Puberty in perinatal HIV-1 infection: a multicentre longitudinal study of 212 children

Objective: To define age at entry into Tanner stages in children with perinatal HIV-1 infection. Design: Multicentre longitudinal study including 212 perinatally HIV-1-infected children (107 girls and 105 boys) followed-up during puberty (from 8 and 9 years onwards in girls and boys, respectively). Healthy children (843 girls and 821 boys) provided reference percentiles. P2 or B2 stages in girls and P2 or G2 stages in boys defined onset of puberty. Methods: The cumulative probability [95% confidence limit (CI)] of entry into each stage at different ages was estimated by the Kaplan-Meier product-limit method; differences were evaluated by log rank test. Relationships were tested using the Spearman's rank correlation coefficient. Results: Ages of girls [years (95%CI)] at P2 [12.9 (12.6-13.2)], P3 [13.4 (13.0-13.8)], P4 [14.6 (14.0-15.2)], B2 [12.7 (12.2-13.2)], B3 [13.3 (12.8-14.0)] and B4 [14.6 (14.0-15.2)] stages were > 97th percentile (greater than or equal to 21 month delay) of controls. Ages of boys [years(95%CI)] at P2 [12.6(12.1-13.1)], P3 [13.9 (13.4-14.4)], P4 [14.9 (14.2-15.6)], G2 [12.1 (11.5-12.7)], G3 [13.6 (13.1-14.1)] and G4 [14.9 (14.1-15.7)] stages were at the 75-97th percentiles (less than or equal to 15 month delay). Age at onset of puberty was not related to clinical and immunological condition, antiretroviral treatment, weigh for height and age at onset of severe disease or immune suppression. Conclusion: Perinatal HIV-1 infection interferes with sexual maturation. The mechanisms by which this occurs should be elucidated and intervention strategies designed. Intervention could save much psychological distress, since associated linear growthfailure can exacerbate adolescents' feelings of being different and unwell

Italian guidelines for antiretroviral therapy in children with human immunodeficiency virus-type 1 infection

Human immunodeficiency virus-type 1 (HIV-1) infection and its treatment are peculiar in children. Adherence and compliance must be carefully taken into account before initiating or changing therapy and in the choice of drugs. Even in the absence of paediatric-specific trial results and notwithstanding drug-labelling notations, all antiretroviral drugs should be used when indicated. A combined therapy is compulsory. Therapy is highly recommended in category C or category 3 and recommended in category B children. Indications in categories N1, N2, A1 or A2 are limited. A triple association is recommended in category C or category 3 children or in those with a high viral load, when compliance is guaranteed. A step-down strategy is not advisable. Infants' treatment should be inserted into controlled studies. Therapy should be changed when serious side effects or poor tolerance (choose drugs with a different toxicity and greater tolerance), poor compliance (individualize the motives) or treatment failure (evaluate progression and adherence) occurs

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 HN 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 rumors 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 nor restricted to symptomatic and/or immune-compromised children. Cancer-directed treatment should be given promptly to these patients, who have ct fair chance to survive their tumor in view of potential highly aggressive antiretroviral therapy-associated improvement in survival and quality of life

Reduction in mortality with availability of antiretroviral therapy for children with perinatal HIV-1 infection

