A. De Nicolò

Significant early higher ribavirin plasma concentrations in patients receiving a triple therapy with pegylated interferon, ribavirin and telaprevir

The new standard of care for treatment for infection with genotype 1a/b of HCV now is the combination of telaprevir (TLV) with ribavirin (RBV) and pegylated interferon (Peg‐IFN). Although this new therapy gives a higher response rate than the Peg‐IFNα plus RBV treatment, a greatly higher rate of anaemia onset has been reported in all clinical trials. Because haemolysis is a typical concentration‐dependent side effect of RBV, modulated by ITPA gene polymorphisms, we aimed to compare the early RBV plasma exposure of nine patients after 2 weeks of treatment with triple therapy with RBV concentrations of 187 patients treated with RBV and Peg‐IFNα over the same time scale; this comparison was performed also stratifying patients according to ITPA polymorphism genotype and anaemia onset after 1 month of treatment. All TLV‐treated patients had unfavourable ITPA genetic profile and developed anaemia. Moreover, both the rate of anaemia onset and the haemoglobin loss at 1 month were significantly higher in patients treated with TLV. This observation has been confirmed also in patients with the same ITPA genetic profile in double therapy. Strikingly, also early RBV plasma concentrations were significantly higher in patients treated with TLV. These unbiased results confirm the observations recently reported and suggest that the high rate of anaemia onset could be mainly due to the increased RBV exposure, probably caused by a ‘boosting effect’ by TLV. These data highlight the great importance of early therapeutic drug monitoring of RBV in the management of anaemia in the triple therapy.

Role of CYP27B1+2838 promoter polymorphism in the treatment of chronic hepatitis B HBeAg negative with PEG‐interferon

In HBV‐infected patients, the vitamin D deficiency has been related to chronic liver diseases, progression of hepatic fibrosis and poor response to the treatment. The CYP27B1 gene, which encodes the 1‐α‐hidroxylase and involved in the 1,25‐dihydroxyvitamin D synthesis, was recently associated to type‐1 diabetes, autoimmune disorders and treatment response in HCV. Then, we aimed to investigate the role of CYP27B1 polymorphisms in HBV treatment with PEG‐IFN. We retrospectively enrolled 190 patients with chronic hepatitis B HBeAg negative treated for 48 weeks with PEG‐IFN α‐2a. We examined the role of rs4646536 CYP27B1 SNP (CYP27B1+2838) according to virological and serological response. Our results showed that the TT genotype of CYP27B1+2838 was significantly prevalent in patients with end‐of‐therapy virological response (37.6%) vs CT/CC (9.4%) (P < 0.001). Virological relapse was prevalent in patients with CT/CC genotype (12.6%) vs TT genotype (2.1%) (P < 0.001). TT genotype was also related to HBsAg loss (P = 0.004) and anti‐HBs appearance (P = 0.002). In the multivariate analysis, the TT genotype resulted to be a good positive predictor of sustained virological response (OR = 5.632, IC = 1.938–16.368, P = 0.001) and serological response (OR = 6.161, IC = 1.856–20.457, P = 0.003). The CYP27B1+2838 polymorphism may be useful as pretreatment factor to selection of patients with higher probability of response to therapy.

Treatment with direct-acting antiviral agents of hepatitis C virus infection in injecting drug users: A prospective study

In this prospective study, we evaluated the effectiveness and tolerability of novel therapies against hepatitis C virus (HCV) in a cohort of PWID enrolled at our centre from April 2015 to July 2016. In this analysis, a total of 174 patients were included: eleven (6.3%) were treated with pegylated interferon (PEG‐IFN) and ribavirin (RBV) containing regimens, 163 (93.7%) with IFN‐free treatments. RBV has been used in 70 patients (40.2%); 59 (33.9%) patients were in opioid substitution therapy (OST) with methadone or buprenorphine. Overall, sustained virological response (SVR) has been observed in 162 subject (93.1%), breakthrough (BT) in three (1.7%), relapse in one (0.6%) and dropout in eight (4.6%). Treatment was interrupted for clinical conditions in seven patients: six (3.4%) had hepatic decompensation and one died for hepatocellular carcinoma (HCC). In multivariate analysis, predictive factors of treatment failure were as follows: albumin level below 3 g/dL (OR=7.190; 95% IC=1.236‐41.837; P<.001), MELD score >10 (OR=5.886; 95% IC=1.411‐35.994; P<.001) and years of HCV infection >20 (OR=1.286; 95% IC=0.556‐9.455; P=.016). In conclusion, treatment with DAAs was effective and well tolerated in PWID; cirrhotic subjects with MELD > 10 and albumin low level showed a higher risk of developing serious adverse events and treatment failure.

