Introduction: HIV+ people carry a higher risk of developing lymphomas. Combined antiretroviral therapy (cART) improves survival, but HIV+ patients (pts) with lymphoma are still considered poorly treatable. Our aim was to describe biopathological features of a cohort of HIV+ pts affected by lymphoma and their clinical implications. Methods: we conducted a retrospective and prospective multicentre study collecting clinical and immunovirological data in HIV+ pts affected by non-Hodgkin lymphoma (NHL) from 2003 and 2017 in six centres in Northern Italy, to evaluate overall (OS) and progression-free survivals (PFS). We collected biopathological data in 50 NHLs to better define the differences in term of outcome among diffuse large B-cell lymphomas (DLBCL) not otherwise specified (NOS), DLBCL double/triple expressors (DE/TE) and high grade B-cell lymphomas (HGBL). Differences in survival were tested with χ2 or Mann-Withney tests. OS was estimated by Kaplan Meyer. Hazard ratios (HR) for mortality for each biopathological subtype were corrected for IPI score and T CD4+ lymphocyte count (CD4+) at diagnosis. Results: 127 pts were enrolled: 86 DLBCL, 18 Burkitt lymphomas (BL), 6 primary central nervous system lymphomas (PCNSL), 11 plasmablastic lymphomas (PBL), 3 primary effusive lymphomas (PEL) and 3 anaplastic large T-cell lymphoma (ALCL). Median age was 48.9 years. 30% of the pts were on cART at NHL diagnosis. The burden of disease was usually high at diagnosis. 80/127pts received R-CHOP and 40/127 pts R-DA-EPOCH or more intensive regimens. Median follow up is 28 months. 2-years OS and PFS were 69.3% and 61.3%, respectively. No differences in OS among different lymphoma subtypes were noted. We observed 33 progressions and 3 relapses after 1° line treatment (36/127, 28.3%). Factors significantly associated with a worse survival in multivariate analysis were Age, high IPI score and CD4+ < 200/μl at diagnosis. Pts with CD4+ < 200 cells/μl at diagnosis had a significantly higher HR for lymphoma-related deaths, especially those with a low disease burden (HR 4,136 if IPI ≤ 3). The use of cART at diagnosis had no impact on OS. The 50 pts screened for biopathological features resulted in 36 DLBCL NOS, 8 DLBCL DE/TE and 6 HGBL. HGBL showed a particularly high risk of poor response and early mortality as 6/6 pts died within 13 months, despite aggressive treatment schedules (Figure 1). Keywords: high-grade B-cell lymphoma with or without rearrangement of MYC and BCL2 and/or BCL6; human immunodeficiency virus (HIV).

Raltegravir (RAL) is the only licensed human immunodeficiency virus (HIV) integrase inhibitor. The factors associated with the virological response to RAL-containing regimens and the prevalence of integrase mutations associated with RAL failure deserve further investigation. From the Antiretroviral Resistance Cohort Analysis database, we selected triple-class-experienced subjects failing their current treatment with complete treatment history available. Selection criteria included HIV-RNA, CD4 count and HIV genotype within 3 months of RAL initiation. Factors associated with 24-week response were analysed; genotypic sensitivity scores (GSS) and weighted-GSS were evaluated. Virological response was achieved in 74.3% of 105 subjects. Mutations associated with RAL failure were detected in 12/24 subjects with an integrase genotype, with the prevalence of Q148H + G140S. Each extra unit of GSS (p 0.05, OR 2.62; 95% CI 1.00-6.87). was found to be a associated with response. Weighted-GSS had borderline statistical significance (p 0.063, OR 2.04; 95% CI 0.96-4.33) When stratifying for different cut-offs (<1 as reference, 1-1.49, ≥1.5), a borderline significant increase in the probability of response appeared for GSS ≥1.5 (p 0.053, OR 4.00; 95% CI 0.98-16.25). GSS ≥1 showed the highest sensitivity, 82.6%. Receiver operating characteristic curves depicted the widest area under the curve (0.663, p 0.054) of GSS ≥1. Unresponsiveness to RAL-containing regimens among triple-class-experienced subjects was low. The activity of the background regimen was strongly associated with response. Although few integrase genotypes were available at failure, half of these were without integrase resistance mutations. The substantial rate of RAL failure in the absence of known RAL-resistance mutations may be associated with adherence issues and this issue warrants further analysis in longer observations.

