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Objective: The goal of the OSCAR programme is to evaluate the performances of genotypic HIV-1 tropism testing in clinical practice using the enhanced sensitivity version of Trafile (ESTA) as reference-assay. Methods: HIV-1 coreceptor-usage was assessed using plasma samples from 406 HIV-1 infected patients by ESTA and by gp120 V3 population-sequencing followed by Geno2pheno (set at a False Positive Rate [FPR] of 10% and 5%). Results: ESTA was successful in 365 (89.9%) samples indicating R5 in 254 (69.6%), and DM/X4 in 111 (30.4% of samples (104 [28.5%] DM and 7 [1.9%] X4). Genotypic-testing successfully assessed viral tropism for all 406 samples, including the 41 with undetermined result by ESTA. Genotypic-tropism testing at a FPR of 5% and 10% was 81.1% and 78.4% concordant with ESTA, respectively. Despite a sensitivity of 48.7% and 55.9% at a FPR of 5% and 10%, respectively, a high concordance (specificity: 95.3% for FPR of 5% and 88.2% for FPR of 10%) between genotypic-tropism testing and ESTA was reached in the detection of R5-tropic viruses. Conclusion: Our results are in line with other European studies, and support the routine use of genotypic tropism testing in clinical-settings for monitoring of HIV-1 infected patients candidate to or failing CCR5-antagonists.

"Objective: The DIVA study is aimed at setting up a standardized genotypic tropism-testing on proviral-DNA for the routine clinical diagnostic-laboratory Methods: Twelve local centres and 5 reference centres (previously cross-validated) were identified. For inter-center validation-procedure, 60 peripheral-blood mononuclear cells (PBMCs) aliquots from 45 HAART-treated patients were randomly chosen for population V3 sequencing on proviral-DNA at local HIV centre and at reference-laboratory Viral tropism was predicted by Geno2Pheno algorithm (False Positive Rate [FPR] = 20%) as proposed by the European-Guidelines. Quantification of total HIV-1 DNA was based on a method described by Viard (2004). Results: Quantification of HIV-1 DNA was available for 35\/45 (77.8%) samples, and gave a median value of 598 (IQR:252-1,203) copies\/10(6) PBMCs. A total of 56\/60 (93.3%) samples were successfully amplified by both the reference and the local virological centers. The overall concordance of tropism prediction between local and reference centers was 54\/56 (96.4%). Results of tropism prediction by local centers were: 33\/54 (61.1%) R5 and 21\/54 (38.9%) X4\/DM. Conclusion: There was high concordance in the genotypic tropism prediction based on proviral DNA among different virological centers throughout Italy. Our results are in line with other European studies, and support the use of genotypic tropism testing on proviral DNA in patients with suppressed plasma HIV-1 RNA candidate to CCR5-antagonist treatment."

OBJECTIVES An observational, prospective, cohort study was performed to assess changes in insulin sensitivity and serum leptin level after a switch from a ritonavir-boosted PI (PI/r) to raltegravir or dolutegravir in HIV-infected adults on stable combination ART (cART). METHODS Non-diabetic HIV-infected patients receiving suppressive cART including tenofovir disoproxil fumarate/emtricitabine plus one PI/r, who underwent a switch from the PI/r to raltegravir (group A) or dolutegravir (group B), were enrolled in the study. Serum levels of insulin, leptin and the homeostasis model assessment of insulin resistance (HOMA) index were evaluated during a 12 month follow-up. RESULTS Overall, 86 patients were enrolled: 45 patients were included in group A and 41 were included in group B. The mean age was 45.7 years and 74 (86%) patients were male. After 12 months of follow-up, a significant reduction in the mean concentration of leptin and insulin was reported both in group A [-0.61 ng/mL (P

Background: Nucleoside reverse transcriptase inhibitor (NRTI)-sparing antiretroviral therapies may be useful in HIV-infected patients with resistance or intolerance to this class. Methods: We performed an observational study of patients on suppressive antiretroviral therapy containing two NRTIs plus one ritonavir-boosted protease inhibitor who switched to a dual regimen containing raltegravir (400 mg twice daily) and darunavir/ritonavir (800/100 mg once daily) and were followed-up for 48 weeks. Results: As a whole, 82 patients were enrolled. Mean duration of current regimen was 4.6 years and mean duration of plasma HIV RNA < 50 copies/mL before the switch was 46.2 months. Reason for simplification was toxicity in 76 patients and resistance to NRTIs in 13. After switching, the percentage of patients with HIV RNA < 50 copies/mL at week 48 was 92.7% in the intent-to-treat-exposed analysis and 97.6% in the per-protocol analysis. The switch led to a significant reduction in the mean triglyceride value (-85.2 mg/dL), in the prevalence of tubular proteinuria (-56%) and in the mean level of interleukin-6 (-0.94 pg/mL), with a significant increase in the mean phosphoremia (+0.58 mg/dL). Mean trough concentrations of both raltegravir and darunavir were within the therapeutic range. Two patients (2.4%) had virological failure due to suboptimal adherence and 4 subjects (4.9%) discontinued treatment due to adverse events, but no patients experienced Grade 3 or 4 adverse events. Conclusion: In our study, simplification to a dual therapy containing raltegravir plus darunavir/ritonavir after 48 weeks maintained viral suppression in more than 90% of patients and showed a good tolerability with a favourable effect on proteinuria, ipophosphoremia, and lipid metabolism.

