Transcript Document
Guidelines for Prevention and
Treatment of Opportunistic Infections
among HIV-Infected Children
Recommendations from Centers for Disease Control and Prevention,
the National Institutes of Health, the HIV Medicine Association of
the Infectious Diseases Society of America, the Pediatric Infectious
Diseases Society, and the American Academy of Pediatrics
About This Presentation
These slides were developed using the April 2008
Guidelines. The intended audience is clinicians
involved in the care of patients with HIV.
Users are cautioned that, because of 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become out of date quickly.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. Expert opinion should be sought
for complex treatment regimens.
– AETC NRC
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Contents
Introduction (slide 7)
Bacterial infections
(slide 13)
Serious and recurrent
bacterial infections,
bartonellosis, syphilis
Mycobacterial
infections (slide 45)
TB, MAC
3
Fungal infections (slide 76)
Aspergillosis, candidiasis,
coccidiomycosis, cryptococcosis,
histoplasmosis, PCP
Parasitic infections (slide 138)
Cryptosporidiosis/microsporidiosis,
malaria, toxoplasmosis
Viral infections (slide 167)
CMV, HBV, HCV, HHV-6/7, HHV-8,
HSV, HPV, PML, VZV
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Diagnosis of HIV in HIV-Exposed Infants
HIV infected:
HIV positive by HIV DNA or RNA PCR on 2
separate samples
or
If >18 months and not breast-fed, positive by
either antibody or PCR
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ART and Management of OIs
Highly active antiretroviral therapy (ART)
reduces the incidence of OIs and improves
survival independent of antimicrobial
prophylaxis
ART does not replace the need for OI
prophylaxis in children with severe
immunosuppression
ART in the setting of acute or latent OIs can
lead to immune reconstitution inflammatory
syndrome (IRIS)
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Immune Reconstitution Inflammatory
Syndrome (IRIS)
Definition: temporarily worsening of symptoms
of inflammation or infection related to starting
ART
Occurs after initiation of ART as immunity is
restored
Results from an exaggerated immune
response (eg, activation of latent or occult TB)
Treatment consists of nonsteroidal
antiinflammatory drugs for moderate cases
and corticosteroids for severe cases
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Introduction
Mother-to-child transmission of OI is an
important mode of acquisition
HIV-infected women coinfected with OI are
more likely to transmit (eg, CMV, HCV)
HIV-infected women or HIV-infected family
members are sources of horizontal
transmission (eg, TB)
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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 TB)
Classical features of infection may not be
present
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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
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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,
TB, systemic fungal infections
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Changes in Frequency of OI among
HIV-Infected Children
Infection
11
Pre-HAART Rate
per 100 Child
Years
Post-HAART
Rate per 100
Child Years
Bacterial
pneumonia
11.1
2.2
Herpes zoster
2.9
1.1
Disseminated
Mycobacterium
avium
1.8
0.14
Pneumocystis
jiroveci
1.3
0.09
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Treating OI among HIV-Infected Children
Rating of treatment recommendations is
based on opinion of working group
Letter indicating strength of
recommendation (eg, A, B, C)
Roman numeral indicating
nature of evidence (eg, I, II, III)
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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
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Serious Recurrent Bacterial Infections:
Epidemiology (2)
Bacteria isolated include Streptococcus
pneumoniae, Haemophilus influenzae type B,
Staphylococcus aureus, Escherichia coli,
Pseudomonas aeruginosa, nontyphoid
Salmonella
S pneumoniae accounts for >50% of
bacteremia
Incidence of S pneumoniae and H influenzae
may be lower in regions where vaccines are
administered
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Serious Recurrent Bacterial Infections:
Epidemiology (3)
Increased risk of Haemophilus influenzae B,
invasive meningococcal disease
Gram-negative bacteremia more common in
children with advanced disease
Case mortality with gram-negative bacteremia
>40%
Central venous catheter increases risk of
bacterial infections
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Serious Recurrent Bacterial Infections:
Clinical Manifestations
Clinical presentation dependent on type of
bacterial infection
(eg, bacteremia, sepsis, vasculitis, septic
arthritis, pneumonia, meningitis, sinusitis)
Presentation similar to that of HIV-uninfected
children
Classical signs, symptoms, and laboratory tests
may be missing in many HIV-infected children
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Serious Recurrent Bacterial Infections:
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
Sputum cultures may be difficult to obtain
Additional studies such as ultrasound should be
considered
Assays for detection of bacterial antigens when
available may be helpful
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Serious Recurrent Bacterial Infections:
Prevention
Routine use of conjugated pneumococcal and
Haemophilus influenzae B vaccine (not
routinely available in resource-poor countries)
Avoid raw and undercooked foods, unsterilized
water, unpasteurized milk products
Hand washing and other precautions
Avoid pets
Caution with all foods when traveling
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Serious Recurrent Bacterial Infections:
Prevention – H influenza B
Children <5 years of age should be given H
influenza B (Hib) conjugate vaccine
Consider use in children >5 years
Incompletely immunized children should
receive 2 doses >8 weeks apart
Pneumococcal conjugate vaccines (A II)
>5 years: consider Hib conjugate vaccine 2
doses 1-2 months apart
Children 2-59 months should receive the
heptavalent pneumococcal vaccine (PCV) at
2, 4, 6, and 12-15 months
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Serious Recurrent Bacterial Infections:
Prevention – S pneumoniae
Previously unimmunized children aged 7-23
months should receive 2-3 doses of PCV
Incompletely immunized children should
receive 2 doses of PCV >8 weeks apart
Children >2 years of age should receive 23
valent PCV (>2 months after last conjugate
vaccine)
Reimmunize with PCV in 3-5 years in children
aged <10 years or after 5 years in children
aged >10 years
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Serious Recurrent Bacterial Infections:
Prevention
Trimethoprim sulfamethoxazole (TMP-SMX)
prophylaxis reduces bacterial infection and new
and recurrent episodes of malaria
Atovaquone plus azithromycin provides
prophylaxis for MAC as well as PCP
Discontinue prophylaxis in children on ART with
CD4 percentage >15% with caution
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Serious Recurrent Bacterial Infections:
Treatment
Patients with suspected serious bacterial
infections should be treated empirically and
promptly without waiting for laboratory results
Consider local prevalence of resistance of
common infectious agents
Response of mildly immunodeficient children
is similar to that of HIV-uninfected children
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Serious Recurrent Bacterial Infections:
Treatment (2)
Treat HIV-infected children outside the neonatal
period with empiric therapy until cultures are
available (A III)
Use extended spectrum cephalosporin such as
ceftriaxone or cefotaxime
Consider addition of azithromycin for hospitalized
patients with pneumonia
Add clindamycin or vancomycin if MRSA is
suspected
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Serious Recurrent Bacterial Infections:
Treatment Failure
Consider bacterial resistance if treatment
failure occurs
Consider nonbacterial cause such as TB,
PCP, meningitis (Cryptococcus or TB)
Look for catheter-related infections
Occult abscess
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Bartonellosis: Epidemiology
Bartonella henselae and Bartonella quintana
are primary species causing bacillary
angiomatosis and peliosis
Bartonella bacteremia also occurs in HIVinfected individuals but is relatively uncommon
in HIV-infected children
Bartonella henselae is associated with cat
scratch disease in the general population
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Bartonellosis: Epidemiology (2)
Household cat is the primary vector
Eradication of flea infestation may be important
in preventing infection, as contamination of cat
claws is a possible mechanism of human
infection
90% of patients with cat scratch disease have a
history of recent contact with cats
The vector for Bartonella quintana is the human
body louse
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Bartonellosis: Clinical Manifestations
Clinical manifestations determined by host
response
Localized disease consisting of suppurative
regional lymphadenopathy is most common in
patients with an intact immune system
Systemic infection is more common among
immunocompromised individuals
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Bartonellosis: Clinical Manifestations –
Bacillary angiomatosis
Rare disorder occurring in severely
immunocompromised individuals
Characterized by cutaneous and subcutaneous
angiomatous papules
Can be confused with Kaposi sarcoma
Nodules may be observed in the subcutaneous
tissue and can erode to the skin
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Bartonellosis: Clinical Manifestations –
Bacillary peliosis
Characterized by angiomatous masses in the
visceral organs
The liver is most frequently infected
Individuals with bacillary peliosis and bacillary
angiomatosis may have relapsing fevers
Dissemination can result in osteomyelitis,
endocarditis, encephalopathy, seizures,
neuroretinitis, and transverse myelitis
Nonspecific symptoms include fever, chills,
night sweats, anorexia, weight loss, abdominal
pain, vomiting, and diarrhea
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Bartonellosis: Diagnosis
Diagnosis usually made by means of a biopsy
with demonstration of small gram-negative
bacilli
Isolated with difficulty from blood and tissue
culture
Indirect fluorescent antibody and enzyme
immunoassay tests are available at some
laboratories
Cross-reactivity among Bartonella species and
other bacteria is common
PCR is the most sensitive means of diagnosis
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Bartonellosis: Prevention
Reduce exposure to cats and cat fleas
Treat infestations of body lice
Consider risk of ownership of cats, especially
for individuals who are severely
immunocompromised
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Bartonellosis: Treatment
Treatment of cat scratch disease in
immunocompetent individuals is mainly
supportive
In vitro and in vivo antibiotic susceptibilities do
not correlate well with efficacy
Drug of choice is erythromycin or doxycycline
Clarithromycin and azithromycin treatment has
been associated with clinical responses
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Bartonellosis: Treatment (2)
Severe disease requires IV administration
Treatment should be given for 3 months for
bacillary angiomatosis and 4 months for
bacillary peliosis central nervous system
disease, osteomyelitis and other severe
systemic infections
Add rifampin to either erythromycin or
doxycycline for severely infected
immunocompromised individuals
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Bartonellosis: Treatment Failure
Immunocompromised individuals who
experience treatment failure should be retreated for 4-6 months
Immunocompromised HIV-infected adults who
experience relapse have been treated with
long-term suppression with doxycycline or a
macrolide when CD4 counts are <200 cells/µL
There are no data for children
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Syphilis: Epidemiology
Perinatal transmission of Treponema pallidum at
any stage of pregnancy or during delivery
Illicit 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
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Syphilis: Clinical Manifestations
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
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Syphilis: Clinical Manifestations (2)
60% of infants with congenital syphilis have
hepatomegaly, jaundice, skin rash, nasal
discharge, anemia, thrombocytopenia, osteitis,
periostitis, osteochondritis, or pseudoparalysis
Late manifestations include mental retardation,
keratitis, deafness, frontal bossing, Hutchinson
