Early anakinra treatment improves cardiac outcome of multisystem inflammatory syndrome in children, regardless of disease severity.

OBJECTIVE: The main aim of this study was to define the best treatment option for multisystem inflammatory syndrome in children (MIS-C) and to analyse the role of anakinra. METHODS: This is a multicentre retrospective cohort study. Patients were treated according to the attending physician's decision. The patients were divided into four groups on the basis of the first treatment at time of admittance: (i) IVIG, (ii) IVIG and methylprednisolone (≤2 mg/kg/day), (iii) IVIG with high-dose methylprednisolone (>2 mg/kg/day) and (iv) anakinra with or without IVIG and/or methylprednisolone. Primary outcomes were defined as the presence of at least one of the following features: death, the failure of initial treatment, meaning the need for additional treatment for clinical worsening and cardiac involvement at the end of follow-up. RESULTS: Two hundred thirty-nine patients were recruited. At univariate analysis, persistent heart involvement at discharge was more frequent in those not receiving anakinra as initial treatment (3/21 vs 66/189; P = 0.047). After comparisons between the four treatment regimens, adjusting for the propensity score, we observed that early treatment with anakinra was associated with a lower probability of developing persistent heart disease at the end of follow-up (odds ratio: 0.6; 95% CI: 0.4-1.0). CONCLUSION: We report that early treatment with anakinra is safe and very effective in patients with severe MIS-C. In addition, our study suggests that early treatment with anakinra is the most favourable option for patients with a higher risk of developing a severe disease outcome.

Immune-checkpoint inhibitors in anal squamous cell carcinoma: a systematic review and meta-analysis.

INTRODUCTION: Squamous cell carcinoma of the anus (SCCA) is a rare tumor. While most patients with locally advanced disease are cured with chemo-radiotherapy, about a quarter eventually experience metastatic recurrence. Standard treatment for advanced disease is chemotherapy, but recently evidence on the activity of immunotherapy has been reported. We performed a systematic review and meta-analysis of prospective trials testing immune-checkpoint inhibitors (ICIs) in patients with SCCA. OBJECTIVE: We aimed to evaluate the overall response rate (ORR) and the disease control rate (DCR) of ICIs in patients with advanced SCCA. METHODS: We systematically searched PubMed, Embase, and Scopus, through December 31, 2022, for prospective trials assessing ICIs in patients with advanced SCCA. The primary and secondary endpoints were respectively ORR and DCR. RESULTS: Six prospective trials were included in the analysis, one of which was randomized. Overall, seven treatment arms and 347 patients have been analyzed. Five treatment arms tested ICIs as monotherapy and two arms examined ICIs in combination with cetuximab and bevacizumab, respectively. The pooled ORR was 13% (95%CI, 10%-17%), with a DCR of 57% (95%CI, 40%-74%). Results did not change in a sensitivity analysis, which excluded the two treatment arms testing the combination of ICIs with other drugs. CONCLUSIONS: The efficacy of ICIs in SCCAs is low. Combination strategies with targeted drugs or chemotherapy might represent a better therapeutic strategy for these patients. Further studies are awaited to identify resistance mechanisms to ICIs and optimize their efficacy.

Improved outcomes in women with BRAF-mutant melanoma treated with BRAF/MEK-targeted therapy across randomized clinical trials. A systematic review and meta-analysis.

Available evidence suggests that in patients with advanced BRAF V600-mutant melanoma treated with the combination of BRAF and MEK inhibitors, gender could be associated with survival outcome. We performed a systematic review and meta-analysis of all randomized clinical trials (RCTs) testing the combination of BRAF and MEK inhibitors, to assess the interaction between treatment effect and patients' gender. We searched PubMed, MEDLINE, Embase, and Scopus, for phase II and III RCTs up to January 30, 2022. We included all RCTs that enrolled patients with BRAF V600-mutant advanced cutaneous melanoma and assessed combinations of BRAF and MEK inhibitors versus BRAF inhibitor monotherapy. Our aim was to assess differences if any in treatment efficacy between men and women, measured in terms of the differences in progression-free survival (PFS) and overall survival (OS) log-hazard ratios (log-HRs). We calculated the pooled PFS- and OS-HRs with 95% confidence intervals (CIs) in men and women using a random-effects model and assessed the heterogeneity between the estimates using an interaction test. Five RCTs that enrolled a total of 2,113 patients were included in the analysis. In women, the combination of BRAF and MEK inhibitors halved the risk of progression or death as compared with BRAF inhibitor monotherapy with a pooled PFS-HR of 0.50 (95%CI 0.41-0.61). In men, the benefit obtained with BRAF and MEK inhibitors was smaller with a pooled PFS-HR of 0.63 (95%CI 0.54-0.74), P-heterogeneity = .05. A similar trend was observed for OS where the pooled OS-HR was 0.62 (95%CI 0.48-0.80) in women and only 0.78, (95%CI 0.67-0.92) in men, P-heterogeneity = 0.11. These results support meaningful gender-based heterogeneity of response to combination of BRAF and MEK inhibitors targeted therapy in patients with advanced BRAF-mutant melanoma, that should be considered in future research to improve treatment effectiveness.

