Opportunistic Infections: Prophylaxis
Case 2: Discussion
Transmission of Toxoplasma gondii
Toxoplasma gondii is a protozoan parasite that can infect most mammals, but the definitive hosts are felines. Humans can be incidentally infected (Figure 1) if they ingest either oocysts from cat feces or viable tissue cysts contained in raw or undercooked red meat. Approximately 40% of domestic cats and 60% of strays are seropositive for T. gondii. Cats, however, generally excrete oocysts for only a limited time (2 to 3 weeks) during an acute infection. Kittens suffer more symptomatic primary infections than older cats and cats of any age can be re-infected. Excreted oocysts can remain viable for up to a year. Toxoplasma tissue cysts can be found in all types of mammalian meat, but humans appear to have the greatest risk of becoming infected from ingesting undercooked lamb, beef, pork, or venison.
Primary Toxoplasma infection in humans is usually asymptomatic, although some patients experience a mononucleosis-like syndrome. In all mammals, initial infection with T. gondii leads to latent infection with inactive tissue cysts residing in a number of organs, including skeletal muscle, heart muscle, and brain. Symptomatic disease in HIV-infected patients almost always results from reactivation of latent organisms as host immunity wanes. Eighty five percent of HIV-infected patients with active Toxoplasma infection have a CD4 count less than 100 cells/mm3 and typically present with a focal encephalitis. Patients with symptomatic primary infection (and occasionally reactivation infection) can present with retinitis, pneumonitis, and disseminated disease, but this is unusual. Historically, the lifetime risk of developing Toxoplasma encephalitis in a Toxoplasma-seropositive AIDS patient not taking prophylaxis ranges from 10 to 50%.
Epidemiology of Toxoplasma Infection
The incidence rate of Toxoplasma encephalitis in the United States among AIDS patients with a CD4 count less than 100 cells/mm3 in the pre-HAART era (1990-1995) was 40 cases per 1,000 patient-years and Toxoplasma encephalitis was the AIDS-defining illness in 5.1% of patients through 1992. In recent years, the incidence of Toxoplasma encephalitis has declined significantly (Figure 2), predominantly due to widespread use antiretroviral therapy and the use of trimethoprim-sulfamethoxazole for Pneumocystis pneumonia prophylaxis. Disease rates parallel seroprevalence rates that vary by geographic region. Within the United States, seropositivity is highest in those living east of the Mississippi River (up to 33%) compared with other regions (up to 15% in military recruits from the West coast). Rates of disease and seroprevalence are also higher among blacks than whites and among injection-drug users than men who have sex with men. Although cat ownership is not a risk factor for seroconversion[4,5], a recent US study found having three or more kittens was a risk factor for recent Toxoplasma infection. This same study confirmed ingestion of raw or undercooked beef or lamb or locally cured, dried or smoked meats as risk factors for Toxoplasma infection, but also found that working with meat, drinking unpasteurized goat's milk, and eating raw oysters, clams, or mussels increased the risk of infection. Overt disease and seropositivity are higher in countries where dietary habits and environmental factors favor transmission. For example, Toxoplasma seroprevalence rates in France are greater than 60%.
Recommendations for Preventing Exposure
The 2009 guidelines for the prevention and treatment of opportunistic infections guidelines published by the CDC, National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America, recommends all HIV-infected persons, particularly those who are Toxoplasma seronegative, should receive counseling regarding sources for Toxoplasma infection. In addition, they should receive the specific recommendations regarding (Figure 3) practices that prevent exposure to Toxoplasma.
Recommendations for Initiating Primary Prophylaxis
Prophylaxis for Toxoplasma encephalitis is classified as either primary prophylaxis (preventing first episode of Toxoplasma encephalitis) or secondary prophylaxis (preventing recurrence of Toxoplasma encephalitis). Patients should be tested for IgG antibody to Toxoplasma soon after their diagnosis of HIV infection. The 2009 guidelines for the prevention and treatment of opportunistic infections provides specific recommendations for initiating primary prophylaxis of Toxoplasma encephalitis (Figure 4); these recommendations include a rating scheme (Figure 5) indicating the strength of the recommendation (A-E) and the quality of evidence supporting the recommendation (I-III). Patients with a CD4 count less than 100 cells/mm3 who are also seropositive for Toxoplasma should receive primary prophylaxis for Toxoplasma encephalitis. Patients who previously had a negative IgG antibody to Toxoplasma, and experience a CD4 count decline to less than 100 cells/mm3 should undergo repeat toxoplasma IgG antibody testing if they are not taking trimethoprim-sulfamethoxazole for Pneumocystis pneumonia prophylaxis. In this situation, patients should initiate Toxoplasma encephalitis prophylaxis if they have evidence of Toxoplasma seroconversion.
