Dysmetabolism, Diabetes and Clinical Outcomes in Patients Cured of Chronic Hepatitis C: A Real-Life Cohort Study.

The aim of this study was to examine the impact of features of dysmetabolism on liver disease severity, evolution, and clinical outcomes in a real-life cohort of patients treated with direct acting antivirals for chronic hepatitis C virus (HCV) infection. To this end, we considered 7,007 patients treated between 2014 and 2018, 65.3% with advanced fibrosis, of whom 97.7% achieved viral eradication (NAVIGATORE-Lombardia registry). In a subset (n = 748), liver stiffness measurement (LSM) was available at baseline and follow-up. Higher body mass index (BMI; odds ratio [OR] 1.06 per kg/m2 , 1.03-1.09) and diabetes (OR 2.01 [1.65-2.46]) were independently associated with advanced fibrosis at baseline, whereas statin use was protective (OR 0.46 [0.35-0.60]; P < 0.0001 for all). The impact of BMI was greater in those without diabetes (P = 0.003). Diabetes was independently associated with less pronounced LSM improvement after viral eradication (P = 0.001) and in patients with advanced fibrosis was an independent predictor of the most frequent clinical events, namely de novo hepatocellular carcinoma (HCC; hazard ratio [HR] 2.09 [1.20-3.63]; P = 0.009) and cardiovascular events (HR 2.73 [1.16-6.43]; P = 0.021). Metformin showed a protective association against HCC (HR 0.32 [0.11-0.96]; P = 0.043), which was confirmed after adjustment for propensity score (P = 0.038). Diabetes diagnosis further refined HCC prediction in patients with compensated advanced chronic liver disease at high baseline risk (P = 0.024). Conclusion: Metabolic comorbidities were associated with advanced liver fibrosis at baseline, whereas statins were protective. In patients with advanced fibrosis, diabetes increased the risk of de novo HCC and of cardiovascular events. Optimization of metabolic comorbidities treatment by a multi-disciplinary management approach may improve cardiovascular and possibly liver-related outcomes.

SLAM Project - Second-Level Diagnostic Assessment: Multidisciplinary approach to HIV Patients.

The aim of the study is to propose a multidimensional second-level diagnostic assessment to allow follow- up in the event physicians observe the presence of risk factors and/or active co-morbidities in HIV-infected patients. To develop our proposal, we chose the Delphi method that has been used for about 30 years in the healthcare field. The CISAI Group (Coordinamento Italiano per lo Studio dell'Allergia in Infezione da HIV) conducted this study. The first phase of the study provided identification of the questionnaire for second-level diagnostic assessment of HIV-infected patients. From March to July 2018 the questionnaire was submitted to 48 experts from 10 Italian HIV-dedicated sites. The questionnaire consisted of 102 items divided into 7 survey areas. The results can be summarized as follows: infectious disease diagnostics, 18 items reached agreement in 9 cases; osteoporosis diagnostics 12 items with 3 agreements; metabolic and cardiovascular diagnostics 13 items with 4 agreements; nephrology diagnostics 19 items with 8 agreements; hepatology diagnostics 12 items with 9 agreements; CNS diagnostics: 18 items with 7 agreements; psychological diagnostics and quality of life assessment (QoL) 10 items with no agreement. If these considerations are confirmed in required discussions and in-depth analyses, they will be able to produce an important indication in the drafting of national guidelines.

Managing the long surviving HIV patient: a proposal for a multidimensional first-level diagnostic assessment.

