A Machine Learning Approach to Predict Weight Change in ART-Experienced People Living With HIV.

INTRODUCTION: The objective of the study was to develop machine learning (ML) models that predict the percentage weight change in each interval of time in antiretroviral therapy-experienced people living with HIV. METHODS: This was an observational study that comprised consecutive people living with HIV attending Modena HIV Metabolic Clinic with at least 2 visits. Data were partitioned in an 80/20 training/test set to generate 10 progressively parsimonious predictive ML models. Weight gain was defined as any weight change >5%, at the next visit. SHapley Additive exPlanations values were used to quantify the positive or negative impact of any single variable included in each model on the predicted weight changes. RESULTS: A total of 3,321 patients generated 18,322 observations. At the last observation, the median age was 50 years and 69% patients were male. Model 1 (the only 1 including body composition assessed with dual-energy x-ray absorptiometry) had an accuracy greater than 90%. This model could predict weight at the next visit with an error of <5%. CONCLUSIONS: ML models with the inclusion of body composition and metabolic and endocrinological variables had an excellent performance. The parsimonious models available in standard clinical evaluation are insufficient to obtain reliable prediction, but are good enough to predict who will not experience weight gain.

Patients with HIV and cirrhosis: the risk for hepatocellular carcinoma after direct-acting antivirals for hepatitis C virus.

OBJECTIVES: Hepatocellular carcinoma (HCC) has become a major issue in coinfected HIV/HCV patients with liver cirrhosis. We aimed to determine the rate of HCC occurrence after a direct-acting antiviral (DAA) treatment and to evaluate the factors associated with the risk of HCC in this population. DESIGN: We conducted a retrospective multicenter observational study including cirrhotic HIV/HCV-coinfected patients treated with DAAs, between October 2014 and January 2017. METHODS: We collected demographics characteristics, data regarding HIV and HCV infections and treatment with DAAs. We investigated the rate and the time of occurrence of HCC. Statistical analysis explored the factors associated to development of liver cancer. RESULTS: During a median follow-up of 55 months, 24 out of 232 patients developed HCC, after a median of 22.5 months from starting DAAs. Factors associated with HCC were a higher Child--Pugh Turcotte (CPT) score (P = 0.002), HCV genotype 3 (P = 0.04), previous HCC (P < 0.001) and CD4+ cell count nadir greater than 350 cells/µl (P = 0.001), whereas antiretroviral therapy (ART) was associated to a lower rate of cancer (P = 0.02). At multivariable analysis CPT score and a history of HCC remained independently associated with HCC after DAAs (P = 0.003 and P < 0.001, respectively), and ART administration maintained its protective role (P = 0.047), regardless of HIV RNA at baseline. CONCLUSION: Our study highlights the importance of a long-lasting follow-up for HCC after HCV eradication, mostly in those patients with advanced cirrhosis and history of HCC. Furthermore, our data showed a potential role of ART itself (and not of undetectable HIV RNA) in reducing the risk for HCC development.

Anti-Tat immunity defines CD4+ T-cell dynamics in people living with HIV on long-term cART.

BACKGROUND: Low-level HIV viremia originating from virus reactivation in HIV reservoirs is often present in cART treated individuals and represents a persisting source of immune stimulation associated with sub-optimal recovery of CD4+ T cells. The HIV-1 Tat protein is released in the extracellular milieu and activates immune cells and latent HIV, leading to virus production and release. However, the relation of anti-Tat immunity with residual viremia, persistent immune activation and CD4+ T-cell dynamics has not yet been defined. METHODS: Volunteers enrolled in a 3-year longitudinal observational study were stratified by residual viremia, Tat serostatus and frequency of anti-Tat cellular immune responses. The impact of anti-Tat immunity on low-level viremia, persistent immune activation and CD4+ T-cell recovery was investigated by test for partitions, longitudinal regression analysis for repeated measures and generalized estimating equations. FINDINGS: Anti-Tat immunity is significantly associated with higher nadir CD4+ T-cell numbers, control of low-level viremia and long-lasting CD4+ T-cell recovery, but not with decreased immune activation. In adjusted analysis, the extent of CD4+ T-cell restoration reflects the interplay among Tat immunity, residual viremia and immunological determinants including CD8+ T cells and B cells. Anti-Env immunity was not related to CD4+ T-cell recovery. INTERPRETATION: Therapeutic approaches aiming at reinforcing anti-Tat immunity should be investigated to improve immune reconstitution in people living with HIV on long-term cART. TRIAL REGISTRATION: ISS OBS T-002 ClinicalTrials.gov identifier: NCT01024556 FUNDING: Italian Ministry of Health, special project on the Development of a vaccine against HIV based on the Tat protein and Ricerca Corrente 2019/2020.

