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Daily assumption of antiretroviral drugs and HIV-related immune activation lead to important side effects, which are particularly evident in vertically infected patients. Bone homeostasis impairment and reduction of bone mineral density (BMD) is one of the most important side effects. Primary aim of this study is to assess the prevalence of bone homeostasis alterations in a group of vertically infected patients; secondary aim is to analyze the relationship between bone homeostasis alterations and anthropometric data, severity of HIV infection, and antiretroviral therapy. We studied 67 patients with vertically transmitted HIV-1 (aged 6-31 years), followed by the Pediatric Infectious Disease Unit of the University Hospital of Padua, Italy. We analyzed bone turnover markers (P1NP and CTx) and we performed lumbar spine and femoral dual energy X-ray absorption densitometry (DXA). Personal and anthropometric data and information on HIV-infection severity and antiretroviral therapy were collected for all patients. We found that BMD values recorded by DXA showed a significant correlation with age, race, BMI, physical activity, and antiretroviral therapy duration. P1NP was increased in 43% of patients, while CTX in 61% of them. P1NP alteration was related to age, race, BMI, physical activity, therapy duration, and ever use of protease inhibitors and nucleotide reverse transcriptase inhibitors. CTX alteration was found to be correlated only with age. In conclusion, our study confirms that a wide percentage of HIV vertically infected patients show reduced BMD and impaired bone homeostasis. Strict monitoring is needed in order to early identify and treat these conditions.

Background. We performed a review of published case studies of osteomyelitis associated with cat-scratch disease to consolidate existing information on clinical presentation, diagnostic tools, therapy, and outcome, as well as presenting a case of disseminated cat-scratch disease in a 12-year-old female with skull osteomyelitis and spleen involvement. Methods. A search for articles indexed in PubMed, Embase, and Google Scholar was performed with the search terms “Bartonella,” “bone,” “osteomyelitis,” “osteolytic,” and “cat-scratch disease” limited to the immunocompetent pediatric population and articles in English. Results. 51 cases were identified. The average age was 7.8 years with equal sex distribution. Fever (84.3%), often with a prolonged course (64.7%), and osteoarticular pain (88.2%) were the most common clinical findings. Lymphadenopathy was present in 64.7% of patients. Vertebral body was mainly involved (51.9%). MRI (50%) and bone scintigraphy (48.1%) were favored to confirm osteomyelitis, while serology was the preferred microbiological diagnostic. Various antibiotics were prescribed in combined or sequential regimens, with median duration of therapy of 23 days. About 12.5% of patients did not receive any treatment. Most patients had excellent prognosis; in particular, all patients not receiving any therapy showed complete recovery and no recurrence of symptoms. Conclusions. Bartonella henselae should be considered in differential diagnosis of localized lymphadentitis. Osteoarticular pain or limitation during cat-scratch disease in children should always be investigated for bone spreading. Owing to good prognosis, invasive procedures to obtain the bone material should be avoided. Serology is the gold standard diagnostic tool and MRI is the best radiographic technique to define bone and surrounding tissue involvement. Treatment represents a never-ending dilemma: surgical intervention or use of antibiotics is still controversial, and more studies are needed to define the best antimicrobial regimen.

Despite receiving antiretroviral therapy (ART), an increasing number of adolescents and young adults with perinatally acquired HIV (PHIVAYA) are at risk of developing premature senescence and aging-associated illnesses, including cancer. Given this concern, it is crucial to assess aging biomarkers and their correlation with the HIV reservoir in order to comprehensively characterize and monitor these individuals. Fifty-five PHIVAYA (median age: 23, interquartile range [IQR]: 20-27 years, and 21 [18-23] years on ART at the time of study sampling) were studied along with 23 age-matched healthy controls. The PHIVAYA exhibited significantly higher percentages of activated, senescent, exhausted CD4 and CD8 T cells, shorter telomeres, reduced thymic output, and higher levels of circulating inflammatory markers (PAMPs, DAMPs, and pro-inflammatory cytokines IL-6, IL-8, and TNFα) as well as denervation biomarkers (neural cell adhesion molecule 1 [NCAM1] and C-terminal Agrin fragment [CAF]), compared to controls. HIV-DNA levels positively correlated with activated, senescent, exhausted CD4 and CD8 T cells, circulating biomarkers levels, and inversely with regulatory T and B cells and telomere length. According to their viremia over time, PHIVAYA were subgrouped into 14 Not Suppressed (NS)-PHIVAYA and 41 Suppressed (S)-PHIVAYA, of whom 6 who initiated ART within one year of age and maintained sustained viral suppression overtime were defined as Early Suppressed (ES)-PHIVAYA and the other 35 as Late Suppressed (LS)-PHIVAYA. ES-PHIVAYA exhibited significantly lower HIV-DNA reservoir, decreased percentages of senescent and exhausted CD4 and CD8 T cells, reduced levels of circulating inflammatory and denervation biomarkers, but longer telomere compared to LS- and NS-PHIVAYA. They differed significantly from healthy controls only in a few markers, including higher percentages of regulatory T and B cells, and higher levels of DAMPs. Overall, these results underscore the importance of initiating ART early and maintaining viral suppression to limit the establishment of the viral reservoir and to counteract immune and cellular premature aging. These findings also suggest new approaches for minimally invasive monitoring of individuals at high risk of developing premature aging and age-related illnesses., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Petrara et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Cytomegalovirus causes the most common congenital infection worldwide. With most infants asymptomatic at birth, the few affected may present with variable clinical scenarios, from isolated hearing loss to severe neurologic impairment. Public health interventions include all actions at the health system, community, and individual levels that aim at reducing the burden of congenital Cytomegalovirus. This review examines the literature on maternal and neonatal screening programs in light of current evidence for treatment and the development of vaccines against Cytomegalovirus. Potential biases and benefits of these interventions are outlined, with the objective of increasing awareness about the problem and providing readers with data and critical tools to participate in this ongoing debate.

