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(Hiv) pediatrics
1. G . E R I C ™ M D 4
HUMAN
IMMUNODEFICIENCY VIRUS
(HIV) PEDIATRICS
2. HIV infection has become an important contributor to
childhood morbidity and mortality, especially in many
developing countries. Worldwide, it is estimated that
nearly 2 million require
antiretroviral treatment. At present only 25% of such
children have an access to the antiretroviral therapy.
Without access to antiretroviral therapy, 20% of vertically
infected children will progress to the acquired
immunodeficiency
syndrome (AIDS) or death in their first yr of
life and more than half of HIV-infected children will die
before their fifth birthday.a
3. Natural History
Before highly active antiretroviral therapy (HAART) was
available, three distinct patterns of disease were described
in children. Approximately 10-20% of HIV-infected
newborns in developed countries presented with a rapid
disease course, with onset of AIDS and symptoms during
the first few months of life and, if untreated, death from
AIDS-related complications by 4 yr of age. In resourcepoor
countries, >85% of the HIV-infected newborns may
have such a rapidly progressing disease.
4. It has been suggested that if intrauterine infection
coincides with the period of rapid expansion of CD4 cells
in the fetus, it could effectively infect the majority of the
body's immunocompetent cells. Most children in this
group have a positive HIV-1 culture and/or detectable
virus in the plasma in the first 48 hr of life. This early
evidence of viral presence suggests that the newborn was
infected in utero. In contrast to the viral load in adults, the
viral load in infants stays high for at least the first 2 yr of
life.
5. The majority of perinatally infected newborns (60-80%)
present with a second pattern-that of a much slower
progression of disease with a median survival time of 6 yr.
Many patients in this group have a negative viral culture
or PCR in the 1st week of life and are therefore considered
to be infected intrapartum. In a typical patient, the viral
load rapidly increases by 2-3 months of age (median
100,000 copies/ml) and then slowly declines over a period
of 24 months. This observation can be explained partially
by the immaturity of the immune system in newborns and
infants.
6. The third pattern of disease (i.e. longterm survivors)
occurs in a small percentage ( <5%) of perinatally infected
children who have minimal or no progression of disease
with relatively normal CD4 counts and very low viral
loads for longer than 8 yr.
HIV-infected children have changes in the immune
system that are similar to those in HIV-infected adults.
CD4 cell depletion may be less dramatic because infants
normally have a relative lymphocytosis. Therefore, for
example, a value of 1,500 CD4 cells/mm3 in children <1
yr of age is indicative of severe CD4 depletion and is
comparable to <200 CD4 cells/ mm3 in adults.
7. Clinical Manifestations
The clinical manifestations of HIV infection vary widely
among infants, children and adolescents. In most infants,
physical examination at birth is normal. Initial signs and
symptoms may be subtle and nonspecific, such as
lymphadenopathy, hepatosplenomegaly, failure to thrive,
chronic or recurrent diarrhea, interstitial pneumonia, or
oral thrush and may be distinguishable from other causes
only by their persistence.
8. Whereas systemic and pulmonary
findings are common in the United States and Europe,
chronic diarrhea, wasting and severe malnutrition
predominate in Africa. Symptoms found more commonly
in children than adults with HIV infection include
recurrent bacterial infections, chronic parotid swelling,
lymphocytic interstitial pneumonitis and early onset of
progressive neurologic deteriorationThe pediatric HIV
disease is staged by using two
parameters: clinical status and degree of
immunologic impairment
10. Clinical stage 3
Unexplained• moderate malnutrition or wasting not adequately responding to
standard therapy
Unexplained• persistent diarrhea (14 days or more)
Unexplained• persistent fever (above 37.5
°
C intermittent or constant, for longer than one month)
Persistent oral candidiasis (after the first 6-8 weeks of life)
Oral hairy leukoplakia
Acute necrotizing ulcerative gingivitis/periodontitis
Lymph node tuberculosis
Pulmonary tuberculosis
Severe recurrent bacterial pneumonia
Symptomatic lymphoid interstitial pneumonitis
Chronic HIV-associated lung disease including bronchiectasis
Unexplained anemia ( <8 g/ dl), neutropenia ( <0.5 x 109 /1) or chronic
thrombocytopenia ( <50 x 109 /1).
