Transcript Fungal Infections-

Guidelines for Prevention and Treatment of Opportunistic
Infections in HIV-Infected Adults and Adolescents
Fungal Infections Slide Set
Prepared by the AETC National Coordinating Resource Center based on
recommendations from the CDC, National Institutes of Health, and HIV
Medicine Association/Infectious Diseases Society of America
About This Presentation
These slides were developed using recommendations
published in May 2013. The intended audience is clinicians
involved in the care of patients with HIV.
Users are cautioned that, owing to the rapidly changing
field of HIV care, this information could become out of date
quickly. Finally, it is intended that these slides be used as
prepared, without changes in either content or attribution.
Users are asked to honor this intent.
-AETC National Coordinating Resource Center
http://www.aidsetc.org
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Fungal Infections
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Pneumocystis jiroveci pneumonia
Mucocutaneous candidiasis
Cryptococcosis
Histoplasmosis
Coccidiomycosis
Aspergillosis
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Pneumocystis jiroveci Pneumonia (PCP)
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Epidemiology
Clinical Manifestations
Diagnosis
Prevention
Treatment
Considerations in Pregnancy
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PCP: Epidemiology
 Caused by P jiroveci (formerly P carinii)
 Ubiquitous in the environment
 Initial infection usually occurs in early childhood
 PCP may result from reactivation or new
exposure
 In immunosuppressed patients, possible airborne
spread
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PCP: Epidemiology (2)
 Before widespread use of PCP prophylaxis &
effective ART, PCP seen in 70-80% of AIDS patients
in the U.S.
 In advanced immunosuppression, treated PCP associated
with 20-40% mortality
 Substantial decline in incidence in U.S. & W. Europe,
owing to prophylaxis and ART
 Most cases occur in patients unaware of their HIV
infection, in those who are not in care, and in those
with advanced AIDS (CD4 count <100 cells/µL)
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PCP: Epidemiology (3)
Risk factors:
 CD4 count <200 cells/µL
 CD4 percentage <14%
 Prior PCP
 Oral thrush
 Recurrent bacterial pneumonia
 Unintentional weight loss
 High HIV RNA
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PCP: Clinical Manifestations
 Progressive exertional dyspnea, fever,
nonproductive cough, chest discomfort
 Subacute onset, worsens over days-weeks
(fulminant pneumonia is uncommon)
 Chest exam may be normal, or diffuse dry rales,
tachypnea, tachycardia (especially with exertion)
 Extrapulmonary disease seen rarely; occurs in
any organ, associated with aerosolized
pentamidine prophylaxis
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PCP: Diagnosis
 Clinical presentation, blood tests, radiographs
suggestive but not diagnostic
 Organism cannot be cultured
 Definitive diagnosis should be sought
 Hypoxemia: characteristic, may be mild or severe
(PO2 <70 mmHg or A-a gradient >35 mmHg)
 LDH >500 mg/dL is common but nonspecific
 1,3β-D-glycan may be elevated; uncertain sensitivity
and specificity
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PCP: Diagnosis (2)
 CXR: various presentations
 May be normal in early disease
 Typical: diffuse bilateral, symmetrical interstitial
infiltrates
 May see atypical presentations, including nodules,
asymmetric disease, blebs, cysts, pneumothorax
 Cavitation, intrathoracic adenopathy, and pleural
effusion are uncommon (unless caused by a second
concurrent process)
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PCP: Diagnosis (3)
 Chest CT, thin-section
 Patchy ground-glass attenuation
 May be normal
 Gallium scan
 Pulmonary uptake
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PCP: Diagnosis (Imaging)
Chest X ray: PCP with bilateral,
diffuse granular opacities.
Chest X ray: PCP with bilateral
perihilar opacities, interstitial
prominence, hyperlucent cystic lesions.
(Credit: L. Huang, MD; HIVInSite)
(Credit: HIV Web Study, hivwebstudy.org,
© University of Washington)
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PCP: Diagnosis (Imaging) (2)
High-resolution computed tomograph (HRCT) scan of the chest showing PCP. Bilateral patchy
areas of ground-glass opacity are suggestive of PCP. Credit: L. Huang, MD; HIV InSite
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PCP: Diagnosis (4)
 Definitive diagnosis requires demonstrating
organism:
 Induced sputum (sensitivity <50% to >90%)
 Spontaneously expectorated sputum: low sensitivity
 Bronchoscopy with bronchoalveolar lavage (sensitivity
90-99%)
 Transbronchial biopsy (sensitivity 95-100%)
 Open-lung biopsy (sensitivity 95-100%)
 PCR: high sensitivity for BAL sample; may not
distinguish disease from colonization
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PCP: Diagnosis (Histopathology)
Lung biopsy using silver stain to demonstrate P jiroveci organisms in tissue
Credit: A. Ammann, MD; UCSF Center for HIV Information Image Library
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PCP: Diagnosis (5)
 Treatment may be initiated before definitive
diagnosis is established
 Organism persists for days/weeks after start of
treatment
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PCP: Preventing Exposure
 Insufficient data to support isolation as a
standard practice, but data suggest high-risk
patients may benefit from isolation from persons
with known PCP
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PCP: Primary Prophylaxis
 Initiate:
 CD4 <200 cells/µL or history of oropharyngeal
candidiasis
 Consider for:
 CD4% <14% or history of AIDS-defining illness
 CD4 200-250 cells/µL if Q 3-month CD4 monitoring is not
possible
 Discontinue:
 On ART with CD4 >200 cells/µL for >3 months
 Reinitiate:
 CD4 decreases to <200 cells/µL
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PCP: Primary Prophylaxis (2)
 Preferred:
 Trimethoprim-sulfamethoxazole (TMP-SMX) DS 1
tablet PO QD*
 TMP-SMX SS 1 tablet PO QD
 For patients who experience non life-threatening
