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Toxoplasmosis
Toxoplasmosis and HIV
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Introduction
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Epidemiology
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Congenital Transmission of T gondii Infection in HIV-Infected Women
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Pathogenesis
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Clinical Presentation
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Diagnosis
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transparent imageSerology
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transparent imageCerebrospinal Fluid Studies
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transparent imageDNA Detection
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transparent imageIsolation Studies
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transparent imageNeuroradiologic Studies
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transparent imageHistopathology
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Differential Diagnosis
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Management of Toxoplasmosis in HIV-Infected Patients
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transparent imageAcute Therapy
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transparent imageMaintenance Therapy (Secondary Prophylaxis)
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transparent imagePrevention (Primary Prophylaxis)
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transparent imageDiscontinuation of Primary and Secondary Prophylaxis
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References
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Tables
Table 1.Acute or Primary Therapy for Toxoplasmic Encephalitis in Patients with AIDS
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Table 2.Maintenance Therapy for Toxoplasmic Encephalitis in Patients with AIDS
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Table 3.Regimens Used for Primary Prophylaxis Against Toxoplasmosis
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Related Resources
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Introduction
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Toxoplasma gondii is an obligate intracellular protozoan of worldwide distribution. Development of cell-mediated immunity after acute infection with T gondii results in control but not eradication of the infection.(1) The ensuing chronic or latent phase of infection is characterized by the persistence of the organism in tissues of the infected individual (primarily brain, skeletal muscle, and heart). Indeed, T gondii is one of the most common causes of chronic infection with an intracellular organism in humans. A chronically infected individual who develops defects in cell-mediated immunity is at risk for reactivation of the infection.(1,2) Toxoplasmosis in this setting manifests primarily as toxoplasmic encephalitis.

T gondii exists in three forms: tachyzoite, tissue cyst (containing bradyzoites), and oocyst (containing sporozoites). The latter form of the parasite is produced during the sexual cycle in the intestine of felines (the definitive host). The asexual life cycle takes place in all intermediary hosts (including humans) as well as in felines. Ingestion of tissue cysts or oocysts is followed by infection of intestinal epithelial cells by bradyzoites or sporozoites, respectively. After transformation into tachyzoites, the organisms disseminate throughout the body via the blood or lymphatics. The parasite transforms into tissue cysts once it reaches peripheral tissues. This form of the parasite appears to persist for the life of the host.(1) Tissue cysts present in meat are rendered nonviable by heating to 67°C, freezing to -20°C or by gamma-irradiation. The entero-epithelial sexual cycle with formation of oocysts takes place in cats that become acutely infected after ingestion of meat containing tissue cysts. Excretion of oocysts lasts for 7-20 days, and rarely recurs. Oocysts become infectious after they are excreted and sporulation occurs. The duration of this process depends on environmental conditions, but usually takes 2-3 days following excretion. Oocysts remain infectious in the environment for more than a year.

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Epidemiology
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The prevalence of serologic evidence of T gondii infection varies depending on geographic locale and population group. Between 3% and 67% of adults in the United Sates are seropositive for antibodies against T gondii.(1) The rate of seroprevalence can be as high as 90% in Western Europe and tropical countries.

Transmission to humans occurs primarily by ingestion of undercooked pork or lamb meat that contains tissue cysts, or by exposure to oocysts either through ingestion of contaminated vegetables or direct contact with cat feces.(1) Other modes of transmission include the transplacental route, blood product transfusion, and organ transplantation. Acute infection in immunocompetent individuals is usually asymptomatic.

Toxoplasmic encephalitis usually occurs in HIV-infected patients with CD4 T-cell counts <100/µL.(2) Toxoplasmic encephalitis in AIDS patients in the United States is almost always caused by reactivation of a chronic infection. Thus, the incidence of this disease correlates directly with the prevalence of anti-T gondii antibodies. Between 10% and 40% of HIV-infected patients in the United Sates have antibodies against T gondii.(2,3) Early studies indicated that 24-47% of T gondii-seropositive AIDS patients ultimately developed toxoplasmic encephalitis.(2-4) The risk of toxoplasmosis decreased after introduction of primary prophylaxis against T gondii and effective antiretroviral therapy (ART). The incidence in the United States of toxoplasmic encephalitis among patients diagnosed with AIDS declined from 2.1/100 person-years in 1992 to 0.7/100 person-years in 1997.(5)

