401 research outputs found
Novel methods to estimate antiretroviral adherence: protocol for a longitudinal study.
BackgroundThere is currently no gold standard for assessing antiretroviral (ARV) adherence, so researchers often resort to the most feasible and cost-effective methods possible (eg, self-report), which may be biased or inaccurate. The goal of our study was to evaluate the feasibility and acceptability of innovative and remote methods to estimate ARV adherence, which can potentially be conducted with less time and financial resources in a wide range of clinic and research settings. Here, we describe the research protocol for studying these novel methods and some lessons learned.MethodsThe 6-month pilot study aimed to examine the feasibility and acceptability of a remotely conducted study to evaluate the correlation between: 1) text-messaged photographs of pharmacy refill dates for refill-based adherence; 2) text-messaged photographs of pills for pill count-based adherence; and 3) home-collected hair sample measures of ARV concentration for pharmacologic-based adherence. Participants were sent monthly automated text messages to collect refill dates and pill counts that were taken and sent via mobile telephone photographs, and hair collection kits every 2 months by mail. At the study end, feasibility was calculated by specific metrics, such as the receipt of hair samples and responses to text messages. Participants completed a quantitative survey and qualitative exit interviews to examine the acceptability of these adherence evaluation methods. The relationship between the 3 novel metrics of adherence and self-reported adherence will be assessed.DiscussionInvestigators conducting adherence research are often limited to using either self-reported adherence, which is subjective, biased, and often overestimated, or other more complex methods. Here, we describe the protocol for evaluating the feasibility and acceptability of 3 novel and remote methods of estimating adherence, with the aim of evaluating the relationships between them. Additionally, we note the lessons learned from the protocol implementation to date. We expect that these novel measures will be feasible and acceptable. The implications of this research will be the identification and evaluation of innovative and accurate metrics of ARV adherence for future implementation
Quantifying Isoniazid Levels in Small Hair Samples: A Novel Method for Assessing Adherence during the Treatment of Latent and Active Tuberculosis.
BackgroundTuberculosis (TB) is the leading cause of death from an infectious pathogen worldwide and the most prevalent opportunistic infection in people living with HIV. Isoniazid preventive therapy (IPT) reduces the incidence of active TB and reduces morbidity and mortality in HIV-infected patients independently of antiretroviral therapy. However, treatment of latent or active TB is lengthy and inter-patient variability in pharmacokinetics and adherence common. Current methods of assessing adherence to TB treatment using drug levels in plasma or urine assess short-term exposure and pose logistical challenges. Drug concentrations in hair assess long-term exposure and have demonstrated pharmacodynamic relevance in HIV.MethodsA large hair sample from a patient with active TB was obtained for assay development. Methods to pulverize hair and extract isoniazid were optimized and then the drug detected by liquid chromatography/ tandem mass spectrometry (LC/MS-MS). The method was validated for specificity, accuracy, precision, recovery, linearity and stability to establish the assay's suitability for therapeutic drug monitoring (TDM). Hair samples from patients on directly-observe isoniazid-based latent or active TB therapy from the San Francisco Department of Public Health TB clinic were then tested.ResultsOur LC/MS-MS-based assay detected isoniazid in quantities as low as 0.02ng/mg using 10-25 strands hair. Concentrations in spiked samples demonstrated linearity from 0.05-50ng/mg. Assay precision and accuracy for spiked quality-control samples were high, with an overall recovery rate of 79.5%. In 18 patients with latent or active TB on treatment, isoniazid was detected across a wide linear dynamic range.ConclusionsAn LC-MS/MS-based assay to quantify isoniazid levels in hair with performance characteristics suitable for TDM was developed and validated. Hair concentrations of isoniazid assess long-term exposure and may be useful for monitoring adherence to latent or active TB treatment in the setting of HIV
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Estrogen receptor-1 is a key regulator of HIV-1 latency that imparts gender-specific restrictions on the latent reservoir.
Unbiased shRNA library screens revealed that the estrogen receptor-1 (ESR-1) is a key factor regulating HIV-1 latency. In both Jurkat T cells and a Th17 primary cell model for HIV-1 latency, selective estrogen receptor modulators (SERMs, i.e., fulvestrant, raloxifene, and tamoxifen) are weak proviral activators and sensitize cells to latency-reversing agents (LRAs) including low doses of TNF-α (an NF-κB inducer), the histone deacetylase inhibitor vorinostat (soruberoylanilide hydroxamic acid, SAHA), and IL-15. To probe the physiologic relevance of these observations, leukapheresis samples from a cohort of 12 well-matched reproductive-age women and men on fully suppressive antiretroviral therapy were evaluated by an assay measuring the production of spliced envelope (env) mRNA (the EDITS assay) by next-generation sequencing. The cells were activated by T cell receptor (TCR) stimulation, IL-15, or SAHA in the presence of either β-estradiol or an SERM. β-Estradiol potently inhibited TCR activation of HIV-1 transcription, while SERMs enhanced the activity of most LRAs. Although both sexes responded to SERMs and β-estradiol, females showed much higher levels of inhibition in response to the hormone and higher reactivity in response to ESR-1 modulators than males. Importantly, the total inducible RNA reservoir, as measured by the EDITS assay, was significantly smaller in the women than in the men. We conclude that concurrent exposure to estrogen is likely to limit the efficacy of viral emergence from latency and that ESR-1 is a pharmacologically attractive target that can be exploited in the design of therapeutic strategies for latency reversal
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Mentoring the Mentors: Implementation and Evaluation of Four Fogarty-Sponsored Mentoring Training Workshops in Low-and Middle-Income Countries.
