Current Pediatric Reviews - Volume 7, Issue 3, 2011

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About 30 years ago the first cases of AIDS among adults were reported in MMWR [1]. It was soon clear that the HIV epidemic was affecting not only adults but also children [2]. The search for a treatment started almost immediately and the first drug identified for antiretroviral treatment (ART) was zidovudine for both adults and children [3, 4]. In less than ten years the time of Highly Active Antiretroviral Treatment (HAART) came for adults [5]. It took some more time to have a triple combination of antiretroviral drugs as the standard of care in children, too [6]. Excellent results arrived soon, but it rapidly became clear that ART management presented several challenges [7, 8]. Nowadays, we are facing a pediatric HIV epidemic that has virtually stopped expanding in developed countries. Conversely, in developing countries there is still an ongoing epidemic, although progressing slower than in the past [9]. In particular, the majority of new pediatric cases of HIV infection are concentrated in this latter area of the world. When planning for this special issue it was considered interesting to collect updated information that could support pediatricians working where most cases of HIV infection in children are (i.e. first- and second-line ART in resource-limited settings; TB/HIV co-infection). Nevertheless, issues not strictly related to developing countries, but also challenges for pediatric ART that could be relevant for all settings (i.e. adherence; pharmacokinetics; immune recovery) were addressed. This special issue could not necessarily cover all possible issues of pediatric HIV-infection management in all possible settings. However, it can surely provide a source of highly qualified information for those who want to improve management of HIV-infected children in their Institutions.

The scale-up of pediatric antiretroviral therapy (ART) in sub-Saharan Africa over the past decade involved unprecedented political and donor commitment. These pediatric ART programs have demonstrated they can provide ART to human immunodeficiency virus (HIV)-infected children and that these children achieve treatment outcomes comparable to children in high-resource settings. Several obstacles, however, have hindered program implementation and impacted treatment outcomes. Challenges particularly affecting children include shortages of properly trained healthcare providers, lack of laboratory capacity for infant diagnosis and pediatric treatment monitoring, poor adherence, disclosure of HIV infection status and attrition. Innovative solutions to these challenges have been developed and programs are demonstrating they can successfully expand services to increase ART coverage in affected communities. As programs optimize the care and treatment of children, and more efficiently provide HIV services within the health care system, new challenges arise, including integration of child and family health services, use of electronic health records and the potential need for rationing antiretroviral drugs. Further evaluation of innovative solutions to these challenges and barriers to care, as well as continued commitment on the part of governments and donors, will be required if all HIV-infected children are to receive proper care.

Modern pediatric combination antiretroviral therapy faces a difficult challenge of preserving the focus on an individual child while addressing the globalization of antiretroviral exposure. While the gains from pediatric antiretroviral therapies have been tremendous, minimizing the lag between the approval of new antiretroviral agents in adults and getting these therapies into infants and children, using appropriate formulations and dosages, has been challenging. Fortunately, the development of antiretroviral therapies has coincided with several important initiatives designed to enhance the drug approval process in children. With increased antiretroviral therapy exposure among pediatric patients worldwide, the concerns for long-term adherence, antiretroviral drug resistance and long-term antiretroviral therapy associated toxicities, some of which are only now beginning to be investigated in children, have arisen. This manuscript reviews the major milestones in the evolution and changes in the design of the clinical trials of antiretroviral drugs in HIV-infected children throughout the development of pediatric antiretroviral therapy. It further investigates the role of therapeutic drug monitoring in the clinical trials and clinical practice and discusses challenges of pediatric HIV therapy and antiretroviral drug development

HIV-infected children experience a high burden of tuberculosis. With recent advances in international pediatric HIV treatment guidelines significant numbers of infants and children will require simultaneous treatment for both TB and HIV. This article attempts to concisely outline strategies for effective co-treatment of both infections. Rifamycins, an essential component of short course TB chemotherapy, alter the metabolism of a number of antiretroviral drugs. These interactions and their consequences are considered. Options for antiretroviral therapy and the optimal timing of its initiation in the presence of antituberculosis therapy are discussed.

Pediatric antiretroviral treatment programs have been rolled out in resource limited settings, providing lifesaving treatment to approximately 300,000 HIV-infected children. The standard first-line antiretroviral regimen is a nonnucleoside reverse transcriptase plus 2 nucleoside reverse transcriptase inhibitors (NRTIs). A meta-analysis showed that 70% of children achieved virologic suppression after 12 months of first line therapy. This article presents the challenges in diagnosis of treatment failure in resource limited settings and reviews the current guidelines for management of HIV-infected children with second-line antiretroviral therapy. The details of antiretroviral drugs recommended for second line regimens are summarized. The current standard second-line regimen is a boostedprotease inhibitor-based regimen plus recycling NRTIs. The potential role of new ARV drug classes for second-line regimen is addressed.

