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.

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.

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.

Performance of genotypic tropism testing in clinical practice using the enhanced sensitivity version of Trofile as reference assay: results from the OSCAR Study Group.

OBJECTIVE: The goal of the OSCAR programme is to evaluate the performances of genotypic HIV-1 tropism testing in clinical practice using the enhanced sensitivity version of Trofile (ESTA) as reference-assay. METHODS: HIV-1 coreceptor-usage was assessed using plasma samples from 406 HIV-1 infected patients by ESTA and by gp120 V3 population-sequencing followed by Geno2pheno (set at a False Positive Rate [FPR] of 10% and 5%). RESULTS: ESTA was successful in 365 (89.9%) samples indicating R5 in 254 (69.6%), and DM/X4 in 111 (30.4% of samples (104 [28.5%] DM and 7 [1.9%] X4). Genotypic-testing successfully assessed viral tropism for all 406 samples, including the 41 with undetermined result by ESTA. Genotypic-tropism testing at a FPR of 5% and 10% was 81.1% and 78.4% concordant with ESTA, respectively. Despite a sensitivity of 48.7% and 55.9% at a FPR of 5% and 10%, respectively, a high concordance (specificity: 95.3% for FPR of 5% and 88.2% for FPR of 10%) between genotypic-tropism testing and ESTA was reached in the detection of R5-tropic viruses. CONCLUSION: Our results are in line with other European studies, and support the routine use of genotypic tropism testing in clinical-settings for monitoring of HIV-1 infected patients candidate to or failing CCR5-antagonists.

Early impairment of gut function and gut flora supporting a role for alteration of gastrointestinal mucosa in human immunodeficiency virus pathogenesis.

Our results show that impairment of the gastrointestinal tracts in human immunodeficiency virus (HIV)-positive patients is present in the early phases of HIV disease. This impairment is associated with alterations in gut microbiota and intestinal inflammatory parameters. These findings support the hypothesis that alterations at the gastrointestinal-tract level are a key factor in HIV pathogenesis.

Cholesterol levels in HIV-HCV infected patients treated with lopinavir/r: results from the SCOLTA project.

BACKGROUND: It is not known whether antiretroviral therapy (ART) including lopinavir/r has a different effect on the lipid metabolism in HIV patients co-infected with HCV. This study investigated changes in lipid levels, comparing patients with HIV infection alone and those with HCV too, in the lopinavir/r cohort of the SCOLTA project. METHODS: We analyzed the data for the lopinavir/r nationwide cohort from 25 Italian infectious disease departments, which comprises 743 HIV-infected patients followed prospectively, comparing subjects with HIV-HCV co-infection and those with single-infection. RESULTS: At enrolment, co-infected patients had significantly lower mean cholesterol than HCV negative cases (162+/-43mg/dL vs. 185+/-52mg/dL, p=0.0009). Total and non-HDL cholesterol and triglycerides rose significantly from baseline in HIV single-infection patients, but not in those with co-infection. The patients with dual HIV-HCV infection, treated with an ART regimen including lopinavir/r, have only limited increases in total and non-HDL cholesterol and triglycerides. CONCLUSIONS: Changes in serum lipids in co-infected patients differed significantly from those in patients without HCV. It remains to be seen whether this is associated with a lower risk of progression of atherosclerotic disease.

Tenofovir renal safety in HIV-infected patients: results from the SCOLTA Project.

OBJECTIVE: To evaluate the prevalence and incidence of nephrotoxicity in HIV-infected patients enrolled in the SCOLTA Project tenofovir cohort and to identify possible risk factors. DESIGN: The SCOLTA Project is a prospective, observational, multicenter study involving 25 infectious disease departments in Italy created to assess the incidence of severe adverse events in patients receiving new antiretroviral drugs. PATIENTS: The SCOLTA Project tenofovir cohort includes a total of 754 HIV infected patients. RESULTS: Data including grade II-IV creatinine elevations according to ACTG scale were available in 354 patients, 237 (67%) males with a mean age of 40.1+/-7.6 years enrolled in the SCOLTA Project tenofovir cohort. During a mean follow up of 19.5+/-11.5 months creatinine elevations were reported in 9/354 (2.5%) patients, all males. Mean duration of tenofovir therapy at the event was 9.5+/-5 months. The overall incidence was 1.6 (95% CI 1.5-1.7) per 100 person-years (p-y) and 0.5 (95% CI 0.4-0.6) p-y for grade III. No grade IV creatinine elevations were reported. Patients with nephrotoxicity were older and more frequently male, HCV infected, in CDC stage C and their CD4 cell count was significantly lower than those without nephrotoxicity. No significant difference was found between tenofovir co-administered antiretroviral drugs. CONCLUSIONS: Both prevalence and incidence of nephrotoxicity were low in patients receiving tenofovir in a non-selected clinical setting. Renal injury in patients receiving tenofovir seems associated with the presence of co-morbidities and with advanced HIV infection.

