Guidelines for Prevention and Treatment of Opportunistic Infections among HIV-Infected Children Mycobacterial Infections

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Guidelines for Prevention and Treatment of
Opportunistic Infections among HIV-Infected
ChildrenMycobacterial 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

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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could become out of date quickly.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 tuberculosisEpidemiology

• 14,000 new cases of TB in United States in 2006
  (6 among children lt15 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 lt4 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 tuberculosisClinical
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
  HIV-infected and HIV-uninfected children
• Extrapulmonary marrow, lymph node, bone, pleura,
  pericardium, peritoneal

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Mycobacterium tuberculosisDiagnosis

• 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 tuberculosisDiagnosis (2)

• Cornerstone for latent TB is the TST
• TST not of value if BCG immunization has been
  administered
• Annual TB testing recommended for HIV-infected
  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 tuberculosisDiagnosis (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 tuberculosisDiagnosis (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 tuberculosisPrevention

• 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 tuberculosisPrevention (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 tuberculosisTreatment

• 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 tuberculosisTreatment (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 tuberculosisTreatment (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 tuberculosisTreatment (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 tuberculosisTreatment (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 tuberculosisTreatment (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 tuberculosisTreatment (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 tuberculosisTreatment (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 tuberculosisTreatment (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 gt3
  years of age whereas nevirapine is preferred for
  children lt3 years of age

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Mycobacterium tuberculosisTreatment (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 tuberculosisMonitoring 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 usedin
  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
• lt750 cells/µL lt1 year lt500 cells/µL 1-2 years
  lt75 cells/µL 2-5 years lt 50 cells/µL gt6 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