The predictive role of NLR and PLR for solid non-AIDS defining cancer incidence in HIV-infected subjects: a MASTER cohort study

Patients’ characteristics according to lost to follow-up at 3-years. Table S2. Distribution of non-AIDS defining cancer. Table S3. Multivariate analysis: time dependent Cox regression model. Variables included in the full model. (DOCX 20 kb

Cabotegravir Exposure of Zebrafish (Danio rerio) Embryos Impacts on Neurodevelopment and Behavior

As most new medications, Cabotegravir (CAB) was recently approved as an antiretroviral treatment of HIV infection without in-depth safety information on in utero exposure. Although no developmental toxicity in rats and rabbits was reported, recent studies demonstrated that CAB decreases pluripotency of human embryonic stem cells. CAB exposure effects during development were assessed in zebrafish embryos by the Fish Embryo Toxicity test after exposure at subtherapeutic concentrations up to 25x the human C-max. Larvae behavior was assessed by the light-dark locomotion test. The expression of factors involved in neurogenesis was evaluated by whole-mount in situ hybridization. CAB did not cause gross morphological defects at low doses, although pericardial edema, uninflated swim bladder, decreased heartbeats, growth delay, and decreased hatching rate were observed at the highest concentrations. Decreased locomotion was observed even at the subtherapeutic dose, suggesting alterations of nervous system integrity. This hypothesis was supported by the observation of decreased expression of crucial factors involved in early neuronal differentiation in diencephalic and telencephalic dopaminergic areas, midbrain/hindbrain boundary, and craniofacial ganglia. These findings support CAB effects on neurogenesis in zebrafish embryos and suggest long-term follow-up of exposed infants to provide data on drug safety during pregnancy

The burden of chronic diseases and cost-of-care in subjects with HIV infection in a Health District of Northern Italy over a 12-year period compared to that of the general population

The increase in life expectancy of HIV-infected patients has driven increased costs due to life-long HIV treatment and concurrent age-related comorbidities. This population-based study aimed to investigate the burden of chronic diseases and health costs for HIV(+) subjects compared to the general population living in Brescia Local health Agency (LHA) over a 12-year period

Comparison of Efavirenz and Doravirine Developmental Toxicity in an Embryo Animal Model

: In the past, one of the most widely used non-nucleoside reverse transcriptase inhibitors (NNRTI) in first-line antiretroviral therapy (ART) of HIV infection was efavirenz (EFV), which is already used as a cost-effective treatment in developing countries due to its efficacy, tolerability, and availability. However, EFV also demonstrates several adverse effects, like hepatotoxicity, altered lipid profile, neuropsychological symptoms, and behavioral effects in children after in utero exposure. In 2018, another NNRTI, doravirine (DOR), was approved due to its similar efficacy but better safety profile. Preclinical safety studies demonstrated that DOR is not genotoxic and exhibits no developmental toxicity or effects on fertility in rats. Zebrafish (Danio rerio) embryos have been widely accepted as a vertebrate model for pharmacological and developmental studies. We used zebrafish embryos as an in vivo model to investigate the developmental toxicity of DOR compared to EFV. After exposure of the embryos to the drugs from the gastrula stage up to different developmental stages (30 embryos for each arm, in three independent experiments), we assessed their survival, morphology, hatching rate, apoptosis in the developing head, locomotion behavior, vasculature development, and neutral lipid distribution. Overall, DOR showed a better safety profile than EFV in our model. Therapeutic and supra-therapeutic doses of DOR induced very low mortality [survival rates: 92, 90, 88, 88, and 81% at 1, 5, 10, 25, and 50 μM, respectively, at 24 h post fecundation (hpf), and 88, 85, 88, 89, and 75% at the same doses, respectively, at 48 hpf] and mild morphological alterations compared to EFV exposure also in the sub-therapeutic ranges (survival rates: 80, 77, 69, 63, and 44% at 1, 5, 10, 25, and 50 μM, respectively, at 24 hpf and 72, 70, 63, 52, and 0% at the same doses, respectively, at 48 hpf). Further, DOR only slightly affected the hatching rate at supra-therapeutic doses (97, 98, 96, 87, and 83% at 1, 5, 10, 25, and 50 μM, respectively, at 72 hpf), while EFV already strongly reduced hatching at sub-therapeutic doses (83, 49, 11, 0, and 0% at 1, 5, 10, 25, and 50 μM, respectively, at the same time endpoint). Both DOR at therapeutic doses and most severely EFV at sub-therapeutic doses enhanced apoptosis in the developing head during crucial phases of embryo neurodevelopment and perturbed the locomotor behavior. Furthermore, EFV strongly affected angiogenesis and disturbed neutral lipid homeostasis even at sub-therapeutic doses compared to DOR at therapeutic concentrations. Our findings in zebrafish embryos add further data confirming the higher safety of DOR with respect to EFV regarding embryo development, neurogenesis, angiogenesis, and lipid metabolism. Further studies are needed to explore the molecular mechanisms underlying the better pharmacological safety profile of DOR, and further human studies are required to confirm these results in the zebrafish animal model

