INTRODUCTION — Toxoplasmosis is the most common central nervous system infection in patients with the acquired immunodeficiency syndrome (AIDS) who are not receiving appropriate prophylaxis [1,2]. This infection has a worldwide distribution and is caused by the intracellular protozoan parasite, Toxoplasma gondii. Immunocompetent persons with primary toxoplasmosis are usually asymptomatic, and latent infection can persist for the life of the host. In immunosuppressed patients, especially patients with AIDS, the parasite can reactivate and cause disease, usually when the CD4 count falls below 100 cells/microL [1,3,4].
This topic will focus on the clinical manifestations, diagnosis, and treatment of toxoplasmosis in patients with HIV. A discussion of toxoplasmosis in immunocompetent hosts is found elsewhere. (See "Toxoplasmosis: Acute systemic disease".)
EPIDEMIOLOGY — The probability of developing reactivated toxoplasmosis is as high as 30 percent among AIDS patients with a CD4 count <100 cells/microL who are toxoplasma seropositive and are not receiving effective prophylaxis or antiretroviral therapy [5-8]. The most common site of reactivation is the central nervous system (CNS).
Transmission — In humans, toxoplasmosis is typically acquired through ingestion of infectious oocysts, usually from soil or cat litter contaminated with feline feces, or undercooked meat from an infected animal. When humans ingest T. gondii oocysts, the organisms invade the intestinal epithelium and disseminate throughout the body. They then encyst in any type of nucleated cell and can lie dormant within tissues for the life of the host. A more detailed discussion on the transmission of toxoplasmosis is found elsewhere. (See "Toxoplasmosis: Acute systemic disease".)
Prevalence of infection — The prevalence of infection with T. gondii varies substantially among different countries and ranges from approximately 11 percent in the United States to more than 80 percent in certain European, Latin American, and African countries [9]. In general, the seroprevalence of antibodies to T. gondii among patients with HIV mirrors the rate of seropositivity in the general population and is not related to owning a cat [10,11]. However, the prevalence may be associated with age. As an example, in a study of women with HIV in the United States, those who were ≥50 years old were more likely to be seropositive compared with younger women (odds ratio 2.4, 95% CI 1.4 to 3.9) [10].
Prior to the introduction of effective antiretroviral therapy (ART), the incidence of toxoplasmic encephalitis (TE) in AIDS patients reflected the seropositivity rates in this population [12]. However, effective ART has decreased the incidence of TE. As an example, among patients with HIV in the United States, the annual number of toxoplasmosis-related hospitalizations peaked at more than 10,000 in 1995, dropped sharply to 3643 in 2001, and then decreased to 2985 in 2008 [13]. (See "The natural history and clinical features of HIV infection in adults and adolescents".)
Extracerebral toxoplasmosis is much less common than CNS disease. This was illustrated in a series of 1699 patients with HIV from France, of whom 116 had confirmed, probable, or possible toxoplasmosis [14]. Cerebral toxoplasmosis was identified in 89 percent of patients, with pulmonary, ocular, and disseminated infection responsible for 6, 3.5, and 1.7 percent of cases, respectively.
The most prominent risk factor for the development of extracerebral toxoplasmosis is advanced immunosuppression (eg, CD4 count <100 cells/microL) [14,15]. In addition, concurrent CNS disease is often seen. In one series of 199 patients with extracerebral toxoplasmosis, CNS disease was also present in 41 percent of patients [15].
CLINICAL PRESENTATION — Reactivation of toxoplasmosis most frequently presents with signs and symptoms of central nervous system disease in patients with HIV and a CD4 count <100 cells/microL. (See 'Toxoplasmic encephalitis' below.)
Extracerebral disease can also occur, and may be present at more than one site [15]. (See 'Extracerebral toxoplasmosis' below.)
There are no routine laboratory findings that are specific for toxoplasmosis. However, the LDH can be markedly increased in patients with disseminated toxoplasmosis and pulmonary disease [16,17]. Evaluation of cerebrospinal fluid (CSF) typically reveals a mild mononuclear pleocytosis and an elevated protein.
Toxoplasmic encephalitis — Patients with toxoplasmic encephalitis typically present with headache and/or other neurologic symptoms. Fever is usually, but not reliably, present. As an example, in a retrospective review of 115 cases, 55, 52, and 47 percent had headache, confusion, and fever, respectively [1]. Focal neurologic deficits or seizures are also common. Mental status changes range from dull affect to stupor and coma and can result from global encephalitis and/or increased intracranial pressure.
