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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Users are cautioned that, owing to the rapidly changing field of HIV care, this information could become out of date quickly.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

May 2013 www.aidsetc.org

Fungal Infections



Pneumocystis jiroveci

pneumonia  Mucocutaneous candidiasis  Cryptococcosis  Histoplasmosis  Coccidiomycosis  Aspergillosis

May 2013 www.aidsetc.org

Fungal Infections

Pneumocystis jiroveci

pneumonia

Pneumocystis jiroveci

Epidemiology Pneumonia:    Caused by

P jiroveci

(formerly Ubiquitous in the environment

P carinii

 Initial infection usually occurs in early childhood  PCP may result from reactivation or new exposure In immunosuppressed patients, possible airborne spread )

May 2013 www.aidsetc.org

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)

May 2013 www.aidsetc.org

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

May 2013 www.aidsetc.org

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 (PO mmHg) 2 <70 mmHg or A-a gradient >35 LDH >500 mg/dL is common but nonspecific 1,3 β-D-glycan may be elevated; uncertain sensitivity and specificity

May 2013 www.aidsetc.org

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 Credit: L. Huang, MD; HIV InSite Chest X ray: PCP with bilateral perihilar opacities, interstitial prominence, hyperlucent cystic lesions Credit: HIV Web Study, www.hivwebstudy. org, © 2006 University of Washington

May 2013 www.aidsetc.org

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

May 2013 www.aidsetc.org

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 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)

May 2013 www.aidsetc.org

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*   Aerosolized pentamidine 300 mg Q month via Respirgard II nebulizer (other devices not recommended)  Dapsone 200 mg + pyrimethamine 75 mg + leucovorin 25 mg, all Q week* Atovaquone 1,500 mg PO QD* * Effective as toxoplasmosis prophylaxis (for CD4 count <100 cells/µL + positive serology)

May 2013 www.aidsetc.org

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

May 2013 www.aidsetc.org

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

May 2013 www.aidsetc.org

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

May 2013 www.aidsetc.org

PCP:

Treatment (4)  Adjunctive:  Corticosteroids  For moderate-to-severe disease (room air PO 2 <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

May 2013 www.aidsetc.org

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

May 2013 www.aidsetc.org

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

May 2013 www.aidsetc.org

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

May 2013 www.aidsetc.org

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

May 2013 www.aidsetc.org

Mucocutaneous Candidiasis:

Clinical Manifestations (2) Pseudomembranous candidiasis

Credit: Pediatric AIDS Pictorial Atlas, Baylor International Pediatric AIDS Initiative Erythematous candidiasis 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

May 2013 www.aidsetc.org

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

May 2013 www.aidsetc.org

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 .

*  information on drug interactions before coadministering with ARVs.

May 2013 www.aidsetc.org

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.

May 2013 www.aidsetc.org

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

May 2013 www.aidsetc.org

Mucocutaneous Candidiasis:

Initiation ART  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

May 2013 www.aidsetc.org

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

May 2013 www.aidsetc.org

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)

May 2013 www.aidsetc.org

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

May 2013 www.aidsetc.org

Fungal Infections

Cryptococcosis

Cryptococcosis:

Epidemiology   Most cases seen in patients with CD4 count <100 cells/µL  Caused by

Cryptococcus neoformans

(occasionally

Cryptococcus gattii

) 5-8% prevalence among HIV-infected patients in developed countries before widespread use of effective ART  Incidence much lower with use of ART

May 2013 www.aidsetc.org

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)

May 2013 www.aidsetc.org

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 H 2 O in 60-80%)

May 2013 www.aidsetc.org

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)

May 2013 www.aidsetc.org

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

May 2013 www.aidsetc.org

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

May 2013 www.aidsetc.org

Cryptococcosis:

Treatment  Cryptococcal meningitis is fatal if not treated  Treatment consists of 3 phases:   Consolidation (8 weeks or until CSF cultures are sterile)  Induction (at least 2 weeks

plus

improvement) clinical Maintenance therapy (lifelong, unless immune reconstitution on ART)

May 2013 www.aidsetc.org

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

May 2013 www.aidsetc.org

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

May 2013 www.aidsetc.org

Cryptococcosis:

Treatment (3)  Alternative:  Consolidation ( ≥8 weeks):  Itraconazole 200 mg PO BID  Maintenance:  No Alternatives are recommended (use fluconazole as in Preferred)

May 2013 www.aidsetc.org

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

May 2013 www.aidsetc.org

Cryptococcosis:

Treatment (5)

  Elevated intracranial pressure (ICP) associated with cerebral edema, clinical deterioration, and higher risk of death  More likely if >25 cm H 2 O 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

May 2013 www.aidsetc.org

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)

May 2013 www.aidsetc.org

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

May 2013 www.aidsetc.org

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

May 2013 www.aidsetc.org

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

May 2013 www.aidsetc.org

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

May 2013 www.aidsetc.org

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

May 2013 www.aidsetc.org

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

May 2013 www.aidsetc.org

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

May 2013 www.aidsetc.org

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

May 2013 www.aidsetc.org

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

May 2013 www.aidsetc.org

Cryptococcosis:

Considerations in Pregnancy (4)  Postpartum period may be high-risk period for IRIS

May 2013 www.aidsetc.org

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

May 2013 www.aidsetc.org

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

May 2013 www.aidsetc.org

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

or urine antigen in serum  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

May 2013 www.aidsetc.org

Histoplasmosis:

Diagnosis (3)  Diagnosis of meningitis may be difficult:   Antigen and antibody tests positive in up to 70% of cases  CSF cultures and fungal stains ≤50% sensitive 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

May 2013 www.aidsetc.org

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

May 2013 www.aidsetc.org

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

* Adjust dosage based on interactions with ARVs and itraconazole serum concentration

May 2013 www.aidsetc.org

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

May 2013 www.aidsetc.org

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

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Histoplasmosis:

Treatment (5)  Other antifungals:  Echinocandins: not active against

H capsulatum

; should not be used

May 2013 www.aidsetc.org

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

May 2013 www.aidsetc.org

Histoplasmosis:

Events Monitoring and Adverse  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

May 2013 www.aidsetc.org

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

May 2013 www.aidsetc.org

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

May 2013 www.aidsetc.org

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

May 2013 www.aidsetc.org

Fungal Infections

Coccidioidomycosis

Coccidioidomycosis:

Epidemiology

       Caused by

Coccidioides immitis

and

posadasii C

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

May 2013 www.aidsetc.org

Coccidioidomycosis

: Clinical Manifestations

100

 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

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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

May 2013 www.aidsetc.org

Coccidioidomycosis:

Manifestations

102

Chest X ray: disseminated coccidioidomycosis Credit: Huang L, MD; HIV InSite

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Coccidioidomycosis

: Diagnosis

103

    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

May 2013 www.aidsetc.org

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

May 2013 www.aidsetc.org

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

: Pregnancy Considerations in  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

May 2013 www.aidsetc.org

Coccidioidomycosis

: Pregnancy (2) Considerations in  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

118

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

May 2013 www.aidsetc.org

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

122

 Duration of therapy: not established; continue at least until CD4 >200 cells/µL and infection appears resolved

May 2013 www.aidsetc.org

Aspergillosis

: Treatment (2)

123

 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

May 2013 www.aidsetc.org

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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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126

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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127

Aspergillosis:

Preventing Recurrence  Chronic maintenance: insufficient data to recommend for or against

May 2013 www.aidsetc.org

Aspergillosis:

Considerations in Pregnancy

128

 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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129

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

May 2013 www.aidsetc.org