TAG: The OI Report - toxoplasmosis

THE OI REPORT:
A Critical Review of the Treatment & Prophylaxis of
AIDS-Related Opportunistic Infections (OIs)

TOXOPLASMOSIS
by Theo Smart

INTRODUCTION
The most frequent source of lesions in the central nervous system (CNS) in people with AIDS (PWAs) is toxoplasmosis or toxoplasmic encephalitis (TE). The causative agent, Toxoplasma gondii is a ubiquitous obligate intracellular protozoan. Besides the brain, the parasite can also infect other organs including the lung, eye, skin, heart, liver and gastrointestinal tract. Infection is asymptomatic or self-limited in an immunocompetent host.

T. gondii is transmitted by eating contaminated and undercooked meat, eggs or through exposure to cat feces (Luft 1990). Cat litter boxes especially have become notorious as a potential source of T. gondii infection. The only researchers to carefully investigate the issue, however, dismiss cat ownership as a major risk factor for exposure to T. gondii among people with HIV (at least among those who clean the litter box frequently and wash their hands afterward) (Wallace 1993).

About one-third of people with HIV have been exposed to T gondii and are Toxoplasma-antibody positive in the US; this proportion is higher elsewhere in the world. TE usually occurs in people with CD4 counts below 100. In 1992, it was estimated that between 27 and 40% of PWAs who had antibodies to the parasite, and a total of 10 to 20% of PWAs each year developed TE (Luft 1992). The incidence of TE appears to have decreased dramatically in the last several years, most probably because of the increased use of Pneumocystis carinii pneumonia (PCP) prophylaxes such as trimethoprim-sulfamethoxazole (TMP/SMX) or dapsone. Several studies suggest that these agents reduce or prevent reactivation of T. gondii.

The most common initial symptoms of TE are headache, confusion, lethargy and low-grade fever. This may lead to uni- or multifocal symptoms, which depending upon the particular affected sites within the CNS can include weakness, speech disorders, ataxia (gait disturbances), apraxia (inability to carry out customary motions), seizures and sensory loss. Lesions in the basal ganglia may lead to motor disorders.

DIAGNOSIS
The clinical presentation of TE may be difficult to distinguish from other multifocal neurologic conditions. Serology and neuroimaging are useful but not definitive tools in making a diagnosis of TE. Antibodies to T. gondii are generally present in persons with TE, but Porter and Sande reported a negative serology in 22% of patients with TE (Porter & Sande 1992). The same pattern appears to be emerging with polymerase chain reaction (PCR) tests for T. gondii DNA (Lamoril 1996). While the presence of Toxoplasma DNA in the cerebral spinal fluid (CSF) suggests active infection, PCR sometimes fails to detect it. There may be a slightly elevated protein level and mild pleocytosis (cell infiltration) in the CSF, but these findings may be present in a number of other conditions, as well.

There is no reliable way to differentiate the focal lesions caused by TE from those caused by CNS lymphoma on a brain scan by CT (X-ray) or MRI. The most rapid and definitive diagnostic procedure, a stereotaxic brain biopsy, is so invasive and expensive that most neurologists are reluctant to perform the operation. Nevertheless, since TE is the most common cause of focal lesions in people with HIV, empiric therapy is used to confirm the diagnosis. Failure to respond within two weeks suggests an alternative diagnosis and should prompt a brain biopsy.

TREATMENT
In 1988, pyrimethamine/sulfadiazine (PS) was established as the standard of care treatment for TE by a retrospective study (Leport 1988). The regimen consists of a 4 to 8 week induction course of a 100-200 milligram (mg) loading dose of pyrimethamine followed by 50 to 75 milligrams a day (mg/day) plus 4 to 8 grams a day (gm/d) of sulfadiazine. This is followed with a maintenance or secondary prophylaxis regimen of pyrimethamine 25 to 50 mg/day and sulfadiazine 2 to 4 gm/day. Leucovorin 5-50 mg/d is also administered to prevent pyrimethamine-associated folinic acid deficiency (Van Voorhis 1990; Behbahani 1995). The dosage of leucovorin is adjusted depending upon the patient's blood counts.

PS is poorly tolerated by many patients. Pyrimethamine causes hematological toxicity, and a substantial number of patients are allergic to sulfadiazine, which also may cause crystalluria leading to kidney failure.

