Association of Tenofovir Use With Risk of Incident Heart Failure in HIV-Infected Patients.

BackgroundThe antiretroviral medication, tenofovir disoproxil fumarate (TDF), is used by most human immunodeficiency virus-infected persons in the United States despite higher risks of chronic kidney disease. Although chronic kidney disease is a strong risk factor for heart failure (HF), the association of TDF with incident HF is unclear.Methods and resultsWe identified 21 435 human immunodeficiency virus-infected patients in the United States Veterans Health Administration actively using antiretrovirals between 2002 and 2011. We excluded patients with a prior diagnosis of HF. TDF was analyzed categorically (current, past, or never use) and continuously (per year of use). Proportional hazards regression and fully adjusted marginal structural models were used to determine the association of TDF exposure with risk of incident HF after adjustment for demographic, human immunodeficiency virus-related, and cardiovascular risk factors. During follow-up, 438 incident HF events occurred. Unadjusted 5-year event rates for current, past, and never users of TDF were 0.9 (95%CI 0.7-1.1), 1.7 (1.4-2.2), and 4.5 (3.9-5.0), respectively. In fully adjusted analyses, HF risk was markedly lower in current TDF users (HR=0.68; 95%CI 0.53-0.86) compared with never users. Among current TDF users, each additional year of TDF exposure was associated with a 21% lower risk of incident HF (95%CI: 0.68-0.92). When limited to antiretroviral-naive patients, HF risk remained lower in current TDF users (HR=0.53; 95%CI 0.36-0.78) compared to never users.ConclusionsAmong a large national cohort of human immunodeficiency virus-infected patients, TDF use was strongly associated with lower risk of incident HF. These findings warrant confirmation in other populations, both with TDF and the recently approved tenofovir alafenamide fumarate

Tenofovir disoproxil fumarate induces peripheral neuropathy and alters inflammation and mitochondrial biogenesis in the brains of mice.

Mounting evidence suggests that antiretroviral therapy (ART) drugs may contribute to the prevalence of HIV-associated neurological dysfunction. The HIV envelope glycoprotein (gp120) is neurotoxic and has been linked to alterations in mitochondrial function and increased inflammatory gene expression, which are common neuropathological findings in HIV+ cases on ART with neurological disorders. Tenofovir disproxil fumarate (TDF) has been shown to affect neurogenesis in brains of mice and mitochondria in neurons. In this study, we hypothesized that TDF contributes to neurotoxicity by modulating mitochondrial biogenesis and inflammatory pathways. TDF administered to wild-type (wt) and GFAP-gp120 transgenic (tg) mice caused peripheral neuropathy, as indicated by nerve conduction slowing and thermal hyperalgesia. Conversely TDF protected gp120-tg mice from cognitive dysfunction. In the brains of wt and gp120-tg mice, TDF decreased expression of mitochondrial transcription factor A (TFAM). However, double immunolabelling revealed that TFAM was reduced in neurons and increased in astroglia in the hippocampi of TDF-treated wt and gp120-tg mice. TDF also increased expression of GFAP and decreased expression of IBA1 in the wt and gp120-tg mice. TDF increased tumor necrosis factor (TNF) α in wt mice. However, TDF reduced interleukin (IL) 1β and TNFα mRNA in gp120-tg mouse brains. Primary human astroglia were exposed to increasing doses of TDF for 24 hours and then analyzed for mitochondrial alterations and inflammatory gene expression. In astroglia, TDF caused a dose-dependent increase in oxygen consumption rate, extracellular acidification rate and spare respiratory capacity, changes consistent with increased metabolism. TDF also reduced IL-1β-mediated increases in IL-1β and TNFα mRNA. These data demonstrate that TDF causes peripheral neuropathy in mice and alterations in inflammatory signaling and mitochondrial activity in the brain

Theories of behaviour change synthesised into a set of theoretical groupings: Introducing a thematic series on the Theoretical Domains Framework

