Module 3

Unit 4: HIV and ART in Children

OBJECTIVES Describe the epidemiology and natural history of

HIV in infants and children Describe how to diagnose paediatric HIV infection Describe the staging of paediatric HIV infection Discuss the use of ART in pediatric population

including: When to start treatment When to stop treatment Monitoring therapy Adherence and support

Epidemiology 1 million live births in Kenya annually 10% born to HIV infected mothers Without PMTCT 30% of these become

infected About 20,000 neonates acquire HIV

annually About 10,000 (50%) die within first 2 years HIV has made a huge impact on infant

mortality

Epidemiology - Transmission

> 90% pediatric HIV infection acquired from HIV positive mothers through vertical transmission and breast feeding. (Mother to child transmission –MTCT) Transmission occurs in 25-30% infants born

to mothers with HIV infection 5% - intrauterine 10-20% - during delivery 10-20% - breastfeeding

Epidemiology - Transmission

Factors facilitating MTCT Maternal disease status

High viral load/low CD4 count Maternal acquisition of HIV in

pregnancy or lactation Vaginal infections, chorioamnionitis

Epidemiology - Transmission

Factors facilitating MTCT Labor

Prematurity Prolonged/difficult Duration of membrane rupture

>4hours/PROM Invasive monitoring and procedures

Epidemiology - Transmission Factors facilitating MTCT Infant feeding

Prolonged breast feeding Breast health – sore

nipples/abscesses/mastitis Mixed feeding. Exclusive BF for 3-6 months

results in no excess transmission compared to formula feeding alone

Exclusive BF = BF only without additional fluids, water, food, teats or pacifiers AND no demand feeding

Oral thrush in breast fed infant

Epidemiology - Transmission Other routes of transmission

Contaminated needles and instruments

Transfusion of blood and blood products

Hemophiliacs Sicklers

Sexual

Natural History Of HIV Infection

Natural History Viral transmission Acute retroviral syndrome

High plasma viremia and rapid CD4 decline Seroconversion with recovery

Development of immunity Rapid decline in viremia and slowing down of CD4 cell

loss Asymptomatic chronic HIV infection

Continuing CD4 loss depends on plasma viral load Symptomatic HIV infection/AIDS

Increasing viremia Rate of CD4 decline increases

Death

NATURAL HISTORY

In uninfected children Absolute CD4 counts

high in young children

Decline to adult levels by 6 yrs

CD4% does not change much with age

Age-related Decrease in CD4+ Number

0

2000

4000

6000

Age in Months

CD

+ N

um

ber/

mm

3

5th percentile95th percentile

4 12 24 6090

Age-related Decrease in CD4+ Percentage

0

20

40

60

80

Age in Months

CD

4+ % 5th percentile

95th percentile

4 12 24 6090

Natural History In HIV infected children

Low viral loads 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”

Infants < 12 months with very high viral loads (>100,000) may be at high risk for disease progression and death

Predictive value of VL not good in young infants Much overlap with rapid and non-rapid progressors Evaluate CD4+ counts and percentages as well

Very high HIV RNA levels may be correlated with disease progression and death.

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

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 Failure to thrive

(FTT), wasting syndrome

Developmental delay or regression

Recurrent bacterial infections

TB Chronic fever and

diarrhea

Infective and non-infective dermatoses hair changes

Generalized lymphadenopathy, hepato-splenomegally

Parotid enlargement Unexplained organ

disease affecting the heart, kidney, liver, brain and bone marrow (hematological)

World Health Organization Clinical Staging for Pediatric HIVStage I (mild)

Asymptomatic, or persistent generalized LN

Stage II (moderate) Unexplained, chronic diarrhea (> 1 month) Severe, persistent, or recurrent candidiasis

outside the neonatal period Weight loss or FTT Persistent fever (> 1 month) Recurrent severe bacterial infections

WHO Clinical Staging

Stage III (severe) AIDS defining OI (PCP, TB, Crypto, CMV

etc) Wasting syndrome (severe FTT) Progressive encephalopathy Malignancy Recurrent septicemia or meningitis

CDC Classification (staging) of Pediatric HIV Infection

Category

Disease

N Not symptomatic (or only One category A condition)

A Mildly symptomatic with 2 or more of following:LymphadenopathyHepatomegalySplenomegalyDermatitisParotitisRecurrent or persistent URTI, sinusitis or otitis media