To Do or Not to Do? Neurorrhaphy in Great Toe Pulp Flap Fingertip Reconstruction.

Since its inception, the great toe pulp (GTP) flap has represented a valid therapeutic choice in the reconstruction of defects of the hand. This study illustrates the clinical outcomes of GTP free flaps performed without nerve anastomosis' mainly for fingertip defect reconstruction. Methods: We performed a retrospective, monocentric cohort study. All patients included in this study presented with fingertip traumatic injury, with tendon or bone exposure; reconstruction with GTP flap, without nerve reconstruction, was performed by the first author (L.T.) from May 2019 to October 2021. Results: All 37 flaps survived completely. Due to COVID restrictions' we had to send the tests and PROMs to our patients; 28 of them replied. Cold intolerance was reported by 12 patients (moderate in two cases and mild in ten cases). No pain was complained about either in hand or donor site (Visual Analog Score 0, at rest and at movement). Complete range of motion was achieved in 22 of 28 patients. All flaps recovered protective sensitivity. In every section of the Michigan Hand Outcome Questionnaire, all patients expressed a high level of satisfaction based on the reconstruction's function and aesthetics. Regarding the donor site morbidity, no patient complained about gait disturbance. Conclusions: This study showed that the GTP flap is the optimal choice for fingertip reconstruction, providing excellent functional and aesthetic results with durable and glabrous skin, satisfactory pulp contour, and sensory restoration. These results could be achieved with no need for nerve suture, especially in defects with no injuries proximal to the loss of substance.

Thinking Out of the Box: Use of the Radial Artery Distally to the Snuffbox as Recipient Vessel.

The use of the radial artery (RA) as a recipient vessel in the hand is mainly described in the snuffbox. However, we believe that employing the RA distally to the extensor pollicis longus (EPL) tendon may provide remarkable advantages. Methods: We conducted a prospective study from June 2019 until December 2021, which included all patients who underwent reconstructive procedures with the RA distally to the snuffbox as the recipient vessel. We reviewed patients' medical records: demographics, type of trauma, defect characteristics, microsurgical procedure, reoperations, and short- and long-term complications. Results: We found 23 patients eligible for this study; 22 patients required a reconstructive procedure due to a trauma and one for a congenital malformation. RA distal to snuffbox was always identified and judged reliable and apt as a recipient vessel. There were no issues with the anastomosis and no total flap failure in all cases. The morbidity in the recipient area was also minimal, with no mobility deficits, loss of sensation, or neuroma development. Conclusions: The RA is the primary vessel in the dorsum of the distal upper limb; performing the anastomosis distally to the EPL tendon may offer various advantages, making the surgery safer and less invasive.

Beauty and Function: The Use of Trimmed Great Toe in Thumb and Finger Reconstruction.

Finger amputations are one of the most common traumas of daily life. Regularization of the digital stump is the most widely used option in the literature today. The aim of this study was to evaluate a valid functional and aesthetic alternative to amputation. Methods: We retrospectively investigated our prospective database' selecting the patients who underwent trimmed great toe flap reconstruction for the amputation of a digit from September 2019 to November 2021. All the operations were performed by the first author (L.T.) in the Reconstructive Microsurgery Service of the University Department of Hand Surgery and Rehabilitation of MultiMedica Group. Results: No flap required anastomosis revision or had major complications. The length of the amputated finger was maintained, with a high functional and aesthetic result achieved. Conclusions: The trimmed great toe flap has proven to be a viable alternative to finger amputation in the reconstruction of thumb and long finger defects, leading to high aesthetic results. The morbidity of the donor site is reduced compared with the classic great toe flap, allowing a direct closure in most cases.

