[Show abstract][Hide abstract] ABSTRACT: Adult patients receiving anti-TNFα drugs are at increased risk of tuberculosis (TB), but studies in pediatric populations are limited, and the best strategy for latent tuberculosis infection (LTBI) screening in this population remains controversial. We describe the prevalence of LTBI prior to anti-TNFα therapy and the long-term follow-up after biological treatment initiation in a cohort of children and adolescents.
Cohort observational study in children and adolescents receiving anti-TNFα agents in a tertiary-care pediatric hospital. LTBI was ruled out prior to the implementation of anti-TNFα drugs by tuberculin skin test (TST), and, from March 2012 on, QuantiFERON Gold-In Tube ® test (QTF-G). During anti-TNFα treatment, patients were evaluated every 6 months for TB with history and physical examination. TST/QTF-G were not repeated unless signs or symptoms consistent with TB arose or there was proven TB contact.
The final cohort consisted of 221 patients (56.1 % female; 261 treatments), of whom 51.7 %/30.0 %/17.3 % were treated with etanercept/adalimumab/infliximab, respectively, for a variety of rheumatic diseases (75.6 %), inflammatory bowel disease (20.8 %), and inflammatory eye diseases (3.6 %). The median (IQR) age at diagnosis of the primary condition was 6.8 years (2.7–11.0) and the duration of the disease before implementing the anti-TNFα agent was 1.8 years (0.6–4.2). LTBI was diagnosed in 3 adolescent girls (prevalence rate: 1.4 %; 95 % CI: 0.4–4.2) affected with juvenile idiopathic arthritis: TST tested positive in only 1, while QTF-G was positive in all cases (including 2 patients already on etanercept). They all received antiTB chemoprophylaxis and were later (re)treated with etanercept for 24–29 months, without incidences. No incident cases of TB disease were observed during the follow-up period under anti-TNFα treatment of 641 patients-year, with a median (IQR) time per patient of 2.3 years (1.4–4.3).
In our study, the prevalence of LTBI (1.4 %) was similar to that reported in population screening studies in Spain; no incident cases of TB disease were observed. In low-burden TB settings, initial screening for TB in children prior to anti-TNFα treatment should include both TST and an IGRA test, but systematic repetition of LTBI immunodiagnostic tests seems unnecessary in the absence of symptoms or known TB contact.
Full-text · Article · Dec 2015 · Pediatric Rheumatology
[Show abstract][Hide abstract] ABSTRACT: Background:
Renal disease is a leading cause of morbidity in HIV-infected adults in the HAART era. Cystatin C has been proposed as a more sensitive marker of renal function, but it may be affected by ongoing inflammation. We aimed to study cystatin C levels in a cohort of HIV-infected pediatric patients at 3 Spanish centers.
Multicenter cross-sectional observational study. Renal function was assessed by means of first morning urine protein/creatinine and albumin/creatinine ratios and creatinine-estimated glomerular filtration rates (GFR), together with the following inflammation markers: cystatin C, reactive C protein, beta-2-microglobulin and 25(OH)-vitamin D levels. A control group of healthy children and adolescents was used.
Eighty-three patients (51 females, median age 13.3 years; 32 males, 13.6 years) and 44 controls (24 females, median age 12.2 years; 20 males, 10.9 years) were included. Among the former, mean CD4 cell count was 860/mm, 29(35%) patients had a previous AIDS diagnosis, 73(88%) were on HAART and HIV viremia was undetectable in 61(73%). No differences in cystatin C levels were observed between the two groups.In HIV-infected patients, cystatin C levels correlated with GFR (r=-0.27; p=0.01), age at first HAART (r=-0.21; p=0.05), and beta-2-microglobulin (r=0.569; p<0.01). In multivariate analysis, lower GFR (p=0.014) and higher beta-2-microglobulin levels (p=0.001) remained as independent risk factors for higher cystatin C values.
Cystatin C values were associated with GFR and beta-2-microglobulin. Cystatin C may be useful as a marker of renal function in HIV-infected pediatric patients, independently of ongoing inflammation or viremia.
No preview · Article · Oct 2015 · The Pediatric Infectious Disease Journal
[Show abstract][Hide abstract] ABSTRACT: Background:
Antiretroviral (ARV)-associated mitochondrial toxicity in HIV/ARV-exposed healthy infants is a concern. Clinically relevant toxicity is rare. Hyperlactatemia is common but non-specific, both elevated and decreased mitochondrial DNA (mtDNA) has been reported. Mitochondrial function has scarcely been investigated.