Context Since the introduction of combined antiretroviral therapy, mortality rates in adults with human immunodeficiency virus type 1 (HIV-1) infection have decreased. However, little information is available outside the setting of controlled trials on survival of perinatally HIV-infected children treated with antiretroviral therapy. Objective To assess effect of availability of antiretroviral therapy on decreasing mortality in perinatally HIV-infected children, Design Population-based, multicenter longitudinal study involving data collected by the Italian Register for HIV Infection in Children. Setting A network of 106 pediatric clinical centers. Subjects A total of 1142 children born between November 1980 and December 1997 with perinatally acquired HIV infection with a median follow-up of 5.9 years. Main Outcome Measure Time to HIV-related death calculated for birth cohort and calendar period and grouped by distribution of predominant type of antiretroviral therapy administered over time. Results Survival was longer in the 1996-1997 birth cohort (crude relative hazard [RH] of death, 0.39; 95% confidence interval [CI], 0.15-0.96) and 1996-1998 calendar period (crude RH of death, 0.65; 95% CI, 0.45-0.95) than in birth cohort and calendar period 1980-1995, but not when adjusted for maternal antiretroviral treatment during pregnancy and clinical condition at time of delivery, gestational age, and birth weight (adjusted RH of death, 0.55; 95% CI, 0.20-1.50, for birth cohort; and adjusted RH of death, 0.71, 95% CI, 0.43-1.16, for calendar period). in a multivariate model with 1980-1995 as comparison, the 1996-1997 birth cohort had an RH of 0.57 (95% CI, 0.22-1.47; P=.27) but RH for calendar period 1996-1998 was 0.63 (95% CI, 0.47-0.85; P<.01). When the effects of birth cohort, calendar period, and type of antiretroviral therapy were evaluated simultaneously in the same model, the RH of death was not significantly different from 1.0 for the 1996-1997 birth cohort (P=.19) and calendar period 1996-1998 (P=.83) suggesting a causal relationship between decreased risk of death and use of combination therapy. The RH of death in children receiving monotherapy or double or triple combination therapy was 0.77 (95% CI, 0.55-1.08), 0.70 (95% CI, 0.42-1.17), and 0.29 (95% CI, 0.13-0.67), respectively, vs no antiretroviral therapy. Conclusion Survival of perinatally HIV-infected children improved in 1996-1998 as a result of the introduction of combined antiretroviral therapie

Rapid disease progression in HIV-1 perinatally infected children born to mothers receiving zidovudine monotherapy during pregnancy

Objective: To investigate the outcome in children perinatally infected with HIV-1 whose mothers received zidovudine (ZDV) monotherapy in pregnancy. Design: Observational retrospective study of a prospectively recruited cohort. Setting: Italian Register for HIV Infection in Children. Patients: A group of 216 children perinatally infected with HIV-1, born in 1992-1997 and derived prospectively from birth: 38 children had mothers receiving ZDV monotherapy and for 178 children the mothers received no antiretroviral treatment during pregnancy. Main outcome measures: The estimated probability of developing severe disease or severe immune suppression, survival probability [95% confidence interval (CI)] within 3 years, and the hazard ratio (95% CI), adjusted for year of birth, maternal clinical condition at delivery, birthweight and treatments (Pneumocystis carinii pneumonia chemoprophylaxis and/or antiretroviral therapy before the onset of severe disease, severe immune suppression or death) were compared. Results: Comparison of HIV-1-infected children whose mothers were treated with ZDV with children whose mothers were not treated showed that the former group had a higher probability of developing severe disease [57.3% (95% CI 40.9-74.3) versus 37.2% (95% CI 30.0-45.4); log-rank test 7.83, P = 0.005; adjusted hazard ratio 1.8 (95% CI 1.1-3.1)] or severe immune suppression [53.9% (95% CI 36.3-73.5) versus 37.5% (95% CI 30.0-46.2); log-rank test 5.58, P = 0.018; adjusted hazard ratio 2.4, (95% CI: 1.3-4.3)] and a lower survival [72.2% (95% CI 50.4-85.7) versus 81.0% (95% CI 73.7-86.5); log-rank test 4.23, P = 0.039; adjusted hazard ratio of death 1.9 (95% CI 1.1-3.6)]. Conclusions: This epidemiological observation could stimulate virologic studies to elucidate whether this rapid progression depends on in utero infection or transmission of resistant virus. Findings may suggest a need to hasten HIV-1 diagnosis in infants of ZDV-treated mothers and undertake an aggressive antiretroviral therapy in those found to be infected

Pertussis immunization in HIV-1-infected infants: a model to assess the effects of repeated T cell-dependent antigen administrations on HIV-1 progression. Italian Register for HIV infection in children

Several data evidence that HIV-1 replication may increase in temporal association with immunizations, raising concerns on potential negative effects of vaccinations on HIV-1 progression. Among patients prospectively followed by the "Italian Register for HIV infection in children", we evaluated, using the Cox-Mantel method, conditional probabilities of progressing to CDC clinical categories 'B' or 'C', and immunological categories '2' or '3' in 88 children immunized against pertussis and 244 non-immunized. No selection criteria were followed in vaccinating children. No significant differences were observed between the two groups. The lack of a significant impact on clinical and immunological deterioration by the repeated administrations of a T cell-dependent vaccine endorses the current recommendations for routine immunizations in HIV-1-infected children. (C) 2000 Elsevier Science Ltd. All rights reserved

Short-term risk of disease progression in HIV-1-infected children receiving no antiretroviral therapy for 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