teeth, saddle nose, Clutton joints
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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 tests should be
evaluated with a quantitative nontreponemal
test (eg, slide test, RPR, automated reagin test)
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Syphilis: Diagnosis (2)
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
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Syphilis: Prevention – Congenital
Syphilis
Routinely screen all pregnant women with
serologic testing during first prenatal visit
Obtain information regarding the treatment of
sexual partners for sexually transmitted diseases
Serologic testing of mothers serum is preferable
Routine screening of newborns’ serum or
umbilical cord blood is not recommended
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Syphilis: Prevention – Acquired Syphilis
Routine discussion of sexual behaviors that
place individuals at risk of syphilis and HIV
Routine serologic screening for syphilis annually
for all sexually active HIV-infected individuals
The occurrence of syphilis in an HIV infected
individual is an indication of high-risk behavior
Individuals undergoing screening or treatment
for syphilis should be evaluated for all sexually
transmitted diseases
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Syphilis: Treatment – Congenital Syphilis
Treat all infants whose mothers have untreated or
inadequately treated syphilis; not treated or initiated
treatment 4 weeks prior to delivery
Treat if mother treated with penicillin but no 4-fold
decrease in nontreponemal antibody titer, or a 4-fold
increase suggesting relapse or reinfection
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 level (A II)
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Syphilis: Treatment – Congenital Syphilis (2)
Aqueous crystalline penicillin G: 100,000150,000 units/kg/day given as 50,000
units/kg/dose IV Q12H for 7 days, followed by
Q8H for a total of 10 days (A II)
Diagnosis after 1 month of age, increase
dosage to 50,000 units/kg IV Q6H for 10 days
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Syphilis: Treatment – Acquired Syphilis
Treat acquired syphilis with single dose of benzathine
penicillin G 50,000 units/kg IM
Treat late latent disease with 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
Treat neurosyphilis with aqueous penicillin G 200,000
to 300,000 units/kg IV Q6H for 10-14 days
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)
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Mycobacterium tuberculosis:
Epidemiology
14,000 new cases of TB in United States in
2006 (6% among children <15 years of age)
1.1% of these were HIV infected
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
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Mycobacterium tuberculosis:
Epidemiology (2)
CD4 count is not a sufficient indicator of TB
risk
Primarily infection by contact with adults in
daily environment
In most cases, TB represents the progression
of primary infection rather than a reactivation of
disease
All confirmed and suspected TB cases should
be reported to health authorities
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Mycobacterium tuberculosis:
Epidemiology (3)
BCG induced M tuberculosis has been
reported in HIV-infected children vaccinated
at birth
In the United States, resistance to any of the
first-line anti-TB drugs occurs in 15% of
children
Internationally, rate of multiple drug-resistant
(MDR) TB is increasing
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Mycobacterium tuberculosis:
Epidemiology (4)
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
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Mycobacterium tuberculosis:
Clinical Manifestations
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 HIVinfected and HIV-uninfected children
Extrapulmonary: marrow, lymph node, bone,
pleura, pericardium, peritoneal
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Mycobacterium tuberculosis:
Diagnosis
Difficult to diagnose; maintain a degree of
suspicion
M tuberculosis detected in up to 50% of gastric
aspirate in HIV-uninfected children (obtain 3
consecutive morning gastric aspirates)
Usually requires linking TB in child to contact
along with positive radiograph, positive skin
test (TST), or physical examination
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Mycobacterium tuberculosis:
Diagnosis (2)
Cornerstone for latent TB is the TST
TST not of value if BCG immunization has been
administered
Annual TB testing recommended for HIVinfected children
HIV-infected children may have a negative TST
Sensitivity to TST may be reduced if other viral
infection, such as measles, is present
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Mycobacterium tuberculosis:
Diagnosis (3)
Assays for interferon gamma release following
stimulation of lymphocytes have been approved
by the FDA for diagnosis of TB
(eg, QuantiFERON-TB)
Tests for sputum using nucleic acid amplification
approved but not fully evaluated in children
Patients with a positive test for latent TB infection
(LTBI) should have any chest radiograph and
clinical evaluation to rule on active disease
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Mycobacterium tuberculosis:
Diagnosis (4)
MDR TB should be suspected in a child with TB
disease if the child has:
Close contact with the patient with MDR TB
Contact with a TB patient who died while on treatment when
there is reason to suspect MDR TB
Bacteriologically proven TB that has not responded to first-line
drugs
Exposure to source cases that remain smear or culture positive
2 months after treatment
History of living in a region with a high prevalence of MDR TB
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Mycobacterium tuberculosis:
Prevention
Children who are homeless, live in institutional
settings, or have close family contacts in
communities with high rates of coinfection with
TB and HIV are particularly susceptible
BCG immunization is not routinely administered
in the United States and should NOT be
administered to HIV-infected children because
of risk of BCG dissemination
Treat HIV-infected children for LTBI if they have
a positive TST result
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Mycobacterium tuberculosis:
Prevention (2)
HIV-infected children should be treated if they
are exposed to a person who has contagious
TB
Duration of preventive treatment for children
should be 9 months with isoniazid 10-15
mg/kg/day (A II) or 20-30 mg/kg twice weekly
(B II)
If isoniazid resistance is suspected, use
rifampin for 4-6 months
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Mycobacterium tuberculosis:
Treatment
Treatment principles similar in HIV-infected and
HIV-uninfected children
Initiate treatment as soon as possible in children
with suspected TB
If already on ART, review drug interactions
Use of DOT increases adherence, decreases
resistance, treatment failure, and relapse
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Mycobacterium tuberculosis:
Treatment (2)
Initial treatment (induction phase)
4 drugs: isoniazid, rifampin, pyrazinamide,
plus either ethambutol or streptomycin (A I)
If the organism is found to be susceptible to
isoniazid, rifampin, and pyrazinamide during
the 2-month intensive phase, ethambutol (or
streptomycin) can be discontinued
Use ethionamide as alternative to ethambutol
for CNS disease (A III)
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Mycobacterium tuberculosis:
Treatment (3)
If clinical response occurs and organism is susceptible
to isoniazid and rifampin after 2 months, continue
treatment with isoniazid and rifampin 2-3 times weekly
or daily during the continuation phase
Children with severe immunosuppression should
receive only daily or 3-times-weekly treatment during
the continuation phase
Ethionamide can be used as alternative to ethambutol
for TB meningitis
Minimum treatment is 6-9 months for children with
active pulmonary TB and 12 months for
extrapulmonary disease (A III)
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Mycobacterium tuberculosis:
Treatment (4)
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
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Mycobacterium tuberculosis:
Treatment (5)
Rifampin
Dosage: 10-20 mg/kg orally once daily
(maximum 600 mg daily)
Side effects include rash; hepatitis;
jaundice; GI upset; orange coloring of
urine, tears, sweat
Rifampin can accelerate clearance of
PIs (except RTV) and NNRTIs
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Mycobacterium tuberculosis:
Treatment (6)
Rifabutin (B III)
Dosage: 10-20 mg/kg orally once daily
Limited data in children
Peripheral leukopenia, elevated liver enzymes,
pseudojaundice, GI upset
Increases hepatic metabolism of certain PIs:
reduce rifabutin dosage by 50% when given
with RTV, IDV, NFV, APV
Increase dosage of rifabutin by 50-100% when
given with EFV
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Mycobacterium tuberculosis:
Treatment (7)
Pyrazinamide
Dosage: 20-40 mg/kg orally once daily
(maximum 2 g daily)
Hepatic toxicity, rash, arthralgia, GI upset
Ethambutol
Dosage: 15-25 mg/kg orally daily
(maximum 2.5 g daily)
Toxicity includes optic neuritis, rash, nausea
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Mycobacterium tuberculosis:
Treatment (8)
Secondary drugs
Ethionamide: 15-20 mg/kg orally divided into 2
or 3 doses daily (maximum dosage 1 g daily)
Streptomycin: 20-40 mg/kg daily IM (maximum
dosage 1 g daily)
Alternatives: kanamycin, amikacin, capreomycin,
quinolones, cycloserine, paraaminosalicylic acid
Steroids may be indicated for TB meningitis
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Mycobacterium tuberculosis:
Treatment (9)
Treatment of TB in setting of ART may be complicated
by unfavorable pharmacokinetic interactions and
overlapping toxicities
Use of rifampin precludes treatment with protease
inhibitors but may allow treatment with NNRTIs
Starting treatment with NNRTIs is preferred because of
fewer interactions with rifampin-based TB therapy (B II)
Efavirenz is the preferred NNRTI for children >3 years
of age whereas nevirapine is preferred for children <3
years of age
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Mycobacterium tuberculosis:
Treatment (10)
Children already receiving ART should receive
immediate treatment for TB accompanied by a
review of overlapping toxicities and drug-drug
interactions
Drug-resistant TB should be treated with a
minimum of 3 drugs, including 2 or more
bactericidal isolate-susceptible drugs
Regimens may include 3-6 drugs
Adjunct treatment with corticosteroids may be
indicated for children with TB meningitis
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Mycobacterium tuberculosis:
Monitoring and Adverse Effects
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Monthly monitoring of clinical and bacteriological
responses to treatment
Side effects of drugs include nausea, vomiting,
hepatotoxicity, nephrotoxicity, and optic neuritis
with ethambutol
IRIS associated with new onset of systemic
symptoms in HIV-infected individuals receiving
ART
Data on occurrence of IRIS in children are
incomplete
Treatment with corticosteroids has been used
in severe cases
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Mycobacterium avium Complex Disease:
Epidemiology
Multiple related species of non-TB mycobacteria:
M avium, M intracellulare, M paratuberculosis
Second most common OI in children after PCP
but decreases in incidence with ART
Associated with soil exposure and racial
susceptibility
Acquired by means of inhalation, ingestion, or
inoculation
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Mycobacterium avium Complex Disease:
Epidemiology (2)
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
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Mycobacterium avium Complex Disease:
Prevention
Most effective means of prevention is to
preserve immune function with ART
Offer prophylaxis for MAC as follows: (A II)
CD4 T-cell risk factor for occurrence:
<750 cells/µL <1 year; <500 cells/µL 1-2 years;
<75 cells/µL 2-5 years; < 50 cells/µL >6 years
Use either clarithromycin or azithromycin (A II)
Studies suggest that prophylaxis may be
discontinued when CD4 percentages reach
20% to 25% while on stable ART
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Mycobacterium avium Complex Disease:
Clinical Manifestations
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
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Mycobacterium avium Complex Disease:
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
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Mycobacterium avium Complex Disease:
Treatment
Preserve immune function through optimal
treatment of HIV infection
Initiate treatment with 2 or more drugs (eg,
