HIV opportunistic infection toxoplasma gondii encephalitis: prevention and treatment guidelines

# Overview
Toxoplasmic encephalitis (TE) is caused by the protozoan Toxoplasma gondii. Disease appears to occur almost exclusively because of reactivation of latent tissue cysts.

# Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents
Outline of the Guideline:
- Preventing Exposure
- Preventing Disease
Initiating Primary Prophylaxis
Discontinuing Primary Prophylaxis
- Initiating Primary Prophylaxis
- Discontinuing Primary Prophylaxis
- Treatment of Disease
- Monitoring and Adverse Events
- Management of Treatment Failure
- Prevention of Recurrence
- Special Considerations During Pregnancy

# Preventing Exposure
HIV-infected persons should be tested for IgG antibody to Toxoplasma soon after the diagnosis of HIV infection to detect latent infection with T. gondii (BIII).
HIV-infected persons, including those who lack IgG antibody to Toxoplasma, should be counseled regarding sources of Toxoplasma infection. To minimize risk for acquiring toxoplasmosis, HIV-infected persons should be advised not to eat raw or undercooked meat, including undercooked lamb, beef, pork, or venison (BIII). Specifically, lamb, beef, venison, and pork should be cooked to an internal temperature of 165oF--170oF; meat cooked until it is no longer pink inside usually has an internal temperature of 165oF--170oF and therefore, from a more practical perspective, satisfies this requirement. To minimize the risk for acquiring toxoplasmosis, HIV-infected persons should wash their hands after contact with raw meat and after gardening or other contact with soil; in addition, they should wash fruits and vegetables well before eating them raw (BIII).  If the patient owns a cat, the litter box should be changed daily, preferably by an HIV-negative, nonpregnant person; alternatively, patients should wash their hands thoroughly after changing the litter box (BIII). Patients should be encouraged to keep their cats inside and not to adopt or handle stray cats (BIII). Cats should be fed only canned or dried commercial food or well-cooked table food, not raw or undercooked meats (BIII). Patients need not be advised to part with their cats or to have their cats tested for toxoplasmosis (EII)

# Preventing Disease

## Initiating Primary Prophylaxis
Toxoplasma-seropositive patients who have a CD4+ count of <100 cells/L should be administered prophylaxis against TE (AII). The double-strength tablet daily dose of TMP-SMX recommended as the preferred regimen for PCP prophylaxis also is effective against TE and is therefore recommended (AII). TMP-SMX, one double-strength tablet three times weekly, is an alternative (BIII).  If patients cannot tolerate TMP-SMX, the recommended alternative is dapsone-pyrimethamine plus leucovorin, which is also effective against PCP (BI).Atovaquone with or without pyrimethamine/leucovorin also can be considered (CIII). Prophylactic monotherapy with dapsone, pyrimethamine, azithromycin, or clarithromycin cannot be recommended on the basis of available data (DII). Aerosolized pentamidine does not protect against TE and is not recommended (EI).
Toxoplasma-seronegative persons who are not taking a PCP prophylactic regimen known to be active against TE (e.g., aerosolized pentamidine) should be retested for IgG antibody to Toxoplasma when their CD4+ counts decline to <100 cells/L to determine whether they have seroconverted and are therefore at risk for TE (CIII). Patients who have seroconverted should be administered prophylaxis for TE as described previously (AII).

## Discontinuing Primary Prophylaxis
Prophylaxis against TE should be discontinued among adult and adolescent patients who have responded to ART with an increase in CD4+ counts to >200 cells/L for >3 months (AI). Multiple observational studies and two randomized trials  have reported that primary prophylaxis can be discontinued with minimal risk for developing TE among patients who have responded to ART with an increase in CD4+ count from 200 cells/L for >3 months. In these studies, the majority of patients were taking PI-containing regimens and the median CD4+ count at the time prophylaxis was discontinued was >300 cells/L. At the time prophylaxis was discontinued, the majority of patients had sustained suppression of plasma HIV RNA levels below the detection limits of available assays; the median follow-up was 7--22 months. Although patients with CD4+ counts of 200 cells/L. Thus, the recommendation specifies discontinuing prophylaxis after an increase to >200 cells/L. Discontinuing primary TE prophylaxis is recommended because prophylaxis at CD4+ count >200 cells/ L adds limited disease prevention for toxoplasmosis and because discontinuing drugs reduces pill burden, potential for drug toxicity, drug interaction, selection of drug-resistant pathogens, and cost. Prophylaxis for TE should be reintroduced if the CD4+ count decreases to <100--200 cells/L (AIII).