Recommended Preferred Regimens for Primary Prophylaxis
The 2009 opportunistic infection guidelines recommend (Figure 4) trimethoprim-sulfamethoxazole (Bactrim, Septra) at a dose of one double-strength tablet daily as the first choice for prophylaxis against Toxoplasma encephalitis. Trimethoprim-sulfamethoxazole is the preferred drug for Toxoplasma encephalitis prophylaxis because it is highly effective, inexpensive, and provides concomitant protection against Pneumocystis pneumonia, Isospora belli, and some community acquired bacterial pathogens[8,9]. In 1992, investigators published the first study demonstrating the usefulness of trimethoprim-sulfamethoxazole for preventing Toxoplasma encephalitis. This small, retrospective study reported no cases of Toxoplasma encephalitis among 22 patients taking low dose trimethoprim-sulfamethoxazole (one double strength twice daily 2 days per week for Pneumocystis prophylaxis) compared with 12 cases that occurred in 36 patients treated with aerosolized pentamidine. Several subsequent prospective studies confirmed the efficacy of trimethoprim-sulfamethoxazole for prophylaxis of Toxoplasma encephalitis[1,11,12], one of which demonstrated improved efficacy with high doses (greater than 4 double strength tablets per week).
Recommended Alternative Regimens for Primary Prophylaxis
Acceptable alternatives include one double-strength trimethoprim-sulfamethoxazole given three times weekly or one single-strength given daily. For patients intolerant of trimethoprim-sulfamethoxazole, the recommended alternative regimens consist of dapsone plus pyrimethamine plus leucovorin, or atovaquone (Mepron) with or without pyrimethamine and leucovorin. The combination of dapsone plus pyrimethamine was compared with trimethoprim-sulfamethoxazole in a head-to-head trial of 230 patients and found to be equally effective in preventing Toxoplasma encephalitis, although the number of patients at risk for Toxoplasma encephalitis was small (130 Toxoplasma-seropositive patients). Subsequently a meta-analysis of 22 trials of prophylaxis for Pneumocystis pneumonia and Toxoplasma encephalitis concluded that dapsone plus pyrimethamine was equivalent to trimethoprim-sulfamethoxazole, and both of these regimens showed greater effectiveness than pentamidine. This meta-analysis included two large studies comparing dapsone plus pyrimethamine versus pentamidine[14,15]. The recommendation for atovaquone is primarily based on data from two maintenance therapy (secondary prophylaxis) studies; the use of atovaquone alone or with pyrimethamine was well tolerated and effective in preventing relapse of Toxoplasma encephalitis [8,16]. Based on available data, prophylactic monotherapy with dapsone, pyrimethamine, azithromycin (Zithromax), or clarithromycin (Biaxin) is not recommended. In addition, aerosolized pentamidine does not provide protection against Toxoplasma encephalitis.
Recommendations for Discontinuing Prophylaxis
Several studies involving HIV-infected persons have shown that primary prophylaxis for Toxoplasma encephalitis can be safely discontinued in patients who have a CD4 count that increases above the 200 cells/mm3 level (for at least 3 months) in response to effective antiretroviral therapy[8,18,19]. In these studies, patients had excellent and sustained responses to antiretroviral therapy, generally with HIV RNA levels consistently below the detectable range. The 2009 opportunistic infections guidelines recommend patients discontinue primary Toxoplasma encephalitis prophylaxis if they have responded to effective antiretroviral therapy with an increase in CD4 count to greater than 200 cells/mm3 for at least 3 months. Discontinuing prophylaxis can reduce pill burden, cost, potential for drug toxicity, and risk of developing resistant infectious pathogens. If patients experience a decline in CD4 counts to less than 100 to 200 cells/mm3, they should restart prophylaxis for Toxoplasma encephalitis.
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