1. Unit 4: HIV and ART in Children
Module 3
Unit 4: HIV and ART in Children

2. 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

3. 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

4. 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

5. 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

6. Epidemiology - Transmission
Factors facilitating MTCT
Labor
Prematurity
Prolonged/difficult
Duration of membrane rupture >4hours/PROM
Invasive monitoring and procedures

7. 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

8. Epidemiology - Transmission
Other routes of transmission
Contaminated needles and instruments
Transfusion of blood and blood products
Hemophiliacs
Sicklers
Sexual

9. Natural History Of HIV Infection

10. 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

11. NATURAL HISTORY Absolute CD4 counts high in young children
In uninfected children
Absolute CD4 counts high in young children
Decline to adult levels by 6 yrs
CD4% does not change much with age

12. 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.

13. 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

14. 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)

15. World Health Organization Clinical Staging for Pediatric HIV
Stage 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

16. 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

17. 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:
Lymphadenopathy
Hepatomegaly
Splenomegaly
Dermatitis
Parotitis
Recurrent or persistent URTI, sinusitis or otitis media

18. B C Category(CDC) Disease Moderately symptomatic
Diarrhoea, recurrent or chronic
Bacterial infection – pneumonia, meningitis, sepsis (1 episode)
Fungal infection - Oropharyngeal candidiasis
Viral infection – CMV, Herpes simplex (stomatitis, bronchitis, pneumonitis, esophagitis), Herpes zoster, disseminated Varicella
Other OI – Toxoplasma before 1 month, Nocardiosis
Major organ dx – Cardiomyopathy, nephropathy, hepatitis.
Persistent fever > 1 month
Lymphoid interstitial pneumonia C
Severely symptomatic – AIDS defining conditions
HIV wasting disease
Esophageal candidiasis
Disseminated or extrapulmonary tuberculosis
HIV encephalopathy
Cryptococcal meningitis, Cryptosporidiosis
Lymphomas, Kaposis sarcoma

19. Clinical category (CDC)
Diagnosis C
(Continued)
Severely symptomatic:
Multiple recurrent severe bacterial infection
Esophageal or pulmonary candiadiasis
Disseminated coccidioidomycosis
Extra pulmonary cryptococcosis
Cryptosporidiosis or isosporiasis
CMV infection > 1 month of age
Disseminated histoplasmosis
Kaposi’s sarcoma
Primary lymphoma of the brain
Burkitt’s or immunoblastic lymphoma
Disseminated or extrapulmonary tuberculosis
Disseminated other or unspecified mycobacteria sp.
Disseminated Mycobacteria avium
Pneumocystis carinnii pneumonia
Herpes simplex virus infection > 1 month of age
Progressive multi focal leucoencephalopathy
Recurrent salmonella (nontyphoidal) septicemia
Toxoplasma of the brain (> 1 month of age)
Wasting syndrome

20. IMMUNOLOGIC STAGING Immune category < 12 months 1-5 years
CD4 counts
CD4 percentage
1-5 years
6-12 years
Category 1:
Not immunosuppressed
> 1500
> 25%
> 1000
> 500
Category 2:
Moderately immunosuppressed
750-1,499
15-24%
Category 3:
Severely immunosuppressed
< 750
< 15%
< 500
< 200

21. 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)

22. Diagnosis Before 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

23. Diagnosis After 18 months: HIV ELISA antibody test
By 18 months, maternal antibodies have cleared

24. 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.

25. 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

26. 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

27. 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

28. 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

29. Pretreatment Assessment
Information 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

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

31. 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.

32. 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

33. 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

34. When to Start: < 18 months
PCR available and positive
WHO Stage I or II – CD4%<20%
WHO Stage III – regardless of CD4

35. 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

36. 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)

37. INITIAL REGIMENS Stavudine + Lamivudine Nevirapine Zidovudine +or
NB: Stavudine syrup is unstable at room temperature. If a liquid needs to be used, and no refrigeration at home, use AZT

38. 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

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

40. If 1st line is AZT+3TC+NVP
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/r Or
AZT + ddI+NFV

41. WHY REGIMENS CAN FAIL Consider who administers
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

42. CLINICAL FAILURE - Progressive neuro-developmental deterioration
- Growth failure despite adequate nutritional support and with no other explanation
- Disease progression (advance to another clinical category)

43. WHEN TO STOP Life threatening side effects or adverse reactions
Poor compliance

44. MONITORING required Clinical Laboratory Treatment adherence
Appointment adherence

45. 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

46. 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

47. 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