Paediatric HIV MSD 2010

Overview

Epidemiology Paediatric disease progression Diagnosing HIV in children Clinical Staging (WHO) Common Signs and Symptoms

Western & Central Europe

13001300[<1000 – 1800][<1000 – 1800]

Middle East & North Africa26 00026 000

[18 000 – 34 000][18 000 – 34 000]Sub-Saharan Africa

1.8 million1.8 million[1.7 – 2.0 million][1.7 – 2.0 million]

Eastern Europe & Central Asia

12 000 12 000 [9100 – 15 000][9100 – 15 000]

South & South-East Asia

140 000140 000[[110 000 – 180 000110 000 – 180 000]]Oceania

11001100[1200][1200]

North America4400

[2600 – 7300]

Latin America44 00044 000

[37 000 – 58 000][37 000 – 58 000]

East Asia78007800

[5300 – 11 000][5300 – 11 000]Caribbean

11 000[9400 – 12 000]

Children (<15 years) estimated to be living with HIV, 2007

Total: 2.0 million (1.9 – 2.3 million)

Paediatric HIV/AIDS

More than 95% of HIV-infected children in Africa acquire HIV through MTCT

HIV infection in foetus and newborn occurs in the setting of an immature immune system

Feeble immune responses to HIV

More rapid and extensive virus replication than in older hosts

More rapid disease progression

Viral load in adults

Plasma HIV RNA levels in Adults

1

100

10000

1000000

1 2 3 4 years 1 2 3

Months/Years

Vir

al lo

ad n

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mL

(lo

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Viral load in children

Plasma HIV RNA levels in Infants

110

1001000

10000100000

1000000

1 2 years 2 2.5 3Months/Years

Vir

al lo

ad n

o. o

f co

pie

s/m

L (l

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)

Disease Progression in Children

age < 2 years

age 3-10 years

•50% of all perinatally infected children will die before 2 years of age – “rapid progressors”

•Half will die between 3 and 10 years of age – “slow progressors”

•A child that presents early (< 1 year of age) is more likely to die quickly

Laboratory diagnosis of HIV

Antibody tests (lab Elisa, rapid tests) can be reliably used in children > 18 months old

PCR testing is reliable from 6 weeks of age, if the baby has not been breastfed for the preceding 6 weeks• On whole blood

• On Dry Blood Spots

Absolute CD4 Count vs. CD4%

CD4 count - higher in infancy than adulthood and variable

CD4 percentage remains constant

CD4 percentage correlates with disease progression in children

CDC Immunological Classification for human immunodeficiency virus infection

in children less than 13 years of age. MMWR 1994;43.

AGE OF CHILD

<12 MONTHS 1-5 YEARS 6-12 YEARS

IMMUNOLOGICAL CATEGORY

CD4+/ul CD4+ % CD4+/ul CD4+% CD4+/ul CD4+ %

1. No Immunosuppression

> 1500 > 25 >1 000 > 25 > 500 > 25

2. Moderate Immuno-suppression

750–1499 15–24 500–999 15–24 200-499 15 –24

3. SevereImmuno-suppression

< 750 < 15 < 500 < 15 < 200 < 15

Revised WHO Clinical Staging of HIV/AIDS for Infants and Children

‘HIV-infected’ ‘AIDS’

Stage 1Asymptomatic

Stage 2Mild disease

Stage 3Advanced

Stage 4Severe

WHO Clinical Stage 1

Asymptomatic Persistent generalized lymphadenopathy

(PGL)

Lymphadenopathy

Significant lymph node enlargement is more than 0,5cm in size, at more than 2 sites (bilateral =1 site)

WHO Clinical Stage 2 Hepatosplenomegaly Recurrent or chronic URTI Papular pruritic eruptions Seborrhoeic dermatitis Extensive human papilloma virus infection Extensive molluscum infection Herpes zoster Fungal nail infections Recurrent oral ulcerations Lineal Gingival Erythema (LGE) Angular chelitis Parotid enlargement

