1. Prepared by the AETC National Coordinating Resource Center based on recommendations from the CDC, National Institutes of Health, and HIV Medicine Association/Infectious Diseases Society of America Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents Fungal Infections Slide Set

2. These slides were developed using recommendations published in May 2013. The intended audience is clinicians involved in the care of patients with HIV. Users are cautioned that, owing to the rapidly changing field of HIV care, this information could become out of date quickly. Finally, it is intended that these slides be used as prepared, without changes in either content or attribution. Users are asked to honor this intent. -AETC National Coordinating Resource Center http://www.aidsetc.org About This Presentation May 2013www.aidsetc.org 2

3.  Pneumocystis jiroveci pneumonia  Mucocutaneous candidiasis  Cryptococcosis  Histoplasmosis  Coccidiomycosis  Aspergillosis Fungal Infections May 2013www.aidsetc.org 3

4.  Epidemiology  Clinical Manifestations  Diagnosis  Prevention  Treatment  Considerations in Pregnancy Pneumocystis jiroveci Pneumonia (PCP) May 2013www.aidsetc.org 4

5.  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 PCP: Epidemiology May 2013www.aidsetc.org 5

6.  Before widespread use of PCP prophylaxis & effective ART, PCP seen in 70-80% of AIDS patients in the U.S.  In advanced immunosuppression, treated PCP associated with 20-40% mortality  Substantial decline in incidence in U.S. & W. Europe, owing to prophylaxis and ART  Most cases occur in patients unaware of their HIV infection, in those who are not in care, and in those with advanced AIDS (CD4 count <100 cells/µL) PCP: Epidemiology (2) May 2013www.aidsetc.org 6

7. Risk factors:  CD4 count <200 cells/µL  CD4 percentage <14%  Prior PCP  Oral thrush  Recurrent bacterial pneumonia  Unintentional weight loss  High HIV RNA PCP: Epidemiology (3) May 2013www.aidsetc.org 7

8.  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 PCP: Clinical Manifestations May 2013www.aidsetc.org 8

9.  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 35 mmHg)  LDH >500 mg/dL is common but nonspecific  1,3β-D-glycan may be elevated; uncertain sensitivity and specificity PCP: Diagnosis May 2013www.aidsetc.org 9

10.  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) PCP: Diagnosis (2) May 2013www.aidsetc.org 10

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

12. May 2013www.aidsetc.org 12 Chest X ray: PCP with bilateral perihilar opacities, interstitial prominence, hyperlucent cystic lesions. (Credit: HIV Web Study, hivwebstudy.org, © University of Washington) Chest X ray: PCP with bilateral, diffuse granular opacities. (Credit: L. Huang, MD; HIVInSite) PCP: Diagnosis (Imaging)

13. 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 PCP: Diagnosis (Imaging) (2) May 2013www.aidsetc.org 13

14.  Definitive diagnosis requires demonstrating organism:  Induced sputum (sensitivity 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 PCP: Diagnosis (4) May 2013www.aidsetc.org 14

15. Lung biopsy using silver stain to demonstrate P jiroveci organisms in tissue Credit: A. Ammann, MD; UCSF Center for HIV Information Image Library PCP: Diagnosis (Histopathology) May 2013www.aidsetc.org 15

16.  Treatment may be initiated before definitive diagnosis is established  Organism persists for days/weeks after start of treatment PCP: Diagnosis (5) May 2013www.aidsetc.org 16

17.  Insufficient data to support isolation as a standard practice, but data suggest high-risk patients may benefit from isolation from persons with known PCP PCP: Preventing Exposure May 2013www.aidsetc.org 17

18.  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 PCP: Primary Prophylaxis May 2013www.aidsetc.org 18

19.  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) PCP: Primary Prophylaxis (2) May 2013www.aidsetc.org 19

20.  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) PCP: Primary Prophylaxis (3) May 2013www.aidsetc.org 20

21.  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 PCP: Treatment May 2013www.aidsetc.org 21

22.  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 PCP: Treatment (2) May 2013www.aidsetc.org 22

23.  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 PCP: Treatment (3) May 2013www.aidsetc.org 23

24.  Adjunctive:  Corticosteroids  For moderate-to-severe disease (room air PO2 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 PCP: Treatment (4) May 2013www.aidsetc.org 24