Extracerebral toxoplasmosis — Pulmonary and ocular findings are the most common extracerebral manifestations, although disseminated disease can also occur.
Pneumonitis — Toxoplasmic pneumonitis presents with fever, dyspnea, and a non-productive cough [18]. Chest radiographs typically have reticulonodular infiltrates. The clinical picture may be indistinguishable from Pneumocystis jirovecii (formerly carinii) pneumonia (ie, PCP). (See "Toxoplasma pneumonia and other parasitic pulmonary infections in patients with HIV".)
Chorioretinitis — Patients with toxoplasmic chorioretinitis (a posterior uveitis) usually present with eye pain and decreased visual acuity. Toxoplasmic chorioretinitis appears as raised, yellow-white cottony lesions in a non-vascular distribution (unlike the perivascular exudates of CMV retinitis). Chorioretinitis due to T. gondii can rarely mimic acute retinal necrosis [19].
Other manifestations — Toxoplasmosis can rarely present at a variety of other sites, including the gastrointestinal tract, liver, musculoskeletal system, heart, bone marrow, bladder, spinal cord, and testes [15,20,21]. Disseminated disease presenting with septic shock has also been reported and can result from reactivation disease or primary infection [22]. In some cases, involvement of the organ system may only be appreciated on autopsy [23].
DIAGNOSIS
Approach to diagnosis — In the majority of patients, therapy is initiated after making a presumptive, rather than definitive, diagnosis of toxoplasmic encephalitis (TE). (See 'Treatment' below.)
A definitive diagnosis of TE requires a compatible clinical syndrome (eg, headache, neurological symptoms, fever), identification of one or more mass lesions by brain imaging, and detection of the organism in a biopsy specimen [9]. However, for most patients presenting with central nervous system (CNS) disease, a presumptive diagnosis of TE is made in order to avoid a brain biopsy, given the associated morbidity and mortality of the procedure. (See "Approach to the patient with HIV and central nervous system lesions", section on 'Brain biopsy'.)
A presumptive diagnosis can be made if the patient has a CD4 count <100 cells/microL, has not been receiving effective prophylaxis to prevent toxoplasmosis (see 'Primary prophylaxis' below), and has all of the following:
●A compatible clinical syndrome (see 'Toxoplasmic encephalitis' above)
●A positive T. gondii IgG antibody (see 'Serology' below)
●Brain imaging (preferably magnetic resonance imaging) that demonstrates a typical radiographic appearance (eg, multiple ring-enhancing lesions) (see 'Imaging' below)
If these criteria are present, there is a 90 percent probability that the diagnosis is TE [4,24]. For patients who can safely undergo lumbar puncture, analysis of cerebrospinal fluid (CSF) should also be performed to evaluate for evidence of T. gondii, as well as other infectious and non-infectious causes of CNS lesions. If toxoplasmosis is identified using polymerase chain reaction (PCR), the diagnosis of TE is even more likely (see 'Polymerase chain reaction' below). A detailed discussion on the evaluation of individuals with HIV and CNS lesions is found elsewhere. (See "Approach to the patient with HIV and central nervous system lesions".)
An alternative diagnosis becomes more likely if all of the above criteria are not met, CSF evaluation reveals an alternative diagnosis, or the patient has not responded to initial therapy (see 'Response to therapy' below). In such cases, other diagnostic tests and/or brain biopsy should be performed. As an example, if a solitary CNS lesion is detected, even if toxoplasma serology is positive, then evaluation for CNS lymphoma should be performed [25]. Which tests to order depends upon the clinical presentation. (See 'Differential diagnosis' below.)
Establishing a diagnosis of extracerebral toxoplasmosis also depends upon the clinical presentation. For those with pulmonary disease, demonstration of tachyzoites in tissue or fluid (eg, bronchoalveolar lavage) is usually required (see "Approach to the HIV-infected patient with pulmonary symptoms"). For those with ocular manifestations, the diagnosis is made based upon clinical findings consistent with toxoplasmosis. (See 'Chorioretinitis' above.)
