Cohort Of HIV-infected Children Research Articles

Commentary: Reducing HIV-associated tuberculosis in children

In both adults and children, the increased risk of tuberculosis as a result of advancing human immunodeficiency virus (HIV) infection is a major contributor to HIV-associated morbidity and mortality. This is especially so in African settings, where the background risk of tuberculosis is already high. It is predictable that anti-retroviral therapy (ART), through allowing recovery of immune function, should reduce this increased risk in patients with HIV, and a number of studies in adults have indeed demonstrated such reductions. 1–3 Quantifying this reduction is complicated by the fact that the same clinical parameters that determine tuberculosis risk are also determinants of who starts ART and are themselves affected by ART, leading to potential time-varying confounding. Statistical methods appropriate to causal questions of this nature are increasingly being used in observational clinical studies. 4 In this issue, Edmonds and colleagues describe the impact of ART on tuberculosis risk in a cohort of HIV-infected children, based on a Cox proportional hazards marginal structural model. 5 The only other quantification of tuberculosis risk reduction due to ART that has, to date, employed such an approach was a study in South African adults, in which the risk reduction due to ART was 39%. 6 In the present study, the equivalent estimate is 49%. These estimates are much lower than many would have anticipated and than some of the prior estimates in adults and children. A recent study in HIV-infected South Africa children, which did not adjust for time-varying confounding, estimated the risk reduction on ART to be 70% for all tuberculosis cases as well as for microbio

Effect of micronutrient supplementation on diarrhoeal disease among stunted children in rural South Africa

BackgroundThe efficacy of zinc combined with vitamin A or multiple micronutrients in preventing diarrhoea is unclear in African countries with high prevalence of HIV-exposed children. Potential modifying factors such as stunting need addressing.ObjectiveTo determine whether adding zinc, or zinc plus multiple micronutrients, to vitamin A reduces diarrhoea incidence, and whether this differs between strata of stunted or HIV-infected children.MethodsWe analyzed data from a randomized, controlled double-blinded trial (ClinicalTrials.gov NCT00156832) of prophylactic micronutrient supplementation to children aged 6–24 months. Three cohorts of children: 32 HIV-infected children, 154 HIV-uninfected children born to HIV-infected mothers, and 187 uninfected children born to HIV-uninfected mothers, received vitamin A, vitamin A plus zinc, or multiple micronutrients that included vitamin A and zinc. The main outcome was incidence of diarrhoea. Poisson regression was used in intent-to-treat analyses. Stratified analyses followed testing for statistical interaction between intervention and stunting.ResultsWe observed no significant differences in overall diarrhoea incidence among treatment arms. Stunting modified this effect with stunted HIV-uninfected children having significantly lower diarrhoea incidence if supplemented with zinc or multiple micronutrients compared to vitamin A alone (2.04 and 2.23 vs 3.92 episodes/year respectively, P=0.024). No meaningful sub-group analyses could be done in the cohort of HIV-infected children.ConclusionCompared with vitamin A alone, supplementation with zinc, and with zinc and multiple micronutrients, reduced diarrhoea morbidity in stunted rural South African children. Efficacy of zinc supplementation in HIV-infected children needs confirmation in studies that represent the spectrum of disease severity and age groups.

Long-term Follow-up of 414 HIV-Infected Romanian Children and Adolescents Receiving Lopinavir/Ritonavir-Containing Highly Active Antiretroviral Therapy

