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Treating Opportunistic Infection Among HIV-Infected Children
2
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
3
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)
4
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 tuberculosis)
Differences between Adults and Children
5
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
6
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,
tuberculosis, systemic fungal infections
7
Treating OI among HIV-Infected Children
Letter indicating strength of recommendation (e.g., A, B, C)
Roman numeral indicating nature of evidence (e.g., I, II, III)
Rating of treatment recommendations is based on opinion of working group
8
Serious Recurrent Bacterial InfectionsEpidemiology
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
9
Serious Recurrent Bacterial InfectionsEpidemiology
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
10
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
11
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
12
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
13
Serious Recurrent Bacterial InfectionsTreatment
Children <5 years should be given H influenza B and heptavalent pneumococcal conjugate vaccines (A II)
Children >2 years should receive 23 valent pneumococcal vaccine (>2 months after conjugate vaccine)
Reimmunize with pneumococcal vaccine in 3-5 years in children <10 years or after 5 years in children >10 years
14
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
15
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
16
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
17
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)
18
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
19
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)
20
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
21
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)
22
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
23
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
<1% of AIDS-defining illnesses in children
24
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
25
Toxoplasmosis Clinical Manifestations
Toxoplasmosis acquired after birth is initially asymptomatic, followed by infectious mononucleosis-like syndrome
Chronic toxoplasmosis can reactivate in HIV-infected children
26
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
27
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
28
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
29
Toxoplasmosis Treatment
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
Treatment of HIV-infected children with acquired CNS, ocular, or systemic toxoplasmosis
30
Toxoplasmosis Treatment
Pyrimethamine: rash, Stevens-Johnson syndrome, nausea, reversible bone marrow toxicity
Sulfadiazine: rash, fever, leukopenia, hepatitis, nausea, vomiting, diarrhea, crystalluria
31
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
32
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
33
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
34
Cryptosporidiosis/MicrosporidiosisDiagnosis
Cryptosporidiosis Concentrated stool samples to demonstrating oocysts Evaluate at least 3 separate stool samples
35
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 >2 months duration
PCR techniques still in research
36
Cryptosporidiosis/MicrosporidiosisTreatment
Immune restoration following antiretroviral treatment frequently results in clearing
Supportive care, hydration, electrolyte replenishment, nutritional supplements
Available treatment inconsistently effective
37
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
38
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
39
Mycobacterium tuberculosisEpidemiology
15,000 new cases of tuberculosis in United States in 2002 (6% among children <15 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
40
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
Mycobacterium tuberculosisEpidemiology
41
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
42
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
43
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
44
Mycobacterium tuberculosisTreatment
Treatment principles similar in HIV-positive and HIV-negative children
Initiate treatment as soon as possible in children <4 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
45
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)
46
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
47
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
48
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
49
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
50
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
51
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
52
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
53
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
54
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:
<750 mL <1 year; <500 mL 1-2 years; <75 mL 2-6 years; <50 mL >6 years
55
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
56
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
57
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)
58
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
59
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)
60
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)
61
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 <1 year pre-HAART CD4 T-cell count not a good indicator of risk in infants <1
year old Infection now unusual due to routine prophylaxis with
trimethoprim/sulfamethoxazole
62
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
63
Pneumocystis jiroveci (carinii) Diagnosis
Hypoxia with low arterial oxygen pressure (alveolar-arterial oxygen gradient >30 mm/Hg)
Definitive diagnosis requires demonstrating organism
Induced sputum (difficult <2 years) Bronchoscopy with bronchoalevolar lavage Fiberoptic bronchoscopy with biopsy – generally
not recommended
64
Pneumocystis jiroveci (carinii) Diagnosis
Open lung biopsy most sensitive Requires thorachotomy, chest tube drainage Organisms seen on biopsy with:
Gomori’s methenamine silver stain Toluidine blue stain Giemsa or Wright’s stain Monoclonal antibody
DNA PCR in fluids, lavage – mostly research
65
Pneumocystis jiroveci (carinii) Treatment
Trimethoprim/sulfamethoxazole (TMP/SMX) (A I) >2 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
66
Pneumocystis jiroveci (carinii) Treatment
Adverse reactions: Rash Stevens-Johnson syndrome (rare) Neutropenia, thrombocytopenia,
megaloblastic or aplastic anemia
67
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)
68
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
69
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
70
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
71
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
72
Pneumocystis jiroveci (carinii) Treatment Alternatives
Dapsone/trimethoprim Use for mild to moderate PCP in adults – no
data in children (C III) Dapsone dose <13 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
73
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
74
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
75
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
76
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 >90% from disseminated candidiasis in children with fever and symptoms >14 days
77
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
78
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
79
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
80
Candida InfectionsTreatment
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 twice daily 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
81
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)
82
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; <50 kg dosage range 0.8-1.6 mg/kg daily; >50 kg, adult dosing
83
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
84
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)
85
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
86
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)
87
CryptococcosisEpidemiology
Low incidence of infection in children Children usually infected during 6-12 age range Usually severely immunosuppressed
88
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
89
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
90
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)
91
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
92
CryptococcosisTreatment
Flucytosine toxicity Bone marrow: anemia, leukopenia,
thrombocytopenia Liver, GI, and renal toxicity
93
HistoplasmosisEpidemiology
Incidence of disseminated histoplasmosis in HIV-infected children in the United States <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