Background: Intravenous administration of zidovudine (ZDV) during labour is a key step for vertical HIV transmission (VT) prevention, but there is no evidence of benefit when maternal HIV-RNA at delivery is <50 copies/mL. The aim of this study is evaluating the appropriateness of intrapartum ZDV use in Italy., Methods: Observational study including mother-infant pairs with perinatal HIV exposure during 2002-2019, enrolled in the Italian Register for HIV Infection in Children. Univariable and multivariable logistic regression were used to evaluate factors associated with VT., Results: A total of 3,861 infants, born from 3,791 pregnancies were included. The frequency of ZDV use was 79.9%, 92.1%, 93.7% and 92.8% when HIV-RNA was not available, ≥400 copies, between 50 and 399 copies, and <50 copies/mL. Thirty-three out of 3861 (0.85%) infants were subsequently diagnosed with HIV, 25/3861 (0.6%) of them born to mothers receiving intrapartum ZDV, and 31 (93.9%) to mothers with HIV-RNA ≥50 copies/mL or not available. In women with HIV-RNA < 50 copies/mL, ART discontinuation during pregnancy was the strongest risk factor for VT (odds ratio, OR, 23.1, 95%CI 2.4-219.3), while a higher gestational age (OR 0.6, 95%CI 0.4-0.8) and PEP administration to the newborn (aOR 0.004, 95%CI <0.0001-0.4) were protective factors. Intrapartum ZDV administration did not influence the final outcome in this group., Conclusions: In ART era, more transmission events may occur in utero, limiting value of intrapartum ZDV, particularly for women with suppressed HIV-RNA load. More attention to the HIV-RNA testing of mothers before delivery may avoid unnecessary ZDV use., Competing Interests: Declaration of Competing Interest None of the authors declare conflicts of interest relevant to the present study., (Copyright © 2022. Published by Elsevier Ltd.)

Parenteral artesunate (AS) is the WHO first-line treatment recommended in adults and children for severe malaria. Post-artesunate delayed haemolysis (PADH) is an uncommon adverse reaction to AS with a mechanism that is not fully understood, occurring in adults and children. Neutropenia is another possible finding after AS treatment, albeit rare. We present the case of a child who experienced both effects after treatment with AS for imported severe Falciparum malaria with very high parasitaemia. In addition, thirty-five paediatric cases of PADH, five cases of delayed anaemia without known haemolysis, and fourteen cases of neutropenia after artesunate treatment were identified from the literature review. PADH seems to be a dose-independent reaction and is not strongly related to hyperparasitaemia, although it is more frequent in this case. To date, the benefits of AS outweigh its potential side effects. However, haematological follow-up is mandatory to avoid possible complications from anaemia and neutropenia, especially in children treated with other contemporary drugs.

Background: Early start of highly active antiretroviral therapy (HAART) in perinatally HIV-1 infected children is the optimal strategy to prevent immunological and clinical deterioration. To date, according to EMA, only 35% of antiretroviral drugs are licenced in children < 2 years of age and 60% in those aged 2-12 years, due to the lack of adequate paediatric clinical studies on pharmacokinetics, pharmacodynamics and drug safety in children., Methods: An observational retrospective study investigating the rate and the outcomes of off-label prescription of HAART was conducted on 225 perinatally HIV-1 infected children enrolled in the Italian Register for HIV Infection in Children and followed-up from 2001 to 2018., Results: 22.2% (50/225) of included children were receiving an off-label HAART regimen at last check. Only 26% (13/50) of off-label children had an undetectable viral load (VL) before the commencing of the regimen and the 52.0% (26/50) had a CD4 + T lymphocyte percentage > 25%. At last check, during the off label regimen, the 80% (40/50) of patients had an undetectable VL, and 90% (45/50) of them displayed CD4 + T lymphocyte percentage > 25%. The most widely used off-label drugs were: dolutegravir/abacavir/lamivudine (16%; 8/50), emtricitbine/tenofovir disoproxil (22%; 11/50), lopinavir/ritonavir (20%; 10/50) and elvitegravir/cobicistat/emtricitabine/ tenofovir alafenamide (10%; 10/50). At logistic regression analysis, detectable VL before starting the current HAART regimen was a risk factor for receiving an off-label therapy (OR: 2.41; 95% CI 1.13-5.19; p = 0.024). Moreover, children < 2 years of age were at increased risk for receiving off-label HAART with respect to older children (OR: 3.24; 95% CI 1063-7.3; p = 0.001). Even if our safety data regarding off-label regimens where poor, no adverse event was reported., Conclusion: The prescription of an off-label HAART regimen in perinatally HIV-1 infected children was common, in particular in children with detectable VL despite previous HAART and in younger children, especially those receiving their first regimen. Our data suggest similar proportions of virological and immunological successes at last check among children receiving off-label or on-label HAART. Larger studies are needed to better clarify efficacy and safety of off-label HAART regimens in children, in order to allow the enlargement of on-label prescription in children., (© 2022. The Author(s).)

Background: HIV infection and lifelong cART are responsible of an increase in cardiovascular risk. The aim of this study was to describe the subclinical cardiovascular disease and to identify early markers of cardiovascular damage in adolescents and young adults vertically infected with HIV on cART, through an innovative multi-parametric approach., Methods: We enrolled 52 patients vertically infected with HIV. Demographic records, traditional cardiovascular risk factors, laboratory findings and echocardiographic measurements were collected in a one-year routine follow up. The echocardiographic examination included measurements of the 2D and 3D ejection fraction (EF), E/A ratio, E/E' ratio, carotid intima media thickness (cIMT), flow-mediated dilation (FMD) and global longitudinal strain (GLS)., Results: At the time of enrolment, all the patients were on cART therapy. The viral load was suppressed in 95% of them. EF was normal in 94.2% of patients (66 ± 7.2%), and GLS (mean value: -20.0 ± 2.5%) was reduced in 29% of patients. The cIMT mean value was higher than the 95th centile for sex and age in 73%, and FMD was impaired in 45% of patients. Clinically evident disease was found in three patients: dilative cardiomyopathy in one, thoracic-abdominal aneurysm Crawford type II with a bilateral carotid dilation in one and carotid plaque with 30% of stenosis in a third patient., Conclusions: This study confirms the presence of clinical and subclinical cardiovascular disease in a very young population vertically infected with HIV, underlining the importance of an early, multi-parametric cardiovascular follow up.