We propose a multidimensional first-level diagnostic assessment easy to use in routine clinical practice to allow infectious disease specialists to have a general and complete overview of persons living with HIV. Following the Delphi method, articles published from January 1, 2011 on controlled trials, clinical reports and observational studies dealing specifically with HIV and its co-morbidities were selected for review by the authors. Participants in the poll were selected among clinicians and infectious diseases specialists, working in 38 different dedicated HIV centres in Italy. The participants were given access to a website dedicated to the project and received a standardized information package containing a synopsis of the study and a description of the Delphi process and the selected literature. A total of 131 Items were divided into 10 first-level survey areas: anamnesis, objective examination, infectious diseases, osteoporosis diagnosis, metabolic pathologies diagnosis, cardiovascular diagnosis, nephrologic diagnosis, hepatological diagnosis, central nervous system diagnosis, evaluation of quality of life (QoL). This simple and concise first level tool identifies a few areas of multi-organ diagnostic assessment beyond the infectivity area. The identification of these areas will allow us to find shared and validated evaluation procedures with the intent to increase the likelihood of early recognition of patients at risk of comorbidity development, in order to facilitate more effective prevention, thereby reducing the overall impact on the quality of life of patients affected by this chronic illness.

High parathyroid hormone concentration in tenofovir-treated patients are due to inhibition of calcium-sensing receptor activity.

Bone health impairment is a common finding in HIV-infected patients on antiretroviral treatment. High serum parathyroid hormone (PTH) concentration in patients on antiretroviral treatment containing tenofovir disoproxil fumarate (TDF) has been reported. Hyperparathyroidism was not always sustained by a reduction in vitamin D concentration. We thus hypothesized a direct inhibitory effect of TDF on the Calcium-sensing receptor (CaSR), leading to hyperparathyroidism. Human embryonic kidney cells were transfected with CASR wild-type gene or mutated in different sites (N124K, T1051G, C788T, T888M). Cells were grown in standard conditions and the activity of CaSR was assessed after stimulation with CaCl2 with and without TDF (100 nM-1 µM). We evaluated by western blot phospho-p44/42 ERK expression levels as a marker of CaSR activity. In silico structure models were obtained for wild-type and N124K mutant. Molecular docking with TDF was also evaluated. The stimulation by CaCl2 and TDF 100 nM led to a decrease of 55% of CaSR activity (P < 0.001), whereas the stimulation by CaCl2 and TDF 1 µM reduced the activity by 68% (P < 0.001). The decreased CaSR activity was comparable to that observed from known CASR gene inactivating mutations (T1051G, C788T), which inhibit the receptor activity by 56% and 78%, respectively. The TDF inhibits the CaSR activity carrying a gain of function mutation in the intracellular domain (T888M), but it does not influence the activity of the receptor carrying the N124K activating mutation. Our data show that TDF is able to inhibit the activity of CaSR in a dose-dependent manner. Hyperparathyroidism observed in TDF-treated patients may be therefore promoted by the direct effect of the drug on CaSR.

PrEP in Italy: The time may be ripe but who's paying the bill? A nationwide survey on physicians' attitudes towards using antiretrovirals to prevent HIV infection.

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

Safety and tolerability of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil fumarate in a real life setting: Data from surveillance cohort long-term toxicity antiretrovirals/antivirals (SCOLTA) project.

OBJECTIVES: The study aim was to evaluate the impact on Liver and Kidney toxicity of the single tablet regimen Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Fumarate (EVG/COBI/FTC/TDF) on Antiretroviral Therapy (ART) experienced or naïve patients. METHODS: Patients initiating EVG/COBI/FTC/TDF were enrolled in the SCOLTA project, a multicenter observational study reporting grade 3-4 Adverse Events in subjects beginning new antiretroviral drug regimens. In this analysis, patients were evaluated at T0 (baseline), T1 (six months) and at T2 (twelve months). RESULTS: A total of 329 patients were enrolled, and 280 (85.1%) of these had at least one follow-up visit. Median observation time was 11 months (IQR 7.0-15.5). Two hundred and two patients (72.1%) were ART experienced and 78 (27.9%) ART naive. Prevalence of HCV-co-infection was 21.4%. At T1, we observed a significant decline in estimated glomerular filtration rate (eGFR), both in experienced and naive patients (mean change from T0-7.5 ± 12.8 ml/min, -15.5 ± 17.8 ml/min, respectively, p = 0.0005), which was confirmed at T2 (mean change from T0-8.2 ± 15.8 ml/min, -17.6 ± 19.4 ml/min, respectively, p = 0.001). Regarding aspartate aminotransferase (AST) and alanine transaminase (ALT) grade 1-2 modifications, no significant differences were observed between experienced and naïve subjects, but an increased prevalence of abnormal liver function test was observed in patients with chronic HCV infection (p<0.001). CONCLUSIONS: A significant decline in eGFR was observed in patients initiating EVG/COBI/FTC/TDF in the first 6 months, with no significant worsening occurring at 12 months vs. 6 months of therapy. Patients with chronic HCV infection were at higher risk to develop abnormal liver tests.

