Transcript PEDIATRIC HIV UPDATE

PEDIATRIC HIV UPDATE
NAZHA ABUGHALI, MD
5/31/02
Dr. Nazha Abughali is Assistant Professor of Pediatrics
Case Western Reserve University
Head of Pediatrics TB Services, MetroHealth Medical Center
Global Epidemiology Of HIV
• 34.3 million individuals living with HIV/AIDS
world wide.
• 24.5 million are living in sub-Saharan Africa.
• 620,000 of children were estimated to be newly
infected in 1999.
• 1.3 million children estimated to be living with
HIV/AIDS.
• 3.8 million death in children due to HIV/AIDS
and 13.2 million AIDS orphans since the
beginning of the epidemics.
* Report on the global HIV/AIDS epidemic, 6/ 2000.
Pediatric AIDS Cases Reported in 2000
N = 196
2
0
0
0
1
0
0
0
0
24
3
1
26
2
15
11
1
0
0
1
1
0
7
3
2
3
1
0
4
1
0
3
16
0
4
2
10
6
24
0
1
PR 2
MA
RI
CT
NJ
DE
MD
DC
0
0
11
0
3
1
0
1
1
0
VI 0
Guam 0
N um ber of Cases
<5
5 - 10
> 10
Children < 13 Years of Age Living with HIV Infection*
and AIDS, Reported through 2000
11
0
1 1
13 5
3 0
5
24 9
2
4
17 11
1 1
0 1
73 23
5 5
5 4
21 10
6 3
10 3
28 9
0 6
11 6
152
54 36
107 27 13
18 1
155
503
4 4
35 16
14
61 69
93 37
54 17
15 20
82 26
38 23
32 17
84
88 49
PR
VI
GUAM
89
2 7
1 0
5
HIV
AIDS
N= 1,662** N = 2,70
236 125
0 1
MA
5
RI
CT 74 5
NJ 314 1
DE
1
MD
12
8
DC
165
475
Confidential
HIV Reporting
Required
Pediatric only
or areas with confidential HIV infection surveillance reported by patient name. Age based on current age as of December 2000.
otal includes cases missing state of residence data.
AIDS Rates per 100,000 Children < 13 Years of Age
by Race/ Ethnicity, Reported in 2000*, United States
Rate per 100,000
5
4
3
2
1.7
1
0
0.3
0.1
White
not Hispanic
Black
not Hispanic
N= 31
N= 127
Hispanic
N= 33
Race/ Ethnicity
*US Rate= 0.4/ 100,000 N= 196
Total includes 1 case whose race/ ethnicity is unknown
0.1
Asian/ Pacific
Islander
N= 3
0.2
American
Indian/
Alaska Native
N= 1
AIDS Cases in Children < 13 Years of Age, Reported in 2000
and 2000 Population Estimates of Children, by Race/ Ethnicity
United States
U.S. Children
N= 53,282,000
AIDS Cases
N= 196
63%
65%
16%
1%
2%
1%
4%
17%
18%
14%
White, not Hispanic
Black, not Hispanic
Hispanic
Asian/ Pacific Islander
American Indian/
Alaska Native
AIDS in Children < 13 Years of Age by Exposure Category
Reported in 2000 and Cumulative, United States
Exposure Category
Perinatally acquired
Transfusion-associated
Hemophilia
O ther/ not reported
Total
Cumulative
1982-2000
2000
N umber
%
N umber
%
177
90
8,133
91
2
1
1
1
382
4
237
3
16
8
156
2
196
100
8,908
100
Perinatally Acquired AIDS Cases by Age at Diagnosis
1982 - 2000, United States
2000
1800
1600
1400
1200
1000
800
600
400
200
0
0-5 6-11 12-1718-23
Age in Months
2
3
4
5
6
7
8
Age in Years
9
10
11 12
Percent of Cases
Mother's Exposure Category* by Year of Diagnosis fo
Perinatally Acquired AIDS, 1982 -1999, United State
70
In jectio n d rug use
60
50
40
H etero sexua l co n ta ct
30
M other's risk no t sp ec ifi ed
20
Tra nsfu sio n
10
0
1982
1984
1986
1988
1990
1992
Year of Diagnosis
*Data adjusted for reporting delays and estimated proportional redistribution of cases
reported without a risk.
