Clinical Manual for Management of the HIV-Infected Adult
2006 Edition

Section 6: Disease-Specific Treatment

Toxoplasmosis

Background

Toxoplasma gondii is a common intracellular protozoan that preferentially infects the central nervous system (CNS) of immunodeficient patients, causing severe neurologic disease. T gondii also can cause local disease such as chorioretinitis or pneumonia. Toxoplasma has an infectious reservoir in almost all animals; humans acquire infection either through ingestion of tissue cysts contained in undercooked meat (usually pork or lamb) or oocysts on contaminated vegetables or through exposure to cat feces containing oocysts. There is no transmission by person-to-person contact.

Clinical disease usually occurs through reactivation of latent infection in patients who have CD4 counts of <100 cells/µL. Seroprevalence varies widely, from 15% in the United States to 75% in some European countries, and even higher in certain resource-limited countries. In the absence of prophylaxis, toxoplasmic encephalitis occurs in more than 30% of patients with advanced HIV disease who are seropositive for T gondii.

CNS toxoplasmosis is an AIDS-defining condition that can be progressive and fatal. However, antimicrobial therapy, especially if given in conjunction with antiretroviral therapy (ART) that results in immune reconstitution, can be successful in treating toxoplasmosis. Specific prophylaxis and effective ART also may be used to prevent toxoplasmosis in patients with advanced AIDS who have latent T gondii infection (as demonstrated by the presence of anti-Toxoplasma immunoglobulin G [IgG] antibodies; see chapter Preventing Exposure to Opportunistic and Other Infections).

S: Subjective

The patient may complain of subacute onset of dull, constant headache, fever, visual changes or other focal neurologic symptoms, confusion, or disorientation. Seizures may occur. Caregivers may report subtle alterations in mental status or mood.

Take a careful history from the patient and caregivers about the symptoms listed above and their duration, progression, and severity. Inquire about other related symptoms. Ask whether the patient is taking Toxoplasma prophylaxis or ART.

O: Objective

• Measure vital signs (temperature, heart rate, blood pressure, respiratory rate).
• Perform a full physical examination including a thorough neurologic examination, looking for focal or nonfocal neurologic deficits, particularly weakness, cranial nerve abnormalities, visual field defects, gait disturbances, and abnormalities in speech, cognitive, or affective functions.
• Review previous laboratory values, particularly:
  • CD4 count (which usually is <50-100 cells/µL in patients with toxoplasmosis)
  • Toxoplasma IgG (>95% of patients with toxoplasmosis have positive IgG)

A: Assessment

Rule out other infectious or neoplastic causes of headache, fever, and neurologic changes. A partial differential diagnosis includes:

• CNS lymphoma
• Cryptococcal meningitis
• Progressive multifocal leukoencephalopathy (PML)
• Tuberculous meningitis
• Brain abscesses of bacterial, fungal, or mycobacterial etiologies
• Herpes simplex virus or cytomegalovirus (CMV) encephalitis
• Primary HIV encephalopathy
• AIDS dementia complex
• Cerebrovascular accident secondary to hemorrhage, hypoxia, or emboli from vegetative endocarditis
• Neurosyphilis
• Other causes of chorioretinitis such as CMV, HIV, and cryptosporidiosis

P: Plan

Diagnostic Evaluation

Definitive diagnosis requires identification of T gondii in tissue biopsy or body fluid samples. Brain biopsy usually is not performed if toxoplasmosis is strongly suspected; instead, presumptive diagnosis is made on the basis of clinical presentation, laboratory and imaging tests, and response to therapy. Brain biopsy should be considered in patients who do not respond to therapy or in whom the diagnosis is unclear.

