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2. Improving clinical trial interpretation with ACCEPT analyses

Author

Clements, Michelle N., White, Ian R., Copas, Andrew J., Cornelius, Victoria, Cro, Suzie, Dunn, David T, Quartagno, Matteo, Turner, Rebecca M., Tweed, Conor D., and Walker, A. Sarah

Subjects
Statistics - Applications
Abstract

Effective decision making from randomised controlled clinical trials relies on robust interpretation of the numerical results. However, the language we use to describe clinical trials can cause confusion both in trial design and in comparing results across trials. ACceptability Curve Estimation using Probability Above Threshold (ACCEPT) aids comparison between trials (even where of different designs) by harmonising reporting of results, acknowledging different interpretations of the results may be valid in different situations, and moving the focus from comparison to a pre-specified value to interpretation of the trial data. ACCEPT can be applied to historical trials or incorporated into statistical analysis plans for future analyses. An online tool enables ACCEPT on up to three trials simultaneously.

Published
2022

3. Long-term efficacy and safety of a treatment strategy for HIV infection using protease inhibitor monotherapy: 8-year routine clinical care follow-up from a randomised, controlled, open-label pragmatic trial (PIVOT)

Author

Fisher, Martin, Clarke, Amanda, Hadley, Wendy, Stacey, David, Johnson, Margaret, Byrne, Pat, Williams, Ian, De Esteban, Nahum, Pellegrino, Pierre, Haddow, Lewis, Arenas-Pinto, Alejandro, Orkin, Chloe, Hand, James, De Souza, Carl, Murthen, Lisa, Crawford-Jones, Andrew, Chen, Fabian, Wilson, Ruth, Green, Elizabeth, Masterson, John, Lee, Vincent, Patel, Kamlesh, Howe, Rebecca, Winston, Alan, Mullaney, Scott, Gompels, Mark, Jennings, Louise, Beeching, Nicholas, Tamaklo, Rebecca, Fox, Julie, Teague, Alistair, Jendrulek, Isabelle, Tiraboschi, Juan Manuel, Wilkins, Ed, Clowes, Yvonne, Thompson, Andrew, Brook, Gary, Trivedi, Manoj, Aderogba, Kazeem, Jones, Martin, DeBurgh-Thomas, Andrew, Jones, Liz, Reeves, Iain, Mguni, Sifiso, Chadwick, David, Spence, Pauline, Nkhoma, Nellie, Warwick, Zoe, Price, Suzanne, Read, Sally, Herieka, Elbushra, Walker, James, Woodward, Ruth, Day, John, Hilton, Laura, Harinda, Veerakathy, Blackman, Helen, Hay, Phillip, Mejewska, Wendy, Okolo, Olanike, Ong, Edmund, Martin, Karen, Munro, Lee, Dockrell, David, Smart, Lynne, Ainsworth, Jonathan, Waters, Anele, Kegg, Stephen, McNamara, Sara, Taylor, Steve, Gilleran, Gerry, Gazzard, Brian, Rowlands, Jane, Allan, Sris, Sandhu, Rumun, O'Farrell, Nigel, Quaid, Sheena, Martin, Fabiola, Bennett, Caroline, Kapembwa, Moses, Minton, Jane, Calderwood, James, Post, Frank, Campbell, Lucy, Wandolo, Emily, Palfreeman, Adrian, Mashonganyika, Linda, Balachandran, Thambiah, Kakowa, Memory, O'Connell, Rebecca, Tanawa, Cheryl, Jebakumar, Sinna, Hagger, Lesley, Quah, Say, McKernan, Sinead, Lacey, Charles, Douglas, Sarah, Russell-Sharpe, Sarah, Brewer, Christine, Leen, Clifford, Morris, Sheila, Obeyesekera, Sharmin, Williams, Shirley, David, Nelson, Roberts, Mark, Wollaston, Julie, Paton, Nicholas, Stöhr, Wolfgang, Scott, Karen, Dunn, David, Beaumont, Emma, Fleck, Sue, Hall, Mark, Hennings, Susie, Kummeling, Ischa, Martins, Sara, Owen-Powell, Ellen, Sanders, Karen, van Hooff, Fionna, Vivas, Livia, White, Ellen, Angus, Brian, Freedman, Andrew, Cromerty, Ben, Mercey, Danielle, Fidler, Sarah, Torok, Estee, Babiker, Abdel, Peto, Tim, Lalloo, David, Phillips, Andrew, James, Robert, Paton, Nicholas I., and Dunn, David T.

