The HIV positive Child handout. Heidelberg October 2017 Dr. Charlotte Adamczick

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1 The HIV positive Child handout Heidelberg October 2017 Dr. Charlotte Adamczick

2 Outline of the presentation 1. Some facts 2. The infected patient: early and late presentation 3. Treatment of the HIV related conditions and ART regime 4. The Adolescent 5. PMTCT 6. Iris

Successes but (WHO 2017) 36.7 Mio people living with HIV Only 19.5 Mio are on ART (5.5. Mio in 2015) These are 53% (39-65%) (With new cut-off 350 CD4, 15 Mio qualify for ART in 2015) 2.

3 Successes but (WHO 2017) 36.7 Mio people living with HIV Only 19.5 Mio are on ART (5.5. Mio in 2015) These are 53% (39-65%) (With new cut-off 350 CD4, 15 Mio qualify for ART in 2015) 2.6 Mio kids < 15 yrs (90% infected perinatally, living in SSA) newly infected in 2015 (>50% less than 2001) died of AIDS ( in 2012; in 2005) only 43% of those in need are on treatment and 13.3 Mio HIV/AIDS orphans Special Group adolescents:

4 Clinical classification for perinatal HIV infected children Without treatment, (fast progressors ) 30 % die before 1 yr, 60% before 2 yrs, 80% before they turn 5 yrs; Slow progressors: symptoms in the first years of life, AIDS with 6-9 yrs Rest: long term survivor (5-10%) beyond 8 yrs Survival with early treatment 92% Needs early and accurate diagnosis of HIV infection Establish exposure Confirmation of infection

5 Diagnostics Serological testing: Detection of IgG-AB (cave window period, age <18 months) Rapid AB assay (recommended by WHO for low resource countries) < 18 months of age: screening assay to determine HIV exposure > 18 months of age: diagnostic assay to confirm HIV infection Identification of not HIV-infected among infants & children < 18 months of age never breastfed or stopped breastfeeding > 6 weeks

6 Diagnostics Virological testing: HIV RNA, DNA & p24ag detection with PCR Confirmation of HIV infection at all ages, esp. children < 18 months of age (cave: low sensitivity in the first weeks of life) Exclusion of HIV infection in infants (> 4-6 weeks of age!) never breastfed or stopped breastfeeding on the past 6 weeks

7 Diagnostics Confirm exposure around birth or at least at 4-6 weeks. Confirm HIV infection If serological test positive: virological test by 4-6 weeks of age If no virological test available for < 18 months of age: Start ART based on positive serological test and a clinical algorithm (presumptive diagnose: Sepsis, oral thrush, severe pneumonia) Confirm status with serological test > 18 months

8 Clinical Staging paeds WHO Stage 1: Asymptomatic, persistent generalized lymphadenopathy Stage 2: Persistent unexplained hepatosplenomegaly, angular cheilitis, extensive wart virus infection, extensive molluscum contagiosum, recurrent oral ulcerations, parotic enlargement, herpes zoster, recurrent or chronic upper respiratory tract infections Stage 3: Unexplained moderate malnutrition or wasting not responding to standard therapy, unexplained persistent diarrhoea, fever, persistent oral candidiasis, oral hairy leukoplakia, TB adenitis, PTB, severe recurrent bact pneumonia, unexplained anaemia, neutropaenia or chronic thrombocytopenia Stage 4: Severe wasting, PCP, recurrent severe infection, chronic herpes simplex infection, Oesophageal candidiasis, Kaposi Sarkoma, CMV infection, Toxoplasmosis, HIV encephalitis, Cryptosporidiosis, chronic Isosporiasis, NHL

CDC WHO Clinical categories: N: no symptoms A: mild symptoms

Immunological stages: 1: no/mild impairment 2: intermediate

symptoms 3: advanced symptoms 4: severe symptoms / AIDS

9 CDC WHO Clinical categories: N: no symptoms A: mild symptoms B: moderate C: severe symptoms / AIDS / HIV infection stage 3 Immunological stages: 1: no/mild impairment 2: intermediate 3: severe / AIDS Clinical stages: 1: no symptoms 2: mild symptoms 3: advanced symptoms 4: severe symptoms / AIDS Immunological stages: 1: no impairment 2: mild 3: advanced 4: severe / AIDS