Failure on voxilaprevir, velpatasvir, sofosbuvir and efficacy of rescue therapy.

BACKGROUND & AIMS: There are limited data on patients with chronic HCV infection in whom combination voxilaprevir (VOX), velpatasvir (VEL), sofosbuvir (SOF) retreatment fails. Thus, we aimed to assess treatment failure and rescue treatment options in these patients. METHODS: Samples from 40 patients with HCV genotypes (GT) 1-4 in whom VOX/VEL/SOF retreatment failed were collected within the European Resistance Study Group. Population-based resistance analyses were conducted and clinical parameters and retreatment efficacies were evaluated retrospectively in 22 patients. RESULTS: Most VOX/VEL/SOF failure patients were infected with HCV GT3a (n = 18, 45%) or GT1a (n = 11, 28%) and had cirrhosis (n = 28, 70%). Previous treatments included an NS3-inhibitor (30%), an NS5A-inhibitor (100%) and SOF (85%). Baseline RAS data from a subgroup of patients before VOX/VEL/SOF retreatment (78%) showed few NS3 RASs apart from Q80K in GT1a (40%), typical NS5A RAS patterns in most patients (74%) and no S282T in NS5B. Sequencing after VOX/VEL/SOF failure was available in 98% of patients and showed only minor changes for NS3 and NS5A RASs. In 22 patients, rescue treatment was initiated with glecaprevir, pibrentasvir alone (n = 2) or with SOF±ribavirin (n = 15), VOX/VEL/SOF±ribavirin (n = 4) or VEL/SOF and ribavirin (n = 1) for 12 to 24 weeks. Sustained virologic response was achieved in 17/21 (81%) patients with a final treatment outcome. Of these, 2 GT3a-infected patients had virologic failure after rescue treatment with VEL/SOF or glecaprevir/pibrentasvir+SOF+ribavirin, and 2 patients with cirrhosis died during treatment or before reaching SVR12. CONCLUSIONS: VOX/VEL/SOF failure was mainly observed in HCV GT3- and GT1a-infected patients with cirrhosis and was not associated with specific RAS patterns within NS3, NS5A or NS5B target regions. Rescue treatment with multiple targeted therapies was effective in most patients. LAY SUMMARY: The advent of direct-acting antivirals has enabled the effective cure of chronic hepatitis C in most patients. However, treatment failure occurs in some patients, who are often retreated with a combination regimen called VOX/VEL/SOF, which is associated with very high rates of cure. However, VOX/VEL/SOF retreatment also fails in some patients. Herein, we analysed samples from patients in whom VOX/VEL/SOF retreatment failed and we assessed the efficacy of different rescue therapies, showing that rescue treatment is effective in most patients (81%).

A comparison between different anti-retroviral therapy regimes on soluble inflammation markers: a pilot study.

