Clara Gabiano

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.

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.

HIV-1 transmission through breast-milk: appraisal of risk according to duration of feeding.

ObjectivesTo estimate the risk of HIV-1 transmission through breast-milk in children born to infected mothers, and to determine the relationship between duration of breast-feeding and risk. Design and methodsThe study population included 168 breast-fed and 793 bottle-fed children born to seropositive mothers. All subjects were enrolled and followed-up in the Italian Register for HIV Infection in Children; HIV serostatus was defined in all children. Multivariate analysis was performed using a logistic regression model. Independent variables included biological factors (duration of breast-feeding, gestational age, clinical condition of mother at delivery, mode of delivery, birth-weight and sex). Year of birth and age when HIV infection was diagnosed were also considered in the analysis attempting to control for possible selection biases. ResultsBreast-feeding increased the risk of HIV-1 transmission. The estimated adjusted odds ratio for 1 day of breast- versus bottle-feeding was 1.19 (95% confidence interval, 1.10–1.28). The infection odds ratio of breast- versus bottle-feeding increased with the natural logarithm of the duration of practice. ConclusionsThese results are the first to provide an appraisal of the additional risk of HIV-1 transmission associated with a seropositive mother breast-feeding her child. Biological significance of this route of transmission was supported by demonstration of a relationship between duration of breast-feeding and risk of HIV-1 transmission.

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

Virologic, immunologic, and clinical benefits from early combined antiretroviral therapy in infants with perinatal HIV-1 infection.

Objective:To investigate the impact of early versus deferred combined antiretroviral treatment (ART) in asymptomatic or moderately symptomatic [Centers for Disease Control and Prevention (CDC) category N, A or B] infants with perinatal HIV-1 infection. Methods:A multi-centre nationwide case–control study was conducted. Data from 30 infants treated with combined ART with three or more drugs before 6 months of age were compared with data from 103 infants starting ART with three or more drugs after 6 months of age. The median follow-up time was 4.1 years (range, 1.0–6.5 years). Results:No difference was evident in the first available viral load and CD4 T-lymphocyte percentage between the two groups of children. Early-treated infants showed significantly lower viral loads than infants receiving deferred treatment at all the follow-up periods. A higher proportion of early-treated infants than infants receiving deferred treatment (73.3% versus 30.1%; P < 0.0001) reached an undetectable viral load. Higher CD4 T-lymphocyte percentages were found in early-treated infants at 13–24 (P < 0.0001), 25–36 (P < 0.0001), and 37–48 (P = 0.003) months of age. No early-treated infant versus 20 of 103 (19.4%) infants receiving deferred ART (P = 0.02) showed a CD4 T-lymphocyte percentage of less than 15% at one time point during follow-up. No CDC category A, B or C clinical event occurred in early-treated infants over the follow-up period while 44 of 103 (42.7%) infants receiving deferred treatment presented a decline in the CDC category. Kaplan–Meier analyses revealed significant differences in CDC category A (P = 0.0002), B (P = 0.0003), and C (P = 0.0018) event-free survivals. Conclusion:The data suggest virologic, immunologic, and clinical benefits from early administration of ART.

Adherence to antiretroviral therapy and its determinants in children with human immunodeficiency virus infection: a multicentre, national study

Aim: To investigate rates and determinants of adherence to antiretroviral therapy in Italian children infected with the human immunodeficiency virus (HIV). Methods: An observational, cross‐sectional multicentre study was performed through a structured interview with the caregivers of HIV‐infected children. The interview included quantitative information on adherence in the 4 d before interview. Sociodemographic, clinical and psychosocial characteristics of children were recorded. Results: 129 children (median age 96 mo) were enrolled, of whom 94 were on highly active antiretroviral therapy (HAART). Twenty‐one (16%) omitted more than 5% of total doses in 4 d and were considered non‐adherent. However, only 11% of caregivers reported that therapy had been administered at the correct times. No significant difference was found between age and the stage of HIV infection. Children aware of their HIV status were less adherent. Individual drugs showed a broad adherence pattern and children who received HAART were more adherent. Children receiving therapy from foster parents were more adherent than those receiving drugs from biological parents or relatives.

Prognostic significance of immunologic changes in 675 infants perinatally exposed to human immunodeficiency virus

Neutrophil, lymphocyte, and T-cell subset numbers and immunoglobulin levels were evaluated at birth to age 2 years in 675 children born to mothers infected with the human immunodeficiency virus type 1 (58 infected symptom-free subjects (P-1), 203 infected subjects with symptoms (P-2), and 414 uninfected subjects). The P-2 patients had (even at birth to age 1 month) lower CD4+ lymphocyte and higher IgA and IgM values than P-1 and uninfected children had. Increased IgG values (from 1 to 6 months of age) and increased CD8+ lymphocyte numbers (at 13 to 24 months of age) were also observed. The P-1 children differed from uninfected children only at 13 to 24 months of age (decreased CD4+ and increased CD8+ lymphocytes). Progressive immunologic changes were found in P-2 patients who had severe clinical conditions and in those who died. To evaluate the predictive meaning of the immunologic changes, we selected 164 children (25 P-2, 15 P-1, and 124 uninfected children) because they had been examined sequentially from birth and they were classified as in the indeterminate state of infection (P-0) at immunologic evaluations at birth to age 1 and at 1 to 6 months of age. During the 1- to 6-month period, P-2 patients had higher immunoglobulin and lower CD4+ lymphocyte values than P-1 and uninfected children had; no difference was found between P-1 and uninfected subjects. These results indicate that in infants with perinatal human immunodeficiency virus type 1 infection, immunologic abnormalities correlate with the clinical condition and are predictive of the clinical outcome rather than the infection status.

Mode of delivery and gestational age influence perinatal HIV-1 transmission

Some data suggest that cesarean section reduces mother-to-child HIV-1 transmission. To assess the influence of mode of delivery and other maternal and infant factors on the rate of transmission, we analyzed the data of 1,624 children prospectively followed from birth. Of these, at the last visit 1,033 were > 18 months of age or would have been had they not died of HIV-related illness. Among the 975 first singleton children, 180 [18.5%; 95% confidence limits (CL), 16.1-20.9] acquired infection, as did 8 of 56 (14.3%; 95% CL, 5.1-23.5) second-born children. Multivariate stepwise analysis showed that vaginal delivery and development of symptoms in the mother were significantly and independently associated with a higher transmission rate (vaginal delivery; odds ratio, 1.69; 95% CL, 1.14-2.5; symptoms: odds ratio, 1.61; 95% CL, 1.12-2.3). In contrast, a history of maternal drug use, birth weight, breast-feeding (only 37 infants were breast-fed), and childs sex did not have a significant impact on viral transmission. The percentage of infected children was highest (30.7%) among very premature infants (< or = 32 weeks of gestation); this significant trend subsequently decreased to 11.9% at the week 42 (p < 0.001), suggesting a parallel reduction in peripartum transmission. The reduced rate of infection observed in infants born by cesarean section underlines the urgent need for randomized controlled trials to evaluate the protective role of surgical delivery in preventing perinatal HIV-1 transmission.

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.