evaluate CD4 counts and percentages
as well
 Natural History
Two commonly seen patterns of
progression

Slow Progressors
 Low viral loads at birth
 Stable CD4 counts for 2-10 years
 Growth stunting, skin problems and recurrent
bacterial infections common
 Opportunistic infections, AIDS related
conditions with progressive immunosuppression
 Encephalopathy rare
 Natural History
Patterns of progression

Rapid Progressors
 High viral load at birth

 Rapidly declining CD4

 Low Birth Weight

 Chronically unwell
 Persistent or recurrent diarrhea
 Recurrent bacterial and fungal infections
 Severe encephalopathy before 18 months
Clinical presentation of HIV in
Children

MODULE 2: UNIT I
Clinical suspicion of HIV
 First do an initial clinical assessment of
child, and suspect HIV
 Certain clinical conditions, if present,
point to high probability of HIV infection
in the child
Clinical signs & conditions suggestive
of HIV infection in a child
Very specific for HIV infection:
 Oesophageal candidiasis

 Herpes zoster (shingles)

 Invasive salmonella infection

 Pneumocystis carinii pneumonia

 Extrapulmonary cryptococcosis

 Lymphoma

 Kaposi’s sarcoma
Clinical signs & conditions suggestive
of HIV infection in a child
Common in HIV, uncommon in HIV uninfected
child
 Recurrent severe bacterial infection

 Persistent or recurrent oral thrush

 Parotid enlargement

 Generalized lymphadenopathy

 Hepatosplenomegaly (non-malaria areas)

 Persistent or recurrent fever

 Neurologic dysfunction

 Persistent generalized dermatitis

Clinical signs & conditions suggestive
of HIV infection in a child

Common in both HIV+ and HIV-

children
 Otitis media - persistent or recurrent

 Diarrhoea – persistent or recurrent

 Severe pneumonia

 Tuberculosis

 Failure to thrive
Clinical suspicion of HIV
 The Integrated management of
childhood illness (IMCI) gives a quick
easy method to identify children likely
to have symptomatic HIV.
IMCI definition of symptomatic
HIV infection
Presence of 3 or more of the following:
 TB in any parent in the last 5 years

 Pneumonia (now or previously)

 2 or more episodes persistent diarrhoea (>14

days)
 Growth faltering or weight < 3 rd centile

(below “very low weight curve” in card

 Enlarged lymph nodes in 2 or more of the
following sites (neck, axilla, groin)
 Oral thrush
Clinical suspicion of pediatric
HIV
 Using IMCI tool one can easily identify
children highly likely to have HIV
infection.
 Disease Staging
TWO international clinical staging systems:

 World Health Organization (WHO)

 Centers for Disease Control (CDC)
 One staging system should be used consistently for
children in a unit

FOUR stages – asymptomatic, mild, moderate,

severe
 Disease Staging
 WHO Clinical Staging designed to
 Be used where HIV infection is confirmed with an
antibody/virological test
 Help monitor patients and determine prognosis
 Help determine prioritize need for preventive therapies
 Provide guidance as to when to start or review ARV drug
therapy
 Help assess clinical response to therapy in the absence
of appropriate laboratory tests
 Revised for consistency between adult and
pediatric staging and for ease of use
WHO clinical staging
STAGES
 1 – asymptomatic

 2 – mildly symptomatic

 3 – moderately symptomatic

 4 – severely symptomatic (AIDS)

For use in those 12 years or under with

confirmed laboratory evidence of HIV
infection.
 Revised
WHO Clinical Staging for HIV Infected
Children
Stage Selected Symptoms
Stage I 1. Asymptomatic
(asymptomatic) 2. Persistent generalized lymphadenopathy
3. Hepatosplenomegaly