There are no published reports of the long-term safety and effectiveness of highly active antiretroviral therapy for children and adolescents living in resource-limited settings or of large cohorts of HIV-infected children and adolescents treated long-term (>48 weeks) with lopinavir/ritonavir-containing highly active antiretroviral therapy. The purpose of this work was to evaluate the long-term outcomes of treatment of HIV-infected children and adolescents with lopinavir/ritonavir-containing highly active antiretroviral therapy in a resource-limited setting. We studied an inception cohort of 414 HIV-infected children receiving lopinavir/ritonavir-containing highly active antiretroviral therapy between November 2001 and August 2006 at the Romanian-American Children's Center in Constanta, Romania. The center provides comprehensive primary and HIV specialty care and treatment to all known HIV-infected children and adolescents living in Constanta. We measured safety and effectiveness by the percentage of children remaining on treatment, rates of mortality, and changes in plasma HIV RNA concentrations and CD4+ lymphocyte counts. The study population consisted predominantly of antiretroviral drug-experienced older children and adolescents with advanced HIV disease. Treatment was well tolerated, with 337 children (81%) remaining on therapy after a median duration of >4 years. Thirty-seven deaths occurred; the death rate compared favorably to prospectively collected historical data. The most recent on-treatment plasma HIV RNA concentration was <400 copies per milliliter in 192 of 265 children tested. The mean baseline CD4+ lymphocyte count was 292 cells per microliter (n = 299); the mean change from baseline was +266 (n = 284), +317 (n = 260), +343 (n = 176), and +270 cells per microliter (n = 121) after 1, 2, 3, and 4 years of treatment, respectively. Highly active antiretroviral therapy can be administered safely and effectively to children and adolescents in resource-limited settings. Lopinavir/ritonavir-containing highly active antiretroviral therapy is a safe, effective, and durable treatment option for antiretroviral drug-experienced older children and adolescents with advanced HIV disease.

Actualités thérapeutiques dans l'infection à Virus de l'immunodéficience humaine (VIH) de l'enfant

More than 2 millions of children worldwide are HIV-infected. Recently, the HIV related mortality and morbidity has dramatically decreased due to the use of antiretroviral multitherapies in the HIV-infected children. However the therapeutic management of HIV-infected children is complex and may be complicated by socio-familial issues. Short and long term toxicity of antiretrovirals but also of HIV itself are of concern. Despite the good clinical and immunological results of antiretroviral multitherapies, virological failure may occur. Paediatric pharmacokinetic specificities and inadequate galenic presentation of drugs could lead to virological failure. However, the use of more potent drugs with more adapted presentation actually reduces this risk of failure. Prospective cohorts of HIV-infected children and new antiretroviral drugs paediatric evaluation are of key importance and can improve the paediatric therapeutic management. Finally, universal access to antiretroviral drugs in children, particularly in developing countries is the major actual and future challenge.

Effectiveness of dual and triple antiretroviral therapy in the treatment of HIV-infected children

The use of antiretroviral therapy in HIV-infected children has been a widely discussed issue. The aim of this study was to compare the effectiveness of dual nucleoside analogue reverse transcriptase inhibitor (NRTI) regimens and three-drug regimens [2NRTI+ non-nucleoside reverse transcriptase inhibitor (NNRTI) or protease inhibitor (PI)] in a cohort of HIV-infected children. The study was carried out in a referral center for the management of infected children, which is affiliated with the School of Medicine of Universidade Federal de Minas Gerais (UFMG). Those children whose antiretroviral therapy was implemented between January 1998 and December 2000 and who were followed until December 2001 were included in the study. Therapeutic failure or death was regarded as the endpoint in our analysis. A total of 101 patients were assessed, 58 (57.4%) on dual therapy and 43 (42.6%) on triple therapy. No statistically significant difference was observed between the groups in terms of gender, age, CD4+ count and baseline viral load. The average duration of dual therapy was 26.3 months (95%CI 21.3-31.3) and that of triple therapy was 34.3 months (95%CI 29.2-39.5%). There was therapeutic failure in 33 (56.9%) patients on dual therapy and in 11 (25.6%) patients on triple therapy (log rank = 5.03; p = 0.025). The relative risk of therapeutic failure of the dual therapy was 2.2 times higher (95%CI 1.3-3.9). The percentage of initial CD4+ T cells was a predictor of risk for therapeutic failure (p = 0.001). Patients on triple therapy showed a more remarkable reduction in their viral load (p = 0.001). Triple therapy was efficient for a longer time period and showed better virologic response than dual therapy in this cohort of HIV-infected children. Therefore, triple therapy should be the treatment of choice.

