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

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

Recommendations from CDC, the National Institutes of Health, the HIV Medicine Association of the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society, and the American Academy of Pediatrics

Prepared by
Lynne M. Mofenson, MD1
Michael T. Brady, MD2
Susie P. Danner3
Kenneth L. Dominguez, MD, MPH3
Rohan Hazra, MD1
Edward Handelsman, MD1
Peter Havens, MD4
Steve Nesheim, MD3
Jennifer S. Read, MD, MS, MPH, DTM&H1
Leslie Serchuck, MD1
Russell Van Dyke, MD5

1National Institutes of Health, Bethesda, Maryland
2Nationwide Children's Hospital, Columbus, Ohio
3Centers from Disease Control and Prevention, Atlanta, Georgia
4Childrens Hospital of Wisconsin, Milwaukee, Wisconsin
5Tulane University School of Medicine, New Orleans, Louisiana

The material in this report originated in the National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, Kevin Fenton, MD, Director.

Corresponding preparer: Kenneth L. Dominguez, MD, MPH, Division of HIV/AIDS Prevention, Surveillance and Epidemiology, NCHHSTP, CDC, 1600 Clifton Rd. NE, MS E-45, Atlanta, GA 30333, Telephone: 404-639-6129, Fax: 404-639-6127, Email: kld0@cdc.gov.

Summary
This report updates and combines into one document earlier versions of guidelines for preventing and treating opportunistic infections (OIs) among HIV-exposed and HIV-infected children, last published in 2002 and 2004, respectively. These guidelines are intended for use by clinicians and other health-care workers providing medical care for HIV-exposed and HIV-infected children in the United States. The guidelines discuss opportunistic pathogens that occur in the United States and one that might be acquired during international travel (i.e., malaria). Topic areas covered for each OI include a brief description of the epidemiology, clinical presentation, and diagnosis of the OI in children; prevention of exposure; prevention of disease by chemoprophylaxis and/or vaccination; discontinuation of primary prophylaxis after immune reconstitution; treatment of disease; monitoring for adverse effects during treatment; management of treatment failure; prevention of disease recurrence; and discontinuation of secondary prophylaxis after immune reconstitution. A separate document about preventing and treating of OIs among HIV-infected adults and postpubertal adolescents (Guidelines for the Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents) was prepared by a working group of adult HIV and infectious disease specialists.

The guidelines were developed by a panel of specialists in pediatric HIV infection and infectious diseases (the Pediatric Opportunistic Infections Working Group) from the U.S. government and academic institutions. For each OI, a pediatric specialist with content-matter expertise reviewed the literature for new information since the last guidelines were published; they then proposed revised recommendations at a meeting at the National Institutes of Health (NIH) in June 2007. After these presentations and discussions, the guidelines underwent further revision, with review and approval by the Working Group, and final endorsement by NIH, CDC, the HIV Medicine Association (HIVMA) of the Infectious Diseases Society of America (IDSA), the Pediatric Infectious Disease Society (PIDS), and the American Academy of Pediatrics (AAP). The recommendations are rated by a letter that indicates the strength of the recommendation and a Roman numeral that indicates the quality of the evidence supporting the recommendation so readers can ascertain how best to apply the recommendations in their practice environments.

An important mode of acquisition of OIs, as well as HIV infection among children, is from their infected mother; HIV-infected women coinfected with opportunistic pathogens might be more likely than women without HIV infection to transmit these infections to their infants. In addition, HIV-infected women or HIV-infected family members coinfected with certain opportunistic pathogens might be more likely to transmit these infections horizontally to their children, resulting in increased likelihood of primary acquisition of such infections in the young child. Therefore, infections with opportunistic pathogens might affect not just HIV-infected infants but also HIV-exposed but uninfected infants who become infected by the pathogen because of transmission from HIV-infected mothers or family members with coinfections. These guidelines for treating OIs in children therefore consider treatment of infections among all children, both HIV-infected and uninfected, born to HIV-infected women.

