Mark W. Kline

Lipodystrophy syndrome in human immunodeficiency virus-infected children.

Background. Lipodystrophy syndrome in HIV-infected adults is characterized by a variety of physical and/or metabolic abnormalities, including fat redistribution, hyperlipidemia (hypercholesterolemia and/or hypertriglyceridemia) and peripheral insulin resistance. Many studies suggest that antiretroviral therapy is the underlying cause of the condition. Few data exist for HIV-infected children. Methods. This is a cross-sectional study evaluating HIV-infected children age 2 to 16 years. Fat redistribution was identified by physical examination and parental questionnaire. Fasting blood analysis included cholesterol, triglycerides, high density lipoprotein, low density lipoprotein, glucose, insulin and C-peptide. Results. Forty HIV-infected children were recruited. Seven children (18%) exhibited physical signs of fat redistribution. Twenty-seven (68%), 11 (28%) and 3 (8%) children exhibited evidence for hypercholesterolemia, hypertriglyceridemia and insulin resistance, respectively. Eleven children (28%) had no physical signs or laboratory evidence of lipodystrophy. Statistical analysis did not reveal any significant association between the presence of lipodystrophic features and patient age, HIV-1 viral load, exposure to specific antiretroviral medications or duration of protease inhibitor or nucleoside reverse transcriptase inhibitor therapy. Drug dosing was significantly associated with the development of lipodystrophy features. Children receiving pediatric dosing regimens vs. adult dosing regimens were less likely to develop lipodystrophy (P = 0.003). Conclusions. Features associated with lipodystrophy syndrome arise in some HIV-infected children. Subjects receiving pediatric dosing regimens were less likely than those receiving adult regimens to develop lipodystrophy.

The detection of viral genomes by polymerase chain reaction in the myocardium of pediatric patients with advanced HIV disease

OBJECTIVES The aim of this study was to investigate the frequency of viral nucleic acid detection in the myocardium of human immunodeficiency virus (HIV)-infected children to determine whether an association exists with the development of heart disease. BACKGROUND As improved medical interventions increase the life expectancy of HIV-infected patients, increased incidences of myocarditis and dilated cardiomyopathy (DCM) are becoming more apparent, even in patients without clinical symptoms. METHODS Myocardial samples were obtained from the postmortem hearts of 32 HIV-infected children and from 32 age-matched controls consisting of patients with structural congenital heart disease and no myocardial inflammation and no cardiac or systemic viral infection. The hearts were examined histologically and analyzed for the presence of viral sequences by polymerase chain reaction (PCR) or reverse transcription-PCR. RESULTS Myocarditis was detected histologically in 11 of the 32 HIV-infected patients, and borderline myocarditis was diagnosed in another 13 cases. Infiltrates were confined to the epicardium in two additional hearts. Virus sequences were detected by PCR in 11 of these 26 cases (42.3%); adenovirus in 6, CMV in 3 and both adenovirus and CMV in 2. Two cases without infiltrates were also positive for adenovirus: one had congestive heart failure (CHF) and the other adenoviral pneumonia. No other viruses were detected by PCR, including HIV proviral DNA. All control samples were negative for all viruses tested. CONCLUSIONS These data suggest that the presence of viral nucleic acid in the myocardium is common in HIV-infected children, and may relate to the development of myocarditis, DCM or CHF and may contribute to the rapid progression of HIV disease.

Inadequate coordination of maternal and infant HIV services detrimentally affects early infant diagnosis outcomes in Lilongwe, Malawi.

Objective:To assess the continuity of care and outcome of pediatric HIV prevention, testing, and treatment services, focusing on early infant diagnosis with DNA polymerase chain reaction (PCR). Design:A retrospective observational cohort. Methods:Maternal HIV antibody, infant HIV DNA PCR test results, and outcome data from HIV-infected infants from the prevention of mother-to-child transmission, early infant diagnosis, and pediatric HIV treatment programs operating in Lilongwe, Malawi, between 2004 and 2008 were collected, merged, and analyzed. Results:Of the 14,669 pregnant women who tested HIV antibody positive, 7875 infants (53.7%) received HIV DNA PCR testing. One thousand eighty-four infants (13.8%) were HIV infected. Three hundred twenty (29.5%) children enrolled into pediatric HIV care, with 202 (63.1%) at the Baylor Center of Excellence. Among these, antiretroviral therapy was initiated on 110 infants (54.5%) whose median age was 9.1 months (interquartile range, 5.4-13.8) and a median of 2.5 months (interquartile range, 1.4-5.2) after HIV clinic registration. Sixty-nine HIV-infected infants (34.2%) died or were lost by December 2008. Initiation of antiretroviral therapy increased the likelihood of survival 7-fold (odds ratio, 7.1; 95% confidence interval, 3.68 to 13.70). Conclusions:Separate programs for maternal and infant HIV prevention and care services demonstrated high attrition rates of HIV-exposed and HIV-infected infants, elevated levels of mother-to-child transmission, late infant diagnosis, delayed pediatric antiretroviral therapy initiation, and high HIV-infected infant mortality. Antiretroviral therapy increased HIV-infected infant survival, emphasizing the urgent need for improved service coordination and strategies that increase access to infant HIV diagnosis, improve patient retention, and reduce antiretroviral therapy initiation delays.