Five-year follow-up of children with perinatal HIV-1 infection receiving early highly active antiretroviral therapy

Background: Early highly active antiretroviral therapy ( HAART), started within the first months of age, has been proven to be the optimal strategy to prevent immunological and clinical deterioration in perinatally HIV-infected children. Nevertheless, data about long-term follow-up of early treated children are lacking. Methods: We report data from 40 perinatally HIV-infected-children receiving early HAART, with a median follow-up period of 5.96 years (interquartile range [IQR]: 4.21-7.62). Children were enrolled at birth in the Italian Register for HIV Infection in Children. Comparison with 91 infected children born in the same period, followed-up from birth, and receiving deferred treatment was also provided. Results: Nineteen children (47.5%) were still receiving their first HAART regimen at last follow-up. In the remaining children the first regimen was discontinued, after a median period of 3.77 years (IQR: 1.71-5.71) because of viral failure (8 cases), liver toxicity (1 case), structured therapy interruption (3 cases), or simplification/switch to a PI-sparing regimen (9 cases). Thirty-nine (97.5%) children showed CD4(+) T-lymphocyte values>25%, and undetectable viral load was reached in 31 (77.5%) children at last visit. Early treated children displayed significantly lower viral load than not-early treated children, until 6 years of age, and higher median CD4(+) T-lymphocyte percentages until 4 years of age. Twenty-seven (29.7%) not-early treated vs. 0/40 early treated children were in clinical category C at last follow-up (P < 0.0001). Conclusion: Our findings suggest that clinical, virologic and immunological advantages from early-HAART are long-lasting. Recommendations indicating the long-term management of early treated children are needed

LOW PREVALENCE OF SELECTIVE IgA DEFICIENCY IN INFECTED CHILDREN BORN TO HIV-SEROPOSITIVE MOTHERS: AN IN VIVO MODEL FOR SPECULATION ON SELECTIVE IgA DEFICIENCY PATHOGENESIS

Anecdotal reports of restored immunoglobulin production in individuals with common variable immunodeficiency after acquiring HIV infection suggest that perturbation of the immune system occurring during HIV infection may force some underlying functional defects. These findings raise intriguing questions about the pathogenesis of common variable immunodeficiency. No study has investigated the possible influence of HIV infection on the development: of selective IgA deficiency, a primary immunologic defect genetically related to common variable immunodeficiency. IgA serum levels were evaluated in a large cohort of children born to HIV-infected mothers from 1985 to 2006. To avoid differences possibly due to different follow-up durations we considered only infected and noninfected children aged over 4 years at last-follow-up. The study included 1,157 non-infected children and 964 infected children, aged >= 4 years at last-follow-up and with availability of two or more serum IgA determinations over six months of age. No child displayed immunoglobulin values compatible with diagnosis of common variable immunodeficiency. However, 0/964 infected children vs. 5/1157 noninfected children had selective IgA deficiency (P=0.048). It may be speculated that several immunological alterations, occurring simultaneously in perinatal HIV infection, surpass the functional defect exhibited in some children with selective IgA deficiency. Our data may shed light on the pathogenesis of selective IgA deficiency

Antiretroviral use in Italian children with perinatal HIV infection over a 14-year period

Background: Information on the use of new antiretroviral drugs in children in the real setting of clinical fields is largely unknown. Methods: Data from 2554 combined antiretroviral therapy (cART) regimens administered to 911 children enrolled in the Italian Register for HIV infection in children, between 1996 and 2009, were analysed. Factors potentially associated with undetectable viral load and immunological response to cART were explored by Cox regression analysis. Results: Proportion of protease inhibitor (PI)-based regimens significantly decreased from 88.0% to 51.2% and 54.9%, while proportion on non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimens increased from 4.5% to 38.8% and 40.2% in 19961999, 20002004 and 20052009, respectively (p < 0.0001). Significant change in the use of each antiretroviral drug occurred over the time periods (p < 0.0001). Factors independently associated with virological and immunological success were as follows: later calendar periods, younger age at regimen (only for virological success) and higher CD4+ T-lymphocyte percentage at baseline. Use of unboosted PI was associated with lower adjusted hazard ratio (aHR) of virological or immunological success with respect to NNRTI- and boosted PI-based regimens, with no difference among these two latter types. Conclusion: Use of new generation antiretroviral drugs in Italian HIV-infected children is increasing. No different viro-immunological outcomes between NNRTI- and boosted PI-based cART were observe