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Immune activation associated with HIV-1 infection contributes to morbidity and mortality. We studied whether chloroquine, through Toll-like receptor (TLR) antagonist properties, could reduce immune activation thought to be driven by TLR ligands, such as gut-derived bacterial elements and HIV-1 RNAs. AIDS Clinical Trials Group A5258 was a randomized, double-blind, placebo-controlled study in 33 HIV-1-infected participants off antiretroviral therapy (ART) and 37 participants on ART. Study participants in each cohort were randomized 1:1 to receive chloroquine 250 mg orally for the first 12 weeks then cross over to placebo for 12 weeks or placebo first and then chloroquine. Combining the periods of chloroquine use in both arms of the on-ART cohort yielded a modest reduction in the proportions of CD8 T cells co-expressing CD38 and DR (median decrease = 3.0%, p = .003). The effect on immune activation in the off-ART cohort was likely confounded by increased plasma HIV-1 RNA during chloroquine administration (median 0.29 log10 increase, p

With the advent of highly effective antiretroviral therapy (ART), infection with human immunodeficiency virus (HIV) has become a chronic disease rather than a death sentence. Nevertheless, effectively treated individuals have a higher than normal risk for developing noninfectious comorbidities, including cardiovascular and renal disease. Although traditional risk factors of aging as well as treatment toxicity contribute to this risk, many investigators consider chronic HIV-associated inflammation a significant factor in such end-organ disease. Despite effective viral suppression, chronic inflammation persists at levels higher than in uninfected people, yet the stimuli for the inflammation and the mechanism by which inflammation persists and promotes disease pathology remain incompletely understood. This critical gap in scientific understanding complicates and hampers effective decision making about appropriate medical intervention. To better understand the mechanism(s) of chronic immune activation in treated HIV disease, three questions need answers: (1) what is the cause of persistent immune activation during treated HIV infection, (2) what are the best surrogate markers of chronic immune activation in this setting, and (3) what therapeutic intervention(s) could prevent or reverse this process? The NIH sponsored and convened a meeting to discuss the state of knowledge concerning these questions and the best course for developing effective therapeutic strategies. This report summarizes the findings of that NIH meeting.