In a prospective observational study of 133 HIV/ARV-exposed infants, mtDNA content was measured with quantitative-real-time PCR, and mitochondrial respiratory chain enzymatic activity of complex IV (CIV) and mitochondrial mass (MM) were assessed spectrophotometrically from cryopreserved peripheral blood mononuclear cells obtained at 6 weeks, and 3, 6, and 12 months of age, and compared to a control group.
Most mothers (88%) received combined ARV therapy during pregnancy, and 92% of infants received zidovudine monotherapy. No infant had clinical evidence of mitochondrial disease during follow-up. Non-significant higher MM and lower mtDNA levels (normalized by MM) were observed over time in HIV/ARV-exposed infants. MM-normalized CIV activity was consistently lower in HIV/ARV-exposed children than in controls over time (0.09 vs 0.35, 0.12 vs 0.38, 0.13 vs 0.24 and 0.14 vs 0.24 nmol/min/mg at 6 weeks and 3, 6 and 12 months; p=.014, p<.0001, p=.065 and p=.011, respectively) and showed a linear trend towards normalization with age (p<.01). In HIV/ARV-exposed infants, an inverse correlation between CIV activity and mtDNA levels was observed until 6 months of age (r=-.327, p=.016; r=-.311, p=.040; r=-.275, p=.046).
Mitochondrial-encoded CIV activity was consistently lower among HIV/ARVexposed healthy infants and inversely correlated with mtDNA levels, suggesting upregulation of the latter.
No preview · Article · Sep 2015 · The Pediatric Infectious Disease Journal
[Show abstract][Hide abstract] ABSTRACT: Background:
Combination antiretroviral therapy (cART) generally suppresses the replication of the human immunodeficiency virus type 1 (HIV-1) but does not cure the infection, because proviruses persist in stable latent reservoirs. It has been proposed that low-level proviral reservoirs might predict longer virologic control after discontinuation of treatment. Our objective was to evaluate the impact of very early initiation of cART and temporary treatment interruption on the size of the latent HIV-1 reservoir in vertically infected children.
This retrospective study included 23 perinatally HIV-1-infected children who initiated very early treatment within 12 weeks after birth (n = 14), or early treatment between week 12 and 1 year (n = 9). We measured the proviral reservoir (CD4(+) T-cell-associated HIV-1 DNA) in blood samples collected beyond the first year of sustained virologic suppression.
There is a strong positive correlation between the time to initiation of cART and the size of the proviral reservoir. Children who initiated cART within the first 12 weeks of life showed a proviral reservoir 6-fold smaller than children initiating cART beyond this time (P < .01). Rapid virologic control after initiation of cART also limits the size of the viral reservoir. However, patients who underwent transient treatment interruptions showed a dramatic increase in the size of the viral reservoir after discontinuation.
Initiation of cART during the first 12 weeks of life in perinatally HIV-1-infected children limits the size of the viral reservoir. Treatment interruptions should be undertaken with caution, as they might lead to fast and irreversible replenishment of the viral reservoir.
Full-text · Article · Jun 2015 · Clinical Infectious Diseases
[Show abstract][Hide abstract] ABSTRACT: During the last decades remarkable scientific advances have been made toward the prevention of HIV mother-to-child transmission, in particular in developed nations. The aim of this review was to analyze the latest findings and available international recommendations on the prevention of HIV mother-to-child transmission in high-income countries.
We performed a literature search of the Cochrane Library, MEDLINE by PubMed and EMBASE from database inception through June 2014, using the following terms: HIV, mother-to-child transmission and mother-to-child-transmission prevention. All types of articles in the English language were included. US and available European guidelines were searched and included in the analysis.
One hundred fifty articles were selected for inclusion in this review.
Global epidemiology of HIV infection is rapidly evolving, in particular in high-resource countries. The interpretation of clinical and epidemiological studies is crucial for the development of evidence-based recommendations to guide the management of HIV mother-to-child transmission. Although significant progress has been made, heterogeneity between countries in specific interventions still exists, which may address future research.
No preview · Article · May 2015 · The Pediatric Infectious Disease Journal
[Show abstract][Hide abstract] ABSTRACT: This is a cross-sectional study of 15 aviremic chronic HIV-infected children revealing no differences in immune activation (IA; HLA-DRCD38 CD4 and CD8 T cells, and sCD14) and microbial translocation (MT; lipopolysaccharides (LPS) and 16S rDNA) among HIV-infected patients under combined antiretroviral treatment (cART; n = 10) or ritonavir-boosted protease inhibitor monotherapy (mtPI/rtv; n = 5). In both cases, IA and MT were lower in healthy control children (n = 32). This observational study suggests that ritonavir boosted protease inhibitor monotherapy (mtPI/rtv) is not associated with an increased state of IA or MT as compared with children receiving cART.
