7
Concepts Specific to Children With HIV/AIDS

HIV infection in children is given unique consideration in practice and research due to the distinct ways the virus is transmitted and how therapy affects the maturing body. The majority of children with HIV infection were infected by their mother via perinatal transmission during pregnancy or delivery, or postpartum through breastfeeding. Perinatal transmission was first recognized in 1985. The number of new cases increased steadily until its peak in the early 1990s. The identification of HIV infection during pregnancy and use of antiretroviral therapy during pregnancy and postpartum to the infant specifically to reduce transmission has been a remarkable success in preventing new HIV infections in children. Through aggressive testing and prophylaxis implementation, the incidence of perinatal HIV infection declined throughout the 2000s. In 2007, the estimated number of new HIV infections among children under age 13 in the 34 states and 5 territories with name-based reporting was 159, a decline from 2004 of 25 percent (CDC, 2009). However, because of increased survival of perinatally infected children, in 2007, nearly 15,500 U.S. children under age 13 lived in the United States (CDC, 2009).

Prior to the availability of antiretroviral therapy, many perinatally infected infants died before their second birthday. As noted below, survival is now markedly improved and many perinatally infected children are aging into adolescence and young adulthood. Understanding of the consequences of early HIV infection in this population is a rapidly evolving field and is the main focus of the majority of current research in pediatric HIV. Consideration of disabilities in this population will need ongoing review to take advantage of new information and findings as they become available.



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7 Concepts Specific to Children With HIV/AIDS HIV infection in children is given unique consideration in practice and research due to the distinct ways the virus is transmitted and how therapy affects the maturing body. The majority of children with HIV infection were infected by their mother via perinatal transmission during pregnancy or delivery, or postpartum through breastfeeding. Perinatal transmission was first recognized in 1985. The number of new cases increased steadily until its peak in the early 1990s. The identification of HIV infection during pregnancy and use of antiretroviral therapy during pregnancy and postpar- tum to the infant specifically to reduce transmission has been a remarkable success in preventing new HIV infections in children. Through aggressive testing and prophylaxis implementation, the incidence of perinatal HIV infection declined throughout the 2000s. In 2007, the estimated number of new HIV infections among children under age 13 in the 34 states and 5 territories with name-based reporting was 159, a decline from 2004 of 25 percent (CDC, 2009). However, because of increased survival of perinatally infected children, in 2007, nearly 15,500 U.S. children under age 13 lived in the United States (CDC, 2009). Prior to the availability of antiretroviral therapy, many perinatally in- fected infants died before their second birthday. As noted below, survival is now markedly improved and many perinatally infected children are aging into adolescence and young adulthood. Understanding of the consequences of early HIV infection in this population is a rapidly evolving field and is the main focus of the majority of current research in pediatric HIV. Con- sideration of disabilities in this population will need ongoing review to take advantage of new information and findings as they become available. 

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 HIV AND DISABILITY SURVIVAL AND PROGNOSIS Children have benefited from advances in treatment in the same pat- terns as adults. The Pediatric Spectrum of Disease Cohort has clearly dem- onstrated this improvement as a function of birth year and correlates with the available antiretroviral treatments. Clinical trials to approve antiretrovi- rals for children were on a delayed timetable compared to adults. By 1994, most children were on a therapy regimen of one or two antiretrovirals. In 1997, combination antiretroviral therapy of two or three drugs, usually including a protease inhibitor, became standard. The birth cohort of 1997 to 2001 had a significantly higher survival than earlier birth cohorts. The benefits of combination antiretroviral therapy beyond reduced mortality include improved functioning of the immune system and reduced complica- tions from comorbid and opportunistic disease (McConnell et al., 2005). Because of reductions in new infections and improvements in therapy leading to improved survival for infected infants and children, the median age of surviving perinatally infected children was 14.8 years in 2007 and continues to increase. Additionally, the median age of death has increased from 7.2 years in 1994 to 18.2 years in 2006 (Patel et al., 2008). Successful antiretroviral therapy in young infants and children is chal- lenged by the limited number of agents available as a liquid or powder for- mulation. Liquid formulations can also require special storage conditions and are often unpalatable. Children with HIV infection have benefited from legislation aimed at expanding available agents for children. Many new agents are being used in children a little over one year from the date they become available for use in adults. Despite these successes, perinatally infected children who are aging up into adolescence are challenged by decreasing options for therapy. Many of these children received each new antiretroviral when it became available and had sequential courses of mono or dual therapy, resulting in the pres- ence of multiple resistance mutations, especially to the nucleoside reverse transcriptase inhibitor class of agents. These resistance mutations often necessitate the use of complex regimens that further challenge medication adherence (Rakhmanina et al., 2008). Complications of Perinatal HIV in Growing Children and Adolescents Although antiretroviral treatment improves prognosis, complications associated with HIV infection and its treatments may occur. Complications include growth abnormalities, developmental and pubertal delay, abnormal metabolic profiles and fat distribution, decreased bone mineral density, and increased mental health disorders. Furthermore, as these perinatally infected children age into adolescence and young adulthood and become

