HIV AIDS opportunistic infections

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-In-Chief:, Ujjwal Rastogi, MBBS [2]

Overview

Before the widespread use of potent combination antiretroviral therapy (ART), opportunistic infections (OIs), which have been defined as infections that are more frequent or more severe because of immunosuppression in HIV-infected persons, were the principal cause of morbidity and mortality in this population. In the early 1990s, the use of chemoprophylaxis, immunization, and better strategies for managing acute OIs contributed to improved quality of life and improved survival.[1] However, the widespread use of ART starting in the mid-1990s has had the most profound influence on reducing OI-related mortality in HIV-infected persons in those countries in which these therapies are accessible and affordable.

Etiology

Despite the availability of ART in the United States and other industrialized countries, OIs continue to cause considerable morbidity and mortality for three primary reasons:

  • Many patients are unaware of their HIV infection and seek medical care when an OI becomes the initial indicator of their disease.
  • Certain patients are aware of their HIV infection, but do not take ART because of psychosocial or economic factors.
  • Certain patients are prescribed ART, but fail to attain adequate virologic and immunologic response because of factors related to adherence, pharmacokinetics, or unexplained biologic factors.[2][3]

Thus, although hospitalizations and deaths have decreased since the implementation of ART, OIs remain a leading cause of morbidity and mortality in HIV-infected persons.[4][5][6]

Pathophysiology

Recognizing that the relation between OIs and HIV infection is bidirectional is important. HIV leads to immunosuppression that allows opportunistic pathogens to cause disease in HIV-infected persons. OIs and other coinfections that might be common in HIV-infected persons, such as sexually transmitted infections, can also have adverse effects on the natural history of HIV infection. Certain OIs are associated with reversible increases in circulating viral load and these increases could lead to accelerated HIV progression or increased transmission of HIV. Thus, although chemoprophylaxis and vaccination directly prevent pathogen-specific morbidity and mortality, they might also contribute to reduced rate of progression of HIV disease. For instance, randomized trials using trimethoprim-sulfamethoxazole (TMP-SMX) have documented that chemoprophylaxis can both decrease OI-related morbidity and improve survival.

Historical Perspective

The first guidelines for Prophylaxis against Pneumocystis carinii Pneumonia for persons infected with the human immunodeficiency virus became the first HIV-related treatment guideline published by the U.S. Public Health Service in 1989. This report was followed by guideline on prevention of Mycobacterium avium complex (MAC) disease in 1993.

Treatment

Initiation of ART in the Setting of an Acute OI (Treatment-Naïve Patients)

When an acute OI is present, initiation of ART is usually expected to improve immune function and contribute to faster resolution of the OI.

Initiation of ART has been documented to be effective for OIs for which effective therapy does not exist; cryptosporidiosis, microsporidiosis, and progressive multifocal leukoencephalopathy (PML) might resolve or at least stabilize after the institution of effective ART. For kaposi's sarcoma (KS), initiation of ART has been documented to lead to resolution of lesions in the absence of specific therapy for the sarcoma.[7]

Benefits of ART in preventing OI:

The initiation of ART in the setting of an acute OI also has preventive benefit; a second OI is less likely to occur if ART is started promptly rather than delaying the initiation of ART.

Disadvantages:

Starting ART in the setting of an acute OI has several potential disadvantages.

  • Severely ill patients might not absorb ART drugs, leading to subtherapeutic serum levels and the development of antiretroviral drug resistance.
  • ART toxicities might be confused with disease manifestations or toxicities associated with drugs used for treating patients with an OI. Drug-drug interactions among ART and anti-OI drugs might be difficult to manage.
  • Renal or hepatic dysfunction during acute OIs might make dosing of ART drugs difficult to estimate.
  • IRIS events can occur and cause manifestations that are difficult to distinguish from other clinical conditions.

When to start the therapy?

For above mentioned reasons, no consensus has been reached concerning the optimal time to start ART in the setting of a recently diagnosed OI. However, one recently completed randomized clinical trial has demonstrated a clinical and survival benefit of starting ART early, within the first 2 weeks, of initiation of treatment for an acute OI, excluding TB.[8]

Management of Acute OIs in Patients Receiving ART

OIs that occur after patients have been started on ART can be categorized into three groups.

  • The first group includes OIs that occur shortly after initiating ART (within 12 weeks).
    • These cases might be subclinical infections that have been unmasked by early immune reconstitution or simply OIs that occurred because of advanced immunosuppression and are not considered to represent early failure of ART. Many of these cases represent IRIS.[9][10]
    • When an OI occurs within 12 weeks of starting ART, treatment for the OI should be started and ART should be continued.
  • The second group includes OIs that occur >12 weeks after initiation of ART among patients with suppressed HIV ribonucleic acid. levels and sustained CD4+ counts >200 cells/µL[11][12] Determining whether these represent a form of IRIS rather than incomplete immunity with the occurrence of a new OI is difficult.
    • When an OI occurs despite complete virologic suppression (i.e., late OI), therapy for the OI should be initiated and ART should be continued.
    • If the CD4+ response to ART has been suboptimal, modification of the ART regimen may be considered, although no evidence exists to indicate that changing the ART regimen in this setting will improve the CD4+ response.
  • The third group includes OIs that occur among patients who are experiencing virologic and immunologic failure while on ART. These represent clinical failure of ART.
    • When an OI occurs in the setting of virologic failure, OI therapy should be started, antiretroviral resistance testing should be performed, and the ART regimen should be modified, if possible, to achieve better virologic control.

Treatment Failure

Clinical failure is defined as lack of improvement or worsening of respiratory function documented by arterial blood gases (ABGs) after at least 4--8 days of anti-PCP treatment. Treatment failure attributed to treatment-limiting toxicities occurs in up to one third of patients.[13]

Special Considerations During Pregnancy

Physiologic changes during pregnancy can complicate the recognition of OIs and complicate pharmacokinetics. Factors to consider include the following:

  • Increased cardiac output by 30%--50% with concomitant increase in glomerular filtration rate and renal clearance.
  • Increased plasma volume by 45%--50% while red cell mass increases only by 20%--30%, leading to dilutional anemia.
  • Tidal volume and pulmonary blood flow increase, possibly leading to increased absorption of aerosolized medications. The tidal volume increase of 30%--40% should be considered if ventilatory assistance is required.
  • Placental transfer of drugs, increased renal clearance, altered gastrointestinal absorption, and metabolism by the fetus might affect maternal drug levels.
  • Limited pharmacokinetic data are available; use usual adult doses based on current weight, monitor levels if available, and consider the need to increase doses if the patient is not responding as expected.

