Carlo Giaquinto

Mother to child transmission of HIV infection in the era of highly active antiretroviral therapy

BACKGROUND Very low rates of mother-to-child transmission (MTCT) of human immunodeficiency virus (HIV) are achievable with use of highly active antiretroviral therapy (HAART). We examine risk factors for MTCT in the HAART era and describe infants who were vertically infected, despite exposure to prophylactic MTCT interventions. METHODS Of the 4525 mother-child pairs in this prospective cohort study, 1983 were enrolled during the period of January 1997 through May 2004. Factors examined included use of antiretroviral therapy during pregnancy, maternal CD4 cell count and HIV RNA level, mode of delivery, and gestational age in logistic regression analysis. RESULTS Receipt of antenatal antiretroviral therapy increased from 5% at the start of the HAART era to 92% in 2001-2003. The overall MTCT rate in this period was 2.87% (95% confidence interval [CI], 2.11%-3.81%), but it was 0.99% (95% CI, 0.32%-2.30%) during 2001-2003. In logistic regression analysis that included 885 mother-child pairs, MTCT risk was associated with high maternal viral load (adjusted odds ratio [AOR], 12.1; P=.003) and elective Caesarean section (AOR, 0.33; P=.04). Detection of maternal HIV RNA was significantly associated with antenatal use of antiretroviral therapy, CD4 cell count, and mode of delivery. Among 560 women with undetectable HIV RNA levels, elective Caesarean section was associated with a 90% reduction in MTCT risk (odds ratio, 0.10; 95% CI, 0.03-0.33), compared with vaginal delivery or emergency Caesarean section. CONCLUSIONS Our results suggest that offering an elective Caesarean section delivery to all HIV-infected women, even in areas where HAART is available, is appropriate clinical management, especially for persons with detectable viral loads. Our results also suggest that previously identified risk factors remain important.

Combining electronic healthcare databases in Europe to allow for large-scale drug safety monitoring: the EU-ADR Project

In this proof‐of‐concept paper we describe the framework, process, and preliminary results of combining data from European electronic healthcare record (EHR) databases for large‐scale monitoring of drug safety.

Short-term risk of disease progression in HIV-1-infected children receiving no antiretroviral therapy or zidovudine monotherapy: a meta-analysis.

BACKGROUND Data on the short-term risk of disease progression in HIV-1-infected children are needed to address the question of when to begin combination antiretroviral therapy. We estimated 12-month risks of progression to AIDS and death, by age and most recent measurement of CD4 T-cell percentage (CD4%) or viral load, in children receiving no antiretroviral therapy or zidovudine monotherapy only. METHODS We undertook a meta-analysis of individual longitudinal data for 3941 children from eight cohort studies and nine randomised trials in Europe and the USA. Estimates of risk were derived from parametric survival models. FINDINGS 997 AIDS-defining events were recorded over 7297 person-years of follow-up in the analysis of CD4%, and 284 events over 2282 person-years in the viral load analysis, corresponding to 568 deaths (9087 person-years) and 129 deaths (2816 person-years), respectively. In children older than 2 years, risk of death increased sharply when CD4% was less than about 10%, or 15% for risk of AIDS, with a low and fairly stable risk at greater CD4%. Children younger than 2 years had worse outlook than older children with the same CD4%. Risk of progression increased when viral load exceeded about 10(5) copies per mL, although this association was more gradual compared with CD4%. Both markers had independent predictive value for disease progression; CD4% was the stronger predictor. INTERPRETATION This information is important for paediatricians making decisions, and for researchers designing trials, about when to initiate or restart antiretroviral therapy.

Multicenter Prospective Study of the Burden of Rotavirus Acute Gastroenteritis in Europe, 2004–2005: The Reveal Study

BACKGROUND Rotavirus is recognized as a significant cause of pediatric gastroenteritis worldwide. Comprehensive data on the burden of rotavirus disease in Europe were lacking. METHODS A prospective, multicenter, observational study was conducted during the 2004-2005 season in selected areas of Belgium, France, Germany, Italy, Spain, Sweden, and the United Kingdom, to estimate the incidence of acute gastroenteritis (AGE) and rotavirus gastroenteritis (RVGE) in children <5 years of age who require medical care in primary care, emergency department, and hospital settings. RESULTS A total of 2846 children with AGE were included in the study, and, of the 2712 children for whom ELISA results were available, 1102 (40.6%) were found to be rotavirus positive. The estimated annual incidence of RVGE was 2.07-4.97 cases/100 children <5 years of age, and it was highest among children 6-23 months of age, with 56.7%-74.2% of all RVGE cases occurring in children in this age group. Overall, RVGE was estimated to account for 27.8%-52.0% of AGE cases, and it was responsible for up to two-thirds of hospitalizations and emergency department consultations, as well as one-third of primary care consultations for AGE. CONCLUSIONS Rotavirus infections account for a significant proportion of AGE cases in children <5 years of age in Europe, many of whom require frequent primary care consultations or care in emergency department and/or hospital settings. The results of the present study suggest that routine rotavirus vaccination for infants <6 months of age could significantly reduce the substantial burden of this potentially serious childhood disease.

