Nancy Hutton

A stable latent reservoir for HIV-1 in resting CD4+ T lymphocytes in infected children

HIV-1 persists in a latent state in resting CD4(+) T lymphocytes of infected adults despite prolonged highly active antiretroviral therapy (HAART). To determine whether a latent reservoir for HIV-1 exists in infected children, we performed a quantitative viral culture assay on highly purified resting CD4(+) T cells from 21 children with perinatally acquired infection. Replication-competent HIV-1 was recovered from all 18 children from whom sufficient cells were obtained. The frequency of latently infected resting CD4(+) T cells directly correlated with plasma virus levels, suggesting that in children with ongoing viral replication, most latently infected cells are in the labile preintegration state of latency. However, in each of 7 children who had suppression of viral replication to undetectable levels for 1-3 years on HAART, latent replication-competent HIV-1 persisted with little decay, owing to a stable reservoir of infected cells in the postintegration stage of latency. Drug-resistance mutations generated by previous nonsuppressive regimens persisted in this compartment despite more than 1 year of fully suppressive HAART, rendering untenable the idea of recycling drugs that were part of failed regimens. Thus the latent reservoir for HIV-1 in resting CD4(+) T cells will be a major obstacle to HIV-1 eradication in children.

Persistence of Wild-Type Virus and Lack of Temporal Structure in the Latent Reservoir for Human Immunodeficiency Virus Type 1 in Pediatric Patients with Extensive Antiretroviral Exposure

ABSTRACT Although highly active antiretroviral therapy (HAART) for human immunodeficiency virus type 1 (HIV-1) infection can reduce levels of HIV-1 RNA in plasma to below the limit of detection, replication-competent forms of the virus persist in all infected individuals. One form of persistence involves a stable reservoir of latent but potentially infectious virus that resides in resting memory CD4+ T cells. The mechanisms involved in maintaining this latent reservoir are incompletely understood. In the present study, we examined the dynamic characteristics of this reservoir in a cohort of children who developed drug-resistant HIV-1 as a result of extensive exposure to inadequately suppressive one- or two-drug regimens prior to the advent of HAART. We have previously shown that drug-resistant viruses selected by nonsuppressive pre-HAART regimens can enter and persist in this reservoir. We have extended these findings here by demonstrating that archival wild-type HIV-1 persists in this reservoir despite the fact that in these patients drug-resistant mutants have been favored by the selective conditions for many years. Phylogenetic analysis of replication-competent viruses persisting in resting CD4+ T cells revealed a striking lack of temporal structure in the sense that isolates obtained at later time points did not show greater sequence divergence than isolates from earlier time points. The persistence of drug-sensitive virus and the lack of temporal structure in the latent reservoir provide genetic evidence for the idea that HIV-1 can persist in a latent form free of selective pressure from antiretroviral drugs in long-lived resting memory CD4+ T cells. Although there may be other mechanisms for viral persistence, this stable pool of latently infected cells is of significant concern because of its potential to serve as a lasting source of replication-competent viruses, including the infecting wild-type form and all drug-resistant variants that have arisen subsequently.

Continued Production of Drug-Sensitive Human Immunodeficiency Virus Type 1 in Children on Combination Antiretroviral Therapy Who Have Undetectable Viral Loads

ABSTRACT Highly active antiretroviral therapy (HAART) can suppress plasma human immunodeficiency virus type 1 (HIV-1) levels to below the detection limit of ultrasensitive clinical assays. However, HIV-1 persists in cellular reservoirs, and in adults, persistent low-level viremia is detected with more sensitive assays. The nature of this viremia is poorly understood, and it is unclear whether viremia persists in children on HAART, particularly those who start therapy shortly after birth. We therefore developed a reverse transcriptase PCR (RT-PCR) assay that allows genotyping of HIV-1 protease even when viremia is present at levels as low as 5 copies of HIV-1 RNA/ml. We demonstrated that viremia persists in children with plasma virus levels below the limit of detection of clinical assays. Viremia was detected even in children who began HAART in early infancy and maintained such strong suppression of viremia that HIV-1-specific antibody responses were absent or minimal. The low-level plasma virus lacked protease inhibitor resistance mutations despite the frequent use of nelfinavir, which has a low mutational barrier to resistance. Protease sequences resembled those of viruses in the latent reservoir in resting CD4+ T cells. Thus, in most children on HAART with clinically undetectable viremia, there is continued virus production without evolution of resistance in the protease gene.