Prise en charge thérapeutique de l’infection à Virus de l’Immunodéficience Humaine de type-1 chez l’enfant

More than 2 millions of children worldwide are HIV infected predominantly in developing countries. Recently, in industrialised countries mother-to-child-transmission of HIV has decreased to less than 1-2% due to the use of antiretrovirals during pregnancy. Since 1996, HIV related mortality and morbidity has dramatically decreased due to the use of antiretroviral multitherapies in HIV infected children. Initiation of antiretroviral treatment is based on clinical symptoms, CD4 cells count and plasma HIV RNA viral load. However, immuno-virological criteria may be difficult to understand especially in the infants in whom there is a rare but concerning risk of HIV encephalopathy. Despite the good clinical and immunological results of antiretroviral multitherapies, virological failure may occur. Paediatric pharmacokinetic features and inadequate galenic presentation of drugs could lead to virological failures. However, the use of more potent drugs with more adapted presentation actually reduces this risk of failure. Prospective cohorts of HIV infected children are of importance and can participate in the improvement of the paediatric therapeutic management.

Role of antiretroviral therapies in mucocutaneous manifestations in HIV-infected children over a period of two decades

Human immunodeficiency virus (HIV) infection causes a severe cellular immunodeficiency, which results in a greater susceptibility to infectious, inflammatory and malignant conditions. Among these, pathologies of the skin seem to be those most frequently observed in HIV+ patients. However, there are few reports on how antiretroviral therapy affects skin disorders in HIV-infected children. To study the incidence and prevalence of skin disorders in a cohort of HIV-infected children, in relation to the antiviral therapy [nontreated, monotherapy, combined therapy and highly active antiretroviral therapy (HAART)] received, and their impact on immunological and virological markers. The treatments were those available in different calendar periods in the history of antiviral treatment. A retrospective, observational study in a cohort of 210 HIV-infected children was carried out. These children were followed up every 3 months throughout 22 years. The viral load (HIV RNA copies mL(-1)) was quantified using reverse transcriptase-polymerase chain reaction and the viral phenotype of HIV-1 isolates was determined by in vitro culture. T-lymphocyte subsets in peripheral blood were quantified by flow cytometry. Mucocutaneous manifestations were diagnosed in 17% of the untreated infected children. Of the treated children in different treatment periods, 22% in the monotherapy period, 25% in the combined therapy period but only 10% on HAART had some type of mucocutaneous manifestation, concordant with a higher number of CD4+ T cells, a lower viral load and less cytopathic virus in the last group. Mucocutaneous manifestations of infectious aetiology were most frequently observed; they were detected in 13% of the children during the first calendar period (untreated children), 16% during the second and third periods (monotherapy and combined therapy) and only 5% in the last period (HAART). Interestingly, syncytium-inducing virus was present in 69% of all children with mucocutaneous manifestations of infectious aetiology. Only in the last calendar period (HAART) was a significant decrease observed in the prevalence of mucocutaneous manifestations with HIV infection associated with an increase in CD4+ T cells. In addition, we found a strong association between children who had mucocutaneous manifestations with an infectious aetiology and a more cytopathic (X4/SI) viral phenotype.

Immunogenicity and tolerability of a trivalent virosomal influenza vaccine in a cohort of HIV-infected children.

Twenty-three children infected with the human immunodeficiency virus (HIV) were vaccinated with a trivalent inactivated virosomal influenza vaccine. Serum haemagglutinin inhibition antibody titres were determined for the three viral strains at the time of vaccination and 1 month later. CD4 cell counts and HIV viral loads were measured to evaluate the effect of vaccination on HIV status. Adverse reactions were monitored during the first hour following vaccination by an investigator and then on a continuous basis by the parents. Seroconversion rates against the three viral strains A/H3N2, A/H1N1 and B were 73.9%, 56.5% and 52.2%, respectively. Geometric mean antibody titres increased after 1 month compared with baseline values (A/H3N2: 70.9 versus 13.5; A/H1N1: 24.7 versus 5.8; B: 34.4 versus 9.1). No significant changes were observed in either HIV viral load or CD4 cell count following vaccination. Vaccination was well tolerated with only a few mild, transient symptoms.

