HIV Infection in Children

AIDS and Other Manifestations of HIV Infection Fourth Edition, edited by Gary P. Wormser Copyright © 2004, Elsevier (USA). All rights reserved

Chapter 15

HIV Infection in Children Sharon Nachman

In a discussion of human immunodeficiency virus (HIV) infection in infants, children, and adolescents, one must be cognizant of the fact that information on prevention and transmission, treatment of opportunistic infections, primary therapy, and toxicities from medications is constantly changing and expanding. This chapter will discuss HIV infection in infants, children, and adolescents. Several websites are available including: www.cdc.gov, www.hivatis.org, and www.pedhivaids.org for updating of this knowledge base.

EPIDEMIOLOGY AND TRANSMISSION The cumulative number of AIDS cases reported by June 2001 to the CDC was 793,026. Adult and adolescent AIDS cases accounted for about 784,000, with the remainder of them (9,000) being children under 13 years of age (1). Of the children with AIDS, 26% were from New York, 16% were from Florida, 9% were from New Jersey and 7% were from California. The estimated total number of HIVinfected children in the U.S. is currently between 10,000 and 20,000. Most of these are between the ages of 7 and 15 (1). With the aging of the perinatally infected population and the increasing number of adolescents infected through adult behaviors, it is anticipated that the number of adolescents with HIV infection will increase over the next decade. Although fewer than 1% of the current reported cases of AIDS in the U.S. have been among adolescents, the impact of HIV infection in this age group is more serious than this figure might suggest. Adolescence is a developmental stage of life normally characterized by experimentation, risk taking, and sexual exploration within the context of feelings of invulnerability, which makes it a uniquely highrisk period for acquisition of HIV. Of all reported AIDS

Sharon Nachman: Department of Pediatrics, HSC T11-031, Stony Brook University, Stony Brook, New York NY 11794.

cases in the U.S. through 2000, 18% were among those aged 20–29, with almost 4% of the total among those aged 20–24. The latency period from acquisition of HIV infection to development of AIDS in adults suggest that a significant proportion of HIV-infected young adults aged under 29 years will have acquired their infection as teenagers. Seroprevalence data from the Job Corp in the U.S. indicates that disadvantaged and out-of-school youth are at highest risk for HIV infection (2). The rising rates of other sexually transmitted diseases (STDs) and unplanned pregnancies among adolescents are suggestive of a substantial risk for sexually transmitted HIV infection in this age group. Sexual exposure, including heterosexual, homosexual, bisexual, and sexual abuse, has been a prominent mode of HIV transmission among adolescents with AIDS, with heterosexual transmission the identified risk factor in 33% of adolescent females with AIDS and homosexual transmission in 42% of adolescent males diagnosed with AIDS in 2001. Although IV drug use is relatively uncommon among adolescents, the disinhibiting effects of drug use, particularly alcohol, cocaine, and crack, as well as the cost of dependence result in increased sexual risk taking, including prostitution, and contribute to the further spread of HIV (3). Approximately 8,000 infants are born to HIV-infected women in the U.S. each year. In 1994 the Pediatric AIDS Clinical Trials Group demonstrated that zidovudine therapy administered to selected HIV-infected pregnant women and their newborn infants reduced the rate of perinatal HIV transmission from 25% to 8% (4). In 1995, the U.S. Public Health Service published the first set of guidelines calling for universal, routine HIV counseling and voluntary HIV testing of pregnant women. The rapid implementation of these guidelines by health care workers (and acceptance by HIV-infected pregnant women) has resulted in a dramatic decrease in perinatal HIV transmission in the past seven years. Prior to the routine use of antiretrovirals in pregnancy, perinatal transmission of HIV occurred in 25% of all deliveries. Since the advent of

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routine use of HAART in these women, transmission now occurs in less than 5% of all pregnancies (5). This interruption of transmission is the single most important development in the care of HIV-infected women and their families. Between 1992 and 1998, perinatally acquired AIDS cases declined 75% in the U.S. For further discussion of prevention of perinatal transmission please refer to the current guidelines on the Web @ http:/ /www.hivatis.org. Postpartum transmission of HIV infection from mother to newborn via breast-feeding has been reported and documented in women who acquired HIV infection after delivery through sexual relations (6) and blood transfusion (7,8). In an Australian cohort of 11 women with documented postpartum acquisition of HIV who were breast-feeding their newborns, three transmitted HIV to their infants, yielding an estimated risk of 27% for breastfeeding during primary maternal HIV infection. These cases may be accounted for by the significant HIV viremia and presumed increased level of infectivity in the first three to six months after acquisition of HIV infection (9). Whether breastfeeding is a significant mode of transmission in women who are already HIV-infected during pregnancy and clinically stable was recently elucidated. A metanalysis of studies with varying perinatal transmission rates from different parts of the world suggests that breastfeeding increases the rate of perinatal transmission of HIV by 14% (95% confidence interval 7–22%) (10). This risk was highest in women who intermittently breastfed their infants. The risk-benefit ratio for breastfeeding in HIV-infected women is affected by the infant mortality rate associated with infectious disease or malnutrition in conjunction with the relative risk for bottle-fed infants (11). Where sterile formula is readily available, this ratio clearly favors bottle-feeding, and infected women should bottle-feed rather than breastfeed their infants. For parts of Africa and many other Third World areas, however, the situation is much less clear and favors breastfeeding in areas where the infant mortality attributable to bottle-feeding is greater than one in seven (12). Iatrogenic acquisition of HIV through transfusions and the use of non-sterile needles are ongoing problems in many countries where blood products are not screened and disposable needles are not used. Reports of hospitalacquired HIV infection in Romania and the former Soviet Union are examples of this problem. The scope of this problem may be even larger than anticipated with many third world countries lacking the resources to obtain sterile needles for routine use in clinics or hospitals. Data on needle stick injuries have not revealed any transmission of HIV to a child from an infected health care provider (13). More than 200,000 children are sexually abused in the U.S. each year (14), and sexual abuse of infants, children, and adolescents is a documented mode of transmission of HIV infection (15,16). Nonetheless, sexual transmission of HIV is not a reportable category of HIV exposure for

children, and many barriers exist to identifying children infected with HIV through sexual abuse (17). Recent guidelines regarding both needle stick injuries and sexual post exposure prophylaxis are now available on the Web @ http://www.hivatis.org.

DIAGNOSIS In adolescents, children, and infants older than 18 months, definitive diagnosis of HIV infection is made in the same was as it is in adults, by using the enzyme-linked immunosorbent assay (ELISA) and Western blot assays, which provide serological confirmatory evidence of a humoral immune response to HIV by detecting HIVspecific IgG antibodies; however, because maternal IgG antibody is transferred to infants across the placenta, all infants born to HIV-infected women are antibody positive at birth. An IgG antibody response cannot be used to diagnose HIV infection in infants until they are 18 months of age, when maternal antibody is no longer present and the infant’s own humoral immune response should have been mounted. To determine infection status before age 18 months, several viral detection assays are currently used, including HIV DNA PCR, HIV RNA PCR and HIV viral culture. HIV DNA PCR is the preferred virologic method for diagnosing HIV infection during infancy. A meta-analysis of published data from 271 HIV-infected children indicated that HIV DNA PCR was sensitive and specific for the diagnosis of HIV infection during the neonatal period. 38% of infected children had positive PCR tests by age 48 hours. The sensitivity of this test increased by the second week to 93% testing positive by 14 days of life (18). It can be argued that HIV RNA PCR can also be used to identify HIV-infected infants, however, data are limited comparing it to HIV DNA PCR in this age group. Thus a positive HIV RNA PCR is indicative of HIV infection, but a negative test (below the limits of detection = 400 copies/ml) is not indicative of the absence of infection. The use of these assays for diagnostic purposes has been recommended for all infants born to HIV-infected women (19). A presumptive diagnosis of HIV infection can be made with one positive HIV culture or PCR assay on noncord blood and a definitive diagnosis made with a confirmatory test on a different blood sample. HIV infection can be reasonably excluded with two negative HIV culture or PCR results, one obtained at age 1 month or later, the other at age four months or later (20). Some experienced clinicians are comfortable in excluding HIV infection using these assays at earlier ages. The current standard of care requires a negative HIV ELISA and Western blot at age 18 months to exclude HIV infection definitively.

