Management of PCP, Toxoplasmosis, and HSV Infections in Patients With HIV Disease continued...
[HIV Clinical Management - Volume 7. c 1999 Medscape, Inc.] Toxoplasmosis

Toxoplasma gondii infection is widespread, although in the vast majority of infected people it is carried as a latent infection without causing disease. The onset of the AIDS epidemic has lead to increasing incidence rates of Toxoplasma encephalitis. It has been estimated that 20,000-40,000 cases of Toxoplasma encephalitis occurred in AIDS patients in the United States by 1991; it is the most common cause of encephalitis in the United States.^[34] Toxoplasma encephalitis is both preventable and treatable. Caretakers of HIV infected patients need to be alert for manifestations of the infection and therapeutic options.

Epidemiology of Toxoplasmosis

T gondii is a zoonotic infection. The parasite infects all orders of mammals, but cats are the definitive hosts. Cats excrete T gondii oocysts in their feces, and ingestion of fecally contaminated material by humans leads to primary T gondii infection. In addition, 25% of lamb and pork samples have been found to contain T gondii cysts, and ingestion of undercooked meat is a second route of infection.^[35] Aside from oral infection, T gondii can be congenitally transmitted with passage across the placenta from mother to infant. This route of fetal infection appears to be restricted to mothers who are exposed to T gondii during gestation.^[36]

In the United States the prevalence of latent T gondii infection is 10-40%^[34,37]; however, in areas of Europe such as France, Germany, Switzerland, and Spain the prevalence is considerably higher, with reports of 50-70% of the population testing seropositive for anti-Toxoplasma antibodies.^[38] Seropositivity rates in Australia are intermediate at approximately 30%. Without prophylaxis approximately one-third of patients with HIV infection and latent T gondii will develop toxoplasmosis.^[39] In the United States, patients with AIDS have a 5-10% prevalence rate of Toxoplasma encephalitis, while in Germany, France, Belgium, and Switzerland the prevalence rate is 10-40%. The risk of Toxoplasma encephalitis is highest in patients who have evidence of latent infection and CD4+ counts below 100 cells/mm³.^[40] Longitudinal studies reveal that T gondii is acquired at a rate of approximately 2-5% per year in patients with HIV infection^[41]; hence, it is crucial that clinicians educate patients with HIV about the risks of exposure to cats and poorly cooked meat.

Pathogenesis of Toxoplasmosis

Toxoplasma gondii occurs in three different forms: the oocyst, the tachyzoite, and the tissue cyst.

• Oocysts are 10-12чm ovoid shaped organisms which are shed in cat feces. They remain viable for as long as 18 months in soil and are resistant to many extremes of environmental conditions.^[42]
• Tachyzoites are 3-7чm crescentic forms which are obligatory intracellular parasites. These are the invasive forms that proliferate during acute infection. Tachyzoites are capable of infecting virtually any type of mammalian cell and multiply within the cytoplasmic space inside vacuoles.^[43]
• Tissue cysts are 10-200чm forms which appear in human tissues including the myocardium, skeletal muscle, and the brain.^[44] These are the forms in which the infection remains latent within the human host. The tissue cysts are also present in animal flesh and can transmit disease if meat is undercooked. Tissue cysts are killed by gamma irradiation or temperatures greater than 61╦C for 4 minutes.

Following infection by T gondii, IgG and IgM are produced. The humoral response assists in the control of toxoplasmosis, but is not fully protective.^[45] Cell mediated immunity is believed to be the critical determinate in controlling toxoplasmosis. Cytokines such as interferon gamma and IL-2 have been shown to play an important role in animal models.

Toxoplasma encephalitis in AIDS patients is believed to result from reactivation of quiescent tissue cysts.^[34] Reactivation leads to brain abscesses with a central avascular area, a surrounding region of hyperemia with inflammatory infiltrates, and perivascular cuffing by lymphocytes in the outer zone where Toxoplasma cysts are found.^[46] The most commonly affected area is the basal ganglia, but cerebellar and brain stem legions are also seen.^[47] Extracranial toxoplasmosis may occur; the most common sites are lung, retina, and myocardium.

Figure 5. Brain biopsy specimen from a patient with Toxoplasma encephalitis. The specimen, which was stained with hematoxylin and eosin and viewed a 100x, shows a Toxoplasma gondii tissue cyst surrounded by mononuclear inflammatory cells. (Photo courtesy of J. MacArthur)

©Diagnostic Options for Toxoplasmosis

Toxoplasmosis in AIDS patients manifests in three ways: Toxoplasma encephalitis, Toxoplasma pneumonitis, and Toxoplasma chorioretinitis. Encephalitis is the most common form in AIDS patients.^[34] The typical presentation is an altered mental status, seizures, weakness, cranial nerve abnormalities, or neuropsychiatric disorders.^[48] The onset is usually subacute, but in nearly 90% of cases focal neurologic signs develop. In patients with such presentations the differential diagnosis includes: CNS lymphoma, progressive multifocal leukoencephalopathy (PML), CMV encephalitis, cerebral infection by Cryptococcus neoformans, Mycobacterium tuberculosis, or Aspergillus spp..^[47] There are four categories of diagnostic procedures in the diagnosis of Toxoplasma encephalitis: neuroradiologic scans, histologic diagnosis, serologic diagnostics, and PCR-based assays.