Nosocomial rotavirus infection in European countries: a review of the epidemiology, severity and economic burden of hospital-acquired rotavirus disease.

The data currently available on the epidemiology, severity and economic burden of nosocomial rotavirus (RV) infections in children younger than 5 years of age in the major European countries are reviewed. In most studies, RV was found to be the major etiologic agent of pediatric nosocomial diarrhea (31–87%), although the number of diarrhea cases associated with other virus infections (eg, noroviruses, astroviruses, adenoviruses) is increasing quickly and almost equals that caused by RVs. Nosocomial RV (NRV) infections are mainly associated with infants 0–5 months of age, whereas community-acquired RV disease is more prevalent in children 6–23 months of age. NRV infections are seasonal in most countries, occurring in winter; this coincides with the winter seasonal peak of other childhood virus infections (eg, respiratory syncytial virus and influenza viruses), thus placing a heavy burden on health infrastructures. A significant proportion (20–40%) of infections are asymptomatic, which contributes to the spread of the virus and might reduce the efficiency of prevention measures given as they are implemented too late. The absence of effective surveillance and of reporting of NRV infections in any of the 6 countries studied (France, Germany, Italy, Poland, Spain and the United Kingdom) results in severe underreporting of NRV cases in hospital databases and therefore in limited awareness of the importance of NRV disease at country level. The burden reported in the medical literature is potentially significant and includes temporary reduction in the quality of children’s lives, increased costs associated with the additional consumption of medical resources (increased length of hospital stay) and constraints on parents’/hospital staff’s professional lives. The limited robustness and comparability of studies, together with an evolving baseline caused by national changes in health care systems, do not presently allow a complete and accurate overview of NRV disease at country level to be obtained. RV is highly contagious, and the efficiency of existing prevention measures (such as handwashing, isolation and cohorting) is variable, but low at the global level because of the existence of numerous barriers to implementation (eg, lack of staff, high staff turnover, inadequate hospital infrastructure). Prevention of RV infection by mass vaccination could have a positive impact on the incidence of NRV by reducing the number of children hospitalized for gastroenteritis, therefore reducing the number of hospital cross-infections and associated costs.

INFANTS BORN TO MOTHERS SEROPOSITIVE FOR HUMAN IMMUNODEFICIENCY VIRUS: Preliminary Findings from a Multicentre European Study

As part of a project within the European Community research activities on acquired immunodeficiency syndrome (AIDS), infants born to human-immunodeficiency-virus-seropositive mothers are being followed up from birth. By October, 1986, 71 infants from Padua, Berlin, and Edinburgh had been followed up to a median age of 6 months (range 1-15 months). Symptoms of AIDS or AIDS-related complex (ARC) had developed in 5, 3 of whom had died. The median age at antibody loss was during the 10th month. An estimated 75% will have lost maternal antibody by 12 months, but loss of antibody did not exclude infection confirmed by virus culture. Numbers were too small to draw conclusions about the risk of AIDS/ARC and mode of delivery or breast-feeding. The study suggested that the risk of AIDS/ARC is higher in infants born to mothers who have AIDS symptoms during pregnancy.

Drug use in children: Cohort study in three European countries

Objective To provide an overview of drug use in children in three European countries. Design Retrospective cohort study, 2000-5. Setting Primary care research databases in the Netherlands (IPCI), United Kingdom (IMS-DA), and Italy (Pedianet). Participants 675 868 children aged up to 14 (Italy) or 18 (UK and Netherlands). Main outcome measure Prevalence of use per year calculated by drug class (anatomical and therapeutic). Prevalence of “recurrent/chronic” use (three or more prescriptions a year) and “non-recurrent” or “acute” use (less than three prescriptions a year) within each therapeutic class. Descriptions of the top five most commonly used drugs evaluated for off label status within each anatomical class. Results Three levels of drug use could be distinguished in the study population: high (>10/100 children per year), moderate (1-10/100 children per year), and low (<1/100 children per year). For all age categories, anti-infective, dermatological, and respiratory drugs were in the high use group, whereas cardiovascular and antineoplastic drugs were always in the low use group. Emollients, topical steroids, and asthma drugs had the highest prevalence of recurrent use, but relative use of low prevalence drugs was more often recurrent than acute. In the top five highest prevalence drugs topical inhaled and systemic steroids, oral contraceptives, and topical or systemic antifungal drugs were most commonly used off label. Conclusion This overview of outpatient paediatric prescription patterns in a large European population could provide information to prioritise paediatric therapeutic research needs.