The natural course of HIV infection causes a severe depletion of CD4+ T cells, phenotypic alterations of T-cell subsets and a decline in thymic function, which in turn produces a progressive impairment of the immune function. HIVinfected children present some distinct features when compared to adults mainly due to the immaturity of immune system and the preserved capacity of thymic renewal of immune cells. The introduction of highly active antiretroviral therapy (HAART) decreased mortality rates in HIV-infected children, and proved to be effective in suppressing plasma viral loads and increasing CD4+ T-cell counts and T-cell rearrangement excision circles (TREC) levels in young HIV-infected patients. These findings indicate that recovery of thymic function is a pivotal event in immune reconstitution. Among the cytokines and hormones identified as possible regulators of thymopoiesis, IL-7 may play an essential role promoting the differentiation of thymocytes into mature T cells that will leave the thymus and move to the periphery in response to Tcell depletion. HAART provides appropriate functional immune reconstitution in children to withdraw prophylaxis against some opportunistic infections, but a revaccination or antigenic reexposure could be required to restore the protective immunity to some vaccine-preventable diseases. The immune reconstitution associated to HAART could also produce an immune reconstitution inflammatory syndrome (IRIS). In conclusion, HAART treatment in HIV-infected children has shown to be effective in decreasing viral load (VL) and recovering the T-cell population due to a preserved thymic function as well as the homeostatic mechanisms of IL-7.

Combination antiretroviral therapy (ART) for the treatment of HIV infection requires sustained adherence to maintain its efficacy. Adherence to ART presents several challenges for children receiving it and for their caregivers and pediatricians. Many factors can affect adherence to ART; they can be divided into: 1) Factors related to the patient and the family; 2) Factors related to the drug/medication; and 3) Factors related to the health care system. Different strategies can be employed to overcome some of the obstacles identified in these three groups. Some of these strategies are of proven efficacy; others have been proposed and tested only in small cohorts. Tailoring ART regimen on the daily activities of the child and his/her family, coupled with an intensive education programme on adherence for child and caregivers, prior to starting the treatment is probably one of the most effective interventions. Specific medication-related problems (depending on drug pharmacokinetic and pharmacodynamic, taste and palatability, food restrictions, etc.) exist; such problems cannot be solved solely by clinicians or by families. In this area, greater commitment of the pharmaceutical industry is still needed, and innovative solutions have to be identified by clinicians in partnership with drug manufacturers. Furthermore, an “adherence strategy/programme” should be a key component of the ART delivery strategy of any institution treating HIV-infected children. Most of the necessary interventions to be included in such programmes can be easily implemented, but they require trained and committed staff (and institutions), and time to be spent with patients and their caregivers.

When a child is having difficulty listening in noisy situations e.g. classroom, a hearing test should be considered as a first diagnostic step. If however, the hearing test is normal and the symptom persists, the pediatrician should consider requesting an auditory processing assessment. Hearing loss in childhood is known to interfere with communication, learning, language acquisition, social life and academic achievements. Similarly Auditory Processing Disorder (APD) may affect a child's ability to communicate, normally acquire reading skills and it may interfere with social life and academic achievements. An estimated 5% of school aged children may be affected by the disorder, which in many cases remains undiagnosed. This is a monothematic issue on pediatric (Central) Auditory Processing Disorder (APD or CAPD). The word monothematic is compound and of Greek origin, “mono” meaning only one and “thematic” meaning topic. It focuses on raising awareness of this disorder and providing evidence and data on speech perception in noise, comorbidity of APD and reading disabilities (Dyslexia), the neural substrate of the disorder and objective biological measures as a supplement for assessment and monitoring of management outcome. The aim is to provide a well-structured overview of presenting symptomatology, comorbidity and neurobiological origin. It should be noted that APD is too complex for all its features and controversies to be presented in a single issue. Nevertheless, authors in this issue are presenting this disorder mainly from the clinician's point of view largely incorporating current research. The core deficit in APD is difficulty perceiving speech in noise in the presence of a normal hearing test (audiogram). A key point to be remembered by the general practice pediatrician is as Bantwal & Hall state “A normal audiogram does not rule out a hearing deficit. Indeed, we really hear with our brains, not our ears”. Both parental and child's concern about hearing should be adequately addressed. Diagnosis of normal hearing sensitivity does not exclude the possibility of APD being present. As a result of this core deficit a child's ability to communicate and learn may be impaired and comorbidity with reading disabilities may present. These impairments have been shown to be associated with anxiety, low self-esteem and difficulty in acquiring friends as possible presenting psychosocial problems and may ultimately lead to academic failure. 30-50% of children with reading disabilities and/or learning disorders present with APD. Causality of this comorbidity is not conclusively defined at the present time. In this issue, preliminary results by Veuillet, Bouilhol & Thai-Van, are presented showing on one end differences in developmental trajectories of auditory descending pathway function between normal reading and dyslexic children and on the other end deficient high level process. Hearing is a sensation requiring bottom-up functionality, which is information conveyed and decoded from the peripheral auditory organ to the central auditory nervous system and the brain cortex. However, cognitive elements play a significant role accelerating information processing and this is denoted as top-down functionality. Top-down and bottom-up functioning in the auditory system are synergistically processing information accomplishing auditory perception. Even though this mentioned relation exists, yet “Too rarely to this day, health professionals faced with children with learning difficulties ask whether an APD is present” as noted in the conclusion paragraph of Veuillet et al.....