WHO Clinical Stage 3

Unexplained moderate malnutrition Unexplained persistent diarrhoea (14 days or more) Unexplained persistent fever, for longer than 1month) Oral candidiasis (outside neonatal period ) Pulmonary TB Severe recurrent presumed bacterial pneumonia Lymphoid interstitial pneumonitis (LIP) Unexplained anaemia, neutropenia or thrombocytopenia for

more than 1 month Chronic HIV associated lung disease Oral hairy leukoplakia Necrotising ulcerative gingivitis/periodontitis

WHO Clinical Stage 4

Unexplained severe wasting PCP Recurrent severe presumed bacterial infections (excl.

pneumonia) Chronic Herpes simplex infection Extrapulmonary tuberculosis Kaposi's sarcoma Disseminated non-tuberculous mycobacteria infection HIV encephalopathy Disseminated endemic mycosis (extrapulmonary histoplasmosis,

coccidiomycosis, penicilliosis) CNS toxoplasmosis (outside the neonatal period) Cytomegalovirus (CMV) infection

• Extrapulmonary cryptococcosis including meningitis• Chronic Cryptosporidiosis, Isosporiasis

Cotrimoxazole (CTX) prophylaxis

CTX can reduce mortality by 43% in children (Chintu et

al)

Activity against PCP, invasive bacterial infections ( respiratory and diarhoeal pathogens), toxoplasmosis and malaria

Side effects are rare 3.5 million children in Sub-Saharan Africa need CTX

prophylaxis (WHO) If early diagnosis is implemented can ↓ to 1.9 million

CTX ProphylaxisWhich children should get it?

All HIV-exposed infants from 6 weeks of age

All HIV-infected children not on ART

Stop if HIV infection excluded or child on ART with evidence of immune reconstitution for 6 months

•CD4% > 20%

Common Presenting Signs & Symptoms

• Respiratory conditions

• Gastrointestinal conditions

• Skin and Mucosal conditions

• Nutritional conditions

• CNS

LRTI

Common organisms still most frequent Out-patient or in-patient ?

• Out-patient • Amoxil (7-10 days)

• Inpatient • IV Ampicillin (+ Gentamycin) or Cefuroxime

• Oxygen, fluids, monitoring (7-10 days)

• CXR, Bloods, PPD +/- AAFB (GW,Sputim)

LRTIs

LRTIs

Community Acquired Pneumonia• Bacterial

• Viral

Differential Diagnosis Pulmonary TB PCP LIP

Pneumocystis Jiroveci Pneumonia (PCP)

Suspect a PCP infection if the child: <12 months old Has severe tachypnoea

• (> 50 breaths/minute in infants, >40 breaths/minute in children)

Is dyspnoeic Has few crackles relative to degree of dyspnoea and

decreased breath sound intensity on auscultation Has cyanosis

Begin treating for PCP immediately on suspicion

(in addition to usual treatment of pneumonia), even if the

HIV status of the child is not yet known

Pneumocystis Jiroveci Pneumonia (PCP)

• Requires admission • Maximal oxygen supplementation• NPO for first 24-48hrs / NGT feeds• Co-Trimoxazole 20mg/kg qid IVI/oral

(3wks)• Prednisone 1-2mg/kg x 14 days• Adequate fluids, but do not overhydrate !

“BCGosis” BCG (Bacille Calmette Guerin) Routine vaccine at birth Given to ALL babies BCGosis = BCGitis may be localized or

generalized (disseminated) Occurs in both HIV infected and non –

infected children May occur prior to HAART or as IRIS

BCG adenitis

Mycobacterium Avium Complex

M. avium M. intracellulare M.paratuberculosis Disseminated infection with MAC in pediatric

HIV infection rarely occurs in infancy Frequency with age and declining CD4

count,

Diagnosis

Definitive diagnosis is accomplished by isolation of the organism from the BLOOD or from BIOPSY SPECIMENS from normally sterile sites (e.g. bone marrow, lymph node, or other tissues).

Multiple mycobacterial blood cultures over time might be required to yield a positive result.

