Transcript Document

Guidelines for Prevention and
Treatment of Opportunistic Infections
among HIV-Infected Children
Mycobacterial Infections
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become out of date quickly.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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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
 Monthly monitoring of clinical and bacteriological
responses to treatment
 Side effects of drugs include nausea, vomiting,
hepatotoxicity, nephrotoxicity, and optic neuritis
with ethambutol
 IRIS associated with new onset of systemic
symptoms in HIV-infected individuals receiving
ART
 Data on occurrence of IRIS in children are
incomplete
 Treatment with corticosteroids has been used
in severe cases
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Mycobacterium avium Complex Disease:
Epidemiology
 Multiple related species of non-TB mycobacteria:
M avium, M intracellulare, M paratuberculosis
 Second most common OI in children after PCP
but decreases in incidence with ART
 Associated with soil exposure and racial
susceptibility
 Acquired by means of inhalation, ingestion, or
inoculation
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Mycobacterium avium Complex Disease:
Epidemiology (2)
 72% of children with isolated pulmonary MAC
develop disseminated MAC by 8 months
 May appear as isolated lymphadenitis
 Frequency increases with age and declining CD4
T-cell count
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Mycobacterium avium Complex Disease:
Prevention
 Most effective means of prevention is to
preserve immune function with ART
 Offer prophylaxis for MAC as follows: (A II)
 CD4 T-cell risk factor for occurrence:
 <750 cells/µL <1 year; <500 cells/µL 1-2 years;
<75 cells/µL 2-5 years; < 50 cells/µL >6 years
 Use either clarithromycin or azithromycin (A II)
 Studies suggest that prophylaxis may be
discontinued when CD4 percentages reach
20% to 25% while on stable ART
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Mycobacterium avium Complex Disease:
Clinical Manifestations
 Recurrent fever, weight loss, failure to thrive,
neutropenia, night sweats, chronic diarrhea,
malabsorption, abdominal pain
 Lymphadenopathy, hepatomegaly, splenomegaly
 Respiratory symptoms uncommon among
children
 Laboratory abnormalities include anemia,
leukopenia, and thrombocytopenia
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Mycobacterium avium Complex Disease:
Diagnosis
 Isolation of organism from biopsy, blood,
bone marrow, lymph node, or other tissue
 Histology demonstrating macrophage
containing acid-fast bacilli strongly
indicates MAC
 Culture is essential for differentiating from
TB
 Isolation from stool or respiratory does
not necessarily indicate invasive disease
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Mycobacterium avium Complex Disease:
Treatment
 Preserve immune function through optimal
treatment of HIV infection
 Initiate treatment with 2 or more drugs (eg,
clarithromycin or azithromycin plus ethambutol)
(A I)
 Consider rifabutin as third drug in severely ill
patients (C I)
 Caution in using rifabutin as it may increase
toxicity of other ARVs and increase clearance of
PIs and NNRTIs
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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
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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)
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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)
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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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