PEDIATRIC HIV UPDATE

NAZHA ABUGHALI, MD

5/31/02

Dr. Nazha Abughali is Assistant Professor of PediatricsCase Western Reserve UniversityHead 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.

1

MARI

NJDEMDDC

CT

0

160

3

10

42

2 4

0

2 6

1 5

0

1 0

61 1

3

2 4 00

2

1

0

1

0

0

0

0

0

0

2

1

1

0

0

11

0

1

1 1

3

1

2

3

4

3

7

0

Pediatric AIDS Cases Reported in 2000N=196

<5

5 - 10

10>

N umber of Cases

10

PR 2 VI 0 Guam 0

Children <13 Years of Age Living with HIV Infection*and AIDS, Reported through 2000

NJDEMDDC

CTRIMA

1

4

14

5

42

3

6

5

5

1

1

1

6

9

11

4

2373

1336

586

58

16

2017

23

49

17

2682

37

185

12913

8469

11

3

9

21

0

03

0

5

10

5

1

1

11

24

17

427

54

35

1554

38

88

32

93

31474

6118

106

280

0

13 5

155

107

125236

84

152

503

475

HIVN=1,662** N=2,703**

165

AIDS

1

ConfidentialHIV Reporting

RequiredPediatric only

* For areas with confidential HIV infection surveillance reported by patient name. Age based on current age as of December 2000.** Total includes cases missing state of residence data.

PR

789 2

VI

01

GUAM

N=1Race/Ethnicity N=3N=33

N=127N=31

*US Rate=0.4/100,000 N=196Total includes 1 case whose race/ethnicity is unknown

AmericanIndian/

Alaska Native

0.1

1.7

0.30.1 0.2

Whitenot Hispanic

Blacknot Hispanic

Hispanic Asian/PacificIslander

0

1

2

3

4

5

Rate

per

100,0

00

AIDS Rates per 100,000 Children <13 Years of Ageby Race/Ethnicity, Reported in 2000*, United States

AIDS CasesN=196

U.S. ChildrenN=53,282,000

AIDS Cases in Children <13 Years of Age, Reported in 2000and 2000 Population Estimates of Children, by Race/Ethnicity

United States

White, not HispanicBlack, not HispanicHispanic

Asian/Pacific IslanderAmerican Indian/ Alaska Native

63%

18%14%

1%4%

1%2%

65%

17%

16%

Exposure Category

%

90

1

100

91

4

3

2

Perinatally acquired

Transfusion-associated

Hemophilia

Number

177

2

1

196

1

Other/not reported 16 8

2000

Number %

1982-2000

8,133

382

237

8,908Total 100

156

Cumulative

AIDS in Children <13 Years of Age by Exposure CategoryReported in 2000 and Cumulative, United States

40

0-5 6-1112-1718-23 2 3 5 6 7 8 9 10 11 12

Perinatally Acquired AIDS Cases by Age at Diagnosis1982 - 2000, United States

A g e i n M o n th s A g e i n Y e a r s

200

400

600

800

1000

1200

1400

1600

1800

2000

Perc

ent o

f Cas

es

Mother's Exposure Category* by Year of Diagnosis forPerinatally Acquired AIDS, 1982 -1999, United States

0

1 0

2 0

3 0

4 0

5 0

6 0

7 0

Injection drug use

Heterosexual contact

Mother's risk not specified

Transfusion

Year of Diagnosis1 9 8 2 1 9 8 4 1 9 8 6 1 9 8 8 1 9 9 0 1 9 9 2 1 9 9 4 1 9 9 6 1 9 9 8

*Data adjusted for reporting delays and estimated proportional redistribution of cases reported without a risk.

Mother's Exposure Category* for Perinatally Acquired AIDS by Year of Diagnosis, 1996-1999 and

Cumulative, United States

1996-1999

Injection drug useHeterosexual contact

Mother's risk not specifiedTransfusion

1%

1980-1999

39%22%

36%39%38% 23%

2%

*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 14-34 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 United States985-1999,

Quarter-Year of Diagnosis*Adjusted for reporting delays and estimated proportional redistribution of cases reported without a risk;data reported through December 2000

Num

ber

of C

ases

19861985 1987 1988 1989 1990 1991 1992 19941993 1995 1996 1997 1998 19990

50

100

150

200

250

300

Quarter-Year of Birth

1993N=1451

1994N=1382

1995N=1361

1996N=1321

1997N=1417

1998N=1456

1999N=1346

Perc

ent R

ecei

ving

Zid

ovud

ine

0

2 0

4 0

6 0

8 0

1 0 0

Percent of Perinatally HIV Exposed or Infected Childrenwho Received or whose Mothers Received any ZDV*

Born 1993 - 1999 in 36 States, United States

* A n y Z D V = P r e n a t a l , i n t r a p a r t u m , o r n e o n a t a l r e c e i p t o f Z i d o v u d i n e t o r e d u c e p e r i n a t a l H I V t r a n s m i s s i o n

I n c l u d e s 3 6 a r e a s t h a t c o n d u c t p e d i a t r i c H I V S u r v e i l l a n c e ; d a t a r e p o r t e d t h r o u g h D e c e m b e r 2 0 0 0

Time of Maternal HIV Testing among Children PerinatallyExposed or Infected or with AIDS, Reported in 2000,

United States

Time of maternal HIV test

PerinatallyAcquired AIDS*N=177

No.

75Before or at birth

60After birth

42Unknown

No.

3,167

94

64

No.

105

53

38

%

42

34

24

%

95

3

2

%

54

27

19

HIV Exposed**N=3,325

HIV Infected**N=196

** From 36 areas with confidential pediatric HIV infection surveillance

* Excludes 19 children with AIDS reported in 2000 whose HIV exposure category was unknown or other than perinatal

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% 200-499 15-24%

3 <750 <15% <500 <15% <200 <15%

Mycobacterium avium infection

Condition

Lymphoid interstitial pneumonitisRecurrent bacterial infectionsHIV wasting syndrome

Candida esophagitis

Number

29592100183616141495

% of Cases*

3324211817

Pneumocystis carinii pneumonia

HIV encephalopathy1414 16

Cytomegalovirus disease 902 10

Pulmonary candidiasis 432 5

Severe herpes simplex infection 445 5Cryptosporidiosis

335 4

732 8

*>1 diagnosis reported for some children

AIDS-Defining Conditions Most Commonly Reported for Children <13 Years of Age, N=8,908,

Reported through 2000, United States

AIDS-Defining Conditions by Age at Diagnosis for Perinatally-Acquired AIDS Cases

Reported through 2000, United States

Age in Months0

0

50

100

150

200

250

300

350

400

450

2 4 6 8 10 12 14 16 18 20 22 24

Other AIDS-definingconditions

Pneumocystis carinii pneumonia

Num

ber

of C

ases

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 childImmunization: Give same vaccine as non-

infected, 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 childrenRational 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.