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.

Varicella-Zoster Virus

Last Updated: December 9, 2019; Last Reviewed: December 9, 2019

Panel's Recommendations for Varicella-Zoster Virus
Panel's Recommendations
I. Should children with HIV without evidence of immunity to varicella receive the varicella vaccine, compared to not receiving the vaccine?
  • Vaccination with the varicella vaccine should be considered for children with HIV without evidence of immunity to varicella. Administration is considered safe for children with CD4 T lymphocyte (CD4) cell percentage ≥15%. Two doses of varicella vaccine should be given, starting as early as 12 months of age, with an interval of 3 months. Preferably the child will have been on effective antiretroviral therapy (ART) for ≥3 months prior to immunization. (strong, low)
II. Should children with HIV who are without evidence of immunity to varicella and exposed to varicella or herpes zoster (HZ) receive prophylaxis with human varicella-zoster immunoglobulin, compared to not receiving varicella-zoster immunoglobulin?
  • Children with HIV who are susceptible to varicella and have had a significant exposure to varicella or HZ, and are severely immune compromised, should receive varicella zoster immune globulin (available as VariZIG) as soon as possible within the first 10 days after exposure. The extent of immune compromise should be considered in making this decision. VariZig is given intramuscularly at the recommended dose of 125 units/10 kg, up to a maximum of 625 units (i.e., 5 vials). (strong, low)
III. Should children with HIV with varicella be treated with acyclovir, compared to not being treated with acyclovir?
  • Intravenous (IV) acyclovir therapy is recommended for children with HIV with significant immune compromise who have varicella or for any child with HIV with severe varicella. Therapy initiated early in the course of the illness, especially within 24 hours of rash onset, maximizes efficacy. For select patients with HIV perceived to be at lower risk of developing severe varicella, many experts use oral acyclovir. This decision is made for patients with relatively normal concentrations of CD4 cells, especially if they are receiving ART. (strong, moderate)
IV. Should children with HIV with HZ be treated with acyclovir, compared to not being treated with acyclovir?
  • Oral therapy with acyclovir for 7 days to 10 days is recommended for children with HIV with HZ, although longer therapy duration should be considered when lesions are slow to resolve. Initial IV administration is recommended for children with HIV with severe immunosuppression, extensive multidermatomal HZ, disseminated infection, visceral involvement, or otherwise complicated HZ. IV acyclovir should be continued until cutaneous lesions and visceral disease are clearly resolving, after which oral administration can be considered to complete therapy. (strong, moderate)
V. Is foscarnet the best choice for anti-varicella-zoster virus (VZV) therapy for children with HIV in whom therapy is failing because of acyclovir-resistant VZV?
  • When acyclovir resistance is considered, if possible, virus isolation should be attempted for susceptibility testing. All acyclovir-resistant VZV strains are resistant to valacyclovir, famciclovir, and ganciclovir. VZV Infections caused by acyclovir-resistant VZV strains should be treated with parenteral foscarnet. (strong, very low)
Rating System
Strength of Recommendation: Strong; Weak
Quality of Evidence: High; Moderate; Low; or Very Low