BACKGROUND: Although HIV-related deaths have decreased dramatically following the introduction of antiretroviral therapy (ART), HIV infection itself causes increased morbidity and mortality for both non-AIDS-related events or chronic inflammation and immune activation. The use of certain antiretroviral drugs can contribute to this process. METHODS: We investigated 26 potential biomarkers in serum samples from HIV-1 infected patients virologically suppressed under ART. The main objective of our study was to evaluate if virological suppression achieved with a triple drug regimen containing tenofovir disoproxil fumarate co-formulated with emtricitabine (TDF/FTC) as backbone, could correlate with a better immunological and inflammatory profile in relation to the third class of antiretroviral drug administered. The eligible patients were then divided into 3 groups in relation to the third drug associated with TDF/FTC: nucleoside reverse transcriptase inhibitors (NNRTI) (Group 1, n = 16), protease inhibitors (PI) (Group 2, n = 17) and integrase inhibitors (INI) (Group 3, n = 16). RESULTS: Inflammatory cytokines and chemokines were more represented in Group 2 than in Group 3 (IL-1Ra, p = 0.013; IL-12p70 p = 0.039; TNF-α p = 0.041; IL-8, p = 0.027; MIP1 ß, p = 0.033). Eotaxin showed lower levels in Group 1 compared to Group 2 (p = 0.010), while IP-10 was significantly lower in Group 1 compared to both Group 2 and Group 3 (p = 0.003 and p = 0.007, respectively). CONCLUSIONS: Our results seem to discourage the administration of PI as a third drug in a virologically effective antiretroviral regimen, as its use is linked to the detection of higher levels of pro-inflammatory mediators in comparison with INI and NNRTI.

Is physician assessment of alcohol consumption useful in predicting risk of severe liver disease among people with HIV and HIV/HCV co-infection?

BACKGROUND: Alcohol consumption is a known risk factor for liver disease in HIV-infected populations. Therefore, knowledge of alcohol consumption behaviour and risk of disease progression associated with hazardous drinking are important in the overall management of HIV disease. We aimed at assessing the usefulness of routine data collected on alcohol consumption in predicting risk of severe liver disease (SLD) among people living with HIV (PLWHIV) with or without hepatitis C infection seen for routine clinical care in Italy. METHODS: We included PLWHIV from two observational cohorts in Italy (ICONA and HepaICONA). Alcohol consumption was assessed by physician interview and categorized according to the National Institute for Food and Nutrition Italian guidelines into four categories: abstainer; moderate; hazardous and unknown. SLD was defined as presence of FIB4 > 3.25 or a clinical diagnosis of liver disease or liver-related death. Cox regression analysis was used to evaluate the association between level of alcohol consumption at baseline and risk of SLD. RESULTS: Among 9542 included PLWHIV the distribution of alcohol consumption categories was: abstainers 3422 (36%), moderate drinkers 2279 (23%), hazardous drinkers 637 (7%) and unknown 3204 (34%). Compared to moderate drinkers, hazardous drinking was associated with higher risk of SLD (adjusted hazard ratio, aHR = 1.45; 95% CI: 1.03-2.03). After additionally controlling for mode of HIV transmission, HCV infection and smoking, the association was attenuated (aHR = 1.32; 95% CI: 0.94-1.85). There was no evidence that the association was stronger when restricting to the HIV/HCV co-infected population. CONCLUSIONS: Using a brief physician interview, we found evidence for an association between hazardous alcohol consumption and subsequent risk of SLD among PLWHIV, but this was not independent of HIV mode of transmission, HCV-infection and smoking. More efforts should be made to improve quality and validity of data on alcohol consumption in cohorts of HIV/HCV-infected individuals.

Durability of different initial regimens in HIV-infected patients starting antiretroviral therapy with CD4+ counts <200 cells/mm3 and HIV-RNA >5 log10 copies/mL.

