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Liver fibrosis is accelerated in human immunodeficiency virus/hepatitis C virus (HIV/HCV) coinfected compared with HCV monoinfected patients, due to multiple cofactors. Recently, HLA-B18 haplotype has been associated with short-term liver disease progression in this population. Our aim was to assess the influence of HLA-B18 on the fibrosis process in HIV/HCV coinfected individuals, untreated for HCV, during a long-term follow-up. All consecutive HIV/HCV co-infectedcoinfected patients followed in our center, with positive HCV-RNA and available human leukocyte antigen (HLA) haplotypes (determined by sequence-specific oligonucleotide primed polymerase chain reaction and simple sequence repeats polymerase chain reaction using Luminex Technology) were included. Liver fibrosis progression was assessed by means of fibrosis-4 index for liver fibrosis (FIB-4) and AST to platelet ratio index. The association between FIB-4 score over time and laboratory and clinical parameters, including HLA, was evaluated by univariate and multivariate multilevel generalized linear models. A total of 29 out of 148 screened patients were excluded because of spontaneous HCV clearance (27% were HLA-B18+). Among the remaining 119 individuals (82% males; median age at first visit = 30 years [interquartile range, IQR, 26-35]; median follow-up = 21.5 years [IQR, 15-25]), 26% were HLA-B18+. No baseline differences were evidenced between HLA-B18+ and B18- patients. Fibrosis progression was significantly faster in HLA-B18+ than in HLA-B18- patients ( P < 0.001) (Figure 1). At univariate analysis, age ( P < 0.001), HLA-B18 haplotype ( P = 0.02) and HIV-RNA viral load overtime ( P < 0.001) were associated with liver disease progression. At multivariate analysis, only age ( P < 0.001) remained independently associated with liver fibrosis progression. Our data suggest a possible association between HLA-B18 and an accelerated liver fibrosis in HIV/HCV coinfected with a long-term follow-up., (© 2018 Wiley Periodicals, Inc.)

Background and Objectives: We aimed to investigate to what extent a first-line DTG-based ART regimen reduces HIV-RNA in semen compared to plasma., Study Design: In this prospective, observational study, ART-naïve, HIV-infected males starting their first ART regimen with DTG plus TDF/FTC or ABC/3TC were enrolled. Paired blood (BP) and seminal plasma (SP) samples were collected at baseline (T0) and at week-2/4/12/24 after ART initiation. Sexually transmitted infections (STI) were ruled out before enrolment., Results: Median baseline HIV-RNA levels were lower in SP compared to BP (657 versus 38.200 copies/ml, p < 0.001), three subjects had undetectable semen HIV-RNA. After 12 weeks of treatment, HIV-RNA was below the quantification limit in both BP and SP of 11 pts (61.1%). Discordant results were obtained in 6 subjects (33.3%), showing quantifiable HIV-RNA in blood only (2 cases) and in semen only (4 cases). Finally, one subject had a positive HIV-RNA in SP/BP. At W24, only in 2/16 subjects (12.5%) HIV-RNA was detectable in semen, while in the others it was negative on SP/BP. No concurrent STI was found in subjects with detectable VL in semen., Conclusions: DTG demonstrated effectiveness in reducing VL with different kinetics in blood and semen, despite seminal viral suppression after 6 months of ART was not obtained in the totality of subjects., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Direct-acting antiviral (DAA)-based treatment of hepatitis C virus (HCV) has been associated with high sustained virological response (SVR) rates and good tolerability in randomized clinical trials. This study was performed to assess the safety and effectiveness of DAAs in both HCV mono-infected and HIV/HCV co-infected patients., Methods: All consecutive HCV-infected patients, including HIV/HCV co-infected patients, receiving DAA-based treatment from February 2015 to September 2016 at the study clinic were included. Clinical, virological, and biochemical data were retrieved. The primary end-point was the SVR12 (HCV RNA undetectable 12 weeks after the end of treatment) is commonly used worldwide. The secondary end-point was the safety profile of DAAs during the treatment period., Results: A total of 382 patients were included; 62 were HIV/HCV co-infected. Cirrhosis was found in 256 patients (67.4%). SVR12 was achieved in 365/382 (95.5%) individuals (58/62 HIV/HCV co-infected, 93.5%) in the intention-to-treat (ITT) analysis. A platelet count <90×10 9 /l (odds ratio (OR) 4.12, 95% confidence interval (CI) 1.5-11.3, p=0.006), HCV genotype 3 infection (OR 5.49, 95% CI 1.9-15.7, p=0.002), liver stiffness >20kPa (OR 3.05, 95% CI 1.03-8.96, p=0.04), and Model for End-Stage Liver Disease (MELD) score >10 (OR 5.27, 95% CI 1.16-23.8, p=0.03) were associated with lower SVR rates. On multivariate analysis, only genotype 3 infection remained a negative predictor of SVR (OR 21.6, 95% CI 3.81-123, p=0.001). Treatment discontinuation was observed in 10 subjects. Severe adverse events (SAEs) occurred in 17 patients (4.5%)., Conclusions: High SVR12 rates were observed in both HCV mono-infected and HIV/HCV co-infected individuals. Overall, DAA-based treatment was safe and there were no differences in terms of SAEs and treatment discontinuation between the two groups., (Copyright © 2017 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background and Aims: PREVALEAT (PREmature VAscular LEsions and Antiretroviral Therapy) II is a multicenter, longitudinal cohort study aimed at the evaluation of cardiovascular risk among advanced HIV-positive, treatment-naïve patients starting their first therapy. We hypothesized that these patients, present a higher cardiovascular (CV) risk., Methods: The study included all consecutive naïve patients with less than 200 CD4 cells/ml starting antiretroviral therapy. Our primary objective was to evaluate changes in carotid intima- media thickness (IMT). Secondary endpoints included changes in flow mediated vasodilation (FMD), inflammatory markers, triglycerides and cholesterol. Patients were evaluated at time 0, and after 3, 6 and 12 months., Results: We enrolled 119 patients, stratified into three different groups: patients receiving atazanavir/ritonavir boosted (ATV/r) based regimens, efavirenz (EFV) based regimens and darunavir/ritonavir boosted (DRV/r) based regimens. At baseline, advanced naïve patients showed a relevant deterioration of CV conditions in terms of traditional CV risk factors, endothelial dysfunction and serum biomarkers. During the 12-month follow up period, mean blood lipids significantly increased: total cholesterol from 159 to 190 mg/dL, HDL-C from 31 to 41 mg/dL, and LDL-C from 99 to 117 mg/dL. D-dimers steadily decreased (median level 624 at baseline and 214 at T3), whereas ICAM and VCAM consistently raised. DRV/r and ATV/r determined a more marked decrease of D-dimers as compared to EFV. Regarding the epi-aortic changes (IMT >1 mm or presence of atherosclerotic plaques), patients in the DRV/r group were at risk of developing pathological IMT during the study (OR 6.0, 95% CI 0.9-36.9), as compared to EFV ones., Conclusions: CV risk was elevated in advanced naïve patients and tended to remain high in the first year of therapy., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Several studies have demonstrated the efficacy of the oral pre-exposure prophylaxis (PrEP) with tenofovir (with or without emtricitabine) on preventing HIV-negative partners of HIV infected patients to become infected through sexual contacts. PrEP is already available in the United States and now is approved by European Medicine Agency. In this setting we would like to gauge physicians' knowledge, acquaintance with and attitude to include PrEP in their clinical practice. A cross sectional survey was conducted among Italian physicians expert on antiretroviral therapy. Out of 146 physicians, 35% of participants declared to be familiar with PrEP but only 46% of them believed that, currently, there are not enough reasons to make it available in Italy. 51% of physicians have already been attracted to prescribe it and 63.4% have been openly asked about PrEP. The main concerns noticed were: the risk of acquire other sexual transmitted diseases (STDs) (70% of physicians feared that PrEP could favor STDs spread), the potential harmful of PrEP if not adequately implemented and, especially the risk of possible side effects if not properly used. Nevertheless, 55.9% of participants believed that Health Authorities face an ethical obligation to make PrEP available as part of the strategies to protect from HIV transmission and half of the respondents asked for further researches to better define the role for PrEP. Attitudes regarding PrEP impact on Italian National Health Organization were also very interesting: 57.5% of participants did not believe that investing in PrEP would be an appropriate use of healthcare resources, while 70.6% affirmed that PrEP's financial coverage should not be funded by the Italian National System of Health (SSN). This survey showed a high awareness of PrEP potential among Italian physicians coupled with a great deal of skepticism about how and if implementing it in clinical practice.

Background: Atazanavir (ATV) not boosted by ritonavir (uATV) has been frequently used in the past for switching combination antiretroviral therapy (cART). However, the clinical outcomes and predictors of such strategy are unknown., Methods: An observational study was carried out on the Italian MASTER, selecting HIV infected patients on cART switching to an uATV-containing regimen. Baseline was set as the last visit before uATV initiation. In the primary analysis, a composite clinical end-point was defined as the first occurring of any condition among: liver, cardiovascular, kidney, diabetes, non AIDS related cancer or death events. Incidence of AIDS events and incidence of composite clinical end-point were estimated. Kaplan-Meier and multivariable Cox regression analysis were used to assess predictors of the composite clinical end-point., Results: 436 patients were observed. The majority of patients were males (61.5%) and Italians (85.3%), mean age was 42.7 years (IQR: 37.7-42), the most frequent route of transmission was heterosexual intercourse (47%), followed by injection drug use (25%) and homosexual contact (24%); the rate of HCV-Ab positivity was 16.3%. Patients were observed for a median time of 882 days (IQR: 252-1,769) under uATV. We recorded 93 clinical events (3 cardiovascular events, 20 kidney diseases, 33 liver diseases, 9 non AIDS related cancers, 21 diabetes, 7 AIDS events), and 19 deaths, accounting for an incidence of 3.7 (composite) events per 100 PYFU. At multivariable analysis, factors associated with the composite clinical end-point were intravenous drug use as risk factor for HIV acquisition vs. heterosexual intercourses [HR: 2.608, 95% CI 1.31-5.19, p = 0.0063], HIV RNA per Log 10 copies/ml higher [HR: 1.612, 95% CI 1.278-2.034, p < 0.0001], number of switches in the nucleoside/nucleotide (NRTI) backbone of cART (performed to compose the uATV regimen under study or occurred in the past) per each more [HR: 1.085, 95% CI 1.025-1.15, p = 0.0051], Fib-4 score per unit higher [HR: 1.03, 95% CI 1.018-1.043, p < 0.0001] and Neutrophil/lymphocytes ratio (NLR inflammation score) per Log 10 higher [HR: 1.319, 95% CI 1.047-1.662, p = 0.0188]., Conclusions: Intravenous drug users with high HIV RNA, high Fib-4 levels and more heavily exposed to antiretroviral drugs appeared to be more at risk of clinical events. Interestingly, high levels of inflammation measured through NLR, were also associated with clinical events. So, these patients should be monitored more strictly.