The influence of disclosure of HIV diagnosis on time to disease progression in a cohort of Romanian children and teens

Abstract The Joint United Nations Programme on HIV/AIDS (UNAIDS) estimates that in 2004, there were 39.4 million people living with HIV/AIDS worldwide (UNAIDS/WHO Report on the global HIV/AIDS epidemic, 2004). Children less than 15 years of age comprise 2.2 million of these individuals. As more children globally gain access to highly active antiretroviral therapy (HAART), more children are growing to the age when disclosure of their HIV status is inevitable. This information may affect a childs disease trajectory, and in the context of HAART, may have wide-ranging impact in the management of paediatric HIV infection. This study is an investigation of the effect of disclosure of a childs own HIV infection status on death and CD4 decline in a cohort of 325 HIV-infected Romanian children receiving highly active antiretroviral therapy (HAART). A retrospective database analysis was conducted. Data from a nearly three-year period were examined. Children who were aware of their HIV diagnosis were compared with those who were not aware. We found significant associations between not knowing the HIV diagnosis and death, and not knowing the HIV diagnosis and disease progression defined as either death or CD4 decline. Our results imply that in the context of HAART, knowledge of ones own HIV infection status is associated with delayed HIV disease progression.

Pharmacologic Characteristics of Indinavir, Didanosine, and Stavudine in Human Immunodeficiency Virus-Infected Children Receiving Combination Therapy

ABSTRACT The use of human immunodeficiency virus (HIV) protease inhibitors in children has lagged behind that in adults because of the lack of suitable pediatric formulations and information on safe and effective dosing regimens. This study was designed to obtain pharmacokinetic information on indinavir, administered to HIV-infected children also receiving therapy with two nucleoside agents, and to explore relationships between pharmacokinetic parameters and anti-HIV effect. Indinavir was initiated at a dose of 500 mg/m2 every 8 h. Plasma indinavir concentrations were measured every 4 weeks; the dose or dosing interval was adjusted to maintain trough concentrations of ≥0.1 mg/liter. All children were evaluated clinically at baseline and every 4 weeks. Plasma HIV RNA was quantitated at baseline and at weeks 4, 12, and 24. Eighteen children participated in this study. The average daily dose of indinavir was 2,043 mg/m2; nine children received indinavir at 6-h intervals. Pharmacokinetic characteristics of indinavir (mean ± standard deviation) were the following: oral clearance, 1.4 ± 0.5 liters/h/kg; half-life, 1.1 ± 0.43 h; and trough concentration, 0.29 ± 0.32 mg/liter. In nine children that completed 24 weeks of therapy, the baseline-to-week-24 change in HIV RNA level was related to indinavir trough concentration and didanosine area under the curve. This study illustrates the ability to obtain pharmacokinetic information from children during routine clinic visits and to use this information to provide a safeguard against underdosing. The incorporation of pharmacologic knowledge with virologic, immunologic, and behavioral considerations should result in improved clinical outcomes for children infected with HIV.

The pediatric pulmonary and cardiovascular complications of vertically transmitted human immunodeficiency virus (P2C2 HIV) infection study: Design and methods

The P2C2 HIV Study is a prospective natural history study initiated by the National Heart, Lung, and Blood Institute in order to describe the types and incidence of cardiovascular and pulmonary disorders that occur in children with vertically transmitted HIV infection (i.e., transmitted from mother to child in utero or perinatally). This article describes the study design and methods. Patients were recruited from five clinical centers in the United States. The cohort is composed of 205 infants and children enrolled after 28 days of age (Group I) and 612 fetuses and infants of HIV-infected mothers, enrolled prenatally (73%) or postnatally at age < 28 days (Group II). The maternal-to-infant transmission rate in Group II was 17%. The HIV-negative infants in Group II (Group IIb) serves as a control group for the HIV-infected children (Group IIa). The cohort is followed at specified intervals for clinical examination, cardiac, pulmonary, immunologic, and infectious studies and for intercurrent illnesses. In Group IIa, the cumulative loss-to-follow-up rate at 3 years was 10.5%, and the 3-year cumulative mortality rate was 24.9%. The findings will be relevant to clinical and epidemiologic aspects of HIV infection in children.

