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      HIV drug therapy duration; a Swedish real world nationwide cohort study on InfCareHIV 2009-2014

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          Abstract

          Background

          As HIV infection needs a lifelong treatment, studying drug therapy duration and factors influencing treatment durability is crucial. The Swedish database InfCareHIV includes high quality data from more than 99% of all patients diagnosed with HIV infection in Sweden and provides a unique opportunity to examine outcomes in a nationwide real world cohort.

          Methods

          Adult patients who started a new therapy defined as a new 3 rd agent (all antiretrovirals that are not N[t]RTIs) 2009–2014 with more than 100 observations in treatment-naive or treatment-experienced patients were included. Dolutegravir was excluded due to short follow up period. Multivariate Cox proportional hazards models were used to estimate hazard ratios for treatment discontinuation.

          Results

          In treatment-naïve 2541 patients started 2583 episodes of treatments with a 3 rd agent. Efavirenz was most commonly used (n = 1096) followed by darunavir (n = 504), atazanavir (n = 386), lopinavir (n = 292), rilpivirine (n = 156) and raltegravir (n = 149). In comparison with efavirenz, patients on rilpivirine were least likely to discontinue treatment (adjusted HR 0.33; 95% CI 0.20–0.54, p<0.001), while patients on lopinavir were most likely to discontinue treatment (adjusted HR 2.80; 95% CI 2.30–3.40, p<0.001). Also raltegravir was associated with early treatment discontinuation (adjusted HR 1.47; 95% CI 1.12–1.92, p = 0.005). The adjusted HR for atazanavir and darunavir were not significantly different from efavirenz. In treatment-experienced 2991 patients started 4552 episodes of treatments with a 3 rd agent. Darunavir was most commonly used (n = 1285), followed by atazanavir (n = 806), efavirenz (n = 694), raltegravir (n = 622), rilpivirine (n = 592), lopinavir (n = 291) and etravirine (n = 262). Compared to darunavir all other drugs except for rilpivirine (HR 0.66; 95% CI 0.52–0.83, p<0.001) had higher risk for discontinuation in the multivariate adjusted analyses; atazanavir (HR 1.71; 95% CI 1.48–1.97, p<0.001), efavirenz (HR 1.86; 95% CI 1.59–2.17, p<0.001), raltegravir (HR 1.35; 95% CI 1.15–1.58, p<0.001), lopinavir (HR 3.58; 95% CI 3.02–4.25, p<0.001) and etravirine (HR 1.61; 95% CI 1.31–1.98, p<0.001).Besides the 3 rd agent chosen also certain baseline characteristics of patients were independently associated with differences in treatment duration. In naive patients, presence of an AIDS-defining diagnosis and the use of other backbone than TDF/FTC or ABC/3TC increased the risk for early treatment discontinuation. In treatment-experienced patients, detectable plasma viral load at the time of switch or being highly treatment experienced increased the risk for early treatment discontinuation.

          Conclusions

          Treatment durability is dependent on several factors among others patient characteristics and ART guidelines. The choice of 3 rd agent has a strong impact and significant differences between different drugs on treatment duration exist.

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          Most cited references18

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          A literature review on the representativeness of randomized controlled trial samples and implications for the external validity of trial results

          Randomized controlled trials (RCTs) are conducted under idealized and rigorously controlled conditions that may compromise their external validity. A literature review was conducted of published English language articles that reported the findings of studies assessing external validity by a comparison of the patient sample included in RCTs reporting on pharmaceutical interventions with patients from everyday clinical practice. The review focused on publications in the fields of cardiology, mental health, and oncology. A range of databases were interrogated (MEDLINE; EMBASE; Science Citation Index; Cochrane Methodology Register). Double-abstract review and data extraction were performed as per protocol specifications. Out of 5,456 de-duplicated abstracts, 52 studies met the inclusion criteria (cardiology, n = 20; mental health, n = 17; oncology, n = 15). Studies either performed an analysis of the baseline characteristics (demographic, socioeconomic, and clinical parameters) of RCT-enrolled patients compared with a real-world population, or assessed the proportion of real-world patients who would have been eligible for RCT inclusion following the application of RCT inclusion/exclusion criteria. Many of the included studies concluded that RCT samples are highly selected and have a lower risk profile than real-world populations, with the frequent exclusion of elderly patients and patients with co-morbidities. Calculation of ineligibility rates in individual studies showed that a high proportion of the general disease population was often excluded from trials. The majority of studies (n = 37 [71.2 %]) explicitly concluded that RCT samples were not broadly representative of real-world patients and that this may limit the external validity of the RCT. Authors made a number of recommendations to improve external validity. Findings from this review indicate that there is a need to improve the external validity of RCTs such that physicians treating patients in real-world settings have the appropriate evidence on which to base their clinical decisions. This goal could be achieved by trial design modification to include a more representative patient sample and by supplementing RCT evidence with data generated from observational studies. In general, a thoughtful approach to clinical evidence generation is required in which the trade-offs between internal and external validity are considered in a holistic and balanced manner. Electronic supplementary material The online version of this article (doi:10.1186/s13063-015-1023-4) contains supplementary material, which is available to authorized users.
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            Adherence to highly active antiretroviral therapy (HAART): a meta-analysis.