Infections and other causes of death in HIV-infected children in Africa

The human immunodeficiency virus (HIV) pandemic has dramatically reversed improvements in infant mortality and child survival in sub-Saharan Africa. However, accurate information on the specific causes of HIV-related morbidity and mortality arising from vertical transmission is infrequent and is constrained in resource-poor settings by infrastructure and local access to health care. Such knowledge is essential to improve clinical management of HIV-infected children in Africa. In this review, a global overview of the clinical aspects of HIV infection in children is given. Factors influencing HIV disease progression, morbidity and mortality are discussed from studies on a cohort of HIV-infected children that were followed at an orphanage in Nairobi between 1999 and 2001. These parameters are contrasted with available data on HIV-infected children residing in community settings in Africa.

Paediatric HIV in 2002--a treatable and preventable infection.

World wide 40 million people are estimated to be infected with HIV with more than 2000 new infections per day in children, the majority living in Sub-Saharan Africa (www.UNAIDS.org). Paediatric HIV infection is a rare disease in Europe with only 865 cases reported to the National Survey of HIV in Pregnany and Childhood in the UK up to 2001 (National Study of HIV, 2002). Currently, there are nearly 600 children alive with HIV infection in the UK, 80% living in/around London, and more than 80% of African origin. The Paediatric European Network for the Treatment of AIDS (PENTA) was estabilshed in 1991, and a number of treatment studies have been undertaken (www.pentatrials.org ). Centres in the UK which have participated in PENTA studies have collaborated to form the CHIPS (Collaborative HIV Paediatric Surveillance) cohort of HIV infected children so that progress in management in the UK can be monitored. The cohort comprises 586 children, more than 80% of infected children in the UK. In this cohort the mortality rate for infected children has declined from 8.2% in 1996 to 0.8% in 2000 with the advent of more effective treatment (Duong et al., 2002).

Respuesta al tratamiento antirretroviral en niños infectados verticalmente por el virus de la inmunodeficiencia humana tipo 1

Our goal was to determine the probability of achieving a fall-off of viral load (VL) and an increase of CD4+T-lymphocytes by 36 months from the initiation of antiretroviral therapy (ART) in a cohort of HIV-infected children according to their baseline data. This was retrospective multicenter observational study of virologic and immunologic markers in 128 HIV-1-vertically infected children on ART: 55 HIV-infected children on combination therapy (CT), and 73 HIV-infected children on highly active antiretroviral therapy (HAART). Viral load (VL) was quantified using a standard molecular assay. CD4+ and CD8+ T-cells subsets were determined by flow cytometry. The median time for a 10% rise of CD4+ T-lymphocytes was 35.7 months (95% confidence interval [95% CI], 15.5-55.9) after starting CT, and 11 months (95% CI, 7,7-14.3) after starting HAART. The median time for a VL fall to < 400 copies/ml was 29.6 months (95% CI, 9.4-49.7) after starting CT, and the median time for a VL fall to < 400 copies/ml was 10.9 months (95% CI, 0-21.9) after starting HAART. A 10% increase of CD4+ T-cells over baseline was associated with HAART, low CD4+ T-cells and high VL. On the other hand, a VL fall lower than 400 copies/ml was associated with HAART and low baseline VL. Our data indicate that HAART was better than CT in the control of VL and CD4+ T-cell increase. Also, baseline CD4+ T-cell and VL values helped to determine the response to ART in HIV-1 infected children.

Distal sensory polyneuropathy in a cohort of HIV-infected children over five years of age.

Peripheral neuropathy in children with human immunodeficiency virus (HIV) infection has not been systematically studied. Objectives. To describe the symptoms and signs of peripheral neuropathy in HIV-infected children and to determine their frequency. A cross-sectional study was conducted on a convenience sample from a cohort of children older than 5 years of age at the pediatric HIV outpatient clinic of the Federal University of Rio de Janeiro. Those patients were interviewed and examined systematically for peripheral nerve symptoms and signs. A total of 39 patients were clinically evaluated. Their ages ranged from 5 to 14 years, and 13 patients (34%) had symptoms and signs of peripheral nerve involvement. Distal paresthesia and/or pain plus diminished ankle jerks and/or diminished vibration sense were the most common clinical findings. Symptoms were chronic and fluctuating, and pain was, in general, not severe. Nerve conduction studies primarily revealed axonal changes. Peripheral neuropathy occurs in one third of HIV-infected children, and, in general, has less severe features than the distal sensory polyneuropathy described in adults. peripheral neuropathy, human immunodeficiency virus, children.

