Pier-Angelo Tovo

Response to combination antiretroviral therapy: variation by age.

Objective:To provide information on responses to combination antiretroviral therapy in children, adolescents and older HIV-infected persons. Design and setting:Multicohort collaboration of 33 European cohorts. Subjects:Forty-nine thousand nine hundred and twenty-one antiretroviral-naive individuals starting combination antiretroviral therapy from 1998 to 2006. Outcome measures:Time from combination antiretroviral therapy initiation to HIV RNA less than 50 copies/ml (virological response), CD4 increase of more than 100 cells/μl (immunological response) and new AIDS/death were analysed using survival methods. Ten age strata were chosen: less than 2, 2–5, 6–12, 13–17, 18–29, 30–39 (reference group), 40–49, 50–54, 55–59 and 60 years or older; those aged 6 years or more were included in multivariable analyses. Results:The four youngest age groups had 223, 184, 219 and 201 individuals and the three oldest age groups had 2693, 1656 and 1613 individuals. Precombination antiretroviral therapy CD4 cell counts were highest in young children and declined with age. By 12 months, 53.7% (95% confidence interval: 53.2–54.1%) and 59.2% (58.7–59.6%) had experienced a virological and immunological response. The probability of virological response was lower in those aged 6–12 (adjusted hazard ratio: 0.87) and 13–17 (0.78) years, but was higher in those aged 50–54 (1.24), 55–59 (1.24) and at least 60 (1.18) years. The probability of immunological response was higher in children and younger adults and reduced in those 60 years or older. Those aged 55–59 and 60 years or older had poorer clinical outcomes after adjusting for the latest CD4 cell count. Conclusion:Better virological responses but poorer immunological responses in older individuals, together with low precombination antiretroviral therapy CD4 cell counts, may place this group at increased clinical risk. The poorer virological responses in children may increase the likelihood of emergence of resistance.

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.

Onset of clinical signs in children with HIV-1 perinatal infection

Objective: To investigate the timing of onset of each clinical sign in infants and children with HIV‐1 perinatal infection. Design and methods: A total of 200 HIV‐1‐infected children followed‐up from birth were studied. Failure and conditional probabilities were estimated by the Kaplan‐Meier product‐limit method. Cox proportional hazard analysis was used to evaluate independently associated factors. Results of 934 seroreverters were used to calculate reference values of CD4+ cell counts and predictivity of early signs. Results: Median age at the onset of any sign was 5.2 months (range, 0.03‐56 months). The probability of remaining asymptomatic was 19% [95% confidence interval (CI), 14‐25.1] at 12 months and 6.1% (95% Cl, 2.6‐11.7) at 5 years. Lymphadenopathy (69.5%), splenomegaly (62.4%) and hepatomegaly (58.4%) were the most common signs in the first year of life. Peculiar to the first year of life (compared with subsequent ages) was the onset of primary HIV‐1 hepatitis and diarrhoea (rate ratios, 23.3 and 15.2, respectively). When CD4+ cell counts in the asymptomatic stage (age, 2 months; range, 0.03‐5.9 months) were below rather than above the fifth percentile in seroreverters, onset of signs was earlier [3 (range, 0.03‐19) versus 5 (range, 0.03‐56) months]. Children manifesting signs before the 5.2‐month breakpoint had a lower survival rate [74% (range, 65.9‐82%) at 12 months and 45% (range, 32.9‐57%) at 5 years] than children manifesting signs later 198% (range, 92.2‐100%) at 12 months and 74% (range, 60.3‐87.7%) at 5 years]. Children whose birthweight was ≤2400g had an earlier onset (24 months; range, 1‐57 months) of severe conditions than children with higher birthweight (71 months; range, 1‐71 months). Development of lymphadenopathy or hepatosplenomegaly within 3 months of life were reliable indicators of infection. Conclusions: This study describes the sequence of onset of signs in perinatal HIV‐1 infection. Infection is shown to progress faster than in adults and in a different manner. Low birthweight, early decreased CD4+ cell counts, and early onset of signs are predictive of rapid progression. AIDS 1995, 9:455‐461