clarithromycin or azithromycin plus ethambutol)
(A I)
Consider rifabutin as third drug in severely ill
patients (C I)
Caution in using rifabutin as it may increase
toxicity of other ARVs and increase clearance of
PIs and NNRTIs
72
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Mycobacterium avium Complex Disease:
Treatment (2)
Note cautions in use of these drugs with ARVs
If rifabutin cannot be used or if drug failure occurs,
consider ciprofloxacin, amikacin, streptomycin, and a
quinolone
Lifelong suppressive therapy required after initial therapy
IRIS may occur as indicated by new onset of symptoms
Toxicities of drugs include nausea, vomiting, liver
toxicity, hypersensitivity reactions and, with ethambutol,
optic neuritis
73
July 2009
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Mycobacterium avium Complex Disease:
Treatment (3)
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)
74
July 2009
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Mycobacterium avium Complex Disease:
Treatment (4)
Rifabutin: 10-20 mg/kg orally once daily
(maximum 300 mg daily) (A I)
Ciprofloxacin: 20-30 mg/kg IV or orally once
daily (maximum 1.5 g)
Amikacin: 15-30 mg/kg/day IV divided every
12-24 hours (maximum 1.5 g) (C III)
75
July 2009
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Aspergillosis: Epidemiology
Aspergillus species are ubiquitous molds found
in soil, on plants, and in decomposing organic
materials
The most common species causing aspergillosis
are A fumigatus and A flavus
Rare but frequently lethal infection
Risk factors include low CD4 count, neutropenia,
corticosteroids, concurrent malignancy with
chemotherapy, HIV-related phagocytic
impairment, previous respiratory infections,
broad-spectrum antibiotic exposure
76
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Aspergillosis: Clinical Manifestations
Pulmonary aspergillosis is the most common
presentation
Invasive pulmonary aspergillosis associated
with fever, cough, dyspnea, pleuritic pain
Additional manifestations include necrotizing
tracheobronchitis, pseudomembranous
tracheobronchitis, CNS involvement,
cutaneous, sinus, middle ear and mastoid
infection
77
July 2009
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Aspergillosis: Diagnosis
Usually isolated from the blood but also
readily isolated from lung, sinus, brain, and
skin biopsy
Definitive diagnosis includes histopathologic
demonstration of organisms in biopsy
specimens
Presumptive diagnosis of respiratory tract
infection can be made if Aspergillus species
is recovered from respiratory sample
78
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Aspergillosis: Diagnosis (2)
Chest radiograph demonstrates either
diffuse interstitial pneumonitis or
localized wedge-shaped infiltrates
CT of chest may be used to identify a
“halo” sign
Cavitation and air crescent formation
in chest CDT more frequent in older
children and adults
79
July 2009
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Aspergillosis: Prevention
Consider excluding plants and flowers
from rooms and avoiding food items
such as nuts and spices
Erect suitable barriers between patient
care and construction sites, clean
shower heads routinely as well as hotwater faucets and air-handling systems
80
July 2009
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Aspergillosis: Treatment
Voriconazole is recommended for treatment of
invasive aspergillosis
Adult data indicate that voriconazole is superior
to amphotericin B but data in children are
limited
Recommended dosage for children is 6-8
mg/kg IV (or 8 mg/kg orally) Q12H, followed by
7 mg/kg IV or orally twice daily
Treatment is continued for 12 weeks
81
July 2009
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Aspergillosis: Adverse Effects
and Treatment Failure
Voriconazole side effects include reversible
dose-dependent visual disturbances, elevated
liver enzymes, and occasional skin rash
Amphotericin toxicity is associated primarily
with fever, chills, and nephrotoxicity
Efficacy of antifungal therapy for aspergillosis
is poor
Experimental approaches include evaluation
of caspofungin
82
July 2009
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Candida Infections: Epidemiology
Most common fungal infections in HIV-infected
children
Thrush and diaper dermatitis occur in 50-85%
of HIV-infected children
In pre-ART era, oropharyngeal candidiasis
found in 94% of children with Candida
esophagitis
Disseminated candidiasis rare in children
except those with CMV or HSV coinfection,
and those with central venous catheter
83
July 2009
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Candida Infections: Epidemiology (2)
A substantial percentage of children with
fungemia receive oral, systemically absorbable
azole antifungals (eg, ketoconazole)
Complications include disseminated infection of
bone, liver, and kidney; endophthalmitis
Mortality from disseminated candidiasis >90%
in children with fever and symptoms >14 days
84
July 2009
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Candida Infections: Clinical Manifestations
Thrush and erythematous, hyperplastic, 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
85
July 2009
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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
Research studies or evaluating detection of
candidate antigens for early diagnosis
86
July 2009
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Candida Infections: Prevention
Routine primary prophylaxis of candidiasis
in HIV-infected children is not indicated
Candida organisms are common
commensals on mucosal surfaces in
healthy individuals and no measures are
available to reduce exposure
87
July 2009
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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
88
July 2009
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Candida Infections: Treatment (2)
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 BID 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
89
July 2009
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Candida Infections: Treatment (3)
Esophageal disease
Treat both diagnosed esophageal disease and
children with OPC and esophageal symptoms (A I)
Initiate treatment with:
Fluconazole 6 mg/kg/day orally or IV 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)
90
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Candida Infections: Treatment (4)
Esophageal disease
Other therapies not fully evaluated in children
Voriconazole: loading dose of 6 mg/kg IV Q12H on
day 1, followed by 4 mg/kg Q12H 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
91
July 2009
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Candida Infections: Treatment (5)
Invasive disease
Remove central venous catheter
Amphotericin B (A I)
0.5-1.5 mg/kg once daily IV over course of 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
92
July 2009
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Candida Infections: Treatment (6)
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)
93
July 2009
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Candida Infections: Treatment (7)
Treatment under development
Caspofungin, micafungin, and anidulafungin
have been studied in battles with HIV
infection, neutropenic children at risk of
fungal infection in children with documented
candidiasis
Data on HIV-infected children are limited
94
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Candida Infections: Treatment (8)
Amphotericin toxicity
Nephrotoxicity: azotemia, hypokalemia
Nephrotoxicity can be minimized by hydration
with 0.9% saline intravenously 30 minutes
before amphotericin B infusion
Infusion-related chills, fever, and vomiting;
pretreat with acetaminophen or
diphenhydramine
Rarely: hypotension, arrhythmias,
neurotoxicity, hepatic toxicity
95
July 2009
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Candida Infections: Treatment (9)
Fluconazole, itraconazole, ketoconazole
toxicity
Inhibition of CYP450-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, pruritus, Stevens-Johnson
syndrome (rare), increased liver enzymes, hepatitis,
leukopenia, anemia, hemolytic anemia, alopecia
(fluconazole)
96
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Candida Infections: Treatment Failure
Oral pharyngeal and esophageal candidiasis
Initial failure should be treated with oral fluconazole,
itraconazole, oral amphotericin B, or low-dose IV
amphotericin B
Invasive disease
Amphotericin B lipid formulations can be used for
children who cannot tolerate amphotericin B, have
disseminated Candida infection that is resistance to
amphotericin B, or are at risk of nephrotoxicity
97
July 2009
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Coccidioidomycosis: Epidemiology
Increased risk of infection with Coccidioides
immitis and Coccidioides posadasii among
HIV-infected children in endemic areas (eg,
southwestern United States, northern Mexico,
Central and South America)
Primary infection of newborn rare
In utero and perinatal transmission of
C immitis reported
Reports of infection in nonendemic areas
usually due to reactivation
98
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Coccidioidomycosis: Clinical
Manifestations
Fever and dyspnea most common presentation
Chills, weight loss, lymphadenopathy, chest pain,
diffuse reticulonodular pulmonary infiltrates,
meningitis
Disseminated disease associated with erythema
multiforme; erythema nodosum; erythematous
maculopapular rash; arthralgia; bone, joint, and CNS
infection
99
July 2009
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Coccidioidomycosis: Diagnosis
Direct examination and culture of respiratory
secretions and CSF or biopsy of lesions
Blood cultures positive in 15% of cases
Complement fixation assay detects IgG
antibody, positive IgM assays suggest active or
recent infection, complement fixation titers >
1:16 correlate with presence and severity of
extrapulmonary infection
100
July 2009
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Coccidioidomycosis: Prevention
Difficult to avoid exposure in endemic areas
Exposure can be reduced by avoiding
activities that predispose to inhalation of
spores such as disturbing contaminated
soil, being outdoors during dust storms
101
July 2009
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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 BID or
itraconazole 4-10 mg/kg BID for 3 days followed
by 2-5 mg/kg BID (B III)
102
July 2009
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Coccidioidomycosis: Treatment (2)
CNS infection, including meningitis
High-dose fluconazole 5-6 mg/kg BID
If unresponsive to fluconazole, use IV amphotericin
B augmented by intrathecal amphotericin B (C I)
103
July 2009
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Coccidioidomycosis:
Monitoring, Adverse Events and Toxicity
Monitoring of complement fixing IgG antibody
is useful
Toxicity of antifungal drugs includes fevers,
chills, nausea and vomiting, nephrotoxicity
Interaction of all antifungal agents with ARVs
should be investigated; fluconazole and
itraconazole appear to be safe in combination
with ARVs
Voriconazole should be avoided in patients on
PIs or NNRTIs
104
July 2009
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Cryptococcosis: Epidemiology
Most infections caused by Cryptococcosis
neoformans and Cryptococcosis gattii
Infection occurs primarily in tropical and
subtropical areas
Low incidence of infection in children,
especially with use of ART
Children usually infected during 6-12 year
age range
Usually severely immunosuppressed
105
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Cryptococcosis: Clinical Manifestations
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
106
July 2009
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Cryptococcosis: Diagnosis
Microscopic examination of CSF on India ink-stained
wet mounts
Detection of cryptococcal antigen in CSF, serum,
bronchoalveolar lavage fluid (can be negative in
culture-positive meningitis)
Fungal cultures from CSF, sputum, and blood
cultures can identify the organism
Antigen levels useful in evaluating response to
treatment and relapse
Pulmonary disease diagnosed by bronchoalveolar
lavage and direct examination of India ink-stained
specimens
107
July 2009
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Cryptococcosis: Prevention
No proven strategies to prevent
exposure
Believed to be acquired by
inhalation of aerosolized particles
from the environment
108
July 2009
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Cryptococcosis: Treatment
Not well studied in children; infection is often fatal in
the absence of treatment
CNS Disease
Amphotericin B induction (0.7-1.5 mg/kg/day IV) combined
with 2 weeks of flucytosine (25 mg/kg/dose given 4 times
daily) followed by fluconazole for a minimum of 8 weeks
