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Is it time to treat HIV elite controllers with combined antiretroviral therapy?

To the Editor—I read with interest the article by Sedaghat et al [1], who reported long-term dynamics in human immunodeficiency virus (HIV) elite controllers. Sedaghat and colleagues also observed an elite controller with a progressive decrease in the CD4 cell counts, who experienced a marked decrease in immune activation that was not accompanied by the increase in the CD4 cell count. The article by Sedaghat and colleagues raises an intriguing issue regarding combined antiretroviral therapy (cART) in elite controllers who experience progressive decreases in the CD4 cell count despite having undetectable virus loads. Although the estimated frequency of elite controllers is !1% of persons with chronic HIV infection [2], in an international study (the CASCADE study) of recently HIV-infected patients [3], 10 (7%) of 145 persons with virologically controlled HIV infection eventually experienced an AIDS-defining illness, and 5 (3.5%) experienced evidence of a progressive decrease in the CD4 T cell count while plasma HIV RNA levels remained undetectable, while not receiving cART. In a more recent study, Hunt et al [4] observed a proportion of elite controllers among untreated patients who progressed to AIDS—similar to the population from the CASCADE study. Moreover, Hatano et al [5] demonstrated that the majority (98%) of elite controllers have measurable plasma HIV RNA levels, often at levels higher than those observed in antiretroviral-treated patients. It has also been demonstrated that higher CD8 T cell activation levels are associated with more rapid CD4 T cell count decreases and clinical progression among untreated patients [6]. In particular, elite controllers demonstrated abnormal levels of T cell activation despite maintaining clinically undetectable levels of viral replication along with higher CD8 T cell activation levels [4]. In December 2009, the Department of Health and Human Services has published up to date guidelines for HIV treatment [7], and the panel members revised the criteria when cART has to be started. The panel recommends treatment of patients with CD4 cell counts of 350–500 cells/ mm, whereas for those with CD4 cell counts 1500 cells/mm, the panel favors treatment as optional. In addition, the panel states that cART may be theoretically beneficial for elite controllers, although clinical data supporting treatment for these patients are lacking. I fully agree with Sedaghat et al [1] that cART can reduce chronic immune activation and subsequently can block progressive decreases in the CD4 cell count, which may lead to AIDS-defining illnesses and to non–AIDS-defining illnesses—particularly in patients with CD4 cell counts 1350 cells/mm. Thus, taken together, clinical data and suggestions from the panel members indicate that it may be time for elite controllers with progressive decreases in the CD4 cell count to be treated with cART, and it is desirable to design studies to test the efficacy of cART in preventing progression of HIV infection for elite controllers with progressive decreases in the CD4 cell count.