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Guidelines for the Prevention and Treatment of Opportunistic Infections in HIV-Exposed and HIV-Infected Children
Background and Recommendations Rating Scheme
(Last updated: November 6, 2013; last reviewed: November 6, 2013)
Opportunistic Infections in HIV-Infected Children in the Era of Combination Antiretroviral Therapy
In the era before development of potent 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. 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 ART 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, concomitant OI prophylactic drugs may only exacerbate the existing difficulties in adhering to ART. Multiple drug-drug interactions between 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, prevention and treatment of OIs in HIV-infected children remains important even in the cART era.
History of the Guidelines
In 1995, the U.S. Public Health Service (USPHS) and IDSA developed guidelines for preventing OIs in 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 2002.7-9 In 2001, NIH, 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 2004.10 In 2009, recommendations for preventing and treating OIs in HIV-exposed and HIV-infected children were updated and combined into one document; a similar document on preventing and treating OIs among HIV-infected adults, prepared by a separate group of adult HIV and infectious disease specialists, was developed at the same time. Both sets of guidelines were prepared by the Opportunistic Infections Working Group under the auspices of the Office of AIDS Research (OAR) of the NIH. For the current document, the Opportunistic Infections Working Group, again under the auspices of OAR, convened a new panel of pediatric specialists with expertise in specific OIs. The Panel reviewed the literature since the last publication of the prevention and treatment guidelines, conferred over several months, and produced draft guidelines. These draft guidelines were revised based on review by the full Panel and review and approval by the core writing group members. The final report was further reviewed by OAR, experts at CDC, the HIVMA of IDSA, the PIDS, and AAP before final approval and publication.
Why Pediatric Prevention and Treatment Guidelines?
Mother-to-child transmission is an important mode of acquisition of HIV infection and of OIs in children. HIV-infected women coinfected with opportunistic pathogens may be more likely than HIV-uninfected women to transmit these infections to their infants. For example, higher rates of perinatal transmission of hepatitis C and cytomegalovirus (CMV) have been reported from HIV-infected than from HIV-uninfected women.11,12 In addition, HIV-infected women or HIV-infected family members coinfected with certain opportunistic pathogens may be more likely to transmit these infections horizontally to their children, increasing the likelihood of primary acquisition of such infections in young children. For example, Mycobacterium tuberculosis infection in children primarily reflects acquisition from family members who have active tuberculosis (TB) disease, and increased incidence and prevalence of TB among HIV-infected individuals is well documented. HIV-exposed or HIV-infected children in the United States may have a higher risk of exposure to M. tuberculosis than would comparably aged children in the general U.S. population because of residence in households with HIV-infected adults.13 Furthermore, HIV-infected women may have transplacental transfer of lower levels of antibodies that protect their infants against serious bacterial infections than women who are not infected with HIV.14 Therefore, these guidelines for treatment and prevention of OIs consider both HIV-infected and HIV-uninfected children born to HIV-infected women.
The natural history of OIs in children may differ from that in 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 in 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 at a time when the child’s immune system already may 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 extrapulmonary 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 such as hepatitis C (for which diagnosis is made by laboratory detection of specific antibodies), transplacental transfer of maternal antibodies that can persist in infants 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 they usually do not produce sputum, and more invasive procedures (e.g., gastric aspirates, bronchoscopy, lung biopsy) may be needed to make a more definitive diagnosis.
Data related to the efficacy of various therapies for OIs in adults are often extrapolated to children, but issues related to drug PK, formulation, ease of administration, 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 opportunistic pathogens in HIV-infected children during the pre-ART era varied by child age, previous OI, immunologic status, and pathogen.1 During the pre-ART era, the most common OIs in children in the United States (event rates >1 per 100 child-years) were serious bacterial infections (most commonly pneumonia, often presumptively diagnosed, and bacteremia), herpes zoster, disseminated Mycobacterium avium complex (MAC), Pneumocystis jirovecii pneumonia (PCP), and candidiasis (esophageal and tracheobronchial disease). Less commonly observed OIs (event rate <1 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 in substantially immunocompromised children, serious bacterial infections, herpes zoster, and TB occurred across the spectrum of immune status.
Descriptions of pediatric OIs in children receiving cART have been limited. Substantial decreases in mortality and morbidity, including OIs, have been observed among children receiving cART, as in HIV-infected adults.3,5 Although the number of OIs has substantially decreased during the cART era, HIV-associated OIs and other related infections continue to occur in HIV-infected children.3,15
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 cART, resulting in improved immune status, has been established as the most important factor in controlling OIs in both HIV-infected adults and children. For many OIs, after treatment of the initial infectious episode, secondary prophylaxis in the form of suppressive therapy is indicated to prevent a recurrence of clinical disease as a result of re-activation or re-infection.
