Toxoplasmosis is one of the most common opportunistic infections seen in patients with advanced HIV disease, especially in areas of the world where the rate of toxoplasma infection is high. It is also one of the most easily prevented OIs. Even before the advent of maximally suppressive multidrug therapy -- which has dramatically reduced both the incidence and the severity of AIDS-related OIs -- it was possible to protect at-risk individuals against toxoplasmosis with single-drug prophylaxis. Primary and secondary prophylaxis regimens are even more effective today, thanks largely to the degree of immune reconstitution that occurs in patients who respond to combination antiretroviral therapy.

Toxoplasmosis is caused by Toxoplasma gondii, an obligate intracellular parasite. This common parasite has a two-stage life cycle: a feline, sexual phase, which occurs chiefly in cats, and an intermediate, non-sexual phase, which can take place in any mammal or bird. Although organ transplantation and blood transfusion can result in toxoplasma infection, transmission generally occurs when the intermediate host ingests the toxoplasma oocyst, whereupon bradyzoites and sporozoites are released in the host's GI tract. These enter the small bowel epithelium and transform into tachyzoites that are able to replicate in the cells of the host.

This replication process continues until the cellular and the humoral immune systems of the host are able to bring the parasite under control. At this point tissue cysts develop, each containing multiple bradyzoites, and with the formation of these cysts the host and the parasite reach an equilibrium that usually remains in effect for the life of the host. In immunosuppressed patients, the immunologic factors that control the replication of the tachyzoite are depleted, and in such patients infection is characterized by progressive focal destruction. Most clinical toxoplasma infections in HIV patients represent reactivation of an old infection rather than newly acquired disease.

The Toxoplasma gondii parasite is widely distributed around the world, and seroprevalence in humans increases with age. In the United States, for example, 5% to 10% of young adults are seropositive for toxoplasma, and this rate rises to 50% at 50 years of age. There is also wide geographical variance in the incidence of T. gondii infection, a variability that seems to depend on the amount of uncooked or undercooked meat, especially lamb, that a given population consumes, and/or the amount of contact a given population has with cats. Among the cat-loving French, for instance, the incidence of toxoplasma infection is greater than 90% in adults.

Toxoplasmosis is the principal opportunistic infection of the central nervous system in persons with advanced HIV disease, and individuals who are seropositive for T. gondii are at very high risk for developing encephalitis as immune suppression progresses. In the past, approximately one-third of AIDS patients who were seropositive for T. gondii and did not receive prophylaxis developed toxoplasma encephalitis (TE). With the widespread adoption of triple-drug antiretroviral therapy, this figure has fallen drastically, perhaps by as much as 75% (1).

Diagnosing and treating toxoplasmosis

In patients with advanced HIV infection, toxoplasmosis characteristically presents as single or multiple focal neurologic deficits. Presentations with more generalized symptoms, or with disseminated infection affecting the lungs or the heart, are possible but are much less common. In affected individuals CT imaging will demonstrate one or more ring-enhancing lesions in the CNS, usually located in the basal ganglia or the corticomedular junction. As might be expected, magnetic resonance imaging is more sensitive than CT scanning, and it is therefore the technique of choice for diagnosing suspected TE (2).

As a general rule, the diagnosis of toxoplasmosis is made on a clinical basis -- when CNS masses are seen on CT or MRI in the brain of a patient with advanced HIV infection and positive toxoplasma serology. When a definitive diagnosis cannot be made in patients with brain lesions, it is common practice to treat suspected cases of TE empirically for two weeks with antitoxoplasmosis agents and then re-evaluate the patient clinically and radiographically (3).

In patients with a negative toxoplasmosis IgG whose lesions are more suggestive of lymphoma than TE on MRI, the likelihood of toxoplasmosis is less than 1%. These patients should undergo an immediate brain biopsy for a more definitive diagnosis and prompt, appropriate intervention (4).

Pyrimethamine is the principal drug used to treat toxoplasmosis (Table 1). When combined with sulfonamides or clindamycin, it has proven highly effective as first-line therapy (5). Folinic acid is routinely added to this regimen to prevent the bone-marrow toxicity that is frequently associated with pyrimethamine therapy. Patients who do not tolerate this regimen often respond to atovaquone (6). Induction therapy should be given for at least six weeks, until the patient's brain lesions have either resolved or stabilized at a reduced size. Upward of 90% of patients will show clinical and/or radiographic improvement within 10 to 14 days of the initiation of therapy. If the lesions have not improved within two weeks, the clinician should reconsider his diagnosis and consult a neurosurgeon with the aim of obtaining a stereotactic guided biopsy.

