Switching from TDF to TAF or dual therapy (DT)-based regimens in HIV-infected individuals with viral load <=50 copies/ml: does eGFR matter?

Our aim was to evaluate the association between most recent eGFR values and the risk of switching from TDF to TAF or to dual therapy (DT) separately for the two strategies in a real-life setting. HIV-positive patients, achieving HIV-RNA≤50 copies/ml for the first time after starting a TDF-based regimen (baseline) were included. Kaplan-Meier (KM) curves and Cox regression models were used to estimate the time from TDF to switch to TAF or DT. A total of 1,486 participants were included: median (IQR) age 36y(30-42), baseline CKD-EPI eGFR 99.92 (86.47,111.4) mL/min/1.73m2. We observed a consistently higher proportion of people with a HIV-RNA≤50copies/mL who have switched from TDF to TAF rather than to DT. By competing risk analysis, the 2 years from baseline, the probability of switching was 3.5% (95% CI 2.6-4.7) to DT and 46.7% (95% CI 42.8-48.5) to TAF. A significant higher probability of switching to TAF was found for patients receiving INSTI at baseline versus NNRTIs and PI/b (KM: 65.6%, 95%CI 61.7, 69.4; vs. 4.0%, 95%CI 1.8, 6.1 and 59.9%, 95%CI 52.7, 67.2, respectively; p<.0001). A eGFR<60 ml/min/1.73m2 both as time-fixed covariate at baseline or as current value, was associated with a higher risk of switching to DT [aHR 6.68, 95%CI 2.69, 16.60 and 8.18, 95% CI 3.54, 18.90; p-value <0.001] but not to TAF-based cART [aHR= 0.94, 95%CI 0.39, 2.31, p=0.897 and 1.19, 95%CI 0.60, 2.38, p=0.617)]. In conclusion, counter to our original hypothesis, current eGFR value is used by clinician to guide switches to DT but does not seems to be a key determinant for switching to TAF. This should be taken into account when managing people on TAF-based regimens

Drop in CD4(+) Counts Below 200 Cells/mu L After Reaching (or Starting From) Values Higher than 350 Cells/mu L in HIV-Infected Patients With Virological Suppression

BACKGROUND: The aim of the study was to quantify the risk of a drop in CD4+ counts below 200 cells/μL after reaching values >350 cells/μL on antiretroviral therapy (ART) (or after starting ART with CD4+ count >350 cells/μL) in the absence of virological failure. SETTING: Ambulatory care services, Italy. METHODS: Prospective cohort study of patients enrolled in the ICONA Foundation Study cohort who started ART with >350 CD4+/μL or with ≤350 CD4+/μL and reached values >350 cells/μL after virological suppression (VS, defined by 2 consecutive viral loads ≤50 copies/mL). The date of CD4 count >350 was the baseline for the analysis and those with ≥1 viral load and CD4+ count after baseline were included. The primary end point was the cumulative risk (estimated using the Kaplan–Meier method) of a CD4+ drop below 200 cells/μL over follow-up, which was censored at the date of virological failure (confirmed HIV-RNA >50 copies/mL), death, or last visit. RESULTS: Six thousand six hundred sixty-three patients were included. A confirmed CD4+ drop below 200 cells/μL was never observed over a median follow-up of 45 (Q1: 21, Q3: 89) months, as long as VS was maintained. Upper limits of the 97.5% confidence interval of rates of confirmed CD4+ drop below 200 cells/μL were 0.28 and 0.38/1000 person-years of follow-up for patients with ≤350 and >350 CD4+ cells/μL at starting ART. CONCLUSIONS: In patients who started ART in Italy with >350 CD4+ cells/μL or reached >350 CD4+ cells/μL after VS, the risk of a CD4+ drop below 200 cells/μL in those maintaining VS was negligible

Cellular and molecular changes and immune response in the intestinal mucosa during Trichinella spiralis early infection in rats