adverse events, consider desensitization or
dosage reduction
* Effective as toxoplasmosis prophylaxis (for CD4 count <100 cells/µL +
positive serology)
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PCP: Primary Prophylaxis (3)
 Alternative:
 TMP-SMX DS 1 tablet PO 3 times Q week
 Dapsone 100 mg PO QD or 50 mg BID
 Dapsone 50 mg QD + pyrimethamine 50 mg Q week +
leucovorin 25 mg Q week*
 Dapsone 200 mg + pyrimethamine 75 mg + leucovorin 25
mg, all Q week*
 Aerosolized pentamidine 300 mg Q month via Respirgard II
nebulizer (other devices not recommended)
 Atovaquone 1,500 mg PO QD*
* Effective as toxoplasmosis prophylaxis (for CD4 count <100 cells/µL + positive
serology)
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PCP: Treatment
 Duration: 21 days for all treatment regimens
 Preferred: TMP-SMX is treatment of choice
 Moderate-severe PCP
 TMP-SMX: 15-20 mg/kg/day TMP and 75-100 mg/kg/day SMX
IV or PO in divided doses Q6-8H
 Mild-moderate PCP
 As above, or TMP-SMX DS 2 tablets TID
 Adjust dosage for renal insufficiency
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PCP: Treatment (2)
 Alternatives
 Moderate-severe PCP
 Pentamidine 4 mg/kg IV QD
 Recommended for patients who cannot tolerate TMP-SMX or
experience clinical failure with TMP-SMX; do not combine use
 Primaquine 30 mg (base) PO QD + clindamycin 600 mg IV
Q6H or 900 mg IV Q8H or 300 mg PO Q6H or 450 mg PO Q8H
 More effective than pentamidine, less toxicity
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PCP: Treatment (3)
 Alternatives
 Mild-moderate PCP
 Dapsone 100 mg PO QD + TMP 15 mg/kg/day PO in divided
doses TID
 Similar efficacy, fewer side effects than TMP-SMX, but more pills
 Primaquine 30 mg (base) PO QD + clindamycin 300 mg PO
Q6H or 450 mg PO Q8H
 Atovaquone 750 mg PO BID
 Less effective than TMP-SMX, but fewer side effects
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PCP: Treatment (4)
 Adjunctive:
 Corticosteroids
 For moderate-to-severe disease (room air PO2 <70 mmHg or
A-a gradient >35 mmHg)
 Give as early as possible (within 72 hours)
 Prednisone 40 mg BID days 1-5, 40 mg QD days 6-10, 20 mg
QD days 11-21, or methylprednisolone at 75% of respective
prednisone dosage
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PCP: ART Initiation
 For patients not on ART, start ART within 2
weeks of PCP diagnosis, if possible
 In one study, lower rates of AIDS progression or death
with early ART initiation (no data on patients with
respiratory failure requiring intubation)
 IRIS has been reported; follow for recurrence of
symptoms
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PCP: Monitoring and Adverse Events
 Monitor closely for response to treatment, and for
adverse effects of treatment
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PCP: Monitoring & Adverse Events (2)
 TMP-SMX: rash, Stevens-Johnson syndrome, fever,
leukopenia, thrombocytopenia, azotemia, hepatitis,
hyperkalemia
 Atovaquone: headache, nausea, diarrhea, rash,
fever, transaminase elevations
 Dapsone: methemoglobinemia and hemolysis, rash,
fever
 Pentamidine: pancreatitis, hypo- or hyperglycemia,
leukopenia, fever, electrolyte abnormalities, cardiac
dysrhythmia
 Primaquine and clindamycin: methemoglobinemia
and hemolysis, anemia, rash, fever, diarrhea
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PCP: Treatment Failure
 Lack of clinical improvement or worsening of
respiratory function after at least 4-8 days of
treatment
 If patient not on corticosteroid therapy, early
deterioration (day 3-5) may be caused by
inflammatory response to lysis of P jiroveci
organisms
 Rule out concomitant infection
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PCP: Treatment Failure (2)
 Treatment failure resulting from drug toxicities in
up to 1/3 of patients
 Treat adverse reactions or switch regimen
 Treatment failure caused by lack of drug efficacy
in 10% of patients
 No data to guide treatment decisions
 For TMP-SMX failure in moderate-to-severe PCP,
consider IV pentamidine or primaquine + IV
clindamycin
 For mild disease, may consider atovaquone
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PCP: Preventing Recurrence
 Secondary prophylaxis (chronic maintenance
therapy) for life unless immune reconstitution on ART
 Preferred: TMP-SMX 1 DS PO QD, or 1 SS PO QD
 Alternatives:
 TMP-SMX DS 1 tablet PO 3 times Q week
 Dapsone 100 mg PO QD or 50 mg BID
 Dapsone 50 mg QD + pyrimethamine 50 mg Q week
+ leucovorin 25 mg Q week
 Dapsone 200 mg + pyrimethamine 75 mg + leucovorin 25 mg, all
Q week*
 Aerosolized pentamidine 300 mg Q month via Respirgard II
nebulizer (other devices not recommended)
 Atovaquone 1,500 mg PO QD
 Atovaquone 1,500 mg PO QD + pyrimethamine
25 mg QD + leucovorin 10 mg PO QD
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PCP: Preventing Recurrence (2)
 Discontinue secondary prophylaxis for patients
on ART with sustained increase in CD4 count
from <200 cells/µL to >200 cells/µL for ≥3 months
 If PCP occurred at CD4 count >200 cells/µL, prudent to
continue prophylaxis for life (regardless of CD4 count)
 Restart maintenance therapy if CD4 count
decreases to <200 cells/µL or if PCP recurs at
CD4 count >200 cells/µL
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PCP: Considerations in Pregnancy
 Diagnosis and indications for treatment: as in
nonpregnant women
 Preferred treatment: TMP-SMX
 Limited data suggest small increased risk of birth
defects after 1st trimester TMP exposure, but pregnant
women with PCP should be treated with TMP-SMX
 Consider increased doses of folic acid (>0.4 mg/day) in 1st
trimester: may decrease risk of congenital anomaly but may
increase risk of therapeutic failure
 Pentamidine embryotoxic in animals
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PCP: Considerations in Pregnancy (2)
 Dapsone: risk of mild maternal hemolysis with
long-term therapy; risk of hemolytic anemia in
fetuses with G6PD deficiency
 Pentamidine embryotoxic in animals
 Primaquine: not generally used in pregnancy, risk
of hemolysis; risk of hemolytic anemia in fetuses
with G6PD deficiency
 Clindamycin, atovaquone: appear safe in
pregnancy