The Tingathe programme: A pilot intervention using community health workers to create a continuum of care in the prevention of mother to child transmission of HIV (PMTCT) cascade of services in Malawi

Loss to follow‐up is a major challenge in the prevention of mother to child transmission of HIV (PMTCT) programme in Malawi with reported loss to follow‐up of greater than 70%. Tingathe‐PMTCT is a pilot intervention that utilizes dedicated community health workers (CHWs) to create a complete continuum of care within the PMTCT cascade, improving service utilization and retention of mothers and infants. We describe the impact of the intervention on longitudinal care starting with diagnosis of the mother at antenatal care (ANC) through final diagnosis of the infant.

Growth in HIV-infected children receiving antiretroviral therapy at a pediatric infectious diseases clinic in Uganda.

Antiretroviral therapy (ART) improves growth and survival of HIV-infected individuals. We designed a retrospective cohort study to assess clinical factors associated with growth in HIV-infected children on ART in Uganda between July 2003 and March 2006. Height and weight measurements taken pre- and post-ART initiation for at least 6 months were age- and gender-standardized to CDC 2000 reference. We analyzed medical records of 749 children receiving ART. Descriptive and logistic regression analyses were conducted to identify covariates associated with risk of either stunting or being underweight. Longitudinal regression analysis with a mixed model using autoregressive covariance structure was used to compare change in height and weight before and after initiation of ART. The mean age of the study population at first visit was 7.5 years. Mean height-for-age, weight-for-age, and weight-for-height percentiles at first visit were 8.6, 7.7, and 7.9, respectively. At last visit mean height-for-age, weight-for-age, and weight-for-height percentiles were 8.6, 13.3, and 13.8, respectively. Baseline weight-for-age z score of 1 or more was protective against stunting (odds ratio [OR] 0.25, confidence interval [CI] 0.18-0.35) while baseline height-for-age z score of 1 or more was protective against becoming underweight (OR 0.75, CI 0.63-0.88). Children in World Health Organization (WHO) stages II, III, and IV at baseline were 1.5 times more likely to become underweight (OR 1.51, CI 1.07-2.14). Initiation of ART resulted in improvement in mean standardized weight-for-age z score and weight-for-age percentiles (p < 0.001). Weight-for-age percentile and z score improved significantly after initiation of ART. This pediatric population gained weight more rapidly than height after initiation of ART.

Perspectives on the Pediatric HIV/AIDS Pandemic: Catalyzing Access of Children to Care and Treatment

The successes of the United States and other developed countries in the prevention and treatment of pediatric HIV/AIDS have not been replicated in the developing world, where children continue to become infected with HIV and die from HIV/AIDS at astounding rates. Children are underrepresented among recipients of antiretroviral therapy in almost every setting worldwide where treatment programs have been established. The barriers to scaling up HIV/AIDS care and treatment globally are substantial. Nevertheless, nearly a decade after the introduction of pediatric highly active antiretroviral therapy in the United States, the opportunity finally exists to provide treatment to huge numbers of HIV-infected children in the developing world, changing forever the way that pediatric HIV/AIDS is perceived and managed. We propose the creation of a Clinical Centers of Excellence Network and Pediatric AIDS Corps of US pediatric health professionals, increased support for pediatric research relevant to resource-poor settings, commitment of the US government and others to proportionate funding for pediatric HIV/AIDS care and treatment, expanded availability of pediatric antiretroviral drug formulations, and a renewed commitment to collaborative partnerships as practical steps that can be taken to dramatically expand access of HIV-infected children and families in the developing world to health-restoring, life-prolonging care and treatment.

Treatment-Mediated Changes in Human Immunodeficiency Virus (HIV) Type 1 RNA and CD4 Cell Counts as Predictors of Weight Growth Failure, Cognitive Decline, and Survival in HIV-Infected Children

This meta-analysis of 5 large studies of the Pediatric AIDS Clinical Trials Group was undertaken to evaluate the predictive value of antiretroviral treatment-mediated changes in 3 markers of human immunodeficiency virus (HIV) type 1 disease progression-HIV-1 RNA level, CD4 cell count, and CD4 percentage-for weight growth failure, cognitive decline, and survival in HIV-infected children. Proportional hazards models were used to assess the prognostic value of the markers at baseline and after 24 weeks of treatment, with data from 1089 children. Among children receiving nucleoside with or without nonnucleoside reverse-transcriptase inhibitors, higher immunologic and lower virologic markers at baseline and after 24 weeks were significant independent predictors of survival, whereas virologic markers were significant predictors of weight growth and cognitive failure in children >1 year old. The finding of differential age effects on pediatric-specific clinical outcomes emphasizes the need for continued investigation of treatment effects in children.