Symptoms and quality of life in HIV-infected patients with benign prostatic hyperplasia are improved by the consumption of a newly developed whole tomato-based food supplement. A phase II prospective, randomized double-blinded, placebo-controlled study

Abstract Carotenoid rich diets have proven to be beneficial in decreasing urinary symptoms of benign prostatic hyperplasia (BHP) and cardiovascular risk factors, especially following the consumption of whole tomato, the major source of dietary lycopene. Here, we describe the results of a phase II prospective, randomized double-blinded, placebo-controlled study undertaken to determine the efficacy and safety of a novel whole tomato-based food supplement (WTFS) containing lycopene in highly bioavailable form in 31 HIV+ patients with proved BPH. The consecutive enrolled patients received daily, for 12 weeks, 5 g of WTFS or placebo. The study demonstrates that WTFS consumption is associated with a statistically significant improvement of all BPH symptoms and quality of life, free/total prostate specific antigen ratio, and diastolic blood pressure, with a trend in interleukin 6 level reduction. WTFS may offer a side effect-free food supplement for the management of BPH in HIV+ patients

The impact of antiretroviral therapy on iron homeostasis and inflammation markers in HIV-infected patients with mild anemia

BACKGROUND: Anemia is frequent during HIV infection and is predictive of mortality. Although cART has demonstrated to reduce its prevalence, several patients still experience unresolved anemia. We aimed to characterize iron homeostasis and inflammation in HIV-infected individuals with mild anemia in relation to cART. METHODS: In this retrospective cohort study, HIV-infected patients with mild anemia, CD4+ cells > 200/mm3 at baseline, maintaining virological response for 12 months after cART starting were selected within the Standardized Management of Antiretroviral Therapy Cohort (MASTER) cohort. Several inflammation and immune activation markers and iron homeostasis indexes were measured in stored samples, obtained at cART initiation (T0) and 12 months later (T1). Patients were grouped on the basis of hemoglobin values at T1: group A (> 13 g/dl) and B (< 13 g/dl). Wilcoxon rank sum test was used to compare biomarker values. Pearson correlation coefficients were calculated for all variables. RESULTS: cART improved CD4+ and CD8+ cell counts and their ratio, but this effect was significant only in group A. Only these patients had mild iron deficiency at T0 and showed higher transferrin and lower percentage of transferrin saturation than patients of group B, but differences disappeared with cART. cART decreased inflammation in all patients, but group B had higher levels of all markers than group A, reaching statistical significance only for IL-8 values at T1 (16 vs 2.9 pg/ml; p = 0.017). Hepcidin and IL-6 levels did not show significant differences between groups. Hemoglobin levels both at T0 and T1 did not correlate with any marker. CONCLUSIONS: Baseline mild anemia in HIV-infected patients cannot always be resolved with durable efficient cART, possibly due to residual inflammation or immune activation rather than unbalanced iron homeostasis. Further research is needed on cytokine profiling to understand the mechanisms that induce anemia in HIV with suppressive cART

Trends in methicillin-resistant Staphylococcus aureus (MRSA) bloodstream infections: effect of the MRSA "search and isolate" strategy in a hospital in Italy with hyperendemic MRSA

