Effectiveness of different local actions to control vitamin D prescription in Italy.

INTRODUCTION: In the last decade, the significant expenditure and consumption increase of vitamin D in Italy led some regions to adopt strategies to improve prescribing appropriateness and contain expenditure. MATERIALS AND METHODS: Using the statistical analysis method of interrupted time series for consumption and expenditure of cholecalciferol, different types of interventions adopted in four Italian regions and their efficacy were evaluated. RESULTS: Molise achieved the best results by adopting a health professionals' education program in addition to a prescriber-sanction system. Emilia-Romagna also opted for a medical education strategy, but the results were less relevant due to the lack of penalties. Lazio obtained a slowdown in consumption growth by targeting on the utilization of lower-cost per defined daily dose (DDD) packs and adopting a therapeutic plan. Sardinia showed a decrease in expenditure by adopting a target threshold of lower-cost formulation. CONCLUSION: The reimbursement of the lowest-cost packs within the National Health Service (NHS) undoubtedly influences spending trend, but it does not solve prescriptive inappropriateness.

[Prescribing appropriateness, use and consumption of antibiotics in Italy. An extract from the National Report 2018.] / Appropriatezza prescrittiva, uso e consumo degli antibiotici in Italia Un estratto del Rapporto Nazionale 2018 sull'uso degli antibiotici in Italia.

INTRODUCTION: Antimicrobial resistance is a major global public health concern. In Italy, in 2017, the National Plan to Fight Antimicrobial Resistance (PNCAR 2017-2020) was approved, in line with the Global One Health Action Plan. Despite the decreasing trend, the consumption of antibiotics in Italy continues to be higher than the European average, with a great variability between regions. In the European investigation on the distribution of resistant bacteria in Europe, Italy holds together with Greece the record for the spread of resistant germs. OBJECTIVE: The present study, dedicated to antibiotics for human use, allows to monitor the trend of consumption and expenditure in Italy and at the same time to identify areas of potential inappropriateness of use. METHODS: The analyses presented concern the use of antibiotics in the community setting, with a focus on consumption in the paediatric population and on the prescription of fluoroquinolones in specific population subgroups. In addition, the analysis on the use of antibiotics in hospital settings, the analysis on the private purchase of reimbursed antibiotics and the evaluation of indicators of appropriateness of antibiotic prescribing were also included. The analyses are based on the reading and integration of the data collected through different administrative healthcare databases: OsMed, Purchase by public health facilities, Direct distribution, Hospital consumption, Monitoring of pharmaceutical prescriptions, Private purchase by citizens, Hospital Discharge Records (Schede di Dimissione Ospedaliera, SDO), InfluNet surveillance. RESULTS: The consumption of antibiotics in Italy in 2018 stood at 21.4 DDD/1000 ab. die and, despite the downward trend, is still above the European average. In terms of consumption within the territory (community setting), there is a considerable regional variety - ranging from 8.9 of the provincial government of Bolzano to 23.4 DDD/1000 ab. die of Campania (national average 16.1 DDD) - with higher values in the South and the Islands and lower in the North. The differences in drug use concern not only the number of prescriptions but also the type of antibiotics prescribed (type of molecules; broad spectrum vs. narrow spectrum). The association amoxicillin/clavulanic acid is the most widely used antibiotic both in the community and in hospitals. In the paediatric population (0-13 years) there is a peak prevalence of use of 50% in the first year of life of the child, with no differences between males and females. The consumption of antibiotics in hospitals is increasing in the three-year period 2016-2018 and presents a wide variability between different geographical areas.

Safety and efficacy of ombitasvir/paritaprevir/ritonavir/dasabuvir plus ribavirin in patients over 65 years with HCV genotype 1 cirrhosis.