If the patient cannot be desensitized to sulfadiazine by dose-escalation regimens, several studies show that pyrimethamine/clindamycin (PC) (1200-2400 mg/day) is a possible alternative. There was no major difference between PC and PS in one randomized study of 59 people with TE. In this study, clindamycin (1200 mg/day) was intravenously administered for three weeks, followed by three weeks of oral clindamycin 300 mg four times a day. Clinical and radiological responses on the regimens were comparable, although there was a trend toward more complete response in patients on clindamycin. The study was too small to detect any significant difference between the arms, though. Furthermore, the results may also have been confounded by the use of corticosteroids at the investigator's discretion.

Slightly more people died on the clindamycin-containing regimen (5 of 26 versus 2 of 33 patients), but the difference was not statistically significant, and the deaths were not associated with TE. There were no differences in the rate of adverse events (clindamycin can cause rash as well as considerable gastrointestinal distress, colitis and diarrhea) (Dennemann 1992).

Other open-label or retrospective studies report similar activity for PC (Foppa 1991, Rolston 1991; Luft 1993). Foppa and colleagues used a maintenance dose of pyrimethamine 25 mg/day plus clindamycin 300 mg every six hours or 450 mg every eight hours (Foppa 1991). This falls in line with the recommended maintenance dose of clindamycin 1200 mg/d in three or four divided doses (Remington 1991).

At least one researcher has found activity at a dosage that may be easier for patients to tolerate. Rolston evaluated 3 to 14 months of PC maintenance therapy in seven patients using 25 mg/day pyrimethamine and clindamycin 300 mg thrice daily three times a week (Rolston 1991). None of the patients on this regimen suffered relapses, even though the doses are lower than generally recommended (Behbahani 1995). As there is such a high rate of adverse events on PC, further evaluation of the low dose maintenance regimen seems warranted. Indeed, the most effective and best-tolerated doses of either PS or PC have never been established in controlled studies for induction or maintenance therapy.

Both PS and PC are quick and effective treatments of TE. There is clearly room, though, for treatments or regimens that are easier to tolerate. The search for less toxic regimens has focused primarily on newer and more expensive antimicrobials, such as the macrolide antibiotics -- azithromycin and clarithromycin -- and atovaquone. Unfortunately, the rate of adverse events on some of these regimens has not been as low as hoped. Furthermore, few of these mostly pharmaceutical company-sponsored studies risked a direct comparison to the standard treatments. Although cross-study comparisons are generally not valid, the response rates reported in the studies of these new treatments are not as impressive as reported in studies of PS or PC. Moreover, the definitions of clinical or radiologic responses in the more recent studies are often not as rigorous as those used in the studies of PC or PS.

The macrolide antibiotics azithromycin and clarithromycin have activity in vitro and in animal models against T. gondii (Derouin 1990). There is some suggestion in the animal model that azithromycin by itself did not delay dissemination of T. gondii to the brain, although it is active against other sites of infection such as the lungs (Derouin 1992). Azithromycin, however, was synergistic with both pyrimethamine and sulfadiazine in the animal model.

Conflicting data have been reported in the case studies in the literature (Farthing 1992; Lane 1994). The largest open-label study treated 8 of 14 evaluable patients with pyrimethamine (200 mg loading dose, then 75 mg/day) plus azithromycin (1000 mg loading dose, then 500 mg/d). Five out of 8 had at least a partial clinical response and 6 of 9 had a radiological response within 21 days. Toxicities included rash, abnormal liver function, vomiting and hypoacusia (diminished hearing).

Clarithromycin, in combination with various agents, has been studied in clinical trials for patients with TE (Fernandez-Martin 1991; Lacassin 1995). In one open-label study, 13 patients with TE were treated with clarithromycin 2 gm/day, pyrimethamine 75 mg/day, and leucovorin 20 mg/day. 84% of the patients at week three had a clinical response. Only 30 and 50% had a greater than 50% radiological response at weeks three and six respectively. The regimen was not well tolerated - 90% of the patients experienced adverse events (nausea, vomiting, rash, hearing loss, liver enzyme elevations, and abnormal hematology); only 8 patients completed six weeks of treatment. Clearly a lower dose of clarithromycin should be studied (Fernandez-Martin 1991).