Stage 2 (mild) 1. Recurrent or chronic upper respiratory

tract infections
2. Skin problems: PPE, Herpes zoster,
extensive warts or Molluscum
contagiosum
3. Recurrent oral ulcerations, angular cheilitis
4. Parotid enlargement
 WHO Stage 3: Selected Symptoms
(moderate)
1. Unexplained moderate malnutrition not responding to
therapy
2. Unexplained persistent diarrhea; unexplained
persistent fever
3. Oral candidiasis (outside neonatal period ); OHL
4. Pulmonary tuberculosis
5. Severe recurrent bacterial pneumonia
6. Lymphoid interstitial pneumonitis (LIP)
7. Unexplained blood disorder for > 1 month (anemia,
neutropenia, thrombocytopenia)
 WHO Stage 4 (severe)
Conditions where a presumptive diagnosis can be made
using clinical signs or simple investigations:
1. Unexplained severe wasting not responding to therapy
2. Pneumocystis pneumonia (PCP)
3. Recurrent severe presumed bacterial infections
4. Chronic orolabial or cutaneous HSV (>1 month duration)
5. Extrapulmonary tuberculosis
6. Kaposi's sarcoma
7. Esophageal Candidiasis
8. HIV encephalopathy
 WHO Stage 4 (severe)
Conditions where confirmatory tests
necessary
 Cryptococcal meningitis

 Candida of trachea, bronchi or lungs

 Cryptosporidiosis, isosporiasis

 Disseminated non-tuberculous

mycobacterial infection
 CMV infection
Pediatric HIV Disease Staging: CDC

Clinical: N- Not symptomatic

A- Mildly symptomatic
B- Moderately symptomatic
C- Severely symptomatic
(see appendix for specific conditions)
Clinical Staging
Stage WHO CDC

Asymptomatic 1 N

Mild 2 A

Moderate 3 B

Severe 4 C
 Immunological Staging
Using Absolute CD4 count

Immune category < 12 1-5 years 6-12 years

months CD4 CD4 counts
CD4 counts counts
1: Not
immunosuppresse > 1500 > 1000 > 500
d
2: Moderately
immunosuppresse 750-1,499 500-999 200-499
d
3: Severely
immunosuppresse < 750 < 500 < 200
d
Revised Immunological Staging
(WHO)
Immune category < 12 months 1-12 years
CD4 % CD4 %

1. Not
immunosuppressed 30% or more 25% or more
2. Mildly
immunosuppressed 25-29% 20-24%

3. Moderately
immunosuppressed 20-24% 15-19%

4: Severely
immunosuppressed < 20% < 15%
 CDC Immunological staging
Immune category < 12 months 1-5 years 6-12 years
CD4 counts CD4 counts CD4 counts
CD4 percentage CD4 CD4 percentage
percentage
Category 1: > 1500 > 1000 > 500
Not > 25% > 25% > 25%
immunosuppressed

Category 2: 750-1,499 500-999 200-499

Moderately 15-24% 15-24% 15-24%
immunosuppressed

Category 3: < 750 < 500 < 200

Severely < 15% < 15% < 15%
immunosuppressed
Relationship between CD4 and
Lymphocyte count (TLC)
Age CD4 Lymphocyte
count
< 18 < 20 % < 2500
months
> 18 < 15 % < 1500
months
> 6 years < 15% or < 1200
CD4 count < 200
LABORATORY DIAGNOSIS
 Diagnostic testing of HIV exposed infants
using DNA or RNA PCR
 Child < 18 months
 Positive antibody test may be a false positive
result reflecting maternal antibodies.
 An alternative test therefore required to confirm the
diagnosis
 A negative HIV antibody test in an exposed infant
< 18 months suggests that the infant is HIV
negative and should be confirmed 3 months after
cessation of breast feeding
 When to do PCR for HIV
diagnosis in infants
If child NOT breastfeeding:
 Do PCR from age 1 month, repeat after 3 months

If child IS breastfeeding:
 Do PCR from age 1 month, repeat 3 months after
stops breastfeeding
(if positive at 1 month, encourage mother to
continue breastfeeding, if negative, encourage
mother to stop or shorten* duration of
breastfeeding)
*If feasible and acceptable
Diagnosis: Child < 18 months
 HIV is diagnosed by 2 positive HIV virologic
tests performed on blood samples on 2
separate dates.

