Evaluation of Myo-Intimal Media Thickness and Atheromatous Plaques in People Living with HIV from the Archiprevaleat Cohort vs. HIV-Negative Subjects.

BACKGROUND: Antiretroviral therapy has allowed a clear improvement in prognosis for HIV patients, but metabolic problems, such as dyslipidemia, remain. This can lead to the development of atheromatous plaques. Our study aims to evaluate whether HIV-positive (HIV+) patients show higher myo-intimal media thickness (IMT) and atheromatous plaques compared to HIV-negative (HIV-) patients. METHODS: To evaluate the association between HIV infection in experienced patients and vascular pathology, we performed a cross-sectional study, observing 1006 patients, 380 HIV+ enrolled in the Archiprevaleat cohort, and 626 HIV- as a control group. All patients underwent a Doppler scan of the supra-aortic vessels. We compared the prevalence of IMT > 1.0 mm and plaques in the two groups. RESULTS: Patients in the HIV+ group were younger than those in the HIV- group, with a lower prevalence of hypertension and diabetes and higher dyslipidemia. The prevalence of plaques in strata of age was higher in the HIV+ group than in the HIV- group and was associated with the length of ART exposure. CONCLUSIONS: Our cross-sectional, retrospective study shows that HIV+ experienced patients are at greater risk of IMT and atheromatous plaques compared to HIV-. The risk is associated with being HIV+ and with the length of ART exposure. This finding may be useful in preventing cardiovascular risk.

Risk of Cardiovascular Events in People with HIV (PWH) Treated with Integrase Strand-Transfer Inhibitors: The Debate Is Not Over; Results of the SCOLTA Study.

Cardiovascular disease (CVD) is common in people with HIV (PWH), and has great impact in terms of morbidity and mortality. Several intertwined mechanisms are believed to play a role in determining the increased risk of CVD, including the effect of certain antiretrovirals; among these, the role of integrase strand-transfer inhibitors (INSTIs) is yet to be fully elucidated. We conducted a multicenter, observational study comprising 4984 PWH evaluating the antiretroviral therapy (ART)-related nature of CVD in real life settings, both in naïve vs. treatment-experienced people. A comparison was conducted between INSTIs vs. either protease inhibitors (PIs) or non-nucleoside reverse transcriptase inhibitors (NNRTIs) considering demographic, baseline clinical characteristics, incidence of CVD in both 2-year and complete follow-up periods. Among 2357 PWH exposed to INSTIs, 24 people experienced CVD; the corresponding figure was 12 cases out of 2599 PWH exposed to other ART classes. At univariate and multivariate analysis, a tendency towards an increased risk of CVD was observed in the 2-year follow-up period in PWH exposed to INSTIs in the absence, however, of statistical significance. These findings leave open the hypothesis that INSTIs may play a role, albeit minimal, in determining an increased risk of CVD in PWH.

Evaluation of Lipid Profile and Intima Media Thickness in Antiretroviral-Experienced HIV-Infected Patients Treated with Protease Inhibitor-Based Regimens versus Protease Inhibitor-Sparing Regimens.

BACKGROUND: Antiretroviral therapy has increasingly improved management of HIV infection, ensuring long-term efficacy and tolerability. Each class of antiretrovirals has, however, different characteristics and different tolerability profiles. The literature data show that protease inhibitors (PIs) are associated with a higher incidence of dyslipidemia. The aim of our study was to evaluate whether patients treated with PIs have both greater dyslipidemia and increased intima media thickness (IMT) and atheromatous plaques compared to patients treated without PIs. MATERIALS AND METHODS: A total of 110 HIV-experienced patients screened with Doppler ultrasonography of the supra-aortic trunks in December 2019 were enrolled in a retrospective cross-sectional observational study. Patients were divided into two groups: 59 in the PI-based group, treated with PIs, and 51 in the PI-sparing group. In the two groups, we evaluated lipids, cardiovascular risk factors (smoking, BMI, age, hypertension), increased pathological IMT (a value > 1 mm), and possible atheromatous plaque. RESULTS: Serum LDL (p 0.04) and percentage of patients with hypercholesterolemia (p 0.03) were higher in the PI-based than in the PI-sparing group. Doppler data showed a trend in increase of IMT > 1 in the PI-based group, which appeared statistically significant for the section of the left common carotid artery (p 0.03). However, in multivariate logistic regression models, none of the evaluated variables were significantly associated with IMT > 1. CONCLUSIONS: Our real-life data show that patients treated with PIs have a trend of developing both greater dyslipidemia and increased pathological IMT and atheromatous plaques These findings may be useful to optimize antiretrovirals for patients with cardiovascular risk factors.