[Show abstract][Hide abstract] ABSTRACT: Worldwide, the benefits of combined antiretroviral therapy in morbidity and mortality due to perinatally-acquired human immunodeficiency virus infection are beyond question and outweigh the toxicity these drugs have been associated with in HIV-infected children and adolescents to date. In puberty, abnormal body fat distribution is stigmatizating and leads to low adherence to antiretroviral treatment. The other metabolic co-morbidities (mitochondrial toxicity, dyslipidemias, insulin resistance and low bone mineral density) and renal toxicity, albeit non-symptomatic in most children, are increasingly being reported and potentially put this population at risk for early cardiovascular or cerebrovascular atherosclerotic disease, diabetes, pathologic fractures or premature renal failure in the 3 and 4 decades of life. Evidence from available studies is limited because of methodological limitations and also because of several HIV-unrelated factors influencing, to some degree, the development of these conditions. Current recommendations for the prevention, diagnosis, monitoring and treatment of metabolic and renal adverse effects in HIV-children and adolescents are based on adult studies, observational pediatric studies and experts' consensus. Healthy lifestyle habits (regarding diet, exercise and refraining from toxic substances) and wise use of antiretroviral options are the only preventive tools for the majority of patients. Should abnormal findings arise, switches in one or more antiretroviral drugs have proved useful. Specific therapies are also available for some of these co-morbidities, although the experience in the pediatric age is still very scarce. We aim to summarize the epidemiological, clinical and therapeutic aspects of metabolic and renal adverse effects in vertically-HIV-infected children and adolescents.
No preview · Article · Jan 2015 · The Pediatric Infectious Disease Journal
[Show abstract][Hide abstract] ABSTRACT: Background and aims HCMV reshapes NKR distribution, promoting an expansion of CD94/NKG2C+ NK and T cells. The dynamic of this process following primary HCMV infection is ill-defined. The role of NK cells in antiviral defence in preterm infants is unknown.
Aim To assess the dynamics of NKR expression in preterm infants with postnatal HCMV infection.
Methods NKR expression was analysed by flow cytometry at enrolment, 4 and 10 months in 19 initially HCMV-free infants (mean GA 34 w, range 32–36 w) and 6 infants with symptomatic postnatal HCMV infection (mean GA 29 w, range 26–41 w).
Results As compared to infants not infected at enrolment, those with symptomatic HCMV infection had increased proportions of NKG2C+ (40% vs 16%, p = 0.008) and KIR+ (60% vs 36%, p < 0.001) NK cells, but decreased percentages of NKG2A+ NK cells (60% vs 78%, p = 0.001). Increased proportions of NKG2C+, NKG2A+, LILRB1+, KIR+ and CD161+ T cells were also associated to HCMV infection (p < 0.05).
Four of the 7 initially HCMV-negative infants undergoing follow-up became asymptomatically HCMV-infected by 4 months and showed significant differences in the proportions of NKG2C+ and NKG2A+ NK cells in the second and third analyses with respect to patients remaining uninfected (p < 0.05).
NKG2C+ and KIR+ NK cell expansion in symptomatic infants persisted in the second and third samples (n = 5) and it was comparable to that observed in asymptomatic infection.
Conclusions HCMV infection is associated with a specific and persistent expansion of NKG2C+ NK cells. Innate immune response plays a role in HCMV infection control in preterm infants.
No preview · Article · Oct 2014 · Archives of Disease in Childhood
[Show abstract][Hide abstract] ABSTRACT: A cross-sectional study of 77 chronic HIV-infected children revealed higher levels of biomarkers of inflammation (ultrasensitive C-reactive protein, D-dimer and β-2-microglobulin), immune activation (HLA-DRCD38 CD4 and CD8 T cells) and microbial translocation [lipopolysaccaride (LPS), microbial 16S rDNA and sCD14] than 32 healthy controls. Immune activation was higher in viremic children, but microbial translocation occurred independently of viraemia and T cell activation. Our results do not support a relevant role of microbial translocation in T cell activation in chronic HIV-infected children, proposing a need to develop strategies to minimize microbial translocation in the future.