11. Clinical stage 4b
Unexplained• severe wasting, stunting or severe malnutrition not responding to standard
therapy
Pneumocystis pneumonia
Recurrent severe bacterial infections (e.g. empyema, pyomyositis, bone or joint infection,
meningitis, but excluding pneumonia)
Chronic herpes simplex infection (orolabial or cutaneous of more than one month's duration or
visceral at any site)
Esophageal candidiasis (or candidiasis of trachea, bronchi or lungs)
Extra pulmonary/ disseminated TB
Kaposi sarcoma
Cytomegalovirus infection: retinitis or CMV infection affecting another organ, with onset at age
> 1 mo
Central nervous system toxoplasmosis (after one month of life)
Extrapulmonary cryptococcosis (including meningitis)
HIV encephalopathy
Disseminated endemic mycosis (extrapulmonary histoplasmosis, coccidioidomycosis)
Disseminated nontuberculous mycobacterial infection
Chronic cryptosporidiosis (with diarrhea)
Chronic isosporiasis
Cerebral or B cell non-Hodgkin lymphoma
Progressive multifocal leukoencephalopathy
Symptomatic HIV-associated nephropathy or HIV-associated cardiomyopathy
12. Opportunistic Infections
Children with HIV infection and advanced or severe
immunosuppression are susceptible to develop various
opportunistic infections. The important pathogens
include
Pneumocystis jiroveci, Cryptosporidium,
Cryptococcus,
Isospora and CMV.
13. Respiratory Diseases
Pneumocystis pneumonia Pneumocystis jiroveci (previously
P. carinii) pneumonia (PCP) is the opportunistic
infection that led to the initial description of AIDS. PCP is
one of the commonest AIDS defining illnesses in children
in the US and Europe. However, data regarding the
incidence of PCP in children in other parts of the world
are scarce. The majority of the cases occur between 3rd
and 6th months of life.
Even if a child develops PCP while on prophylaxis,
therapy may be started with cotrimoxazole. This is because
the prophylaxis may have failed because of poor
compliance, or unusual pharmacokinetics. Untreated, PCP
is universally fatal. With the use of appropriate therapy,
the mortality decreases to less than 10%.
14. Recurrent bacterial infections In various studies from
developing countries, up to 90% of HIV-infected children
had history of recurrent pneumonias. Initial episodes of
pneumonia often occur before the development of
significant immunosupression. As the immunosupression
increases the frequency increases. In various studies from
developing countries, up to 90% of HIV-infected children
had history of recurrent pneumonias. Initial episodes of
pneumonia often occur before the development of
significant immunosupression. As the immunosupression
increases the frequency increases.
15. Tuberculosis With the spread of the HIV infection, there
has been resurgence in tuberculosis. Coexistent TB and HIV
infections accelerate the progression of both the diseases.
HIV infected children are more likely to have extrapulmonary
and disseminated tuberculosis; the course is also
likely to be more rapid. An HIV infected child with
tubercular infection is more likely to develop the disease
than a child without HIV infection. The overall risk of active
TB in children infected with HIV is at least 5- to 10-fold
higher than that in children not infected with HIV.
All HIV-infected children with active TB should receive
longer duration of antitubercular therapy. A 9-12 month
therapy is preferred.
16. Viral infections Infections caused by respiratory
syncytial
virus, influenza and parainfluenza viruses result in
symptomatic disease more often in HIV infected
children
in comparison to noninfected children. Infections with
other viruses such as adenovirus and measles virus are
more likely to lead to serious sequelae than with the
previously mentioned viruses.
17. Fungal infections Pulmonary fungal infections usually
present as a part of disseminated disease in
immunocompromised
children. Primary pulmonary fungal infections
are uncommon.
