Bacteria associated with periodontal disease are also increased in health.

BACKGROUND: The objective of this cross-sectional clinical study was to analyze the differences in the microbiome in gingival sulci of adult patients in the presence or absence of chronic periodontitis. MATERIAL AND METHODS: Patients with or without periodontal disease were included in this cross-sectional study. Subgingival biofilm samples were collected and analyzed by 16S massive pyrosequencing. Functional analyses were also performed. RESULTS: A total of 15 phyla, 154 genera and 351 species were detected globally. Differences between disease and non-disease samples were observed in all taxonomical levels which suggest functional profile changes in the community. It was found that the main species associated with non-disease samples were reduced in disease but not completely suppressed. Analysis of the functional potential of the biofilms revealed a significantly higher activity related to endocytosis and phosphatidylinositol signaling in the disease group but lower cell adhesion molecules. CONCLUSIONS: Specific differences between health and disease suggest functional profile changes in the community, although bacteria associated with periodontal disease are also increased in health. Transcriptome studies should be conducted to confirm and deepen metabolic dysfunctions.

Virological Failure in HIV to Triple Therapy With Dolutegravir-Based Firstline Treatment: Rare but Possible.

We describe a case of virological failure during initial treatment with tenofovir disoproxil fumarate/emtricitabine/dolutegravir twice daily, with concomitant rifampin treatment of staphylococcal infection, selection of R263K + E157Q, and low plasma dolutegravir levels. Using rifampin together with dolutegravir may require closer follow-up, and, if possible, plasma dolutegravir levels should be monitored.

Immunomodulatory tetracyclines shape the intestinal inflammatory response inducing mucosal healing and resolution.

BACKGROUND AND PURPOSE: Immunomodulatory tetracyclines are well-characterized drugs with a pharmacological potential beyond their antibiotic properties. Specifically, minocycline and doxycycline have shown beneficial effects in experimental colitis, although pro-inflammatory actions have also been described in macrophages. Therefore, we aimed to characterize the mechanism behind their effect in acute intestinal inflammation. EXPERIMENTAL APPROACH: A comparative pharmacological study was initially used to elucidate the most relevant actions of immunomodulatory tetracyclines: doxycycline, minocycline and tigecycline; other antibiotic or immunomodulatory drugs were assessed in bone marrow-derived macrophages and in dextran sodium sulfate (DSS)-induced mouse colitis, where different barrier markers, inflammatory mediators, microRNAs, TLRs, and the gut microbiota composition were evaluated. The sequential immune events that mediate the intestinal anti-inflammatory effect of minocycline in DSS-colitis were then characterized. KEY RESULTS: Novel immunomodulatory activity of tetracyclines was identifed; they potentiated the innate immune response and enhanced resolution of inflammation. This is also the first report describing the intestinal anti-inflammatory effect of tigecycline. A minor therapeutic benefit seems to derive from their antibiotic properties. Conversely, immunomodulatory tetracyclines potentiated macrophage cytokine release in vitro, and while improving mucosal recovery in colitic mice, they up-regulated Ccl2, miR-142, miR-375 and Tlr4. In particular, minocycline initially enhanced IL-1ß, IL-6, IL-22, GM-CSF and IL-4 colonic production and monocyte recruitment to the intestine, subsequently increasing Ly6C- MHCII+ macrophages, Tregs and type 2 intestinal immune responses. CONCLUSIONS AND IMPLICATIONS: Immunomodulatory tetracyclines potentiate protective immune pathways leading to mucosal healing and resolution, representing a promising drug reposition strategy for the treatment of intestinal inflammation.

Immunomodulatory tetracyclines ameliorate DNBS-colitis: Impact on microRNA expression and microbiota composition.

OBJECTIVE: The use of immunomodulatory antibiotics to simultaneously target different factors involved in intestinal inflammatory conditions is an interesting but understudied pharmacological strategy. A great therapeutic potential has been obtained with minocycline and doxycycline in experimental colitis. Therefore, understanding the contribution of the different activities of immunomodulatory tetracyclines is crucial for the improvement and translation of their use into clinic. DESIGN: A comparative pharmacological study including tetracyclines and other antibiotic or immunomodulatory drugs was performed in 2,4-dinitrobenzene sulfonic acid (DNBS)-induced colitis in mice. The correlation between the therapeutic efficacy of each drug and changes in the gut microbiota composition, markers of barrier integrity, inflammatory mediators, microRNAs and TLRs was analysed to identify the main mechanisms of action. RESULTS: Tetracyclines counteracted most of the markers found altered in DNBS-colitis, which differed from effects of corticosteroid treatment. Of note, administration of tetracyclines led to increased mucosal protection, associated with up-regulated expression of CCL2, miR-142 and miR-375. All drugs with antibiotic activity ameliorated the progression of inflammation and reduced neutrophil-related genes, such as miR-223, despite their effects were not associated with restored intestinal dysbiosis. However, reduced bacterial richness was correlated with increased expression of TLR2 and TLR9 in antibiotic-treated groups and TLR6 was also up-regulated by the immunomodulatory tetracyclines with higher efficacy (doxycycline, minocycline and tigecycline). CONCLUSION: The anti-inflammatory effect of tetracyclines involves specific modifications in TLR and microRNA expression leading to an improved microbial-derived signalling and mucosal protection. These results support the potential of immunomodulatory tetracyclines to prevent inflammation-associated tissue damage in acute intestinal inflammation.