OBJECTIVES: Our aim was to investigate the durability of different initial regimens in patients starting ART with CD4+ counts <200 cells/mm3 and HIV-RNA >5 log10 copies/mL. METHODS: This was a retrospective study of HIV-infected patients prospectively followed in the ICONA cohort. Those who started ART with boosted protease inhibitors (bPIs), NNRTIs or integrase strand transfer inhibitors (InSTIs), with CD4+ <200 cells/mm3 and HIV-RNA >5 log10 copies/mL, were included. The primary endpoint was treatment failure (TF), a composite endpoint defined as virological failure (VF, first of two consecutive HIV-RNA >50 copies/mL after 6 months of treatment), discontinuation of class of the anchor drug or death. Independent associations were investigated by Poisson regression analysis in a model including age, gender, mode of HIV transmission, CDC stage, HCV and HBV co-infection, pre-treatment HIV-RNA, CD4+ count and CD4+/CD8+ ratio, ongoing opportunistic disease, fibrosis FIB-4 index, estimated glomerular filtration rate, haemoglobin, platelets, neutrophils, calendar year of ART initiation, anchor drug class (treatment group) and nucleos(t)ide backbone. RESULTS: A total of 1195 patients fulfilled the inclusion criteria: 696 started ART with a bPI, 315 with an InSTI and 184 with an NNRTI. During 2759 person-years of follow up, 642 patients experienced TF. Starting ART with bPIs [adjusted incidence rate ratio (aIRR) (95% CI) 1.62 (1.29-2.03) versus starting with NNRTIs; P < 0.001] and starting ART with InSTIs [aIRR (95% CI) 0.68 (0.48-0.96) versus starting with NNRTIs; P = 0.03] were independently associated with TF. CONCLUSIONS: In patients starting ART with <200 CD4+ cells/mm3 and >5 log10 HIV-RNA copies/mL, the durability of regimens based on InSTIs was longer than that of NNRTI- and bPI-based regimens.

Continued Decay of HIV Proviral DNA Upon Vaccination With HIV-1 Tat of Subjects on Long-Term ART: An 8-Year Follow-Up Study.

Introduction: Tat, a key HIV virulence protein, has been targeted for the development of a therapeutic vaccine aimed at cART intensification. Results from phase II clinical trials in Italy (ISS T-002) and South Africa (ISS T-003) indicated that Tat vaccination promotes increases of CD4+ T-cells and return to immune homeostasis while reducing the virus reservoir in chronically cART-treated patients. Here we present data of 92 vaccinees (59% of total vaccinees) enrolled in the ISS T-002 8-year extended follow-up study (ISS T-002 EF-UP, ClinicalTrials.gov NCT02118168). Results: Anti-Tat antibodies (Abs) induced upon vaccination persisted for the entire follow-up in 34/92 (37%) vaccinees, particularly when all 3 Ab classes (A/G/M) were present (66% of vaccinees), as most frequently observed with Tat 30 µg regimens. CD4+ T cells increased above study-entry levels reaching a stable plateau at year 5 post-vaccination, with the highest increase (165 cells/µL) in the Tat 30 µg, 3 × regimen. CD4+ T-cell increase occurred even in subjects with CD4+ nadir ≤ 250 cells/uL and in poor immunological responders and was associated with a concomitant increase of the CD4+/CD8+ T-cell ratio, a prognostic marker of morbidity/mortality inversely related to HIV reservoir size. Proviral DNA load decreased over time, with a half-life of 2 years and an estimated 90% reduction at year 8 in the Tat 30 µg, 3 × group. In multivariate analysis the kinetic and amplitude of both CD4+ T-cell increase and proviral DNA reduction were fastest and highest in subjects with all 3 anti-Tat Ab classes and in the 30 µg, 3 × group, irrespective of drug regimens (NNRTI/NRTI vs. PI). HIV proviral DNA changes from baseline were inversely related to CD4+/CD8+ T-cell ratio and CD4+ T-cell changes, and directly related to the changes of CD8+ T cells. Further, HIV DNA decay kinetics were inversely related to the frequency and levels of intermittent viremia. Finally, Tat vaccination was similarly effective irrespective of the individual immunological status or HIV reservoir size at study entry. Conclusions: Tat immunization induces progressive immune restoration and reduction of virus reservoirs above levels reached with long-term cART, and may represent an optimal vaccine candidate for cART intensification toward HIV reservoirs depletion, functional cure, and eradication strategies.