 HIV is reasonably excluded with 2 or more

negative virologic tests at >age 1 month, one
of which is performed at age >4 months in a
non-breastfed infant
Diagnosis: Child > 18 months
 Antibody tests: 2 or more antibody tests
after 18 months confirm diagnosis.
Diagnosis – combining lab and
clinical criteria
 PCR not yet widely available or
accessible
 A diagnosis of HIV infection can still be
made in child < 18 months by
combining simple lab and clinical
parameters
HIV diagnosis in children age < 18
months (virologic test unavailable)

Must fulfill the following 3 criteria:

WHO stage 3 or 4
PLUS
HIV ELISA positive (child or mother)
PLUS
CD4 < 20% (or CD4 count < 750)
OR TLC < 2500
Summary - Approach to diagnosis
1. Do clinical assessment – suspect HIV
2. Do clinical staging (WHO)
3. Do HIV test - < 18 months PCR, > 18
months ELISA
4. If PCR not available for child < 18 months
do CD4 test (% or absolute count)
5. If CD4 not available
do TLC
ART
 When to Initiate Treatment:
WHO Recommendations –CD4 count Available

Children with confirmed HIV infection with:

 WHO stage 3 or 4 irrespective of CD4%

 CD4 < 20% for children <18months

 CD4 < 15% for children > 18months

 CD4 count < 200 (in children > 6 years) irrespective of

clinical stage

 Antibody-positive children under 18 months with no virologic

test but with WHO stage 3 or 4 and CD4 below 20%
 How to Initiate
 Should be done by experienced, qualified
person.
 Starting is not an emergency.
 Considerations
 Parental and child readiness
 Adherence assessment
 Availability and suitability of
formulations
 Cost and affordability
 Psychosocial and family support
 Disclosure
 Considerations
 Stage of development
 Dosing frequency
 Side effects
 Co-infections
 Meal requirements
 Storage requirements
 Relative Contraindications
C.Indications Definition Comments Recommendations
Severe Anaemia Hb≤ 6.9g/dl ZDV CI Use d4T
Severe ANC ZDV to be Change to d4T if ANC
Neutropenia ≤250mm3 monitored drops after 2 wks.
Severe renal Creatinine> ARVS CI Defer Rxn
insufficiency 3 X normal Consult expert
Severe Hepatic LFTs > NVP CI Use EFV for > 3yrs/10kg
Insufficiency 5 x normal Use PIs for < 3yrs
Previous ARV intolerance Consult expert
Prior ARV use other than pMCTC ( >4wks) Consult expert
Currently on Rifampicin Interaction Defer ART or
with NVP use EFV if > 3yrs/10kg; use
PI if<3yrs
 DONT’S
 Never prescribe ARV drugs in absence of
adherence counseling and support
 Never prescribe mono or dual therapy for
treatment of HIV infection
 If ARVs are to be discontinued, stop all
drugs as instructed
 Never change a prescription unless it is
absolutely necessary.
 First Line Regimens
 1st Line
 AZT+3TC+ NVP

OR
 D4T+3TC+ NVP

 For those >3years and /or >10kg EFV can be

used instead of NVP

 Where anemia a problem and d4T syrup
cannot be used (requires refrigeration)
 Abacavir + 3TC + NVP/EFV
 2nd Line Regimens
AZT+3TC+ NVP/EFV ddI + ABC +LPV/r
(or NLF where fridge unavailable)

D4T+3TC+ NVP/EFV ddI + ABC + LPV/r

(or NLF where fridge unavailable)

ABC + 3TC + NVP/EFV ddI + AZT/d4T + LPVr

(or NLF)
 NRTIs I
Drug Formulation Dose Adverse Comments
effects
Stavudine Syrup 1mg/ml, 1mg/kg/dose BD Peripheral Reconstituted syrup
200ml; Max: Wt 30-60kg neuropathy; needs refrigeration </=
Caps 15, 30mg; Wt >60kg lipodystrophy 1mth;
20,30,40mg 40mg Not to be used with

FDCs AZT
No food restrictions

Dose adjustment in

Renal Failure
Lamivudine Oral solution 4mg/kg/dose BD, Well tolerated  Solution stable at-25
10mg/ml, 100mls, >12yrs or 60kg+ May be
0
C for </= 1mth
240mls; 150mg BD associated with No food restrictions