The cobas® HCV GT is a new tool that accurately identifies Hepatitis C virus genotypes for clinical practice.

OBJECTIVE: We aimed to evaluate the correct assignment of HCV genotype/subtypes 1a and 1b by cobas® HCV genotyping (GT) assay (Roche Molecular Diagnostics) compared with nonstructural protein 5B (NS5B) sequencing. PATIENTS AND METHODS: Clinical samples from 153 patients submitted for HCV genotyping were studied. After genotyping with the cobas® HCV GT, sequencing of a 387 bp fragment in the NS5B gene and phylogenetic analysis was employed to compare genotyping results. Major discrepancies were defined as differences in the assigned genotype by cobas® HCV GT and NS5B sequencing (including genotype 1 subtypes 1a and 1b misclassification). RESULTS: Overall agreement between the cobas® HCV GT and NS5B sequencing was 98%; all the 1a, 1b, 2, 3 and 4 genotypes identified by cobas® HCV GT were concordant with NS5B sequencing. Three samples tested "indetermined" by cobas® HCV GT assay and were genotyped as 1a, 3a, and 4d by NS5B sequencing. CONCLUSSION: These results indicate that the cobas® HCV GT assay correctly identifies HCV genotypes, and points out the importance of additional methods based on DNA sequencing for resolving indeterminate results.

Transmitted drug resistance to rilpivirine in newly diagnosed antiretroviral naive adults.

We characterized transmitted drug resistance to rilpivirine and the predicted efficacy of first-line rilpivirine-containing regimens in antiretroviral-naive Spanish patients. International Antiviral Society-USA mutations were detected in 138 of 2781 patients (4.9%), E138A (3.4%) being the most prevalent. Using the Stanford Algorithm, 121 patients (4.4%) showed low-level or intermediate resistance. No differences in the predicted efficacy of first-line non-nucleoside reverse transcriptase inhibitor-based regimens were observed. As rilpivirine becomes more widely used in clinical practice, the evolution of its transmitted drug resistance will need to be monitored. In addition, the exact role of E138A singletons on rilpivirine activity as part of first-line regimens merits further evaluation.

Efficacy and safety of once-daily maraviroc plus ritonavir-boosted darunavir in pretreated HIV-infected patients in a real-life setting.

OBJECTIVES: Nucleoside reverse transcriptase inhibitor (NRTI)-sparing regimens may be needed in patients with NRTI toxicity. Maraviroc (MVC) plus ritonavir-boosted darunavir (DRV-r) or atazanavir is associated with slightly lower response rates than triple therapy in drug-naïve patients. No information is available on these combinations in pretreated patients. The aim of this study was to assess the efficacy and safety of MVC plus DRV/r once-daily (qd) in HIV-infected pretreated patients. METHODS: A retrospective cohort study including patients starting MVC 150 mg plus DRV/r 800/100 mg qd, with CCR5 tropism and no resistance mutations for DRV/r, was performed. The primary efficacy endpoint was the achievement of plasma HIV RNA < 50 HIV-1 RNA copies/mL after 48 weeks. The frequency of serious adverse effects was investigated. RESULTS: Sixty patients were recruited to the study, of whom 48 (80%) had HIV RNA < 50 copies/mL at baseline. Reasons for starting MVC plus DRV/r were: adverse effects in 38 individuals (63%), simplification in 15 (25%) and virological failure in seven (12%). The main analysis (intention to treat, noncompleter = failure) showed that 47 patients (78%) achieved HIV RNA < 50 copies/mL at 48 weeks (paired comparison with baseline, P = 1.0). On-treatment analysis showed that 42 (86%) of 49 patients presented HIV RNA < 50 copies/mL at 48 weeks (paired comparison with baseline, P = 1.0). Median (interquartile range) CD4 cell counts increased from 491 (301-729) to 561 (367-793) cells/µL at 48 weeks (P = 0.013). Only one patient discontinued therapy because of adverse effects. CONCLUSIONS: Most individuals starting MVC plus DRV/r qd because of simplification or adverse effects maintained HIV suppression after 48 weeks of follow-up.