Published
2024
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6. Using the adherence‐efficacy relationship of emtricitabine and tenofovir disoproxil fumarate to calculate background HIV incidence: a secondary analysis of a randomized, controlled trial

Author

Glidden, David V, Das, Moupali, Dunn, David T, Ebrahimi, Ramin, Zhao, Yongwu, Stirrup, Oliver T, Baeten, Jared M, and Anderson, Peter L

Subjects
HIV/AIDS, Sexual and Gender Minorities (SGM/LGBT*), Prevention, Clinical Trials and Supportive Activities, Infectious Diseases, Clinical Research, 6.1 Pharmaceuticals, Evaluation of treatments and therapeutic interventions, Infection, Good Health and Well Being, Anti-HIV Agents, Bayes Theorem, Emtricitabine, Female, HIV Infections, Homosexuality, Male, Humans, Male, Pre-Exposure Prophylaxis, Sexual and Gender Minorities, Tenofovir, counterfactual, PrEP, clinical trial design, tenofovir alafenamide, tenofovir disoproxil fumarate, Bayesian inference, Clinical Sciences, Public Health and Health Services, Other Medical and Health Sciences
Abstract

IntroductionRandomized trials of new agents for HIV pre-exposure prophylaxis (PrEP) compare against emtricitabine and tenofovir disoproxil fumarate (F/TDF), without a placebo group. We used the well-characterized adherence-efficacy relationship for F/TDF to back-calculate the (non-PrEP) counterfactual background HIV incidence (bHIV) in a randomized trial of a novel PrEP agent and estimate comparative efficacy (to counterfactual bHIV).MethodsThe DISCOVER trial (ClinicalTrials.gov: NCT02842086) randomized 5387 men who have sex with men (MSM) and transgender women who have sex with men and demonstrated non-inferiority of emtricitabine and tenofovir alafenamide (F/TAF) to F/TDF (HIV incidence rate ratio [IRR] 0·47, 95% CI: 0·19 to 1.15). Tenofovir diphosphate (TFV-DP) levels in dried blood spots (DBS) were assessed for all diagnosed with HIV and in a random 10% of the cohort. We used a Bayesian model with a diffuse prior distribution, derived from established data relating tenofovir diphosphate levels to HIV prevention efficacy. This prior, combined with the F/TDF seroconversion rate and tenofovir diphosphate levels in DISCOVER, yielded Bayesian inferences on the counterfactual bHIV.ResultsThere were six versus 11 postbaseline HIV infections (0.14 vs. 0.25/100 person-years [PY]) on F/TAF and F/TDF respectively. Of the 11 on F/TDF, 10 had low, none had medium and one had high tenofovir diphosphate levels; among HIV-negative controls, 5% of the person-time years had low, 9% had medium and 86% had high TFV-DP levels. A non-informative prior distribution for counterfactual bHIV, combined with the prior for TFV-DP level-efficacy relationship, yielded a posterior counterfactual bHIV of 3·4 infections/100 PY (0.80 Bayesian credible interval [CrI] 1·9 to 5·9), which suggests a median HIV efficacy of 96% (0.95 CrI [88% to 99%]) for F/TAF and 93% (0.95 CrI [87% to 96%]) for F/TDF compared to bHIV.ConclusionsBased on the established connection of drug concentrations to PrEP prevention efficacy, a Bayesian framework can be used to estimate a synthetic non-PrEP control group in randomized, active-controlled PrEP trials that include a F/TDF-comparator group.

Published
2021

7. Confidence limits for the averted infections ratio estimated via the counterfactual placebo incidence rate

Author

Dunn, David T, Stirrup, Oliver T, and Glidden, David V

Subjects
Clinical Trials and Supportive Activities, Clinical Research, active-control trial, averted infections, confidence limits, non-inferiority, Statistics, Microbiology, Medical Microbiology
Abstract

ObjectivesThe averted infections ratio (AIR) is a novel measure for quantifying the preservation-of-effect in active-control non-inferiority clinical trials with a time-to-event outcome. In the main formulation, the AIR requires an estimate of the counterfactual placebo incidence rate. We describe two approaches for calculating confidence limits for the AIR given a point estimate of this parameter, a closed-form solution based on a Taylor series expansion (delta method) and an iterative method based on the profile-likelihood.MethodsFor each approach, exact coverage probabilities for the lower and upper confidence limits were computed over a grid of values of (1) the true value of the AIR (2) the expected number of counterfactual events (3) the effectiveness of the active-control treatment.ResultsFocussing on the lower confidence limit, which determines whether non-inferiority can be declared, the coverage achieved by the delta method is either less than or greater than the nominal coverage, depending on the true value of the AIR. In contrast, the coverage achieved by the profile-likelihood method is consistently accurate.ConclusionsThe profile-likelihood method is preferred because of better coverage properties, but the simpler delta method is valid when the experimental treatment is no less effective than the control treatment. A complementary Bayesian approach, which can be applied when the counterfactual incidence rate can be represented as a prior distribution, is also outlined.