Recommendations on Varicella Zoster Virus
Recommendations
Prevention

I. Should children with HIV without evidence of immunity to varicella receive the varicella vaccine, compared to not receiving the varicella vaccine?
  • Children with HIV without evidence of immunity to varicella should be considered for the varicella vaccine. Vaccine administration is considered safe for children with CD4 percentage ≥15%. Two doses of varicella vaccine should be given, starting as early as 12 months of age, with an interval of 3 months. Preferably the child will have been on effective ART for ≥3 months prior to vaccination. (strong, low)
  • Vaccine administration is considered safe for children with HIV with CD4 percentage ≥15%. Limited data from clinical trials in such children indicate that the vaccine was well-tolerated and that >80% of the children had detectable VZV-specific immune responses (either antibody or cell-mediated immune response or both) at 1 year after vaccination.37,38 Two doses of varicella vaccine should be given, starting as soon as possible after 12 months of age, with an interval of 3 months. Preferably the child will have been on ART for ≥3 months prior to immunization. In the absence of specific safety and immunogenicity data, the combination measles-mumps-rubella-varicella vaccine should not be administered in place of the single-antigen varicella vaccine to children with HIV. Effectiveness of the varicella vaccine in children with HIV is suggested by long-term follow-up studies.13,21 Vaccination was 82% effective against varicella, and no cases of HZ were observed in vaccinees. Comparable efficacy was reported in vaccinated healthy children (after one dose) and in vaccinated children with underlying leukemia (after two doses), where an efficacy of 80% to 85% was observed for prevention of clinical infection.
II. Should children with HIV who are without evidence of immunity to varicella and exposed to varicella or HZ receive prophylaxis with human varicella-zoster immunoglobulin, compared to not receiving varicella-zoster immunoglobulin?
  • Children with HIV who are susceptible to varicella and have had a significant exposure to varicella or HZ, and are severely immune compromised, should receive varicella zoster immune globulin (available as VariZig) as soon as possible within 10 days after exposure. The extent of immune compromise should be considered in making this decision. VariZig is given intramuscularly at the recommended dose of 125 units/10 kg, up to a maximum of 625 units (i.e., 5 vials). (strong, low)
  • Children with HIV who are susceptible to varicella and are severely immunocompromised, and have had an exposure to varicella or HZ, are likely to develop severe varicella with complications. A large observational study of immunocompromised children, without HIV infection, indicated that varicella zoster immune globulin (currently available as VariZig) given within 72 hours of exposure reduced varicella severity compared to historical controls.49 Subsequent studies indicated that some protection occurred with passive immunization as long as 10 days after exposure.77 Thus, varicella- or HZ-exposed children with HIV are likely to benefit from passive immunization (strong, low), although most experts limit this recommendation to those who are considered to be severely immunocompromised. VariZig is given intramuscularly at the recommended dose of 125 units/10 kg, up to a maximum of 625 units (i.e., 5 vials). If VariZig is unavailable, immune globulin for IV administration can be used at the dose of 400 mg/kg. VariZIG may attenuate, but not prevent varicella, in which case the patient will be potentially infectious. If passive immunization is not possible for severely immunocompromised patients, some experts recommend oral acyclovir for post-exposure prophylaxis.
Treatment