Background:: The main targets of the host's immune system in Trichinella spiralis infection are the adult worms (AW), at the gut level, and the migrant or newborn larvae (NBL), at systemic and pulmonary levels. Most of the studies carried out in the gut mucosa have been performed on the Payer's patches and/or the mesenteric lymph nodes but not on the lamina propria, therefore, knowledge on the gut immune response against T. spiralis remains incomplete. Methods: This study aimed at characterizing the early mucosal immune response against T. spiralis, particularly, the events taking place between 1 and 13 dpi. For this purpose, Wistar rats were orally infected with muscle larvae of T. spiralis and the humoral and cellular parameters of the gut immunity were analysed, including the evaluation of the ADCC mechanism exerted by lamina propria cells. Results: A marked inflammation and structural alteration of the mucosa was found. The changes involved an increase in goblet cells, eosinophils and mast cells, and B and T lymphocytes, initially displaying a Th1 profile, characterised by the secretion of IFN-γand IL-12, followed by a polarization towards a Th2 profile, with a marked increase in IgE, IgG1, IL-4, IL-5 and IL-13 levels, which occurred once the infection was established. In addition, the helminthotoxic activity of lamina propria cells demonstrated the role of the intestine as a place of migrant larvae destruction, indicating that not all the NBLs released in the gut will be able to reach the muscles. Conclusions: The characterization of the immune response triggered in the gut mucosa during T. spiralis infection showed that not only an effector mechanism is directed toward the AW but also towards the NBL as a cytotoxic activity was observed against NBL exerted by lamina propria cells.Fil: Saracino, María Priscila. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Estudios de la Inmunidad Humoral Prof. Ricardo A. Margni. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Estudios de la Inmunidad Humoral Prof. Ricardo A. Margni; ArgentinaFil: Vila, Cecilia Celeste. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Estudios de la Inmunidad Humoral Prof. Ricardo A. Margni. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Estudios de la Inmunidad Humoral Prof. Ricardo A. Margni; ArgentinaFil: Cohen, Melina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Estudios de la Inmunidad Humoral Prof. Ricardo A. Margni. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Estudios de la Inmunidad Humoral Prof. Ricardo A. Margni; ArgentinaFil: Gentilini, Maria Virginia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Estudios de la Inmunidad Humoral Prof. Ricardo A. Margni. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Estudios de la Inmunidad Humoral Prof. Ricardo A. Margni; ArgentinaFil: Falduto, Guido Hernán. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Estudios de la Inmunidad Humoral Prof. Ricardo A. Margni. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Estudios de la Inmunidad Humoral Prof. Ricardo A. Margni; ArgentinaFil: Calcagno, Marcela Adriana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Estudios de la Inmunidad Humoral Prof. Ricardo A. Margni. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Estudios de la Inmunidad Humoral Prof. Ricardo A. Margni; ArgentinaFil: Roux, Estela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Cardiológicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Cardiológicas; ArgentinaFil: Venturiello, Stella Maris. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Estudios de la Inmunidad Humoral Prof. Ricardo A. Margni. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Estudios de la Inmunidad Humoral Prof. Ricardo A. Margni; ArgentinaFil: Malchiodi, Emilio Luis. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Estudios de la Inmunidad Humoral Prof. Ricardo A. Margni. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Estudios de la Inmunidad Humoral Prof. Ricardo A. Margni; Argentin

A new era for understanding amyloid structures and disease

The aggregation of proteins into amyloid fibrils and their deposition into plaques and intracellular inclusions is the hallmark of amyloid disease. The accumulation and deposition of amyloid fibrils, collectively known as amyloidosis, is associated with many pathological conditions that can be associated with ageing, such as Alzheimer disease, Parkinson disease, type II diabetes and dialysis-related amyloidosis. However, elucidation of the atomic structure of amyloid fibrils formed from their intact protein precursors and how fibril formation relates to disease has remained elusive. Recent advances in structural biology techniques, including cryo-electron microscopy and solid-state NMR spectroscopy, have finally broken this impasse. The first near-atomic-resolution structures of amyloid fibrils formed in vitro, seeded from plaque material and analysed directly ex vivo are now available. The results reveal cross-β structures that are far more intricate than anticipated. Here, we describe these structures, highlighting their similarities and differences, and the basis for their toxicity. We discuss how amyloid structure may affect the ability of fibrils to spread to different sites in the cell and between organisms in a prion-like manner, along with their roles in disease. These molecular insights will aid in understanding the development and spread of amyloid diseases and are inspiring new strategies for therapeutic intervention

Nanoparticles-Based Treatment for Bone Metastasis.

