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1. Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and AdolescentsToxoplasma gondii 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 Users are cautioned that, because of the rapidly changing field of HIV care, this information could become out of date quickly.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. Toxoplasma gondii Encephalitis:Epidemiology • Caused by the T gondii protozoan • Disease almost always caused by reactivation of latent tissue cysts • Primary infection may be associated with acute cerebral or disseminated disease • Seroprevalence varies widely: 11% in the United States, 50-80% in some European, Latin American, and African countries www.aidsetc.org

4. Toxoplasma gondii Encephalitis: Epidemiology (2) • In advanced AIDS, 12-month incidence of TE was 33% among Toxoplasma-seropositive patients who were not on prophylaxis or ART • Among seronegative persons, toxoplasmosis is rare • Occurs primarily in patients with CD4 counts of <200 cells/µL, especially <50 cells/µL • Incidence and mortality lower in United States and Europe owing to widespread use of prophylaxis and potent ART www.aidsetc.org

5. Toxoplasma gondii Encephalitis: Epidemiology (3) • Primary infection acquired from tissue cysts in undercooked meat or raw shellfish, or ingestion of sporulated oocysts (from cat feces) in soil, water, or food • No transmission by person-to-person contact www.aidsetc.org

6. Toxoplasma gondii Encephalitis: Clinical Manifestations • Focal encephalitis with headache, confusion, or motor weakness and fever • May have nonfocal symptoms, including nonspecific headache and psychiatric symptoms • May have focal neurological abnormalities; may progress to seizures, altered mental status, coma • Retinochoroiditis, pneumonia, other organ involvement are rare www.aidsetc.org

7. Toxoplasma gondii Encephalitis: Clinical Manifestations • CT or MRI: • Typical findings are multiple contrast-enhancing lesions in gray matter of cortex or basal ganglia, often associated edema • May show single brain lesion, or diffuse encephalitis without focal lesions www.aidsetc.org

8. Toxoplasma gondii Encephalitis: Diagnosis • Serum anti-Toxoplasma IgG • Positive in almost all patients with TE; negative IgG makes diagnosis unlikely but not impossible • IgM usually negative • Definitive diagnosis: compatible clinical syndrome + mass lesion(s) on imaging + detection of organism in a clinical sample (brain biopsy) • CT, MRI of brain: typically multiple contrast-enhancing lesions, often with edema • MRI better than CT for radiological diagnosis • PET or SPECT may help distinguish TE from lymphoma www.aidsetc.org

9. Toxoplasma gondii Encephalitis: Diagnosis (2) • Check CSF (if safe and feasible) for T gondii PCR, cytology, culture, cryptococcal antigen, PCR for M tuberculosis, EBV, JC virus • CSF PCR specificity for T gondii is 96-100%, sensitivity 50% www.aidsetc.org

10. Toxoplasma gondii Encephalitis: Diagnosis (3) • Differential diagnosis of focal neurological disease • CNS lymphoma, PML, mycobacterial infection (TB), fungal infection, Chagas disease, abscess www.aidsetc.org

11. Toxoplasma gondii Encephalitis: Diagnosis (4) CT scan of the brain showing contrast-enhancing lesion of toxoplasmosis Credit: P. Volberding, MD; UCSF Center for HIV Information Image Library www.aidsetc.org

12. Toxoplasma gondii Encephalitis: Diagnosis (5) • May initially make empiric diagnosis, established on basis of clinical and radiographic improvement to TE therapy, in absence of a likely alternative diagnosis • Brain biopsy if failure to respond to therapy, or if initial studies suggest etiology other than TE www.aidsetc.org

13. Toxoplasma gondii Encephalitis: Preventing Exposure • All HIV+ should be tested for IgG to Toxoplasma at baseline, to detect latent infection • Toxoplasma seronegative: counsel about sources of infection • Patients: avoid eating raw or undercooked meat or shellfish; wash hands after handling raw meat and after contact with soil; wash fruits/vegetables; clean cat-litter boxes daily and wash hands afterward; cats should notbe fed raw/undercooked meats www.aidsetc.org