PURPOSE: To analyse safety and efficacy of treatment based on ombitasvir/paritaprevir/ritonavir/dasabuvir plus ribavirin in the sub-group of GT1 patients older than 65 years. METHODS: We collected data extracted from the ABACUS compassionate-use nationwide Italian programme, in patients with cirrhosis due to hepatitis C virus (HCV) Genotype-1 (GT1) or 4 and at high risk of decompensation. GT1-HCV-infected patients received once-daily ombitasvir/paritaprevir, with the pharmacokinetic enhancer ritonavir (25/150/100 mg) and twice-daily dasabuvir (250 mg) plus Ribavirin (RBV) (OBV/PTV/r + DSV + RBV) for 12 (GT1b) or 24 (GT1a) weeks. Endpoints were to evaluate safety and efficacy, the latter defined as HCV RNA negative 12 weeks after the end of treatment (SVR12). RESULTS: Patients who suffered any adverse event (AE) were 74/240 (30.8%); 13/240 (5.4%) discontinued the treatment. A multivariate analysis found albumin < 3.5 g/dL (OR 2.04: 95% CI 1.0-4.2, p < 0.05) and hypertension (OR 4.6: 95% CI 2.3-9.2, p < 0.001) as variables independently associated with AE occurrence. The SVR12 was 95% (228/240). Multivariate analysis identified baseline bilirubin < 2 mg/dL (OR 4.9: 95% CI 1.17-20.71, p = 0.029) as the only variable independently associated with SVR12. CONCLUSION: Our findings suggest that OBV/PTV/r + DSV + RBV is safe and effective in real-life use in patients with compensated cirrhosis, HCV-GT1 infection, and age over 65.

The Italian compassionate use of sofosbuvir in HCV patients waitlisted for liver transplantation: A national real-life experience.

BACKGROUND & AIMS: This study aimed to assess the real-life clinical and virological outcomes of HCV waitlisted patients for liver transplantation (LT) who received sofosbuvir/ribavirin (SOF/R) within the Italian compassionate use program. METHODS: Clinical and virological data were collected in 224 patients with decompensated cirrhosis and/or hepatocellular carcinoma (HCC) receiving daily SOF/R until LT or up a maximum of 48 weeks. RESULTS: Of 100 transplanted patients, 51 were HCV-RNA negative for >4 weeks before LT (SVR12: 88%) and 49 negative for <4 weeks or still viraemic at transplant: 34 patients continued treatment after LT (bridging therapy) (SVR12: 88%), while 15 stopped treatment (SVR12: 53%). 98 patients completed SOF/R without LT (SVR12: 73%). In patients with advanced decompensated cirrhosis (basal MELD ≥15 and/or C-P ≥B8), a marked improvement of the scores occurred in about 50% of cases and almost 20% of decompensated patients without HCC reached a condition suitable for inactivation and delisting. CONCLUSIONS: These real-life data indicate that in waitlisted patients: (i) bridging antiviral therapy can be an option for patients still viraemic or negative <4 weeks at LT; and (ii) clinical improvement to a condition suitable for delisting can occur even in patients with advanced decompensated cirrhosis.

The Italian compassionate use of sofosbuvir observational cohort study for the treatment of recurrent hepatitis C: clinical and virological outcomes.

Direct antivirals are available for treating recurrent hepatitis C (RHC). This study reported outcomes of 424 patients with METAVIR F3-F4 RHC who were treated for 24 weeks with sofosbuvir/ribavirin and followed for 12 weeks within the Italian sofosbuvir compassionate use program. In 55 patients, daclatasvir or simeprevir were added. Child-Pugh class and model of end stage liver disease (MELD) scores were evaluated at baseline and 36 weeks after the start of therapy. The sustained viral response (SVR) was 86.7% (316/365) in patients who received sofosbuvir/ribavirin and 98.3% (58/59) in patients who received a second antiviral (P < 0.01). In patients treated with sofosbuvir/ribavirin, a significant difference in SVR was observed between patients diagnosed with METAVIR F4 (211/250; 84.4%), METAVIR F3 (95/105; 90.5%) and fibrosing cholestatic hepatitis (10/10; 100%) (P = 0.049). A significant association was found between patients who worsened from Child-Pugh class A and who experienced viral relapse (4/26 vs. 8/189, P = 0.02). In patients with a baseline MELD score <15, a significant association was found between maintaining a final MELD score <15 and the achievement of SVR (187/219 vs. 6/10, P = 0.031). This real-world study indicates that sofosbuvir/ribavirin treatment for 24 weeks was effective, and the achievement of SVR was associated with a reduced probability of developing worsening liver function.

Role of serum free light chains in predicting HIV-associated non-Hodgkin lymphoma and Hodgkin's lymphoma and its correlation with antiretroviral therapy.

