Long-term clinical, virological and immunological outcomes following planned treatment interruption in HIV-infected children.

OBJECTIVES: Planned treatment interruption (PTI) of antiretroviral therapy (ART) in adults is associated with adverse outcomes. The PENTA 11 trial randomized HIV-infected children to continuous ART (CT) vs. CD4-driven PTIs. We report 5 years' follow-up after the end of main trial. METHODS: Post-trial, all children resumed ART. Clinical, immunological, virological and treatment data were collected annually. A sub-study investigated more detailed immunophenotype. CT and PTI arms were compared using intention-to-treat. Laboratory parameters were compared using linear regression, adjusting for baseline values; mixed models were used to include all data over time. RESULTS: In all, 101 children (51 CT, 50 PTI) contributed a median of 7.6 years, including 5.1 years of post-trial follow-up. Post-trial, there were no deaths, one pulmonary tuberculosis and no other CDC stage B/C events. At 5 years post-trial, 90% of children in the CT vs. 82% in the PTI arm had HIV RNA < 50 copies/mL (P = 0.26). A persistent increase in CD8 cells was observed in the PTI arm. The sub-study (54 children) suggested that both naïve and memory populations contributed to higher CD8 cells following PTI. Mean CD4/CD8 ratios at 5 years post-trial were 1.22 and 1.08 in CT and PTI arms, respectively [difference (CT - PTI) = -0.15; 95% CI: -0.34-0.05), P = 0.14]. The sub-study also suggested that during the trial and at early timepoints after the end of the trial, reduction in CD4 in the PTI arm was mainly from loss of CD4 memory cells. CONCLUSIONS: Children tolerated PTI with few long-term clinical, virological or immunological consequences.

Missed opportunities to prevent mother-to-child transmission of HIV in Italy.

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.

Paediatric European Network for Treatment of AIDS (PENTA) guidelines for treatment of paediatric HIV-1 infection 2015: optimizing health in preparation for adult life.

The 2015 Paediatric European Network for Treatment of AIDS (PENTA) guidelines provide practical recommendations on the management of HIV-1 infection in children in Europe and are an update to those published in 2009. Aims of treatment have progressed significantly over the last decade, moving far beyond limitation of short-term morbidity and mortality to optimizing health status for adult life and minimizing the impact of chronic HIV infection on immune system development and health in general. Additionally, there is a greater need for increased awareness and minimization of long-term drug toxicity. The main updates to the previous guidelines include: an increase in the number of indications for antiretroviral therapy (ART) at all ages (higher CD4 thresholds for consideration of ART initiation and additional clinical indications), revised guidance on first- and second-line ART recommendations, including more recently available drug classes, expanded guidance on management of coinfections (including tuberculosis, hepatitis B and hepatitis C) and additional emphasis on the needs of adolescents as they approach transition to adult services. There is a new section on the current ART 'pipeline' of drug development, a comprehensive summary table of currently recommended ART with dosing recommendations. Differences between PENTA and current US and World Health Organization guidelines are highlighted and explained.

Antibiotics Prescriptions in the Neonatal Intensive Care Unit: How to Overcome Everyday Challenges.

Antimicrobial prescriptions in neonatal intensive care units (NICUs) represent a point of concern for the emergence of MDROs and for morbidity associated with prolonged antibiotic exposure (e.g., invasive candidiasis, necrotizing enterocolitis, and late-onset sepsis). Antimicrobial stewardship programs (ASPs) have shown to be a valuable tool for the prevention of resistance with the goals of optimizing clinical outcomes while decreasing unnecessary prescribing. The most frequent ASP strategies include the correct collection and interpretation of microbiological specimens, prescription of the narrowest-spectrum antibiotic appropriate for a particular case, and de-escalation or discontinuation of therapy in defined situations. A robust ASP requires everyday multidisciplinary collaboration between ID physicians, neonatologist, clinical pharmacists, clinical microbiologists, infection control professionals, hospital epidemiologists, and information services specialists. Education and clinical pathways (e.g., sepsis or surgical prophylaxis pathways) are an excellent starting point if followed by proactive interventions such as prospective audits and feedback and formulary restriction with prior antimicrobial authorization. The current review outlines the problems faced in NICU antimicrobial prescribing and presents various solutions from the literature.

Unravelling the Paediatric and Perinatal Zika Virus Epidemic through Population-based Research.

Zika virus epidemic now involves 72 countries, worldwide. Transmission is multimodal through mosquito bites and blood and body fluids. Zika virus causes Guillain Barre Syndrome syndrome and pregnancy complications including perinatal microcephaly. Diagnosis is complicated by subclinical infection in 80%, co-circulation with dengue and chikungunya fevers with similar presentations and cross-reactivity in serological tests. There is no cure, or preventive vaccine. Large population-based studies will help to elucidate ZIKV epidemiology, vertical transmission, risks to the fetus of maternal ZIKV infection and natural history of congenital and non-congenital ZIKV infection as provided by the activities in the "ZIKAction" research consortium in Latin America, Europe and the Caribbean, which was recently funded by the European Commission.

