Ppediatric hiv june06

Module 7: Paediatric HIV, KMA

Management of HIV infected Children

KMA CurriculumModule 7June 2006


Objectives To outline the epidemiology of HIV in children To describe various modes of HIV transmission to

children. To discuss the natural disease progression of HIV in

children. Outline diagnostic criteria for paediatric HIV –

laboratory as well as clinical. To impart knowledge on prevention and treatment of

common HIV related conditions in HIV infected children

To describe how and when to provide antiretroviral therapy in children, , including initiation, pre-ART preparation, monitoring, when to change/withdraw ART.


Epidemiology and HIV transmission in Children

Unit 1Management of HIV infected

Children


Epidemiology - Kenya 1 million live births in Kenya annually 8% born to HIV infected mothers Without PMTCT 30% of these become

infected About 24,000 neonates acquire HIV

annually About 12,000 (50%) die within first 2 years HIV has had a negative impact on infant

survival


Modes of HIV transmission to Children

Mother to child transmission – 95% of paediatric infections Intrauterine During delivery During breastfeeding


Mother to Child HIV Transmission

30% babies born to HIV+ womenbecome infected through MTCT

5% intrauterine

10-20% during delivery

10-20% via breastfeeding


Modes of HIV transmission to Children

Horizontal transmission - < 5% of paediatric infections Sexual transmission Transfusion of blood and blood products Exposure to other body fluids Use of contaminated needles and other

skin piercing/cutting instruments (circumcision, uvulectomy).


Natural history of HIV in Children

Unit 2:Management of HIV infected

Children


Natural history – patterns of disease progression in African children

HIV disease progresses at differing rates in children

Rapid progressors (25 – 30%): Develop AIDS and die within 1-2 years. Disease acquired in utero or perinatally.

Intermediate progressors (50 – 60%): Children who develop symptoms early in life. Deteriorate and die by 3 to 5 years.

Slow progressors (5 – 25%): Long-term survivors who live beyond 8 years of age.


Natural history – patterns of disease progression in African children

Slow Progressors Low viral loads at birth Stable CD4 counts for 2-

10 years Growth stunting Initial year(s) well,

opportunistic infections as disease progresses

Encephalopathy rare

Rapid Progressors High viral load at birth Rapidly declining CD4 Low Birth Weight Chronically unwell first

year Persistent or recurrent

diarrhea Recurrent bacterial and

fungal infections Severe encephalopathy

before 18 months


Natural History – Immunological changesImmunologic Parameters Absolute CD4 count higher in healthy

children than in adults. Absolute CD4 count declines steadily

during the first 5 yrs in healthy children to achieve adult levels by age 6

CD4 percentage does not change with age.

In children < 6 yr CD4 percentage is the preferred immunological parameter for monitoring disease progression.


Natural History – Immunological changes

Age-related Decrease in CD4+ Number

0

2000

4000

6000

Age in Months

CD

+ N

umbe

r/m

m3

5th percentile

95th percentile

4 12 24 6090


Natural History – Immunological changes

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 – Viral load patterns in children

The HIV viral load (RNA) pattern in perinatally infected infants differs from infected adults.

Among infants infected before the age of 1 month:

Viral load (RNA) levels are zero or low at birth.

Increase to high levels above 100,000 copies/ml by 3-6 months of age.

Thereafter RNA declines slowly over several years to “set point”.


Clinical signs & conditions suggestive of HIV infection in a child

Very specific for HIV infection: Oesophageal candidiasis Herpes zoster (shingles) Pneumocystis carinii pneumonia Extrapulmonary cryptococcosis Kaposi’s sarcoma



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



Common in both HIV+ and HIV- children

Otitis media - persistent or recurrent Diarrhoea – persistent or recurrent Severe pneumonia Tuberculosis Failure to thrive Persistent dermatitis


Diagnosis and Staging of HIV in Children


Children


DIAGNOSIS OF PEDIATRIC HIV


Clinical DiagnosisIMCI definition of symptomatic HIV

infectionPresence 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 < 3rd 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.


Laboratory DiagnosisChild < 18 monthsChild < 18 months, HIV Ab may come from: Maternal Ab passively transferred to infant

maternal Ab may persist in her infant up to 18 months

so Ab test is +ve in ALL children born to HIV+ women, including those that are NOT infected (gives false +ve results)

Infant generated Ab if infant is HIV infected.