Serology — The vast majority of patients with TE are seropositive for anti-toxoplasma IgG antibodies [26]. The absence of antibodies to toxoplasma makes the diagnosis less likely, but does not completely exclude the possibility of TE [9]. Anti-toxoplasma IgM antibodies are usually absent and quantitative IgG antibody titers are not helpful.
Imaging — Magnetic resonance imaging (MRI), if available, is the imaging modality of choice for evaluating patients with possible TE. Most AIDS patients with TE have multiple ring-enhancing brain lesions, often associated with edema. In a report of 45 patients with TE who underwent computed tomography (CT) or MRI, for example, 31 (69 percent) had multiple lesions and 14 had single lesions [27]. There is a predilection for involvement of the basal ganglia [20].
MRI is more sensitive than CT for identifying the lesions associated with TE [28,29]. This was illustrated in a prospective study of 50 patients with AIDS and neurologic symptoms that compared MRI and CT for the evaluation of TE [28]. The MRI influenced the diagnosis and treatment of 20 patients (40 percent) whose lesions were not characterized by CT. However, neither CT nor MRI can adequately distinguish toxoplasmosis from other CNS lesions (eg, CNS lymphoma, cryptococcoma). A discussion on the differential diagnosis of patients with HIV presenting with CNS lesions is found elsewhere. (See 'Differential diagnosis' below and "Approach to the patient with HIV and central nervous system lesions".)
Occasionally performed tests
Nuclear imaging — Thallium single photon emission computed tomography (SPECT) and positron emission tomography (PET) can be useful in distinguishing CNS lymphoma from TE or other infections. Lymphoma has greater thallium uptake on SPECT, and greater glucose and methionine metabolism on PET, compared with TE or other infections [30-32]. This imaging modality is particularly useful for patients with solitary lesions who are poor candidates for brain biopsy [33,34].
Visualization of the organism — A definitive diagnosis of TE is made by visualization of organisms on brain tissue obtained by open or stereotactic brain biopsy. Organisms are typically demonstrated on hematoxylin and eosin stains; however, immunoperoxidase staining may increase the diagnostic sensitivity [35]. Tachyzoites can also been seen in fluid specimens including cytocentrifuged cerebrospinal fluid samples and bronchoalveolar lavage. The sensitivity of brain biopsy is as high as 93 percent [36].
Polymerase chain reaction — Detection of T. gondii by PCR in cerebrospinal fluid has demonstrated high specificity (96 to 100 percent), but variable sensitivity (50 to 98 percent), depending upon the primers used [37-39]. Treatment also affects diagnostic sensitivity. Thus, a positive PCR result establishes the diagnosis of TE, but a negative one does not rule it out.
DIFFERENTIAL DIAGNOSIS
Central nervous system disease — The differential diagnosis of toxoplasmic encephalitis (TE) includes central nervous system (CNS) lymphoma, mycobacterial infection, cryptococcosis, bacterial abscess, and uncommonly, progressive multifocal leukoencephalopathy. Testing of cerebrospinal fluid for pathogens associated with these conditions (eg, Epstein-Barr virus [EBV], JC virus, Mycobacterium tuberculosis, Cryptococcus neoformans) can be used to help identify these alternative causes of infection [36]. A detailed discussion on the evaluation of patients with HIV and central nervous system lesions is found elsewhere (algorithm 1). (See "Approach to the patient with HIV and central nervous system lesions".)
Extracerebral disease — For patients with extracerebral toxoplasmosis, the differential depends upon the organ system involved. As examples:
●The differential diagnosis of pulmonary symptoms in individuals with HIV is broad and can include bacterial, viral, mycobacterial, and fungal pathogens. A discussion on the differential diagnosis of individuals with HIV and pulmonary symptoms and the approach to diagnosis are discussed separately. (See "Clinical presentation and diagnosis of Pneumocystis pulmonary infection in patients with HIV", section on 'Differential diagnosis' and "Approach to the HIV-infected patient with pulmonary symptoms".)
●The ocular manifestations of toxoplasmosis can be confused with other infections in HIV, such as retinitis resulting from cytomegalovirus and acute retinal necrosis due to varicella-zoster virus. (See "Pathogenesis, clinical manifestations, and diagnosis of AIDS-related cytomegalovirus retinitis", section on 'Clinical manifestations' and "Epidemiology, clinical manifestations, and diagnosis of herpes zoster", section on 'Acute retinal necrosis'.)
