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Episodes of HIV Viremia and the Risk of Non-AIDS Diseases in Patients on Suppressive Antiretroviral Therapy

Zhang, Shuangjie MSc, MD*; van Sighem, Ard PhD*; Kesselring, Anouk MSc, MD*; Gras, Luuk MSc*; Smit, Colette PhD*; Prins, Jan M. PhD, MD; Kauffmann, Robert PhD, MD; Richter, Clemens PhD, MD§; de Wolf, Frank PhD, MD*,‖; Reiss, Peter PhD, MD†,¶

JAIDS Journal of Acquired Immune Deficiency Syndromes: July 1st, 2012 - Volume 60 - Issue 3 - p 265–272
doi: 10.1097/QAI.0b013e318258c651
Clinical Science

Background: Several studies reported an association between immunodeficiency and non–AIDS-defining diseases. We investigated whether nonstructured treatment interruptions and episodes of viremia during suppressive combination antiretroviral therapy were independently associated with non-AIDS diseases.

Methods: Six thousand four hundred forty patients with viral suppression (<50 copies/mL) within 48 weeks of starting combination antiretroviral therapy were selected from the Dutch ATHENA cohort. In proportional hazards models, associations between treatment interruptions, viral suppression, low-level (50–400 copies/mL), and high-level viremia (>400), and serious non-AIDS diseases (cardiovascular disease, chronic renal failure, liver fibrosis/cirrhosis) were investigated by including time-updated cumulative exposure to either viremia and interruptions or HIV RNA >400 copies per milliliter.

Results: During 24,603 person-years, of which 88.5% occurred during viral suppression, 102 patients developed cardiovascular disease, 54 chronic renal failure, and 70 liver fibrosis/cirrhosis. Overall incidence of non-AIDS diseases ranged from 1.41 (95% confidence interval: 0.73 to 2.46) per 100 person-years for CD4 counts <200 to 0.71 (0.49 to 1.00) for CD4 ≥500 cells per cubic millimeter. Compared with viral suppression, high-level viremia was associated only with cardiovascular disease (relative hazard: 1.37, 1.04 to 1.81 per year longer), whereas interruptions and low-level viremia were not associated with non-AIDS diseases. Relative hazards for cumulative exposure to RNA >400 versus ≤400 copies per milliliter were 1.32 (1.01 to 1.73) for cardiovascular disease, 1.13 (0.66 to 1.92) for renal failure, and 0.86 (0.51 to 1.44) for fibrosis/cirrhosis.

Conclusions: Lower CD4 counts are associated with increased risk of non-AIDS diseases, whereas high-level viremia seems to be independently associated with cardiovascular disease. However, the power to detect associations with viremia or interruptions may have been limited as most events occurred during viral suppression.

*Stichting HIV Monitoring, Amsterdam, the Netherlands

Centre for Infection and Immunity Amsterdam (CINIMA), Division of Infectious Diseases, Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands

Department of Internal Medicine, HAGA Hospital, Den Haag, the Netherlands

§Department of Internal Medicine, Rijnstate Hospital, Arnhem, the Netherlands

Department of Infectious Disease Epidemiology, Imperial College London, London, United Kingdom

Department of Global Health, Amsterdam Institute for Global Health and Development, Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands.

Correspondence to: Ard van Sighem, PhD, Stichting HIV Monitoring, Academic Medical Centre, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, the Netherlands (e-mail:

The ATHENA database is supported by a grant from the Dutch Health Ministry and was set up and is maintained by Stichting HIV Monitoring.

Presented in part at the 17th Conference on Retroviruses and Opportunistic Infections, San Francisco, CA, February 16–19, 2010. Abstract 503.

S.Z. designed the study, interpreted the data, carried out the analyses, and wrote the article. A.V.S. was involved in the design of the study, supervised the analyses, and contributed to writing of the article. A.K., L.G., and C.S. were involved in the statistical analyses and interpretation of the data. J.M.P., R.K., C.R., and P.R. contributed to the design of the study and the interpretation of the results. F.D.W. was involved in the design of the study and was the overall supervisor of the study. All authors critically reviewed and edited the article.

The authors have no conflicts of interest to disclose.

Physicians and data analysts are listed in listed in Appendix I.

Received October 20, 2011

Accepted April 3, 2012

© 2012 Lippincott Williams & Wilkins, Inc.