Tablets 150mg hepatitis Dose adjustment in

FDCs Renal Failure

Zidovudine Syrup 10mg/ml, Bone marrow No food restrictions

240ml; 240mg/m2/dose suppression Syrup stable at 15-25o x
Caps/Tab 100mg, BD; (anemia and/or 1mth
300mg; >12yrs, 300mg BD neutropenia) Not to be used with d4T
Inj. IV 10mg/ml, HIV Dose adjustment in
5ml; encephalopathy: Renal/Hepatic
FDCs 300mg/m2/dose Failure
BD
 NRTIs II
Drug Formulation Dose Adverse Comments
effects
Abacavir Oral solution 8mg/kg/dose Hypersensitivity 1.Not to be used in
20mg/ml, 240ml; BD, max reactions (i.e. children< 3mths
Tablets 300mg 300mg BD. rash, fever, GI 2.No food restrictions
Over 37.5kg or and RT
3.Educate
over 16 years: symptoms)
patient/carer re:
300mg BD hypersensitivity
reaction
3. DO NOT re-challenge
after reaction

Tenofovir Tabs 300mg 300 mg OD Well tolerated Not recommended in

FDC with Renal combination with
Emtricitabine impairment ddI
reported Take with meal
Didanosine Dispersible buffered 100-120 Pancreatitis Take on empty stomach
tablets mg/m2/dose Peripheral (>1/2 hour pre
25/100/200mg/400 BD neuropathy or> 2hour post
mg GI intolerance
meal)
Chewable/dissolved
in water/apple juice
 NNRTIs
Drug Formulation Dose Adverse Comments
effects
Nevirapine Oral Suspension 4mg/kg OD for RASH Store suspension at
10mg/ml, 100mls, 14 days, then Hepatoxicity
room temperature.
240ml 7mg/kg BD for Need to monitor LFTs
Tablets 200mg <8yrs. in first few months
For >8 years Educate patient/carer
4mg/kg BD max about rash.
200mg Auto induced
metabolism in the
first 2-4 weeks with a
2 fold increase in
clearance hence
higher dosing after 2
weeks.

Efavirenz Capsules CNS Avoid high fat meal

50mg/200mg/600m 10-14kg: 200mg, disturbances as increases
g 15-19kg: 250mg, Teratogenic absorption, drug
Syrup 30mg/ml., 20-24kg: 300mg; (DO NOT use in levels and side effects
180ml 25-32.5kg: pregnancy)
350mg 33- Hepatitis
39kg:400mg
> 40kg: 600mg
 PIs
Drug Formulation Dose Adverse Comments
effects
Ritonavir 100 mg capsule Now used GI Intolerance Used as PI booster.
Syrup 80mg/ml predominantly as a Taste perversion. Refrigeration required if solution
transaminases,
mini-dose for or caps kept for > 30 days
purposes of CPK uric acid
Class side effects Oral solution contains alcohol
“boosting” other 12%.
PIs

Lopinavir/r Capsules 7-15kg-0.15ml/kg GI Intolerance Refrigerate reconstituted

itonavir 133.3mg/33.3mg BD Taste perversion solution. Stable for 30
Oral solution 15-40kg- days.
(KaletraTM) Hepatitis
80mg/20mg per ml 0.125ml/kg BD Class side effects
Give with food. Moderate fat meal
> 40kg: 3 capsules increases bioavailability.
BD (400/100) Storage at <25OC for up to 2
months
Nelfinavir 250 mg capsules 55-75mg/kg/dose Diarrhea Food increases levels by 2-3X.
50mg/g oral BD, max 1250mg Class side effects Take with meals,
powder BD preferably high fat meal
Or 750mg TDS
Indinavir 200, 333, 400mg 800 mg TDS Kidney stones Separate from buffered ddI by
capsules OR (take >2litres 2hours
800mg with RTV fluid/day) Take on empty stomach (1 hr pre
Inc indirect or 2hr post meals)
BD
bilirubin No food effect when taken with
Class side effects RTV
 Monitoring Treatment
Why monitor ART?
 Adherence to treatment

 Treatment efficacy

 Toxicity

How do you monitor ART?