A growing body of evidence highlights the importance of competent mentoring in academic research. We describe the development, implementation, and evaluation of four regional 2-day intensive workshops to train mid- and senior-level investigators conducting public health, clinical, and basic science research across multiple academic institutions in low- and middle-income countries (LMICs) on tools and techniques of effective mentoring. Sponsored by the Fogarty International Center, workshops included didactic presentations, interactive discussions, and small-group problem-based learning and were conducted in Lima, Peru; Mombasa, Kenya; Bangalore, India; and Johannesburg, South Africa, from 2013 to 2016. Mid- or senior-level faculty from multiple academic institutions within each region applied and were selected. Thirty faculty from 12 South America-based institutions, 29 faculty from eight East Africa-based institutions, 37 faculty from 14 South Asia-based institutions, and 36 faculty from 13 Africa-based institutions participated, with diverse representation across disciplines, gender, and academic rank. Discussions and evaluations revealed important comparisons and contrasts in the practice of mentoring, and specific barriers and facilitators to mentoring within each cultural and regional context. Specific regional issues related to hierarchy, the post-colonial legacy, and diversity arose as challenges to mentoring in different parts of the world. Common barriers included a lack of a culture of mentoring, time constraints, lack of formal training, and a lack of recognition for mentoring. These workshops provided valuable training, were among the first of their kind, were well-attended, rated highly, and provided concepts and a structure for the development and strengthening of formal mentoring programs across LMIC institutions
Predicting death over 8 years in a prospective cohort of HIV-infected women: the Women's Interagency HIV Study.
ObjectivesPredicting mortality in middle-aged HIV-infected (HIV+) women on antiretroviral therapies (ART) is important for understanding the impact of HIV infection. Several health indices have been used to predict mortality in women with HIV infection. We evaluated: (1) an HIV biological index, Veterans Aging Cohort Study (VACS); (2) a physical index, Fried Frailty Index (FFI); and (3) a mental health index, Center for Epidemiologic Studies-Depression (CES-D). Proportional hazards regression analyses were used to predict death and included relevant covariates.DesignProspective, observational cohort.SettingMulticentre, across six sites in the USA.Participants1385 multirace/ethnic ART-experienced HIV+ women in 2005.Primary and secondary outcomesAll deaths, AIDS deaths and non-AIDS deaths up to ~8 years from baseline.ResultsIncluded together in one model, VACS Index was the dominant, significant independent predictor of all deaths within 3 years (HR=2.20, 95% CI 1.83, 2.65, χ2=69.04, p<0.0001), and later than 3 years (HR=1.55, 95% CI 1.30, 1.84, χ2=23.88, p<0.0001); followed by FFI within 3 years (HR=2.06, 95% CI 1.19, 3.57, χ2=6.73, p=0.01) and later than 3 years (HR=2.43, 95% CI 1.58, 3.75, χ2=16.18, p=0.0001). CES-D score was not independently associated with mortality.Conclusions and relevanceThis is the first simultaneous evaluation of three common health indices in HIV+ adults. Indices reflecting physical and biological ageing were associated with death
Environmental Monitoring of Water Quality as a Planning and Management Tool: A Case Study of the Rodrigo de Freitas Lagoon, Rio de Janeiro, Brazil
The Rodrigo de Freitas Lagoon is an urban water body, representing one of the most popular spots for the local community. It underwent serious environmental degradation, at first through its water mirror reduction and more recently through sewer inflows. Concurrently, the difficulty in renewing the water combined with adverse climatic conditions has repeatedly led to an alarming fish mortality rate. The monitoring of its water quality has been carried out as a management and planning tool that lead to the improvement of the environmental conditions. This study seeks to assess monitoring results by correlating the factors that might be the cause of a failure to comply with environmental regulations. Although it is evident that particular places in the Lagoon might be more often affected by illegal sewer discharges, no evidence could be found of any variations between the six sampling points. However, the rise in the levels of Escherichia coli, nitrogen and phosphorus, and the general temperature conditions, pH, and salinity of the water shows that the most significant alterations occurred in spring 2018.The complexity of the period of phytoplankton growth followed by the fish mortality from anoxia underlines the need for monitoring as a tool for a better understanding of the alterations, providing guidance with regard to the planning and management of the ecosystem
Low lopinavir plasma or hair concentrations explain second-line protease inhibitor failures in a resource-limited setting.
In resource-limited settings, many patients, with no prior protease inhibitor (PI) treatment on a second-line, high genetic barrier, ritonavir-boosted PI-containing regimen have virologic failure
Isoniazid concentrations in hair and plasma area-under-the-curve exposure among children with tuberculosis.
We measured hair and plasma concentrations of isoniazid among sixteen children with tuberculosis who underwent personal or video-assisted directly observed therapy and thus had 100% adherence. This study therefore defined typical isoniazid exposure parameters after two months of treatment among fully-adherent patients in both hair and plasma (plasma area under the concentration-time curve, AUC, estimated using pharmacokinetic data collected 0, 2, 4, and 6 hours after drug administration). We found that INH levels in hair among highly-adherent individuals did not correlate well with plasma AUC or trough concentrations, suggesting that each measure may provide incremental and complementary information regarding drug exposure in the context of TB treatment
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