Guidelines for the Prevention and Treatment of Opportunistic Infections in HIV-Exposed and HIV-Infected Children

The information in the brief version is excerpted directly from the full-text guidelines. The brief version is a compilation of the tables and boxed recommendations.

Toxoplasmosis

Last Updated: October 29, 2015; Last Reviewed: October 29, 2015

Panel's Recommendations for Toxoplasmosis
Panel's Recommendations

Preventing Exposure

  • Ingestion of undercooked meats that could contain tissue cysts and contact with cat feces that could contain sporulated oocysts should be avoided (AIII).

Initiaiting Primary Prophylaxis

  • Toxoplasma-seropositive children aged <6 years with CD4 T lymphocyte (CD4) cell percentage <15% and children aged ≥6 years with CD4 <100 cells/mm3 should be administered prophylaxis against Toxoplasma encephalitis (TE) (AIII). The preferred agent for prophylaxis of TE is trimethoprim-sulfamethoxazole, one double-strength tablet daily for adolescents and adults (or weight-equivalent dosing for children) (AII*).
  • Primary preventive therapy can be discontinued once a child responds to combination antiretroviral therapy (cART) with a sustained rise in CD4 percentage above 15% for children <6 years of age, and >200 cells/mm3 for children aged ≥6 years (BIII)
  • Most experts recommend treating pregnant women with acute toxoplasmosis in an attempt to prevent fetal infection (BII). For more extensive information on diagnosis, prevention, and treatment of pregnant women with toxoplasmosis, please see the Guidelines for the Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents.
  • Empiric therapy should be strongly considered for newborns of HIV-infected mothers who had symptomatic or asymptomatic primary Toxoplasma infection during pregnancy, regardless of whether treatment was administered during pregnancy (BIII)
  • The preferred treatment for congenital toxoplasmosis is pyrimethamine combined with sulfadiazine, with supplementary leucovorin (AII)
  • The recommended duration of treatment of congenital toxoplasmosis in HIV-infected infants is 12 months (AIII).
  • Therapy for acquired toxoplasmosis in HIV-infected children is sulfadiazine plus pyrimethamine and leucovorin (AI*). Please refer to http://www.daraprimdirect.com for information regarding access to pyrimethamine. If pyrimethamine is unavailable clinicians may substitute trimethoprim-sulfamethoxazole, dosed according to age and weight, in place of the combination of sulfadiazine, pyrimethamine, and leucovorin.
  • Corticosteroids are recommended for HIV-infected children with central nervous system toxoplasmosis when cerebrospinal fluid protein is highly elevated (i.e., >1,000 mg/dL) or who have focal lesions with substantial mass effect (BIII). Anticonvulsants should be administered only to children with TE who have a history of or current seizures (AIII)
  • Complete blood count should be monitored weekly in patients taking daily pyrimethamine (AIII). Patients who have completed initial therapy for TE should be given suppressive therapy (i.e., secondary prophylaxis or chronic maintenance therapy) unless cART results in immune reconstitution (AI*)
  • The preferred regimen for suppressive therapy for TE is sulfadiazine plus pyrimethamine and leucovorin (AI*). Please refer to http://www.daraprimdirect.com for information regarding access to pyrimethamine. If pyrimethamine is unavailable clinicians may substitute trimethoprim-sulfamethoxazole dosed according to age and weight.
Rating of Recommendations: A = Strong; B = Moderate; C = Optional
Rating of Evidence: I = One or more randomized trials in children with clinical outcomes and/or validated endpoints; I* = One or more randomized trials in adults with clinical outcomes and/or validated laboratory endpoints with accompanying data in children from one or more well-designed, nonrandomized trials or observational cohort studies with long-term clinical outcomes; II = One or more well-designed, nonrandomized trials or observational cohort studies in children† with long-term outcomes; II* = One or more well-designed, nonrandomized trials or observational studies in adults with long-term clinical outcomes with accompanying data in children from one or more similar nonrandomized trials or cohort studies with clinical outcome data; III = Expert opinion