Tailored Skin Flaps for Hand Reconstruction.

Acquired soft-tissue defects of the hand can be a result of different types of trauma, infection, tumor resection, or burns. The evolution of the design and types of flaps have optimized the reconstruction and, nowadays, it is important to achieve not only a functional result but also an aesthetic result. The aim of the present study is to propose a model for treating a wide variety of skin defects in the hands based on our flap experience. Methods: We conducted a retrospective study from February 2019 to January 2022, which included all patients who underwent a skin flap for hand reconstruction. Patients' medical records were reviewed and data collected included demographics, smoking status, presence of risk factors, type of trauma, flap reconstruction, dimensions, reoperations, and long-term complications. Results: A total of 99 patients underwent skin flap-based reconstruction for hand trauma between February 2019 until January 2022. The mean age was 43.9 (range 38.3-49.5), 87.9% of patients were male, and follow-up was between 2 and 30 months; 90.9% of the flaps were free flaps, and the rest were pedicle flaps (3% of them being propeller flaps). Conclusions: When planning a hand reconstruction, it is vital to ensure that the outcomes are not only functional but also aesthetic, with minimum donor site morbidity; in this study, we showed a variety of flaps that can be applied to achieve this goal. We believe that the final decision should be made after comprehending the defect and the patient's preferences.

End-to-side Anastomosis on Digital Arteries: Just a Technical Choice or a Real Benefit?

High-quality evidence is currently poor regarding the benefits of end-to-end (ETE) or end-to-side (ETS) anastomosis in arterial and venous anastomoses, despite being postulated as a potential influence on outcomes. A sufficient microvascular anastomosis is indispensable for the success of any free tissue transfer. ETS microvascular anastomoses have been becoming increasingly important as they allow reconstruction even in patients with impaired vascular status. To the authors' knowledge, no studies have examined the choice of ETE or ETS anastomoses specifically for digital arteries. Methods: We conducted a retrospective study of ETE and ETS anastomosis cases; the only inclusion criteria was that digital arteries (proper, common) were the recipient vessels. Results: Fifty-seven cases met the inclusion criteria. All the venous anastomoses were ETE. Of these cases, four total intraoperative complications (immediate thrombosis) and only one case of complete failure were registered. The ETE group consisted of 49 patients and the ETS group of eight patients. A comparison of the mean ischemia time in the two groups showed no statistically significant difference (P = 0.121). Conclusions: We observed no difference in the reconstructive outcomes of hand free-flaps and reconstruction between ETE or ETS digital arteries anastomoses. The successful microsurgical reconstruction was independent of anastomotic technique. In particular, the results of our study demonstrated no statistically significant increase of the ischemia time; thus, no prolongation of operative time can be attributed to the higher technical challenge of the anastomosis.

Avelumab plus axitinib in unresectable or metastatic type B3 thymomas and thymic carcinomas (CAVEATT): a single-arm, multicentre, phase 2 trial.

BACKGROUND: Patients with advanced type B3 thymoma and thymic carcinoma resistant to chemotherapy have few treatment options. We report the efficacy and safety results of the combination of the anti-PD-L1 inhibitor avelumab with the anti-angiogenesis drug axitinib in patients with advanced type B3 thymoma and thymic carcinoma. METHODS: CAVEATT was a single-arm, multicentre, phase 2 trial, conducted in two Italian centres (the European Instituteof Oncology and the Humanitas Institute, Milan) in patients with histologically confirmed type B3 thymoma or thymic carcinoma, with advanced stage of disease who had progressed after at least one line of platinum-based chemotherapy. Previous treatment with an anti-angiogenesis drug was allowed but not with immune checkpoint inhibitors. Other inclusion criteria were age 18 years or older, an Eastern Cooperative Oncology Group performance status of 0-2, progressive disease, and presence of measurable disease according to Response Evaluation Criteria In Solid Tumours (RECIST) version 1.1. Patients received avelumab 10 mg/kg intravenously every 2 weeks and axitinib 5 mg orally twice daily until disease progression or unacceptable toxicity. The primary endpoint was the centrally assessed overall response rate according to RECIST version 1.1. Patients who received at least one cycle of treatment and had at least one CT scan after treatment start at scheduled time point by protocol were judged assessable for response and were included in efficacy and safety analyses. This study is registered with EUDRACT, 2017-004048-38; enrolment is completed and follow-up is ongoing. FINDINGS: Between April 22, 2019, and June 30, 2021, 32 patients were enrolled. 27 patients had a thymic carcinoma, three a type B3 thymoma, and two a mixed type B3 thymoma and thymic carcinoma. 29 (91%) of 32 patients had stage IVB disease and 13 (41%) of 32 had been pretreated with an anti-angiogenesis drug. 11 of 32 patients had an overall response; thus the overall response rate was 34% (90% CI 21-50); no patients had a complete response, 11 (34%) had a partial response, 18 (56%) had stable disease, and in two patients (6%) progressive disease was the best response. The most common grade 3 or 4 adverse event was hypertension (grade 3 in six [19%] of 32 patients). Four (12%) of 32 patients developed serious adverse events that were new-onset immune-related adverse events, including one grade 3 interstitial pneumonitis, one grade 4 polymyositis, and two grade 3 polymyositis. There were no treatment-related deaths. INTERPRETATION: Avelumab combined with axitinib has promising anti-tumour activity and acceptable toxicity in patients with advanced type B3 thymoma and thymic carcinoma progressing after chemotherapy, and could emerge as a new standard treatment option in this setting. FUNDING: Pfizer.