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 CONCEPTS SPECIFIC TO CHILDREN WITH HIV/AIDS sexually active, they are at risk of sexually transmitted diseases and preg- nancy. Aside from the increased risk of resistance mutations necessitating more complex antiretroviral regimens, few data are available to detect differences in these complications between birth cohorts that received se- quential therapy and those that benefited from combination antiretroviral therapy soon after birth. Growth Delayed growth was a common finding in perinatally infected children who were documented to have lower Z scores for health and weight com- pared to normal values. Slower growth in these children was associated with higher HIV viral loads. With the availability of combination antiret- roviral regimens, there were small improvements in height and weight Z scores demonstrated in the PACTG 219C and other international cohorts (Buchacz et al., 2001; Hirschfeld, 1996; Steiner et al., 2001; Verweel et al., 2002). Not surprisingly, the children who demonstrated virologic suppres- sion had better gains than the ones who did not. In addition to delayed growth, delayed pubertal development has also been reported. Puberty was delayed in HIV-infected girls by 21 months and boys by 15 months. Children with more severe immunosuppression were more likely to experience delayed puberty (Buchacz et al., 2003; de Martino et al., 2001). Similar to adults with HIV infection, perinatally infected children can also develop lipoatrophy or lipohypertrophy, or a combination of both. These abnormalities can occur in 10 to 33 percent of children and adoles- cents and can be associated with increases in cholesterol, triglycerides, and insulin resistance. Fat redistribution often becomes apparent during puberty (Aurpibul et al., 2007; Carter et al., 2006; Ene et al., 2007; Lapphra et al., 2005; Rosso et al., 2007; Taylor et al., 2004; Verkauskiene et al., 2006). The physical appearance of perinatally infected children can be in- fluenced by these aberrations in growth, pubertal development, and fat distribution. Because early adolescent development is characterized by the rapid physiologic body changes of puberty with a heightened awareness of their body image and concern for physical attraction, perinatally infected children may have altered self-images. Metabolic Metabolic abnormalities in cholesterol, triglycerides, and insulin that may have long-term effects on cardiac health also have been observed in perinatally HIV-infected children. Abnormal lipid profiles have been re- ported in 13 to 83 percent of children and are more frequent with the use