Lymphoid Interstitial Pneumonitis (LIP)

Age usually greater than 2 years

Suggestive CXR findings:• bilateral reticulonodular infiltrates • mediastinal lymphadenopathy• indistinguishable from miliary TB

Child with slowly progressive hypoxia, tachypnoea and exertion fatigue.

Child with clubbing and enlarged parotid glands

LIP vs. Miliary TB

Digital Clubbing

LIP Treatment

No treatment for asymptomatic LIP

Symptomatic LIP - i.e. oxygen sats < 92% or developing signs of cor pulmonale• Prednisone 2mg/kg x 4 weeks then taper dose.

• Need to exclude PTB and/or treat prior to steroid use

• Indication for HAART – to decrease need for steroid

Gastrointestinal Conditions

Oral and/or oesophageal candidiasis Gastroenteritis – acute, persistent, chronic

• Infectious – Enteric / Parenteric (eg UTI)

• Villous atrophy

• Enzyme deficiencies – lactase

• Drug related (Kaletra®)

Perianal fistulae Colitis – CMV Fistulae – RV fistulae

Dermatological conditions• Seborrhoiec dermatitis • Eczema• Scabies• Warts • Varicella-Zoster • Molluscum contagiosum• Tinea – (all)

Think Immunodeficiency if …..

any common condition shows the following charactersitics

ATYPICAL presentation INTRACTABLE to conventional

treatment SEVERE & EXTENSIVE RECURRENT

Shingles (Zoster)

Dermatitis

• Treat with Procutan (1% hydrocortisone) cream to face 12 hourly until improves

• Use Aqueous cream as soap• On the body use betnovate 1 in 10 with aqueous cream • 12 hourly until improves (usually for 7-14 days).

Seborrhoeic Dermatitis

Treat with Procutan (1% hydrocortisone) or betnovate 1 in 10 with

aqueous cream twice a day until rash resolves

Molluscum Contagiosum

• HAART indicated•Apply topical tincture of iodine BP to the core of each lesion using an applicator•At hospital: cryotherapy/surgical excision

Ringworm (Tinea Capitis)

• If mild, try Whitfield ointment (6% benzoic acid and 3 % salicylic acid ) 2-3 times daily for 4-6 weeks

• For nail and scalp infections need Griseofulvin 10mg/kg daily for 8 weeks

Oral Candidiasis

Note – Oral candidiasis common condition in very young infants, not necessarily associated with HIV

Nutritional conditions

• Failure to Thrive (FTT)

• Marasmus

• Kwashiorkor

CNS Direct effect of virus – HIV Encephalopathy Indirect effect – secondary to illnesses and

therefore delayed development Opportunistic infections Neoplasia Vasculitides Immune reconsitution phenomena Drug related phenomena Unrelated to HIV in child e.g. birth related brain

injury, fetal alcohol syndrome, etc

HIV Encephalopathy

Indicates advanced clinical disease (WHO IV) HAART indicated with good but variable result and

reversibility Diagnosis

• Take a good birth history• Slow achievement or loss of milestones or loss of intellectual ability• Acquired microcephaly• Acquired symmetrical motor deficits in an alert child - increased

tone, pathologic reflexes, ataxia, gait disturbances, paresis• CSF is normal or has non-specific findings• CT scan shows diffuse brain atrophy• Rule out CNS infections/conditions

CNS complications OIs:

• Bacterial meningitis,

• TBM,

• Cryptococcus,

• CMV encephalitis

• Varicella reactivation

• Toxoplasmosis Vasculitides: well described, varied presentation Malignancy: lymphoma PML - JCV

HAARTOverview

When and how to start ART Paediatric ART Regimens Monitoring Adverse effects Immune Reconstitution Drug interactions Adherence

When do we start?

When to start? (DOH Guidelines)

Recurrent hospitalisations (> 2 admissions per year) or prolonged hospitalisation (> 4 weeks) for HIV complications

WHO Stage III or IV

For relatively asymptomatic patients:• CD4 percentage <20% if < 18 months • CD4 percentage <15% if > 18 months.