 Clinical

 Immunological

 Virological
Clinical Monitoring
 Initial ARV visit: family education
 Review understanding of HIV disease,
progression, adherence and adherence
strategies
 Request demonstration of accurate dosing
and administration of medication
 Return visit in a week
 Interval history, physical examination
including growth
 Clinical Monitoring
 Growth monitoring (weight, height, skull circ)
 Assess for new problems and treat any new
infections; (new OIs may indicate
deterioration)
 Review re: predictable toxicity
 Review medication and how administered
 Review adherence
Laboratory Monitoring
 Baseline tests and follow up according to
medication and recommended schedule to
assess for toxicity

 Efficacy
 Immunological (CD4 every 6 months)
 Virological (if possible every 6 months; due to
scarce resources may be limited to few patients –
e.g. where failure is suspected, adherence
questionable; CD4 response not as expected)
Laboratory Monitoring
 CD4 every 6 months (earlier if
indicated)
 CBC, LFTs in the first 3 months depends
on regimen (HB if on AZT; ALT if on
NVP as appropriate)
 Others as appropriate for toxicity or
inter-current illnesses
Changing/Stopping Treatment
Reasons for Changing/Stopping
Treatment
 Toxicity or intolerance (change/
substitute offending agent)
 Failure (change entire regimen)
 Co-morbidity/interactions
 Treatment interruption
 New and better regimens
Clinical Indications for Change
 Severe vomiting
 Bloody diarrhoea
 Unexplained fever
 Severe headache
 Allergic reaction
 Severe peripheral neuropathy
 Fatigue, reduced activity to 50%
 Laboratory Indications for
Changing ART
 Hb < 7gm/dl (if on AZT)
 Platelets < 49000 (AZT or cotrimoxazole)
 Neutrophils < 250
 Bilirubin 3-7x upper normal
 SGPT 10x upper normal
 Amylase, lipase: 2-3x upper normal
WHEN TO STOP
 Life threatening side effects or adverse
reactions
 Poor compliance
 Unsustainable supply of drugs
Failure
 Clinical Failure
 Progressive neuro-developmental
deterioration
 Growth failure despite adequate
nutritional support and with no other
explanation
 Disease progression (advance to
another clinical category
 Immunologic Failure
 Change in immune classification
 Persistent decline of 5 percentiles or
more (for children with <15% CD4)
 Rapid and extensive decrease in CD4
count
 Virologic Failure
 Less than minimally acceptable response after 12
weeks of suppressive therapy
 Triple combination = < 10-fold (1.0 log)

decrease from baseline

 Lack of suppression of HIV RNA levels to
undetectable by 6 months (depends on baseline
level, other issues)
 Repeated detection of HIV RNA after initially
achieving undetectable level
 Persistent rise in HIV RNA levels after a significant
and sustained decrease
 Why is Regimen Failing?
 Adherence
 Consider who administers
 How drug is administered
 Is drug appropriate, taste, vomiting, food
 Resistance
 3 or more drugs are needed to provide adequate
genetic barrier to resistance
 Sub-therapeutic levels provide selective pressure
for resistance
 Within days, resistance develops to NVP, EFV,
3TC if not taken appropriately
Adherence Issues
 Children depend upon adults to administer
drugs
 Adherence may be affected by stage of
development (spitting, vomiting, running
away)
 Providers need to teach families techniques of
giving medicine to young children
 Use of syringe for measurement and
administration.
 Crashing of meds
 Mixing in apple juice, other foods
 Opening of caps
 Repeat if vomited
Adherence Issues
 Drugs must be available in a palatable, liquid or
mixable formulations for infants/young children.
 Administering drugs with food or not with food can
be difficult because of children’s eating schedules.
 Children are dependent on caregivers for
administration.
 Families’ reluctance to disclose HIV diagnosis may
limit medication administration at daycare/school.
 Children’s developmental level influences ability and
willingness to take medications.
Group Work and Case Studies
Computing Total Lymphocyte
Count
 If WCC = 4.0 X 109/litre
 Differential count Lymph = 50%

What is the total lymphocyte count?

Give the TLC in two different units – per
litre and per mm3
Computing Total Lymphocyte
Count
Answer
 TLC = 50% of 4.0 x 109

2.0 x 109 /litre

Divide by 106 to convert TLC to per mm3

Above example,
TLC = (2.0 x 109) / 106 = 2,000/mm3
Computing CD4%
CD4% = Absolute CD4 count per mm3 x 100
Total lymphocyte count per mm3

OR = Absolute CD4 count per litre x 100

Total lymphocyte count per litre