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0 HIV AND DISABILITY of protease inhibitors and greater with the use of boosted protease inhibi- tors. This also occurs in children at a younger age and those who are more adherent and have undetectable viral loads (Tassiopoulos et al., 2008). In- sulin resistance has been reported in up to 13 percent and hyperinsulinemia in 60 percent (Carter et al., 2006; Ergun-Longmire et al., 2006; Farley et al., 2005; Lapphra et al., 2005). In addition to metabolic abnormalities, at least three studies have now shown increased intima medial thickness in the carotids of HIV-infected children and adolescents. Older age, protease inhibitor therapy, and duration of antiretroviral therapy appear to increase the risk; however, there was no association with lipid abnormalities or diet. Elevations of inflammatory markers have also been seen (Charakida et al., 2005; Giuliano et al., 2008; McComsey et al., 2007). Taken together, these findings may implicate significant cardiac abnormalities and risk for earlier cardiac disease in this population. Neurologic Neurological manifestations of HIV infections are seen more frequently in children than in adults. In the early years of the epidemic, 50 to 90 percent of HIV-infected children showed signs of progressive central nervous system disorders (Lindsey et al., 2007; Singh et al., 2010), which include HIV- associated encephalopathy manifested by limitations in cognitive, language, motor, and behavior functioning. Children can experience delayed acquisi- tion of new developmental milestones or rapid loss of previously attained milestones. Motor abnormalities include hypertonicity, which results in ab- normally rigid muscle tone, and hyperreflexia, which are overactive or over- responsive reflexes. The presence of neurologic symptoms can contribute to disability in children by affecting the main domains of childhood functional equivalence recognized by the Social Security Administration—acquiring and using information; attending and completing tasks; interacting and relating with others; moving about and manipulating objects; caring for yourself; and maintaining health and physical well-being. The institution of antiretroviral therapy has resulted in significant improvements in neurologic findings (Faye et al., 2004; Pizzo et al., 1988). Because neurodevelopment is most rapid in the early years of life, earlier HIV treatment may reduce HIV encephalopathy. In the French Perinatal Cohort, HIV-infected infants receiving combination antiretroviral therapy before age 6 months had less encephalopathy compared with those for whom this therapy was initiated after age 6 months (Faye et al., 2004). Developmental testing has been performed in a subset of the Children with HIV Early Antiretroviral Therapy trial in South Africa. In this clinical trial, HIV-infected infants were randomized to early (beginning within the first 12 weeks of life) as compared to delayed (beginning with clinical or

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 CONCEPTS SPECIFIC TO CHILDREN WITH HIV/AIDS CD4 indications) combination antiretroviral therapy. Infants in the early therapy group had improved overall and locomotor scores using the Griffiths Mental Development test compared to the delayed group (Laughton et al., 2009). Even in the era of combination antiretroviral therapy, neurological manifestations still present serious challenges for children. Adherence and Behavioral Challenges As previously discussed, treatment adherence is a challenge among HIV-infected populations, and is problematic because of the potential of viral mutations resulting in resistance to antiretrovirals. Although children share many of the structural and social barriers to adherence as adults, ad- herence can be particularly challenging in children due to (1) the frequency of doses or (2) the number of pills to administer per dose, which can cre- ate a burden on caregivers who are responsible for ensuring very young children receive their treatment. Furthermore, the treatments available in liquid form are often not palatable. In addition, many perinatally infected children aging into adolescence demonstrate independence and rebellion via nonadherence. Other behavioral issues associated with adolescence, including sexual debut, have been studied in perinatally infected children. Surprisingly, in one U.S. study, 40 percent of perinatally infected youth ages 9 to 16 re- ported having unprotected sex (Mellins et al., 2009). Pregnancies have also begun to occur in perinatally infected young women. In the PACTG 219C cohort, 38 of 638 girls became pregnant (6 percent, first pregnancy rate of 18.8/1,000 person years). Thirty-two of these resulted in live births; 29 were HIV uninfected, 1 was HIV infected, and 2 were of unknown status (Brogly et al., 2007). There is a growing body of literature examining the mental health status of perinatally HIV-infected children. However, isolating the role of HIV infection remains difficult because many of the risk factors associated with mental health disorders overlap with those for HIV (e.g., poverty, disrupted home life, history of mental illness, substance abuse) (Jeremy et al., 2005). Rigorous study designs using validated instruments are just beginning to become available. Mellins et al. (2009) have demonstrated that infected children have greater risk of developing any psychiatric con- dition, predominantly attention deficit hyperactivity disorder, compared to uninfected control subjects. No differences in risk for developing anxiety or mood disorders or substance abuse were observed. The presence of a mental health disorder was associated with sex and drug use risk behaviors. The use of psychotropic medications is common in HIV-infected youth, with ap- proximately one third receiving some medications in 2003, most commonly antidepressants, stimulants, and antipsychotics (Wiener et al., 2006).