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PCP: Considerations in Pregnancy (3)
 Corticosteroid indications as in nonpregnant
women; monitor for hyperglycemia
 Increased risk of preterm labor and delivery;
monitor if pneumonia occurs after 20 weeks of
gestation
 Prophylaxis as in nonpregnant adults
 Consider aerosolized pentamidine or atovaquone
during 1st trimester, if risk of teratogenicity caused by
systemic agents is a concern
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Mucocutaneous Candidiasis
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Epidemiology
Clinical Manifestations
Diagnosis
Prevention
Treatment
Considerations in Pregnancy
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Mucocutaneous Candidiasis:
Epidemiology
 Oropharyngeal and esophageal candidiasis are
common
 Most common in patients with CD4 count <200 cells/µL
 Prevalence lower in patients on ART
 Vulvovaginal candidiasis
 Occurs in HIV-noninfected women; does not indicate
immunosuppression
 In advanced immunosuppression, may be more severe or
recur more frequently
 Usually caused by Candida albicans; other species
(especially C glabrata) seen in advanced
immunosuppression, refractory cases
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Mucocutaneous Candidiasis:
Clinical Manifestations
 Oropharyngeal (thrush):
 Pseudomembranous: painless, creamy white plaques on
buccal or oropharyngeal mucosa or tongue; can be scraped
off easily
 Erythematous: patches on anterior or posterior upper palate
or tongue
 Angular cheilosis
 Esophageal:
 Retrosternal burning pain or discomfort, odynophagia, fever;
on endoscopy, whitish plaques with or without mucosal
ulceration
 Vulvovaginal:
 Creamy discharge, mucosal burning and itching
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Mucocutaneous Candidiasis:
Clinical Manifestations (2)
Pseudomembranous candidiasis
Erythematous candidiasis
Credit: Pediatric AIDS Pictorial Atlas,
Baylor International Pediatric AIDS
Initiative
Credit: D. Greenspan, DSC, BDS;
HIV InSite
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Mucocutaneous Candidiasis:
Clinical Manifestations (3)
Esophageal candidiasis
Credit: P. Volberding, MD; UCSF Center for HIV Information Image Library
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Mucocutaneous Candidiasis:
Diagnosis
 Oropharyngeal:
 Usually clinical diagnosis
 For laboratory confirmation: KOH preparation; culture
 Esophageal:
 Empiric diagnosis: symptoms and response to trial of
therapy (usually appropriate before endoscopy);
visualization of lesions + fungal smear or brushings
 Endoscopy with histopathology and culture
 Vulvovaginal:
 Clinical diagnosis, and KOH preparation
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Mucocutaneous Candidiasis:
Prevention
 Preventing exposure
 Candida are common mucosal commensals; no
measures to reduce exposure
 Primary prophylaxis
 Not recommended: mucosal disease has low mortality;
acute therapy is effective; concern for drug resistance,
drug interactions, expense
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Mucocutaneous Candidiasis:
Treatment
 Oropharyngeal
 Preferred (7-14 days)
 Fluconazole 100 mg PO QD
 Clotrimazole troches 10 mg PO 5 times daily
 Miconazole mucoadhesive buccal tablet 50 mg QD to canine fossa
 Alternative
 Itraconazole* oral solution 200 mg PO QD
 Posaconazole* oral suspension 400 mg PO BID x 1, then 400 mg
QD
 Nystatin suspension 4-6 mL QID or 1-2 flavored pastilles 4-5 times
daily
* May have significant drug interactions with certain ARV medications;
consult information on drug interactions before coadministering with ARVs.
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Mucocutaneous Candidiasis:
Treatment (3)
 Esophageal
 Systemic therapy required
 Preferred (14-21 days)
 Fluconazole 100 mg (up to 400 mg) PO or IV QD
 Itraconazole* oral solution 200 mg PO QD
 Alternative
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Voriconazole* 200 mg PO BID
Caspofungin 50 mg IV QD
Micafungin 150 mg IV QD
Anidulafungin 100 mg IV x 1, then 50 mg IV QD
Amphotericin B deoxycholate 0.6 mg/kg IV QD
Amphotericin B (lipid formulation) 3-4 mg/kg IV QD
* May have significant drug interactions with certain ARV medications; consult
information on drug interactions before coadministering with ARVs.
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Mucocutaneous Candidiasis:
Treatment (5)
 Vulvovaginal, uncomplicated
 Preferred
 Fluconazole 150 mg PO for 1 dose
 Topical azoles for 3-7 days
 Alternative
 Topical nystatin 100,000 units/day for 14 days
 Itraconazole oral solution 200 mg QD for 3 days
 Severe or recurrent
 Fluconazole 100-20 mg PO or topical antifungal for ≥7
days
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Mucocutaneous Candidiasis: ART
Initiation
 No special considerations regarding ART
initiation
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Mucocutaneous Candidiasis:
Monitoring
 Response usually rapid (48-72 hours)
 Adverse effects:
 Rare with topical treatment
 For prolonged oral azole treatment (>21 days), monitor
for hepatoxicity
 No reports of IRIS
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Mucocutaneous Candidiasis:
Treatment Failure
 Persistence of signs and symptoms after 7-14 days
of appropriate therapy
 Testing (eg, culture) needed to confirm treatment
failure owing to azole resistance
 Refractory disease:
 Posaconazole effective in 75% of azole-refractory
candidiasis
 Oral itraconazole effective in most fluconazole-refractory
mucosal candidiasis
 Consider anidulafungin, caspofungin, micafungin,
voriconazole
 Amphotericin B usually effective
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Mucocutaneous Candidiasis:
Preventing Recurrence
 ART and immune reconstitution reduce recurrences
 For oropharyngeal or vulvovaginal, chronic
suppressive therapy generally not recommended
 If frequent or severe recurrences, consider fluconazole 100
mg PO QD or TIW (oral); fluconazole 150 mg PO weekly
(vaginal)
 For esophageal, consider fluconazole 100-200 mg
PO QD or posaconazole suspension 400 mg PO BID
 Azole-refractory oropharyngeal or esophageal
candidiasis: recommended until immune
reconstitution on ART (if responded to