Background: Two biomarkers, the neutrophil to lymphocyte ratio (NLR) and platelet to lymphocyte ratio (PLR), have been shown to be indicative of systemic inflammation and predictive of mortality in general population. We aimed to assess the association of NLR and PLR, with risk of death in HIV-infected subjects when also taking account of HIV-related factors., Methods: We conducted a multicenter Italian cohort study from 2000 to 2012 including HIV-infected subjects naïve at antiretroviral treatment. The associations of NLR and PLR with all-cause mortality were tested by univariate and multivariate analyses using both time independent and dependent Cox proportional hazard models. We also fitted models with a cubic-spline for PLR and NLR to evaluate the possible non-linear relationship between biomarkers values and risk of death., Results: Eight-thousand and two hundred thirty patients (73.1% males) with a mean age of 38.4 years (SD 10.1) were enrolled. During a median follow-up of 3.9 years, 539 patients died. PLR < 100 and ≥ 200, as compared to PLR of 100-200, and NLR ≥ 2, as compared to < 2, were associated with risk of death at both univariate and multivariate analyses. Using multivariate models with restricted cubic-splines, we found a linear relationship of increasing risk of death with increasing values for NRL over 1.1, and an U-shape curve for PLR, with higher mortality risk for values higher or lower than 120., Conclusions: Our data suggest that NLR and PLR can reflect the severity of the underlying systemic disturbance of the inflammatory process and coagulation leading to augmented mortality in HIV positive subjects.

The combination of sofosbuvir and simeprevir ± ribavirin (SOF + SMV ± RBV) for hepatitis C virus (HCV) treatment has been associated with high rates of sustained virological response (SVR). Few data are available regarding this regimen in HIV/HCV co-infected patients. This study evaluated the effectiveness and safety of a 12-week course of SOF + SMV ± RBV in a cohort of HCV monoinfected and HIV/HCV co-infected individuals. HCV-infected patients, with or without HIV infection, receiving a 12-week course of SOF + SMV ± RBV in four Italian centres from February to October 2015, were included in this retrospective observational study. Clinical and biochemical data were retrieved for all patients. A total of 88 individuals were evaluated: 29 (33.0%) HIV/HCV co-infected and 59 (67.0%) monoinfected. Most patients were males with HCV genotype 1b (62.5%) and 1a (25%) infection. RBV was used in 41 HCV monoinfected and 6 HIV/HCV co-infected patients. Cirrhosis was found in 67 patients (76.1%). The most common adverse events (AEs) were rash and/or pruritus (23.9%), fatigue (13.6%) and anaemia (9.1%). Serious AEs occurred in three patients (3.4%). No treatment discontinuations were observed. RBV use was associated with multiple AEs (P = 0.02). An overall SVR12 of 93.2% was achieved; 96.6% in HCV monoinfected and 86.2% in HIV/HCV co-infected individuals, without significance both in univariate (P = 0.09) and multivariate analyses (P = 0.12). A baseline platelet count ≥90 000/mm 3 was associated with higher rates of SVR (P = 0.005). A 12-week course of SOF + SMV ± RBV was associated with good safety and high SVR12 rate both in HCV monoinfected and HIV-HCV co-infected individuals., (Copyright © 2017 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.)

Aim: To evaluate, in human immunodeficiency virus-hepatitis C virus co-infected patients, the impact of C-C chemokine receptor type 5 (CCR5) antagonist maraviroc-based antiretroviral therapy on the carotid intima media thickness and on atheromasic plaques., Patients and Methods: In this pilot prospective study, 12 HIV-HCV co-infected patients underwent color-Doppler ultrasonography before and 48 weeks after switching to a dual therapy based on maraviroc plus protease inhibitors boosted with ritonavir. Changes of intima media thickness, inflammatory and endothelial adhesion biomarkers levels, Veterans Aging Cohort Study index and Framingham risk score were evaluated., Results: At baseline 11 (91.6%) patients showed pathological ultrasonographic findings. After 48 weeks, two patients showed an amelioration of intima media thickness. Of the remaining patients with plaques, four showed a reduction of the previously diagnosed plaque; no patients worsened., Conclusion: Our data suggest that CCR5 inhibition could reduce the development of atherosclerosis especially in the non-calcific stage and could play an important role in the blockade of atheromasic plaque progression., (Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

There is limited information on the variations of HIV-1 DNA mutation profile in reverse transcriptase (RT) and protease (PR) genes during suppressive antiretroviral treatment (plasma HIV-1 RNA continuously <50 copies/ml) with raltegravir (RAL)-based regimens in patients with baseline RT/PR resistant HIV. Twelve multidrug resistant (RT: 12/12, PR: 8/12) HIV-infected patients were followed during effectively suppressive RAL-based therapy. Total and integrated HIV-1 DNA were assessed by real time PCR at baseline and every 6 months. Ultrasensitive (threshold: 2.5 copies/ml) plasma HIV-1 RNA and genotypic analysis of RT and PR in proviral DNA were performed at baseline and at 24 months. Half of the patients had full viral suppression (plasma HIV-RNA < 2.5 copies/ml) at month 12. Total HIV-1 DNA declined significantly after 12 months of therapy (from 249.2 to 145.7 copies/10 6 cells, P = 0.023), and remained stable until 24 months, when total HIV-1 DNA levels raised, concomitantly with a less stringent suppression of HIV-1 RNA (81.8% of patients with >2.5 copies/ml). Integrated HIV-1 DNA did not show fluctuations during the study period. Sequencing of the PR and RT regions from HIV-1 DNA revealed changes in the resistance mutation profile in five patients. Total HIV-1 DNA declined after the introduction of RAL-based therapy, with a rebound after 2 years. No changes were observed in levels of integrated DNA, suggesting limited effect on archived HIV. The RT and PR sequence changes in archived HIV-1 DNA suggest that variation of the mutation profile can occur even in the absence of detectable HIV-1 RNA. J. Med. Virol. 88:2115-2124, 2016. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Background: Tenofovir (TDF) can cause kidney injury through tubular dysfunction, with or without drop of estimated glomerular filtration rate (eGFR). Whether mild eGFR reductions during treatment should be considered a reason for prompt TDF discontinuation, however, remains unclear., Methods: Patients with normal pre-TDF eGFR levels, who had developed mild renal impairment (i.e., two consecutive eGFR results between 89-60 ml/min) on TDF, were observed until onset of chronic kidney disease (CKD), defined as two eGFR<60 ml/min 3 to 6 months apart. Multivariable Poisson regression analysis was used to investigate whether outcome was associated with current and cumulative use of TDF (modeled as time-varying covariates)., Results: 2023 (29%) out of 6984 patients developed mild renal impairment on TDF. Among them, 191 progressed to CKD. The incidence of CKD did not significantly differ during TDF treatment (2.6 per 100 PYFU; 95%CI 2.2-3.2) or after its discontinuation (2.2 per 100 PYFU; 95%CI 1.8-2.6). However, the rate of CKD was significantly higher among patients continuing with TDF treatment compared to those who had discontinued it within 6 months of occurrence of mild renal impairment (aIRR 4, 95%CI 2.4-6.8). In contrast, among patients who had maintained TDF >6 months despite mild renal impairment, current TDF use was not associated with a significantly higher rate of CKD. Other significant predictors of CKD were older age, intravenous drug use, diabetes, hypertension, lower pre-TDF eGFR, higher eGFR drop since TDF introduction and longer exposure to TDF., Conclusions: Prompt discontinuation of TDF among patients developing mild renal impairment may prevent further progression of renal damage., Competing Interests: GL received speaker or consultancy grants from Janssen-Cilag, Gilead and Bristol-Myers Squibb and travel grants from Bristol-Myers Squibb, ViiV and Gilead. FM has served as a consultant on advisory boards for Boehringer Ingelheim, Bristol-Myers Squibb, Gilead, GlaxoSmithKline, Tibotec; he has received lecture fees from Bristol-Myers Squibb, Gilead, GlaxoSmithKline, Merck Sharp and Dome, and has received research and educational grants from Boehringer Ingelheim, Bristol-Myers Squibb, GlaxoSmithKline, Jansen-Cilag and Roche. RC served as advisor for Gilead and Janssen-Cilag, received speakers’ honoraria from ViiV, Bristol-Myers Squibb, Merck Sharp and Dohme and Janssen-Cilag. NL is member of the advisory board of Abbvie. MdP is member of the advisory boards of Abbvie and Gilead and received speaker grants from Abbvie, Bristol-Myers Squibb and ViiV. SC has been an employee of Gilead between 2012 and 2013, received speaker or consultancy grants from BMS, Abbvie, Gilead and Merck and travel grants from Bristol-Myers Squibb and ViiV. CT is member of the advisory boards of Gilead and ViiV, received research grants from Gilead, speakers grants from Bristol-Myers Squibb, Gilead and ViiV and travel grants from Gilead. AG is member of the advisory boards of Gilead, ViiV, Bristol-Myers Squibb, Janssen-Cilag, Merck Sharp-Dome and Abbvie, received speaker grants from Gilead and travel grants from Gilead, ViiV, Bristol-Myers Squibb, Janssen-Cilag and Merck Sharp-Dome. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background: We aimed at evaluating frequency and factors associated with late presentation and advanced HIV disease and excess risk of death due to these conditions from 1985 to 2013 among naïve HIV infected patients enrolled in the Italian MASTER Cohort., Methods: All antiretroviral naive adults with available CD4+ T cell count after diagnosis of HIV infection were included. Multivariable logistic regression analysis investigated factors associated either with late presentation or advanced HIV disease. Probabilities of survival were estimated both at year-1 and at year-5 according to the Kaplan-Meier method. Flexible parametric models were used to evaluate changes in risk of death overtime according to late presentation and advanced HIV disease. The analyses were stratified for calendar periods., Results: 19,391 patients were included (54 % were late presenters and 37.6 % were advanced presenters). At multivariable analysis, the following factors were positively associated with late presentation: male gender (OR = 1.29), older age (≥55 years vs. <25 years; OR = 7.45), migration (OR = 1.54), and heterosexual risk factor for HIV acquisition (OR = 1.52) or IDU (OR = 1.27) compared to homosexual risk. Survival rates at year-5 increased steadily and reached 92.1 % for late presenters vs. 97.4 % for non-late presenters enrolled in the period 2004-2009. Using flexible parametric models we found a sustained reduction of hazard ratios over time for any cause deaths between late and non-late presenters over time. Similar results were found for advanced HIV disease., Conclusion: Screening polices need to be urgently implemented, particularly in most-at-risk categories for late presentation, such as migrants, older patients and those with heterosexual intercourse or IDU as risk factors for HIV acquisition. Although in recent years the impact of late presentation on survival decreased, about 10 % of patients diagnosed in more recent years remains at increased risk of death over a long-term follow-up.

