Systemic inflammation and residual viraemia in HIV-positive adults on protease inhibitor monotherapy: a cross-sectional study.

Increased levels of markers of systemic inflammation have been associated with serious non-AIDS events even in patients on fully suppressive antiretroviral therapy. We explored residual viremia and systemic inflammation markers in patients effectively treated with ritonavir-boosted protease inhibitor monotherapy (PImono)

Risky Alcohol Consumption and Associated Health Behaviour Among HIV-Positive and HIV-Negative Patients in a UK Sexual Health and HIV Clinic: A Cross-Sectional Questionnaire Study

Alcohol misuse has been associated with negative consequences among HIV-positive patients. Data on real prevalence of risky alcohol consumption among the HIV-positive population in the UK are lacking. A cross-sectional questionnaire study using standardised validated instruments among HIV-positive (n = 227) and HIV-negative (n = 69) patients was performed. The prevalence of risky alcohol consumption (AUDIT) and associations with depressive symptoms (PHQ-9), problematic drug use (DUDIT), adherence to ART (CASE Adherence Index), sexual behaviour and demographic characteristics were assessed among both patient groups independently. A quarter (25.1%) of HIV-positive patients and 36.1% of HIV-negative patients reported risky alcohol consumption (AUDIT-score ≥ 8). In the multivariable analysis among HIV-positive patients depressive symptoms (p = 0.03) and problematic drug use (p = 0.007) were associated with risky alcohol consumption. Among HIV-negative patients these associations were not present. Risky alcohol consumption among HIV-positive patients is prevalent, and together with depressive symptoms and problematic drug use, may influence HIV-disease progression and patients’ wellbeing

Studies on clinical and epidemiological factors associated with peripheral neuropathy and severe hyperlactatemia or lactic acidosis in HIV-infected adults exposed to nucleoside analogues reverse transcriptase inhibitors.

Studies on mitochondrial dysfunction in HIV-infected adults exposed to anti-retroviral therapy. A significant proportion of HIV-infected patients who require anti-retroviral therapy are or have been exposed to nucleoside analogue reverse transcriptase inhibitors (NRTIs). It has been consistently suggested that most of the NRTI-attributed adverse drug reactions (ADR) are due to mitochondrial dysfunction. In a sub-analysis of a large randomised clinical trial (Delta) the incidence of peripheral neuropathy (PN) was constant over time in all study arms, which does not support the hypothesis of cumulative toxicity previously proposed for NRTI-induced ADR. Patients taking zidovudine (AZT)/zalcitabine (ddC) combination were more likely to develop PN than patients on AZT monotherapy (RH= 2.30 95%CI= 1.62 - 3.28). The incidence of PN among patients exposed to zidovudine/didanosine (AZT/ddl) combination was not different from that observed in patients on AZT. In a multi-centre case-control study including 110 cases of lactic acidosis (LA) or severe hyperlactataemia (HL) patients with < 200 CD4 cell/pl were more likely to develop HL/LA than patients with higher levels of CD4 cells (OR=3.44 95%CI= 1.64 - 7.22). Female patients were found to be at higher risk for HULA than men (OR= 4.75 95%CI= 1.96 - 11.53). Patients exposed to either d4T, ddl or the combination of these two were four to six times more likely to develop HL/LA than patients taking other NRTIs based combinations. Interestingly, cases of HL/LA were exposed to d4T for shorter periods of time than controls. Almost 10 % of the cases included in the study were asymptomatic at the time of diagnosis. All these symptom-free cases had blood lactate ranging between 5 and 7 mmol/l. Therefore, case definitions for HL or LA based on clinical presentation may underestimate the magnitude of the problem

Interaction strength between different grazers and macroalgae mediated by ocean acidification over warming gradients