Published
2021

8. A Bayesian averted infection framework for PrEP trials with low numbers of HIV infections: application to the results of the DISCOVER trial

Author

Glidden, David V, Stirrup, Oliver T, and Dunn, David T

Subjects
HIV/AIDS, Prevention, Clinical Research, Clinical Trials and Supportive Activities, Infectious Diseases, Infection, Good Health and Well Being, Adenine, Anti-HIV Agents, Bayes Theorem, Emtricitabine, Equivalence Trials as Topic, HIV Infections, Humans, Outcome Assessment, Health Care, Pre-Exposure Prophylaxis, Sample Size, Tenofovir, Medical and Health Sciences
Abstract

Trials of candidate agents for HIV pre-exposure prophylaxis (PrEP) might randomly assign participants to be given a new PrEP agent or oral coformulated tenofovir disoproxil fumarate plus emtricitabine. This design presents unique challenges in interpretation. First, with two active arms, HIV incidence might be low. Second, the effectiveness of tenofovir disoproxil fumarate plus emtricitabine varies across populations; thus, similar HIV incidence between groups could be consistent with a wide range of effectiveness for the new PrEP. We propose a two-part approach to trial results. First, we use Bayesian methods to incorporate assumptions about the background incidence of HIV in the trial in the absence of PrEP, possibly augmented by external data. On the basis of the estimated background incidence, we estimate and compare the number of averted (or prevented) HIV infections in each of the two trial groups, calculating the averted infections ratio. We apply these methods to a completed trial of tenofovir alafenamide plus emtricitabine for PrEP. Our framework shows that leveraging external information to estimate averted infections and the averted infections ratio enhances the efficiency and interpretation of active-controlled PrEP trials.

Published
2020

9. COVAC1 phase 2a expanded safety and immunogenicity study of a self-amplifying RNA vaccine against SARS-CoV-2

Author

Szubert, Alex J., Pollock, Katrina M., Cheeseman, Hannah M., Alagaratnam, Jasmini, Bern, Henry, Bird, Olivia, Boffito, Marta, Byrne, Ruth, Cole, Tom, Cosgrove, Catherine A., Faust, Saul N., Fidler, Sarah, Galiza, Eva, Hassanin, Hana, Kalyan, Mohini, Libri, Vincenzo, McFarlane, Leon R., Milinkovic, Ana, O'Hara, Jessica, Owen, David R., Owens, Daniel, Pacurar, Mihaela, Rampling, Tommy, Skene, Simon, Winston, Alan, Woolley, James, Yim, Yee Ting N., Dunn, David T., McCormack, Sheena, and Shattock, Robin J.

Published
2023
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10. Mosaic effectiveness: measuring the impact of novel PrEP methods

Author

Glidden, David V, Mehrotra, Megha L, Dunn, David T, and Geng, Elvin H

Subjects
Biomedical and Clinical Sciences, Public Health, Health Sciences, Comparative Effectiveness Research, Clinical Trials and Supportive Activities, Prevention, Clinical Research, Administration, Oral, Anti-HIV Agents, Clinical Trials as Topic, Combined Modality Therapy, Delayed-Action Preparations, Drug Therapy, Combination, Emtricitabine, HIV Infections, Humans, Pre-Exposure Prophylaxis, Tenofovir, Treatment Outcome, Medical and Health Sciences, Biomedical and clinical sciences, Health sciences
Abstract

Various ongoing trials seek to evaluate long-acting pre-exposure prophylaxis (PrEP) agents by showing that they are non-inferior to daily oral tenofovir disoproxil fumarate and emtricitabine. Trials comparing oral PrEP to new methods examine effectiveness in a setting where only one or the other is provided; however, a new product will probably be delivered in a context where oral PrEP is also available. The effectiveness of a new PrEP product is best measured by its potential effect in a context that also includes oral tenofovir disoproxil fumarate and emtricitabine as an option. We offer an alternative standard for long-acting products-a measure of the effectiveness of the new product in addition to oral tenofovir disoproxil fumarate and emtricitabine as compared with oral PrEP alone. We term this measure mosaic effectiveness. We illustrate scenarios where a novel product can fail to show non-inferiority but show substantial mosaic effectiveness, thus implying the public health value of the novel product even if it is less effective than oral PrEP. Regulatory standards should consider mosaic effectiveness, not just comparative effectiveness. We assert that measurements that combine rigor with public health relevance can accelerate progress against the HIV epidemic.

