Children who either have been exposed to HIV or who are infected with HIV are at increased risk for certain opportunistic diseases, according to new recommendations published online August 26 in the Morbidity and Mortality Weekly Report.

The new guidelines were issued jointly by the US Centers for Disease Control and Prevention, the National Institutes of Health (NIH), the HIV Medicine Association of the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society, and the American Academy of Pediatrics.

These guidelines update previous recommendations for clinicians and other healthcare practitioners providing medical care for HIV-exposed or HIV-infected children. Earlier guidelines were last published in 2002 and 2004, respectively.

"In the pre-antiretroviral era and before development of potent combination highly active antiretroviral treatment (HAART) regimens, opportunistic infections (OIs) were the primary cause of death in [HIV]-infected children," write Lynne M. Mofenson, MD, from the NIH in Bethesda, Maryland, and colleagues.

"Current HAART 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.... Despite this progress, prevention and management of OIs remain critical components of care for HIV-infected children."

Development of Updated Guidelines

The Pediatric Opportunistic Infections Working Group, a panel of experts from the US government and academic institutions specializing in pediatric HIV infection and other infectious diseases, developed recommendations for the most effective strategies for diagnosis, prevention, and treatment of OIs.

For each OI, a pediatric specialist expert in that OI reviewed the literature for new information published since the previous guidelines were issued. In June 2007, revised recommendations were proposed at an NIH meeting, and the draft guidelines were revised further, reviewed and approved by the working group, and approved by the issuing organizations.

In addition to covering the management of opportunistic diseases encountered in the United States (Pneumocystis pneumoniaToxoplasma gondiiMycobacterium avium complex, Coccidioides species, Cryptococcus neoformans,Histoplasma capsulatum, microsporidiosis, cytomegalovirus, invasive bacterial infections, bartonellosis, Candida [esophageal], and herpes simplex virus), the guidelines also discuss malaria — an OI that could be acquired during international travel.

For each OI, the report summarizes epidemiology, clinical presentation, and diagnosis in children. Main topics include preventing exposure to OIs, using chemoprophylaxis and/or vaccination to prevent infection, discontinuing primary prophylaxis after immune reconstitution, treating OIs, monitoring for adverse effects during treatment, managing treatment failure, preventing recurrence of OIs, and discontinuing secondary prophylaxis after immune reconstitution.

A working group of experts specializing in adult HIV and infectious disease prepared a separate report on the prevention and treatment of OIs in HIV-infected adults and postpubertal adolescents, titled "Guidelines for the Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents."

Populations Affected by OIs

Because HIV-infected women coinfected with opportunistic pathogens may be more likely than women uninfected with HIV to transmit these OIs to their infants, an infected mother is an important pathway for OI transmission, as well as for HIV infection, among children. Furthermore, mothers and other family members coinfected with HIV and certain opportunistic pathogens may be more likely to transmit these infections horizontally to young children, increasing the probability that the child will primarily acquire these infections.

OIs may therefore affect not just HIV-infected infants but also HIV-exposed but uninfected infants who become infected by the pathogen via HIV-infected mothers or family members with coinfections. For these reasons, the updated guidelines for treating OIs in children consider treatment of infections among all children — both HIV-infected and uninfected — born to HIV-infected women.

Incidence of HIV infection is rising both among adolescents with perinatal infection who have survived into their teenage years and among youth with behaviorally acquired HIV infection. The adult OI guidelines are applicable to postpubertal adolescents, but younger prepubertal or pubertal adolescents may have differing drug pharmacokinetics and response to treatment, with management best served by the pediatric guidelines.

Updated Recommendations

Since the previous versions of these guidelines, major changes in the new recommendations are as follows:

  • Increased emphasis on the importance of antiretroviral therapy to prevent and treat OIs, particularly those OIs for which no specific treatment is available.
  • New evidence regarding diagnosis and management of immune reconstitution inflammatory syndromes.
  • New information concerning management of antiretroviral therapy in children with OIs, including potential drug–drug interactions.
  • New strategies for diagnosis of HIV infection and for presumptively ruling out HIV infection in infants that affect the need to start prophylaxis for the prevention of Pneumocystis jirovecii pneumonia in neonates. Prophylaxis against Pneumocystis carinii should be considered in all infants exposed to HIV.
  • Updated recommendations for immunizing HIV-exposed and HIV-infected children against hepatitis A, human papillomavirus, meningococcus, and rotavirus. Children with HIV infection and good immune function should be routinely vaccinated against varicella, measles-mumps-rubella, and human papillomavirus. To weigh potential risks and benefits of vaccination against rotavirus in an infant exposed to HIV infection, expert consultation may be needed.
  • New sections on aspergillosis; bartonella; human herpes viruses 6, 7, and 8; malaria; and progressive multifocal leukodystrophy. Children infected with HIV do not require routine prophylaxis against aspergillosis, coccidiomycosis, or cryptococcal disease.
  • New guidelines for discontinuing OI prophylaxis after immune reconstitution in children.