Also in regards with risk in Fetus, pregnancy should not preclude usual diagnostic evaluation when an OI is suspected.[14][15][16] Experience with use of magnetic resonance imaging (MRI) in pregnancy is limited, but no adverse fetal effects have been noted.[14]

Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents

Outline of the Guideline:

I: Pneumocystis Pneumonia

II: Toxoplasma gondii Encephalitis


Disease Specific Recommendations

Pneumocystis Pneumonia

Preventing Exposure

Certain authorities might recommend that persons who are at risk for PCP not share a hospital room with a patient who has PCP, a recommendations based on animal studies and anecdotal human experience. Data are insufficient to support this recommendation as standard practice (CIII).

Preventing Disease
Initiating Primary Prophylaxis
  • HIV-infected adults and adolescents, including pregnant women and those on ART, should receive chemoprophylaxis against PCP if they have a CD4+ count of <200 cells/µL (AI) or a history of oropharyngeal candidiasis (AII).[17][18]
  • Persons who have a CD4+ cell percentage of <14% or a history of an AIDS-defining illness, but do not otherwise qualify, should be considered for prophylaxis (BII). [17][18]
  • When monitoring CD4+ counts frequently (e.g., every 1--3 months) is not possible, initiating chemoprophylaxis at a CD4+ count of >200, but <250 cells/µL, also should be considered (BII). [18]
  • TMP-SMX is the recommended prophylactic agent (AI).[19][20][21] One double-strength tablet daily is the preferred regimen (AI). However, one single-strength tablet daily also is effective and might be better tolerated than one double-strength tablet daily (AI).[21] One double-strength tablet three times weekly also is effective (BI)[22]. TMP-SMX at a dose of one double-strength tablet daily confers cross-protection against toxoplasmosis[23] and selected common respiratory bacterial infections.[19][24] Lower doses of TMP-SMX also likely confer such protection. For patients who have an adverse reaction that is not life threatening, chemoprophylaxis with TMP-SMX should be continued if clinically feasible; for those who have discontinued such therapy because of an adverse reaction, reinstituting TMP-SMX should be strongly considered after the adverse event has resolved (AII). Patients who have experienced adverse events, including fever and rash, might better tolerate reintroduction of the drug with a gradual increase in dose (i.e., desensitization), according to published regimens (BI) [25][26] or reintroduction of TMP-SMX at a reduced dose or frequency (CIII); as many as 70% of patients can tolerate such reinstitution of therapy.[24]
  • If TMP-SMX cannot be tolerated, alternative prophylactic regimens include dapsone (BI)[19], dapsone plus pyrimethamine plus leucovorin (BI)[27][28][29], erosolized pentamidine administered by the Respirgard II nebulizer (manufactured by Marquest, Englewood, Colorado) (BI)[20], and atovaquone (BI)[30][31] Atovaquone is as effective as aerosolized pentamidine[30] or dapsone (BI) [31] but is substantially more expensive than the other regimens. For patients seropositive for Toxoplasma gondii who cannot tolerate TMP-SMX, recommended alternatives to TMP-SMX for prophylaxis against both PCP and toxoplasmosis include dapsone plus pyrimethamine plus leucovorin (BI)[27][28][29], erosolized pentamidine administered by the Respirgard II nebulizer (manufactured by Marquest, Englewood, Colorado) (BI)[20], and atovaquone (BI)[30][31] or atovaquone with or without pyrimethamine plus leucovorin (CIII).
  • Oral pyrimethamine plus sulfadoxine also has activity in preventing PCP (CIII)[32][33][34] This combination should not be used in patients with hypersensitivity to sulfonamides. Pyrimethamine plus sulfadoxine has an increased risk for severe cutaneous reactions, including Stevens-Johnson syndrome[35], and the long half-life of both pyrimethamine and sulfadoxine will result in a delayed clearance when the drug is stopped. Largely because TMP-SMX has superior safety, widespread availability, and is low cost, oral pyrimethamine plus sulfadoxine should be used rarely in the United States (CIII).
  • The following regimens cannot be recommended as alternatives because data regarding their efficacy for PCP prophylaxis are insufficient:
    • Aerosolized pentamidine administered by other nebulization devices.
    • Intermittently administered parenteral pentamidine.
    • Oral clindamycin plus primaquine.

However, clinicians might consider using these agents in unusual situations in which the recommended agents cannot be administered (CIII).

Discontinuing Primary Prophylaxis
  • Primary pneumocystis prophylaxis should be discontinued for adult and adolescent patients who have responded to ART with an increase in CD4+ counts to >200 cells/µL for >3 months (AI). In observational and randomized studies supporting this recommendation, the majority of patients were taking antiretroviral regimens that included a protease inhibitor (PI), and the majority had a CD4+ count of >200 cells/µL for >3 months before discontinuing PCP prophylaxis.[36][37] The median CD4+ count at the time prophylaxis was discontinued was >300 cells/µL, most had a CD4+ cell percentage of >14 %, and many patients had a sustained suppression of HIV plasma RNA levels below detection limits of the assay employed. Median follow-up was 6 - 19 months.
  • Discontinuing primary prophylaxis among these patients is recommended because prophylaxis adds limited disease prevention (i.e., for PCP, toxoplasmosis, or bacterial infections).[37][38]
  • Prophylaxis should be reintroduced if the CD4+ count decreases to <200 cells/µL (AIII).
Treatment of Disease
  • TMP-SMX is the treatment of choice (AI).[39] The dose must be adjusted for abnormal renal function. Multiple randomized clinical trials indicate that TMP-SMX is as effective as parenteral pentamidine and more effective than other regimens. Adding leucovorin to prevent myelosuppression during acute treatment is not recommended because of questionable efficacy and some evidence for a higher failure rate (DII). Oral outpatient therapy of TMP-SMX is highly effective among patients with mild-to-moderate disease (AI).
  • Mutations associated with resistance to sulfa drugs have been documented, but their effect on clinical outcome is uncertain. Patients who have PCP despite TMP-SMX prophylaxis are usually effectively treated with standard doses of TMP-SMX (BIII).
  • Patients with documented or suspected PCP and moderate-to-severe disease, as defined by room air pO2 <70 mm Hg or arterial-alveolar O2 gradient >35 mm Hg, should receive adjunctive corticosteroids as early as possible, and certainly within 72 hours after starting specific PCP therapy (AI).[40][41][42][43][44] If steroids are started at a later time, their benefits are unclear, although the majority of clinicians would use them in such circumstances for patients with moderate-to-severe disease (BIII). Methylprednisolone at 75% of the respective prednisone dose can be used if parenteral administration is necessary.
  • Alternative therapeutic regimens for mild-to-moderate disease include :
    • Dapsone and TMP (BI) (this regimen might have similar efficacy and fewer side effects than TMP-SMX but is less convenient because of the number of pills).[13][45]
    • Primaquine plus clindamycin (BI) (the clindamycin component can be administered intravenously for more severe cases.[46]
    • Atovaquone suspension (BI) (this is less effective than TMP-SMX for mild-to-moderate disease but has fewer side effects).
  • Patients should be tested for G6PD deficiency whenever possible before administration of primaquine.
  • Alternative therapeutic regimens for patients with moderate-to-severe disease include clindamycin-primaquine or intravenous (IV) pentamidine (AI) (usually the drug of second choice for severe disease). Certain clinicians prefer IV pentamidine because of convincing data regarding its high degree of efficacy. Other clinicians prefer clindamycin-primaquine because this combination is better tolerated than pentamidine, although data regarding efficacy are not as robust as the data supporting pentamidine. Aerosolized pentamidine should not be used for the treatment of PCP because of limited efficacy and more frequent relapse (DI). Trimetrexate is no longer available commercially.
  • The recommended duration of therapy for PCP is 21 days (AII).[47] The probability and rate of response to therapy depend on:
    • The agent used.
    • Number of previous PCP episodes.
    • Severity of illness.
    • Degree of immunodeficiency.
    • Timing of initiation of therapy.
  • Although the overall prognosis of patients whose degree of hypoxemia requires intensive care unit (ICU) admission or mechanical ventilation remains poor, survival in up to 50% of patients requiring ventilatory support has been reported in recent years.[48][49] Because long-term survival is possible for patients in whom ART is effective, certain patients with AIDS and severe PCP should be offered intensive care unit (ICU) admission or mechanical ventilation when appropriate (e.g., when they have reasonable functional status) (AII).
  • Because of the potential for additive or synergistic toxicities associated with anti-PCP and antiretroviral therapies, certain health-care providers delay initiation of ART until after the completion of anti-PCP therapy, or until at least 2 weeks after initiating anti-PCP therapy, despite some suggestion of potential benefit of early ART in the treatment of PCP (CIII). [49][50]
Monitoring and Adverse Events, Including Immune Reconstitution Inflammatory Syndrome (IRIS)