Studies that include children or children/adolescents, but not studies limited to post-pubertal adolescents

Dosing Recommendations for Prevention and Treatment of Toxoplasmosis
Indication First Choice Alternative Comments/Special Issues
Primary Prophylaxis
TMP-SMX 150/750 mg/m2 body surface area once daily by mouth  For Children Aged ≥1 Month:
  • Dapsone 2 mg/kg body weight or 15 mg/m2 body surface area (maximum 25 mg) by mouth once daily, plus
  • Pyrimethamine 1 mg/kg body weight (maximum 25 mg) by mouth once daily, plus
  • Leucovorin 5 mg by mouth every 3 days
For Children Aged 1–3 Months and >24 Months:
  • Atovaquone 30 mg/kg body weight by mouth once daily
Children Aged 4–24 Months:
  • Atovaquone 45 mg/kg body weight by mouth once daily, with or without pyrimethamine 1 mg/kg body weight or 15 mg/m2 body surface area (maximum 25 mg) by mouth once daily, plus
  • Leucovorin 5 mg by mouth every 3 days
Acceptable Alternative Dosage Schedules for TMP-SMX:
  • TMP-SMX 150/750 mg/m2 body surface area per dose once daily by mouth 3 times weekly on 3 consecutive days per week
  • TMP-SMX 75/375 mg/m2 body surface area per dose twice daily by mouth every day 
  • TMP-SMX 75/375 mg/m2 body surface area per dose twice daily by mouth 3 times weekly on alternate days
Primary Prophylaxis Indicated For:
IgG Antibody to Toxoplasma and Severe Immunosuppression:
  • HIV-infected children aged <6 years with CD4 percentage <15%; HIV-infected children aged ≥6 years with CD4 count <100 cells/mm3
Criteria for Discontinuing Primary Prophylaxis:
Note: Do not discontinue in children aged <1 year
  • After ≥6 months of cART, and
  • Aged 1 to <6 years; CD4 percentage is ≥15% for >3 consecutive months
  • Aged ≥6 years; CD4 count >200 cells/mm3 for >3 consecutive months
Criteria for Restarting Primary Prophylaxis:
  • Aged 1 to <6 years with CD4 percentage <15%
  • Aged ≥6 years with CD4 count <100 to 200 cells/mm3
Secondary Prophylaxis
(Suppressive Therapy)
  • Sulfadiazine 42.5–60 mg/kg body weight per dose twice daily* (maximum 2–4 g per day) by mouth, plus
  • Pyrimethamine 1 mg/kg body weight or 15 mg/m2 body surface area (maximum 25 mg) by mouth once daily, plus
  • Leucovorin 5 mg by mouth once every 3 days
  • Clindamycin 7–10 mg/kg body weight per dose by mouth 3 times daily, plus
  • Pyrimethamine 1 mg/kg body weight or 15 mg/m2 body surface area (maximum 25 mg) by mouth once daily, plus
  • Leucovorin 5 mg by mouth once every 3 days
Children Aged 1–3 Months and >24 Months:
  • Atovaquone 30 mg/kg body weight by mouth once daily
  • Leucovorin, 5 mg by mouth every 3 days
  • TMP-SMX, 150/750 mg/m2 body surface area once daily by mouth
Children Aged 4–24 Months:
  • Atovaquone 45 mg/kg body weight by mouth once daily, with or without pyrimethamine 1 mg/kg body weight or 15 mg/m2 body surface area (maximum 25 mg) by mouth once daily, plus
  • Leucovorin, 5 mg by mouth every 3 days
  • TMP-SMX, 150/750 mg/m2 body surface area once daily by mouth
Secondary Prophylaxis Indicated:
  • Prior toxoplasmic encephalitis
Note: Alternate regimens with very limited data in children. TMP-SMX only to be used if patient intolerant to other regimens