Background: Combined antiretroviral therapy (cART) has been associated with a steep decrease in mortality and morbidity in HIV-1 infected children. New antiretroviral molecules and drug classes have been developed and the management of HIV-infected children has improved, but recent data on survival are limited. Methods: An observational retrospective study investigating changes in mortality and morbidity was conducted on 1,091 perinatally HIV-1 infected children enrolled in the Italian Register for HIV Infection in Children and followed-up from 2001 to 2018. Results: Three hundred and fifty-four (32%) AIDS events and 26 (2%) deaths occurred overtime. Mortality rates decreased from 0.4/100 person-years in 2001-2006 to 0.27/100 person-years in 2007-2012 and 0.07/100 person-years in 2013-2018. Notably, 92% of the dead children were born in Italy, but only 50% were followed-up since birth or within three months of age. Seventy three percent of children had started cART at age ≥6 months; 23% were treated for <30 days before death. B and C clinical events progressively decreased ( P < 0.0001). Opportunistic infections significantly decreased over time, but still were the most common events in all the periods (6.76/100 person-years in 2013-2018). In the last period, severe bacterial infections were the most common ones. Cancer rates were 0.07/100; 0.17/100; 0.07/100 person-years in the three periods, respectively. Conclusions: Progressive reductions both in mortality and in rates of class B and C clinical events and OIs have been observed during the cART era. However, deaths were still registered; more than half of dead children were enrolled after birth and had belatedly started cART., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Chiappini, Larotonda, Lisi, Giacomet, Erba, Bernardi, Zangari, Di Biagio, Taramasso, Giaquinto, Rampon, Gabiano, Garazzino, Tagliabue, Esposito, Bruzzese, Badolato, Zanaboni, Cellini, Dedoni, Mazza, Pession, Giannini, Salvini, Dodi, Carloni, Cazzato, Tovo, de Martino and Galli.)

Objectives: Vertical transmission of HIV can be effectively controlled through antenatal screening, antiretroviral treatment and the services provided during and after childbirth for mother and newborn. In Italy, the National Health Service guarantees universal access to prenatal care for all women, including women with HIV infection. Despite this, children are diagnosed with HIV infection every year. The aim of the study was to identify missed opportunities for prevention of mother-to-child transmission of HIV., Methods: The Italian Register for HIV Infection in Children, which was started in 1985 and involves 106 hospitals throughout the country, collects data on all new cases of HIV infection in children. For this analysis, we reviewed the database for the period 2005 to 2015., Results: We found 79 HIV-1-infected children newly diagnosed after birth in Italy. Thirty-two of the mothers were Italian. During the pregnancy, only 15 of 19 women with a known HIV diagnosis were treated with antiretroviral treatment, while, of 34 women who had received an HIV diagnosis before labour began, only 23 delivered by caesarean section and 17 received intrapartum prophylaxis. In 25 mothers, HIV infection was diagnosed during pregnancy or in the peripartum period. Thirty-one newborns received antiretroviral prophylaxis and 39 received infant formula., Conclusions: We found an unacceptable number of missed opportunities to prevent mother-to-child transmission (MCTC). Eliminating HIV MTCT is a universal World Health Organization goal. Elucidating organization failures in Italy over the past decade should help to improve early diagnosis and to reach the zero transmission target in newborns., (© 2019 British HIV Association.)

Background: Strategies for prevention of HIV-1 mother-to-child transmission (PMTCT) have been continuously optimized. However, cases of vertical transmission continue to occur in high-income countries., Objectives: To investigate changes in PMTCT strategies adopted by Italian clinicians over time and to evaluate risk factors for transmission., Methods: Data from mother-child pairs prospectively collected by the Italian Register, born in Italy in 1996-2016, were analyzed. Risk factors for MTCT were explored by logistic regression analyses., Results: Six thousand five hundred three children (348 infections) were included. In our cohort, the proportion of children born to foreign mothers increased from 18.3% (563/3078) in 1996%-2003% to 66.2% (559/857) in 2011-2016 (P < 0.0001). Combination neonatal prophylaxis use significantly (P < 0.0001) increased over time, reaching 6.3% (56/857) after 2010, and it was largely (4.2%) adopted in early preterm infants. The proportion of vaginal deliveries in women with undetectable viral load (VL) increased over time and was 9.9% (85/857) in 2011-2016; no infection occurred among them. In children followed up since birth MTCT, rate was 3.5% (96/2783) in 1996-2003; 1.4% (36/2480) in 2004-2010; and 1.1% (9/835) in 2011-2016. At a multivariate analysis, factors associated with MTCT were vaginal delivery with detectable or missing VL or nonelective caesarean delivery, prematurity, breastfeeding, lack of maternal or neonatal antiretroviral therapy, detectable maternal VL, and age at first observation. Previously described increased risk of offspring of immigrant women was not confirmed., Conclusions: Risk of MTCT in Italy is ongoing, even in recent years, underling the need for implementation of the current screening program in pregnancy. Large combination neonatal prophylaxis use in preterm infants was observed, even if data on safety and efficacy in prematures are poor.

We describe the case of a young girl with vertically-transmitted HIV infection who presented with chronic ocular inflammation characterized by several relapses and remissions. Good viral and immunological status made infective or neoplastic causes unlikely; the diagnosis was challenging and finally spontaneous remission was observed after several months. Clinical and histopathological findings made idiopathic orbital inflammatory syndrome the most probable diagnosis for our patient., (© The Author(s) 2016.)