Improvement of ALT decay kinetics by all-oral HCV treatment: Role of NS5A inhibitors and differences with IFN-based regimens.

BACKGROUND: Intracellular HCV-RNA reduction is a proposed mechanism of action of direct-acting antivirals (DAAs), alternative to hepatocytes elimination by pegylated-interferon plus ribavirin (PR). We modeled ALT and HCV-RNA kinetics in cirrhotic patients treated with currently-used all-DAA combinations to evaluate their mode of action and cytotoxicity compared with telaprevir (TVR)+PR. STUDY DESIGN: Mathematical modeling of ALT and HCV-RNA kinetics was performed in 111 HCV-1 cirrhotic patients, 81 treated with all-DAA regimens and 30 with TVR+PR. Kinetic-models and Cox-analysis were used to assess determinants of ALT-decay and normalization. RESULTS: HCV-RNA kinetics was biphasic, reflecting a mean effectiveness in blocking viral production >99.8%. The first-phase of viral-decline was faster in patients receiving NS5A-inhibitors compared to TVR+PR or sofosbuvir+simeprevir (p<0.001), reflecting higher efficacy in blocking assembly/secretion. The second-phase, noted δ and attributed to infected-cell loss, was faster in patients receiving TVR+PR or sofosbuvir+simeprevir compared to NS5A-inhibitors (0.27 vs 0.21 d-1, respectively, p = 0.0012). In contrast the rate of ALT-normalization, noted λ, was slower in patients receiving TVR+PR or sofosbuvir+simeprevir compared to NS5A-inhibitors (0.17 vs 0.27 d-1, respectively, p<0.001). There was no significant association between the second-phase of viral-decline and ALT normalization rate and, for a given level of viral reduction, ALT-normalization was more profound in patients receiving DAA, and NS5A in particular, than TVR+PR. CONCLUSIONS: Our data support a process of HCV-clearance by all-DAA regimens potentiated by NS5A-inhibitor, and less relying upon hepatocyte death than IFN-containing regimens. This may underline a process of "cell-cure" by DAAs, leading to a fast improvement of liver homeostasis.

HIV Clinical Pathway: A New Approach to Combine Guidelines and Sustainability of Anti-Retroviral Treatment in Italy.

The present article describes the case study of a "real world" HIV practice within the debate concerning the strategic role of Clinical Governance (CG) tools in the management of a National Healthcare System's sustainability. The study aimed at assessing the impact of a Clinical Pathway (CP) implementation, required by the Regional Healthcare Service, in terms of effectiveness (virological and immunological conditions) and efficiency (economic resources absorption), from the budget holder perspective. Data derived from a multi-centre cohort of patients treated in 6 Hospitals that provided care to approximately 42% of the total HIV+ patients, in Lombardy Region, Italy. Two phases were compared: Pre-CP (2009-2010) vs. Post-CP implementation (2011-2012). All HIV infected adults, observed in the participating hospitals during the study periods, were enrolled and stratified into the 3 categories defined by the Regional CP: first-line, switch for toxicity/other, and switch for failure. The study population was composed of 1,284 patients (Pre-CP phase) and 1,135 patients (Post-CP phase). The results showed that the same level of virological and immunological effectiveness was guaranteed to HIV+ patients: 81.2% of Pre-CP phase population and 83.2% of Post-CP phase population had undetectable HIV-RNA (defined as <50 copies/mL) at 12-month follow up. CD4+ cell counts increased by 28 ± 4 cells/mm3 in Pre-CP Phase and 39 ± 5 cells/mm3 in Post-CP Phase. From an economic point of view, the CP implementation led to a substantial advantage: the mean total costs related to the management of the HIV disease (ART, hospital admission and laboratory tests) decreased (-8.60%) in the Post-CP phase (p-value < 0.0001). Results confirmed that the CP provided appropriateness and quality of care, with a cost reduction for the budget holder.