echinocandins, voriconazole, or posaconazole)
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Mucocutaneous Candidiasis:
Preventing Recurrence (2)
 Stopping chronic suppressive therapy:
 No data; reasonable to stop when CD4 >200 cells/µL
after ART initiation
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Mucocutaneous Candidiasis:
Considerations in Pregnancy
 Diagnosis: as in nonpregnant adults
 Oral or vaginal candidiasis: topical therapy preferred
 For invasive or refractory esophageal candidiasis in 1st
trimester, amphotericin B recommended (rather than
fluconazole or itraconazole)
 High-dose fluconazole and itraconazole: teratogenic in
animal studies; teratogenic effects not seen in infants
born to women receiving single doses
 Systemically absorbed azoles should not be used for
prophylaxis during pregnancy
 Anidulafungin, caspofungin, micafungin, posaconazole,
voriconazole are teratogenic in animals; no human data:
not recommended
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Cryptococcosis
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Epidemiology
Clinical Manifestations
Diagnosis
Prevention
Treatment
Considerations in Pregnancy
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Cryptococcosis: Epidemiology
 Caused by Cryptococcus neoformans
(occasionally Cryptococcus gattii)
 Most cases seen in patients with CD4 count
<100 cells/µL
 5-8% prevalence among HIV-infected patients in
developed countries before widespread use of
effective ART
 Incidence much lower with use of ART
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Cryptococcosis: Clinical
Manifestations
 Subacute meningitis or meningoencephalitis
(most common presentation)
 Fever, malaise, headache
 Neck stiffness, photophobia, or other classic meningeal
signs and symptoms in 25-35% of cases
 Lethargy, altered mental status, personality changes
(less common)
www.aidsetc.org
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Cryptococcosis: Clinical
Manifestations (2)
 Disseminated disease is common: any organ can
be involved
 Isolated pulmonary infection possible
 Cough, dyspnea, abnormal chest X ray
 Skin lesions
 Papules, nodules, ulcers, infiltrated plaques seen in
disseminated disease
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Cryptococcosis: Clinical Manifestations (3)
Skin lesions caused by Cryptococcus neoformans
Credit: © I-TECH
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Cryptococcosis: Diagnosis
 Detection of cryptococcal antigen (CrAg) in CSF,
serum, bronchoalveolar lavage fluid (can have falsenegative results)
 India ink stain (lower sensitivity)
 Culture of blood or CSF (blood culture positive in
55% of those with cryptococcal meningitis)
 Patients with positive serum CrAg should have CSF
evaluation to exclude CNS disease
 CSF findings
 Mildly elevated protein, normal or low glucose, pleocytosis
(mostly lymphocytes), many yeast (Gram or India ink stain)
 Elevated opening pressure (≥25 cm H2O in 60-80%)
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Cryptococcosis: Diagnosis (2)
Cerebrospinal fluid with C neoformans, India ink stain. Budding yeast indicated by arrow.
Credit: Images courtesy AIDS Images Library (www.aids-images.ch)
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Cryptococcosis: Prevention
 Preventing exposure
 Cryptococcus is ubiquitous in the environment, cannot
be avoided completely
 Exposure to bird droppings may increase risk of
infection
 Primary prophylaxis
 Routine screening (serum CrAg) not recommended
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Cryptococcosis: Prevention (2)
 Primary prophylaxis:
 Prophylaxis with fluconazole or itraconazole can
reduce risk in patients with CD4 <100 cells/µL
 Not recommended: incidence of disease is relatively
low; not proven to increase survival; issues of drug
interactions, resistance, cost
 Routine screening (serum CrAg) not recommended
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Cryptococcosis: Treatment
 Cryptococcal meningitis is fatal if not treated
 Treatment consists of 3 phases:
 Induction (at least 2 weeks plus clinical improvement)
 Consolidation (8 weeks or until CSF cultures are
sterile)
 Maintenance therapy (lifelong, unless immune
reconstitution on ART)
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Cryptococcosis: Treatment (2)
 Preferred:
 Induction (≥2 weeks):
 Liposomal amphotericin B 3-4 mg/kg IV QD + flucytosine 25
mg/kg PO QID
 Consolidation (≥ 8 weeks):
 Fluconazole 400 mg PO QD
 Maintenance (at least 1 year):
 Fluconazole 200 mg PO QD
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Cryptococcosis: Treatment (3)
 Alternative:
 Induction (≥2 weeks): :
 Amphotericin B lipid complex 5 mg/kg IV QD + flucytosine 25
mg/kg PO QID
 Amphotericin B deoxycholate 0.7-1.0 mg/kg IV QD + flucytosine
25 mg/kg PO QID
 Liposomal amphotericin B 3-4 mg/kg IV QD + fluconazole 800 mg
PO or IV QD
 Amphotericin deoxycholate 0.7-1.0 mg/kg IV QD + fluconazole
800 mg PO or IV QD
 Liposomal amphotericin B 3-4 mg/kg IV QD alone
 Fluconazole 400-800 mg PO or IV QD + flucytosine 25 mg/kg PO
QID for 4-6 weeks (inferior efficacy)
 Fluconazole 1,200 mg PO or IV QD alone
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Cryptococcosis: Treatment (4)
 Alternative:
 Consolidation (≥8 weeks):
 Itraconazole 200 mg PO BID
 Maintenance:
 No Alternatives are recommended (use fluconazole as in
Preferred)
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Cryptococcosis: Treatment (5)
 Flucytosine increases rate of CSF sterilization
during induction therapy
 Consolidation therapy should not be started until
≥2 weeks of successful induction therapy:
 Significant clinical improvement
 Negative CSF culture on repeat lumbar puncture
 Fluconazole more effective than itraconazole for
consolidation therapy
www.aidsetc.org
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64
Cryptococcosis: Treatment (6)
 Elevated intracranial pressure (ICP) associated with
cerebral edema, clinical deterioration, and higher risk
of death
 More likely if >25 cm H2O
 Opening pressure always should be measured when
lumbar puncture (LP) is performed
 Management of elevated ICP:
