Treating Opportunistic Infection Among HIV-Infected Children

1
Treating Opportunistic Infection Among
HIV-Infected Children

• Recommendations from the CDC, the National
  Institutes of Health, and the Infectious Diseases
  Society of America
• December 3, 2004

2
About This Presentation
These slides were developed using the December
2004 Guidelines. The intended audience is
clinicians involved in the care of patients with
HIV. The user is cautioned that, due to the
rapidly changing field of HIV care, this
information could become out of date quickly.
Finally, it is intended that these slides be used
as prepared, without changes in either content or
attribution. Users are asked to honor this
intent. -AETC NRC http//www.aidsetc.org
3
Contents

• Introduction (slide 3)
• Bacterial, parasitic, and other infections (slide
  8)
• Serious and recurrent bacterial infections,
  syphilis, toxoplasmosis, crypto/microsporidiosis
• Mycobacterial infections (slide 39)
• MTB, MAC

• Fungal infections(slide 61)
• Pneumocystis jiroveci pneumonia, Candida,
  cryptococcosis, histoplasmosis,
  coccidioidomycosis
• Viral infections(slide 104)
• CMV, HSV, HZV, HPV, HCV, HBV

4
Introduction

• Mother-to-child transmission of OI is an
  important mode of acquisition
• HIV-infected women coinfected with OI more likely
  to transmit (e.g., CMV, HCV)
• HIV-infected women or HIV-infected family members
  are sources of horizontal transmission (eg,
  tuberculosis)

5
Differences between Adults and Children

• OI in children often reflects primary infection
  rather than reactivation
• OI occurs at a time when infants immune system
  is immature
• Different disease manifestations (eg, children
  more likely to have nonpulmonic and disseminated
  tuberculosis)

6
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

7
Frequency of OI among HIV-Infected Children

• Pre-HAART era, most common OIs occurring at gt1
  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 lt1
  events/100 child years
• Cytomegalovirus, toxoplasmosis,
  cryptosporidiosis, tuberculosis, systemic fungal
  infections

8
Treating OI among HIV-Infected Children
Rating of treatment recommendations is based on
opinion of working group

• Letter indicating strength of recommendation
  (e.g., A, B, C)
• Roman numeral indicating nature of evidence
  (e.g., I, II, III)

9
Serious Recurrent Bacterial InfectionsEpidemiolog
y

• 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

10
Serious Recurrent Bacterial InfectionsEpidemiolog
y

• Isolated bacteria include Streptococcus
  pneumoniae, Haemophilus influenzae type B,
  Staphylococcus aureus, Escherichia coli,
  Pseudomonas aeruginosa, nontyphoid Salmonella
• Incidence of S pneumoniae and H influenzae may be
  lower in regions where vaccines are administered

11
Serious Recurrent Bacterial InfectionsClinical
Manifestations

• Clinical presentation dependent on type of
  bacterial infection, e.g., bacteremia, sepsis,
  vasculitis, septic arthritis, pneumonia,
  meningitis, sinusitis
• Presentation similar to that of HIV-uninfected
  children

12
Serious Recurrent Bacterial InfectionsDiagnosis

• Isolation of pathogenic organism from normally
  sterile sites blood, bone marrow, CSF
• Diagnosis of pneumonia by radiograph and physical
  findings
• Culture of catheter tips

13
Serious Recurrent Bacterial InfectionsTreatment

• Consider local prevalence of resistance of common
  infectious agents
• Response of mildly immunodeficient children is
  similar to that of HIV-uninfected children
• Treat HIV-infected children outside the neonatal
  period with empiric therapy until cultures are
  available (A III)
• Ceftriaxone 80-100 mg/kg in 1 or 2 divided
  doses, or
• Cefotaxime 150-200 mg/kg divided into 3 or 4
  doses, or
• Cefuroxime 100-150 mg/kg divided into 3 doses

14
Serious Recurrent Bacterial InfectionsTreatment

• Children lt5 years should be given H influenza B
  and heptavalent pneumococcal conjugate vaccines
  (A II)
• Children gt2 years should receive 23 valent
  pneumococcal vaccine (gt2 months after conjugate
  vaccine)
• Reimmunize with pneumococcal vaccine in 3-5 years
  in children lt10 years or after 5 years in
  children gt10 years

15
SyphilisEpidemiology

• Perinatal transmission of Treponema pallidum at
  any stage of pregnancy or during delivery
• Drug use during pregnancy increases risk of
  maternal and congenital syphilis
• Rate of congenital syphilis 50 times greater
  among infants born to HIV-infected mothers
• Half of new infections are in women 15-24 years
  of age

16
SyphilisClinical 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

17
SyphilisClinical Manifestations

• 60 of infants with congenital syphilis have
  hepatomegaly, jaundice, skin rash, nasal
  discharge, anemia, thrombocytopenia,
  osteochondritis, or pseudoparalysis
• Late manifestations include mental retardation,
  keratitis, deafness, frontal bossing, Hutchinson
  teeth, saddle nose, Clutton joints

18
SyphilisDiagnosis

• Use combination of physical, radiologic,
  serologic, and direct microscopic results, as
  standard serologic tests detect only IgG
• All infants born to mothers with reactive
  nontreponemal and treponemal test should be
  evaluated with a quantitative nontreponemal test,
  e.g., slide test, rapid plasma reagin (RPR)

19
SyphilisDiagnosis

• 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

20
SyphilisTreatment

• Treat all infants whose mothers have untreated or
  inadequately treated syphilis treated or
  initiated treatment 4 weeks prior to delivery
• Treat infants regardless of maternal history if
  examination suggests syphilis darkfield or
  fluorescent antibody test positive or
  nontreponemal serologic titer 4-fold higher
  than maternal (A II)