HIV Infection in Children 391 TABLE 15.1. Immunologic categories for HIV-infected children based on age-specific CD4 T-lymphocyte counts and percentage of total lymphocytes Immunologic Category

No evidence of suppression Evidence of moderate suppression Severe suppression

Age < 12 Months Cells/mm3 (%)*

1–5 Years Cells/mm3 (%)

6–12 Years Cells/mm3 (%)

> 1,500 ( > 25)

> 1,000 ( > 25)

> 500 ( > 25)

750–1,499 (15–24)

500–999 (15–24)

200–499 (15–24)

< 750 ( < 15)

< 500 ( < 15)

< 200 ( < 15)

* Percentage of total lymphocytes.

Viral culture is performed on peripheral blood mononuclear cells co-cultured with uninfected mononuclear cells that can support HIV growth and detect latent HIVinfected cells by stimulating viral replication. Evidence of p24 antigen, reverse transcriptase activity, or syncytium formation indicates the presence of HIV in such samples. The sensitivity of this test is age dependent. Results of studies indicate a sensitivity of 24% during the first week of life, 85% at one month, exceeding 90% in infants by two to three months of age, and nearly 100% by six months of age (21,22). In one large cohort study, two negative cultures taken between one and six months of age had a specificity of 99.2–100% in defining an uninfected infant (22). HIV culture is more complex and expensive to perform than DNA PCR, and definitive results may not be available for two to four weeks. Although use of standard and immune-complex dissociated p24 antigen tests are highly specific for HIV infection, the sensitivity of these tests is less than the sensitivity of other HIV virologic tests (23). The use of p24 antigen testing alone is not recommended to exclude infection in infants less than one month because of a high frequency of false negative assays during this time. HIV exposed infants should be tested soon after birth, at age one to two months, and again at three to six months. Some investigators suggest that in addition to testing soon after birth, testing at two weeks should also be included as part of a diagnostic evaluation. In developing countries, virologic diagnostic assays are unfortunately not universally available to many practitioners, and a presumptive diagnosis frequently requires correlating clinical symptomatology with surrogate laboratory parameters in HIV-exposed infants. In these settings, diagnosis of HIV may include CD4 cell depletion, clinical symptomatology and a positive HIV ELISA and Western Blot. The 1994 CDC classification system for HIV infection for infants defined an HIV-infected infant using HIVspecific clinical symptomatology in conjunction with laboratory evidence of both cellular and humoral immune dysfunction. The most frequently used laboratory parameter of immune function is the CD4 + lymphocyte count. In

infants and children, as in adults, a depressed CD4 + lymphocyte count or reversed CD4/CD8 ratio is indicative of immunocompromise; however, healthy infants and children normally have much higher CD4 cell counts than healthy adults. The median CD4 + lymphocyte count for adults in a sample of uninfected subjects was 1,027, whereas the median CD4 + lymphocyte count for infants aged one to six months in the same study was 3,211 and for those aged seven to twelve months 3,128. Whereas the absolute number of CD4 + lymphocytes is higher in infants and children, the percentage of CD4 + lymphocytes is relatively stable from infancy to adulthood. It is important to be familiar with the normal age-specific lymphocyte counts when evaluating the immune status of infants and children. This classification system (Table 15.1) includes three immunologic categories of HIV-infected children based on age-adjusted CD4 + cell values (24). Most infants and children with HIV infection have hypergammaglobulinemia, which is indicative of polyclonal B-cell activation (25,26). Hypergammaglobulinemia has been described as the most common laboratory abnormality in HIV-infected children followed by a reversal of CD4/CD8 ratio (27). Normal immunoglobulin levels in infants and children are also age specific and need to be considered when evaluating a child for hypergammaglobulinemia. Elevated beta-2-microgloublin and neopterin levels have been reported in HIV-infected children. Other laboratory abnormalities commonly seen in pediatric HIV infection (some of them nonspecific) include (1) hypogammaglobulinemia, seen in 3–5% of cases; (b) anemia, which is usually secondary to chronic disease and has been associated with disease progression (other causes, such as iron deficiency, sickle cell, and lead toxicity must be ruled out); (c) thrombocytopenia, seen in about 10–20% of HIV-infected children and documented to be associated with antiplatelet antibody in 80% of these (28); and (d) leukopenia. Other clinical manifestations possibly indicative of pediatric HIV infection are discussed below. The laboratory abnormalities seen in adolescent HIV infection are similar to those seen in adults and discussed elsewhere in this volume.

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Chapter 15 TABLE 15.2. 1994 revised HIV pediatric classification system clinical categories

Category N: Not Symptomatic Children who have no signs or symptoms considered to be the result of HIV infection or who have only one of the conditions listed in Category A Category A: Mildly Symptomatic Children with two or more of the following conditions but none of the conditions listed in Categories B and C: • • • • • •

Lymphadenopathy ( > 0.5 cm at more than two sites; bilateral = one site) Hepatomegaly Splenomegaly Dermatitis Parotitis Recurrent or persistent upper respiratory infection, sinusitis, or otitis media

Category B: Moderately Symptomatic Children who have symptomatic conditions other than those listed for Categories A or C that are attributed to HIV infection. Examples of conditions in clinical Category B include but are not limited to the following: • • • • • • • • • • • • • • • • •

Anemia ( < 8 gm/dL), neutropenia ( < 1,000 mm3), or thrombocytopenia ( < 100,000 mm3), persisting > 30 days Bacterial meningitis, pneumonia, or sepsis (single episode) Candidiasis, oropharyngeal (i.e. thrush) persisting for more than two months in children aged more than six months Cardiomyopathy Cytomegalovirus infection with onset before age one month Diarrhea, recurrent or chronic Hepatitis Herpes simplex virus (HSV) stomatitis, recurrent (i.e. more than two episodes within one year) HSV bronchitis, pneumonitis, or esophagitis with onset before age one month Herpes Zoster (i.e. shingles) involving at least two distinct episodes or more than one dermatome Leiomyosarcoma Lymphoid interstitial pneumonia (LIP) or pulmonary lymphoid hyperplasia complex Nephropathy Nocardiosis Fever lasting more than one month Toxoplasmosis with onset before age one month Varicella, disseminated (i.e. complicated chickenpox)

Category C: Severely Symptomatic • Children who have any condition listed in the 1987 surveillance case definition (51) for acquired immunodeficiency syndrome, with the exception of LIP (which is a Category B condition)

CLINICAL MANIFESTATIONS AND PRESENTATIONS In infants and children, HIV infection is a chronic disease with multiorgan system involvement; indeed, there is probably not an organ system that is not affected by HIV. As in adults, HIV disease presents in infants and children with a broad spectrum of manifestations, some specific to young people. The 1994 CDC classification system (24) (Table 15.2) of HIV disease in children divides cases into four clinical categories: (a) N for no signs or symptoms, (b) A for mild signs or symptoms, (c) B for moderate signs or symptoms, and (d) C for severe signs or symptoms (25). Most of the symptomatic clinical manifestations of pediatric HIV disease are related directly to HIV infection or to the immunosuppression secondary to it. There is a wide range of clinical symptomatology from nonspecific findings to severe manifestations of common childhood illnesses, AIDS-defining conditions, and end-organ dysfunction.