Background: In HIV-HCV co-infected patients, the long-term effects of HCV eradication on HIV disease progression are still unclear., Objectives: This study aims to determine if CD4 and CD4/CD8 ratio slopes improved after anti-HCV treatment in patients achieving a sustained virological response (SVR)., Study Design: A total of 116 HIV-HCV co-infected patients, previously treated with Peg-IFN/RBV, were divided into two groups: SVR (55 patients who had achieved SVR), and non-SVR (61 patients). Retrospective data before and after anti-HCV therapy were obtained for all patients, with a median 8 year-follow-up. Multilevel mixed models were fitted to assess the trends over time of FIB-4 score, APRI score, CD4, CD8 cell count and CD4/CD8 ratio., Results: Median HIV-infection duration, HCV-RNA and GGT baseline levels were higher in non-SVR compared to the SVR group. A significantly decreased FIB-4 (p<0.001) and APRI trend (p<0.001) after SVR was observed in SVR patients compared to those non-SVR. After adjustment for HIV duration, there was no significant difference between the two groups for absolute CD4 (p=0.08) or percentage CD4 slope (p=0.6) over time. The CD4/CD8 ratio trend also demonstrated a similar progressive increase in both groups (p=0.2). During follow-up, six deaths were reported in the non-SVR group versus no death for the SVR group, while no difference in AIDS and non-AIDS events was observed., Conclusions: Achievement of SVR determines an important beneficial impact in terms of liver-related mortality and fibrosis regression, but does not seem to alter neither the slope of long term CD4 gain nor the CD4/CD8 ratio evolution in ART-treated HIV-HCV co-infected patients., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Background and Objectives: Renal toxicity due to tenofovir (TDF) has been largely described in patients with HIV infection. However, other antiretroviral drugs (such as atazanavir [ATV], especially when boosted by ritonavir, ATV/r) could perpetuate some degrees of renal impairment with or without TDF co-administration. Also, possible benefits of stopping TDF in patients without renal diseases is not well known. This study aimed at exploring evolution of renal function and lipid profile after switching from tenofovir/emtricitabine (TDF/FTC) to abacavir/lamivudine (ABC/3TC), maintaining the ATV/r component of the regimen., Methods: Patients in the Italian MASTER Cohort, who switched from TDF/FTC plus ATV/r to ABC/3TC plus ATV/r were included, provided that major renal diseases were not diagnosed before switching (i.e., baseline). Serum creatinine, estimated glomerular filtration rate (eGFR), total cholesterol, HDL and triglycerides were evaluated at baseline and at month 18 after switching., Results: 126 patients were selected (80% males). Patients were mostly Italians (92%). 79% had undetectable HIV-RNA and 44% were co-infected by HBV and/or HCV. Median age at switch was 47 years (IQR 43-55). A small but significant decrease in serum creatinine [from 1.06 mg/dl (SD: 0.3) to 0.94 mg/dl (SD: 0.2); p<0.001] with an improvement in eGFR [from 86.8 ml/min (SD: 33) to 96.4 ml/min (SD: 37); p<0.001] were observed in per protocol analysis at month 18. Also ITT analysis showed a decrease in mean serum creatinine [from 1.08 mg/dl (SD: 0.35) to 0.95 mg/dl (SD: 0.24); p<0.001] with an improvement in mean eGFR [from 86.9 ml/min/1.73m2 (SD: 24.11) to 95.8 ml/min/1.73m2 (SD: 19.99); p<0.001]. Total cholesterol increased [from 188 mg/dl (SD: 42) to 206 mg/dl (SD: 44); p<0.001] but also HDL increased as well [from 46 mg/dl (SD: 14) to 54 mg/dl (SD: 19); p=0.015]. An increase in triglycerides concentration was observed [from 162 mg/dl (SD: 144) to 214 mg/dl (SD: 109); p=0.027] in per protocol analysis. Also ITT analysis showed increases of both total cholesterol [from 187 mg/dl (SD: 43.69) to 203 mg/dl (SD: 44.10); p<0.001] and HDL fraction [from 46 mg/dl (SD: 15.49) to 52 mg/dl (SD: 17.13); p=0.002] at month 18., Conclusion: This analysis reports an improvement in eGFR and an increase in total cholesterol and HDL fraction at month 18 after switching to ABC/3TC plus ATV/r. Given the fact that renal function was not significantly affected at baseline, our findings may suggest the utility of a proactive switch from TDF to ABC, when otherwise indicated, in patients who cannot avoid using a nucleoside backbone.

Aim: The aim of the present study was the evaluation of liver fibrosis in a population of patients monoinfected with HIV using the transient liver elastography (FibroScan) method., Patients and Methods: A total of 228 consecutive patients with HIV were evaluated: 80 (35.09%) were HIV-1 monoinfected and 148 (64.91%) (HIV)/hepatitis C virus (HCV) co-infected. Echoic liver diagnosis was also performed., Results: F2 Metavir-score fibrosis or higher was found to be associated with drug addiction, alanine aminotransferase >80 UI/l, cluster of differentiation 4 (CD4(+)) T lymphocytes nadir <200 copies/ml, therapy duration, protease inhibitor (PI)-based antiretroviral regimen, HCV infection and AIDS diagnosis. Multivariate analysis highlighted a significant association with drug addiction, AIDS diagnosis, therapy duration and HCV co-infection. Echoic liver diagnosis showed signs of damage among 43.75% of monoinfected patients vs. 62.84% among co-infected., Conclusion: Monoinfected patients showed pathological signs both at liver ultrasonography and at FibroScan. In the onset of these changes, a significant role by HIV disease and duration of therapy is observed., (Copyright © 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Background: Recently, some systemic inflammation-based biomarkers have been demonstrated useful for predicting risk of death in patients with solid cancer independently of tumor characteristics. This study aimed to investigate the prognostic role of systemic inflammation-based biomarkers in HIV-infected patients with solid tumors and to propose a risk score for mortality in these subjects., Methods: Clinical and pathological data on solid AIDS-defining cancer (ADC) and non-AIDS-defining cancer (NADC), diagnosed between 1998 and 2012 in an Italian cohort, were analyzed. To evaluate the prognostic role of systemic inflammation- and nutrition-based markers, univariate and multivariable Cox regression models were applied. To compute the risk score equation, the patients were randomly assigned to a derivation and a validation sample., Results: A total of 573 patients (76.3% males) with a mean age of 46.2 years (SD = 10.3) were enrolled. 178 patients died during a median of 3.2 years of follow-up. For solid NADCs, elevated Glasgow Prognostic Score, modified Glasgow Prognostic Score, neutrophil/lymphocyte ratio, platelet/lymphocyte ratio, and Prognostic Nutritional Index were independently associated with risk of death; for solid ADCs, none of these markers was associated with risk of death. For solid NADCs, we computed a mortality risk score on the basis of age at cancer diagnosis, intravenous drug use, and Prognostic Nutritional Index. The areas under the receiver operating characteristic curve were 0.67 (95% confidence interval: 0.58 to 0.75) in the derivation sample and 0.66 (95% confidence interval: 0.54 to 0.79) in the validation sample., Conclusions: Inflammatory biomarkers were associated with risk of death in HIV-infected patients with solid NADCs but not with ADCs.