21
SyphilisTreatment

• Aqueous crystalline penicillin G 100,000-150,000
  units/kg/day given as 50,000 units/kg/dose
  intravenously every 12 hours for 7 days followed
  by every 8 hours for a total of 10 days (A II)
• Diagnosis after 1 month of age, increase dosage
  to 200,000-300,000 units/kg intravenously every 6
  hours daily for 10 days

22
SyphilisTreatment

• Treat acquired syphilis with single dose of
  benzathine penicillin G 50,000 units/kg IM
• Treat late latent disease with 3 doses of
  benzathine penicillin G 50,000 units/kg IM once
  weekly for 3 doses (A III)
• Alternative therapies among HIV-infected patients
  have not been evaluated
• Follow up with examinations at 1, 2, 3, 6, and 12
  months and serologic tests at 3, 6, and 12
  months if titers continue to be positive or
  increase, consider retreatment (A III)

23
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

24
Toxoplasmosis Epidemiology

• Risk of transmission in HIV-uninfected mothers
  with primary infection during pregnancy 29
  (lower if maternal infection in first trimester)
• Perinatal toxoplasmosis infection may occur in
  HIV-positive women with chronic infection
• lt1 of AIDS-defining illnesses in children

25
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

26
Toxoplasmosis Clinical Manifestations

• Toxoplasmosis acquired after birth is initially
  asymptomatic, followed by infectious
  mononucleosis-like syndrome
• Chronic toxoplasmosis can reactivate in
  HIV-infected children

27
Toxoplasmosis Diagnosis

• Test all HIV-infected pregnant women for
  toxoplasmosis
• If positive, evaluate infant for congenital
  toxoplasmosis
• Use antibody assay to detect IgM-, IgA-, or
  IgE-specific antibody in first 6 moths or
  persistence of IgG antibody after 12 months

28
Toxoplasmosis Diagnosis

• Additional methods include isolation of
  toxoplasmosis from body fluids or blood
• Negative antibody does not exclude toxoplasmosis
  may require CT, MRI, or brain biopsy in case of
  encephalitis

29
ToxoplasmosisTreatment

• If HIV-positive mother has symptomatic
  toxoplasmosis during pregnancy, infant should be
  treated (B III)
• Preferred treatment congenital toxoplasmosis
• Pyrimethamine loading dose of 2 mg/kg orally once
  daily for 2 days then 1 mg/kg orally once daily
  for 2-6 months then 1 mg/kg orally 3 times/week
  with sulfadiazine 50 gm/kg/dose twice daily and
  with leucovorin (folinic acid) 10 mg orally with
  each dose of sulfadiazine (A II)
• Optimal duration of treatment 12 months

30
Toxoplasmosis Treatment
Treatment of HIV-infected children with acquired
CNS, ocular, or systemic toxoplasmosis

• Pyrimethamine 2 mg/kg/day (maximum 50 mg/kg)
  orally for 3 days then 1 mg/kg/day orally and
  leucovorin 10-25 mg/day plus sulfadiazine 25-50
  mg/kg/dose orally given 4 times daily
• Continue acute therapy for 6 weeks
• Lifelong prophylaxis required

31
Toxoplasmosis Treatment

• Pyrimethamine rash, Stevens-Johnson syndrome,
  nausea, reversible bone marrow toxicity
• Sulfadiazine rash, fever, leukopenia, hepatitis,
  nausea, vomiting, diarrhea, crystalluria

32
ToxoplasmosisAlternative Treatment

• Azithromycin 900-1,200 mg/kg/day with
  pyrimethamine and leucovorin (B II), but not
  evaluated in children
• Adults atovaquone 1,500 mg orally twice daily
  plus pyrimethamine and leucovorin (C III), but
  not evaluated in children
• Limited use of corticosteroids as adjuvant
  therapy with CNS disease

33
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

34
Cryptosporidiosis/MicrosporidiosisClinical
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

35
Cryptosporidiosis/MicrosporidiosisDiagnosis

• Cryptosporidiosis
• Concentrated stool samples to demonstrating
  oocysts
• Evaluate at least 3 separate stool samples

36
Cryptosporidiosis/MicrosporidiosisDiagnosis

• Microsporidiosis
• Use thin smears of unconcentrated stool-formalin
  suspension or duodenal aspirates stained with
  trichrome or chemofluorescent agents
• Consider endoscopy in all patients with diarrhea
  gt2 months duration
• PCR techniques still in research

37
Cryptosporidiosis/MicrosporidiosisTreatment

• Immune restoration following antiretroviral
  treatment frequently results in clearing
• Supportive care, hydration, electrolyte
  replenishment, nutritional supplements
• Available treatment inconsistently effective

38
Cryptosporidiosis Treatment

• Nitazoxanide effective for Cryptosporidium and
  Giardia lamblia (B I for children and C III for
  HIV-infected children)
• Nitazoxanide dose 100 mg orally twice daily for
  children 1-3 years 200 mg twice daily for
  children 4-11 years
• Limited data paromomycin, azithromycin

39
Microsporidiosis Treatment

• Albendazole 7.5 mg/kg orally twice daily
  maximum dose 400 mg orally twice daily (A II)
• Fumagillin limited data for adults, no data for
  HIV-infected children

40
Mycobacterium tuberculosisEpidemiology

• 15,000 new cases of tuberculosis in United States
  in 2002 (6 among children lt15 years of age)
• Number of these that were HIV infected is
  uncertain
• Incidence of TB in HIV-infected children 100
  times higher than in uninfected
• In South Africa, as many as 48 of children with
  TB were coinfected with HIV

41

Mycobacterium tuberculosis Epidemiology

• 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

42
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-positive and HIV-negative children
• Extrapulmonary marrow, lymph node, bone, pleura,
  pericardium, peritoneal

