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Evaluation of Rapid Progressors in HIV Infection as an Extreme Phenotype

Olson, Ashley D. MA; Guiguet, Marguerite PhD†,‡; Zangerle, Robert§; Gill, John MD; Perez-Hoyos, Santiago PhD; Lodi, Sara PhD#; Ghosn, Jade PhD**; Dorrucci, Maria PhD††; Johnson, Anne PhD‡‡; Sannes, Mette PhD§§; Moreno, Santiago PhD‖‖; Porter, Kholoud*; for CASCADE Collaboration in EuroCoord

JAIDS Journal of Acquired Immune Deficiency Syndromes: 1 September 2014 - Volume 67 - Issue 1 - p 15–21
doi: 10.1097/QAI.0000000000000240
Basic and Translational Science

Design: Rapid CD4 cell loss represents an HIV phenotype used to identify causal variants of accelerated disease progression. The optimal rate and threshold for identifying this extreme phenotype in recently infected individuals is unclear.

Methods: Using a cohort of patients with known dates of HIV-1 seroconversion (SC), CASCADE (Concerted Action on SeroConversion on AIDS and Death in Europe), we identified proportions experiencing nadir CD4 cell levels within 1 year of SC, and assessed their mean AIDS-free survival time at 10-year follow-up and hazard of AIDS/death, compared with those whose CD4 remained >500 cells per cubic millimeter. Follow-up was censored at December 31, 1996 to avoid bias due to combination antiretroviral therapy initiation.

Results: Of 4876 individuals, 2.8%, 7.3%, and 24.9% experienced ≥1 CD4 <100, 200, and 350 cells per cubic millimeter, respectively, within 1 year of SC. Minimum CD4 levels of 30, 166, 231, and 506 cells per cubic millimeter were experienced during this period by 1%, 5%, 10%, and 50% of individuals, respectively. Mean (95% confidence interval) AIDS-free survival at 10 years follow-up was 2.9 (2.3 to 3.6), 5.5 (5.0 to 6.1), 6.7 (6.5 to 7.0), 7.4 (7.2 to 7.6), and 8.1 (7.9 to 8.3), for those with minimum counts ≤100, 100–200, 200–350, 350–500, >500 cells per cubic millimeter, respectively. Using counts of >500 cells per cubic millimeter as reference, the hazard ratios (95% confidence interval) of AIDS/death were 15.0 (11.9 to 18.9), 3.6 (2.9 to 4.5), 2.1 (1.8 to 2.4), and 1.5 (1.3 to 1.7), respectively. The hazard ratio increased to 37.5 (26.5 to 53.1) when a minimum CD4 count <100 was confirmed within 1 year of SC.

Conclusion: At least 1 CD4 ≤100 cells per cubic millimeter within the first year of SC identifies a rare group of individuals at high risk of disease progression and could form the basis for defining the rapid progressor phenotype.

*Medical Research Council Clinical Trials Unit, University College London, London, United Kingdom;

INSERM U943, Paris, France;

UPMC, Paris, France;

§Innsbruck Medical University, Innsbruck, Austria;

University of Calgary, Calgary, Alberta, Canada;

Vall d'Hebrón Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain;

#Instituto de Salud Carlos III, Madrid, Spain;

**Service de Médecine Interne et Maladies Infectieuses, CHU Bicêtre, Paris, France;

††Department of Infectious, Parasitic and Immune-mediated Diseases, Istituto Superiore di Sanità, Rome, Italy;

‡‡Institute of Epidemiology and Health Care, University College London, London, United Kingdom;

§§Ulleval University Hospital, Oslo, Norway; and

‖‖Hospital Universitário Ramón y Cajal, Madrid, Spain.

Correspondence to: Ashley D. Olson, Medical Research Council Clinical Trials Unit, University College London, Aviation House, 125 Kingsway, London WC2B 6NH, United Kingdom (e-mail:

Supported by European Union Seventh Framework Program (FP7/2007-2013) under EuroCoord grant agreement no. 260694.

The authors have no conflicts of interest to disclose.

For a complete list of CASCADE Collaboration in EuroCoord, see Appendix 1.

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Received February 12, 2014

Accepted April 23, 2014

© 2014 by Lippincott Williams & Wilkins