Careful monitoring during therapy is important to evaluate response to treatment and to detect toxicity as soon as possible. Follow-up after therapy includes assessment for early relapse, especially when therapy has been with an agent other than TMP-SMX or was shortened for toxicity. PCP prophylaxis should be initiated immediately upon completion of therapy and maintained until the CD4+ count is >200 cells/µL.

Adverse reaction rates among patients with AIDS are high for TMP-SMX (20%--85%).[39][40][45] Common adverse effects are rash (30%--55%) (including Stevens-Johnson syndrome), fever (30%--40%),leukopenia (30%--40%), thrombocytopenia (15%), azotemia (1%--5%), hepatitis (20%), and hyperkalemia. Supportive care for common adverse effects should be attempted before discontinuing TMP-SMX (AIII). Rashes can often be "treated through" with antihistamines, nausea can be controlled with antiemetics, and fever can be managed with antipyretics.

The most common adverse effects of alternative therapies include methemoglobinemia and hemolysis with dapsone or primaquine (especially in those with G6PD deficiency); rash and fever with dapsone; azotemia, pancreatitis, hypo- or hyperglycemia, leukopenia, electrolyte abnormalities, and cardiac dysrhythmia with pentamidine; anemia, rash, fever, and diarrhea with primaquine and clindamycin; and headache, nausea, diarrhea, rash, and transaminase elevations with atovaquone.

IRIS has been reported following PCP. Most cases have occurred within weeks of the episode of PCP. Reported cases are not sufficient to provide guidance on the optimal time to start ART following a mild or severe case of PCP.[51][52]

Management of Treatment Failure

Switching to another regimen is the appropriate management for treatment-related toxicity (BII). Failure attributed to lack of drug efficacy occurs in approximately 10% of those with mild-to-moderate disease. No convincing clinical trials exist on which to base recommendations for the management of treatment failure attributed to lack of drug efficacy. Clinicians should wait at least 4--8 days before switching therapy for lack of clinical improvement (BIII) In the absence of corticosteroid therapy, early and reversible deterioration within the first 3--5 days of therapy is typical, probably because of the inflammatory response caused by antibiotic-induced lysis of organisms in the lung. Other concomitant infections must be excluded as a cause for clinical failure ;[53][54] bronchoscopy with bronchoalveolar lavage should be strongly considered to evaluate for this possibility, even if it was conducted before initiating therapy.

If TMP-SMX has failed or must be avoided for toxicity in moderate-to-severe disease, the common practice is to use parenteral pentamidine or primaquine combined with clindamycin (BII).[55][56][57] For mild disease, atovaquone is a reasonable alternative (BII). Although one meta-analysis concluded that the combination of clindamycin and primaquine might be the most effective regimen for salvage therapy, no prospective clinical trials have evaluated the optimal approach to patients who experience a therapy failure with TMP-SMX.[58]

Preventing Recurrence

Patients who have a history of PCP should be administered chemoprophylaxis for life (i.e., secondary prophylaxis or chronic maintenance therapy) with TMP-SMX unless immune reconstitution occurs as a result of ART (AI).[59] For patients who are intolerant of TMP-SMX, alternatives are dapsone, dapsone combined with pyrimethamine, atovaquone, or aerosolized pentamidine.

Discontinuing Secondary Prophylaxis (Chronic Maintenance Therapy)

Secondary prophylaxis should be discontinued for adult and adolescent patients whose CD4+ count has increased from <200 cells/µL to >200 cells/µL for >3 months as a result of ART (BII). Reports from observational studies[36][60][61][62] and from two randomized trials [63][38]and a combined analysis of eight European cohorts being followed prospectively[64] support this recommendation.

In these studies, patients had responded to ART with an increase in CD4+ counts to >200 cells/µL for >3 months. The majority of patients were taking PI-containing regimens. The median CD4+ count at the time prophylaxis was discontinued was >300 cells/µL and most had a CD4+ cell percentage of >14%. The majority of patients had sustained suppression of plasma HIV RNA levels below the detection limits of the assay employed; the longest follow-up was 40 months. If the episode of PCP occurred at a CD4+ count of >200 cells/µL, continuing PCP prophylaxis for life, regardless of how high the CD4+ count rises as a consequence of ART, would be prudent (CIII); however, data regarding the most appropriate approach in this setting are limited.

Discontinuing secondary prophylaxis for patients is recommended because prophylaxis adds limited disease prevention (i.e., for PCP, toxoplasmosis, or bacterial infections) and because discontinuing drugs reduces pill burden, potential for drug toxicity, drug interactions, selection of drug-resistant pathogens, and cost.

Prophylaxis should be reintroduced if the CD4+ count decreases to <200 cells/µL (AIII). If PCP recurs at a CD4+ count of >200 cells/µL, lifelong prophylaxis should be administered (CIII).