A positive HIV Ab test at this age is therefore not diagnostic, only shows child has been HIV exposed


Laboratory DiagnosisChild < 18 months Need to do Virologic test – detect HIV virus

in blood

Various types:- RNA PCR - most available, also gives viral load- DNA PCR – not widely available- P24 antigen (immune-complex dissociated)

When to do virologic test: 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.


Diagnosis – combining lab and clinical criteria May not have access to PCR as is

not widely available or affordable. You can still make a diagnosis in

child < 18 months combining simple lab and clinical parameters.


HIV Diagnosis before age 18 mth without virologic test

Must fulfil the following 3 criteria: WHO stage 3 or 4

PLUS HIV ELISA positive (child or mother)

PLUSCD4 < 25% (or CD4 count < 1500)(OR TLC < 3400)


Diagnosis

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

antibodies have cleared


DIAGNOSIS - summary In children < 18 months 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.


STAGING PEDIATRIC HIV


Clinical Staging

TWO international clinical staging systems:

World Health Organisation (WHO)Four stages – 1, 2, 3, 4

Centres for Disease Control (CDC)Four stages – N, A, B, C


Disease Staging Limitations of Staging Systems

WHO Does not include immunological Does not capture some diagnoses

CDC Assumes availability of advanced

diagnostic technology Some conditions seen in resource-limited

settings not included


Clinical Staging

Stage WHO CDC

Asymptomatic 1 N

Mild 2 A

Moderate 3 B

Severe (AIDS) 4 C


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


WHO Clinical Staging – stage 1

Stage I Asymptomatic Persistent generalized

lymphadenopathy (PGL) Hepatosplenomegaly


WHO Clinical Staging - stage 2

Papular pruritic eruptions Seborrheic dermatitis Fungal nail infections Angular cheilitis Linear gingival erythema Extensive HPV or molluscum infection (>5% of

body area/face) Recurrent oral ulcerations (>2 episodes/g mos) Parotid enlargement Herpes zoster (>1 episode/12 mos) Recurrent or chronic upper respiratory infection

(URI): otitis media, otorrhea, sinusitis (>2 episodes/6 mos)


WHO Clinical Stage 2

Mild conditions of the: Skin - Papular pruritic eruptions,

seborrheic dermatitis, fungal nail infections

Upper resp tract Mouth


WHO Clinical Staging – Stage 3 Unexplained moderate malnutrition (-2SD

or Z score) not responding to standard therapy

Unexplained persistent diarrhea (>14 days) Unexplained persistent fever (intermittent

or constant, > 1mo) Oral candidiasis (outside neonatal period) Oral hairy leukoplakia Pulmonary tuberculosis Severe recurrent presumed bacterial

pneumonia (>2 episodes/12 mos)


WHO Clinical Staging – Stage 3 (continued) Acute necrotizing ulcerative

gingivitis/periodontitis Lymphoid interstitial pneumonitis (LIP) Unexplained anemia (<8g/dL),

neutropenia (<1000/mm3), or thrombocytopenia (<30,000/mm3) for >1 mo.

HIV-related cardiomyopathy HIV-related nephropathy


WHO stage 4 – all agesConditions where a presumptive diagnosis can be made using

clinical signs or simple investigations: Unexplained severe wasting or severe malnutrition not

adequately responding to standard therapy Pneumocystis pneumonia Recurrent severe presumed bacterial infections (2 or >

episodes within one year e.g. empyema, pyomyositis, bone or joint infection, meningitis, but excluding pneumonia )

Chronic orolabial or cutaneous Herpes simplex infection (of more 1 month duration)

Extrapulmonary tuberculosis Kaposi's sarcoma Oesophageal Candida CNS Toxoplasmosis HIV encephalopathy


WHO stage 4 – all ages (continued)Conditions where confirmatory diagnostic testing is

necessary: CMV infection (CMV retinitis or infection of organ other

than liver, spleen, or lymph nodes onset at age 1 month or more)

Cryptococcal meningitis (or other extrapulmonary disease)

Any disseminated endemic mycosis(e.g. extra-pulmonary Histoplasmosis, Coccidiomycosis, Penicilliosis)

Cryptosporidiosis Isosporiasis Disseminated non-tuberculous mycobacteria infection Candida of trachea, bronchi or lungs Acquired HIV related recto-vesico fistula


WHO – Stage 4: Child < 18 mths - when PCR testing not availablePresumptive Stage 4 diagnosis in children less than

eighteen months old where virological confirmation of infection is not available

Symptomatic HIV-antibody positive infant age < 18 mos with two or more of the following:

Oral candidiasis/thrush Severe pneumonia Severe wasting/malnutrition Severe sepsisSevere immunosuppression should be suspected and ARV

treatment is indicated CD4 values where available should be used to guide decision

making CD4 below 24% requires urgent ARV treatment Other factors that support the diagnosis of clinical stage 4 HIV

infection in an HIV seropositive infant are recent maternal death or advanced HIV disease in mother.


