EACS 6th Advanced HIV Course

1

• Paediatric HIV
• Cases 1, 2, 3, Rebecca, Melanie, Lucy
• Carlo Giaquinto
• Department of Paediatrics,
• Padova, Italy

2
When to start therapy
3
PaediatricsCase 1 Rebecca

• 5 month old, 7.5kg
• Just tested HIV-1 positive by DNA PCR
• Asymptomatic
• CD4 34 CD4 count 2913 cells/mm3, HIV RNA
  207,000 copies/ml
• Would you
• Start ART immediately, or
• Defer until CD4 lt25 or until clinical symptoms
  (whichever is earlier)

4
Treat Rebecca Now
PaediatricsCase 1 Rebecca

• HIV-associated mortality and morbidity rates are
  very high in infants

5
Rapid Rate of Disease Progression and Death in
HIV-Infected Infants
6
Estimated probability of AIDS within 12 months by
age and CD4 percentage
Lancet 20033621605-11
7
AIDS or Death by Age CD4 Count in HPPMCS
CASCADE
8
Treat Rebecca Now
PaediatricsCase 1 Rebecca

• HIV-associated mortality and morbidity rates are
  very high in infants
• Very effective treatment available

9
In the HAART era there was a 10-fold decrease in
the incidence of HIV encephalopathyPatel et al
WAIDS 2008
on HAART
Incidence rate
10
Virologic Response to Lopinavir/R in 26 Children
lt 6 mo of Age (PACTG 1030)
11
Recovery of immune status with HAART is dependent
on CD4 at time HAART is initiatedPatel K et al.
Clin infect dis 2008 46 507-515
40
35
Notimmunedeficient
30
25
20
Immunedeficient
Mean CD4
15
10
CD4 lt15
CD4 1524
5
CD4 gt25
0
0
1
2
3
4
5
6
Years since HAART initiation
1,236 children enrolled in PACTG 219 not on HAART
at study initiation
12
Treat Rebecca Now
PaediatricsCase 1 Rebecca

• HIV-associated mortality and morbidity rates are
  very high in infants
• Very effective treatment available
• Current regimens are easier to take and we are
  more cognizant of toxicities

13
Treat Rebecca Now
PaediatricsCase 1 Rebecca

• HIV-associated mortality and morbidity rates are
  very high in infants
• Very effective treatment available
• Current regimens are much easier to take and less
  toxic than they used to be
• Immunological response to treatment is better in
  infants than in older children

14
Short-term CD4 Response by Age
Walker AS et al, AIDS 2004
15
Treat Rebecca Later
PaediatricsCase 1 Rebecca

• Treatment is a life-long commitment which
  increases the risk of non-adherence
• Adherence is fragile, varies with a wide variety
  of factors including patient as well as
  medication characteristics and cannot be
  predicted for an individual patient

16
Issues for dosing of antiretroviral drugs in
children
PaediatricsCase 1 Rebecca

• PK data by age group are sparse
• Few data on the effect of race, nutritional
  status
• Young children require higher doses
• - high clearance of many ARVs
• Unclear exactly when to change to adult doses
• Dose recommendations according to weight or
  surface area
• - somewhat arbitrary
• - where both available, may not correspond well
  (eg NVP)

17

• Lots of generic solutions and syrups .

18
ARV Formulations for kids in resource-limited
settings

• Medecins sans Frontieres Perspective
• Dr Lisa Frigati for the MSF International AIDS
  Working Group

19
Treat Rebecca Later
PaediatricsCase 1 Rebecca

• Treatment is a life-long commitment which
  increases the risk of non-adherence

20
Treat Rebecca Later
PaediatricsCase 1 Rebecca

• Treatment is a life-long commitment which
  increases the risk of non-adherence
• Drugs are toxic and difficult to take
• Limited ARV choices for infants

21
Relying on cutting tablets in half is not always
feasible
22
Treat Rebecca Later
PaediatricsCase 1 Rebecca

• Treatment is a life-long commitment which
  increases the risk of non-adherence
• Drugs are toxic and difficult to take
• Virologic response in infants is not as good as
  in older children, so there is danger of drug
  resistance developing and limiting future
  treatment options

23
(No Transcript)
24
Treat Rebecca Later
PaediatricsCase 1 Rebecca

• Treatment is a life-long commitment which
  increases the risk of non-adherence
• Drugs are toxic and difficult to take
• Virologic response in infants is not as good as
  in older children, so there is danger of drug
  resistance developing and limiting future
  treatment options
• If it aint broke dont fix it With high CD4
  and CD4 count, Rebecca is likely to be a slow
  progressor monitor carefully and treat only if
  CD4 drops fast or there are indications of
  symptoms