7-11 November 2010, Tenth International Congress on Drug Therapy in HIV Infection, Glasgow, UK 15-30% of HAART-treated HIV-1-positive patients (pts) lack CD4+ increase despite full HIV viremia suppression. The increased risk for INR to progress till AIDS led us to investigate maraviroc (MVC) as a tool to intensify HAART in terms of immunological recovery. Randomised, multicentre, proof-of-concept study enrolling 100 pts divided into 2 arms (1:1), A:HAART+MVC, B:HAART. Inclusion criteria were: CD4 count ≥200 cells/µL and/or a recovery of CD4 cells <25% compared to the HAART initiation and with a stable virologic suppression after 1 year of HAART. Ultrasensitive HIV-RNA was quantified via Amplicor HIV-1 Monitor Kit v1.5. Naive CD45RA+, memory CD45RA-, activated HLA-DR+CD38+, proliferating Ki67+, CD4+, CD8+ T-cells were measured by flow cytometry. T-test was used for intra and inter-group comparisons. 100 pts have been randomized 64 pts reached week(w) 12: 37 in A and 27 in B arms. At baseline (BL), CD4/CD8 and immune-phenotype were comparable in arm A and B. At w12 no significant changes in mean CD4 recovery (+41.9 vs +24.5/µL; p=.241) and a statistically significant change in mean CD8+ count (+164.2 vs -27.3/µL; p=.004) were observed between pts in arm A and B. At BL and w12 an immunological study was carried out in 24 pts (13:arm A, 11:arm B): at w12, while B pts experienced a contraction of naïve CD4 (81 to 67%; p=.02) and CD8 (81 to 77%; p=.04) with a parallel rise in memory CD4 (16 to 30%; p=.02) and CD8 (13 to 17%; p=.06), no significant loss of naive CD4 (70 to 57%; p=.18) and CD8 (69 to 66%; p=.42) was displayed by A pts with a tendency to higher gain in memory CD4 (24 to 40%; p=.06) and CD8 (11 to 25%; p=.008). By w12, a similar reduction in activated HLA-DR+CD38+ CD8 and CD4 was shown in B (p=.05) and A pts (p=.03 and p=.02 for CD8 and CD4). A trend to Ki67+CD8 reduction was shown in A (p=.06) and not in B pts (p=.45). HIV-RNA quantification evidenced a trend to higher median values (BL vs w12) in B pts: 2 vs 5 cp/mL (p=.37). MVC does not seem to increase CD4 amount at significant level compared to arm B. Treatment with MVC is associated with a significant CD8+ gain, a preservation of phenotypically naïve CD4+ and parallel rise of memory pool, suggesting a role of MVC in reducing peripheral antigen-driven T-cell death, possibly preserving new T-cell production. MVC is able to further reduce T-cell activation and proliferation, suggesting a possible influence in better controlling the pro-inflammatory status. We acknowledge the participation of all investigators of the HSL/MVC01/2008 Study Group (NCT00884858).

s ICAR 2010 Italian Conference on AIDS and Retroviruses

Objectives To evaluate whether etravirine (TMC125) might be effective in patients failing therapy with current nonnucleoside reverse transcriptase inhibitors (NNRTIs), we analysed the prevalence of TMC125 mutations and the possible determinants of genotypic resistance to this drug among sequences reported to a large database in Italy [Antiretroviral Resistance Cohort Analysis (ARCA)]. Methods We analysed the prevalence of TMC125 resistance‐associated mutations (RAMs) and the TMC125 weighted genotypic score (WGS) together with the determinants of genotypic resistance. A total of 5011 sequences from 2955 patients failing NNRTI therapy were evaluated. Results Among the sequences in ARCA, 68% had at least one and 9.8% at least three TMC125 RAMs, whereas 31% had a WGS>2. Frequent RAMs were Y181C, G190A, K101E and A98G, whereas V179F, Y181V and G190S appeared in <5% of sequences. Multivariate analysis revealed a higher risk of developing at least three TMC125 RAMs associated with both nevirapine and efavirenz exposure, whereas CD4 counts ≥200 cells/μL retained their protective effect. An increased risk of WGS>2 was linked to higher HIV RNA values (maximum risk at >5 log 10 copies/mL) and nevirapine exposure; CD4 counts ≥200 cells/μL were protective. Conclusions The prevalence of TMC125 resistance mutations in the ARCA cohort was 68%. The DUET studies showed that at least three TMC125‐associated mutations were required to impair the efficacy of the drug and Y181C/V, V179F and G190S had the greatest effect on response. The prevalence of these mutations among the patients examined in our study was low. However, WGS>2 was found for one‐third of our sequences. Previous nevirapine exposure was associated with an increased risk of having WGS>2 (adjusted odds ratio 1.76).