Inflammatory effects of atazanavir/ritonavir versus darunavir/ritonavir in treatment naïve, HIV-1-infected patients.

BACKGROUND: Limited studies have compared the impact of different antiretroviral regimens on soluble markers of inflammation with discordant results. METHODS: In this prospective study, treatment naïve HIV-1-infected patients were included if they started their current regimen with atazanavir/ritonavir (ATV/r) (N = 73, Group 1) or darunavir/ritonavir (DRV/r) (N = 85, Group 2) plus tenofovir/emtricitabine. The analysis of IL-6, MCP-1, sCD163, VCAM-1, ox-LDL, and adiponectine was performed on two stored plasma samples, the first prior to antiretroviral therapy initiation and the second one year after initiation. RESULTS: The results of our analysis show a difference in ox-LDL between the two groups with higher mean (SD) values in ATV/r based group 608.5 ± 137.4 versus 519.1 ± 119.6 in DRV/r group, after controlling for baseline levels of ox-LDL as well as other potential confounding factors controlled by means of matching design or linear regression modelling. CONCLUSIONS: Our analysis provides further data examining the association between the modulation of vascular inflammatory and of activation markers with specific protease inhibitors-based treatments over one year of exposure to these drugs. The data show little evidence for an association, supporting the notion that antiretroviral regimens has generally poor efficiency in downregulating these soluble markers.

Entheseal involvement in asymptomatic human immunodeficiency virus infected patients: preliminary results of a clinical and ultrasonographic study.

OBJECTIVES: As a strong association between human immunodeficiency virus (HIV) infection and spondyloarthritis (SpA) has been hypothesised, our main objective was to explore by power Doppler ultrasonography (PDUS) the presence of subclinical enthesitis in asymptomatic HIV patients. The presence of subclinical synovitis was also evaluated. METHODS: Consecutive asymptomatic HIV patients were studied and compared with asymptomatic HCV patients and healthy controls (HC). All subjects underwent a clinical and PDUS bilateral examination of the following entheses and joints: epicondyle, quadriceps, patellar, Achilles and plantar fascia; wrists, II and III metacarpo-phalangeal, knee and ankle. RESULTS: Twenty-nine HIV, 32 HCV and 25 HC were recruited; 1.032 entheses and 860 joints were examined. Clinical diagnosis of enthesitis was made in 10.3% HIV patients, 6.2% HCV patients (p=0.66) and none HC (p=0.24). PDUS enthesitis was found in 72.4% HIV, 28.1% HCV (p=0.0008) and 12% HC (p<0.0001). Clinical diagnosis of synovitis was made in 3.4% HIV patients, 9.3% HCV patients (p=0.61) and none HC (p=1). PDUS abnormalities were documented in 24.1% HIV patients, 71.8% HCV patients (p=0.0003) and none HC (p=0.0001). In detecting enthesitis and synovitis, PDUS was more sensitive than clinical examination both in HIV and HCV patients. CONCLUSIONS: Our preliminary study shows the high frequency of PDUS enthesitis in asymptomatic HIV patients, which highlights the close link between HIV and SpA. Further studies are desirable on a larger number of HIV patients to confirm these results. PDUS proved to be more sensitive than clinical examination in detecting subclinical involvement of entheses and joints.

Adipokines levels in HIV infected patients: lipocalin-2 and fatty acid binding protein-4 as possible markers of HIV and antiretroviral therapy-related adipose tissue inflammation.