Lipids and Transaminase in Antiretroviral-Treatment-Experienced People Living with HIV, Switching to a Doravirine-Based vs. a Rilpivirine-Based Regimen: Data from a Real-Life Setting.

Doravirine (DOR) is a newly approved non-nucleoside reverse transcriptase inhibitor (NNRTI). We aimed to investigate, in a real-life setting, how switching to a DOR-based regimen rather than a rilpivirine (RPV)-based regimen impacted metabolic and hepatic safety. The analysis included 551 antiretroviral treatment (ART)-experienced people living with HIV (PLWH), starting RPV-based or DOR-based regimens with viral load < 200 copies/mL, baseline (T0), and at least one control visit (6-month visit, T1). We enrolled 295 PLWH in the RPV and 256 in the DOR cohort. At T1, total cholesterol (TC), low-density lipoprotein-C (LDL-C), and triglycerides significantly decreased in both DOR and RPV cohorts, while high-density lipoprotein-C (HDL-C) only decreased in RPV-treated people. Consistently, the TC/HDL-C ratio declined more markedly in the DOR (-0.36, p < 0.0001) than in the RPV cohort (-0.08, p = 0.25) (comparison p = 0.39). Similar trends were observed when excluding the PLWH on lipid-lowering treatment from the analysis. People with normal alanine aminotransferase (ALT) levels showed a slight ALT increase in both cohorts, and those with baseline ALT > 40 IU/L experienced a significant decline (-14 IU/L, p = 0.008) only in the DOR cohort. Lipid profile improved in both cohorts, and there was a significant reduction in ALT in PLWH with higher-than-normal baseline levels on DOR-based ART.

Obesity as a Risk Factor of Severe Outcome of COVID-19: A Pair-Matched 1:2 Case-Control Study.

BACKGROUND AND AIM: The nature of the association between obesity and poor prognosis of COVID-19 without the evaluation of other co-pathologies associated has not yet been clearly evaluated. The aim of the present pair-matched case-control study was to investigate the outcome of patients with SARS-CoV-2 infection in obese and non-obese patients matched considering gender, age, number of comorbidities, and Charlson Comorbidity Index. METHODS: All the adults hospitalized for SARS-CoV-2 infection and with BMI ≥ 30 kg/m2 were included (Cases). For each Case, two patients with BMI < 30 kg/m2 pair matched for gender, age (±5 years), number of comorbidities (excluding obesity), and Charlson Comorbidity Index (±1) were enrolled (Controls). RESULTS: Of the 1282 patients with SARS-CoV-2 infection followed during the study period, 141 patients with obesity and 282 patients without were enrolled in the case and control groups, respectively. Considering matching variables, there was no statistical difference between the two groups. Patients in the Control group developed more frequently a mild-moderate disease (67% vs. 46.1%, respectively), whereas obese patients were more prone to need intensive care treatment (41.8% vs. 26.6%, respectively; p = 0.001). Moreover, the prevalence of death during hospitalization was higher in the Case group than in the Control group (12.1% vs. 6.4%, p = 0.046). DISCUSSION: We confirmed an association between obesity and severe outcome of patients with COVID-19, also considering other factors associated with a severe outcome of COVID-19. Thus, in the case of SARS-CoV-2 infection, the subjects with BMI ≥ 30 kg/m2 should be evaluated for early antiviral treatment to avoid the development of a severe course.

Dynamics of Lipid Profile in Antiretroviral-Naïve HIV-Infected Patients, Treated with TAF-Based Regimens: A Multicenter Observational Study.

