This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.ABSTRACT This is a prospective cohort study designed to define the impact of HIV infection and antiretroviral therapy on pre-adolescents and adolescents with perinatal HIV infection. A group of HIV-uninfected children with perinatal exposure to HIV from a similar sociodemographic background and age distribution will be enrolled for comparison.Domains to be investigated include growth and sexual maturation, metabolic risk factors for cardiovascular disease, cardiac function, bone health, neurologic, neurodevelopment, language, hearing and behavioral function, and human papillomavirus(HPV); infection.I. HYPOTHESIS The impact of HIV infection and its treatment on the growth and development of children who have been living with HIV infection since birth is not fully known. The PHACS AMP protocol is designed to study the effect of HIV infection on key processes of maturation such as pubertal development, bone growth, fat distribution, and hepatic, renal and cardiovascular functions. In addition, behavior in adolescents plays a major role in adherence to medications, treatment failure, evolution of viral resistance, and secondary transmission of HIV, including the transmission of resistant virus, to others. This knowledge can form the basis for interventions to improve the quality of life of infected children. Unfortunately, the number of HIV-infected infants, children and adolescents worldwide is growing substantially in both resource-poor countries and in countries with increasing levels of health care. Thus the information gained from this study will benefit the increasing number of infected youth worldwide.II.
SPECIFIC AIMS To define the impact of HIV infection and ART on growth and pubertal development (and their hormonal regulation), along with the cognitive, academic, and social development, of pre-adolescents and adolescents with perinatal HIV infection as they move through adolescence into adulthood.To identify infectious and non-infectious complications of HIV disease and evaluate their associations with ART. These include toxicities resulting from ART, including mitochondrial toxicity, lipid abnormalities, and end-organ damage.To investigate:Changes in glucose metabolism, body composition, and bone mineralization;Changes in lipid metabolism and other risk factors for cardiovascular disease;Cognitive and behavioral changes over time, including medication adherence, family and social function, and high risk behaviors such as risky sexual behavior, licit drug abuse, illicit drug use, tobacco and alcohol use; Risk factors for secondary transmission of HIV; andThe occurrence and clinical course of cervical HPV infections among females.DOMAIN-SPECIFIC AIMS AND HYPOTHESESGrowth and Sexual MaturationSpecific AimTo longitudinally track height, weight, body mass index (BMI), and sexual maturation in perinatally exposed HIV-infected and uninfected children and to correlate measurements with parental stature (if available), lifestyle (diet and physical exercise)and disease and treatment status.Hypothesis:Perinatally HIV-infected children who reach adolescence manifest reduced growth, and delayed onset and altered trajectory of sexual maturation compared to HIV-exposed but uninfected children of similar socioedemographic background.Metabolic Risk Factors for Cardiovascular Disease Specific AimTo characterize the emergence and estimate the occurrence of insulin resistance and abnormal glucose tolerance, dyslipidemia, hypertension, and abnormal body composition and their relationship to HIV disease status and specific ART regimens in HIV-infected children over time. HypothesesCompared to non-infected children, there will be an increase in central adiposity or peripheral fat wasting prior to additional morbidity associated with lipodystrophy. The onset of puberty will be associated with progression of these changes. Specific ART regimens and classes of ART agents will have different effects on these metabolic and anthropometric outcomes.Subjects with insulin resistance will have a high likelihood of abnormal glucose tolerance and increased total body and trunk fat. Subjects with abnormal lipid levels will also have the greatest percentages of total and trunk fat and will have elevated vascular inflammatory markers. Together these factors have the potential to contribute to early atherosclerotic cardiovascular disease.Cardiac FunctionSpecific AimTo estimate the prevalence of cardiac structural and functional abnormalities in HIV-infected and uninfected children and youth with perinatal HIV exposure.HypothesesThe prevalence of cardiac myocardial dysfunction is increased in children with perinatal HIV infection and is related to both HIV infection and ART.The magnitude of the abnormal physiologic indices of cardiac structure and function is positively correlated with both the intensity and duration