10 3. HIV related conditions: Kaposi Sarkoma Named after Hungarian Dermatologist Moritz Kaposi 1994 Chang and Moore discovered an additional Herpes Virus, Human herpes virus 8 (HHV 8), (closely related to EBV). identified as being the aetiological agent for KS. Virus transforms epithelial cells of lymphatics or blood vessels and causes their proliferation Affected sites are mainly skin, lymphe nodes, lung and gastrointestinal tract Since ART, incidence decreased and aggressiveness

11 Treatment options Best are ARVs Vincristine (side effects: peripheral neuropathy, myelo-suppression, constipation) Child dosing: 1.4 mg/m², 0.05 mg/kg if < 10kg weekly for 6 weeks, than 2 weekly for 6 weeks Adults: 2 mg Bleomycin (side effects: allergic reaction, myelo-suppression, pulmonary fibrosis, pneumonitis) Indicated with rapid disease progression, relapse considering Vincristin failure Child dosing: 15 units / m² i.m. weekly for 2 weeks, than once every two weeks (not exceeding 250 mg/m²) Adult dosing: 15 mg i.m. Thalidomide Doxorubicin 20mg/m2 (cave cardio and myelotoxic) Interferon

12 Pulmonary manifestations Pneumocystis carinii/jiroveci pneumonia (PCP) Lymphocytic interstitial pneumonia (LIP) Pulmonary TB Karposi Sarkoma

13 Pneumocystis carinii/jiroveci pneumonia Some Facts: Yeast like fungus The agent is widespread worldwide; 75% seropositivity by the age of 4 yrs. Reduction of severe infection through Co- Trimoxazole (!Prophylaxis right after diagnosis!)

Stage 4 Pneumocystis carinii/jiroveci pneumonia Clinical Characteristics: In the young patient < 6 months And major cause of death in infants < 1 yr

14 Stage 4 Pneumocystis carinii/jiroveci pneumonia Clinical Characteristics: In the young patient < 6 months And major cause of death in infants < 1 yr (before Cotrim) Mainly good condition with mormal CD4 count Fever Non productive cough Toronto Western Hospital 2009, Brockmeier Weight loss, night sweats

Pneumocystis carinii/jiroveci pneumonia very few symptoms initially, later with increasing wheeze and SOB (respiratory distress) Invasion of visceral

15 Pneumocystis carinii/jiroveci pneumonia very few symptoms initially, later with increasing wheeze and SOB (respiratory distress) Invasion of visceral organs Biopsy: thickened alveolar septa with eosinophilic exudate in the alveoli CxR: No pleural effusion Less hili enlargement than in PTB milky glas appearance

16 Pneumocystis carinii/jiroveci pneumonia Therapy: 1. Steroids 2. Co-Trimoxazole Alternatives: Pentamidine, Dapsone, Atovaquone, Primaquine, Clindamycin Cave Pentamidine: Pancreatitis, renal failure, Hepatotoxicity, Leucopenia, Rash, Hypoglycaemia

Lymphocytic interstitial pneumonitis (LIP) Not uncommenly the first presentation of vertical HIV transmisssion Aethiology: Infiltration of alveolar septa by plasma cells containing EBV DNA Clinic: >

17 Lymphocytic interstitial pneumonitis (LIP) Not uncommenly the first presentation of vertical HIV transmisssion Aethiology: Infiltration of alveolar septa by plasma cells containing EBV DNA Clinic: > 2 yrs Asymptomatic or with SOB, wheezing Recurrent infections Clubbing Lymphadenopathy Hepatosplenomegaly Enlarged Saliva glands DD miliary TB Therapy: Bronchodilator ARVs CXR: Bilateral, symmetircal, reticular, nodular shadowing Hilar lymphadenopathy

18 DD Tb and LIP Miliary TB LIP (nodular) note clinical signs: not acutely sick, clubbing

HIV Treatment International Journal of Epidemiology, 2017, 453 465 doi: 10.