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Congenital Transmission of T gondii Infection in HIV-Infected Women
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T gondii infection can be transmitted to a fetus when a woman becomes acutely infected with the parasite during pregnancy.(6) Maternal-fetal transmission of T gondii can also occur in HIV-infected pregnant women who are chronically infected with T gondii, although the risk of transmission is low (no more than 4%).(7,8) The risk of transmission may be higher in severely immunocompromised HIV-infected women. In one study, 1 of the 3 dually infected mothers with CD4 T-cell counts of <100/µL who were not receiving prophylaxis transmitted T gondii infection to her baby.(7)

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Pathogenesis
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Following oral infection, the tachyzoite or invasive form of the parasite disseminates throughout the body. Tachyzoites infect any nucleated cell, where they multiply and lead to cell destruction and production of necrotic foci surrounded by inflammation. The onset of cell-mediated immunity against T gondii is accompanied by the transformation of the parasite into tissue cysts resulting in lifelong chronic infection.

Cellular immunity mediated by T cells, macrophages, and activity of type 1 cytokines (interleukin [IL]-12 and interferon [IFN]-gamma) is necessary for maintaining quiescence of chronic T gondii infection.(9) IL-12 is produced by antigen-presenting cells such as dendritic cells and macrophages. IL-12 stimulates production of IFN-gamma, a major mediator of host protection against intracellular pathogens. IFN-gamma stimulates anti-T gondii activity, not only of macrophages, but also of nonphagocytic cells. The production of IL-12 and IFN-gamma is stimulated by CD154 (also known as CD40 ligand) in human models of T gondii infection.(10) CD154 (expressed primarily on activated CD4 T cells) acts by triggering dendritic cells and macrophages to secrete IL-12, which in turn enhances production of IFN-gamma by T cells.(10) TNF-alpha is another cytokine essential for control of chronic infection with T gondii.(11)

The mechanisms by which HIV induces susceptibility to opportunistic infections such as toxoplasmosis are likely multiple. These include depletion of CD4 T cells; impaired production of IL-2, IL-12, and IFN-gamma; and impaired cytotoxic T-lymphocyte activity.(12) Cells from HIV-infected patients exhibit decreased in vitro production of IL-12 and IFN-gamma, and decreased expression of CD154 in response to T gondii.(13-15) These deficiencies may play a role in the development of toxoplasmosis associated with HIV infection.

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Clinical Presentation
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Toxoplasmosis associated with HIV infection is typically caused by reactivation of a chronic infection and manifests primarily as toxoplasmic encephalitis. This disease is an important cause of focal brain lesions in HIV-infected patients.(2) Characteristically, toxoplasmic encephalitis has a subacute onset with focal neurologic abnormalities frequently accompanied by headache, altered mental status, and fever.(16-18) The most common focal neurologic signs are motor weakness and speech disturbances. Patients can also present with seizures, cranial nerve abnormalities, visual field defects, sensory disturbances, cerebellar dysfunction, meningismus, movement disorders, and neuropsychiatric manifestations.(16-18) Toxoplasmosis rarely presents as a rapidly fatal form of diffuse encephalitis.(19) Diffuse toxoplasmic encephalitis should be considered in patients with anti-T gondii immunoglobulin G (IgG) antibodies and CD4 T-cell counts of <100/µL who present with unexplained neurologic disease.

HIV-infected patients may develop extracerebral toxoplasmosis with or without concomitant encephalitis. Ocular and pulmonary disease are the most common presentations in patients with extracerebral toxoplasmosis.(20) Patients with chorioretinitis present with blurred vision, scotoma, pain, or photophobia.(20) Ophthalmologic examination reveals multifocal, bilateral lesions that typically are more confluent, thick, and opaque than those caused by cytomegalovirus (CMV).(21) Vitritis may be accompanied by anterior uveitis. T gondii is a much less common cause of chorioretinitis in HIV-infected patients than CMV.

Patients with pulmonary toxoplasmosis have a clinical presentation that may be difficult to distinguish from Pneumocystis jiroveci pneumonia.(22,23) A highly lethal syndrome of disseminated toxoplasmosis that consists of fever and sepsislike syndrome with hypotension, disseminated intravascular coagulation, elevated lactic dehydrogenase, and pulmonary infiltrates has been described in HIV-infected patients.(20,22)

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Diagnosis
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T gondii infection is detected by serologic studies. Disease caused by the parasite (toxoplasmosis) can be diagnosed by demonstration of tachyzoites in tissue biopsies or cytologic preparations of body fluids, isolation of T gondii from body fluids or blood, or amplification of parasite DNA in body fluids or blood.