Background: The risk of liver enzyme elevation (LEE) after different ritonavir-boosted protease inhibitors (PI/r) has not been fully assessed in real-life settings and in populations with high rates of hepatitis C virus (HCV) coinfection., Methods: Patients introducing a new PI/r between 1998 and 2012 were included, if transaminases and HCV antibody (Ab) were assessed before treatment initiation. Time to grade 3 and 4 LEE were assessed using univariable and multivariable conditional Cox analyses, stratified by HCV serostatus., Results: A total of 6193 HIV-infected patients (3242 HCV-Ab negative and 2951 HCV-Ab positive) were included. Incidence of grade 3 LEE was 1.05, 7.66, and 8.08 per 100 patient-years of follow-up among HCV-Ab negative, HCV-Ab-positive and HCV-RNA-positive patients, respectively. Among HCV-Ab-negative patients, no differences were detected between different PI/r. Use of darunavir/ritonavir was not associated with LEE among HCV-coinfected patients. Atazanavir/ritonavir use was associated with grade 3 LEE but only among HCV-Ab-positive patients (versus LPV/r, hazard ratio: 1.39; 95% confidence interval: 1.1 to 1.75). This risk was not confirmed in a subanalysis restricted to HCV-RNA-positive patients (versus LPV/r, hazard ratio: 1.16; 95% confidence interval: 0.87 to 1.55). Other independent predictors of grade 3 LEE among HCV-Ab-positive patients were older age, male gender, being treatment naive, nonnucleoside reverse transcriptase inhibitor coadministration, increased aspartate aminotransferase at baseline, overweight, positive HCV-RNA, and advanced estimated liver fibrosis., Conclusions: Occurrence of hepatotoxicity was a rare finding among HCV-Ab-negative patients and was not influenced by the type of PI/r. In particular, the use of darunavir/ritonavir, previously linked with severe cases of hepatotoxicity, was not associated with a greater risk of LEE, irrespective from HCV serostatus.

Background: Immunological non-response (INR) despite virological suppression is associated with AIDS-defining events/death (ADE). Little is known about its association with serious non-AIDS-defining events (nADE)., Methods: Patients highly-active antiretroviral therapy (HAART) with <200 CD4+/μl and achieving HIV-RNA <50 copies/ml within 12 (±3) months were categorized as INR if CD4+ T-cell count at year 1 was <200/μl. Predictors of nADE (malignancies, severe infections, renal failure--ie, estimated glomerular filtration rate <30 ml/min, cardiovascular events and liver decompensation) were assessed using multivariable Cox models. Follow-up was right-censored in case of HAART discontinuation or confirmed HIV-RNA>50., Results: 1221 patients were observed for a median of 3 (IQR: 1.3-6.1) years. Pre-HAART CD4+ were 77/μl (IQR: 28-142) and 56% of patients had experienced an ADE. After 1 year, CD4+ increased to 286 (IQR: 197-387), but 26.1% of patients were INR. Thereafter, 86 nADE (30.2% malignancies, 27.9% infectious, 17.4% renal, 17.4% cardiovascular, 7% hepatic) were observed, accounting for an incidence of 1.83 events (95%CI: 1.73-2.61) per 100 PYFU. After adjusting for measurable confounders, INR had a significantly greater risk of nADE (HR 1.65; 95%CI: 1.06-2.56). Older age (per year, HR 1.03; 95%CI: 1.01-1.05), hepatitis C co-infection (HR 2.09; 95%CI: 1.19-3.7), a history of previous nADE (HR 2.16; 95%CI: 1.06-4.4) and the occurrence of ADE during the follow-up (HR 2.2; 95%CI: 1.15-4.21) were other independent predictors of newly diagnosed nADE., Conclusions: Patients failing to restore CD4+ to >200 cells/μl run a greater risk of serious nADE, which is intertwined or predicted by AIDS progression. Improved management of this fragile population and innovative therapy able to induce immune-reconstitution are urgently needed. Also, our results strengthen the importance of earlier diagnosis and HAART introduction.

Background: The systemic inflammatory response has been postulated as having prognostic significance in a wide range of different cancer types. We aimed to assess the prognostic role of inflammatory markers on survival in HIV-infected patients with Non-Hodgkin Lymphoma (NHL), and to compute a prognostic score based on inflammatory biomarkers., Methods: We evaluated data on HIV patients with NLH diagnosis between 1998 and 2012 in a HIV Italian Cohort. Using Cox proportional regression model, we assessed the prognostic role of Neutrophil-Lymphocyte Ratio (NLR), Platelet-Lymphocyte Ratio (PLR), Glasgow Prognostic Score (GPS), modified Glasgow Prognostic Score (mGPS), Prognostic Index (PI), and Prognostic Nutritional Index (PNI). We also computed a risk score equation, assigning patients to a derivation and a validation sample. The area under the curve (AUC) was use to evaluate the predictive ability of this score., Results: 215 non-Hodgkin lymphoma cases (80.0% males) with a mean age of 43.2 years were included. Deaths were observed in 98 (45.6%) patients during a median follow up of 5 years. GPS, mGPS, PI and PNI were independently associated with risk of death. We also computed a mortality risk score which included PNI and occurrence of an AIDS event within six months from NHL diagnosis. The AUCs were 0.69 (95% CI 0.58 to 0.81) and 0.69 (95% CI 0.57 to 0.81) at 3 and 5 years of the follow-up, respectively., Conclusions: GPS, mGPS, PI and PNI are independent prognostic factors for survival of HIV patients with NHL.

Background: We aimed to assess cancer incidence and mortality for all-causes and factors related to risk of death in an Italian cohort of HIV infected unselected patients as compared to the general population., Methods: We conducted a retrospective (1986-2012) cohort study on 16 268 HIV infected patients enrolled in the MASTER cohort. The standardized incidence ratios (SIRs) and standardized mortality ratios (SMRs) were computed using cancer incidence rates of Italian Cancer Registries and official national data for overall mortality. The risk factors for death from all causes were assessed using Poisson regression models., Results: 1,195 cancer cases were diagnosed from 1986 to 2012: 700 AIDS-defining-cancers (ADCs) and 495 non-AIDS-defining-cancers (NADCs). ADC incidence was much higher than the Italian population (SIR = 30.8, 95% confidence interval 27.9-34.0) whereas NADC incidence was similar to the general population (SIR = 0.9, 95% CI 0.8-1.1). The SMR for all causes was 11.6 (11.1-12.0) in the period, and it decreased over time, mainly after 1996, up to 3.53 (2.5-4.8) in 2012. Male gender, year of enrolment before 1993, older age at enrolment, intravenous drug use, low CD4 cell count, AIDS event, cancer occurrence and the absence of antiretroviral therapy were all associated independently with risk of death., Conclusions: In HIV infected patients, ADC but not NADC incidence rates were higher than the general population. Although overall mortality in HIV infected subjects decreased over time, it is about three-fold higher than the general population at present.

Single nucleotide polymorphisms (SNPs) rs12979860 and rs8099917 near the interleukin 28B gene are predictors of virological response (SVR) to IFN-based therapy for monoinfected chronic hepatitis C patients. We retrospectively evaluated the impact of IL28B SNPs and other factors on SVR in a cohort of 102 HIV-1/HCV-coinfected patients treated with pegylated interferon-? (peg-INF?) and ribavirin. Data on baseline features and virological response at different time-points were collected. Overall, 89/102 patients (87%) were males, 44 (43%) of whom infected with HCV genotype 1; SVR was achieved by 50 patients (49%). A univariate logistic regression analysis demonstrated that rs129679860 SNP genotype CC (p<0.034), rs8099917 SNP genotype TT (p<0.01), HCV genotype 2 or 3 (p<0.0001), low HCV viral load (p<0.028) and RVR (rapid virological response) (p<0.0001) were associated with a higher likelihood of SVR. Multivariate analysis confirmed only RVR and HCV genotype as independent predictors of SVR. In a real life setting, the importance of RVR and IL28B SNPs was confirmed as predictive of SVR to identify patients with a higher likelihood of SVR to Peg-INF?+RBV, and also to designate a deferred therapy for patients with a low likelihood of SVR for whom it is preferable to wait for more successful options.

Residual HIV viremia, defined by low levels of plasma HIV RNA with enhanced-sensitivity assays, may persist even in the presence of successful antiretroviral therapy, but little is known about its determinants. Our objective was to evaluate the rate and determinants of residual viremia in patients who show stable undetectable plasma HIV-1 RNA with conventional assays. Forty-four multidrug-experienced patients with undetectable levels of HIV RNA for at least 2 years under raltegravir-based regimens were evaluated. An ultrasensitive (2.5 copies/ml) real-time PCR method was used to quantify plasma HIV RNA. After 12 months of salvage treatment, 48.3% of the patients had residual viremia between 2.5 and 37 copies/ml. The proportion of patients with plasma HIV RNA below 2.5 copies/ml decreased from 51.7% at 12 months to 30.8% at 24 months. The presence of residual viremia was not associated with levels of viremia before starting raltegravir. Considering CD4 counts, hepatitis B or C virus (HBV or HCV) coinfection, or other demographic characteristics, for the time interval between HIV diagnosis and initiation of antiretroviral therapy, patients with a longer interval (>1 year) were significant less likely to have RNA levels below 2.5 copies/ml at 12 months compared to patients who started therapy within 1 year of HIV diagnosis (28.6% vs. 73.3%, p=0.027). Half of the patients showing undetectable HIV viremia with conventional assays had low-level viremia with ultrasensitive assays, with no predictive role of viroimmunological status at the start of the regimen. The potential influence of the interval between HIV diagnosis and initiation of treatment should be confirmed in subjects with a known date of seroconversion.

In HIV-infected patients a low CD4:CD8 ratio can persist despite CD4 recovery with long-term antiretroviral treatment (ART). As CD4:CD8 inversion is considered a marker of immune-senescence, we aimed to assess if it was associated with the chronic inflammation state in aging patients with HIV. A total of 112 patients with a >15 year history of HIV infection and ART were included, 85 of whom were suppressed. All subjects were tested for interleukin (IL)-6, high-sensitivity (hs)-PCR, and D-dimer levels. Complete clinical, therapeutic, and hematochemical data were retrieved. Coreceptor tropism based on HIV-DNA gp120 genotyping was also available within the past 6 months. A progressive increase in the CD4:CD8 ratio over time was observed without reaching a plateau. Based on the CD4:CD8 ratio at the time of testing, patients were classified into group A (normal ratio ≥0.9) and group B (<0.9). A normal ratio was observed in 37% of patients. Variables associated with an inverted CD4:CD8 ratio were older age, nadir CD4, and detectable HIV viremia. No association between HIV subtype, coreceptor tropism, cytomegalovirus (CMV), hepatitis B virus (HBV), and hepatitis C virus (HCV) coinfections and CD4:CD8 ratio was observed. Group B patients showed a trend for a higher frequency of diabetes and hypertriglyceridemia compared to group A patients, but they did not differ in IL-6, hs-PCR, and D-dimer levels or in frequency of severe non-AIDS-associated events. In conclusion, CD4:CD8 ratio normalization occurs rarely, even after several years of ART. Chronic inflammation in patients aging with HIV does not seem to be directly dependent on the CD4:CD8 ratio. However, the persistent immune dysregulation expressed by a CD4:CD8 inversion might be linked to a higher risk of non-AIDS events, especially metabolic disorders.

