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      Renal Dysfunction during Tenofovir Use in a Regional Cohort of HIV-Infected Individuals in the Asia-Pacific

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          Abstract

          Background

          In resource-limited settings, routine monitoring of renal function during antiretroviral therapy (ART) has not been recommended. However, concerns for tenofovir disoproxil fumarate (TDF)-related nephrotoxicity persist with increased use.

          Methods

          We investigated serum creatinine (S-Cr) monitoring rates before and during ART and the incidence and prevalence of renal dysfunction after starting TDF by using data from a regional cohort of HIV-infected individuals in the Asia-Pacific. Time to renal dysfunction was defined as time from TDF initiation to the decline in estimated glomerular filtration rate (eGFR) to <60 ml/min/1.73m 2 with >30% reduction from baseline using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation or the decision to stop TDF for reported TDF-nephrotoxicity. Predictors of S-Cr monitoring rates were assessed by Poisson regression and risk factors for developing renal dysfunction were assessed by Cox regression.

          Results

          Among 2,425 patients who received TDF, S-Cr monitoring rates increased from 1.01 to 1.84 per person per year after starting TDF (incidence rate ratio 1.68, 95%CI 1.62–1.74, p <0.001). Renal dysfunction on TDF occurred in 103 patients over 5,368 person-years of TDF use (4.2%; incidence 1.75 per 100 person-years). Risk factors for developing renal dysfunction included older age (>50 vs. ≤30, hazard ratio [HR] 5.39, 95%CI 2.52–11.50, p <0.001; and using PI-based regimen (HR 1.93, 95%CI 1.22–3.07, p = 0.005). Having an eGFR prior to TDF (pre-TDF eGFR) of ≥60 ml/min/1.73m 2 showed a protective effect (HR 0.38, 95%CI, 0.17–0.85, p = 0.018).

          Conclusions

          Renal dysfunction on commencing TDF use was not common, however, older age, lower baseline eGFR and PI-based ART were associated with higher risk of renal dysfunction during TDF use in adult HIV-infected individuals in the Asia-Pacific region.

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          Most cited references13

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          Chronic kidney disease as a global public health problem: approaches and initiatives - a position statement from Kidney Disease Improving Global Outcomes.

          Chronic kidney disease (CKD) is increasingly recognized as a global public health problem. There is now convincing evidence that CKD can be detected using simple laboratory tests, and that treatment can prevent or delay complications of decreased kidney function, slow the progression of kidney disease, and reduce the risk of cardiovascular disease (CVD). Translating these advances to simple and applicable public health measures must be adopted as a goal worldwide. Understanding the relationship between CKD and other chronic diseases is important to developing a public health policy to improve outcomes. The 2004 Kidney Disease Improving Global Outcomes (KDIGO) Controversies Conference on 'Definition and Classification of Chronic Kidney Disease' represented an important endorsement of the Kidney Disease Outcome Quality Initiative definition and classification of CKD by the international community. The 2006 KDIGO Controversies Conference on CKD was convened to consider six major topics: (1) CKD classification, (2) CKD screening and surveillance, (3) public policy for CKD, (4) CVD and CVD risk factors as risk factors for development and progression of CKD, (5) association of CKD with chronic infections, and (6) association of CKD with cancer. This report contains the recommendations from the meeting. It has been reviewed by the conference participants and approved as position statement by the KDIGO Board of Directors. KDIGO will work in collaboration with international and national public health organizations to facilitate implementation of these recommendations.
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            Evaluation of the Chronic Kidney Disease Epidemiology Collaboration equation for estimating the glomerular filtration rate in multiple ethnicities.

            An equation from the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) provides more accurate estimates of the glomerular filtration rate (eGFR) than that from the modification of diet in renal disease (MDRD) Study, although both include a two-level variable for race (Black and White and other). Since creatinine generation differs among ethnic groups, it is possible that a multilevel ethnic variable would allow more accurate estimates across all groups. To evaluate this, we developed an equation to calculate eGFR that includes a four-level race variable (Black, Asian, Native American and Hispanic, and White and other) using a database of 8254 patients pooled from 10 studies. This equation was then validated in 4014 patients using 17 additional studies from the United States and Europe (validation database), and in 1022 patients from China (675), Japan (248), and South Africa (99). Coefficients for the Black, Asian, and Native American and Hispanic groups resulted in 15, 5, and 1% higher levels of eGFR, respectively, compared with the White and other group. In the validation database, the two-level race equation had minimal bias in Black, Native American and Hispanic, and White and other cohorts. The four-level ethnicity equation significantly improved bias in Asians of the validation data set and in Chinese. Both equations had a large bias in Japanese and South African patients. Thus, heterogeneity in performance among the ethnic and geographic groups precludes use of the four-level race equation. The CKD-EPI two-level race equation can be used in the United States and Europe across a wide range of ethnicity.
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              Clinical practice guideline for the management of chronic kidney disease in patients infected with HIV: 2014 update by the HIV Medicine Association of the Infectious Diseases Society of America.