In addition, there are 6 tables with information concerning prevention and treatment of OIs in children and 2 figures depicting immunization recommendations for children aged 0 to 6 years and 7 to 18 years. The guidelines authors acknowledge that treatment of OIs is an evolving science and that therapeutic options and preferences may change on the basis of the availability of new agents or clinical data on existing agents. The recommendations in these guidelines will therefore be updated periodically and posted on the NIH AIDSinfo Web site.

Morb Mortal Wkly Rep. Published online August 26, 2009.

Clinical Context

 

The main cause of HIV infection among children is vertical transmission from their mother, and the current guidelines highlight that the mother and nuclear family unit continue to be a strong potential reservoir for OIs as these children grow. These OIs may also infect infants without HIV infection. Therefore, the authors of the current guidelines focus their recommendations regarding OI prevention and treatment to all children born to women with HIV infection.

The guidelines regarding OIs among children were last updated in 2004. The current revised recommendations were initially proposed by an expert panel at a meeting of the NIH in 2007 and were then endorsed by multiple governmental and physician specialty groups.

 

STUDY HIGHLIGHTS

 

  • The use of HAART among children can be useful to both prevent and treat OIs for which specific treatments are less effective, including infections such as cryptosporidiosis and microsporidiosis.
  • Immune reconstitution inflammatory syndrome (IRIS) can occur in children after the initiation of treatment of HIV infection. However, among adults, up to 30% of cases of IRIS may be present at 3 months after initiation of HAART. HAART should be continued in cases of IRIS, and nonsteroidal anti-inflammatory drugs should be added, along with close supervision, for adequate treatment of most moderate cases. Antibiotics are unnecessary in the treatment of IRIS.
  • The best timing to initiate HAART after an OI remains unclear and needs to be individualized to the patient's needs.
  • Vaccination against varicella and measles-mumps-rubella may be considered among HIV-infected children with age-specific CD4 levels of at least 15%.
  • Although vaccine immune response may be less than among immunocompetent peers, the human papillomavirus vaccine may be administered to girls with HIV infection.
  • There are no safety data regarding the application of the rotavirus vaccine to infants who are potentially immunocompromised, and the diagnosis of HIV infection in the infant may not even be established at the time of the first vaccination. Whether to provide vaccination against rotavirus among infants exposed to HIV may require consultation with an expert in infectious disease or immunology.
  • Bartenellosis may be prevented by the avoidance of body lice, cats, and cat fleas. Moderate cat-scratch disease among children with HIV infection typically does not respond to antibiotic therapy, and treatment is supportive.
  • Previous estimates have found that 1.1% of children with tuberculosis have a coinfection with HIV, a lower rate vs the adult population. Children with HIV infection should receive annual tuberculin skin tests. Treatment of active tuberculosis is similar among children with and without HIV, although the concurrent use of HAART can complicate tuberculosis treatment (particularly the use of rifamycins). The usual treatment period is 6 months.
  • Clarithromycin and azithromycin may be used to prevent M avium complex disease in children, but children with a sustained positive immune response to HAART for 3 months or longer may discontinue antibiotic prophylaxis against M avium complex.
  • Prophylaxis against aspergillosis and coccidiomycosis among children with HIV infection is not recommended. Voriconazole is the first-line therapy for active aspergillosis, and disseminated coccidiomycosis infection requires treatment with amphotericin B.
  • Children with HIV infection do not require routine testing for the cryptococcal antigen or prophylaxis against infection with cryptococcus.
  • Conversely, infants born to mothers with HIV infection should be considered for antibiotic prophylaxis againstP carinii beginning at ages 4 to 6 weeks. Trimethoprim-sulfamethoxazole is the first-line agent for prophylaxis.
  • Children with HIV infection traveling to endemic areas of malaria infection should receive prophylactic antibiotics against malaria, and care must be taken to avoid significant interactions with HAART, if possible. Trimethoprim-sulfamethoxazole should not be used as prophylaxis against malaria.

 

Clinical Implications

 

  • The current study recommends routine vaccination against varicella, measles-mumps-rubella, and human papillomavirus among children with HIV infection and good immune function. However, vaccination against rotavirus may require consultation with an expert to weigh potential risks and benefits in an infant exposed to HIV infection.
  • Children with HIV infection do not require routine prophylaxis against aspergillosis, coccidiomycosis, or cryptococcus, but all infants exposed to HIV should be considered for prophylaxis against P carinii.
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