Executive Summary: 2013 Update of the Guidelines for the Prevention and Treatment of Opportunistic Infections in HIV-Exposed and HIV-Infected Children

George K. Siberry, MD, MPH; Mark J. Abzug, MD; Sharon Nachman, MD

Pediatr Infect Dis J. 2013;32(12):1303-1307.

Opportunistic Infections in HIV-Infected Children in the Era of Potent Antiretroviral Therapy

In the era before development of potent combination antiretroviral (ARV) treatment (cART) regimens, OIs were the primary cause of death in HIV-infected children.^[1] Current ART regimens suppress viral replication, provide significant immune reconstitution and have resulted in a substantial and dramatic decrease in AIDS-related OIs and deaths in both adults and children.^[2–5]

Despite this progress, prevention and treatment of OIs remain critical components of care for HIV-infected children. HIV-associated OIs and other related infections continue to occur in HIV-infected children.^[3,6] OIs continue to be the presenting symptom of HIV infection among children whose HIV-exposure status is unknown because of lack of maternal antenatal HIV testing. For infants and children with known HIV infection, barriers such as inadequate medical care, lack of availability of suppressive ARV regimens in the face of extensive prior treatment and drug resistance, caregiver substance abuse or mental illness and multifactorial adherence difficulties may hinder effective HIV treatment and put them at risk of OIs even in the ART era. These same barriers may then impede provision of primary or secondary OI prophylaxis to children for whom such prophylaxis is indicated. In addition, the addition of concomitant OI prophylactic drugs may only exacerbate the existing difficulties in adhering to ART. Multiple drug-drug interactions of OI, ARV and other compounds that result in increased adverse events and decreased treatment efficacy may limit the choice and continuation of both cART and prophylactic regimens. Finally, IRIS, initially described in HIV-infected adults but also seen in HIV-infected children, can complicate treatment of OIs when cART is started or when optimization of a failing regimen is attempted in patients with acute OIs. Thus, preventing and treating OIs in HIV-infected children remain important even in the cART era.

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Next Section

Introduction
Opportunistic Infections in HIV-Infected Children in the Era of Potent Antiretroviral Therapy
The Need for Specific Prevention and Treatment Guidelines for Children
Immune Reconstitution Inflammatory Syndrome
Initiation of cART for an Acute OI in Treatment-Naive Children
Change in OI Sections and Section With Major Updates
References
Appendix

Table 1. System for Grading Strength of Recommendations and Quality of Supporting Evidence
Strength of Recommendation	Quality of Evidence for Recommendation*
A: Strong recommendation for the statement B: Moderate recommendation for the statement C: Optional recommendation for the statement	I: One or more randomized trials in children† with clinical outcomes and/or validated laboratory endpoints I: One or more randomized trials in adults with clinical outcomes and/or validated laboratory endpoints with accompanying data in children† from 1 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 clinical outcomes II: One or more well-designed, nonrandomized trials or observational cohort studies in adults with long-term clinical outcomes with accompanying data in children† from 1 or more smaller nonrandomized trials or cohort studies with clinical outcome data III: Expert opinion

*In circumstances where there is level I or level II evidence from studies in adults with accompanying data in children that come only from nonrandomized trials or cohort studies with clinical outcomes, experts assigned a rating of I* or II*, respectively, if they judged the evidence from children sufficient to support findings from adult studies. In circumstances where there is level I or level II evidence from studies in adults with no or almost no accompanying data in children, experts assigned a rating of III.
†Studies that include children or children/adolescents but not studies limited to postpubertal adolescents.

