1. 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

2. About This Presentation
These slides were developed using recommendations published in May 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Users are cautioned that, owing to the rapidly changing field of HIV care, this information could become out of date quickly.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
May 2013

3. Fungal Infections Pneumocystis jiroveci pneumonia
Mucocutaneous candidiasis
Cryptococcosis
Histoplasmosis
Coccidiomycosis
Aspergillosis
May 2013

4. Fungal Infections
Pneumocystis jiroveci pneumonia

5. 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
May 2013

6. 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

7. 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
May 2013

8. 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

9. 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
May 2013

10. 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)
May 2013

11. PCP: Diagnosis (3) Chest CT, thin-section Gallium scan
Patchy ground-glass attenuation
May be normal
Gallium scan
Pulmonary uptake
May 2013

12. 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, org, © 2006 University of Washington
May 2013

13. 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

14. 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 %)
Open-lung biopsy (sensitivity %)
PCR: high sensitivity for BAL sample; may not distinguish disease from colonization
May 2013

15. 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
May 2013

16. PCP: Diagnosis
Treatment may be initiated before definitive diagnosis is established
Organism persists for days/weeks after start of treatment
May 2013

17. 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
May 2013

18. PCP: Primary Prophylaxis
Initiate:
CD4 <200 cells/µL or history of oropharyngeal candidiasis
Consider for:
CD4% <14% or history of AIDS-defining illness
CD 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
May 2013

19. 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

20. 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)
May 2013

21. PCP: Treatment Duration: 21 days for all treatment regimens
Preferred: TMP-SMX is treatment of choice
Moderate-severe PCP
TMP-SMX: mg/kg/day TMP and 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

22. 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

23. 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

24. 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
May 2013

25. 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
May 2013

26. PCP: Monitoring and Adverse Events
Monitor closely for response to treatment, and for adverse effects of treatment
May 2013

27. 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

28. 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
May 2013

29. 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
May 2013

30. 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

31. 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
May 2013

32. 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

33. 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
May 2013

34. 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
May 2013

35. Mucocutaneous Candidiasis
Fungal Infections
Mucocutaneous Candidiasis

36. 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
November 2014

37. 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
November 2014

38. 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
November 2014

39. Mucocutaneous Candidiasis: Clinical Manifestations (3)
Esophageal candidiasis
Credit: P. Volberding, MD; UCSF Center for HIV Information Image Library
November 2014

40. 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
November 2014

41. 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
November 2014

42. Mucocutaneous Candidiasis: Treatment
Oropharyngeal
Preferred (7-14 days)
Fluconazole 100 mg PO QD
Clotrimazole troches 10 mg PO 5 times daily
Miconazole mucoadhesive buccal tablet 50 mg QD to canine fossa
Alternative
Itraconazole* oral solution 200 mg PO QD
Posaconazole* oral suspension 400 mg PO BID x 1, then 400 mg QD
Nystatin suspension 4-6 mL QID or 1-2 flavored pastilles 4-5 times daily
* May have significant drug interactions with certain ARV medications; consult information on drug interactions before coadministering with ARVs. .
November 2014

43. 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
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.
November 2014

44. 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 mg PO or topical antifungal for ≥7 days
November 2014

45. Mucocutaneous Candidiasis: ART Initiation
No special considerations regarding ART initiation
November 2014

46. 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
November 2014

47. 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
November 2014

48. Mucocutaneous Candidiasis: Preventing Recurrence
ART and immune reconstitution reduce recurrences
For oropharyngeal or vulvovaginal, chronic suppressive therapy generally not recommended
If frequent or severe recurrences, consider fluconazole 100 mg PO QD or TIW (oral); fluconazole 150 mg PO weekly (vaginal)
For esophageal, consider fluconazole mg PO QD or posaconazole suspension 400 mg PO BID
Azole-refractory oropharyngeal or esophageal candidiasis: recommended until immune reconstitution on ART (if responded to echinocandins, voriconazole, or posaconazole)
November 2014

49. Mucocutaneous Candidiasis: Preventing Recurrence
Stopping chronic suppressive therapy:
No data; reasonable to stop when CD4 >200 cells/µL after ART initiation
November 2014