• Serum Toxoplasma IgG antibody test results are positive in nearly all patients with toxoplasmic encephalitis. A negative IgG test result makes the diagnosis very unlikely but does not rule it out. (Antibody titer changes are uncommon in reactivation disease and are not useful in making a diagnosis.)
• CNS imaging with computed tomography (CT) typically shows multiple contrast-enhancing mass lesions, but may show a single lesion or no lesions. Magnetic resonance imaging (MRI) is more sensitive than CT for CNS toxoplasmosis. Other imaging studies, such as single photon emission CT (SPECT), may be useful in distinguishing toxoplasmic lesions from CNS lymphoma.
• Polymerase chain reaction (PCR) tests for T gondii in the cerebrospinal fluid have poor sensitivity.
• Other diagnostic tests should be performed as indicated to rule out other potential causes of the patient's symptoms.
• Patients with toxoplasmic encephalitis typically respond quickly to treatment. If clinical improvement is not seen after 10-14 days of appropriate treatment, or if clinical worsening is seen in the first week, consider brain biopsy for alternative diagnoses.

Treatment

Treatment consists of 2 phases: acute therapy and chronic maintenance therapy.

Presumptive treatment often is begun on the basis of clinical presentation, positive Toxoplasma IgG, and results of brain imaging studies. If patients do not respond quickly to treatment, other diagnoses should be considered. The following recommendations are based on treatment guidelines published by the Centers for Disease Control and Prevention, National Institutes of Health, and HIV Medicine Association/Infectious Diseases Society of America (see References below).

Acute Therapy

Preferred

• Pyrimethamine 200 mg orally as a single loading dose, then 50 mg (<60 kg body weight) to 75 mg (>60 kg body weight) daily + sulfadiazine 1,000 mg (<60 kg body weight) to 1,500 mg orally every 6 hours (>60 kg body weight) + folinic acid (leucovorin) 10-20 mg daily.

Dosage adjustments to the lower end of therapeutic range of pyrimethamine and sulfadiazine may be considered for patients who have significant bone marrow suppression despite folinic acid supplementation. Monitor patients carefully for cytopenias, especially if they are on other agents that cause bone marrow suppression, such as zidovudine, valganciclovir, and ganciclovir.

Note: Patients at risk for G6PD deficiency should be checked for G6PD deficiency before starting pyrimethamine.

Alternatives

• Pyrimethamine + folinic acid (administered as described above) + 1 of the following:
  • Clindamycin 600 mg orally or intravenously every 6 hours; recommended for patients with significant allergic reactions to sulfa medications
  • Atovaquone 1500 mg orally every 12 hours
  • Azithromycin 900-1,200 mg orally once daily
• Trimethoprim-sulfamethoxazole (TMP-SMX) 5 mg/kg TMP and 25 mg/kg SMX orally or intravenously every 12 hours. This can be considered when the availability of other regimens is limited or when patients need intravenous therapy.
• Atovaquone 1,500 mg orally twice daily + sulfadiazine 1,000-1,500 mg orally every 6 hours.

Note: The regimens that contain sulfadiazine, TMP-SMX, or atovaquone also are effective in preventing Pneumocystis jiroveci pneumonia (PCP), so patients on these regimens do not need additional PCP prophylaxis.

Adjunctive corticosteroids (eg, dexamethasone 4 mg orally or intravenously every 6 hours) may be indicated for patients with significant CNS edema or mass effect. Use is based on clinical judgment and should be discontinued as soon as clinically feasible.

Anticonvulsant therapy should be given to patients with seizures.

Ventilatory support may be necessary if severe CNS symptomatology is present.

Chronic Maintenance Therapy

After at least 6 weeks of initial therapy, and significant clinical and radiologic improvement, chronic maintenance therapy can be considered.

Preferred

• Pyrimethamine 25-50 mg orally once daily + sulfadiazine 500-1,000 mg orally every 6 hours + folinic acid 10 mg orally once daily (also effective as PCP prophylaxis).