In general there are two common patterns of presentation of HIV infection in children. One pattern, representing about a third of all perinatally acquired infections, involves early onset of severe disease with rapid progression and, if untreated with antiretrovirals, poor prognosis. Infants in this group usually present with severe opportunistic infections (most often Pneumocystis carinii pneumonia (PCP)) or encephalopathy within the first two years of life. Data from the Pediatric Spectrum of Disease Project delineate this group of patients as rapid progressors, i.e. those with early onset of disease manifestations and death before 48 months of age (29). Many of these children become identified as HIV infected because of severe illnesses that arise abruptly. In this group, PCP is seldom insidious; infants may be seen by a physician during one week with some mild general symptoms and have fulminant, life-threatening PCP the next. It is because of the presentation of illness in this group of patients that early PCP prophylaxis is required. These children are rarely seen in the post perinatal prophylaxis era, with most HIV infected women receiving antiretroviral therapy

HIV Infection in Children during pregnancy, labor and delivery and babies receiving ART therapy for six weeks postnatally. When infants are identified as HIV infected during the postnatal period, their virus is often sensitive to most antiretroviral therapies (30). However, most experts agree that it is reasonable to evaluate for presence of resistant virus when designing treatment regimens for these infants (31). The second presentation pattern of pediatric HIV infection involves later onset of disease symptomatology and is associated with a better prognosis. These children generally present after the first year of life with a more indolent disease course, consisting of a variety of the more general clinical manifestations including failure to thrive, severe varicella (or zoster), or recurrent bacterial infections. Relative to children diagnosed with AIDS in the first year of life, LIP is more common in this group, as are other signs of lymphoproliferation, such as generalized lymphadenopathy and parotitis. It is not unusual for school-aged children to be identified with perinatal HIV infection as a result of this type of presentation; some of these children are not diagnosed with AIDS or HIV infection until they are aged 10 or 11 years. In a cohort of 42 perinatally infected children aged 9–16 years followed up at CHAP in NJ, the mean age at diagnosis with HIV infection was 88 months. Although most children in this cohort had HIV-related symptomatology, many with significant disease, almost a quarter of the children remained asymptomatic with relatively intact immune systems at a mean age of 136 months (32). Children who present later in life may be clinically similar to asymptomatic adults or show only subtle HIV-related signs and symptoms before presenting with more obvious conditions, such as thrush. Recurrent bacterial infections are likely to occur as AIDS-defining conditions in both early and late onset presentations of HIV. Renal and cardiac involvement may occur as later manifestations of illness after other significant HIV-related disease is diagnosed (33). A number of factors are believed to contribute to the rapidity of clinical progression in some children compared with others. Rapid progressors are suspected to have been infected during the early prenatal period or to have been born to women with more advanced disease. An analysis of 162 HIV-infected infants from the French Prospective Multicenter Cohort revealed that the infants’ risk of opportunistic infection (OI) or encephalopathy in the first 18 months of life correlated directly with the degree of maternal HIV-related symptomatology and p24 antigen level, and inversely with maternal CD4 + lymphocyte count at the time of delivery. Fifty percent of infants in this study born to mothers with AIDS developed OIs or encephalopathy by 18 months compared with 14% of infants born to mothers who were either asymptomatic or had generalized lymphadenopathy (34–36). Recent data indicate that infants who have positive virologic tests within the first week of life are more likely to progress rapidly to AIDS within the first year (37). A prospective

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study evaluating RNA PCR levels in HIV-infected infants reported higher levels than in adults, with almost all infants having levels over 100,000 copies/ml (38). Rapidly progressing infants have higher peak plasma HIV RNA copy number, with a peak viral load of 724,000 copies/ml, compared with a peak of 219,000 copies/ml in slower progressors (38,39). Additionally, no infant in that study with a peak HIV RNA copy number of less than 80,000 copies/ml had rapidly progressive disease. Two major clinical factors affect the prognosis of children with HIV infections: their specific HIV-related diseases and their age at presentation. A study of 172 perinatally infected children treated at a Miami hospital (40), prior to HAART therapy availability, showed median survival rates from diagnosis of one month for those with PCP, five months for those with nephropathy, 11 months for those with encephalopathy, 12 months for those with candida esophagitis, 50 months for those with recurrent bacterial infections, and 72 months for those with LIP. Thus, both later presentation and later infection appear to be associated with longer survival. It is important to note that an AIDS diagnosis in and of itself is not an accurate prognostic indicator for children. The variability in prognosis is a function of the conditions responsible for the AIDS diagnosis. Although OIs, encephalopathy, and recurrent bacterial infections are all AIDS-defining conditions, the first two were often associated with a significantly worse prognosis than the latter. However, this is no longer the case with most children, who, after being identified as HIV infected are treated and despite initial severe depletion can repopulate their CD4 cell populations. Common signs and symptoms seen in children with HIV infection that are not AIDS defining include lymphadenopathy, hepatomegaly, splenomegaly, parotitis, recurrent diarrhea, failure to thrive, and recurrent fevers. It is important to evaluate children for specific infectious etiologies for these conditions, although HIV or the ensuing immunodeficiency may be the sole cause. Common oropharyngeal signs include persistent thrush, severe painful gingivitis, HIV-specific periodontal disease, recurrent aphthous stomatitis, and recurrent herpetic gingivostomatitis. Some of these conditions are extremely common and, as with adults, lymphoproliferation manifesting as lymphadenopathy may be the first objective sign of disease. As in other immunosuppressed conditions, children with HIV infection may have severe manifestations of relatively self-limited and usually non-life-threatening conditions common in childhood. There are several childhood illnesses that manifest themselves more seriously in children with HIV infection and include severe recurrent fungal skin and nail infections (tinea, candida), recalcitrant molluscum contagiosum, severe condylomata, recurrent and chronic otitis media and sinusitis, recurrent upper respiratory tract infections, and asthma.

