Treating Opportunistic Infection Among HIV-Infected Children

Treating Opportunistic Infection
Among HIV-Infected Children

Recommendations from the
CDC, the National Institutes of
Health, and the Infectious
Diseases Society of America
December 3, 2004
About This Presentation
These slides were developed using the December
2004 Guidelines. The intended audience is clinicians
involved in the care of patients with HIV.
The user is cautioned that, due to the rapidly
changing field of HIV care, this information could
become out of date quickly. Finally, it is intended that
these slides be used as prepared, without changes in
either content or attribution. Users are asked to honor
this intent.
-AETC NRC
http://www.aidsetc.org
2
Contents
 Introduction (slide 3)
 Bacterial, parasitic, and  Fungal infections
other infections (slide 8) (slide 61)
 Serious and recurrent  Pneumocystis jiroveci
bacterial infections, syphilis, pneumonia, Candida,
toxoplasmosis, cryptococcosis,
crypto/microsporidiosis histoplasmosis,
 Mycobacterial infections coccidioidomycosis
(slide 39)  Viral infections
(slide 104)
 MTB, MAC
 CMV, HSV, HZV, HPV,
HCV, HBV
3
Introduction
 Mother-to-child transmission of OI is an
important mode of acquisition
 HIV-infected women coinfected with OI
more likely to transmit (e.g., CMV, HCV)
 HIV-infected women or HIV-infected family
members are sources of horizontal
transmission (eg, tuberculosis)
4
Differences between Adults and
Children
 OI in children often reflects primary
infection rather than reactivation
 OI occurs at a time when infant’s immune
system is immature
 Different disease manifestations (eg,
children more likely to have nonpulmonic
and disseminated tuberculosis)
5
Difficulty of Diagnosing OI
in Children
 Inability to describe symptoms

 Antibody-based tests confounded by
maternal transfer of antibody
 Sputum difficult to obtain without invasive
procedures
6
Frequency of OI among HIV-
Infected Children
 Pre-HAART era, most common OIs occurring at
>1 events/100 child years
 Serious bacterial infections (bacteremia and
pneumonia), herpes zoster, Pneumocystis jiroveci
(carinii) pneumonia, candidiasis, Mycobacterium
avium complex
 Pre-HAART era, most common OIs occurring at
<1 events/100 child years
 Cytomegalovirus, toxoplasmosis, cryptosporidiosis,
tuberculosis, systemic fungal infections
7
Treating OI among HIV-Infected
Children
Rating of treatment recommendations is
based on opinion of working group
 Letter indicating strength of
recommendation (e.g., A, B, C)
 Roman numeral indicating nature of
evidence (e.g., I, II, III)
8
Serious Recurrent Bacterial Infections
Epidemiology
 Most common infection in pre-HAART era

(15/100 child years)
 Because of difficulties in obtaining appropriate
diagnostic specimens, bacterial pneumonia is
often a presumptive diagnosis in a child with
fever, pulmonary symptoms, and an abnormal
chest radiogram
 Bacteremia more common in HIV-infected
children with pneumonia
9
Epidemiology
 Isolated bacteria include Streptococcus

pneumoniae, Haemophilus influenzae type B,
Staphylococcus aureus, Escherichia coli,
Pseudomonas aeruginosa, nontyphoid
Salmonella
 Incidence of S pneumoniae and H influenzae
may be lower in regions where vaccines are
administered
10
Clinical Manifestations
 Clinical presentation dependent on type of

bacterial infection, e.g., bacteremia, sepsis,
vasculitis, septic arthritis, pneumonia,
meningitis, sinusitis
 Presentation similar to that of HIV-uninfected
children
11
Diagnosis
 Isolation of pathogenic organism from normally

sterile sites – blood, bone marrow, CSF
 Diagnosis of pneumonia by radiograph and
physical findings
 Culture of catheter tips
12
Treatment
 Consider local prevalence of resistance of common
infectious agents
 Response of mildly immunodeficient children is similar to
that of HIV-uninfected children
 Treat HIV-infected children outside the neonatal period
with empiric therapy until cultures are available (A III)
 Ceftriaxone: 80-100 mg/kg in 1 or 2 divided doses, or
 Cefotaxime: 150-200 mg/kg divided into 3 or 4 doses, or
 Cefuroxime: 100-150 mg/kg divided into 3 doses
13
Treatment
 Children <5 years should be given H influenza B

and heptavalent pneumococcal conjugate
vaccines (A II)
 Children >2 years should receive 23 valent
pneumococcal vaccine (>2 months after
conjugate vaccine)
 Reimmunize with pneumococcal vaccine in 3-5
years in children <10 years or after 5 years in
children >10 years
14
Syphilis
Epidemiology
 Perinatal transmission of Treponema pallidum at
any stage of pregnancy or during delivery
 Drug use during pregnancy increases risk of
maternal and congenital syphilis
 Rate of congenital syphilis 50 times greater
among infants born to HIV-infected mothers
 Half of new infections are in women 15-24 years
of age
15
Syphilis
 Untreated early syphilis in pregnancy leads to

spontaneous abortion, stillbirth, hydrops,
preterm delivery, death in up to 40% of
pregnancies
 47% of infants born to mothers with
inadequately treated syphilis have clinical,
radiographic, or laboratory findings consistent
with congenital syphilis
16
Syphilis
 60% of infants with congenital syphilis have

hepatomegaly, jaundice, skin rash, nasal
discharge, anemia, thrombocytopenia,
osteochondritis, or pseudoparalysis
 Late manifestations include mental retardation,
keratitis, deafness, frontal bossing, Hutchinson
teeth, saddle nose, Clutton joints
17
Syphilis
Diagnosis
 Use combination of physical, radiologic,

serologic, and direct microscopic results, as
standard serologic tests detect only IgG
 All infants born to mothers with reactive
nontreponemal and treponemal test should be
evaluated with a quantitative nontreponemal
test, e.g., slide test, rapid plasma reagin (RPR)
18
Syphilis
Diagnosis
 Darkfield microscopy or direct fluorescent

antibody staining
 Presumptive diagnosis – any infant, regardless
of physical findings, born to an untreated or
inadequately treated mother with syphilis
19
Syphilis
Treatment
 Treat all infants whose mothers have untreated

or inadequately treated syphilis; treated or
initiated treatment 4 weeks prior to delivery
 Treat infants regardless of maternal history if
examination suggests syphilis; darkfield or
fluorescent antibody test positive or
nontreponemal serologic titer = 4-fold higher
than maternal (A II)
20
Syphilis
Treatment
 Aqueous crystalline penicillin G: 100,000-
150,000 units/kg/day given as 50,000
units/kg/dose intravenously every 12 hours for 7
days followed by every 8 hours for a total of 10
days (A II)
 Diagnosis after 1 month of age, increase dosage
to 200,000-300,000 units/kg intravenously every
6 hours daily for 10 days
21
Syphilis
Treatment
 Treat acquired syphilis with single dose of benzathine penicillin