Additionally, HIV infection is increasingly seen among adolescents with perinatal infection now surviving into their teens and among youth with behaviorally acquired HIV infection. Although guidelines for postpubertal adolescents can be found in the adult OI guidelines, drug pharmacokinetics and response to treatment may differ for younger prepubertal or pubertal adolescents. Therefore, these guidelines also apply to treatment of HIV-infected youth who have not yet completed pubertal development.

Major changes in the guidelines include 1) greater emphasis on the importance of antiretroviral therapy for preventing and treating OIs, especially those OIs for which no specific therapy exists; 2) information about the diagnosis and management of immune reconstitution inflammatory syndromes; 3) information about managing antiretroviral therapy in children with OIs, including potential drug--drug interactions; 4) new guidance on diagnosing of HIV infection and presumptively excluding HIV infection in infants that affect the need for initiation of prophylaxis to prevent Pneumocystis jirovecii pneumonia (PCP) in neonates; 5) updated immunization recommendations for HIV-exposed and HIV-infected children, including hepatitis A, human papillomavirus, meningococcal, and rotavirus vaccines; 6) addition of sections on aspergillosis; bartonella; human herpes virus-6, -7, and -8; malaria; and progressive multifocal leukodystrophy (PML); and 7) new recommendations on discontinuation of OI prophylaxis after immune reconstitution in children. The report includes six tables pertinent to preventing and treating OIs in children and two figures describing immunization recommendations for children aged 0--6 years and 7--18 years.

Because treatment of OIs is an evolving science, and availability of new agents or clinical data on existing agents might change therapeutic options and preferences, these recommendations will be periodically updated and will be available at http://AIDSInfo.nih.gov.

Background
Opportunistic Infections in HIV-Infected Children in the Era of Potent Antiretroviral Therapy
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 human immunodeficiency virus (HIV)-infected children (1). Current HAART regimens suppress viral replication, provide significant immune reconstitution, and have resulted in a substantial and dramatic decrease in acquired immunodeficiency syndrome (AIDS)-related OIs and deaths in both adults and children (2--4). In an observational study from pediatric clinical trial sites in the United States, Pediatric AIDS Clinical Trials Group (PACTG) 219, the incidence of the most common initial OIs in children during the potent HAART era (study period 2000--2004) was substantially lower than the incidence in children followed at the same sites during the pre-HAART era (study period 1988--1998) (1,3). For example, the incidence for bacterial pneumonia decreased from 11.1 per 100 child-years during the pre-HAART era to 2.2 during the HAART era; bacteremia from 3.3 to 0.4 per 100 child-years; herpes zoster from 2.9 to 1.1 per 100 child-years; disseminated Mycobacterium avium complex (MAC) from 1.8 to 0.14 per 100 child-years; and Pneumocystis jirovecii pneumonia (PCP) from 1.3 to 0.09 per 100 child-years.

Despite this progress, prevention and management of OIs remain critical components of care for HIV-infected children. OIs continue to be the presenting symptom of HIV infection among children whose HIV-exposure status is not known (e.g., because of lack of maternal antenatal HIV testing). For children with known HIV infection, barriers such as parental substance abuse may limit links to appropriate care where indications for prophylaxis would be evaluated. HIV-infected children eligible for primary or secondary OI prophylaxis might fail to be treated because they are receiving suboptimal medical care. Additionally, adherence to multiple drugs (antiretroviral drugs and concomitant OI prophylactic drugs) may prove difficult for the child or family. Multiple drug-drug interactions of OI, antiretroviral, and other drugs resulting in increased adverse events and decreased treatment efficacy may limit the choice and continuation of both HAART and prophylactic regimens. OIs continue to occur in children in whom drug resistance causes virologic and immunologic failure. In PACTG 219, lack of a sustained response to HAART predicted OIs in children (5). Finally, immune reconstitution inflammatory syndrome (IRIS), initially described in HIV-infected adults but also seen in HIV-infected children, can complicate treatment of OIs when HAART is started or when optimization of a failing regimen is attempted in a patient with acute OI. Thus, preventing and treating OIs in HIV-infected children remains important even in an era of potent HAART.