              It is important to realize that guidelines cannot always account for individual variation among patients. They are not intended to supplant physician judgment with respect to particular patients or special clinical situations. IDSA considers adherence to these guidelines to be voluntary, with the ultimate determination regarding their application to be made by the physician in the light of each patient's individual circumstances.
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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
                25 August 2016
                2016
                : 11
                : 8
                : e0161562
                Affiliations
                [1 ]AIDS Clinical Center, National Center for Global Health and Medicine, Tokyo, Japan
                [2 ]The Kirby Institute, UNSW Australia, Sydney, Australia
                [3 ]Institute of Infectious Diseases, Pune, India
                [4 ]The Netherland Australia Thailand Research Collaboration/Thai Red Cross AIDS Research Centre, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
                [5 ]Department of Infectious Disease and Communicable Disease Centre, Tan Tock Seng Hospital, Singapore, Singapore
                [6 ]Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
                [7 ]Research Institute for Health Sciences, Chiang Mai, Thailand
                [8 ]Chennai Antiviral Research and Treatment Clinical Research Site, Y.R. Gaitonde Centre for AIDS Research and Education, Chennai, India
                [9 ]National Hospital of Tropical Diseases, Hanoi, Vietnam
                [10 ]Infectious Disease Department, Bach Mai Hospital, Hanoi, Vietnam
                [11 ]Department of Medicine, Queen Elizabeth Hospital, Hong Kong, China
                [12 ]Department of Health, Research Institute for Tropical Medicine, Manila, Philippines
                [13 ]Faculty of Medicine, Udayana University & Sanglah Hospital, Bali, Indonesia
                [14 ]Division of Infectious Diseases, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea
                [15 ]Infectious Diseases and AIDS Unit, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
                [16 ]Faculty of Medicine, University Malaya Medical Centre, Kuala Lumpur, Malaysia
                [17 ]Faculty of Medicine, University of Indonesia, Cipto Mangunkusumo Hospital, Jakarta, Indonesia
                [18 ]Department of Medicine, Hospital Sungai Buloh, Sungai Buloh, Malaysia
                [19 ]Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand
                [20 ]Department of Medicine, Chiangrai Prachanukroh Hospital, Chiang Rai, Thailand
                [21 ]Beijing Ditan Hospital, Capital Medical University, Beijing, China
                [22 ]Medical Department, Hospital Raja Perempuan Zainab II, Kota Bharu, Malaysia
                [23 ]National Center for HIV/AIDS, Dermatology & STDs, University of Health Sciences, Phnom Penh, Cambodia
                [24 ]Institute of Infectious Diseases, Pune, India
                [25 ]TREAT Asia, amfAR – The Foundation for AIDS Research, Bangkok, Thailand
                University of Sao Paulo Medical School, BRAZIL
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                • Conceptualization: JT AJ AM.

                • Formal analysis: AJ.

                • Funding acquisition: AHS.

                • Investigation: JT AM AA OTN SK RC NK KVN TTP MPL RD TPM JYC WWW AK EY BLHS WR PK FZ MM VS SP AHS.

                • Methodology: JT AJ AM.

                • Project administration: AHS.

                • Supervision: AHS.

                • Writing – original draft: JT AJ.

                • Writing – review & editing: JT AJ AHS.

                ¶ Membership of the TREAT Asia HIV Observational Databases (TAHOD) can be found in the Acknowledgments.

                Article
                PONE-D-15-52349
                10.1371/journal.pone.0161562
                4999237
                27560968
                2abf797d-b9c0-4934-a44b-2ad755c85aed
                © 2016 Tanuma 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
                : 3 December 2015
                : 8 August 2016
                Page count
                Figures: 0, Tables: 4, Pages: 14
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/100000009, Foundation for the National Institutes of Health;
                Funded by: funder-id http://dx.doi.org/10.13039/100000071, National Institute of Child Health and Human Development;
                Funded by: funder-id http://dx.doi.org/10.13039/100000054, National Cancer Institute;
                Funded by: The Dutch Ministry of Foreign Affairs
                Funded by: Hong Kong Council for AIDS Trust Fund
                Funded by: ViiV Healthcare
                Funded by: The Australian Government Department of Health and Ageing
                This work was supported through the U.S. National Institutes of Health’s National Institute of Allergy and Infectious Diseases Eunice Kennedy Shriver National Institute of Child Health and Human Development, and National Cancer Institute, as part of the International Epidemiologic Databases to Evaluate AIDS (IeDEA; U01AI069907, http://www.iedea.org/), and the Dutch Ministry of Foreign Affairs through a partnership with Stichting Aids Fonds. Queen Elizabeth Hospital and the Integrated Treatment Centre received additional support from the Hong Kong Council for AIDS Trust Fund. TREAT Asia (Therapeutics Research Education and AIDS Training - Foundation for AIDS Research) is also supported by ViiV Healthcare ( https://www.viivhealthcare.com/community-partnerships/project-tours/amfar-treat-asia/introduction.aspx). The Kirby Institute is funded by the Australian Government Department of Health and Ageing, and is affiliated with the Faculty of Medicine, UNSW Australia. The content of this analysis is solely the responsibility of the authors and does not necessarily represent the official views of any of the governments or institutions. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
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                Custom metadata
                Due to restrictions from the study organizers and ethics committee, the data in TAHOD cannot be made publicly available. External investigator(s) wishing to access the study data can contact the study Project Manager based in Bangkok, Thailand for further information. Boondarika (Tor) Petersen Project Manager, TAHOD TREAT Asia, amfAR – The Foundation for AIDS Research Exchange Tower, 21st Floor, Suite 2104 388 Sukhumvit Road, Klongtoey, Bangkok 10110 Thailand T: +66 (0) 2663 7561 x113 F: +66 (0) 2663 7562 tor.nakornsri@ 123456treatasia.org .

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