Published
2019

11. The Connection between the Averted Infections Ratio and the Rate Ratio in Active-control Trials of Pre-exposure Prophylaxis Agents

Author

Dunn, David T and Glidden, David V

Subjects
Mathematical Sciences, Statistics, Infectious Diseases, Prevention, Clinical Research, HIV/AIDS, Clinical Trials and Supportive Activities, Infection, active-control trials, hiv, non-inferiority, Microbiology, Medical Microbiology
Abstract

The design and analysis of active-control trials to evaluate experimental HIV pre-exposure prophylaxis (PrEP) agents pose serious statistical challenges. We recently proposed a new outcome measure, the averted infections ratio (AIR) - the proportion of infections that would be averted by using the experimental agent rather than the control agent (compared to no intervention). The main aim of the current paper is to examine the mathematical connection between AIR and the HIV incidence rate ratio, the standard outcome measure. We also consider the sample size implications of the choice of primary outcome measure and explore the connection between effectiveness and efficacy under a simplified model of adherence.

Published
2019

12. The averted infections ratio: a novel measure of effectiveness of experimental HIV pre-exposure prophylaxis agents

Author

Dunn, David T, Glidden, David V, Stirrup, Oliver T, and McCormack, Sheena

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Clinical Research, Clinical Trials and Supportive Activities, HIV/AIDS, Prevention, Infection, Anti-HIV Agents, Drug Therapy, Combination, Emtricitabine, HIV Infections, Health Services Accessibility, Humans, Pre-Exposure Prophylaxis, Tenofovir, Treatment Outcome, Medical and Health Sciences, Biomedical and clinical sciences, Health sciences
Abstract

Tenofovir disoproxil fumarate combined with emtricitabine is a highly effective oral pre-exposure prophylaxis (PrEP) agent for preventing the acquisition of HIV. This effectiveness has consequences for the design and analysis of trials assessing experimental PrEP regimens, which now generally include an active-control tenofovir disoproxil fumarate plus emtricitabine group, rather than a placebo group, as a comparator. Herein, we describe major problems in the interpretation of the primary measure of effectiveness proposed for these trials, namely the ratio of HIV incidence in the experimental agent group to that in the active-control group. We argue that valid interpretation requires an assumption about one of two parameters: either the incidence among trial participants had they not received PrEP or the effectiveness of tenofovir disoproxil fumarate plus emtricitabine within the trial. However, neither parameter is directly observed because of the absence of a no-treatment group, thus requiring the use of external evidence or subjective judgment. We propose an alternative measure of effectiveness based on the concept of averted infections, which incorporates one of these parameters. The measure is simple to interpret, has clinical and public health relevance, and is a natural preservation-of-effect criterion for assessing statistical non-inferiority. Its adoption could also allow the use of smaller sample sizes, currently a major barrier to the assessment of experimental PrEP regimens.

Published
2018

13. HIV prevention trial design in an era of effective pre-exposure prophylaxis

Author

Cutrell, Amy, Donnell, Deborah, Dunn, David T, Glidden, David V, Grobler, Anneke, Hanscom, Brett, Stancil, Britt S, Meyer, R Daniel, Wang, Ronnie, and Cuffe, Robert L

Subjects
HIV/AIDS, Clinical Trials and Supportive Activities, Clinical Research, Prevention, Infection, Chemoprevention, Equivalence Trials as Topic, HIV Infections, Humans, Pre-Exposure Prophylaxis, Randomized Controlled Trials as Topic, Research Design, Treatment Outcome, PrEP, pre-exposure prophylaxis, HIV-1, trial design, non-inferiority trials, tenofovir disoproxil fumarate/emtricitabine, TDF/FTC
Abstract

