Toxoplasmosis in patients with HIV

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

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 [5]. 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 [6,7]. 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) [6]. (See "Toxoplasmosis: Acute systemic disease", section on 'Epidemiology'.)

Risk of reactivation — The probability of developing reactivated toxoplasmosis is as high as 30 percent among patients with a CD4 count <100 cells/microL who are toxoplasma seropositive and are not receiving effective prophylaxis or antiretroviral therapy [8-11]. The most common site of reactivation is the central nervous system (CNS).

Prior to the introduction of effective antiretroviral therapy (ART), the incidence of toxoplasmic encephalitis (TE) in patients with AIDS 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 [5]. 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 "Evaluation of pulmonary symptoms in persons with HIV"). 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 [5]. 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 "Epidemiology, clinical presentation, and diagnosis of Pneumocystis pulmonary infection in patients with HIV", section on 'Differential diagnosis' and "Evaluation of pulmonary symptoms in persons with HIV".)

●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. Extracerebral toxoplasmosis is treated with the same regimens as toxoplasmic encephalitis (TE), although the response may not be as favorable [15].

Antimicrobial therapy

Initial therapy — Antimicrobial therapy targeted against T. gondii involves an initial phase to treat the acute symptoms. For patients who respond to treatment, the duration is typically six weeks. Following that, patients should be transitioned to maintenance therapy to reduce the risk of recurrence. (See 'Maintenance therapy' below.)

Preferred regimens — For patients with toxoplasmosis we suggest either of the following regimens:

●Sulfadiazine plus pyrimethamine – This drug regimen is only given orally and should be dosed as follows [5,27,40-42]:

•Sulfadiazine (1000 mg orally four times daily among patients <60 kg or 1500 mg four times daily among patients ≥60 kg). If there are concerns about nonadherence, 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) should also be administered to prevent pyrimethamine-induced hematologic toxicity.

●Trimethoprim-sulfamethoxazole (TMP-SMX) – 5 mg/kg trimethoprim and 25 mg/kg sulfamethoxazole given orally or intravenously twice daily.

Patients receiving either of these regimens do not require additional prophylaxis against P. jirovecii infections (ie, PCP). (See "Overview of prevention of opportunistic infections in patients with HIV".)

Traditionally, sulfadiazine plus pyrimethamine was the preferred regimen since early studies found it to be more effective compared with alternative choices, such as clindamycin plus pyrimethamine [41], and there was most experience with this regimen. However, TMP-SMX is frequently used in resource-limited settings given the low cost [44] and has been increasingly used in resource-rich settings since access to pyrimethamine has been limited [45]. Available data suggest TMP-SMX is as effective as sulfadiazine plus pyrimethamine, and it may be better tolerated [46-48]. In a systematic review that compared sulfadiazine plus pyrimethamine with several regimens, including TMP-SMX, these two regimens had similar rates of partial or complete clinical response as well as a similar risk of adverse events such as skin rash [48].

Patients with sulfonamide allergy — There are several treatment options for patients with a sulfonamide allergy. These include:

●Clindamycin plus pyrimethamine – For patients who cannot take sulfonamides, we typically prefer 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). Patients who receive clindamycin plus pyrimethamine must receive an additional agent for prevention of Pneumocystis pneumonia. (See "Treatment and prevention of Pneumocystis infection in patients with HIV", section on 'Patients with a sulfa allergy'.)

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, people receiving this regimen may be more likely to relapse compared to those receiving sulfadiazine plus pyrimethamine [41].

●Sulfa desensitization – If pyrimethamine is not available, sulfa desensitization should be attempted in those without a history of a severe reaction (eg, Stevens Johnson Syndrome). Atovaquone (1500 mg orally twice daily) should be administered until the patient is able to tolerate a therapeutic dose of TMP-SMX [5]. Additional information on sulfonamide allergy and TMP-SMX desensitization are presented 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'.)

●Atovaquone containing regimen – Several different atovaquone containing regimens can be used for treatment of toxoplasmosis. These include [49-52]:

•Atovaquone (1500 mg orally 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 orally once daily).

•Atovaquone (1500 mg orally twice daily) plus sulfadiazine (1000 mg orally four times daily among patients <60 kg or 1500 mg orally four times daily among patients ≥60 kg).

•Atovaquone (1500 mg orally twice daily).

Although atovaquone is usually well tolerated, we prefer one of the other approaches for treatment of toxoplasmosis since there is variable absorption of atovaquone.

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 [5]. Careful attention needs to be paid to any potential drug interactions.

Patient monitoring — 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 [5]. 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 [27,51]. 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.

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 [5]. Although pyrimethamine has been associated with birth defects in animals, limited human data have not suggested an increased risk of teratogenicity, and guidelines endorse its use in pregnant women after the first trimester [5,53]. In addition, ultrasound examination of the fetus should be performed to assess for evidence of congenital infection (eg, hydrocephalus, cerebral calcifications, and growth restriction) [5]. 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. (See 'Initial therapy' above.)

The goal of maintenance therapy (also referred to as secondary prophylaxis) is to prevent relapse of infection. Antimicrobial therapy is only active against the tachyzoite form (not the cyst form); thus, relapse of infection may occur after initial therapy unless the patient has immunologic recovery [4].