Course of Sars-CoV2 Infection in Patients with Cancer Treated with anti-PD-1: A Case Presentation and Review of the Literature.

The outbreak of COVID-19 pandemia is a major health worldwide concern. Patients with cancer might have a worse outcome, because of the immunosuppression determined by the tumor itself and anti-cancer treatments, including chemotherapy and radiotherapy. The impact and course of viral infection in patients receiving immunotherapy remains unknown. We report the case of a patient with metastatic melanoma, long responder to anti PD-1 blockade who got infected with Sars CoV-2, recovering without sequelae. A critical review of literature was performed. Limited data available in literature support the possibility to continue the immunotherapy in patients with cancer under control.

How many research nurses for how many clinical trials in an oncology setting? Definition of the Nursing Time Required by Clinical Trial-Assessment Tool (NTRCT-AT).

Few resources are available to quantify clinical trial-associated workload, needed to guide staffing and budgetary planning. The aim of the study is to describe a tool to measure clinical trials nurses' workload expressed in time spent to complete core activities. Clinical trials nurses drew up a list of nursing core activities, integrating results from literature searches with personal experience. The final 30 core activities were timed for each research nurse by an outside observer during daily practice in May and June 2014. Average times spent by nurses for each activity were calculated. The "Nursing Time Required by Clinical Trial-Assessment Tool" was created as an electronic sheet that combines the average times per specified activities and mathematic functions to return the total estimated time required by a research nurse for each specific trial. The tool was tested retrospectively on 141 clinical trials. The increasing complexity of clinical research requires structured approaches to determine workforce requirements. This study provides a tool to describe the activities of a clinical trials nurse and to estimate the associated time required to deliver individual trials. The application of the proposed tool in clinical research practice could provide a consistent structure for clinical trials nursing workload estimation internationally.

Long-term body composition and metabolic changes in HIV-infected children switched from stavudine to tenofovir and from protease inhibitors to efavirenz.

UNLABELLED: This is an 8-year cohort study of 24 HIV-infected patients aged 5-17 years to assess body composition and metabolic changes after switching from lamivudine + stavudine (d4T) + protease inhibitors (PI) to lamivudine + tenofovir (TDF) + efavirenz (EFV). Body composition (dual-energy X-ray absorptiometry) and cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides, glucose and insulin were measured annually. Linear mixed models and generalized linear mixed models were used to evaluate time changes of the outcome of interest. Body mass index increased linearly by 0.3 kg/m(2)/year (p < 0.001); waist circumference increased non-linearly from 68 to 74 cm (p = 0.004 for the linear term and p = 0.04 for the quadratic term). Percent body fat, percent trunk fat and percent bone mineral content increased linearly by 0.6%/year (p = 0.005), 1.2%/year (p < 0.001) and 0.02%/year (p = 0.04), respectively. Percent arm fat remained stable (p = 0.5), and percent leg fat decreased linearly by 1.2%/year (p < 0.001). The probability of low HDL was 0.2% at baseline and remained stable during the study. The probability of high triglycerides was 3% at baseline and increased linearly to become 11% at the 8th year of follow-up (p = ns). The probability of high glucose was 1% for the whole study duration. CONCLUSIONS: patients, after switching from d4T to TDF and from PI to EFV, show most of the changes in anthropometry and body composition associated with normal growth and no frankly pathological change in metabolic parameters.