Objective: Several pieces of evidence indicate that HIV-infected adults undergo premature aging. The effect of HIV and antiretroviral therapy (ART) exposure on the aging process of HIV-infected children may be more deleterious since their immune system coevolves from birth with HIV., Design: Seventy-one HIV-infected (HIV+), 65 HIV-exposed-uninfected (HEU), and 56 HIV-unexposed-uninfected (HUU) children, all aged 0-5 years, were studied for biological aging and immune senescence., Methods: Telomere length and T-cell receptor rearrangement excision circle levels were quantified in peripheral blood cells by real-time PCR. CD4 and CD8 cells were analysed for differentiation, senescence, and activation/exhaustion markers by flow cytometry., Results: Telomere lengths were significantly shorter in HIV+ than in HEU and HUU children (overall, P < 0.001 adjusted for age); HIV+ ART-naive (42%) children had shorter telomere length compared with children on ART (P = 0.003 adjusted for age). T-cell receptor rearrangement excision circle levels and CD8 recent thymic emigrant cells (CD45RACD31) were significantly lower in the HIV+ than in control groups (overall, P = 0.025 and P = 0.005, respectively). Percentages of senescent (CD28CD57), activated (CD38HLA-DR), and exhausted (PD1) CD8 cells were significantly higher in HIV+ than in HEU and HUU children (P = 0.004, P < 0.001, and P < 0.001, respectively). Within the CD4 cell subset, the percentage of senescent cells did not differ between HIV+ and controls, but programmed cell death receptor-1 expression was upregulated in the former., Conclusions: HIV-infected children exhibit premature biological aging with accelerated immune senescence, which particularly affects the CD8 cell subset. HIV infection per se seems to influence the aging process, rather than exposure to ART for prophylaxis or treatment.

Background: Excess risks for death/opportunistic disease in adults randomized to CD4-driven planned treatment interruption (PTI) in the Strategies for Management of Antiretroviral Therapy (SMART) trial remained after antiretroviral therapy (ART) re-initiation. Risks for children following PTI were evaluated in long-term follow-up of children in the PENTA 11 trial., Methods: Children with HIV RNA below 50 copies/ml and CD4 at least 30% (2-6 years) or at least 500 cells/μl (7-15 years) were randomized to continuous ART (cART) or PTI in PENTA 11 (ISRCTN 36694210). After the end of the trial, all were recommended to resume ART. Data were collected annually and analysed up to the second year of visit., Results: One hundred and one (51 cART, 50 PTI; median baseline age 9.2 years) children had median overall follow-up 4.6 (range 3.7-5.0) years. During 2-year post-trial period, there were no deaths or new Centers for Disease Control and Prevention (CDC) stage B/C events. Rate of clinical grade of at least two events was similar between PTI and cART [relative risk (RR) 1.03; 95% confidence interval (CI) 0.43, 2.50; P = 0.94]. At 2 years, difference in absolute CD4% between PTI and cART was -1.6% (-4.5%; 1.3%; P = 0.27), and proportions with HIV RNA below 50 copies/ml were 82 versus 86% (P = 0.57), respectively; no differences in growth or fasting lipids were observed. Key predictors of greater CD4% recovery after re-initiating ART were higher CD4% at baseline (P < 0.001) and longer time since ART re-initiation (P < 0.001). During overall follow-up, 4 (8%) PTI versus 5 (10%) CT children switched ART for failure (P = 0.75) and 9 (18%) versus 1 (2%) (P = 0.008) substituted ART for simplification., Conclusions: No adverse clinical, immunological or virological consequences of PTI were observed 2 years after the end of PENTA 11 trial. Although ART interruption is not generally recommended, it may be an acceptable option for children, particularly when there is high risk of unplanned treatment interruptions.

There have been no paediatric randomised trials describing the effect of planned treatment interruptions (PTIs) of antiretroviral therapy (ART) on adherence, or evaluating acceptability of such a strategy. In PENTA 11, HIV-infected children were randomised to CD4-guided PTIs (n = 53) or continuous therapy (CT, n = 56). Carers, and children if appropriate, completed questionnaires on adherence to ART and acceptability of PTIs. There was no difference in reported adherence on ART between CT and PTI groups; non-adherence (reporting missed doses over the last 3 days or marking <100 % adherence since the last clinical visit on a visual analogue scale) was 18 % (20/111) and 14 % (12/83) on carer questionnaires in the CT and PTI groups respectively (odds ratios, OR (95 % CI) = 1.04 (0.20, 5.41), χ(2) (1) = 0.003, p = 0.96). Carers in Europe/USA reported non-adherence more often (31/121, 26 %) than in Thailand (1/73, 1 %; OR (95 % CI) = 54.65 (3.68, 810.55), χ(2) (1) = 8.45, p = 0.004). The majority of families indicated they were happy to have further PTIs (carer: 23/36, 64 %; children: 8/13, 62 %), however many reported more clinic visits during PTI were a problem (carer: 15/36, 42 %; children: 6/12, 50 %).

This multicenter, prospective, observational study assessed the global economic impact of HIV care in a large cohort of HIV-infected children and adolescents in Italy. Three pediatric departments of reference participated on a voluntary basis. Centers were asked to enroll all their children during the period April 2010-March 2011. At enrollment, a pediatrician completed a questionnaire for each patient, including the type of service at access (outpatient consultation or day hospital), laboratory tests, instrumental examinations, specialists' consultations, antiretroviral therapy and opportunistic illness prophylaxis. Eligible patients had a confirmed diagnosis of HIV infection caused by direct vertical maternal-fetal transmission, their age ranging from 0 to 24 years. Since patients routinely have quarterly check-ups in all three centers, we adopted a three-month time horizon. Health-care services were priced using outpatient and inpatient tariffs. Drug costs were calculated by multiplying the daily dose by the public price for each active ingredient. A total of 142 patients were enrolled. More than half the patients were female and the mean age was 14 years, with no significant differences by center. There were substantial differences in health-care management among the three centers, particularly as regards the type of access. One center enrolled the majority of its patients in day-hospital and prescribed a large number of clinical tests, while children accessed another center almost exclusively through outpatient consultation. Drug therapy was the main cost component and was very similar in all three centers. The day-hospital was the second highest cost component, much higher than outpatient consultation (including examinations), leading to significant differences between total costs per center. These findings suggest that a recommendation to the Italian National Health Service would be to use more outpatient consultation for patients' access in order to increase their efficiency in treating pediatric HIV infection.