Pulmonary candidiasis should be suspected in any sick
HIV-infected child with lower respiratory tract infection
that does not respond to the common therapeutic
modalities.
A positive blood culture supports the diagnosis of
invasive candidiasis.
18. Lymphoid interstitial pneumonitis (LIP) LIP has been
recognized as a distinctive marker for pediatric HIV
infection and is included as a Class B conditio11 in the
revised CDC criteria for AIDS in children. In absence of
antiretroviral therapy, nearly 20% of HIV-infected children
developed LIP.
The etiology and pathogenesis of LIP are not well
understood. Suggested etiologies include: an exaggerated
immunologic response to inhaled or circulating antigens,
and/or primary infection of the lung with HIV, EpsteinBarr
virus (EBV), or both. LIP is characterized by nodule formation and diffuse
infiltration of the alveolar septae by lymphocytes,
plasmacytoid lymphocytes, plasma cells and immunoblasts.
There is no involvement of the blood vessels or destruction
of the lung tissue. Children with LIP have a relatively good
prognosis compared to other children who meet the
surveillance definition of AIDS.
19. Gastrointestinal Diseases
The pathologic changes in the gastrointestinal tract of
children with AIDS are variable and can be clinically
significant.
A variety of microbes can cause gastrointestinal disease,
including bacteria (salmonella, campylobacter, Mycabacterium
avium intracellulare complex), protozoa (giardia,
cryptosporidium, isospora, microsporidia), viruses (CMV,
HSV, rotavirus) and fungi (Candida). The protozoa!
infections are most severe and can be protracted in
children with severe immunosuppression. Children with
cryptosporidium infestation can have severe diarrhea
leading to hypovolemic shock. AIDS enteropathy, a syndrome
of malabsorption with partial villous atrophy not
associated with a specific pathogen, is probably the result
of direct HIV infection of the gut.
20. Neurologic Diseases
The incidence of central nervous system involvement in
perinatally infected children may be more than 50% in
developing countries but lower in developed countries,
with a median onset at about one and a half yr of age. The
most common presentation is progressive encephalopathy
with loss or plateau of developmental milestones,
cognitive deterioration, impaired brain growth resulting
in acquired microcephaly and symmetric motor
dysfunction.
21. Meningitis due to bacterial pathogens, fungi such
as Cryptococcus and a number of viruses may be
responsible. Toxoplasmosis of the nervous system is
exceedingly rare in young infants, but may occur in
HIVinfected
adolescents; the overwhelming majority of these
cases have serum IgG antitoxoplasma antibodies as a
marker of infection. The management of these conditions
is similar to that in non-HIV-infected children; the
response rates and outcomes may be poorer.
22. Cardiovascular Involvement
Cardiac abnormalities in HIV-infected children are
common, persistent and often progressive; however, the
majority of these are subclinical. Left ventricular structure
and function progressively may deteriorate in the first 3 yr
of life, resulting in increased ventricular mass in
HIVinfected
children. Electrocardiography and echocardiography are
helpful in
assessing cardiac function before the onset of clinical
symptoms.
23.
24. Renal Involvement
Nephropathy is an unusual presenting symptom of
HIV
infection, more commonly occurring in older
symptomatic
children. Nephrotic syndrome is the most common
manifestation of pediatric renal disease, with azotemia
and
normal blood pressure. Polyuria, oliguria and
hematuria
have also been observed in some patients.
25. Diagnosis
All infants born to HIV-infected mothers test antibodypositive
at birth because of passive transfer of maternal
HIV antibody across the placenta. Most uninfected infants
lose maternal antibody between 6 and 12 months of age. As a
small proportion of uninfected infants continue to
have maternal HIV antibody in the blood up to 18 months
of age, positive IgG antibody tests cannot be used to make
a definitive diagnosis of HIV infection in infants younger
than this age. In a child older than 18 months of age,
demonstration of IgG antibody to HIV by a repeatedly
reactive enzyme immunoassay (EIA) and confirmatory
test (e.g. Western blot or immunofluorescence assay) can
establish the diagnosis of HIV infection.