25
Immunologic Response to ART by Age, Lusaka Zambia
Stringer J et al
Stringer J et al, in press
26
Historically weve been back and forth, early and
late, high and low

• 1991 - Treat sickest individuals
• 1997 - Hit early, Hit hard
• Eradicate infection
• 2000 - Hit late, Hit hard
• Cant eradicate, drugs toxic, adherence difficult
  
• Treat symptomatic, immunologically compromised,
  viremic
• 2007 Hit earlier, Hit hard
• Regional differences in guidelines approaches
• Guidelines not based on randomized evidence but
  expert opinion and cohort data

27
Considerations to Determine When to Start

• What do we know about the disease?
• Rate of progression in the population
• Predictors of progression
• What are the goals for treatment?
• Prevent disease progression
• PREVENT MORTALITY
• Prevent morbidity how much morbidity is
  acceptable?
• Minimize treatment related toxicity
• Maximize quality of life disease manifestations
  toxicity adherence
• Prevent development of ART resistance
• Prolong duration and optimize options for long
  term treatment

28
Early Initiation of Antiretroviral Therapy in
HIV-Infected Children Dramatically Decreases Risk
of Death Study design(Violari et al IAS 2007,
Abs WESS103).
29
CHER 76 reduction in the risk of death with
immediate (arms 2 3) compared to deferred (arm
1) HAARTCROI 2008 Abs 76, Abs 600
1
Deferred
p 0.0002
Immediate
0.80
0.60
Failure probability
0.40
16
0.20
4
0
0
3
6
9
12
Time to death (months)
Patients at risk Arm 1 Arm 2 Arm 3
125 252
104 213
72 145
44 99
22 52
30
(No Transcript)
31
European Infant Collaboration
32
WHO 2008 Revised Guidelines When to Start
Antiretroviral Therapy in HIV-Infected Children
If lack ability for viral test, use WHO
presumptive diagnosis of severe HIV (thrush,
severe pneumonia or sepsis) in infants with HIV
antibody test and with clinical symptoms of
severe HIV need to confirm infection status as
soon as possible.
33
PaediatricsCase 1 Rebecca
Treat earlier
But we need to have a long term strategy !!!
34
PaediatricsCase 2 Abel

• 12 month old male from Central Asia who developed
  respiratory distress requiring oxygen 4 hours
  prior to landing in April 2007
• Initial PE significant for respiratory distress
  with RR 46, oxygen sat of 88 on room air weight
  8.3 kg (lt5ile), ht 27.5 cm (lt5ile), icteric
  sclera, decreased BS on right, and
  hepatosplenomegaly

Courtesy of Dr Neu
35
PaediatricsCase 2 Abel

• Hospital Course
• Immediately intubated
• CXR revealed pneumonia with large right sided
  pleural effusion
• Chest CT with heterogeneous high density
  collections in the right lung
• Started on vancomycin, piperacillin/tazobactam
  and tobramycin
• Blood, pleural fluid and sputum grow ESBL
  Klebsiella pneumoniae

36
Chest CT
PaediatricsCase 2 Abel
37
Past Medical History
PaediatricsCase 2 Abel

• Born full term, NSVD, no complications
• Breast fed x 6 months during that time, normal
  growth and development
• Immunizations
• DTAP x 3
• Polio x 4
• Hep B x 3
• Hib x 1

38
Past Medical History cont.
PaediatricsCase 2 Abel

• At 6 months of age developed recurrent vomiting,
  diarrhea, fever and severe anemia
• Treatments - IV fluids, IM injections,
  anti-diarrheals, multiple transfusions (gt10) of
  blood, plasma, and platelets from family members
  and doctors
• During the next 6 months, diagnosed with acute
  gastroenteritis, CMV, hepatitis A, anemia and
  thrombocytopenia

39
ID Consulted for Chronic Infection!
PaediatricsCase 2 Abel

• What labs do you request?
• CBC and differential
• NBT test
• Total immunoglobulins with subclasses
• HIV ELISA
• HIV DNA/RNA PCR

40
Laboratory Findings
PaediatricsCase 2 Abel

• Initial WBC 11.8K (83 PMN,8 lymph), platelets
  19 x 109/L
• Hgb 6 gms/dL, Hct 19
• AST/ALT 83/30 U/l Total bili 5.4 mg/dL (DB 2.7)
• PT/PTT 15.1/57.5 sec, Fibrinogen 247 mg/dL,
  DDimer 5.65 µg/ml, ferritin 1904
• IgA 12, IgG 603, IgM 22 (low), IgE 153 mg/dL

