PAEDIATRIC HIV INFECTION Dr Ashendri Pillay Paediatric Infectious Diseases Specialist
Paediatric HIV Infection Epidemiology Immuno-pathogenesis Antiretroviral therapy Transmission Diagnostics Clinical manifestations Universal Test & Treat PMTCT Vaccine Development
P D r A s h e n d r i
Immunopathogenesis
reverse transcriptase inhibitors DS dna COMPLEX integrase inhibitors protease inhibitors chemokine receptor inhibitors fusion inhibitors HIV entry inhibitors
Nucleoside Reverse Transcriptase Inhibitors (NRTIs) Zidovudine (ZDV, AZT) Didanosine (ddi) Stavudine (d4t) Lamivudine (3TC) Abacavir (ABC) Tenofovir (TDF)
Non- Nucleoside Reverse Transcriptase Inhibitors (NNRTIs): Nevirapine (NVP) Efavirenz (EFV) (>3years/ 13 kg) Etravirine Rilpilvarine
Protease Inhibitors (PIs): Lopinavir/rtv (LPV/r) Ritonavir (full dose) Atazanavir/rtv (ATZ/r) Daurinavir/rtv (DRV/r)
Children Are Not Little Adults What s Different? Transmission Presentation of HIV Progression Diagnostic Issues Drug Distribution Dosing Occurrence of toxicities Adherence and Psychosocial Issues Physical, Emotional and social needs Dependence / Vulnerability
Transmission >90% occurs vertically breast feeding In utero Intra partum Risk has declined from 30-45% to as low as 1% with ART
Transmission Sexual abuse by an HIV infected adult Unprotected sexual intercourse in adolescents Use of contaminated blood & blood products Drug abuse Scarification by traditional healers, body piercings
Diagnosis
Clinical Manifestations of In-utero Infection
Systemic Manifestations Malnutrition & Growth Failure
Skin
Haematological Multi-factorial causes of anaemia Direct effect of HIV on marrow Iron Deficiency Antiretroviral therapy Recurrent Infections Parvovirus induced red cell aplasia CMV infections
Central Nervous System HIV encephalopathy Seizures CNS infections Malignancy
Respiratory
Gastrointestinal System Acute infective diarrhoea Persistent diarrhoea with failure to thrive Malabsorption Opportunistic intestinal infections Microbiome
Cardiovascular System HIV associated cardiomyopathy Pericardial Effusion Conduction abnormalities Pulmonary hypertension
Renal HIVAN Glomerulonephritis Nephrotic Syndrome
Musculoskeletal Low bone mineral density is commonly observed among children infected with HIV compared with their uninfected peers, with rates ranging from 7% to 32% Associated risk factors include time on ART, treatment with tenofovir and protease inhibitors, advanced HIV disease, and delayed puberty. Initial studies have not found a higher rate of fractures but the longterm effects as these children age into adulthood are unknown
Universal Test & Treat
Benefits of early initiation of ART Controls viral replication while genetic quasispecies are relatively homogeneous and before significant viral mutations occur Could control development of heterogeneous viral strains/mutations Potentially leads to less drug resistance Could lower viral setpoint fewer viral strains Slows immune system destruction preserving immune function and preventing clinical progression
Plasma HIV RNA levels in Adults Plasma HIV RNA levels in Infants Viral load no.copies/ml (log) 1000000 10000 100 1 1 2 3 4 years 1 2 3 Months/Years Viral load no. of copies/ml 1000000 100000 10000 1000 100 10 1 1 2 years 2 2.5 3 Months/Years
First Line Therapy < 3 years (<10kg) > 3 years > 10kg
Changing ARV Therapy Failure based on virologic, immunologic, or clinical parameters Toxicity or intolerance on the current therapy
Clinical Failure
Immunological Failure A persistent decline of 5 percentiles or more in CD4% (15% to 10%) A rapid decrease in absolute CD4 count (>30% decline in <6 months)
Virological Failure Persistent detectable viral load > 1000 copies/ml after 6 months on HAART
Adherence Issues in Children Availability of drugs in palatable, liquid or mixable formulations Difficulty of giving drugs that have food restrictions, because of children s (particularly infant) eating schedules Children s dependence on caregivers for administration
Failure of 1 st line therapy Patients on NNRTI based regimen can be changed to 2 nd line therapy Zidovudine, Lamivudine, Lopinavir/Ritonavir Patients on a PI based regimen, due to high genetic barrier of resistance of PIs, concern is development of class resistance to NRTIs, NNRTIs These patients should be referred for HIV resistance testing Third line therapy
PMTCT
Newly Diagnosed HIV Positive: Unbooked women & previously HIV negative In-labour management: Stat sd NVP Stat sdtruvada (FTC/TDF) 3 hourly AZT Baby: Birth PCR 12 weeks NVP Repeat PCR at 18 weeks FDC dispensed before discharge to start the following day 37
Dried Blood Spot (DBS)
Birth PCR WHO? ALL HIV EXPOSED NEONATES 39
Infant Prophylaxis Choice of infant prophylaxis regimen depends on risk profile of mother Prophylaxis to be started immediately or soon after birth Counsel re adherence to maternal ART and infant prophylaxis
Most Infants
Infants who need additional prophylaxis 12 weeks NVP 6 weeks NVP plus AZT Infants born to mothers who have not been on ART for long enough to be virally suppressed by the time the infant is 6 weeks old: < 4 weeks on ART Diagnosed in labour/delivery Diagnosed during breastfeeding and still breastfeeding Infants born to mothers who have been on ART for > 3 months and still have a viral load >1000 copies/ml. These women may have poor adherence These women may have ART resistance 42
Mother diagnosed HIV+ve after delivery If the mother is breastfeeding: Initiate infant onto NVP plus AZT immediately. Initiate mother on FDC immediately Review infant PCR result within 7 days. If the infant s HIV PCR is negative: Stop AZT. Continue infant NVP for a total of 12 weeks.
Mothers Failing 2 nd /3 rd Line If mother has VL> 1000 copies/ml and is on SECOND or THIRD LINE therapy: This baby should preferably not be BREASTFED Prescribe infant formula (medically indicated) Need to ensure facilities have stock If formula not available: Careful counselling of mother Intensive adherence support Exclusive breastfeeding These mother-baby pairs should be referred/ telephonically discussed 44
PMTCT Testing Schedule
Vaccine Development HIV infection does not induce broadly neutralising antibodies Goals for HIV vaccine induction of neutralising antibodies Hypervariability of HIV