G 50,000 units/kg IM
 Treat late latent disease with 3 doses of benzathine penicillin
G 50,000 units/kg IM once weekly for 3 doses (A III)
 Alternative therapies among HIV-infected patients have not
been evaluated
 Follow up with examinations at 1, 2, 3, 6, and 12 months and
serologic tests at 3, 6, and 12 months; if titers continue to be
positive or increase, consider retreatment (A III)
22
Toxoplasmosis
Epidemiology
 Primarily perinatal transmission from primary

infection of mothers during pregnancy
 Older children acquire toxoplasmosis from poorly
cooked food and from ingestion of sporulated
oocysts in soil, water, or food
23
Toxoplasmosis
Epidemiology
 Risk of transmission in HIV-uninfected mothers

with primary infection during pregnancy = 29%
(lower if maternal infection in first trimester)
 Perinatal toxoplasmosis infection may occur in
HIV-positive women with chronic infection
 <1% of AIDS-defining illnesses in children
24
Toxoplasmosis
 Non-immunocompromised infants are usually

asymptomatic at birth but majority develop late
manifestations – retinitis, neurologic impairment
 Newborn symptoms can include:
 Rash, lymphadenopathy, jaundice, hematologic
abnormalities, seizures, microcephaly, chorioretinitis,
hydrocephalus
25
Toxoplasmosis
 Toxoplasmosis acquired after birth is initially

asymptomatic, followed by infectious
mononucleosis-like syndrome
 Chronic toxoplasmosis can reactivate in HIV-
infected children
26
Toxoplasmosis
Diagnosis
 Test all HIV-infected pregnant women for

toxoplasmosis
 If positive, evaluate infant for congenital
toxoplasmosis
 Use antibody assay to detect IgM-, IgA-, or IgE-
specific antibody in first 6 moths or persistence
of IgG antibody after 12 months
27
Toxoplasmosis
Diagnosis
 Additional methods include isolation of

toxoplasmosis from body fluids or blood
 Negative antibody does not exclude
toxoplasmosis – may require CT, MRI, or brain
biopsy in case of encephalitis
28
Toxoplasmosis
Treatment
 If HIV-positive mother has symptomatic toxoplasmosis
during pregnancy, infant should be treated (B III)
 Preferred treatment – congenital toxoplasmosis:
 Pyrimethamine loading dose of 2 mg/kg orally once
daily for 2 days; then 1 mg/kg orally once daily for 2-6
months; then 1 mg/kg orally 3 times/week with
sulfadiazine 50 gm/kg/dose twice daily and with
leucovorin (folinic acid) 10 mg orally with each dose
of sulfadiazine (A II)
 Optimal duration of treatment: 12 months
29
Toxoplasmosis
Treatment
Treatment of HIV-infected children with acquired
CNS, ocular, or systemic toxoplasmosis
 Pyrimethamine: 2 mg/kg/day (maximum 50
mg/kg) orally for 3 days; then 1 mg/kg/day orally
and leucovorin 10-25 mg/day plus sulfadiazine
25-50 mg/kg/dose orally given 4 times daily
 Continue acute therapy for 6 weeks
 Lifelong prophylaxis required
30
Toxoplasmosis
Treatment
 Pyrimethamine: rash, Stevens-Johnson

syndrome, nausea, reversible bone marrow
toxicity
 Sulfadiazine: rash, fever, leukopenia, hepatitis,
nausea, vomiting, diarrhea, crystalluria
31
Toxoplasmosis
Alternative Treatment
 Azithromycin: 900-1,200 mg/kg/day with

pyrimethamine and leucovorin (B II), but not
evaluated in children
 Adults – atovaquone: 1,500 mg orally twice daily
plus pyrimethamine and leucovorin (C III), but
not evaluated in children
 Limited use of corticosteroids as adjuvant
therapy with CNS disease
32
Cryptosporidiosis/Microsporidiosis
Epidemiology
 Protozoal parasites that cause enteric illness in humans
and animals
 Human infection primarily caused by C hominis,
C parvum, C meleagridis
 Microsporida include E bieneusi and E intestinalis
 Infection results from ingestion of oocysts excreted in
feces of humans or animals
 Invade intestinal tract mucosa causing watery,
nonbloody diarrhea, dehydration, malnutrition
33
 Frequent watery, nonbloody diarrhea

 Abdominal cramps, fatigue, vomiting, anorexia, weight
loss, poor weight gain
 Fever and vomiting more common in children
 Liver involvement causes abdominal pain and elevated
alkaline phosphatase
 Less common – myositis, cholangitis, sinusitis, hepatitis,
CNS disease
34
Diagnosis
Cryptosporidiosis
 Concentrated stool samples to demonstrating oocysts
 Evaluate at least 3 separate stool samples
35
Diagnosis
Microsporidiosis
 Use thin smears of unconcentrated stool-formalin
suspension or duodenal aspirates stained with trichrome
or chemofluorescent agents
 Consider endoscopy in all patients with diarrhea >2
months duration
 PCR techniques still in research
36
Treatment
 Immune restoration following antiretroviral

treatment frequently results in clearing
 Supportive care, hydration, electrolyte
replenishment, nutritional supplements
 Available treatment inconsistently effective
37
Cryptosporidiosis
Treatment
 Nitazoxanide – effective for Cryptosporidium and

Giardia lamblia (B I for children and C III for HIV-
infected children)
 Nitazoxanide dose – 100 mg orally twice daily
for children 1-3 years; 200 mg twice daily for
children 4-11 years
 Limited data – paromomycin, azithromycin
38
Microsporidiosis
Treatment
 Albendazole: 7.5 mg/kg orally twice daily;

maximum dose 400 mg orally twice daily (A II)
 Fumagillin: limited data for adults, no data for
HIV-infected children
39
Mycobacterium tuberculosis
Epidemiology
 15,000 new cases of tuberculosis in United
States in 2002 (6% among children <15 years of
age)
 Number of these that were HIV infected is
uncertain
 Incidence of TB in HIV-infected children 100
times higher than in uninfected
 In South Africa, as many as 48% of children with
TB were coinfected with HIV
40
Epidemiology
 Extrapulmonary and miliary TB more common in
children <4 years old
 Congenital TB has been reported
 Drug-resistant TB can be transmitted
 Patients should be treated under assumption
that drug resistance profiles of source and
patient are similar
41
 Younger children progress more rapidly (possibly due
to delayed diagnosis)
 Nonspecific symptoms: fever, weight loss, failure to
thrive
 Pulmonary TB most likely appears as infiltrate with
hilar adenopathy
 Clinical presentation of TB similar in HIV-positive and
HIV-negative children
 Extrapulmonary: marrow, lymph node, bone, pleura,
pericardium, peritoneal
42
Diagnosis
 Difficult to diagnose; maintain a degree of
suspicion
 M tuberculosis detected in up to 50% of gastric
aspirate in non-HIV-infected children (obtain 3
consecutive morning gastric aspirates)
 Usually requires linking TB in child to contact
along with + radiograph, + skin test (TST) or PE
43
Diagnosis
 About 10% of culture-positive children have

negative TST
 Perform annual TST beginning at 3-12 months
using 5 TU PPD intradermally
 DNA and RNA PCR not fully evaluated
44
Treatment
 Treatment principles similar in HIV-positive and HIV-
negative children
 Initiate treatment as soon as possible in children <4
years old with suspected TB
 Begin TB treatment 4-8 weeks before ARVs
(B III)
 If already on ARV, review drug interactions
 Use of DOT increases adherence, decreases
resistance, treatment failure, and relapse
45
Treatment
Initial treatment (induction phase)
 4 drugs: isoniazid, rifampin, pyrazinamide, plus
either ethambutol or streptomycin (A I)
 Use ethionamide as alternative to ethambutol for
CNS disease (A III)
46
Treatment
 If clinical response occurs and organism is
susceptible to isoniazid, discontinue ethambutol
after 2 months
 If severe disease, treat for 9-12 months
 If multidrug resistance is found, treat with expert
consultation
47
Treatment
Isoniazid
 Dosage: 10-15 mg/kg orally once daily
(maximum 300 mg daily)
 Hepatic toxicity increases with rifampin
 Peripheral neuritis, mild CNS toxicity, gastric

upset
48
Treatment
Rifampin
(maximum 600 mg daily)
 Side effects include rash; hepatitis; jaundice; GI
upset; orange coloring of urine, tears, sweat
 Rifampin can accelerate clearance of protease
inhibitors (except ritonavir) and NNRTIs
49
Treatment
Rifabutin (B III)
 Limited data in children
 Peripheral leukopenia, elevated liver enzymes,

