Objective: Determine concentrations of antiretroviral therapy (ART) drugs in the human brain.Design: Cohort study of persons with HIV (PWH) who consented to antemortem assessment and postmortem autopsy.Methods: Eleven PWH who were taking ART at the time of death and had detectable concentrations of at least one ART drug in intracardiac aspirate at autopsy were evaluated. Autopsies were performed within 24 hours of death and brain tissue was stored at -80 o C. Concentrations of 11 ART drugs were measured in three brain regions [globus pallidus (GP), cortical gray matter (CGM), white matter (WM)] by high performance liquid chromatography tandem mass spectrometry with a lower limit of quantification of 25 ng/mL. Results:Participants were mostly men (82%) with a mean age of 40.4 years. Drug concentrations in brain tissue were highly variable and exceeded published concentrations in CSF for several drugs, including for tenofovir, efavirenz, and lopinavir. Drug concentrations correlated most strongly between CGM and GP (rho=0.70) but less well between GP and WM (rho=0.43). Combining all drugs and brain regions (n=89), higher drug concentrations in brain were associated with longer estimated duration of HIV infection (p=0.015), lower HIV RNA in plasma (p=0.0001), lower nadir CD4+ T-cell count (p=0.053), and worse neurocognitive performance (p=0.017).Conclusions: This is the first analysis of ART drug concentrations in human brain tissue.Concentrations of several drugs in this analysis were similar to published concentrations in CSF but others exceeded published concentrations. The association between higher drug concentrations in the brain and worse neurocognitive performance may indicate ART neurotoxicity.

Background: Viral load peak and immune activation occur shortly after exposure during acute or early HIV infection (AEHI). We aimed to define the benefit of early start of antiretroviral treatment (ART) during AEHI in terms of immunological recovery, virological suppression, and treatment discontinuation.Setting: Patients diagnosed with AEHI (Fiebig stages I-V) during 2008-2014 from an analysis of 20 Italian centers.Methods: This was an observational, retrospective, and multicenter study. We investigated the effect of early ART (defined as initiation within 3 months from AEHI diagnosis) on time to virological suppression, optimal immunological recovery (defined as CD4 count ≥ 500/µL, CD4 ≥ 30%, and CD4/CD8 ≥ 1), and first-line ART regimen discontinuation by Cox regression analysis. Results: There were 321 patients with AEHI included in the study (82.9% in Fiebig stage III-V). At diagnosis, the median viral load was 5.67 log10copies/mL and the median CD4 count was 456 cells/µL. Overall, 70.6% of patients started early ART (median time from HIV diagnosis to ART initiation 12 days, IQR 6-27). Higher baseline viral load and AEHI diagnosis during 2012-2014 were independently associated with early ART. HBV co-infection, baseline CD4/CD8 ≥ 1, lower baseline HIV-RNA, and AEHI diagnosis in recent years (2012-2014) were independently associated with a shorter time to virological suppression. Early ART emerged as an independent predictor of optimal immunological recovery after adjustment for baseline CD4 (absolute and percentage count) and CD4/CD8 ratio. The only independent predictor of first-line ART discontinuation was an initial ART regimen including > 3 drugs.Conclusions: In a large cohort of well-characterized patients with AEHI, we confirmed the beneficial role of early ART on CD4+ T-cell recovery and on rates of CD4/CD8 ratio normalization. Moreover, we recognized baseline CD4/CD8 ratio as an independent factor influencing time to virological response in the setting of AEHI, thus giving new insights into research of immunological markers associated with virological control.

Background Currently, no data are available on the burden of morbidity and mortality in people living with HIV-1 (PLWH) harboring a 4-class drug resistant (4DR) virus (NRTI, NNRTI, PI, INSTI). The study aimed to assess the incidence of clinical events or death in this population. Methods Cohort study on PLWH, from the PRESTIGIO Registry, with a documented 4DR virus.The burden of disease was defined as the occurrence of any new event including AIDS-defining event (ADE) or non-AIDS-defining event (NADE) or death for any cause, after 4DR evidence (baseline).Cox regression models evaluated factors associated with the risk of new clinical events/death. Results Among 148 PLWH followed for a median of 47 months (IQR=32-84) since 4DR evidence, 38 PLWH had 62 new events or died for any cause [incidence rate, 9.12/100-PYFU (95%CI=6.85-11.39)]: 12 deaths (6 AIDS-related and 6 non-AIDS-related), 18 ADE, 32 NADE; 20 of the 38 NADE (45%) of the incident clinical events were malignancies. The 4-year cumulative incidence of death was 6% (95%CI=3%-13%) and that of ≥1 event or death was 22% (95%CI=16%-31%). A higher risk of new clinical events/death was more likely in PLWH with previous clinical events (aHR=2.67, 95%CI=1.07-6.67) and marginally associated with lower baseline CD4+/CD8+ ratio (aHR=0.82, 95%CI=0.65-1.02). Conclusions PLWH harbouring 4DR have a high burden of disease with a worrying incidence of malignancies, strongly advising for close prevention and monitoring interventions as well as access to innovative therapeutic strategies, especially in people with a history of clinical events and low CD4+/CD8+ ratio.