 Daily LP with removal of CSF, or CSF shunting if LP is not
effective or not tolerated
 Corticosteroids, mannitol, and acetazolamide are not
recommended
www.aidsetc.org
May 2013
65
Cryptococcosis: ART Initiation
 Optimal timing for ART initiation is not clear – small
studies have reported increased morbidity/mortality
with very early ART
 For patients with severe cryptococcal CNS disease
(especially if ICP is elevated), it may be prudent to
delay start of ART until induction or consolidation
phase is completed (2 or 10 weeks)
 For patients with advanced AIDS (CD4 <50 cells/µL),
earlier ART initiation may be needed
 If ART is started early, monitor closely for
signs/symptoms of IRIS (eg, elevated ICP)
www.aidsetc.org
May 2013
66
Cryptococcosis: Monitoring
 Repeat LP after initial 2 weeks of treatment to
check clearance of cryptococcus (CSF culture)
 Positive CSF cultures after 2 weeks of therapy predict
future relapse; some experts recommend amphoteracin
B + flucytosine until CSF cultures are negative
 If new symptoms or signs after 2 weeks of
treatment, repeat LP (opening pressure, CSF
culture)
 Serum and CSF CrAg titers do not correlate with
clinical response; monitoring is not useful in
management; not recommended
www.aidsetc.org
May 2013
67
Cryptococcosis: Adverse Events
 IRIS
 Up to 30% develop IRIS after initiation of ART
 Distinguishing from treatment failure may be difficult
(in treatment failure, usually cultures remain positive)
 Management: continue ART and antifungal therapy;
reduce ICP, if elevated
 If severe IRIS symptoms, consider short course of
corticosteroids
 Consider delaying initiation of ART at least
until completion of induction therapy
www.aidsetc.org
May 2013
68
Cryptococcosis: Adverse Events (2)
 Amphotericin toxicity
 Nephrotoxicity: azotemia, hypokalemia
 Mitigated by IV hydration before amphotericin B infusion
 Monitor electrolytes, creatinine
 Infusion related: chills, fever, headache, vomiting
 Mitigated by pretreatment with acetaminophen, diphenhydramine, or
corticosteroids




Rarely: hypotension, arrhythmia, neurotoxicity, hepatic toxicity
Flucytosine toxicity
Bone marrow: anemia, leukopenia, thrombocytopenia
Liver, GI, and renal toxicity (requires dosage adjustment for
renal dysfunction)
 Monitor blood levels or follow blood counts closely
www.aidsetc.org
May 2013
69
Cryptococcosis: Treatment Failure
 Lack of clinical improvement after 2 weeks of
appropriate therapy (including management of
elevated ICP), with positive cultures
 Relapse after initial clinical response
 Recurrence of symptoms, positive CSF culture after ≥4
weeks of treatment
www.aidsetc.org
May 2013
70
Cryptococcosis: Treatment Failure (2)
 Evaluation:
 Repeat LP to check for elevated ICP, culture
 Check for antifungal susceptibility
 Management:
 Optimal therapy not known; if failure on fluconazole, treat with
amphotericin B (with or without flucytosine); continue until clinical
response
 Consider liposomal amphotericin or amphotericin B lipid complex (may be
more effective)
 Consider higher dosage of fluconazole, combined with flucytosine
 Fluconazole resistance is rare
 Consider voriconazole, posaconazole if fluconazole resistance
 Echinocandins not recommended
www.aidsetc.org
May 2013
71
Cryptococcosis: Preventing
Recurrence
 Secondary prophylaxis:
 Lifelong suppressive treatment (after completion of initial
therapy), unless immune reconstitution on ART
 Preferred: fluconazole 200 mg QD
 Consider discontinuing maintenance therapy in
asymptomatic patients on ART with suppressed HIV
RNA and sustained increase in CD4 count to ≥100
cells/µL for >3 months, after ≥1 year of azole
antifungal chronic maintenance therapy
 Restart secondary prophylaxis if CD4 count
decreases to <100 cells/µL
www.aidsetc.org
May 2013
72
Cryptococcosis: Considerations in
Pregnancy
 Diagnosis: as in nonpregnant women; initiate
treatment promptly
 Treatment:
 Lipid formulations of amphotericin B are preferred for
initial treatment (to avoid potential teratogenicity of
azoles)
 If chronic amphotericin B at time of delivery: evaluate
neonate for renal dysfunction and hypokalemia
www.aidsetc.org
May 2013
73
Cryptococcosis: Considerations in
Pregnancy (2)
 Treatment:
 Flucytosine: teratogenic in animal studies; use only
when benefits outweigh fetal risks
 Fluconazole ≥400 mg/day through or beyond 1st
trimester is associated with congenital malformations;
FDA Pregnancy Category D; not recommended in 1st
trimester unless benefits clearly outweigh risks
www.aidsetc.org
May 2013
74
Cryptococcosis: Considerations in
Pregnancy (3)
 Treatment:
 Itraconazole: limited data, not recommended in 1st
trimester
 Voriconazole and posaconazole: teratogenic and
embryotoxic in animal studies; should be avoided
 Postpartum period may be high-risk period for
IRIS
www.aidsetc.org
May 2013
75
Histoplasmosis






Epidemiology
Clinical Manifestations
Diagnosis
Prevention
Treatment
Considerations in Pregnancy
www.aidsetc.org
May 2013
76
Histoplasmosis: Epidemiology
 Caused by Histoplasma capsulatum
 Endemic in midwest United States, Puerto Rico,
Latin America
 Occurs in up to 5% of HIV-infected individuals in
endemic areas
 In nonendemic areas, usually seen in those who
previously lived in endemic area
www.aidsetc.org
May 2013
77
Histoplasmosis: Epidemiology (2)
 Acquired by inhalation
 Risks include: working with surface soil, cleaning
chicken coops contaminated with droppings; disturbing
bird or bat droppings; exploring caves; cleaning,
remodeling, or demolishing old buildings
www.aidsetc.org
May 2013
78
Histoplasmosis: Epidemiology (3)
 Reactivation of latent infection may occur
 Systemic illness more likely in patients with CD4
count <150 cells/µL
 Pulmonary histoplasmosis may occur with CD4
count >300 cells/µL
 Incidence has declined with use of potent ART
www.aidsetc.org
May 2013
79
Histoplasmosis: Clinical
Manifestations
 Disseminated disease: fever, fatigue, weight loss,
hepatosplenomegaly
 Cough, chest pain, dyspnea in 50%
 Shock and multiorgan failure in 10%
 Most common in patients with low CD4 count
 Isolated pulmonary disease: usually occurs in
patients with CD4 count >300 cells/µL
 CNS, GI, and skin manifestations possible