pseudojaundice, GI upset
50
Treatment
Rifabutin
 Increases hepatic metabolism of certain
protease inhibitors: reduce rifabutin dosage by
50% when given with ritonavir, indinavir,
nelfinavir, amprenavir
 Increase dosage of rifabutin by 50-100% when
given with efavirenz
51
Treatment
Pyrazinamide
 Dosage: 10-15 mg/kg orally once daily (maximum
2 g daily)
 Hepatic toxicity, rash, arthralgia, GI upset
Ethambutol
 Dosage: 15-25 mg/kg orally daily
(maximum 1 g daily)
 Toxicity includes optic neuritis, rash, nausea
52
Treatment
Secondary drugs
 Ethionamide: 15-20 mg/kg orally divided into 2
or 3 doses daily
 Streptomycin: 20-40 mg/kg daily intramuscularly
(maximum dosage 1 g daily)
 Alternatives: kanamycin, amikacin, capreomycin,
quinolones, cycloserine, paraaminosalicylic acid
 Steroids may be indicated for TB meningitis
53
Mycobacterium avium Complex
Epidemiology
 Multiple related species of nontuberculosis

mycobacteria: M avium, M intracellulare, M
paratuberculosis
 Second most common opportunistic infection in
children
 Acquired by means of innovation, ingestion, or
inoculation
54
Epidemiology
 72% of children with isolated pulmonary MAC
develop disseminated MAC by 8 months
 May appear as isolated lymphadenitis
 Frequency increases with age and declining
CD4 T-cell count
 CD4 T-cell risk factor for occurrence:
 <750 mL <1 year; <500 mL 1-2 years; <75 mL 2-6
years; <50 mL >6 years
55
 Recurrent fever, weight loss, failure to thrive,
neutropenia, night sweats, chronic diarrhea,
malabsorption, abdominal pain
 Lymphadenopathy, hepatomegaly,
splenomegaly
 Respiratory symptoms uncommon among
children
 Laboratory abnormalities include anemia,
leukopenia, and thrombocytopenia
56
Diagnosis
 Isolation of organism from biopsy, blood, bone

marrow, lymph node, or other tissue
 Histology demonstrating macrophage containing
acid fast bacilli strongly indicates MAC
 Culture is essential for differentiating from TB
 Isolation from stool or respiratory does not
necessarily indicate invasive disease
57
Treatment
 Preserve immune function through optimal treatment
of HIV infection
 Consider delaying initiation of ART for 1-2 weeks to
avoid immune reconstitution syndrome
 Initiate treatment with clarithromycin or azithromycin
plus ethambutol (A I)
 Consider rifabutin as third drug with severely ill
patients (A I)
58
Treatment
 Note cautions in use of these drugs with ART

 If rifabutin cannot be used, consider
ciprofloxacin, levofloxacin, amikacin,
streptomycin
 Lifelong suppressive therapy required after initial
therapy
59
Treatment
 Clarithromycin: 7.5-15 mg/kg orally twice daily
(maximum 500 mg twice daily) (A I)
 Azithromycin: 10-12 mg/kg once daily (maximum
500 mg daily) (A II)
 Ethambutol: 15-25 mg/kg single oral dose
(maximum 1 g) (A I)
60
Treatment
 Rifabutin: 10-20 mg/kg orally once daily (maximum 300 mg

daily) (A I)
 Ciprofloxacin: 20-30 mg/kg intravenously or orally once daily
(maximum 1.5 g)
 Amikacin: 15-30 mg/kg/day intravenously divided every 12-
24 hours (maximum 1.5 g)
(C III)
61
Pneumocystis jiroveci (carinii)
Epidemiology
 Antibody in 80% of normal children by 4 years
 Most common AIDS indicator disease in children
 Incidence highest in first year of life, peaking at 3-6
months
 Accounted for 57% of AIDS-defining illnesses in infants
age <1 year pre-HAART
 CD4 T-cell count not a good indicator of risk in infants <1
year old
 Infection now unusual due to routine prophylaxis with
trimethoprim/sulfamethoxazole
62
 Fever, tachypnea, cough, dyspnea, poor feeding,
weight loss
 Abrupt or insidious onset
 Bibasilar rales with evidence of hypoxia and
respiratory distress
 Extrapulmonary locations – spleen, liver,colon,
pancreas, ear, eye, GI tract, bone marrow, heart,
kidney, lymph nodes, CNS
63
Diagnosis
 Hypoxia with low arterial oxygen pressure (alveolar-
arterial oxygen gradient >30 mm/Hg)
 Definitive diagnosis requires demonstrating organism
 Induced sputum (difficult <2 years)
 Bronchoscopy with bronchoalevolar lavage
 Fiberoptic bronchoscopy with biopsy – generally not
recommended
64
Diagnosis
 Open lung biopsy most sensitive
 Requires thorachotomy, chest tube drainage
 Organisms seen on biopsy with:
 Gomori’s methenamine silver stain
 Toluidine blue stain
 Giemsa or Wright’s stain
 Monoclonal antibody
 DNA PCR in fluids, lavage – mostly research
65
Treatment
Trimethoprim/sulfamethoxazole (TMP/SMX) (A I)
 >2 months 15-20 mg/kg/day of TMP component
intravenously in 3-4 divided doses
 Infuse over course of 1 hour
 Administer for 21 days
 Can be given orally in children with mild to
moderate disease
 Lifelong prophylaxis indicated
66
Treatment
 Adverse reactions:
 Rash
 Stevens-Johnson syndrome (rare)
 Neutropenia, thrombocytopenia,
megaloblastic or aplastic anemia
67
Treatment
Pentamidine isothionate
 Recommended for patients intolerant of
TMP/SMX or clinical failure with TMP/SMX (A I);
do not combine use
 4 mg/kg/day intravenously once daily over 60-90
minutes
 Consider oral atovaquone after 7-10 days (B III)
68
Treatment Alternatives
Atovaquone (B I)
 Limited data in children
 30-40 mg/kg/day divided into 2 doses, given with

fatty foods
 Infants 3-24 months may require 45 mg/kg/day
divided into 2 doses, given with fatty foods (A II)
 Adverse reactions include rash, nausea,
diarrhea, increased liver enzymes
69
Clindamycin/primaquine
 Used for mild to moderate PCP in adults – no
data in children (C III)
 Primaquine contraindicated in G6PD deficiency
70
Clindamycin/primaquine
 Pediatric clindamycin dosing based on other
uses: 20-40 mg/kg/day intravenously divided
into 3 or 4 doses, administered for 21 days
 Primaquine dosing based on malaria: 0.3 mg/kg
daily of the base, administered orally for 21 days
 Adverse reactions include rash, nausea,
diarrhea, pseudomembraneous colitis
71
Trimetrexate glucuronate plus leucovorin (folinic

acid)
 Used for severe PCP in adults – limited data in
children (C III)
 Trimetrexate – 45 mg/m2 for 21 days
 Leucovorin – 20 mg/m2 every 6 hours for 24

days
72
Dapsone/trimethoprim
 Use for mild to moderate PCP in adults – no
data in children (C III)
 Dapsone dose <13 years 2 mg/kg/day orally
once daily (A II) for 21 days
 Trimethoprim Isolationg/kg/day orally divided
into 3 daily doses for 21 days
 Adverse reactions include rash, anemia,
thrombocytopenia, increased liver enzymes
73
Treatment
Corticosteroids
 Consider use in moderate to severe PCP
 Use within 72 hours of diagnosis
 Results in reduced respiratory failure, decreased

ventilation requirements, and decreased
mortality
74
Treatment
Corticosteroids
 Dosing recommendations vary
 Prednisone: 40 mg twice daily for 1-5 days;
40 mg once daily days 6-10; 20 mg once daily