Immunological Staging Differences in CD4 counts between

adults and children


Immunological Staging Using Absolute CD4 count

Immune category < 12 monthsCD4 counts

1-5 yearsCD4 counts

6-12 yearsCD4 counts

1: Not immunosuppressed

> 1500 > 1000 > 500

2: Moderately immunosuppressed

750-1,499 500-999 200-499

3: Severely immunosuppressed

< 750 < 500 < 200


Immunological Staging Using CD4 percentage

Immune category < 12 monthsCD4 %

1-5 yearsCD4 %

6-12 yearsCD4 %


> 25% > 25% > 25%


15-24% 15-24% 15-24%


< 15% < 15% < 15%


CDC Immunological staging

Immune category

< 12 monthsCD4 countsCD4 percentage

1-5 yearsCD4 countsCD4 percentage

6-12 yearsCD4 countsCD4 percentage


> 1500> 25%

> 1000> 25%

> 500> 25%


750-1,49915-24%

500-99915-24%

200-49915-24%


< 750< 15%

< 500< 15%

< 200< 15%


Total Lymphocyte Count Where cannot perform CD4 assays,

TLC provides a rough guide to level of immunosuppression.

This is only useful for baseline evaluation for immunosuppression.



Relationship between CD4 and Lymphocyte count (TLC)

Age CD4 Lymphocyte count/mm3

(Lymph count/litre)

< 18 mo < 20 % < 3400/mm3

(< 3.4 x 109/l)

18mo-5yr

< 15 % < 2300/mm3

(< 2.3 x 109/l)

6 yrs or more

< 15% or CD4 count < 200

< 1200/mm3

(< 1.2 x 109/l)


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


Computing Total Lymphocyte Count

TLC = Lymphocyte percentage per litre x 100

White cell count per litre

TLC = Lymphocyte percentage per mm3 x 100

White cell count per mm3


HIV – Related Conditions:Prevention and Treatment


Children


Vaccination concerns in child with HIVBroad concerns include, is the child able: To mount an effective immune response to the

vaccine? To sustain their immune response as CD4

declines? Do they require re-vaccination after CD4 is

restored following successful antiretroviral therapy?

Safety of live vaccines - can live vaccines result in severe vaccine-associated disease in immunocompromised individuals?


World Health Organization/UNICEF recommendations

For the Immunization of HIV-infected children and women

of childbearing age


Vaccine Asymptomatic HIV

Symptomatic HIV

Optimal timing of immunization

BCG yes no birth

DPT yes yes 6,10,14 wks

OPV* Yes Yes 0, 6,10,14 wks

Measles Yes Yes 6 and 9 months

Hepatitis B

Yes Yes As for uninfected children

Yellow fever

Yes No**

Tetanus toxoid

Yes Yes 5 doses***

* IPV an alternative for children with symptomatic HIV** Pending further studies*** 5 doses TT for women of child-bearing age


HIV-related Diseases

Infections that complicate HIV disease in children include:

Infections that are commonly seen even in HIV uninfected children

Opportunistic infections rare in HIV negative children more common with advancing immune

compromise.