25.  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 PCP: ART Initiation May 2013www.aidsetc.org 25

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

27.  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 PCP: Monitoring & Adverse Events (2) May 2013www.aidsetc.org 27

28.  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 PCP: Treatment Failure May 2013www.aidsetc.org 28

29.  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 PCP: Treatment Failure (2) May 2013www.aidsetc.org 29

30.  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 PCP: Preventing Recurrence May 2013www.aidsetc.org 30

31.  Discontinue secondary prophylaxis for patients on ART with sustained increase in CD4 count from 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 PCP: Preventing Recurrence (2) May 2013www.aidsetc.org 31

32.  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 PCP: Considerations in Pregnancy May 2013www.aidsetc.org 32

33.  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 PCP: Considerations in Pregnancy (2) May 2013www.aidsetc.org 33

34.  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 PCP: Considerations in Pregnancy (3) May 2013www.aidsetc.org 34

35. May 2013www.aidsetc.org 35  Epidemiology  Clinical Manifestations  Diagnosis  Prevention  Treatment  Considerations in Pregnancy Mucocutaneous Candidiasis

36.  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 Mucocutaneous Candidiasis: Epidemiology May 2013www.aidsetc.org 36

37.  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 Mucocutaneous Candidiasis: Clinical Manifestations May 2013www.aidsetc.org 37

38. May 2013www.aidsetc.org 38 Erythematous candidiasis Credit: D. Greenspan, DSC, BDS; HIV InSite Pseudomembranous candidiasis Credit: Pediatric AIDS Pictorial Atlas, Baylor International Pediatric AIDS Initiative Mucocutaneous Candidiasis: Clinical Manifestations (2)

39. May 2013www.aidsetc.org 39 Esophageal candidiasis Credit: P. Volberding, MD; UCSF Center for HIV Information Image Library Mucocutaneous Candidiasis: Clinical Manifestations (3)

40.  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 Mucocutaneous Candidiasis: Diagnosis May 2013www.aidsetc.org 40

41.  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 Mucocutaneous Candidiasis: Prevention May 2013www.aidsetc.org 41

42. May 2013www.aidsetc.org 42  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. Mucocutaneous Candidiasis: Treatment

43.  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. Mucocutaneous Candidiasis: Treatment (3) May 2013www.aidsetc.org 43

44.  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 Mucocutaneous Candidiasis: Treatment (5) May 2013www.aidsetc.org 44

45.  No special considerations regarding ART initiation Mucocutaneous Candidiasis: ART Initiation May 2013www.aidsetc.org 45

46.  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 Mucocutaneous Candidiasis: Monitoring May 2013www.aidsetc.org 46

47.  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 Mucocutaneous Candidiasis: Treatment Failure May 2013www.aidsetc.org 47

48.  ART and immune reconstitution reduce recurrences  For oropharyngeal or vulvovaginal, chronic suppressive therapy generally not recommended  If frequent or severe recurrences, consider fluconazole 100 mg PO QD or TIW (oral); fluconazole 150 mg PO weekly (vaginal)  For esophageal, consider fluconazole 100-200 mg PO QD or posaconazole suspension 400 mg PO BID  Azole-refractory oropharyngeal or esophageal candidiasis: recommended until immune reconstitution on ART (if responded to echinocandins, voriconazole, or posaconazole) Mucocutaneous Candidiasis: Preventing Recurrence May 2013www.aidsetc.org 48

49.  Stopping chronic suppressive therapy:  No data; reasonable to stop when CD4 >200 cells/µL after ART initiation Mucocutaneous Candidiasis: Preventing Recurrence (2) May 2013www.aidsetc.org 49

50. May 2013  www.aidsetc.org 50  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 Mucocutaneous Candidiasis: Considerations in Pregnancy

51. May 2013www.aidsetc.org 51  Epidemiology  Clinical Manifestations  Diagnosis  Prevention  Treatment  Considerations in Pregnancy Cryptococcosis

52. May 2013www.aidsetc.org 52  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 Cryptococcosis: Epidemiology

53. May 2013  www.aidsetc.org 53  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) Cryptococcosis: Clinical Manifestations

54.  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 Cryptococcosis: Clinical Manifestations (2) May 2013www.aidsetc.org 54