Because the guidelines target HIV-exposed and HIV-infected children in the United States, the opportunistic pathogens discussed are those common to the United States and do not include certain pathogens such as Penicillium marneffei that may be seen almost exclusively outside the United States, that are common but seldom cause chronic infection (e.g., chronic parvovirus B19 infection), or that have the same risk, disease course, and approach to prevention and treatment in all children regardless of HIV status (e.g., streptococcal pharyngitis). The document is organized to provide information about the epidemiology, clinical presentation, diagnosis, and treatment of each pathogen. Major recommendations are accompanied by ratings that include a letter that indicates the strength of the recommendation and a Roman numeral that indicates the quality of the evidence supporting the recommendation; this rating system is similar to the rating systems used in other USPHS/IDSA guidelines. Because licensure of drugs for children often relies on efficacy data from adult trials in combination with safety data in children, recommendations sometimes may need to rely on data from clinical trials or studies in adults. Thus, the quality of evidence level is accompanied by a * notation to indicate that evidence supporting the recommendation is a hybrid of higher-quality adult study evidence and consistent but lower-quality pediatric study evidence. This modification to the rating system is the same as that used by the HHS Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection groups.
The tables at the end of this document summarize recommendations for dosing of medications used for treatment and prevention of OIs in children (Tables 1–3), drug preparation and toxicity information for children (Table 4), and drug-drug interactions (Table 5). Vaccination recommendations for HIV-infected children and adolescents are presented in Figures 1 and 2 at the end of the document.
Rating Scheme for Pediatric Opportunistic Infections Recommendations
Recommendations are rated using the rating system noted in the Pediatric Opportunistic Infections Recommendations Rating Scheme below. The rating scheme includes explanatory text that reviews the evidence and the panel’s assessment. The letters A, B, and C represent the strength of the recommendation for or against a preventive or therapeutic measure and are based on assessing the balance of benefits and risks of adhering compared to not adhering to the recommendation, and Roman numerals I, I*, II, II*, and III indicate the quality of evidence supporting the recommendation and are based on study design. Roman numerals with asterisks describe types of evidence where a higher quality of evidence exists for adults compared to children.
Strength of Recommendation Rating A—Strong. The benefit associated with adhering to the recommendation nearly always outweighs the risk of not adhering to the recommendation. The recommendation applies to most patients in most circumstances and should be adhered to by clinicians unless there exists a compelling rationale for an alternative approach.
Strength of Recommendation Rating B—Moderate. The benefit associated with adhering to the recommendation outweighs the risks of not adhering to the recommendation more often than not but not as frequently as a recommendation with an A Rating. The recommendation applies to many patients in some circumstances.
Strength of Recommendation Rating C—Optional. It is unclear whether the benefits associated with adhering to the recommendation outweigh the risks of not adhering to the recommendation; other alternatives may be equally reasonable.
Quality of Evidence Rating I—Randomized Clinical Trial Data. In the absence of large pediatric randomized trials, adult data may be used if there are substantial pediatric data consistent with high-quality adult studies. Quality of Evidence Rating I will be used if there are data from large randomized trials in children with clinical and/or validated laboratory endpoints. Quality of Evidence Rating I* will be used if there are high-quality randomized clinical trial data in adults with clinical and/or validated laboratory endpoints and pediatric data from well designed, non-randomized trials or observational cohort studies with long-term clinical outcomes that are consistent with the adult studies. A rating of I* may be used for quality of evidence if, for example, a randomized Phase III clinical trial in adults demonstrates a drug is effective in ARV-naive patients and data from a nonrandomized pediatric trial demonstrate adequate and consistent safety and PK data in the pediatric population.
Quality of Evidence Rating II—Non-Randomized Clinical Trials or Observational Cohort Data. In the absence of large, well-designed, pediatric, non-randomized trials or observational data, adult data may be used if there are sufficient pediatric data consistent with high-quality adult studies. Quality of Evidence Rating II will be used if there are data from well-designed, non-randomized trials or observational cohorts in children. Quality of Evidence Rating II* will be used if there are well-designed, non-randomized trials or observational cohort studies in adults with supporting and consistent information from smaller nonrandomized trials or cohort studies with clinical outcome data in children. A rating of II* may be used for quality of evidence if, for example, a large observational study in adults demonstrates clinical benefit to initiating treatment at a certain CD4 T lymphocyte (CD4) cell count and data from smaller observational studies in children indicate that a similar CD4 count is associated with clinical benefit.