BACKGROUND: Metabolic and cardiovascular diseases (CVD) represent a major problem in HIV infection. The aim of this study was to evaluate the relationship of HIV infection and antiretroviral therapy (ART) with circulating levels of two adipokines (Lipocalin-2 and Fatty Acid Binding Protein-4, FABP-4), known to be associated with adipose tissue dysfunction and cardiovascular disease in the general population. METHODS: We enrolled 40 non-obese HIV-infected patients and 10 healthy controls of similar age and Body Mass Index (BMI). Body composition, metabolic syndrome, lipid profile, 10-years CVD risk score, and adipokines levels were compared between groups. ART-regimen status (naïve, non-nucleoside reverse transcriptase inhibitors - NNRTIs - and protease inhibitors - PIs) association with adipokines levels was tested with linear regression models. RESULTS: HIV patients showed a worse metabolic profile than controls. Lipocalin-2 levels were higher in HIV-infected subjects (+53%; p = 0.007), with a significant trend (p = 0.003) for higher levels among subjects taking NNRTIs. Association of lipocalin-2 with fat-mass and BMI was modulated by ART regimens, being positive among subjects treated with NNRTIs and negative among those treated with PIs ("ART-regimens-by-BMI" interaction p = 0.0009). FABP-4 levels were correlated with age, fat mass, BMI, lipid profile and CVD risk (all R ≥ 0.32, p < 0.05), but not influenced by HIV-status (+20%; p = 0.12) or ART-regimen (p = 0.4). CONCLUSIONS: Our data confirm that HIV-infection is associated with adipose tissue inflammation, as measured by Lipocalin-2 levels, and ART does not attenuate this association. While FABP-4 is a marker of worse metabolic and CVD profile independently of HIV status or ART regimen, lipocalin-2 could represent a useful marker for HIV- and ART-related adipose tissue dysfunction.

Viro-immunological response of drug-naive HIV-1-infected patients starting a first-line regimen with viraemia >500,000 copies/ml in clinical practice.

BACKGROUND: Virological success (VS) and immunological reconstitution (IR) of antiretroviral-naive HIV-1-infected patients with pre-therapy viral load (VL) >500,000 copies/ml was assessed after 12 months of treatment according to initial drug-class regimens. METHODS: An observational multicentre retrospective study was performed. VS was defined as the first VL <50 copies/ml from treatment start. IR was defined as an increase of at least 150 CD4+ T-lymphocytes from treatment start. Survival analysis was used to estimate the probability and predictors of VS and IR by 12 months of therapy. RESULTS: 428 HIV-1-infected patients were analysed. Patients were grouped according to the different first-line drug-classes used: a non-nucleoside reverse transcriptase inhibitor (NNRTI) plus two nucleoside reverse transcriptase inhibitors (NRTIs; NNRTI-group; n=105 [24.5%]); a protease inhibitor (PI) plus two NRTIs (PI-group; n=260 [60.8%]); a four-drug regimen containing a PI-regimen plus an integrase inhibitor (PI+INI-group; n=63 [14.7%]). Patients in the PI-group showed the lowest probability of VS (PI-group: 72.4%; NNRTI-group: 75.5%; PI+INI-group: 81.0%; P<0.0001). By Cox regression, patients in PI+INI and NNRTI-groups showed a higher adjusted hazard ratio (95% CI) of VS compared to those in the PI-group (PI+INI-group: 1.48 [1.08, 2.03]; P=0.014; NNRTI-group: 1.37 [1.06-1.78]; P=0.015). The probability of IR was 76.2%, and was similar among groups. Patients with AIDS showed a lower adjusted hazard ratio (95% CI) of IR compared to non-AIDS presenters (0.70 [0.54, 0.90]; P=0.005). CONCLUSIONS: In this multicentre retrospective study, patients with viraemia >500,000 copies/ml who start a first-line regimen containing PI+INI or NNRTI yield a better VS compared to those receiving a PI-based regimen.

Cardiovascular risk and dyslipidemia among persons living with HIV: a review.