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

56.  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%) Cryptococcosis: Diagnosis May 2013www.aidsetc.org 56

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

58.  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 Cryptococcosis: Prevention May 2013www.aidsetc.org 58

59.  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 Cryptococcosis: Prevention (2) May 2013www.aidsetc.org 59

60.  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) Cryptococcosis: Treatment May 2013www.aidsetc.org 60

61.  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 Cryptococcosis: Treatment (2) May 2013www.aidsetc.org 61

62.  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 Cryptococcosis: Treatment (3) May 2013www.aidsetc.org 62

63.  Alternative:  Consolidation (≥8 weeks):  Itraconazole 200 mg PO BID  Maintenance:  No Alternatives are recommended (use fluconazole as in Preferred) Cryptococcosis: Treatment (4) May 2013www.aidsetc.org 63

64.  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 Cryptococcosis: Treatment (5) May 2013www.aidsetc.org 64

65.  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 Cryptococcosis: Treatment (6) May 2013www.aidsetc.org 65

66.  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) Cryptococcosis: ART Initiation May 2013www.aidsetc.org 66

67.  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 Cryptococcosis: Monitoring May 2013www.aidsetc.org 67

68.  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 Cryptococcosis: Adverse Events May 2013www.aidsetc.org 68

69.  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 Cryptococcosis: Adverse Events (2) May 2013www.aidsetc.org 69

70.  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 Cryptococcosis: Treatment Failure May 2013www.aidsetc.org 70

71.  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 Cryptococcosis: Treatment Failure (2) May 2013www.aidsetc.org 71

72.  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 Cryptococcosis: Preventing Recurrence May 2013www.aidsetc.org 72

73.  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 Cryptococcosis: Considerations in Pregnancy May 2013www.aidsetc.org 73

74.  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 Cryptococcosis: Considerations in Pregnancy (2) May 2013www.aidsetc.org 74

75.  Treatment:  Itraconazole: limited data, not recommended in 1st trimester  Voriconazole and posaconazole: teratogenic and embryotoxic in animal studies; should be avoided  Postpartum period may be high-risk period for IRIS Cryptococcosis: Considerations in Pregnancy (3) May 2013www.aidsetc.org 75

76. May 2013www.aidsetc.org 76  Epidemiology  Clinical Manifestations  Diagnosis  Prevention  Treatment  Considerations in Pregnancy Histoplasmosis

77.  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 Histoplasmosis: Epidemiology May 2013www.aidsetc.org 77

78.  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 Histoplasmosis: Epidemiology (2) May 2013www.aidsetc.org 78

79.  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 Histoplasmosis: Epidemiology (3) May 2013www.aidsetc.org 79

80.  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 Histoplasmosis: Clinical Manifestations May 2013www.aidsetc.org 80

81. May 2013www.aidsetc.org 81 Acute disseminated histoplasmosis, chest X ray (L) and CT scan (R) Histoplasmosis: Clinical Manifestations (2)

82. May 2013www.aidsetc.org 82 Skin lesions of histoplasmosis Credit: Image courtesy AIDS Images Library (www.aids-images.ch) Histoplasmosis: Clinical Manifestations (3)

83.  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 Histoplasmosis: Diagnosis May 2013www.aidsetc.org 83

84.  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 Histoplasmosis: Diagnosis (2) May 2013www.aidsetc.org 84

85.  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 Histoplasmosis: Diagnosis (3) May 2013www.aidsetc.org 85

86.  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 10 cases/100 patient-years])  Discontinuing primary prophylaxis  Discontinue when CD4 count ≥150 cells/µL for 6 months on effective ART Histoplasmosis: Prevention May 2013www.aidsetc.org 86

87.  Acute treatment consists of 2 phases: induction and maintenance  Total duration of therapy ≥12 months Histoplasmosis: Treatment May 2013www.aidsetc.org 87

88. May 2013www.aidsetc.org 88  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 Histoplasmosis: Treatment (2)

89.  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 Histoplasmosis: Treatment (3) May 2013www.aidsetc.org 89

90.  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 Histoplasmosis: Treatment (4) May 2013www.aidsetc.org 90

91.  Other antifungals:  Echinocandins: not active against H capsulatum; should not be used Histoplasmosis: Treatment (5) May 2013www.aidsetc.org 91

