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1. Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and AdolescentsHistoplasmosis 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 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 Users are cautioned that, owing to the rapidly changing field of HIV care, this information could become out of date quickly.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 www.aidsetc.org

3. Histoplasmosis:Epidemiology • Caused by Histoplasma capsulatum • Endemic in midwest United States, Puerto Rico, Latin America • Occurs in up to 5% of HIV-infected individuals in endemic areas • In nonendemic areas, usually seen in those who previously lived in endemic area www.aidsetc.org

4. Histoplasmosis:Epidemiology (2) • Acquired by inhalation • Risks include: working with surface soil, cleaning chicken coops contaminated with droppings; disturbing bird or bat droppings; exploring caves; cleaning, remodeling, or demolishing old buildings www.aidsetc.org

5. Histoplasmosis:Epidemiology (3) • Reactivation of latent infection may occur • Systemic illness more likely in patients with CD4 count <150 cells/µL • Pulmonary histoplasmosis may occur with CD4 count >300 cells/µL • Incidence has declined with use of potent ART www.aidsetc.org

6. Histoplasmosis:Clinical Manifestations • Disseminated disease: fever, fatigue, weight loss, hepatosplenomegaly • Cough, chest pain, dyspnea in 50% • Shock and multiorgan failure in 10% • Most common in patients with low CD4 count • Isolated pulmonary disease: usually occurs in patients with CD4 count >300 cells/µL • CNS, GI, and skin manifestations possible • CNS: fever, headache, seizures, focal neurological deficits, altered mental status • GI: fever, diarrhea, abdominal pain, weight loss www.aidsetc.org

7. 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) www.aidsetc.org

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

9. Histoplasmosis:Diagnosis • Detection of Histoplasma antigen in serum or urine • Sensitive for disseminated histoplasmosis and acute pulmonary infection • In disseminated disease, urine Ag test positive in up to 100%, serum Ag test positive in up to 92% • Ag detection in BAL fluid appears sensitive • Insensitive for chronic pulmonary infection • Biopsy with histopathologic examination shows characteristic budding yeast www.aidsetc.org

10. Histoplasmosis:Diagnosis (2) • Culture from blood, bone marrow, respiratory secretions, other involved sites (positive in >85%, but may take 2-4 weeks) • Serologic tests usually less useful in AIDS patients with disseminated disease, may be helpful in patients with higher CD4 counts and pulmonary disease www.aidsetc.org

11. Histoplasmosis:Diagnosis (3) • Diagnosis of meningitis may be difficult: • CSF cultures and fungal stains ≤50% sensitive • Antigen and antibody tests positive in up to 70% of cases • Consider presumptive diagnosis of Histoplasma meningitis if patient has disseminated histoplasmosis and CNS infection that is otherwise unexplained • CSF findings: lymphocytic pleocytosis, elevated protein, low glucose www.aidsetc.org

12. 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 monthson effective ART www.aidsetc.org

13. Histoplasmosis:Treatment • Acute treatment consists of 2 phases: induction and maintenance • Total duration of therapy ≥12 months www.aidsetc.org

14. Histoplasmosis:Treatment (2) Disseminated histoplasmosis • Moderate-severe disease • Induction (2 weeks or until clinically improved): • Preferred: liposomal amphotericin B 3 mg/kg IV QD • Alternative: • Amphotericin B lipid complex or cholesteryl sulfate complex 3 mg/kg IV QD • Maintenance: itraconazole 200 mg PO TID for 3 days, then BID* (liquid formulation preferred) • Duration of therapy: ≥12 months * Adjust dosage based on interactions with ARVs and itraconazole serum concentration www.aidsetc.org

15. Histoplasmosis:Treatment (3) Disseminated histoplasmosis • Less-severe disease • Induction and maintenance • Preferred: Itraconazole 200 mg PO TID for 3 days, then BID* (liquid formulation preferred) • Alternative (limited data): • Posaconazole 400 mg PO BID • Voriconazole 400 mg PO BID for 1 day, then 200 mg PO BID • Fluconazole 800 mg PO QD • Duration of therapy: ≥12 months * Adjust dosage based on interactions with ARVs and itraconazole serum concentration www.aidsetc.org

16. Histoplasmosis:Treatment (4) Meningitis • Preferred induction (4-6 weeks): • Liposomal amphotericin B 5 mg/kg IV QD • Preferred maintenance (≥12 months plus resolution of CSF abnormalities): • Itraconazole 200 mg PO BID or TID* Acute pulmonary histoplasmosis in patients with CD4 count >300 cells/µL • Manage as in nonimmunocompromised * Adjust dosage based on interactions with ARVs and itraconazole serum concentration www.aidsetc.org

17. Histoplasmosis: Treatment (5) • Other antifungals: • Echinocandins: not active against H capsulatum; should not be used www.aidsetc.org

18. Histoplasmosis:ART Initiation • Start ART as soon as possible after starting antifungal therapy • IRIS appears to be uncommon • Triazoles have complex, sometimes bidirectional interactions with certain ARVs; dosage adjustments may be needed www.aidsetc.org

19. Histoplasmosis:Monitoring and Adverse Events • Monitor serum or urine Histoplasma antigen: useful for determining response to therapy • Increase in level suggests relapse • Check serum itraconazole levels after 2 weeks of therapy or if potential drug interactions (absorption of itraconazole can be erratic) • IRIS is uncommon; ART should not be withheld because of concern for IRIS www.aidsetc.org

20. Histoplasmosis:Treatment Failure • Use liposomal amphotericin B for severely ill patients and those who do not respond to initial azole therapy • Consider posaconazole or voriconazole for moderately ill patients intolerant of itraconazole • Note: significant interactions between voriconazole and NNRTIs or ritonavir www.aidsetc.org

21. Histoplasmosis: Preventing Recurrence • Secondary prophylaxis: • Long-term suppressive therapy for patients with severe disseminated or CNS infection, after ≥12 months of treatment; and in those who relapse despite appropriate therapy • Preferred: itraconazole 200 mg PO • Alternative: fluconazole 400 mg PO QD (less effective than itraconazole) • Voriconazole or posaconazole: no data • May discontinue if: ≥12 months of itraconazole, and negative blood cultures, and Histoplasma serum Ag <2 ng/mL, and CD4 count ≥150 cells/µL on ART for ≥6 months on ART • Restart if CD4 count decreases to <150 cells/µL www.aidsetc.org

22. Histoplasmosis:Considerations in Pregnancy • Amphotericin B or its lipid formulations are preferred initial regimen • At delivery, evaluate neonate for renal dysfunction and hypokalemia • Azoles: avoid in 1st trimester--risk of teratogenicity • Voriconazole and posaconazole: teratogenic and embryotoxic in animals: avoid throughout pregnancy www.aidsetc.org

23. Websites to Access the Guidelines • http://www.aidsetc.org • http://aidsinfo.nih.gov www.aidsetc.org

24. 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 www.aidsetc.org