1994
1996
1998
Mother's Exposure Category* for Perinatally Acquired
AIDS by Year of Diagnosis, 1996-1999 and
Cumulative, United States
1996-1999
22%
1980-1999
1%
39%
2%
39%
38%
Injection drug use
Heterosexual contact
36%
23%
Mother's risk not specified
Transfusion
*Data adjusted for reporting delays and estimated proportional redistribution of cases reported
without a risk.
Timing of maternal -infant
transmission
• Intrauterine: 25-40%
• Intrapartum: 60-75%.
• Added risk of breast -feeding : 12-14%.
Maternal- Infant Transmission
• In the absence of antiretroviral use
transmission rates 16-40%.
• AZT prophylaxis and the use of HAART in
pregnant women had resulted in a persistent
drop in rates of perinatal HIV transmission
to rates of 5-6% and even 2% in those with
undetectable viral loads.
Pediatric AIDS Clinical Trial
Group (PACTG) 076
• In placebo -controlled clinical trial the use
of AZT in pregnant women starting at 1434 weeks till delivery, intravenous AZT
during labor and oral AZT to the infants
from birth till 6 weeks of age resulted in a
67.5% reduction in HIV transmission:
25.5% in the placebo compared to 8.5% in
the AZT group.
•In August 1994, the US Public Health Services
recommended the use of AZT to reduced the risk of
perinatal HIV transmission.
•In 1995 the USPHS and the AAP recommended
routine HIV counseling and voluntary testing to all
pregnant women.
•Since then there had been persistent decrease in the
rate of perinatal transmission.
Perinatally Acquired AIDS Cases by Quarter-Year
of Diagnosis,* 1 985-1999, United States
300
Number of Cases
250
200
150
100
50
0
1985 1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999
Quarter-Year of Diagnosis
*Adjusted for reporting delays and estimated proportional redistribution of cases reported without a risk;
data reported through December 2000
Percent of Perinatally HIV Exposed or Infected Children
who Received or whose Mothers Received any ZDV*
Born 1993 - 1999 in 36 States, United States
Percent Receiving Zidovudine
10 0
80
60
40
20
0
1993
N= 1451
1994
N= 1382
1995
N= 1361
1996
N= 1321
1997
N= 1417
1998
N= 1456
Q uarter-Year of Birth
*Any ZDV= Prenatal, intrapartum, or neonatal receipt of Zidovudine to reduce perinatal HIV transmission
Includes 36 areas that conduct pediatric HIV Survei llance; data reported through December 2000
1999
N= 1346
Time of Maternal HIV Testing among Children Perinatally
Exposed or Infected or with AIDS, Reported in 2000,
United States
Perinatally
Acquired AIDS*
N= 177
HIV Exposed**
N= 3,325
HIV Infected**
N= 196
Time of maternal HIV test
No.
%
No.
%
No.
%
Before or at birth
75
42
3,167
95
105
54
After birth
60
34
94
3
53
27
Unknown
42
24
64
2
38
19
* Excludes 19 children with AIDS reported in 2000 whose HIV exposure category
was unknown or other than perinatal
** From 36 areas with confidential pediatric HIV infection surveillance
PREVENTION OF PEDIATRIC
HIV
• Early identification of HIV infected women
before pregnancy, during pregnancy or during
labor is crucial for :
- prevention of HIV vertical transmission to the
neonates.
- Counseling against breast-feeding in the U.S.
- Early identification of infected newborns, and thus,
early initiation of HAART and PCP prophylaxis.
- Early initiation of appropriate medical care for the
mother.
Guidelines for prevention of perinatal
HIV transmission
• Early maternal HIV diagnosis and initiation of
appropriate antiretoviral therapy before or during
pregnancy. Try to incorporate AZT.
• Use of standard AZT prophylaxis regimen:
intrapartum and neonatal AZT for 6 weeks.
• C-section: recommended for mothers with HIV
viral load > 1000 copies/ml (obtained at 36
weeks).*
* exceptions: PROM and /or labor> 4 hours.
Recommendation for for HIV-infected
mother in labor who had no prior therapy
1. Single dose Nevirapine during labor and a
single dose to the neonate at age 48h.
2.Oral AZT and 3TC during labor, and one
week of this combination to the neonate.
3. Intrapartum AZT, the 6 weeks of AZT to
the neonate.
4. The two dose Nevirapine combined with
the intrapartum and 6 weeks AZT regimen.