HCV novel therapeutic regimens in Wonderland: A budget impact analysis in the Lombardy Region.

BACKGROUND: The advent of new HCV drugs has generated widespread economic concerns, particularly within the Italian setting, characterized by continuous linear cuts and spending review actions. The overall trade-off between investments and savings needs an in depth analysis. AIMS: The study aimed to estimate the budget impact of the introduction of the novel drugs approved during the year 2015, compared with the historical situation based on the different treatment options available prior to 2015. METHODS: A three-year budget impact model was developed, taking into consideration the Lombardy Region (Northern Italy) Health Service perspective. The degree of liver fibrosis, genotypes, presence of only HCV or HIV/HCV co-infections, presence or absence of sustained virological response, and direct healthcare total costs were the variables of the model. RESULTS: With the introduction of the novel regimens, a higher number of HCV patients achieved a sustained virological response (+20%). Further analysis showed that an investment in innovative technologies would have given the Regional System significant economic savings within the 36-month period (-6.64%/-7.15%). CONCLUSIONS: Treating HCV-infected persons in the Lombardy Region with the new drugs would reduce healthcare expenditure on this specific disease, in each forecast implemented, thus reducing the economic burden of the pathology.

Response to First-Line Ritonavir-Boosted Protease Inhibitors (PI/r)-Based Regimens in HIV Positive Patients Presenting to Care with Low CD4 Counts: Data from the Icona Foundation Cohort.

BACKGROUND: There are no data comparing the response to PI/r-based regimens in people presenting for care with low CD4 counts or AIDS (LC). AIM: To compare the response to LPV/r-, DRV/r- or ATV/r-based cART regimens in LC initiating cART from ART-naive. METHODS: We included people enrolled in Icona with either CD4 counts ≤350 cells/mm3 (low CD4-LC) or CD4 counts ≤200 cells/mm3 (very low CD4-VLC) and/or AIDS, starting their first PI/r-based regimen after 2008. Initial regimens were compared by intention-to-treat: i) time to viral failure (VF) (first of 2 consecutive VL>200 copies/mL after≥6 months); II) time to PI/r discontinuation/switching for any cause (TD) and for toxicity (TDT); III) treatment failure (TF) (VF or TD). Kaplan-Meier and Cox analyses were used. RESULTS: 1,362 LC patients were included (DRV/r 607; ATV/r 552; LPV/r 203); 813 VLC. In a median of 18 months (IQR:7-35), the 1-year probability of VF and TF were 2.8% (1.9-3.8) and 21.1% (18.7-23.4). In the adjusted analysis, patients initiating ATV/r had a 53% lower chance, and those initiating DRV/r a 61% lower chance of TD, as compared to LPV/r; the risk of TF was more likely in people starting LPV/r. Results were similar among VLC; in this subgroup LPV/r including regimens demonstrated a lower chance of VF. CONCLUSIONS: We confirmed in LC a low chance of virological failure by 1 year, with small differences according to PI/r. However, larger differences were observed when comparing longer-term endpoints such as treatment failure. These results are important for people presenting late for care.

Discontinuation of Initial Antiretroviral Therapy in Clinical Practice: Moving Toward Individualized Therapy.