Features of children perinatally infected with HIV-1 surviving longer than 5 years. Italian Register for HIV Infection in Children

Children infected with HIV do not necessarily develop AIDS to a set pattern but can be divided into long-term and short-term survivors. We examined long-term survival in children perinatally infected with HIV-1. Out of a total of 624, we studied 182 children who survived longer than 5 years (long-term survivors [LTS]) and 120 children who died of HIV-1-related disease before 5 years (defined as short-term survivors [STS]). 28 (15%) LTS were symptomless (Centers for Disease Control [CDC] P-1 children). 154 (85%) had symptoms (CDC P-2). The proportion of LTS with less than 0.2 x 10(9)/CD4 cells per L was 24/116 (21%) at 61-72 months, rising to 11/26 (41%) at more than 96 months. On at least one occasion, p24 antigenaemia was observed in 112 (62%) LTS. Annual rate of CD4 cell loss was lower in LTS (25% [95% CI: 21-29]) than in STS (53% [45-60]) and in LTS symptomless or with solitary P-2A signs (17%; [13-21]) than in LTS with severe manifestations (30% [25-35]). A new outlook emerges. A substantial number of children do survive after early childhood; severe diseases; low CD4 cell numbers, and p24 antigenaemia do not necessarily preclude long-term survival. The study shows that a CD4 cell decrease early in life can be predictive of outcome.

Costs of Community-Acquired Pediatric Rotavirus Gastroenteritis in 7 European Countries: The Reveal Study

BACKGROUND Morbidity and resource use due to rotavirus gastroenteritis (RVGE) are substantial in Europe, although comprehensive data on the economic impact of the disease are lacking. METHODS A cost study was conducted to assess health care resource use data collected during a prospective epidemiologic study of acute gastroenteritis in children <5 years of age in selected areas of Belgium, France, Germany, Italy, Spain, Sweden, and the United Kingdom. We calculated the average cost (direct and indirect) per episode of confirmed RVGE in primary care, emergency department, and hospital settings. RESULTS The total societal cost (including direct medical, direct nonmedical, and indirect costs) per episode of RVGE ranged from 166 euros to 473 euros in the primary care setting, from 334 euros to 770 euros in the emergency department setting, and from 1525 euros to 2101 euros in the hospital setting. The majority of hospital-related costs were reimbursed by national health care payers, but the percentage of reimbursed costs declined progressively in the emergency department and primary care settings. The mean number of workdays lost by parents and other relatives varied between study areas and settings, ranging from 2.3 to 7.5 days, and this represented the major cost not reimbursed by national health care payers. CONCLUSIONS RVGE incurs considerable resource utilization in all health care settings and substantial costs for national health care payers, families of patients, and employers. Routine rotavirus vaccination in infants could significantly reduce the health and economic burden of pediatric RVGE.

Antigen detection, virus culture, polymerase chain reaction, and in vitro antibody production in the diagnosis of vertically transmitted HIV-1 infection

Polymerase chain reaction (PCR), virus culture (V), antigen detection (Ag), and in vitro antibody production (IVAP) assays may be useful for the early detection of vertically transmitted HIV-1 infection in infants under 18 months of age, when a diagnosis cannot be based on seropositivity because of maternal antibody persistence. To assess the reliability of these procedures and to correlate diagnostic results with infection status, 101 children born to HIV-1-seropositive mothers were evaluated by all these techniques within the first 6 months of life. The children were then followed up to the age of at least 18 months, when diagnosis was made on the basis of AIDS or AIDS-related complex (ARC) onset or persistence of HIV-1 seropositivity. Out of 27 children classified as infected according to the above criteria, 25 (92.5%) were repeatedly positive in IVAP test, 22 (81.5%) in the first PCR analysis, and only 19 (70.3%) in the initial V assay. On further testing, a total of 24 children (88.9%) were found positive in PCR assay, and 23 (85.2%) in V test. All these assays were found to be more sensitive than antigen detection for HIV-1 infection diagnosis, but the antigenaemia was shown to be a useful prognostic marker of disease onset. We also found that both Ag and IVAP assays could give false-positive results in the first 2 months of life, which severely limits their diagnostic value during this period of time. False-positive results in PCR assay could occur at any time of the tested period and were unrelated to the childs age.(ABSTRACT TRUNCATED AT 250 WORDS)