Are there clinical and laboratory predictors of 5-year mortality in HIV-infected children and adolescents with hemophilia?

To determine factors associated with survival in a cohort of HIV-infected children and adolescents with hemophilia, an analysis of the 5-year mortality data for 207 HIV-infected young men was performed to examine the effect of selected clinical covariates on survival. The subjects were enrolled into the Hemophilia Growth and Development Study cohort from 1989 to 1990. Estimated mean time since infection at baseline was 6.7 years and mean estimated age at infection was 6.5 years. The baseline characteristics examined for their association with the hazard of death over the 5-year follow-up period were the following: absolute CD4+ cell count, hemoglobin status, skin test anergy, results of brain magnetic resonance imaging, non-hemophilia-related muscle atrophy (NHRMA), height for age, and impaired neuropsychological functioning as measured by the Vineland Adaptive Behavior and the Pediatric Behavior Scales. In all, 66 deaths occurred over the 5-year follow-up, 62 of whom met the 1987 (n = 56) or 1993 (n = 6) U.S. Centers for Disease Control and Prevention (CDC) definition of AIDS. Although each of the characteristics listed previously significantly increased the hazard of death by Cox proportional hazard regression models, only NHRMA remained a significant predictor of AIDS-related death when added to models that included each of the other cited baseline covariates.

Serum and Plasma Markers of Nutritional Status in Children Infected with the Human Immunodeficiency Virus

Objective To determine whether reduced serum or plasma protein and micronutrient levels are common in children infected with the human immunodeficiency virus (HIV) and whether these levels are different in children with growth retardation compared to those with normal growth. Subjects Children were separated into three groups: (a) HIV-infected with growth retardation (HIV+Gr); (b) HIV-infected with normal growth (HIV+); (c) HIV-uninfected with normal growth (HIV-). All children were afebrile and free of acute infection at the time of study. During a 24-hour stay in the Pediatric Clinical Research Unit, blood was drawn for analysis of total protein, albumin, zinc, selenium, and vitamin A levels; growth measurements were obtained; and dietary intake was assessed by 24-hour weighed food intake and 24-hour dietary recall. Statistical analysis Mean differences between groups were assessed by analysis of variance, and differences in the frequency of nutrient deficiency were determined by χ 2 analysis. Results Thirty-eight children between 2 and 11 years of age were studied: 10 HIV+Gr, 18 HIV+, and 10 HIV-. No statistically significantly differences were noted in mean levels of albumin, prealbumin, zinc, and selenium. Mean serum level of vitamin A was significantly higher in the HIV+Gr group than in the other two groups. There were no significant differences between groups in the frequency of deficiency for any nutrient studied. Mean energy and nutrient intake was similar among groups. Applications/conclusions Abnormal serum or plasma protein or micronutrient levels were uncommon in this cohort of HIV-infected children, even in children with growth retardation. Routine monitoring of the level of proteins and micronutrients studied is unnecessary in the absence of specific clinical indicators of deficiency. J Am Diet Assoc. 1997-97:1377-1381.

Characteristics of human immunodeficiency virus-infected children at the time of death: an experience in the 1990s.