Features of children perinatally infected with HIV‐1 surviving longer than 5 years

ly surveillance for the occurrence of diarrhea. Stool specimens collected at the onset of diarrhea were evaluated for enteropathogens. Infants who were infected with HIV were compared with uninfected infants. Subjects: Infants born to HIV-infected women at the University of Maryland Hospital, Baltimore, were recruited at 0 to 3 months of age. This analysis included 58 infants enrolled in the cohort and followed up at least 15 months (unless death intervened) whose HIV status was established (18 HIV-infected infants and 40 HIVuninfected infants). Measurements and Results: The overall incidence of diarrhea in HIV-infected infants was 3.2 episodes per 12 child-months compared with 1.5 episodes per 12 childmonths among HIV-uninfected infants (incidence density ratio, 2.2; P < 0.05). An enteropathogen was identified in stool specimens collected during 20% of diarrhea1 episodes occurring in HIV-infected infants and during 25% of diarrhea1 episodes occurring in HIV-uninfected infants. Episodes that persisted for 14 days or longer were significantly more common among HIV-infected infants. The peak incidence of diarrhea occurred at 0 to 5 months of age for HIV-infected infants compared with 6 to 1 I months for HIV-uninfected infants. Early onset of diarrhea (< 6 months old) in HIV-infected infants was associated with the later development of persistent episodes of diarrhea, and those with persistent episodes had more severe HIV infection, characterized by a significantly higher frequency of opportunistic infections and lower CD4+ T lymphocyte counts by 1 year of age. Conclusions: Both acute and persistent episodes of diarrhea are major sources of morbidity in HIVinfected infants. Moreover, persistent diarrhea is a marker for rapid progression of HIV disease.

Human Immunodeficiency Virus–Related Cancer in Children: Incidence and Treatment Outcome—Report of the Italian Register

PURPOSE To outline the incidence, presenting features, treatment response, and outcome of human immunodeficiency virus (HIV)-associated malignancies in infancy and childhood, together with the estimated risk of HIV-associated cancer in children born to mothers infected with HIV. PATIENTS AND METHODS The Italian Register for HIV Infection in Children collected data by specific registration and follow-up forms. By March 1999, 5,060 children were recruited, including 4,889 with perinatal exposure to HIV-1. Overall, 1,331 infected children were enrolled onto the Register and classified according to current Centers for Disease Control criteria; of them, 1,163 were vertically infected (24% of those with perinatal exposure). Of these 1,163, 569 (49%) were considered to have been prospectively followed-up since they had been registered at birth or within the first 3 months of age. RESULTS Of the 1,331 children observed for a median time of 6.5 years, 35 developed 36 malignancies, four of which occurred in patients with blood-borne risk. For the 1,163 vertically infected children, the cumulative number of years of observation was 7,178 child-years and the cumulative incidence of HIV-associated tumors was 4.18 per 1,000 children/yr (95% confidence interval [CI], 2.92 to 5.98). When only the 569 vertically infected children prospectively followed up since birth were considered, the cumulative number of years of observation was 2,803 child-years. In this group, 10 tumors were observed, with a cumulative incidence of HIV-associated tumors of 3.57 per 1,000 children per year (95% CI, 1.92 to 6.63). CONCLUSION The risk of cancer was significantly higher but not restricted to symptomatic and/or immune-compromised children. Cancer-directed treatment should be given promptly to these patients, who have a fair chance to survive their tumor in view of potential highly aggressive antiretroviral therapy-associated improvement in survival and quality of life.

Nosocomial infections in pediatric cardiac surgery, Italy.

OBJECTIVE To evaluate the incidence of nosocomial infection (NI) in pediatric patients who received cardiothoracic surgery and to identify possible associated risk factors. DESIGN Prospective observational study. SETTING The cardiac surgery and cardiac intensive care units at the Regina Margherita Childrens Hospital, Turin, Italy. PATIENTS All patients who underwent surgery from July 20, 1998, to July 19, 1999, were enrolled, except patients with operative catheterization only. METHODS Clinical data were collected daily from July 20, 1998, to July 19, 1999. NIs were diagnosed according to US Centers for Disease Control and Prevention criteria. RESULTS 104 patients were included in the present study, 80 (76.9%) of whom underwent extracorporeal circulation. The NI ratio was 48.1% (50/104); the percentage of patients with NI was 30.8% (32/104): 23.1% developed one infection, 7.7% two or more. The rate of NI was 2.17 per 100 days of hospitalization (50/2,304). The most common pathogen was Pseudomonas aeruginosa. Important risk factors were length of preoperative admission >5 days, total length of admission >10 days, open chest during postoperative phase, and cyanotic heart disease. There was a significant association between sepsis and central venous catheterization for 3 days or more. Rate of sepsis was 19 per 1,000 catheter days (16/852). CONCLUSION NIs represent a frequent complication for children who undergo heart surgery. Based on our data, we suggest decreasing the preoperative stay as much as possible. The higher NI incidence in patients with an open chest postoperatively suggests that an alternative antibiotic strategy should be considered for these patients.