92.  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 Histoplasmosis: ART Initiation May 2013www.aidsetc.org 92

93.  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 Histoplasmosis: Monitoring and Adverse Events May 2013www.aidsetc.org 93

94.  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 Histoplasmosis: Treatment Failure May 2013www.aidsetc.org 94

95.  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 Histoplasmosis: Preventing Recurrence May 2013www.aidsetc.org 95

96.  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 Histoplasmosis: Considerations in Pregnancy May 2013www.aidsetc.org 96

97. May 2013www.aidsetc.org 97  Epidemiology  Clinical Manifestations  Diagnosis  Prevention  Treatment  Considerations in Pregnancy Coccidioidomycosis

98.  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 Coccidioidomycosis: Epidemiology May 2013www.aidsetc.org 98

99.  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 Coccidioidomycosis: Clinical Manifestations May 2013www.aidsetc.org 99

100.  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 Coccidioidomycosis: Clinical Manifestations (2) May 2013www.aidsetc.org 100

101. May 2013www.aidsetc.org 101 Chest X ray: disseminated coccidioidomycosis Coccidioidomycosis: Manifestations

102.  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 Coccidioidomycosis: Diagnosis May 2013www.aidsetc.org 102

103.  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) Coccidioidomycosis: Prevention May 2013www.aidsetc.org 103

104.  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 Coccidioidomycosis: Prevention (2) May 2013www.aidsetc.org 104

105.  Treatment consists of 2 phases: induction and maintenance  Total duration of therapy ≥12 months Coccidioidomycosis: Treatment May 2013www.aidsetc.org 105

106.  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 Coccidioidomycosis: Treatment (2) May 2013www.aidsetc.org 106

107.  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 Coccidioidomycosis: Treatment (3) May 2013www.aidsetc.org 107

108.  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 Coccidioidomycosis: Treatment (4) May 2013www.aidsetc.org 108

109.  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 Coccidioidomycosis: ART Initiation May 2013www.aidsetc.org 109

110.  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 Coccidioidomycosis: Monitoring and Adverse Events May 2013www.aidsetc.org 110

111.  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 Coccidioidomycosis: Treatment Failure May 2013www.aidsetc.org 111

112.  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 Coccidioidomycosis: Preventing Recurrence May 2013www.aidsetc.org 112

113.  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 Coccidioidomycosis: Preventing Recurrence (2) May 2013www.aidsetc.org 113

114.  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 Coccidioidomycosis: Considerations in Pregnancy May 2013www.aidsetc.org 114

115.  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 Coccidioidomycosis: Considerations in Pregnancy (2) May 2013www.aidsetc.org 115

116. May 2013www.aidsetc.org 116  Epidemiology  Clinical Manifestations  Diagnosis  Prevention  Treatment  Considerations in Pregnancy Aspergillosis

117.  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 Aspergillosis: Epidemiology May 2013www.aidsetc.org 117

118.  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 Aspergillosis: Clinical Manifestations May 2013www.aidsetc.org 118

119.  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 Aspergillosis: Diagnosis May 2013www.aidsetc.org 119

120.  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 Aspergillosis: Preventing Disease May 2013www.aidsetc.org 120

121.  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 Aspergillosis: Treatment May 2013www.aidsetc.org 121

122.  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 Aspergillosis: Treatment (2) May 2013www.aidsetc.org 122

123.  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 Aspergillosis: ART Initiation May 2013www.aidsetc.org 123

124.  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 Aspergillosis: Monitoring and Adverse Events May 2013www.aidsetc.org 124

125.  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 Aspergillosis: Treatment Failure May 2013www.aidsetc.org 125

126.  Chronic maintenance: insufficient data to recommend for or against Aspergillosis: Preventing Recurrence May 2013www.aidsetc.org 126

127.  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 Aspergillosis: Considerations in Pregnancy May 2013www.aidsetc.org 127

128.  AIDS Info: http://aidsinfo.nih.gov Online Access the Guidelines May 2013www.aidsetc.org 128

129. May 2013www.aidsetc.org 129  This presentation was prepared by Susa Coffey, MD, for the AETC National Resource Center in May 2013  See the AETC NCRC website for the most current version of this presentation: http://www.aidsetc.org About This Slide Set