Elite controller is a term applied to the rare group of HIV-positive individuals who maintain undetectable viral loads in the absence of any treatment. The precise criteria for defining elite controllers often varies from study to study, particularly when it comes to the duration of viral load control. A research group based in the UK has recently published two companion papers—a systematic review and a research study—that attempt to document the various definitions that have been used in the scientific literature and identify the most accurate using data from a large cohort of HIV-positive individuals.
The review appears in the journal AIDS and has been made open access. The authors, led by Deepti Gurdasani, evaluated a staggering 501 papers to assess the definitions employed for groups of HIV-positive individuals at both ends of the disease progression spectrum, including rapid progressors, slow progressors, long-term non-progressors and elite controllers. The findings show that definitions for each group can vary, but in many cases overlap. In some instances, however, small differences can lead to similar definitions capturing significantly different populations. The authors recommend using their work as a starting point to try and achieve broad consensus in the research community about the most appropriate definitions for each group, so that there is consistency from study to study.
For elite controllers, a total of 50 unique definitions were identified. Viral load thresholds varied from 40 to 500 copies, with 50 being the most common. Slightly less than half the definitions included a minimum duration of follow up, which ranged from six months to 16 years.
In the second paper, published by PLoS One, the researchers take 10 of the identified elite controller definitions and analyze their performance using data from 25,692 participants in the CASCADE cohort, which comprises HIV-positive individuals followed since seroconversion. For participants that fell under each different elite controller definition, a variety of outcomes were assessed including how long they continued to meet the definition, disease progression, viral load, CD4 T cell count and CD4 T cell slope.
The results confirmed the rarity of elite controllers, with most definitions capturing around 1% or less of participants. Table 4 in the paper shows how many individuals fell under each different definition, and, of those, how many progressed to a composite endpoint of AIDS, death, initiation of ART, or CD4 T cell count of less than 350 cells. Only four people met the strictest definition of HIV-positive for 10 years or more with all viral load measurements below 50 copies. The definitions with the lowest number of progression events included:
- HIV-positive for 6 months or more, with two or three consecutive viral load measurements below 75 copies.
- HIV-positive for 10 years or more, with 90% of viral load measurements below 400 copies.
While risk of progression was greatly reduced among all elite controllers compared to non-elite controllers, the researchers note that some progression events were documented among all definitions. Furthermore, there was strong evidence of CD4 T cell declines for five out of the 10 definitions during the period considered as elite control. Based on these findings they conclude that it is unlikely that most elite controllers will remain so indefinitely. This conclusion echoes other recent studies documenting that elite control is associated with elevated levels of immune activation, which can in some cases lead to CD4 T cell loss and progression to AIDS. Although it has been proposed that elite control might be considered a model for a functional cure of HIV infection, these findings reinforce that it does not necessarily represent complete protection from the development of disease. This also has implications for examples of post treatment control such as the VISCONTI cohort and the first Berlin patient (see yesterday’s post), since it is as yet uncertain if the duration of control will be lifelong or, as with some elite controllers, progression might ultimately occur.
AIDS. 2014 Jan 14;28(2):149-62. doi: 10.1097/QAD.0000000000000049.
Gurdasani D, Iles L, Dillon DG, Young EH, Olson AD, Naranbhai V, Fidler S, Gkrania-Klotsas E, Post FA, Kellam P, Porter K, Sandhu MS.
The study of individuals at opposite ends of the HIV clinical spectrum can provide invaluable insights into HIV biology. Heterogeneity in criteria used to define these individuals can introduce inconsistencies in results from research and make it difficult to identify biological mechanisms underlying these phenotypes. In this systematic review, we formally quantified the heterogeneity in definitions used for terms referring to extreme phenotypes in the literature, and identified common definitions and components used to describe these phenotypes. We assessed 714 definitions of HIV extreme phenotypes in 501 eligible studies published between 1 January 2000 and 15 March 2012, and identified substantial variation among these. This heterogeneity in definitions may represent important differences in biological endophenotypes and clinical progression profiles of individuals selected by these, suggesting the need for harmonized definitions. In this context, we were able to identify common components in existing definitions that may provide a framework for developing consensus definitions for these phenotypes in HIV infection.
PLoS One. 2014 Jan 28;9(1):e86719. doi: 10.1371/journal.pone.0086719. eCollection 2014.
Olson AD1, Meyer L2, Prins M3, Thiebaut R4, Gurdasani D5, Guiguet M6, Chaix ML7, Amornkul P8, Babiker A1, Sandhu MS5, Porter K1; for C. A. S. C. A. D. E. Collaboration in EuroCoord.
BACKGROUND: Understanding the mechanisms underlying viral control is highly relevant to vaccine studies and elite control (EC) of HIV infection. Although numerous definitions of EC exist, it is not clear which, if any, best identify this rare phenotype.
METHODS: We assessed a number of EC definitions used in the literature using CASCADE data of 25,692 HIVseroconverters. We estimated proportions maintaining EC of total ART-naïve follow-up time, and disease progression, comparing to non-EC. We also examined HIV-RNA and CD4 values and CD4 slope during EC and beyond (while ART naïve).
RESULTS: Most definitions classify ∼1% as ECs with median HIV-RNA 43-903 copies/ml and median CD4>500 cells/mm(3). Beyond EC status, median HIV-RNA levels remained low, although often detectable, and CD4 values high but with strong evidence of decline for all definitions. Median % ART-naïve time as EC was ≥92% although overlap between definitions was low. EC definitions with consecutive HIV-RNA measurements <75 copies/ml with follow-up≥ six months, or with 90% of measurements <400 copies/ml over ≥10 year follow-up preformed best overall. Individuals thus defined were less likely to progress to endpoint (hazard ratios ranged from 12.5-19.0 for non-ECs compared to ECs).
CONCLUSIONS: ECs are rare, less likely to progress to clinical disease, but may eventually lose control. We suggest definitions requiring individuals to have consecutive undetectable HIV-RNA measurements for ≥ six months or otherwise with >90% of measurements <400 copies/ml over ≥10 years be used to define this phenotype.