43
Mycobacterium tuberculosis Diagnosis

• Difficult to diagnose maintain a degree of
  suspicion
• M tuberculosis detected in up to 50 of gastric
  aspirate in non-HIV-infected children (obtain 3
  consecutive morning gastric aspirates)
• Usually requires linking TB in child to contact
  along with radiograph, skin test (TST) or PE

44
Mycobacterium tuberculosisDiagnosis

• About 10 of culture-positive children have
  negative TST
• Perform annual TST beginning at 3-12 months using
  5 TU PPD intradermally
• DNA and RNA PCR not fully evaluated

45
Mycobacterium tuberculosisTreatment

• Treatment principles similar in HIV-positive and
  HIV-negative children
• Initiate treatment as soon as possible in
  children lt4 years old with suspected TB
• Begin TB treatment 4-8 weeks before ARVs(B III)
• If already on ARV, review drug interactions
• Use of DOT increases adherence, decreases
  resistance, treatment failure, and relapse

46
Mycobacterium tuberculosisTreatment

• Initial treatment (induction phase)
• 4 drugs isoniazid, rifampin, pyrazinamide, plus
  either ethambutol or streptomycin (A I)
• Use ethionamide as alternative to ethambutol for
  CNS disease (A III)

47
Mycobacterium tuberculosisTreatment

• If clinical response occurs and organism is
  susceptible to isoniazid, discontinue ethambutol
  after 2 months
• If severe disease, treat for 9-12 months
• If multidrug resistance is found, treat with
  expert consultation

48
Mycobacterium tuberculosisTreatment

• 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

49
Mycobacterium tuberculosisTreatment

• 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 protease
  inhibitors (except ritonavir) and NNRTIs

50
Mycobacterium tuberculosisTreatment

• Rifabutin (B III)
• Dosage 10-20 mg/kg orally once daily
• Limited data in children
• Peripheral leukopenia, elevated liver enzymes,
  pseudojaundice, GI upset

51
Mycobacterium tuberculosisTreatment

• Rifabutin
• Increases hepatic metabolism of certain protease
  inhibitors reduce rifabutin dosage by 50 when
  given with ritonavir, indinavir, nelfinavir,
  amprenavir
• Increase dosage of rifabutin by 50-100 when
  given with efavirenz

52
Mycobacterium tuberculosisTreatment

• Pyrazinamide
• Dosage 10-15 mg/kg orally once daily (maximum 2
  g daily)
• Hepatic toxicity, rash, arthralgia, GI upset
• Ethambutol
• Dosage 15-25 mg/kg orally daily(maximum 1 g
  daily)
• Toxicity includes optic neuritis, rash, nausea

53
Mycobacterium tuberculosisTreatment

• Secondary drugs
• Ethionamide 15-20 mg/kg orally divided into 2 or
  3 doses daily
• Streptomycin 20-40 mg/kg daily intramuscularly
  (maximum dosage 1 g daily)
• Alternatives kanamycin, amikacin, capreomycin,
  quinolones, cycloserine, paraaminosalicylic acid
• Steroids may be indicated for TB meningitis

54
Mycobacterium avium Complex Epidemiology

• Multiple related species of nontuberculosis
  mycobacteria M avium, M intracellulare, M
  paratuberculosis
• Second most common opportunistic infection in
  children
• Acquired by means of innovation, ingestion, or
  inoculation

55
Mycobacterium avium ComplexEpidemiology

• 72 of children with isolated pulmonary MAC
  develop disseminated MAC by 8 months
• May appear as isolated lymphadenitis
• Frequency increases with age and declining CD4
  T-cell count
• CD4 T-cell risk factor for occurrence
• lt750 mL lt1 year lt500 mL 1-2 years lt75 mL 2-6
  years lt50 mL gt6 years

56
Mycobacterium avium Complex 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

57
Mycobacterium avium Complex 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

58
Mycobacterium avium Complex Treatment

• Preserve immune function through optimal
  treatment of HIV infection
• Consider delaying initiation of ART for 1-2 weeks
  to avoid immune reconstitution syndrome
• Initiate treatment with clarithromycin or
  azithromycin plus ethambutol (A I)
• Consider rifabutin as third drug with severely
  ill patients (A I)

59
Mycobacterium avium ComplexTreatment

• Note cautions in use of these drugs with ART
• If rifabutin cannot be used, consider
  ciprofloxacin, levofloxacin, amikacin,
  streptomycin
• Lifelong suppressive therapy required after
  initial therapy

60
Mycobacterium avium Complex Treatment

• Clarithromycin 7.5-15 mg/kg orally twice daily
  (maximum 500 mg twice daily) (A I)
• Azithromycin 10-12 mg/kg once daily (maximum 500
  mg daily) (A II)
• Ethambutol 15-25 mg/kg single oral dose (maximum
  1 g) (A I)

61
Mycobacterium avium ComplexTreatment

• Rifabutin 10-20 mg/kg orally once daily (maximum
  300 mg daily) (A I)
• Ciprofloxacin 20-30 mg/kg intravenously or
  orally once daily (maximum 1.5 g)
• Amikacin 15-30 mg/kg/day intravenously divided
  every 12-24 hours (maximum 1.5 g)(C III)

62
Pneumocystis jiroveci (carinii) Epidemiology

• Antibody in 80 of normal children by 4 years
• Most common AIDS indicator disease in children
• Incidence highest in first year of life, peaking
  at 3-6 months
• Accounted for 57 of AIDS-defining illnesses in
  infants age lt1 year pre-HAART
• CD4 T-cell count not a good indicator of risk in
  infants lt1 year old
• Infection now unusual due to routine prophylaxis
  with trimethoprim/sulfamethoxazole