Behaviour change is key to increasing the uptake of evidence into healthcare practice. Designing behaviour-change interventions first requires problem analysis, ideally informed by theory. Yet the large number of partly overlapping theories of behaviour makes it difficult to select the most appropriate theory. The need for an overarching theoretical framework of behaviour change was addressed in research in which 128 explanatory constructs from 33 theories of behaviour were identified and grouped. The resulting Theoretical Domains Framework (TDF) appears to be a helpful basis for investigating implementation problems. Research groups in several countries have conducted TDF-based studies. It seems timely to bring together the experience of these teams in a thematic series to demonstrate further applications and to report key developments. This overview article describes the TDF, provides a brief critique of the framework, and introduces this thematic series. In a brief review to assess the extent of TDF-based research, we identified 133 papers that cite the framework. Of these, 17 used the TDF as the basis for empirical studies to explore health professionals’ behaviour. The identified papers provide evidence of the impact of the TDF on implementation research. Two major strengths of the framework are its theoretical coverage and its capacity to elicit beliefs that could signify key mediators of behaviour change. The TDF provides a useful conceptual basis for assessing implementation problems, designing interventions to enhance healthcare practice, and understanding behaviour-change processes. We discuss limitations and research challenges and introduce papers in this series

A cost utility and cost effectiveness analysis of different oral antiviral medications in patients with HBeAg-Negative chronic hepatitis B in Iran: an economic microsimulation decision model

Background: Although hepatitis B infection is the major cause of chronic liver disease in Iran, no studies have employed economic evaluations of the medications used to treat Iranian patients with chronic hepatitis B (CHB). Therefore, the cost-effectiveness of the different treatment options for this disease in Iran is unknown. Objectives: The aim of this study was to compare the cost utility and cost-effectiveness of medication strategies tailored to local conditions in patients with HB e antigen (HBeAg)-negative CHB infection in Iran. Methods: An economic evaluation of the cost utility of the following five oral medication strategies was conducted: adefovir (ADV), lamivudine (LAM), ADV + LAM, entecavir (ETV), and tenofovir (TDF). A Markov microsimulation model was used to estimate the clinical and economic outcomes over the course of the patient’s lifetime and based on a societal perspective. Medical and nonmedical direct costs and indirect costs were included in the study and life-years gained (LYG) and quality-adjusted life-years (QALY) were determined as measures of effectiveness. The results are presented in terms of the incremental cost-effectiveness ratio (ICER) per QALY or LYG. The model consisted of nine stages of the disease. The transition probabilities for the movement between the different stages were based on clinical evidence and international expert opinion. A probabilistic sensitivity analysis (PSA) was used to measure the effects of uncertainty in the model parameters. Results: The results revealed that the TDF treatment strategy was more effective and less costly than the other options. In addition, TDF had the highest QALY and LYG in the HBeAg-negative CHB patients, with 13.58 and 21.26 (discounted) in all comparisons. The PSA proved the robustness of the model results. The cost-effectiveness acceptability curves showed that TDF was the most cost-effective treatment in 59% - 78% of the simulations of HBeAg-negative patients, with WTP thresholds less than $14010 (maximum WTP per QALY). Conclusions: The use of TDF in patients with HBeAg-negative CHB seemed to be a highly cost-effective strategy. Compared with the other available medication options, TDF was the most cost-saving strategy. Thus, TDF may be the best option as a first-line medication. Patients can also be switched from other medications to TDF

Measurement of the rate of stellar tidal disruption flares

We report an observational estimate of the rate of stellar tidal disruption flares (TDFs) in inactive galaxies, based on a successful search for these events among transients in galaxies using archival SDSS multi-epoch imaging data (Stripe 82). This search yielded 186 nuclear flares in galaxies, of which two are excellent TDF candidates. Because of the systematic nature of the search, the very large number of galaxies, the long time of observation, and the fact that non-TDFs were excluded without resorting to assumptions about TDF characteristics, this study provides an unparalleled opportunity to measure the TDF rate. To compute the rate of optical stellar tidal disruption events, we simulate our entire pipeline to obtain the efficiency of detection. The rate depends on the light curves of TDFs, which are presently still poorly constrained. Using only the observed part of the SDSS light curves gives a model-independent upper limit to the optical TDF rate: < 2 10^-4 per year per galaxy (90% CL). We develop three empirical models of the light curves, based on the two SDSS light curves and two more recent and better-sampled Pan-STARRS TDF light curves, leading to our best-estimate of the rate: (1.5 - 2.0)_{-1.3}^{+2.7} 10^-5 per year per galaxy. We explore the modeling uncertainties by considering two theoretically motivated light curve models, as well as two different relationships between black hole mass and galaxy luminosity, and two different treatments of the cutoff in the visibility of TDFs at large black hole mass. From this we conclude that these sources of uncertainty are not significantly larger than the statistical ones. Our results are applicable for galaxies hosting black holes with mass in the range of few million to 10^8 solar masses, and translates to a volumetric TDF rate of (4 - 8) 10^-8 per year per cubic Mpc.Comment: Published in Ap

What are the ‘active ingredients’ of interventions targeting the public's engagement with antimicrobial resistance and how might they work?