• Neuroradiologic Scans. For HIV-positive patients suspected of having Toxoplasma encephalitis, contrast-enhanced CT or MRI scans are indicated. Typically these scans show multiple bilateral cerebral lesions, although occasionally single lesions may be identified. The abscesses tend to occur in the basal ganglia and are hypodense with ring-enhancement after IV contrast. MRI scanning with gadolinium is the preferred radiologic test, however CT scanning is often performed initially due to greater availability. Radiologic imaging may also be utilized to monitor the response to therapy in Toxoplasma encephalitis. Reductions in the size of the brain abscesses are seen 90% of patients after two to three weeks of treatment.^[49] When Toxoplasma encephalitis is suspected based on clinical and radiologic findings, an empiric trial of anti-Toxoplasma therapy is warranted. If a clinical and radiographic response is achieved within two to three weeks, the diagnosis is established. The solitary cerebral legion presents a diagnostic dilemma. In such cases the probability of CNS lymphoma is greater than that of Toxoplasma encephalitis.^[48] A brain biopsy may be indicated in these cases in order to clarify the diagnosis.

Figure 6. Head CT (left) and MRI (right) both given with contrast of the same patient with new seizures, focal weakness, and HIV infection. Multiple ring-enhancing lesions are seen in the periventricular white matter. The lesions are consistent with Toxoplasma encephalitis. The images point out the enhanced sensitivity of MRI scanning over CT scanning in this instance. (Photo courtesy of J. MacArthur)

• Histologic Diagnosis. Brain biopsy or BAL specimens may be submitted for histologic evaluation for Toxoplasma gondii forms. Demonstration of tachyzoites establishes the diagnosis of acute infection, and multiple tissue cysts in an inflammatory lesion are highly suggestive of disease (see Figure 5). A number of staining techniques are used by histopathologists including fluorescent antibody staining, peroxidase/anti-peroxidase immunostaining techniques, and Wright-Giemsa staining.
• Serologic Assays. Toxoplasma IgG antibody is generally present even in patients with advanced AIDS and Toxoplasma encephalitis. This test should be performed if there is doubt of the diagnosis; a negative Toxoplasma IgG antibody test makes the diagnosis of Toxoplasma encephalitis less likely. IgM antibody tests play no role in the diagnosis of toxoplasmosis in patients with HIV, as the disease is almost always the result of reactivation.
• Polymerase Chain Reaction. Recently PCR amplification techniques have been used to detect T gondii DNA in several types of body fluids and tissues. Assays detecting the organism in both CNS tissue and cerebrospinal spinal fluid have been reported^[50,51]. Currently these assays remain available in research laboratories only and are not available as FDA-approved kits. It is recommended that the assay be repeated at least twice before relying upon positive findings due to the high rate of false positives and artifacts with PCR.

Case History (continued)
The patient's CD4+ cell count and viral load respond poorly to several different combinations of antiretroviral therapy. Six months after having PCP she has a tonic-clonic seizure. A neurologic examination reveals a mild left facial droop and some right sided upper extremity weakness. Her CD4+ count is 18 cells/mm³, and the viral load is 1,170,000 copies/mL. An MRI with contrast showed three 0.5cm ring enhancing lesions in the periventricular white matter (see Figure 6). A presumptive diagnosis of Toxoplasma encephalitis is made. She is treated with dilantin, pyrimethamine 200mg po daily as a loading dose, followed by 50mg po daily, sulfadiazine 1g po daily, and folinic acid 10mg po daily.

Her facial droop and upper extremity weakness improves over the next eight weeks. She has no further seizures.

The patient is currently maintained on three antiretroviral medications, and azithromycin 1200mg po once weekly for MAC prophylaxis. In addition, she receives chronic pyrimethamine 25mg po daily, clindamycin 300mg twice daily, and folinic acid 10mg po daily for toxoplasmosis suppression and one single-strength TMP-SMX tablet daily for PCP prophylaxis.

Preventive Therapies for Toxoplasmosis

While there have not been prospective clinical trials testing prophylaxis for toxoplasmosis, retrospective analyses have indicated that sulfa drug-containing regimens, such as those used to prevent PCP, are also effective in preventing toxoplasmosis. In trials testing TMP-SMX versus aerosolized pentamidine for PCP prophylaxis, it was observed that the rate of toxoplasmosis was less than 1% for TMP-SMX recipients as compared with 3-12% in patients receiving aerosolized pentamidine or other therapies for PCP. Hence, it is widely believed that toxoplasmosis can be prevented by sulfa drug-containing regimens, in particular trimethoprim/sulfamethoxazole,^[52] but also dapsone/pyrimethamine.^{[53, 54]}. It is also likely that clarithromycin and azithromycin, when given for MAC prophylaxis, reduce the incidence of toxoplasmosis.