Pre-exposure prophylaxis (PrEP) has demonstrated remarkable effectiveness protecting at-risk individuals from HIV-1 infection. Despite this record of effectiveness, concerns persist about the diminished protective effect observed in women compared with men and the influence of adherence and risk behaviors on effectiveness in targeted subpopulations. Furthermore, the high prophylactic efficacy of the first PrEP agent, tenofovir disoproxil fumarate/emtricitabine (TDF/FTC), presents challenges for demonstrating the efficacy of new candidates. Trials of new agents would typically require use of non-inferiority (NI) designs in which acceptable efficacy for an experimental agent is determined using pre-defined margins based on the efficacy of the proven active comparator (i.e. TDF/FTC) in placebo-controlled trials. Setting NI margins is a critical step in designing registrational studies. Under- or over-estimation of the margin can call into question the utility of the study in the registration package. The dependence on previous placebo-controlled trials introduces the same issues as external/historical controls. These issues will need to be addressed using trial design features such as re-estimated NI margins, enrichment strategies, run-in periods, crossover between study arms, and adaptive re-estimation of sample sizes. These measures and other innovations can help to ensure that new PrEP agents are made available to the public using stringent standards of evidence.

Published
2017

15. Statistical issues in trials of preexposure prophylaxis

Author

Dunn, David T and Glidden, David V

Subjects
Biomedical and Clinical Sciences, Public Health, Health Sciences, Prevention, Infectious Diseases, HIV/AIDS, Clinical Trials and Supportive Activities, Clinical Research, Evaluation of treatments and therapeutic interventions, 6.1 Pharmaceuticals, Infection, Good Health and Well Being, Administration, Oral, Anti-HIV Agents, Biostatistics, Chemoprevention, Clinical Trials as Topic, Disease Transmission, Infectious, Double-Blind Method, HIV Infections, Humans, Placebos, Pre-Exposure Prophylaxis, intention-to-treat, noninferiority, open-label, placebo-controlled, risk compensation, Public Health and Health Services, Virology, Clinical sciences, Medical microbiology, Epidemiology
Abstract

Purpose of reviewWe discuss selected statistical issues in the design and analysis of preexposure prophylaxis (PrEP) trials. The general principles may inform thinking for other interventions in HIV prevention.Recent findingsTo date, four different designs have been used to determine the effectiveness of PrEP: randomized, double-blind, placebo-controlled; randomized, open-label, immediate or delayed access; nonrandomized comparison of HIV incidence according to the level of drug detected; comparison of the observed HIV incidence to the expected rate using historical control data. Open-label trials of PrEP, which assess public health effectiveness, complement the placebo-controlled trials which established the biological efficacy of TDF/FTC. Future trials of PrEP will be highly challenging to design since a no PrEP group is difficult to justify and the natural control regimen, TDF/FTC, is highly efficacious.SummaryStandard statistical paradigms for noninferiority trials should be reconsidered for evaluating alternative PrEP regimens.

Published
2016

17. Associations between baseline characteristics, CD4 cell count response and virological failure on first-line efavirenz + tenofovir + emtricitabine for HIV

Author

Stirrup, Oliver T., Sabin, Caroline A., Phillips, Andrew N., Williams, Ian, Churchill, Duncan, Tostevin, Anna, Hill, Teresa, Dunn, David T., Asboe, David, Pozniak, Anton, Cane, Patricia, Chadwick, David, Clark, Duncan, Collins, Simon, Delpech, Valerie, Douthwaite, Samuel, Dunn, David, Fearnhill, Esther, Porter, Kholoud, Stirrup, Oliver, Fraser, Christophe, Geretti, Anna Maria, Gunson, Rory, Hale, Antony, Hué, Stéphane, Lazarus, Linda, Leigh-Brown, Andrew, Mbisa, Tamyo, Mackie, Nicola, Orkin, Chloe, Nastouli, Eleni, Pillay, Deenan, Phillips, Andrew, Sabin, Caroline, Smit, Erasmus, Templeton, Kate, Tilston, Peter, Volz, Erik, Zhang, Hongyi, Fairbrother, Keith, Dawkins, Justine, O’Shea, Siobhan, Mullen, Jane, Cox, Alison, Tandy, Richard, Fawcett, Tracy, Hopkins, Mark, Booth, Clare, Renwick, Lynne, Schmid, Matthias L., Payne, Brendan, Hubb, Jonathan, Dustan, Simon, Kirk, Stuart, Bradley-Stewart, Amanda, Jose, Sophie, Thornton, Alicia, Huntington, Susie, Glabay, Adam, Shidfar, Shaadi, Lynch, Janet, Hand, James, de Souza, Carl, Perry, Nicky, Tilbury, Stuart, Youssef, Elaney, Gazzard, Brian, Nelson, Mark, Mabika, Tracey, Mandalia, Sundhiya, Anderson, Jane, Munshi, Sajid, Post, Frank, Adefisan, Ade, Taylor, Chris, Gleisner, Zachary, Ibrahim, Fowzia, Campbell, Lucy, Baillie, Kirsty, Gilson, Richard, Brima, Nataliya, Ainsworth, Jonathan, Schwenk, Achim, Miller, Sheila, Wood, Chris, Johnson, Margaret, Youle, Mike, Lampe, Fiona, Smith, Colette, Tsintas, Rob, Chaloner, Clinton, Hutchinson, Samantha, Walsh, John, Mackie, Nicky, Winston, Alan, Weber, Jonathan, Ramzan, Farhan, Carder, Mark, Leen, Clifford, Wilson, Alan, Morris, Sheila, Gompels, Mark, Allan, Sue, Palfreeman, Adrian, Lewszuk, Adam, Kegg, Stephen, Faleye, Akin, Ogunbiyi, Victoria, Mitchell, Sue, Hay, Phillip, Kemble, Christian, Martin, Fabiola, Russell-Sharpe, Sarah, Gravely, Janet, Allan, Sris, Harte, Andrew, Tariq, Anjum, Spencer, Hazel, Jones, Ron, Pritchard, Jillian, Cumming, Shirley, Atkinson, Claire, Mital, Dushyant, Edgell, Veronica, Allen, Juli, Ustianowski, Andy, Murphy, Cynthia, Gunder, Ilise, Trevelion, Roy, and Babiker, Abdel