Criteria for Discontinuing Secondary Prophylaxis
If All of the Following Criteria are Fulfilled:
  • Completed ≥6 months of cART, completed initial therapy for TE, asymptomatic for TE, and
  • Aged 1 to < 6 years; CD4 percentage ≥15% for >6 consecutive months
  • Aged ≥6 years; CD4 cell count >200 cells/mm3 for >6 consecutive months
Criteria For Restarting Secondary Prophylaxis:
  • Aged 1 to <6 years with CD4 percentage <15%
  • Aged ≥6 years with CD4 cell count <200 cells/mm3
Treatment Congenital Toxoplasmosis:
  • Pyrimethamine loading dose–2 mg/kg body weight by mouth once daily for 2 days, then 1 mg/kg body weight by mouth once daily for 2–6 months, then 1 mg/kg body weight by mouth 3 times weekly, plus
  • Leucovorin (folinic acid) 10 mg by mouth or IM with each dose of pyrimethamine, plus
  • Sulfadiazine 50 mg/kg body weight by mouth twice daily
Treatment Duration:
  • 12 months
Acquired Toxoplasmosis
Acute Induction Therapy (Followed by Chronic Suppressive Therapy):
  • Pyrimethamine: loading dose—2 mg/kg body weight (maximum 50 mg) by mouth once daily for 3 days, then 1 mg/kg body weight (maximum 25 mg) by mouth once daily, plus
  • Sulfadiazine 25–50 mg/kg body weight (maximum 1–1.5 g/dose) by mouth per dose 4 times daily, plus
  • Leucovorin 10–25 mg by mouth once daily, followed by chronic suppressive therapy
Treatment Duration (Followed by Chronic Suppressive Therapy):
  • ≥6 weeks (longer duration if clinical or radiologic disease is extensive or response in incomplete at 6 weeks)
For Sulfonamide-Intolerant Patients:
  • Clindamycin 5–7.5 mg/kg body weight (maximum 600 mg/dose) by mouth or IV per dose given 4 times a day can be substituted for sulfadiazine combined with pyrimethamine and leucovorin
Congenital Toxoplasmosis:
  • For infants born to mothers with symptomatic Toxoplasma infection during pregnancy, empiric therapy of the newborn should be strongly considered irrespective of the mother’s treatment during pregnancy.
Acquired Toxoplasmosis:
  • Pyrimethamine use requires CBC monitoring at least weekly while on daily dosing and at least monthly while on less than daily dosing.
  • TMP-SMX—TMP 5 mg/kg body weight plus SMX 25 mg/kg body weight per dose IV or by mouth given twice daily has been used as an alternative to pyrimethamine-sulfadiazine in adults, but has not been studied in children.
  • Atovaquone (for adults, 1.5 g by mouth twice daily—double the prophylaxis dose) in regimens combined with pyrimethamine/leucovorin, with sulfadiazine alone, or as a single agent in patients intolerant to both pyrimethamine and sulfadiazine, has been used in adults, but these regimens have not been studied in children.
  • Azithromycin (for adults, 900–1,200 mg/day, corresponding to 20 mg/kg/day in children) has also been used in adults combined with pyrimethamine-sulfadiazine, but has not been studied in children.
  • Corticosteroids (e.g., prednisone, dexamethasone) have been used in children with CNS disease when CSF protein is very elevated (>1,000 mg/dL) or there are focal lesions with significant mass effects, with discontinuation as soon as clinically feasible. 
  • Anticonvulsants should be administered to patients with a history of seizures and continued through the acute treatment; but should not be used prophylactically.
Note: Sulfadiazine may be given as 2–4 equal doses per day as long as the total daily dose is 85–120 mg/kg body weight.

Key to Acronyms: cART = combination antiretroviral therapy; CBC = complete blood count; CD4 = CD4 T lymphocyte; CNS = central nervous system; CSF = cerebrospinal fluid; IgG = Immunoglobulin G; IM = intramuscular; IV = intravenous; TE = toxoplasmic encephalitis; TMP-SMX = trimethoprim-sulfamethoxazole

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