394 Chapter 15 Also included in this group are severe and lifethreatening manifestations of varicella and measles. While most HIV-infected children have little problem with varicella, prolonged disease with varicella may be seen in those children with severe immune compromise. In one study of HIV-infected children with varicella, seven of eight children had evidence suggestive of varicella pneumonitis (41). In another study, seven of 17 HIV-infected children with varicella developed chronic, recurrent, or persistent disease (42). Some clinicians suggest treating all HIV-infected children with varicella aggressively with acyclovir as soon as there is evidence of disease. Varicellaexposed severely immune compromised children should be given varicella zoster immune globulin in an attempt to prevent or modify the course of disease. The incidence of zoster in HIV-infected children is close to that of children with leukaemia (42). Measles can also be life-threatening in the severely immune compromised HIV-infected child (43). Even with appropriate immunization, many HIV-infected children, especially those with low CD4 + lymphocyte counts, do not mount protective antibody responses against most routine childhood vaccinations and continue to be susceptible because of their impaired humoral immune response (44). Any HIV-infected child who is exposed to measles should receive intramuscular immune globulin as prophylaxis. Children already on intravenous gamma globulin (IVIG) therapy may be protected but should receive an additional dose of IVIG if the exposure occurs more than two weeks after their last infusion. In both adults and children, the OIs related to the immunodeficiency caused by HIV are varied and frequently difficult to treat. In children, AIDS-defining OIs often represent primary infection with the organism rather than the recrudescence that is typically the case in adults, which may be why PCP is a more severe illness in infants than in adults. Adult OIs that are rarely seen in children aged under eight years include toxoplasmosis, cryptococcal disease, and other disseminated fungal infections, such as coccidioidomycosis and histoplasmosis. Their relative scarcity in children probably relates to lack of exposure to the etiologic agents. These infections, however, are seen in adolescents. On the other hand, tuberculosis has become a problem in children born into households in which adults may be infected with both HIV and tuberculosis. HIV-infected children, like adults, are more susceptible to the rapid progression of Mycobacterium tuberculosis from infection to disease (tuberculosis) (45). Whereas space limitations preclude a comprehensive review of OIs in children, OI prevention and treatment guidelines are available on the web. In the pre-HAART era, the most common OI in infants and children was PCP (20). Before widespread use of PCP prophylaxis beginning in 1991–1992, PCP accounted for a higher percentage of reported AIDS indicator diseases and up to 65% of OIs in the pediatric population (40,46,47). Currently, the most common infections seen in HIV-

infected infants and children are those of bacterial origin, specifically pneumococcal.

RECURRENT BACTERIAL INFECTIONS HIV infection is associated with significant abnormalities in B-cell-mediated immune responses. In infants, laboratory-documented B-cell dysfunction usually precedes T-cell abnormalities (48,49), possibly the result of an interference with normal B-cell maturation, as humoral immune responses are incomplete at birth. The normal maturation of B cells, including the ability to produce antigen-specific antibodies, requires lymphokines produced by functioning CD4 + lymphocytes. Most adults with HIV infection were exposed to the common bacterial pathogens before becoming HIV infected; therefore, they tend to have circulating protective antibodies against them and circulating B cells with a retained anamnestic response to these pathogens. Thus, adults tend to get serious bacterial infections with common pathogens only late in the course of disease, when they are severely immunocompromised. With improved survival in a more immunocompromised state, however, the problem of severe bacterial infections in adults is on the rise. In contrast, HIV-infected children have defective primary and secondary antibody production to T-celldependent and independent antigens (48,50); when children are exposed to common bacterial pathogens for the first time, these abnormalities result in severe manifestations of infection early in the course of their HIV infection. Since 1987, recurrent serious bacterial infections have been part of the CDC case definition of AIDS for children (51). The most common infections that meet the case definition are bacteremia and pneumonia. The most common organisms include Streptococcus pneumoniae, Haemophilus influenzae, Salmonella spp., and Staphylococcus aureus (52,53).

CENTRAL NERVOUS SYSTEM (CNS) CNS involvement is a more common manifestation of HIV infection in infants and children than in adults, and although its true incidence is unknown, it is believed to occur in most of those infected. HIV is believed to enter the CNS through HIV-infected macrophages, which can cross the blood-brain barrier. In infants, entry of HIV into the CNS may be facilitated by infection with HIV in utero before establishment of this barrier (53a). It is unclear exactly how HIV causes neurological dysfunction; direct HIV effects and indirect effects through cells of the macrophage lineage and the elaboration of toxic cytokines have been postulated. There is a broad clinical spectrum of neurological abnormalities seen in pediatric HIV infection (54–58). There may be relatively normal development suddenly

HIV Infection in Children 395 followed by either loss of milestones or failure to attain new milestones. The onset of developmental delay may be followed by periods of relative stability in neurological function or rapid neurodevelopmental deterioration. Pyramidal tract involvement may be seen, with resulting spastic paresis. Hypertonicity and hyperreflexia are common manifestations of motor involvement. Prior to the widespread use of antiretrovirals, static encephalopathy was seen in about one quarter of children with HIV infection. It is characterized by developmental delay of varying severity without loss of previously attained milestones. Children in this group can have improvement in neurological function with continued acquisition of developmental skills, but usually in a delayed fashion. Progressive encephalopathy, characterized by progressive deterioration in cognitive, motor, or language skills and loss of previously attained developmental milestones, often is seen in patients with severe immune compromise (59). Progressive encephalopathy, which is associated with a poor prognosis, can be characterized by a plateau course without continued loss of milestones, or a rapidly progressive course. Neuroimaging studies of HIV infection in children include findings of ventricular enlargement, cerebral atrophy, white matter attenuation, and cerebral and basal ganglia calcification (60). The possibility of CNS lymphoma (61) always must be considered in the child who develops new neurological signs and symptoms. Antiretroviral therapy improves the neurodevelopmental functioning of infants and children with HIV infection (62–64). Children can regain lost motor and developmental milestones with therapy. In some children, this is dramatic, with the reversal of incontinence, gait abnormalities, or lost cognitive milestones after initiation therapy (65,66). GROWTH Assessment of growth is an integral part of the care of any pediatric patient. This is especially true in the care of HIV-infected children. Growth delay is common in HIVinfected children and thought to be due to disease progression (67–69). The basal metabolism of children with HIV infection is increased when compared to uninfected children, and when stressed, caloric needs increase, on average 12% for each degree Celsius increase in temperature, 25% for acute diarrhea and 60% for sepsis (70–72). Growth failure is often the first sign of HIV associated symptoms. However, recent data seem to suggest that antiretrovirals may also play a part in growth delay, as even a cohort of children with undetectable virus in plasma continued to have growth failure (73). HEMATOLOGIC Anemia in patients with HIV infection is not uncommon and may be due to many causes. The most common causes

include nutritional deficiencies such as iron, folic acid and B12, and immune hemolysis, hemorrhage, drug toxicities and finally bone marrow suppression secondary to HIV infection itself. Other causes of anemia such as parvovirus infection, Mycobacterium avium complex infection, CMV and malignancy may also need to be investigated. Evaluation for anemia typically includes a complete blood and reticulocyte count, iron level, total iron binding capacity and transferrin level. It is recommended to evaluate the erythropoietin level as well. If the erythropoietin level is less than 500 IU/L a trial of erythropoietin may be warranted. Neutropenia, like anemia, is a common finding in HIVinfected children. It is defined as an absolute neutrophil count of less than 1500 cells/mL. It can be seen secondary to infection, nutritional deficiencies or drug toxicity. In some cases neutropenia may respond to initiation or a change in antiretroviral therapy. It is recommended that granulocyte colony stimulating factor be used to treat neutropenia instead of dose modification of antiretrovirals, because of the narrow therapeutic range of these drugs (74). Thrombocytopenia may also be seen in HIV-infected children, and this used to be a common presenting sign of HIV infection (75). Intervention is usually not required, especially if the platelet count exceeds 50,000. In some cases the thrombocytopenia responds to initiation of HAART therapy. For those children whose platelet counts do not respond to HAART therapy, RHo (D) immune globulin is suggested. Other treatment options may include IVIG and steroids (see Treatment of HIV on p. 397).

