Very Early ART and Persistent Inflammation in Treated HIV

There is unequivocal evidence that earlier antiretroviral therapy (ART) initiation, even among those with CD4+ T-cell counts >500 cells/mm, reduces morbidity in human immunodeficiency virus (HIV)– infected individuals. The Strategic Timing of Antiretroviral Therapy (START) and Temprano trials both demonstrated an approximately 50% reduced risk of AIDS or non-AIDS events in HIV-infected individuals randomized to immediate ART initiation compared to delayed ART initiation [1, 2]. These unambiguous results prompted changes to international treatment guidelines, which now recommend initiating ART in all HIV-infected individuals regardless of CD4+ T-cell count. Nevertheless, there was also a suggestion from both of these trials that immediate ART initiation failed to completely restore normal health. For example, there was a 1% risk of AIDS at 5 years even in the immediate ART arm of START and a 5%–8% incidence of serious morbidity and mortality (largely from tuberculosis) at 30 months in the Temprano trial, even among those who initiated ART at a high CD4+ T-cell count. These rates of infectious complications and cancer are much higher than are observed in the general population in these settings. Thus, while very early ART initiation clearly improves health, it may not completely restore normal health. The study by Sereti et al in this issue of Clinical Infectious Diseases offers important new insights into why very early ART initiation improves but fails to normalize health in HIV-infected individuals [3]. It is now well appreciated that immune activation and inflammation persist at abnormally high levels in many HIVinfected individuals despite suppressive ART, particularly when ART initiation is delayed to more advanced disease stages. This persistent inflammatory state has been linked to an increased risk of subsequent morbidity and mortality in several studies and has emerged as an important target for interventions in the modern treatment era [4]. What has been less clear is whether very early ART initiation could prevent this persistent inflammatory state. In their study, Sereti et al characterized longitudinal changes in immune activation among HIV-infected Thai individuals who initiated ART extremely early, that is, within the first 2–3 weeks of their infection. They found that many markers of immune activation and inflammation were already abnormally elevated in these acutely HIVinfected participants relative to a cohort of at-risk but HIV-uninfected controls. Furthermore, most markers declined during suppressive antiretroviral therapy to levels that were significantly lower than observed in a cohort of HIV-infected Thai individuals who initiated ART during chronic HIV infection and at much lower CD4+ T-cell counts. This provided strong evidence that there is likely to be a cost of delaying antiretroviral therapy on the persistent inflammatory state once ART-mediated viral suppression is established and may at least partially explain why early ART initiation in the START and Temprano trials decreased morbidity. On the other hand, many markers of immune activation and inflammation remained abnormally elevated in the individuals with very early ART initiation, even after 2 years of ART-mediated viral suppression compared to at-risk but HIV-uninfected controls. Abnormal immune activation persisted even among the subgroup of individuals who initiated ART before HIV-specific antibodies were even detectable by fourth generation assays (typically <14 days of infection). This important observation might provide a reason why the risk of infectious and neoplastic complications remained abnormally high in the immediate ART groups in the START and Temprano trials relative to the general population. While it certainly appears from the study by Sereti et al that many markers of immune activation fail to normalize even when ART is initiated during the earliest stages of acute HIV infection, there are several caveats that need to be considered. First, it is possible that the HIV-uninfected E D I T O R I A L C O M M E N T A R Y