Antiretroviral therapy and pregnancy: effect on cortical bone status of human immunodeficiency virus-infected Caucasian women as assessed by quantitative ultrasonography.

Treatment with antiretroviral agents (ARVs) during pregnancy is important to prevent mother-to-child transmission of the human immunodeficiency virus (HIV), but their use has been associated with low bone mineral density in adult patients. Currently, there are no data regarding the bone status of HIV-infected women who received ARV during pregnancy. The aim of this study was to evaluate cortical bone status at delivery in a group of HIV-infected women who received ARV during pregnancy and to monitor the changes occurring during the first year postpartum. We studied 33 HIV-infected and 116 HIV-uninfected healthy Caucasian women within 4 days from delivery. Follow-up measurements were performed at 4 and 12 months postpartum in 17 HIV-infected and 55 healthy women. Cortical bone status was evaluated by quantitative ultrasonography at the mid-tibia, and bone measurements were expressed as the speed of sound (SOS). HIV-infected women after delivery had a median SOS of 3,985 (3,567-4,242) m/s, while the median SOS of healthy women was 4,025 (3,643-4,250) m/s. The difference was not significant (t = 0.39, P = 0.69). No significant differences were observed between ARV-exposed and control subjects at 4 and 12 months. Our data suggest that ARV during pregnancy and the first year after delivery does not affect negatively cortical bone status.

Exposure to antiretroviral agents during pregnancy does not alter bone status in infants.

The use of combined antiretroviral agents during pregnancy is important to prevent mother-to-child transmission of human immunodeficiency virus (HIV). Antiretroviral treatment (ARV) is associated with reduced bone mass and altered bone metabolism in HIV-infected patients. There are no data regarding the effect of ARV exposure during pregnancy on newborns and infants. We therefore studied 38 subjects born from HIV-infected mothers, and we measured the speed-of-sound (SOS) at the tibia by quantitative ultrasonography (QUS) just after birth. QUS measurements at mid-tibia is easily performed in infants with the appropriate probe. Nevertheless, at this skeletal site only cortical bone is present, and therefore QUS measurements reflect the status of only one kind of bone tissue. We also measured bone alkaline phosphatase (BAP) and C-terminal telopeptide of type I collagen (CTX) in the cord blood as bone formation and resorption markers, respectively. SOS measurements were repeated at 4 and 12 months of age. As a control group we studied 94 subjects born from HIV-negative mothers. At birth the median (range) SOS of ARV-exposed neonates was 3006 (2870-3168) m/s, while that of control subjects was 3007 (2757-3311) m/s. The difference was not significant. BAP concentration of ARV-exposed was 103.6 (31.6-182.8) U/L, not different from that of control subjects (104.4 [43.2-227.2] U/L). CTX concentrations were 1.07 (0.26-2.8) ng/mL, and 1.38 (0.34-4.2) ng/mL in ARV-exposed and control subjects, respectively. SOS measurements at 4 months and 12 months of age were available for 17 ARV-exposed subjects and for 57 control subjects. SOS values changed significantly over time in both groups (F=6.1; P<0.0001). No differences were present between ARV-exposed and control subjects at 4 and 12 months. Our study suggests that ARV exposure during intrauterine life does not affect negatively bone metabolism and bone development, and that the changes occurring in bone QUS measurements during the first year of life in ARV-exposed subjects are similar to those occurring in healthy control infants.

In utero exposure to tenofovir disoproxil fumarate does not impair growth and bone health in HIV-uninfected children born to HIV-infected mothers.