days 11-21
 Alternative: prednisone 1 mg/kg twice daily
days 1-5; 0.5 mg/kg twice daily days 6-10; 0.5

mg/kg once daily days 11-21
75
Candida Infections
Epidemiology
 Most common fungal infections in HIV-infected children
 Thrush and diaper dermatitis occur in 50-85% of HIV-
infected children
 Pre-HAART era oropharyngeal candidiasis found in 94%
of children with Candida esophagitis
 Disseminated candidiasis rare in children except those
with CMV, HSV coinfection or with central venous
catheter
76
Candida Infections
Epidemiology
 A substantial percentage of children with fungemia

receive oral systemically absorbable azole antifungals,
e.g., ketoconazole
 Complications include disseminated infection of bone,
liver, and kidney; endophthalmitis
 Mortality >90% from disseminated candidiasis in children
with fever and symptoms >14 days
77
Candida Infections
 Thrush and erythematous, hyperplasic, and angular
cheilitis
 Esophageal candidiasis may present with odynophagia,
dysphagia, or retrosternal pain
 Children may develop nausea, vomiting, or weight loss
and dehydration
 New onset of fever in individuals with central venous
catheters
 Systemic fungemia may lead to endophthalmitis
78
Candida Infections
Diagnosis
 Culture and KOH preparation with microscopic

demonstration of budding yeast cells in wet mounts or
biopsy
 Blood culture using lysis centrifugation
 “Cobblestone” appearance on barium swallow
 Perform endoscopy in refractory cases to look for CMV,
HSV, MAC coinfections
79
Candida Infections
Treatment
Treat early uncomplicated oropharyngeal candidiasis
(OPC) with topical therapy
 Cotrimoxazole: 10 mg troches 4-5 times/day for 2 weeks
(B II)
 Nystatin suspension: 4-6 mL (400,000-600,000 units/mL)
4 times/day
 Amphotericin B suspension: (100 mg/mL) 1 mL 4
times/day
80
Candida Infections
Treatment
Oral systemic therapy for OPC
 Fluconazole: 3-6 mg/kg orally once daily for
7-14 days (A I)
 Itraconazole: 2.5 mg/kg orally twice daily for
7-14 days (A I)
 Ketoconazole: 5-10 mg/kg/day orally divided into 2
doses given for 14 days (D II)
 Amphotericin oral suspension or IV for OPC refractory to
other treatment
81
Candida Infections
Treatment
Esophageal disease
 Treat both diagnosed esophageal disease and children
with OPC and esophageal symptoms
 Initiate treatment with:
 Fluconazole 6 mg/kg/day orally or intravenously on
day 1 followed by 3-6 mg/kg for 14-21 days (A I)
 Itraconazole oral solution 2.5 mg/kg/dose given twice
daily or 5 mg/kg once daily for 14-21 days (A I)
 Consider low-dose IV amphotericin B minimum of 7 days
for refractory disease (B II)
82
Candida Infections
Treatment
Esophageal disease
 Other therapies not fully evaluated in children
 Voriconazole: loading dose of 6 mg/kg intravenously
every 12 hours on day 1, followed by 4 mg/kg every 12
hours thereafter; after stabilization, change to oral
dosing
 Caspofungin: available only in IV form; <50 kg dosage
range 0.8-1.6 mg/kg daily; >50 kg, adult dosing
83
Candida Infections
Treatment
Invasive disease
 Remove central venous catheter
 Amphotericin B (A I)
 0.5-1.5 mg/kg once daily intravenously over 1-2 hours,
administered in 5% dextrose at final concentration of 0.1
mg/mL
 For mild to moderate disease, begin at 0.25-0.5 mg/kg and
increase as tolerated to 1.5 mg/kg
 Once stabilized, administer 1.5 mg/kg every other day (B III)
 Treat for 3 weeks after last positive blood culture of symptoms
84
Candida Infections
Treatment
Invasive disease: alternative therapy
 Fluconazole in stable patients with uncomplicated
candidemia without previous azole treatment
(identification of Candida species essential; C krusei and
C glabrata are resistant) (E III)
 Amphotericin lipid formulations (limited pediatric
experience)
 Amphotericin lipid complex (ABLC, Abelcet)
 Liposomal amphotericin lipid complex (AmBisome)
 Amphotericin B cholesteryl sulfate complex (ABCD)
85
Candida Infections
Treatment
Amphotericin toxicity
 Nephrotoxicity: azotemia, hypokalemia
 Nephrotoxicity can be minimized by hydration with 0.9%
saline intravenously 30 minutes prior to amphotericin B
infusion
 Infusion-related chills, fever, and vomiting; pretreat with
acetaminophen or diphenhydramine
 Rarely: hypotension, arrhythmias, neurotoxicity, hepatic
toxicity
86
Candida Infections
Treatment
Fluconazole, itraconazole, ketoconazole toxicity
 Inhibition of cytochrome P-450 dependent hepatic
enzymes can result in either decreased levels of azole
when administered with other drugs with hepatic
metabolism or increased levels of other drugs with
hepatic metabolism
 Nausea, vomiting, rash, pruritis, Stevens-Johnson
syndrome (rare), increased liver enzymes, hepatitis,
leukopenia, anemia, hemolytic anemia, alopecia
(fluconazole)
87
Cryptococcosis
Epidemiology
 Low incidence of infection in children

 Children usually infected during 6-12 age range
 Usually severely immunosuppressed
88
Cryptococcosis
 Meningoencephalitis most common manifestation
 Fever, headache, altered mental status evolving over
days to weeks
 Acute illness with nuchal rigidity, seizures, focal
neurologic signs observed in developing countries
 Translucent, umbilicated, papules, nodules, ulcers,
infiltrated plaques seen in disseminated disease
 Pulmonary cryptococcosis unusual in children
89
Cryptococcosis
Diagnosis
 Microscopic examination of CSF on India ink-stained wet
mounts
 Detection of cryptococcal antigen in CSF, serum,
bronchoalevolar lavage fluid (can be negative in culture-
positive meningitis)
 Antigen levels useful in evaluating response to treatment
and relapse
 Pulmonary disease diagnosed by bronchoalevolar
lavage and direct examination of India ink-stained
specimens
90
Cryptococcosis
Treatment
 Not well studied in children
 Amphotericin B induction (0.7-1.5 mg/kg/day
intravenously) combined with 2 weeks of flucytosine
(25 mg/kg/dose given 4 times daily) until symptoms
controlled (A I)
 After symptoms are controlled, treat with fluconazole or
itraconazole maintenance
 Use amphotericin B alone if flucytosine is not tolerated
 Fluconazole plus flucytosine is an alternate to
amphotericin B (limited data in children)
91
Cryptococcosis
Treatment
Amphotericin toxicity
 Nephrotoxicity: azotemia, hypokalemia
 Nephrotoxicity can be minimized by hydration with 0.9%
saline intravenously 30 minutes prior to amphotericin B
infusion
 Infusion-related chills, fever, and vomiting; pretreat with
acetaminophen or diphenhydramine
 Rarely: hypotension, arrhythmias, neurotoxicity, hepatic
toxicity
92
Cryptococcosis
Treatment
Flucytosine toxicity
 Bone marrow: anemia, leukopenia,
thrombocytopenia
 Liver, GI, and renal toxicity
93
Histoplasmosis
Epidemiology
 Incidence of disseminated histoplasmosis in

HIV-infected children in the United States <0.4%
 Incidence is higher in countries such as Brazil,
Argentina, and Mexico (2.7% to 3.8%)
 No evidence of dissemination of maternal
infection to the fetus or greater severity of
infection during pregnancy
94
Histoplasmosis
 Prolonged fever is the most common presentation