Selenium Deficiency and Cardiomyopathy in Acquired Immunodeficiency Syndrome

Selenium deficiency is common in patients with human immunodeficiency virus infection and may contribute to the development of cardiomyopathy. A 5-year-old boy with congenital human immunodeficiency virus infection developed cardiomyopathy. Evaluation for reversible causes of cardiomyopathy was notable for the diagnosis of selenium deficiency. Cardiac function improved on selenium supplementation. The role of selenium in cardiac dysfunction and the need for nutritional evaluation and supplementation of malnourished patients with acquired immunodeficiency syndrome is discussed.

Effect of Enteral Tube Feeding on Growth of Children with Symptomatic Human Immunodeficiency Virus Infection

Summary Malnutrition and growth failure are frequent clinical consequences of human immunodeficiency virus (HIV) infection in children. Tube feeding is a means by which to increase the enteral intake of nutrients. We examined the effect of tube feeding in 18 children, median age 6 months (range, 3–159). Tube feedings were initiated due to growth failure in all, which was also associated with dysfunctional swallowing or aspiration in seven children and gastroesophageal reflux in two. Tube feedings were infused via nasogastric tube (n = 4) or gastrostomy tube (n = 14) and were continued for a median of 8.5 months (range, 2–24). Stoma complications developed in three children with gastrostomy tubes; these were the only tube-related side effect. Tube feedings were discontinued due to noncompliance (n = 3), gastrostomy leakage (n = 2), intolerance (n = 2), and death (n = 3). Anthropometric changes were evaluated comparing mean standard deviation scores (Z) before and after tube feeding. Tube feeding resulted in significantly increased weight for age (Z, −2.13 + 0.7 vs. −1.46 + 1.4; p = 0.04), weight for height (Z, −1.07 + 1.0 vs. −0.13 + 1.0; p = 0.004), and arm fat area (Z, −1.75 + 1.3 vs. −0.62 + 1.2; p = 0.01). However, tube feeding did not result in significant changes in height for age (Z, −1.93 + 0.8 vs. −1.74 + 1.6) or arm muscle area (Z, −1.24 + 0.9 vs. −0.57 + 1.2). Tube feedings effectively increased the weight of HIV-infected children in this study, but they were not sufficient to correct linear growth deficits.

Mindfulness-based stress reduction for HIV-infected youth: a pilot study.

Youth with HIV infection experience stress from many sources, including their health, stigma associated with HIV, and economic concerns. 1 Stress experienced by HIV-positive adolescents can have serious negative consequences on their physical and psychosocial health. Exposure to stress is associated with HIV progression, 2,3 and stress frequently results in maladaptive behavioral responses—poor HIV medication adherence, selfmedication through substance use, risky sexual behavior, and other high-risk behaviors. 4 In adults with HIV, stress reduction programs have been shown to improve behavioral, psychological, and immunologic domains. 5 Mindfulness-based stress reduction (MBSR) as developed by Kabat-Zinn 6 is a structured 8- to 10-week program designed to cultivate focused, nonjudgmental awareness of the present moment. 6 Mindfulness-based stress reduction has been used and studied since 1979 in adult populations with heterogeneous chronic illnesses. Weekly MBSR classes provide instruction in mindfulness techniques, such as mindful meditation, mindful yoga, and the body scan, to enhance participants’ appreciation for moment-to-moment awareness instead of attendingtoworriesaboutthefutureorpast.AlthoughMBSRhasbeen studied widely in adults, we are aware of few published studies of MBSR for youth 7-9 and none in HIV-positive youth. We are interested in investigating the potential benefit of MBSR for urban HIV-infected youth. As a first step, we conducted a pilot study to investigate the feasibility (through enrollment and attendance) and acceptability (through participant interview)ofMBSRinanurbanHIV-infectedyouthpopulation.If MBSR is feasible and acceptable in this population, we will plan a larger randomized trial to evaluate MBSR’s effect on psychological and physical well-being and quality of life.