41
Cultures and Serologies
PaediatricsCase 2 Abel

• HAV , HCV negative, HBV positive (Ag negative)
• CMV PCR lt600 copies/ml
• ( CMV IgM negative, IgG )
• HIV ELISA negative
• Blood ()Klebsiella pneumoniae (sensitive to
  imi, mero, amikacin, and cipro/levo resistant to
  gent)
• Sputum ()Parainfluenza 3 by DFA
• Sputum negative AFB, TST negative, culture
  negative for TB, negative for Pneumocystis

42
Immunology Work Up
PaediatricsCase 2 Abel

• CD4 14, CD4 96 cells/µL
• Started on treatment doses of Trimethoprim/sulfame
  thoxasole
• HIV-1 RNA PCR gt750,000 copies/ml
• Mother and father
• HIV ELISA negative
• HIV RNA PCR negative

43
Efficacy of HIV TransmissionInfect Cont Hosp
Epidemiol 2006 27 944-52
Low risk procedure 0.5-3 risk High risk
procedure 10-20 risk
44
Clinical Course
PaediatricsCase 2 Abel

• Rapid respiratory failure - high O2, treated with
  steroids right lung pneumatocoeles developed and
  eventually placed on oscillator
• Endoscopy to evaluate anemia revealed chronic
  gastritis and erosions
• CT of abdomen - HSM, small ascites, calcification
  in right adrenal gland

45
Would You Start ARVs?
PaediatricsCase 2 Abel

• I would start antiretroviral therapy
• immediately.
• once the patient reaches his viral set point.
• once the patient can take oral medications.
• after I treat the patients pneumonia and
  pancytopenia first.

46
PaediatricsCase 2 Abel

• Clinical Course
• Started on Lopinavir/ritonavir, Zerit, and Epivir
  via G tube
• Sporadic treatment due to pancytopenia and
  pancreatitis
• CD4 ?ed 20 and 156, VL still gt750,000
• Continued respiratory distress
• 2 weeks later developed CMV early Ag in sputum
  culture
• CMV PCR increased to 3990
• 1 month into illness developed decreased movement
  of lower extremities, hypotonia, clonus

47
PaediatricsCase 2 Abel

• Clinical course
• LP WBC 0/mm3, protein 19 mg/dl, glucose 88 mg/dl
• CMV PCR gt100,000 copies/ml
• CT head - atrophy but no lesions
• Started ganciclovir
• Deceased 2 weeks later- no autopsy granted by
  family

48
CMV and HIV Disease Progression in Infants
49
PaediatricsCase 3 Lucy

• History of present illness
• 5 mo born in SE Asia, abandoned at the National
  Childrens Hospital at 1 month of age
• While at hospital noted to have cough, fever, and
  hemoptysis
• CXR - RUL infiltrate
• PCR of gastric aspirates for TB
• Transferred to TB hospital

50
PaediatricsCase 3 Lucy

• What would you do for the baby?
• I would send the following tests
• HIV DNA PCR and/ or HIV ELISA/WB
• TB culture- gastric aspirates or bronchoscopy?
• Complete blood count and CD4 if available
• Screen for Cystic fibrosis with a sweat test

51
PaediatricsCase 3 Lucy

• Hospital Course
• After 3 days of therapy on rifampin, INH and
  pyrazinamide, child developed liver test
  abnormalities gt1000, medications stopped
• 3 months later restarted INH and ethambutol.
• 1 month later continued to have hemoptysis, poor
  weight gain (3.4 kg ltlt3 ile), and progressive
  neurodevelopment delayed.
• CD4 15

52
PaediatricsCase 3 Lucy

• What would you do?
• TB management
• I would use rifampin, INH, pyrazinamide, and
  ethambutol as the initial regimen.
• I would modify my initial regimen given the age
  and poor condition of the baby.
• I would avoid using rifampin due to LFT
  abnormalities.
• I use intensive treatment for 2 months and then
  change to maintenance therapy.

53
PaediatricsCase 3 Lucy

• Other considerations?
• What else are you worried about in the baby?
• CNS disease?
• HIV?
• Wasting syndrome?
• Hepatitis?

54
TB and HIV cont.
55
TB and HIV
TB/HIV Clinical Manual. WHO. 2004. 2nd Edition