TREATMENT — The treatment of toxoplasmosis in patients with HIV includes antimicrobial therapy directed against T. gondii, as well as antiretroviral therapy (ART) for immune recovery. A more detailed discussion on the use of ART is found elsewhere. (See "Selecting antiretroviral regimens for treatment-naïve persons with HIV-1: General approach" and 'When to initiate antiretroviral therapy' below.)
Antimicrobial therapy targeted against T. gondii involves an initial phase to treat the acute symptoms, followed by maintenance therapy to reduce the risk of recurrence. Extracerebral toxoplasmosis is treated with the same regimens as toxoplasmic encephalitis (TE), although the response may not be as favorable [15]. For certain patients (eg, those on ART with immune recovery), maintenance therapy can be discontinued.
Initial therapy
Preferred regimens — We prefer an initial regimen containing sulfadiazine and pyrimethamine. This regimen is more effective compared with the alternative choices (eg, pyrimethamine plus clindamycin); however, it is associated with a higher incidence of cutaneous hypersensitivity reactions [40]. Patients receiving sulfadiazine therapy do not require additional trimethoprim-sulfamethoxazole (TMP-SMX) for prophylaxis against P. jirovecii infections (ie, PCP). (See "Overview of prevention of opportunistic infections in patients with HIV".)
The initial drug regimen is given orally and should be dosed as follows [9,27,40-42]:
●Sulfadiazine (1000 mg four times daily among patients <60 kg or 1500 mg four times daily among patients ≥60 kg). If there are concerns about non-adherence, 2000 mg of sulfadiazine can be administered twice daily; one study documented equivalent pharmacokinetic parameters of this dosing schedule compared with 1000 mg given four times a day [43].
●Pyrimethamine (200 mg loading dose followed by 50 mg daily among patients <60 kg or 75 mg daily among patients ≥60 kg).
●Leucovorin (10 to 25 mg daily). This agent should be administered to prevent pyrimethamine-induced hematologic toxicity.
Parenteral TMP-SMX can be used for treatment of toxoplasmic encephalitis in severely ill patients who cannot take oral therapy [9] (see 'Alternative regimens' below). Patients can then transition to the above regimen when they are more stable.
The approach to treatment if pyrimethamine is not available expeditiously and a discussion of patient monitoring on treatment (including potential adverse reactions) are found below. (See 'If pyrimethamine is not available' below and 'Monitoring of initial therapy' below.)
Alternative regimens — For patients who cannot take sulfadiazine, we administer clindamycin (600 mg intravenously or orally four times a day) plus oral pyrimethamine (200 mg loading dose followed by 50 mg daily among patients <60 kg or 75 mg daily among patients ≥60 kg) plus oral leucovorin (10 to 25 mg daily).
For patients without a sulfa allergy, trimethoprim-sulfamethoxazole (TMP-SMX; 5 mg/kg trimethoprim and 25 mg/kg sulfamethoxazole given orally or intravenously twice daily) is another alternative. In a randomized study involving 77 patients, TMP-SMX was as effective as pyrimethamine-sulfadiazine [44]. Observational studies and a systematic review also support the choice of TMP-SMX when pyrimethamine cannot be used or is not available [45,46]. TMP-SMX is frequently used in resource-limited settings given the low cost [47]. Similarly, TMP-SMX should be used in the United States if pyrimethamine cannot be obtained expeditiously because of its high price [44,45]. (See 'If pyrimethamine is not available' below.)
Several other alternatives have been used for patients who are unable to tolerate more commonly used regimens [48-51]. These include:
●Atovaquone (1500 mg PO twice daily) plus pyrimethamine (200 mg loading dose followed by 50 mg daily among patients <60 kg or 75 mg daily among patients ≥60 kg) plus leucovorin (10 to 25 mg PO once daily).
●Atovaquone (1500 mg PO twice daily) plus sulfadiazine (1000 mg PO four times daily among patients <60 kg or 1500 mg PO four times daily among patients ≥60 kg).
●Atovaquone (1500 mg PO twice daily).
If the alternative regimen does not include TMP-SMX or atovaquone, an additional agent should be administered to prevent Pneumocystis pneumonia. (See "Treatment and prevention of Pneumocystis infection in patients with HIV", section on 'Regimens for prophylaxis'.)
