Impact of monotherapy on HIV-1 reservoir, immune activation, and co-infection with Epstein-Barr virus

Abstract Objectives Although monotherapy (mART) effectiveness in maintaining viral suppression and CD4 cell count has been extensively examined in HIV-1-infected patients, its impact on HIV-1 reservoir, immune activation, microbial translocation and co-infection with Epstein-Barr Virus (EBV) is unclear. Methods This retrospective study involved 32 patients who switched to mART; patients were studied at baseline, 48 and 96 weeks after mART initiation. Thirty-two patients who continued combined antiretroviral therapy (cART) over the same period of time were included in the study. Markers of HIV-1 reservoir (HIV-1 DNA and intracellular HIV-1 RNA) were quantified by real-time PCR. Markers of T-(CD3(+)CD8(+)CD38(+)) and B-(CD19(+)CD80/86(+) and CD19(+)CD10-CD21(low)CD27(+)) cell activation were evaluated by flow cytometry. Plasma levels of microbial translocation markers were quantified by real-time PCR (16S ribosomal DNA and mitochondrial [mt] DNA) or by ELISA (LPS and sCD14). EBV was typed and quantified by multiplex real-time PCR. Results At baseline, no differences were found between mART and cART groups. Three (10%) mART-treated patients had a virological failure vs none in the cART group. Levels of HIV-1 DNA, intracellular HIV-1 RNA and EBV-DNA remained stable in the mART group, while decreased significantly in the cART group. Percentages of T-and B-activated cells significantly increased in the mART-treated patients, while remained at low levels in the cART-treated ones (p = 0.014 and p<0.001, respectively). Notably, levels of mtDNA remained stable in the cART group, but significantly rose in the mART one (p<0.001). Conclusions Long-term mART is associated with higher levels of T-and B-cell activation and, conversely to cART, does not reduce the size of HIV-1 reservoir and EBV co-infection

Reasons why HIV-positive women do not want to have a child: the questionnaire-based DIDI study

Given that the majority of HIV‐positive women are of reproductive age, it is necessary to understand the interaction between HIV and family planning, especially as antiretroviral medications allow to live longer, healthier lives. Aim of this analysis form the DIDI study was to assess prevalence of motherhood desire in current years and to identify variables associated pregnancy decision‐making in HIV‐infected women. DIDI is an Italian, 16‐center, questionnaire‐based survey performed in 585 HIV‐positive women between Nov. 2010 and Feb. 2011. The items covered in the self‐administered questionnaire included: socio‐demographic characteristics, sexual and gynecological health, motherhood desire, strategies adopted to become pregnant, reasons for not wanting a child, partnership, HIV disclosure, physical and mental health, ART adherence, drug use. For the present analysis only women aged<45 years and engaged in a partnership were included. Absence of motherhood desire was defined by a negative answer at the question whether the women at present would like to have a child. 178 women were included: mean age 39 (IQR, 33–42), HIV transmission heterosexual 75%, IVDU 11%, heterosexual/IVDU 2.5%, not known 7.5%; mean CD4 and HIV‐RNA were 552/mmc (+252) and 3.85 c/ml (+4.7), respectively. Absence of motherhood desire was found in 61% of women; 50% of women declared that HIV negatively affected motherhood desire, and 22% declared a decrease in desire after start of ART. The probability of vertical transmission was estimated higher than 50% by 19% of women, even when adopting all preventive measures. Not wanting a child was associated with: fear of vertical transmission (p<0.001), fear of not being able to raise the child (p<0.001), decline in motherhood desire after HIV (p=0.007), unstable partnership (p=0.02). At multivariable analysis, variables found to be significantly associated with negative pregnancy decision‐making were: fear of vertical transmission (AOR 3.75; 95%CI 1.18–11.89), economic restrictions (AOR 0.28; 95% CI 0.10–0.76 In conclusion, absent motherhood desire in HIV‐positive women with child‐bearing potential is frequent and essential information on vertical HIV transmission is lacking. HIV‐positive women of childbearing age may benefit from counseling interventions sensitive to factors that influence infected women's pregnancy decisions

Antiretroviral therapy in HIV/HCV co-infection Italian consensus workshop

About 50% of people living with the HIV infection in Italy are co-infected with HCV. In this group of patients, the primary cause of mortality is liver disease, which accounts for up to 14% of deaths. HIV/HCV co-infection also exposes patients to a higher risk of progression to AIDS, a faster evolution towards cirrhosis, more frequent drug toxicity, and lower tolerance for antiretroviral therapy. Moreover, HCV infection can play a part in increasing immune system depression; neurological, cognitive and renal damage; and bone fragility. Hence an optimal antiretroviral regimen needs to be chosen for co-administration with anti-HCV therapy and timed appropriately to improve the prognosis of co-infected HIV/HCV patients. Unfortunately, however, data on the safety and efficacy of antiretroviral drugs in these patients is scarce, as are studies of pharmacokinetics in patients with advanced liver impairment. Furthermore, restoring adequate immune constitution seems not to slow the progression of liver disease, and the metabolic and hepatic toxicity of some antiretroviral drugs can even contribute to inflammatory and fibrogenic processes. It is therefore essential that HIV/HCV co-infected patients receive only medications capable of ensuring the best immune recovery but possessing the lowest potential to trigger immune reconstitution syndrome or hepatic and metabolic damage