            This meta-analysis synthesizes eighty-four observational studies, conducted across twenty countries, to determine the mean proportion of people who reported ≥90% adherence to prescribed highly active antiretroviral therapy (HAART) and to identify the factors associated with high levels of adherence. Eight electronic databases were searched to locate all relevant studies available by January 2010, which were then coded for sample characteristics and adherence levels. The average rate of reporting ≥90% adherent HAART adherence is 62%. However, this proportion varies greatly across studies. In particular, a greater proportion of individuals maintaining ≥90% adherence to HAART is more likely in studies with higher proportions of men who have sex with men (MSM) and lower proportions of injection drug users (IDU), with participants in an earlier stage of infection, and in studies conducted in countries characterized by lower Human Development Index (HDI) scores.
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              Rilpivirine versus efavirenz with tenofovir and emtricitabine in treatment-naive adults infected with HIV-1 (ECHO): a phase 3 randomised double-blind active-controlled trial.

              Efavirenz with tenofovir-disoproxil-fumarate and emtricitabine is a preferred antiretroviral regimen for treatment-naive patients infected with HIV-1. Rilpivirine, a new non-nucleoside reverse transcriptase inhibitor, has shown similar antiviral efficacy to efavirenz in a phase 2b trial with two nucleoside/nucleotide reverse transcriptase inhibitors. We aimed to assess the efficacy, safety, and tolerability of rilpivirine versus efavirenz, each combined with tenofovir-disoproxil-fumarate and emtricitabine. We did a phase 3, randomised, double-blind, double-dummy, active-controlled trial, in patients infected with HIV-1 who were treatment-naive. The patients were aged 18 years or older with a plasma viral load at screening of 5000 copies per mL or greater, and viral sensitivity to all study drugs. Our trial was done at 112 sites across 21 countries. Patients were randomly assigned by a computer-generated interactive web response system to receive either once-daily 25 mg rilpivirine or once-daily 600 mg efavirenz, each with tenofovir-disoproxil-fumarate and emtricitabine. Our primary objective was to show non-inferiority (12% margin) of rilpivirine to efavirenz in terms of the percentage of patients with confirmed response (viral load <50 copies per mL intention-to-treat time-to-loss-of-virological-response [ITT-TLOVR] algorithm) at week 48. Our primary analysis was by intention-to-treat. We also used logistic regression to adjust for baseline viral load. This trial is registered with ClinicalTrials.gov, number NCT00540449. 346 patients were randomly assigned to receive rilpivirine and 344 to receive efavirenz and received at least one dose of study drug, with 287 (83%) and 285 (83%) in the respective groups having a confirmed response at week 48. The point estimate from a logistic regression model for the percentage difference in response was -0.4 (95% CI -5.9 to 5.2), confirming non-inferiority with a 12% margin (primary endpoint). The incidence of virological failures was 13% (rilpivirine) versus 6% (efavirenz; 11%vs 4% by ITT-TLOVR). Grade 2-4 adverse events (55 [16%] on rilpivirine vs 108 [31%] on efavirenz, p<0.0001), discontinuations due to adverse events (eight [2%] on rilpivirine vs 27 [8%] on efavirenz), rash, dizziness, and abnormal dreams or nightmares were more common with efavirenz. Increases in plasma lipids were significantly lower with rilpivirine. Rilpivirine showed non-inferior efficacy compared with efavirenz, with a higher virological-failure rate, but a more favourable safety and tolerability profile. Tibotec. Copyright © 2011 Elsevier Ltd. All rights reserved.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                16 February 2017
                2017
                : 12
                : 2
                : e0171227
                Affiliations
                [1 ]Department of Infectious Diseases, County Council of Gävleborg, Gävle, Sweden
                [2 ]Unit of Infectious diseases, Department of Medicine Huddinge, Karolinska Institute, Sweden
                [3 ]Janssen Nordics, Solna, Stockholm, Sweden
                [4 ]Department of Infectious Diseases, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
                [5 ]Department of Infectious Diseases, Malmö University Hospital, Malmö, Sweden
                [6 ]Department of Infectious Diseases, Venhälsan-Södersjukhuset, Stockholm, Sweden
                [7 ]Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden
                [8 ]Department of Infectious Diseases, Karolinska University Hospital, Huddinge, Sweden
                Azienda Ospedaliera Universitaria di Perugia, ITALY
                Author notes

                Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: S Lindbäck, A Palmborg, A Leval and S Valgardsson are employed by Janssen Nordics. V Svedhem has received research grant from Gilead Nordic Fellowship Program and Stockholm County Council and honoraria as speaker and/or scientific advisor from Gilead EMEA England and Nordic, Merk SharpDohme. M. Gisslén has received research grants from Gilead Sciences. He has received honoraria as speaker and/or scientific advisor from Abbvie, Boehringer-Ingelheim, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline/ViiV, Janssen-Cilag, and Merck. L Flamholc has received honoraria as speaker and/or scientific advisor from Abbvie, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline/ViiV, Janssen-Cilag. A Häggblom has received research grant from doctors against AIDS and Gilead Nordic and honoraria as speaker from Gilead. B Heijdeman has no conflicts of interest. There are no patents, products in development or marketed products to declare. This does not alter our adherence to all the PLOS ONE policies on sharing data and materials.

                • Conceptualization: SL MG VS SV.

                • Data curation: SL VS.

                • Formal analysis: AH EH.

                • Investigation: AH MG BH LF VS.

                • Methodology: SL MG VS AH SV AL AP.

                • Project administration: SL VS.

                • Resources: AH MG LF BH VS.

                • Software: AL EH.

                • Supervision: VS.

                • Validation: SL VS EH.

                • Visualization: EH LF.

                • Writing – original draft: AH AP.

                • Writing – review & editing: AH MG LF BH VS AP.

                Article
                PONE-D-16-35308
                10.1371/journal.pone.0171227
                5313128
                28207816
                875b28e4-aa71-48ca-8fad-65c2878c2b22
                © 2017 Häggblom et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 2 September 2016
                : 17 January 2017
                Page count
                Figures: 2, Tables: 5, Pages: 18
                Funding
                Funded by: AbbVie Nordic
                Award Recipient :
                Funded by: AbbVie (US)
                Award Recipient :
                Funded by: Gilead Sciences (US)
                Award Recipient :
                Funded by: GlaxoSmithKline/ViiV
                Award Recipient :
                Funded by: Gilead Nordic
                Award Recipient :
                Funded by: Läkare mot AIDS
                Award Recipient :
                Funded by: Stockholms Läns Landsting (SE)
                Award Recipient :
                Funded by: Gilead Nordic Fellowship Program
                Award Recipient :
                Funded by: Merk SharpDohme
                Award Recipient :
                Funded by: Merk SharpDohme
                Award Recipient :
                Funded by: Boehringer-Ingelheim
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100002491, Bristol-Myers Squibb;
                Award Recipient :
                Funded by: GlaxoSmithKline/ViiV
                Award Recipient :
                Funded by: Janssen-Cilag
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100002491, Bristol-Myers Squibb;
                Award Recipient :
                Funded by: Janssen-Cilag
                Award Recipient :
                The author(s) received no specific funding for this work. S Lindbäck, A Palmborg, A Leval and S Valgardsson are employed by Janssen Nordics. The ten authors of this manuscript have all contributed to the study according to what is stated in the Author Contributions section. Five of the authors are HIV clinicians and affiliated with academia (AH, MG, LF, BH,VS), one was a PhD student at Karolinska Institute at the time of the data analysis and manuscript preparation (EH) and four of the authors are employees at and receive salaries from Janssen (SL, AP, AL, SV). This does not alter our adherence to PLOS ONE policies on sharing data and materials. Janssen has in no other way contributed financially to this study and did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of all authors are articulated in author contribution.
                Categories
                Research Article
                Medicine and Health Sciences
                Pharmaceutics
                Drug Therapy
                Biology and Life Sciences
                Microbiology
                Virology
                Viral Transmission and Infection
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                Biology and Life Sciences
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                Microbial Pathogens
                Viral Pathogens
                Immunodeficiency Viruses
                HIV
                Medicine and Health Sciences
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                Pathogens
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                Custom metadata
                Data are available from the Registrar of InfCareHIV: Veronica SvedhemJohansson Department of Infectious Diseases, Karolinska University Hospital, Huddinge SE-141 86, Stockholm Sweden. The Registrar will mediate the request for researchers who meet the criteria for access to confidential data to the steering committee of InfCareHIV.Email: veronica.svedhem-johansson@ 123456karolinska.se .

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