14. Toxoplasma gondii Encephalitis: Primary Prophylaxis For all Toxoplasma IgG positive with CD4 count <100 cells/µL • Recommended: • TMP-SMX 1 DS QD • Alternative: • TMP-SMX 1 DS PO TIW • TMP-SMX 1 SS QD • Dapsone* 50 mg PO QD + pyrimethamine 50 mg PO Q week + leucovorin 25 mg PO Q week • Dapsone* 200 mg PO Q week + pyrimethamine 75 mg PO Q week + leucovorin 25 mg PO Q week • Atovaquone 1,500 mg PO QD +/- pyrimethamine 25 mg PO QD + leucovorin 10 mg PO QD * Avoid dapsone if patient has G6PD deficiency; screen before treatmentwith dapsone, if possible. www.aidsetc.org

15. Toxoplasma gondii Encephalitis: Primary Prophylaxis (2) • Toxoplasma seronegative patients: retest for Toxoplasma IgG if CD4 count declines to <100 cells/µL, unless taking PCP prophylaxis that also is active against TE www.aidsetc.org

16. Toxoplasma gondii Encephalitis: Discontinuing Primary Prophylaxis • Discontinue if on effective ART with CD4 count of >200 cells/µL for >3 months • Restart prophylaxis if CD4 count decreases to <100-200 cells/µL www.aidsetc.org

17. Toxoplasma gondii Encephalitis: Treatment • Preferred: • Pyrimethamine 200 mg PO 1 dose, then: • For weight ≤60 kg: pyrimethamine 50 mg PO QD + sulfadiazine 1,000 mg PO Q6H + leucovorin 10-25 mg PO QD • For weight >60 kg: pyrimethamine 75 mg PO QD + sulfadiazine 1,500 mg PO Q6H + leucovorin 10-25 mg PO QD • Duration: ≥6 weeks, longer if extensive disease or incomplete response at 6 weeks www.aidsetc.org

18. Toxoplasma gondii Encephalitis: Treatment (2) • Alternative: • Pyrimethamine as above + clindamycin 600 mg IV or PO Q6H + leucovorin as above • TMP-SMX (5 mg/kg TMP and 25 mg/kg SMX) IV or PO BID • Atovaquone 1,500 mg PO BID + pyrimethamine, as above + leucovorin as above • Atovaquone 1,500 mg PO BID + sulfadiazine (weight-based as above) • Atovaquone 1,500 mg PO BID (variable absorption) • Pyrimethamine as above + azithromycin 900-1,200 mg PO QD + leucovorin as above www.aidsetc.org

19. Toxoplasma gondii Encephalitis: Treatment (3) • Adjunctive corticosteroids only if indicated for treatment of mass effect; monitor closely and discontinue as soon as possible • Anticonvulsants if history of seizures; continue at least through period of acute therapy • Should not be given prophylactically to all patients www.aidsetc.org

20. Toxoplasma gondii Encephalitis: ART Initiation • No data to guide recommendation on when to start ART • Many recommend starting ART within 2-3 weeks after diagnosis of TE • In one study, lower rate of AIDS progression or death with early ART www.aidsetc.org

21. Toxoplasma gondii Encephalitis: Monitoring and Adverse Events • Follow clinical and radiologic improvement • Ab titers not useful • Monitor for adverse events • Pyrimethamine: rash, nausea, bone marrow suppression • May be reversed with increase in leucovorin dosage • Sulfadiazine: rash, fever, leukopenia, hepatitis, nausea, vomiting, diarrhea, renal insufficiency, crystalluria • Clindamycin: rash, fever, nausea, diarrhea (including Clostridium difficile colitis), hepatotoxicity • TMP-SMX: rash, fever, leukopenia, thrombocytopenia, hepatotoxicity • Atovaquone: nausea, vomiting, diarrhea, rash, headache, hyperglycemia, fever www.aidsetc.org