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Serology
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The most commonly used serologic tests detect the presence of anti-T gondii IgG and IgM. IgG antibodies can be detected with the Sabin-Feldman dye test (considered the gold standard), indirect fluorescent antibody (IFA), agglutination, or enzyme-linked immunosorbent assay (ELISA).(1) IgG titers peak within 1-2 months after infection but remain elevated for life. Tests that detect IgM antibodies include double sandwich ELISA, IFA, and immunosorbent agglutination assay (ISAGA).(1) These tests can be helpful because the absence of anti-T gondii IgM virtually excludes recent infection in immunocompetent patients. Although IgM antibodies typically disappear a few weeks or months after infection, they can remain elevated for more than 1 year.(1) Thus, the presence of anti-T gondii IgM antibodies does not necessarily indicate that the infection was acquired recently. This issue is important in the evaluation of pregnant women because congenital transmission of T gondii in immunocompetent women occurs almost exclusively when infection is acquired during gestation. Differential agglutination compares titers obtained with methanol-fixed tachyzoites (AC antigen) and formalin-fixed tachyzoites (HS antigen). The AC/HS ratio is useful to distinguish acute from chronic infection.(1)

Serologic diagnosis of a recent infection usually requires additional tests.(1) Recent T gondii infection is likely when serial specimens obtained at least 3 weeks apart and tested in parallel reveal at least a fourfold increase in IgG titers, or when elevated IgM, IgA, or IgE titers are present in conjunction with an acute profile in the differential agglutination (AC/HS) test.

T gondii serology is useful to identify HIV-infected patients at risk for developing toxoplasmosis. Between 97% and 100% of HIV-infected patients with toxoplasmic encephalitis have anti-T gondii IgG antibodies.(3,16,24) Thus, the absence of antibodies against T gondii makes the diagnosis of toxoplasmosis unlikely in these patients. Most patients with AIDS-associated toxoplasmosis in the United States lack detectable anti-T gondii IgM antibodies because the illness represents reactivation of a chronic infection.

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Cerebrospinal Fluid Studies
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Cerebrospinal fluid (CSF) from patients with toxoplasmic encephalitis may reveal mild pleocytosis of mononuclear predominance and protein elevation.(1) Intrathecal production of anti-T gondii IgG can be calculated with the following formula:

Intrathecal production of anti-T gondii IgG

A ratio >1 indicates intrathecal production of anti-T gondii IgG and supports the diagnosis of toxoplasmic encephalitis.(1) Caution should be exercised when considering lumbar puncture due to the risk of brain herniation if mass effect is present.

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DNA Detection
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Polymerase chain reaction (PCR)-based detection of T gondii DNA can be useful in the diagnosis of toxoplasmosis. PCR in CSF has a sensitivity that varies from 12% to 70% (usually 50-60%) and a specificity of approximately 100% in patients with toxoplasmic encephalitis.(25-27) PCR for T gondii can also be positive in bronchoalveolar lavage fluid and vitreous and aqueous humor of HIV-infected patients with toxoplasmosis.(28,29) A positive PCR in brain tissue does not necessarily indicate active infection because tissue cysts persist in the brain long after acute infection. PCR in blood samples has a low sensitivity for diagnosis of toxoplasmic encephalitis in AIDS patients.(30) Detection of T gondii DNA in amniotic fluid enables diagnosis of intrauterine infection.(31)

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Isolation Studies
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Toxoplasmosis can be diagnosed by isolation of T gondii from cultures of body fluids (blood, CSF, bronchoalveolar lavage fluid) or tissue biopsy specimen in the appropriate clinical setting. Unfortunately, isolation studies may not be helpful for a rapid diagnosis of toxoplasmosis because up to 6 weeks of culture may be required.