63
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

64
Pneumocystis jiroveci (carinii) Diagnosis

• Hypoxia with low arterial oxygen pressure
  (alveolar-arterial oxygen gradient gt30 mm/Hg)
• Definitive diagnosis requires demonstrating
  organism
• Induced sputum (difficult lt2 years)
• Bronchoscopy with bronchoalevolar lavage
• Fiberoptic bronchoscopy with biopsy generally
  not recommended

65
Pneumocystis jiroveci (carinii) Diagnosis

• Open lung biopsy most sensitive
• Requires thorachotomy, chest tube drainage
• Organisms seen on biopsy with
• Gomoris methenamine silver stain
• Toluidine blue stain
• Giemsa or Wrights stain
• Monoclonal antibody
• DNA PCR in fluids, lavage mostly research

66
Pneumocystis jiroveci (carinii) Treatment

• Trimethoprim/sulfamethoxazole (TMP/SMX) (A I)
• gt2 months 15-20 mg/kg/day of TMP component
  intravenously in 3-4 divided doses
• Infuse over course of 1 hour
• Administer for 21 days
• Can be given orally in children with mild to
  moderate disease
• Lifelong prophylaxis indicated

67
Pneumocystis jiroveci (carinii) Treatment

• Adverse reactions
• Rash
• Stevens-Johnson syndrome (rare)
• Neutropenia, thrombocytopenia, megaloblastic or
  aplastic anemia

68
Pneumocystis jiroveci (carinii) Treatment

• Pentamidine isothionate
• Recommended for patients intolerant of TMP/SMX or
  clinical failure with TMP/SMX (A I) do not
  combine use
• 4 mg/kg/day intravenously once daily over 60-90
  minutes
• Consider oral atovaquone after 7-10 days (B III)

69
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

70
Pneumocystis jiroveci (carinii) Treatment
Alternatives

• Clindamycin/primaquine
• Used for mild to moderate PCP in adults no data
  in children (C III)
• Primaquine contraindicated in G6PD deficiency

71
Pneumocystis jiroveci (carinii) Treatment
Alternatives

• Clindamycin/primaquine
• Pediatric clindamycin dosing based on other uses
  20-40 mg/kg/day intravenously divided into 3 or 4
  doses, administered for 21 days
• Primaquine dosing based on malaria 0.3 mg/kg
  daily of the base, administered orally for 21
  days
• Adverse reactions include rash, nausea, diarrhea,
  pseudomembraneous colitis

72
Pneumocystis jiroveci (carinii) Treatment
Alternatives

• Trimetrexate glucuronate plus leucovorin (folinic
  acid)
• Used for severe PCP in adults limited data in
  children (C III)
• Trimetrexate 45 mg/m2 for 21 days
• Leucovorin 20 mg/m2 every 6 hours for 24 days

73
Pneumocystis jiroveci (carinii) Treatment
Alternatives

• Dapsone/trimethoprim
• Use for mild to moderate PCP in adults no data
  in children (C III)
• Dapsone dose lt13 years 2 mg/kg/day orally once
  daily (A II) for 21 days
• Trimethoprim Isolationg/kg/day orally divided
  into 3 daily doses for 21 days
• Adverse reactions include rash, anemia,
  thrombocytopenia, increased liver enzymes

74
Pneumocystis jiroveci (carinii) Treatment

• Corticosteroids
• Consider use in moderate to severe PCP
• Use within 72 hours of diagnosis
• Results in reduced respiratory failure, decreased
  ventilation requirements, and decreased mortality

75
Pneumocystis jiroveci (carinii) Treatment

• Corticosteroids
• Dosing recommendations vary
• Prednisone 40 mg twice daily for 1-5 days 40 mg
  once daily days 6-10 20 mg once daily days 11-21
• Alternative prednisone 1 mg/kg twice daily days
  1-5 0.5 mg/kg twice daily days 6-10 0.5 mg/kg
  once daily days 11-21

76
Candida InfectionsEpidemiology

• Most common fungal infections in HIV-infected
  children
• Thrush and diaper dermatitis occur in 50-85 of
  HIV-infected children
• Pre-HAART era oropharyngeal candidiasis found in
  94 of children with Candida esophagitis
• Disseminated candidiasis rare in children except
  those with CMV, HSV coinfection or with central
  venous catheter

77
Candida InfectionsEpidemiology

• A substantial percentage of children with
  fungemia receive oral systemically absorbable
  azole antifungals, e.g., ketoconazole
• Complications include disseminated infection of
  bone, liver, and kidney endophthalmitis
• Mortality gt90 from disseminated candidiasis in
  children with fever and symptoms gt14 days

78
Candida InfectionsClinical Manifestations

• Thrush and erythematous, hyperplasic, and angular
  cheilitis
• Esophageal candidiasis may present with
  odynophagia, dysphagia, or retrosternal pain
• Children may develop nausea, vomiting, or weight
  loss and dehydration
• New onset of fever in individuals with central
  venous catheters
• Systemic fungemia may lead to endophthalmitis

79
Candida InfectionsDiagnosis

• 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

80
Candida InfectionsTreatment

• 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

81
Candida InfectionsTreatment

• Oral systemic therapy for OPC
• Fluconazole 3-6 mg/kg orally once daily for7-14
  days (A I)
• Itraconazole 2.5 mg/kg orally twice daily
  for7-14 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

82
Candida InfectionsTreatment

• Esophageal disease
• Treat both diagnosed esophageal disease and
  children with OPC and esophageal symptoms
• Initiate treatment with
• Fluconazole 6 mg/kg/day orally or intravenously
  on day 1 followed by 3-6 mg/kg for 14-21 days (A
  I)
• Itraconazole oral solution 2.5 mg/kg/dose given
  twice daily or 5 mg/kg once daily for 14-21 days
  (A I)
• Consider low-dose IV amphotericin B minimum of 7
  days for refractory disease (B II)