Published
2019
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19. Low frequency of genotypic resistance in HIV-1-infected patients failing an atazanavir-containing regimen: a clinical cohort study

Author

Dolling, David I, Dunn, David T, Sutherland, Katherine A, Pillay, Deenan, Mbisa, Jean L, Parry, Chris M, Post, Frank A, Sabin, Caroline A, Cane, Patricia A, Aitken, Celia, Asboe, David, Webster, Daniel, Cane, Patricia, Castro, Hannah, Dunn, David, Dolling, David, Chadwick, David, Churchill, Duncan, Clark, Duncan, Collins, Simon, Delpech, Valerie, Geretti, Anna Maria, Goldberg, David, Hale, Antony, Hué, Stéphane, Kaye, Steve, Kellam, Paul, Lazarus, Linda, Leigh-Brown, Andrew, Mackie, Nicola, Orkin, Chloe, Rice, Philip, Phillips, Andrew, Sabin, Caroline, Smit, Erasmus, Templeton, Kate, Tilston, Peter, Tong, William, Williams, Ian, Zhang, Hongyi, Zuckerman, Mark, Greatorex, Jane, Wildfire, Adrian, O'Shea, Siobhan, Mullen, Jane, Mbisa, Tamyo, Cox, Alison, Tandy, Richard, Hale, Tony, Fawcett, Tracy, Hopkins, Mark, Ashton, Lynn, Booth, Claire, Garcia-Diaz, Ana, Shepherd, Jill, Schmid, Matthias L, Payne, Brendan, Hay, Phillip, Rice, Phillip, Paynter, Mary, Bibby, David, Kirk, Stuart, MacLean, Alasdair, Gunson, Rory, Coughlin, Kate, Fearnhill, Esther, Fradette, Lorraine, Porter, Kholoud, Ainsworth, Jonathan, Anderson, Jane, Babiker, Abdel, Fisher, Martin, Gazzard, Brian, Gilson, Richard, Gompels, Mark, Hill, Teresa, Johnson, Margaret, Kegg, Stephen, Leen, Clifford, Nelson, Mark, Palfreeman, Adrian, Post, Frank, Sachikonye, Memory, Schwenk, Achim, Walsh, John, Huntington, Susie, Jose, Sophie, Thornton, Alicia, Glabay, Adam, Orkin, C, Garrett, N, Lynch, J, Hand, J, de Souza, C, Fisher, M, Perry, N, Tilbury, S, Gazzard, B, and Nelson, M

Subjects
Medical Microbiology, Biomedical and Clinical Sciences, Clinical Sciences, Clinical Trials and Supportive Activities, Infectious Diseases, Antimicrobial Resistance, Clinical Research, Infection, Adult, Anti-HIV Agents, Atazanavir Sulfate, Cohort Studies, Drug Resistance, Viral, Female, HIV Infections, HIV Protease, HIV-1, Humans, Male, Medication Adherence, Middle Aged, Mutation Rate, Mutation, Missense, Oligopeptides, Pyridines, Treatment Failure, United States, UK HIV Drug Resistance Database, UK Collaborative HIV Cohort Study, HIV, drug resistance mutations, naive patients, protease inhibitors, virological failure, Microbiology, Pharmacology and Pharmaceutical Sciences, Clinical sciences, Pharmacology and pharmaceutical sciences
Abstract