Perceptions, experiences, and shifts in perspective occurring among urban youth participating in a mindfulness-based stress reduction program

Interest in mindfulness as a tool to improve health and well-being has increased rapidly over the past two decades. Limited qualitative research has been conducted on mindfulness and health. This study utilized in-depth interviews to explore the context, perceptions, and experiences of a sub-set of participants engaged in an acceptability study of mindfulness-based stress reduction (MBSR) among urban youth. Content analysis revealed that all in-depth interview participants reported experiencing some form of positive benefit and enhanced self-awareness as a result of MBSR program participation. Significant variation in the types and intensity of changes occurring was identified, ranging from a reframing and reduction of daily stressors to transformational shifts in life orientation and well-being. Variations in perceptions of and experiences with mindfulness should be studied in further depth in the context of prospective intervention research, including their potentially differential influence on mental and physical health outcomes.

HIV-infected women and infants: Social and health factors impeding utilization of health care☆

The utilization of health care by HIV-seropositive pregnant women and their infants was studied in an indigent urban population. Ninety HIV-seropositive women delivered 99 HIV-exposed infants at the Johns Hopkins Hospital from August 1, 1988, to April 1, 1991. Repeat pregnancies occurred in 17 (18.9%) women during the study period. Completion of the primary immunization series by age nine months was the criteria for infant adherence to medical care. Of all infants, 72.9% achieved adequate immunization status by nine months. However, only 41 (45.6%) women reported ever seeking HIV-related health care. Factors associated with maternal adherence with HIV-related health care included HIV status of her infant, maternal drug use, and incarceration. Number of living children, maternal age, educational level, marital status, and repeat pregnancy were not associated with mothers seeking HIV-related health care. Despite low adherence to HIV-related health care in this sample of HIV-seropositive women, the majority of their infants did receive adequate immunizations, one proxy measure of adequate infant health care.

Ritonavir-fluticasone interaction causing Cushing syndrome in HIV-infected children and adolescents.

Background: Ritonavir, a potent inhibitor of CYP3A4 enzyme, can lead to high systemic concentrations of fluticasone when these 2 drugs are coadministered. Exogenous Cushing syndrome (CS) in HIV-infected patients receiving ritonavir and fluticasone has been reported frequently in adults but not in children. Three patients, all receiving ritonavir–fluticasone, developed weight gain and altered fat distribution concerning for either lipodystrophy or CS. Methods: Three patients were initially identified by their clinicians as having weight gain and altered fat distribution concerning for either lipodystrophy or CS. All 3 patients were receiving fluticasone and ritonavir, leading to concern about a potential medication interaction. After suspecting exogenous CS, all patient medication lists were reviewed to identify all children prescribed ritonavir–fluticasone. Blood adrenocorticotropic hormone (ACTH) and cortisol were obtained during routine clinic visits. Medication history, laboratory data and physical examination findings were abstracted from medical records. Results: Seventeen (9%) of 189 patients in this pediatric HIV clinic had been prescribed ritonavir–fluticasone. Of 7 patients still taking ritonavir–fluticasone, CS features were present in 4 (57%) patients, including the 3 patients initially suspected of CS or lipodystrophy. Five (71%) patients, including all 4 with CS features, had low serum concentrations: median cortisol <0.2 μg/dL (normal, <0.2 μg/dL). Three of these 5 had ACTH measured, all of which were low: median ACTH 3.0 pmol/L (range, 2.2–<5.0 pmol/L). One patient taking ritonavir–fluticasone had suppressed cortisol but no CS features. The 2 patients with normal serum cortisol and ACTH values had persistent HIV viremia and were suspected of medication nonadherence. Clinical and laboratory abnormalities generally normalized in affected patients within 3 months after discontinuation of fluticasone alone (2) and ritonavir–fluticasone (3). Conclusions: Pediatric HIV physicians frequently prescribe fluticasone and ritonavir together. The combination can cause CS and adrenal suppression in children, potentially leading to misdiagnosis of lipodystrophy syndrome and to increased risk of adrenal crisis during acute illness. Alternatives to fluticasone should be used for treating children receiving ritonavir.

Antibody Response To Hepatitis A Immunization Among Human Immunodeficiency Virus-infected Children And Adolescents

Seventy-one of 84 human immunodeficiency virus (HIV)-infected children [84.5% (95% confidence interval: 75–91.5%)] were hepatitis A virus (HAV) seropositive after 2 doses of HAV vaccine. Higher CD4% and HIV suppression were significantly associated with increased HAV seropositivity rate. In multivariate analysis, CD4 ≥25% and young age were independent predictors of HAV seropositivity. Of 7 children given a third HAV vaccine dose because of negative HAV antibody after 2 doses, 2 (29%) became seropositive.