Immune Activation, Inflammation and HIV DNA after 96 Weeks of ATV/r Monotherapy: A MODAt Substudy

We read with interest the article by Oldenbuettel et al. [1] on dolutegravir monotherapy as treatment de-escalation in successfully cART-treated HIV-infected individuals. Although these results provided important insights into the safety and feasibility of integrase inhibitor monotherapy in selected patients, it remains unclear whether these effects might impact the persistence of chronic immune dysfunction. In the past few years, antiretroviral therapy with less than 3 drugs (less drug regimen [LDR]), including monotherapy with a ritonavir-boosted protease inhibitor (PImono) have been investigated, due to less toxicity, fewer drug–drug interactions, pill burden and costs [2–5]. However, while increased inflammation and immune activation persist upon virally-suppressive cART and are associated with clinical progression [6–8], few studies have assessed the effect of LDR strategies on immune activation and inflammation [9–12]. We therefore reasoned that assessing inflammation/ immune activation in a PImono might be informative on the effect of LDR strategies on inflammation. Thus, we investigated immune activation/senescence and inflammation, as well as HIV reservoirs, in a subgroup of HIV-positive patients enrolled in the Monotherapy Once a Day with Atazanavir/r (MODAt) study [13,14], for whom we had plasma and peripheral blood mononuclear cells (PBMCs) available at baseline, week 48 (W48) and week 96 (W96). The MODAt study is a prospective, multicentre, open-label, non-inferiority, randomized, 96-week trial (NCT01511809) on patients with atazanavir/ritonavir plus two NRTIs, fully suppressed and without previous virological failure, whose study design and methodology have been previously reported [14]. Patients were randomly assigned 1:1 to continue the ongoing triple-based regimen or to maintain only ritonavir-boosted atazanavir (ATV/r) 300/100 mg daily [14]. In the present sub-study, we included 40 individuals, 22/40 on triple therapy (tATV/r) and 18/40 on mono ATV/r regimen (mATV/r), similar for demographic and clinical features (Table 1). In both arms, we observed stable CD4+ T-cell counts over time (not shown); two mATV/r patients and one mATV/r patient showed detectable HIV RNA (>49 copies/ml) at W48 and at W96, respectively, whereas no HIV viraemia changes were evident in the tATV/r arm. Furthermore, self-reported adherence was similar between the two arms over time, with a not significant decrease in mATV/r between W48 and W96, likely due to the limited sample size. As we previously demonstrated inferior virological efficacy of mATV/r [13], we first investigated HIV reservoir (qPCR, ABIPrism 790 VIR/MET/016; Applied Biosystems, Foster City, CA, USA). In mATV/r, total HIV DNA declined over time, reaching significance at W48 (baseline: 55 copies/10×5 cells [IQR 9–175], W48: 18 copies/10×5 cells [IQR 9–54], P=0.014; W96: 25 copies/10×5 cells [IQR 9–68], P=0.102; Figure 1A). On the contrary, in tATV/r total HIV DNA trended to significant reduction at W96 (16 copies/10×5 cells [9–61], 10 copies/10×5 cells [9–23], P=0.216; 9 copies/10×5 cells [9–16], P=0.054; Figure 1A), resulting in significantly lower levels than mATV/r (P=0.013; Figure 1A). We next investigated T-cell immune phenotypes on cryopreserved PBMCs (fluorochrome-labelled antibodies and FACSVerse cytometer from BD Bioscience, San Jose, CA, USA). Baseline values are listed in Table 1. While the mATV/r group showed a reduction of activated HLA-DR+CD38+CD4+ at W48 (8.4% Letter