The approach to treatment if pyrimethamine is not available and a discussion of patient monitoring on treatment (including potential adverse reactions) are found below. (See 'If pyrimethamine is not available' below and 'Monitoring of initial therapy' below.)
If pyrimethamine is not available — Most of the preferred and alternative regimens for the treatment of toxoplasmosis include pyrimethamine. However, as of June 2015, access to pyrimethamine has been limited in the United States because of its high price, and this agent must be obtained through a manufacturer-run program or from a compounding pharmacy. Information on how to obtain pyrimethamine can be found through online resources provided in the Lexicomp drug monograph within UpToDate.
If pyrimethamine cannot be obtained expeditiously, TMP-SMX (in patients without a sulfonamide allergy) or atovaquone (in patients with a sulfonamide allergy) should be used instead [52]. (See 'Alternative regimens' above.)
For patients with a sulfonamide allergy, sulfa desensitization should be attempted in those without a history of a severe reaction (eg, Stevens Johnson Syndrome); atovaquone should be administered until patients are receiving a therapeutic dose of TMP-SMX [9]. More detailed discussions on sulfonamide allergy and desensitization are found elsewhere. (See "Sulfonamide allergy in HIV-uninfected patients", section on 'Types of hypersensitivity reactions' and "Treatment and prevention of Pneumocystis infection in patients with HIV", section on 'Desensitization for patients with a sulfa allergy'.)
Adjunctive therapies — There are several therapies that can be administered to help manage the complications of TE. These include:
●Corticosteroids – Adjunctive corticosteroids should only be used for patients with mass effect related to focal brain lesions or edema (eg, individuals with radiographic evidence of midline shift). Dexamethasone (4 mg every six hours) is usually chosen and is generally tapered over several days.
When corticosteroids are used, it may be difficult to assess response to therapy since corticosteroids can result in a rapid improvement in symptoms. Radiographic assessments may also be affected since the corticosteroids will reduce the intensity of ring-enhancement and the amount of surrounding edema. Patients should also be carefully monitored for the development of other opportunistic infections.
●Anticonvulsants – Anticonvulsants should be administered to patients who present with seizures. They should not be given routinely for prophylaxis to all patients with a presumed diagnosis of TE [9]. Careful attention needs to be paid to any potential drug interactions.
Monitoring of initial therapy — The monitoring of patients with TE includes assessment for adverse drug reactions and clinical improvement, as well as serial brain imaging. There is no value of following IgG toxoplasma antibody titers. (See 'Serology' above.)
Adverse reactions — Common side effects of pyrimethamine include rash, nausea, and bone marrow suppression. Higher doses of leucovorin, (50 mg daily or twice daily), can be administered for management of hematologic abnormalities [9]. Sulfadiazine can lead to rash, fever, leukopenia, hepatitis, nausea, vomiting, diarrhea, and crystalluria (leading to renal insufficiency). Clindamycin can also lead to fever, rash, and nausea; its use is also associated with diarrhea related to production of Clostridioides difficile toxin.
Response to therapy — For patients with TE, we assess for clinical improvement during the first two weeks of therapy. Clinical improvement usually precedes radiographic improvement. Thus, careful daily neurologic examinations are more important than radiographic studies in assessing the initial response to therapy.
We perform neuroimaging after two to three weeks of treatment, or sooner if the patient has not demonstrated clinical improvement within the first week or has shown any worsening. Lack of clinical and/or radiographic improvement within 10 to 14 days of starting empiric therapy for TE should raise the possibility of an alternative diagnosis. Brain biopsy should be considered in such patients. (See "Approach to the patient with HIV and central nervous system lesions".)
Approximately 75 to 80 percent of patients treated for TE demonstrate clinical and radiologic improvement [27,50]. As an example, in a study of 49 patients treated for TE with pyrimethamine plus clindamycin, 35 (71 percent) responded overall with the vast majority demonstrating ≥50 percent improvement in their baseline abnormalities by day 14 of therapy [27]. However, the literature dealing with response to therapy is hampered by presumptive diagnoses, cross-over treatments, and discontinuation for toxicity, rather than lack of clinical response.
Duration of initial therapy — For patients who respond to treatment, the duration of initial therapy is typically six weeks at the doses recommended above (see 'Initial therapy' above). Following that, it is usually safe to administer lower doses for chronic maintenance therapy (also referred to as secondary prophylaxis). (See 'Maintenance therapy' below.)