• IN case of maternal HIV antiretroviral
resistance:
AZT is still recommended to the infant, plus
other medications based on maternal HIV
resistance pattern.
Diagnosis of HIV
Child aged < 18 months:
• HIV can be diagnosed : two positive virological
assays* obtained from two different blood
samples, excluding cord blood.
• HIV can be excluded: 1) 2 negative HIV
virological tests, 1 performed age >1 month and
the other age > 4 months. 2) 2 negative HIV
antibody tests performed after age 6 months,
obtained one month apart.
• * HIV viral culture, HIV PCR DNA/RNA
Child aged > 18 months, or adolescents/adults:
•HIV can be diagnosed by: 1)A repeatedly positive HIV
antibody test , followed by a confirmatory test (western
blot).
2) A positive HIV virological test result: HIV PCR
RNA/DNA, viral culture…
•HIV can be excluded: 0ne negative HIV antibody, in the
absence of hypoglobulinemia with negative virological
tests and no clinical symptoms of HIV.
HIV pediatric classification:
clinical Categories
• Category N: Not symptomatic or have one
clinical entity of category A.
• Category A: 2 of the following with none of
B or C:
Lymphadenopathy (more thane one site),
hepatomegaly, Splenomegaly, dermatitis,
parotitis, recurrent or persistent URI,
sinusitis or otitis media.
Category B: Moderately symptomatic
• Anemia( <8mg/dl), neutropenia (<1000/ml) or
thrombocytopenia (<100,000/ml) persisting >30 days.
• Bacterial meningitis, pneumonia, sepsis.
• Candidiasis>2 months in older than 6 months old children.
• CMV infection with onset before 1 month of age.
• Chronic or recurrent diarrhea
• Recurrent HSV stomatitis, HSV bronchitis, or esophagitis
in age <1 month.
• Herpes zoster involving more than one dermatome or at
least 2 episodes. Or disseminated varicella
• Toxoplasmosis starting <one month of age.
• Others: cardiomyopathy, leiomyosarcoma, Nocardiosis,
nephropathy, and fever> 1 month.
• Category C : Severely symptomatic( AIDS
• serious bacterial infections: multiple or recurrent (culture
positive events, pneumonia, meningitis, septicemia).
• Candida: esophageal or pulmonary.
• Disseminated coccidioidmycosis, disseminated
Histoplasmosis
• Cryptococosis, crypotosporidiosis, isopspriosis with
diarrhea >1 month.
• CMV disease in children>1 months of age.
• Encephalopathy, PML, Wasting syndrome.
• HSV: pneumonitis, esophagitis children >1 months old.
• PCP, MTB disseminated or extrapulmonary, Salmonella
septicemia, Toxoplasmosis.
• Disseminated non-tuberculous mycobacteria.
• Malignancies: Kaposis sarcoma, lymphomas.
Immunological Classification of
Pediatric HIV
Age specific CD4+ T-lymphocyte count and % of total
Class
<12mo
1-5Y
6-12Y
1
1500 25%
1000 25%
500 25%
2
750-1499 15-24%
500-999 15-24%
3
<750 <15%
<500 <15%
200-499 15-24%
<200
<15%
AIDS-Defining Conditions Most Commonly Reported
for Children < 13 Years of Age, N= 8,908,
Reported through 2000, United States
Condition
Pneumocystis carinii pneumonia
Lymphoid interstitial pneumonitis
Recurrent bacterial infections
HIV wasting syndrome
HIV encephalopathy
Candida esophagitis
Cytomegalovirus disease
Mycobacterium avium infection
Severe herpes simplex infection
Cryptosporidiosis
Pulmonary candidiasis
*> 1 diagnosis reported for some children
Number
2959
2100
1836
1614
1495
1414
902
732
445
432
335
% of Cases*
33
24
21
18
17
16
10
8
5
5
4
AIDS-Defining Conditions by Age at Diagnosis for
Perinatally-Acquired AIDS Cases
Reported through 2000, United States
450
Number of Cases
400
Pneumocystis carinii pneumonia
350
300
O ther AIDS-defining
conditions
250
200
150
100
50
0
0
2
4
6
8
10
12
14
Age in Months
16
18
20
22
24
Care of the HIV- Exposed
Neonate
• After Birth:
• AZT : 2mg/kg Q 6 hr for 6 weeks.