Atovaquone liquid suspension was shown to be as effective as dapsone in preventing toxoplasmosis in ACTG 034/CPCRA 277. Cell culture and animal studies showed activity against T. gondii (Huskinson-Mark 1991; Haile 1993). Atovaquone was better tolerated than dapsone in those patients intolerant to TMP/SMX (El-Sadr 1997).

Kovacs administered atovaquone 750 mg four times daily with meals six weeks in 8 patients intolerant to PS. Seven of these had at least a partial response and one patient remained stable. However, a response was defined as only a 25% clinical improvement, reduction in at least one lesion on brain scan, or improvement in one clinical finding. The author claimed that six had a "substantial clinical response," one remained stable, and one patient died but with no evidence of TE. In contrast to the macrolide regimens, this drug appears well tolerated (Kovacs 1992).

Another open-label study conducted by Burroughs-Wellcome used the same regimen of atovaquone in 62 patients (Behbahani 1995). In this study, 71%, of the patients had some response or were stable clinically, and 61% improved or were stable radiologically .

Torres and colleagues studied atovaquone (750 mg four times daily) in 93 patients who had failed or were intolerant to PS. Torres found that patients with a higher plasma concentration of atovaquone (more than 13 痢/mL) had a superior response (88%), while only 54% improved with lower levels of drug. The treatment was generally well tolerated (Torres 1993). This study was conducted with an old, poorly bioavailable atovaquone formulation. ACTG 237 is studying the new and purportedly better-absorbed formulation of atovaquone (1500 mg twice daily) with either pyrimethamine or sulfadiazine for acute TE. For maintenance therapy, patients will receive pyrimethamine plus folinic acid or, if sulfa-intolerant, clarithromycin at 500 mg twice daily.

Considering how effective a prophylaxis TMP/SMX appears to be (see below), it is surprising that there have not been more attempts to evaluate its use as a treatment for TE. One 24-patient TE study investigated two different doses of the combination (Canessa 1992). Half were treated with 40/mg/kg/day (TMP 6.6 mg/kg) and half with 120 mg/kg/day (TMP 20 mg/kg) for an average of 25 days. Nine out of 12 in each group experienced a complete remission of clinical symptoms and more than a 50% reduction in the number or size of lesions on brain scan. There were three cases of rash and two cases of hematological toxicity.

There are several alternatives of last resort for those who fail or are intolerant to all of the above. Trimetrexate (plus leucovorin) has significant in vitro activity, but its clinical performance has been disappointing. Masur and colleagues used 30 to 120 mg/m2/d of intravenous trimetrexate and 30 to 120 milligrams per meter squared per day of leucovorin calcium in 9 patients who were intolerant to sulfadiazine. The dose of trimetrexate was increased to 280 mg/kg/day if the patient had a life-threatening case, failed to respond, or relapsed. Five of 8 patients had a clinical response within 16 days, but the radiologic response was slow to occur (3 to 53 days). No patient had a complete response, and after initial improvement TE continued to worsen in the patients despite high-dose treatment (Masur 1993). Keep in mind, though, that no drug has been shown to work as a monotherapy against TE. Further study of trimetrexate should evaluate it in combination with other agents. There are some anecdotal data on the use of spiramycin or 5-fluoro-uracil (5FU). In one study, though, the addition of 9 million units of spiramycin to PC produced no greater activity than PC alone (St. Georgiev 1993).

PROPHYLAXIS
Many of the data on the prevention of TE come from studies of PCP prophylaxis, particularly TMP/SMX. As such, the studies do not always evaluate the number of study participants with positive T. gondii serologies at baseline, and though authors may note the number of TE diagnoses, the criteria used for such diagnoses are often omitted from the reported data. Nevertheless, most of the agents with activity against P. carinii also suppress T. gondii reactivation. The notable exception is pentamidine, which has little in vitro activity against the parasite, and is not systemically absorbed when administered in aerosolized form.

In the first retrospective study, TMP/SMX 160/800 mg (one double-strength tablet) 3 times a week was used by 116 patients with previous PCP or CD4 counts below 200. Not one case of TE occurred within the 18.5 months of follow-up in the patients on secondary prophylaxis, or within the 24 months of follow-up in those on primary prophylaxis (Ruskin 1991). No patient on TMP/SMX developed TE while on a twice-weekly regimen of the same dose of TMP/SMX in another retrospective study of 155 patients. TE did occur in 12 out of the 95 patients on aerosolized pentamidine in the same study (a third of the 36 seropositive patients) (Carr 1992). O'Farrell and colleagues also found no TE among 233 patients who took TMP/SMX, except in 6 who switched to pentamidine (O'Farrell 1991). Lipman and colleagues conducted a chart review of their center and found 8 cases of TE in their 210 patients taking pentamidine (3.8%) as opposed to only one in 154 on TMP/SMX (0.6%) (Lipman 1993).