94
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
95
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
96
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
97
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)
98
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
99
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 of
C immitis reported
100
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
101
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
102
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)
103
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
104
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
105
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)
106
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
107
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
108
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
CytomegalovirusClinical Manifestations
109
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
CytomegalovirusClinical Manifestations
110
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
CytomegalovirusClinical Manifestations
111
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
CytomegalovirusDiagnosis
112
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
CytomegalovirusDiagnosis
113
Symptomatic congenital CMV Ganciclovir: 4-6 mg/kg intravenously every 12 hours for
6 weeks Neutropenia may occur and may require dosage
modification
CytomegalovirusTreatment
114
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
CytomegalovirusTreatment
115
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
CytomegalovirusTreatment
116
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
CytomegalovirusTreatment
117
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
118
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
119
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
120
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%)
121
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
122
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
123
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 HSV
1 and 2 Direct immunofluorescence for HSV antigen in samples HSV DNA PCR has replaced brain biopsy
124
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)
125
Varicella-Zoster VirusEpidemiology
9% of children <10 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
126
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 >1 month
May develop VZV retinitis
127
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
128
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 <1 year of age: 10 mg/kg/dose intravenously every 8
hours as 1-hour infusion for 7 days >1 year of age: dose as above or 500 mg/m2/dose
intravenously every 8 hours as 1-hour infusion for 7 days
129
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
130
Varicella-Zoster Virus Treatment
Toxicities include phlebitis, nausea, vomiting, rash, impaired renal function, neutropenia
Oral acyclovir data limited in children <2 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
131
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
132
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)
133
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
134
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
135
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
136
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
137
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)
138
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
139
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
140
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
141
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
>40% of those who are viremic have persistent features of hepatitis
142
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
143
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
144
Hepatitis CDiagnosis
HCV antibody passively transferred; not useful for diagnosis of infection until >18 months of age
Diagnosis confirmed using recombinant immunoblot assay (RIBA)
Infants <18 months use HCV RNA PCR (wait until >2 months of age)
If positive, repeat HCV RNA PCR Liver biopsy best for evaluation of hepatic disease;
should be considered before initiating treatment
145
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
146
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
147
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
148
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
149
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.
150
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
151
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
152
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
153
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
154
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
155
Hepatitis B Epidemiology
HBV infection risk increased through sexual activity in adolescents who are HIV coinfected
Immunize HBV-susceptible adolescents Risk of chronic HBV infection in children without
HIV infection is inversely related to age at time of infection
156
Hepatitis BClinical 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 sometimes present with hepatosplenomegaly
157
Hepatitis BClinical Manifestations
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
158
Hepatitis BDiagnosis
HBsAg is the first detectible marker and precedes 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
159
Hepatitis BDiagnosis
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 are usually present
Following immunization, only anti-HBs develops
160
Hepatitis BDiagnosis
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
161
Hepatitis BDiagnosis
All pregnant women should be tested for HBV surface antigen (HBsAg)
Repeat test late in pregnancy for women at high risk for HBV infection
162
Hepatitis BTreatment
Administer hepatitis A vaccine to susceptible children >2 years of age
Indications for treatment are the same in 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 moths
Persistent elevation of transaminases (2 times upper limit of normal)
Evidence of chronic hepatitis on liver biopsy (B II)
163
Hepatitis BTreatment
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
164
Hepatitis BTreatment
IFN alfa, lamivudine (3TC), and adefovir approved for treatment of HBV in adults
IFN alfa and 3TC approved for children Some recommend IFN alfa monotherapy for HBV/HIV-
coinfected patients not yet requiring ART (to decrease possibility of resistance to 3TC and adefovir) (C III)
Some recommend 3TC monotherapy for HBV/HIV-coinfected patients who require ART (B III) (similar for children)
165
Hepatitis BTreatment
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
166
Hepatitis BTreatment
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
167
Hepatitis BTreatment
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
168
Hepatitis B Treatment
Children who do not respond to IFN alfa may respond to IFN beta (C III)
IFN beta shares biologic functions but is antigenically different
Dose 5 million units/m2 intramuscularly 3 times a week for 6 months
In some studies, 45% of children were HBV DNA negative 18 months after therapy completion; 50% normalized transaminases; 32% became anti-HBe antibody positive
169
Hepatitis B Treatment
Lamivudine (3TC) Preferred therapy for HIV-coinfected children with
compensated chronic liver disease who require ARVs for HIV infection (B III)
Results in rapid decline in HBV DNA levels Used for HBV HIV uninfected children but persistent
virologic response rates are low Used as both primary and secondary treatment in HBV-
infected, HIV-negative children Extended monotherapy treatment can lead to resistance
170
Hepatitis BTreatment
Lamivudne (3TC) Do not use 3TC monotherapy in HIV/HBV-
coinfected children (3TC resistance develops) Dosage: 3 mg/kg once daily (lower than that
required for HIV) If 3TC is used to treat HBV/HIV-coinfected
children, treat with 4 mg/kg twice daily in the context of ARV combination therapy
171
Hepatitis BTreatment
Adefovir Some recommend combined adefovir or tenofovir in
addition to 3TC as part of suppressive ART to reduce development of resistance
Continue 3TC along with ARVs in children who respond; exacerbations of HBV can occur when therapy is discontinued
Combination 3TC and IFN alfa not well studied Adefovir dipivoxil (10 mg once daily in adults) active
against HBV with minimal anti-HIV effect (insufficient data in children)
172
This presentation was prepared by Arthur Ammann, MD, for the AETC National Resource Center in April 2005.
See the AETC NRC Web site for the most current version of this presentation - http://www.aidsetc.org.
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