Bone is the principal site of metastasis for many carcinomas, including prostate. Once bone metastases are established, the chances of survival dramatically drop. Bone metastases place patients at increased risk of skeletal-related events, including pathologic fractures, bone pain and hypercalcemia. Indeed, skeletal metastases represent the prevalent cause of morbidity and mortality for many tumors. They are the result of interactions among tumour cells, bone marrow environment and bone cells (vicious cycle). In the last few years many efforts were undertaken to identify new therapeutic approaches for bone metastasis. Current therapies target the several players of bone vicious cycle. However many adverse effects are associated with these treatments. This review will focus on the new emerging sector of nanomedicine, that could be important to identify more specific and safe treatments for bone metastasi

Cerebrospinal fluid HIV RNA escape symptomatology.

OBJECTIVE: To characterise the clinical, laboratory and radiological characteristics of persons with HIV (PWH) presenting with cerebrospinal fluid (CSF) HIV RNA escape. DESIGN: Retrospective case review of PWH presenting with symptomatic CSF HIV RNA escape at seven tertiary HIV clinical sites in UK and Italy. METHOD: PWH with symptomatic CSF HIV RNA escape episodes were identified and data obtained from medical records. CSF HIV RNA escape was defined as quantifiable CSF HIV RNA in unquantifiable plasma HIV RNA or CSF HIV RNA greater than plasma HIV RNA in cases where plasma HIV RNA was quantifiable. The onset of clinical symptoms was classified as acute (6 months) and differences in presentation in those with CSF HIV RNA below and above 1000 copies/mL determined. RESULTS: We identified 106 PWH with CSF HIV RNA escape (65 male); 68 (64%) PWH had acute presentations and 38 (36%) had chronic presentations. Cognitive decline (n = 54, 50.9%), confusion (n = 20, 18.9%) and headache (n = 28, 26.4%) were the most common presentations, with cognitive decline being more common in PWH who presented chronically compared with PWH who presented acutely (73.7% vs 35.3%, p = 0.0002). Sixty PWH had CSF HIV RNA ≥1000 copies/mL and presented more frequently with confusion (n = 15/60, 25.0%) compared to PWH with CSF HIV RNA <1000 copies/mL at presentation (n = 5/46, 10.9%; p = 0.03). CONCLUSION: Cognitive decline, confusion and headache are the most frequent presenting symptoms of CSF HIV RNA escape and their relative frequency varied according to symptom onset and CSF HIV RNA concentration

Very high pre-therapy viral load is a predictor of virological rebound in HIV-1-infected patients starting a modern first-line regimen

BACKGROUND: Pre-cART (combined antiretroviral therapy) plasma viral load >500,000 copies/mL has been associated with a lower probability of achieving virological suppression, while few data about its role on maintenance of virological suppression are available. In this study we aimed to clarify whether high levels of pre-cART viremia are associated with virological rebound (VR) after virological suppression. METHODS: HIV-infected individuals who achieved virological suppression after first-line cART were included. VR was defined as the first of two consecutive viremia >50 copies/mL (VR50) or, in an alternative analysis, >200 copies/mL (VR200). The impact of pre-cART viremia on the risk of VR was evaluated by survival analyses. RESULTS: Among 5,766 patients included, 59.2%, 31.4%, 5.2% and 4.2% had pre-cART viremia ≤100,000, 100,001-500,000, 500,001-1,000,000, and >1,000,000 copies/mL, respectively. CONCLUSIONS: Pre-cART plasma viral load levels >500,000 copies/mL can identify fragile patients with poorer chance of maintaining virological control after an initial response. An effort in defining effective treatment strategies is mandatory for these patients that remain difficult to treat