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Guidelines for Prevention and Treatment of
Opportunistic Infections in HIV-Infected
Adults and Adolescents
Fungal Infections Slide Set
Prepared by the AETC National 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become out of date quickly.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 Resource Center
http://www.aidsetc.org
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Fungal Infections
 Pneumocystis jiroveci pneumonia
 Mucocutaneous candidiasis
 Cryptococcosis
 Histoplasmosis
 Coccidiomycosis
 Aspergillosis
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Fungal Infections
Pneumocystis jiroveci pneumonia
Pneumocystis jiroveci Pneumonia:
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 and
effective ART, PCP seen in 70-80% of AIDS
patients in the United States
 In advanced immunosuppression, treated PCP
associated with 20-40% mortality
 Substantial decline in incidence in United
States and Western 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
 Recurrent bacterial
pneumonia
 CD4 percentage
<14%
 Unintentional
weight loss
 Prior PCP
 High HIV RNA
 Oral thrush
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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)
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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; HIV InSite
Credit: HIV Web Study, www.hivwebstudy.
org, © 2006 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
 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
 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 highrisk 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 lifethreatening 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 TMPSMX 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 and 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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Fungal Infections
Mucocutaneous Candidiasis
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)
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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 solution 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
 have significant drug interactions with certain ARV medications; consult
* May
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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

Voriconazole* 200 mg PO BID

Posaconazole* 400 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
maintenance 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 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
 Stopping secondary prophylaxis:
 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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Fungal Infections
Cryptococcosis
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)
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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 false-negative
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
 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 (2)
 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 (3)
 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 (4)
 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
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Cryptococcosis: Treatment (5)
 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
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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)
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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
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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
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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
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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
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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
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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
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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
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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
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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
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Cryptococcosis:
Considerations in Pregnancy (4)
 Postpartum period may be high-risk period
for IRIS
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Fungal Infections
Histoplasmosis
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
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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
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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
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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
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Histoplasmosis: Clinical Manifestations (2)
Acute disseminated histoplasmosis, chest X ray (L) and CT scan (R)
Credit: Images courtesy AIDS Images Library (www.aids-images.ch)
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Histoplasmosis: Clinical Manifestations (3)
Skin lesions of
histoplasmosis
Credit: Image courtesy AIDS Images Library (www.aids-images.ch)
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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
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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
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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
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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
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Histoplasmosis: Treatment
 Acute treatment consists of 2 phases:
induction and maintenance
 Total duration of therapy ≥12 months
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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
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* Adjust dosage based on interactions with ARVs and itraconazole
serum concentration
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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
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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
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* Adjust dosage based on interactions with ARVs and
itraconazole serum concentration
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Histoplasmosis: Treatment (5)
 Other antifungals:
 Echinocandins: not active against H
capsulatum; should not be used
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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
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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
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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
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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
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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
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Fungal Infections
Coccidioidomycosis
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
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Coccidioidomycosis:
Clinical Manifestations
 Severity associated with lower CD4
counts, lack of HIV suppression
 In HIV infection, 6 common syndromes:






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Focal pneumonia
Diffuse pneumonia (presents like PCP)
Cutaneous involvement
Meningitis
Liver or lymph node involvement
Positive coccidioidal serology tests without
evidence of localized infections
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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
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Coccidioidomycosis: Manifestations
Chest X ray: disseminated coccidioidomycosis
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Credit: Huang L, MD; HIV InSite
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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
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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)
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Coccidioidomycosis: Prevention
 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
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Coccidioidomycosis: Treatment
 Treatment consists of 2 phases:
induction and maintenance
 Total duration of therapy ≥12 months
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Coccidioidomycosis: Treatment
 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
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Coccidioidomycosis: Treatment (2)
 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
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Coccidioidomycosis: Treatment (3)
 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
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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
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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
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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
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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
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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
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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
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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
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Fungal Infections
Aspergillosis
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
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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
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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
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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
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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
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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
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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
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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
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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
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Aspergillosis: Preventing Recurrence
 Chronic maintenance: insufficient
data to recommend for or against
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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
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Websites to Access the Guidelines
 http://www.aidsetc.org
 http://aidsinfo.nih.gov
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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 NRC website for the most
current version of this presentation:
http://www.aidsetc.org
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