 Malaise, weight loss, and nonproductive cough
 Primary pulmonary focus leads to widespread
dissemination in children
 Physical findings include hepatosplenomegaly,
erythematous nodular coetaneous lesions, CNS
involvement with meningitis
 Anemia, thrombocytopenia, elevated liver transaminases
95
Histoplasmosis
Diagnosis
 Culture of Histoplasma for blood or other sources
 Detection of H capsulatum polysaccharide antigen in urine,
blood, CSF, or bronchoalevolar lavage using EIA assay
 EIA sensitivity greater in disseminated disease or acute
pulmonary disease; greater in urine than in serum
 Antigen levels decline with treatment and correlate with
both response to treatment and relapse
96
Histoplasmosis
Diagnosis
 Antibody positive in most patients but not useful

for diagnosis of acute infection
 For diagnosis of CNS disease, a combination of
CSF antibody, antigen, and culture is most
sensitive
 Skin testing not recommended for diagnosis
97
Histoplasmosis
Treatment
 Limited data for children; recommendations
based on adult data
 Nonimmunocompromised not requiring
hospitalization:
 Itraconazole dosage 6-8 mg/kg for 3-12
months (A II)
 Alternative: fluconazole, but less effective and
resistance can develop (C II)
98
Histoplasmosis
Treatment
 Amphotericin B for patients with severe disseminated
disease requiring hospitalization and those who are
immunocompromised
 Amphotericin B induction dosage: 1 mg/kg for 4-6 weeks
followed by itraconazole chronic suppressive therapy
(A I)
 After successful treatment of acute disease, use chronic
lifelong suppressive therapy with itraconazole
 Liposomal amphotericin B alternative in event of
amphotericin B intolerance
99
Coccidioidomycosis
Epidemiology
 Increased risk for infection with Coccidioides

immitis among HIV-infected children in endemic
areas (e.g., southwestern United States,
northern Mexico, Central and South America)
 Primary infection of newborn rare
 In utero and perinatal transmission of
C immitis reported
100
Coccidioidomycosis
 Fever and dyspnea most common presentation

 Chills, weight loss, lymphadenapaothy, chest pain,
diffuse reticulonodular pulmonary infiltrates, meningitis
 Disseminated disease associated with erythema
multiforme; erythema nodosum; erythematous
maculopapular rash; arthralgia; bone, joint, and CNS
infection
101
Coccidioidomycosis
Diagnosis
 Direct examination and culture of respiratory

secretions and CSF or biopsy of lesions
 Blood cultures positive in 15% of cases
 IgM antibody detected by latex agglutination,
EIA; immunodiffusion of tube precipitin appears
early and indicates acute infection
102
Coccidioidomycosis
Treatment
 Limited data in children; recommendations based on
adult data
 Treat diffuse pulmonary disease or disseminated
disease with amphotericin B dosage of 0.5-1.5
mg/kg/day until clinical improvement occurs (A II)
 Follow with chronic suppressive fluconazole or
itraconazole therapy (A II)
 Alterative therapy: fluconazole 5-6 mg/kg twice daily or
itraconazole 4-10 mg/kg twice daily for 3 days followed
by 2-5 mg/kg twice daily (B III)
103
Coccidioidomycosis
Treatment
CNS infection including meningitis

 High-dose fluconazole 5-6 mg/kg twice daily
 If unresponsive to fluconazole, use IV
amphotericin B augmented by intrathecal
amphotericin B (C I)
 Surgical debridement or excision of localized
persistent or resistant lesions in bone and lung
may be helpful
104
Cytomegalovirus
Epidemiology
 Infection with CMV common and often inapparent
 50-80% of women of childbearing age in United States
are CMV antibody positive
 90% of HIV-infected women are CMV antibody positive
 Infection occurs:
 During infancy, early childhood, adolescence
 Via contact with virus containing salvia, urine, sexual

fluid, blood, organ transplantation
 Perinatally – most common
105
Cytomegalovirus
Epidemiology
 In utero infection occurs most commonly among infants

born to mothers with primary infection during pregnancy
 30-40% rate of CMV transmission to fetus following
primary infection during pregnancy
 0.2-1% rate of CMV transmission to fetus following
recurrent infection during pregnancy (reactivation of
infection or reinfection with a different strain of CMV)
106
Cytomegalovirus
Epidemiology
 CMV may be transmitted intrapartum or

postpartum
 57% of infants whose mothers shed CMV
become infected
 53% of infants who are breast-fed with milk that
contains CMV become infected
107
Cytomegalovirus
Epidemiology
 HIV-coinfected women have a higher rate of CMV
shedding
 HIV-coinfected women have a higher rate of HIV
transmission
 HIV-infected children at greater risk of acquiring CMV
during early childhood
 CMV causes 8-10% of AIDS-defining illnesses
 Children with positive CMV urine cultures have lower
survival rates
108
Cytomegalovirus
 10% of infants infected in utero are symptomatic at birth

with congenital CMV syndrome
 Infants with congenital infection: small for gestational
age, purpura/petechiae, jaundice, hepatosplenomegaly,
chorioretinitis, microcephaly, intracranial calcification,
hearing loss
 Delayed manifestations of congenital infections include
developmental abnormalities, sensorineural hearing loss,
chorioretinitis, neurologic defects
109
Cytomegalovirus
 HIV-infected children with CMV coinfection have
accelerated HIV progression
 Coinfected children more likely to develop HIV CNS
disease
 CMV retinitis most frequent severe manifestation of CMV
disease, accounting for 25% of CMV AIDS-defining
illnesses
 CMV retinitis is frequently asymptomatic
 Older children may have floaters or loss of peripheral
central vision
110
Cytomegalovirus
 End organ disease reported in liver, lung, GI tract,
pancreas, kidney, sinuses, CNS
 Nonspecific symptoms include weight loss, loss of
developmental milestones, fever, anemia,
thrombocytopenia
 Also observed: oral and esophageal ulcers, ascending
cholangiopathy, CMV colitis, CMV pneumonia with
shortness of breath and dry nonproductive cough
 CNS manifestations include encephalopathy, myelitis,
polyradiculopathy with nonspecific or normal CSF
111
Cytomegalovirus
Diagnosis
 Antibody assays indicative of maternal transfer of IgG in children <12
months; indicative of previous infection in children >12 months
 Positive cell culture from urine, tissues, blood leukocytes
 DNA PCR assays more sensitive than buffy coat or urine culture
 Quantitative DNA PCR can be used to monitor disease and treatment
 Other methods include monoclonal antibody staining and immunostaining
for antigen
112
Cytomegalovirus
Diagnosis
Recommendations include:
 Testing all HIV-infected infants with urine culture for CMV in the
first months of life to identify congenital, perinatal, or early
postnatal infection
 Testing annually for CMV antibody in infants previously negative
by culture and antibody to identify occult CMV infections
permitting appropriate screening for retinitis
 Dilated retinal examinations for coinfected children every 4-6
months; older children should report floaters and visual changes
113
Cytomegalovirus
Treatment
Symptomatic congenital CMV

 Ganciclovir: 4-6 mg/kg intravenously every 12 hours for
6 weeks
 Neutropenia may occur and may require dosage
modification
114
Cytomegalovirus
Treatment
Initial treatment of disseminated CMV and retinitis

 Ganciclovir: 5 mg/kg/dose intravenously over 1-
2 hours twice daily for 14-21 days, followed by
lifelong maintenance therapy (A I)
 Resistance and myelosuppression can occur
 Other toxic effects include renal impairment,
CNS effects, GI dysfunction, increased liver
enzymes
115
Cytomegalovirus
Treatment
Alternative treatment for ganciclovir resistance