Introduction: PREVALEAT II (PREmature VAscular LEsions and Antiretroviral Therapy II) is an ongoing multicenter, longitudinal cohort study aimed to the evaluation of cardiovascular (CV) risk in advanced HIV-infected antiretroviral (ARV) naïve patients starting their first antiretroviral therapy (ART)., Patients and Methods: All consecutive naïve patients with CD4 cell count<200/mL starting any PI/r-based or NNRTI-based + 2 NRTIs regimen from January 2010 to January 2013 in the participant centres were enrolled. At baseline and after 3 (T1), 6 (T2) and 12 (T3) months patients were subjected to epi-aortic vessels ultrasonography and brachial artery flow mediated dilation (FMD). Viral load, CD4+ cell count, serum lipid values, serum glucose, endothelial activation (ICAM-1 and VCAM-1) and inflammatory markers (IL-6 and hsCRP) values were recorded at the same time. Data about independent risk factors for HIV infection and CV disease are taken at time 0. We enrolled 94 patients: 81% males, 87% caucasians, 40% smokers, 8.2% HCV co-infected and 3.5% with lipodystrophy; 33% of them were homosexuals, 12% drug addicts; 23% were AIDS at presentation. Statistical data analysis has been conducted by the χ(2) nonparametric method., Results: In Table 1 it is reported the percentage of patients with pathologic values, moreover, at T3, 60.46% showed undetectable viraemia and 69.77% had CD4 + > 200., Conclusions: Our data evidence at baseline has a relevant deterioration of CV conditions in terms of ultrasonographic data, FMD, inflammation and cytokine markers among advanced naïves. During follow-up epi-aortic lesions tend to worsen but not significantly, percentage of pathologic FMD remains stable. Regarding markers of endothelial activation ICAM-1 significantly worsens during the period of observation; also VCAM-1 has a trend towards the worsening while not significantly. Conversely, a significant improvement was observed for the markers of inflammation D-dimers and high sensitivity C-reactive protein (hsCRP). IL-6 improved but not significantly. Serum lipid profile shows an increase of HDLc and total cholesterol, but not of LDLc. In conclusion, after a twelve-month follow-up period, CV risk of the patients remains high. ARV therapy seems in fact to improve only non-specific and poor sensitive inflammation biomarkers and HDLc; markers of endothelial activations tend to worsen, intima-media ultrasonography and FMD do not show relevant modifications. Further data are warranted to better understand the role of the different ARV regimens.

Background: Health-related quality of life (HRQoL) has been recognized as a central measure of the overall health status in HIV patients. With the availability of different highly effective drug combinations, maximizing quality-adjusted survival has become a major target of HIV treatment. Although the association of HIV RNA and CD4 cell count with clinical HIV progression has been well established, the relation between these markers and HRQoL measures is still unclear., Method: This cross-sectional study investigated the relationship linking HIV RNA and CD4 to HRQoL measures in 181 triple-class-experienced patients with advanced HIV disease. The instrument used was the ISSQoL, a self-administered and HIV-specific HRQoL questionnaire., Results: Data showed no correlation between HRQoL measures and CD4 counts. Higher HIV RNA levels were, however, associated with poor HRQoL scores in 3 out of 9 scales of social functioning, depression and anxiety, and satisfaction with quality of life. In multivariable analyses, only the satisfaction with quality of life mean score remained significantly lower for the HIV RNA ≯100,000 copies/mL group compared to the HIV RNA 50 to 10,000 copies/mL group., Conclusions: Although other determinants of HRQoL in people with HIV should also be considered, this finding suggests a negative impact of high viral load on perceived HRQoL that adds to other described determinants of lower quality of life in people with HIV, such as lower social support and self-reported symptoms.

Background: Tat is a key HIV-1 virulence factor, which plays pivotal roles in virus gene expression, replication, transmission and disease progression. After release, extracellular Tat accumulates in tissues and exerts effects on both the virus and the immune system, promoting immune activation and virus spreading while disabling the host immune defense. In particular, Tat binds Env spikes on virus particles forming a virus entry complex, which favors infection of dendritic cells and efficient transmission to T cells via RGD-binding integrins. Tat also shields the CCR5-binding sites of Env rendering ineffective virus neutralization by anti-Env antibodies (Abs). This is reversed by the anti-Tat Abs present in natural infection or induced by vaccination., Findings: Here we present the results of a cohort study, showing that the presence of anti-Tat Abs in asymptomatic and treatment-naïve HIV-infected subjects is associated with containment of CD4+ T-cell loss and viral load and with a delay of disease progression. In fact, no subjects with high anti-Tat Ab titers initiated antiretroviral therapy during the three years of follow-up. In contrast, no significant effects were seen for anti-Env and anti-Gag Abs. The increase of anti-Env Ab titers was associated with a reduced risk of starting therapy only in the presence of anti-Tat Abs, suggesting an effect of combined anti-Tat and anti-Env Abs on the Tat/Env virus entry complex and on virus neutralization., Conclusions: Anti-Tat immunity may help delay HIV disease progression, thus, targeting Tat may offer a novel therapeutic intervention to postpone antiretroviral treatment or to increase its efficacy.

Objectives: We studied survival and associated risk factors in an Italian nationwide cohort of HIV-infected individuals after an AIDS-defining cancer (ADC) or non-AIDS-defining cancer (NADC) diagnosis in the modern cART era., Methods: Multi-center, retrospective, observational study of HIV patients included in the MASTER Italian Cohort with a cancer diagnosis from January 1998 to September 2012. Malignancies were divided into ADC or NADC on the basis of the Centre for Disease Control-1993 classification. Recurrence of cancer and metastases were excluded. Survivals were estimated according to the Kaplan-Meier method and compared according to the log-rank test. Statistically significant variables at univariate analysis were entered in a multivariate Cox regression model., Results: Eight hundred and sixty-six cancer diagnoses were recorded among 13,388 subjects in the MASTER Database after 1998: 435 (51%) were ADCs and 431 (49%) were NADCs. Survival was more favorable after an ADC diagnosis than a NADC diagnosis (10-year survival: 62.7%±2.9% vs. 46%±4.2%; p = 0.017). Non-Hodgkin lymphoma had lower survival rates than patients with Kaposi sarcoma or cervical cancer (10-year survival: 48.2%±4.3% vs. 72.8%±4.0% vs. 78.5%±9.9%; p<0.001). Regarding NADCs, breast cancer showed better survival (10-year survival: 65.1%±14%) than lung cancer (1-year survival: 28%±8.7%), liver cancer (5-year survival: 31.9%±6.4%) or Hodgkin lymphoma (10-year survival: 24.8%±11.2%). Lower CD4+ count and intravenous drug use were significantly associated with decreased survival after ADCs or NADCs diagnosis. Exposure to cART was found to be associated with prolonged survival only in the case of ADCs., Conclusions: cART has improved survival in patients with an ADC diagnosis, whereas the prognosis after a diagnosis of NADCs is poor. Low CD4+ counts and intravenous drug use are risk factors for survival following a diagnosis of ADCs and Hodgkin lymphoma in the NADC group.

Background: In HIV/HCV co-infected patients, HIV-1 gp120 activates human hepatic stellate cells (HSCs) which play a key role in fibrosis pathogenesis. It is still unclear whether pro-fibrogenic effects are more attributable to X4 or R5 strains in vivo., Objective: To assess if HIV-1 X4 or R5 variants are associated with a different progression of fibrosis., Study Design: A total of 105 HIV/HCV co-infected patients were submitted to gp120 sequencing on proviral DNA and classified as X4 or R5 based on g2p (20% false positive rate). The fibrosis evolution was retrospectively determined by means of APRI and FIB-4 scores at 3-month intervals from the first anti-HCV-positive test. The association of co-receptor tropism with increased fibrosis scores was evaluated by linear mixed models., Results: X4 variants were found in 41 patients (39%). The median observation period was similar in X4 and R5 patients (17 years). No difference was observed between the two groups of patients, except for nadir CD4 which was lower in X4 compared to R5 (percentage, p=0.005, and absolute number, p=0.005). X4 and R5 patients did not significantly differ for FIB-4 and APRI score over time (p=0.5, and p=0.1, respectively). No association between HCV-RNA levels over time and co-receptor tropism was noted (p=0.9). Conversely, a significant correlation of fibrosis scores with gamma-glutamyl transferase levels, lower current CD4 count, HIV viremia and use of antiretrovirals was observed., Conclusions: This retrospective analysis of fibrosis evolution did not support the evidence of a differing pro-fibrogenic activity for X4 and R5 HIV-1 variants in HIV/HCV co-infected patients., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Background: Co-receptor tropism (CRT) in patients with a long history of HIV-1 infection and antiretroviral treatment has been rarely investigated to date. The aim of this study was to determine the prevalence of X4 and R5 strains in patients with a >15-year follow-up and to investigate the demographical, viral, immunological, clinical and therapeutic determinants of CRT in this population. The possible influence of CRT on the inflammation state related to chronic HIV infection was also examined., Methods: A total of 118 HIV-1 infected patients with an initial HIV-1-positive test before 1997, and still on follow-up, were enrolled and consecutively submitted to blood sampling. Of these, 111 were on antiretroviral therapy and 89/111 (80.2%) had a plasma viral load (pVL) <25 copies/ml at testing. HIV-1 DNA was extracted and amplified from PBMCs for env gp120 sequencing. CRT was assigned by using geno2pheno and isolates were classified as X4 (FPR ≤20%) or R5 (FPR >20%). Level of serological inflammation biomarkers including IL-6, hsPCR, and D-dimers were measured., Results: An X4 virus was evidenced in HIV-1 proviral DNA of 50 patients (42%) while the remaining 68 patients were classified as R5. The median follow-up was 19 years (range 15-25). No association was observed between CRT and sex, age, nationality, subtype, HIV risk factor, HBV/HCV co-infection, baseline CD4+ cell count and pVL, overall duration of antiretroviral therapy, past exposure to mono-or dual therapies, and duration of NNRTI or PI-based therapy. The presence of an X4 strain was associated with CD4 nadir (p = 0.005), CD4 absolute count over time (p < 0.001), and cumulative positive (copy/years) viremia (p <0.001) during the whole patient history. No differences were found between R5 and X4 patients regarding inflammation marker levels including Il-6, hsPCR and D-dimers., Conclusions: An archived X4 virus was demonstrated in 42% of patients with a >15-year-history of HIV infection. This presence was clearly associated with a greater exposure to positive viremia and a poorer CD4 trend over time compared to R5, independent of type and duration of antiretroviral treatment. CRT does not seem to influence the inflammation rate of patients aging with HIV.