# Treatment of Disease
The initial therapy of choice for TE consists of the combination of pyrimethamine plus sulfadiazine plus leucovorin (AI). Pyrimethamine penetrates the brain parenchyma efficiently even in the absence of inflammation. Use of leucovorin reduces the likelihood of the hematologic toxicities associated with pyrimethamine therapy. The preferred alternative regimen for patients with TE who are unable to tolerate or who fail to respond to first-line therapy is pyrimethamine plus clindamycin plus leucovorin (AI). 
TMP-SMX was reported in a small (77 patient) randomized trial to be effective and better tolerated than pyrimethamine-sulfadiazine. On the basis of less in vitro activity and less experience with this regimen, pyrimethamine plus sulfadiazine with leucovorin is the preferred therapy (BI). For patients who cannot take an oral regimen, no well-studied options exist. No parenteral formulation of pyrimethamine exists; the only widely available parenteral sulfonamide is the sulfamethoxazole component of TMP-SMX. Therefore, certain specialists will treat severely ill patients requiring parenteral therapy initially with oral pyrimethamine plus parenteral TMP-SMX or parenteral clindamycin (CIII).
At least three regimens have activity in the treatment of TE in at least two, nonrandomized, uncontrolled trials, although their relative efficacy compared with the previous regimens is unknown:
- 1) atovaquone (with meals or oral nutritional supplements) plus pyrimethamine plus leucovorin (BII)
- 2) Atovaquone combined with sulfadiazine or, for patients intolerant of both pyrimethamine and sulfadiazine, as a single agent  (BII) (if atovaquone is used alone, measuring plasma levels might be helpful given the high variability of absorption of the drug among different patients; plasma levels of >18.5 g/mL are associated with an improved response rate).
- 3) Azithromycin plus pyrimethamine plus leucovorin daily (BII).
The following regimens have been reported to have activity in the treatment of TE in small cohorts of patients or in case reports of one or a few patients: clarithromycin plus pyrimethamine (CIII); 5-fluoro-uracil plus clindamycin (CIII)  dapsone plus pyrimethamine plus leucovorin (CIII) ; and minocycline or doxycycline combined with either pyrimethamine plus leucovorin, sulfadiazine, or clarithromycin (CIII). Although the clarithromycin dose used in the only published study was 1 g twice a day, doses >500 mg have been associated with increased mortality in HIV-1--infected patients treated for disseminated MAC. Doses >500 mg twice a day should not be used (DIII).
Acute therapy should be continued for at least 6 weeks, if there is clinical and radiologic improvement (BII). Longer courses might be appropriate if clinical or radiologic disease is extensive or response is incomplete at 6 weeks. Adjunctive corticosteroids (e.g. dexamethasone) should be administered when clinically indicated only for treatment of a mass effect associated with focal lesions or associated edema (BIII). Because of the potential immunosuppressive effects of corticosteroids, they should be discontinued as soon as clinically feasible. Patients receiving corticosteroids should be closely monitored for the development of other OIs, including cytomegalovirus retinitis and TB disease.
Anticonvulsants should be administered to patients with a history of seizures (AIII), but should not be administered prophylactically to all patients (DIII). Anticonvulsants, if administered, should be continued at least through the period of acute therapy.