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Neuroradiologic Studies
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Imaging studies of the brain are indispensable for diagnosis and management of patients with toxoplasmic encephalitis. Computed tomography (CT) scan reveals multiple, bilateral, hypodense, contrast-enhancing focal brain lesions in 70-80% of patients.(32,33) These lesions tend to involve the basal ganglia and hemispheric corticomedullary junction.(32,33) Contrast enhancement often creates a ringlike pattern surrounding the lesion. Toxoplasmic encephalitis may less frequently present with a single lesion or with no lesions on CT scan.(32,33) Magnetic resonance imaging (MRI) is more sensitive than CT scan and thus is the preferred imaging technique, especially in patients without focal neurologic abnormalities.(34,35) Patients with only one lesion or no lesions on CT scan should undergo MRI to determine whether more than one lesion is present. Although toxoplasmic encephalitis can occasionally cause a single brain lesion on MRI, such a finding suggests an alternative diagnosis (primarily CNS lymphoma).(36)

Findings on MRI and CT scans are not pathognomonic for toxoplasmic encephalitis. Primary CNS lymphoma cannot be distinguished from toxoplasmosis solely on the basis of neuroradiologic criteria (both present as contrast-enhancing lesions with mass effect). However, the presence of hyperattenuation on nonenhanced CT scans and subependymal location suggests the possibility of lymphoma.(37)

Newer imaging techniques appear to be useful for distinction between CNS lymphoma and infectious processes in HIV-infected patients with focal brain lesions. Increased uptake on Thallium 201 single-photon emission computed tomography ([201Tl]-SPECT) is an indicator of malignancy (CNS lymphoma) in HIV-infected patients.(38-41) The sensitivity and specificity of this finding for the diagnosis of CNS lymphoma range from 86% to 100% and from 76% to 100%, respectively.(38-41) Delayed imaging to detect persistent increased uptake (retention index) increases the specificity for CNS lymphoma from 76% to 100%.(40) Fluoride 18 [18F]-fluoro-2-deoxyglucose positron emission tomography (FDG-PET) is another imaging technique reported to differentiate accurately between CNS lymphoma and nonmalignant brain lesions in AIDS patients.(42,43) Whereas areas of decreased glucose metabolism were seen in all patients with toxoplasmic encephalitis, areas with increased glucose metabolism were observed in all patients with CNS lymphoma.(42,43)

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Histopathology
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Excisional brain biopsy can provide a definitive diagnosis of toxoplasmic encephalitis. Findings range from a granulomatous reaction with gliosis and microglial nodules to necrotizing encephalitis.(16,44) The presence of tachyzoites or cysts surrounded by inflammation is considered diagnostic. Detection of the parasite can be improved by the use of immunohistochemistry.(45) Wright-Giemsa stain of CSF, of bronchoalveolar lavage fluid, or of touch preparations of tissue biopsy specimens may reveal the presence of the parasite.

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Differential Diagnosis
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The main differential diagnosis of focal brain lesions in HIV-infected patients is between CNS lymphoma and toxoplasmic encephalitis. In T gondii-seropositive, HIV-infected patients with CD4 T-cell counts <100/µL, who are not receiving anti-T gondii prophylaxis, the presence of multiple enhancing lesions is strongly suggestive of toxoplasmic encephalitis. In patients on prophylaxis, or those with a single brain lesion, the differential diagnosis includes CNS lymphoma, fungal abscess, mycobacterial or cytomegaloviral disease, or Kaposi sarcoma in addition to toxoplasmic encephalitis. The absence of anti-T gondii IgG in serum strongly argues against the diagnosis of toxoplasmic encephalitis.

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Management of Toxoplasmosis in HIV-Infected Patients
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Prior to the widespread use of Toxoplasma prophylaxis and effective ART, empiric anti-T gondii therapy was deemed appropriate for all T gondii-seropositive, HIV-infected patients with focal brain lesions. Improvement on therapy constituted empiric evidence of toxoplasmosis, and brain biopsy was reserved for those who did not improve clinically. Because toxoplasmic encephalitis was the most common cause of focal brain lesions in AIDS patients, many unnecessary brain biopsies were avoided by this approach. However, the incidence of toxoplasmic encephalitis in patients with AIDS has decreased in recent years owing to the use of primary anti-T gondii prophylaxis and effective ART.(5,46-49) In contrast, the frequency of CNS lymphoma has increased in patients with focal brain lesions.(47) Therefore, empiric anti-T gondii therapy for all patients with focal brain lesion without an aggressive diagnostic work up may delay initiation of appropriate therapy and expose patients to potentially unnecessary and toxic regimens.