Background: The HIV integrase inhibitor raltegravir (RAL) can exacerbate autoimmune diseases in genetically predisposed mice. To evaluate whether this may occur in clinical practice, we clinically monitored HIV-positive patients treated with RAL and measured a panel of autoantibodies (auto-Abs) during the first year of RAL treatment., Methods: This was a longitudinal study in 109 antiretroviral-experienced patients who started a RAL-based regimen and were followed up for more than 2 years. A total of 45 patients were tested at baseline (before starting RAL) and after 12 months for the presence of the following auto-Abs: anti-nuclear antibodies, anti-double-stranded DNA, anti-smooth-muscle antibodies, anti-thyreoglobulin and anti-thyroid peroxidase antibodies, anti-cardiolipin immunoglobulin G and immunoglobulin M and anti-nuclear extractable antigens, including anti-SM ribonucleoprotein antigen, anti-Ro antigen and anti-La antigen., Results: A low rate of clinically relevant autoimmune diseases was observed at study entry (3/109; 2.8%; 95% CI 0.004, 0.059). No exacerbations were observed during follow-up. During the second year of RAL-based therapy a previously healthy patient developed psoriasis. At baseline, 17/45 (37.8%) patients tested for the presence of auto-Abs were positive. Most patients (n=13) were positive for anti-cardiolipin. After 12 months of RAL exposure, 9/45 patients were positive (20%; P=0.063). A positive correlation was found between HIV-1 RNA and anti-cardiolipin antibody concentration (P=0.010)., Conclusions: According to these results, RAL does not promote antibody-mediated immune disorders, at least not in the mid-term. A prolonged follow-up and an extension of the panel of auto-Abs are recommended to support these results.

Objectives: To define the impact of coinfection with hepatitis B virus (HBV) or hepatitis C virus (HCV) on viroimmunological response to raltegravir-based salvage regimens that also include new HIV inhibitors such as maraviroc, darunavir and etravirine., Methods: We used data from a national observational study of patients starting raltegravir-based regimens to compare virological suppression and CD4 cell change from baseline in patients with and without concomitant HBV or HCV infection., Results: Overall, 275 patients (107 coinfected and 168 non-coinfected) were evaluated. Coinfected patients were more commonly former intravenous drug users and had a longer history of HIV infection and higher baseline aminotransferase levels. Both HIV-RNA and CD4 response were similar in the two groups. Mean time to first HIV-RNA copy number <50 copies/mL was 4.1 months (95% CI 3.5-4.6) in non-coinfected patients and 3.9 months (95% CI 3.3-4.5) in coinfected patients (hazard ratio 1.039, 95% CI 0.761-1.418, P = 0.766, log-rank test). The risk of developing new grade 3-4 hepatic adverse events was significantly higher in coinfected patients (hazard ratio 1.779, 95% CI 1.123-2.817, P = 0.009). The two groups of coinfected and non-coinfected patients had similar rates of interruption of any baseline drug (hazard ratio 1.075, 95% CI 0.649-1.781, P = 0.776) and of raltegravir (hazard ratio 1.520, 95% CI 0.671-3.447, P = 0.311). Few AIDS-defining events and deaths occurred., Conclusions: Viroimmunological response to regimens based on raltegravir and other recent anti-HIV inhibitors is not negatively affected by coinfection with HBV or HCV. Liver toxicity, either pre-existing or new, is more common in coinfected patients, but with no increased risk of treatment interruption.

Objectives: The aim of the study was to investigate whether HIV diagnosis affected reproductive planning over time and to assess independent predictors of abortion overall and following HIV diagnosis., Methods: Donne con Infezione da HIV (DIDI) is an Italian multicentre study based on a questionnaire survey carried out in 585 HIV-positive women between November 2010 and February 2011. The incidence and predictors of abortion were measured by person-years analysis and Poisson regression., Results: The crude incidence rate of abortion was 18.8 [95% confidence interval (CI) 16.5-21.4] per 1000 person-years of follow-up (PYFU). Compared with women who terminated their pregnancy before HIV diagnosis, women who terminated their pregnancy after HIV diagnosis but before 1990 showed a 2.56-fold (95% CI 1.41-4.65) higher risk. During 1990-1999 and 2000-2010, HIV diagnosis was not significantly associated with outcome [adjusted rate ratio (ARR) 0.93 (95% CI 0.55-1.59) and ARR 0.69 (95% CI 0.32-1.48), respectively]. Age [ARR 0.96 (95% CI 0.94-0.99) per 1 year older] and injecting drug use [ARR 1.38 (95% CI 0.98-1.94)] were found to be predictors of abortion overall. After HIV diagnosis, being on combination antiretroviral therapy [ARR 0.54 (95% CI 0.28-1.02)], monthly income  < €800 [ARR 1.76 (95% CI 0.99-3.12)], younger age [ARR 0.95 (95% CI 0.91-1.00) per 1 year older] and fear of vertical transmission [ARR 1.95 (95% CI 1.04-3.67)] were found to be independently associated with abortion., Conclusions: We observed a higher incidence of abortion compared with data available for the general Italian population. Awareness of HIV diagnosis was predictive of abortion only in the 1980s. Women with HIV infection are still worried about vertical HIV transmission. Interventions promoting HIV screening among women who plan to have an abortion and informative counselling on motherhood planning in the setting of HIV care are needed., (© 2012 British HIV Association.)

Background: In Western Europe, a previously subtype B HIV-1 restricted area, BC recombinants have been rarely reported., Objective: To describe an outbreak of HIV-1 BC recombinants in southern Italy., Study Design: We analyzed pol (protease/reverse transcriptase) sequences from 135 newly diagnosed HIV-1-infected patients during the years 2009-2011. For phylogenetic relationships, sequences were aligned to the most recent reference data set from the Los Alamos database using BioEdit (version 7.1.3). The resulting alignment was analyzed with the Phylip package (version 3.67) building a neighbor-joining tree based on the Kimura two-parameter substitution model. The reliability of the tree topology was assessed through bootstrapping using 1000 replicates. The recombination pattern was characterized using SimPlot 3.5.1 and SplitsTree 4., Results: At phylogenetic analysis, 22 (16.2%) isolates whose sequences were not unequivocally assigned to a pure subtype or known CRF, formed a distinct monophyletic clade (100% of bootstrap value). For these isolates, the recombination analysis identified a BC mosaic pattern with two breakpoints at positions 2778±5 and 3162±8 (HXB2 numbering) which differed from those of known BC CRFs. All patients from whom these sequences were derived were highly educated youth Italians, 91% males and 82% MSM. Sequences of pol integrase, gp120 and gp41 from these same patients were classified as C subtype., Conclusions: This outbreak which further reflects the increasing heterogeneity of HIV epidemic in our country is the first report of an Italian outbreak of a BC recombinant, possibly a novel candidate CRF., (Copyright © 2012 Elsevier B.V. All rights reserved.)

We evaluated rates and determinants of virological failure in triple-class experienced patients receiving raltegravir-based regimens from a national observational study over 48 weeks, defined by any one of the following: (1) no HIV-RNA suppression to undetectable levels (<50 copies/mL) during follow-up; (2) detectable viral load after obtaining undetectable levels; and (3) leaving the study before 48 weeks. Among 101 eligible patients, 26 (25.7%; 95% CI 17.2-34.2) had virological failure. No significant differences between patients with and without virological failure were observed for gender, age, route of transmission, baseline CD4/HIV-RNA, CDC group, hepatitis B or C co-infections, resistance (based on the last genotype available), type and number of concomitant drug classes, concomitant use of darunavir, atazanavir, etravirine, enfuvirtide or maraviroc, and health-related quality-of-life measures. A high rate of treatment response was observed. The analyses did not identify any baseline factor associated with failure, including resistance status. Even if we cannot exclude the presence of pre-existing minority resistant variants not captured by genotypic tests, the lack of baseline predictors of failure suggests the need to monitor patients closely during follow up for other factors, such as potential drug interactions and reduced levels of adherence, which may favour virological failure.