This experimental retrospective multicenter study carried out on 30 seropositive children treated with Highly Active Antiretroviral Therapy (HAART), between the ages of 18 months and 14 years, in the clinical categories Centers for Disease Control (CDC) classification 1993 A (mildly symptomatic), B (moderately symptomatic) and C (severely symptomatic) aims to: 1) clinically and immunologically demonstrate the therapeutic benefits of HAART; 2) monitor the frequency of AIDS-related oral diseases in seropositive children with HAART therapy; 3) monitor the plasma levels of total CD4, CD4 percent, CD8 percent, CD4-CD8 lymphocytes and viral load from 1997 to 30 April, 2011. The statistic methods used are the analysis of covariance and the Bonferroni Test. More than 100 AIDS-related oral diseases were found in the study samples, the most frequent being: oral candidiasis, oropharyngeal candidiasis, HSV-1 herpetic esophagyitis, herpetic gingivolstomatitis (RHOG), recurrent aphthous stomatitis (RAS), parotid swelling, oral hairy leukoplakia (OHL), Herpes simplex 1 (HSV-1), linear gingival erythema (LGE), necrotizing gingivitis (NUG), facial lipodistrophy, facial-cervical lymphadenopathy (FCL), xerostomia, dysgeusia, hyposmia, oral mucosa hyperpigmentation (OMP). The Bonferroni test showed a significant difference between the mean plasma values (mpVTL) of total CD4, CD4 percentage, CD4-CD8 T lymphocytes and Viral Load (VL) of the various oral diseases found in the study samples. The therapeutic benefits of HAART are: immune reconstitution; reduction of the HIV/AIDS-related stomatology diseases; prevention and cure of the AIDS correlated neoplasias; reduction in maternal-fetal transmission of the HIV virus. The negative effects of HAART in relation to odontostomatolgy are: increase in oral lesions from HPV; xerostomia; dysgeusia/ageusia, hyposmia, perioral paresthesia; hyperpigmentation of oral mucosa; facial lipodystrophy, recurrent aphthous stomatitis (RAS). No case of immune reconstitution inflammatory syndrome or human papillomavirus (HPV)-related oral diseases were found in this study.

Toll-like receptors (TLRs) and defensins (DEFs) play a crucial role in the host's innate immunity and may influence HIV-1 disease progression. We investigated the impact of TLR9 +1174G > A, 1635A > G and DEFβ1 -44C > G, -52G > A single nucleotide polymorphisms on the clinical outcome of 95 HIV-1-infected children. The TLR9 1635AG genotype and TLR9 [G;G] haplotype were associated with rapid disease progression, whereas the DEFβ1 -44CG genotype and DEFβ1 [G;G] haplotype correlated with a better clinical outcome.

Stromal cell-Derived Factor 1 (SDF1) is the natural ligand of CXCR4, the coreceptor of HIV-1 X4 viruses. This study investigated the role of the single nucleotide polymorphism (SNP) rs1801157 (NM&#95;000609.5:c.*519G>A) of the SDF1 gene in the natural history of mother-to-child transmission of HIV-1 and disease progression of HIV-1-infected children. The study was conducted in 428 children born to HIV-1-seropositive mothers, who had not undergone antiretroviral therapy (ART) during pregnancy, and in 120 HIV-1-infected children for whom the end-point was the onset of AIDS or the initiation of ART; 16 children developed early AIDS (<24 months of life), 13 from 24 to 84 months of age, and 14 had late AIDS (>84 months). The rs1801157 SNP was not associated with risk of perinatal infection in any genetic models tested. By contrast, this SNP influenced disease progression in a time-dependent manner. rs1801157 GA heterozygous children had a higher risk of late AIDS (HR = 6.3, 95%CI 1.9-20.7, p = 0.002) than children with the rs1801157 GG genotype. Children were studied for viral coreceptor usage at birth, after 84 months of age and/or at AIDS onset. While R5 viruses using CCR5 coreceptor were predominant at birth (94%) and at early AIDS (85%), viruses using CXCR4 coreceptor emerged during the course of infection and were detected in 49% of children older than 84 months and in 62% of late AIDS. The rs1801157 SNP did not influence the emergence of R5X4 viruses, but children with the rs1801157 GA genotype and R5X4 viruses were at significantly higher risk of late AIDS than children with rs1801157 GG genotype (OR = 8.0, 95% CI 1.2-52.2, p = 0.029). Our results indicate that the rs1801157 SNP does not influence perinatal infection, but impacts disease progression. This effect is time-dependent and linked to the coreceptor-usage of viral variants that undergo evolution during the course of HIV-1 infection.

The function of CD4(+) T cells with regulatory activity (T(regs)) is the down-regulation of immune responses. This suppressive activity may limit the magnitude of effector responses, resulting in failure to control human immunodeficiency virus 1 (HIV-1) infection, but may also suppress chronic immune activation, a characteristic feature of HIV-1 disease. We evaluated the correlation between viral load, immune activation and T(regs) in HIV-1-infected children. Eighty-nine HIV-1-infected children (aged 6-14 years) were included in the study and analysed for HIV-1 plasmaviraemia, HIV-1 DNA load, CD4 and CD8 cell subsets. T(reg) cells [CD4(+)CD25(high)CD127(low) forkhead box P3 (FoxP3(high))] and CD8-activated T cells (CD8(+)CD38(+)) were determined by flow cytometry. Results showed that the number of activated CD8(+)CD38(+)T cells increased in relation to HIV-1 RNA plasmaviraemia (r = 0·403, P < 0·0001). The proportion of T(regs) also correlated positively with HIV-1 plasmaviraemia (r = 0·323, P = 0·002), but correlated inversely with CD4(+) cells (r = -0·312, P = 0·004), thus suggesting a selective expansion along with increased viraemia and CD4(+) depletion. Interestingly, a positive correlation was found between the levels of T(regs) and CD8(+)CD38(+)T cells (r = 0·305, P = 0·005), and the percentage of T(regs) tended to correlate with HIV-1 DNA load (r = 0·224, P = 0·062). Overall, these findings suggest that immune activation contributes to the expansion of T(reg) cells. In turn, the suppressive activity of T(regs) may impair effector responses against HIV-1, but appears to be ineffective in limiting immune activation., (© 2011 The Authors; Clinical and Experimental Immunology © 2011 British Society for Immunology.)