PULMONARY Pulmonary complications from HIV range from chronic lymphocytic infiltrative disease of the lung (LIP) to bacterial pneumonias to opportunistic infections such as PCP and MAC. The diagnosis of LIP is usually based on a typical chest radiograph with persistent reticulonodular bilateral infiltrates. Treatment includes HAART therapy and prednisone if hypoxia is present. When evaluating bacterial pneumonias, blood and sputum cultures should be sent. Therapy is directed at the specific pathogens isolated. Unfortunately, these cultures yield an organism in < 30% of cases and therapy must be directed at the usual pathogens involved in community acquired pneumonias. Special care must be taken to consider expanding therapy to cover resistant pneumococci when warranted. Children with HIV infection who have bronchiectasis or frequent episodes of bacterial pneumonia may benefit from daily prophylaxis with TMP/SMX. Patients with severe immune depletion may present with PCP or MAC, and bronchoscopy or bronchoalveolar lavage may be needed in order to make the correct diagnosis. Updated guidelines for the prophylaxis and treatment of opportunistic infections can be viewed @ http://www.hivatis.org

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RENAL HIV associated nephropathy in children presents as a spectrum of disease that ranges from mild to moderate proteinuria that is persistent, hematuria, renal tubular acidosis and end-stage renal disease. Because the progression of disease in children is not as rapid as in adults, the first approach is to observe these patients over a period of time, monitoring electrolytes, blood urea nitrogen and creatinine. Drug toxicity often contributes to hematuria and certain antiretroviral and other drugs should be avoided in these patients. When end stage renal disease has developed these patients must be managed in conjunction with the pediatric nephrology team. In the future, decisions regarding renal transplants must be considered, especially in patients with successful long-term suppression of viral load and a normal CD4 cell repertoire.

CARDIAC Cardiac involvement in HIV infection has been known since 1983. The spectrum of cardiac disease ranges from silent lesions to dilated cardiomyopathy to myocarditis (76,77). Depressed left ventricular function is common in HIV-infected children, and has lead to some experts recommending yearly cardiac echocardiograms in these children. Other factors that could be involved in the pathogenesis of cardiomyopathy include infections such as Coxsackie B, CMV, Epstein-Barr virus, toxoplasma, pulmonary diseases, wasting, nutritional deficiencies (selenium and carnitine), antiretrovirals (and other pharmacological agents such as pentamidine, amphotericin B, or foscarnet), and illicit drug use. Mild manifestations of congestive heart failure (CHF) are treated with angiotensin-converting enzyme inhibitors. The two most commonly used agents are enalapril and captopril. Renal function, electrolytes and blood pressure must be closely monitored. Antihypertensive and antiarrhythmic agents are prescribed when appropriate in conjunction with a pediatric cardiologist.

ROUTINE EVALUATION It is suggested that all HIV-infected infants and children be managed by an expert in Pediatric HIV infection. Ideally the pediatric care team should consist of physicians and other experts in pediatrics, social workers, a nutritionist as well as a psychologist. This team should be able to consult with other pediatric subspecialists, as children with HIV often will have multi-organ involvement from their HIV infection. The following tests and services should be performed for all HIV infected children:

• Chest x-ray (78) This test identifies mediastinal enlargement, lung lesions and cardiomegaly. Patients with chronic lung disease should have pulse oximetry measured routinely as well. • Baseline brain CT (79) This scan may show calcification as well as brain atrophy. It may be more helpful in the perinatally infected adolescent who comes in with new CNS signs and symptoms. • A regular strength tuberculin skin test (78) • Visual screening (78) • Children with immune category 3 may need to be examined every six months, especially if they are seropositive for CMV or toxoplasmosis. • Psychometric testing (80,81) • GYN exam (78) Female adolescents should be referred for GYN care. Baseline and annual GYN visits should be provided for all adolescents who are sexually active to evaluate for STDs and for performing cervical PAP smears. All adolescents should be aware of their diagnosis and receive counseling regarding transmission of HIV, safe sex practices, birth control and the risk of perinatal transmission during pregnancy. • Baseline antibody titers should be considered to evaluate toxoplasma, CMV, Epstein-Barr virus, varicella– zoster virus and hepatitis viruses (78). • In addition, annual visits to a dentist are also strongly suggested (82–84). Routine evaluations should occur at three to four month intervals and should include a complete physical exam (including height, weight and vital sign monitoring), and routine labs such as CBC, liver function profile, and HIV RNA viral load and CD4 cell count. Other laboratory tests may include cholesterol, triglyceride and glucose monitoring, as well as urinalysis and electrolyte monitoring. Other non-routine evaluations may include EKG and echocardiograms (78). PCP Prophylaxis In children with HIV infection, PCP is associated with a high rate of morbidity and mortality. It often presents acutely with a peak incidence in the first three to six months of life. In March 1991 recommendations for PCP prophylaxis for infants and children were based on agedependent CD4 + lymphocyte counts (84a), which differ from values in adults. The guidelines called for initiation of PCP prophylaxis for HIV-exposed children aged 1 to 11 months with CD4 + counts below 1,500 cells/ul, for children 12 to 23 months of age with CD4 + lymphocyte counts below 750, for those aged 24 months to five years with CD4 + lymphocyte counts below 500, and for children aged six years or older with CD4 + lymphocyte counts below 200.

HIV Infection in Children 397 In 1994, these guidelines were revised to recommend that all HIV-infected infants be placed on prophylaxis regardless of CD4 + lymphocyte counts, beginning at one month of age (19). Because it was difficult to determine with certainty which infants born to HIV-infected women were themselves infected, and especially those who are uninfected, these new guidelines recommended initiating prophylaxis in all infants born to HIV-infected women at one month of age and continuing prophylaxis until HIV infection can be reasonably excluded. After the first year of life, the use of prophylaxis is recommended in HIVinfected children based on CD4 + lymphocyte values. A detailed discussion of prophylaxis and treatment of other OIs in infants and children is beyond the scope of this chapter and is covered elsewhere in this volume as they relate to the adult population.

TREATMENT OF HIV HIV-Specific Treatment At least 11 of the antiretroviral agents approved by the U.S. Food and Drug administration for treatment of HIV infections are approved for use in children. Two classes of drugs target the reverse transcriptase enzyme, while a third class targets the viral protease enzyme. Unfortunately, more information is still needed regarding optimal dosing in children due to the wide variability of drug absorption and metabolism among children and drug interactions that affect pharmacokinetic parameters.

When to Initiate Therapy There is much discussion in the literature regarding the best time to start antiretroviral therapy in children. Unfortunately, there is no one correct answer. Most experts agree that treatment should be initiated in children with severe immune suppression or those with clinical disease progression, but for those children with good immune function and no clinical symptoms, no such clear consensus is available. Antiretroviral therapy has provided substantial clinical benefit to HIV-infected children. Initial clinical trials with monotherapy demonstrated clinical improvement in growth, neurodevelopmental, immunologic and virologic parameters. Subsequent clinical trials have demonstrated combination therapy to be superior to monotherapy. In a longitudinal study which evaluated children in the preHAART and post HAART era, HAART therapy has been demonstrated to enhance survival. Mortality was only 1% in 1997/1998 compared to 5% in 1995/1996 (47). Data from clinical trials of antiretroviral therapy with one and two drug combinations (in antiretroviral children) (84b) and three and four drug combinations (in nucleoside alone exposed) children (84c) showed that initiation of

