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Importance HIV-infected individuals with suppressed viremia on combined antiretroviral therapy (ART) have an increased risk of myocardial infarction (MI) versus uninfected control subjects. Effects of ART on arterial inflammation among treatment-naïve individuals with HIV are unknown. Objective To determine the effects of newly initiated ART on arterial inflammation and other immune/inflammatory indices in ART-naïve HIV-infected patients. Design, Setting, Participants 12 treatment-naïve HIV-infected subjects underwent 18fluorine-2-deoxy-D-glucose positron emission tomography (18F-FDG-PET) scanning for assessment of arterial inflammation, coronary CT angiography (CCTA) for assessment of subclinical atherosclerosis, and systemic immune/metabolic phenotyping prior to and 6 months after the initiation of elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate (E/C/F/TDF). Systemic immune / metabolic parameters were also assessed in 12 prospectively recruited, non-HIV control subjects. The study began in July 2012 and was completed in May 2015. Intervention E/C/F/TDF in the HIV-infected cohort Results In addition to suppressing viral load (P<0.0001) and increasing CD4 count (P=0.0005), E/C/F/TDF markedly reduced the percentages of circulating activated CD4+ T cells (HLA-DR+CD38+CD4+) (P=0.008) and CD8+ T cells (HLA-DR+CD38+CD8+) (P=0.008), increased the percentage of circulating classical CD14+CD16− monocytes (P=0.04), and reduced levels of CXCL10 (P=0.03). With E/C/F/TDF, uptake of 18F-FDG in the axillary lymph nodes, as measured by target-to-background ratio (TBR), decreased from 3.7 (1.3, 7.0) at baseline to 1.4 (0.9, 1.9) [median (IQR) (P=0.01)] at study end. In contrast, no decrease was seen in aortic TBR in response to E/C/F/TDF (1.9±0.2 [2.0 (1.8, 2.1)] at baseline to 2.2±0.4 [2.1 (1.9, 2.6)] at study end, P=0.04 by two-way test; P=0.98 for test of decrease by one-way test). Changes in aortic TBR during E/C/F/TDF were significantly associated with changes in lipoprotein-associated phospholipase A2 (Lp-PLA2) (r=0.67, P=0.03). Coronary plaque increased among those HIV-infected participants with baseline plaque (n=3) and developed de novo in one participant during treatment with E/C/F/TDF. Conclusions and Relevance Newly initiated E/C/F/TDF in treatment-naïve HIV-infected subjects had discordant effects to restore immune homeostasis and dampen systemic immune activation without reducing arterial inflammation over the duration of treatment in this study. Complementary strategies to reduce arterial inflammation among ART-treated HIV-infected individuals may be needed. Clinical Trial Registration Number NCT01766726.

Objective Persistent immune activation is thought to contribute to increased CVD risk in HIV and statins may help modulate systemic immune activation. We aimed to compare the effects of two key statins on markers of systemic immune activation and arterial inflammation in the HIV population. Design Double-blind, active-controlled, parallel-group comparative trial performed in 45 sites Methods 252 ART-treated HIV-infected participants with dyslipidemia were randomized (1:1) to pitavastatin 4mg daily vs. pravastatin 40mg daily in the INTREPID Trial. In this analysis of the INTREPID Trial, we assessed markers of immune activation and arterial inflammation using a modified intent to treat population. This trial is registered with ClinicalTrials.gov (NCT01301066). Results 126 participants were randomized to receive pitavastatin and 126 to pravastatin. 99 participants in the pitavastatin group and 91 participants in the pravastatin group completed the study. Median age was 50(45,56) years [median(IQR)]. Baseline, LDL-C was 153(135,171) mg/dL, log HIV-1 viral load was 1.1±0.2 copies/mL and CD4 count was 580(439,794) cells/mm3. At Week 52, the pitavastatin group had a significantly greater reduction (% change) compared to pravastatin in sCD14 (−10.0 vs. 0.6%, P=0.02), oxLDL (−26.9 vs. −17.5%, P=0.02), and Lp-PLA2 (−26.6 vs. −15.5%, P=0.005) (pitavastatin vs. pravastatin). Conclusions 52 weeks of pitavastatin 4mg daily (vs. pravastatin 40mg daily) led to a greater reduction in select markers of immune activation and arterial inflammation (sCD14, oxLDL and LpPLA2) among HIV-infected participants. Further work is needed to assess whether immune-modulatory effects of pitavastatin reduce CVD risk in HIV.