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 HIV AND DISABILITY It is now becoming necessary to transition aging up youth to adult care providers. As with many chronic diseases, this can be challenging due to reluctance to leave pediatric and adolescent clinics. Successful transitioning necessitates initiating discussion long before the move occurs and creating an individualized plan. Independence must be encouraged and facilitated, and adolescents need to be educated about their disease state and how to maneu- ver adult health care systems. A successful transition has the fewest “gaps” in services and results in no decline in HIV-disease status (Judd et al., 2007; Spiegel and Futterman, 2009; Vijayan et al., 2009; Wiener et al., 2007). RATIONALE FOR LISTING RECOMMENDATIONS FOR PEDIATRIC PATIENTS Children receiving benefits under Part B (114.08) are required to be reviewed under Part A (14.08) when they reach age 18. Given that many adolescents will be transitioning to adult care around this time, it is es- pecially critical for comprehensive records to be available for disability reassessment. If not readily available, records should be sought from both current and previous providers. To allow for a smooth transition, the committee recommends that the listing specific to children should follow as closely as possible to the Listing in Part A of the SSA Listing of Impairments. RECOMMENDATION 6. SSA should ensure that the HIV Infection Listings in Parts A and B of the SSA Listing of Impairments are con- structed similarly. However, conditions specific to children not found in adults should also be listed in Part B, including age-appropriate CD4 and developmental criteria, neurological manifestations of HIV infec- tion, and HIV-related growth disturbance. Listings Based on Age-Specific CD4 Criteria As discussed in Chapter 3, CD4 count has a strong relationship with out- comes in adults. Based on these findings, the committee has recommended a listing based on CD4 count in adults. Similarly, outcome measures such as CD4 count and percentage, viral load, and number of hospitalizations help to characterize morbidity associated with HIV infection in children. The significance of prognostic measures differs in pediatric patients from those of adults. CD4 count and percentage in healthy, non-HIV-infected infants and young children are significantly higher than those observed in non- HIV-infected adults. As children mature, CD4 counts fluctuate irregularly, slowly declining to correspond with adult values by the time children reach age 5 (Working Group on Antiretroviral Therapy, 2009). Accordingly, CD4

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 CONCEPTS SPECIFIC TO CHILDREN WITH HIV/AIDS percentage has been most often used as a valid predictive value of a growing child’s immune status. The HIV Pediatric Prognostic Markers Collabora- tive Study assessed laboratory and clinical data from 3,941 HIV-infected children and demonstrated the prognostic value of CD4 percentage and HIV RNA copy number. As in adults, as CD4 declined, there was evidence of HIV progression (Dunn, 2003). Although HIV RNA copy number was also predictive of HIV progression, it was not as strong a predictor as CD4 percentage. This group also studied the predictive value of CD4 count for disease progression and found that patterns in children ages 4 to 5 or older were similar to that observed in adults (HIV Paediatric Prognostic Markers Collaborative Study, 2006). Because of the differences in CD4 count and percentage and prognosis between children and adults, Recommendation 1 for adults needs to be modified for children. It is desirable to keep the recommendation as similar as possible, and documentation should be easily abstracted from the medi- cal record. Count, percentage, or both may be available in medical records, but research indicates CD4 percentage has little or no prognostic value over and above that of CD4 count (Dunn, 2010). Thus, even though the pediat- ric guidelines emphasize there is stronger predictability using CD4 percent- age in children less than age 4 (Working Group on Antiretroviral Therapy, 2009), CD4 count may be more acceptable at any age (Dunn, 2010). Based on approximate equivalency for the various age groups for HIV disease progression and death, the committee recommends the age-specific CD4 count and percentage criteria for children depicted in Table 7-1 (Dunn, 2010; Dunn et al., 2008). As in adults, the committee believes claimants allowed under such a listing should be reevaluated periodically for disability status in accordance with the usual SSA process. Imminently Fatal or Severely Disabling HIV-Associated Conditions The specific conditions listed in Recommendation 2 in Chapter 4 (HIV- associated dementia, multicentric Castleman’s disease, Kaposi’s sarcoma TABLE 7-1 Proposed Disabling CD4 Count Ranges for Children Suggested CD4 Suggested CD4 Age Range Count Percentage ≤ 500 cells/mm3 < 1 year < 15 percent ≤ 200 cells/mm3 1–5 years < 15 percent ≤ 50 cells/mm3 > 5 years N/A NOTE: N/A = not applicable.

