An evaluation of HIV elite controller definitions within a large seroconverter cohort collaboration

Abstract

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 HIV seroconverters. 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.

Figure 1. Total ART-naïve follow-up time spent as an elite controller for 4 of the best performing definitions: a) A ^ŧ, b) E ^ŧ, c) F ^ŧ,and d) J ^ŧ using the CSCADE dataset.

^ŧ A: HIV-positive ≥6 months, with ≥2 consecutive HIV-RNA <75 copies/ml; E: HIV- positive ≥1 year, with ≥3 consecutive HIV-RNA <75 copies/ml spanning ≥12 months F: HIV- positive ≥1 year, with ≥3 consecutive HIV-RNA <75 copies/ml spanning ≥12 months with no previous blips ≥1000 copies/ml, J: HIV- positive ≥10 years, with ≥90% of HIV-RNA (≥2 HIV-RNA ever) <400 copies/ml.