History of the Guidelines
In 1995, the U.S. Public Health Service and the Infectious Diseases Society of America (IDSA) developed guidelines for preventing OIs among adults, adolescents, and children infected with HIV (6). These guidelines, developed for health-care providers and their HIV-infected patients, were revised in 1997, 1999, and 2002 (7,8). In 2001, the National Institutes of Health, IDSA, and CDC convened a working group to develop guidelines for treating HIV-associated OIs, with a goal of providing evidence-based guidelines on treatment and prophylaxis. In recognition of unique considerations for HIV-infected infants, children, and adolescents---including differences between adults and children in mode of acquisition, natural history, diagnosis, and treatment of HIV-related OIs---a separate pediatric OI guidelines writing group was established. The pediatric OI treatment guidelines were initially published in December 2004 (9).

The current document combines recommendations for preventing and treating OIs in HIV-exposed and HIV-infected children into one document; it accompanies a similar document on preventing and treating OIs among HIV-infected adults prepared by a separate group of adult HIV and infectious disease specialists. Both sets of guidelines were prepared by the Opportunistic Infections Working Group under the auspices of the Office of AIDS Research (OAR) of the National Institutes of Health. Pediatric specialists with expertise in specific OIs reviewed the literature since the last publication of the prevention and treatment guidelines, conferred over several months, and produced draft guidelines. The Pediatric OI Working Group reviewed and discussed recommendations at a meeting in Bethesda, Maryland, on June 25--26, 2007. After the meeting, the document was revised, then reviewed and electronically approved by the writing group members. The final report was further reviewed by the core Writing Group, the Office of AIDS Research, experts at CDC, the HIV Medicine Association of IDSA, the Pediatric Infectious Diseases Society, and the American Academy of Pediatrics before final approval and publication.

Why Pediatric Prevention and Treatment Guidelines?
Mother-to-child transmission is an important mode of acquisition of OIs and HIV infection in children. HIV-infected women coinfected with opportunistic pathogens might be more likely than women without HIV infection to transmit these infections to their infants. For example, greater rates of perinatal transmission of hepatitis C and cytomegalovirus (CMV) have been reported from HIV-infected than HIV-uninfected women (10,11). In addition, HIV-infected women or HIV-infected family members coinfected with certain opportunistic pathogens might be more likely to transmit these infections horizontally to their children, increasing the likelihood of primary acquisition of such infections in the young child. For example, Mycobacterium tuberculosis infection among children primarily reflects acquisition from family members who have active tuberculosis (TB) disease, and increased incidence and prevalence of TB among HIV-infected persons is well documented. HIV-exposed or -infected children in the United States might have a higher risk for exposure to M. tuberculosis than would comparably aged children in the general U.S. population because of residence in households with HIV-infected adults (12). Therefore, OIs might affect not only HIV-infected infants but also HIV-exposed but uninfected infants who become infected with opportunistic pathogens because of transmission from HIV-infected mothers or family members with coinfections. Guidelines for treating OIs in children must consider treatment of infections among all children---both HIV-infected and HIV-uninfected---born to HIV-infected women.

The natural history of OIs among children might differ from that among HIV-infected adults. Many OIs in adults are secondary to reactivation of opportunistic pathogens, which often were acquired before HIV infection when host immunity was intact. However, OIs among HIV-infected children more often reflect primary infection with the pathogen. In addition, among children with perinatal HIV infection, the primary infection with the opportunistic pathogen occurs after HIV infection is established and the child's immune system already might be compromised. This can lead to different manifestations of specific OIs in children than in adults. For example, young children with TB are more likely than adults to have nonpulmonic and disseminated infection, even without concurrent HIV infection.