If mother has HIV resistant to AZT then
might give additional meds.
• HIV PCR DNA with-in 48 hour of birth.
• Base-line CBC.
• Hepatitis B vaccine.
• 2 weeks :
• HCT. Check for compliance with meds.
• Optional HIV DNA PCR.
•
•
•
•
•
•
•
•
•
•
•
•
•
•
2 Months:
Well child visit.
HIV PCR, CBC.
AZT stopped at 6 weeks.
Start Bactrim prophylaxis.
Give the usual immunizations.
4 Months:
Well child visit.
HIV PCR.
Immunizations.
6 Months:
Well child visit.
Immunizations
Stop Bactrim if all HIV PCR’s are negative.
•
•
•
•
•
•
•
•
•
•
12 Months:
well child visit.
Immunizations.
15 Months:
Well Child visit .
Immunizations.
18 Months:
Well child visit.
Immunizations.
HIV antibody. If negative and child asymptomatic
the patient is discharged of the HIV clinic.
• All HIV exposed children who were
exposed to antiretroviral therapy in utero,
should be followed up till adulthood for any
potential future carcinogenicity . If any of
those children develop significant organ
system abnormalities of unknown etiology,
particularly involving the CNS and the heart.
They should be evaluated for potential
mitochondrial dysfunction. Pap smears
should be performed on adolescent girls.
Care of the HIV infected child:
• Start HAART as soon as possible.
• Obtain CBC, CD4+ T-cell count, HIV viral load Q2-3
months.
• Blood for chemistries, LFT’s, amylase lipase, lipid
profile are obtained Q3-6 months.
• Immunoglobulins yearly.
• PPD yearly
• CXR and urine analysis yearly.
• Clinic visit: Q2-3 months. Emphasis on growth and
development, social issues and compliance.
Care of the infected child
Immunization: Give same vaccine as noninfected, except for :
• Prevnar is recommended even in older children
plus the pneumoccocal polysaccharide vaccine.
• Flu vaccine is recommended for > 6 months of
age.
• Varicella vaccine consider only for
ClassA1N1.
• MMR is contraindicated for immunological
class 3.
Antiretroviral Therapy
• 1993 AZT monotherapy was recommended
as the standard of care for the treatment of
symptomatic HIV infected children.
• 1998 recommended the use of HAART and
the monitoring of HIV RNA viral load and
CD4+ T-cell counts as tools to assess
treatment progress.
Antiretroviral Therapy in children
Rational and considerations
• The majority of children acquire their HIV
infection close to the time of birth and
therefore, are considered to have primary
HIV infection. Thus, the importance of
initiation of HAART early on.
• The immune system of the neonates is in
the developing period, thus their virological
and immunological markers are different
than the adults.
Considerations for Antiretroviral
therapy in children
• Treatment in neonates occur in the context
of previous antiretroviral therapy in utero
and intrapartum.
• Drug pharmacokinetics changes in the
transition from infancy to adulthood.
• Special social issues in general and
compliance issues in particular are
important in the management of pediatric
HIV.
Monitoring of treatment progress
• Immunological parameters: absolute CD4+ T-cells
and their %.
• HIV viral load.
• Clinical parameters: growth and development and
the occurrence of infectious complications.
• Check for drug toxicity.
Indications for initiation of
HAART
• Clinical symptoms: class A, B or C.
• Immunological indications: category 2 or 3.
• Age 12 months initiate therapy regardless of
clinical, immunological or virological indications.
Indications for initiation of
HAART
• Asymptomatic children Age >12 months with
normal immune status:
1) Initiate therapy regardless of age or symptoms
2) Defer treatment in situations where the risk of
progression is low and other factors favor
postponing treatment. Follow closely and start if: A. High or increasing viral load.
B. Rapidly declining CD4 count or %.
C. Development of clinical symptoms.
HIV RNA PCR Assay Caveats
• Biological variations in the same individual ( up to
three fold.
• Viral load in perinatally infected children can be
very high in the first year of life, then gradually
decrease spontaneously, without therapy : average
of 0.6 log/year in the first 2 years of life. Slower
decline continues till age 4-5 years (average 0.3
log/year).
• Concurrent infection or even immunizations can
cause an increase in the viral load.
HIV viral RNA load as an indication
for initiation of therapy
• Regardless of age viral RNA >100,000
copies/ml is associated with high risk of
mortality.
