1. Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents Pneumocystis jiroveci Pneumonia 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. May 2013www.aidsetc.org 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 Users are cautioned that, owing to the rapidly changing field of HIV care, this information could become out of date quickly.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

3. May 2013www.aidsetc.org 3 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

4. May 2013www.aidsetc.org 4 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)

5. May 2013www.aidsetc.org 5 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

6. May 2013www.aidsetc.org 6 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

7. May 2013www.aidsetc.org 7 PCP: Diagnosis  Clinical presentation, blood tests, radiographs suggestive but not diagnostic  Organism cannot be cultured  Definitive diagnosis should be sought  Hypoxemia: characteristic, may be mild or severe (PO 2 35 mmHg)  LDH >500 mg/dL is common but nonspecific  1,3β-D-glycan may be elevated; uncertain sensitivity and specificity

8. May 2013www.aidsetc.org 8 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)

9. May 2013www.aidsetc.org 9 PCP: Diagnosis (3)  Chest CT, thin-section  Patchy ground-glass attenuation  May be normal  Gallium scan  Pulmonary uptake

10. May 2013www.aidsetc.org 10 PCP: Diagnosis (Imaging) Chest X ray: PCP with bilateral, diffuse granular opacities Credit: L. Huang, MD; HIV InSite Chest X ray: PCP with bilateral perihilar opacities, interstitial prominence, hyperlucent cystic lesions Credit: HIV Web Study, www.hivwebstudy. org, © 2006 University of Washington

11. May 2013www.aidsetc.org 11 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

12. May 2013www.aidsetc.org 12 PCP: Diagnosis  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

13. May 2013www.aidsetc.org 13 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

14. May 2013www.aidsetc.org 14 PCP: Diagnosis  Treatment may be initiated before definitive diagnosis is established  Organism persists for days/weeks after start of treatment

15. May 2013www.aidsetc.org 15 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

16. May 2013www.aidsetc.org 16 PCP: Primary Prophylaxis  Initiate:  CD4 <200 cells/µL or history of oropharyngeal candidiasis  Consider for:  CD4% <14% or history of AIDS-defining illness  CD4 200-250 cells/µL if Q 3-month CD4 monitoring is not possible  Discontinue:  On ART with CD4 >200 cells/µL for >3 months  Reinitiate:  CD4 decreases to <200 cells/µL

17. May 2013www.aidsetc.org 17 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)

18. May 2013www.aidsetc.org 18 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)

19. May 2013www.aidsetc.org 19 PCP: Treatment  Duration: 21 days for all treatment regimens  Preferred: TMP-SMX is treatment of choice  Moderate-severe PCP  TMP-SMX: 15-20 mg/kg/day TMP and 75-100 mg/kg/day SMX IV or PO in divided doses Q6-8H  Mild-moderate PCP  As above, or TMP-SMX DS 2 tablets TID  Adjust dosage for renal insufficiency

20. May 2013www.aidsetc.org 20 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

21. May 2013www.aidsetc.org 21 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

22. May 2013www.aidsetc.org 22 PCP: Treatment (4)  Adjunctive:  Corticosteroids  For moderate-to-severe disease (room air PO 2 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

23. May 2013www.aidsetc.org 23 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

24. May 2013www.aidsetc.org 24 PCP: Monitoring and Adverse Events  Monitor closely for response to treatment, and for adverse effects of treatment

25. May 2013www.aidsetc.org 25 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

26. May 2013www.aidsetc.org 26 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

27. May 2013www.aidsetc.org 27 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

28. May 2013www.aidsetc.org 28 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

29. May 2013www.aidsetc.org 29 PCP: Preventing Recurrence (2)  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

30. May 2013www.aidsetc.org 30 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

31. May 2013www.aidsetc.org 31 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

32. May 2013www.aidsetc.org 32 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

33. May 2013www.aidsetc.org 33 Websites to Access the Guidelines  http://www.aidsetc.org  http://aidsinfo.nih.gov

34. May 2013www.aidsetc.org 34  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 About This Slide Set