Pneumocystis Pneumonia: Special considerations during pregnancy

PCP diagnostic considerations for pregnant women are the same as for nonpregnant women. Indications for therapy are the same as for nonpregnant women. The preferred initial therapy during pregnancy is TMP-SMX, although alternate therapies can be used if patients are unable to tolerate or are unresponsive to TMP-SMX (AI).[65] In case-control studies, trimethoprim has been associated with an increased risk for neural tube defects and cardiovascular, urinary tract, and multiple anomalies after first-trimester exposure.[66][67][68] Epidemiologic data suggest that folic acid supplementation might reduce this risk,[67][68] but no controlled studies have been done. In a small study, an increased risk for birth defects among infants born to women receiving antiretrovirals and folate antagonists, primarily trimethoprim, was reported, whereas no increase was observed among those with either antiretroviral or folate antagonist exposure alone.[69] Although first-trimester exposure to trimethoprim might be related to a small increased risk for birth defects, pregnant women in their first trimester with PCP should be treated with TMP-SMX (AIII). Although folic acid supplementation of 0.4 mg/day is routinely recommended for all pregnant women, data do not indicate if higher levels of supplementation, such as the 4 mg/day recommended for pregnant women with a previous infant with a neural tube defect, would provide added benefit in this situation. Follow-up ultrasound to assess fetal anatomy at 18--20 weeks is recommended (BIII).

Neonatal-care providers should be informed of maternal sulfa or dapsone therapy if used near the delivery date because of the theoretical increased risk for hyperbilirubinemia and kernicterus.

Pentamidine is embryotoxic but not teratogenic among rats and rabbits.[70] Adjunctive corticosteroid therapy should be used as indicated in nonpregnant adults (AIII).[71][72][73][74] Maternal fasting and postprandial glucose levels should be monitored closely when corticosteroids are used in the third trimester because the risk for glucose intolerance is increased.

Rates of preterm labor and preterm delivery are increased with pneumonia during pregnancy. Pregnant women with pneumonia after 20 weeks of gestation should be monitored for evidence of contractions(BII).

Chemoprophylaxis for PCP should be administered to pregnant women the same as for other adults and adolescents (AIII). TMP-SMX is the recommended prophylactic agent; dapsone is an alternative. Because of theoretical concerns regarding possible teratogenicity associated with drug exposures during the first trimester, health-care providers might withhold prophylaxis during the first trimester. In such cases, aerosolized pentamidine can be considered because of its lack of systemic absorption and the resultant lack of exposure of the developing embryo to the drug (CIII).

Toxoplasma gondii Encephalitis

Toxoplasmic encephalitis (TE) is caused by the protozoan Toxoplasma gondii. Disease appears to occur almost exclusively because of reactivation of latent tissue cysts.

Toxoplasma gondii: Preventing Exposure

HIV-infected persons should be tested for IgG antibody to Toxoplasma soon after the diagnosis of HIV infection to detect latent infection with T. gondii (BIII).

HIV-infected persons, including those who lack IgG antibody to Toxoplasma, should be counseled regarding sources of Toxoplasma infection. To minimize risk for acquiring toxoplasmosis, HIV-infected persons should be advised not to eat raw or undercooked meat, including undercooked lamb, beef, pork, or venison (BIII). Specifically, lamb, beef, venison, and pork should be cooked to an internal temperature of 165ºF--170ºF; meat cooked until it is no longer pink inside usually has an internal temperature of 165ºF--170ºF and therefore, from a more practical perspective, satisfies this requirement. To minimize the risk for acquiring toxoplasmosis, HIV-infected persons should wash their hands after contact with raw meat and after gardening or other contact with soil; in addition, they should wash fruits and vegetables well before eating them raw (BIII). If the patient owns a cat, the litter box should be changed daily, preferably by an HIV-negative, nonpregnant person; alternatively, patients should wash their hands thoroughly after changing the litter box (BIII). Patients should be encouraged to keep their cats inside and not to adopt or handle stray cats (BIII). Cats should be fed only canned or dried commercial food or well-cooked table food, not raw or undercooked meats (BIII). Patients need not be advised to part with their cats or to have their cats tested for toxoplasmosis (EII)

Toxoplasma gondii: Preventing Disease

Toxoplasma gondii: Initiating Primary Prophylaxis

Toxoplasma-seropositive patients who have a CD4+ count of <100 cells/µL should be administered prophylaxis against TE (AII).[23] The double-strength tablet daily dose of TMP-SMX recommended as the preferred regimen for PCP prophylaxis also is effective against TE and is therefore recommended (AII). TMP-SMX, one double-strength tablet three times weekly, is an alternative (BIII). If patients cannot tolerate TMP-SMX, the recommended alternative is dapsone-pyrimethamine plus leucovorin, which is also effective against PCP (BI).[27][28][29] Atovaquone with or without pyrimethamine/leucovorin also can be considered (CIII). Prophylactic monotherapy with dapsone, pyrimethamine, azithromycin, or clarithromycin cannot be recommended on the basis of available data (DII). Aerosolized pentamidine does not protect against TE and is not recommended (EI).[19][23]

Toxoplasma-seronegative persons who are not taking a PCP prophylactic regimen known to be active against TE (e.g., aerosolized pentamidine) should be retested for IgG antibody to Toxoplasma when their CD4+ counts decline to <100 cells/µL to determine whether they have seroconverted and are therefore at risk for TE (CIII). Patients who have seroconverted should be administered prophylaxis for TE as described previously (AII).

Toxoplasma gondii: Discontinuing Primary Prophylaxis

Prophylaxis against TE should be discontinued among adult and adolescent patients who have responded to ART with an increase in CD4+ counts to >200 cells/µL for >3 months (AI). Multiple observational studies[36][60][75] and two randomized trials[76][37] have reported that primary prophylaxis can be discontinued with minimal risk for developing TE among patients who have responded to ART with an increase in CD4+ count from <200 cells/µL to >200 cells/µL for >3 months. In these studies, the majority of patients were taking PI-containing regimens and the median CD4+ count at the time prophylaxis was discontinued was >300 cells/µL. At the time prophylaxis was discontinued, the majority of patients had sustained suppression of plasma HIV RNA levels below the detection limits of available assays; the median follow-up was 7--22 months. Although patients with CD4+ counts of <100 cells/µL are at greatest risk for having TE, the risk for TE occurring when the CD4+ count has increased to 100--200 cells/µL has not been studied as rigorously as an increase to >200 cells/µL. Thus, the recommendation specifies discontinuing prophylaxis after an increase to >200 cells/µL. Discontinuing primary TE prophylaxis is recommended because prophylaxis at CD4+ count >200 cells/ µL adds limited disease prevention for toxoplasmosis and because discontinuing drugs reduces pill burden, potential for drug toxicity, drug interaction, selection of drug-resistant pathogens, and cost. Prophylaxis for TE should be reintroduced if the CD4+ count decreases to <100--200 cells/µL (AIII).