ObjectivesTo determine protease mutations that develop at viral failure for protease inhibitor (PI)-naive patients on a regimen containing the PI atazanavir.MethodsResistance tests on patients failing atazanavir, conducted as part of routine clinical care in a multicentre observational study, were randomly matched by subtype to resistance tests from PI-naive controls to account for natural polymorphisms. Mutations from the consensus B sequence across the protease region were analysed for association and defined using the IAS-USA 2011 classification list.ResultsFour hundred and five of 2528 (16%) patients failed therapy containing atazanavir as a first PI over a median (IQR) follow-up of 1.76 (0.84-3.15) years and 322 resistance tests were available for analysis. Recognized major atazanavir mutations were found in six atazanavir-experienced patients (P < 0.001), including I50L and N88S. The minor mutations most strongly associated with atazanavir experience were M36I, M46I, F53L, A71V, V82T and I85V (P < 0.05). Multiple novel mutations, I15S, L19T, K43T, L63P/V, K70Q, V77I and L89I/T/V, were also associated with atazanavir experience.ConclusionsViral failure on atazanavir-containing regimens was not common and major resistance mutations were rare, suggesting that adherence may be a major contributor to viral failure. Novel mutations were described that have not been previously documented.

Published
2013

23. Pre-exposure prophylaxis to prevent the acquisition of HIV-1 infection (PROUD): effectiveness results from the pilot phase of a pragmatic open-label randomised trial

Author

McCormack, Sheena, Dunn, David T, Desai, Monica, Dolling, David I, Gafos, Mitzy, Gilson, Richard, Sullivan, Ann K, Clarke, Amanda, Reeves, Iain, Schembri, Gabriel, Mackie, Nicola, Bowman, Christine, Lacey, Charles J, Apea, Vanessa, Brady, Michael, Fox, Julie, Taylor, Stephen, Antonucci, Simone, Khoo, Saye H, Rooney, James, Nardone, Anthony, Fisher, Martin, McOwan, Alan, Phillips, Andrew N, Johnson, Anne M, Gazzard, Brian, and Gill, Owen N

Published
2016
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24. Long-term virological suppression on first-line efavirenz + tenofovir + emtricitabine/lamivudine for HIV-1

Author

Stirrup, Oliver, Sterne, Jonathan, Dunn, David T., Grabmeier-Pfistershammer, Katharina, Papastamopoulos, Vasileios, Vandenhende, Marie-Anne, Wit, Ferdinand, Porter, Kholoud, Gunsenheimer-Bartmeyer, Barbara, Jarrin, Inma, Garcia, Federico, Fätkenheuer, Gerd, Obel, Niels, Schultze, Anna, Antinori, Andrea, Ceccherini-Silberstein, Francesca, Mussini, Cristina, Chêne, Geneviève, Neesgaard, Bastian, Castagna, Antonella, Kouyos, Roger, De Wit, Stéphane, Sönnerborg, Anders, Sabin, Caroline, Merino, Dolores, Barger, Diana, and Phillips, Andrew

Published
2019
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25. Pilot phase of an internet-based RCT of HIVST targeting MSM and transgender people in England and Wales: advertising strategies and acceptability of the intervention

Author

Witzel, T. Charles, Gabriel, Michelle M., McCabe, Leanne, Weatherburn, Peter, Gafos, Mitzy, Speakman, Andrew, Pebody, Roger, Burns, Fiona M., Bonell, Chris, Lampe, Fiona C., Dunn, David T., Ward, Denise, Harbottle, Justin, Phillips, Andrew N., McCormack, Sheena, and Rodger, Alison J.

Published
2019
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28. Protocol, rationale and design of SELPHI: a randomised controlled trial assessing whether offering free HIV self-testing kits via the internet increases the rate of HIV diagnosis

Author

Gabriel, Michelle M., Dunn, David T., Speakman, Andrew, McCabe, Leanne, Ward, Denise, Witzel, T. Charles, Harbottle, Justin, Collins, Simon, Gafos, Mitzy, Burns, Fiona M., Lampe, Fiona C., Weatherburn, Peter, Phillips, Andrew, McCormack, Sheena, and Rodger, Alison J.

Published
2018
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35. Does Discordancy Between the CD4 Count and CD4 Percentage in HIV-Positive Individuals Influence Outcomes on Highly Active Antiretroviral Therapy?