83
Candida InfectionsTreatment

• Esophageal disease
• Other therapies not fully evaluated in children
• Voriconazole loading dose of 6 mg/kg
  intravenously every 12 hours on day 1, followed
  by 4 mg/kg every 12 hours thereafter after
  stabilization, change to oral dosing
• Caspofungin available only in IV form lt50 kg
  dosage range 0.8-1.6 mg/kg daily gt50 kg, adult
  dosing

84
Candida InfectionsTreatment

• Invasive disease
• Remove central venous catheter
• Amphotericin B (A I)
• 0.5-1.5 mg/kg once daily intravenously over 1-2
  hours, administered in 5 dextrose at final
  concentration of 0.1 mg/mL
• For mild to moderate disease, begin at 0.25-0.5
  mg/kg and increase as tolerated to 1.5 mg/kg
• Once stabilized, administer 1.5 mg/kg every other
  day (B III)
• Treat for 3 weeks after last positive blood
  culture of symptoms

85
Candida InfectionsTreatment

• 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)

86
Candida InfectionsTreatment

• Amphotericin toxicity
• Nephrotoxicity azotemia, hypokalemia
• Nephrotoxicity can be minimized by hydration with
  0.9 saline intravenously 30 minutes prior to
  amphotericin B infusion
• Infusion-related chills, fever, and vomiting
  pretreat with acetaminophen or diphenhydramine
• Rarely hypotension, arrhythmias, neurotoxicity,
  hepatic toxicity

87
Candida InfectionsTreatment

• Fluconazole, itraconazole, ketoconazole toxicity
• Inhibition of cytochrome P-450 dependent hepatic
  enzymes can result in either decreased levels of
  azole when administered with other drugs with
  hepatic metabolism or increased levels of other
  drugs with hepatic metabolism
• Nausea, vomiting, rash, pruritis, Stevens-Johnson
  syndrome (rare), increased liver enzymes,
  hepatitis, leukopenia, anemia, hemolytic anemia,
  alopecia (fluconazole)

88
CryptococcosisEpidemiology

• Low incidence of infection in children
• Children usually infected during 6-12 age range
• Usually severely immunosuppressed

89
CryptococcosisClinical 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

90
CryptococcosisDiagnosis

• Microscopic examination of CSF on India
  ink-stained wet mounts
• Detection of cryptococcal antigen in CSF, serum,
  bronchoalevolar lavage fluid (can be negative in
  culture-positive meningitis)
• Antigen levels useful in evaluating response to
  treatment and relapse
• Pulmonary disease diagnosed by bronchoalevolar
  lavage and direct examination of India
  ink-stained specimens

91
CryptococcosisTreatment

• Not well studied in children
• Amphotericin B induction (0.7-1.5 mg/kg/day
  intravenously) combined with 2 weeks of
  flucytosine(25 mg/kg/dose given 4 times daily)
  until symptoms controlled (A I)
• After symptoms are controlled, treat with
  fluconazole or itraconazole maintenance
• Use amphotericin B alone if flucytosine is not
  tolerated
• Fluconazole plus flucytosine is an alternate to
  amphotericin B (limited data in children)

92
CryptococcosisTreatment

• Amphotericin toxicity
• Nephrotoxicity azotemia, hypokalemia
• Nephrotoxicity can be minimized by hydration with
  0.9 saline intravenously 30 minutes prior to
  amphotericin B infusion
• Infusion-related chills, fever, and vomiting
  pretreat with acetaminophen or diphenhydramine
• Rarely hypotension, arrhythmias, neurotoxicity,
  hepatic toxicity

93
CryptococcosisTreatment

• Flucytosine toxicity
• Bone marrow anemia, leukopenia, thrombocytopenia
• Liver, GI, and renal toxicity

94
HistoplasmosisEpidemiology

• Incidence of disseminated histoplasmosis in
  HIV-infected children in the United States lt0.4
• 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

95
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
• Physical findings include hepatosplenomegaly,
  erythematous nodular coetaneous lesions, CNS
  involvement with meningitis
• Anemia, thrombocytopenia, elevated liver
  transaminases

96
HistoplasmosisDiagnosis

• Culture of Histoplasma for blood or other sources
• Detection of H capsulatum polysaccharide antigen
  in urine, blood, CSF, or bronchoalevolar lavage
  using EIA assay
• EIA sensitivity greater in disseminated disease
  or acute pulmonary disease greater in urine than
  in serum
• Antigen levels decline with treatment and
  correlate with both response to treatment and
  relapse

97
HistoplasmosisDiagnosis

• Antibody positive in most patients but not useful
  for diagnosis of acute infection
• For diagnosis of CNS disease, a combination of
  CSF antibody, antigen, and culture is most
  sensitive
• Skin testing not recommended for diagnosis

98
HistoplasmosisTreatment

• Limited data for children recommendations based
  on adult data
• Nonimmunocompromised not requiring
  hospitalization
• Itraconazole dosage 6-8 mg/kg for 3-12 months (A
  II)
• Alternative fluconazole, but less effective and
  resistance can develop (C II)

99
HistoplasmosisTreatment

• Amphotericin B for patients with severe
  disseminated disease requiring hospitalization
  and those who are immunocompromised
• Amphotericin B induction dosage 1 mg/kg for 4-6
  weeks followed by itraconazole chronic
  suppressive therapy(A I)
• After successful treatment of acute disease, use
  chronic lifelong suppressive therapy with
  itraconazole
• Liposomal amphotericin B alternative in event of
  amphotericin B intolerance

100
CoccidioidomycosisEpidemiology

• Increased risk for infection with Coccidioides
  immitis among HIV-infected children in endemic
  areas (e.g., southwestern United States, northern
  Mexico, Central and South America)
• Primary infection of newborn rare
• In utero and perinatal transmission ofC immitis
  reported