19 HIV Treatment International Journal of Epidemiology, 2017, doi: /ije/dyw097 Advance Access Publication Date: 22 June 2016 Original article Optimal timing of antiretroviral treatment initiation in HIV-positive children and adolescents: a multiregional analysis from Southern Africa, West Africa and Europe Michael Schomaker, 1 * Valeriane Leroy, 2 Tom Wolfs, 3 and mortality outcomes. 4, Conclusions: Immediate ART is associated with lower mortality and better growth for up to 5 years in children < 10 years old. Our results on adolescents were inconclusive. Age It took a long way WHO clinical staging and/or CD4 value <2 All Independent >2-5 WHO III-IV CD4 < 750 cells/mm³ >5 WHO III-IV CD4 < 350 cells/mm³ all TB or Hepatitis B

20 ARTs NRTI (Nucleoside reverse transcriptase inhibitor) approved for children (e.g. Lamivudine 3TC, Zidovudine AZT) 2 NRTIs recommended for all regimes as backbone Few side effects, well tolerated and few drug interactions NNRTI (Non nucleoside reverse transcriptase inhibitor) approved for children (Nevirapine NVP, Efavirenz EFV) Rapid emerge of resistance Side effects: commonly cutaneous reactions

21 ART PI (Protease inhibitor) 7 approved for children (e.g. Lopinavir ritonavir-boosted LPV/r, Atazanavir ATV/r) Mortality reduction 65% Entry inhibitors (fusion inhibitors) 2 approved for children Integrase Inhibitors

23 Principles cont. ARTs in special situations: Infant and child with previous NNRTI exposure: start on PI + 2 NRTIs Children with severe anaemia or neutropenia: avoid AZT Adolescents > 12 yrs with Hep B: start on: TDF(Tenofovir) + FTC(Emtricitabine) or 3TC(Lamivudine) + NNRTI.

25 Monitoring CD4 monitoring: At diagnosis Every 6 months thereafter More frequent when decreasing towards the threshold of ART start (given the child is > 24 month, has no TB or no Hep B) Prior to ART initiation Every 6 months after initiation In case of any clinical change (delay in growth, neurodevelopment)

26 Clinical significance of VL and CD4 count

27 Monitoring cont. VL Not essential before initiation Assessment is desirable to assess and diagnose immunological failure Clinical and laboratory Baseline HB and WBC at initiation Every 8 weeks HB in AZT regimes Growth and nutritional status (dose adjustment) LFT, Serum Lipids

28 Interrupted treatment Significant drug toxicity Acute gastrointestinal illness Surgery STI (structrued treatment interruptions) poor data. Known in PMTCT

29 Neurodevelopment in HIV PRE ART area Severe CNS manifestations in 50-90% children Greatest risk for HIV encephalopathy within the first year of life and dependant on viral load Progressive HIV encephalopathy (PHE): usually death in 2 yrs POST ART Severe CNS manifestations such as PHE < 2% (Chiriboga, 2005)

30 Neurodevelopment in HIV Clinical relevance Early ART is protecting the developing brain (better learning!) In adolescents decrease of the high prevalence of psychiatric and behavioural illness

31 4. disclosure to adolescents (Liz Lowenthal, Baylor) Disclosure: Age is very individual It s a process Young pt is focal person, not the guardian, but disclosure plan should be done with the caring person Overall aim: 1. Better understanding 2. Psychological adjustment and self-esteem 3. no more secrets 4. Each visit positive reinforcement and messages 5. Advise, what and how to tell others 6. Encourage to daily routines

32 Disclosure With appropriate materials and terms, even small children can get an understanding of their condition. Eg. Good soldiers need good nutrition, medicine, to keep them strong. Later introduce the terms of CD4, viral load etc.

33 Avoid assigning blame NOT: your mother gave it to you INSTEAD: some children are born with the virus, we think that is what happened to you Support materials: Paediatric adherence support curriculum on South to south

37 youth club Special clinic days for adolescents Adherence often only 30% Side effects due to long treatment buddy Education on protection Family planning Papilloma vaccination Other professionals: social worker, psychhologist

38 6. PMTCT (prevention of mother to child transmission) Importance of PMTCT 3.3 million children with HIV infection 90% acquired MTCT High 2 year mortality Risk of transmission approximately 35% 25% in-utero, 60% intra-partum, 15% breast feeding Decreased to 10% with the 3-step AZT PACTG regimen (1994) Decreased to <1% with HAART, formula feeding and elective C/S as appropriate