Toxoplasma gondii: Treatment of Disease

The initial therapy of choice for TE consists of the combination of pyrimethamine plus sulfadiazine plus leucovorin (AI).[77][78][79][80] Pyrimethamine penetrates the brain parenchyma efficiently even in the absence of inflammation.[81] Use of leucovorin reduces the likelihood of the hematologic toxicities associated with pyrimethamine therapy. The preferred alternative regimen for patients with TE who are unable to tolerate or who fail to respond to first-line therapy is pyrimethamine plus clindamycin plus leucovorin (AI). [77][78]

TMP-SMX was reported in a small (77 patient) randomized trial to be effective and better tolerated than pyrimethamine-sulfadiazine.[82] On the basis of less in vitro activity and less experience with this regimen, pyrimethamine plus sulfadiazine with leucovorin is the preferred therapy (BI). For patients who cannot take an oral regimen, no well-studied options exist. No parenteral formulation of pyrimethamine exists; the only widely available parenteral sulfonamide is the sulfamethoxazole component of TMP-SMX. Therefore, certain specialists will treat severely ill patients requiring parenteral therapy initially with oral pyrimethamine plus parenteral TMP-SMX or parenteral clindamycin (CIII).

At least three regimens have activity in the treatment of TE in at least two, nonrandomized, uncontrolled trials, although their relative efficacy compared with the previous regimens is unknown:

  • 1) atovaquone (with meals or oral nutritional supplements) plus pyrimethamine plus leucovorin (BII)[83]
  • 2) Atovaquone combined with sulfadiazine or, for patients intolerant of both pyrimethamine and sulfadiazine, as a single agent (BII) (if atovaquone is used alone, measuring plasma levels might be helpful given the high variability of absorption of the drug among different patients; plasma levels of >18.5 µg/mL are associated with an improved response rate).[84][85][86]
  • 3) Azithromycin plus pyrimethamine plus leucovorin daily (BII).[87][88]

The following regimens have been reported to have activity in the treatment of TE in small cohorts of patients or in case reports of one or a few patients: clarithromycin plus pyrimethamine (CIII)[89]; 5-fluoro-uracil plus clindamycin (CIII) [90] dapsone plus pyrimethamine plus leucovorin (CIII)