Patients who are treated for TE should receive lifelong suppressive therapy to prevent recurrent infections (Table 2). The combination of daily pyrimethamine plus sulfadiazine and leucovorin is highly effective in preventing recurrences (7). In the patient who cannot tolerate sulfa drugs, pyrimethamine plus clindamycin is a reasonable alternative.

 

 

Preventing toxoplasmosis

Earlier this year a group of Spanish investigators established that thrice-weekly prophylaxis against toxoplasmosis is as effective as daily prophylaxis (8). Clinicians will want to think twice about recommending this regimen to their patients, however, because experience suggests that it is more difficult for patients to remember to take medicines three times a week than to take them daily.

Prophylaxis is extremely effective in preventing toxoplasmosis in individuals at high risk of infection (Table 3. page 116). Retrospective analyses of studies of PCP prophylaxis have shown that TMP-SMX is a very potent inhibitor of toxoplasmosis in seropositive patients (9). Pyrimethamine, although it is the mainstay of acute treatment of toxoplasmosis, does not work as well when used as single-drug prophylaxis, and it should not be used for this purpose (10). If patients cannot tolerate TMP-SMX, regimens that combine dapsone and pyrimethamine are recommended to provide protection against toxoplasmosis, just as they do against PCP in TMP-SMX-intolerant individuals (11, 12).

Both the U.S. Public Health Service and the Infectious Disease Society of America recently issued guidelines for the prevention of a wide range of opportunistic infections in HIV-positive individuals (13). Where toxoplasmosis is concerned, the U.S.P.H.S./I.D.S.A. guidelines are based as much on common sense as they are on data from clinical studies. At-risk individuals should be told not to eat raw or undercooked meat, particularly undercooked pork, lamb, or venison, and all meats should be cooked until they are no longer pink at the center (that is, to an internal temperature of 165° F or 73.8° C).

All HIV-infected persons should also be instructed to wash their hands after handling raw meat and after gardening or other contact with soil. In addition, they should be encouraged to wash fruits and vegetables thoroughly before eating them raw. If an at-risk individual owns a cat or lives with someone who does, the cat's litter box should be changed daily, preferably by an HIV-negative, nonpregnant person. Alternatively, the patient should be urged to wear disposable latex gloves while changing the litter box and should wash his or her hands and forearms thoroughly afterward.

Patients should be encouraged to keep their cats inside and not to handle or adopt stray cats. Cats should be fed only canned or dried commercial food or well-cooked table food, not raw or undercooked meats. Patients need not be advised to part with their cats or to have their cats tested for toxoplasmosis.

Recent advances in the diagnosis of toxoplasmosis

Polymerase chain-reaction assays can now be used as a diagnostic aid in patients with CNS lesions and suspected toxoplasmosis. The only available assay appears to be very specific but not very sensitive (14, 15). Multiplex PCR tests that combine primers for both Epstein-Barr virus and toxoplasma have also been developed, and they can help clinicians to differentiate between primary CNS lymphoma and TE. However, lack of sensitivity is a problem with this assay as well: a positive test for toxoplasma is diagnostic, but a negative test does not rule out this possibility.

In patients with advanced HIV disease and CNS masses, SPECT scans have also been used to make the diagnosis of TE (16). Because toxoplasma is a "cool" lesion, whereas CNS lymphoma is "hot," SPECT analysis allows the clinician to establish the probable cause of a patient's CNS masses. Further studies are needed to determine what role, if any, this technique will play in the diagnosis of an HIV-positive patient with CNS lesions (17, 18).

Recent advances in the management of toxoplasmosis

The advent of maximally suppressive antiretroviral therapy has reduced the incidence of toxoplasmosis among patients who have access to this therapy and respond well to it. Several recently published cohort studies have demonstrated a decrease in the incidence of toxoplasmosis in patients who respond to combination anti-HIV therapy -- showing, once again, that the best prophylaxis against opportunistic infections is a potent antiretroviral regimen. In a cohort of HIV-infected patients being followed at Johns Hopkins, the rate of toxoplasma infections fell 75% following the widespread adoption of protease-inhibitor-containing multidrug therapies (1). Similar but less dramatic reductions were also seen in cohorts in New Orleans and in France (19, 20).