Risk Factors and Outcomes Related to Pediatric Intensive Care Unit Admission after Hematopoietic Stem Cell Transplantation: A Single-Center Experience

Abstract To describe incidence, causes, and outcomes related to pediatric intensive care unit (PICU) admission for patients undergoing hematopoietic stem cell transplantation (HSCT), we investigated the risk factors predisposing to PICU admission and prognostic factors in terms of patient survival. From October 1998 to April 2015, 496 children and young adults (0 to 23 years) underwent transplantation in the HSCT unit. Among them, 70 (14.1%) were admitted to PICU. The 3-year cumulative incidence of PICU admission was 14.3%. The main causes of PICU admission were respiratory failure (36%), multiple organ failure (16%), and septic shock (13%). The overall 90-day cumulative probability of survival after PICU admission was 34.3% (95% confidence interval, 24.8% to 47.4%). In multivariate analysis, risk factors predisposing to PICU admission were allogeneic HSCT (versus autologous HSCT, P  = .030) and second or third HSCT ( P  = .018). Characteristics significantly associated with mortality were mismatched HSCT ( P  = .011), relapse of underlying disease before PICU admission ( P P  = .012), hepatic failure at admission ( P  = .021), and need for invasive ventilation during PICU course (

Elderly HIV-positive women: A gender-based analysis from the Multicenter Italian \u201cGEPPO\u201d Cohort

BACKGROUND: HIV-positive patients are facing age-and disease-related comorbidities. Since gender differences in viro-immunological, clinical and therapeutic features have been described, aim of this analysis was to explore such differences in elderly HIV-positive females compared to males coming from the same cohort. DESIGN: Cross-sectional study. SETTING: Ten Infectious Diseases Center participating to a new multicenter Italian geriatric Cohort aiming at describing health transition over time in HIV-positive individuals. PARTICIPANTS: HIV-positive patients aged 6565 years old. MEASUREMENTS: We recorded clinical, viro-immunological and therapeutical data. RESULTS: We included 210 women (17%) out of 1237 patients. Compared to males, elderly females were less likely to present a HIV-RNA &lt;50 copies/mL (74.3% vs. 81.8%, OR 0.64, 95%CI 0.44-0.93); they showed higher CD4+/CD8+ ratio (p = 0.016). Combined antiretroviral therapy (cART) strategies were similar between genders (p&gt;0.05), although women were less likely to be treated with protease Inhibitors (PIs) (p = 0.05); specifically, in triple-drug regimens females received less PIs (28% vs 38% p = 0.022) and more integrase inhibitors (30% vs. 20% p = 0.012). Bone disease was more common in females (p&lt;0.001) while males presented more frequently cardiovascular disease (CVD) (p&lt;0.001). In females with bone disease, PIs and boosted regimens (38% vs. 53.7% p = 0.026 and 30.4 vs 44.0% p = 0.048 respectively) were prescribed less frequently. Polypharmacy was common and similar in both genders (20% vs. 22.8%, p = &gt;0.05). A higher use of lipid-lowering drugs (20.5% vs. 14.8%, p = 0.04) was observed in females and yet they were less likely to receive anti-thrombotic agents (18.6% vs. 26.3%, p = 0.019) even when CVD was recorded (57.1% vs. 83.1%, p = 0.018). In multivariate analysis, we found that female gender was independently associated with a higher CD4+/CD8+ ratio but not with virological suppression. CONCLUSIONS: Elderly HIV-positive women display a worse virologic response despite a better immune reconstitution compared to males. The burden of comorbidities as well as the medications received (including cART) may slightly differ according to gender. Our data suggest that more efforts and focused interventions are needed in this population

Growth rate and myofibroblast differentiation of desmoid fibroblast-like cells are modulated by TGF-\u3b2 signaling

Abstract Desmoid-like fibromatosis (DF) is a rare myofibroblastic benign tumor, often associated with local and repeated injuries, spontaneous regression and stabilization of disease progression suggesting the involvement of altered Wnt/-catenin signaling activation and/or aberrant response of the DF cells to external environmental stimuli. The aim of this study was to investigate the response of DF cells to microenvironmental factors such as inflammatory and growth factors or hormones. We observed that the inflammatory cytokine, transforming growth factor- (TGF-1) stimulated cell growth and myofibroblast differentiation of DF cells regardless of the presence of a -catenin mutation. The role of TGF-1 in cell growth and myogenic differentiation of in vitro cultures of primary DF cells and normal fibroblasts was investigated by gene and protein expression analyses. We demonstrated that TGF-1 exerted its role via the canonical Smad pathway with the phosphorylation of Smad3 being crucial for TGF-1 dependent DF cell growth and myofibroblastic differentiation. Furthermore we demonstrated that cell confluence is a critical determinant of TGF-1 inducing the DF myofibroblast differentiation, implying that the intercellular communications have an important role on the DF myofibroblast behavior. We observed the formation of an increased stress-fiber pattern in DF cells with increased projected cell area and stronger cell-cell contacts in presence of TGF-1. These results demonstrated that TGF-1 plays a crucial role in the DF cells growth and, together with cell-cell interactions, in DF myofibroblast conversion; we also highlighted that the cellular sensitivity to this cytokine was an intrinsic feature of the DF cells