III. Should children with HIV with varicella be treated with acyclovir, compared to not being treated with acyclovir?
  • IV acyclovir therapy is recommended for children with HIV with significant immune compromise who have varicella or for any child with HIV with severe varicella. Therapy initiated early in the course of the illness, especially within 24 hours of rash onset, maximizes efficacy. For select patients with HIV perceived to be at lower risk of developing severe varicella, many experts use oral acyclovir. This decision is made for patients with relatively normal concentrations of CD4 cells, especially if they are receiving ART. (strong, moderate)
  • On the basis of controlled trials treating severe varicella in children with malignancy55,56 and of observational studies treating the disease in children with HIV,22 IV acyclovir is recommended as initial therapy in children with HIV with severe immunosuppression. Treatment should be initiated as soon as possible (especially within 24 hours) after varicella lesions appear to maximize efficacy. Many experts use oral acyclovir for select children with HIV perceived to be at lower risk of developing severe varicella. However, the decision to use oral acyclovir is reserved for patients with relatively normal concentrations of CD4 cells, especially if they are receiving ART. IV administration should also be considered for children with high fever; abdominal pain; respiratory symptoms; numerous or deep, necrotic, or hemorrhagic skin lesions; disseminated infection; or visceral involvement. Administration is for 7 days to 10 days, provided that new lesions have ceased to appear for at least 48 hours. The decision may be made to complete 10 days to 14 days of therapy with oral acyclovir.
IV. Should children with HIV with HZ be treated with acyclovir, compared to not being treated with acyclovir?
  • Oral therapy with acyclovir for 7 days to 10 days is recommended for children with HIV with HZ, although longer therapy duration should be considered if lesions are slow to resolve. Initial IV administration is recommended for children with HIV with severe immunosuppression, extensive multidermatomal HZ, disseminated infection, visceral involvement, or otherwise complicated HZ. IV acyclovir should be continued until cutaneous lesions and visceral disease are clearly resolving, after which oral administration can be considered to complete therapy. (strong, moderate)
  • Oral acyclovir therapy for HZ for 7 days is established therapy in immune competent patients,78 and IV therapy was demonstrably efficacious in a controlled trial in immunocompromised patients, including those with disseminated HZ.79 Oral acyclovir for 7 days to 10 days is recommended for HZ in children with HIV, although longer therapy duration should be considered if lesions are slow to resolve. However, initial IV administration is recommended for children with HIV with severe immunosuppression, extensive multidermatomal HZ, disseminated infection, visceral involvement, or otherwise complicated HZ. IV acyclovir should be continued until cutaneous lesions and visceral disease are clearly resolving, after which oral administration can be considered to complete 10 to 14 days of therapy.
V. Is foscarnet the best choice for anti-varicella-zoster virus (VZV) therapy for children with HIV in whom therapy is failing because of acyclovir-resistant VZV?
  • When acyclovir resistance is considered, if possible, virus isolation should be attempted for susceptibility testing. All acyclovir-resistant VZV strains are resistant to valacyclovir, famciclovir, and ganciclovir. VZV infections caused by acyclovir-resistant VZV strains should be treated with parenteral foscarnet. (strong, very low)
  • Children in whom lesions continue to develop, fail to heal, or continue to progress after 7 days of treatment may have acyclovir-resistant VZV.71 Isolation of persisting virus should be attempted so that susceptibility testing can be performed to confirm drug resistance. Since this involves considerable delay, the decision to change therapy is often based on clinical observations. All acyclovir-resistant VZV strains are resistant to valacyclovir, famciclovir, and ganciclovir. Based on this finding and three observational or open-label studies, primarily in adults, that documented responses to foscarnet, this second line drug is the therapeutic choice for acyclovir-resistant VZV.72,80,81 Foscarnet (40–60 mg/kg/dose IV every 8 hours) is administered for 7 days to 10 days or until no new lesions appear.

 

 

Dosing Recommendations for Preventing and Treating Varicella-Zoster Virus
Indication First Choice Alternative Comments/Special Issues
Pre-Exposure Prophylaxis Varicella vaccine N/A See Figure 1 for detailed vaccine recommendations.
Primary (Post-Exposure) Prophylaxis VariZIG 125 IU/10 kg body weight (maximum 625 IU) IM, administered ideally within 96 hours (potentially beneficial up to 10 days) after exposure If VariZIG is not available, IVIG 400 mg/kg body weight, administered once should be considered. IVIG should ideally be administered within 96 hours of exposure.

When passive immunization is not possible, some experts recommend prophylaxis with acyclovir 20 mg/kg body weight/dose (maximum dose acyclovir 800 mg) by mouth, administered four times a day for 7 days, beginning 7–10 days after exposure.
Primary Post-Exposure Prophylaxis Indicated for:
  • Patients with substantial exposure to varicella or zoster who have no verified history of varicella or zoster, or who are seronegative for VZV on a sensitive, specific antibody assay, or who lack evidence of vaccination.
  • Many experts limit the recommendation for passive immunization to varicella- or zoster-exposed children with HIV considered severely immunocompromised (i.e., CDC Immunologic Category 3), especially if severely symptomatic (i.e., CDC Clinical Category Ca) and experiencing a high HIV RNA plasma viral load.
  • Some experts start acyclovir at first appearance of rash in children with HIV, rather than providing acyclovir as prophylaxis.
Note: VariZIG is commercially available in the United States from a broad network of specialty distributors.