HIV-related Diseases (cont) Other clinical problems not

commonly seen in other children Lymphoid interstitial pneumonitis Malignancies HIV encephalopathy


Pneumocystis Pneumonia Caused by a fungus, Pneumocystis jiroveci*, that

is commonly found in the environment Commoner under the age of 1 year and in

severely immunosuppressed children Clinical presentation:

Usually less than 1 year Tachypnoea Dyspnoea Low grade fever or afebrile Cough Hypoxemia (paO2 < 90%) Clear chest or fine crepitations Poor response to standard antibiotics


Investigations

Chest X-ray: hyperinflation, diffuse infiltrates or may be normal

Sputum induction or nasopharyngeal aspirate, stained with Silver or Immunofluorescent stain

Bronchoalveolar lavage washing stained as above


PCP Treatment

Cotrimoxazole I.V (or oral if IV not available) Trimethoprim (TMP): 4 mg/kg/dose qid Sulphamethoxazole (SMX): 20mg/kg/dose

qidOR

IV Pentamidine 4mg/kg/day ODDuration of treatment: 3 weeks

Add prednisone 2mg/kg for 7-14 days in severely ill children (taper off)


Prevention of PCP PCP prevented by cotrimoxazole Co-trimoxazole prophylaxis

All children born to HIV infected women should receive CTZ prophylaxis from age of 6 weeks till HIV is ruled out.

Those confirmed to be HIV infected should continue CTZ prophylaxis indefinitely.

Dose 25mg SMX / 5mg TMP per kg o.d. (30mg cotrimoxazole/kg o.d.)


Candidiasis Oral candidiasis a frequent OI May extend to oesophagus and

disseminate when CD4 severely depressed

Oesophageal candidiasis assoc with difficulty in swallowing/dysphagia


Treatment of CandidiasisOral thrush: Clotrimazole mouth paint 10-20 drops p.o

qid 7 days (after feeds) or until thrush clears.

Or clotrimazole 10 mg troches (older children only)

Or: 0.25%-0.5% gentian violet solution 2% miconazole gel, 2.5 ml (young child) or

5 ml (older child) two times a day


Treatment of Candidiasis

Oesophageal candidiasis: Oral ketoconazole , 3-6mg/kg/day for

7 days OR Oral fluconazole 3-6 mg/kg/day for 2-

3 weeks or until resolution of symptoms.


Antiretroviral Therapy in Children


Children


Antiretroviral Therapy

Will cover the following: Indications for ART initiation National ART Regimens Monitoring Indications for change or withdrawal of

ART National second line regimens ART and tuberculosis


Criteria for ART Initiation

There are two broad criteria to consider prior to ART initiation

Medical criteria

Psychosocial criteria


Criteria for ART InitiationMedical criteria WHO stage 3 or 4 disease (irrespective of CD4 counts or

%). Low CD4 count or percentage as follows (irrespective of

WHO stage): Child < 18 months – CD4 < 25% or absolute CD4

count < 1500 Child 18 months to 5 years – CD4 < 15% or absolute

CD4 count < 500 Child older than 5 years – CD4 < 15% or absolute

CD4 count < 200 Recurrent hospitalizations (> 2 admissions in previous

year) for HIV-related disease, or prolonged hospitalization (> 4 weeks) in previous year.


Criteria For ART InitiationPsychosocial criteria An identifiable parent or guardian who is able

to understand the regimen, and consistently administer the child’s medication.

Adolescent – disclosure of HIV diagnosis before ART initiation recommended where possible

Ability to regularly attend the HIV clinic appointments.

Sustainable long-term access to antiretroviral drugs (either through programs providing ART, or financially able to purchase ARV drugs).


Preparing a Child for ART

Prior to initiating ART, the following preparations should take place

Medical Preparation

Counseling Preparation


Preparing a Child for ART (2)Medical Preparation Baseline tests to check haematological,

liver and kidney function: Full blood count (resources limited, do Hb) Liver function tests (resources limited, do

alanine transaminase or ALT) Renal function tests (resources limited, do

serum creatinine) Do baseline CD4 if possible Do baseline viral load (RNA PCR – this is

optional if resources limited)


Preparing a Child for ART (3)Medical Preparation (continued) Baseline clinical assessment including

weight, height, surface area. If current TB suspected, investigate for

TB (If TB confirmed, consider delaying ART initiation)

Initiate co-trimoxazole prophylaxis (as in module 5)

Treat any inter-current illnesses


Prior to starting ARV in childrenStart in haste, repent at leisure!!Starting ART is never an emergencyTake time to counsel, prepare, educate the

familyCounsel the caregiver on: Cost – drugs, monitoring tests, food security Adherence to therapy – strict time scheduling Support, support, support. Child can’t do it

alone. Older child – disclosure to childDo careful social assessment of family situation

prior to starting therapy.


Goals of ARV Therapy Maximal and durable

suppression of HIV replication. Restoration and preservation

of immune function. Reduce HIV related Morbidity

& Mortality. Improve quality of life.