Simulation-based approaches to disease progression allow us to make counterfactual predictions about the effects of an untried series of treatment choices. However, building accurate simulators of disease progression is challenging, limiting the utility of these approaches for real world treatment planning. In this work, we present a novel simulation-based reinforcement learning approach that mixes between models and kernel-based approaches to make its forward predictions. On two real world tasks, managing sepsis and treating HIV, we demonstrate that our approach both learns state-of-the-art treatment policies and can make accurate forward predictions about the effects of treatments on unseen patients.

Background: The ritonavir-boosted protease inhibitor (PI/r)-based dual regimens are warranted in order to optimize the combination antiretroviral therapy (cART), prevent the long-term toxicity and reduce the cost of treatments. Methods: We performed an observational, retrospective study of HIV-infected patients on suppressive antiretroviral therapy who switched to a dual regimen containing lamivudine (3TC) plus darunavir/ritonavir (DRV/r) 800/100 mg qd or atazanavir/ritonavir (ATV/r) 300/100 mg qd. Results: As a whole, 122 well-treated patients (mean age, 45.2 years; mean CD4 T + lymphocyte count, 589 cells/mm3; mean duration of current cART, 3.1 years) were enrolled. Current antiretroviral regimen included tenofovir/emtricitabine in 91 subjects, abacavir/lamivudine in 25, lopinavir/r in 41, DRV/r in 38 and ATV/r in 33. Baseline mean estimated glomerular filtration rate (eGFR) was 94.2 mL/min/1.73 m2, and proteinuria was detected in 46 subjects (38%). Overall 70 subjects switched to 3TC + DRV/r (group A) and 52 to 3TC + ATV/r (group B). After 12 months, 65 patients (92.8%) in group A and 46 (88.4%) in group B showed HIV RNA 

Background: Persistent residual viremia (RV) and low grade inflammation and immune activation have been associated with non-AIDS defining events. The impact of persistent RV and HIV-DNA load on immune activation/inflammation remains unclear. The purpose of this study was to gain new insights into the relation between viremia, markers of inflammation and HIV-DNA levels. Methods: Three hundred and twenty-one HIV-infected patients were studied. A retrospective analysis of viremia values, prospectively collected for 48 months, was performed. Patients were separated into three groups: 113 TND (Target Not Detected, patients with sustained undetectable viremia); 113 RV (Residual Viremia, patients who had at least three detectable viral load (VL) values 37 but

Objectives: An observational, prospective, cohort study was performed to compare efficacy and safety of a switch from ritonavir-boosted protease inhibitor (PI/r) to nevirapine or raltegravir with that of rosuvastatin addition to current antiretroviral therapy in HIV-infected patients with hyperlipidaemia. Methods: All HIV-infected patients receiving a stable PI/r-based antiretroviral regimen, with persistently suppressed viremia, naïve to non-nucleoside analogues and to integrase strand transfer inhibitors, with mixed hyperlipidaemia, and who underwent a switch from PI/r to nevirapine (Group A) or raltegravir (Group B) or who started rosuvastatin at 10 mg daily (group C) with unchanged antiretroviral regimen were enrolled into the study. Results: Overall, 136 patients were enrolled: 43 patients were included in the group A, 46 in the group B, and 47 in the group C. The mean age was 46.6 years, and 108 (79.4%) were males. After 48 weeks of follow-up, a significantly greater reduction in the mean low-density lipoprotein (LDL) cholesterol level was reported in group C (-28.2%) than in group A (−10.2%; p