BACKGROUND: Growth impairment and bone toxicity due to tenofovir disoproxil fumarate (TDF) fetal exposure has been described mainly in animals. We evaluated growth pattern and bone health in TDF-exposed HIV-uninfected children born to HIV-infected mothers, defined as seroreverters (SR). METHODS: This was a multicentre observational cross-sectional cohort study enrolling 68 SR who were in utero exposed to an antiretroviral regimen including (TDF+) or not including (TDF-) tenofovir. Neonatal data and duration of antiretroviral exposure were recorded. At enrolment, anthropometric measures, tibial speed of sound (SOS) by quantitative ultrasound and several parameters of bone metabolism were assessed. RESULTS: Gestational age and median in utero antiretroviral exposure were similar in subjects exposed to TDF (n=33) and those non-exposed (n =35). Age at enrolment was comparable in the two groups (TDF-exposed range 11.8-76.2 months and TDF non-exposed range 11.8-77.9 months). The incidence of low weight and length measurements (<10th percentiles) at birth was similar in TDF-exposed and TDF non-exposed. Normal growth development was found in both groups of subjects at enrolment. The median (0.6; range -2.4-2.6) SOS z-score of TDF-exposed was similar to the median (0.8; range -2.2-4.4) SOS z-score of TDF non-exposed (Student's t=0.84; P=0.40). Parameters of bone metabolism were similar in the two groups. CONCLUSIONS: Exposure to TDF during pregnancy does not impair growth patterns, bone health and markers of bone metabolism in SR infants and young children born to HIV-infected women.

Lipodystrophy, insulin resistance, and adiponectin concentration in HIV-infected children and adolescents.

Alterations of fat distribution and insulin resistance are associated with increased risk of metabolic derangements and cardiovascular disease. HIV-infected adult patients on antiretroviral treatment often show lipodystrophy, insulin resistance and hypoadiponectinemia, but data in children are controversial. We investigated serum adiponectin concentration in a cohort of HIV-infected youths, and we assessed the relationships with lipodystrophy and insulin resistance. We studied 36 HIV-infected patients (aged 5.0 - 19.4 years), and 171 healthy subjects (aged 4.9 - 17.9 years) for adiponectin measurements. All patients underwent body composition assessment by dual-energy x-ray absorptiometry, and an oral glucose tolerance test to determine the fasting insulin concentration, the insulin area under the curve (AUC), and the HOMA index. Adiponectin serum concentration was measured by an immunoenzymatic assay. Sixteen patients had central fat accumulation, 6 had peripheral lipoatrophy, 5 had a mixed phenotype, and the remaining 9 were non-lipodystrophic. Fasting insulin, insulin AUC, and HOMA index were significantly higher in patients with central fat adiposity and mixed phenotype than in the other two groups. The patients of the former two groups had adiponectin concentration much lower than healthy controls, and patients with peripheral lipoatrophy or normal phenotype had normal concentration. Low adiponectin concentration is associated to central fat and mixed lipohypertrophy, and to signs of insulin resistance in HIV-infected youths. Strict monitoring of metabolic and cardiovascular evolution should be performed in these patients.

Morbidity rates in late preterms born to HIV-mothers.

The rate of late preterm delivery has increased in the general population, and the late preterm infants have a higher incidence of morbidity compared to term newborns. Late preterm data are lacking in born to HIV-infected mother. We showed that, among 202 live births, late preterm delivery was higher in born to HIV-infected mothers than in the general population while their morbidity was lower.

Both HIV-infection and long-term antiretroviral therapy are associated with increased common carotid intima-media thickness in HIV-infected adolescents and young adults.

OBJECTIVE: To evaluate common carotid artery intima-media thickness (CCIMT) and cardiovascular risk factors in HIV-infected adolescents on combination antiretroviral therapy (cART). METHODS: 23 HIV-infected adolescents were matched with 19 healthy subjects by gender, age and body mass index (BMI). CCIMT was measured by Echo-Doppler ultrasound. Bootstrapped multiple linear regression was used to identify potential predictors of CCIMT including HIV status, gender, age, BMI, waist circumference, HDL-cholesterol, LDL- cholesterol, triglycerides, folate, homocysteine, insulin resistance as detected by the homeostasis model assessment, mean blood pressure, and CD36 expression. RESULTS: In the pooled sample, age ranged from 17 to 23 years and BMI between 16.0 and 25.6 kg/m(2). Mean (SD) CCIMT was higher in HIV-infected than in healthy subjects [0.5 (0.1) vs. 0.1 (0.4) mm, p < 0.001]. Higher values of CCIMT were associated with HIV infection (p < 0.001) and male gender (p < 0.001). CCIMT was also associated with the duration of treatment in subjects with the longest cART exposure, i.e. those exposed to a PI-based and/or NNRTI-based regimen plus a single or double NRTI (p = 0.019). CONCLUSION: HIV infection and longer duration of cART are associated with higher CCIMT in adolescents and young adults.

Antiretroviral therapy and bone mineral measurements in HIV-infected youths.

