Unit 4: HIV and ART in Children 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 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

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 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

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

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

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

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% 500-999 200-499 Category 3: Severely immunosuppressed < 750 < 15% < 500 < 200

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)

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

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 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

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 + 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

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

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

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