The combination of pyrimethamine plus sulfadiazine is the regimen of choice for acute therapy because it has been associated with a lower rate of failure due to disease progression than has pyrimethamine-clindamycin, although adverse reactions requiring discontinuation of therapy are common [1-3]. Leucovorin should always be coadministered with pyrimethamine to minimize toxicities. For acute therapy, 4 to 8 g of sulfadiazine and 50 to 75 mg of pyrimethamine per day are usually administered. Whether a regimen using lower drug doses is as effective but less toxic is currently unknown. As has been shown in controlled trials, pyrimethamine-clindamycin is clearly an efficacious and acceptable alternative [2, 3]. Other regimens with some activity in treating toxoplasmosis related to the acquired immunodeficiency syndrome (AIDS) include atovaquone, trimethoprim-sulfamethoxazole, pyrimethamine-dapsone, pyrimethamine-azithromycin, and pyrimethamine-clarithromycin [6-10]. These regimens have primarily been evaluated only during acute therapy in small numbers of patients.

Because early experiences showed a high clinical relapse rate (50% to 80% or more) in responding patients after discontinuation of therapy, the current standard is to try to prevent relapse by continuing a suppressive antitoxoplasma regimen for the life of the patient [1, 5]. Common practice has been to continue to administer the drugs used for acute therapy, but at lower doses. The efficacy and the toxicity of this approach, however, have not been systematically compared with those of other strategies, such as indefinitely continuing to administer full doses of the acute therapeutic regimen or using other agents for suppression. Retrospective studies suggest that long-term pyrimethamine-sulfadiazine is associated with fewer relapses than is pyrimethamine-clindamycin [2, 5, 11, 12], and regimens using pyrimethamine-sulfadiazine in varying doses are recommended for suppression [1].

Defining optimal suppressive therapies for patients with advanced HIV disease can play an important role in facilitating the medical management and improving the quality of life of these severely immunosuppressed patients. These patients are at risk for multiple opportunistic infections, including Pneumocystis carinii pneumonia, cryptococcosis, cytomegalovirus disease, and Mycobacterium avium complex infection. They often take numerous medications, in addition to antiretroviral agents, to treat or prevent these infections. Minimizing drug toxicities, drug interactions, or total pill intake per day (to improve compliance) is thus an important goal.

In this issue, Podzamczer and colleagues [13] present the results of the first randomized trial to specifically compare the efficacy of two regimens in suppressing toxoplasmic encephalitis after successful induction therapy [13]. Their study focused exclusively on patients able to tolerate 4 to 8 weeks of initial therapy with sulfadiazine (4 g/d) plus pyrimethamine (50 mg/d). Because of retrospective data suggesting that intermittent therapy is effective in preventing relapses [11], they compared daily administration of suppressive therapy using sulfadiazine (2 g/d) plus pyrimethamine (25 mg/d) with an intermittent regimen of the same doses administered 2 days per week. The study found that daily therapy was superior: It had an estimated 1-year relapse rate of 6% compared with 30% for the intermittent regimen, using an intention-to-treat analysis. In this population with documented previous tolerance to pyrimethamine-sulfadiazine, toxicities requiring discontinuation of therapy did not occur significantly more often in those receiving daily therapy. No cases of P. carinii pneumonia were seen in either arm of this highly immunosuppressed population, even though only three patients received additional prophylaxis for P. carinii pneumonia.

This controlled study establishes daily administration of pyrimethamine-sulfadiazine at the indicated doses as a highly effective suppressive regimen for patients tolerant of sulfa drugs. Additional therapy to prevent P. carinii pneumonia is unnecessary [14]. The intermittent regimen used in this study is associated with an unacceptably high relapse rate. Whether lower daily doses or alternative intermittent regimens would be as effective for maintenance suppression is currently unknown. Failures in the intermittent therapy group may be related to erratic and inadequate levels of pyrimethamine because pyrimethamine serum half-lives and peak serum levels among HIV-infected patients vary greatly [15], or to the need for continuous rather than intermittent exposure to suppressive therapy. It is intriguing that in a retrospective study [16], twice-weekly administration of trimethoprim-sulfamethoxazole appeared to be effective in preventing initial episodes of toxoplasmosis, suggesting that results with primary prophylaxis may not be applicable to suppressive therapy. Patient compliance is probably also an important factor: Daily dosing may be easier to remember than twice-weekly dosing, and the consequences of a single missed dose are probably greater during intermittent dosing. Development of resistance to the drug combination is an unlikely explanation for relapse because 10 of 11 patients responded to subsequent therapy with full-dose pyrimethamine-sulfadiazine.

Unfortunately, as many as one third of patients treated with pyrimethamine-sulfadiazine discontinue therapy because of adverse effects, either during the initial induction phase or during the suppressive phase [2, 3, 5]. Given the high relapse rate that occurs without suppressive therapy, lifelong therapy with some regimen active against T. gondii is essential. In the absence of data from controlled studies, the most common approach is to continue the last tolerated therapeutic regimen at either full or reduced doses. Pyrimethamine-clindamycin (at least 1200 mg of clindamycin per day in divided doses) is the most commonly used alternative to pyrimethamine-sulfadiazine, but it is also associated with dose-limiting toxicities and a substantial relapse rate [1-3, 12]. Long-term experience with pyrimethamine combined with dapsone or the newer macrolides, azithromycin or clarithromycin, as suppressive therapy is limited, as is the experience with atovaquone (alone or combined with pyrimethamine). Twice-weekly administration of pyrimethamine-sulfadoxine has been reported to have had efficacy in a retrospective study [17], but the advantages of this combination over pyrimethamine-sulfadiazine are unclear, and concerns about severe allergic reactions have limited its use. Pyrimethamine alone (25 or 50 mg/d) has been used, but high breakthrough rates were reported in one retrospective study [18]. Because no comparative studies have been done, the relative efficacy of these alternative regimens is unknown. Further, because most of these alternatives have no proven efficacy in preventing P. carinii pneumonia, additional prophylaxis (such as aerosol pentamidine) needs to be provided.

How should patients who relapse while receiving alternative therapies be managed? Options have not been well studied, but a common approach is to treat using a different, often less extensively evaluated, alternative regimen. Given that the toxicities requiring the discontinuation of pyrimethamine-sulfadiazine therapy are rarely life-threatening, and that recurrent toxoplasmosis potentially is, another approach is to rechallenge such patients with pyrimethamine-sulfadiazine at either full or reduced doses. Desensitization may be beneficial, but its utility has not been validated in controlled trials [19]. Even if intolerance recurs, patients may tolerate rechallenge for a few weeks, which is often long enough to induce a therapeutic response [4, 19]. Identifying the minimally effective dose of pyrimethamine-sulfadiazine may improve tolerance because lower doses of the related drugs, trimethoprim and sulfamethoxazole, are associated with a reduced incidence of adverse reactions [20].

Although the ultimate goal in management is the prevention of toxoplasmosis through either primary prophylaxis, identification of drugs that will eradicate the latent forms of T. gondii, or prevention of progressive HIV-induced immunodeficiency, studies such as the one by Podzamczer and colleagues provide important guidance for the clinician managing patients with active toxoplasmosis. Such controlled studies examining common community practices should be applauded and supported by funding agencies and the health care community.