The objective of this document is to identify and reinforce current recommendations concerning the management of HIV infection in infants and children in the context of good resource availability. All recommendations were graded according to the strength and quality of the evidence and were voted on by the 57 participants attending the first Italian Consensus on Paediatric HIV, held in Siracusa in 2008. Paediatricians and HIV/AIDS care specialists were requested to agree on different statements summarizing key issues in the management of paediatric HIV. The comprehensive approach on preventing mother-to-child transmission (PMTCT) has clearly reduced the number of children acquiring the infection in Italy. Although further reduction of MTCT should be attempted, efforts to personalize intervention to specific cases are now required in order to optimise the treatment and care of HIV-infected children. The prompt initiation of treatment and careful selection of first-line regimen, taking into consideration potency and tolerance, remain central. In addition, opportunistic infection prevention, adherence to treatment, and long-term psychosocial consequences are becoming increasingly relevant in the era of effective antiretroviral combination therapies (ART). The increasing proportion of infected children achieving adulthood highlights the need for multidisciplinary strategies to facilitate transition to adult care and maintain strategies specific to perinatally acquired HIV infection.

This review provides an update on the most relevant issues concerning the current management of HIV infection in infants and children. Tremendous progress has been made over the last few years to diagnose and treat infants and children with HIV infection, yet much remains to be done. Every day there are nearly 1150 new infections in children under 15 years of age, more than 90% of them occurring in the developing world and most being the result of transmission from mother-to-child (WHO 2008). The comprehensive approach to preventing mother-to-child transmission (MTCT) has clearly reduced the number of children acquiring the infection in Western countries; while a further reduction of mother-to-child transmission should be aimed for personalized setting, specific intervention needs to be put in place and new efforts are now required in order to optimise treatment and care in HIV-infected children. The prompt initiation of treatment and a careful selection of first-line regimen, which considers potency as well as tolerability remain central. In addition, occurrence and prevention of opportunistic infections, adherence as well as long-term psychosocial consequences are becoming more and more relevant in the era of effective antiretroviral therapy. This article forms part of a special issue of Antiviral Research marking the 25th anniversary of Antiretroviral Drug Discovery and Development, vol. 85, issue 1, 2010., (Copyright 2009 Elsevier B.V. All rights reserved.)

Background: Perinatal HIV-1 infection is acquired in the milieu of a developing immune system, leading to high levels of uncontrolled viral replication. Few data have been reported that address the viral dynamics and immunological response in infants who initiated aggressive antiretroviral therapy (ART) shortly after birth., Methods: Six HIV-1-infected infants who started ART within 3 months of age were studied. The median followup was 61 months. Plasma HIV-1 RNA, cell-associated HIV-1 DNA, unspliced and multiply spliced HIV-1 mRNAs, HIV-1 antibodies, and CD4+ and CD8+ T-cell subsets were assessed in sequential peripheral blood samples. HIV-1 cellular immune response was measured by EliSpot assay., Results: All children showed a decline in plasma viraemia to undetectable levels. HIV-1 DNA persisted in four children, but only two of these had detectable HIV-1 mRNA. All viral parameters remained persistently negative in two children. Only two children produced HIV-1 antibodies, while the others, after having lost maternal antibodies, remained seronegative. No HIV-1 cellular immune response was observed in any child. Therapy interruption was performed in two children: one HIV-1-seropositive and one HIV-1-seronegative with persistently undetectable levels of all viral parameters. Rebound of HIV-1 plasma viraemia in the seronegative child was more rapid and higher than that observed in the seropositive child., Conclusions: Early ART treatment in infants modifies the natural course of infection by controlling HIV-1 replication and reducing viral load to below the threshold levels required for onset of HIV-1 immune response, but does not prevent the establishment of a reservoir of latently infected cells that precludes virus eradication.

Because of a lack of prevention policies or problems in implementing prevention of mother-to-child transmission (P-MTCT), most of the 1500 daily new HIV infections in children aged<15 years are caused by MTCT. Fifteen percent of all HIV-infected individuals are children, but the vast majority lack access to highly active antiretroviral therapy (HAART), which can drastically reduce morbidity and mortality. There are 22 antiretroviral drugs currently approved by the US FDA for use in the treatment of HIV-infected adults and adolescents, but only 12 of these drugs are approved for use in children. Antiretroviral drugs belong to four major classes: nucleoside and nucleotide analogue reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors and fusion inhibitors. According to international guidelines developed by organizations including WHO, the Paediatric European Network for Treatment of AIDS (PENTA) and the US National Institutes of Health (US-NIH), the treatment of choice for HIV-infected children and adults is a combination of two NRTIs (backbone treatment) plus a third potent agent from a different class, either an NNRTI or a ritonavir-boosted protease inhibitor. There are specific challenges in treating HIV-infected children, including uncertainty about the best time to start treatment, the need for more paediatric formulations, the lack of pharmacokinetic studies for new drugs, and incomplete dosing guidelines. Furthermore, the most appropriate regimen for an individual child depends on a variety of factors, including the age of the child; the availability of appropriate drug formulations; the potency, complexity and toxicity of the drug regimen; the home situation; the child and caregiver's ability to adhere to the regimen; and the child's antiretroviral treatment history. In addition, antiretroviral drugs are not licensed for all age groups and the drugs are often not affordable. This review describes NNRTI and protease inhibitors as key components of first- and second-line antiretroviral therapy (ART), focusing on the rationale for choosing an NNRTI- versus protease inhibitor-based regimen based on the results of available phase II and III studies. Some of the new agents available for children as second-line and salvage therapy both on- and off-label are also discussed. The drug regimens described in this review are relevant to clinicians in developed and developing countries. The availability of new, potent compounds with different resistance and toxicity profiles may represent an alternative option to interclass switching and could redefine ART strategy, including the option of first-line NRTI-sparing regimens.

Immune repopulation, despite virological failure, often occurs in children under highly active anti-retroviral therapy (HAART). The aim of this study was to analyse the characteristics of immune repopulation and activation in children with and without virological response to HAART. Fourteen human immunodeficiency virus type 1 (HIV-1)-infected children with suppression of HIV-1 plasma viraemia (virological responders, VR) and 16 virological non-responders (VNR) to therapy were studied at baseline and after approximately 2 years of HAART. During therapy, CD4+ T cells increased in both groups, but were higher in the VR than in the VNR group. All CD4+ T cell subsets (naive, central memory, effector/memory and CD38+) increased significantly in VR children, while there was a significant increase only in naive cells in VNR children. Naive CD8+ T cells and T cell receptor rearrangement excision circles (TREC), an indicator of thymic output, increased in both VR and VNR children. Activated CD8+ CD38+ T cells decreased in VR but remained high in VNR children. Levels of circulating lipopolysaccharide (LPS), an indicator of microbial translocation, further increased in VNR children. In conclusion, HAART induced an increase in naive cells in all children, regardless of their virological response. However, the persistence of viraemia resulted in an impaired expansion of memory CD4+ T cells susceptible to HIV-1 infection, and together with the microbial translocation sustained the persistence of a high level of immune activation.