Related Chapters

Reference

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  7. ↑ Murdaca G, Campelli A, Setti M, Indiveri F, Puppo F (2002). "Complete remission of AIDS/Kaposi's sarcoma after treatment with a combination of two nucleoside reverse transcriptase inhibitors and one non-nucleoside reverse transcriptase inhibitor". AIDS. 16 (2): 304–5. PMID 11807324. Retrieved 2012-04-06. Unknown parameter |month= ignored (help)
  8. ↑ Jacobson MA, Zegans M, Pavan PR, O'Donnell JJ, Sattler F, Rao N, Owens S, Pollard R (1997). "Cytomegalovirus retinitis after initiation of highly active antiretroviral therapy". Lancet. 349 (9063): 1443–5. doi:10.1016/S0140-6736(96)11431-8. PMID 9164318. Retrieved 2012-04-06. Unknown parameter |month= ignored (help)
  9. ↑ Egger M, May M, Chêne G, Phillips AN, Ledergerber B, Dabis F, Costagliola D, D'Arminio Monforte A, de Wolf F, Reiss P, Lundgren JD, Justice AC, Staszewski S, Leport C, Hogg RS, Sabin CA, Gill MJ, Salzberger B, Sterne JA (2002). "Prognosis of HIV-1-infected patients starting highly active antiretroviral therapy: a collaborative analysis of prospective studies". Lancet. 360 (9327): 119–29. PMID 12126821. Retrieved 2012-04-06. Unknown parameter |month= ignored (help)
  10. ↑ Race EM, Adelson-Mitty J, Kriegel GR, Barlam TF, Reimann KA, Letvin NL, Japour AJ (1998). "Focal mycobacterial lymphadenitis following initiation of protease-inhibitor therapy in patients with advanced HIV-1 disease". Lancet. 351 (9098): 252–5. doi:10.1016/S0140-6736(97)04352-3. PMID 9457095. Retrieved 2012-04-06. Unknown parameter |month= ignored (help)
  11. ↑ Currier JS, Williams PL, Koletar SL, Cohn SE, Murphy RL, Heald AE, Hafner R, Bassily EL, Lederman HM, Knirsch C, Benson CA, Valdez H, Aberg JA, McCutchan JA (2000). "Discontinuation of Mycobacterium avium complex prophylaxis in patients with antiretroviral therapy-induced increases in CD4+ cell count. A randomized, double-blind, placebo-controlled trial. AIDS Clinical Trials Group 362 Study Team". Ann. Intern. Med. 133 (7): 493–503. PMID 11015162. Retrieved 2012-04-06. Unknown parameter |month= ignored (help)
  12. ↑ Cinti SK, Kaul DR, Sax PE, Crane LR, Kazanjian PH (2000). "Recurrence of Mycobacterium avium infection in patients receiving highly active antiretroviral therapy and antimycobacterial agents". Clin. Infect. Dis. 30 (3): 511–4. doi:10.1086/313705. PMID 10722436. Retrieved 2012-04-06. Unknown parameter |month= ignored (help)
  13. ↑ 13.0 13.1 Safrin S, Finkelstein DM, Feinberg J, Frame P, Simpson G, Wu A, Cheung T, Soeiro R, Hojczyk P, Black JR (1996). "Comparison of three regimens for treatment of mild to moderate Pneumocystis carinii pneumonia in patients with AIDS. A double-blind, randomized, trial of oral trimethoprim-sulfamethoxazole, dapsone-trimethoprim, and clindamycin-primaquine. ACTG 108 Study Group". Ann. Intern. Med. 124 (9): 792–802. PMID 8610948. Unknown parameter |month= ignored (help); |access-date= requires |url= (help)
  14. ↑ 14.0 14.1 "ACOG Committee Opinion. Number 299, September 2004 (replaces No. 158, September 1995). Guidelines for diagnostic imaging during pregnancy". Obstet Gynecol. 104 (3): 647–51. 2004. PMID 15339791. Unknown parameter |month= ignored (help); |access-date= requires |url= (help)
  15. ↑ Toppenberg KS, Hill DA, Miller DP (1999). "Safety of radiographic imaging during pregnancy". Am Fam Physician. 59 (7): 1813–8, 1820. PMID 10208701. Retrieved 2012-04-06. Unknown parameter |month= ignored (help)
  16. ↑ Adelstein SJ (1999). <236::AID-TERA9>3.0.CO;2-6 "Administered radionuclides in pregnancy". Teratology. 59 (4): 236–9. doi:10.1002/(SICI)1096-9926(199904)59:4<236::AID-TERA9>3.0.CO;2-6. PMID 10331526. Retrieved 2012-04-06. Unknown parameter |month= ignored (help)
  17. ↑ 17.0 17.1 Phair J, Muñoz A, Detels R, Kaslow R, Rinaldo C, Saah A (1990). "The risk of Pneumocystis carinii pneumonia among men infected with human immunodeficiency virus type 1. Multicenter AIDS Cohort Study Group". N. Engl. J. Med. 322 (3): 161–5. doi:10.1056/NEJM199001183220304. PMID 1967190. Retrieved 2012-04-06. Unknown parameter |month= ignored (help)
  18. ↑ 18.0 18.1 18.2 Kaplan JE, Hanson DL, Navin TR, Jones JL (1998). "Risk factors for primary Pneumocystis carinii pneumonia in human immunodeficiency virus-infected adolescents and adults in the United States: reassessment of indications for chemoprophylaxis". J. Infect. Dis. 178 (4): 1126–32. PMID 9806044. Retrieved 2012-04-06. Unknown parameter |month= ignored (help)
  19. ↑ 19.0 19.1 19.2 19.3 Bozzette SA, Finkelstein DM, Spector SA, Frame P, Powderly WG, He W, Phillips L, Craven D, van der Horst C, Feinberg J (1995). "A randomized trial of three antipneumocystis agents in patients with advanced human immunodeficiency virus infection. NIAID AIDS Clinical Trials Group". N. Engl. J. Med. 332 (11): 693–9. doi:10.1056/NEJM199503163321101. PMID 7854375. Retrieved 2012-04-06. Unknown parameter |month= ignored (help)
  20. ↑ 20.0 20.1 20.2 Schneider MM, Hoepelman AI, Eeftinck Schattenkerk JK, Nielsen TL, van der Graaf Y, Frissen JP, van der Ende IM, Kolsters AF, Borleffs JC (1992). "A controlled trial of aerosolized pentamidine or trimethoprim-sulfamethoxazole as primary prophylaxis against Pneumocystis carinii pneumonia in patients with human immunodeficiency virus infection. The Dutch AIDS Treatment Group". N. Engl. J. Med. 327 (26): 1836–41. doi:10.1056/NEJM199212243272603. PMID 1360145. Retrieved 2012-04-06. Unknown parameter |month= ignored (help)
  21. ↑ 21.0 21.1 Schneider MM, Nielsen TL, Nelsing S, Hoepelman AI, Eeftinck Schattenkerk JK, van der Graaf Y, Kolsters AF, Borleffs JC (1995). "Efficacy and toxicity of two doses of trimethoprim-sulfamethoxazole as primary prophylaxis against Pneumocystis carinii pneumonia in patients with human immunodeficiency virus. Dutch AIDS Treatment Group". J. Infect. Dis. 171 (6): 1632–6. PMID 7769306. Retrieved 2012-04-06. Unknown parameter |month= ignored (help)
  22. ↑ El-Sadr WM, Luskin-Hawk R, Yurik TM, Walker J, Abrams D, John SL, Sherer R, Crane L, Labriola A, Caras S, Pulling C, Hafner R (1999). "A randomized trial of daily and thrice-weekly trimethoprim-sulfamethoxazole for the prevention of Pneumocystis carinii pneumonia in human immunodeficiency virus-infected persons. Terry Beirn Community Programs for Clinical Research on AIDS (CPCRA)". Clin. Infect. Dis. 29 (4): 775–83. doi:10.1086/520433. PMID 10589887. Retrieved 2012-04-06. Unknown parameter |month= ignored (help)
  23. ↑ 23.0 23.1 23.2 Carr A, Tindall B, Brew BJ, Marriott DJ, Harkness JL, Penny R, Cooper DA (1992). "Low-dose trimethoprim-sulfamethoxazole prophylaxis for toxoplasmic encephalitis in patients with AIDS". Ann. Intern. Med. 117 (2): 106–11. PMID 1351371. Unknown parameter |month= ignored (help); |access-date= requires |url= (help)