Since the past century, rising CO2 levels have led to global changes (ocean warming and acidification) with subsequent effects on marine ecosystems and organisms. Macroalgae-herbivore interactions have a main role in the regulation of marine community structure (top-down control). Gradients of warming prompt complex non-linear effects on organism metabolism, cascading into altered trophic interactions and community dynamics. However, not much is known on how will acidification and grazer assemblage composition shape these effects. Within this context, we aimed to assess the combined effects of warming gradients and acidification on macroalgae-herbivore interactions, using three cosmopolitan species, abundant in the Iberian Peninsula and closely associated in nature: the amphipod Melita palmata, the gastropod Gibbula umbilicalis, and the green macroalga Ulva rigida. Under two CO2 treatments (triangle CO2 similar or equal to 450 mu atm) across a temperature gradient (13.5, 16.6, 19.9 and 22.1 degrees C), two mesocosm experiments were performed to assess grazer consumption rates and macroalgae-herbivore interaction, respectively. Warming (Experiment I and II) and acidification (Experiment II) prompted negative effects in grazer's survival and species-specific differences in consumption rates. M. palmata was shown to be the stronger grazer per biomass (but not per capita), and also the most affected by climate stressors. Macroalgae-herbivore interaction strength was markedly shaped by the temperature gradient, while simultaneous acidification lowered thermal optimal threshold. In the near future, warming and acidification are likely to strengthen top-down control, but further increases in disturbances may lead to bottom-up regulated communities. Finally, our results suggest that grazer assemblage composition may modulate future macroalgae-herbivore interactions. (C) 2017 Elsevier Ltd. All rights reserved.Peer reviewe

Cost Effectiveness of Protease Inhibitor Monotherapy Versus Standard Triple Therapy in the Long-Term Management of HIV Patients: Analysis Using Evidence from the PIVOT Trial

BACKGROUND: Protease inhibitor (PI) monotherapy can maintain virological suppression in the majority of patients once it has been established on triple therapy and may also have the potential for substantial cost savings arising from the use of fewer drugs. However, the cost effectiveness of PI monotherapy has yet to be demonstrated. OBJECTIVES: In this study we examine the cost effectiveness of PI monotherapy with prompt return to combination therapy in the event of viral load rebound compared with ongoing triple therapy (OT) in patients with suppressed viral load on combination antiretroviral therapy (ART) in the UK. METHODS: The analysis used data from the PIVOT trial in which HIV-positive adults with suppressed viral load for ≥24 weeks on combination ART were randomised to maintain OT or to a strategy of PI monotherapy with prompt return to combination therapy if viral load rebounded. A cost-effectiveness analysis including long-term modelling was conducted. Main outcomes included UK National Health Service (NHS) costs and quality-adjusted life-years (QALYs) with comparative results presented as incremental cost-effectiveness ratios. RESULTS: PI monotherapy was cost saving as a result of large savings in ART drug costs while being no less effective in terms of QALYs in the within-trial analysis and marginally less effective with lifetime modelling. In the base-case analysis over 3 years, the incremental total cost per patient was -£6424.11 (95 % confidence interval -7418.84 to -5429.38) and incremental QALYs were 0.0051 (95 % CI -0.0479 to 0.0582), resulting in PI monotherapy 'dominating' OT. Multiple scenario analyses found that PI monotherapy was cost saving with no marked differences in QALYs. Modelling of lifetime costs and QALYs showed that PI monotherapy was associated with significant cost savings and was marginally less effective; PI monotherapy was cost effective at accepted cost-effectiveness thresholds in all but one scenario analysis. CONCLUSIONS: Under most assumptions, PI monotherapy appears to be a cost-effective treatment strategy compared with OT for HIV-infected patients who have achieved sustained virological suppression

Peripheral neuropathy in HIV patients in sub-Saharan Africa failing first-line therapy and the response to second-line ART in the EARNEST trial.

Sensory peripheral neuropathy (PN) remains a common complication in HIV-positive patients despite effective combination anti-retroviral therapy (ART). Data on PN on second-line ART is scarce. We assessed PN using a standard tool in patients failing first-line ART and for 96 weeks following a switch to PI-based second-line ART in a large Randomised Clinical Trial in Sub-Saharan Africa. Factors associated with PN were investigated using logistic regression. Symptomatic PN (SPN) prevalence was 22 % at entry (N = 1,251) and was associated (p < 0.05) with older age (OR = 1.04 per year), female gender (OR = 1.64), Tuberculosis (TB; OR = 1.86), smoking (OR = 1.60), higher plasma creatinine (OR = 1.09 per 0.1 mg/dl increase), CD4 count (OR = 0.83 per doubling) and not consuming alcohol (OR = 0.55). SPN prevalence decreased to 17 % by week 96 (p = 0.0002) following similar trends in all study groups (p = 0.30). Asymptomatic PN (APN) increased over the same period from 21 to 29 % (p = 0.0002). Signs suggestive of PN (regardless of symptoms) returned to baseline levels by week 96. At weeks 48 and 96, after adjusting for time-updated associations above and baseline CD4 count and viral load, SPN was strongly associated with TB (p < 0.0001). In summary, SPN prevalence was significantly reduced with PI-based second-line therapy across all treatment groups, but we did not find any advantage to the NRTI-free regimens. The increase of APN and stability of PN-signs regardless of symptoms suggest an underlying trend of neuropathy progression that may be masked by reduction of symptoms accompanying general health improvement induced by second-line ART. SPN was strongly associated with isoniazid given for TB treatment