 CNS: fever, headache, seizures, focal neurological deficits,
altered mental status
 GI: fever, diarrhea, abdominal pain, weight loss
www.aidsetc.org
May 2013
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Histoplasmosis: Clinical Manifestations (2)
Acute disseminated histoplasmosis, chest X ray (L) and CT scan (R)
www.aidsetc.org
May 2013
81
Histoplasmosis: Clinical Manifestations (3)
Skin lesions of histoplasmosis
Credit: Image courtesy AIDS Images Library (www.aids-images.ch)
www.aidsetc.org
May 2013
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Histoplasmosis: Diagnosis
 Detection of Histoplasma antigen in serum or
urine
 Sensitive for disseminated histoplasmosis and acute
pulmonary infection
 In disseminated disease, urine Ag test positive in up to 100%,
serum Ag test positive in up to 92%
 Ag detection in BAL fluid appears sensitive
 Insensitive for chronic pulmonary infection
 Biopsy with histopathologic examination shows
characteristic budding yeast
www.aidsetc.org
May 2013
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Histoplasmosis: Diagnosis (2)
 Culture from blood, bone marrow, respiratory
secretions, other involved sites (positive in >85%,
but may take 2-4 weeks)
 Serologic tests usually less useful in AIDS
patients with disseminated disease, may be
helpful in patients with higher CD4 counts and
pulmonary disease
www.aidsetc.org
May 2013
84
Histoplasmosis: Diagnosis (3)
 Diagnosis of meningitis may be difficult:
 CSF cultures and fungal stains ≤50% sensitive
 Antigen and antibody tests positive in up to 70% of
cases
 Consider presumptive diagnosis of Histoplasma
meningitis if patient has disseminated histoplasmosis
and CNS infection that is otherwise unexplained
 CSF findings: lymphocytic pleocytosis, elevated
protein, low glucose
www.aidsetc.org
May 2013
85
Histoplasmosis: Prevention
 Preventing exposure:
 In endemic areas, impossible to avoid exposure completely
 Avoid higher-risk activities if CD4 <150 cells/µL
 Primary prophylaxis
 Itraconazole can reduce frequency of disease in patients with
advanced HIV infection in highly endemic areas, but no survival
benefit
 Consider itraconazole 200 mg QD for patients with CD4 counts
<150 cells/µL who are at high risk of infection (occupational
exposure or hyperendemic area [>10 cases/100 patient-years])
 Discontinuing primary prophylaxis
 Discontinue when CD4 count ≥150 cells/µL for 6 months
on effective ART
www.aidsetc.org
May 2013
86
Histoplasmosis: Treatment
 Acute treatment consists of 2 phases: induction
and maintenance
 Total duration of therapy ≥12 months
www.aidsetc.org
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Histoplasmosis: Treatment (2)
 Disseminated histoplasmosis
 Moderate-severe disease
 Induction (2 weeks or until clinically improved):
 Preferred: liposomal amphotericin B 3 mg/kg IV QD
 Alternative:
 Amphotericin B lipid complex or cholesteryl sulfate complex 3 mg/kg IV
QD
 Maintenance: itraconazole 200 mg PO TID for 3 days, then
BID* (liquid formulation preferred)
 Duration of therapy: ≥12 months
* Adjust dosage based on interactions with ARVs and itraconazole
serum concentration
www.aidsetc.org
May 2013
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Histoplasmosis: Treatment (3)
 Disseminated histoplasmosis
 Less-severe disease
 Induction and maintenance
 Preferred: Itraconazole 200 mg PO TID for 3 days, then BID*
(liquid formulation preferred)
 Alternative (limited data):
 Posaconazole 400 mg PO BID
 Voriconazole 400 mg PO BID for 1 day, then 200 mg PO BID
 Fluconazole 800 mg PO QD
 Duration of therapy: ≥12 months
* Adjust dosage based on interactions with ARVs and itraconazole serum
concentration
www.aidsetc.org
May 2013
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Histoplasmosis: Treatment (4)
 Meningitis
 Preferred induction (4-6 weeks):
 Liposomal amphotericin B 5 mg/kg IV QD
 Preferred maintenance (≥12 months plus resolution
of CSF abnormalities):
 Itraconazole 200 mg PO BID or TID*
 Acute pulmonary histoplasmosis in patients with CD4
count >300 cells/µL
 Manage as in nonimmunocompromised
* Adjust dosage based on interactions with ARVs and itraconazole
serum concentration
www.aidsetc.org
May 2013
90
Histoplasmosis: Treatment (5)
 Other antifungals:
 Echinocandins: not active against H capsulatum;
should not be used
www.aidsetc.org
May 2013
91
Histoplasmosis: ART Initiation
 Start ART as soon as possible after starting
antifungal therapy
 IRIS appears to be uncommon
 Triazoles have complex, sometimes bidirectional
interactions with certain ARVs; dosage
adjustments may be needed
www.aidsetc.org
May 2013
92
Histoplasmosis: Monitoring and
Adverse Events
 Monitor serum or urine Histoplasma antigen:
useful for determining response to therapy
 Increase in level suggests relapse
 Check serum itraconazole levels after 2 weeks of
therapy or if potential drug interactions
(absorption of itraconazole can be erratic)
 IRIS is uncommon; ART should not be withheld
because of concern for IRIS
www.aidsetc.org
May 2013
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Histoplasmosis: Treatment Failure
 Use liposomal amphotericin B for severely ill
patients and those who do not respond to initial
azole therapy
 Consider posaconazole or voriconazole for
moderately ill patients intolerant of itraconazole
 Note: significant interactions between voriconazole and
NNRTIs or ritonavir
www.aidsetc.org
May 2013
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Histoplasmosis: Preventing
Recurrence
 Secondary prophylaxis:
 Long-term suppressive therapy for patients with severe
disseminated or CNS infection, after ≥12 months of treatment; and
in those who relapse despite appropriate therapy
 Preferred: itraconazole 200 mg PO
 Alternative: fluconazole 400 mg PO QD (less effective than
itraconazole)
 Voriconazole or posaconazole: no data
 May discontinue if: ≥12 months of itraconazole, and
negative blood cultures, and Histoplasma serum Ag <2
ng/mL, and CD4 count ≥150 cells/µL on ART for ≥6
months on ART
 Restart if CD4 count decreases to <150 cells/µL
www.aidsetc.org
May 2013
95
Histoplasmosis: Considerations in
Pregnancy
 Amphotericin B or its lipid formulations are
preferred initial regimen