After symptoms are controlled, treat with fluconazole or
itraconazole maintenance
Use amphotericin B alone if flucytosine is not tolerated
Fluconazole plus flucytosine is an alternative to
amphotericin B (limited data in children)
109
July 2009
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Cryptococcosis: Treatment (2)
Pulmonary and extrapulmonary cryptococcosis
No clinical trials on the outcome of non-CNS
cryptococcosis in HIV-infected patients
Treat with amphotericin B with or without the
addition of fluconazole (A III)
Fluconazole or itraconazole should be continued
long-term
110
July 2009
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Cryptococcosis: Monitoring
and Drug Toxicity
Amphotericin toxicity
Nephrotoxicity: azotemia, hypokalemia
Nephrotoxicity can be minimized by hydration with
0.9% saline intravenously 30 minutes before
amphotericin B infusion
Infusion-related chills, fever, and vomiting; pretreat
with acetaminophen or diphenhydramine
Rarely: hypotension, arrhythmias, neurotoxicity,
hepatic toxicity
111
July 2009
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Cryptococcosis: Monitoring
and Drug Toxicity (2)
Flucytosine toxicity
Bone marrow: anemia, leukopenia,
thrombocytopenia
Liver, GI, and renal toxicity
Fluconazole toxicity
Potential interaction with ARV should be
evaluated before initiating treatment (A III)
112
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Cryptococcosis:
IRIS and Treatment Failure
IRIS related to cryptococcosis can present
within weeks
Optimal treatment of patients experiencing
treatment failure has not been defined
Patients failing initial azole treatment should be
switched to amphotericin B in combination with
flucytosine
Consider use of liposomal amphotericin B
Experience with posaconazole or voriconazole
is limited
113
July 2009
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Histoplasmosis: Epidemiology
Pathogen is Histoplasma capsulatum
Incidence of disseminated histoplasmosis in
HIV-infected children in the United States is
<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
114
July 2009
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Histoplasmosis: Clinical Manifestations
Prolonged fever is the most common presentation
Malaise, weight loss, and nonproductive cough
Primary pulmonary focus leads to widespread
dissemination in children
Pulmonary manifestations common
Physical findings include hepatosplenomegaly,
erythematous nodular coetaneous lesions, CNS
involvement with meningitis
Anemia, thrombocytopenia, elevated liver transaminases
Progressive disseminated histoplasmosis (PDH) is fatal
if untreated
115
July 2009
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Histoplasmosis: Diagnosis
Serologic testing using CF and
immunodiffusion is insensitive in the presence
of HIV infection.
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
116
July 2009
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Histoplasmosis: Diagnosis (2)
Culture of Histoplasma from blood or other
sources
Detection of H capsulatum polysaccharide
antigen in urine, blood, CSF, or
bronchoalveolar lavage using EIA
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
117
July 2009
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Histoplasmosis: Prevention
Most infections occur without a recognized
history of exposure
Sites and conditions commonly implicated
include outbreaks of soil contamination
with bird or bat droppings, older urban and
rural structures, and decaying vegetation
118
July 2009
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Histoplasmosis: Treatment
Limited data for children; recommendations
based on adult data
PDH is fatal without treatment and should be
treated with either amphotericin B or
itraconazole
Fluconazole has been used successfully as an
alternative for patients with mild disease and
for those who cannot tolerate itraconazole
119
July 2009
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Histoplasmosis: Treatment (2)
Amphotericin B for patients with severe disseminated
disease requiring hospitalization and for those who
are immunocompromised
Amphotericin B induction dosage: 1 mg/kg for 4-6
weeks followed by itraconazole chronic suppressive
therapy for 12 months (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
120
July 2009
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Histoplasmosis:
Monitoring and Adverse Effects
Antigen levels should be monitored during
treatment and for 1 year thereafter
Adverse effects of amphotericin B include
nephrotoxicity, infusion related fever, chills,
nausea, and vomiting
Azole drugs inhibit CYP450-dependent hepatic
enzymes, warranting careful review of drug
interactions when using ARVs
121
July 2009
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Pneumocystis jiroveci (carinii):
Epidemiology
Organisms are found worldwide in the lungs of
humans and lower animals
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-ART
CD4 T-cell count not a good indicator of risk in
infants <1 year old
Infection now unusual owing to routine prophylaxis
with TMP-SMX
122
July 2009
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Pneumocystis jiroveci (carinii):
Clinical Manifestations
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
123
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Pneumocystis jiroveci (carinii):
Diagnosis
Hypoxia with low arterial oxygen pressure
(alveolar-arterial oxygen gradient >30 mmHg)
Definitive diagnosis requires demonstrating
organism
Induced sputum (difficult <2 years)
Bronchoscopy with bronchoalveolar lavage
Fiberoptic bronchoscopy with biopsy –
generally not recommended
124
July 2009
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Pneumocystis jiroveci (carinii):
Diagnosis (2)
Open lung biopsy most sensitive
Requires thoracotomy, chest tube drainage
Organisms seen on biopsy with:
Gomori methenamine silver stain
Toluidine blue stain
Giemsa or Wright stain
Monoclonal antibody
DNA PCR for Pneumocystis MSG gene in
fluids, lavage – sensitive but less specific
than histology
125
July 2009
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Pneumocystis jiroveci (carinii):
Prevention
Need for isolation of hospitalized patients
has not been demonstrated, but when
prophylaxis cannot be given, may need to
isolate patient or susceptible contacts
Infants born to HIV-infected mothers should
be considered for prophylaxis at 4-6 weeks
of age and continued until 1 year of age (A II)
126
July 2009
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Pneumocystis jiroveci (carinii):
Prevention (2)
Chemoprophylaxis with TMP-SMX recommended
as follows, based on CD4 counts and patient
age:
6 years: CD4 count <200 cells/µL or CD4
percentage <15%
1 to 5 years: CD4 count <500 cells/µL or CD4
percentage <15%
All HIV-infected infants <12 months of age
regardless of CD4 count or percentage
127
July 2009
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Pneumocystis jiroveci (carinii):
Treatment
TMP-SMX (A I)
>2 months 15-20 mg/kg/day of TMP
component IV 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
128
July 2009
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Pneumocystis jiroveci (carinii):
Treatment (2)
Adverse reactions:
Rash
Stevens-Johnson syndrome (rare)
Neutropenia, thrombocytopenia,
megaloblastic or aplastic anemia
129
July 2009
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Pneumocystis jiroveci (carinii):
Treatment (3)
Pentamidine isethionate
Recommended for patients with intolerance
to TMP-SMX or clinical failure with TMP-SMX
(A I); do not combine use
4 mg/kg/day IV once daily over period of 6090 minutes
Consider oral atovaquone after 7-10 days
(B III)
130
July 2009
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Pneumocystis jiroveci (carinii):
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
131
July 2009
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Pneumocystis jiroveci (carinii):
Treatment Alternatives (2)
Clindamycin/primaquine
Used for mild to moderate PCP in adults;
no data in children (C III)
Primaquine contraindicated in G6PD
deficiency
132
July 2009
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Pneumocystis jiroveci (carinii):
Treatment Alternatives (3)
Clindamycin/primaquine
Pediatric clindamycin dosing based on other
uses: 20-40 mg/kg/day IV 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, pseudomembranous colitis
133
July 2009
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Pneumocystis jiroveci (carinii):
Treatment Alternatives (4)
Dapsone/TMP
Use for mild to moderate PCP in adults; no
data in children (C III)
Dapsone dosage <13 years 2 mg/kg/day
orally once daily (A II) for 21 days
TMP 15/mg/kg/day orally divided into 3 daily
doses for 21 days
Adverse reactions include rash, anemia,
thrombocytopenia, increased liver enzymes
134
July 2009
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Pneumocystis jiroveci (carinii):
Treatment Adjunct
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
135
July 2009
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Pneumocystis jiroveci (carinii):
Treatment Adjunct (2)
Corticosteroids
Dosing recommendations vary
Prednisone: 40 mg BID for 1-5 days; 40
mg once daily days 6-10; 20 mg once
daily days 11-21
Alternative: prednisone 1 mg/kg BID days
1-5; 0.5 mg/kg BID days 6-10; 0.5 mg/kg
once daily days 11-21
136
July 2009
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Pneumocystis jiroveci (carinii):
Monitoring and Adverse Events
Short courses of corticosteroids have been used in
some cases of PCP of moderate to severe intensity
starting within 72 hours of diagnosis (A I)
As with other coinfection, IRIS may occur following
initiation of ART but has been described infrequently
in PCP
Most common adverse reaction to TMP-SMX includes
rash and rarely erythema multiforme or StevensJohnson syndrome
Pentamidine is associated with renal toxicity, usually
occurring 2 weeks after initiation of treatment
137
July 2009
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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
138
July 2009
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Cryptosporidiosis/Microsporidiosis:
Epidemiology (2)
Person-to-person transmission in child care
centers
Oocysts can contaminate water supplies
Outbreaks associated with contaminated
drinking water and swimming pools
Incidence declined since advent of ART
139
July 2009
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Cryptosporidiosis/Microsporidiosis:
Clinical Manifestations
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
Different species may cause different clinical
syndromes (eg, Encephalitozoon hellem associated
with keratoconjunctivitis, sinusitis, prostatic abscess)
140
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Cryptosporidiosis/Microsporidiosis:
Diagnosis
Cryptosporidiosis
Concentrated stool samples demonstrating
oocysts
Evaluate at least 3 separate stool samples
Monoclonal antibody fluorescein stain and EIA
for antigen have enhanced specificity and
sensitivity
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Cryptosporidiosis/Microsporidiosis:
Diagnosis (2)
Microsporidia
Use thin smears of unconcentrated stoolformalin 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
142
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Cryptosporidiosis/Microsporidiosis:
Prevention
Avoid direct contact with fecal material from adults,
diaper-age children, and infected animals
Carefully investigate sources of drinking water and
recreational activities involving water
HIV-infected children should not be allowed to drink
water directly from lakes or rivers
Outbreaks of cryptosporidiosis occasionally have been
linked to municipal water contamination
Some experts recommend that severely
immunocompromised HIV-infected patients should not
share a room with patients who have cryptosporidiosis
143
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Cryptosporidiosis/Microsporidiosis:
Treatment
Immune restoration following antiretroviral
treatment frequently results in clearing
Supportive care, hydration, electrolyte
replenishment, nutritional supplements
Available treatment inconsistently effective
144
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Cryptosporidiosis: Treatment
No agents have been consistently effective
Nitazoxanide: effective for Cryptosporidium and
Giardia lamblia (B I for children and C III for HIVinfected children)
Nitazoxanide dosage: 100 mg orally BID for
children 1-3 years; 200 mg BID for children 4-11
years
Limited data: paromomycin, azithromycin
145
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Microsporidiosis: Treatment
Albendazole: 7.5 mg/kg orally BID; maximum
dosage 400 mg orally BID (A II)
Fumagillin: limited data for adults, no data for
HIV-infected children
146
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Malaria: Epidemiology