Multiple difficulties exist in making laboratory diagnoses of various infections in children. A child's inability to describe the symptoms of disease often makes diagnosis more difficult. For infections for which diagnosis is made by laboratory detection of specific antibodies (e.g., the hepatitis viruses and CMV), transplacental transfer of maternal antibodies that can persist in the infant for up to 18 months complicates the ability to make a diagnosis in young infants. Assays capable of directly detecting the pathogen are required to diagnose such infections definitively in infants. In addition, diagnosing the etiology of lung infections in children can be difficult because children usually do not produce sputum, and more invasive procedures, such as bronchoscopy or lung biopsy, might be needed to make a more definitive diagnosis.

Data related to the efficacy of various therapies for OIs in adults usually can be extrapolated to children, but issues related to drug pharmacokinetics, formulation, ease of administration, and dosing and toxicity require special considerations for children. Young children in particular metabolize drugs differently from adults and older children, and the volume of distribution differs. Unfortunately, data often are lacking on appropriate drug dosing recommendations for children aged <2 years.

The prevalence of different opportunistic pathogens among HIV-infected children during the pre-HAART era varied by child age, previous OI, immunologic status, and pathogen (1). During the pre-HAART era, the most common OIs among children in the United States (event rates >1.0 per 100 child-years) were serious bacterial infections (most commonly pneumonia, often presumptively diagnosed, and bacteremia), herpes zoster, disseminated MAC, PCP, and candidiasis (esophageal and tracheobronchial disease). Less commonly observed OIs (event rate <1.0 per 100 child-years) included CMV disease, cryptosporidiosis, TB, systemic fungal infections, and toxoplasmosis (3,4). History of a previous AIDS-defining OI predicted development of a new infection. Although most infections occurred among substantially immunocompromised children, serious bacterial infections, herpes zoster, and TB occurred across the spectrum of immune status.

Descriptions of pediatric OIs in children receiving HAART have been limited. As with HIV-infected adults, substantial decreases in mortality and morbidity, including OIs, have been observed among children receiving HAART (2). Although the number of OIs has substantially decreased during the HAART era, HIV-associated OIs and other related infections continue to occur among HIV-infected children (3,13).

In contrast to recurrent serious bacterial infections, some of the protozoan, fungal, or viral OIs complicating HIV are not curable with available treatments. Sustained, effective HAART, resulting in improved immune status, has been established as the most important factor in controlling OIs among both HIV-infected adults and children (14). For many OIs, after treatment of the initial infectious episode, secondary prophylaxis in the form of suppressive therapy is indicated to prevent recurrent clinical disease from reactivation or reinfection (15).

These guidelines are a companion to the Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents (16). Treatment of OIs is an evolving science, and availability of new agents or clinical data on existing agents might change therapeutic options and preferences. As a result, these recommendations will need to be periodically updated.

Because the guidelines target HIV-exposed and -infected children in the United States, the opportunistic pathogens discussed are those common to the United States and do not include certain pathogens (e.g., Penicillium marneffei) that might be seen more frequently in resource-limited countries or that are common but seldom cause chronic infection (e.g., chronic parvovirus B19 infection). The document is organized to provide information about the epidemiology, clinical presentation, diagnosis, and treatment for each pathogen. The most critical treatment recommendation is accompanied by a rating that includes a letter and a roman numeral and is similar to the rating systems used in other U.S. Public Health Service/Infectious Diseases Society of America guidelines (17). Recommendations unrelated to treatment were not graded, with some exceptions. The letter indicates the strength of the recommendation, which is based on the opinion of the Working Group, and the roman numeral reflects the nature of the evidence supporting the recommendation (Box 1). Because licensure of drugs for children often relies on efficacy data from adult trials and safety data in children, recommendations sometimes may need to rely on data from clinical trials or studies in adults.

Tables at the end of this document summarize recommendations for preventing OIs in children (Tables 1--3); treatment of OIs in children (Table 4); drug preparation and toxicity information for children (Table 5); drug-drug interactions (Table 6), and vaccination recommendations for HIV-infected children and adolescents (Figures 1 and 2).


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