By the end of 2006, approximately 2.3 million children worldwide were living with HIV infection, representing about 15% of all HIV-infected individuals but only 5-7% of the total population of treated patients worldwide. Despite a general increase in the use of antiretroviral therapy (ART) in resource-limited settings, appropriate care and ART remain inaccessible for most of the world's HIV-infected children. ART of children is challenging because of a general lack of paediatric formulations (including tablets in paediatric strengths), limited options of drugs available for children (some have been approved only for use in adults), different viral and immunological responses, dependency on caregivers for administration of the therapy, and specific issues of toxicity in long-term therapy related to maturation and development. As in adults, nucleoside reverse transcriptase inhibitors (NRTIs) are a key component of any ART schedule in children, being the recommended 'backbone' treatment in US, European and WHO guidelines, and, indeed, NRTIs have been extensively studied in children. NRTIs are the class of antiretroviral drugs that have more drugs licensed for paediatric use and more paediatric formulations.Generally, the dual NRTI backbone treatment of combination with a non-NRTI (NNRTI) or protease inhibitor (PI) should comprise a cytidine analogue (lamivudine, emtricitabine) and a thymidine analogue (stavudine, zidovudine), guanosine analogue (i.e. abacavir), or nucleotide RTI (NtRTI; i.e. tenofovir). European and US guidelines recommend the use of triple NRTI therapy (abacavir/lamivudine/zidovudine) in children with anticipated poor adherence to other treatment regimens because of tablet burden. In conclusion, while use of ART in children needs to be dramatically increased, selecting and administering the best drug combination for children is still limited by a lack of paediatric formulations and knowledge of drug metabolism, safety and efficacy in children. NRTIs are already a key component of paediatric ART, but fixed-dose combinations and specific research in children are needed to optimise their use. In this article we review the available information to facilitate selection of the best NRTI for backbone treatment in combination ART for HIV-infected children.

Purpose: To evaluate the impact of highly active antiretroviral therapy (HAART) on cancer incidence in HIV-infected children throughout a 20-year period., Patients and Methods: An observational population study was conducted on 1,190 perinatally HIV-infected children enrolled onto the Italian Register for HIV Infection in Children from 1985 to 2004 and never lost to follow-up (total observation time, 10,037.66 years). Cancer rates were calculated in the pre-HAART (1985 to 1995), early HAART (1996 to 1999), and late HAART (2000 to 2004) periods and compared using Poisson regression adjusted for age. The proportion of HAART-treated children increased from 4.1% in 1996 to 60.4% in 1999 and to 81.5% in 2004. In the same time frame, the proportion of children receiving HAART for at least 2 years increased from 3.1% to 77.0%., Results: Overall, 35 cancers occurred. Cancer rates were 4.49 (95% CI, 2.37 to 6.64), 4.09 (95% CI, 1.68 to 6.50), and 0.76 (95% CI, 0.00 to 1.80) per 1,000 children per year in 1985 to 1995, 1996 to 1999, and 2000 to 2004, respectively. Notably, there was no significant difference comparing the periods from 1985 to 1995 and 1996 to 1999 (P = .081). By contrast, cancer rates were significantly lower in the period from 2000 to 2004 than in 1996 to 1999 (P < .0001). Results were confirmed by separately analyzing data from children observed from birth (P = .418 for 1985 to 1995 v 1996 to 1999; P = .001 for 1996 to 1999 v 2000 to 2004)., Conclusion: Dramatically reduced cancer rates were observed only in the late HAART period in parallel to the increasing proportion of children receiving HAART therapy.

To investigate the decay of the human immunodeficiency virus type 1 (HIV-1) reservoir in children receiving highly active antiretroviral therapy (HAART), we measured HIV-1 DNA in peripheral blood mononuclear cells from 14 children who achieved and maintained suppression of plasma viremia up to 48 months after the initiation of HAART. Levels of intracellular unspliced and multiply spliced HIV-1 RNA were used as markers of residual viral replication. During the first month of HAART, there were significant decays in levels of both plasma HIV-1 RNA and multiply spliced HIV-1 RNA, yet unspliced HIV-1 RNA persisted in most of the children. Greater HIV-1 DNA decay during the first month of HAART correlated with a higher concomitant increase in CD4(+) cell counts (P=.028) and a smaller subsequent HIV-1 DNA decay (P=.0012). Furthermore, HIV-1 DNA decayed faster from 1 to 9 months of HAART (median half-life, 5 months) than during the subsequent follow-up period (median half-life, 30 months). Moreover, after 9 months of HAART, HIV-1 DNA tended to decay more slowly in children with detectable levels of unspliced HIV-1 RNA. These findings suggest that clearance of the viral reservoir in HAART-treated children may be influenced by immune repopulation and residual viral replication and may help in refining long-term treatment strategies.

Objectives: Lopinavir/ritonavir is approved for treatment of HIV-infected children at a dosage regimen of 230/57.5 mg/m(2) twice daily. However, once daily administration could increase convenience and patient adherence. Our study aimed at evaluating whether inhibitory concentrations are maintained in plasma following administration of lopinavir/ritonavir once daily., Patients and Methods: Lopinavir/ritonavir was administered at the standard twice daily regimen to 21 HIV-infected children, as a component of their antiretroviral treatment. Following at least 1 month of administration, seven patients received a dose of 460/115 mg/m(2) once daily for three consecutive days. After the third dose of once daily administration, blood samples were drawn at the following times: 0 (pre-dose), 1, 2 and 4 h following administration. The pre-dose (C(min)) and the peak (C(max)) concentrations were compared with the values obtained following twice daily administration in all the study patients., Results: Median (interquartile range) C(min) with the once daily regimen was 1.59 (0.77-6.85) mg/L versus 7.90 (5.45-9.77) mg/L with the twice daily regimen (P < 0.05). C(min) was considered inhibitory for wild-type virus (>1.0 mg/L) in four out of seven patients. C(max) did not differ significantly between the once daily and twice daily regimens., Conclusions: Our small pilot study suggests that lopinavir/ritonavir once daily may be a suitable regimen for antiretroviral-naive children. However, due to the high interindividual variability and low concentrations in some patients, therapeutic drug monitoring may be necessary to ensure that concentrations are adequate to inhibit viral replication. A formal clinical study of lopinavir/ritonavir once daily in treatment-naive children is warranted.