  24. ↑ 24.0 24.1 Hardy WD, Feinberg J, Finkelstein DM, Power ME, He W, Kaczka C, Frame PT, Holmes M, Waskin H, Fass RJ (1992). "A controlled trial of trimethoprim-sulfamethoxazole or aerosolized pentamidine for secondary prophylaxis of Pneumocystis carinii pneumonia in patients with the acquired immunodeficiency syndrome. AIDS Clinical Trials Group Protocol 021". N. Engl. J. Med. 327 (26): 1842–8. doi:10.1056/NEJM199212243272604. PMID 1448121. Retrieved 2012-04-06. Unknown parameter |month= ignored (help)
  25. ↑ Para MF, Finkelstein D, Becker S, Dohn M, Walawander A, Black JR (2000). "Reduced toxicity with gradual initiation of trimethoprim-sulfamethoxazole as primary prophylaxis for Pneumocystis carinii pneumonia: AIDS Clinical Trials Group 268". J. Acquir. Immune Defic. Syndr. 24 (4): 337–43. PMID 11015150. Retrieved 2012-04-06. Unknown parameter |month= ignored (help)
  26. ↑ Leoung GS, Stanford JF, Giordano MF, Stein A, Torres RA, Giffen CA, Wesley M, Sarracco T, Cooper EC, Dratter V, Smith JJ, Frost KR (2001). "Trimethoprim-sulfamethoxazole (TMP-SMZ) dose escalation versus direct rechallenge for Pneumocystis Carinii pneumonia prophylaxis in human immunodeficiency virus-infected patients with previous adverse reaction to TMP-SMZ". J. Infect. Dis. 184 (8): 992–7. doi:10.1086/323353. PMID 11574913. Retrieved 2012-04-06. Unknown parameter |month= ignored (help)
  27. ↑ 27.0 27.1 27.2 Podzamczer D, Salazar A, Jiménez J, Consiglio E, Santín M, Casanova A, Rufí G, Gudiol F (1995). "Intermittent trimethoprim-sulfamethoxazole compared with dapsone-pyrimethamine for the simultaneous primary prophylaxis of Pneumocystis pneumonia and toxoplasmosis in patients infected with HIV". Ann. Intern. Med. 122 (10): 755–61. PMID 7717598. Unknown parameter |month= ignored (help); |access-date= requires |url= (help)
  28. ↑ 28.0 28.1 28.2 Opravil M, Hirschel B, Lazzarin A, Heald A, Pechère M, Rüttimann S, Iten A, von Overbeck J, Oertle D, Praz G (1995). "Once-weekly administration of dapsone/pyrimethamine vs. aerosolized pentamidine as combined prophylaxis for Pneumocystis carinii pneumonia and toxoplasmic encephalitis in human immunodeficiency virus-infected patients". Clin. Infect. Dis. 20 (3): 531–41. PMID 7756472. Retrieved 2012-04-06. Unknown parameter |month= ignored (help)
  29. ↑ 29.0 29.1 29.2 Girard PM, Landman R, Gaudebout C, Olivares R, Saimot AG, Jelazko P, Gaudebout C, Certain A, Boué F, Bouvet E (1993). "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. 328 (21): 1514–20. doi:10.1056/NEJM199305273282102. PMID 8479488. Retrieved 2012-04-06. Unknown parameter |month= ignored (help)
  30. ↑ 30.0 30.1 30.2 Chan C, Montaner J, Lefebvre EA, Morey G, Dohn M, McIvor RA, Scott J, Marina R, Caldwell P (1999). "Atovaquone suspension compared with aerosolized pentamidine for prevention of Pneumocystis carinii pneumonia in human immunodeficiency virus-infected subjects intolerant of trimethoprim or sulfonamides". J. Infect. Dis. 180 (2): 369–76. doi:10.1086/314893. PMID 10395851. Retrieved 2012-04-06. Unknown parameter |month= ignored (help)
  31. ↑ 31.0 31.1 31.2 El-Sadr WM, Murphy RL, Yurik TM, Luskin-Hawk R, Cheung TW, Balfour HH, Eng R, Hooton TM, Kerkering TM, Schutz M, van der Horst C, Hafner R (1998). "Atovaquone compared with dapsone for the prevention of Pneumocystis carinii pneumonia in patients with HIV infection who cannot tolerate trimethoprim, sulfonamides, or both. Community Program for Clinical Research on AIDS and the AIDS Clinical Trials Group". N. Engl. J. Med. 339 (26): 1889–95. doi:10.1056/NEJM199812243392604. PMID 9862944. Retrieved 2012-04-06. Unknown parameter |month= ignored (help)
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  33. ↑ Payen MC, De Wit S, Sommereijns B, Clumeck N (1997). "A controlled trial of dapsone versus pyrimethamine-sulfadoxine for primary prophylaxis of Pneumocystis carinii pneumonia and toxoplasmosis in patients with AIDS". Biomed. Pharmacother. 51 (10): 439–45. PMID 9863502. Retrieved 2012-04-06.
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  36. ↑ 36.0 36.1 36.2 Dworkin MS, Hanson DL, Kaplan JE, Jones JL, Ward JW (2000). "Risk for preventable opportunistic infections in persons with AIDS after antiretroviral therapy increases CD4+ T lymphocyte counts above prophylaxis thresholds". J. Infect. Dis. 182 (2): 611–5. doi:10.1086/315734. PMID 10915098. Retrieved 2012-04-06. Unknown parameter |month= ignored (help)
  37. ↑ 37.0 37.1 37.2 Mussini C, Pezzotti P, Govoni A, Borghi V, Antinori A, d'Arminio Monforte A, De Luca A, Mongiardo N, Cerri MC, Chiodo F, Concia E, Bonazzi L, Moroni M, Ortona L, Esposito R, Cossarizza A, De Rienzo B (2000). "Discontinuation of primary prophylaxis for Pneumocystis carinii pneumonia and toxoplasmic encephalitis in human immunodeficiency virus type I-infected patients: the changes in opportunistic prophylaxis study". J. Infect. Dis. 181 (5): 1635–42. doi:10.1086/315471. PMID 10823763. Retrieved 2012-04-06. Unknown parameter |month= ignored (help)
  38. ↑ 38.0 38.1 Lopez Bernaldo de Quiros JC, Miro JM, Peña JM, Podzamczer D, Alberdi JC, Martínez E, Cosin J, Claramonte X, Gonzalez J, Domingo P, Casado JL, Ribera E (2001). "A randomized trial of the discontinuation of primary and secondary prophylaxis against Pneumocystis carinii pneumonia after highly active antiretroviral therapy in patients with HIV infection. Grupo de Estudio del SIDA 04/98". N. Engl. J. Med. 344 (3): 159–67. doi:10.1056/NEJM200101183440301. PMID 11172138. Retrieved 2012-04-06. Unknown parameter |month= ignored (help)
  39. ↑ 39.0 39.1 Hughes W, Leoung G, Kramer F, Bozzette SA, Safrin S, Frame P, Clumeck N, Masur H, Lancaster D, Chan C (1993). "Comparison of atovaquone (566C80) with trimethoprim-sulfamethoxazole to treat Pneumocystis carinii pneumonia in patients with AIDS". N. Engl. J. Med. 328 (21): 1521–7. doi:10.1056/NEJM199305273282103. PMID 8479489. Retrieved 2012-04-06. Unknown parameter |month= ignored (help)
  40. ↑ 40.0 40.1 Nielsen TL, Eeftinck Schattenkerk JK, Jensen BN, Lundgren JD, Gerstoft J, van Steenwijk RP, Bentsen K, Frissen PH, Gaub J, Orholm M (1992). "Adjunctive corticosteroid therapy for Pneumocystis carinii pneumonia in AIDS: a randomized European multicenter open label study". J. Acquir. Immune Defic. Syndr. 5 (7): 726–31. PMID 1613673. |access-date= requires |url= (help)
  41. ↑ Bozzette SA, Sattler FR, Chiu J, Wu AW, Gluckstein D, Kemper C, Bartok A, Niosi J, Abramson I, Coffman J (1990). "A controlled trial of early adjunctive treatment with corticosteroids for Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome. California Collaborative Treatment Group". N. Engl. J. Med. 323 (21): 1451–7. doi:10.1056/NEJM199011223232104. PMID 2233917. Retrieved 2012-04-07. Unknown parameter |month= ignored (help)
  42. ↑ Montaner JS, Lawson LM, Levitt N, Belzberg A, Schechter MT, Ruedy J (1990). "Corticosteroids prevent early deterioration in patients with moderately severe Pneumocystis carinii pneumonia and the acquired immunodeficiency syndrome (AIDS)". Ann. Intern. Med. 113 (1): 14–20. PMID 2190515. Unknown parameter |month= ignored (help); |access-date= requires |url= (help)