• In children aged >30 months the risk of
death is very low at viral load <15,000
copies/ml, above that level risk increases to
>13%.
HIV viral RNA load as an indication
for initiation of therapy
• Children age <2 years with >0.7 log or 5
fold increase should be offered HAART.
• Children ages >2 years with >0.5 log or 3
fold increase should be offered HAART.
Choice of Antiretroviral therapy
• The goal of the medications is to:
1)maximally suppress viral replications,
2)preserve/restore immune function and
3)minimize toxicity.
• Before starting therapy: It is important to
discuss with the caregiver the importance of
compliance with the medications.
ANTIRETROVIRAL
MEDICATIONS
• Nucleoside reverse transcripatse inhibitors:
AZT, DDI, DDC, 3TC, D4T, Abacavir. Tenofovir
and Adefovir.
Toxicity: Mitochondrial dysfunction due to the
inhibition of mitochondrial DNA polymerase
gamma. Toxicity include: lactic acidosis, hepatic
steatosis, pancreatitis, myopathy and peripheral
neuropathy. Some toxicities are specific to
individual meds: ex: hematological with AZT,
fatal hypersensitivity reaction due to Abacavir.
• Non-nucleoside reverse transcriptase inhibitors:
ex: Nevirapine, Delaviradine, Efavirenz. .
Resistance can occur very rapidly and can confer
resistance to the whole class.
Toxicity: rashes, hepatotoxicity.
• Protease Inhibitors:
Ritonavir, Nelfinavir, Indinavir, Saquinavir,
Saquinavir soft Gel Cap, Amprenavir,
Lopinavir/ritonavir( Kaletra).
Toxicity: lipodystrophy with fat redistribution and
hyperlipidemia. Hyperglycemia. Kidney stones
with Indinavir
Recommended Antiretroviral
Regimens for initial Treatment
• Strongly recommended:
• PI (nelfinavir or Ritonavir) and 2 NRTI *.
• NNRTI ( sustiva) plus 2 NRTI, or one NRTI
and PI ( nelfinavir).
* NRTI combinations: AZT/ddI, AZT/3TC,
d4T/ddI, d4T/3TC.
Recommended as Alternative
therapy
• Nevirapine (NNRTI) and 2 NRTI’s.
• Abacavir (NRTI) and AZT, 3TC.
• Kaletra ( Lopinavir/ritonavir)and 2 NRTIs,
or one NRTI and one NNRTI.
• Indinavir or Saquinavir soft gel capsules
and 2 NRTI.
Offered in special circumstances:
• Two NRTIs.
• Amprenavir with either 2 NRTIs or
Abacavir.
Not recommended:
• Any monotherpay.
• d4T/AZT
• ddC with either ddI or d4T or 3TC.
Indications for changing therapy
• Evidence of disease progression based on:
immunological, virological or clinical
parameters.
• Toxicity or intolerance to current therapy.
The decision to change medications should
be a team decision involving the caregivers
and child. Intensive family education and
training in the administration of medications
and compliance should be reemphasized.
• If there is evidence of disease progression:
suspect either:
1- compliance problem: discuss with family the
pattern of medications intake , and repeat lab tests.
3- viral resistance: send the virus for genotypic
testing ( while the patient is on medications) and
then change meds accordingly.
Indications for Changing Therapy
1)Virological considerations:
• Inadequate initial response to meds after 8-12
weeks : If on HAART < one log(10 fold) drop in
viral load.
• Repeated detection of HIV RNA in children who
initially responded and achieved undetectable
levels.
• Viral load not suppressed to undetectable levels
after 4-6 months of therapy.( excluding those with
very high viral load who sustain a 1.5-2 log drop.
• A reproducible increase in HIV RNA in children
who initially had substantial drop in their viral
load: >0.5 log in children ages<2 years, and >0.7
log for those younger than 2 years old
Immunulogical considerations
• Change in the immunological classification.
• For children with CD4+ T-cell % < 15%:
a persistent 5% or more drop.
• A rapid and substantial decrease in absolute
CD4+ T-cell count ( >30% drop in 6
months).
Clinical considerations
• Progressive neurodevelopmental
deterioration.
• Growth failure with adequate nutrition and
the absence of other obvious reasons.
• Disease progression: Advancement from
one clinical category to another.