Administration of potent antiretroviral combination therapy in the second and third trimester of pregnancy and during delivery, and for 6 weeks postpartum to the infant, may reduce HIV transmission from the mother to the child to <2% in formula-fed infants. In resource-constrained settings where women have limited access to antenatal care, use of shorter and more practical regimens, including nucleoside reverse transcriptase inhibitors (NRTIs) and/or non-NRTIs (NNRTIs) commenced later in pregnancy, has demonstrated efficacies ranging from 18% to 70% in breast- and bottle-fed populations. Because shorter interventions include regimens such as single-dose nevirapine or zidovudine monotherapy, which do not provide maximal suppression of viral replication, emergence of resistant mutations in mother and infant occurs frequently, primarily after exposure to drugs with low genetic barriers (i.e. those requiring only one genotypic mutation to develop resistance), such as nevirapine. Different studies have reported nevirapine resistance rates ranging from 25% to 69% in mothers receiving single-dose nevirapine alone. Because NNRTI-based combinations of antiretroviral agents are recommended as first-line therapy in countries where single-dose nevirapine is the main option for preventing mother-to-child transmission of HIV, concerns have been raised as to whether single-dose nevirapine prophylaxis can compromise the efficacy of subsequent NNRTI-based antiretroviral therapy regimens. However, although some studies have shown that nevirapine exposure may impact on short-term virological outcome, the clinical relevance of nevirapine resistance remains unclear, especially in women who start treatment >6 months after delivery or in those who are not severely immunocompromised. Furthermore, studies have shown that adding short-course (up to 7 days) zidovudine or zidovudine/lamivudine prophylaxis after delivery may dramatically reduce the occurrence of nevirapine resistance in both mothers and infants. Until data are available that allow a better understanding of the relevance of antiretroviral drug resistance acquired as a result of mother-to-child HIV transmission prophylaxis, women and children who have previously received single- dose nevirapine as part of a mother-to-child transmission prevention strategy should be considered eligible for NNRTI-based regimens and should not be denied access to antiretroviral therapy.

The aim of this prospective, self-controlled, single-blind study was to assess the effect of montelukast added to maintenance therapy with inhaled corticosteroids (ICS) on fractional exhaled nitric oxide (FENO) in asthmatic children. Thirty-five children (age 11.2+/-0.4 yrs (mean+/-SEM)) with mild-to-moderate persistent asthma treated with low to medium doses of ICS and FENO > 20 parts per billion (ppb) were included. The patients were randomly assigned to two groups: 17 patients continued ICS (group C) and 18 had montelukast added to ICS for 3 weeks (group M). FENO measurements were performed in both groups at baseline (T1) and after 3 weeks (T2), and in group M also after 2 weeks of washout. FENO was measured by a chemiluminescence analyser using an on-line method (50 mL x s(-1)) with nitric oxide-free air. The overall mean daily dose of ICS was equivalent to 530+/-58 microg x day(-1) of beclomethasone in group M and to 564+/-55 microg x day(-1) of beclomethasone in group C. There were no significant differences in baseline FENO and forced expiratory volume in one second (FEV1) between the two groups. After 3 weeks there was a significant reduction of FENO values in patients of group M (T1 52.2+/-7.8 ppb, T2 36.1+/-4.6 ppb) but no significant changes in group C (T1 43.5+/-6.0 ppb, T2 47.8+/-9.4 ppb). In group M after 2 weeks of montelukast withdrawal, FENO rose to baseline values (55.6+/-8.7 ppb). In conclusion, after montelukast treatment there is a fractional exhaled nitric oxide reduction in asthmatic children receiving maintenance therapy with inhaled corticosteroids. This suggests an anti-inflammatory effect of montelukast additive to that of inhaled corticosteroids.

The effect of CC-chemokine receptor 5 (CCR5) promoter polymorphisms on the natural history of human immunodeficiency virus (HIV) disease was studied in 73 HIV-1-infected children. The CCR5(59338-59537) promoter haplotype, CCR5-59029A/G polymorphism, and CCR5Delta32 and CCR2-64I alterations were investigated. After exclusion of carriers of CCR5Delta32 or CCR2-64I, Kaplan-Meier analysis disclosed that children with the P1/P1(59353C,59356C,59402A) genotype progressed faster to disease than did children with other haplotypes (P=.016). When CCR2-64I carriers were included, this effect had borderline significance (P=.065) and was lost when CCR5Delta32 carriers were also considered (P=.387). The P1/P1 effect was strongest early after infection, when progression to disease was mainly associated with CCR5 coreceptor-using viruses. These results indicate that the P1/P1 genotype is predictive of rapid progression in HIV-1-infected children lacking CCR5Delta32 or CCR5-64I alleles. The observation of a linkage disequilibrium between P1 and 59029A might explain the previously reported association between 59029A homozygosity and rapid disease progression.

It is estimated that approximately 6000 women of childbearing age, mostly living in the developing world, acquire HIV infection every day. Taking into account that approximately 98% of HIV infected children have acquired HIV from the mother, during pregnancy, at delivery or through breastfeeding, therefore, prevention of mother-to-child transmission (MTCT) is a major health priority. Several studies have showed how MTCT of HIV may be prevented using antiretrovirals. Results from a study conducted in Thailand have also recently showed how a short oral zidovudine course during pregnancy and labor may reduce the risk of HIV transmission by approximately 50%. These findings represent a major challenge for the International Health Agencies and Organizations that will have the major obligation to provide HIV tests, counseling and antiviral drugs in settings with high HIV prevalence.