Background: The introduction of tenofovir alafenamide (TAF) in antiretroviral therapy has deeply modified the choice of the backbone for different treatment regimens, allowing the prevention of the bone and renal toxicity that was related to the previous formulation of tenofovir disoproxil fumarate (TDF). At the same time, literature data show an onset of dyslipidemia after a switch from TDF to TAF. To better understand the possible role of TAF in dyslipidemia, antiretroviral-naïve HIV-infected patients were evaluated, comparing those treated with TAF/emtricitabine with those with abacavir/lamivudine. Methods: We enrolled 270 antiretroviral-naïve HIV-infected patients in an observational, retrospective, longitudinal, multicenter study; they started treatment from 2017 to 2019 and were followed up for at least 72 weeks. We divided patients into two groups, one treated with a TAF-based backbone in their antiretroviral regimens (TAF group) and one without TAF (NO TAF group), to evaluate possible differences in the dynamics of lipid profiles from baseline(T0) to week 24 (T24), 48 (T48) and 72 (T72). Results: No significant differences were observed at baseline between the 2 groups. In the TAF group we observed a significant development of hypercholesterolemia throughout the follow-up (p < 0.0001), not evident in the NO TAF group, that instead showed a significant increase in high-density lipoprotein (HDL). There were no significant differences between the two groups regarding triglycerides, low-density lipoprotein (LDL) and cardiovascular risk index (CRI). A cholesterol-lowering treatment with statin, finally, was prescribed in 6 patients in both groups during the study. At binary logistic regression analysis, no factor was independently associated with hypercholesterolemia, except for higher age at T0. Conclusions: This real-life study shows that in HIV-naïve patients, TAF was associated with hypercholesterolemia throughout the follow-up. The clinical significance of this hypercholesterolemia will have to be clarified in further studies.

Changing epidemiology of patients treated with direct acting antivirals for HCV and persistently high SVR12 in an endemic area for HCV infection in Italy: real-life 'LIver Network Activity' (LINA) cohort update results.

BACKGROUND: Second generation direct acting antivirals (DAAs) drastically changed the landscape of chronic HCV (CHCV). Aim of this paper was to assess the effectiveness of DAAs, also looking at the demographic characteristics of subjects enrolled. RESEARCH DESIGN AND METHODS: Ambispective multi-center real-life study conducted among patients with CHCV treated with DAAs in Campania Region (Southern Italy). Patient were enrolled in two cohorts according to time of enrolment. RESULTS: 1,479 patients were enrolled. Patients aged ≥60 years were 74.7% in the historic cohort (953 patients) and 70.2% in the prospective cohort (526 patients. Patients aged ≥ 60 years showed a higher prevalence of genotype 1b (p<0.001) and 2 (p<0.001), while patients aged < 60 years showed a higher prevalence of genotype 1a (p<0.001), 3 (p<0.001) and 4 (p<0.05). SVR12 was 98.5% in both cohorts. SVR12 was similar among patients of the prospective cohort aged < and ≥ 60 years (99.4% vs 98.1%). SVR12 among patients with and without cirrhosis was 96.0% and 98.9%, respectively. CONCLUSIONS: DAAs provide high efficacy also in harder to treat patients. The effectiveness of DAAs is leading to a shift in patients characteristics with a greater prevalence of younger subjects and persons with mild liver disease.

Risk of failure in dual therapy versus triple therapy in naïve HIV patients: a systematic review and meta-analysis.