Another possible approach to TE prophylaxis is to use dapsone, though most of the studies also add pyrimethamine to the regimen. Podzamczer and colleagues randomized 166 patients to receive TMP/SMX 800 mg twice daily, three 3 times a week, as opposed to 100 mg of dapsone plus 25 mg of pyrimethamine once a week as prophylaxis for TE and PCP. After a median follow-up of 380 days, the rate of TE was not significantly different in the two arms (3.7% on TMP versus 2.3% on dapsone/pyrimethamine) (Podzamczer 1993). A similar Italian study of TMP/SMX versus dapsone plus pyrimethamine plus folinic acid is also underway.

Clotet and colleagues reported no new cases of TE in an open-label prospective study of dapsone 100 mg plus pyrimethamine 25 mg both twice weekly in 109 patients (54 of whom were T. gondii seropositive). The mean follow-up in this study was 15 months, but other important details, such as baseline CD4 counts, were not reported in the study abstract. The authors did note that the combination was well tolerated and cheap (Clotet 1992).

In CPCRA 034/ACTG 277, atovaquone liquid suspension was shown to be equally effective as dapsone in preventing toxoplasmosis in patients with positive T. gondii serologies. Atovaquone was also more tolerable (El-Sadr 1997).

Girard and colleagues randomized 349 patients (262 seropositive) to dapsone 50 mg/day plus pyrimethamine 50 mg (plus leucovorin 25 mg/week) once a week or aerosolized pentamidine 300 mg once a month. After 539 days median follow-up, the study was discontinued after an interim analysis found a statistically significant difference in the development of TE (32 cases on pentamidine and 19 on dapsone (p=0.02) (Girard 1993). In another PCP and TE prophylaxis study, Opravil and colleagues randomized 533 patients (47% of whom were had antibodies to T. gondii) to receive aerosolized pentamidine or dapsone/pyrimethamine (DP) 25/200 mg week. 14/291 (4.8%) of those on DP developed TE, compared with 20/242 (8.3%) of those on pentamidine. The difference was statistically significant. Intolerance to DP was more common, however (Opravil 1995).

It is not entirely clear whether the use of pyrimethamine (with its significant toxicity) with dapsone is truly necessary. Torres and colleagues randomized 278 patients to dapsone alone 100 mg twice weekly or pentamidine. After a mean of 43 weeks follow-up, there was no TE among the patients on dapsone, while six cases occurred in those on pentamidine (Torres 1993).

Standard treatments for TE are generally not used for TE prophylaxis because of their toxicity and unimpressive activity. These treatments may not work against the form of the protozoal parasite which predominates during clinical latency. In CPCRA 001, Jacobson and colleagues randomized 84 patients to receive clindamycin 300 mg twice daily or pyrimethamine 25 mg three times a week or placebo. The clindamycin arm was stopped early because of severe adverse events (diarrhea/rash) in more than 40% of patients. There was no difference in the development of TE between the placebo and pyrimethamine arms, though there was a statistically significant survival benefit in favor of placebo. The higher rate of mortality may have been due to pyrimethamine's antifolate activity, since the rate of death was much higher in those with low hemoglobin at baseline. Only those with hematological toxicity were treated with leucovorin. Other prophylaxis studies using pyrimethamine have not observed this difference in mortality, but generally leucovorin is coadministered (Jacobson 1994).

A number of other studies also suggest that pyrimethamine monotherapy is also a suboptimal prophylaxis for TE. After 20 months in a 49-patient study conducted by Stellini and colleagues, only one T. gondii seropositive patient developed TE on TMP/SMX (800 mg every other day) as opposed to seven diagnosed cases on pyrimethamine (50 mg twice weekly) (p=0.03) (Stellini 1993). In ACTG 154, a French/American collaborative study of 554 patients, no difference could be found in the development of TE between those randomized to pyrimethamine 50 mg per week plus leucovorin (12%) and those who received placebo (13%). Unsurprisingly, the side effects were worse on pyrimethamine (mostly rash and hematological) (Leport 1996).

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