If available, [201Tl]-SPECT or FDG-PET studies should be obtained in patients with brain lesions not typical of toxoplasmic encephalitis by virtue of their appearance on imaging or other clinical features (such as negative serology for T gondii IgG antibodies, CD4 T-cell count >100/µL, single lesion on MRI, or multiple lesions on MRI or CT scan while receiving primary T gondii prophylaxis). If lumbar puncture is not contraindicated (for example, by the presence of a lesion with mass effect), CSF for PCR studies should also be considered. If these tests are not available, early brain biopsy without awaiting response to anti-T gondii therapy should be considered in these patients. As discussed below, brain biopsy should also be considered in patients who fail to respond to anti-T gondii therapy. The presence of multiple brain lesions in a T gondii-seropositive, HIV-infected patient with a CD4 T-cell count <100/µL who is not receiving anti-T gondii prophylaxis is still considered highly predictive of toxoplasmic encephalitis.(50,51) Thus, awaiting clinical response to empiric anti-T gondii therapy still appears to be an appropriate approach in this setting.(50)

Patients with toxoplasmic encephalitis typically exhibit rapid improvement after initiation of appropriate therapy. Neurologic response is noted in 51% of patients by day 3, and in 91% of patients by day 14.(52) Thus, brain biopsy should be considered when there is no clinical improvement by 10-14 days of therapy, or when there is deterioration by day 3.(52) Most patients will also experience radiologic improvement by the third week of treatment.(33,53) Therefore, neuroradiologic study should be repeated 2-4 weeks after initiation of therapy.

Corticosteroids can be administered to patients with toxoplasmic encephalitis with cerebral edema and intracranial hypertension. Duration of corticosteroid administration should be as short as possible (preferably no more than 2 weeks). The outcome of empiric regimens that include steroids should be interpreted with caution; improvement may be caused exclusively by reduction of inflammation or by response of CNS lymphoma to corticosteroid treatment.

Treatment of AIDS-associated toxoplasmic encephalitis is divided into acute and maintenance therapy. Acute therapy should be administered for no less than 3 weeks, and preferably for 6 weeks if tolerated. More prolonged acute therapy may be required in patients with severe illness who have not achieved a complete response. Thereafter, maintenance therapy is continued to avoid relapse. The improvement in immune function achieved by antiretroviral agents supports their prompt initiation in patients with toxoplasmic encephalitis. Currently, there is no definitive evidence that immune reconstitution inflammatory syndrome occurs in patients with toxoplasmic encephalitis started on antiretroviral therapy.

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Acute Therapy
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Pyrimethamine is considered the cornerstone in the treatment of toxoplasmosis. The combination of pyrimethamine (a dihydrofolate reductase inhibitor) plus sulfadiazine (a dihydrofolate synthase inhibitor) is the standard regimen for treatment of toxoplasmic encephalitis (Table 1). This regimen exhibits synergistic activity against T gondii because it causes a sequential blockade in the pathway of folic acid synthesis. Sulfonamides other than sulfadiazine and trisulfapyrimidines (not available in the United States) are less effective against T gondii. Patients receiving pyrimethamine should also be given folinic acid to prevent hematologic adverse effects. The recommended dose of folinic acid is 10-20 mg orally per day. Higher doses may be necessary in patients with persistent bone marrow suppression.

An initial response to pyrimethamine plus sulfadiazine is noted in 65-90% of patients.(53-55) Unfortunately, adverse effects (primarily rash) may lead to discontinuation of this regimen in up to 40% of patients.(53) Continuation of therapy and administration of antihistamines may be considered in patients with non-life-threatening dermatologic reactions. Sulfadiazine can also cause crystal-induced nephrotoxicity.

The combination of pyrimethamine plus clindamycin is as effective as pyrimethamine plus sulfadiazine during the acute phase of therapy.(55,56) Rash and diarrhea are common adverse effects of pyrimethamine plus clindamycin. A randomized, prospective study reported that trimethoprim-sulfamethoxazole is as effective as pyrimethamine plus sulfadiazine for the treatment of toxoplasmic encephalitis.(57)

Alternative regimens are needed for patients intolerant to sulfonamides and clindamycin. A number of agents exhibit anti-T gondii activity in vitro or in animal models, as well as in case reports. Additional studies are required before these agents can be recommended for routine use in patients with toxoplasmic encephalitis. These agents should be used in combination with pyrimethamine.

It appears that atovaquone oral suspension in combination with either pyrimethamine or sulfadiazine is an effective alternative for treatment of toxoplasmic encephalitis. These regimens resulted in a 77% clinical and radiologic response rate at 6 weeks, and a 5% rate of relapse during maintenance therapy.(58)

Azithromycin and clarithromycin are effective either in vitro or in animal models of toxoplasmosis. A small study of toxoplasmic encephalitis in patients with AIDS reported that clarithromycin plus pyrimethamine resulted in clinical and radiologic response rates of 80% and 50%, respectively.(59) A phase I/II study of azithromycin in combination with pyrimethamine reported a 67% response rate during the acute phase of therapy.(60) Unfortunately, this regimen was associated with a 47% relapse rate.