Background and aims HIV‐1 RNA viral load (VL) in plasma samples of HIV‐1–positive patients is used to assess the level of viral replication, the risk of disease progression, and the response and efficacy to antiretroviral treatment. Knowing the performance of different tests for HIV‐1 RNA detection is, therefore, important for clinical care. This study compared the performance of the recently introduced Aptima HIV‐1 Quant Dx assay (Hologic, Inc) and the standard COBAS AmpliPrep/COBAS TaqMan HIV‐1 v2.0 Test (CAP/CTM2) (Roche Molecular System, Inc) for HIV‐1 RNA quantitation. Methods Assay performance was assessed using 335 clinical samples, a standard HIV‐1 low VL panel, and 2 diluted samples from well‐characterized patients infected with different HIV‐1 subtypes tested in 5 replicates over 3 days. All samples were tested on both assays to evaluate inter‐assay agreement, both qualitatively and quantitively. Altogether, we evaluated assay sensitivity, linearity, accuracy, precision, repeatability, and reproducibility. Results Assay agreement for qualitative results in 335 clinical samples was fair (80.6%). Correlation of quantitative assay results (n = 164) was excellent (R 2 = 0.97), with 96.3% of the results within the 95% limit of assay agreement (−0.42 to +0.86 log), and 98.8% within 1 log of each other. Aptima‐HIV‐1 yielded results, on average, 0.22 log higher than CAP/CTM2. Both assays accurately quantitated the HIV‐1 standard at low VL (R 2 ≥ 0.94), with all samples within 0.5 log of the target. Conclusion Aptima‐HIV‐1 assay demonstrated sensitivity, accuracy, reproducibility, and precision for the detection and quantitation of HIV‐1 RNA across a wide dynamic range of VLs. Its performance, together with full automation and high throughput, suggests that Aptima‐HIV‐1 could be a suitable assay for reliable monitoring of HIV‐1 VL in patients undergoing treatment.

Activation of interferon (IFN) mediated responses and the consequent expression of restriction factors (RFs) represent an early line of defense against HIV-1 infection. The levels of viral replication and the antiviral are among the determinants influencing RFs' expression pattern. A deeper understanding of the molecular mechanisms regulating RFs activity and their relationship with viral replication factors might lead to new therapeutic strategies based on the enhancement of immune response against the virus. The aim of this study is to perform a longitudinal evaluation of the variations in the levels of a group of selected RFs (APOBEC3G, BST2, TRIM5α, MX2, SAMHD1, SERINC3/5, IFI16 and STING) to determine the impact of cART on their expression in HIV-1 positive patients. Together with RFs expression, immunological and virological parameters (plasma HIV1-RNA load and total HIV1-DNA) were longitudinally evaluated in a cohorts fourteen HIV-1 cART na ve patients, who were evaluated at diagnosis (T0) and followed at 4 (T1) and 8 (T2) months after starting cART. Fourteen long-term treated patients who achieved sustained undetectable viremia for at least 2 years were also included in the study as a reference group. We observed a restoration of immunological conditions during cART, together with a progressive decrease of HIV1-RNA load, which became undetectable at 8 months after starting treatment. On the other hand, despite showing a trend towards decrease, total HIV1-DNA remained detectable after reaching viral suppression, similarly to what observed in long term treated patients. The expression of APOBEC3G, SAMHD1, BST2, IFI16, SERINC3, and SERINC5 was higher at the time of diagnosis and decreased significantly during therapy, reaching levels similar to the ones observed in virally suppressed patients. On the other hand, MX2 and TRIM5a high expression values up to T0, reaching lower levels immediately after the initiation of cART treatment. Correlation analysis showed a positive association between the expression levels of APOBEC3G, IFI16, MX2, SAMHD1, SERINC3 and TRIM5α with the HIV-1 viral load. On the contrary, no significant association was observed for BST2, SERINC5 and STING, even BST2 expression showed a tendency to correlate with viral load. We observed a tendency for a positive association of MX2, SAMHD1 and SERINC5 with the size of viral reservoir and a trend for a negative association for STING. STING appeared also as the only one factor whose expression correlates with the CD4 count and the CD4/CD8 ratio. Our data confirm the correlation between viral replication and expression of RFs, with, the levels of cellular defense proteins decreasing in parallel to the reduction of viral replication.

It is crucial to establish the timing of infection and distinguish between early and long-lasting HIV-1 infections not only for partner notification and epidemiological surveillance, but also to offer early drug treatment and contain the spread of infection. This study analyzed serum and/or plasma samples with a first positive HIV antibody/antigen result coming from different Medical Centers in the Emilia Romagna Region, North East Italy, using the avidity assay, Western Blotting, RNA viral load, CD4 cell counts and genotyping assay. From May 2013 to May 2016, we certified 845 new HIV-1 infections, 18.7% of which were classified on the basis of avidity index as recent infections and 81.3% as long-lasting infections, with an estimated conversion time exceeding six months at the time of study. Western Blotting showed reactivity to only one or two HIV-1 proteins in recently infected patients (RIPs), while a complete pattern to gag, env and pol proteins was observed in most long-lasting infected patients (LLIPs). The median age, gender, nationality and risk transmission factors were comparable in RIPs and LLIPs. Phylogenetic analysis performed in available plasma disclosed B strains, non-B subtypes and circulating recombinant forms (CRFs) in both groups of patients, with a major presence of CRFs in non-Italian HIV subjects. The large number of patients unaware of their HIV status makes it crucial to discover hidden epidemics and implement appropriate targeted public health interventions.