Reduced bone mass measurements are often found in HIV-infected youths. Both in vitro and human studies demonstrated a role of antiretroviral treatment in determining bone mass alteration. Nevertheless, the data regarding the responsibility of different antiretroviral drugs on bone health in children and adolescents are highly controversial. The purpose of the current study was to relate antiretroviral treatment to bone mass measurements in a large cohort of HIV-infected children and adolescents. Bone mineral content (BMC) was measured in 86 HIV-infected youths (aged 4.8-22.1 years), and in 194 healthy controls (aged 4.9-21.9 years). Fifteen patients were naive to antiretroviral treatment, 11 were receiving a dual nucleoside reverse transcriptase inhibitor (NRTIs) combination, 32 a protease inhibitor (PI)-based antiretroviral treatment, and 28 a non-nucleoside reverse transcriptase inhibitor (NNRTIs)-based regimen. Comparisons between healthy and HIV-infected children and adolescents have been performed by multiple regression analyses to correct for differences in age, sex, and anthropometric measurements. Patients receiving a PI-based treatment had lumbar spine and whole body BMC values significantly lower than healthy children (P<0.05). BMC measurements of patients on other therapeutic regimens or naive to antiretroviral treatment did not differ significantly from those of healthy children. Among patients receiving a PI-based regimen, those receiving full dose Ritonavir had significantly lower lumbar spine BMC values compared to other patients. Lumbar spine and whole body BMC measurements of patients receiving a Stavudine-containing regimen were lower compared to healthy controls, naive patients, and patients on other antiretroviral regimens. Multivariate analyses showed that patients receiving both Stavudine and full dose Ritonavir had significantly lower BMC values both at the lumbar spine (P=0.0033), and in the whole skeleton (P=0.05). In conclusion, antiretroviral treatment may have a detrimental effect on bone health of HIV-infected youths: the use of Ritonavir full dose alone or in combination with Stavudine is associated to lower bone mass measurements. The use of antiretroviral regimens including these drugs should thus be monitored closely in HIV-infected youths.

Long-term evaluation of glucose homeostasis in a cohort of HAART-treated HIV-infected children: a longitudinal, observational cohort study.

BACKGROUND AND OBJECTIVES: Few and mainly cross-sectional studies of glucose homeostasis are available in HIV-infected children treated with highly active antiretroviral therapy (HAART). The aim of the present study was to describe a 4-year course of glucose homeostasis in a cohort of HAART-treated children and adolescents, using glucose and insulin levels during an oral glucose tolerance test (OGTT) as outcome measures. In addition, we investigated possible risk factors, both related and unrelated to antiretroviral therapy, associated with insulin resistance. METHODS: We assessed glucose metabolism yearly for 4 consecutive years in 37 HIV-infected children receiving a protease inhibitor (PI)-based HAART regimen containing lamivudine/stavudine plus indinavir or ritonavir or nelfinavir or a non-nucleoside reverse transcriptase inhibitor (NNRTI)-based HAART regimen containing lamivudine/tenofovir/efavirenz. Generalized estimating equations were used to evaluate the relationship between the loge-transformed area under the serum concentration-time curve (AUC) of insulin during OGTT and antiretroviral therapy, controlling for time, sex, baseline age, puberty, body mass index and CD4+ T cells percentage. RESULTS: Ritonavir-unboosted PI-based HAART regimens were administered to most children at baseline; however, their use decreased during follow-up in favour of an NNRTI-based regimen. The nelfinavir/lamivudine/stavudine (regression coefficient=-0.69, p<0.05) and efavirenz/lamivudine/tenofovir (regression coefficient=-0.93, p<0.05) regimens, but not the ritonavir/lamivudine/stavudine regimen, were negatively associated with loge-transformed insulin AUC compared with indinavir/lamivudine/stavudine. Puberty was positively associated with loge-transformed insulin AUC. CONCLUSIONS: This 4-year prospective study of HAART-treated HIV-infected children shows that: (i) the nelfinavir/lamivudine/stavudine and the efavirenz/lamivudine/tenofovir regimens but not the ritonavir/lamivudine/stavudine regimen were associated with higher insulin sensivity, i.e. lower insulin AUC, compared with indinavir/lamivudine/stavudine; (ii) the treatment switched substantially in favour of NNRTI from the third year on and this change was associated with an improvement in insulin sensitivity compared with the previous HAART-based regimens; and (iii) puberty is a primary determinant of insulin sensitivity.