Successful private-public funding of paediatric medicines research: lessons from the EU programme to fund research into off-patent medicines.

UNLABELLED: The European Paediatric Regulation mandated the European Commission to fund research on off-patent medicines with demonstrated therapeutic interest for children. Responding to this mandate, five FP7 project calls were launched and 20 projects were granted. This paper aims to detail the funded projects and their preliminary results. Publicly available sources have been consulted and a descriptive analysis has been performed. Twenty Research Consortia including 246 partners in 29 European and non-European countries were created (involving 129 universities or public-funded research organisations, 51 private companies with 40 SMEs, 7 patient associations). The funded projects investigate 24 medicines, covering 10 therapeutic areas in all paediatric age groups. In response to the Paediatric Regulation and to apply for a Paediatric Use Marketing Authorisation, 15 Paediatric Investigation Plans have been granted by the EMA-Paediatric Committee, including 71 studies of whom 29 paediatric clinical trials, leading to a total of 7,300 children to be recruited in more than 380 investigational centres. CONCLUSION: Notwithstanding the EU contribution for each study is lower than similar publicly funded projects, and also considering the complexity of paediatric research, these projects are performing high-quality research and are progressing towards the increase of new paediatric medicines on the market. Private-public partnerships have been effectively implemented, providing a good example for future collaborative actions. Since these projects cover a limited number of off-patent drugs and many unmet therapeutic needs in paediatrics remain, it is crucial foreseeing new similar initiatives in forthcoming European funding programmes.

Incidence and clinical presentation of acute otitis media in children aged <6 years in European medical practices.

We conducted an epidemiological, observational cohort study to determine the incidence and complications of acute otitis media (AOM) in children aged <6 years. Data on physician-diagnosed AOM were collected from retrospective review of medical charts for the year preceding enrolment and then prospectively in the year following enrolment. The study included 5776 children in Germany, Italy, Spain, Sweden, and the UK. AOM incidence was 256/1000 person-years [95% confidence interval (CI) 243-270] in the prospective study period. Incidence was lowest in Italy (195, 95% CI 171-222) and highest in Spain (328, 95% CI 296-363). Complications were documented in <1% of episodes. Spontaneous tympanic membrane perforation was documented in 7% of episodes. Both retrospective and prospective study results were similar and show the high incidence during childhood in these five European countries. Differences by country may reflect true differences and differences in social structure and diagnostic procedures.

Preparedness for admission of patients with suspected Ebola virus disease in European hospitals: a survey, August-September 2014.

In response to the Ebola virus disease (EVD) outbreak in West Africa, the World Health Organization has advised all nations to prepare for the detection, investigation and management of confirmed and suspected EVD cases in order to prevent further spread through international travel. To gain insights into the state of preparedness of European hospitals, an electronic survey was circulated in August­September 2014 to 984 medical professionals representing 736 hospitals in 40 countries. The survey addressed the willingness and capacity to admit patients with suspected EVD as well as specific preparedness activities in response to the current Ebola crisis. Evaluable responses were received from representatives of 254 (32%) hospitals in 38 countries, mostly tertiary care centres, of which 46% indicated that they would admit patients with suspected EVD. Patient transfer agreements were in place for the majority of hospitals that would not admit patients. Compared with non-admitting hospitals, admitting hospitals were more frequently engaged in various preparedness activities and more often contained basic infrastructural characteristics such as admission rooms and laboratories considered important for infection control, but some gaps and concerns were also identified. The results of this survey help to provide direction towards further preparedness activities and prioritisation thereof.

Background rates of 41 adverse events of special interest for COVID-19 vaccines in 10 European healthcare databases - an ACCESS cohort study.