of ART exposure.An association exists between abnormal CV structure and function and mtDNA mutations and suggests that mitochondrial abnormalities may lead to impaired CV functioning.Bone Mineral DensitySpecific AimsTo estimate the differences in BMD of HIV-infected children when compared to HIV-exposed but uninfected children and normal healthy children from a pre-existing research database. To identify virologic, immunologic, therapeutic, hormonal, nutritional, and environmental factors associated with abnormal bone mineralization in HIV-infected and HIV-exposed, -uninfected children.HypothesesBMD of HIV-infected children, after adjusting for growth and pubertal status, will be significantly lower than HIV-exposed, -uninfected children and HIV-unexposed children of the same sex and age.For HIV-infected children, significant factors adversely affecting normal BMD will include delayed puberty, advanced HIV disease, and exposure to tenofovir or protease inhibitors. Factors associated with better BMD will include higher BMI, African-American race, and exposure to nevirapine or other NNRTIs.Subjects with BMD z-score, corrected for bone age will have evidence of increased bone resorption and decreased bone formation. Levels of calcium and vitamin D will not be related to a lower BMD.Neurologic, Neurodevelopment, Language, Hearing, and Behavioral FunctionSpecific AimsTo examine occurrence and patterns of change of the following cognitive and behavioral outcomes among HIV-infected and HIV-exposed but uninfected children: Emotional and behavioral health problems; High risk behaviors including risky sexual behavior, licit drug abuse, illicit drug use, and tobacco and alcohol use; Neurodevelopmental impairment including cognitive function, academic achievement, executive function, adaptive functioning, hearing, and language development ; andAdherence to antiretroviral therapy among infected subjects. To examine the association between HIV infection status and the rates and types of behavioral outcomes specified above (except non-adherence) by comparing perinatally HIV-infected youth to HIV-exposed but uninfected youth from similar backgrounds.To examine rates of non-adherence to ART and the predictors of non-adherence among HIV-infected subjects, including youth factors;e.g., age, sex, mental health, sexual risk behavior, substance use, and neurodevelopment(caregiver factors;e.g., mental health, substance use, education, and cognitive function), and other sociodemographic factors. To examine the association between family and psychosocial factors;e.g., caregiver cognitive function, caregiver health, caregiver substance use and mental health, stressful life events, and caregiver-child relationships; and emotional and behavioral problems in the child.HypothesesBehavioral outcomes among HIV-exposed but uninfected children are better than those of children with perinatal HIV infection.There will be high rates of health risk behaviors among perinatally HIV-infected youth that increase with age and that are associated with each other (e.g., sexual and drug risk behaviors and non-adherence to treatment).Family and psychosocial factors (e.g., caregiver cognitive function, caregiver health, caregiver substance use and mental health, stressful life events, and caregiver-child relationships)and child factors (e.g., cognitive status, behavioral problems, and age are associated with adherence.Adolescent Gynecology and HPV InfectionSpecific AimsIn perinatally HIV-infected and HIV-exposed but uninfected females who are having gynecologic exams performed as standard of care:To evaluate the incidence of and risk factors for developing cervical LSIL and HSIL as determined by cytology and histology; andTo estimate the rate of regression of LSIL.HypothesesThe risk of developing LSIL and HSIL is higher in HIV-infected youth than that reported for HIV-uninfected youth. Risk factors for LSIL and HSIL will include low CD4+ T-cell counts, smoking, substance use, and oral contraceptive use.LSIL is less likely to regress among perinatally HIV-infected youth than among HIV-uninfected youth. Risk factors for HPV persistence will include smoking, immunosuppression, and oral contraceptive use. Infection at multiple sites reflects global immune failure at mucosal sites reflected by a lower rate or regression. III. BACKGROUND AND SIGNIFICANCE Impact of HIV Infection on Pre-adolescents and AdolescentsThe advances in treatment to prevent maternal HIV transmission to neonates have been groundbreaking. As a result, the number of new perinatally-infected children in the U.S. is now small. Subsequent improvements in the treatment of HIV-infected infants and children have been equally remarkable, ensuring that most previously infected American children have survived and are approaching adolescence. It is estimated that there are about 10,000 HIV-infected children and perinatally HIV-infected