Clinical experience with linezolid in infants and children

The worldwide spread of multidrug-resistant organisms has required the development of new antimicrobials. Linezolid, the first oxazolidinone, has a broad spectrum of activity against Gram-positive bacteria, including resistant strains. Although approved by the Food and Drug Administration in 2002, the clinical experience with linezolid in the paediatric population is still limited, also given the fact that in most European countries the paediatric use of linezolid is off-label. In this paper we summarize the actual evidence on both licensed and off-label clinical uses of linezolid in children, including efficacy, safety and tolerability issues. Taking into account the potential bias in comparing heterogeneous clinical trials and reports, the available literature data suggest that linezolid is a safe and effective agent for the treatment of serious Gram-positive bacterial infections in neonates and children. At present, linezolid is reserved for those children who are intolerant to or fail conventional agents. A linezolid-containing regimen can be a valuable option for treating multidrug-resistant and extensively drug-resistant tuberculosis in children as well as disseminated non-tuberculous mycobacterial infections. Given the rare occurrence of serious side effects, careful monitoring of haematological parameters, possible drug interactions and neurological manifestations is recommended in linezolid-treated children, especially in case of prolonged treatments. Appropriate linezolid dosage and hospital infection control measures are essential to avoid the spread of linezolid resistance. Further studies are needed to establish novel paediatric indications for linezolid use and to assess the tolerability of long-term treatments.

HIV-I infection in perinatally exposed siblings and twins. The Italian Register for HIV Infection in Children.

In a multicentre study on perinatal HIV-I infection including 1493 children born from 1471 pregnancies to 1415 infected mothers, 22 twin pairs and 56 sibships (115 children) were recorded. The frequency of twin pregnancies was 1.5 (22/1471) and 3.9% (56/1415) seropositive women had more than one at risk pregnancy. In 18 twin pairs with a known infection status nine of the 36 children (25%) were infected. Discordance in infection status was present in only one (5.5%) dizygous pair. A high relative risk of infection (23.1) in a twin was observed when the other was infected. Infection was unrelated to gestational age, mode of delivery, or birth weight. Infection status was defined in 41 sibships (84 children including one first born twin pair and one third born child). When the first born was infected, 11/26 (42.3%) second born children were also infected, whereas this happened in only 2/16 (12.5%) second or third born children when the first born was uninfected. Two out of nine first born (22.2%) and 5/21 (23.8%) second born children prospectively followed up from birth acquired the infection. Results of this study demonstrate that neither twin nor second pregnancies are at increased risk of mother to child HIV-I transmission. Overall data suggest that non-casual factors in mother and/or child influence perinatal infection.

Drug use and upper gastrointestinal complications in children: a case-control study

Objective To evaluate the risk of upper gastrointestinal complications (UGIC) associated with drug use in the paediatric population. Methods This study is part of a large Italian prospective multicentre study. The study population included children hospitalised for acute conditions through the emergency departments of eight clinical centres. Patients admitted for UGIC (defined as endoscopically confirmed gastroduodenal lesions or clinically defined haematemesis or melena) comprised the case series; children hospitalised for neurological disorders formed the control group. Information on drug and vaccine exposure was collected through parental interview during the childrens hospitalisation. Logistic regression was used to estimate ORs for the occurrence of UGIC associated with drug use adjusted for age, clinical centre and concomitant use of any drug. Results 486 children hospitalised for UGIC and 1930 for neurological disorders were enrolled between November 1999 and November 2010. Drug use was higher in cases than in controls (73% vs 54%; p<0.001). UGICs were associated with the use of non-steroidal anti-inflammatory drugs (NSAIDs) (adjusted OR 2.9, 95% CI 2.1 to 4.0), oral steroids (adjusted OR 2.9, 95% CI 1.7 to 4.8) and antibiotics (adjusted OR 2.3, 95% CI 1.8 to 3.1). The duration of use of these drug categories was short (range 1–8 days). Paracetamol showed a lower risk (adjusted OR 2.0, 95% CI 1.5 to 2.6) compared to ibuprofen (adjusted OR 3.7, 95% CI 2.3 to 5.9), although with partially overlapping CIs. Conclusions NSAIDs, oral steroids and antibiotics, even when administered for a short period, were associated with an increased risk of UGIC.

European paediatric hepatitis C virus network. Antenatal hepatitis C virus screening and management of infected women and their children: policies in Europe.

Abstract A postal survey of 31 European centres was conducted to document current practices regarding screening and management of hepatitis C virus (HCV)-infected pregnant women and their children. Antenatal HCV prevalence was low. Universal antenatal screening programmes were in place in ten centres, selective screening occurred in ten other centres, two did not specify the type of policy, and there was no screening programme in nine centres. Numbers of HCV-infected children were low. Breastfeeding was recommended for infants of infected mothers in ten centres, discouraged in ten centres, in three centres women were merely informed of the risks, and there were no guidelines in eight centres. Polymerase chain reaction was available in all centres. In 17 centres children born to HCV-infected women were seen every 3 months for at least the 1st year. Conclusion The optimum antenatal hepatitis C virus screening approach and the appropriateness of breastfeeding recommendations are unclear and this survey highlights the lack of uniformity in current practice.