50. 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
November 2014

51. Fungal Infections
Cryptococcosis

52. 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
May 2013

53. 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

54. 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
May 2013

55. Cryptococcosis: Clinical Manifestations (3)
Skin lesions caused by Cryptococcus neoformans
Credit: © I-TECH
May 2013

56. 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%)
May 2013

57. Cryptococcosis: Diagnosis (2)
Cerebrospinal fluid with C neoformans, India ink stain. Budding yeast indicated by arrow.
Credit: Images courtesy AIDS Images Library (
May 2013

58. 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

59. 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

60. 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)
May 2013

61. 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

62. 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 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 mg/kg IV QD + fluconazole 800 mg PO or IV QD
Liposomal amphotericin B 3-4 mg/kg IV QD alone
Fluconazole 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

63. Cryptococcosis: Treatment (3)
Alternative:
Consolidation (≥8 weeks):
Itraconazole 200 mg PO BID
Maintenance:
No Alternatives are recommended (use fluconazole as in Preferred)
May 2013

64. 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

65. 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
May 2013

66. 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

67. 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

68. 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

69. 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

70. 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

71. 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

72. 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

73. 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

74. 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

75. 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

76. Cryptococcosis: Considerations in Pregnancy (4)
Postpartum period may be high-risk period for IRIS
May 2013

77. Fungal Infections
Histoplasmosis

78. 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

79. 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

80. 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
May 2013

81. 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
May 2013

82. Histoplasmosis: Clinical Manifestations (2)
Acute disseminated histoplasmosis, chest X ray (L) and CT scan (R)
Credit: Images courtesy AIDS Images Library (
May 2013

83. Histoplasmosis: Clinical Manifestations (3)
Skin lesions of histoplasmosis
Credit: Image courtesy AIDS Images Library (
May 2013

84. 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
May 2013

85. 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

86. 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
May 2013

87. 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

88. Histoplasmosis: Treatment
Acute treatment consists of 2 phases: induction and maintenance
Total duration of therapy ≥12 months
May 2013

89. 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

90. 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

91. 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
May 2013

92. Histoplasmosis: Treatment (5)
Other antifungals:
Echinocandins: not active against H capsulatum; should not be used
May 2013

93. 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

94. 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
May 2013

95. 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

96. 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

97. 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

98. Fungal Infections
Coccidioidomycosis

99. 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
May 2013

100. Coccidioidomycosis: Clinical Manifestations
Severity associated with lower CD4 counts, lack of HIV suppression
In HIV infection, 6 common syndromes:
Focal pneumonia
Diffuse pneumonia (presents like PCP)
Cutaneous involvement
Meningitis
Liver or lymph node involvement
Positive coccidioidal serology tests without evidence of localized infections
May 2013

101. 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

102. Coccidioidomycosis: Manifestations
Chest X ray: disseminated coccidioidomycosis
Credit: Huang L, MD; HIV InSite
May 2013

103. 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
May 2013

104. 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)
May 2013

105. 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
May 2013

106. Coccidioidomycosis: Treatment
Treatment consists of 2 phases: induction and maintenance
Total duration of therapy ≥12 months
May 2013

107. Coccidioidomycosis: Treatment
Severe nonmeningeal infection: diffuse pulmonary or severely ill with disseminated disease
Acute phase (continue until clinical improvement):
Preferred:
Amphotericin B deoxycholate 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
May 2013

108. Coccidioidomycosis: Treatment (2)
Mild disease: focal pneumonia
Preferred:
Fluconazole 400 mg PO QD
Itraconazole 200 mg PO BID
Alternative (limited data):
Posaconazole mg PO BID
Voriconazole 200 mg PO BID
May 2013

109. Coccidioidomycosis: Treatment (3)
Meningeal infection
Consult with specialist
Acute phase
Preferred: fluconazole mg IV or PO QD
Alternative:
Itraconazole 200 mg PO BID
Posaconazole mg PO BID
Voriconazole 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
May 2013

110. 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
May 2013

111. 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
May 2013

112. 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
May 2013

113. 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
May 2013

114. 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
May 2013

115. 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
May 2013

116. 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
May 2013

117. 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
May 2013

119. 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
May 2013

120. 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
May 2013

121. 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

122. 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
May 2013

123. 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 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
May 2013

124. 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

125. 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
May 2013

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
May 2013

127. Aspergillosis: Preventing Recurrence
Chronic maintenance: insufficient data to recommend for or against
May 2013

128. 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
May 2013

129. Websites to Access the Guidelines
May 2013

130. 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:
May 2013