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.

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.

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.

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.

Antiviral efficacy and genotypic resistance patterns of combination therapy with stavudine/tenofovir in highly active antiretroviral therapy experienced patients.

OBJECTIVES: To evaluate antiviral efficacy of stavudine/tenofovir (d4T/TDF) backbone combination in late-line antiretroviral therapy, and to assess clinical and virological determinants of treatment success. DESIGN: Multicentric retrospective analysis on patients starting d4T/TDF after highly active antiretroviral therapy (HAART) failure. METHODS: The primary endpoint was the change in plasma HIV-1 RNA from the baseline (time of d4T/TDF initiation) to 6 months of therapy; secondary endpoint was the risk of virological failure. RESULTS: Among 172 patients included, a mean change in HIV-1 RNA of -1.69 (+1.23) and -1.53 (+1.43) log10 cp/ml was observed respectively at weeks 24 and 48 after starting d4T/TDF combination. Any single type-1 thymidine analogue mutation (TAM; M41L, L210W, T215Y) had a negative effort on the change in HIV RNA at 6 months, whereas among type-2 TAMs (D67N, K70R, K219Q), only D67N showed a trend for a negative effect. Presence of M184V mutation was related with a greater reduction in HIV RNA during d4T/TDF exposure. The risk of virological failure at 6 months after d4T/TDF starting was 22%. Type-1 TAMs were associated with a greater risk of failure (adjusted hazard ratio [HR]=1.65; 95% confidence interval [CI] 1.19-2.29). Conversely, M184V showed a protective effect. In 17 genotypic tests available at failure, no K65R mutation was detected, whereas a trend for an increasing prevalence of d4T-associated mutations was found. CONCLUSIONS: Combining TDF with a thymidine analogue as d4T may be effective as component of antiretroviral rescue regimens in HIV-infected patients with previous exposure to nucleoside analogue reverse transcriptase inhibitor. Previous selection of type-1 TAMs induces a detrimental effect over virological response.

An immunological comparison of third companion in advanced drug-naive HIV-infected patients.

An immunological comparison of three different third companions (abacavir [ABC], efavirenz [EFV], ritonavir-boosted indinavir [IDVr]) on a backbone of either zidovudine plus didanosine (AZT/ddI) or zidovudine plus lamivudine (AZT/3TC) was performed in 76 HIV-infected, advanced-naive patients. Baseline median CD4 count and viremia were 217/microL and 238,301 copies/mL, respectively. Immunologic parameters were measured at baseline and after months of therapy. By the end of the study, 36 patients (mostly in the protease inhibitor [PI]-containing arms) had dropped out of the study; 22/36 cases of drop out were due to tolerability issues. All regimens resulted in increases in CD4 counts, with the most solid changes seen in patients using ABC as a third companion. Median HIV plasma viremia at month 12 was <50 copies/mL, and viremia was undetectable in 26/38 patients (68%). At the end of the study period, HIV antigen- and mitogen-stimulated proliferation overall was better in patients using either of the PI-boosted third companions. In these patients, the strongest down-modulation of activation marker-bearing cells was also observed. Finally, CD8+/28-/CD45RA+ lymphocytes (effector cells) were increased in all groups of patients with the exception of individuals receiving PI-boosted therapies. Results of this pilot study, although very preliminary, suggest that different combinations of antivirals result in a range of effects on immune cell functions. The clinical implications of these results need to be further analyzed in follow-up studies and in larger cohorts of patients.

[Renal toxicity in HIV-infected patients receiving HAART including tenofovir]. / Tossicità renale in pazienti con infezione da HIV in trattamento con HAART contenente tenofovir.

HIV-infected patients may undergo renal damage related to the HIV infection itself, to the presence of co-infections, arterial hypertension, diabetes or to the exposure to nephrotoxic drugs. Tenofovir has been associated with the development of acute renal failure with Fanconi syndrome and acute tubular necrosis and, albeit rarely, with chronic liver disease. Patients with low CD4 cell count, low body weight and with concomitant diseases such as arterial hypertension and diabetes or co-infections with HCV, HBV or Treponema pallidum seem at higher risk of tenofovir-related nephrotoxicity. Other risk factors include previous exposure to nephrotoxic drugs and the association of tenofovir with boosted protease inhibitors or with didanosine. However, from the analysis of published papers the incidence of tenofovir-related renal toxicity seems low, as confirmed also by our personal casuistry (SCOLTA Project). Thus, a careful selection of patients including the evaluation of existent renal disease before starting an antiretroviral regimen including tenofovir is necessary to prevent renal damage. Furthermore, frequent monitoring of renal function in patients at higher risk of renal damage is strongly recommended, as well as a tenofovir dose adjustment if an alteration of renal function is detected.

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.

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.

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.