Objectives. Changing public awareness of antimicrobial resistance (AMR) represents a global public health priority. A systematic review of interventions that targeted public AMR awareness and associated behaviour was previously conducted. Here, we focus on identifying the active content of these interventions and explore potential mechanisms of action. Methods. The project took a novel approach to intervention mapping utilizing the following steps: (1) an exploration of explicit and tacit theory and theoretical constructs within the interventions using the Theoretical Domains Framework (TDFv2), (2) retrospective coding of behaviour change techniques (BCTs) using the BCT Taxonomy v1, and (3) an investigation of coherent links between the TDF domains and BCTs across the interventions. Results. Of 20 studies included, only four reported an explicit theoretical basis to their intervention. However, TDF analysis revealed that nine of the 14 TDF domains were utilized, most commonly ‘Knowledge’ and ‘Environmental context and resources’. The BCT analysis showed that all interventions contained at least one BCT, and 14 of 93 (15%) BCTs were coded, most commonly ‘Information about health consequences’, ‘Credible source’, and ‘Instruction on how to perform the behaviour’. Conclusions. We identified nine relevant TDF domains and 14 BCTs used in these interventions. Only 15% of BCTs have been applied in AMR interventions thus providing a clear opportunity for the development of novel interventions in this context. This methodological approach provides a useful way of retrospectively mapping theoretical constructs and BCTs when reviewing studies that provide limited information on theory and intervention content

Defining the content and delivery of an intervention to Change AdhereNce to treatment in BonchiEctasis (CAN-BE): a qualitative approach incorporating the Theoretical Domains Framework, behavioural change techniques and stakeholder expert panels

BACKGROUND: Low patient adherence to treatment is associated with poorer health outcomes in bronchiectasis. We sought to use the Theoretical Domains Framework (TDF) (a framework derived from 33 psychological theories) and behavioural change techniques (BCTs) to define the content of an intervention to change patients' adherence in bronchiectasis (Stage 1 and 2) and stakeholder expert panels to define its delivery (Stage 3). METHODS: We conducted semi-structured interviews with patients with bronchiectasis about barriers and motivators to adherence to treatment and focus groups or interviews with bronchiectasis healthcare professionals (HCPs) about their ability to change patients' adherence to treatment. We coded these data to the 12 domain TDF to identify relevant domains for patients and HCPs (Stage 1). Three researchers independently mapped relevant domains for patients and HCPs to a list of 35 BCTs to identify two lists (patient and HCP) of potential BCTs for inclusion (Stage 2). We presented these lists to three expert panels (two with patients and one with HCPs/academics from across the UK). We asked panels who the intervention should target, who should deliver it, at what intensity, in what format and setting, and using which outcome measures (Stage 3). RESULTS: Eight TDF domains were perceived to influence patients' and HCPs' behaviours: Knowledge, Skills, Beliefs about capability, Beliefs about consequences, Motivation, Social influences, Behavioural regulation and Nature of behaviours (Stage 1). Twelve BCTs common to patients and HCPs were included in the intervention: Monitoring, Self-monitoring, Feedback, Action planning, Problem solving, Persuasive communication, Goal/target specified:behaviour/outcome, Information regarding behaviour/outcome, Role play, Social support and Cognitive restructuring (Stage 2). Participants thought that an individualised combination of these BCTs should be delivered to all patients, by a member of staff, over several one-to-one and/or group visits in secondary care. Efficacy should be measured using pulmonary exacerbations, hospital admissions and quality of life (Stage 3). CONCLUSIONS: Twelve BCTs form the intervention content. An individualised selection from these 12 BCTs will be delivered to all patients over several face-to-face visits in secondary care. Future research should focus on developing physical materials to aid delivery of the intervention prior to feasibility and pilot testing. If effective, this intervention may improve adherence and health outcomes for those with bronchiectasis in the future

Cost and cost-effectiveness of switching from d4T or AZT to a TDF-based first-line regimen in a resource-limited setting in rural Lesotho

Article approval pendingLatest World Health Organization guidelines recommend shifting away from Stavudine (d4T)-based regimens due to severe side effects. However, widespread replacement of d4T by Tenofovir (TDF) or Zidovudine (AZT) is hampered by cost concerns