Quality of Evidence Rating III—Expert Opinion. Where neither clinical trial nor observational data exist, we rely on expert opinion.
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 one or more well-designed, nonrandomized trials or observational cohort studies with long-term clinical outcomes II: One or more well-designed, non-randomized trials or observational cohort studies in children† with long-term clinical outcomes II*: One or more well-designed, non-randomized trials or observational cohort studies in adults with long-term clinical outcomes with accompanying data in children† from one or more smaller 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
Note: In circumstances where there is level I or level II evidence from studies in adults with accompanying data in children that come only from small, non-randomized 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.
Antiretroviral Therapy and Management of Opportunistic Infections
Studies in adults and children have demonstrated that cART reduces the incidence of OIs and improves survival, independent of the use of OI antimicrobial prophylaxis. Recommendations for cART for HIV-infected children have been developed and can be found here. cART can lead to improvement or resolution of certain OIs, such as progressive multifocal leukoencephalopathy (PML) or microsporidiosis, for which effective specific treatments are not available. However, potent cART does not replace the need for OI prophylaxis in children with severe immune suppression. In addition, initiation of cART in individuals with an acute or latent OI can lead to IRIS, an exaggerated inflammatory reaction that can present with paradoxical worsening or new appearance of an OI (see IRIS section below).
Specific data are limited to inform recommendations on when to start cART in children with an acute OI and how to manage cART when an acute OI occurs in a child already receiving cART. Decisions about when to start cART in children with acute or latent OIs need to be individualized and will vary by the degree of immunologic suppression in a child before he or she starts cART. The benefit of initiating cART early is improved immune function, which could result in faster resolution of the OI. However, potential problems, such as drug-drug interactions that compromise efficacy and increase toxicity, exist when cART and treatment for the OI are initiated simultaneously. The primary disadvantage of delaying cART until after initial treatment of the acute OI is risk of additional OIs or death during the delay. Similarly, in children already receiving cART who develop an OI, management will need to account for each individual’s clinical, viral, and immune status on cART and the potential drug-drug interactions between cART and the required OI drug regimen. Disease-specific information and recommendations for managing cART in context of treating an OI are included in individual sections, as appropriate.
Immune Reconstitution Inflammatory Syndrome
ART improves immune function and CD4 count in HIV-infected children as in adults; within the first few months after starting treatment, HIV viral load sharply decreases and the CD4 count rapidly increases. This results in increased capacity to mount inflammatory reactions. After initiation of cART, in some patients, reconstitution of the immune system produces a paradoxical inflammatory response to infectious or non-infectious antigens, which results in apparent clinical worsening of an existing OI or appearance of a new OI. IRIS primarily has been reported in adults initiating therapy, but it also has been seen in children.17-20
IRIS can occur after initiation of cART as worsening of symptoms of an existing active OI (paradoxical IRIS) or as appearance of new symptoms of a latent or occult OI (unmasking IRIS), where infectious pathogens previously not recognized by the immune system now evoke an immune response. This inflammatory response often is exaggerated in comparison with the response in patients who have normal immune systems. An example of unmaking IRIS is activation of latent or occult TB after initiation of ART in patients without TB disease at cART initiation. Clinical recrudescence or symptomatic worsening of TB disease despite microbiologic treatment success and sterile cultures is typical of paradoxical IRIS. In this case, reconstitution of antigen-specific, T-cell-mediated immunity occurs after initiation of cART, with activation of the immune system against persisting antigens, whether present as viable organisms, non-viable organisms, or organism debris.
The pathologic process of IRIS is inflammatory and not microbiologic in etiology. Thus, distinguishing IRIS from treatment failure is important. In therapeutic failure, a microbiologic culture should reveal the continued presence of an infectious organism, whereas in paradoxical IRIS, follow-up cultures most often are sterile. However, with unmasking IRIS, viable pathogens may be isolated.