 At delivery, evaluate neonate for renal dysfunction and
hypokalemia
 Azoles: avoid in 1st trimester--risk of
teratogenicity
 Voriconazole and posaconazole: teratogenic and
embryotoxic in animals: avoid throughout pregnancy
www.aidsetc.org
May 2013
96
Coccidioidomycosis






Epidemiology
Clinical Manifestations
Diagnosis
Prevention
Treatment
Considerations in Pregnancy
www.aidsetc.org
May 2013
97
Coccidioidomycosis: Epidemiology
 Caused by Coccidioides immitis and C posadasii
 Endemic in southwest United States, parts of Central
and South America
 Increased risk with extensive exposure to soil
 May cause disease via reactivation of previous
infection
 Disease may occur in those with no discernible
immunodeficiency
 Increased risk in HIV patients with CD4 count <250
cells/µL
 Incidence and severity lower after broader
use of ART
www.aidsetc.org
May 2013
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Coccidioidomycosis: Clinical
Manifestations
 Severity associated with lower CD4 counts, lack
of HIV suppression
 In HIV infection, 6 common syndromes:
 Focal pneumonia
 Diffuse pneumonia (presents like PCP)
 Cutaneous involvement
 Meningitis
 Liver or lymph node involvement
 Positive coccidioidal serology tests without evidence of
localized infections
www.aidsetc.org
May 2013
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Coccidioidomycosis: Clinical
Manifestations (2)
 Focal pneumonia most common if CD4 count
>250 cells/µL
 Other syndromes usually occur with more
advanced immunosuppression
 Meningitis: headache, progressive lethargy,
fever, nausea or vomiting, confusion
www.aidsetc.org
May 2013
100
Coccidioidomycosis: Manifestations
Chest X ray: disseminated coccidioidomycosis
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Coccidioidomycosis: Diagnosis
 Culture of clinical specimens
 Histopathology
 Blood cultures (positive in <50%)
 Coccidioidal IgM and IgG serology (EIA,
immunodiffusion, classical tube precipitin, complement
fixation): useful but poorer sensitivity in patients with low
CD4 counts
 CSF analysis: typically shows lymphocytic pleocytosis,
CSF glucose <50 mg/dL, CSF protein normal or mildly
elevated; complement fixation usually positive;
culture positive in <1/3
 Newer coccidioidomycosis-specific antigen assay:
detects antigen in urine and serum
www.aidsetc.org
May 2013
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Coccidioidomycosis: Prevention
 Preventing exposure
 In endemic areas, impossible to avoid exposure
completely
 HIV-infected persons: avoid extensive exposure to
disturbed soil in endemic areas (eg, excavation sites,
dust storms)
www.aidsetc.org
May 2013
103
Coccidioidomycosis: Prevention (2)
 Preventing disease
 Primary prophylaxis not recommended
 For HIV-infected persons in endemic regions: yearly
serologic testing is reasonable
 If new positive IgM or IgG serologic test and CD4 count <250
cells/µL
 Fluconazole 400 mg PO QD
 Outside endemic regions: routine testing not useful and
should not be done
www.aidsetc.org
May 2013
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Coccidioidomycosis: Treatment
 Treatment consists of 2 phases: induction and
maintenance
 Total duration of therapy ≥12 months
www.aidsetc.org
May 2013
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Coccidioidomycosis: Treatment (2)
 Severe nonmeningeal infection: diffuse pulmonary or
severely ill with disseminated disease
 Acute phase (continue until clinical improvement):
 Preferred:
 Amphotericin B deoxycholate 0.7-1.0 mg/kg IV QD
 Lipid-formulation amphotericin B 4-6 mg/kg IV QD
 Alternative: add fluconazole or itraconazole to amphotericin
B (itraconazole preferred for bone disease)
 Maintenance therapy (continue indefinitely)
 Fluconazole 400 mg PO QD
 Itraconazole 200 mg PO BID
www.aidsetc.org
May 2013
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Coccidioidomycosis: Treatment (3)
 Mild disease: focal pneumonia
 Preferred:
 Fluconazole 400 mg PO QD
 Itraconazole 200 mg PO BID
 Alternative (limited data):
 Posaconazole 200-400 mg PO BID
 Voriconazole 200 mg PO BID
www.aidsetc.org
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Coccidioidomycosis: Treatment (4)
 Meningeal infection
 Consult with specialist
 Acute phase
 Preferred: fluconazole 400-800 mg IV or PO QD
 Alternative:




Itraconazole 200 mg PO BID
Posaconazole 200-400 mg PO BID
Voriconazole 200-400 mg PO BID
Intrathecal amphotericin B if azoles not effective
 Hydrocephalus may develop: may need CSF shunt
 Lifelong therapy required: relapse in 80% of HIV
patients with azole therapy discontinued
www.aidsetc.org
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Coccidioidomycosis: ART Initiation
 Start ART as soon as possible after start of
antifungal therapy
 IRIS has been reported (1 case)
 Triazoles have complex, sometimes bidirectional
interactions with certain ARVs; dosage
adjustments may be needed
www.aidsetc.org
May 2013
109
Coccidioidomycosis: Monitoring and
Adverse Events
 Monitor complement-fixing antibody every 12
weeks: useful in assessing response to therapy
 Increase in titer suggests recurrence or worsening –
reassess management
 IRIS: 1 reported case
www.aidsetc.org
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Coccidioidomycosis: Treatment
Failure
 Failure of fluconazole or itraconazole:
 Severely ill: amphotericin B (deoxycholate or lipid
formulation)
 Not severely ill: consider posaconazole 200 mg PO BID
or voriconazole 200 mg PO BID (limited data for both)
 Note: significant interactions between voriconazole and
NNRTIs or ritonavir
www.aidsetc.org
May 2013
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Coccidioidomycosis: Preventing
Recurrence
 Consider lifelong suppressive therapy if CD4
count remains <250 cells/µL
 Preferred:
 Fluconazole 400 mg PO QD
 Itraconazole 200 mg PO BID
 Alternative (if patient did not initially respond to
fluconazole or itraconazole):
 Posaconazole 200 mg PO BID
 Voriconazole 200 mg PO BID
www.aidsetc.org
May 2013
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Coccidioidomycosis: Preventing
Recurrence (2)
 Discontinuing secondary prophylaxis:
 Focal pneumonia:
 May discontinue after 12 months of therapy if CD4 ≥250 cells/µL