# Monitoring and Adverse Events
Changes in antibody titers are not useful for monitoring responses to therapy. Patients should be routinely monitored for adverse events and clinical and radiologic improvement (AIII). Common pyrimethamine toxicities include rash, nausea, and bone-marrow suppression (neutropenia, anemia, and thrombocytopenia) that can often be reversed by increasing the dose of leucovorin to 50--100 mg/day administered in divided doses (CIII).
Common sulfadiazine toxicities include rash, fever, leukopenia, hepatitis, nausea, vomiting, diarrhea, and crystalluria. Common clindamycin toxicities include fever, rash, nausea, diarrhea (including pseudomembranous colitis or diarrhea related to Clostridium difficile toxin), and hepatotoxicity. Common TMP-SMX toxicities include rash, fever, leukopenia, thrombocytopenia, and hepatotoxicity. Drug interactions between anticonvulsants and antiretroviral agent should be carefully evaluated and doses adjusted according to established guidelines.

# Management of Treatment Failure
A brain biopsy, if not previously performed, should be strongly considered for patients who fail to respond to initial therapy (BII) as defined by clinical or radiologic deterioration during the first week despite adequate therapy or lack of clinical improvement within 2 weeks. For those who undergo brain biopsy and have confirmed histopathologic evidence of TE, a switch to an alternative regimen as previously described should be considered (BIII). Recurrence of disease during secondary maintenance therapy following an initial clinical and radiographic response is unusual if patients adhere to their regimen.

# Prevention of Recurrence
Patients who have successfully completed a 6-week course of initial therapy for TE should be administered lifelong secondary prophylaxis (i.e., chronic maintenance therapy). unless immune reconstitution occurs because of ART (AI). Adult and adolescent patients appear to be at low risk for recurrence of TE when they have successfully completed initial therapy for TE, remain asymptomatic with respect to signs and symptoms of TE, and have a sustained (i.e., >6 months) increase in their CD4+ T lymphocyte counts to >200 cells/L on ART. The numbers of such patients who have been evaluated remain limited. On the basis of these observations and inference from more extensive data about safety of discontinuing secondary prophylaxis for other OIs during advanced HIV-1 disease, discontinuing chronic maintenance therapy among such patients is a reasonable consideration (CIII). Certain health-care providers would obtain an MRI of the brain as part of their evaluation to determine whether discontinuation of therapy is appropriate and might be reluctant to stop therapy if any mass lesion or contrast enhancement persists (CIII). Secondary prophylaxis should be started again if the CD4+ T lymphocyte count decreases to <200 cells/L (AIII).

# Special Considerations During Pregnancy
Documentation of maternal T. gondii serologic status should be obtained during pregnancy. Indications for treatment of T. gondii during pregnancy should be based on confirmed or suspected symptomatic disease in the mother. Pediatric care providers should be informed if the HIV-1--infected mother is seropositive for T. gondii infection to allow evaluation of the neonate for evidence of congenital infection. Pregnant HIV-1--infected women with suspected or confirmed primary T. gondii infection during pregnancy should be managed in consultation with a maternal-fetal medicine or other appropriate specialist (BIII).
Treatment should be the same as in nonpregnant adults (BIII). Although pyrimethamine has been associated with birth defects in animals, limited human data have not suggested an increased risk for defects and, therefore, it can be administered to pregnant women. Pediatric providers should be notified if sulfadiazine is continued until delivery because its use might increase the risk for neonatal hyperbilirubinemia and kernicterus.
Although perinatal transmission of T. gondii normally occurs only with acute infection in the immunocompetent host, case reports have documented occurrences of transmission with reactivation of chronic infection in HIV-1--infected women with severe immunosuppression. Because the risk for transmission with chronic infection appears low, routine evaluation of the fetus for infection with amniocentesis or cordocentesis is not indicated. Detailed ultrasound examination of the fetus specifically evaluating for hydrocephalus, cerebral calcifications, and growth restriction should be done for HIV-1--infected women with suspected primary or symptomatic reactivation of T. gondii during pregnancy.

# Source
Treating Opportunistic Infections Among HIV-Infected Adults and Adolescents. Recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association/Infectious Diseases Society of America

# Related Chapters
- Toxoplasma gondii
- Opportunistic infections
- HIV opportunistic infections
- HIV opportunistic infection pneumocystis pneumonia: prevention and treatment guidelines

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