A nested case-control study was performed within the Italian cohort of naïve to antiretroviral human immunodeficiency virus (HIV) patients (ICONA) cohort to evaluate the role of serum free light chains (sFLC) in predicting non-Hodgkin's lymphoma (NHL) and Hodgkin lymphoma (HL) in HIV-infected individuals. Of 6513 participants, 86 patients developed lymphoma and 46 of these (NHL, 30; HL, 16) were included in this analysis having stored prediagnostic blood. A total of 46 serum case samples matched 1:1 to lymphoma-free serum control samples were assayed for κ and λ sFLC levels and compared by using conditional logistic regression. Because the polyclonal nature of free light chains (FLCs) was the focus of our study, we introduced the k + λ sum as the measurement of choice and as the primary variable studied. κ + λ sFLC values were significantly higher in patient with lymphoma than in controls, especially when considering samples stored 0-2-year period before the lymphoma diagnosis. In the multivariable analysis, the elevation of sFLC predicted the risk of lymphoma independently of CD4 count, (odd ratio of 16.85 for k + λ sFLC >2-fold upper normal limit (UNL) vs. normal value). A significant reduction in the risk of lymphoma (odd ratio of 0.07 in model with k + λ sFLC) was found in people with low sFLC and undetectable HIV viremia lasting more than 6 months. Our analysis indicates that an elevated polyclonal sFLC is a strong and sensitive predictor of the risk of developing lymphomas, and it is an easy to measure biomarker that merits consideration for introduction in routine clinical practice in people with HIV.

Beyond virological suppression: the role of adherence in the late HAART era.

HAART has increased the life expectancy of HIV-infected individuals significantly. Optimal adherence to HAART results in viral suppression and immune recovery in the majority of HIV-infected persons. Data from the early HAART era suggest that adherence levels of greater than 95% are necessary to achieve and maintain virological suppression. However, the optimal threshold of adherence required to maximize the pharmacological benefits of contemporary antiretroviral regimens, particularly in the virologically suppressed patient, is unknown. This review examines new data on the role of adherence in the late HAART era, focusing on virological, immunological and epidemiological aspects. We begin with a discussion of the impact of adherence on viral dynamics and immunological parameters in the virologically suppressed patient. We then review the importance of adherence in emerging antiretroviral treatment strategies. Finally, we summarize accumulating data on the role of antiretroviral adherence in the prevention of HIV transmission. Taken together, the data reviewed reinforce the critical importance of adherence in the management of HIV infection in the late HAART era.

Rate of CD4+ cell count increase over periods of viral load suppression: relationship with the number of previous virological failures.

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.

Impact of metabolic complications on antiretroviral treatment adherence: clinical and public health implications.

Antiretroviral therapy (ART) is an effective strategy for preventing disease progression of HIV infection, particularly when patients adhere closely to the treatment regimen. However, ART medications can cause side effects, including metabolic complications that can impact patients' adherence levels. Selected chronic complications associated with ART include lipodystrophy, hyperlipidemia, insulin resistance and diabetes, peripheral neuropathy, and bone disorders such as osteopenia/osteoporosis. In this article, we review the effects of these metabolic complications on ART adherence and approaches to prevent or reverse them.

Dynamics of NRTI resistance mutations during therapy interruption.

Abstract To date, very little information is available regarding the evolution of drug resistance mutations during treatment interruption (TI). Using a survival analysis approach, we investigated the dynamics of mutations associated with resistance to nucleoside analogue reverse transcriptase inhibitors (NRTIs) during TI. Analyzing 132 patients having at least two consecutive genotypes, one at last NRTI-containing regimen failure, and at least one during TI, we observed that the NRTI resistance mutations disappear at different rates during TI and are lost independently of each other in the majority of patients. The disappearance of the K65R and M184I/V mutations occurred in the majority of patients, was rapid, and was associated with the reemergence of wild-type virus, thus showing their negative impact on viral fitness. Overall, it seems that the loss of NRTI drug resistance mutations during TI is not an ordered process, and in the majority of patients occurs without specific interaction among mutations.

Treatment with the fusion inhibitor enfuvirtide influences the appearance of mutations in the human immunodeficiency virus type 1 regulatory protein rev.