Special considerations during pregnancy — Pregnant women who acquire toxoplasmosis during pregnancy should be managed in conjunction with a maternal-fetal medicine specialist. A detailed discussion on the diagnosis and management of pregnant women with primary toxoplasmosis infection is found elsewhere. (See "Toxoplasmosis and pregnancy".)
Patients with HIV who become pregnant are typically managed by a maternal-fetal medicine specialist in conjunction with an infectious disease specialist. The approach to treatment of such women who develop TE should be the same as in the nonpregnant adult [9]. Although pyrimethamine has been associated with birth defects in animals, limited human data have not suggested an increased risk for defects, and guidelines endorse its use in pregnant women after the first trimester [9,53]. In addition, ultrasound examination of the fetus should be performed to assess for evidence of congenital infection (eg, hydrocephalus, cerebral calcifications, and growth restriction) [9]. There have been case reports of T. gondii transmission from women with HIV and significant immunosuppression and symptomatic reactivation disease to their fetus [54]. Congenital transmission of T. gondii among asymptomatic women with HIV who are not immunosuppressed has not been reported [55-57].
Maintenance therapy — We transition most patients to maintenance therapy after six weeks of treatment with the initial regimen. This includes both patients with TE and extracerebral disease. The goal of maintenance therapy (also referred to as secondary prophylaxis) is to prevent relapse of infection. For patients with TE, we perform neuroimaging prior to this transition to establish a new baseline. This information can be useful if there is concern for relapse or an immune reconstitution inflammatory syndrome (IRIS). (See "Immune reconstitution inflammatory syndrome".)
Regimens for maintenance therapy — For maintenance therapy, a combination of sulfadiazine and pyrimethamine should be continued, but at lower doses than those used for initial treatment. We follow guidelines that suggest sulfadiazine be administered as 2000 to 4000 mg daily in two to four divided doses with pyrimethamine 25 to 50 mg daily and leucovorin 10 to 25 mg daily [9]. We favor twice-daily dosing of sulfadiazine for patient convenience, and typically administer 1000 mg twice daily for individuals <60 kg, and 1500 mg twice daily for individuals ≥60 kg.
Other alternative oral regimens include [9]:
●Clindamycin (600 mg every eight hours) plus pyrimethamine (25 to 50 mg daily) plus leucovorin (10 to 25 mg daily) [9,40]. If this regimen is used, an additional agent should be administered to prevent Pneumocystis pneumonia. (See "Treatment and prevention of Pneumocystis infection in patients with HIV", section on 'Regimens for prophylaxis'.)
●Trimethoprim-sulfamethoxazole one double strength tablet twice daily [44,58].
●Atovaquone (750 to 1500 mg twice daily) with pyrimethamine (25 mg daily) plus leucovorin (10 mg daily) [9,49,59].
●Atovaquone (750 to 1500 mg twice daily) with sulfadiazine (2000 to 4000 mg daily in two to four divided doses).
●Atovaquone monotherapy (750 to 1500 mg twice daily) can be administered to patients who cannot tolerate pyrimethamine, but the one-year relapse rate may be higher (26 percent) [59].
Discontinuing maintenance therapy — Chronic maintenance therapy (ie, secondary prophylaxis) for TE can be discontinued in asymptomatic patients who have completed initial therapy if they are receiving antiretroviral therapy (ART), have a suppressed HIV viral load, and have maintained a CD4 count >200 cells/microL for at least six months [9]. Various studies show that immune responses against T. gondii are restored in such patients [60,61]. Patients who stop maintenance therapy should be educated to seek medical attention for recurrent symptoms since relapses have been reported [60,62-65]. Maintenance therapy should be reinitiated if the CD4 cell count declines to <200 cells/microL. A discussion of when to initiate ART is found below. (See 'When to initiate antiretroviral therapy' below.)
We do not use neuroimaging to guide our decision about when to stop secondary prophylaxis. We repeat neuroimaging after induction therapy to get a post-treatment baseline and monitor patients clinically for relapse. However, some experts obtain magnetic resonance imaging of the brain to decide if it is safe to stop maintenance therapy, and they base their decision upon the presence of residual disease.