on effective ART
 Monitor for recurrence (serial chest X rays and coccidioidal
serology)
 Diffuse pulmonary or nonmeningeal disseminated
disease:
 Relapses in >25% of cases, even in HIV-uninfected patients
 Some would continue therapy indefinitely; consult with expert
 Meningitis:
 Relapses in 80%
 Continue therapy lifelong
www.aidsetc.org
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Coccidioidomycosis: Considerations
in Pregnancy
 More likely to disseminate if acquired during 2nd
or 3rd trimester
 Amphoteracin B or its lipid formulations are
preferred initial regimen
 At delivery, evaluate neonate for renal dysfunction and
hypokalemia
www.aidsetc.org
May 2013
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Coccidioidomycosis: Considerations
in Pregnancy (2)
 Azoles: avoid in 1st trimester--risk of
teratogenicity
 Coccidioidal meningitis:
 Only alternative to azoles is intrathecal amphotericin B
 Choice of treatment should be based on risk/benefit
considerations and in consultation with the mother and with
infectious disease and obstetric experts
 Voriconazole and posaconazole: teratogenic and
embryotoxic in animals: avoid throughout pregnancy
www.aidsetc.org
May 2013
115
Aspergillosis






Epidemiology
Clinical Manifestations
Diagnosis
Prevention
Treatment
Considerations in Pregnancy
www.aidsetc.org
May 2013
116
Aspergillosis: Epidemiology
 Caused by Aspergillus fumigatus, occasionally by
other Aspergillus species
 Invasive aspergillosis is rare in HIV-infected
persons
 Risk factors: low CD4 count (<100 cells/µL),
neutropenia, use of corticosteroids, exposure to
broad-spectrum antibiotics, underlying lung
disease
 Less common with widespread use of potent
ART
www.aidsetc.org
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Aspergillosis: Clinical Manifestations
 Respiratory
 Invasive pneumonia: fever, cough, dyspnea, chest
pain, hemoptysis, hypoxemia; on CXR, diffuse, focal, or
cavitary infiltrates, “halo” of low attenuation around a
pulmonary nodule (or “air crescent” on CT)
 Tracheobronchitis: fever, cough, dyspnea, stridor,
wheezing, airway obstruction; tracheal
pseudomembrane (multiple ulcerative or plaque-like
lesions) seen on bronchoscopy
 Other extrapulmonary forms include: sinusitis,
cutaneous disease, osteomyelitis
www.aidsetc.org
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Aspergillosis: Diagnosis
 Definitive diagnosis:
 Histopathology: tissue invasion by septate hyphae, with
positive culture for Aspergillus spp
 Probable diagnosis of invasive pulmonary
disease:
 Isolation of Aspergillus spp from respiratory secretions
or septate hyphae consistent with Aspergillus in
respiratory samples, with typical CT findings
 ELISA test for galactomannan: sensitivity better for BAL
than for serum; high specificity; not well studied in HIV
www.aidsetc.org
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Aspergillosis: Preventing Disease
 Preventing exposure:
 Aspergillus spp are ubiquitous in the environment;
exposure is not avoidable
 Avoid dusty environments to decrease exposure to
spores
 Preventing disease
 No data in HIV-infected persons; currently not
recommended
 Posaconazole effective in patients with certain
hematologic malignancies and neutropenia
www.aidsetc.org
May 2013
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Aspergillosis: Treatment
 Not systematically evaluated in HIV-infected
patients
 Preferred:
 Voriconazole 6 mg/kg IV Q12H for 1 day, then 4 mg/kg
IV Q12H until clinical improvement, then 200 mg PO
Q12H
 Significant interactions with protease inhibitors and efavirenz
 Duration of therapy: not established; continue at
least until CD4 >200 cells/µL and infection
appears resolved
www.aidsetc.org
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Aspergillosis: Treatment (2)
 Alternative:






Lipid formulation amphotericin B 5 mg/kg IV QD
Amphotericin B deoxycholate 1 mg/kg IV QD
Caspofungin 70 mg IV for 1 dose, then 50 mg IV QD
Micafungin 100-150 mg IV QD
Anidulafungin 200 mg IV for 1 dose, then 100 mg IV QD
Posaconazole 200 mg PO 4 times per day until clinical
improvement, then 400 mg PO BID
 Duration of therapy: not established; continue at
least until CD4 >200 cells/µL and infection appears
resolved
www.aidsetc.org
May 2013
122
Aspergillosis: ART Initiation
 Start ART as soon as possible after start of
antifungal therapy
 IRIS has rarely been reported
 Triazoles have complex, sometimes bidirectional
interactions with certain ARVs; dosage
adjustments may be needed
www.aidsetc.org
May 2013
123
Aspergillosis: Monitoring and Adverse
Events
 If new or recurrent signs and symptoms, evaluate
for relapse or recurrence
 IRIS reported rarely
 Limited data regarding monitoring of
galactomannan levels in response to therapy
www.aidsetc.org
May 2013
124
Aspergillosis: Treatment Failure
 Prognosis is poor in advanced
immunosuppression without effective ART
 No data to guide management of treatment
failure
 If voriconazole used initially, consider change to
amphotericin B, or echinocandins in combination
with voriconazole or amphotericin B
www.aidsetc.org
May 2013
125
Aspergillosis: Preventing Recurrence
 Chronic maintenance: insufficient data to
recommend for or against
www.aidsetc.org
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126
Aspergillosis: Considerations in
Pregnancy
 Amphotericin B or its lipid formulations are
preferred initial regimen
 At delivery, evaluate neonate for renal dysfunction and
hypokalemia
 Voriconazole and posaconazole: teratogenic and
embryotoxic in animals; generally avoid in
pregnancy, especially 1st trimester
 Echinocandins: bone and visceral abnormalities
in animals; avoid in 1st trimester
www.aidsetc.org
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127
Online Access the Guidelines
 AIDS Info: http://aidsinfo.nih.gov
www.aidsetc.org
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About This Slide Set
 This presentation was prepared by Susa Coffey,
MD, for the AETC National Resource Center in
May 2013
 See the AETC NCRC website for the most
current version of this presentation:
http://www.aidsetc.org
www.aidsetc.org
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