therapy may be able to produce long-term suppression of viral replication and preservation of immune function in some children. However, the potential problems with early therapy include the risk of short-term and long-term adverse effects, and concerns about viral mutation, especially in populations who will be on lifelong therapy. Over the past several years, members of the Working Group on Antiretroviral Therapy and Medical Management of HIV Infected Children have developed guidelines for initiation and treatment of HIV-infected children. These guidelines are updated frequently, and the reader is advised to look on the web for the most current guidelines at www.hivatis.org. These guidelines take into account clinical and immunologic status as well as virologic results. Available guidelines for adults are applicable only to newly infected adolescents and most children identified after three years of age. However, due to generally higher viral load measurements in neonates and infants, most experts suggest that babies identified as HIV positive in the first year of life be placed on HAART therapy despite normal CD4 markers. Aggressive antiretroviral therapy with at least three drugs is recommended for initial treatment of infected children because it provides the best opportunity to preserve immune function and delay disease progression. The goal of therapy is to suppress viral replication maximally while preserving immune function and minimizing drug toxicity. Biologic variation in plasma HIV RNA within a person is well documented and repeated measurements of HIV RNA levels in a clinically stable adult can vary by as much as 0.5 log 10. This biologic variation may be greater in infected infants and young children. In children with perinatal infection, RNA copy number rapidly declines during the first 12–24 months after birth (0.6 log 10 per year), then continues to decline slowly over the next three to four years (0.3 log 10 per year), but persists at higher levels than most infected adults. Thus, only changes greater than 0.7 log 10 in infants aged less than two years and greater than 0.5 log 10 in children over two years of age are biologically real (Table 15.3). However, no change in therapy should be made as a result of HIV copy number unless confirmed by a repeat test. A few children and adults with HIV infection do well clinically without therapeutic intervention. They are referred to as long-term nonprogressors. It is estimated that they make up 5% of patients with HIV infection. There are many different theories as to the genetic, immunologic and virologic mechanism of host resistance to disease progression, but unfortunately, clinicians are unable to predict accurately which patient will be part of this cohort of patients. There is no plasma RNA threshold below which an individual is likely to experience longterm nonprogression. Most experts therefore agree that early aggressive therapy in children and adults allows for

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Chapter 15 TABLE 15.3. Viral load reduction conversions*

Viral Load Reduction From Baseline (Logs) 0.3 log 0.5 log 0.7 log 1.0 log 1.5 log 2.0 log 2.5 log 3.0 log

Viral Load Reduction From Baseline (%)

Viral Load Reduction From Baseline (-Fold)

Remaining Viral Load Number

50.0% 75.0% 80.0% 90.0% 96.8% 99.0% 99.7% 99.9%

2-fold 3-fold 5-fold 10-fold 32-fold 100-fold 316-fold 1,000-fold

50,000 c/ml 25,000 c/ml 20,000 c/ml 10,000 c/ml 3,200 c/ml 1,000 c/ml 300 c/ml 100 c/ml

* In a hypothetical patient with a starting viral load of 100,000 copies/ml.

the best opportunity for long-term nonprogression, preservation of the immune system and minimization of the risk for antiretroviral resistance. Issues relating to treatment adherence are important in considering when to initiate therapy and what that therapy should be. Lack of adherence to therapy may enhance the development of drug resistance. Participation by the family and child, when appropriate, in the decision making process, is especially important in situations for which definitive data concerning new treatments are not available. Despite having been treated with agents from all three classes of FDA-approved antiretroviral agents, a growing number of HIV-infected children are not able to sustain viral replication below the level of quantification. Although incomplete adherence may be a factor in some of these cases, other factors include the previous use of these agents in the child (i.e. sequential mono or dual therapies or addition of new agents without changing the backbone of the regimen), inadequate dosing due to poorly described pharmacokinetic parameters, and toxicity management. In these cases, the pros and cons of continuing a treatment regimen versus switching to an alternative treatment regimen need to be closely considered and discussed with the child and family. There is no consensus as to the best approach to treat these patients. Choice of the new regimen should be guided by the child’s antiretroviral drug history and results from resistance assays. If the child has been exposed to all three available groups of antiretroviral agents, it is unlikely that a simple three- or even a four-drug regimen will sustain suppression of virus to undetectable levels. In this setting, viremia alone, in the face of stable clinical and immunologic status, does not require a medication change in a heavily pre-treated child. Reasonable approaches to these patients include: • Continuing a regimen that allows viral replication at a level that will not cause additional immunologic or clinical deterioration while waiting for newer therapeutic approaches and agents to be developed.

• Choosing an aggressive regimen of four to six agents in an attempt to suppress viral replication to undetectable levels with an acceptable level of toxicity. This regimen may contain two nucleoside reverse transcriptase inhibitors, a non-nucleoside reverse transcriptase inhibitor and two to three protease inhibitors. • Opting for a complete drug holiday (months) with the expectation that wild-type virus will once again predominate in the patient. After this interim period, an aggressive regimen can then be instituted. There are limited clinical data on this approach in adults and children, although it is expected that resistant virus is archived in the genome of the patient’s cells and will reappear in due time. Which agent(s) should be used as second- and third-line therapy depends on which agents(s) the patient was started on initially, the resistance profile of the circulating virus and the availability of other agents. A physician experienced in pediatric HIV disease should be consulted when these decisions are made.

Intravenous Immune Globulin Therapy Intravenous immune globulin (IVIG) is often standard therapy for children and adults with primary humoral immunodeficiency disorders such as Bruton’s agammaglobulinemia. Passive immunotherapy in the form of IVIG provides protection against a wide range of bacterial and viral pathogens. As discussed above, children with HIV infection often have functional abnormalities of their Bcell-mediated immune system that place them at risk for infections that require an intact humoral response system. Although most children with HIV infection have elevated immunoglobulin levels, this is believed to represent nonspecific polyclonal B-cell activation. Many children fail to mount an antibody response to routine childhood immunizations (50), indicating a functional immunodeficiency. The National Institute of Child Health and Human Development (NICHD) completed a placebo-controlled

HIV Infection in Children 399 trial using IVIG in HIV-infected children. This trial was completed prior to the availability of HAART therapy. The trial found that IVIG prolonged the time free from serious laboratory-proven bacterial or clinically diagnosed serious or minor bacterial and viral infections in symptomatic HIV-infected children with CD4 counts greater than 200 (85,86). Unfortunately, this trial did not separately evaluate the efficacy in children with documented B-cell defects but looked only at groups based on CD4 counts. Based on clinical experience in treating children with humoral immunodeficiency and HIV with IVIG and the results of the above reports, a group of pediatric HIV specialists agreed that IVIG should be considered for use in HIV-infected children with the following conditions: (a) evidence of humoral immunodeficiency as defined by severe recurrent bacterial infections, hypogammaglobulinemia, poor functional antibody responses to documented infections or a lack of response to immunizations; (b) thrombocytopenia; or (c) chronic bronchiectasis (87).