The gp41-encoding sequence of the env gene contains in two separate regions the Rev-responsive elements (RRE) and the alternative open reading frame of the second exon of the regulatory protein Rev. The binding of Rev to the RRE allows the transport of unspliced/singly spliced viral mRNAs out of the nucleus, an essential step in the life cycle of human immunodeficiency virus type 1 (HIV-1). In this study, we have investigated whether the fusion-inhibitor enfuvirtide (ENF) can induce mutations in Rev and if these mutations correlate with the classical ENF resistance gp41 mutations and with viremia and CD4 cell count. Specific Rev mutations were positively associated with ENF treatment and significantly correlated with classical ENF resistance gp41 mutations. In particular, a cluster was observed for the Rev mutations E57A (E57A(rev)) and N86S(rev) with the ENF resistance gp41 mutations Q40H (Q40H(gp41)) and L45M(gp41). In addition, the presence at week 48 of the E57A(rev) correlates with a significant viremia increase from baseline to week 48 and with a CD4 cell count loss from baseline to week 48. By modeling the RRE structure, we found that the Q40(gp41) and L45(gp41) codons form complementary base pairs in a region of the RRE involved in Rev binding. The conformation of this Rev-binding site is disrupted when Q40H(gp41) and L45M(gp41) occur alone while it is restored when both mutations are present. In conclusion, our study shows that ENF pressure may also affect both Rev and RRE structures and can provide an excellent example of compensatory evolution. This highlights the multiple roles of ENF (and perhaps other entry inhibitors) in modulating the correct interplay between the different HIV-1 genes and proteins during the HIV-1 life cycle.

Self-reported sexual dysfunction is frequent among HIV-infected persons and is associated with suboptimal adherence to antiretrovirals.

Increased occurrence of sexual dysfunction (SD) among patients treated with highly active antiretroviral therapy (HAART) has been reported. To assess prevalence of self-reported SD and to identify factors related to this alteration with special focus to its relationship with adherence behavior, we conducted an intercohort analysis among HIV-infected persons treated with HAART. In an anonymous questionnaire investigating HAART nonadherence, patients were asked to report the occurrence of dysfunction in sexual activity over the previous 4 weeks. Among 612 participants, 125 (21%) reported some degree of SD. "Moderate"/"severe" alterations were reported in 6% and were independently associated with self-reported worsening of viro-immunological parameters (OR 3.90; 95% CI 1.08-14.18), higher symptom score (OR 1.13; 95% CI 1.05-1.22), and reporting abnormal fat accumulation (OR 4.33; 95% CI 1.55-12.11). Furthermore, nonadherent persons had an increased risk of SD (OR 3.44; 95% CI 1.30-9.08). In conclusion, patients' perceived SD represents a relevant problem for HIV-infected persons treated with antiretrovirals and is strongly associated with suboptimal HAART adherence.

Improved interpretation of genotypic changes in the HIV-1 reverse transcriptase coding region that determine the virological response to didanosine.

BACKGROUND: Consensus on the interpretation of mutations in the human immunodeficiency virus (HIV)-1 reverse transcriptase (RT) gene that predict the response to didanosine treatment is needed. METHODS: Baseline HIV-1 RT genotypes and 12-week virological outcomes for patients undergoing didanosine-containing salvage regimens were extracted from prospective studies. Existing didanosine genotypic-resistance interpretation rules were validated in the entire-patient data set. Mutations were given weighted positive or negative scores according to their coefficient of correlation with virological response in a derivation set. The score resulting from the algebraic sum of the mutations was then validated in an independent data set. RESULTS: A total of 485 patients were analyzed. The didanosine-resistance scores derived from the Jaguar and Gesca studies predicted virological outcome. The best correlation with response was found with the derived score (M41L x 2) + E44D/A/G + T69D/S/N/A + (L210W x 2) + T215Y or revertants + L228H/R - D123E/N/G/S, by use of which viruses were categorized as being susceptible (score < or =0), as having intermediate resistance (1-3), and as being resistant (> or =4) to didanosine. In the validation set, the adjusted mean difference in 12-week virological response was +0.34 log(10) copies/mL (95% confidence interval, +0.11 to +0.57; P=.004) per higher resistance category. Correlation with virological response constantly outperformed that obtained with the previous interpretation. CONCLUSION: The improved genotypic-resistance interpretation score can be applied to better guide the use of didanosine in treatment-experienced individuals.

The V118I mutation as a marker of advanced HIV infection and disease progression.