IRIS is described primarily on the basis of reports of cases in adults. A proposed clinical definition is new appearance or worsening of clinical illness temporally related to starting cART accompanied by ≥1 log10 decrease in plasma HIV RNA that is not explained by newly acquired infection or disease, the usual course of a previously acquired disease, or cART toxicity.21
In adults, IRIS most often has been observed after initiation of cART in patients with mycobacterial infections (including MAC and M. tuberculosis), PCP, cryptococcal infection, CMV, varicella zoster or herpes simplex virus (HSV) infections, hepatitis B and C virus infections, toxoplasmosis, and PML. The conditions most commonly associated with IRIS in children include mycobacterial infections, herpes zoster, HSV, and cryptococcal infection. In addition, reactions related to bacille Calmette-Guérin vaccine have been one of the most common IRIS manifestations in children in low-resource settings.17,18,20 In a study of 153 symptomatic children with CD4 counts <15% at initiation of therapy in Thailand, the incidence of IRIS was 19%, with a median time of onset of 4 weeks after start of cART; children who developed IRIS had lower baseline CD4 percentages than did children who did not develop IRIS.20
No randomized controlled trials have been published evaluating treatment of IRIS. Treatment has been based on severity of disease. For mild cases, observation alone with close clinical and laboratory monitoring may be sufficient. For moderate cases, nonsteroidal anti-inflammatory drugs have been used to ameliorate symptoms. For severe cases, corticosteroids such as dexamethasone have been used. However, the optimal dose and duration of therapy are unknown, and inflammation can take weeks to months to subside. During that time, cART generally is continued. Disease-specific information and recommendations for managing IRIS are included in individual sections, as appropriate.
Initiation of cART for an Acute OI in Treatment-Naive Children
The ideal time to initiate cART for an acute OI is unknown. The benefit of initiating cART is improved immune function, which could result in faster resolution of the OI. This is particularly important for OIs for which effective therapeutic options are limited or not available, such as microsporidiosis, PML, and Kaposi sarcoma (KS). However, potential problems exist when cART and treatment for the OI are initiated simultaneously. These include drug-drug interactions between the ARV and antimicrobial drugs, particularly given the more limited repertoire of ARV drugs available for children than for adults; issues related to toxicity, including potential additive toxicity of ARV and OI drugs and difficulty in distinguishing cART toxicity from OI treatment toxicity; and the potential for IRIS to complicate OI management.
The primary consideration in delaying cART until after initial treatment of the acute OI is risk of additional illness or death during the delay. Although the short-term risk of death in the United States during a 2-month cART delay may be relatively low, mortality in resource-limited countries is significant. IRIS is more likely to occur in patients with advanced HIV infection and higher OI-specific antigenic burdens, such as those who have disseminated infections or a shorter time from acute OI onset to start of cART. Most IRIS events have the potential to result in significant morbidity but do not result in death; the exception is OIs with central nervous system (CNS) involvement, the form of IRIS most commonly associated with mortality.22
Randomized trials in adults demonstrate significantly better outcomes when adults with non-CNS OIs begin cART early in the course of OI treatment, but raise concern for potential increased mortality when cART is initiated early in adults (in Africa) with cryptococcal meningitis.23-25 In the absence of trials in children, recommendations about timing of cART initiation in children undergoing OI treatment are not definitive and management should be individualized. The timing is a complex decision based on the severity of HIV disease, efficacy of standard OI-specific treatment, social support system, medical resource availability, potential drug-drug interactions, and risk of IRIS. Most experts believe that the early benefit of potent cART outweighs any increased risk to children who have OIs such as microsporidiosis, PML, or KS for which effective treatment is lacking and that they should begin it as soon as possible.
Management of Acute OIs in HIV-Infected Children Receiving cART
OIs in HIV-infected children soon after initiation of cART (within 12 weeks) may be subclinical infections unmasked by cART-related improvement in immune function (unmasking IRIS), which usually occurs in children who have more severe immune suppression at initiation of cART. This does not represent a failure of cART but rather a sign of immune reconstitution (see IRIS section). In such situations, cART should be continued and treatment for the OI begun. Assessing the potential for drug-drug interactions between the ARV and antimicrobial drugs and whether treatment modifications need to be made is important.
In children who develop an OI after receiving >12 weeks of cART with virologic and immunologic response to therapy, it can be difficult to distinguish between later-onset IRIS and a new OI related to persistent immunosuppression. In such situations, cART should be continued and specific OI-related therapy should be initiated, guided by results of clinical and microbiologic evaluation.
OIs that occur in HIV-infected children with poor virologic response to cART (because of poor adherence, inappropriate ARV regimens, drug resistance, or some combination of these factors) represent failure of therapy. In this situation, treatment of the OI should be initiated, viral resistance testing performed, the child’s cART regimen reassessed, and adherence assessed and barriers addressed, as described in pediatric ARV guidelines.
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Mofenson LM, Oleske J, Serchuck L, Van Dyke R, Wilfert C. Treating opportunistic infections among HIV-exposed and infected children: recommendations from CDC, the National Institutes of Health, and the Infectious Diseases Society of America. Clin Infect Dis. Feb 1 2005;40 Suppl 1:S1-84. Available at http://www.ncbi.nlm.nih.gov/pubmed/15655768.
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