Malaria is caused by the obligate intracellular
protozoa Plasmodium
4 species account for most human infections: P
falciparum (60%), P vivax (25-30%), P ovale and
P malariae
In the United States, 1,200 to 1,400 cases are
reported annually
Most cases of malaria infection in U.S. citizens
are a result of not taking appropriate malaria
chemoprophylaxis
Over 30% of malaria cases in children are
found in newly arrived immigrants
147
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Malaria: Clinical Manifestations
Clinical studies of malaria present differing conclusions
on whether parasitemia, frequency of malaria,
recurrence, and severity of infection differ in HIV-infected
vs HIV-uninfected children
Fever is the most common symptom of malaria,
accompanied by chills, sweating, headache, myalgias,
malaise, nausea, vomiting, diarrhea, and cough
Chronic symptoms include splenomegaly, fever,
thrombocytopenia, and anemia
Congenital malaria is rare
Malaria may be misdiagnosed as a viral infection or HIV
(HIV also may be misdiagnosed as malaria)
148
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Malaria: Diagnosis
Thick blood smears are the most sensitive
technique for detecting infection but are not
helpful in determining the infectious species
Giemsa-stained thin blood smear gives the
malaria parasite’s distinctive appearance
Blood smear examination taken at 12-24 hour
intervals may be needed to rule out a diagnosis
A rapid malaria antigen capture assay (Binax
Now) has been approved by the FDA
The test is less sensitive for asymptomatic
individuals
149
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Malaria: Prevention
HIV-infected children who travel to regions of
endemic malaria should use clothing impregnated
with permethrin
DEET mosquito repellent (30-50% concentration)
is practical and effective
Insecticide-treated bed nets should be provided
Recommendations for chemoprophylaxis are the
same for HIV-infected children and HIVuninfected children
150
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Malaria: Prevention (2)
Prevention includes mefloquine (Lariam) and
Malarone
Mefloquine chemoprophylaxis is less expensive
and more convenient (once a week) but may be
associated with central nervous system effects
Doxycycline is an alternative chemoprophylaxis
agent
Emerging evidence suggests that TMP-SMX
may protect against new or recurrent cases of
malaria
151
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Malaria: Treatment
HIV infection status should not determine the
choice of treatment (A II)
Chloroquine-sensitive P falciparum should be
treated with chloroquine
In the United States, resistant P falciparum
treatment choices include atovaquoneproguanil, quinine with clindamycin, or
doxycycline or mefloquine
152
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Malaria: Treatment (2)
Severe P falciparum should be treated with IV
quinidine gluconate (or IV quinine when
available)
Ritonavir inhibits quinidine metabolism and is
contraindicated
Artemisinin, artesunate and other derivatives
combined with additional antimalarial drugs
have not been approved in the United States
but may be available through the CDC
153
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Malaria: Treatment (3)
P vivax, P ovale, P malariae
The drug of choice for non-P falciparum is
chloroquine
The drug is well tolerated and side effects
are usually limited to itching
Resistance to chloroquine may exist,
warranting treatment with quinine plus
clindamycin or doxycycline, atovaquoneproguanil, or mefloquine
154
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Malaria: Adverse Events
Severe malaria commonly induces
hypoglycemia in children, especially when
treated with IV quinine/quinidine
Cardiac monitoring and intensive care
monitoring are recommended when using
quinine/quinidine
155
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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
156
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Toxoplasmosis: Epidemiology (2)
Risk of transmission in HIV-uninfected
mothers with primary infection during
pregnancy = 29% (lower if maternal
infection in 1st trimester)
Perinatal toxoplasmosis infection may
occur in HIV-positive women with chronic
infection
<1% of AIDS-defining illnesses in
children
157
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Toxoplasmosis: Clinical Manifestations
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
158
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Toxoplasmosis: Clinical Manifestations (2)
Toxoplasmosis acquired after birth is initially
asymptomatic, followed by infectious
mononucleosis-like syndrome
Chronic toxoplasmosis can reactivate in HIVinfected children
Isolated ocular toxoplasmosis is rare is usually
associate with CNS disease
Less frequently observed presentations
include pneumonitis, hepatitis, myocarditis
159
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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 months or
persistence of IgG antibody after 12 months
160
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Toxoplasmosis: Diagnosis (2)
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
In the United States, routine screening for
Toxoplasma is not recommended in HIVinfected children when the mother does not
have Toxoplasma infection
161
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Toxoplasmosis: Prevention
Council all HIV-infected children and their caregivers
regarding sources of Toxoplasma gondii infection
Advise not to eat raw or undercooked meat
Hands should be washed after contact with raw meat or
when gardening or in contact with soil
Vegetables should be washed well and never eaten raw
Stray cats should not be handled or adopted
Toxoplasma-seropositive adolescents and adult
patients with CD4 counts of <100 cells/µL and
Toxoplasma-seropositive children with CD4 percentage
<15% should be administered prophylaxis with TMPSMX
162
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Toxoplasmosis: Treatment
If HIV-infected 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 BID and with leucovorin
(folinic acid) 10 mg orally with each dose of
sulfadiazine (A II)
Optimal duration of treatment: 12 months
163
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Toxoplasmosis: Treatment (2)
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 therapy should be provided
Alternative to pyrimethamine and leucovorin in sulfasensitive individuals is clindamycin
164
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Toxoplasmosis: Alternative Treatment
Azithromycin: 900-1,200 mg/kg/day with
pyrimethamine and leucovorin (B II), but not
evaluated in children
Clindamycin with pyrimethamine leucovorin
Adults – atovaquone: 1,500 mg orally BID
plus pyrimethamine and leucovorin (C III), but
not evaluated in children
Limited use of corticosteroids as adjuvant
therapy with CNS disease
165
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Toxoplasmosis: Adverse Events
Pyrimethamine: rash, Stevens-Johnson
syndrome, nausea, reversible bone marrow
toxicity
Sulfadiazine: rash, fever, leukopenia, hepatitis,
nausea, vomiting, diarrhea, crystalluria
IRIS rare in patients with HIV in toxoplasmosis
166
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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, transplanted organ
Perinatally – most common
167
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Cytomegalovirus: Epidemiology (2)
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)
168
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Cytomegalovirus: Epidemiology (3)
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
169
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Cytomegalovirus: Epidemiology (4)
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
A higher percentage of HIV/CMV-coinfected children
shed CMV than do CMV-infected, HIV-uninfected
children
170
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Cytomegalovirus: Clinical Manifestations
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
171
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Cytomegalovirus: Clinical Manifestations (2)
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
172
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Cytomegalovirus: Clinical Manifestations (3)
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
173
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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
174
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Cytomegalovirus: Diagnosis (2)
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
175
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Cytomegalovirus: Prevention
Administer CMV antibody-negative blood and blood
products if transfusion is required
Begin CMV antibody testing at 1 year of age in
seronegative HIV-infected infants and children who
are severely immunosuppressed
Inform parents and care providers that HIV-infected
children are at risk of CMV in daycare settings
Minimize risk of acquiring CMV infection with optimal
hygienic practices
176
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Cytomegalovirus: Treatment
Symptomatic congenital CMV
Ganciclovir: 6 mg/kg IV Q12H for 6 weeks (B I)
Alternative treatment for ganciclovir-resistant
CMV is foscarnet
177
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Cytomegalovirus: Treatment (2)
Initial and maintenance treatment of disseminated
CMV and CMV retinitis
Ganciclovir: 5 mg/kg/dose IV over period of 1-2 hours BID for
14-21 days, followed by lifelong maintenance therapy (A I)
Combination treatment with ganciclovir and foscarnet delays
progression of retinitis inpatients failing monotherapy (B III)
Maintenance treatment with oral valganciclovir with a
ganciclovir sustained-release ocular implant can be considered
for chronic suppression of CMV retinitis in older children and
adults
178
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Cytomegalovirus: Treatment (3)
Alternative treatment for ganciclovir resistance
Foscarnet (A I) at 60 mg/kg/dose IV (infused at
1 mg/kg/minute) over period of 1-2 hours Q8H for 1421 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
179
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Cytomegalovirus:
Treatment (4)
Treatments for adults (inadequate pediatric data)
Valganciclovir: prodrug of ganciclovir, given orally, effective in
retinitis in adults
Oral ganciclovir (or valganciclovir) plus ganciclovir sustainedrelease intraocular implant used for retinitis
Cidofovir for retinitis
Fomivirsen: antisense nucleotide used as intravitreous
injection
180
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Cytomegalovirus: Adverse Events
Ganciclovir and valganciclovir
Neutropenia may occur and may require dosage
modification
Resistance and myelosuppression can occur
Other toxic effects include renal impairment, CNS
effects, GI dysfunction, increased liver enzymes
Metabolic disturbances can be minimized by slow
infusion rates
Immune recovery uveitis, and immunologic reaction to
CMV, is related to the occurrence of IRIS and other
coinfections following initiation of ART
181
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Cytomegalovirus: Discontinuing Secondary
Prophylaxis
Multiple studies indicate that maintenance therapy can
be discontinued in adults with CMV retinitis whose CD4
counts have increased and who are on ART
Safety of discontinuing maintenance therapy in children
has not been well studied
Discontinuing prophylaxis and children 1-6 years of age
receiving ART and with CD4 percentage of >15% or CD4
count >500 cells/L can be considered (C III)
Patients who have had CMV maintenance therapy
discontinued should undergo ophthalmologic monitoring
at 3-6 month intervals
182
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Hepatitis B: Epidemiology
Acquired by perinatal or mother-to-infant
transmission
Unknown whether there is a greater risk
of HBV transmission to infants from HIVcoinfected mothers
Chronic hepatitis B infection is defined as
persistence of hepatitis B surface antigen
(HbsAg) for >6 months
183
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Hepatitis B: Epidemiology (2)
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
Adolescents are at risk of HBV infection through sexual
activity or injection drug use
All infants previously unimmunized should receive
routine childhood HBV vaccine
184
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Hepatitis B: Epidemiology (3)
HBV infection risk increased through sexual activity in
adolescents who are HIV coinfected
Immunize HBV-susceptible adolescents
Limited data on the prevalence of HBV infection in
HIV-infected children
Risk of chronic HBV infection in children without HIV
infection is inversely related to age at time of infection