The aim of the study was to evaluate the cardiovascular risk factors associated with subclinical carotid atherosclerosis in antiretroviral therapy-naïve HIV-infected patients. The HERMES (HIV Exposure and Risk of Metabolic Syndrome) study enrolled therapy-naïve patients attending hospitals in the Italian coordination group for the study of allergies and HIV infection (CISAI [Coordinamento Italiano per lo Studio Allergia e Infezione da HIV]) in 2007. It was designed to identify metabolic syndrome (MS) and cardiovascular risk factors. The present analysis is a nested cross-sectional study with a subset of patients examined by carotid ultrasonography. Consecutive antiretroviral therapy-naïve HIV patients attending the facilities involved in the CISAI were included. Their 10-year probability of cardiovascular events was calculated using the Framingham Risk Score (FRS) and three other cardiovascular algorithms (the Global Framingham Risk Score - GFRS, 'Progetto Cuore' and 'SCORE'). Vascular age was estimated using a new model derived from GFRS and was compared with chronological age. The diagnosis of MS was based on the National Cholesterol Education Programme and International Diabetes Federation (IDF) definitions. Subclinical atherosclerosis was determined as ultrasound carotid intima-media thickness >0.9 mm. Out of 140 patients enrolled in the HERMES study by the four centres participating in the nested study, a total of 72 (51.4%) subjects, with no overt cardiovascular disease, were examined using carotid ultrasonography. The median age was 40 years, 79.2% men. The vascular age was 7.6 years higher than the chronological age. The factors associated with subclinical atherosclerosis were age (P < 0.0001), vascular age (P = 0.0002), body mass index (P = 0.003), waist circumference (P = 0.0002), MS (IDF definition, P = 0.004) and all the cardiovascular (CV) models (FRS, P = 0.01, GFRS, P = 0.002, Progetto Cuore, P = 0.018, SCORE, P = 0.03). Independent of other significant factors, waist circumference was significantly associated with pathological results (P = 0.007). The GFRS (area under the receiver-operating characteristic curves, 0.78; P < 0.001) had slightly better predictive accuracy than the other three CV models (FRS, areas under the curve [AUC] = 0.71, P = 0.003; Progetto Cuore, AUC = 0.74, P = 0.0005; SCORE, AUC = 0.77, P < 0.0001); 55% of patients at intermediate risk (6-20%) had subclinical carotid lesions. Subclinical carotid lesions had a highly significant direct association with all the CV risk predictors. The GFRS and vascular age were highly predictive. We recommend a carotid ultrasonographic examination at least among HIV patients with GFRS > or =6% or with an elevated waist circumference.

The Challenge of Immune Hyperactivation in HIV/AIDS: from Natural History to Therapeutic Approaches, with an educational contribution from Pfizer Italia s.r.l.Co-ordinator: G. Antonelli (Rome), G

Methods 20 virologically multifailed subjects received a new HAART regimen composed by two NRTI and DRV as boosted PI; 16/20 were under T20 treatment. Immunovirological response was determined through CD4+ cell counts and viral load (VL) detection. Genotypic analysis on HIV-RNA was performed from plasma samples at the baseline (BL) and on proviral DNA from PBMCs at different time points: BL, week 4, 12, 24, 36 and 48. HIV-RNA was extracted from patients with HIV-RNA >400 copies/ mL and processed by RT-PCR. Nested-PCR for all samples was carried out in order to sequence pol and env gene, proviral DNA was quantified by real-time PCR.