Interestingly, the incidence of lymphoma has not been significantly affected by the introduction of protease-inhibitor-based regimens, and as a result lymphoma is proportionally more frequent now than it used to be in AIDS patients with CNS masses (21).

In the most recent issue of HIV Newsline, my colleague Dr. William G. Powderly addressed an issue of concern to all care providers who treat people with HIV infection: whether it is possible to withdraw some types of prophylaxis from patients who respond well to multidrug antiretroviral therapy -- without putting those patients at risk of developing opportunistic infections (see "Prophylaxis in the Age of Protease Inhibitors -- An Update," Vol. 4, No. 5, pages 89-92). Regrettably, no prospective studies have been planned to address the question of what to do about toxoplasmosis prophylaxis in patients who experience immunologic rebound on combination antiretroviral therapy.

In the end this question will probably be answered in the way the question of primary prophylaxis was ultimately answered: by analyzing substudy data from a larger trial of patients being withdrawn from PCP prophylaxis. In a small case-control study presented at ICAAC this fall, there were no cases of PCP or toxoplasmosis among patients who discontinued TMP-SMX after their CD4 cell counts rose above 200 cells/mm3 as a result of multidrug anti-HIV therapy (22). The Swiss HIV Cohort Study presented similar results in Geneva (23).

Within the next year a substudy of ACTG 888 may give us the answer that we need regarding this issue. In this study, 250 subjects who have had at least one CD4 count below 100 cells/mm3 or an episode of pneumocystis pneumonia will be asked to discontinue their PCP prophylaxis if their multidrug antiretroviral therapy has resulted in a sustained CD4 increase to 200 cells/mm3 or more on two measurements taken at least 12 weeks apart. Although the number of patients enrolled in ACTG 888 who prove to be seropositive for toxoplasma will be small, the data that these subjects provide should offer us some guidance in this problematic clinical situation.