a Centers for Disease Control and Prevention. Revised classification system for human immunodeficiency virus infection in children aged <13 years. Official authorized addenda: human immunodeficiency virus infection codes and official guidelines for coding and reporting ICD-9-CM. MMWR Morb Mortal Wkly Rep. 1994;43:1-19. Available at: http://www.cdc.gov/mmwr/PDF/rr/rr4312.pdf.
Secondary Prophylaxis N/A N/A There is no indication for secondary prophylaxis.
Treatment Varicella
Children with No or Moderate Immune Suppression (CDC Immunologic Categories 1 and 2) and Mild Varicella Disease:
  • Acyclovir 20 mg/kg body weight/dose by mouth (maximum 800 mg/dose) four times a day for 7–10 days and until no new lesions for 48 hours
Children with Severe Immune Suppression or Severe Varicella Disease (see text):
  • Acyclovir 10 mg/kg body weight or 500 mg/m2/dose IV every 8 hours for 7–10 days and until no new lesions for 48 hours
Zoster
Children with Uncomplicated Zoster and No or Moderate Immune Suppression:
  • Acyclovir 20 mg/kg body weight/dose (maximum 800 mg/dose) by mouth four times a day for 7–10 days
Children with Severe Immunosuppression (CDC Immunologic Category 3), Trigeminal or Sacral Nerve Involvement, Extensive Multidermatomal, or Disseminated Zoster:
  • Acyclovir 10 mg/kg body weight/dose or 500 mg/m2 IV every 8 hours until cutaneous lesions and visceral disease are clearly resolving, then patient can switch to oral acyclovir to complete a 10–14-day course
Children with Progressive Outer Retinal Necrosis:
  • Acyclovir (10 mg/kg or 500 mg/m2 every 8 hours) or ganciclovir 5 mg/kg body weight/dose IV every 12 hours, plus
  • Foscarnet 90 mg/kg body weight/dose IV every 12 hours, plus
  • Ganciclovir 2 mg/0.05 mL intravitreal injection twice weekly and/or foscarnet 1.2 mg/0.05 mL intravitreal injection twice weekly
Children with Acute Retinal Necrosis:
  • Acyclovir 10–15 mg/kg body weight/dose IV every 8 hours daily for 10–14 days, followed by oral valacyclovir 1 g/dose three times a day for 4–6 weeks (for children old enough to receive adult dose).
  • Alternative to oral valacyclovir is oral acyclovir 20 mg/kg body weight/dose four times a day for 4–6 weeks
Patients Unresponsive to Acyclovir:
  • Foscarnet (40–60 mg/kg body weight/dose IV every 8 hours) for 7-10 days or until no new lesions have appeared for 48 hours
In children aged ≥1 year, some experts base IV acyclovir dosing on body surface area (500 mg/m2 body surface area/dose IV every 8 hours) instead of body weight.

Valacyclovir is approved for use in adults and adolescents with zoster at 1 g/dose by mouth three times a day for 7 days; the same dose has been used for varicella infections. Valacyclovir can be used in children at a dose of 20 to 25 mg/kg body weight administered 2 to 3 times a day. Doses lower than this may be insufficient for children weighing <20 kg. There is no pediatric preparation, although 500-mg capsules can be extemporaneously compounded to make a suspension to administer valacyclovir 20 mg/kg body weight/dose (maximum dose 1 g) given three times a day (see prescribing information).

Famciclovir is approved for use in adults and adolescents with zoster at 500 mg/dose by mouth three times a day for 7 days; the same dose has been used for varicella infections. A sprinkle formulation of famciclovir is available for children who are unable to swallow the available pill formulation. A schedule for weight-adjusted dosing is available to inform dosing of small children.

Involvement of an ophthalmologist with experience in managing HZ ophthalmicus and its complications in children is strongly recommended when ocular involvement is evident.

Optimal management of progressive outer retinal necrosis has not been defined.
Key: CDC = Centers for Disease Control and Prevention; HZ = herpes zoster; IM = intramuscular; IU = international units; IV = intravenous; IVIG = intravenous immunoglobulin; VariZIG = varicella zoster immune globulin; VZV = varicella zoster virus

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