Although there are limited data, it appears that AIDS patients with extracerebral toxoplasmosis respond to pyrimethamine plus either sulfadiazine or clindamycin. The mortality rate in patients with pulmonary or disseminated toxoplasmosis may be higher than in patients with toxoplasmic encephalitis alone.

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Maintenance Therapy (Secondary Prophylaxis)
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Current anti-T gondii regimens do not eradicate tissue cysts. This is likely to explain why, in the absence of effective ART, 50-80% of patients with AIDS who did not receive maintenance therapy experienced relapse of toxoplasmic encephalitis at 12 months.(61,62) Patients with AIDS-associated toxoplasmosis should therefore be placed on a maintenance regimen upon completion of the acute phase of treatment. Maintenance therapy typically consists of the same drugs used for primary therapy but at lower dosages (Table 2).

A prospective randomized study showed no significant differences in clinical outcomes of patients treated with maintenance therapy consisting of pyrimethamine plus sulfadiazine versus pyrimethamine plus clindamycin.(55) However, another study reported a higher rate of relapse in patents receiving maintenance therapy with pyrimethamine plus clindamycin.(56) Of note, patients in the latter study received a low dose of clindamycin (1,200 mg/day). Pyrimethamine plus sulfadiazine (but not pyrimethamine plus clindamycin) also provides prophylaxis against Pneumocystis pneumonia.(63,64)

Pyrimethamine plus sulfadoxine has been reported to be effective as maintenance therapy.(65) Unfortunately, adverse effects are relatively common. Alternatives for patients who do not tolerate conventional regimens include pyrimethamine alone, or pyrimethamine plus either atovaquone, clarithromycin, or azithromycin.

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Prevention (Primary Prophylaxis)
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T gondii-seronegative, HIV-infected persons should be instructed about measures to prevent acquisition of T gondii infection. These individuals should eat meat only if it is well cooked (internal temperature of 116°C, or no longer pink inside), and should wash their hands after touching undercooked meat. Fruits and vegetables should be washed prior to consumption. Patients should avoid contact with materials that may be contaminated with cat feces; handling cat litter boxes should be avoided, and gloves should be worn during gardening. Cat feces should be disposed of daily to avoid maturation of oocysts, and litter box can be cleaned by exposure to boiling water for 5 minutes.

Primary prophylaxis against toxoplasmosis is recommended in T gondii-seropositive patients with CD4 T-cell counts <100/µL regardless of clinical status, and in patients with CD4 T-cell counts <200/µL if an opportunistic infection or malignancy develops. Trimethoprim-sulfamethoxazole, pyrimethamine-dapsone, and pyrimethamine-sulfadoxine are effective in the prevention of toxoplasmic encephalitis in HIV-infected patients (Table 3).(66-71)

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Discontinuation of Primary and Secondary Prophylaxis
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Although in vitro studies indicate that ART does not fully restore cell-mediated immunity against T gondii in all HIV-infected patients,(14,15) the use of effective ART has been associated with a decline in mortality and incidence of opportunistic infections (including toxoplasmic encephalitis) in HIV-infected patients.(5,46,48,49,72) These findings prompted studies that explored the safety of discontinuing prophylaxis against opportunistic pathogens in patients receiving effective ART.

Observational and randomized studies indicate that it is safe to discontinue primary prophylaxis against T gondii in adult and adolescent patients whose CD4 T-cell counts increase to >200/µL for at least 3 months in response to ART.(49,73-76) It is important to note that the majority of these patients were on protease inhibitor-containing regimens, had CD4 T-cell counts >200/µL for an average of 8 months, with median CD4 T-cell count of >300/µL at study entry, and had undetectable plasma viral load.(73)

There are more limited data regarding the safety of discontinuing chronic maintenance therapy against toxoplasmic encephalitis for patients receiving ART. It appears reasonable to consider stopping maintenance therapy in patients who have completed acute phase treatment for toxoplasmic encephalitis, are free of signs and symptoms attributable to this disease, and have experienced sustained (>6 months) increase in CD4 T-cell count to >200/µL on combination ART.(75,77) Although no studies have directly addressed criteria for restarting prophylaxis, it would be prudent to reinitiate primary and secondary prophylaxis in patients whose CD4 T-cell counts decrease to <200/µL.

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