Childhood Immunizations Immunizations represent the cornerstone of preventive medicine for children. The recommended childhood immunization schedule of the Advisory Committee on Immunization Practices and the American Academy of Pediatrics should be used in HIV-infected children with the following alterations. Paralytic poliomyelitis is a potential complication of the oral polio vaccine (OPV) for both the immunocompromised patient and the immunocompromised family members through virus excreted in stool. Use of inactivated polio vaccine (IPV) instead of OPV is recommended for HIV-infected infants and children as well as uninfected infants and children living in households with infected adults. In the early years of the HIV epidemic, infected children in the U.S. received both primary and booster doses of oral polio vaccine without complications, and in developing countries OPV is still considered standard of care for all children. The measles mumps rubella vaccine is a live attenuated viral vaccine given between 12–15 months of age, with a booster at four to six years of age. In areas where there is a high prevalence of measles it may be given as young as six months of age. There has been one reported case of measles pneumonitis following measles, mumps, and rubella vaccine (MMR) in a severely immunocompromised 20-year-old HIV-infected man. Although the use of MMR is recommended for most HIV-infected children, the CDC currently recommends considering withholding MMR in severely immunocompromised HIV-infected children (88). The Advisory Committee on Immunization Practices (ACIP) recommends that the varicella vaccine be considered for asymptomatic or mildly symptomatic HIV-infected children, with an age specific CD4 T lymphocyte percentage greater than 25% (89,90). The

vaccine should be administered in two doses with a threemonth interval between the doses. It is strongly recommended for HIV negative siblings and household members of HIV-infected individuals. Susceptible children with HIV infection exposed to varicella should be considered for passive immunization with varicella-zoster immune globulin. If a child has received IVIG within three weeks before the exposure, then VZIG is not necessary. A yearly influenza vaccine is recommended for infants and children with HIV infection who are over six months of age. Children less than nine years of age who have never received the vaccine should be given two doses, one month apart. For children previously immunized, one dose per year is sufficient. The newly licensed pneumococcal conjugate vaccine should be given to all HIV-infected infants and young children as per ACIP guidelines. A clinical trial is underway evaluating this vaccine in HIV-infected children over the age of two years. However, current recommendations are to give the pneumococcal polysaccharide vaccine every 5 years in HIV-infected children. Other vaccines such as hepatitis B, pertussis, tetanus and H. influenzae type B are the same as for noninfected children. Bacillus Calmette-Guerin (BCG) is a live attenuated vaccine and is contraindicated for children with HIV living in the U.S. The World Health Organization has continued to recommend this vaccine to be given at birth to children living in countries with a high prevalence of tuberculosis. NUTRITIONAL ISSUES IN CHILDREN WITH HIV INFECTION Pediatric HIV infection frequently results in nutritional deficiencies and growth failure. Weight loss and failure to gain weight can occur as early as the first four months of life as well as in children who become symptomatic at an older age. Failure to thrive and malnutrition are due to a number of factors, including (a) decreased intake resulting from oral and gastrointestinal pathology that cause nausea, anorexia, pain, and deceased taste as well as neurological complications that result in ineffective swallowing mechanisms; (b) impaired absorption resulting from HIV-related enteropathy and gastrointestinal infections; (c) increased metabolic requirements secondary to the chronic HIVrelated inflammatory illness; and (d) decreased intake resulting from side effects and toxicities (such as nausea, anorexia, vomiting, hepatitis, and pancreatitis) of various medications used to treat HIV infection and its complications. Particularly in children in end-stage disease, it is important for the clinician to consider these adverse reactions within the risk-to-benefit ratio of therapy with a specific agent. These physical complications of HIV infection further contribute to the marginal nutritional balance frequently seen in children living in communities affected by poverty. Besides protein and caloric deficiencies, a number of trace element and vitamin

400 Chapter 15 deficiencies may complicate the clinical course of HIV infection (91). Specific nutritional deficiencies of selenium, iron, zinc, vitamin B6, vitamin A, and vitamin E may result in neurological or cardiac abnormalities and contribute to the rashes and cytopenias commonly seen in HIV infection. In young infants, when CNS growth is still occurring, nutritional deficiencies may have profound long-term effects. Based on these factors, there should be an aggressive approach to nutritional support for HIV-infected infants and children that includes (a) proactive nutritional assessment including anthropomorphic measurements and dietary intake history with each physician visit and periodic selected laboratory parameter monitoring; (b) diagnosis and treatment of oral-gastrointestinal disease, with special attention to pain management; and (c) aggressive replacement and nutritional supplementation beginning with oral supplementation and progressing as necessary to nasogastric/gastrostomy tube feeding and in advanced disease with malabsorption to total parenteral hyperalimentation. Nutritional care of HIV-infected children needs to receive the attention of the research community as well as those providing direct care. Recently physicians have started evaluating the use of gastrostomy tubes for administration of both medication and food supplementation (92).

DRUG TOXICITIES One of the emerging new syndromes arising from HIV and its treatment is that of lipodystrophy (93). This syndrome, initially thought to be exclusively associated with protease inhibitor therapy, can now be seen with all classes of antiretrovirals. Common signs include extremity fat wasting and excessive deposition of fat on back and trunk. Common metabolic abnormalities include insulin resistance, elevated cholesterol, triglycerides, and abnormal bone metabolism (94).

has been suggested (95). These toxicities may be of particular concern for pregnant women and infants with in utero exposure to nucleoside analogue drugs. Clinical disorders linked to mitochondrial toxicity include neuropathy, myopathy, cardiomyopathy, pancreatitis, hepatic steatosis, and lactic acidosis. Among these disorders, symptomatic lactic acidosis and hepatic steatosis may have a female preponderance (97). These syndromes have similarities to the rare but life-threatening syndromes of acute fatty liver of pregnancy, and hemolysis, elevated liver enzymes and low platelets (the HELLP syndrome) that occur during the third trimester of pregnancy. A number of investigators have correlated these pregnancy-related disorders with a recessively-inherited mitochondrial abnormality in the fetus/infant that results in an inability to oxidize fatty acids (98,99). Since the mother would be a heterozygotic carrier of the abnormal gene, there may be an increased risk of liver toxicity due to an inability to properly oxidize both maternal and accumulating fetal fatty acids (100). Lactic acidosis with microvacuolar hepatic steatosis is a toxicity related to nucleoside analogue drugs that is thought to be related to mitochondrial toxicity; it has been reported in infected individuals treated with nucleoside analogue drugs for long periods of time (more than six months). Initially, most cases were associated with ZDV, but subsequently other nucleoside analogue drugs have been associated with the syndrome, particularly d4T. In a report from the FDA Spontaneous Adverse Event Program of 106 individuals with this syndrome (60 patients receiving combination and 46 receiving single nucleoside analogue therapy), typical initial symptoms included one to six weeks of nausea, vomiting, abdominal pain, dyspnea, and weakness (97). Metabolic acidosis with elevated serum lactate and elevated hepatic enzymes was common. Patients in this report were predominantly female gender and high body weight. The incidence of this syndrome may be increasing, possibly due to increased use of combination nucleoside analogue therapy or increased recognition of the syndrome.