BACKGROUND: Study aim was to estimate the rate and identify predictors of discontinuation of first combination antiretroviral therapy (cART) in recent years. METHODS: Patients who initiated first cART between January 2008 and October 2014 were included. Discontinuation was defined as stop of at least 1 drug of the regimen, regardless of the reason. All causes of discontinuation were evaluated and 3 main endpoints were considered: toxicity, intolerance, and simplification. Predictors of discontinuation were examined separately for all 3 endpoints. Kaplan-Meier analysis was used for the outcome discontinuation of ≥ 1 drug regardless of the reason. Cox regression analysis was used to identify factors associated with treatment discontinuation because of the 3 reasons considered. RESULTS: A total of 4052 patients were included. Main reason for stopping at least 1 drug were simplification (29%), intolerance (21%), toxicity (19%), other causes (18%), failure (8%), planned discontinuation (4%), and nonadherence (2%). In a multivariable Cox model, predictors of discontinuation for simplification were heterosexual transmission (P = 0.007), being immigrant (P = 0.017), higher nadir lymphocyte T CD4 cell (P = 0.011), and higher lymphocyte T CD8 cell count (P = 0.025); for discontinuation due to intolerance: the use of statins (P = 0.029), higher blood glucose levels (P = 0.050). About toxicity: higher blood glucose levels (P = 0.010) and the use of zidovudine/lamivudine as backbone (P = 0.044). CONCLUSIONS: In the late cART era, the main reason for stopping the initial regimen is simplification. This scenario reflects the changes in recommendations aimed to enhance adherence and quality of life, and minimize drug toxicity.

Effectiveness of first-generation HCV protease inhibitors: does HIV coinfection still play a role?

OBJECTIVE: HIV/hepatitis C virus (HCV) coinfected patients are usually considered a difficult-to-treat population. The aim of this study was to assess the effectiveness of telaprevir-based and boceprevir-based treatments with respect to the HIV status. METHODS: A prospective multicentre study was conducted among 22 Infectious Disease centres in Italy. Demographic, HIV and HCV related variables were collected, as well as data on HCV viral decay, sustained virologic response (SVR12) and grade 3-4 adverse events. RESULTS: Overall, 162 patients (24.7% HIV/HCV coinfected) received HCV treatment. Out of 145 evaluable patients, 57.2% achieved SVR12 (49.5% monoinfected, 78.9% coinfected). HIV coinfection was associated with a slight increase in the probability of SVR12 (adjusted odds ratio 1.66, 95% confidence interval 0.59-4.64, P=0.33). Premature discontinuation rates and adverse events were similar irrespective of HIV status, with the exception of skin reactions, which were more frequently in the HIV group. CONCLUSION: In a real-life setting, with a high proportion of cirrhotic and treatment-experienced patients, the overall SVR12 rate was 57.2%. HIV coinfection was not associated with impaired outcome.

Muscle symptoms and creatine phosphokinase elevations in patients receiving raltegravir in clinical practice: Results from the SCOLTA project long-term surveillance.

Muscle alterations ranging from asymptomatic creatine phosphokinase (CPK) increases to rhabdomyolysis and central nervous system (CNS) symptoms have been reported in patients receiving raltegravir. Muscle symptoms and CPK increases were investigated in a cohort of HIV-infected patients receiving raltegravir-based antiretroviral therapy, and possible associated predictors were evaluated. The SCOLTA Project is a prospective, observational, multicentre study created to assess the incidence of adverse events in patients receiving new antiretroviral drugs in clinical practice. In total, 496 HIV-infected patients were enrolled [333 (67.1%) male]. CDC stage was C in 196 patients (39.5%). Mean age at enrolment was 45.9 ± 9.3 years. Median follow-up was 21 months. Twenty-six patients (5.2%) reported muscle symptoms (16 muscle pain and 17 weakness; 7 had both). Of 342 patients with normal baseline CPK values, 72 (21.1%) had a CPK increase. Seven patients (1.4%) discontinued raltegravir because of muscular events (three for muscle pain/weakness and four CPK increases). No cases of rhabdomyolysis were observed. Patients with muscle symptoms were more frequently receiving in their regimen than those not receiving atazanavir (P=0.04) and were more likely to also report CNS symptoms (P<0.0001). Significant predictors of muscle symptoms were CNS symptoms and use of atazanavir. Female sex was associated with a reduced risk of CPK increase. In conclusion, muscle symptoms and CPK elevations occurred frequently and caused most discontinuations due to adverse events. Their monitoring in patients receiving raltegravir should be considered, especially when co-administered with atazanavir or when CNS symptoms are also present.