Chronic hepatitis B infection develops in less than
90% of infants, 25-50% children 1-5 years of age and
6-10% of older children and adolescents
185
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Hepatitis B: Clinical Manifestations
Majority of children are asymptomatic
Children who are coinfected with HIV may have
smoldering chronic infection along with lethargy,
malaise, fatigue, and anorexia
Jaundice is sometimes present with
hepatosplenomegaly
186
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Hepatitis B: Clinical Manifestations (2)
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
Rarely, fulminant hepatic failure may occur during
childhood
25% of infants and children with chronic HBV will
eventually develop cirrhosis or hepatocellular carcinoma
187
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Hepatitis B: Diagnosis
HBsAg is the first detectible marker and it
precedes an 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
188
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Hepatitis B: Diagnosis (2)
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 usually
are present
Following immunization, only anti-HBs develops
189
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Hepatitis B: Diagnosis (3)
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
190
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Hepatitis B: Prevention
All pregnant women should be tested for
HBV surface antigen (HBsAg)
Repeat test late in pregnancy for women
at high risk for HBV infection
Pregnancy is not a contraindication for
hepatitis B immunization
191
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Hepatitis B: Prevention (2)
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; third dose
at 6 months of age
Test for antibody to HBsAg at 9-15 months of age; if
negative, reimmunize
Immunize HBV-susceptible adolescents
All children, including HIV-infected children and those
with HBV coinfection, should receive hepatitis A
immunization
HBV-infected children should not share toothbrushes or
other personal items
192
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Hepatitis B: Treatment
Indications for treatment are the same as those for
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
months
Persistent elevation of transaminases
(2 times upper limit of normal)
Evidence of chronic hepatitis on liver biopsy
(B II)
193
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Hepatitis B: Treatment (2)
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
194
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Hepatitis B: Treatment (3)
6 drugs have been approved for the treatment of HBV
IFN-alfa (standard and pegylated), lamivudine (3TC),
telbivudine, entecavir, and adefovir approved for treatment of
HBV in adults
IFN-alfa and 3TC approved for children
Preferred initial treatment for adults for chronic hepatitis
B infection without HIV infection include pegylated
interferon-alfa, adefovir, or entecavir monotherapy
Some experts would initiate fully suppressive treatment
for HIV/HBV coinfection with 2 drugs that have activity
against both HIV and HBV plus a third agent with
activity against HIV
195
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Hepatitis B: Treatment (4)
If treatment of chronic HBV, but not HIV, is indicated,
standard interferon-alfa is preferred (B III)
Adefovir should be considered in older children
If treatment of HIV, but not chronic HBV, is indicated,
use of ART that avoids drugs with activity against
HBV is suggested
If treatment of both HIV and chronic HBV is indicated
and the patient is naive to 3TC, use an ARV regimen
that includes 3TC (or emtricitabine) (B III)
196
July 2009
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Hepatitis B: Treatment (5)
If treatment for HIV and chronic HBV is indicated
and the child is receiving ART including 3TC or
emtricitabine with HIV suppression but detectable
plasma HBV DNA, HBV 3TC resistance can be
assumed
Treatment options for children who require HBV
therapy include the addition of interferon therapy to
the ARV regimen (B III), tenofovir, or adefovir if the
child can receive adult dosing (B III)
197
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Hepatitis B: Treatment (6)
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
198
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Hepatitis B: Treatment (7)
3TC
Results in rapid decline in HBV DNA levels
Used for HBV-infected, HIV-uninfected children but
sustained virologic response rates are low
Used as both primary and secondary treatment in
HBV-infected, HIV-uninfected children
Extended monotherapy treatment can lead to
resistance
199
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Hepatitis B: Treatment (8)
3TC (cont’d)
Do not use 3TC monotherapy in HIV/HBVcoinfected children (3TC resistance develops)
Dosage: 3 mg/kg once daily
(lower than dosage required for HIV treatment)
If 3TC is used to treat HBV/HIV-coinfected
children, treat with 4 mg/kg BID in the context
of ART (A III)
200
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Hepatitis B: Treatment (9)
Adefovir
Some experts recommend combined
adefovir or TDF in addition to 3TC as part
of suppressive ART to reduce development
of resistance
Development of resistance is less common
with adefovir than with 3TC
Adefovir dipivoxil (10 mg once daily in
adults) active against HBV with minimal
anti-HIV effect (insufficient data in children)
201
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Hepatitis B: Treatment (10)
Tenofovir
Shown to reduce HBV DNA levels in adult
patients with 3TC-resistant virus as well as
wild-type HBV infection
Not approved for use in treatment of chronic
HBV infection or for use in HIV-infected
children <18 years of age
Should not be used for HBV/HIV-coinfected
patients who are not receiving ART
202
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Hepatitis B: Treatment (11)
Entecavir
Compared with 3TC, treatment results in a greater
effect on indicators of chronic HBV infection
Preferred for 3TC-resistant HBV infection
Use only in patients receiving ART in HIV/HBV
coinfection
Telbivudine
Approved for treatment of chronic HBV and adults
Emergence of resistance over time
No data available on HIV/HBV-coinfected adults and
no data on children
203
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Hepatitis B: Adverse Events
IFN-alfa
Flulike syndrome most severe during first
month of therapy, consisting of fever, chills,
headache, myalgia, arthralgia, abdominal
pain, nausea, vomiting
Epistaxis associated with thrombocytopenia
or prolonged prothrombin time
204
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Hepatitis B: Adverse Events (2)
Adverse effects: IFN-alfa
Neutropenia, anemia, thrombocytopenia
Personality changes
Abnormalities of thyroid function
Treatment contraindicated in decompensated liver
disease, cytopenias, cardiac disease, and
autoimmune disease
Monitor patients with complete blood count and serum
TSH level every 3 months
205
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Hepatitis C: Epidemiology
Low seroprevalence among children in United States:
0.1-0.2%
Seroprevalence higher among HIV-infected children:
1.5% in one study
Risk of MTCT about 6%
Mother-to-child transmission is the dominant mode of
HCV infection
HCV infection in older children results from injection
drug use, body piercing, tattoos, accidental needlestick
injury, household contacts, and sexual exposure
Most infections occur at or near time of delivery
206
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Hepatitis C: Epidemiology (2)
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
Chronic HCV infection, defined as the presence of
HCV RNA for >6 months, resolves spontaneously in
15-40% of adults
There are more than 6 HCV genotypes, with
genotype 1 being most common in the United States
207
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Hepatitis C: Epidemiology (3)
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
208
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Hepatitis C: Clinical Manifestations
Most children are asymptomatic with minor
abnormalities including hepatomegaly, fatigue,
myalgia, and poor weight gain
Children have less frequent and slower
progression than adults
In a study of posttransfusion HCV, 55% of
antibody-positive children had detectable HCV
in blood
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Hepatitis C: Clinical Manifestations (2)
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
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Hepatitis C: Diagnosis
Testing is recommended for all children whose mothers
are known to have HCV and for all HIV-infected adults
and adolescents
Serologic and nucleic acid tests are used to diagnose
HCV infection
HCV antibody passively transferred; not useful for
diagnosis of infection until >18 months of age
A third-generation anti-HCV EIA is available for
detection of antibody
HCV RNA first becomes detectable 1-3 weeks following
infection
A single HCV RNA test is not sufficient for diagnosis;
testing should be repeated on 2 separate occasions
between 2-6 months of age
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Hepatitis C: Diagnosis (2)
A positive anti-HCV antibody test result in
a child >18 months of age is indicative of
infection
A positive HCV RNA test confirms the
presence of infection, and if positive for >6
months, suggests chronic infection
Liver biopsy best for evaluation of hepatic
disease; should be considered before
initiating treatment
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Hepatitis C: Prevention
All HIV-infected individuals, including HIV-infected
pregnant women, should be screened for HCV
There is no reliable method for preventing perinatal
HCV transmission; cesarean delivery is not
associated with decreased HCV transmission
Adolescents should be warned about the risks of
tattooing, body piercing, and intravenous drug use
HCV-infected individuals should not share
toothbrushes, razors, and other personal items
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Hepatitis C: Treatment
Limited studies on the treatment of HCV-infected
children
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
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Hepatitis C: Treatment (2)
HIV/HCV-coinfected adults and adolescents
Consider treatment of any nonpregnant HCVinfected adult with abnormal liver enzymes or a liver
biopsy showing chronic hepatitis or significant
fibrosis
Recommended treatment is pegylated interferonalfa 2a or 2b or daily oral ribavirin for 48 weeks
Note: HCV treatment generally is not recommended
during pregnancy because ribavirin is teratogenic
215
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Hepatitis C: Treatment (3)
HCV-infected children without HIV infection
Treatment of HIV-uninfected children with HCV
infection who are <3 years of age is not
recommended
Only interferon-alfa 2b and ribavirin are approved
by the FDA for treatment of children 3-17 years of
age
A 24-week course of treatment is recommended
for genotypes 2 and 3; 48-week course for other
HCV genotypes
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Hepatitis C: Treatment (4)
HIV/HCV-coinfected children
Recommendations for treatment are based primarily
on adult data
Consider treatment for all HIV/HCV-coinfected
individuals including children >3 years of age who
have no contraindication to treatment (B III)
Treatment of HCV-infected children regardless of
HIV status should include combination therapy with
interferon-alfa and ribavirin (B III)
Based on adult studies, 48 weeks of treatment is
recommended for coinfected children
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Hepatitis C: Treatment (5)
Adults and children with HIV disease
Combination therapy with interferon and ribavirin
(A I)
Pegylated interferon-alfa 2a: subcutaneously
180 mcg/kg weekly or alfa 2b subcutaneously 1.5
mcg/kg weekly (adults)
Ribavirin: 400 mg orally BID (adults)
Limited data on use of interferon with children
218
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Hepatitis C: Treatment (6)
HCV RNA levels in serum transaminase should be
monitored every 6-12 months alone with an annual
hemogram and serum AFP
Patients who are on treatment should be monitored at
baseline, and after 12 and 24 weeks of antiviral
therapy
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 1-5 years
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Hepatitis C: Treatment (7)
Interferon-alfa 2a and alfa 2b
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
220
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Hepatitis C: Treatment (8)
Ribavirin oral solution
Dosage: oral solution 40 mg/mL – 15
mg/kg/day divided into 2 doses given BID
25-36 kg: 1 capsule (200 mg) in a.m., 1 in
p.m.