22. Toxoplasma gondii Encephalitis: Monitoring and Adverse Events (2) • IRIS appears to occur rarely www.aidsetc.org

23. Toxoplasma gondii Encephalitis: Treatment Failure • Clinical or radiologic deterioration during first week of therapy, or lack of clinical improvement within 10-14 days • Brain biopsy, if not done previously • If confirmed TE, consider switch to alternative treatment regimen • In patients who adhere to treatment, recurrence is unusual during maintenance therapy following initial clinical and radiographic response www.aidsetc.org

24. Toxoplasma gondii Encephalitis: Preventing Recurrence • Secondary prophylaxis: • Preferred: • Pyrimethamine 25-50 mg PO QD + sulfadiazine 2,000-4,000 mg PO daily in 2-4 divided doses + leucovorin 10-25 mg PO QD • Alternative: • Clindamycin 600 mg PO Q8H + pyrimethamine 25-50 mg PO QD + leucovorin 10-25 mg PO QD (not effective as PCP prophylaxis) • TMP-SMX DS 1 tablet BID • Atovaquone 750-1,500 mg PO BID + pyrimethamine 25 mg PO QD (+ leucovorin 10 mg PO QD) • Atovaquone 750-1,500 mg PO BID + sulfadiazine 2,000-4,000 mg PO daily in 2-4 divided doses • Atovaquone 750-1,500 mg PO BID www.aidsetc.org

25. Toxoplasma gondii Encephalitis: Preventing Recurrence (2) • Discontinuing maintenance therapy: consider in asymptomatic patients after successful initial therapy for TE, resolution of signs and symptoms of TE, and sustained increase in CD4 count to >200 cells/µL for >6 months, on ART • Consider brain MRI before treatment discontinuation; continue therapy if mass lesions present or enhancement persists • Restart secondary prophylaxis if CD4 count decreases to <200 cells/µL www.aidsetc.org

26. Toxoplasma gondii Encephalitis: Considerations in Pregnancy • Check T gondii IgG during pregnancy • If suspected or confirmed T gondii infection, evaluate and manage with a maternal-fetal specialist • Diagnostic considerations same as for nonpregnant women www.aidsetc.org

27. Toxoplasma gondii Encephalitis: Considerations in Pregnancy (2) • Perinatal transmission usually occurs only with acute maternal infection; case reports of transmission with reactivation of chronic infection in women with severe immunosuppression • If toxoplasmosis during pregnancy (primary infection or reactivation of chronic toxoplasmosis): • Detailed ultrasound of fetus • Consider PCR of amniotic fluid in select circumstances • Neonate should be evaluated for evidence of congenital infection www.aidsetc.org

28. Toxoplasma gondii Encephalitis: Considerations in Pregnancy (3) • Primary prophylaxis: recommended • TMP-SMX preferred • Balance possible risks with expected benefits • Treatment: as in nonpregnant adults • Secondary prophylaxis: as in nonpregnant women www.aidsetc.org

29. Toxoplasma gondii Encephalitis: Considerations in Pregnancy (4) • Pyrimethamine appears safe in human pregnancy • Sulfadiazine appears safe though, if given around time of delivery, may increase risk of neonatal kernicterus • Clindamycin considered same in pregnancy • Dapsone: risk of mild maternal hemolysis with long-term therapy; low risk of hemolytic anemia in exposed fetuses with G6PD deficiency www.aidsetc.org

30. Toxoplasma gondii Encephalitis: Considerations in Pregnancy (5) • Consider immediate initiation of ART, to decrease risk of perinatal HIV transmission, especially for women diagnosed with TE in 3rd trimester • Preconception care for women receiving TE prophylaxis: discuss option of deferring pregnancy until TE prophylaxis can be discontinued safely www.aidsetc.org

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

32. About This Slide Set • This presentation was prepared by Susa Coffey, MD, and Oliver Bacon, 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