39 PMTCT options according to maternalneeds (WHO 2010) HAART AZT (Option A) Tripple (Option B) (Palombi 2007) Mother AZT+3TC+ NVP (or EFV) TDF + 3TC (or FTC) + NVP (or EFV) Antepartum AZT bd from 14 weeks, then AZT+3TC during labour and delivery (if AZT given <4weeks: cont. AZT + 3TC for 7 days post partum and give sd-nvp at the onset of labour) From 14 weeks until one week after BF cessation: AZT+3TC+LPV/r or AZT+3TC+ABC or AZT+3TC+EFV or TDF+3TC(or FTC)+EFV Infant Irrespective of feeding mode: NVP od or BF: NVP up to one week after BF cessation Irrespective of feeding mode: NVP od or AZT bd up to 6 weeks AZT bd up to 6 weeks Non BF: NVP or sd-nvp + AZT bd up to 6 week

40 Arguments for HAART in every pregnant woman KEEP THE MOTHER ALIVE HIV pos pregnant women have: 1. Increased risk of prematurity, PROM, IUGR 2. More vulnerable for severe infection 3. Worse outcome placental malaria 4. Infant has higher overall mortality risk, even when remaining HIV neg. Mother on HAART (since 2012: Option B+): 1. Overall better immune status of mother 2. lover viral load during pregnancy with decreased risk of transmission to the child

41 Infant mortality risk in exposed infants ZWITAMBO study, Zimbabwe (Marimba, IAS, Toronto 2006): 2 yr mortality among > infants: Not HIV exposed = 2.9% HIV exposed but uninfected = 9.2% HIV infected = 66.6%

42 PMTCT Mother HIV pos, tested during second Pregnancy and qualified for ART First born presented with severe malnutrition, extensive oral thrush, pos status Sibling, 8 months, PCR neg. and clinically well. BF stopped with 6 months (WHO recommendation: exclusive BF 6 months, BF up to 12 months with food)

43 KEY MESSAGE: PMTCT Best results for reduction in HIV transmission is maternal HAART during early pregnancy, regardless the CD4 value and neonate/infant on AZT regime until cessation of breast feeding Integrate PMTCT into MCH, TB, FP, STI clinics! Note: Elimination of paediatric AIDS through maternal HAART! Botswana conference 2008, 2010 Cotton 2009 SAJHIVMED Becquet 2009 WHO recommendations 2010

45 Pitfalls slipping through the net Mothers get infected later in pregnancy Mothers get infected during breastfeeding Note: Recommendation for multiple testing are lacking Note: first 3 weeks of new infection high viral load; high transmission risk during breastfeeding

46 PrEP

47 Future challenges Adolescence Orphans Non adherence Emerging resistances Organ failure Costs; reliable donors with long-term commitment

48 7. IRIS (Immune reconstitution inflammatory syndrome)

49 IRIS Def: unexpected and paradox clinical aggravation after ART start Mostly after 3 month Common with CD4 < 50 / mm3 Seen in 15-25% of the patients Potentially under-diagnosed Different forms: Latent Infection; f.ex. TB, Cryptococcal Meningitis Known infection, already treated, getting worse

50 IRIS cont. In children up to 21% (BCG adenitis in infancy, TB in older children) Most common form of IRIS is TB. In SSA: high TB incidence in HIV infected children (1600 in ) (Hesseling 2009) Early ARVs decreases the risk of IRIS up to 70% (Martinson 2009)

51 Tb Adenitis Cave BCG vaccination in HIV pos newborn

52 Other forms of IRIS Skin Moluscum contagiosum Tinea capitis warts Impetigo Herpes Zoster Fungal infections others Guillain Barré Myocardiale Dilatation Leukencephalopathie Lepra Karposi Sarkoma CMV PCP Opsoclonus myoclonus Toxoplasmosis

53 Treatment option of IRIS 30% hospitalisation With severe TB IRIS, HAART interruption (cave: evolving resistance with Efavirenz and Nevirapin, less common with PI) NSAID with mild clinic, steroids with severe IRIS

PAEDIATRIC HIV INFECTION. Dr Ashendri Pillay Paediatric Infectious Diseases Specialist

PAEDIATRIC HIV INFECTION. Dr Ashendri Pillay Paediatric Infectious Diseases Specialist PAEDIATRIC HIV INFECTION Dr Ashendri Pillay Paediatric Infectious Diseases Specialist Paediatric HIV Infection Epidemiology Immuno-pathogenesis Antiretroviral therapy Transmission Diagnostics Clinical