101
CoccidioidomycosisClinical Manifestations

• Fever and dyspnea most common presentation
• Chills, weight loss, lymphadenapaothy, chest
  pain, diffuse reticulonodular pulmonary
  infiltrates, meningitis
• Disseminated disease associated with erythema
  multiforme erythema nodosum erythematous
  maculopapular rash arthralgia bone, joint, and
  CNS infection

102
CoccidioidomycosisDiagnosis

• Direct examination and culture of respiratory
  secretions and CSF or biopsy of lesions
• Blood cultures positive in 15 of cases
• IgM antibody detected by latex agglutination,
  EIA immunodiffusion of tube precipitin appears
  early and indicates acute infection

103
CoccidioidomycosisTreatment

• Limited data in children recommendations based
  on adult data
• Treat diffuse pulmonary disease or disseminated
  disease with amphotericin B dosage of 0.5-1.5
  mg/kg/day until clinical improvement occurs (A
  II)
• Follow with chronic suppressive fluconazole or
  itraconazole therapy (A II)
• Alterative therapy fluconazole 5-6 mg/kg twice
  daily or itraconazole 4-10 mg/kg twice daily for
  3 days followed by 2-5 mg/kg twice daily (B III)

104
CoccidioidomycosisTreatment

• CNS infection including meningitis
• High-dose fluconazole 5-6 mg/kg twice daily
• If unresponsive to fluconazole, use IV
  amphotericin B augmented by intrathecal
  amphotericin B (C I)
• Surgical debridement or excision of localized
  persistent or resistant lesions in bone and lung
  may be helpful

105
CytomegalovirusEpidemiology

• Infection with CMV common and often inapparent
• 50-80 of women of childbearing age in United
  States are CMV antibody positive
• 90 of HIV-infected women are CMV antibody
  positive
• Infection occurs
• During infancy, early childhood, adolescence
• Via contact with virus containing salvia, urine,
  sexual fluid, blood, organ transplantation
• Perinatally most common

106
CytomegalovirusEpidemiology

• 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)

107
CytomegalovirusEpidemiology

• 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

108
CytomegalovirusEpidemiology

• 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

109

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

110

Cytomegalovirus Clinical Manifestations

• 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

111

Cytomegalovirus Clinical Manifestations

• 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

112
CytomegalovirusDiagnosis

• Antibody assays indicative of maternal transfer
  of IgG in children lt12 months indicative of
  previous infection in children gt12 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

113

Cytomegalovirus Diagnosis

• Recommendations include
• Testing all HIV-infected infants with urine
  culture for CMV in the first months of life to
  identify congenital, perinatal, or early
  postnatal infection
• Testing annually for CMV antibody in infants
  previously negative by culture and antibody to
  identify occult CMV infections permitting
  appropriate screening for retinitis
• Dilated retinal examinations for coinfected
  children every 4-6 months older children should
  report floaters and visual changes

114

Cytomegalovirus Treatment

• Symptomatic congenital CMV
• Ganciclovir 4-6 mg/kg intravenously every 12
  hours for 6 weeks
• Neutropenia may occur and may require dosage
  modification

115
Cytomegalovirus Treatment

• Initial treatment of disseminated CMV and
  retinitis
• Ganciclovir 5 mg/kg/dose intravenously over 1-2
  hours twice daily for 14-21 days, followed by
  lifelong maintenance therapy (A I)
• Resistance and myelosuppression can occur
• Other toxic effects include renal impairment, CNS
  effects, GI dysfunction, increased liver enzymes

116
Cytomegalovirus Treatment

• Alternative treatment for ganciclovir resistance
• Foscarnet (A I) at 60 mg/kg/dose intravenously
  (infused at 1 mg/kg/minute) over 1-2 hours every
  8 hours for 14-21 days, followed by lifelong
  therapy
• Foscarnet plus ganciclovir delays progression of
  retinitis in certain patients failing monotherapy
• Toxicity decreased renal function, metabolic
  abnormalities, electrolyte imbalances with
  secondary seizures, cardiac dysrhythmia, abnormal
  liver enzymes, and CNS symptoms

117
Cytomegalovirus Treatment

• Treatments for adults (inadequate pediatric data)
• Valganciclovir prodrug of ganciclovir, given
  orally, effective in retinitis in adults
• Oral ganciclovir (or valganciclovir) plus
  ganciclovir sustained release intraocular implant
  used for retinitis
• Cidofovir for retinitis
• Fomivirsen antisense nucleotide used as
  intravitreous injection

118
Herpes Simplex VirusEpidemiology

• Neonatal HSV infection occurs at a rate of
  1/2,000-5,000 deliveries
• Transmitted from infected mother to infant
  primarily through exposure to maternal genital
  fluids during birth, by ascending infection, or
  by invasive procedures (e.g., fetal scalp
  electrodes)
• Congenital (in utero) rare, but severe cutaneous,
  ocular, and CNS damage

119
Herpes Simplex VirusEpidemiology

• 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

120
Herpes Simplex Virus Epidemiology

• In United States, 75 of neonatal HSV caused by
  genital herpes (HSV 1 and 2)
• HSV 2 seroprevalence in women of childbearing age
  is 26 rates may be higher in HIV-infected women
• HIV-infected women shed HSV from genital area
  more frequently than HIV-uninfected women (may be
  asymptomatic)
• No evidence that in utero HSV infection is more
  frequent in HIV-infected pregnant women