Category(CDC)

Disease

B Moderately symptomaticDiarrhoea, recurrent or chronicBacterial infection – pneumonia, meningitis, sepsis (1 episode)Fungal infection - Oropharyngeal candidiasisViral infection – CMV, Herpes simplex (stomatitis, bronchitis, pneumonitis, esophagitis), Herpes zoster, disseminated VaricellaOther OI – Toxoplasma before 1 month, NocardiosisMajor organ dx – Cardiomyopathy, nephropathy, hepatitis.Persistent fever > 1 monthLymphoid interstitial pneumonia

C Severely symptomatic – AIDS defining conditionsHIV wasting diseaseEsophageal candidiasisDisseminated or extrapulmonary tuberculosisHIV encephalopathyCryptococcal meningitis, CryptosporidiosisLymphomas, Kaposis sarcoma

Clinical category

(CDC)

Diagnosis

C(Continued)

Severely symptomatic:Multiple recurrent severe bacterial infectionEsophageal or pulmonary candiadiasisDisseminated coccidioidomycosisExtra pulmonary cryptococcosisCryptosporidiosis or isosporiasisCMV infection > 1 month of ageDisseminated histoplasmosisKaposi’s sarcomaPrimary lymphoma of the brainBurkitt’s or immunoblastic lymphomaDisseminated or extrapulmonary tuberculosisDisseminated other or unspecified mycobacteria sp.Disseminated Mycobacteria aviumPneumocystis carinnii pneumoniaHerpes simplex virus infection > 1 month of ageProgressive multi focal leucoencephalopathy Recurrent salmonella (nontyphoidal) septicemiaToxoplasma of the brain (> 1 month of age)Wasting syndrome

IMMUNOLOGIC STAGING

Immune category

< 12 months

CD4 countsCD4

percentage

1-5 yearsCD4 counts

CD4 percentage

6-12 yearsCD4 counts

CD4 percentage

Category 1:Not immunosuppressed

> 1500> 25%

> 1000> 25%

> 500> 25%

Category 2:Moderately immunosuppressed

750-1,49915-24%

500-99915-24%

200-49915-24%

Category 3:Severely immunosuppressed

< 750< 15%

< 500< 15%

< 200< 15%

CDC - Pediatric HIV Staging

Stage N1 – Asymptomatic, not immunosuppressed (early disease)

Stage A2 – Mildly symptomatic, moderately immunosuppressed

Stage C3 – Severely symptomatic, Severely immunosuppressed (AIDS, Acquired immunodeficiency syndrome)

DiagnosisBefore age 18 months (Maternal antibodies cause positive results in all

infants born to HIV positive mothers) Need to identify virus – usually not possible

HIV DNA PCR HIV RNA PCR P24 antigen- variable sensitivity

Not BF: test at age 1 month repeat 3 months later BF: wait until 3 months after cessation of BF to

confirm final HIV status. Clinical diagnosis

Mother HIV positive + WHO III + CD4<15

Diagnosis

After 18 months: HIV ELISA antibody test By 18 months, maternal

antibodies have cleared

DIAGNOSIS - summary In infants HIV is diagnosed by 2 positive

virological tests performed on blood samples taken on 2 separate dates.

HIV is excluded by 2 or more negative virological tests at >age 1 month, one of which is performed at age >4 months in a non-breastfed infant

If BF wait 3 months after cessation of BF

Antibody tests: 2 or more antibody tests after 18 months confirm or exclude diagnosis.

Antiretroviral Treatment General Concepts

Early recognition and diagnosis of complications results in early treatment and better outcomes for patients

Knowledgeable providers assist in prevention and recognition of complications

Timely intervention with ART results in better clinical outcomes

ARV prescription requires careful assessment and preparation, followed by consistent support

ART General Concepts Ongoing HIV replication leads to immune

system damage Timely ART, before onset of severe

immunosuppression results in better clinical outcomes

ARV prescription requires careful assessment and preparation, followed by consistent support

Adherence to treatment is essential in order to achieve intended goals

Pretreatment Assessment

Goals: Determine if patient needs treatment Ensure safety of ART Rule out underlying problems that

may impact on treatment Treat any active OI’s Prepare patient for treatment

Pretreatment Assessment Clinical and laboratory assessment Preparation of patient should include

Assessment as to whether patient ready and able to start and continue long term treatment