BACKGROUND: In May 2020, the ACCESS (The vACCine covid-19 monitoring readinESS) project was launched to prepare real-world monitoring of COVID-19 vaccines. Within this project, this study aimed to generate background incidence rates of 41 adverse events of special interest (AESI) to contextualize potential safety signals detected following administration of COVID-19 vaccines. METHODS: A dynamic cohort study was conducted using a distributed data network of 10 healthcare databases from 7 European countries (Italy, Spain, Denmark, The Netherlands, Germany, France and United Kingdom) over the period 2017 to 2020. A common protocol (EUPAS37273), common data model, and common analytics programs were applied for syntactic, semantic and analytical harmonization. Incidence rates (IR) for each AESI and each database were calculated by age and sex by dividing the number of incident cases by the total person-time at risk. Age-standardized rates were pooled using random effect models according to the provenance of the events. FINDINGS: A total number of 63,456,074 individuals were included in the study, contributing to 211.7 million person-years. A clear age pattern was observed for most AESIs, rates also varied by provenance of disease diagnosis (primary care, specialist care). Thrombosis with thrombocytopenia rates were extremely low ranging from 0.06 to 4.53/100,000 person-years for cerebral venous sinus thrombosis (CVST) with thrombocytopenia (TP) and mixed venous and arterial thrombosis with TP, respectively. INTERPRETATION: Given the nature of the AESIs and the setting (general practitioners or hospital-based databases or both), background rates from databases that show the highest level of completeness (primary care and specialist care) should be preferred, others can be used for sensitivity. The study was designed to ensure representativeness to the European population and generalizability of the background incidence rates. FUNDING: The project has received support from the European Medicines Agency under the Framework service contract nr EMA/2018/28/PE.

Surveillance of HIV drug resistance in children receiving antiretroviral therapy: a pilot study of the World Health Organization's generic protocol in Maputo, Mozambique.

Between 2007 and 2008, the Mozambique Ministry of Health conducted an assessment of human immunodeficiency virus drug resistance (HIVDR) using World Health Organization (WHO) methods in a cohort of children initiating antiretroviral therapy (ART) at the main pediatric ART referral center in Mozambique. It was shown that prior to ART initiation 5.4% of children had HIVDR that was associated with nevirapine perinatal exposure (P < .001). Twelve months after ART initiation, 77% had viral load suppression (<1000 copies/mL), exceeding the WHO target of ≥ 70%; 10.3% had HIVDR at 12 months. Baseline HIVDR (P = .04), maternal prevention of mother-to-child transmission (P = .02), and estimated days of missed medication (P = .03) predicted HIVDR at 12 months. As efforts to eliminate pediatric AIDS are intensified, implementation of ritonavir-boosted protease inhibitor regimens in children with prevention of mother-to-child transmission exposure may reduce risk of virological failure in our setting.

Correlation between viral load, plasma levels of CD4 - CD8 T lymphocytes and AIDS-related oral diseases: a multicentre study on 30 HIV+ children in the HAART era.

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.

Regulatory T cells and chronic immune activation in human immunodeficiency virus 1 (HIV-1)-infected children.

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.

Italian consensus statement on paediatric HIV infection.

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.

Correction to: Implementation and impact of pediatric antimicrobial stewardship programs: a systematic scoping review.

The original article [1] contains an error in Fig. 1 whereby the number of selected articles of the first box is incorrect.

Implementation and impact of pediatric antimicrobial stewardship programs: a systematic scoping review.

Background: Antibiotics are the most common medicines prescribed to children in hospitals and the community, with a high proportion of potentially inappropriate use. Antibiotic misuse increases the risk of toxicity, raises healthcare costs, and selection of resistance. The primary aim of this systematic review is to summarize the current state of evidence of the implementation and outcomes of pediatric antimicrobial stewardship programs (ASPs) globally. Methods: MEDLINE, Embase and Cochrane Library databases were systematically searched to identify studies reporting on ASP in children aged 0-18 years and conducted in outpatient or in-hospital settings. Three investigators independently reviewed identified articles for inclusion and extracted relevant data. Results: Of the 41,916 studies screened, 113 were eligible for inclusion in this study. Most of the studies originated in the USA (52.2%), while a minority were conducted in Europe (24.7%) or Asia (17.7%). Seventy-four (65.5%) studies used a before-and-after design, and sixteen (14.1%) were randomized trials. The majority (81.4%) described in-hospital ASPs with half of interventions in mixed pediatric wards and ten (8.8%) in emergency departments. Only sixteen (14.1%) studies focused on the costs of ASPs. Almost all the studies (79.6%) showed a significant reduction in inappropriate prescriptions. Compliance after ASP implementation increased. Sixteen of the included studies quantified cost savings related to the intervention with most of the decreases due to lower rates of drug administration. Seven studies showed an increased susceptibility of the bacteria analysed with a decrease in extended spectrum beta-lactamase producers E. coli and K. pneumoniae; a reduction in the rate of P. aeruginosa carbapenem resistance subsequent to an observed reduction in the rate of antimicrobial days of therapy; and, in two studies set in outpatient setting, an increase in erythromycin-sensitive S. pyogenes following a reduction in the use of macrolides. Conclusions: Pediatric ASPs have a significant impact on the reduction of targeted and empiric antibiotic use, healthcare costs, and antimicrobial resistance in both inpatient and outpatient settings. Pediatric ASPs are now widely implemented in the USA, but considerable further adaptation is required to facilitate their uptake in Europe, Asia, Latin America and Africa.