TOXOPLASMOSIS AND IMMUNE RECONSTITUTION SYNDROME (IRIS) — The term "immune reconstitution inflammatory syndrome" (IRIS) describes a collection of inflammatory disorders associated with paradoxical worsening of pre-existing infectious processes following the initiation of effective antiretroviral therapy (ART) in individuals with HIV [66-71]. (See "Immune reconstitution inflammatory syndrome".)
IRIS can complicate central nervous system (CNS) infections, as has been well described for mycobacteria and cryptococcal infections. However, fewer cases of IRIS related to CNS toxoplasmosis have been reported [72,73]. IRIS in association with toxoplasmosis can lead to a paradoxical worsening of symptoms with worsening edema surrounding brain lesions as CD4 cell counts rapidly improve [73]. Management includes continuing treatment for toxoplasmic encephalitis (TE) and antiretroviral treatment for HIV, and increasing the dose of steroids, as needed, to control symptoms. If the diagnosis of IRIS is unclear, a biopsy may be needed to rule out an alternative process, such as lymphoma [73].
In patients without a prior diagnosis of TE, IRIS can present as an "unmasking" of an infection that previously existed, but was not diagnosed until the onset of immune recovery. In one case series of 65 patients with TE, three were diagnosed with CNS disease only after the initiation of ART [74]. In such patients, symptoms occurred at a median time of 41 days after starting antiretroviral therapy and at a median CD4 count of 222 cells/microL.
WHEN TO INITIATE ANTIRETROVIRAL THERAPY — Most patients with toxoplasmosis are not receiving antiretroviral therapy (ART) at the time of diagnosis. We initiate ART within two weeks of starting treatment for toxoplasmosis, typically as soon as it is clear that the patient is tolerating toxoplasmosis therapy. Although there are no definitive studies on the optimal time to initiate antiretroviral therapy in patients with toxoplasmosis, the benefits of early ART (eg, reduced disease progression and death) have been demonstrated in patients with a variety of opportunistic infections, including some with toxoplasmosis [9,75].
PREVENTION — For patients with HIV, the risk of developing toxoplasmosis can be reduced by avoiding exposure to the pathogen or by using prophylactic antibiotics to decrease the risk of reactivation. All patients with HIV should be tested for prior exposure to T. gondii by measuring anti-toxoplasma IgG, ideally when first diagnosed with HIV [76].
●For patients without evidence of prior infection with toxoplasmosis, initial infection can be prevented by taking certain precautions. This is discussed in detail elsewhere. (See "Toxoplasmosis: Acute systemic disease", section on 'Prevention'.)
●For individuals with evidence of prior toxoplasmosis (ie, those with a positive serology), antimicrobial therapy can decrease the risk of developing reactivation disease. This is referred to as primary prophylaxis and is described below.
Primary prophylaxis — Primary prophylaxis is indicated for patients with HIV and CD4 counts <100 cells/microL who are T. gondii IgG-positive. Most data on the efficacy of primary prophylaxis for toxoplasmosis come from retrospective analyses of trials evaluating antimicrobial treatment to prevent Pneumocystis infection [77-80]. The risk of developing toxoplasmic encephalitis (TE) for patients with AIDS who are using primary prophylaxis is 0 to 2.4 percent for TMP-SMX and 0 to 11 percent for dapsone-pyrimethamine [81]. Atovaquone for primary prophylaxis of toxoplasmosis has not been studied, and the recommendation for its use as an alternate agent for primary prophylaxis is based upon its efficacy in the treatment of TE. (See 'Alternative regimens' above.)
We administer trimethoprim-sulfamethoxazole (TMP-SMX) as primary prophylaxis against reactivation. We administer one double strength (DS) tablet (800 mg/160 mg) per day. However, for patients unable to tolerate this dose, TMP-SMX can be given as one DS tablet three times per week or one single strength tablet (400 mg/80 mg) daily. If the patient cannot take TMP-SMX, we use one of the following oral regimens [9]:
●Dapsone (50 mg once daily) plus pyrimethamine (50 mg per week) plus leucovorin (25 mg per week)
●Dapsone (200 mg per week) plus pyrimethamine (75 mg per week) plus leucovorin (25 mg per week)
●Atovaquone (1500 mg once daily) with or without pyrimethamine (25 mg once daily); if pyrimethamine is given, leucovorin (10 mg daily) should also be used
Monotherapy with dapsone, pyrimethamine, azithromycin, or clarithromycin is not recommended.