adolescents currently living with HIV in the U.S. with 15% between 6 and 10 years of age and 50% between 11 and 16 years of age. In the CDC Pediatric Spectrum of HIV Disease study, the median age of HIV-infected children is 11 years. In addition, the number of HIV-infected adolescents worldwide is growing substantially in both resource-poor countries and in countries with increasing levels of health care. Therefore, there is a global cohort of children who have been living with HIV infection since birth who are aging into adolescence. Little is definitively known about the impact of HIV infection and its treatment on the maturation process in these children. Growth, Maturation, and Body Composition in Pre-adolescents and AdolescentsGrowth failure is a frequent manifestation of untreated pediatric HIV infection which can be improved by antiretroviral therapy (ART). Although frank growth hormone (GH) deficiency is not commonly diagnosed in HIV-infected children, it has been suggested that the observed growth failure may be due, at least in part, to resistance to GH and/or to insulin-like growth factor-I (IGF-I), the physiological mediator of the growth-promoting action of GH. A limited number of studies of GH treatment of short children with HIV infection have been reported. High-dose GH, thought to be necessary to overcome endogenous GH resistance, has been shown to ameliorate HIV wasting after 12 weeks of administration to infected adults. In addition to the impact of GH on growth, it is speculated that resistance to GH may contribute to immunodeficiency in HIV infection so that exogenous high-dose GH treatment could be a useful adjunctive therapy to aid immune reconstitution. An additional effect of HIV infection that has been observed in perinatally-infected children and in transfusion-infected hemophiliacs is delayed sexual maturation. In addition to changes in growth and maturation, highly-active antiretroviral therapy (HAART)causes a metabolic syndrome well-characterized in adults as unfavorable body composition (reduction in subcutaneous and increase in visceral fat), insulin resistance and abnormal glucose metabolism, and dyslipidemia. The physiologic effect of the metabolic syndrome places patients at risk for cardiovascular (CV)disorders. There is controversy whether the metabolic syndrome in HIV-infected patients is exclusively related to ART exposure; other causes may include HIV itself (because many of the features of the metabolic syndrome pre-date HAART), underlying family risk factors, or a combination of all of these. Studies in children show similar although not identical findings, including abnormal body composition, insulin resistance, and dyslipidemia, with increased risk at older age and longer duration of HAART. The onset of puberty has been proposed as another factor causing these changes. In adults with HAART-induced metabolic syndrome, growth hormone treatment at pharmacological doses has resulted in significant and sustained improvements in both lean body mass and fat compartments, although data on long-term outcomes are lacking.Most previous studies of growth, puberty, and body composition in HIV-infected children have either been done in small numbers of subjects, in mixed cohorts of vertically and horizontally acquired disease, or analyzed in a cross-sectional as opposed to a longitudinal manner. In addition, a well-matched comparison group is often lacking and a mechanistic component is usually not included. The power of the current proposal is that it allows for longitudinal study of a large, homogeneous population of perinatally HIV-infected children of pubertal age for study of relationships between disease status (e.g., immune deficiency&), ART, and growth, puberty, and body composition. The results could lead to alterations of existing viral-specific therapeutic protocols, as well as to consideration of adjunctive treatments (e.g., human GH) to augment growth, improve immune function, and to counteract abnormal body composition and risk of metabolic syndrome.Cardiovascular Risk Factors in Pre-adolescents and AdolescentsSeveral studies have investigated the relationship between HAART and atherosclerosis. In a report of 102 HIV-infected subjects, a higher prevalence of carotid artery lesions was detected in patients receiving protease inhibitor (PI) therapy than among those receiving PI-sparing regimens or no therapy. A large cohort study of 17,852 patients showed that adverse CV risk factors are associated with non-nucleoside reverse transcriptase inhibitors (NNRTI)and PI use. Several studies have documented a 4 to 7 fold increase in annual incidence of myocardial infarction (MI) among HIV-infected patients after the introduction of HAART, when compared to the pre-HAART era. In a systematic review of the literature, Rhew et al. found that the majority of published studies showed that PI use is associated with