Table 2. Major Changes Since 2009 in the 2013 Update of the Guidelines for the Prevention and Treatment of Opportunistic Infections in HIV-exposed and HIV-infected Children
Opportunistic Illness	Major Changes in 2013 Update	Principal Author(s)	Co-author(s)
Bacterial infections	• Stronger recommendation for discontinuation of antibiotic for primary or secondary SBI prophylaxis in children with sustained immune reconstitution • Updated recommendations for immunizations against bacterial infections	George K. Siberry, MD, MPH
Candidal infections	• Fluconazole, echinocandins or amphotericin B preferred and itraconazole no longer preferred for initial treatment of Candida esophagitis • Voriconazole or itraconzaole recommended for fluconazole-refractory Candida esophagitis • Echinocandins preferred for severely ill children with candidemia	William J. Steinbach, MD
Coccidioidomycosis	No major changes	Martin B. Kleiman. MD
Cryptococcal infections	• Newer formulations of amphotericin B included in recommended treatment of cryptococcal CNS disease	Aditya Gaur, MD	Patricia Flynn, MD
Cryptosporidium infections	No major changes	Patricia Flynn, MD	Gabriela Maron, MD
Cytomegalovirus infections	• Expansion of valganciclovir prophylaxis option for severely immunocompromised, cytomegalovirus seropositive children to those <6 years of age • Limited expansion of recommended use of valganciclovir for treatment of cytomegalovirus disease in children.	Masako Shimamura, MD	David Kimberlin, MD
Giardiasis (New section)	• Emphasis on role of cART in prevention and management of giardiasis • Tinidazole or nitazoxanide recommended as preferred, and metronidazole as alternative, treatment of giardiasis	Patricia Flynn, MD	Gabriela Maron, MD
Hepatitis B virus Infection	• Expansion down to age 2 years of the use of tenofovir disoproxil fumarate in cART regimens for HIV-hepatitis B virus coinfected children who require treatment for both infections	Michael Narkewicz, MD	Cara L. Mack, MD Debika Bhattacharya, MD
Hepatitis C virus Infection	• Recommendation for evaluation to confirm or exclude hepatitis C virus infection in infants born to hepatitis C virus-infected mothers	Cara L. Mack, MD	Michael Narkewicz, MD Debika Bhattacharya, MD
Herpes simplex virus infections	No major changes	Myron J. Levin. MD
Histoplasmosis	• Choice of formulation of amphotericin B for non-CNS histoplasmosis based on cost, availability and tolerability. Liposomal amphotericin B remains the preferred formulation for CNS disease.	Martin B. Kleiman. MD
Human herpesvirus 8 infections	No major changes	Richard Rutstein, MD
Human papillomavirus infections	• Expansion of routine human papillomavirus vaccine recommendation to HIV-infected females and males ages 11–26 years old	Anna-Barbara Moscicki, MD Sharon Nachman, MD
Immunizations	• Recommended schedule summarized in two figures • Updated recommendations for Haemophilus influenzae type b, meningococcal, tetanus-diphtheria-acellular pertussis, human papillomaviruses, measles-mumps-rubella and pneumococcal vaccines	Andrew Kroger, MD, MPH	Jane Seward, MD
Influenza (New section)	• Recommendations for prevention and anti-viral treatment of influenza in HIV-infected children	Kathryn M. Edwards, MD	Jennifer C. Esbenshade, MD, MPH Gregory J. Wilson, MD
Isosporiasis (Cystoisosporiasis) (New section)	• Emphasis on cART to reduce HIV-related risk of (cysto)isosporiasis • Strong recommendation for trimethoprim-sulfamethoxazole to treat (cysto)isosporiasis	Patricia Flynn, MD	Gabriela Maron, MD
Malaria	• Expanded guidance on drug interactions between ARV and antimalarial drugs	Charlotte Victori Hobbs, MD Sharon Nachman, MD
Microsporidiosis	No major changes	Patricia Flynn, MD	Gabriela Maron, MD
Mycobacterium avium Complex Disease	No major changes	James McAuley, MD, MPH
M. tuberculosis infections	• Updated recommendations for use of interferon-gamma release assays for diagnosis of latent TB in children • Change to preference for early (within 2–8 weeks of starting anti-TB therapy) cART initiation for children not already receiving cART	Ben Marais, MD	Heather J. Menzies, MD, MPH
Pharmacology review	• Expanded guidance on toxicities of drugs used for prevention and treatment of opportunistic illnesses • Expanded information on drug interactions and additional resources for drug interaction data	Diana Clarke, Pharm. D.
Pneumocystis jirovecii pneumonia	No major changes	Francis Gigliotti, MD
Progressive multifocal leukoencephalopathy	No major changes	Gail Harrison, MD
Syphilis	• Updated based on 2010 CDC Sexually Transmitted Diseases Treatment Guidelines	Emilia H. Koumans, MD, MPH
Toxoplasmosis	No major changes	James McAuley, MD, MPH
Varicella-Zoster virus infections	• Updated recommendations for prophylaxis after exposure to Varicella-Zoster virus (more selective indications; role of acyclovir)	Myron J. Levin. MD