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 — We suggest one of the following regimens for maintenance therapy:

●Sulfadiazine (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) [5]. 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.

●TMP-SMX (one double strength tablet twice daily) [46,58].

In one study that was conducted before the introduction of effective ART, the relapse rate in patients receiving sulfadiazine plus pyrimethamine maintenance therapy was 11 percent [41]. In a subsequent study of 17 patients who were receiving protease-inhibitor based ART, only one relapse occurred when TMP-SMX was used for maintenance therapy [58].

Alternative oral maintenance regimens include [5]:

●Clindamycin (600 mg every eight hours) plus pyrimethamine (25 to 50 mg daily) plus leucovorin (10 to 25 mg daily) [5,41]. 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'.)

●Atovaquone (750 to 1500 mg twice daily) with pyrimethamine (25 mg daily) plus leucovorin (10 mg daily) [5,50,59].

●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 ART, have a suppressed HIV viral load, and have maintained a CD4 count >200 cells/microL for at least six months [5]. Various studies show that immune responses against T. gondii are restored in such patients [60,61].

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.

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 'Antiretroviral therapy' below.)

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 ART 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 [5,66].

Detailed discussions of ART are found elsewhere. (See "When to initiate antiretroviral therapy in persons with HIV", section on 'Patients with opportunistic infections' and "Selecting antiretroviral regimens for treatment-naïve persons with HIV-1: General approach" and "Selecting antiretroviral regimens for treatment-naive persons with HIV-1: Patients with comorbid conditions".)

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 [67-72]. (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 [73,74]. 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 [74]. 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 [74].

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 [75]. 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.

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.

Assessing for prior exposure — 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. (See 'Primary prophylaxis' below.)

Primary prophylaxis — Patients with HIV and a CD4 count <100 cells/microL should receive antimicrobial prophylaxis to prevent toxoplasmosis if they are T. gondii IgG positive. The probability of developing reactivated toxoplasmosis is as high as 30 percent among patients with a CD4 count <100 cells/microL who are toxoplasma seropositive and are not receiving effective prophylaxis or antiretroviral therapy [8-11].

●Our preferred regimen is trimethoprim-sulfamethoxazole (TMP-SMX) one double strength (DS) tablet (800 mg/160 mg) per day. 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, one of the following oral regimens can be used [5]:

•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.

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]. In patients with AIDS, the risk of developing toxoplasmic encephalitis (TE) in those 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 'Patients with sulfonamide allergy' above.)

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 [5,82,83]. 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 antiretroviral therapy (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 [5].

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 with HIV" and "Society guideline links: Toxoplasmosis".)

SUMMARY AND RECOMMENDATIONS

●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. (See 'Epidemiology' above.)

●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. Extracerebral disease can also occur and may be present at more than one site. (See 'Clinical presentation' above.)

●Diagnosis – 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)

●Differential diagnosis – The differential diagnosis of TE includes central nervous system (CNS) lymphoma, tuberculoma, cryptococcoma, bacterial abscess, and uncommonly, progressive multifocal leukoencephalopathy. (See 'Differential diagnosis' above.)

●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. (See 'Treatment' above.)

•Initial therapy – For most patients, we suggest an initial regimen containing sulfadiazine plus pyrimethamine or trimethoprim-sulfamethoxazole (TMP-SMX) (Grade 2C). While data are limited, these regimens appear to be similarly effective and many people use TMP-SMX as it is more universally available. (See 'Preferred regimens' above.)

If the patient cannot tolerate a sulfonamide, alternative regimens include pyrimethamine plus clindamycin or an atovaquone-containing regimen. (See 'Patients with sulfonamide allergy' above.)

For patients who respond to treatment, the duration of initial therapy is typically six weeks. (See 'Initial therapy' above.)

•Maintenance therapy – For patients who complete initial therapy, we suggest maintenance therapy (ie, secondary prophylaxis) with sulfadiazine plus pyrimethamine or TMP-SMX (Grade 2C). Relapse of infection can occur after initial therapy unless the patient has immunologic recovery. (See 'Regimens for maintenance therapy' above.)

Maintenance therapy can be discontinued in asymptomatic patients who are receiving ART, have a suppressed HIV viral load, and have maintained a CD4 count >200 cells/microL for at least six months. (See 'Discontinuing maintenance therapy' above.)

●Antiretroviral therapy – Most patients with toxoplasmosis are not on 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 'Antiretroviral therapy' above.)

●Primary prevention – For patients with HIV without evidence of prior T. gondii infection (T.gondii IgG negative), the risk of developing toxoplasmosis can be reduced by avoiding exposure to the pathogen.

By contrast, for those who are T.gondii IgG positive with a CD4 cell count <100 cells/microL, we suggest prophylactic TMP-SMX (Grade 2C). Prophylactic therapy with TMP-SMX reduces the risk of reactivating latent T. gondii. Our preferred regimen is one double strength (DS) tablet (800 mg/160 mg) per day. (See 'Prevention' above.)

ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Howard Heller, MD, MPH, who contributed to an earlier version of this topic review.

UpToDate also gratefully acknowledges John G Bartlett, MD (deceased), who contributed as Section Editor on earlier versions of this topic and was a founding Editor-in-Chief for UpToDate in Infectious Diseases.