BACKGROUND: Aim of this review is to focus the attention on people living with HIV infection at risk of developing a cardiovascular event. What is or what would be the most suitable antiretroviral therapy? Which statin or fibrate to reduce the risk? How to influence behavior and lifestyles? DISCUSSION: Prevention of cardiovascular disease (CVD) risk remains the first and essential step in a medical intervention on these patients. The lifestyle modification, including smoking cessation, increased physical activity, weight reduction, and the education on healthy dietary practices are the main instruments. Statins are the cornerstone for the treatment of hypercholesterolemia. They have been shown to slow the progression or promote regression of coronary plaque, and could also exert an anti-inflammatory and immunomodulatory effect. However the current guidelines for the use of these drugs in general population are dissimilar, with important differences between American and European ones. The debate between American and European guidelines is still open and, also considering the independent risk factor represented by HIV, specific guidelines are warranted. Ezetimibe reduces the intestinal absorption of cholesterol. It is effective alone or in combination with rosuvastatin. It does not modify plasmatic concentrations of antiretrovirals. A number of experimental new classes of drugs for the treatment of hypercholesterolemia are being studied. Fibrates represent the first choice for treatment of hypertriglyceridemia, however, the renal toxicity of fibrates and statins should be considered. Omega 3 fatty acids have a good safety profile, but their efficacy is limited. Another concern is the high dose needed. Other drugs are acipimox and tesamorelin. Current antiretroviral therapies are less toxic and more effective than regimens used in the early years. Lipodistrophy and dyslipidemia are the main causes of long-term toxicities. Not all antiretrovirals have similar toxicities. Protease Inhibitors may cause dyslipidemia and lipodystrophy, while integrase inhibitors have a minimal impact on lipids profile, and no evidence of lipodystrophy. There is still much to be written with the introduction of new drugs in clinical practice. CONCLUSIONS: Cardiovascular risk among HIV infected patients, interventions on behavior and lifestyles, use of drugs to reduce the risk, and switch in antiretroviral therapy, remain nowadays major issues in the management of HIV-infected patients.

Role of systemic inflammation scores for prediction of clinical outcomes in patients treated with atazanavir not boosted by ritonavir in the Italian MASTER cohort.

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 Log10 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 Log10 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.

Systemic inflammation-based scores and mortality for all causes in HIV-infected patients: a MASTER cohort study.

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.

Use of statins and aspirin to prevent cardiovascular disease among HIV-positive patients. A survey among Italian HIV physicians.

We conducted a survey among Italian HIV specialists to study the utilization of statins and aspirin, administering a questionnaire aimed at investigating their use, the use of guidelines and scores, and the management of interactions. The answers were uniform in the different geographic areas. The majority directly prescribe statins and 43% of them prescribe aspirin. The majority follows guidelines and utilize scores to calculate the CV risk. Our survey demonstrates the commitment and autonomy in prescribing statins and aspirin of Italian physicians. There is a rationale to generate guidelines to overcome the differences and limitations among current recommendations.

HIV-1 early and late diagnosis in the Emilia Romagna Region (Italy): a three year study.

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

Risk of Chronic Kidney Disease among Patients Developing Mild Renal Impairment during Tenofovir-Containing Antiretroviral Treatment.

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.

Monotherapy with darunavir/ritonavir or lopinavir/ritonavir versus standard antiretroviral therapy: a randomized clinical trial (2pm Study).

In a multicentre, open-label, clinical trial, 43 patients virologically suppressed while receiving a standard triple antiretroviral therapy were randomized (1:1:1) to switch to monotherapy with darunavir/ritonavir (DRV/r-MT arm), monotherapy with lopinavir/ritonavir (LPV/r-MT arm) or to continue on the ongoing regimen (cART arm). The proportion (95% CI) of patients with virological success (Snapshot analysis) at week 48 was 73% (48%-90%) in the DRV/r-MT arm, 69% (42%-88%) in the LPV/r-MT arm and 87% (61%-98%) in the cART arm. Virological failure was detected in only one patient receiving LPV/r-MT. The LPV/r-MT arm showed a modest worsening in lipid profile.