Alternatives

• Pyrimethamine 25-50 mg orally once daily + clindamycin 300-450 mg orally every 6-8 hours + folinic acid 10 mg orally once daily.
• Pyrimethamine 25-50 mg orally once daily + atovaquone 1,500 mg orally once daily + folinic acid 10 mg orally once daily (also effective as PCP prophylaxis).

Chronic maintenance therapy generally should be continued for life. For patients who complete acute therapy successfully, have resolution of signs and symptoms of toxoplasmosis, and have immune reconstitution (with CD4 counts >200 cells/µL) for more than 6 months on ART, it is reasonable to consider discontinuing maintenance therapy. Some specialists would require resolution of CNS lesions on radiologic studies before discontinuation of therapy. Patients must be observed for recurrence of symptoms, and treatment should be restarted if the CD4 count decreases to <200 cells/µL.

Considerations in Pregnancy

All pregnant women should be tested for T gondii. If the result is positive, evaluate the mother for toxoplasmosis and the neonate for evidence of congenital infection. Perinatal transmission usually occurs only with acute maternal infection, but in advanced HIV, it may occur with reactivation of chronic infection. If T gondii infection occurs during pregnancy, consult with a maternal-fetal specialist. Treatment for pregnant women is the same as for nonpregnant adults (see above). Note that sulfadiazine taken at the time of delivery may increase the risk of neonatal hyperbilirubinemia and kernicterus.

Patient Education

• Advise patients that antimicrobial therapy alone will not eradicate toxoplasmosis, but should decrease symptoms and improve quality of life. If medications are discontinued, the disease is likely to recur, unless the CD4 count increases to >100-200 cells/µL in response to ART.
• Inform patients that suppressive therapy must be continued to prevent recurrence. This therapy may be lifelong.
• It is essential for patients to take all medicines exactly as prescribed. If doses are missed, or if the medications are stopped and restarted, Toxoplasma can develop resistance to the medications. If patients are having trouble taking the medication on schedule, they should contact their health care providers immediately.
• Educate patients about the benefits of ART in strengthening the immune system and preventing opportunistic infections such as toxoplasmosis.
• Advise patients to return to clinic promptly if symptoms worsen or new symptoms develop.
• Toxoplasmosis is a late-stage HIV opportunistic infection and indicates profound immune suppression. Some patients may not respond to treatment or to ART. As with any patient who is at risk for a life-threatening HIV-related disease, clinicians should discuss advance directives and durable power of attorney with patients. Referral to a social worker, mental health clinician, or chaplain experienced in such issues may facilitate this discussion.

References

• Bartlett JG, Gallant JE. 2005-2006 Medical Management of HIV Infection. Baltimore: Johns Hopkins University Division of Infectious Diseases; 2005. Available online at hopkins-aids.edu/mmhiv/order.html.
• Centers for Disease Control and Prevention, National Institutes of Health, HIV Medicine Association/Infectious Diseases Society of America. Treating Opportunistic Infections Among HIV-Infected Adults and Adolescents. MMWR Recomm Rep. 2004 Dec 17; 53(RR15);1-112.
• Kirton C, ed. ANAC's Core Curriculum for HIV/AIDS Nursing; 2nd ed. Thousand Oaks, CA: Sage; 2003:87-89.
• Liesenfeld O, Wang SY, Remington JS. Toxoplasmosis in the Setting of AIDS. In: Merigan TC, Bartlett JG, Bolognesi D, eds. Textbook of AIDS Medicine, 2nd Edition. Baltimore: Williams and Wilkins; 1999:225-259.
• Murray HW. Toxoplasmosis. In: Dolin R, Masur H, Saag M,S, eds. AIDS Therapy 1999. Philadelphia: Churchill Livingstone; 1999:307-327.
• Subauste CS. Toxoplasmosis and HIV. In: Peiperl L, Coffey S, Volberding PA, eds. HIV InSite Knowledge Base [textbook online]. San Francisco: UCSF Center for HIV Information; 2006. Accessed June 1, 2006.