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  71. ↑ Albino JA, Shapiro JM (1994). "Respiratory failure in pregnancy due to Pneumocystis carinii: report of a successful outcome". Obstet Gynecol. 83 (5 Pt 2): 823–4. PMID 8159362. Unknown parameter |month= ignored (help); |access-date= requires |url= (help)
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  73. ↑ Koonin LM, Ellerbrock TV, Atrash HK, Rogers MF, Smith JC, Hogue CJ, Harris MA, Chavkin W, Parker AL, Halpin GJ (1989). "Pregnancy-associated deaths due to AIDS in the United States". JAMA. 261 (9): 1306–9. PMID 2783746. Unknown parameter |month= ignored (help); |access-date= requires |url= (help)
  74. ↑ Benedetti TJ, Valle R, Ledger WJ (1982). "Antepartum pneumonia in pregnancy". Am. J. Obstet. Gynecol. 144 (4): 413–7. PMID 7124859. Unknown parameter |month= ignored (help); |access-date= requires |url= (help)
  75. ↑ Furrer H, Opravil M, Bernasconi E, Telenti A, Egger M (2000). "Stopping primary prophylaxis in HIV-1-infected patients at high risk of toxoplasma encephalitis. Swiss HIV Cohort Study". Lancet. 355 (9222): 2217–8. PMID 10881897. Retrieved 2012-04-09. Unknown parameter |month= ignored (help)
  76. ↑ Miro JM, Lopez JC, Podzamczer D, Peña JM, Alberdi JC, Martínez E, Domingo P, Cosin J, Claramonte X, Arribas JR, Santín M, Ribera E (2006). "Discontinuation of primary and secondary Toxoplasma gondii prophylaxis is safe in HIV-infected patients after immunological restoration with highly active antiretroviral therapy: results of an open, randomized, multicenter clinical trial". Clin. Infect. Dis. 43 (1): 79–89. doi:10.1086/504872. PMID 16758422. Retrieved 2012-04-09. Unknown parameter |month= ignored (help)
  77. ↑ 77.0 77.1 Katlama C, De Wit S, O'Doherty E, Van Glabeke M, Clumeck N (1996). "Pyrimethamine-clindamycin vs. pyrimethamine-sulfadiazine as acute and long-term therapy for toxoplasmic encephalitis in patients with AIDS". Clin. Infect. Dis. 22 (2): 268–75. PMID 8838183. Retrieved 2012-04-09. Unknown parameter |month= ignored (help)
  78. ↑ 78.0 78.1 Dannemann B, McCutchan JA, Israelski D, Antoniskis D, Leport C, Luft B, Nussbaum J, Clumeck N, Morlat P, Chiu J (1992). "Treatment of toxoplasmic encephalitis in patients with AIDS. A randomized trial comparing pyrimethamine plus clindamycin to pyrimethamine plus sulfadiazine. The California Collaborative Treatment Group". Ann. Intern. Med. 116 (1): 33–43. PMID 1727093. Unknown parameter |month= ignored (help); |access-date= requires |url= (help)
  79. ↑ Leport C, Raffi F, Matheron S, Katlama C, Regnier B, Saimot AG, Marche C, Vedrenne C, Vilde JL (1988). "Treatment of central nervous system toxoplasmosis with pyrimethamine/sulfadiazine combination in 35 patients with the acquired immunodeficiency syndrome. Efficacy of long-term continuous therapy". Am. J. Med. 84 (1): 94–100. PMID 3337134. Retrieved 2012-04-09. Unknown parameter |month= ignored (help)
  80. ↑ Luft BJ, Hafner R, Korzun AH, Leport C, Antoniskis D, Bosler EM, Bourland DD, Uttamchandani R, Fuhrer J, Jacobson J (1993). "Toxoplasmic encephalitis in patients with the acquired immunodeficiency syndrome. Members of the ACTG 077p/ANRS 009 Study Team". N. Engl. J. Med. 329 (14): 995–1000. doi:10.1056/NEJM199309303291403. PMID 8366923. Retrieved 2012-04-09. Unknown parameter |month= ignored (help)
  81. ↑ Leport C, Meulemans A, Robine D, Dameron G, Vildé JL (1992). "Levels of pyrimethamine in serum and penetration into brain tissue in humans". AIDS. 6 (9): 1040–1. PMID 1388895. Unknown parameter |month= ignored (help); |access-date= requires |url= (help)
  82. ↑ Torre D, Casari S, Speranza F, Donisi A, Gregis G, Poggio A, Ranieri S, Orani A, Angarano G, Chiodo F, Fiori G, Carosi G (1998). "Randomized trial of trimethoprim-sulfamethoxazole versus pyrimethamine-sulfadiazine for therapy of toxoplasmic encephalitis in patients with AIDS. Italian Collaborative Study Group". Antimicrob. Agents Chemother. 42 (6): 1346–9. PMC 105601. PMID 9624473. Unknown parameter |month= ignored (help); |access-date= requires |url= (help)
  83. ↑ Chirgwin K, Hafner R, Leport C, Remington J, Andersen J, Bosler EM, Roque C, Rajicic N, McAuliffe V, Morlat P, Jayaweera DT, Vilde JL, Luft BJ (2002). "Randomized phase II trial of atovaquone with pyrimethamine or sulfadiazine for treatment of toxoplasmic encephalitis in patients with acquired immunodeficiency syndrome: ACTG 237/ANRS 039 Study. AIDS Clinical Trials Group 237/Agence Nationale de Recherche sur le SIDA, Essai 039". Clin. Infect. Dis. 34 (9): 1243–50. doi:10.1086/339551. PMID 11941551. Retrieved 2012-04-18. Unknown parameter |month= ignored (help)
  84. ↑ Kovacs JA (1992). "Efficacy of atovaquone in treatment of toxoplasmosis in patients with AIDS. The NIAID-Clinical Center Intramural AIDS Program". Lancet. 340 (8820): 637–8. PMID 1355212. Unknown parameter |month= ignored (help); |access-date= requires |url= (help)
  85. ↑ Torres RA, Weinberg W, Stansell J, Leoung G, Kovacs J, Rogers M, Scott J (1997). "Atovaquone for salvage treatment and suppression of toxoplasmic encephalitis in patients with AIDS. Atovaquone/Toxoplasmic Encephalitis Study Group". Clin. Infect. Dis. 24 (3): 422–9. PMID 9114194. Retrieved 2012-04-18. Unknown parameter |month= ignored (help)
  86. ↑ Katlama C, Mouthon B, Gourdon D, Lapierre D, Rousseau F (1996). "Atovaquone as long-term suppressive therapy for toxoplasmic encephalitis in patients with AIDS and multiple drug intolerance. Atovaquone Expanded Access Group". AIDS. 10 (10): 1107–12. PMID 8874627. Unknown parameter |month= ignored (help); |access-date= requires |url= (help)
  87. ↑ Saba J, Morlat P, Raffi F, Hazebroucq V, Joly V, Leport C, Vildé JL (1993). "Pyrimethamine plus azithromycin for treatment of acute toxoplasmic encephalitis in patients with AIDS". Eur. J. Clin. Microbiol. Infect. Dis. 12 (11): 853–6. PMID 8112357. Unknown parameter |month= ignored (help); |access-date= requires |url= (help)
  88. ↑ Jacobson JM, Hafner R, Remington J, Farthing C, Holden-Wiltse J, Bosler EM, Harris C, Jayaweera DT, Roque C, Luft BJ (2001). "Dose-escalation, phase I/II study of azithromycin and pyrimethamine for the treatment of toxoplasmic encephalitis in AIDS". AIDS. 15 (5): 583–9. PMID 11316995. Retrieved 2012-04-18. Unknown parameter |month= ignored (help)
  89. ↑ Fernandez-Martin J, Leport C, Morlat P, Meyohas MC, Chauvin JP, Vilde JL (1991). "Pyrimethamine-clarithromycin combination for therapy of acute Toxoplasma encephalitis in patients with AIDS". Antimicrob. Agents Chemother. 35 (10): 2049–52. PMC 245324. PMID 1836943. Retrieved 2012-04-18. Unknown parameter |month= ignored (help)
  90. ↑ Dhiver C, Milandre C, Poizot-Martin I, Drogoul MP, Gastaut JL, Gastaut JA (1993). "5-Fluoro-uracil-clindamycin for treatment of cerebral toxoplasmosis". AIDS. 7 (1): 143–4. PMID 8442914. Unknown parameter |month= ignored (help); |access-date= requires |url= (help)
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