Monotherapy with lopinavir/ritonavir versus standard of care in HIV-infected patients virologically suppressed while on treatment with protease inhibitor-based regimens: results from the MoLo study.

This study compared the cost-efficacy ratios of lopinavir/ritonavir monotherapy (LPV/r-MT) and of standard of care in virologically suppressed HIV-infected patients. The results of the efficacy and safety analyses are presented. We conducted a multicentre, randomised, open-label trial of HIV-infected adults on stable treatment, with HIV- RNA <50 copies/mL, randomised to continue the ongoing regimen (cART-arm) or to switch to LPV/r (400/100 mg BID) MT (MT-arm). Time to virological rebound (VR = confirmed HIV-RNA ?50 copies/mL) was estimated by Ka- plan-Meier method and changes in laboratory values during follow-up were evaluated by univariate mixed-linear models. Ninety-four patients were randomised and analysed (43 in the MT-arm and 51 in the cART-arm). Five (four in the MT and 1 in the cART-arm; p=0.175) had VR, but time to VR did not statistically differ between the two arms (p=0.143). Major PI mutations were not detected at VR. Patients on MT had significant increases in total choles- terol [difference in mean change between MT and cART arm: 0.77 (±0.30) mg/dL per month; p=0.012] and eGFR [difference in mean change between MT and cART arm: 0.24 (±0.11) mL/min/1.73 m2 per month; p=0.029]. LPV/r-MT seems safe in most patients and should be considered in patients who have developed kidney toxicity from tenofovir.

Effectiveness and durability of darunavir/ritonavir (DRV/r) in DRV/r-experienced HIV-1-infected patients in routine clinical practice.

INTRODUCTION: This was a descriptive non-interventional study in HIV-1-infected patients treated with DRV/r conducted in the clinical setting, with a single-arm prospective design. The primary objective was to collect data on utilization of darunavir/ritonavir (DRV/r) under the conditions described in the marketing authorization. Efficacy (measured as viral load [VL] <50 copies/mL and CD4+ cell count) was evaluated for DRV/r in combination with other antiretroviral (ARV) agents in routine clinical practice in Italy. MATERIALS AND METHODS: Here we describe an analysis of effectiveness and durability data from two cohorts of DRV/r-experienced patients with HIV-1 infection, already receiving DRV/r according to usual clinical practice, collected prospectively from June 2009 to December 2012: Cohort 1, data from patients from the DRV/r Early Access Program (TMC114-C226 study; N=235 patients) and Cohort 2, a separate cohort of ARV-DRV/r-experienced patients (N=407 patients), treated with DRV/r in the market. Patient characteristics are shown in Table 1. RESULTS: The median length of DRV/r exposure during the study was 925 days (interquartile range [IQR] 692-1006) in Cohort 1, and 581 (IQR 508-734) days in Cohort 2. Of those patients that completed the study, 94% and 87% of patients were virologically suppressed in Cohort 1 and 2, respectively, at last study visit (LSV). As expected, the virological suppression rate was higher in patients with baseline VL <50 copies/mL (Table 2). Mean CD4+ cell counts improved from baseline to LSV in both cohorts (Cohort 1: +54 cells/µL [95% CI 31, 77] and Cohort 2: +59 cells/µL [95% CI 44, 73]). High persistence rates were seen in both cohorts, with 75.3% of patients in Cohort 1 and 82.6% in Cohort 2 remaining on treatment at LSV; very few patients discontinued due to virologic failure (Table 1). Other reasons for study discontinuation are shown in Table1. Very few patients changed DRV/r dosing during the study, 15 from 1200 to 800 mg o.d. CONCLUSIONS: In patients already treated with DRV/r, DRV/r-based ARV treatment provided effective viral suppression with long-lasting durability, low virological response failure, low discontinuation rates and good tolerability. These data confirm DRV/r to be an effective treatment choice in previously treated patients.

Treatment discontinuation in HIV-1-infected individuals starting their first-line HAART after 2008: data from the ICONA Foundation Study Cohort.