HIV infected patients at risk for toxoplasmosis should receive prophylaxis. The indications for prophylaxis are a positive T gondii serology (IgG), and a CD4+ count less than 100 cells/mm³.

Table 2. Regimens for Toxoplasmosis Prophylaxis

Indications

1. Positive T gondii IgG, plus

2. CD4+ count nadir less than 100 cells/mm³

Regimens

1. 1 TMP-SMX double-strength tablet per day (preferred)

2. 1 TMP-SMX single-strength tablet per day (preferred)

3. 1 TMP-SMX double-strength tablet 3 times per week (preferred)

Alternatives to TMP-SMX:

╨ Dapsone 50mg po daily, plus pyrimethamine 50mg po weekly, plus leucovorin 25mg po weekly

╨ Dapsone 200mg po weekly, plus pyrimethamine 75mg po q week, plus leucovorin 25mg po weekly

Consider: Atovaquone 750mg po bid

Consider: Atovaquone, 750mg po bid, plus pyrimethamine 75mg po q week

Treatment for Active Infection with Toxoplasmosis

The two major regimens for the treatment of acute Toxoplasma encephalitis are:

• pyrimethamine 100-200mg as a loading dose, followed by 50-100mg per day po, plus folinic acid 10mg per day po, plus sulfadiazine 4-8g per day in divided doses (preferred).
• pyrimethamine plus folinic acid (as above) plus clindamycin 900-1200mg IV every 6 hours, or 300-450mg po every 6 hours.

These therapies must be used for at least 6 weeks, but it is preferable that they be given until three weeks after complete resolution of the lesions by radiologic scan, then dosages can be reduced to suppressive therapy levels. A clinical trial involving 340 patients has demonstrated that pyrimethamine/sulfadiazine is superior to pyrimethamine/clindamycin.^[40]

Following treatment for acute infection, suppressive therapy (also known as maintenance therapy) is essential in AIDS patients and must be continued for life. The usual suppressive regimen is pyrimethamine 25-75mg po per day, plus folinic acid 10mg po per day, plus sulfadiazine 0.5-1g po every 6 hours. An alternative regimen is pyrimethamine 25-75mg po per day, plus folinic acid 10mg po per day, plus clindamycin 300-450mg po every 6 to 8 hours.

Relapse of Toxoplasma encephalitis occurs in approximately 20-30% of patients on maintenance therapy. It is likely that non-adherence plays a major role in this high failure rate since the treatment schedules are complex and have high rates of adverse drug reactions.^[55] As in the acute treatment of Toxoplasma encephalitis, pyrimethamine-sulfadiazine is superior in maintenance therapy to pyrimethamine-clindamycin.^[56]

Corticosteroids may be used in patients who have evidence of cerebral edema and increased intracranial pressure. In one study, the clinical response and survival in AIDS patients with Toxoplasma encephalitis was not altered by the use of corticosteroids.^[57]

Due to the high rates of adverse drug reactions with pyrimethamine-sulfadiazine and pyrimethamine-clindamycin, a number of alternative, experimental regimens are currently under evaluation. Typically pyrimethamine and folinic acid (used at the dose for acute infection) are combined with test drugs such as azithromycin (1200-1500mg per day), clarithromycin (500mg po twice daily) or atovaquone (750mg po twice daily). The use of minocycline is also being studied. Utilization of the antifolate drugs, trimetrexate and piritrexim, against Toxoplasma encephalitis is presently being assessed as well. Additionally, certain forms of immunotherapy such as the use of interferon gamma or lymphokine activated killer (LAK) cells have been proposed.

Finally, it is worth remembering that, as a consequence of severe immunosuppression, the best preventive/maintenance therapy against toxoplasmosis is restoration of immune competence. Control of HIV with HAART regimens is likely to offer better long-term suppression of toxoplasmosis - provided a CD4+ response occurs - than specific anti-Toxoplasma medication.

The issue of discontinuing toxoplasmosis prophylaxis among HAART responders was addressed in a recent study by Furrer et al. Among the 262 patients whose CD4+ cell counts rose to above 200 cells/mm³ who stopped prophylaxis, 121 were seropositive for IgG antibodies to Toxoplasma gondii and hence were at risk for toxoplasmic encephalitis. In the 11.3 months of median follow-up time there were no cases of toxoplasmic encephalitis (in a total of 110 person-years of follow-up).^[26]

The 1999 draft recommendations of IDSA/USPHS Opportunistic Infections Working Group acknowledge that based upon the current data, the risk of toxoplasmic encephalitis in HAART responders with CD4+ cell counts greater than 100 cells/mm³ is low. However, more studies of discontinuation of both primary and secondary toxoplasmosis prophylaxis in HAART responders were felt to be important before a recommendation to stop prophylaxis can be made.^[27] Patients and providers are advised to review the current data available and make individualized decisions.