Risk of recurrent venous thromboembolism in patients with HIV infection: A nationwide cohort study

Multiple studies have described a higher incidence of venous thromboembolism (VTE) in people living with an HIV infection (PWH). However, data on the risk of recurrent VTE in this population are lacking, although this question is more important for clinical practice. This study aims to estimate the...

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Published in:PLoS medicine Vol. 17; no. 5; p. e1003101
Main Authors: Rokx, Casper, Borjas Howard, Jaime F., Smit, Colette, Wit, Ferdinand W., Pieterman, Elise D., Reiss, Peter, Cannegieter, Suzanne C., Lijfering, Willem M., Meijer, Karina, Bierman, Wouter, Tichelaar, Vladimir, Rijnders, Bart J. A.
Format: Journal Article
Language:English
Published: United States Public Library of Science 14.05.2020
Public Library of Science (PLoS)
Subjects:
Anticoagulants
Antiretroviral drugs
Antiretroviral therapy
Bacterial infections
Biology and Life Sciences
Care and treatment
CD4 antigen
Cell differentiation
Cohort analysis
Consent
Embolism
Epidemiology
Health aspects
Health risk assessment
Hematology
Highly active antiretroviral therapy
HIV
HIV infections
HIV patients
Human immunodeficiency virus
Immunodeficiency
Infections
Infectious diseases
Internal medicine
Lymphocytes T
Medical research
Medicine
Medicine and Health Sciences
Methods
Pulmonary embolism
Recurrence (Disease)
Recurrent infection
Risk factors
Sensitivity analysis
Supervision
T cells
Thromboembolism
Thrombosis
Netherlands
ISSN:1549-1676, 1549-1277, 1549-1676
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Summary:Multiple studies have described a higher incidence of venous thromboembolism (VTE) in people living with an HIV infection (PWH). However, data on the risk of recurrent VTE in this population are lacking, although this question is more important for clinical practice. This study aims to estimate the risk of recurrent VTE in PWH compared to controls and to identify risk factors for recurrence within this population. PWH with a first VTE were derived from the AIDS Therapy Evaluation in the Netherlands (ATHENA) cohort (2003-2015), a nationwide ongoing cohort following up PWH in care in the Netherlands. Uninfected controls were derived from the Multiple Environmental and Genetic Assessment of risk factors for venous thrombosis (MEGA) follow-up study (1999-2003), a cohort of patients with a first VTE who initially participated in a case-control study in the Netherlands who were followed up for recurrent VTE. Selection was limited to persons with an index VTE suffering from deep vein thrombosis in the lower limbs and/or pulmonary embolism (PE). Participants were followed from withdrawal of anticoagulation to VTE recurrence, loss to follow-up, death, or end of study. We estimated incidence rates, cumulative incidence (accounting for competing risk of death) and hazard ratios (HRs) using Cox proportional hazards regression, adjusting for age, sex, and whether the index event was provoked or unprovoked. When analyzing risk factors among PWH, the main focus of analysis was the role of immune markers (cluster of differentiation 4 [CD4]+ T-cell count). There were 153 PWH (82% men, median 48 years) and 4,005 uninfected controls (45% men, median 49 years) with a first VTE (71% unprovoked in PWH, 34% unprovoked in controls) available for analysis. With 40 VTE recurrences during 774 person-years of follow-up (PYFU) in PWH and 635 VTE recurrences during 20,215 PYFU in controls, the incidence rates were 5.2 and 3.1 per 100 PYFU (HR: 1.70, 95% CI 1.23-2.36, p = 0.003). VTE consistently recurred more frequently per 100 PYFU in PWH in all predefined subgroups of men (5.6 versus 4.8), women (3.6 versus 1.9), and unprovoked (6.0 versus 5.2) or provoked (3.1 versus 2.1) first VTE. After adjustment, the VTE recurrence risk was higher in PWH compared to controls in the first year after anticoagulant discontinuation (HR: 1.67, 95% CI 1.04-2.70, p = 0.03) with higher cumulative incidences in PWH at 1 year (12.5% versus 5.6%) and 5 years (23.4% versus 15.3%) of follow-up. VTE recurred less frequently in PWH who were more immunodeficient at the first VTE, marked by a better CD4+ T-cell recovery on antiretroviral therapy and during anticoagulant therapy for the first VTE (adjusted HR: 0.81 per 100 cells/mm3 increase, 95% CI 0.67-0.97, p = 0.02). Sensitivity analyses addressing potential sources of bias confirmed our principal analyses. The main study limitations are that VTEs were adjudicated differently in the cohorts and that diagnostic practices changed during the 20-year study period. Overall, the risk of recurrent VTE was elevated in PWH compared to controls. Among PWH, recurrence risk appeared to decrease with greater CD4+ T-cell recovery after a first VTE. This is relevant when deciding to (dis)continue anticoagulant therapy in PWH with otherwise unprovoked first VTE.
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I have read the journal's policy and the authors of this manuscript have the following competing interests: CR reports grants from Gilead, Merck, and personal fees from Gilead, ViiV, Janssen-Cilag. JFBH and EDP report no conflicts of interest. YIGVT was employed by the Dutch National Health Institute during analysis and reporting on this study. CS reports grants from Netherlands Ministry of Health, Welfare and Sport, National Institute for Public Health and the Environment, Centre for Infectious Disease Control, during the conduct of the study. FW reports personal fees from Gilead Sciences, personal fees from ViiV Healthcare, outside the submitted work. PR reports independent scientific grant support to his institution from Gilead Sciences, Janssen Pharmaceuticals Inc., Merck & Co., Bristol-Myers Squibb, and ViiV Healthcare; fees to his institution for his participation on scientific advisory boards for Gilead Sciences ViiV Healthcare, Merck & Co., Teva pharmaceutical industries, and on a data safety monitoring committee for Janssen Pharmaceuticals Inc. BR reports grants from Gilead, grants from MSD, nonfinancial support from MSD, nonfinancial support from Gilead, nonfinancial support from BMS, nonfinancial support from Janssen-Cilag, nonfinancial support from ViiV, nonfinancial support from Abbvie, personal fees from Gilead, personal fees from ViiV, personal fees from Great-Lakes pharmaceuticals, outside the submitted work; and financial compensation payed to institution for advisory board participation organized by Gilead, ViiV, BMS, Janssen-Cilag, and MSD. KM received research support from Bayer, Sanquin, and Pfizer; speaker fees from Bayer, Sanquin, Boehringer Ingelheim, BMS, and Aspen; consulting fees from Uniqure (outside the submitted work, all fees go to the institution). WBW reports reimbursement payed to institution for investigator-initiated study from Janssen-Cilag, financial compensation payed to institution for multicenter study by GSK and catering of a symposium by Janssen-Cilag, all outside the submitted work. SCC is a member of the Editorial Board of PLOS Medicine. WML reports no conflicts of interest.
Membership of the ATHENA observational HIV cohort is provided in S1 Supplementary Methods.
ISSN:1549-1676
1549-1277
1549-1676
DOI:10.1371/journal.pmed.1003101