Background: The aim of this study was to explore the effects of HCV co-infection on virological effectiveness and on CD4+ T-cell recovery in patients with an early and sustained virological response after HAART., Methods: We performed a longitudinal analysis of 3,262 patients from the MASTER cohort, who started HAART from 2000 to 2008. Patients were stratified into 6 groups by HCV status and type of anchor class. The early virological outcome was the achievement of HIV RNA <500 copies/ml 4-8 months after HAART initiation. Time to virological response was also evaluated by Kaplan-Meier analysis. The main outcome measure of early immunological response was the achievement of CD4+ T-cell increase by ≥100/mm3 from baseline to month 4-8 in virological responder patients. Late immunological outcome was absolute variation of CD4+ T-cell count with respect to baseline up to month 24. Multivariable analysis (ANCOVA) investigated predictors for this outcome., Results: The early virological response was higher in HCV Ab-negative than HCV Ab-positive patients prescribed PI/r (92.2% versus 88%; p = 0.01) or NNRTI (88.5% versus 84.7%; p = 0.06). HCV Ab-positive serostatus was a significant predictor of a delayed virological suppression independently from other variables, including types of anchor class. Reactivity for HCV antibodies was associated with a lower probability of obtaining ≥100/mm3 CD4+ increase within 8 months from HAART initiation in patients treated with PI/r (62.2% among HCV Ab-positive patients versus 70.9% among HCV Ab-negative patients; p = 0.003) and NNRTI (63.7% versus 74.7%; p < 0.001). Regarding late CD4+ increase, positive HCV Ab appeared to impair immune reconstitution in terms of absolute CD4+ T-cell count increase both in patients treated with PI/r (p = 0.013) and in those treated with NNRTI (p = 0.002). This was confirmed at a multivariable analysis up to 12 months of follow-up., Conclusions: In this large cohort, HCV Ab reactivity was associated with an inferior virological outcome and an independent association between HCV Ab-positivity and smaller CD4+ increase was evident up to 12 months of follow-up. Although the difference in CD4+ T-cell count was modest, a stricter follow-up and optimization of HAART strategy appear to be important in HIV patients co-infected by HCV. Moreover, our data support anti-HCV treatment leading to HCV eradication as a means to facilitate the achievement of the viro-immunological goals of HAART.

Objectives: To evaluate the evolution of HIV-1 coreceptor tropism in proviral DNA of patients during maraviroc-based therapy., Methods: Fourteen heavily high active antiretroviral therapy (HAART)-treated patients with a CCR5 Trofile profile were monitored over a 24 month period from the start of maraviroc therapy. Whole-blood samples were obtained at different timepoints, and coreceptor tropism was determined for proviral DNA from the V3-loop region sequence using the Geno2Pheno algorithm [false positive rate (FPR): 20%]., Results: At the start of maraviroc treatment, 13/14 patients were viraemic (median: 4.33 log copies/mL). Concordance in R5 tropism (R5/R5) was observed between circulating HIV-RNA (Trofile) and HIV-DNA provirus in 10/14 patients (median FPR = 54.0%), while 4 patients showed a CXCR4-tropic R5/X4 variant in their provirus (FPR: 5.8%, 5.7%, 16.6% and 1.1%, respectively). All R5/R5 patients showed a stable HIV-1 DNA coreceptor usage. Two out of four R5/X4 patients showed a tropism shift in their archived provirus and, after 6 months a prevalence of R5-tropic virus was detected in DNA. The other two R5/X4 patients harboured the 11/25 genotype, and maintained X4 tropism in provirus during the study. Virological response did not reveal differences in RNA decay and CD4+ cell recovery in patients with discordant tropism., Conclusions: A relatively good correlation between RNA and DNA tropism was observed at baseline. Proviral DNA tropism remained stable over 24 months of maraviroc-based therapy, indicating that determination of proviral DNA V3 sequence could be used in tropism prediction in clinical practice. The data also confirm the importance of the 11/25 rule in predicting viral tropism.

We evaluated factors associated with normalization of the absolute CD4+ T-cell counts, per cent CD4+ T cells and CD4+/CD8+ T-cell ratio. A multicentre observational study was carried out in patients with sustained HIV-RNA <50 copies/mL. Outcomes were: CD4-count >500/mm(3) and multiple T-cell marker recovery (MTMR), defined as CD4+ T cells >500/mm(3) plus%CD4 T cells >29%plus CD4+/CD8+ T-cell ratio >1. Kaplan-Meier survival analysis and Cox regression analyses to predict odds for achieving outcomes were performed. Three hundred and fifty-two patients were included and followed-up for a median of 4.1 (IQR 2.1-5.9) years, 270 (76.7%) achieving a CD4+ T-cell count >500 cells/mm(3) and 197 (56%) achieving MTMR. Using three separate Cox models for both outcomes we demonstrated that independent predictors were: both absolute CD4+ and CD8+ T-cell counts, %CD4+ T cells, a higher CD4+/CD8+ T-cell ratio, and age. A likelihood-ratio test showed significant improvements in fitness for the prediction of either CD4+ >500/mm(3) or MTMR by multivariable analysis when the other immune markers at baseline, besides the absolute CD4+ count alone, were considered. In addition to baseline absolute CD4+ T-cell counts, pretreatment %CD4+ T cells and the CD4+/CD8+ T-cell ratio influence recovery of T-cell markers, and their consideration should influence the decision to start antiretroviral therapy. However, owing to the small sample size, further studies are needed to confirm these results in relation to clinical endpoints., (© 2011 The Authors. Clinical Microbiology and Infection © 2011 European Society of Clinical Microbiology and Infectious Diseases.)

HIV coreceptor tropism (CTR) testing is a prerequisite for prescribing a coreceptor antagonist. CTR is increasingly deduced by analyzing the V3 loop sequence of gp120. We investigated the impact of mutations outside V3 on CTR as determined by the enhanced-sensitivity Trofile assay (ESTA). Paired ESTA and gp120 sequencing (population sequencing; from codon 32 of the conserved C1 to the variable V5 domains) were obtained from 60 antiretroviral treatment (ART)-naïve patients (15 with AIDS) infected with subtype B HIV-1. For gp120 sequence analysis, nucleotide mixtures were considered when the second highest electropherogram peak was >25%; sequences were translated into all possible permutations and classified as X4, dual/mixed (DM), and R5 based on coincident ESTA results. ESTA identified R5 and DM viruses in 72 and 28% of patients, respectively; no pure X4 was labeled. Forty percent of AIDS patients had R5 strains. Thirty-two positions, mostly outside V3, were significantly (P < 0.05) different between R5 and DM sequences. According to multivariate analysis, amino acid changes at 9 and 7 positions within the C1 to C4 and V1 to V5 regions, respectively, maintained a statistical significance, as did the net charge of V3 and C4. When analyzing only R5 sequences, 6 positions in the variable regions were found which, along with the V4 net charge, were significantly different for sequences from early- and end-stage disease patients. This study identifies specific amino acid changes outside V3 which contribute to CTR. Extending the analysis to include pure X4 and increasing the sample size would be desirable to define gp120 variables/changes which should be included in predictive algorithms.

Background: There is lack of data on the incidence of liver fibrosis (LF) progression in patients with human immunodeficiency virus (HIV) monoinfection and risk factors for LF., Methods: We performed an observational prospective study in a cohort of HIV-infected patients who had initiated highly active antiretroviral therapy (HAART). FIB-4 and aspartate aminotransferase (AST)-to-platelet ratio index (APRI) were assessed. The concordance between the 2 scores was assessed by weighted kappa coefficient. Kaplan-Meier analysis was used to estimate the incidence of LF. Cox regression analysis was used to assess the predictors of transition., Results: A total of 1112 patients were observed for a mean of 2249 days of follow-up. The concordance between FIB-4 and APRI was moderate (kappa = .573). The incidence of transition to higher FIB-4 classes was 0.064 (95% confidence interval [CI], 0.056-0.072) per person-year of follow-up (PYFU), whereas the incidence of transition to higher APRI classes was 0.099 (95% CI, 0.089-0.110) per PYFU. The incidence of transition to FIB-4 >3.25 was 0.013 per PYFU (95% CI, 0.010-0.017) and 0.018 per PYFU (95% CI, 0.014-0.022) for APRI >1.5. In multivariate analyses, for transition to higher classes, HIV RNA level <500 copies/mL was found to be protective for both scores, and higher CD4+ T cell count was found to be protective for FIB-4. Additional risk factors were age ≥ 40 years, male sex, intravenous drug use as an HIV infection risk factor, higher degree of LF, higher gamma-glutamyl transpeptidase (γGT) at baseline, and use of dideoxynucleoside-analogue drugs (DDX). Consistent results for the main study outcomes were obtained for confirmed LF transition and transition to FIB-4 > 3.25 and APR I> 1.5 as study outcomes., Conclusions: Overall, our results suggest a possible benefit associated with earlier HAART initiation, provided that the effectiveness of HAART is sustained and treatment with DDX is avoided.

Background: The prevalence and factors associated with an increased risk of renal dysfunction in HIV-infected patients receiving or not receiving antiretroviral therapy (ART) have been poorly evaluated in observational settings., Methods: Patients in the ICONA Foundation cohort with at least two creatinine values available while still ART-naïve were enrolled in the study. A logistic regression analysis was performed to identify predictors of an estimated glomerular filtration rate (eGFR)<90 mL/min/1.73 m(2) at baseline. The incidence and predictors of a >20% reduction in eGFR from pre-combination ART (cART) levels (or a decrease from ≥90 to <90 mL/min/1.73 m(2) ) were evaluated by Poisson regression., Results: A total of 1505 patients were included in the study; 363 (24%) had eGFR<90 mL/min/1.73 m(2) at baseline. Older patients [odds ratio (OR) 1.58 per 10 years older; P<0.00001], female patients (OR 2.41 vs. male patients; P<0.00001), those who had diabetes and/or hypertension (OR 2.36 vs. neither; P<0.03) and patients with higher baseline CD4 count (OR 1.06 per 100 cells/μL higher; P<0.03) showed a greater risk of eGFR<90 mL/min/1.73 m(2) . Ninety-six patients experienced an eGFR decrease of >20% from pre-cART levels (6.8 per 100 person-years). Older age [relative risk (RR) 1.41 per 10 years older; P=0.005], female gender (RR 2.25 vs. male; P=0.003) and current exposure to didanosine (ddI), tenofovir and protease inhibitors were the major determinants., Conclusions: We observed a relatively high rate of mild renal dysfunction in the absence of ART. In addition to traditional risk factors such as older age and diabetes/hypertension, female gender and current use of ddI, tenofovir and protease inhibitors were associated with a greater risk of decreased renal function as measured by eGFR., (© 2010 British HIV Association.)