37-49 kg: 1 capsule (200 mg) in a.m., 2 in
p.m.
50-61 kg: 2 capsules (200 mg each) in
a.m., 2 in p.m.
221
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Hepatitis C: Adverse Events
Initiation of ART in HIV/HCV coinfection may worsen
hepatitis as evidenced by increased serum
transaminase levels and clinical signs of liver disease
(IRIS)
Adverse effects: interferon-alfa
Flulike syndrome most severe during first month of therapy,
consisting of fever, chills, headache, myalgia, arthralgia,
abdominal pain, nausea, vomiting
Epistaxis associated with thrombocytopenia or prolonged
prothrombin time
Neutropenia, anemia, thrombocytopenia
Personality changes
Abnormalities of thyroid function
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Hepatitis C: Adverse Events (2)
Ribavirin
Flulike syndrome consisting of fever, chills,
headache, myalgia, arthralgia, abdominal
pain, nausea, vomiting
Hemolytic anemia, lymphopenia
Neutropenia, anemia, thrombocytopenia
Depression and suicidal ideation
Do not use in combination with ddI
223
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Human Herpes Virus 6 and 7:
Epidemiology
Human herpes virus 6 (HHV-6) and 7 (HHV7) are closely related members of the
Roseolovirus genus of herpes viruses
Humans are the only known host
Infection is believed to be transmitted through
saliva; sexual transmission may occur and
presumptive in utero infection has been
described
Children become infected early in childhood
with 100% infected by 3 years of age
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Human Herpes Virus 6 and 7:
Epidemiology (2)
HHV-6 has been transmitted from mother to
child
Congenital HHV-6 infection has been
documented in <2% of newborns
HHV-7 is acquired later in life than is HHV-6
Seropositivity for HHV-7 is approximately
50% by 2 years of age
Salivary shedding of HHV-7 is common and
viral DNA has been found in breast milk
225
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Human Herpes Virus 6 and 7:
Clinical Manifestations
HHV-6 primary infection may be asymptomatic or
accompanied by mild nonspecific symptoms
Common symptoms are fever, irritability, and rhinitis
HHV-6 is the causative agent of most cases of
exanthem subitum (also known as roseola infantum)
Primary infection and reactivation associated with
severe central nervous system syndromes in
immunodeficient individuals
Reactivation of infection may include pneumonia,
encephalitis, bone marrow suppression, fever, skin rash,
and leukopenia
Reactivation of HHV-7 also occurs in immunodeficient
individuals
226
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Human Herpes Virus 6 and 7:
Diagnosis
Most often, the diagnosis is based on clinical
features and presence of a distinctive rash
Laboratory confirmation of the infection includes
antibody testing, culture, antigen detection, PCR,
immunohistochemistry
Detection of HHV-6-specific antibodies,
seroconversion, or changing antibody titer indicate
infection
Many of the laboratory tests for the diagnosis of
HHV infection are available only on the research
basis
227
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Human Herpes Virus 6 and 7:
Prevention
HHV-6 and HHV-7 infections are ubiquitous,
making prevention difficult
Prophylactic ganciclovir may decrease the
number of episodes and severity of HHV-6
reactivation and transplantations
There is no vaccine to prevent HHV-6 or
HHV-7 infections
228
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Human Herpes Virus 6 and 7:
Treatment
The majority of HHV-6 primary infections are mild
and self-limited
There are no clear indications for treatment although
treatment might be considered for severe
encephalitis
There are no proven therapies, but based on in vitro
data, there is a suggestion that ganciclovir and
foscarnet are active against HHV-6
Other treatments that have been reported are based
on individual or small numbers of patients
229
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Human Herpes Virus-8:
Epidemiology
Human herpes virus-8 (HHV-8) is a transmissible DNA
virus similar in DNA structure to Epstein-Barr virus
Causally linked to all forms of Kaposi sarcoma (KS)
Also linked to cavity-based lymphoma and multicentric
Castleman disease
In the United States, 1-3% of the general population is
seropositive, with higher rates among homosexual
men
Seropositivity rate in some parts of Africa >80%
230
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Human Herpes Virus-8:
Epidemiology (2)
Transmitted through oral and genital secretions
Immunocompetent HHV-8-infected adults shed
HHV-8 in their oropharyngeal secretions
Seroprevalence increases in endemic areas during
the first 5 years of life
Seropositivity in the United States among HIVuninfected adolescents equals 11%
Seropositivity in the United States among
homosexual males equals 23%
In the United States, KS accounts for <1% of
pediatric AIDS-defining illnesses
231
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Human Herpes Virus 8:
Clinical Manifestations
Primary infection is associated with fever, mild
expiratory symptoms, and a maculopapular rash
Some evidence suggests there may be a more
severe clinical presentation in immunodeficient HIVinfected individuals
KS presentation varies widely and includes
nontender, purplish, indurated skin lesions; intraoral
lesions; visceral dissemination
Multicentric Castleman disease presents with
generalized adenopathy and fever
232
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Human Herpes Virus 8:
Diagnosis
Diagnosis based on serologic assays
including immunofluorescence, ELISA, and
Western blot
Sensitivity varies from 80% to 90%
DNA hybridization and PCR are important
for diagnosis on biologic specimens
Routine screening for HHV-8 by PCR or
serologic testing is not indicated for HIVinfected individuals
233
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Human Herpes Virus 8:
Prevention
Exposure to HHV-8 places HIV-infected
individuals at risk of KS
HIV-infected individuals should be
counseled concerning transmission risk of
HHV-8 to sexual partners
Safe sexual practices are warranted to
reduce the risk of transmission
There is no effective way to prevent
childhood acquisition of HHV-8
234
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Human Herpes Virus 8:
Treatment
Effective suppression of HIV replication with ART
may prevent KS progression or returns of new
lesions
KS requires treatment with cytotoxic chemotherapy
Chemotherapy in combination with potent ART
should be considered for patients with visceral KS or
primary effusion lymphoma (B II)
Castleman disease has been treated with antiherpesvirus drugs (ganciclovir or oral valganciclovir),
leading to substantial clinical improvement
235
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Herpes Simplex Virus: Epidemiology
HSV-1 and HSV-2 affect all populations
HSV-1 is transmitted primarily through contact with
infected oral secretions
HSV-2 is acquired primarily through contact with
infected genital secretions
Neonatal HSV infection occurs at a rate of 1/2,0005,000 deliveries
Transmitted from infected mother to infant primarily
through exposure to maternal genital fluids during
birth, by ascending infection, or by invasive
procedures (eg, fetal scalp electrodes)
Congenital (in utero) rare, but severe cutaneous,
ocular, and CNS damage
236
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Herpes Simplex Virus: Epidemiology (2)
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
237
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Herpes Simplex Virus: Epidemiology (3)
In the United States, 75% of neonatal HSV is caused
by genital herpes (HSV-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
HSV infection may increase the risk of MTCT
238
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Herpes Simplex Virus:
Clinical Manifestations
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%)
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Herpes Simplex Virus:
Clinical Manifestations (2)
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
Outside neonatal period, most common presentation is
orolabial disease with fever, irritability, submandibular
lymphadenopathy, painful ulcers in gingival and oral
mucosa (gingivostomatitis)
240
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Herpes Simplex Virus:
Clinical Manifestations (3)
HSV-2 infection presents as painful, ulcerative
lesions on the perineum as well as on the vaginal
and urethral mucosa
HSV keratitis, neonatal HSV, HSV encephalitis, and
herpetic whitlow have similar presentations in HIVinfected and HIV-uninfected patients but may be
more severe among HIV-infected patients
When severely immunocompromised, may develop
disseminated HIV infection including infection of
esophagus, CNS, liver, lung, kidney, spleen, adrenal
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Herpes Simplex Virus: 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 HSV-2
Direct immunofluorescence for HSV antigen in
samples
HSV DNA PCR has replaced brain biopsy
Definitive diagnosis of HSV esophagitis requires
endoscopy with biopsy
242
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Herpes Simplex Virus: Prevention
Effective ART regimens may decrease but not
prevent the frequency of maternal genital HSV
shedding
Use of acyclovir or valacyclovir in late pregnancy in
HIV-uninfected pregnant women may reduce the
need for cesarean section; not recommended for
HIV-infected women who should have cesarean
section
Avoid sexual contact when herpetic lesions are
present
Use condoms to reduce transmission of HSV and
other sexually transmitted infections
Chronic suppressive therapy with valacyclovir may
reduce HSV-2 transmission
243
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Herpes Simplex Virus: Treatment
Acyclovir is the drug of choice regardless of infection
status (AI) (oral and IV formulations available)
Treat neonatal HSV with 20 mg/kg/dose IV TID 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)
Acyclovir is the drug of choice for disseminated HSV
encephalitis: treat for 21 days
Trifluridine is the treatment of choice for herpes
keratoconjunctivitis
244
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Herpes Simplex Virus: Treatment (2)
Alternatives to acyclovir in older children
include valacyclovir and famciclovir (A I)
No pediatric formulation available for
valacyclovir
Data on the use of famciclovir in children are
not available
245
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Herpes Simplex Virus: Adverse Events
246
Acyclovir toxicity effects primarily renal function
Valacyclovir toxicity is similar to acyclovir
Neutropenia may occur in contents
Treatment failure should be managed with IV
foscarnet (A I)
July 2009
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Human Papillomavirus: Epidemiology
HPV infects cutaneous and mucosal squamous
epithelium
Approximately 100 distinct types
HPV 16, 18, 31, 33, 35, 39, 45, 51, 56, 58, 59 are
considered high risk
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)
247
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Human Papillomavirus: Epidemiology (2)
Latent HPV seen in 5-42% of pregnant women
without HIV infection
HPV infection rates higher among HIV-infected