Abstract OBJECTIVE: To evaluate the secular trends in MRSA BSIs after the introduction of a nosocomial MRSA control intervention. DESIGN: Before-after study. SETTING: An 850-bed community hospital with an ICU and vascular surgery, neurosurgery, bone marrow transplantation, and AIDS units. MRSA is endemic at this hospital; the prevalence of methicillin resistance among patients with S. aureus infection is greater than 50%. PATIENTS: Among all inpatients, MRSA BSI was identified, its origin defined, and incidence rates calculated by ward and origin. INTERVENTION: A MRSA control program was implemented based on active surveillance cultures to identify MRSA-colonized patients, followed by isolation using contact precautions. Incidence rates of MRSA BSI during the intervention (i.e., July 1, 1997, to December 31, 2001) and preintervention (i.e., January 1, 1996, to June 30, 1997) periods were compared. RESULTS: Sixty-nine MRSA BSIs were identified. When compared with the preintervention period, the incidence rate of MRSA BSI was reduced from 0.64 to 0.30 per 1000 admissions (RR, 0.46; CI95, 0.25-0.87; P = .02) during the intervention period. The impact was greater in the ICU, with an 89% reduction (RR, 0.11; CI95, 0.01-0.98; P = .03), and for CVC-associated MRSA BSIs, with an 82% decrease (RR, 0.17; CI95, 0.05-0.55; P = .002). Methicillin resistance among S. aureus blood isolates decreased from 46% to 17% (RR, 0.36; CI95, 0.22-0.62; P = .0002). CONCLUSION: A reduction in MRSA bacteremia is achievable through use of the MRSA "search and isolate" intervention even in a hospital with high rates of endemic MRSA

Heterogeneity and penetration of HIV-1 non-subtype B viruses in an Italian province: Public health implications

SUMMARYThis study assessed changes in prevalence and distribution of HIV-1 non-subtype B viruses in Italian and immigrant patients over two decades in a province in Italy. All HIV-positive patients who underwent genotypic resistance testing were selected. Prevalence of non-subtype B viruses in 3-year periods was calculated. All sequences of non-subtype B and those provided by REGA as unassigned were analysed for phylogenetic relationships. In total, 250/1563 (16%) individuals were infected with a non-subtype B virus. Prevalence increased over time, reaching a peak (31·5%) in 2004–2006. In Italian patients, the most frequent subtypes were B (92·5%) and F1 (4%). F1 subtype was also prevalent in patients from South America (13·6%); in patients of African origin, CRF02_AG (54·9%) and G (12·3%) were the most frequent. HIV-1 non-subtype B infections in Italians were mostly found in patients who acquired HIV sexually. A phylogenetic relationship between F subtypes in Italian and representative HIV-1 sequences from Brazil was found. C subtypes in Italians were phylogenetically related to subtypes circulating in Brazil. Inter-subtype recombinants were also found in the latest years. The HIV-1 epidemic in Brescia province evolved to the point where about 1/3 patients recently diagnosed harboured non-B HIV subtypes. The distribution of HIV-1 non-B subtypes in Italian patients resembled that in South American patients and phylogenetic relatedness between some Italian and South American HIV-1 strains was found. The possible epidemiological link between these two populations would have been missed by looking only at risk factors for HIV acquisition declared by patients. The evidence of inter-subtype recombinants points to significant genetic assortment. Overall our results support phylogenetic analysis as a tool for epidemiological investigation in order to guide targeted prevention strategies

Effects of combined antiretroviral therapy on B- and T-cell release from production sites in long-term treated HIV-1+ patients

BACKGROUND: The immune system reconstitution in HIV-1- infected patients undergoing combined antiretroviral therapy is routinely evaluated by T-cell phenotyping, even though the infection also impairs the B-cell mediated immunity. To find new laboratory markers of therapy effectiveness, both B- and T- immune recovery were evaluated by means of a follow-up study of long-term treated HIV-1- infected patients, with a special focus on the measure of new B- and T-lymphocyte production. METHODS: A longitudinal analysis was performed in samples obtained from HIV-1-infected patients before therapy beginning and after 6, 12, and 72 months with a duplex real-time PCR allowing the detection of K-deleting recombination excision circles (KRECs) and T-cell receptor excision circles (TRECs), as measures of bone-marrow and thymic output, respectively. A cross sectional analysis was performed to detect B- and T-cell subsets by flow cytometry in samples obtained at the end of the follow-up, which were compared to those of untreated HIV-1-infected patients and uninfected controls. RESULTS: The kinetics and the timings of B- and T-cell release from the bone marrow and thymus during antiretroviral therapy were substantially different, with a decreased B-cell release and an increased thymic output after the prolonged therapy. The multivariable regression analysis showed that a longer pre-therapy infection duration predicts a minor TREC increase and a major KREC reduction. CONCLUSIONS: The quantification of KRECs and TRECs represents an improved method to monitor the effects of therapies capable of influencing the immune cell pool composition in HIV-1-infected patients