121
Herpes Simplex VirusClinical 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)

122
Herpes Simplex VirusClinical Manifestations

• 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

123
Herpes Simplex VirusClinical Manifestations

• Outside neonatal period, most common presentation
  is orolabial disease with fever, irritability,
  submandibular lymphadenopathy, painful ulcers in
  gingival and oral mucosa (gingivostomatitis)
• When severely immunocompromised, may develop
  disseminated HIV infection including infection of
  esophagus, CNS, liver, lung, kidney spleen,
  adrenal

124
Herpes Simplex VirusDiagnosis

• 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 HSV1 and 2
• Direct immunofluorescence for HSV antigen in
  samples
• HSV DNA PCR has replaced brain biopsy

125
Herpes Simplex VirusTreatment

• Acyclovir is the drug of choice regardless of
  infection status (oral and IV formulations
  available)
• Treat neonatal HSV with 20 mg/kg/dose
  intravenously 3 times daily for 21 days for CNS
  and disseminated diseases
• For skin, eye, mouth disease, treat for 14 days
• Do not discontinue acyclovir in neonates with CNS
  disease unless CSF DNA PCR is negative at days
  19-21 of treatment (B III)

126
Varicella-Zoster VirusEpidemiology

• 9 of children lt10 years old experience varicella
  infection (before vaccine use)
• 95 of adults have antibody to VZV
• Rare perinatal VZV transmission
• Congenital VZV occurs in 2 of infants whose
  mothers have primary VZV in first trimester
• Zoster occurs only when previously VZV infected
• Rate of zoster as high as 70 in HIV-infected
  children who are immunocompromised at time of
  primary VZV infection

127
Varicella-Zoster VirusClinical Manifestations

• Congenital infection characterized by cicatricial
  skin scarring, limb hypoplasia, microcephaly,
  seizures, mental retardation, chorioretinitis,
  cataracts, microphthalmia, neurogenic bladder,
  hydroureter, abnormalities of swallowing
• Duration of disease longer and complications more
  frequent in HIV-infected children
• May experience chronic infection with continued
  new lesions for gt1 month
• May develop VZV retinitis

128
Varicella-Zoster VirusDiagnosis

• Clinical diagnosis based on typical generalized
  pruritic vesicular rash and fever
• Direct immunofluorescence for VZV antigen on
  cells from skin, conjunctiva, mucosal lesions
• VZV PCR sensitive and specific and can
  differentiate wild type from vaccine type
• VZV antibody response positive 2-3 weeks after
  onset of illness IgM indicates acute infection
  or recurrent infection

129
Varicella-Zoster VirusTreatment

• 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
• lt1 year of age 10 mg/kg/dose intravenously every
  8 hours as 1-hour infusion for 7 days
• gt1 year of age dose as above or 500 mg/m2/dose
  intravenously every 8 hours as 1-hour infusion
  for 7 days

130
Varicella-Zoster Virus Treatment

• Children with HIV coinfection and normal or
  minimal decrease in CD4 T-cell counts
• Acyclovir 20 mg/kg per dose orally 4 times
  daily maximum dose 800 mg (B III)
• Children with zoster and HIV infection
• Oral acyclovir
• Use intravenously if severely immunocompromised,
  trigeminal nerve involvement or extensive
  multidermatomal zoster

131
Varicella-Zoster Virus Treatment

• Toxicities include phlebitis, nausea, vomiting,
  rash, impaired renal function, neutropenia
• Oral acyclovir data limited in children lt2 years
  of age infants who receive long-term suppressive
  therapy (300 mg/kg/m2/dose administered 3 times
  daily) develop frequent neutropenia usually
  self-limited

132
Varicella-Zoster VirusTreatment

• Use foscarnet for treatment of children with
  acyclovir-resistant VZV (B II)
• Dosage 40-60 mg/kg/dose intravenously over 1-2
  hours administered 3 times daily for 7 days or
  until no new lesions appear
• Modify dosage in patients with renal
  insufficiency
• Valacyclovir and famciclovir alternative
  treatments (not active against acyclovir-resistant
  VZV) but no data in children

133
Human Papillomavirus Epidemiology

• HPV infects cutaneous and mucosal squamous
  epithelium
• Approximately 100 distinct types
• HPV 16, 18, 31, 33, and 35 are most often
  associated with intraepithelial malignancy
• Genital HPV types can cause conjunctiva, nasal,
  oral, and laryngeal warts
• Transmission occurs by direct contact or sexual
  contact (genital warts in young children may be a
  sign of sexual abuse)

134
Human PapillomavirusEpidemiology

• Latent HPV seen in 5-42 of pregnant women
  without HIV infection
• HPV infection rates higher in HIV-positive women
  (up to 95)
• Mother-to-child HPV transmission occurs and can
  result in infant laryngeal and juvenile laryngeal
  papillomatosis
• In general, no neonatal abnormalities are
  associated with detection of HPV in neonates

135
Human Papillomavirus Epidemiology

• HPV detected in 13-60 of sexually active
  adolescent girls
• 40-80 of infections in HIV uninfected are
  transient
• Persistent infection with HPV 16, 81, 31, and 33
  associated with high risk for developing
  cervical, vulvovaginal, and anal carcinoma
  cervical and anal intraepithelial neoplasia
• Increased risk if HIV infected

136
Human Papillomavirus Clinical Manifestations

• Hyperplasic, papillomatosis and verrucous
  squamous epithelial lesions on the skin and
  mucous membranes including anal, genital, oral,
  nasal, conjunctiva, GI, and respiratory tract
  mucosa
• Lesions are soft, pink or white
  cauliflower-like sessile growths

137
Human PapillomavirusDiagnosis

• Most cutaneous and anogenital warts diagnosable
  on physical examination
• Diagnosis of laryngeal papillomatosis requires
  laryngoscopy
• DNA PCR can be used for detection of HPV types
  but not necessary for diagnosis or management of
  anogenital or cutaneous warts or papillomas

138
Human PapillomavirusTreatment

• 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)