OBJECTIVES: Several attempts have been made to test different drug-sparing strategies to reduce the drug-burden and drug-related toxicities. The objective of this meta-analysis was to evaluate the relative risk (RR) of failure of dual therapies compared to triple therapies in HIV-naïve patients. METHODS: We searched MEDLINE, Google Scholar and the Cochrane Library. The following criteria were used: present data from original articles comparing the two treatment regimens; published from January 2007 up to January, 2020. No language or study design restriction was applied. Subjects were HIV-positive naïve patients treated with dual or triple antiretroviral therapy (ART). A systematic review and meta-analysis was performed. Treatment failure (TF) was the primary outcome evaluated; heterogeneity was assessed using the Q statistic and I2. RESULTS: Fourteen studies were included, allowing a meta-analysis on 5205 patients. The meta-analysis performed on studies that presented data at 48 weeks showed that the RR of TF (RR > 1 favouring triple therapy) in 10 studies was 1.20 (95% confidence interval (CI): 0.91-1.59, I2: 49.2%); the RR of virological failure (VF) in eight studies was 1.54 (95% CI: 0.84-2.86, I2: 54%); the RR of adverse drug reaction leading to discontinuation of the regimen at 48 weeks in eight studies was 0.76 (95% CI: 0.43-1.33, I2: 17.7%). In patients with less than 200 CD4+, the RR of TF in two studies without maraviroc was 2.09 (95% CI: 1.05-4.17, I2: 0.0%). Regarding the studies at 96 weeks there was no difference except in rate of development of resistance, RR 1.94 (95% CI: 1.06-3.53, I2: 6.2%). CONCLUSION: Dual therapies are as effective as those with three drugs, showing no difference according to the different dual therapies, except in patients with less than 200 CD4; however, they are associated with a higher selection of resistance-associated mutations at 96 weeks of therapy.

DAA-based treatment for HIV-HCV-coinfected patients: analysis of factors of sustained virological response in a real-life study.

BACKGROUND: The aim of the present study was to evaluate in HIV-infected patients treated with a direct-acting antiviral agent (DAA)-based regimen the variables associated with sustained virological response (SVR) and the trend in biochemical parameters and clinical events during and after DAA regimen. METHODS: We performed a multicentre retrospective cohort study, enrolling all 243 HIV-HCV-coinfected adult patients treated with DAAs between January 2015 and December 2018 in one of the nine participating Infectious Disease Centers in southern Italy, eight in Campania and one in Apulia. RESULTS: Of the 243 patients enrolled, 233 (95.9%) obtained an SVR at 12 weeks (SVR12). Of the 10 patients with non-SVR, 7 were tested for NS3, NS5A and NS5B resistance-associated substitutions (RASs) by sequencing analysis and 6 showed at least 1 major RAS in 1 HCV region (all in NS5A, 2 in NS5B and 1 in NS3). Comparing the 233 patients achieving SVR and the 10 non-achievers, no variable was independently associated with non-SVR. During and after DAA regimen, no modification in the biochemical parameters and clinical events was observed; however, the serum cholesterol and low-density lipoprotein (LDL) levels showed an increase (from 159 ±41.3 mg/dl at baseline to 174 ±44.5 mg/dl at week 12 after stopping treatment, P<0.001, and from 92 ±34.6 mg/dl to 109.4 ±73.7 mg/dl, P=0.002, respectively). CONCLUSIONS: The treatment with DAAs led to a high SVR12 rate in HIV-HCV-coinfected subjects, irrespective of epidemiological, clinical or virological characteristics. However, the DAA regimen was associated with an increase in total- and LDL-cholesterol, to be taken into account in the management of HIV infection.

Direct acting antivirals treatment for hepatitis C virus infection does not increase the incidence of de novo hepatocellular carcinoma occurrence: Results from an Italian real-life cohort (LINA cohort).

The effectiveness of direct-acting antivirals (DAAs) against hepatitis C virus (HCV) infection is ascertained. However, some authors raised the issue of an increased incidence of de novo hepatocellular carcinoma (HCC) in patients treated with DAAs. Aim of the study was to evaluate the rate of HCC occurrence in a real-life cohort of patients who received anti-HCV treatment with DAAs.A prospective multicentre study was conducted. All adult patients with HCV infection who received treatment between March 2015 and December 2017 in 4 hospital of Campania region (South Italy) with at least 6 months of follow-up were enrolled.A total of 323 patients were included in the study. Most patients had HCV genotype 1b (61.8%). The overall SVR12 rate was 95.5%. Median time of observation was 10 months. The incidence rate of HCC was 0.2 per 100 person-months (crude incidence rate 3.4%, 95 confidence interval: 1.5%-5.3%). The median time for HCC occurrence was 11 months. HCC occurrence rate was significantly higher among patients who did not achieve SVR12 compared with patients who did (28.6% vs 2.8%, P < 0.05). No patient with F0-F3 fibrosis developed HCC. Among patients with cirrhosis, at the multivariate time-to-event analysis, no covariates were independently associated with the risk of HCC occurrence.Treatment with DAAs did not increase the risk of HCC occurrence. Patients who achieved SVR12 had a lower rate of HCC occurrence. Further studies are needed to estimate the incidence and the risk for HCC in the long-term follow-up among patients undergoing treatment with DAAs.