References

1. Moore RD, Keruly JC, Chaisson RE. Decline in CMV and other opportunistic diseases with combination antiretroviral therapy. 5th Conference on Retroviruses and Opportunistic Infections, Chicago, IL, January 31 to February 5, 1998. Abstract 184.
2. Ciricillo SF, Rosenblum ML. Use of CT and MR imaging to distinguish intracranial lesions and to define the need for biopsy in AIDS patients. J Neurosurg 1990; 73 (5): 720-4.
3. Renold C, Sugar A, Chave JP, et al. Toxoplasma encephalitis in patients with the acquired immunodeficiency syndrome. Medicine 1992; 71 (4): 224-39.
4. Porter SB, Sande MA. Toxoplasmosis of the central nervous system in the acquired immunodeficiency syndrome. N Engl J Med 1992; 327 (23): 1643-8.
5. Katlama C, De Wit S, O'Doherty E, Van Glabeke M, Clumeck N. Pyrimethamine-clindamycin vs. pyrimethamine-sulfadiazine as acute and long-term therapy for toxoplasmic encephalitis in patients with AIDS. Clin Infect Dis 1996; 22 (2): 268-75.
6. Kovacs JA. Efficacy of atovaquone in treatment of toxoplasmosis in patients with AIDS. The NIAID-Clinical Center Intramural AIDS Program. Lancet 1992; 340 (8820): 637-8.
7. Podzamczer D, Miro JM, Bolao F, et al. Twice-weekly maintenance therapy with sulfadiazine-pyrimethamine to prevent recurrent toxoplasmic encephalitis in patients with AIDS. Spanish Toxoplasmosis Study Group. Ann Intern Med 1995; 123 (3): 175-80.
8. Podzamczer D, Miro JM, Ferrer E, Gatell JM. Thrice-weekly vs. daily sulfadiazine-pyrimethamine (SP) for maintenance therapy of toxoplasmic encephalitis (TE). 5th Conference on Retroviruses and Opportunistic Infections, Chicago, IL, January 31 to February 5, 1998. Abstract 468.
9. Carr A, Tindall B, Brew BJ, et al. Low-dose trimethoprim-sulfamethoxazole prophylaxis for toxoplasmic encephalitis in patients with AIDS. Ann Intern Med 1992; 117 (2): 106-11.
10. Jacobson MA, Besch CL, Child C, et al. Primary prophylaxis with pyrimethamine for toxoplasmic encephalitis in patients with advanced human immunodeficiency virus disease: results of a randomized trial. Terry Beirn Community Programs for Clinical Research on AIDS. J Infect Dis 1994; 169 (2): 384-94.
11. Girard PM, Landman R, Gaudebout C, et al. Dapsone-pyrimethamine compared with aerosolized pentamidine as primary prophylaxis against Pneumocystis carinii pneumonia and toxoplasmosis in HIV infection. The PRIO Study Group. N Engl J Med 1993; 328 (21): 1514-20.
12. Antinori A, Murri R, Ammassari A, et al. Aerosolized pentamidine, cotrimoxazole and dapsone-pyrimethamine for primary prophylaxis of Pneumocystis carinii pneumonia and toxoplasmic encephalitis. AIDS 1995; 9 (12): 1343-50.
13. 1997 USPHS/IDSA guidelines for the prevention of opportunistic infections in persons infected with human immunodeficiency virus. USPHS/IDSA Prevention of Opportunistic Infections Working Group. MMWR 1997; 46 (RR-12): 1-46.
14. Cingolani A, De Luca A, Ammassari A, et al. PCR detection of Toxoplasma gondii DNA in CSF for the differential diagnosis of AIDS-related focal brain lesions. J Med Microbiol 1996; 45 (6): 472-6.
15. Antinori A, Ammassari A, De Luca A, et al. Diagnosis of AIDS-related focal brain lesions: a decision-making analysis based on clinical and neuroradiologic characteristics combined with polymerase chain reaction assays in CSF. Neurology 1997; 48 (3): 687-94.
16. Roberts TC, Storch GA. Multiplex PCR for diagnosis of AIDS-related central nervous system lymphoma and toxoplasmosis. J Clin Microbiol 1997; 35 (1): 268-9.
17. Hsiao CB, Naples N, et al. HIV-related brain mass: a diagnostic clinical pathway based upon use of toxoplasma serology, CT/MRI and thallium-201 SPECT of the brain. 5th Conference on Retroviruses and Opportunistic Infections, Chicago, IL, January 31 to February 5, 1998. Abstract 469.
18. Garcia F, Lomena F, Cruceta A, et al. Predictive value of thallium-201 SPECT in the diagnosis of primary central nervous system lymphoma (PCNSL) in AIDS Patients. 12th World AIDS Conference, Geneva, Switzerland, June 27 to July 3, 1998. Abstract 22188.
19. Michaels S, Clark R, Kissinger P. Differences in the incidence rates of opportunistic processes before and after the availability of pro tease inhibitors. 5th Conference on Retrovirus and Opportunistic Infections, Chicago, IL, January 31 to February 5, 1998. Abstract 180.
20. Costagliola D. Trends in incidence of clinical manifestations of HIV infection and antiretroviral prescriptions in French university hospitals. 5th Conference on Retroviruses and Opportunistic Infections, Chicago, IL, January 31 to February 5, 1998. Abstract 182.
21. Costagliola D. Clinical manifestations of HIV infections in the era of highly active antiretroviral treatment (HAART) in France. 12th World AIDS Conference, Geneva, Switzerland, June 27 to July 3, 1998. Abstract 12345.
22. Maradona JA, Rodriguez-Guardado A, Carton JA, Asensi V, Casado L. Pneumocystis carinii prophylaxis withdrawal in highly active antiretroviral therapy-responsive patients. ICAAC, San Diego, CA, September 24-27, 1998. Abstract 206.
23. Furrer H, Opravil M, Bernasconi E, et al. Is it safe to stop primary PCP prophylaxis in patients treated with antiretroviral combination regimens? 12th World AIDS Conference, Geneva, Switzerland, June 27 to July 3, 1998. Abstract 22180.

Pablo Tebas, M.D., is with the AIDS Clinical Trials Unit, Washington University School of Medicine, St. Louis, MO.