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4 HIV AND DISABILITY involving the pulmonary parenchyma, primary central nervous system lym- phomas, primary effusion lymphoma, and progressive multifocal leukoen- cephalopathy) are rare in children, but have been reported. Accordingly, a similar listing should be included in the pediatric HIV Infection Listing. Modifications should include the replacement of HIV-associated dementia with the current listing for neurological manifestations of HIV infection (currently 114.08G). Even in the era of combination antiretroviral therapy, neurological manifestations still present serious challenges for children. Therefore, neurological manifestations in children and adolescents should be maintained under Part B. The presence of neurological manifestations in children serves as an indicator of disease severity and progression resulting in higher mortality rates among those children who have been diagnosed with early onset (Mitchell, 2001). Neurological manifestations can be char- acterized by the following: • Impaired brain growth. Impaired brain growth is the decrease in serial measurements of head circumference velocity and is typically seen in children under age 2 (Mintz, 1996). This condition can lead to microcephaly or brain atrophy. Older children who develop impaired brain growth do so at a slower rate, and it is similar to that seen in adults (Mitchell, 2001). • Progressie motor dysfunction. Progressive motor dysfunction is when motor milestones are not achieved. It is possible to have once attained these milestones, but lose the ability to perform them, resulting in the impairment of fine and gross motor skills (Mintz, 1996). • Loss of preiously acquired or delay of deelopmental milestones and intellectual ability. This is the plateau of acquisition or a re- gression of age-appropriate neurodevelopmental milestones, which can be standard developmental scales or neuropsychological tests. Such loss is often seen more in school-age children, thus labeling them as “at risk” (Mitchell, 2001). In addition, growth development is an important indicator of children’s health and is seen as one of the most sensitive indicators of disease pro- gression (Hirschfeld, 1996). Growth disturbance or failure to grow has been associated with rapid progression from asymptomatic HIV infection to AIDS in children, thus leading to shorter survival (Baylor International Pediatric AIDS Initiative, 2010). As a result, the committee concluded that the current listing for growth disturbance (currently 114.08H) should be retained in Part B.

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 CONCEPTS SPECIFIC TO CHILDREN WITH HIV/AIDS HIV-Associated Comorbidities Currently Without Listings Similar to adults, many of these comorbidities also occur in children, including those related to HIV infection itself and to medications used to treat HIV. Because of these similarities, the committee recommends a paral- lel listing for children. However, the listing should be modified to remove HIV-associated wasting syndrome and neurocognitive disorder, which are similar to the current listings 114.08F and 114.08G and recommended to be retained as discussed above. In addition, functional assessments in children must be age and developmentally appropriate. The listing in Part B would therefore include the following conditions: • Diarrhea; • Distal sensory polyneuropathy; • Kaposi’s sarcoma; • Lipoatrophy or lipohypertrophy; and • Osteoporosis. Recommendation 4 in adults, which focuses on comorbidities, should be modified to replace activities of daily living, maintenance of social func- tioning, and completion of tasks in a timely manner with current Part B listings that address developmental and emotional disorders of newborn and younger infants (currently paragraphs A–E of 112.12) and organic mental disorders (currently paragraphs B1–2 of 112.02). HIV-Associated Comorbidities Currently With Listings While the conditions contained in Recommendation 5 are not common in children (cardiovascular disease, chronic kidney disease, diabetes, hepa- titis, and malignancies), they do occur and may become more evident as perinatally infected children continue to age. Additionally, there are current pediatric listings for these conditions that would be applicable. Therefore, the committee recommends that Recommendation 5 should also apply to the Part B HIV Infection Listing. Lymphocytic Interstitial Pneumonia/Pulmonary Lymphoid Hyperplasia Complex The committee decided the lymphoid interstitial pneumonia/pulmonary lymphoid hyperplasia complex (current 114.08J) should be removed from the HIV Infection Listing. Lymphocytic interstitial pneumonia/pulmonary lymphoid hyperplasia complex is an HIV-associated disease with no known etiology. It was commonly observed in HIV-infected children before the

