1. Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents Toxoplasma 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 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Users are cautioned that, because of the rapidly changing field of HIV care, this information could become out of date quickly.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
May 2013

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
May 2013

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
May 2013

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
May 2013

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
May 2013

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
May 2013

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
May 2013

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 %, sensitivity 50%
May 2013

10. Toxoplasma gondii Encephalitis: Diagnosis (3)
Differential diagnosis of focal neurological disease
CNS lymphoma, PML, mycobacterial infection (TB), fungal infection, Chagas disease, abscess
May 2013

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
May 2013

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
May 2013

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 not be fed raw/undercooked meats
May 2013

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 treatment with dapsone, if possible.
May 2013

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
May 2013

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 < cells/µL
May 2013

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 mg PO QD
For weight >60 kg: pyrimethamine 75 mg PO QD + sulfadiazine 1,500 mg PO Q6H + leucovorin mg PO QD
Duration: ≥6 weeks, longer if extensive disease or incomplete response at 6 weeks
The initial therapy of choice consists of the combination of pyrimethamine plus sulfadiazine plus leucovorin ( ) (AI).
Pyrimethamine penetrates the brain parenchyma efficiently even in the absence of inflammation (126).
Use of leucovorin prevents the hematologic toxicities associated with pyrimethamine therapy (127,128). The
preferred alternative regimen for patients unable to tolerate or who fail to respond to first-line therapy is
pyrimethamine plus clindamycin plus leucovorin (122,123) (AI).
Acute therapy should be continued for at least 6 weeks, if there is clinical and radiologic improvement ( )
(BII). Longer courses might be appropriate if clinical or radiologic disease is extensive or if response is incomplete at
6 weeks.
May 2013

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
TMP-SMX was reported in a small (77 patient) randomized trial to be effective and better tolerated than
pyrimethamine-sulfadiazine (129). On the basis of less in vitro activity and less experience with this regimen,
pyrimethamine plus sulfadiazine with leucovorin is the preferred therapy (BI). For patients who cannot take an oral
regimen, no well-studied options exist. No parenteral formulation of pyrimethamine exists; the only widely available
parenteral sulfonamide is the sulfamethoxazole component of TMP-SMX. Therefore, certain specialists will treat
severely ill patients requiring parenteral therapy initially with oral pyrimethamine plus parenteral TMP-SMX or
parenteral clindamycin (CIII).
Treating Opportunistic Infections Among HIV-Infected Adults and Adolescents – Page 11
At least 3 regimens have activity in the treatment of TE in at least 2 nonrandomized, uncontrolled trials,
although their relative efficacy compared with the previous regimens is unknown: 1) atovaquone (with meals or oral
nutritional supplements) plus pyrimethamine plus leucovorin (130) (BII); 2) atovaquone combined with sulfadiazine
or, for patients intolerant of both pyrimethamine and sulfadiazine, as a single agent (130) (BII) (If atovaquone is
used alone, measuring plasma levels might be helpful, given the high variability of absorption of the drug among
different patients; plasma levels of >18.5 µg/mL are associated with an improved response rate) (131–133); and 3)
azithromycin plus pyrimethamine plus leucovorin daily (134,135) (BII).
The following regimens have been reported to have activity in the treatment of TE in small cohorts of patients or in
case reports of one or a few patients: clarithromycin plus pyrimethamine (136) (CIII); 5-fluoro-uracil plus
clindamycin (137) (CIII), dapsone plus pyrimethamine plus leucovorin (138) (CIII); and minocycline or
doxycycline combined with either pyrimethamine plus leucovorin, sulfadiazine, or clarithromycin (139,140) (CIII).
Although the clarithromycin dosage used in the only published study was 1 g twice a day, dosages >500 mg have been
associated with increased mortality in HIV-1–infected patients treated for disseminated MAC. Dosages >500 mg twice
a day should not be used (DIII).
May 2013

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
Adjunctive corticosteroids (eg, dexamethasone) should be administered when clinically indicated only for
treatment of a mass effect associated with focal lesions or associated edema (BIII). Because of the potential
immunosuppressive effects of corticosteroids, they should be discontinued as soon as clinically feasible. Patients
receiving corticosteroids should be closely monitored for the development of other OIs, including cytomegalovirus
retinitis and TB disease.
Anticonvulsants should be administered to patients with a history of seizures (AIII), but should not be administered
prophylactically to all patients (DIII). Anticonvulsants, if administered, should be continued at least through the
period of acute therapy.
May 2013

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
Adjunctive corticosteroids (eg, dexamethasone) should be administered when clinically indicated only for
treatment of a mass effect associated with focal lesions or associated edema (BIII). Because of the potential
immunosuppressive effects of corticosteroids, they should be discontinued as soon as clinically feasible. Patients
receiving corticosteroids should be closely monitored for the development of other OIs, including cytomegalovirus
retinitis and TB disease.
Anticonvulsants should be administered to patients with a history of seizures (AIII), but should not be administered
prophylactically to all patients (DIII). Anticonvulsants, if administered, should be continued at least through the
period of acute therapy.
May 2013

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
May 2013

22. Toxoplasma gondii Encephalitis: Monitoring and Adverse Events (2)
IRIS appears to occur rarely
May 2013

23. Toxoplasma gondii Encephalitis: Treatment Failure
Clinical or radiologic deterioration during first week of therapy, or lack of clinical improvement within 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
May 2013

24. Toxoplasma gondii Encephalitis: Preventing Recurrence
Secondary prophylaxis:
Preferred:
Pyrimethamine mg PO QD + sulfadiazine 2,000-4,000 mg PO daily in 2-4 divided doses + leucovorin mg PO QD
Alternative:
Clindamycin 600 mg PO Q8H + pyrimethamine mg PO QD + leucovorin 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
May 2013

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
May 2013

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
May 2013

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
May 2013

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
May 2013

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
May 2013

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
May 2013

31. Websites to Access the Guidelines
May 2013

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:
May 2013