oi pediatrics

Treating Opportunistic Infection Among HIV-Infected Children

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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

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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)

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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

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Difficulty of Diagnosing OI in Children

Inability to describe symptoms Antibody-based tests confounded by

maternal transfer of antibody Sputum difficult to obtain without invasive

procedures

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Frequency of OI among HIV-Infected Children

Pre-HAART era, most common OIs occurring at >1 events/100 child years Serious bacterial infections (bacteremia and

pneumonia), herpes zoster, Pneumocystis jiroveci (carinii) pneumonia, candidiasis, Mycobacterium avium complex

Pre-HAART era, most common OIs occurring at <1 events/100 child years Cytomegalovirus, toxoplasmosis, cryptosporidiosis,

tuberculosis, systemic fungal infections

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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)

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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

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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)

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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

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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)

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Toxoplasmosis Epidemiology

Primarily perinatal transmission from primary infection of mothers during pregnancy

Older children acquire toxoplasmosis from poorly cooked food and from ingestion of sporulated oocysts in soil, water, or food

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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

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Toxoplasmosis Clinical Manifestations

Non-immunocompromised infants are usually asymptomatic at birth but majority develop late manifestations – retinitis, neurologic impairment

Newborn symptoms can include: Rash, lymphadenopathy, jaundice, hematologic

abnormalities, seizures, microcephaly, chorioretinitis, hydrocephalus

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Toxoplasmosis Clinical Manifestations

Toxoplasmosis acquired after birth is initially asymptomatic, followed by infectious mononucleosis-like syndrome

Chronic toxoplasmosis can reactivate in HIV-infected children

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Toxoplasmosis Diagnosis

Test all HIV-infected pregnant women for toxoplasmosis

If positive, evaluate infant for congenital toxoplasmosis

Use antibody assay to detect IgM-, IgA-, or IgE-specific antibody in first 6 moths or persistence of IgG antibody after 12 months

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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

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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

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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

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Toxoplasmosis Treatment

Pyrimethamine: rash, Stevens-Johnson syndrome, nausea, reversible bone marrow toxicity

Sulfadiazine: rash, fever, leukopenia, hepatitis, nausea, vomiting, diarrhea, crystalluria

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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

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Cryptosporidiosis/Microsporidiosis Epidemiology

Protozoal parasites that cause enteric illness in humans and animals

Human infection primarily caused by C hominis,C parvum, C meleagridis

Microsporida include E bieneusi and E intestinalis Infection results from ingestion of oocysts excreted in

feces of humans or animals Invade intestinal tract mucosa causing watery,

nonbloody diarrhea, dehydration, malnutrition

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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

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Cryptosporidiosis/MicrosporidiosisDiagnosis

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

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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

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Cryptosporidiosis/MicrosporidiosisTreatment

Immune restoration following antiretroviral treatment frequently results in clearing

Supportive care, hydration, electrolyte replenishment, nutritional supplements

Available treatment inconsistently effective

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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

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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

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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

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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

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Mycobacterium tuberculosisClinical Manifestations

Younger children progress more rapidly (possibly due to delayed diagnosis)

Nonspecific symptoms: fever, weight loss, failure to thrive

Pulmonary TB most likely appears as infiltrate with hilar adenopathy

Clinical presentation of TB similar in HIV-positive and HIV-negative children

Extrapulmonary: marrow, lymph node, bone, pleura, pericardium, peritoneal

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Mycobacterium tuberculosis Diagnosis

Difficult to diagnose; maintain a degree of suspicion

M tuberculosis detected in up to 50% of gastric aspirate in 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

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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

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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

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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)

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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

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Isoniazid Dosage: 10-15 mg/kg orally once daily

(maximum 300 mg daily) Hepatic toxicity increases with rifampin Peripheral neuritis, mild CNS toxicity, gastric

upset

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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

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

pseudojaundice, GI upset

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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

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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

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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

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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

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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

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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

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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

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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)

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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

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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)

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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)

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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

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Pneumocystis jiroveci (carinii)Clinical Manifestations

Fever, tachypnea, cough, dyspnea, poor feeding, weight loss

Abrupt or insidious onset Bibasilar rales with evidence of hypoxia and

respiratory distress Extrapulmonary locations – spleen, liver,colon,

pancreas, ear, eye, GI tract, bone marrow, heart, kidney, lymph nodes, CNS

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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

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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

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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

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Adverse reactions: Rash Stevens-Johnson syndrome (rare) Neutropenia, thrombocytopenia,

megaloblastic or aplastic anemia

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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)

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Pneumocystis jiroveci (carinii) Treatment Alternatives

Atovaquone (B I) Limited data in children 30-40 mg/kg/day divided into 2 doses, given

with fatty foods Infants 3-24 months may require 45 mg/kg/day

divided into 2 doses, given with fatty foods (A II) Adverse reactions include rash, nausea,

diarrhea, increased liver enzymes

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Clindamycin/primaquine Used for mild to moderate PCP in adults – no

data in children (C III) Primaquine contraindicated in G6PD deficiency

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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)

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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

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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

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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)

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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

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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)

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CryptococcosisEpidemiology

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

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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

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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

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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)

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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

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Flucytosine toxicity Bone marrow: anemia, leukopenia,

thrombocytopenia Liver, GI, and renal toxicity

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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

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Histoplasmosis Clinical Manifestations

Prolonged fever is the most common presentation Malaise, weight loss, and nonproductive cough Primary pulmonary focus leads to widespread

dissemination in children Physical findings include hepatosplenomegaly,

erythematous nodular coetaneous lesions, CNS involvement with meningitis

Anemia, thrombocytopenia, elevated liver transaminases

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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

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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

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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)

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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

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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

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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

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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

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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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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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