Reactivation of hepatitis B virus infection in patients with hemo-lymphoproliferative diseases, and its prevention.

Reactivation of hepatitis B virus (HBV) replication is characterized by increased HBV-DNA serum values of about 1 log or by HBV DNA turning positive if previously undetectable in serum, possibly associated with liver damage and seldom life-threatening. Due to HBV reactivation, hepatitis B surface antigen (HBsAg)-negative/anti-HBc-positive subjects may revert to HBsAg-positive. In patients with hemo-lymphoproliferative disease, the frequency of HBV reactivation depends on the type of lymphoproliferative disorder, the individual's HBV serological status and the potency and duration of immunosuppression. In particular, it occurs in 10%-50% of the HBsAg-positive and in 2%-25% of the HBsAg- negative/anti-HBc-positive, the highest incidences being registered in patients receiving rituximab-based therapy. HBV reactivation can be prevented by accurate screening of patients at risk and by a pharmacological prophylaxis with anti-HBV nucleo(t)sides starting 2-3 wk before the beginning of immunosuppressive treatment and covering the entire period of administration of immunosuppressive drugs and a long subsequent period, the duration of which depends substantially on the degree of immunodepression achieved. Patients with significant HBV replication before immunosuppressive therapy should receive anti-HBV nucleo(t)sides as a long-term (may be life-long) treatment. This review article is mainly directed to doctors engaged every day in the treatment of patients with onco-lymphoproliferative diseases, so that they can broaden their knowledge on HBV infection and on its reactivation induced by the drugs with high immunosuppressive potential that they use in the care of their patients.

Quantification of HIV-DNA and residual viremia in patients starting ART by droplet digital PCR: Their dynamic decay and correlations with immunological parameters and virological success.

BACKGROUND: Accurate quantification of total HIV-DNA and residual-viremia by sensitive assays is extremely useful to optimize monitoring of ART-treated patients. OBJECTIVES: To evaluate the performances of two ddPCR-based assays for HIV-DNA and residual-viremia quantification, and the correlations of pre-ART HIV-DNA with plasma HIV-RNA, CD4 + T, CD4/CD8 and virological-success (VS) during first-line ART. STUDY DESIGN: Plasma HIV-RNA, total HIV-DNA, CD4 + T, CD4/CD8 were evaluated at baseline of ART, at VS (viral-load <50copies/ml), and at 6 months after VS (6moVS) in 57 newly-diagnosed HIV-1 infected patients, receiving first-line modern ART. HIV-DNA (log10 copies/106CD4 + T) and residual-viremia (copies/ml) were measured with in-house ddPCR assays. Correlations were assessed by Spearman and Jonckheere-Terpstra tests. RESULTS: HIV-DNA and residual-viremia assays showed a good linear trend between the expected and obtained values (R2 = 0.9913 and 0.9945); lower limits of detection were 32 copies/106CD4 + T and 2 copies/ml, respectively. At baseline, median (IQR) plasma HIV-RNA and HIV-DNA were 4.88(4.28-5.36)log10 copies/ml and 4.00(3.36-4.51) log10 copies/106CD4 + T cells. Residual-viremia was 8(2-26) and 4(2-12) copies/ml at VS and 6moVS. Pre-ART HIV-DNA positively correlated with plasma HIV-RNA at BL (Rho = 0.708, p < 0.001), and with residual-viremia at VS (Rho:0.383,p = 0.002). Notably, higher HIV-DNA correlated with longer time to achieve VS (median[IQR],weeks: 17.8[12.3-29.0] for HIV-DNA ≥4.5 vs. 7.4[4.1-8.7] for HIV-DNA<4.5, p < 0.001). Furthermore, pre-ART HIV-DNA negatively correlated with CD4 + T and CD4/CD8 at baseline, VS and 6moVS. CONCLUSIONS: Our results support the adoption of ddPCR-based assays for both HIV-DNA and residual-viremia quantifications and corroborate that pre-ART HIV-DNA is an excellent indicator in predicting viroimmunological response and VS in patients starting ART.