 Foscarnet (A I) at 60 mg/kg/dose intravenously (infused
at 1 mg/kg/minute) over 1-2 hours every 8 hours for 14-
21 days, followed by lifelong therapy
 Foscarnet plus ganciclovir delays progression of retinitis
in certain patients failing monotherapy
 Toxicity: decreased renal function, metabolic
abnormalities, electrolyte imbalances with secondary
seizures, cardiac dysrhythmia, abnormal liver enzymes,
and CNS symptoms
116
Cytomegalovirus
Treatment
Treatments for adults (inadequate pediatric data)
 Valganciclovir: prodrug of ganciclovir, given orally,
effective in retinitis in adults
 Oral ganciclovir (or valganciclovir) plus ganciclovir
sustained release intraocular implant used for retinitis
 Cidofovir for retinitis
 Fomivirsen: antisense nucleotide used as intravitreous

injection
117
Herpes Simplex Virus
Epidemiology
 Neonatal HSV infection occurs at a rate of 1/2,000-5,000

deliveries
 Transmitted from infected mother to infant primarily
through exposure to maternal genital fluids during birth,
by ascending infection, or by invasive procedures (e.g.,
fetal scalp electrodes)
 Congenital (in utero) rare, but severe cutaneous, ocular,
and CNS damage
118
Epidemiology
 Maternal antibody to HSV predicts likelihood and

severity of transmission to infant
 Risk of neonatal HSV greatest in infant born to mother
with primary HSV infection (30-40%)
 Genital shedding of HSV and prolonged rupture of
membranes increases risk of HSV transmission
 Cesarean section lowers risk of transmission
119
Epidemiology
 In United States, 75% of neonatal HSV caused by
genital herpes (HSV 1 and 2)
 HSV 2 seroprevalence in women of childbearing age is
26%; rates may be higher in HIV-infected women
 HIV-infected women shed HSV from genital area more
frequently than HIV-uninfected women (may be
asymptomatic)
 No evidence that in utero HSV infection is more frequent
in HIV-infected pregnant women
120
Neonatal HSV may appear as:

 Disseminated multiorgan disease (occurring in
about 25% of neonates with infection)
 Localized CNS disease (about 35%)
 Localized infection of skin, eyes, mouth

(about 40%)
121
 Disseminated disease usually manifests at 9-11

days with encephalitis in 60-70% and vesicular
rash in 60%
 Localized disease usually appears at 10-11
days
 Even with treatment, neonates with skin lesions
may have recurrences for first 6 months of life
122
 Outside neonatal period, most common
presentation is orolabial disease with fever,
irritability, submandibular lymphadenopathy, painful
ulcers in gingival and oral mucosa
(gingivostomatitis)
 When severely immunocompromised, may develop
disseminated HIV infection including infection of
esophagus, CNS, liver, lung, kidney spleen,
adrenal
123
Diagnosis
 Appearance of typical ulcers and vesicles

 Isolation of HSV from lesions following culture
 Diagnosis of neonatal HSV based on cultures from blood,
skin vesicles, mouth, eyes, urine, and stool
 CSF using DNA PCR sequence common to HSV
1 and 2
 Direct immunofluorescence for HSV antigen in samples
 HSV DNA PCR has replaced brain biopsy
124
Treatment
 Acyclovir is the drug of choice regardless of infection
status (oral and IV formulations available)
 Treat neonatal HSV with 20 mg/kg/dose intravenously 3
times daily for 21 days for CNS and disseminated
diseases
 For skin, eye, mouth disease, treat for 14 days
 Do not discontinue acyclovir in neonates with CNS
disease unless CSF DNA PCR is negative at days 19-21
of treatment (B III)
125
Varicella-Zoster Virus
Epidemiology
 9% of children <10 years old experience varicella
infection (before vaccine use)
 95% of adults have antibody to VZV
 Rare perinatal VZV transmission
 Congenital VZV occurs in 2% of infants whose mothers
have primary VZV in first trimester
 Zoster occurs only when previously VZV infected
 Rate of zoster as high as 70% in HIV-infected children
who are immunocompromised at time of primary VZV
infection
126
 Congenital infection characterized by cicatricial skin
scarring, limb hypoplasia, microcephaly, seizures,
mental retardation, chorioretinitis, cataracts,
microphthalmia, neurogenic bladder, hydroureter,
abnormalities of swallowing
 Duration of disease longer and complications more
frequent in HIV-infected children
 May experience chronic infection with continued new
lesions for >1 month
 May develop VZV retinitis
127
Diagnosis
 Clinical diagnosis based on typical generalized pruritic
vesicular rash and fever
 Direct immunofluorescence for VZV antigen on cells
from skin, conjunctiva, mucosal lesions
 VZV PCR sensitive and specific and can differentiate
wild type from vaccine type
 VZV antibody response positive 2-3 weeks after onset of
illness – IgM indicates acute infection or recurrent
infection
128
Treatment
 Acyclovir is the drug of choice for HIV-infected children;
should be initiated as soon as possible after diagnosis
(A I)
 New lesions may continue to appear several days after
initiation of treatment
 Dosing
 <1 year of age: 10 mg/kg/dose intravenously every 8
hours as 1-hour infusion for 7 days
 >1 year of age: dose as above or 500 mg/m2/dose
intravenously every 8 hours as 1-hour infusion for 7
days
129
Treatment
Children with HIV coinfection and normal or minimal
decrease in CD4 T-cell counts
 Acyclovir: 20 mg/kg per dose orally 4 times daily;
maximum dose 800 mg (B III)
Children with zoster and HIV infection

 Oral acyclovir
 Use intravenously if severely immunocompromised,
trigeminal nerve involvement or extensive
multidermatomal zoster
130
Treatment
 Toxicities include phlebitis, nausea, vomiting,
rash, impaired renal function, neutropenia
 Oral acyclovir data limited in children <2 years of
age; infants who receive long-term suppressive
therapy (300 mg/kg/m2/dose administered 3
times daily) develop frequent neutropenia –
usually self-limited
131
Treatment
 Use foscarnet for treatment of children with
acyclovir-resistant VZV (B II)
 Dosage: 40-60 mg/kg/dose intravenously over 1-2
hours administered 3 times daily for 7 days or until
no new lesions appear
 Modify dosage in patients with renal insufficiency
 Valacyclovir and famciclovir alternative treatments
(not active against acyclovir-resistant VZV) but no
data in children
132
Human Papillomavirus
Epidemiology
 HPV infects cutaneous and mucosal squamous
epithelium
 Approximately 100 distinct types
 HPV 16, 18, 31, 33, and 35 are most often associated
with intraepithelial malignancy
 Genital HPV types can cause conjunctiva, nasal, oral,
and laryngeal warts
 Transmission occurs by direct contact or sexual contact
(genital warts in young children may be a sign of sexual
abuse)
133
Epidemiology
 Latent HPV seen in 5-42% of pregnant women without

HIV infection
 HPV infection rates higher in HIV-positive women (up to
95%)
 Mother-to-child HPV transmission occurs and can result in
infant laryngeal and juvenile laryngeal papillomatosis
 In general, no neonatal abnormalities are associated with
detection of HPV in neonates
134
Epidemiology
 HPV detected in 13-60% of sexually active

adolescent girls
 40-80% of infections in HIV uninfected are
transient
 Persistent infection with HPV 16, 81, 31, and 33
associated with high risk for developing cervical,
vulvovaginal, and anal carcinoma; cervical and
anal intraepithelial neoplasia
 Increased risk if HIV infected
135
 Hyperplasic, papillomatosis and verrucous

squamous epithelial lesions on the skin and
mucous membranes including anal, genital, oral,
nasal, conjunctiva, GI, and respiratory tract
mucosa
 Lesions are soft, pink or white “cauliflower-like”
sessile growths
136
Diagnosis
 Most cutaneous and anogenital warts

diagnosable on physical examination
 Diagnosis of laryngeal papillomatosis requires
laryngoscopy
 DNA PCR can be used for detection of HPV
types but not necessary for diagnosis or
management of anogenital or cutaneous warts
or papillomas
137
Treatment
Topical Treatment (B III)