BACKGROUND: The V118I mutation is included in the nucleoside analogue mutations (NAMs) set. It contributes to thymidine-analogue resistance and, consequently, to resistance to the whole nucleoside reverse transcriptase inhibitor (NRTI) class. We focused on the V1181 mutation in order to evaluate factors associated with its detection and its relationship with HIV progression. METHODS: Clinical and laboratory data at genotypic resistance test (GRT) of highly active antiretroviral therapy-failing patients were collected and their association with the V1181 mutation was analysed. Patients were also followed over time to determine factors related to progression to a new AIDS-related event or death. RESULTS: Of the 792 patients included, 114 (14.4%) carried the V118I mutation. In univariate analysis, the V118I mutation was significantly associated with a higher HIV RNA level, lower CD4+ T-cell count, Centers for Disease Control and Prevention (CDC) stage C, higher number of pre-GRT regimens and class-wide resistance (CWR) to NRTIs, protease inhibitors and nonnucleoside reverse transcriptase inhibitors. Higher numbers of pre-GRT regimens and NRTI CWR were also associated in the multivariable analysis. Within the post-GRT observation period of up to 6 years (median: 72 months; interquartile range: 33-109) 107 events (58 new AIDS-related diseases and 49 deaths) were observed. Using the Cox proportional hazard model and the major clinical, behavioural and laboratory data, the V118I mutation was found to be associated with the endpoint (hazard ratio: 1.93, 95% confidence interval: 1.06-3.50; P=0.031). Other factors associated with disease progression were CDC stage C and lower CD4+ T-cell count at GRT. CONCLUSIONS: The analysis of our observational database suggests that the onset of the V118I mutation after treatment failure is unfavourable for the patient and can be considered a strong marker of disease progression.

Effectiveness of a multi-disciplinary standardized management model in the treatment of chronic hepatitis C in drug addicts engaged in detoxification programmes.

AIM: To evaluate the effect of a multi-disciplinary standardized management model on the efficacy of pegylated (Peg)-interferon alpha-2b plus ribavirin treatment of chronic hepatitis C in drug addicts undergoing substitutive or antagonist therapy. DESIGN: Observational prospective multi-centre study. SETTING: Six clinical infectious disease centres in collaboration with 11 drug dependency units (DDU) in five Italian regions. PARTICIPANTS: Intravenous drug users affected by chronic hepatitis C engaged in detoxification programmes. METHODS: Application of a multi-disciplinary standardized management model for HCV treatment involving DDU operators, psychologists or psychiatrists and infectious disease specialists. MEASUREMENTS: Very early, early, end-of-treatment and sustained virological response to Peg-interferon alpha-2b plus ribavirin. FINDINGS: Fifty-three subjects were studied [43.4% with hepatitis C virus (HCV) genotypes 1 or 4]. Intent-to-treat analysis showed an end-of-treatment virological response in 58.5% of patients (39.1% genotypes 1 or 4; 73.4% genotype 3) and a sustained virological response in 54.7% (34.8% genotypes 1 or 4; 70.0% genotype 3). There were 19 (35.8%) dropouts and three (5.7%) non-responders: one genotype 1 and two genotype 4. Two (3.8%) patients relapsed: genotypes 1 and 3. On-treatment analysis showed negative HCV-RNA in 40 (93.1%) of 43 subjects who completed the first 12 treatment weeks and in 35 who completed the first 24 treatment weeks. All subjects with an end-of-treatment response, except one with genotype 3 infection, had a sustained response. CONCLUSIONS: Our data show that antiviral treatment in the context of a multi-disciplinary standardized management model helps many HCV-positive drug addicts achieve a good virological response.

Virological response to salvage therapy in HIV-infected persons carrying the reverse transcriptase K65R mutation.

BACKGROUND: The effect of the HIV reverse transcriptase K65R mutation on virological response to salvage therapy has not been clearly defined. METHODS: From six Italian clinical centres, all consecutive patients starting salvage antiretroviral therapy after virological failure in the presence of the K65R mutation identified by a genotypic resistance test were selected. RESULTS: Among 145 subjects included over a 197 person-year follow-up, the estimated probability of virological response (VR, defined as reaching HIV RNA < 50 copies/ml after salvage therapy) at 24 and 48 weeks was 36% and 60%, respectively. The strongest independent predictor of VR was the inclusion of a thymidine analogue (TA) in the salvage regimen. The presence of M184V and the introduction of lopinavir/ritonavir as new drug were both marginally associated with better outcome. After 24 weeks of salvage therapy, the median reduction in HIV-1 RNA was -1.36 log10 copies/ml (interquartile range [IQR] 0.10-2.46): at multivariable regression analysis, salvage regimens containing a TA (beta = +0.80; P = 0.02) and lamivudine (beta = +1.21; P = 0.02) as new drug had a positive effect on the reduction of HIV-1 RNA. CONCLUSIONS: Development of the K65R mutation does not preclude a high rate of virological response to rescue therapy. Inclusion of a TA in the salvage regimen and the presence of a M184V mutation could have a favourable effect on virological outcome.