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.

Histoplasmosis

Last Updated: November 6, 2013; Last Reviewed: November 6, 2013

Panel's Recommendations for Histoplasmosis
Panel's Recommendations
  • Routine use of antifungal medications for primary prophylaxis of histoplasmosis infections in children is not recommended (BIII)
  • Amphotericin B is preferred for initial treatment of moderately severe to severe infections (AI*)
  • Itraconazole is the azole preferred for treatment of histoplasmosis (AIII).  
  • In manifestations of histoplasmosis in which antigenuria is demonstrated, antigen levels should be monitored during therapy and for 1 year thereafter to identify relapse (AIII).
  • For severe or moderately severe acute primary pulmonary histoplasmosis, amphotericin B should be administered for at least 1 to 2 weeks (and clinical improvement) (AIII). After treatment with amphotericin, patients with intact immunity should receive itraconazole for at least 12 weeks (AIII). Adults with CD4 T lymphocyte (CD4) cell counts <150 cells/mm3 and HIV-infected children with severe immunosuppression should receive itraconazole consolidation therapy for at least 12 months (AIII).  
  • The preferred treatment for severe or moderately severe progressive disseminated histoplasmosis is initial (induction) therapy with amphotericin B for ≥2 weeks (and favorable clinical response), followed by consolidation therapy with itraconazole for at least 12 months (AI*).
  • Itraconazole monotherapy for 12 months is recommended for HIV-infected children with mild to moderate progressive disseminated histoplasmosis (AII*).
  • Liposomal amphotericin B for 4 to 6 weeks is the preferred initial treatment in the presence of focal brain lesions (BIII*). Thereafter, children should receive itraconazole consolidation therapy for at least 12 months and until cerebrospinal fluid abnormalities, including histoplasma antigen, have resolved (AII*).  
  • In the event of immune reconstitution inflammatory syndrome, antiretroviral therapy should be continued along with antifungal therapy (AIII)
  • Longer-term suppressive therapy (secondary prophylaxis) with itraconazole may be required in HIV-infected children who are severely immunosuppressed (meaning CD4 percentage <15% at any age or CD4 count <150 cells/mm3 in children aged ≥6 years) and patients who experience relapse despite receipt of appropriate therapy (AIII).
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 Preventing and Treating Histoplasmosis
Indication First Choice Alternative Comments/Special Issues
Primary Prophylaxis
N/A
N/A
Primary Prophylaxis indicated for selected HIV-infected adults but not children.

Criteria for Discontinuing Primary Prophylaxis: 
  • N/A
Criteria for Restarting Primary Prophylaxis:
  • N/A
Secondary Prophylaxis
(Suppresive Therapy)
Itraconazole oral solution 5–10 mg/kg body weight (maximum 200 mg) per dose by mouth daily  Fluconazole 3–6 mg/kg body weight (maximum 200 mg) by mouth once daily  Secondary Prophylaxis Indicated:
  • Documented histoplasmosis in a patient with impaired immune function
Criteria For Discontinuing Secondary Prophylaxis
If All of the Following Criteria Are Fulfilled:
  • CD4 percentage >15% at any age; or CD4 cell count >150 cells/mm3 aged ≥6 years. 
  • Received ≥1 year itraconazole maintenance therapy
  • Established (e.g., ≥6 months) adherence to effective cART 
  • Negative Histoplasma blood cultures
  • Serum Histoplasma antigen <2 ng/mL 
Use same initial itraconazole dosing for capsules as for solution. Itraconazole solution is preferred to the capsule formulation because it is better absorbed; solution can achieve serum concentrations 30% higher than those achieved with the capsules.
Treatment Acute Primary Pulmonary Histoplasmosis:
  • Itraconazole oral solution loading dose of 2–5 mg/kg body weight (maximum 200 mg) per dose by mouth 3 times daily for first 3 days of therapy, followed by 2–5 mg/kg body weight (max 200 mg) per dose by mouth twice daily for 12 months. Duration of 12 weeks is sufficient for HIV-infected children, with functional cellular immunity (CD4 percentage >20% or if aged ≥6, CD4 cell count >300 cells/mm3), provided monitoring confirms clinical improvement and decreased urine antigen concentrations. 