Author

UK Collaborative HIV Cohort (UK CHIC) Study (Appendix), Gompels, Mark, Dunn, David T., Phillips, Andrew, Dooley, Debbie, De Burgh Thomas, Andrew, Anderson, Jane, Post, Frank, Pillay, Deenan, Gazzard, Brian, Hill, Teresa, Johnson, Margaret, Gilson, Richard, Bansi, Loveleen, Easterbrook, Philippa, Fisher, Martin, Walsh, John, Orkin, Chloe, Ainsworth, Jonathan, Leen, Clifford, and Sabin, Caroline

Published
2012
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36. Improving Clinical Trial Interpretation with ACCEPT Analyses

Author

Clements, Michelle N., primary, White, Ian R., additional, Copas, Andrew J., additional, Cornelius, Victoria, additional, Cro, Suzie, additional, Dunn, David T., additional, Quartagno, Matteo, additional, Turner, Rebecca M., additional, Tweed, Conor D., additional, and Walker, A. Sarah, additional

Published
2022
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40. COVAC1 Phase 2a Expanded Safety and Immunogenicity Study of a Self-Amplifying RNA Vaccine Against SARS-CoV-2

Author

Szubert, Alexander J., primary, Pollock, Katrina M., additional, Cheeseman, Hannah M., additional, Alagaratnam, Jasmini, additional, Bern, Henry, additional, Bird, Olivia, additional, Boffito, Marta, additional, Byrne, Ruth, additional, Cole, Tom, additional, Cosgrove, Catherine A., additional, Faust, Saul N., additional, Fidler, Sarah, additional, Galiza, Eva, additional, Hassanin, Hana, additional, Kalyan, Mohini, additional, Libri, Vincenzo, additional, McFarlane, Leon R., additional, Milinkovic, Ana, additional, O’Hara, Jessica, additional, Owen, David R., additional, Owens, Daniel, additional, Pacurar, Mihaela, additional, Rampling, Tommy, additional, Skene, Simon S., additional, Winston, Alan, additional, Woolley, James, additional, Yim, Yee Ting N., additional, Dunn, David T., additional, McCormack, Sheena, additional, and Shattock, Robin John, additional

Published
2022
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46. Effects of Hydroxychloroquine on Immune Activation and Disease Progression Among HIV-Infected Patients Not Receiving Antiretroviral Therapy: A Randomized Controlled Trial

Author

Paton, Nicholas I., Goodall, Ruth L., Dunn, David T., Franzen, Samuel, Collaco-Moraes, Yolanda, Gazzard, Brian G., Williams, Ian G., Fisher, Martin J., Winston, Alan, Fox, Julie, Orkin, Chloe, Herieka, Elbushra A., Ainsworth, Jonathan G., Post, Frank A., Wansbrough-Jones, Mark, and Kelleher, Peter

Published
2012
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47. Safety and Immunogenicity of a Self-Amplifying RNA Vaccine Against COVID-19: COVAC1, a Phase I, Dose-Ranging Trial

Author

Pollock, Katrina M., primary, Cheeseman, Hannah M., additional, Szubert, Alexander J., additional, Libri, Vincenzo, additional, Boffito, Marta, additional, Owen, David, additional, Bern, Henry, additional, O’Hara, Jessica, additional, McFarlane, Leon R., additional, Lemm, Nana-Marie, additional, McKay, Paul F., additional, Rampling, Tommy, additional, Yim, Yee Ting N., additional, Milinkovic, Ana, additional, Kingsley, Cherry, additional, Cole, Tom, additional, Fagerbrink, Susanne, additional, Aban, Marites, additional, Tanaka, Maniola, additional, Mehdipour, Savviz, additional, Robbins, Alexander, additional, Budd, William, additional, Faust, Saul N., additional, Hassanin, Hana, additional, Cosgrove, Catherine A., additional, Winston, Alan, additional, Fidler, Sarah, additional, Dunn, David T., additional, McCormack, Sheena, additional, and Shattock, Robin John, additional

Published
2021
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50. High incidence of Hepatitis C virus infection observed in the PROUD study of HIV pre‐exposure prophylaxis

Author

Desai, Monica, primary, White, Ellen, additional, Vora, Nina, additional, Gilson, Richard, additional, Lacey, Charles, additional, Gafos, Mitzy, additional, Clarke, Amanda, additional, Sullivan, Ann, additional, White, David, additional, Fox, Julie, additional, Piontkowsky, David, additional, McCormack, Sheena, additional, and Dunn, David T., additional

Published
2020
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