INTRODUCTION: The aim of this study was to analyze the likelihood and the predictors of discontinuation of first-line regimen in the late HAART era. METHODOLOGY: An observational multi-center analysis of HIV-positive patients enrolled in ICONA. Patients eligible were those starting a first-line HAART after 1 January 2008. Discontinuation was defined as stop and/or switch of at least one drug of the regimen. All causes of discontinuation, as reported by the treating physician, were evaluated and cumulative risk of stopping was investigated according to age, gender, co-morbidity, years since starting HAART, immuno-virological status, third drug and backbone of the first regimen. Kaplan Meier (KM) analysis and Cox proportional hazards model were used for the outcome discontinuation of ≥1 drug regardless of the reason. For the KM estimates a competing risk approach was used to estimate the contribution of each of the reasons over time to the cumulative risk of stopping over time. RESULTS: Data of 1759 patients who started first HAART and had at least one month of clinical follow-up were analyzed. The overall discontinuation risk was 33% over a median follow-up of 12 months. The likelihood of discontinuation by KM was 27% by one year (95% CI 25-29) and 41% by two years (95% CI 38-44). Main reason for stopping at least one drug in regimen was simplification (10%), followed by intolerance (7%), toxicity (5%), failure (2%) and other causes (8%). Estimates of the cumulative risk of discontinuation of ≥1 drug over time and according to reason are shown in Figure 1. In a multivariable Cox model independent predictors of discontinuation regardless of the reason were: longer time from HIV diagnosis to date of starting HAART (hazard ratio [HR] 0.96; 95% CI 0.93-1.00; p=0.039), regimens containing ZDV/3TC (HR 2.86; 95% CI 1.42-5.76; p=0.003 vs TDF/FTC) and an NNRTI-based regimen (HR 2.47; 95% CI 0.91-6.72; p=0.07 vs regimens not NNRTI-based). CONCLUSIONS: In a previously reported analysis of the ICONA data (1), the overall risk of discontinuation of first-line HAART was 36% with 21% due to intolerance/toxicity. In this updated analysis, the main reason for stopping is simplification (accounting for 32% of stops), reflecting the recent changes in recommendations aimed to minimize drug toxicity, enhancing adherence and quality of life.

Prevalence, awareness, treatment, and control rate of hypertension in HIV-infected patients: the HIV-HY study.

BACKGROUND: We aimed to assess the prevalence of hypertension in an unselected human immunodeficiency virus (HIV)-infected population and to identify factors associated with hypertension prevalence, treatment, and control. METHODS: We used a multicenter, cross-sectional, nationwide study that sampled 1,182 unselected, consecutive, HIV-infected patients. Office blood pressure was accurately measured with standard procedures. RESULTS: Patients were 71% men and 92% white, with a median age of 47 years (range = 18-78); 6% were antiretroviral treatment naive. The overall prevalence of hypertension was 29.3%; high-normal pressure accounted for an additional 12.3%. Among hypertensive subjects, 64.9% were aware of their hypertensive condition, 52.9% were treated, and 33.0% were controlled (blood pressure < 140/90 mm Hg). Blood pressure-lowering medications were used in monotherapy in 54.3% of the subjects. Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers were the most frequently used drugs (76.1%: monotherapy = 39.1%, combination treatment = 37.0%). In multivariable regression models, hypertension was independently predicted by traditional risk factors, including age ≥50 years, male sex, family history of cardiovascular disease, body mass index ≥25 kg/m2, previous cardiovascular events, diabetes, central obesity, and metabolic syndrome, as well as by duration of HIV infection, duration of antiretroviral therapy, and nadir CD4+ T-cell count <200/µl. The choice of protease inhibitors vs. nonnucleoside reverse transcriptase inhibitors as a third antiretroviral drug was irrelevant. CONCLUSIONS: Hypertension affects nearly 30% of HIV adult outpatients in Italy. More than one-third of the hypertensive subjects are unaware of their condition, and more than two-thirds are uncontrolled. A higher level of attention to the diagnosis and treatment of hypertension is mandatory in this setting.