Next generation sequencing of HIV-1 protease in the PIVOT trial of protease inhibitor monotherapy

BACKGROUND: The PIVOT trial examined whether patients with suppressed viral load on combination antiretroviral therapy could be safely switched long-term to ritonavir-boosted protease inhibitor (PI) monotherapy. The main trial publication reported that only one of 296 patients allocated to PI monotherapy experienced a loss of drug options due to protease mutations (identified by local Sanger sequencing resistance tests) likely selected by study drug. OBJECTIVES: To assess if we had missed low frequency mutations, using a more sensitive methodology. STUDY DESIGN: We performed next generation sequencing (NGS) on all available frozen plasma samples with VL >1000 copies/ml from patients who were randomised to PI monotherapy. Assays were performed at Public Health England laboratories using a previously described method. Median coverage depth was 76,000 and the threshold for detection of minority variants was 2%. Drug susceptibility was predicted using the Stanford HIVdb algorithm. RESULTS: 17 of 26 potential samples, all from different patients, were identified and successfully tested. The median viral load was 6780 copies/ml and the median time since randomisation was 43 weeks. NGS revealed previously unidentified minority variant protease mutations (G73D, I54T, L89V) in three samples, at frequencies ranging between 2% and 10%. None of these mutations predicted intermediate or high level resistance, the trial primary outcome. DISCUSSION: This report adds to the body of evidence that ritonavir-boosted PI monotherapy, when used as a switch strategy with prompt detection of viral load rebound and early re-introduction of combination therapy, rarely leads to the development of clinically important protease resistance mutations

Exploring Halo Substructure with Giant Stars III: First Results from the Grid Giant Star Survey and Discovery of a Possible Nearby Sagittarius Tidal Structure in Virgo

We describe first results of a spectroscopic probe of selected fields from the Grid Giant Star Survey. Multifiber spectroscopy of several hundred stars in a strip of eleven fields along delta approximately -17^{circ}, in the range 12 <~ alpha <~ 17 hours, reveals a group of 8 giants that have kinematical characteristics differing from the main field population, but that as a group maintain coherent, smoothly varying distances and radial velocities with position across the fields. Moreover, these stars have roughly the same abundance, according to their MgH+Mgb absorption line strengths. Photometric parallaxes place these stars in a semi-loop structure, arcing in a contiguous distribution between 5.7 and 7.9 kpc from the Galactic center. The spatial, kinematical, and abundance coherence of these stars suggests that they are part of a diffuse stream of tidal debris, and one roughly consistent with a wrapped, leading tidal arm of the Sagittarius dwarf spheroidal galaxy.Comment: 8 pages including 4 figures. Accepted for publication in ApJ

The regime of climate-related disturbance and nutrient enrichment modulate macroalgal invasions in rockpools

Patterns of invasion by the seaweeds Grateloupia turuturu Yamada and Sargassum muticum (Yendo) Fensholt under crossed combinations of the regime (mean intensity and temporal variability) of climate-related mechanical disturbance and constant nutrient enrichment were experimentally examined in rockpools in north Portugal. The cover of both species was larger under high compared to low intensity of disturbance, but this effect was enhanced by events more heterogeneously distributed over a period of 19 months. The invasion by G. turuturu was also larger in enriched pools, but only when disturbance was applied at high intensity. The richness of native taxa was increased by high intensity events of disturbance evenly distributed over time and by low intensity events heterogeneously distributed, while no differences were documented for other treatments. Temporal variability of disturbance and nutrients interactively affected the total cover of native taxa and the availability of bare rock in different directions. Enriched conditions increased the space occupancy by natives and reduced substratum availability only when associated to heterogeneous events of disturbance. At the same time, relatively more variable disturbances caused a reduced cover by native taxa and an increased availability of free space, but only under natural nutrient levels. Present findings contribute to understand the conditions that would be more likely to facilitate the spread of G. turuturu and S. muticum under current and predicted scenarios of compounded environmental changes and in relation to traits of recipient systems that are considered relevant for the success of invasions, including the native richness and the degree of usage of resources, i.e. primarily space