Recreational drug use among individuals living with HIV in Europe: review of the prevalence, comparison with the general population and HIV guidelines recommendations.

BACKGROUND: Adherence problems, interactions and higher rate of risk activities have been observed in HIV individuals using recreational drugs. Our aim was to describe recreational drug use in both HIV individuals and general population in Europe, and to assess at what extent HIV guidelines address this issue. METHODS: Data on recreational drug use across Europe were obtained from the European Monitoring Centre for Drugs and Drug Addiction for the general population, and through Pubmed search. for HIV patients. We assessed the incorporation of recreational drug issues in HIV treatment guidelines for the following topics: (a) recreational drugs; (b) adherence to antiretrovirals; (c) interactions; (d) transmission risk. Guidelines included: World Health Organization; European Aids Clinical Society; U.S. Department of Health and Human Services; International Antiviral Society-USA; and seven European national guidelines. RESULTS: 29 countries reported recreational drug use in general population. The highest prevalences were observed for Cannabis (i.e., 8-10% in Spain, France, and Czech Republic) followed by cocaine, amphetamines and ecstasy. The 13 studies selected in the systematic review showed a great variability in recreational drug use on the HIV population. Apart from classical recreational drugs, we found a relevant use of new drugs including sexual experience enhancers. Polydrug consumption was about 50% in some studies. Most guidelines included general information about recreational drugs, showing great variability on the inclusion of the evaluated topics. We found more specific, evidence-based recommendations on interactions, followed by medication adherence and transmission risk. CONCLUSIONS: Available data on the people living with HIV suggest a higher use of recreational drugs than in the general population, which is already relevant. However, recreational drug issues should be included or addressed more thoroughly in most guidelines.

Subcutaneous preconditioning increases invasion and metastatic dissemination in mouse colorectal cancer models.

Mouse colorectal cancer (CRC) models generated by orthotopic microinjection of human CRC cell lines reproduce the pattern of lymphatic, haematological and transcoelomic spread but generate low metastatic efficiency. Our aim was to develop a new strategy that could increase the metastatic efficiency of these models. We used subcutaneous implantation of the human CRC cell lines HCT116 or SW48 prior to their orthotopic microinjection in the cecum of nude mice (SC+ORT). This subcutaneous preconditioning significantly enhanced metastatic dissemination. In the HCT116 model it increased the number and size of metastatic foci in lymph nodes, lung, liver and peritoneum, whereas, in the SW48 model, it induced a shift from non-metastatic to metastatic. In both models the number of apoptotic bodies in the primary tumour in the SC+ORT group was significantly reduced compared with that in the direct orthotopic injection (ORT) group. Moreover, in HCT116 tumours the number of keratin-positive tumour buddings and single epithelial cells increased at the invasion front in SC+ORT mice. In the SW48 tumour model, we observed a trend towards a higher number of tumour buds and single cells in the SC+ORT group but this did not reach statistical significance. At a molecular level, the enhanced metastatic efficiency observed in the HCT116 SC+ORT model was associated with an increase in AKT activation, VEGF-A overexpression and downregulation of ß1 integrin in primary tumour tissue, whereas, in SW48 SC+ORT mice, the level of expression of these proteins remained unchanged. In summary, subcutaneous preconditioning increased the metastatic dissemination of both orthotopic CRC models by increasing tumour cell survival and invasion at the tumour invasion front. This approach could be useful to simultaneously study the mechanisms of metastases and to evaluate anti-metastatic drugs against CRC.

High RAB25 expression is associated with good clinical outcome in patients with locally advanced head and neck squamous cell carcinoma.

Currently there are no molecular markers able to predict clinical outcome in locally advanced head and neck squamous cell carcinoma (HNSCC). In a previous microarray study, RAB25 was identified as a potential prognostic marker. The aim of this study was to analyze the association between RAB25 expression and clinical outcome in patients with locally advanced HNSCC treated with standard therapy. In a retrospective immunohistochemical study (n = 97), we observed that RAB25-negative tumors had lower survival (log-rank, P = 0.01) than patients bearing positive tumors. In an independent prospective mRNA study (n = 117), low RAB25 mRNA expression was associated with poor prognosis. Using classification and regression tree analysis (CART) we established two groups of patients according to their RAB25 mRNA level and their risk of death. Low mRNA level was associated with poor local recurrence-free (log-rank, P = 0.005), progression-free (log-rank, P = 0.002) and cancer-specific (log-rank, P < 0.001) survival. Multivariate Cox model analysis showed that low expression of RAB25 was an independent poor prognostic factor for survival (hazard ratio: 3.84, 95% confidence interval: 1.93-7.62, P < 0.001). Patients whose tumors showed high RAB25 expression had a low probability of death after treatment. We also found lower RAB25 expression in tumors than in normal tissue (Mann-Whitney U, P < 0.001). Moreover, overexpression of RAB25 in the UM-SCC-74B HNSCC cell line increased cisplatin sensitivity, and reduced cell migration and invasion. Our findings support a tumor suppressor role for RAB25 in HNSCC and its potential use to identify locally advanced patients with a high probability of survival after genotoxic treatment.

Ritonavir boosting dose reduction from 100 to 50 mg does not change the atazanavir steady-state exposure in healthy volunteers.

OBJECTIVES: To evaluate the pharmacokinetics, tolerability and safety of 300 mg of atazanavir boosted with 100 or 50 mg of ritonavir, both once daily, at steady state. METHODS: This was a single-blind, multiple-dose, crossover, sequence-randomized trial. Thirteen healthy HIV-1-negative men received witnessed once-daily doses of atazanavir (300 mg) and 100 or 50 mg of ritonavir for 10 days (15 day washout). Atazanavir and ritonavir plasma concentrations were determined for 24 h on day 10. Log-transformed individual pharmacokinetic parameters were compared between treatments (analysis of variance); the difference between treatments on the log scale and 95% CIs were calculated. Fasting cholesterol, triglycerides, glucose and bilirubin plasma levels were measured at the beginning and end of each period and compared (Wilcoxon signed rank test). Gastrointestinal symptoms and other events were recorded. RESULTS: Ritonavir C(max) and the AUC0₋24 were lower after the 50 mg booster dose than after 100 mg [geometric mean ratio (GMR) (95% CI), 0.40 (0.31-0.51) and 0.35 (0.29-0.42), respectively]. No differences were observed in atazanavir exposure with 50 or 100 mg of ritonavir [GMR C(max) (95% CI), 1.00 (0.79-1.28); GMR AUC0₋24 (95% CI), 0.98 (0.79-1.21)]. Atazanavir trough concentration was >0.15 mg/L in all volunteers. Total and low-density lipoprotein cholesterol increased 0.40 mM (P = 0.01) and 0.37 mM (P = 0.003) from their corresponding baseline value during the 100 mg dosing period; there were no significant changes on 50 mg. Mild increases in bilirubin were detected on day 10 after both treatments without differences between treatments. CONCLUSIONS: In spite of higher exposure to ritonavir with 100 mg, atazanavir exposure was equivalent; the lipid profile was better under the lower booster dose (50 mg).