26. Specific viral diagnostic assays, such as HIV DNA or
RNA PCR, HIV culture, or HIV p24 antigen immune
dissociated p24 (ICD-p24), are essential for diagnosis
of
young infants born to HIV infected mothers. By 6
months
of age, the HIV culture and/or PCR identifies all
infected
infants, who are not having any continued exposure
due
to breast feeding.
27. Management
The management of HIV infected child includes
antiretroviral
therapy, prophylaxis and treatment of opportunistic
infections and common infections, adequate nutrition
and
immunization.
28. Antiretroviral Therapy
Decisions about antiretroviral therapy for pediatric
HIVinfected
patients are based on the magnitude of viral
replication (i.e. viral load), CD4 lymphocyte count or
percentage and clinical condition. A child who has WHO
stage 3 or 4 clinical disease should receive ART irrespective
of the immunologic stage. Children who are asymptomatic
or have stage 1 or 2 disease may be started on ART if they
have evidence of advanced or severe immunosupression.
29. However, current evidence shows that young children less
than 2 yr of age have a higher risk of mortality without
ART. The World Health Organization now recommends
initiation of ART for all HIV infected children less than 2
yr
age irrespective of clinical symptoms and the
immunologic stage. Availability of antiretroviral therapy
has transformed
HIV infection from a uniformly fatal condition to a chronic
infection, where children can lead a near normal life. The
currently available therapy does not eradicate the virus and
cure the child; it rather suppresses the virus replication for
extended periods of time.
30. The 3 main groups of drugs are
nucleoside reverse transcriptase inhibitors (NRTI),
nonnucleoside
reverse transcriptase inhibitors (NNRTI) and
protease inhibitors (PI). Highly active antiretroviral
therapy
(HAART) is a combination of 2 NRTis with a PI or a
NNRTI.
31. The national program for management of HIV infected
children recommends a combination of zidovudine,
lamivudine and nevi.rapine as the first line therapy.
The alternative regimen is a combination of stavudine,
lamivudine and nevirapine and these are
administered using a weight-band based dosing
system
(NACO guidelines).a
32. Cotrimoxazole Prophylaxis
. In resource-limited settings, cotrimoxazole prophylaxis is
recommended for all HIV exposed infants starting at
4-6 weeks of age and continued until HIV infection can be
excluded. Cotrimoxazole is also recommended for
HIVexposed
breastfeeding children of any age and cotrimoxazole
prophylaxis should be continued until HIV infection
can be excluded by HIV antibody testing (beyond 18
months
of age) or virological testing (before 18 months of age) at
least six weeks after complete cessation of breastfeeding.
33. All children younger than one yr of age documented to
be living with HIV should receive cotrimoxazole
prophylaxis
regardless of symptoms or CD4 percentage. After
one yr of age, initiation of cotrimoxazole prophylaxis is
recommended for symptomatic children (WHO clinical
stages 2, 3 or 4 for HIV disease) or children with CD4
<25%. All children who begin cotrimoxazole prophylaxis
(irrespective of whether cotrimoxazole was initiated in the
first yr of life or after that) should continue until the age
of five yr, when they can be reassessed.
34. Nutrition
It is important to provide adequate nutrition to
HIVinfected
children. Many of these children have failure to thrive.
These children will need nutritional rehabilitation.
In addition, micronutrients like zinc may be useful
Immunization
The vaccines that are recommended in the national
schedule can be administered to HIV infected children
except that symptomatic HIV infected children should not
be given the oral polio and BCG vaccines.
