Antiretroviral therapy in the elite controller: justified or premature?

Investigating the immune system of human immunodeficiency virus (HIV) elite controllers, or HIV-infected individuals who maintain undetectable plasma HIV RNA levels without antiretroviral therapy (ART), has led to advances in our understanding of HIV pathogenesis [1] and may be critical to the development of a functional cure for HIV infection [2, 3]. However, although other studies have shown that elite controllers maintain immune control of their viral replication, preventing disease progression in some, these individuals have higher levels of immune activation and chronic inflammation than HIV-infected persons with viral suppression during ART [4–7].Whether or not elevated markers of inflammation in elite controllers are clinically meaningful is relevant to the question of whether elite controllers should be treated with ART. Elite controllers have also demonstrated higher levels of atherosclerosis than chronically HIV-1–infected persons receiving ART with undetectable HIV loads and HIV negative controls [5, 8]. The Strategies for Management of Anti-Retroviral Therapy (SMART) trial very clearly highlighted the association between chronic inflammation, observed in suppressed HIV-infected subjects receiving ART, and excess morbidity and mortality; subjects with elevated levels of the inflammatory markers interleukin 6 and D-dimer had higher all-cause mortality [9] and serious non-AIDS events, such as cardiovascular disease (CVD) [10, 11], than similarly suppressed subjects with lower inflammatory markers. The article by Crowell et al [12] in this issue of the Journal presents a unique analysis of a large cohort of HIV-infected patients, including a fair number of elite controllers (n = 149). To evaluate whether clinical outcomes differed between elite controllers (all not receiving ART) and patients with HIV infection controlled with ART, the authors retrospectively evaluated a multisite cohort and compared hospitalization rates from 2005 to 2011. The major finding was an increased hospitalization rate for elite controllers compared with HIV RNA–suppressed patients receiving ART; surprisingly, hospitalization rates were also higher in elite controller than in subjects with detectable viremia. Differences in hospitalization rates for the elite controllers were largely due to more hospitalizations for cardiovascular and psychiatric disease. On the surface, these findings seem to provide compelling clinical evidence for ART treatment in elite controller despite chronic viral control and high CD4 cell count, and raise questions as to whether immune viral control will be an adequate end point for functional cure strategies (ie, the ability to stop ART and maintain viral suppression after an immune-based intervention). However, potential study limitations, particularly unmeasured confounders (of common known contributors to CVD) and the interpretation of complex cohort analytic techniques, limit our ability to fully interpret these results and may still leave unanswered the clinical question of the need to treat this rare group of HIV immune controllers. As is possible in cohort analyses, when subjects are by definition not randomized to comparison groups, baseline characteristics differed significantly between elite controller and other subjects in the study, including HIV-infected persons controlled with ART and subjects with low and high HIV loads. The elite controller cohort was significantly more likely to be female (P < .001) and black (P < .001) and had higher CD4 T-cell counts (P < .001). Using multivariable models, which adjusted for sex, race and other factors, Crowell et al [12] found that elite controllers still had almost 2fold higher incidence rate ratio for hospitalizations than subjects with controlled viral replication during ART. Received and accepted 11 December 2014; electronically published 15 December 2014. Correspondence: Maile Y. Karris, MD, Department of Medicine, 200 W Arbor Dr, MC 8208, San Diego, CA 92103-8208 ([email protected]). The Journal of Infectious Diseases 2015;211:1689–91 © The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals. [email protected]. DOI: 10.1093/infdis/jiu812