Interferon-free regimens improve kidney function in patients with chronic hepatitis C infection.

BACKGROUND AND AIM: The impact of directly acting antiviral agent (DAA) regimens on renal function is not well defined and quite controversial. We evaluated the effect of DAAs on kidney function and the factors associated with an improvement or worsening. PATIENTS AND METHODS: The changes in estimated glomerular filtration rate (eGFR) in a cohort of 403 patients treated with a DAA regimen were evaluated. RESULTS: The overall sustained virological response (SVR12) rate was 98%. The median eGFR progressively increased throughout treatment from 84.54 ml/min/1.73 m2 (IQR 70.8-97.3) to 88.12 ml/min/1.73 m2. Conversely, rates of patients with a eGFR more than 60 ml/min/1.73 m2 progressively increased from 83.1% at baseline to 87.8% at 12 weeks post-treatment (p < 0.05). Considering the change in eGFR according to the different factors, a significant improvement in eGFR was observed in the patients without diabetes (p < 0.001), in those with cirrhosis (p < 0.05), in those receiving a Sof-based regimen (p < 0.01) or not receiving RBV (p < 0.05), in those with a baseline eGFR less than 60 ml/min/1.73 m2 (p < 0.001) and in those with SVR (p < 0.05). An improvement in eGFR (defined as an increase in baseline eGFR of at least 10 ml/min/1.73 m2) was observed in 148 patients (36.7%). At multivariate analysis, age (aHR 0.96; 95 CI 0.93-0.99, p < 0.01) and a diagnosis of diabetes (aHR 0.02; 95 CI 0.20-0.87, p < 0.05) were inversely and independently associated with improvement in renal function, while the presence of Child-Pugh B cirrhosis at baseline was associated with an improvement in renal function (aHR 3.07; 95 CI 1.49-6.30, p < 0.01). CONCLUSIONS: DAAs correlate with an improvement in renal function, underlining the importance of hepatitis C virus eradication to achieve also an improvement in extra-hepatic disorders.

Efficacy of the "first wave" Direct Acting antivirals against HCV infection: results from the Italian LINA (Liver Network Activity) cohort.

Approximately 71 million people are chronically infected with HCV worldwide. Recently, interferonfree therapies effective against HCV became available and nowadays, therapeutic strategies include a combination of two or three drugs with different mechanisms of action. In the present study, we reported real-life SVR rates in a large cohort of four prescribing centers in a high-endemic area of Southern Italy. We conducted a prospective multicenter study among all the patients with chronic HCV infection, who received therapy with the first available interferon-free therapies between March 2015 and December 2017 and who referred to one of the 4 DAA-prescribing centers in Campania, Southern Italy. Patients with Child C cirrhosis, a diagnosis of active HCC at the baseline or who refused the consent form, were excluded. Nine-hundred fifty-three patients were enrolled. Most of the enrolled patients had HCV genotype 1b infection (66.4%), were older than 65 years (64.1%) and had advanced liver fibrosis (Metavir > F4) (73.5%). The overall SVR12 rate was 98.5%. Patients with clinical cirrhosis had a similar SVR12 rate compared with those without cirrhosis (97.8% vs 99.2%, p=0.09), while patients with decompensated cirrhosis had a significantly lower rate of SVR12 compared with those without decompensated disease (95.3% vs 99.0%, p<0.05). Patients aged more than 65 years had a similar rate of SVR12 compared with patients aged ≤ 65 years (98.6% vs 98.0%, p=0.57). Among patients >65 years, those with clinical cirrhosis, as well as those with advanced liver fibrosis, had a similar SVR12 rate compared with the patients with a Metavir score < F4 (98.3% vs 99.0%, p=0.70 and 98.6% vs 98.6%, p=1.00, respectively). In the present, real-life study, DAA regimens are effective and safe in patients with chronic HCV infection, regardless of age and stage of liver disease, providing very high rates of SVR12 (98.5%).