No preview · Article · Aug 2014 · AIDS (London, England)
[Show abstract][Hide abstract] ABSTRACT: In HIV-infected adults, elevated albumin has been associated with increased inflammatory activity, HIV-related nephropathy, and type 2 diabetes. Data on albuminuria in HIV-infected children are very scarce, and guidelines do not include routine determination of urinary albumin/creatinine ratio in this population.
We performed a cross-sectional study in a cohort of HIV-infected pediatric patients. Urinary protein/creatinine and albumin/creatinine ratios and hematuria were determined from at least three morning urine samples, and glomerular filtration rate (GFR) was estimated from creatinine levels. Persistent renal damage was defined according to the presence of at least two sequentially abnormal values in one of the parameters. The relationship between renal damage, HIV-related variables, and metabolic comorbidities (dyslipidemia, fat redistribution, glucose intolerance, hypertension) was investigated.
Symptom-free renal damage was observed in 13 of 68 patients (19.1 %) and mainly consisted of persistent proteinuria (17.6 %); glomerular proteinuria was twice as prevalent as tubular proteinuria. GFR were normal in all cases. No relationship between renal markers and HIV-related variables or metabolic comorbidities was observed.
Mild proteinuria affected approximately one fifth of patients in our cohort. The determination of albuminuria allowed the differentiation between glomerular and tubular proteinuria, although no relationship with metabolic comorbidities was observed.
[Show abstract][Hide abstract] ABSTRACT: Pharmacokinetics, safety and antiviral activity of twice-daily fosamprenavir with or without ritonavir were evaluated in 2-18 year-old protease inhibitor (PI)-naïve and -experienced, HIV-1-infected children.Methods: Serial pharmacokinetic samples were collected at Week 2 and pre-dose samples every 4-12 weeks. Safety and plasma HIV-1 RNA were monitored every 4-12 weeks.
Twenty PI-naïve 2-<6 year-old subjects received antiretroviral treatment including unboosted fosamprenavir twice-daily, while 89 PI-naïve and -experienced 2-18 year-old subjects received fosamprenavir/ritonavir-containing therapy twice-daily. Median fosamprenavir exposure was 891 days (range 15-1805 days), with 88% exposed >48 weeks. Twice-daily doses of fosamprenavir/ritonavir 23/3 mg/kg in 2-<6 year olds, 18/3 mg/kg in ≥6 year olds and 700/100 mg in adolescents achieved plasma amprenavir exposures comparable to or higher than 700/100 mg twice daily in adults while fosamprenavir 30 mg/kg twice-daily in 2-<6 year olds led to exposures higher than 1400 mg BID in adults. The proportion of subjects with HIV-1 RNA <400 copies/mL at Week 48 was 60% for fosamprenavir and 53-74% for fosamprenavir/ritonavir [Intent-to-Treat (Exposed), Snapshot analysis]. Median increases in absolute and relative (percentage) CD4 counts from Baseline to Week 48 occurred in both the fosamprenavir (340 cells/mm; 8%) and fosamprenavir/ritonavir group (190 cells/mm; 8%). The most common adverse events were vomiting, cough, and diarrhea; 18 subjects experienced serious adverse events, including nine with suspected abacavir hypersensitivity.
Fosamprenavir regimens administered to HIV-1 infected children aged 2-18 years were generally well-tolerated and provided sustained antiviral activity over 48 weeks, with plasma amprenavir exposures comparable to or higher than adults.
Full-text · Article · Jun 2013 · The Pediatric Infectious Disease Journal
[Show abstract][Hide abstract] ABSTRACT: Despite of highly active antiretroviral therapy, the response to vaccines in HIV-infected children is poor and short-lived, probably due to a defect in cellular immune responses. We compared the cellular immune response (assessed in terms of IFN-γ production) to tetanus toxoid and to cytomegalovirus in a series of 13 HIV-perinatally-infected children and adolescents with optimal immunovirological response to first line antiretroviral therapy, implemented during chronic infection. A stronger cellular response to cytomegalovirus (11 out of 13 patients) was observed, as compared to tetanus toxoid (1 out of 13; p=0.003). These results suggest that the repeated exposition to CMV, as opposed to the past exposition to TT, is able to maintain an effective antigen-specific immune response in stable HIV-infected pediatric patients and strengthen current recommendations on immunization practices in these children.