Inconsistent condom use among HIV-positive women in the "Treatment as Prevention Era": data from the Italian DIDI study.

INTRODUCTION: Translation of the evidence regarding the protective role of highly active antiretroviral therapy (HAART) on HIV sexual transmission rates into sexual behaviour patterns of HIV-infected subjects remains largely unexplored. This study aims to describe frequency of self-reported condom use among women living with HIV in Italy and to investigate the variables associated with inconsistent condom use (ICU). METHODS: DIDI (Donne con Infezione Da HIV) is an Italian multicentre study based on a questionnaire survey performed during November 2010 and February 2011. Women-reported frequency of condom use was dichotomized in "always" versus "at times"/"never" (ICU). RESULTS: Among 343 women, prevalence of ICU was 44.3%. Women declared a stable partnership with an HIV-negative (38%) and with an HIV-positive person (43%), or an occasional sexual partner (19%). Among the 194 women engaged in a stable HIV-negative or an occasional partnership, 51% reported fear of infecting the partner. Nonetheless, 43% did not disclose HIV-positive status. Less than 5% of women used contraceptive methods other than condoms. At multivariable analysis, variables associated with ICU in the subgroup of women with a stable HIV-negative or an occasional HIV-unknown partner were: having an occasional partner (AOR 3.51, 95% confidence interval [CI] 1.44-8.54, p=0.005), and reporting fear of infecting the sexual partner (AOR 3.20, 95% CI 1.43-7.16, p=0.004). Current use of HAART together with virological control in plasma level did not predict ICU after adjusting for demographic, behavioural and HIV-related factors. With regard to socio-demographic factors, lower education was the only variable significantly associated with ICU in the multivariate analysis (AOR 2.27, 95% CI 1.07-4.82, p=0.03). No association was found between high adherence to HAART and ICU after adjusting for potential confounders (AOR 0.89, 95% CI 0.39-2.01, p=0.78). CONCLUSIONS: Currently in Italy, the use of HAART with undetectable HIV RNA in plasma as well as antiretroviral adherence is not associated with a specific condom use pattern in women living with HIV and engaged with a sero-discordant or an HIV-unknown partner. This might suggest that the awareness of the protective role of antiretroviral treatment on HIV sexual transmission is still limited among HIV-infected persons, at least in this country.

Safety and durability in a cohort of HIV-1 positive patients treated with once and twice daily darunavir-based therapy (SCOLTA Project).

OBJECTIVE: To evaluate safety and durability of once-daily and twice-daily darunavir/ritonavir (DRV/r)-based treatment in HIV patients in clinical practice. METHODS: The Surveillance Cohort Long-Term Toxicity Antiretrovirals (SCOLTA) project is a prospective, observational, multicenter cohort created to assess the incidence of adverse events in patients receiving new antiretroviral drugs. Twenty-five Italian infectious diseases centers enroll patients and collect their data through this on-line system. Periodical evaluations of these patients, including physical examination and laboratory tests, were performed at baseline and every 6 months. RESULTS: Four hundred and twenty-nine patients were enrolled since May 2006. Eighty-five patients (19.8%) were prescribed once-daily DRV/r; 31 of them were treatment-naïve (36.5%). Among 54 (63.5%) treatment-experienced patients, 21 (38.9%) had undetectable viral load and started once-daily DRV/r as a simplification regimen. Patients on twice-daily regimen were older, more frequently lipodystrophic, HCV-coinfected, and in CDC stage C. In the following 24 months of follow-up, the viral load steadily decreased as well as the CD4 cell count rose. The reason for discontinuation did not significantly differ between groups. Mean blood glucose (BG) change from baseline did not show significant difference between groups, as well as high density lipoprotein cholesterol (HDL-C), triglycerides (TGL) and alanine transaminase (ALT). The survival curve shows that patients in the once-daily regimen withdrew treatment more frequently than those on twice-daily regimen (Log Rank Chi(2)P=0.009). CONCLUSION: Our study showed that DRV/r administrated both once daily or twice daily was safe and well tolerated with few discontinuations due to adverse events.