 Standard topical treatment often ineffective in HIV-
infected children as underlying infection persists and
results in recurrence
 Podofilox 0.5% (antimitotic agent)
 Imiquimod cream 5% (immune enhancer)
 Trichloroacetic or bichloracetic acid 80-90% aqueous

solution (caustic agent)
138
Treatment
 Cidofovir topical gel 1% evaluated primarily in adults;

used successfully for molluscum contagiosum in children
with HIV infection
 Cryotherapy and electrodessication applied to each
lesion; treatment can be repeated every 1-2 weeks
 Treatment of laryngeal papillomatosis directed primarily
to removal of obstructions
 ART not consistently associated with reduced risk for
HPV-related cervical abnormalities
139
Hepatitis C
Epidemiology
 Low seroprevalence in children in United States
– 0.1-0.2%
 Seroprevalence higher in HIV-infected children
– 1.5% in one study
 Risk for mother-to-infant transmission (MTCT)
about 6%
 Most infections occur at or near delivery
140
Hepatitis C
Epidemiology
 Higher risk of MTCT if mother is HIV coinfected, IV drug

user, or viremic; and with intrapartum exposure to
infected blood, perineal or vaginal laceration, and fetal
hypoxia
 No reduction of transmission with Cesarean section
 No increased risk from breast-feeding
 Transmission risk of HIV may be increased with HCV
coinfection
141
Hepatitis C
Epidemiology
 Viremia in HCV-infected, HIV-uninfected

children: persistent 52%; intermittent 42%; not
detectable 6%
 Spontaneous clearing has been reported in
MTCT of HCV
 >40% of those who are viremic have persistent
features of hepatitis
142
Hepatitis C
 Children have less frequent and slower

progression than do adults
 In a study of posttransfusion HCV, 55% of
antibody-positive children had detectable HCV in
blood
 1 child had abnormal liver enzymes
 3/17 had histologic evidence of progressive liver
damage after 21 years
143
Hepatitis C
 Histologic changes can be present in the

absence of symptoms
 No correlation between persistent viremia or
elevated liver enzymes and liver disease
 No evidence of clinical differences between HIV-
coinfected and HIV-uninfected children
144
Hepatitis C
Diagnosis
 HCV antibody passively transferred; not useful for
diagnosis of infection until >18 months of age
 Diagnosis confirmed using recombinant immunoblot
assay (RIBA)
 Infants <18 months use HCV RNA PCR (wait until >2
months of age)
 If positive, repeat HCV RNA PCR
 Liver biopsy best for evaluation of hepatic disease;
should be considered before initiating treatment
145
Hepatitis C
Treatment
 Administer hepatitis A vaccine

 Consideration for treatment includes: symptomatic
disease, advanced pathologic features (bridging
necrosis, active cirrhosis) (B I)
 Response to treatment better with HCV 2 and HCV 3
than with HCV 1
 Use quantitative HCV RNA to access treatment
response
146
Hepatitis C
Treatment
 Individuals with undetectable levels of HCV RNA

following treatment should be retested after 24
weeks
 In HIV-coinfected patients, testing can be
continued for an additional 1-2 years
147
Hepatitis C
Treatment
Adults and children with HIV disease

 Combination therapy with interferon (IFN) and ribavirin
(A I)
 Pegylated IFN alfa 2a: subcutaneously 180 mcg/kg
weekly or alfa 2b subcutaneously 1.5 mcg/kg weekly
(adults)
 Ribavirin: 400 mg orally twice daily (adults)
 Limited data on use of IFN in children
148
Hepatitis C
Treatment – Children
 IFN alpha 2a and alpha 2b monotherapy most widely
evaluated in children with HCV infection (not with HIV
coinfection)
 Pediatric dosage in studies ranged from 1.75 to 5 million
units/m2 (maximum dosage 3-5 million units)
administered subcutaneously or intramuscularly 3 times
weekly for 4-12 months
 Treatment contraindicated in decompensated liver
disease, cytopenia, cardiac disease or autoimmune
disease
149
Hepatitis C
 Ribavirin oral solution used in combination with IFN alfa

 Dosage: oral solution 40 mg/mL – 15 mg/kg/day divided
into 2 doses given twice daily
 25-36 kg: 1 200 mg capsule in a.m., 1 in p.m.
37-49 kg: 1 200 mg capsule in a.m., 2 in p.m.
50-61 kg: 2 200 mg capsules in a.m., 2 in p.m.
150
Hepatitis C
 Use IFN monotherapy when ribavirin cannot be

used, e.g., unstable cardiopulmonary disease,
severe anemia, hemoglobinopathy (B III)
 Treat HCV 1 for 48 weeks; treat HCV 2, HCV 3
for 24 weeks; some treat HIV-coinfected patients
for 48 weeks
151
Hepatitis C
Treatment
Adverse effects – IFN alfa
 Flulike syndrome most severe during first month of
therapy, consisting of fever, chills, headache, myalgia,
arthalgia, abdominal pain, nausea, vomiting
 Epistaxis associated with thrombocytopenia or
prolonged prothrombin time
 Neutropenia, anemia, thrombocytopenia
 Personality changes
 Abnormalities of thyroid function
152
Hepatitis C
Treatment
Adverse effects – ribavirin

 Flulike syndrome consisting of fever, chills, headache,
myalgia, arthalgia, abdominal pain, nausea, vomiting
 Hemolytic anemia, lymphopenia
 Depression and suicidal ideation
 Do not use in combination with didanosine
153
Hepatitis B
Epidemiology
 Acquired by perinatal or mother-to-infant transmission
 Unknown whether there is a greater risk of HBV
transmission to infants from HIV-coinfected mothers
 All infants born to HBV-infected mothers should receive
HBV vaccine and HBV immune globulin (HBIG) within 12
hours of birth
 Second dose of vaccine at 1-2 months of age
 Test for antibody to HBsAg at 9-15 months of age; if
negative, reimmunize
154
Hepatitis B
Epidemiology
 HBV-infected household members may pose risk of

infection
 Infection occurs through contact with infected blood
or body fluids and through sharing of objects such
as toothbrushes
 All infants previously unimmunized should receive
routine childhood HBV vaccine
155
Hepatitis B
Epidemiology
 HBV infection risk increased through sexual

activity in adolescents who are HIV coinfected
 Immunize HBV-susceptible adolescents
 Risk of chronic HBV infection in children without
HIV infection is inversely related to age at time
of infection
156
Hepatitis B
 Majority of children are asymptomatic