35. Prevention of Mother to Child Transmission
(PMTCT)
The risk of MTCT can be reduced to under 2% by
interventions that include antiretroviral (ARV) prophylaxis
given to women during pregnancy and labor and to the
infant in the first weeks of life, obstetrical interventions
including elective cesarean delivery (prior to the onset of
labor and rupture of membranes) and complete avoidance
of breastfeeding
36. Antiretroviral drug regimens for treating pregnant
women For HIV-infected pregnant women in need of
ART for their own health, ART should be administered
irrespective of gestational age and is continued throughout
pregnancy, delivery and thereafter (recommended for
all HIV-infected pregnant women with CD4 cell count
<350 cells/mm3
, irrespective of WHO clinical staging; and
for WHO clinical stage 3 or 4, irrespective of CD4 cell
count).
37. Recommended regimen for pregnant women with
indication for ART is combination of zidovudine (AZT),
lamivudine (3TC) and nevirapine (NVP) or efavirenz
(EFV) during antepartum, intrapartum and postpartum
period; EFV-based regimens should not be newly-
initiated
during the first trimester of pregnancy. Recommended
regimen for pregnant women who are
not eligible for ART for their own health, but for
preventing MTCT is to start ART as early as 14 weeks
gestation or as soon as possible when women present late
in pregnancy, in labor or at delivery.
38. Two options are available
Option 1. Daily AZT in antepartum period, combination
of single dose of NVP at onset of labor and dose of AZT
and 3TC during labor followed by combination of AZT
and 3TC for 7 days in postpartum period.
Option 2. Triple antiretroviral drugs starting as early as
14 week of gestation until one week after all exposure to
breast milk has ended (AZT + 3TC + LPV or AZT + 3TC +
ABC or AZT + 3TC + EFV) where ABC abacavir, LPV
lopinavir.
39. Omission of the single dose-NVP and AZT +3TC
intraand
postpartum may be considered for women who
received at least four week of AZT before delivery. If a
woman received a three-drug regimen during
pregnancy,
a continued regimen of triple therapy is recommended
for mother through the end of the breastfeeding
period.
40. Regimens for Infants Born to HIV Positive
Mothers
(a) If mother received only AZT during antenatal
period:
For breastfeeding infants. Daily NVP from birth until one
wk after all exposure to breast milk has ended. The dose
of nevirapine is 10 mg/ day PO for infants <2.5 kg; 15 mg/
day PO for infants more than 2.5 kg.
For nonbreastfeeding infants. Daily AZT or NVP from
birth
until 6 wk of age. The dose of AZT is 4 mg/kg PO per
dose twice a day.
41. (b) If mother received triple drug ART during
pregnancy and
entire breastfeeding: Daily AZT or NVP from birth
until 6
weeks of age irrespective of feeding
42. lntrapartum lntervetions
Avoid artificial rupture of membranes (ARMs) unless
medically indicated. Delivery by elective cesarean
section
at 38 weeks before onset of labor and rupture of
membranes should be considered. Avoid procedures
increasing risk of exposure of child to maternal blood
and
secretions like use of scalp electrodes.
43. Breastfeeding
Breastfeeding is an important modality of transmission
of HIV infection in developing countries. The risk of HIV
infection via breastfeeding is highest in the early months
of breastfeeding. Factors that increase the likelihood of
transmission include detectable levels of HIV in breast
milk, the presence of mastitis and low maternal CD4+ T
cell count. Exclusive breastfeeding has been reported to carry
a lower risk of HIV transmission than mixed feeding. Mothers
known to be HIV-infected should only give commercial
infant formula milk as a replacement feed when specific
conditions are metWHO recommends that
the transition between exclusive breastfeeding and early
cessation of breastfeeding should be gradual and not an
"early and abrupt cessation". Replacement feeding
should be given by katori spoon
44. Conclusion
HIV infection in children is a serious problem in many
developing countries. The severe manifestations of HIV
infection, conditions resulting from severe immunosupression
and drug toxicities may require intensive care.
Development of a vaccine to prevent HIV infection is the
high priority area. There is also need to find have more
efficacious antiretroviral drugs that have fewer adverse
effects. Making available antiretroviral therapy at an
affordable cost remains a big challenge. On short-term
there is a need to find effective ways to control vertical
transmission from mother to child. It may help in substantial
reduction in childhood HIV infection load.