For pregnant women who have a CD4 cell count <100 cells/microL, the benefit of prophylaxis must be weighed against the risk to the fetus. The specific risks depend upon the type of prophylaxis used. A discussion on the risk of TMP-SMX during pregnancy is found elsewhere. (See "Prenatal evaluation of women with HIV in resource-rich settings", section on 'Chemoprophylaxis for opportunistic infections'.)
Discontinuation of primary prophylaxis — Patients receiving antiretroviral therapy can safely discontinue primary prophylaxis for toxoplasmosis if their HIV viral load is suppressed and their CD4 count is >200 cells/microL for at least three months [9,82,83]. This is supported by a study of 199 patients who discontinued primary prophylaxis for toxoplasmosis after having a sustained increase in their CD4 count (>200 cells/microL) for >12 weeks while receiving ART [82]. None of the patients developed toxoplasmic encephalitis during a follow-up of 272 person-years. Prophylaxis should be reinstated if the CD4 count drops to <100 to 200 cells/microL [9].
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Opportunistic infections in adults and adolescents with HIV" and "Society guideline links: Toxoplasmosis".)
SUMMARY AND RECOMMENDATIONS
●The probability of developing reactivated toxoplasmosis is as high as 30 percent among AIDS patients with a CD4 count <100 cells/microL who are toxoplasma seropositive and are not receiving effective prophylaxis or antiretroviral therapy. (See 'Epidemiology' above.)
●Reactivation of toxoplasmosis most frequently presents with signs and symptoms of central nervous system disease in patients with HIV and a CD4 count <100 cells/microL. Extracerebral disease can also occur and may be present at more than one site. (See 'Clinical presentation' above.)
●In the majority of patients, therapy is initiated after making a presumptive, rather than definitive, diagnosis of toxoplasmic encephalitis (TE). (See 'Approach to diagnosis' above.)
●A presumptive diagnosis of TE can be made if the patient has a CD4 count <100 cells/microL, has not been receiving effective prophylaxis for toxoplasma, and has all of the following (see 'Approach to diagnosis' above):
•A compatible clinical syndrome (see 'Toxoplasmic encephalitis' above)
•A positive T. gondii IgG antibody (see 'Serology' above)
•Brain imaging (preferably magnetic resonance imaging) that demonstrates a typical radiographic appearance (eg, multiple ring-enhancing lesions) (see 'Imaging' above)
●The differential diagnosis of TE includes central nervous system (CNS) lymphoma, tuberculoma, cryptococcoma, bacterial abscess, and uncommonly, progressive multifocal leukoencephalopathy. (See 'Differential diagnosis' above.)
●The treatment of toxoplasmosis in patients with HIV includes antimicrobial therapy directed against T. gondii, as well as antiretroviral therapy (ART) for immune recovery. (See 'Treatment' above.)
●We prefer an initial regimen containing sulfadiazine and pyrimethamine. This regimen is more effective compared with the alternative choices (eg, pyrimethamine plus clindamycin), although it is associated with a higher incidence of cutaneous hypersensitivity reactions. If pyrimethamine cannot be obtained expeditiously because of its high price, then we use trimethoprim-sulfamethoxazole instead. (See 'Initial therapy' above.)
●For patients who respond to treatment, the duration of initial therapy is typically six weeks at the doses recommended above. Following that, it is usually safe to administer lower doses for chronic maintenance therapy. (See 'Duration of initial therapy' above and 'Maintenance therapy' above.)
●Most patients with toxoplasmosis are not on antiretroviral therapy (ART) at the time of diagnosis. We initiate ART within two weeks of starting treatment for toxoplasmosis, typically as soon as it is clear that the patient is tolerating toxoplasmosis therapy. (See 'When to initiate antiretroviral therapy' above.)
●For patients with HIV, the risk of developing toxoplasmosis can be reduced by avoiding exposure to the pathogen or by using prophylactic antibiotics to decrease the risk of reactivation. (See 'Prevention' above.)
ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Howard Heller, MD, MPH, who contributed to an earlier version of this topic review.
We are saddened by the death of John G Bartlett, MD, who passed away in January 2021. UpToDate gratefully acknowledges Dr. Bartlett's role as section editor on this topic, his tenure as the founding Editor-in-Chief for UpToDate in Infectious Diseases, and his dedicated and longstanding involvement with the UpToDate program.