 Children who are coinfected with HIV may have
smoldering chronic infection along with lethargy,
malaise, fatigue, and anorexia
 Jaundice sometimes present with
hepatosplenomegaly
157
Hepatitis B
 Young children may experience a serum

sickness-like illness consisting of asymmetrical
arthropathy and skin lesions
 Papular acrodermatitis and urticarial or purpuric
skin lesions may occur
 Aplastic anemia, polyarteritis nodosa,
glomerulonephritis are occasionally seen
158
Hepatitis B
Diagnosis
 HBsAg is the first detectible marker and
precedes increase in liver enzymes
 Anti-HBV core antibody (anti-HBc) appears 2
weeks after HBsAg and persists for life
 Passively transferred anti-HBc present in infants
up to 12 months of age
 IgM anti-HBc highly specific for acute infection
159
Hepatitis B
Diagnosis
 In self-limited infections, HBsAg is eliminated in
1-2 months
 Anti-HBsAg during convalescence, indicating
immunity to HBV
 After recovery, both anti-HBs and anti-HBc are
usually present
 Following immunization, only anti-HBs develops
160
Hepatitis B
Diagnosis
 Chronically infected individuals are persistently positive
for HBsAg and anti-HBc beyond 24 weeks; anti-HBs not
detectible
 HBe antigen (HBeAg) correlates with viral replication,
DNA polymerase activity, increased infectivity, increased
severity of liver disease
 HBV DNA can be detected in serum and blood
mononuclear cells by PCR or branched DNA
 Quantitative DNA assays may be useful for evaluating
responses to treatment
161
Hepatitis B
Diagnosis
 All pregnant women should be tested for HBV

surface antigen (HBsAg)
 Repeat test late in pregnancy for women at high
risk for HBV infection
162
Hepatitis B
Treatment
 Administer hepatitis A vaccine to susceptible children >2
years of age
 Indications for treatment are the same in children
coinfected with HBV and HIV:
 Evidence of ongoing viral replication as indicated by
presence of detectible HBV DNA with or without
HBeAg positivity for at least 6 moths
 Persistent elevation of transaminases (2 times upper
limit of normal)
 Evidence of chronic hepatitis on liver biopsy (B II)
163
Hepatitis B
Treatment
 Correlates of successful treatment not well
defined
 Current correlates: improved liver histology,
normalization of hepatic transaminases,
decrease in HBV DNA levels, loss of e antigen
with development of anti-HBe
 No target HBV DNA level has been defined
164
Hepatitis B
Treatment
 IFN alfa, lamivudine (3TC), and adefovir approved for

treatment of HBV in adults
 IFN alfa and 3TC approved for children
 Some recommend IFN alfa monotherapy for HBV/HIV-
coinfected patients not yet requiring ART (to decrease
possibility of resistance to 3TC and adefovir) (C III)
 Some recommend 3TC monotherapy for HBV/HIV-
coinfected patients who require ART (B III) (similar for
children)
165
Hepatitis B
Treatment
IFN alfa
 Most widely studied for treatment of compensated HBV liver
disease
 Studies of HBV/HIV coinfection in children have not been
performed
 Dosage range in children for IFN alfa 2a or 2b: 3-10 million
units/m2 subcutaneously 3 times weekly for 3-12 months
 Commonly used regimen is 5 million units/m2 3 times weekly
for 6 months
 Prolonged and higher dosages improve responses
166
Hepatitis B
Treatment

 Flulike syndrome most severe during first month
of therapy, consisting of fever, chills, headache,
myalgia, arthalgia, abdominal pain, nausea,
vomiting
 Epistaxis associated with thrombocytopenia or
prolonged prothrombin time
167
Hepatitis B
Treatment
 Personality changes
 Abnormalities of thyroid function
 Treatment contraindicated in decompensated

liver disease, cytopenias, cardiac disease, and
autoimmune disease
168
Hepatitis B
Treatment
 Children who do not respond to IFN alfa may respond to
IFN beta (C III)
 IFN beta shares biologic functions but is antigenically
different
 Dose 5 million units/m2 intramuscularly 3 times a week
for 6 months
 In some studies, 45% of children were HBV DNA
negative 18 months after therapy completion; 50%
normalized transaminases; 32% became anti-HBe
antibody positive
169
Hepatitis B
Treatment
Lamivudine (3TC)
 Preferred therapy for HIV-coinfected children with
compensated chronic liver disease who require ARVs for
HIV infection (B III)
 Results in rapid decline in HBV DNA levels
 Used for HBV HIV uninfected children but persistent
virologic response rates are low
 Used as both primary and secondary treatment in HBV-
infected, HIV-negative children
 Extended monotherapy treatment can lead to resistance
170
Hepatitis B
Treatment
Lamivudne (3TC)
 Do not use 3TC monotherapy in HIV/HBV-
coinfected children (3TC resistance develops)
 Dosage: 3 mg/kg once daily (lower than that
required for HIV)
 If 3TC is used to treat HBV/HIV-coinfected
children, treat with 4 mg/kg twice daily in the
context of ARV combination therapy
171
Hepatitis B
Treatment
Adefovir
 Some recommend combined adefovir or tenofovir in addition
to 3TC as part of suppressive ART to reduce development of
resistance
 Continue 3TC along with ARVs in children who respond;
exacerbations of HBV can occur when therapy is
discontinued
 Combination 3TC and IFN alfa not well studied
 Adefovir dipivoxil (10 mg once daily in adults) active against
HBV with minimal anti-HIV effect (insufficient data in
children)
172
About This Slide Set
 This presentation was prepared by
Arthur Ammann, MD, for the AETC
National Resource Center in April 2005.
 See the AETC NRC Web site for the
most current version of this presentation
- http://www.aidsetc.org.
173

Treating Opportunistic Infection Among HIV-Infected Children

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Treating Opportunistic Infection Among HIV-Infected Children

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Treating Opportunistic Infection

Among HIV-Infected Children

 Inability to describe symptoms

 Most common infection in pre-HAART era

 Isolated bacteria include Streptococcus

 Clinical presentation dependent on type of

 Isolation of pathogenic organism from normally

 Children <5 years should be given H influenza B

 Untreated early syphilis in pregnancy leads to

 60% of infants with congenital syphilis have

 Use combination of physical, radiologic,

 Darkfield microscopy or direct fluorescent

 Treat all infants whose mothers have untreated

 Treat acquired syphilis with single dose of benzathine penicillin

 Primarily perinatal transmission from primary

 Risk of transmission in HIV-uninfected mothers

 Non-immunocompromised infants are usually

 Toxoplasmosis acquired after birth is initially

 Test all HIV-infected pregnant women for

 Additional methods include isolation of

 Pyrimethamine: rash, Stevens-Johnson

 Azithromycin: 900-1,200 mg/kg/day with

 Frequent watery, nonbloody diarrhea

 Immune restoration following antiretroviral

 Nitazoxanide – effective for Cryptosporidium and

 Albendazole: 7.5 mg/kg orally twice daily;

 About 10% of culture-positive children have

 Peripheral neuritis, mild CNS toxicity, gastric

 Limited data in children

 Peripheral leukopenia, elevated liver enzymes,

 Multiple related species of nontuberculosis

 Isolation of organism from biopsy, blood, bone

 Note cautions in use of these drugs with ART

 Rifabutin: 10-20 mg/kg orally once daily (maximum 300 mg

 Stevens-Johnson syndrome (rare)

megaloblastic or aplastic anemia

 30-40 mg/kg/day divided into 2 doses, given with

Trimetrexate glucuronate plus leucovorin (folinic

 Leucovorin – 20 mg/m2 every 6 hours for 24

 Use within 72 hours of diagnosis

 Results in reduced respiratory failure, decreased

 Prednisone: 40 mg twice daily for 1-5 days;

40 mg once daily days 6-10; 20 mg once daily

days 1-5; 0.5 mg/kg twice daily days 6-10; 0.5

 A substantial percentage of children with fungemia

 Culture and KOH preparation with microscopic

 Treat for 3 weeks after last positive blood culture of symptoms

 Liposomal amphotericin lipid complex (AmBisome)

 Amphotericin B cholesteryl sulfate complex (ABCD)

 Low incidence of infection in children

 Incidence of disseminated histoplasmosis in

 Prolonged fever is the most common presentation

 Antibody positive in most patients but not useful

resistance can develop (C II)

 Increased risk for infection with Coccidioides

 Fever and dyspnea most common presentation

 Direct examination and culture of respiratory

CNS infection including meningitis

 Via contact with virus containing salvia, urine, sexual

 In utero infection occurs most commonly among infants

 CMV may be transmitted intrapartum or

 10% of infants infected in utero are symptomatic at birth