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become out of date quickly.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
July 2009
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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
66
 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
July 2009
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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
67
July 2009
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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
68
July 2009
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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
69
July 2009
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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
70
July 2009
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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
71
July 2009
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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
July 2009
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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
July 2009
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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
July 2009
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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
July 2009
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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
July 2009
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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
July 2009
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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
July 2009
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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
July 2009
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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
July 2009
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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
July 2009
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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)
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
141
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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
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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
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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
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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)
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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
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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
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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)
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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
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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
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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)
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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)
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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
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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
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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
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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
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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
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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
216
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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
217
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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
219
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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
222
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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%)
239
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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
241
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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
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
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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
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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)
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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
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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
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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)
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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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