Unlabelled: Although HAART suppresses HIV replication, it is often unable to restore immune homeostasis. Consequently, non-AIDS-defining diseases are increasingly seen in treated individuals. This is attributed to persistent virus expression in reservoirs and to cell activation. Of note, in CD4(+) T cells and monocyte-macrophages of virologically-suppressed individuals, there is continued expression of multi-spliced transcripts encoding HIV regulatory proteins. Among them, Tat is essential for virus gene expression and replication, either in primary infection or for virus reactivation during HAART, when Tat is expressed, released extracellularly and exerts, on both the virus and the immune system, effects that contribute to disease maintenance. Here we report results of an ad hoc exploratory interim analysis (up to 48 weeks) on 87 virologically-suppressed HAART-treated individuals enrolled in a phase II randomized open-label multicentric clinical trial of therapeutic immunization with Tat (ISS T-002). Eighty-eight virologically-suppressed HAART-treated individuals, enrolled in a parallel prospective observational study at the same sites (ISS OBS T-002), served for intergroup comparison. Immunization with Tat was safe, induced durable immune responses, and modified the pattern of CD4(+) and CD8(+) cellular activation (CD38 and HLA-DR) together with reduction of biochemical activation markers and persistent increases of regulatory T cells. This was accompanied by a progressive increment of CD4(+) T cells and B cells with reduction of CD8(+) T cells and NK cells, which were independent from the type of antiretroviral regimen. Increase in central and effector memory and reduction in terminally-differentiated effector memory CD4(+) and CD8(+) T cells were accompanied by increases of CD4(+) and CD8(+) T cell responses against Env and recall antigens. Of note, more immune-compromised individuals experienced greater therapeutic effects. In contrast, these changes were opposite, absent or partial in the OBS population. These findings support the use of Tat immunization to intensify HAART efficacy and to restore immune homeostasis., Trial Registration: ClinicalTrials.gov NCT00751595.

Background: Although the kinetics of CD4(+) cell counts have been extensively studied in antiretroviral-naive HIV-infected patients, data on individuals who have failed combination antiretroviral therapy (cART) are lacking., Methods: This analysis was based on the ICONA Foundation Study. Subjects with > or = 1 episode of viral suppression after starting first-line cART were included (n = 3537). Following a viral rebound, patients who achieved another episode of viral suppression could reenter the analysis. The percentage of patients with an increase in CD4(+) cell count >300 cells/mm(3) was estimated using Kaplan-Meier techniques; the rate of CD4(+) cell count increase per year was estimated using a multivariable, multilevel linear model with fixed effects of intercept and slope. Multivariable models were also fitted to include several covariates., Results: The median time to reach a CD4(+) cell count increase >300 cells/mm(3) from baseline was significantly associated with the number of failed regimens: 34 months, 41 months, 51 months, and 45 months in subjects without evidence of previous virological failure, or 1, 2, or > or = 3 previous virologically failed regimens, respectively (P < .001, by log-rank test). The annual estimated increases in CD4(+) cell count were 36 cells/mm(3) (95% confidence interval [CI], 34-38 cells/mm(3)), 28 cells/mm(3) (95% CI, 11-21 cells/mm(3)), 31 cells/mm(3) (95% CI, 26-36 cells/mm(3)), and 26 cells/mm(3) (95% CI, 18-33 cells/mm(3)), respectively. Differences in the annual CD4(+) cell count increase were observed between specific antiretrovirals., Conclusions: Subjects with > or = 1 virological failure took a longer time to reach a CD4(+) cell count >300 cell/mm(3) and had a slower annual increase than those without virological failure. Efforts should be made to optimize first-line cART, because this represents the best chance of achieving an effective CD4(+) response.

Background: Raltegravir and maraviroc represent new, important resources for HIV-infected patients with intolerance or resistance to other antiretroviral agents. The safety and efficacy of both drugs have been investigated, but there is no information on possible pharmacokinetic interactions between these 2 drugs in clinical practice., Objective: To evaluate raltegravir plasma concentrations in heavily treatment-experienced patients receiving salvage regimens and explore, in a preliminary assessment, the potential influence of maraviroc coadministration and other cofactors on raltegravir trough concentrations (C(trough))., Methods: Fifty-four HIV-infected patients with triple class (nucleoside reverse transcriptase inhibitor, nonnucleoside reverse transcriptase inhibitor, protease inhibitor) treatment experience starting raltegravir 400 mg twice daily, with (n = 11) or without (n = 43) concomitant maraviroc 300 mg twice daily, were evaluated. All regimens included at least 3 drugs of at least 2 different classes. Raltegravir plasma Ctrough, after at least 1 month of treatment, were analyzed to compare groups of patients taking raltegravir only and raltegravir plus maraviroc. Immunovirological (CD4, HIV-RNA) and clinical data after 6 months of treatment were also collected and described., Results: Raltegravir plasma Ctrough showed a large variability (range <0.020-2.47 microg/mL). Median levels were similar in the 2 groups (raltegravir + maraviroc 0.104 microg/mL, range 0.025-0.826; raltegravir 0.090 microg/mL, range <0.020-2.47, p = 0.400). Detectable (>0.02 microg/mL) raltegravir concentrations were observed in all patients receiving raltegravir + maraviroc and in 74% of patients receiving raltegravir alone (p = 0.060). After 6 months of treatment, the 2 groups had similar clinical, virologic, and immunologic conditions., Conclusions: Coadministration of maraviroc does not seem to have any relevant effects on raltegravir plasma Ctrough in heavily treatment-experienced patients receiving salvage regimens. Further studies should evaluate the potential additional benefits of maraviroc coadministration in terms of virologic and immunologic response.

Objective: The primary objective of this study was to investigate the impact of HCV infection and of HCV genotypes on immune restoration in HIV-infected patients on a successful HAART regimen., Methods: Patients from the MASTER Study were included in this current longitudinal study if they met the following criteria: being on any successful HAART, availability of CD4+ cell count and HIV RNA level before starting the suppressive HAART and 12 months after suppressive therapy, availability of HCV antibodies. The primary endpoints of the study were defined as achieving a difference above 100 cell/mmc between CD4+ at baseline and at time of HIV RNA suppression while on therapy (DeltaCD4+early), or 12 month after a suppressive therapy (DeltaCD4+late)., Results: 844 HIV-positive patients were included in the analysis: 673 were HCV-negative and 171 were HCV-positive [92 (53.8%) subjects had HCV genotype 1; 58 (33.9%), genotype 3; 21 (12.3%), genotype 4]. Plasma HIV RNA (both baseline as highest value), nadir CD4+, being naïve, time to reach undetectable plasma HIV RNA, treatment with PI vs NNRTI were associated with an early immunological recovery; the occurrence of previous AIDS event, a history of injection drug use, and HCV infection were associated with failure to achieve an early immunological recovery. Variables associated with DeltaCD4+late immune recovery were baseline CD4+ value, plasma HIV RNA (both baseline as highest value), being naïve and time to reach undetectable plasma HIV RNA. HCV infection per se was not associated with a worse probability to reach late immunologic response, although among HCV infected patients, having a genotype 3 was associated with a worse immune recovery. At multivariable analysis, factors that remained associated with failure to achieve an early immunological response were being HCV infected and history of injection drug use, while those associated with a failure to achieve a late immunological response were being infected with HCV genotype 3 and older age., Conclusions: A blunted early immune recovery was observed in HCV infected patients, compared with HCV negative subjects, while late immune recovery was not different among HCV infected as a whole and not infected subjects; only the subgroup of subjects infected with genotype 3 showed an impaired late immune recovery.

Background: The extent of short-term CD4(+) T-cell recovery in patients tolerating first-line highly active antiretroviral therapy (HAART) and attaining undetectable HIV RNA levels is inadequately defined., Methods: We retrospectively analysed patients in four Italian cohorts who started HAART between January 1996 and September 2006. All patients had known HCV coinfection status, did not modify the regimen for 6 months and had <50 HIV RNA copies/ml at the end of the sixth month., Results: The analysis involved 1,488 patients (1,096 males, 73.7%) with a median age of 43 years (interquartile range [IQR] 39-49); 435 (29.2%) were positive for HCV, 71 (4.8%) were positive for hepatitis B surface antigen (HBsAg) and 76 (5.1%) had experienced a previous AIDS-defining event. At baseline, patient CD4(+) T-cell counts were 226 cells/microl (IQR 99-332), CD4(+) T-cell percentages were 14.7% (IQR 8.7-21.2) and HIV RNA levels were 4.91 log(10) copies/ml (IQR 4.38-5.34). Overall, 24-week CD4(+) T-cell recovery was 144 cells/microl (IQR 70-240). At multivariable analysis, T-cell recovery was positively related to the use of a boosted protease inhibitor (P<0.0001) or thymidine analogues (P<0.0001), baseline HIV RNA levels (P<0.0001), the baseline percentage of CD4(+) T-cells (P<0.0001) and the absence of HCV coinfection (P=0.006). Age, gender, baseline CD4(+)/CD8(+) T-cell ratio and a history of AIDS-defining events had no independent effect on CD4(+) T-cell recovery., Conclusions: Among HIV-infected patients tolerating first-line HAART and with undetectable HIV RNA after 6 months, CD4(+) T-cell recovery is significantly greater in those without HCV coinfection, with a high baseline viral load, a high baseline percentage of CD4(+) T-cells and in those treated with a boosted protease inhibitor.