Proposed New Start Criteria

ALL HIV-infected infants irrespective of CD4 % or clinical stage

For children 1-5 yrs CD4 < 25% For children > 5 yrs CD4 < 350 cells/ml

Psychosocial Criteria (DOH Guidelines)

MandatoryAt least one identifiable caregiver who is able to

supervise child or administer medication

(Do not exclude orphans and the abandoned)

RecommendedDisclosure to another adult living in the same

house is encouraged so that there is someone else who can assist with the child’s ART

Preparing a child for ART

Establish a definitive HIV diagnosis and WHO stage the patient

Screening CD4% Exclude TB (treat if suspicious) Treat intercurrent illnesses and opportunistic disease

first. Identify responsible person to administer treatment. Optimise caregiver and family health

•Counsel and educate about ART, demonstrate

Regimens for Children (DOH Guidelines)

  Birth - 3years >3 years (>10kg)

1st line stavudine (d4T)lamivudine(3TC)kaletra®

stavudine (d4T)lamivudine(3TC)efavirenz (stocrin)

2nd line zidovudine (AZT)didanosine (ddI)efavirenz (Stocrin)

zidovudine (AZT)didanosine(ddI)kaletra® (Stocrin)

ARV dosing

Body Surface Area (BSA)

Standardised weight tables (WHO) in DOH guidelines

Doses must be adjusted for weight as children grow

BSA (m2) = height (m) x weight (kg) 3600

Monitoring

Baseline CD4, Viral Load, (FBC), (ALT) 1-month visit, and 3-monthly clinical

exam 6-monthly CD4, Viral load unless

indicated otherwise Toxicity depending on drug regimen

Side effectsSome toxicities are class-specific while others are drug-specific

NRTI’s: lactic acidosis, hepatic steatosis, pancreatitis, myopathy, cardiomyopathy and peripheral neuropathy

NNRTI’s: Rash (SJS-nvp), Hepatitis (CNS-efavirenz)

PI’s: Insulin resistance, diabetes, hyperlipidemia, lipodystrophy, increased bleeding episodes in haemophiliacs, hepatitis, and bone disorders

Adverse events

Life threatening:• Lactic acidosis- all NRTI’s (d4T+ddI) no good way of

screening→clinical suspicion• Hypersensitivity (ABC)• Hepatitis (NVP)• SJS (NNRTI)• Pancreatitis• Cardiomyopathy

Other:• Lipodystrophy, lipid profile abn, diabetes (PI)• Peripheral neuropathy (NRTI)• Myopathy (NRTI)• Bone marrow suppression (AZT)

Lactic AcidosisInitial symptoms are variable, cases have occurred as soon

as 1 month and as late as 20 months after starting therapy,Usually associated with combination DDI and D4T

Clinical prodromal syndrome: generalized fatigue, weakness gastrointestinal symptoms (nausea, vomiting, diarrhea,

abdominal pain, hepatomegaly, anorexia, and/or sudden unexplained weight loss)

respiratory symptoms (tachypnea and dyspnea) neurologic symptoms (including motor weakness)

Immune-reconstitution disease

Synonyms : ‘Immune Reconstitution Syndrome’‘Immune Reconstitution Inflammatory Syndrome’

Paradoxical clinical deterioration after starting HAART

Presentation: Usually affects those with very low starting CD4 count

(often CD4 nadirs <100) IRD usually presents during the first 6 weeks after starting

HAART. Clinical presentations depend on the causative organism

and the organ-system that is colonised.

Immune-reconstitution disease

Pathogenesis - improving immune system interacts with organisms that have colonised the body during the early stages of HIV infection.

Disease processes : Infectious Non-Infectious

Immune-reconstitution disease Infectious Diseases : Mycobacterium tuberculosis (MTB),

Mycobacterium avium complex, Mycobacterium leprae, Cryptococcus neoformans, Aspergillus fumigatus, Aspergillus terreus, Candida albicans, Pneumocystis carini, CMV, JC virus, Human Herpes viruses, Human Papilloma virus and hepatitis B and C viruses.

6 weeks later!!!