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
248
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Human Papillomavirus: Epidemiology (3)
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 of developing
cervical, vulvovaginal, and anal carcinoma;
cervical and anal intraepithelial neoplasia
Increased risk if HIV infected
249
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Human Papillomavirus:
Clinical Manifestations
Hyperplastic, 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 “cauliflowerlike” sessile growths
250
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Human Papillomavirus: 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 is not necessary for diagnosis or
management of anogenital or cutaneous warts
or papillomas
251
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Human Papillomavirus: Prevention
A vaccine to prevent HPV types 6, 11, 16, and
18 has been approved
HPV 6 and 11 cause 90% of the external
genital warts
HPV 16 and 18 cause 70% of invasive cervical
cancers
To be fully effective, the HPV vaccine should
be administered before the onset of sexual
activity
252
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Human Papillomavirus: Prevention (2)
Data on safety, immunogenicity and duration of
immunity of HPV vaccine is not available in HIVinfected individuals
Current recommendations are to immunize all
females aged 11-12 years: a secondary should
be given 2 months after the first dose; a third
dose should be administered 6 months after the
first dose
The HPV vaccine has not been shown to have a
therapeutic benefit
253
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Human Papillomavirus: 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)
254
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Human Papillomavirus: Treatment (2)
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 of
HPV-related cervical abnormalities
255
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Human Papillomavirus: Treatment (3)
Genital warts
Standard topical treatment often ineffective in HIVinfected 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)
Podophyllin resin 10-25% in a compound of tincture
of benzoin
256
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Human Papillomavirus: Treatment (4)
Respiratory papillomatosis
Should be managed by a specialist
Treatment is directed toward removing lesions
constructing the airway rather than eliminating the
disease
Lesions are removed by debridement or laser
treatment
Systemic interferon-alfa therapy or intralesional
cidofovir has been used with limited success (C III)
257
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Human Papillomavirus: Treatment (5)
Treatment of histologic CIN
Follow-up with annual cytologic assessment is recommended
for adolescents with CIN 1 (A II)
Either treatment or observation should be implemented for up to
24 months using both colposcopy and cytology for CIN 2 or 3
not otherwise specified
Treatment recommended for histologic diagnosis of CIN 3
Persistent CIN 1, 2, and 3 lesions in HIV-infected women should
be treated as in HIV-uninfected women
Treatment includes cryotherapy, laser therapy, cone biopsy, and
loop electrosurgical excision
258
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Human Papillomavirus:
Role of ART, IRIS, and Adverse Events
ART has not been consistently associated with a
reduced risk of HPV-related cervical abnormalities in
HIV-infected women
Major toxicities are associated with local skin
irritation from topical therapy
Pain is a frequent side effect of surgical procedures
Interferon treatment may induce fever, fatigue,
myalgia, and depression
IRIS associated with oral warts has been observed
in adults
259
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PML: Epidemiology
Rare demyelinating disease of the CNS in
immunocompromised patients
First described in association with chronic lymphocytic
leukemia and Hodgkin disease
Caused by the Jamestown Canyon polyoma virus
(JCV)
50% of children are seropositive by 9-11 years of age
Infection results in chronic asymptomatic carriage of
the virus in kidneys, lymphoid tissue, bone marrow,
and lymphocytes
Reactivation of the virus in immunocompromised
individuals results; virus is spread to the brain by
lymphocytes
260
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PML: Clinical Manifestations
No known symptoms of acute infection exist
PML may initially present with focal neurologic
deficits involving different regions of the brain
Steady progression over course of weeks or
months characterized by ataxia, aphasia,
cranial nerve deficits, visual abnormalities,
hemiparesis or quadriparesis, and eventually
coma
Survival has improved with ART
261
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PML: Diagnosis
Criteria for a clinical diagnosis include
signs and symptoms on neurologic
examination, focal white matter lesions on
MRI or CT, and exclusion of other causes
Brain biopsy with characteristic pathologic
findings
JCV may be demonstrated by in situ
hybridization or by electron microscopy
262
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PML: Prevention
There is no known means of preventing
exposure to JCV
The use of ART can prevent or reverse
the development of severe
immunosuppression, which may
stabilize the disease
263
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PML: Treatment and Adverse Events
There is no effective treatment for JCV or PML
Survival of HIV-infected adults has been substantially
improved with ART in adults but there are no data in
children
A number of studies have evaluated various forms of
treatment, including cytosine arabinoside, cidofovir,
and interferon-alfa, but none have been reported to be
successful
Following ART, patients may have improvement in
their neurologic symptoms, remain stable, or have
worsening of symptoms attributed to IRIS
264
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Varicella-Zoster Virus: Epidemiology
9% of children <10 years of age 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
265
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Varicella-Zoster Virus: Epidemiology (2)
VZV is transmitted primarily from skin lesions during
illness and is highly contagious
Mother-to-child transmission can occur but is unusual
Congenital varicella occurs in <1% of infants born to
women who have VZV before 13 weeks’ gestation
and in approximately 2% of infants born to women
who have VZV between 13 and 20 weeks’ gestation
VZV can be transmitted to the fetus in later gestation,
resulting in acute neonatal infection
Zoster was common in HIV-infected children prior to
the widespread use of ART
266
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Varicella-Zoster Virus:
Clinical Manifestations
Prodrome of malaise and fever, followed by the
appearance of a pruritic vesicle papular lesion
Complications include superinfection of the skin,
neurologic manifestations, transverse myelitis, and
on occasion, vascular stroke, hepatitis, and
pneumonia
Uncommonly, HIV-infected children may experience
persistent chronic infection with continued lesions
for >1 month
Zoster presents with painful pruritic unilateral
vesicular eruptions in a dermatomal distribution
267
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Varicella-Zoster Virus:
Clinical Manifestations (2)
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 develop VZV retinitis
Acute in retinal necrosis occurs as a peripheral
necrotizing retinitis
268
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Varicella-Zoster Virus: 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, can differentiate
wild-type and vaccine-type virus
VZV antibody response positive 2-3 weeks after
onset of illness; IgM indicates acute infection or
recurrent infection
269
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Varicella-Zoster Virus: Prevention
HIV-infected individuals who have no history or
laboratory evidence of VZV should avoid exposure
to individuals with varicella or zoster
Household contacts without evidence of previous
varicella should be immunized with varicella
vaccine
HIV-infected children 1-8 years of age with CD4
percentage >15% should be considered for
immunization
Limited data indicate that varicella vaccine in HIVinfected children is well tolerated and that >80% of
subjects have detectable antibody
270
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Varicella-Zoster Virus: Prevention (2)
HIV-infected children with low CD4 counts may
develop pneumonia and neurologic manifestations
following immunization
Immunization of such children may be considered
following treatment with ART and evidence of immune
restoration
Postexposure prophylaxis against varicella in HIVinfected children should be provided within 96 hours
after close contact using varicella zoster
immunoglobulin
Data are lacking regarding the effectiveness of
acyclovir for preventing varicella in HIV-infected
susceptible children
271
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Varicella-Zoster Virus: 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 IV Q8H as 1-hour
infusion for 7-10 days
>1 year of age: dosage as above or 500 mg/m2/dose
IV Q8H as 1-hour infusion for 7-10 days
272
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Varicella-Zoster Virus: Treatment (2)
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 IV if severely immunocompromised, trigeminal
nerve involvement, or extensive multidermatomal
zoster
273
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Varicella-Zoster Virus: Treatment (3)
Oral acyclovir data limited in children <2 years of age;
infants who receive long-term suppressive therapy (300
mg/kg/m2/dose administered TID) frequently develop
neutropenia (usually self-limited)
Acute retinal necrosis: high-dose acyclovir (10-15 mg/kg
IV Q8H for 10-14 days
Progressive retinal necrosis: combination of ganciclovir
(5 mg/kg Q12H) and foscarnet (90 mg/kg IV Q12H plus
twice weekly intravitreal ganciclovir (2 mg/0.5 mL or
foscarnet 1.2 mg/0.5 mL)
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Varicella-Zoster Virus: Treatment (4)
Use IV foscarnet for treatment of children with
acyclovir-resistant VZV (B II)
Dosage: 40-60 mg/kg/dose IV over period of 1-2
hours administered TID for 7 days or until no new
lesions appear
Modify dosage in patients with renal insufficiency
Valacyclovir and famciclovir are alternative
treatments (not active against acyclovir-resistant
VZV) but data in children are limited
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Varicella-Zoster Virus: Adverse Events
Acyclovir toxicities include phlebitis, nausea, vomiting,
rash, impaired renal function, neutropenia
Foscarnet toxicities include decreased renal function
IRIS has been described in adults and children
following initiation of ART
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About This Slide Set
This presentation was prepared by Arthur Ammann,
MD, Clinical Professor of Pediatrics University of
California and President of Global Strategies for HIV
Prevention for the AETC National Resource Center, in
July 2009
See the AETC NRC website for the most current
version of this presentation:
http://www.aidsetc.org
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