Home environment, lifestyle, social and financial situation

Proximity to treatment centre and any local health care networks

Parental and child readiness Availability and suitability of formulations Cost and affordability Psychosocial and family support Disclosure Adherence assessment

Pretreatment AssessmentInformation to ensure patient

adherence:

Need lifelong treatment even when they may feel well

Expected benefits Potential side effects of (proposed) treatment Necessity for regular follow up to monitor

progress and toxicity Adherence and relation to outcome Drug resistance and consequences Adjusting to changes in living pattern Medication not to be shared Point of contact if needed

CONSIDERATIONS Stage of development Dosing frequency Side effects Co-infections Meal requirements Storage requirements

Never… Never prescribe ARV’s in absence of

adherence counselling and support Never prescribe mono or dual therapy

for treatment of HIV infection If ARV’s are to be discontinued, stop

all drugs as instructed Never change a prescription unless it

is absolutely necessary.

OTHER CONSIDERATIONS Cautions when ART considered in

patients with: Severe anaemia < 6.9gm/dl Severe thrombocytopaenia Severe neutropaenia Renal insufficiency Hepatic insufficiency

History of prior ARV use Current anti-TB medications

ARV Drugs Special considerations in children

Children >3yrs may take tabs/caps formulation

Some caps may be opened and mixed with food/drink for even younger children

Chewable tablets may be crushed and mixed with food or drink

When to Start: < 18 months

PCR available and positive

WHO Stage I or II – CD4%<20%

WHO Stage III – regardless of CD4

When to Start: < 18 months

PCR unavailable, CD4 available

Start if CD4<20% plus clinical stage III

In absence of CD4/PCR

Continue Cotrimoxazole prophylaxis Wait till 18 months when antibody test can be

used

When to Start: >18 months

WHO stage III/CDC stage C Regardless of CD4

WHO Stage I or II - CD4 <15% Absolute CD4 count <200

In children over 6 years (CD4 counts similar to adults at this age)

INITIAL REGIMENS

Stavudine+

Lamivudine+

Nevirapine

Zidovudine+

Lamivudine+

Nevirapine

or

NB: Stavudine syrup is unstable at room temperature. If a liquid needs to be used, and no

refrigeration at home, use AZT

When to Stop/Change Toxicity – replace offending agent with equivalent drug Failure

Immunological CD4 decline > 5 percentile points Rapid decline in CD4 count – >1/3 in less than 6 months

Virological (Usually unavailable) Failure to suppress viral load at 8-12 weeks by at least 5

fold Failure to achieve below assay detection limit by 24 weeks Increase in VL from previously suppressed level (by at

least 3-5 fold)

Clinical deterioration (progression in the clinical stage)

Other – new treatment/formulations; patient/parent reasons

Toxicity Hb < 7gm/dl Platelets < 49,000 Neutrophils < 250 Bilirubin 3-7x upper normal SGPT 10x upper normal Amylase, lipase: 2-3x upper

normal

2nd LINE REGIMES

If 1st line is AZT+3TC+NVP

Change to:

d4T+ddI+LPV/r Or

d4T+ddI+NFV

If 1st line is d4T+3TC+NVP

Change to:

AZT+ ddI+ LPV/rOr

AZT + ddI+NFV

WHY REGIMENS CAN FAIL Poor Adherence

Consider who administers How drug is administered Is drug appropriate, taste, vomiting, food

Resistance: One or 2 drug resistance mutations exist at

baseline by chance 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

CLINICAL FAILURE - Progressive neuro-

developmental

deterioration

- Growth failure despite

adequate nutritional

support and with no

other explanation

- Disease progression

(advance to another

clinical category)

WHEN TO STOP Life threatening side effects or

adverse reactions Poor compliance

MONITORING required Clinical Laboratory Treatment adherence Appointment adherence

MONITORING-check list Initial ARV visit: family education

Review understanding of HIV disease progression, adherence

Request demonstration of accurate dosing and medication administration

Return visit in a week Interval history, physical

examinations including weight and growth

Laboratory Monitoring CD4 every 6 months (earlier if

indicated) FBC, SGPT/ALT 3 monthly or as

appropriate Others as appropriate for toxicity

or inter-current illnesses

Adherence Issues to Consider

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 Crushing of meds Mixing in fruit juice, other foods Opening of capsules Repeat dose if vomited