Mild Disseminated Disease:
  • Itraconazole oral solution loading dose of 2–5 mg/kg body weight (maximum 200 mg) per dose by mouth 3 times daily for first 3 days of therapy, followed by 2–5 mg/kg body weight (maximum 200 mg) per dose by mouth twice daily for 12 months 

Moderately Severe to Severe Disseminated Disease
Acute Therapy (Minimum 2-Week Induction, Longer if Clinical Improvement is Delayed, Followed by Consolidation Therapy):
  • Liposomal amphotericin B 3–5 mg/kg body weight, IV once daily (preferred)
  • Amphotericin B deoxycholate 0.7–1 mg/kg body weight IV once daily (alternative)
Consolidation Therapy (Followed by Chronic Suppressive Therapy):
  • Itraconazole oral solution initial loading dose of 2–5 mg/kg body weight (maximum 200 mg) per dose by mouth 3 times daily for first 3 days of therapy, followed by 2–5 mg/kg body weight (max 200 mg) per dose by mouth given twice daily for 12 months 
Central Nervous System Infection
Acute Therapy (4–6 Weeks, Followed by Consolidation Therapy):
  • Liposomal amphotericin B, 5 mg/kg body weight IV once daily (AII)
Consolidation Therapy (Followed by Chronic Suppressive Therapy):
  • Itraconazole oral solution initial loading dose of 2–5 mg/kg body weight (maximum 200 mg) per dose by mouth 3 times daily for first 3 days of therapy, followed by 2–5 mg/kg body weight (max 200 mg) per dose by mouth given twice daily for ≥12 months and until histoplasma antigen is no longer detected in cerebrospinal fluid
Acute Primary Pulmonary Histoplasmosis:
  • Fluconazole 3–6 mg/kg body weight (maximum 200 mg) by mouth once daily

Mild Disseminated Disease:
  • Fluconazole 5–6 mg/kg body weight IV or by mouth (maximum 300 mg) per dose, twice daily (maximum 600 mg/day) for 12 months 

Moderately Severe to Severe Disseminated Disease:
  • If itraconazole not tolerated, amphotericin alone for 4–6 weeks can be used with monitoring that confirms decline in histoplasma urine and serum antigen levels.
  • Liposomal amphotericin B 3–5 mg/kg body weight IV once daily (preferred) for 4–6 weeks
  • Amphotericin B deoxycholate 0.7–1 mg/kg body weight IV once daily (alternative) for 4–6 weeks
Use same initial itraconazole dosing for capsules as for solution. Itraconazole solution is preferred to the capsule formulation because it is better absorbed; solution can achieve serum concentrations 30% higher than those achieved with the capsules.

Urine antigen concentration should be assessed at diagnosis. If >39 ng/mL, serum concentrations should be followed. When serum levels become undetectable, urine concentrations should be monitored monthly during treatment and followed thereafter to identify relapse. 

Serum concentrations of itraconazole should be monitored and achieve a level of 1 μg/mL at steady-state. Levels exceeding 10 µg/mL should be followed by dose reduction.

High relapse rate with CNS infection occurs in adults and longer therapy may be required; treatment in children is anecdotal and expert consultation should be considered.

Chronic suppressive therapy (secondary prophylaxis) with itraconazole is recommended in adults and children following initial therapy. 

Amphotericin B deoxycholate is better tolerated in children than in adults. Liposomal amphotericin B is preferred for treatment of parenchymal cerebral lesions. 
Key to Acronyms: cART = combination antiretroviral therapy; CD4 = CD4 T lymphocyte; CNS = central nervous system; IV = intravenous

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