Special Considerations for Children and ARVsChoose drugs that: Do not have to be timed around meals Have acceptable taste Suspensions/syrups are stable at room

temperature if patient does not own a refrigerator.

Children older than 6 years may take tablet and capsule formulations

Some capsule formulations may be opened and capsule content mixed with food or drink.

Some chewable tablets may be crushed and mixed with food or drink.


Types of Antiretroviral Drugs

1. Nucleoside reverse transcriptase inhibitors (NRTI)

2. Non-nucleoside reverse transcriptase inhibitors (NNRTI)

3. Protease inhibitors (PI)


Kenya national recommended 1st line ART in childrenAlways give three drugs (triple therapy). National first line regimen – use 2 nucs and 1 non-nuc

Age < 3 years Zidovudine (ZDV) + Lamivudine (3TC) + Nevirapine

(NVP)

Age > 3 years ZDV + 3TC + Efavirenz (EFV) or NVP.

These can be taken with or without food, taste is acceptable, and all are stable at room temperature.

If child very anaemic, ZDV may be substituted by stavudine (D4T)


First line regimen in NVP-exposed child

Child exposed to single dose nevirapine for PMCT may have NVP resistant virus. Avoid non-nucs in their 1st line regimen

AZT (or d4T) + 3TC + Kaletra


ART and TuberculosisRifampicin interacts with nevirapine and most

protease inhibitorsIf possible, complete anti-TB therapy before ART

initiation. If child too sick to wait, and anti-TB therapy must

be given with ART use the following regimen: Child < 3 yr – Replace NVP with abacavir. After

completing anti-TB therapy revert to NVP Child > 3 yr – Two NRTIs with efavirenz


Dosages of ARV drugs Many are calculated using surface area S.A = sq root of ([wt x ht] / 3600) Others calculated using weight for age Failure to compute dosage correctly

leads to under- or over-dosing Suboptimal dose – resistance Overdose – toxicity


Clinical Monitoring Clinical response – anthropometry, physical

exam at every visit Symptoms improving, static, deteriorating? Growth (weight, height) General well-being

Clinical signs of specific adverse effects (depend on class of drugs)


Laboratory Monitoring Response to therapy

CD4 every 6 months (expect rise within 6 months)

Viral load at baseline, month 3 then every 6 months if affordable (aim at 5-fold drop by 8-12 weeks)

Adverse effects FBC, SGPT/ALT at baseline, month 1, then 3

monthly or as appropriate Others (lipids, glucose etc) as appropriate

for toxicity or inter-current illnesses


When to change or stop ART

1. Toxicity – replace only the offending drug

2. Treatment failure – replace all 3 drugs

3. Poor adherence – if cannot rectify, withdraw ART


When to change ART

Toxicity – replace offending agent only with equivalent drug

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


Indications for change of therapy – treatment failure

FIRST CHECK ADHERENCE!!

Clinical indications Progressive neurodevelopmental

deterioration Growth failure Disease progression – move from

one stage to next


Indications for change of therapy – treatment failure

Immunological indications For kids with CD4 below 15%,

decline of ≥ 5 percentile points Rapid decline in absolute CD4

count (loss of > 1/3 of CD4 cells in < 6 months)


Indications for change of therapy – treatment failureVirological indications

Persistent increase in viral load (confirmed by 2 tests)


Second line therapy – factors to consider Change ALL 3 DRUGS. Include a Protease inhibitor. Replace the NRTIs with two new NRTIs Replace the NNRTI with a PI IF initial problem was adherence to

therapy, must address this first. If can’t best to just withdraw therapy altogether


Kenya national recommended 2nd line ART in children

First line ZDV/3TC/NVP or

EFV

d4T/3TC/NVP or EFV

ZDV/3TC/Kaletra

Second line ddI/ABC/LPV/r or

ddI/ABC/NFV

ddI/ABC/LPV/r or NFV

ddI/ABC/PI/ritonavir


When To Stop/withdraw ART.

ART should be withdrawn in the following situations:

Severe adverse effects (lactic acidosis)

Intolerability, inability to take drugs. Poor adherence Interruption of drug supply Patients wish.


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

Ppediatric hiv june06

Health & Medicine

hiv ab

epidemiology of hiv

staging of hiv

child hiv transmission

african children hiv

natural history of hiv

hiv infected mothers

first2 years hiv