Treating Opportunistic Infections Among HIV-Infected Adults and Adolescents Disease Specific Recommendations Toxoplasma gondii Encephalitis       Toxoplasmic encephalitis (TE) is caused by the protozoan Toxoplasma gondii. Disease occurs almost exclusively because of reactivation of latent tissue cysts . Primary infection occasionally is associated with acute cerebral or disseminated disease. Seroprevalence varies substantially among different communities (e.g., approximately 15% in the United States and 50%--75% in certain European cou. In the pre-ART era, for patients with advanced immunosuppression who were seropositive for T. gondii and not receiving prophylaxis with drugs active against T. gondii, the 12-month incidence of TE was approximately 33%. The incidence and associated mortality in Europe and the United States has decreased substantially with the initiation of ART and the broad use of prophylaxis regimens active against T. gondii. Clinical disease is rare among patients with CD4+ T lymphocyte counts >200 cells/µL. The greatest risk is among patients with a CD4+ T lymphocyte count <50 cells/µL. Primary infection occurs after eating undercooked meat containing tissue cysts or ingestion of oocysts that have been shed in cat feces and have sporulated in the environment (which requires at least 24 hours). No transmission of the organism occurs by person-to-person contact. Clinical Manifestations The most common clinical presentation of T. gondii infection among patients with AIDS is a focal encephalitis with headache, confusion, or motor weakness and fever . Physical examination might demonstrate focal neurological abnormalities, and in the absence of treatment, disease progression results in seizures, stupor, and coma. Retinochoroiditis, pneumonia, and evidence of other multifocal organ system involvement can be seen after dissemination of infection but are rare manifestations in this patient population. CT scan or MRI of the brain will typically show multiple contrast-enhancing lesions, often with associated edema . Positron emission tomography (PET) (115) or single-photon emission computed tomography (SPECT) scanning might be helpful for distinguishing between TE and primary central nervous system (CNS) lymphoma, but no imaging technique is completely specific. Diagnosis HIV-1--infected patients with TE are almost uniformly seropositive for anti-toxoplasma IgG antibodies. The absence of IgG antibody makes a diagnosis of toxoplasmosis unlikely but not impossible. Anti-toxoplasma IgM antibodies are usually absent. Quantitative antibody titers are not diagnostically useful. Definitive diagnosis of TE requires a compatible clinical syndrome; identification of one or more mass lesions by CT, MRI, or other radiographic testing; and detection of the organism in a clinical sample. For TE, this requires a brain biopsy, which is most commonly performed by a stereotactic CT-guided needle biopsy. Organisms are demonstrable with hematoxylin and eosin stains, though immunoperoxidase staining by experienced laboratories might increase sensitivity . Detection of T. gondii by polymerase chain reaction (PCR) in cerebrospinal fluid has produced disappointing results; although specificity is high (96%--100%), sensitivity is low (50%) and the results usually are negative once specific anti-toxoplasma therapy has been started  In the presence of neurologic disease, the differential diagnosis  includes CNS lymphoma, mycobacterial infection (especially TB), fungal infection (e.g. cryptococcosis), Chagas disease, bacterial abscess, and rarely PML, which can be distinguished on the basis of imaging studies (PML lesions typically involve white matter rather than gray matter, are noncontrast enhancing, and indicate no mass effect). Certain clinicians rely initially on an empiric diagnosis, which can be established as an objective response, on the basis of clinical and radiographic improvement, to specific anti-T. gondii therapy in the absence of a likely alternative diagnosis. Brain biopsy is reserved for patients failing to respond to specific therapy. Treatment Recommendations The initial therapy of choice 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 prevents the hematologic toxicities associated with pyrimethamine therapy . The preferred alternative regimen for patients 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 µg/mL are associated with an improved response rate) ; and 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 agents 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/µL on ART (144,145). 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/µL (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.