139
Human PapillomavirusTreatment

• Cidofovir topical gel 1 evaluated primarily in
  adults used successfully for molluscum
  contagiosum in children with HIV infection
• Cryotherapy and electrodessication applied to
  each lesion treatment can be repeated every 1-2
  weeks
• Treatment of laryngeal papillomatosis directed
  primarily to removal of obstructions
• ART not consistently associated with reduced risk
  for HPV-related cervical abnormalities

140
Hepatitis CEpidemiology

• Low seroprevalence in children in United States
  0.1-0.2
• Seroprevalence higher in HIV-infected children
  1.5 in one study
• Risk for mother-to-infant transmission (MTCT)
  about 6
• Most infections occur at or near delivery

141
Hepatitis CEpidemiology

• 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

142
Hepatitis CEpidemiology

• Viremia in HCV-infected, HIV-uninfected children
  persistent 52 intermittent 42 not detectable
  6
• Spontaneous clearing has been reported in MTCT of
  HCV
• gt40 of those who are viremic have persistent
  features of hepatitis

143
Hepatitis CClinical Manifestations

• Children have less frequent and slower
  progression than do adults
• In a study of posttransfusion HCV, 55 of
  antibody-positive children had detectable HCV in
  blood
• 1 child had abnormal liver enzymes
• 3/17 had histologic evidence of progressive liver
  damage after 21 years

144
Hepatitis CClinical Manifestations

• 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

145
Hepatitis CDiagnosis

• HCV antibody passively transferred not useful
  for diagnosis of infection until gt18 months of
  age
• Diagnosis confirmed using recombinant immunoblot
  assay (RIBA)
• Infants lt18 months use HCV RNA PCR (wait until gt2
  months of age)
• If positive, repeat HCV RNA PCR
• Liver biopsy best for evaluation of hepatic
  disease should be considered before initiating
  treatment

146
Hepatitis CTreatment

• Administer hepatitis A vaccine
• Consideration for treatment includes symptomatic
  disease, advanced pathologic features (bridging
  necrosis, active cirrhosis) (B I)
• Response to treatment better with HCV 2 and HCV 3
  than with HCV 1
• Use quantitative HCV RNA to access treatment
  response

147
Hepatitis CTreatment

• Individuals with undetectable levels of HCV RNA
  following treatment should be retested after 24
  weeks
• In HIV-coinfected patients, testing can be
  continued for an additional 1-2 years

148
Hepatitis CTreatment

• Adults and children with HIV disease
• Combination therapy with interferon (IFN) and
  ribavirin (A I)
• Pegylated IFN alfa 2a subcutaneously 180 mcg/kg
  weekly or alfa 2b subcutaneously 1.5 mcg/kg
  weekly (adults)
• Ribavirin 400 mg orally twice daily (adults)
• Limited data on use of IFN in children

149
Hepatitis CTreatment Children

• IFN alpha 2a and alpha 2b monotherapy most widely
  evaluated in children with HCV infection (not
  with HIV coinfection)
• Pediatric dosage in studies ranged from 1.75 to 5
  million units/m2 (maximum dosage 3-5 million
  units) administered subcutaneously or
  intramuscularly 3 times weekly for 4-12 months
• Treatment contraindicated in decompensated liver
  disease, cytopenia, cardiac disease or autoimmune
  disease

150
Hepatitis CTreatment Children

• Ribavirin oral solution used in combination with
  IFN alfa
• Dosage oral solution 40 mg/mL 15 mg/kg/day
  divided into 2 doses given twice daily
• 25-36 kg 1 200 mg capsule in a.m., 1 in
  p.m.37-49 kg 1 200 mg capsule in a.m., 2 in
  p.m.50-61 kg 2 200 mg capsules in a.m., 2 in
  p.m.

151
Hepatitis CTreatment Children

• Use IFN monotherapy when ribavirin cannot be
  used, e.g., unstable cardiopulmonary disease,
  severe anemia, hemoglobinopathy (B III)
• Treat HCV 1 for 48 weeks treat HCV 2, HCV 3 for
  24 weeks some treat HIV-coinfected patients for
  48 weeks

152
Hepatitis CTreatment

• Adverse effects IFN alfa
• Flulike syndrome most severe during first month
  of therapy, consisting of fever, chills,
  headache, myalgia, arthalgia, abdominal pain,
  nausea, vomiting
• Epistaxis associated with thrombocytopenia or
  prolonged prothrombin time
• Neutropenia, anemia, thrombocytopenia
• Personality changes
• Abnormalities of thyroid function

153
Hepatitis CTreatment

• Adverse effects ribavirin
• Flulike syndrome consisting of fever, chills,
  headache, myalgia, arthalgia, abdominal pain,
  nausea, vomiting
• Hemolytic anemia, lymphopenia
• Neutropenia, anemia, thrombocytopenia
• Depression and suicidal ideation
• Do not use in combination with didanosine

154
Hepatitis BEpidemiology

• Acquired by perinatal or mother-to-infant
  transmission
• Unknown whether there is a greater risk of HBV
  transmission to infants from HIV-coinfected
  mothers
• All infants born to HBV-infected mothers should
  receive HBV vaccine and HBV immune globulin
  (HBIG) within 12 hours of birth
• Second dose of vaccine at 1-2 months of age
• Test for antibody to HBsAg at 9-15 months of age
  if negative, reimmunize

155
Hepatitis B Epidemiology

• HBV-infected household members may pose risk of
  infection
• Infection occurs through contact with infected
  blood or body fluids and through sharing of
  objects such as toothbrushes
• All infants previously unimmunized should receive
  routine childhood HBV vaccine

156
Hepatitis B Epidemiology

• HBV infection risk increased through sexual
  activity in adolescents who are HIV coinfected
• I