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 HIV AND DISABILITY availability of combination antiretroviral therapy. In 1987, the Centers for Disease Control and Prevention (CDC) classified lymphocytic interstitial pneumonia/pulmonary lymphoid hyperplasia complex as a category C (se- verely symptomatic) AIDS-defining illness in children (Lynch et al., 2001). However, studies have since shown that it is not associated with shorter survival in HIV-infected children and that the presence of lymphocytic in- terstitial pneumonia/pulmonary lymphoid hyperplasia complex is actually seen as having improved the survival rates (de Martino et al., 1991; Lynch et al., 2001). This finding has prompted changes to the way the complex is considered. For example, in 1994 the CDC redefined the classification as a category B (moderately symptomatic) AIDS-defining illness in children (CDC, 1994). REFERENCES Aurpibul, L., T. Puthanakit, B. Lee, A. Mangklabruks, T. Sirisanthana, and V. Sirisanthana. 2007. Lipodystrophy and metabolic changes in HIV-infected children on non-nucleoside reverse transcriptase inhibitor-based antiretroviral therapy. Antiiral Therapy 12(8): 1247–1254. Baylor International Pediatric AIDS Initiative. 2010. In HIV curriculum for the health pro- fessional, edited by G. Waggonner. Houston, TX: Baylor College of Medicine. http:// bayloraids.org/curriculum/files/complete_highres.pdf (accessed April 20, 2010). Brogly, S. B., D. H. Watts, N. Ylitalo, E. L. Franco, G. R. Seage III, J. Oleske, M. Eagle, and R. Van Dyke. 2007. Reproductive health of adolescent girls perinatally infected with HIV. American Journal of Public Health 97(6):1047–1052. Buchacz, K., J. S. Cervia, J. C. Lindsey, M. D. Hughes, G. R. Seage III, W. M. Dankner, J. M. Oleske, and J. Moye. 2001. Impact of protease inhibitor-containing combination antiretroviral therapies on height and weight growth in HIV-infected children. Pediatrics 108(4):e72. Buchacz, K., A. D. Rogol, J. C. Lindsey, C. M. Wilson, M. D. Hughes, G. R. Seage III, J. M. Oleske, A. S. Rogers, and the Pediatric AIDS Clinical Trials Group 219 Study Team. 2003. Delayed onset of pubertal development in children and adolescents with perinatally acquired HIV infection. Journal of Acquired Immune Deficiency Syndromes 33(1):56–65. Carter, R. J., J. Wiener, E. J. Abrams, J. Farley, S. Nesheim, P. Palumbo, and M. Bulterys for the Perinatal AIDS Collaborative Transmission Study—HIV Follow-up after Perinatal Exposure Group. 2006. Dyslipidemia among perinatally HIV-infected children enrolled in the PACTS-HOPE cohort, 1999–2004: A longitudinal analysis. Journal of Acquired Immune Deficiency Syndromes 41(4):453–460. CDC (Centers for Disease Control and Prevention). 1994. Revised classification system for HIV-infection in children less than 13 years of age. Morbidity and Mortality Weekly Report 43:1–10. CDC. 2009. Cases of HIV Infection and AIDS in the United States and Dependent Areas, 00, Table . http://www.cdc.gov/hiv/topics/surveillance/resources/reports/2007report/ pdf/table1.pdf (accessed May 7, 2010). Charakida, M., A. E. Donald, H. Green, C. Storry, M. Clapson, M. Caslake, D. T. Dunn, J. P. Halcox, D. M. Gibb, N. J. Klein, and J. E. Deanfield. 2005. Early structural and functional changes of the vasculature in HIV-infected children: Impact of disease and antiretroviral therapy. Circulation 112(1):103–109.

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