Impact of HIV-1 Infection and Antiretroviral Therapy on Bone Homeostasis and Mineral Density in Vertically Infected Patients.

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.

Antibiotic prescriptions in acute otitis media and pharyngitis in Italian pediatric outpatients.

BACKGROUND: Acute otitis media (AOM) and pharyngitis are very common infections in children and adolescents. Italy is one of the European countries with the highest rate of antibiotic prescriptions. The aim of this study is to describe first-line treatment approaches for AOM and pharyngitis in primary care settings in Italy over six years, including the prevalence of 'wait and see' for AOM, where prescription of antibiotics is delayed 48 h from presentation, and differences in prescribing for pharyngitis when diagnostic tests are used. METHODS: The study is a secondary data analysis using Pedianet, a database including data at outpatient level from children aged 0-14 in Italy. Prescriptions per antibiotic group, per age group and per calendar year were described as percentages. "Wait and see" approach rate was described for AOM and pharyngitis prescriptions were further grouped according to the diagnostic test performed and test results. RESULTS: We identified 120,338 children followed by 125 family pediatricians between January 2010 and December 2015 for a total of 923,780 person-years of follow-up. Among them 30,394 (mean age 44 months) had at least one AOM diagnosis (n = 54,943) and 52,341 (mean age 5 years) had at least one pharyngitis diagnosis (n = 126,098). 82.5% of AOM diagnoses were treated with an antibiotic within 48 h (mainly amoxicillin and amoxicillin/clavulanate) and the "wait and see" approach was adopted only in 17.5% of cases. The trend over time shows an increase in broad spectrum antibiotic prescriptions in the last year (2015). 79,620 (63%) cases of pharyngitis were treated and among GABHS pharyngitis confirmed by rapid test 56% were treated with amoxicillin. The ones not test confirmed were treated mainly with broad spectrum antibiotics. CONCLUSIONS: Despite guidance to use the 'wait and see' approach in the age group analyzed, this strategy is not often used for AOM, as previously noted in other studies in hospital settings. Broad-spectrum antibiotic prescription was more frequent when pharyngitis was not confirmed by rapid test, in keeping with evidence from other studies that diagnostic uncertainty leads to overuse of antibiotics.

Osteomyelitis in Cat-Scratch Disease: A Never-Ending Dilemma-A Case Report and Literature Review.

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.

Lamivudine/abacavir maintains virological superiority over zidovudine/lamivudine and zidovudine/abacavir beyond 5 years in children.

OBJECTIVE: To describe the long-term efficacy over 5 years of regimens including combinations of abacavir, lamivudine and/or zidovudine in previously untreated children in the PENTA 5 trial. DESIGN: PENTA 5 was a 48-week randomised controlled trial comparing three dual nucleoside reverse transcriptase inhibitor (NRTI) combinations as part of first triple antiretroviral therapy (ART). METHODS: 128 ART-naïve children were randomised to zidovudine\lamivudine (n = 36), zidovudine\abacavir (45) or lamivudine\abacavir (47). Asymptomatic children (n = 55) were also randomised to nelfinavir or placebo; all other children received open-label nelfinavir. Analyses are intent-to-treat and adjusted for minor baseline imbalances and receipt of nelfinavir/placebo. RESULTS: Median follow-up was 5.8 years. By 5 years, 17 (47%), 28 (64%) and 18 (39%) children had changed their randomised NRTIs in the zidovudine\lamivudine, zidovudine\abacavir and lamivudine\abacavir groups respectively, but 18%, 50% and 50% of these changes were either early single drug substitutions for toxicity or switches with viral suppression (HIV-1 RNA < 400 copies/ml; e.g. to simplify regimen delivery). At 5 years, 55%/32% zidovudine\lamivudine, 50%/25% zidovudine\abacavir and 79%/63% lamivudine\abacavir had HIV-1 RNA < 400/< 50 copies/ml respectively (p = 0.03/p = 0.003). Mean increase in height-for-age 0.42, 0.68, 1.05 (p = 0.02); weight-for-age 0.03, 0.13, 0.75 (p = 0.02). Reverse transcriptase resistance mutations emerging on therapy differed between the groups: zidovudine\lamivudine (M41L, D67N, K70R, M184V, L210W, T215Y); zidovudine\abacavir (M41L, D67N, K70R, L210W, T215F/Y, K219Q); lamivudine\abacavir (K65R, L74V, Y115F, M184V). CONCLUSIONS: Five year data demonstrate that lamivudine\abacavir is more effective in terms of HIV-1 RNA suppression and growth changes, with lower rates of switching with detectable HIV-1 RNA than zidovudine\lamivudine or zidovudine\abacavir, and should be preferred as first-line NRTI backbone.