Patients with HCV genotype-1 who have failed a direct-acting antiviral regimen: virological characteristics and efficacy of retreatment.

BACKGROUND: This real-world clinical setting study characterized the virological patterns in genotype-1 patients failing interferon (IFN)-free regimens and evaluated the efficacy of re-treatment. METHODS: A total of 73 consecutive patients failing IFN-free regimens were enrolled (17 genotype-1a and 56 -1b). At failure Sanger sequencing of NS3, NS5A and NS5B regions was performed by home-made protocols. RESULTS: In patients having failed an NS3 inhibitor, the prevalence of NS3-RASs was higher in the 10 with genotype-1a than in the 24 with genotype-1b (80% versus 41.6%). In patients treated with an NS5A inhibitor, the prevalence of NS5A-RASs was very high in the 14 with genotype-1a and the 27 with genotype-1b (78.6% and 92.5%, respectively). In patients having failed sofosbuvir, the prevalence of NS5B-RASs was more frequently identified in the 45 with genotype-1b than in the 10 with genotype-1a (37.7% versus 10%). The prevalence of NS5B-RASs in patients having failed dasabuvir was high in both genotypes, 66.6% in the 6 with genotype-1a and 45.5% in the 11 with genotype-1b. The 6 patients re-treated with genotype-1a less frequently (50%) showed sustained virological response (SVR) than the 18 with genotype-1b (88.8%; P=0.07). SVR was more frequent in the 21 patients with an effective second-line direct-acting antiviral (DAA) regimen than the 3 without (90.4% versus 0%; P<0.005). CONCLUSIONS: The prevalence of RASs was high in our real-world population. NS3, NS5A and NS5B sequencing seems mandatory in the choice of DAA re-treatment.

Treatment with direct-acting antivirals improves the clinical outcome in patients with HCV-related decompensated cirrhosis: results from an Italian real-life cohort (Liver Network Activity-LINA cohort).

BACKGROUND: Direct-acting antivirals (DAAs) are safe and effective for the treatment of HCV infection. However, data regarding their efficacy in patients with Child-Pugh B cirrhosis are scarce and their capability in improving liver function is debated. The aim of our study was to assess the clinical benefits of treatment with DAA in subjects with Child-Pugh B cirrhosis. METHODS: We conducted a prospective multicentre study among patients with Child-Pugh B cirrhosis of an Italian real-life HCV cohort (LINA cohort) who received treatment with DAAs. RESULTS: Among 89 patients enrolled, the rate of sustained virologic response 12 was 95.5%. No discontinuation occurred, no patient died during treatment. Most patients had Genotype 1 (1b 61.8%, 1a 11.2%). Conversely, 22.5%, 1.1% and 3.4% of patients had Genotype 2, 3 and 4, respectively. At last observation, 61.8% of patients switched to a Class A cirrhosis, 33.7% remained in Class B and 4.5 worsened to Child C (p < 0.001). Liver parameters significantly improved from baseline to 12 weeks after the end of treatment. Previous anti-HCV treatments and the presence of decompensated cirrhosis at 1 month of treatment were significantly associated with a decompensated cirrhosis at the last observation. CONCLUSIONS: Treatment with DAA in patients with Child-Pugh B cirrhosis is safe and leads to a very high rate of viral clearance, a significant rate of re-compensation and an improvement in liver function. Further studies are needed to assess the impact of treatment on survival and quality of life in long-term follow-up.

Management of HBV reactivation in non-oncological patients.