lipid abnormalities and morphologic signs of CV disease. These data suggest that exposure to PI therapy is an important risk factor for developing a MI. As HIV-infected children and youth live longer and have longer exposure to HAART, premature CV disease becomes an increasing concern. One of the most significant mechanisms of atherosclerotic heart disease is vascular endothelial dysfunction and reduced flow mediated dilation. Vascular endothelial dysfunction is greater in HIV-infected children and adults when compared to controls, independent of known CV risk factors. Activation and/or injury of the endothelium can play a role in the development of vascular complications. Raised plasma levels of endothelial markers such as von Willebrand factor(vWF)antigen, soluble thrombomodulin and soluble vascular cell adhesion molecule-1 have a prognostic and/or diagnostic value. Cell adhesion proteins such as the selectins may be elevated as well. HIV-infected patients have conditions that may contribute to the activation or injury of the endothelium including dyslipidemia, insulin resistance, and chronic inflammation. Although HIV-infected children clearly demonstrate the features of lipodystrophy, very few investigations have focused on early CV risk in these children. In this study, we will describe the prevalence and risk factors associated with fat redistribution in HIV-infected children. Cardiac FunctionAbnormalities in left ventricular (LV) structure and function occur in HIV-infected children and are some of the strongest predictors of subsequent mortality. These abnormalities are likely to result from multiple causes including infection of the myocardial cells with HIV, coinfection with cardiotropic viruses, autonomic dysfunction, and cardiotoxicity resulting from pharmacologic agents and inflammatory cytokins. The abnormalities of LV structure and function associated with HIV cardiomyopathy can be related to depressed contractility from HIV, LV dilation, increased afterload (abnormal LV dimension:wall thickness), and abnormalities of heart rate and blood pressure. Similar abnormalities of LV structure and function are observed with ART that lead to cardiomyopathy in adults and animal models.Children and young adolescents offer a unique opportunity to study the physiologic mechanisms of specific types of cardiomyopathy, as they are less likely than older adolescents and adults to be affected by such confounding factors as hypertension, tobacco smoking, obesity, diabetes mellitus and coronary atherosclerosis. In addition, the need for future growth and longer survival in children suggest that subclinical abnormalities of cardiac structure and function may be more likely to result in subsequent symptomatic cardiomyopathy in children than in adults.Cardiac dysfunction also occurs in HIV-exposed but -uninfected children. The fact that LV dysfunction is found in both HIV-infected and -uninfected children born to HIV-infected women suggest that the dysfunction is related in part to the intrauterine environment. One of the environmental factors may be in utero ART exposure. The effects of ART on the cardiovascular system of HIV-infected children are poorly understood. This is an important area of investigation for two reasons. First, HIV-infected children are routinely exposed to ART therapy for many years even as their cardiovascular system is developing and as HIV infection is affecting their overall development. The potential for ART to cause damage to the cardiovascular system is magnified by both the duration of exposure and its occurrence during critical stages in a child's cardiovascular development. Second, the effects of ART and HIV on the cardiovascular system status of children may interact, given that both act on the cardiovascular system and on each other. Yet, the direction and magnitude of the effects of ART and HIV in combination are unknown.This study will include an assessment of N-terminal plasma N (amino-terminal pro-brain natriuretic peptide (proBNP) as a marker of myocardial dysfunction. ProBNP is a useful biomarker with high sensitivity and specificity for the diagnosis of ventricular dysfunction, heart failure and coronary syndromes in adults, and also is a strong predictive marker for future cardiovascular events in adults and children. Age-related changes in proBNP have been observed. The proBNP will be compared to the echocardiographic assessment of LV structure and function. We have found echocardiogram parameters of LV structure and function to be very sensitive for detecting asymptomatic cardiomyopathies in children with mitochondrial toxicity, a proposed mechanism of ART-associated cardiotoxicity.In addition to studies of structure and function of the heart, studies are currently underway among ART-exposed children born to HIV-infected women to see if there is a link between LV dysfunction and mitochondrial DNA (mtDNA) mutations which are not present in controls. Denaturing gradient gel electrophoresis screening of umbilical cord tissue from infants exposed in utero to zidovudine (ZDV); and lamivudine (3TC) (n greater than or equal to 10) demonstrated a significant 3.7-fold increase in mtDNA mutations/sequence variants compared with unexposed controls (n greater than or equal to 9) (P less than 0.001). Each ZDV-3TC exposed infant had eight additional sets of distinct mutations not found in controls. These data suggest hotspots for drug-induced mtDNA mutations. Similar frequently occurring mtDNA mutations are observed in cord blood lymphocytes of infants exposed prepartum to ZDV-3TC, and in umbilical cords of newborns exposed in utero to ZDV as the only NRTI (40; V. Walker, personal communication, 2006). Thus, exposure to ART in utero may result in permanent changes in mitochondrial function that could have long-term adverse implications. Therefore, the association between in utero ART exposure, mtDNA mutations, and clinical cardiovascular abnormalities is an important area for further study.Bone Mineralization in Pre-adolescents and AdolescentsHIV-infected children have lower bone mineral density (BMD)than healthy age-, sex- and race-matched controls. Yet very few of the HIV-infected children have had longitudinal follow-up of their BMD. During childhood and adolescence, bone mass increases extensively through longitudinal growth and changes in skeletal size and shape. By 18 years of age, as much as 90% of peak bone mass has been attained, and, by the end of the third decade of life, the acquisition of peak bone mass is complete. Several factors influence the peak bone mass attained, including sex, ethnicity, genetics, weight-bearing physical activity, dietary intakes of calcium and vitamin D, and pubertal development through hormonal influences. Various risk factors for low BMD in HIV-infected children have been identified but no consistent pattern has emerged. These include low CD4+ T-cell count, use of HAART, and lipodystrophy. Tenofovir has been associated with a reduction in BMD in children. HIV-infected children receiving HAART and those with calcium insufficiency also showed higher levels of bone resorption markers. Some of these risk factors for low BMD in HIV-infected children are consistent with those identified among HIV-infected adults; these include high lactate levels, specific HAART regimens, CD4+ T-cell count, visceral fat deposition, and glucose intolerance. Indicators of decreased bone formation and increased bone resorption have also been observed. In addition, known risk factors for low BMD in the general population have been found in HIV-infected adults, including smoking, weight loss, low lean body mass, illicit drug and medication use, and perturbations of the hypothalamic-pituitary-gonadal axis. Many gaps remain in our understanding of low BMD in children and youth with perinatal HIV disease.Pre-Adolescent and Adolescent BehaviorWith the advent of ART, perinatally-infected children are reaching older childhood and adolescence in larger numbers. These youth are primarily of ethnic minority status living in low socioeconomic status urban communities and have many barriers to optimizing their mental and behavioral health. Their problems are not only detrimental to themselves, but may place others at risk for HIV. Furthermore, there are many confounding factors related to the HIV infection, such as progression of HIV disease, neurocognitive deficits due to HIV, HIV stigma, and disclosure of infection status, which when combined with environmental factors such as substance use, poverty, inner-city stress, and disrupted family attachments due to substance use and illness, make adolescence a challenging period for these HIV-infected youth. Pre-adolescents and adolescents with HIV face additional unique complexities related to the impact of HIV on health, mental health, and normative developmental process such as school functioning, puberty, growth, peer relationships and sexuality. As these youth reach adolescence, suboptimal adherence to complex medication regimens also becomes a prominent issue which can lead to viral resistance and treatment failure. Additionally, adolescence is a time of increased experimentation with sexual behavior and drug use which provides opportunities for transmission of HIV to others. Studies of perinatally HIV-infected adolescents show high rates of: psychiatric disorders including mood, anxiety, and behavioral problems, high risk sexual behaviors and substance use, and non-adherence to ART. The literature from studies of other populations of inner-city adolescents suggests that these youths are at high risk for poor outcomes through young adulthood, including difficulties functioning independently, engaging in risk behaviors, and developing multi-drug resistance to ART.In most U.S. urban centers where pediatric