Nucleoside Analogs PAIN MANAGEMENT Nucleoside analogue drugs are known to induce mitochondrial dysfunction, as these drugs have varying affinity for mitochondrial gamma DNA polymerase. This affinity can result in interference with mitochondrial replication, resulting in mitochondrial DNA depletion and dysfunction (95). The relative potency of the nucleosides in inhibiting mitochondrial gamma DNA polymerase in vitro is highest for zalcitabine (ddC), followed by didanosine (ddI), stavudine (d4T), lamivudine (3TC), zidovudine (ZDV) and abacavir (ABC) (96). Toxicity related to mitochondrial dysfunction has been reported in infected patients receiving long-term treatment with nucleoside analogues, and generally has resolved with discontinuation of the drug or drugs; a possible genetic susceptibility to these toxicities

Pain management is an especially important but frequently undertreated clinical problem in HIV-infected infants. The prevalence of pain in adults with AIDS ranges from 40–60%, depending on the stage of illness (101). Physicians in general are poorly trained in the control of pain by medication, and many do not appreciate that newborns and infants experience pain. Whereas many fear they will make their patients drug addicts, only 0.4% of patients given narcotics in hospitals ever have a problem with opiate dependence. A much more aggressive approach must be taken to controlling pain in children. Specific barriers to management of pain in HIV-infected children include: (a) the

HIV Infection in Children 401 difficulty of assessing pain in young children; (b) the difficulty of assessing pain in children with neurological impairment; (c) parental denial of their children’s disease; (d) resistance to the use of narcotics by families who have a history of drug use; and (e) resistance by clinicians to treat pain in children because of myths like the following: Children lie about pain to get attention; if children deny pain or do not complain, they are not in pain; and children who can fall asleep or who can play cannot be in pain. Vigorous and proactive use (preferably before the onset of anticipated pain) of appropriate pain medications using weight-adjust dosages, including aspirin, acetaminophen, codeine, ibuprofen, morphine, and methadone, is essential to the overall quality of life for HIV-infected children. The use of EMLA cream as a local anesthetic for blood drawing can make the difference between an agonizing or enjoyable visit to the doctor for a child with chronic illness. Nonpharmacological approaches to pain management (including relaxation, hypnosis, play therapy, visualization, and distraction) also should be applied in pain control, especially when the pain is related to procedures. ADHERENCE Rates of adherence (102) to antiretroviral therapy have been correlated with virologic success. There is considerable interest in clinical strategies to promote improved adherence (Table 15.4). Interventions have included scripted telephone reminder calls, once daily versus twice daily therapies, directly observed therapy (DOT), and reminders via alarm watches. Unfortunately, none has been remarkably successful. Often individuals with worst adherence discontinue therapy sooner than more adherent patients, resulting in less resistance among poorly compliant patients and increased resistance in partially compliant patients (103). Adherence in young children TABLE 15.4. Factors affecting adherence • • • • • • • •

Availability of liquid product vs. pills Quantity (volume) of therapy Frequency (qd, bid, tid, qid) Ability to swallow pills/soft gel caps Taken with or without food, acidity Storage (e.g. refrigeration) Disclosure Psychosocial factors  Parental health  Parental treatment  Parental perception of antiretroviral therapy  Child’s development stage  Belief that medications are beneficial  Reliability of a parent/guardian  Foster care/consent  School/day care  Reputation of therapy in community  Medical provider accessibility

depends on the child’s care provider administering the medications. This can be especially difficult if the medications are bad tasting or smelling, must be given constantly during the day, have large volumes, or cannot be taken with food. This may be compounded by the care providers needs if they are also HIV-infected (104).

SOCIAL ISSUES IN THE DELIVERY OF CARE The conditions of poverty, including inadequate housing, may interfere with the delivery of optimal health care. Typically, mothers are the strongest advocates for their children, but this advocacy may be hindered by the fact that mothers of HIV-infected children are often single parents and poor (105). In some cases, symptomatic HIV infection or drug use may interfere with a mother’s ability to care properly for her child; more often, however, mothers are assertive in seeking care for their children while neglecting their own needs (106). The general shortage of openings in drug treatment programs is especially severe for women who are HIV infected, pregnant, or have children. All these socioeconomic conditions must be addressed in designing effective health care systems for families with HIV infection. Families also can benefit from psychosocial support in dealing with many aspects of an HIV diagnosis in a child. The diagnosis may be the first evidence that a parent is infected and may give rise to guilt or anger, leading to further disruption of the family unit. Apparently resolved emotional issues may require periodic reexamination, as, for example, when parents are confronted repeatedly by the differences between a child who is developmentally delayed and healthy peers. Decisions about the disclosure of an HIV diagnosis may arise on multiple occasions as different audiences are encountered such as family, friends, siblings of the infected child, the child himself or herself, day-care workers, school nurses, and teachers (107). Many parents choose to disclose the diagnosis on a need-to-know basis; however, children and their siblings often find it less stressful to know the diagnosis than to be left in the dark about something unnamed but apparent. Counseling may help parents decide whether and how to disclose the diagnosis, which should be done in a developmentally appropriate way. Clinical experience suggests that under the proper circumstances it is beneficial for children with normal cognitive development to have the opportunity to discuss aspects of their illness with trusted adults. The issue of disclosure of diagnosis is particularly pressing because perinatally infected children live into mid and late adolescence. In a cohort of 42 perinatally infected children aged nine through 16 years followed at CHAP, Newark, NJ, fewer than 60% were specifically told their diagnosis. Uninfected but HIVaffected siblings often have mental health needs as well, especially when they face the eventual loss of siblings and one or both parents. A failure to deal successfully with

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psychosocial issues may impede families from seeking optimal medical care for their children.

CHALLENGE OF HIV INFECTION IN ADOLESCENTS Like other HIV-infected persons, adolescents with HIV infection come disproportionately from minority communities. As a group, adolescents are at high risk of acquiring HIV by nature of their developmental stage. The Agency for Health Care Policy and Research guidelines on Evaluation and Management of Early HIV Infection details the unique set of issues in caring for adolescents with HIV infection. These include: (a) differences in the epidemiology of HIV infection among youth; (b) special barriers to youth both in receiving care for their HIV infection and in prevention services, including counseling and testing, resulting from variable laws regarding consent and confidentiality for those aged under 18 years; (c) lack of HIV-specific clinical services for adolescents; and (d) the limitation on youths participating in clinical trials. One of the major challenges facing those caring for adolescents is the prevention of HIV transmission, both primary and secondary. In general, preventive programs have relied on incomplete or limited information services not linked to care or programs that teach and encourage behavior change. Successful adolescent HIV programs have employed voluntary, confidential, or anonymous counseling and HIV testing with direct linkage to adolescent specific care. Although specifics of medical management of HIV-infected adolescents, in terms of medication use and disease assessment, are similar to those used for adults, many aspects do differ from that which is appropriate for children and adults. The history and physical examination need to be interpreted in the context of age-specific differences and pubertal stage. Historytaking from adolescents needs to detail sexual and drug-using behavior, recognizing the psychosocial and cognitive-developmental stage that may influence the accuracy of the information obtained, and incorporate counseling and coping mechanisms employed by the adolescents. There should be an awareness of the potential for other sexually transmitted diseases. Issues relating to treatment adherence are especially important in caring for adolescents. Of interest are recent data suggesting that perinatally infected adolescents may also exhibit delay in pubertal development, not related to clinical or immunologic conditions or antiretroviral therapy (108). Perhaps most importantly, services for adolescents need to be provided by an experienced physician comfortable in dealing with youth and issues of adolescent sexuality within the context of a developmentally appropriate environment.

DEVELOPING STANDARDS OF CARE FOR CHILDREN WITH HIV Twenty years ago, 95% of children with leukemia died; today, up to 85% are cured. The intensity of effort put into controlling childhood leukemia should serve as a template for our efforts to treat HIV-infected children. Efforts to improve quality of life while working toward a cure for HIV will require a multidisciplinary approach, calling on the skills of physicians, nurses, social workers, nutritionists, pharmacists, dentists, and developmental specialists. This effort must take the child’s entire family into consideration, whether it is the family of birth or a foster family. At most large HIV centers a team approach to the child and the child’s family has resulted in better communication, compliance and better management of children with HIV infection. Team members may include clinicians, nurse and nurse practitioners, psychologists, social workers, nutritionists and dental hygienists. This family centered team approach may be even more necessary in the future with the aging into adolescence of the majority of perinatally HIV-infected children.

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