To describe the changes in the characteristics of human immunodeficiency virus (HIV)-related deaths in children with perinatally acquired infection. A retrospective review of all deaths that occurred in HIV-infected children managed at The New York Hospital-Program for Children with AIDS during a 7-year period from January, 1990, to December, 1996. Differences in the characteristics at death between 15 children who died in 1990 and 10 children who died in 1996 were analyzed. Fifty-eight deaths in our cohort of HIV-infected children were identified during the 7-year period. The mean age at death was 4.43 years. Sixty-nine percent of children were black, 55% were male and 94% were receiving Medicaid. The mean weight/age Z score was -3.9 and the mean CD4 index was 0.067 with 65% having <50 CD4 cells/microl at the time of death (TOD). The most common organ/organ systems to be involved at the TOD were lung (78%) and central nervous system (61%). Mycobacterium avium complex (MAC) was the most common isolate at the TOD (26%) followed by Pneumocystis carinii (20%) and Pseudomonas aeruginosa (17%). The leading non-infectious cause of death was cardiac failure (9%). Comparison of the characteristics at the TOD between 1990 and 1996 revealed significant differences in mean age (2.1 vs. 9.2 years, P < 0.0001), mean CD4 count index (0.18 vs. 0.02, P < 0.03), mean number of organ/organ system involvement (3.9 vs. 5.9, P < 0.05), percent receiving antiretroviral therapy (33% vs. 70%, P < 0.02), mean number of years receiving antiretroviral therapy (0.88 vs. 3.86 years, P < 0.01), percent receiving P. carinii pneumonia prophylaxis (27% vs. 100%, P < 0.001), percent receiving MAC prophylaxis/therapy (0% vs. 100%, P < 0.0001), and cause of death from P. carinii pneumonia (53% vs. 0%, P < 0.01). Compared with children who died in 1990, HIV-infected children who died in 1996 were significantly older, more lymphopenic and more likely to have a greater number of organ system involvements and to have received antiviral therapy and antimicrobial prophylaxis. In 1996 no child died of P. carinii pneumonia. In 1996 MAC and P. aeruginosa were the two most important opportunistic infections causing death. These changes in the characteristics at death will warrant review of resources used in treating these children and may be critical in advising parents and care givers about the prognosis of this chronic infection.

Clinical outcome and survival time in a cohort of HIV-infected children with atypical mycobacterial infection. ♦ 697

Clinical outcome and survival time in a cohort of HIV-infected children with atypical mycobacterial infection. ♦ 697

Viral load analysis in a cohort of Canadian pediatric HIV infected patients. 763

HIV viral load testing has recently become available to HIV infected patients outside of research protocols. The interpretation of viral load measurements, the best laboratory technique for their determination and the frequency with which the test should be performed is the focus of active research in the pediatric population. We report our initial experience with viral load measurements in a cohort of HIV infected children.

Cardiac morbidity and related mortality in children with HIV infection

<h3>Objective.</h3> —Dysrhythmias, hemodynamic instability, congestive heart failure, and sudden death are serious complications of human immunodeficiency virus (HIV) infection that, to our knowledge, have not been studied systematically. We sought to determine the cumulative incidence and clinical predictors of these adverse events in a cohort of HIV-infected children. <h3>Design.</h3> —Historical cohort study. <h3>Setting.</h3> —University-affiliated, primary and tertiary care pediatric hospital and ambulatory care center. <h3>Participants.</h3> —Eighty-one HIV-infected children who had one or more cardiac evaluations between 1984 and 1991 form the study cohort. The initial cardiac evaluation occurred at a median age of 1.5 years, and children were followed up to a median age of 3.6 years. <h3>Main Outcome Measures.</h3> —Mortality (related to cardiac dysfunction as well as noncardiac causes), tachycardia, bradycardia, hypertension, hypotension, marked sinus arrhythmia, cardiac arrest, and chronic congestive heart failure. <h3>Results.</h3> —Hemodynamic abnormalities and dysrhythmias occurred frequently. Eight unexpected cardiorespiratory arrests occurred in seven children (9%). Chronic congestive heart failure was noted in 10% of patients. Thirty children died, 10 with significant cardiac dysfunction. As HIV-infected children progressed from acquired immunodeficiency syndrome (AIDS)—related complex to AIDS, significant cardiac problems were more likely to occur. Both nonneurologic AIDS and encephalopathy were strongly associated with most severe cardiac outcomes. However, encephalopathy was the strongest correlate of cardiorespiratory arrest (<i>P</i>=.002). Epstein-Barr virus coinfection was the strongest correlate of chronic congestive heart failure (<i>P</i>&lt;.001). <h3>Conclusions.</h3> —Cardiac morbidity and mortality are more common with advanced HIV infection. The presence of encephalopathy or Epstein-Barr virus coinfection identifies HIV-infected children at especially high risk for adverse cardiac outcomes. (<i>JAMA</i>. 1993;269:2869-2875)