HIV is most prevalent, pediatric AIDS represents a confluence of two major urban epidemics: HIV disease and substance abuse in the context of poverty. Early drug use exacerbates the problem of early sexual behavior through disinhibition and is associated with high rates of unprotected intercourse, teen pregnancy, and sexually transmitted infections (STIs). HIV-infected youth may be at even greater risk for contracting STIs due to their compromised immune functioning, and the presence of STIs, in turn, increases the chances of transmitting the virus to partners. Thus, adolescence is a particularly vulnerable stage of development with profound physical, behavioral, and emotional consequences. Furthermore, youth entering adolescence with the burden of HIV infection have endured perinatal deficits in growth, maturation, and neurodevelopment as well as years of less than optimal therapy and the psychosocial ramifications of HIV disease. Therefore, understanding the behavioral dimensions of the youth is critical to understanding their outcomes and identifying potential points of intervention. The Adolescent Master Protocol (AMP) study will follow a large number of youth, with and without HIV infection, from the pre-adolescent era through completion of adolescence to evaluate the effect of HIV infection and the multiple confounding issues on their health and mental health outcomes. Complications of HPV Infection in HIV-Infected Children and YouthAmong the STIs confronting sexually active adolescents, human papillomavirus (HPV) is perhaps the most important. HPV is a well-established cause of significant morbidity and is necessary for the development of invasive genital cancers including cervical, vulvar, vaginal, penile, and anal cancers. Other factors associated with cervical cancer development include smoking cigarettes and prolonged oral contraceptive use (greater than 6 years). Certainly, nicotine and its metabolites can be detected directly from cervical mucous. Hence smoking may have direct carcinogenic effects or may alter immunologic responses in cervical mucous. Progesterone levels have also been associated with abnormal cell proliferation. Substance use has been shown to be associated with immune depression and may accelerate progression of HPV. HPV is quite common in healthy adolescents and young women with up to 50% acquiring HPV within a few years after initiating intercourse. Fortunately, the majority of infections in this age group are transient and benign. However, in HIV-infected adolescents and adults, HIV infection is associated with persistence of HPV. This is not unexpected since HPV persistence has been linked to disordered cell mediated immune responses. A recent study of adolescents and young women from the REACH cohort showed that persistence of cervical HPV and the development of high grade squamous intra-epithelial lesions (HSIL)were extremely common. Approximately 45% of the adolescent women demonstrated HPV persistence, particularly with HPV type 16, the most common type seen in invasive cancers. This persistence paralleled progression of HPV infection to significant precancerous lesions. In this same cohort, the incidence of HSIL was higher for HIV infected than uninfected (21.5% vs. 4.8% incidence by end of follow-up). This finding was even more dramatic for HIV-infected adolescents with baseline or early low grade squamous intra-epithelial lesions (LSIL) where 31% progressed to HSIL. In the final multivariate analysis, hormonal contraceptive use, high interleukin-12 (IL-12) concentrations of the cervical mucous, and persistent LSIL prior to HSIL were significantly associated with the development of HSIL. These factors were found to be independent of CD4+ T-cell counts. The high IL-12 concentrations in cervical mucous associated with HSIL may be suggestive of a local immune dysregulation to HPV caused in part by HIV infection. The role of hormonal contraception as a risk factor deserves further investigation given the proposed relationship between hormonal contraceptive use and cervical cancer and the need for adequate but safe birth control in HIV-infected girls. The data regarding ART and HPV control is complicated. It appears that control of HIV replication and improved CD4+ T-cell counts resulting from ART may lower the risk of developing HSIL. However, once HSIL develops, ART does not appear to strongly influence its natural history. Unfortunately, little is known about the natural history of HPV in adolescents with perinatal HIV infection, limiting our ability to adequately care for this group.The REACH study included only adolescents with behavioral acquisition of HIV who had been HIV-infected for a relatively short period of time. Most were not receiving ART. This study allows for HPV to be studied in the context of long-term perinatal HIV infection and ART.
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