An acceptable acoustical environment is necessary for effective communication and learning. Children who experience abnormally poor speech perception in noise, including those with normal hearing sensitivity, are at risk for speech and language delay, reading disorders, psychosocial problems, and academic failure. The biological bases of speech perception in noise are complex and include processes at cortical as well as sub-cortical levels of the auditory nervous system. In children, the ability to perceive speech in degraded listening conditions improves significantly with age in parallel with developmental changes in the auditory nervous system. Difficulty in listening to speech in noisy surroundings is a common symptom associated with auditory processing disorders (APD). Clinical assessment of speech perception in noise quantifies potential problems that a child might face in daily listening situations. Optimally, pediatric speech in noise tests are designed to meet minimal psychometric criteria. A speech in noise test should be appropriate for the child's age and native language so as to minimize the role of linguistic factors. A diagnosis of APD should not be made based solely on a speech in noise test but, rather, on a battery of tests, each exploring a different suprathreshold auditory process. Speech in noise tests should be used and interpreted with extreme caution when assessing auditory processing in children with co-existing peripheral hearing loss. Children with normal hearing sensitivity, whose performance on tests using competing acoustic signals is below normal, can benefit from specific intervention and the use of signal enhancing devices such as FM systems.

Auditory processing disorders (APDs) are associated with an inability to process auditory information which cannot be explained by abnormal hearing thresholds. This review focuses on APDs that are liable to be found in subjects with language-based learning disabilities such as dyslexia. Although the causal relationship between the presence of an APD and reading deficits is still poorly understood, it is clear that in many cases (estimated range between 30-50%) the presence of an APD may serve as a marker of language-based learning problems. While some dyslexic children can be characterized by poor performances in auditory temporal processing (resolution, masking, ordering, integration) they can also experience hearing difficulties with competing or degraded acoustic signals (for example, during dichotic listening or in the presence of a noisy background). Behavioural hearing deficits are not always found in dyslexic children; when present they may be explained, at least partly, by the task complexity which induces strong cognitive load. However, there is no doubt that the co-morbidity of APD and dyslexia can create difficulties in communication and academic skills. In addition to these behavioural indices of APD, evidence for abnormal function of the descending auditory pathway is provided in dyslexia. We here present preliminary results showing 1) differences in the developmental trajectories when normal reading and dyslexic children are compared for auditory descending pathway function and 2) deficient high level process (attention) which appears in literacy problems and auditory processing deficits (dichotic listening) through feedback connections from higher to lower areas. These abnormalities, in turn, may be accompanied by different behavioural manifestations of APD.

Central auditory processing deficits and central auditory processing disorder (CAPD) has been linked to a number of different etiological bases. Reports document CAPD in children stemming from neurological abnormalities, including seizure disorders, neoplasms, degenerative processes, traumatic brain injury, cerebrovascular accidents, metabolic disorders, and genetic disorders across a variety of sites of lesion at all levels of the central auditory nervous system (CANS). Also documented is the efficiency of central auditory behavioral tests and electrophysiological procedures in evaluating pediatric patients with known or suspected neurological involvement. All regions of the CANS can be assessed using auditory evoked potentials, electoacoustic procedures, and central auditory behavioral tests after a careful assessment of the peripheral auditory system. Multidisciplinary evaluation is crucial to both diagnosis and intervention given the potential for multiple system involvement, complex clinical profiles, and frequent co-morbidities in children with neurological problems. The patterns of performance deficits seen in children with documented CANS lesions are comparable to those patterns seen in adult patients with documented CANS lesions. Moreover, central auditory test battery deficit patterns seen in children with auditory-related complaints but with no identifiable lesions of the CANS mirror those patterns seen in pediatric and adult populations with circumscribed disorders of the CANS, and these deficit patterns correlate with neuroimaging results. These common patterns indicate that lesion studies of adult (or pediatric) patients can serve to approximate a ‘ gold standard’ for CAPD in children with no identifiable CANS lesion. Whether the source of CANS dysfunction is benign or the result of neurological lesion or compromise, the underlying source of the resulting CAPD is neurobiological, originating in the central nervous system.

Auditory processing impairments negatively impact language learning, the ability to listen effectively in noisy environments, and the development of reading skills. Behavioral assessments of auditory processing provide valuable insight into auditory function but lack information about the biological health of the auditory pathway, and can be complicated by comorbid disorders, alertness, and motivation. The speech-evoked auditory brainstem response has recently been linked to communication skills such as speech-in-noise perception and reading ability and provides additional insight for the diagnosis and management of auditory processing disorders. This paper reviews how objective biological measures of auditory function can be used to reveal auditory system dysfunction in the absence of hearing loss.