INTRODUCTION: HBV reactivation (HBVr) in patients undergoing immunosuppressive therapy is a well-known event. While there are clear directives on the management of current or resolved HBV infection in onco-hematological diseases, there are few data regarding patients with non-oncological diseases. Thus, the aim of the present review is to evaluate HBVr in patients with non-oncological diseases, and identify the management of these patients to prevent HBVr. Areas covered: Original papers, case reports and meta-analyses reporting data on HBVr of current or resolved infection in gastrointestinal, dermatological, rheumatologic and neurological diseases were evaluated. Expert commentary: In HBsAg-positive subjects, those with HBV-related hepatitis (both HBeAg-positive or negative) should be treated with a high genetic barrier nucleos(t)ide analog. The patients with HBV-infection (both HBeAg-positive and negative) an antiviral prophylaxis should be used, with lamivudine in those HBeAg-negative without signs of advanced liver disease, and with ETV, TDF or TAF in all the HBeAg-positive or in those HBeAg-negative with signs of advanced liver disease. In HBsAg-negative/anti-HBc positive subjects, when the risk of HBV reactivation is moderate (use of B-cell depleting agents), a prophylaxis-strategy may be considered; instead, in those with low risk of HBVr, a pre-emptive therapy strategy may be used.

Virological patterns of HCV patients with failure to interferon-free regimens.

The study characterized the virological patterns and the resistance-associated substitutions (RASs) in patients with failure to IFN-free regimens enrolled in the real-life setting. All 87 consecutive HCV patients with failed IFN-free regimens, observed at the laboratory of the University of Campania, were enrolled. All patients had been treated with DAA regimens according to the HCV genotype, international guidelines, and local availability. Sanger sequencing of NS3, NS5A, and NS5B regions was performed at failure by home-made protocols. Of the 87 patients enrolled, 13 (14.9%) showed a misclassified HCV genotype, probably causing DAA failure, 16 had been treated with a sub-optimal DAA regimen, 19 with a simeprevir-based regimen and 39 with an optimal DAA regimen. A major RAS was identified more frequently in the simeprevir regimen group (68.4%) and in the optimal regimen group (74.4%) than in the sub-optimal regimen group (56.3%). The prevalence of RASs in NS3 was similar in the three groups (30.8-57.9%), that in NS5A higher in the optimal regimen group (71.8%) than in the sub-optimal regimen group (12.5%, P < 0.0001) and in the simeprevir regimen group (31.6%, P < 0.0005), and that in NS5B low in all groups (0-25%). RASs in two or more HCV regions were more frequently identified in the optimal regimen group (46.6%) than in the simeprevir-based regimen group (31.6%) and sub-optimal regimen group (18.7%). In our real-life population the prevalence of RASs was high, especially in NS3 and NS5A and in those treated with suitable DAA regimens.

Effects of treatment with Maraviroc a CCR5 inhibitor on a human hepatic stellate cell line.

After an acute liver damage, tissue regeneration repairs lesions with degradation of deposed fibrotic material, while mechanisms of tissue restoration are persistently activated following several repeated injuries, inducing deposition of extracellular matrix. (ECM). Factors responsible for ECM remodeling have been identified in a pathway involving a family of zinc-dependent enzyme matrix metalloproteinases (MMPs), together with tissue inhibitor of metalloproteinases (TIMPs). Recent experimental models suggested a role of CCR5 receptor in the genesis of liver fibrosis. Drawing from these background we decided to evaluate the effects of the treatment with the CCR5 inhibitor Maraviroc on LX-2, a human hepatic stellate cell line (HSC). Treatment with Maraviroc resulted in a block in S phase of LX-2 cells with increased expression levels of cyclin D1 and p21 while the expression of p53 was reduced. Treatment with Maraviroc was also able to block the accumulation of fibrillar collagens and extracellular matrix proteins (ECM), as demonstrated by the decrease of specific markers as Collagen type I, α-SMA, and TGF-ß1. In addition we observed a down regulation of both metalloproteins (MMP-2, MMP-9), used for the degradation of the extracellular matrix and their inhibitors (TIMP-1, TIMP-2). The identification of a compound that may modulate the dynamic of liver fibrosis could be crucial in all chronic liver diseases. Maraviroc could play an important role because, in addition to its own anti-HIV activity, it could reduce the release of pro-inflammatory citokynes implicated in liver fibrogenesis.