[Show abstract][Hide abstract] ABSTRACT: Abstract Mitochondrial toxicity in perinatally human immunodeficiency virus (HIV)-infected pediatric patients has been scarcely investigated. Limited data are available about HIV or antiretroviral (ARV)-mediated mitochondrial damage in this population group, specifically, regarding oxygen consumption and apoptosis approach. We aimed to elucidate whether a given mitochondrial DNA depletion is reflected at downstream levels, to gain insight on the pathology of HIV and highly active antiretroviral therapy (HAART) in perinatally HIV-infected pediatric patients. We studied 10 healthy control participants and 20 perinatally HIV-infected pediatric patients (10 under ARV treatment and 10 off treatment). We determined mitochondrial mass, subunits II and IV of complex IV, global and specific mitochondrial enzymatic and oxidative activities, and apoptosis from peripheral blood mononuclear cells. Global oxygen consumption was significantly compromised in HIV-infected untreated patients, compared to the control group (0.76 ± 0.01 versus 1.59 ± 0.15; P = 0.014). Apoptosis showed a trend to increase in untreated patients as well. The overall complex (C) CI-III-IV activity of the mitochondrial respiratory chain (MRC) was significantly decreased in HIV-infected treated patients with respect to the control group (1.52 ± 0.38 versus 6.38 ± 1.53; P = 0.02). No statistically significant differences were found between untreated and HAART-treated patients. These findings suggest the pathogenic role of both HIV and HAART in mitochondrial dysfunction in vertical infection. The abnormalities in mitochondrial genome may be downstream reflected through a global alteration of the MRC. Mitochondrial impairment associated with HIV and HAART was generalized, rather than localized, in this series of perinatally HIV-infected patients.
Full-text · Article · Mar 2013 · Drug and Chemical Toxicology
[Show abstract][Hide abstract] ABSTRACT: Regular screening methods may miss the diagnosis of occult hepatitis B infection (OBI) and seronegative hepatitis C virus infection in immunocompromised patients. A cross-sectional study within a Spanish cohort of HIV-Infected children yielded 6/254 (2.4%) possible OBI cases and 2/254 (0.8%) seronegative HCV-infected patients. Implementation of occult hepatitis screening in the routine care of these children may be warranted.
No preview · Article · Feb 2013 · The Pediatric Infectious Disease Journal
[Show abstract][Hide abstract] ABSTRACT: There are approximately from 1,100 to 1,200 HIV-infected children in a follow-up in Spain. In 2008 an open, multicentral, retrospective and prospective Cohort of the Spanish Paediatric HIV Network (CoRISpe) was founded. The CoRISpe is divided into the node 1 and node 2 representing geographically almost the whole territory of Spain. Since 2008 seventy-five hospitals have been participating in the CoRISpe. All the retrospective data of the HIV-infected children have been kept in the CoRISpe since 1995 and prospective data since 2008. In this article we are going to present the notion of CoRISpe, its role, the structure, how the CoRISpe works and the process how a child is transferred from Paediatric to Adults Units.
The main objective of the CoRISpe is to contribute to furthering scientific knowledge on paediatric HIV infection by providing demographic, sociopsychological, clinical and laboratory data from HIV-infected paediatric patients. Its aim is to enable high-quality research studies on HIV-infected children.
Full-text · Article · Jan 2013 · BMC Infectious Diseases
[Show abstract][Hide abstract] ABSTRACT: Human cytomegalovirus (HCMV) has been reported to reshape the NK-cell receptor (NKR) distribution, promoting an expansion of CD94/NKG2C(+) NK and T cells. The role of NK cells in congenital HCMV infection is ill-defined. Here we studied the expression of NKR (i.e. NKG2C, NKG2A, LILRB1, CD161) and the frequency of the NKG2C gene deletion in children with past congenital infection, both symptomatic (n = 15) and asymptomatic (n = 11), including as controls children with postnatal infection (n = 11) and non-infected (n = 20). The expansion of NKG2C(+) NK cells in HCMV-infected individuals appeared particularly marked and was associated with an increased number of LILRB1(+) NK cells in cases with symptomatic congenital infection. Increased numbers of NKG2C(+) , NKG2A(+) and CD161(+) T cells were also associated to HCMV infection. The NKG2C deletion frequency was comparable in children with congenital HCMV infection and controls. Remarkably, the homozygous NKG2C(+/+) genotype appeared associated with increased absolute numbers of NKG2C(+) NK cells. Moreover, HCMV-infected NKG2C(+/+) children displayed higher absolute numbers of NKG2A(+) and total NK cells than NKG2C(+/-) individuals. Our study provides novel insights on the impact of HCMV infection on the homeostasis of the NK-cell compartment in children, revealing a modulatory influence of NKG2C copy number.
Full-text · Article · Dec 2012 · European Journal of Immunology