Relationship between the early Boceprevir-S isomer plasma concentrations and the onset of breakthrough during HCV genotype 1 triple therapy

In a prospective cohort of 18 patients treated with boceprevir, we examined the role of boceprevir plasma concentration at the onset of breakthrough during the treatment. Nine patients experienced breakthrough during therapy. The resistance patterns were as follows: S122S/R, I132V, T54A/I132V, V156S/I170A, V36M/T54S/R155K, V36M/R155K and T54/R155K. Boceprevir-S isomer (SCH 534128) median concentration in patients with breakthrough was 48.3 ng/mL (interquartile range 43-58 ng/mL); in others, it was significantly (p 0.019) higher: 151 ng/mL. Low boceprevir plasma concentration can lead to virologic resistance; therapeutic drug monitoring should be used to prevent the onset of viral breakthrough during triple-regimen therapy with boceprevir.

Efficacy of sofosbuvir and ledipasvir in an HCV+ gastro-resected patient

The second‐generation direct‐acting antivirals represented the first major turning point for the eradication of HCV infection in almost all settings of patients. However, no data were available on use in gastro‐resected patients.

[PP.25.08] THERAPEUTIC DRUG MONITORING IN RESISTANT HYPERTENSIVES PREVIOUSLY TREATED WITH INVASIVE APPROACHES

Objective: Renal denervation (RDN) and baroreflex activation therapy (BAT) are invasive therapeutic approaches for resistant hypertension (RH), indicated when antihypertensive drug therapy is inefficacious. Several reports have found an unsatisfactory response to these approaches; one of the factors called upon to account for the failure of these devices is the lack of therapeutic adherence. The aim of this study was to retrospectively evaluate the therapeutic adherence, using an objective assessment as the therapeutic drug monitoring (TDM), in a group of patients who have undergone invasive approach in previous years, either RDN or BAT, and correlate it with the answer to the invasive procedure. Design and method: We retrospectively analysed 12 patients with RH (9 females). Before performing invasive procedure, all patients were considered adherent according to the physician intuition and the answers given to the Morisky questionnaire. Serum TDM, by Ultra High Performance Liquid Cromatography (UHPLC) method, was done during a routine follow up visit, after at least one year from the last invasive approach. A clinical response to invasive approaches was considered as a reduction in 24 h Ambulatory Blood Pressure Monitoring (ABPM) systolic blood pressure (SBP) of at least 10 mmHg at 12 months from the procedure. Patients were considered adherents (AD) if all the prescribed drugs were found or only one was not found; patients were considered non-adherents (NAD) if none of the prescribed drugs were found. Results: 4 patients were AD and 8 NAD. In the whole sample a clinical response was found in 41% of the patients. Among AD the clinical response rate was 75%, whilst among NAD the clinical response rate dropped to 25%. No significant clinical and social differences were found between NAD and AD, but NAD had significant higher office SBP and 24 h ABPM SBP than AD (p < 0.05). Conclusions: Lack of therapeutic adherence is associated to a limited clinical efficacy of invasive approaches in apparent RH. Our data underlines the importance of adherence therapeutic evaluation before and after performing invasive procedures, whose effectiveness can be undermined by poor therapeutic adherence.

[OP.2B.04] DEVELOPMENT OF AN INNOVATIVE, HIGH THROUGHPUT AND COST-EFFECTIVE UHPLC-MS/MS METHOD FOR THE ASSESSMENT OF THERAPEUTIC ADHERENCE IN PATIENTS WITH “RESISTANT” HYPERTENSION

Objective: Nowadays hypertension affects a large fraction of global population. Moreover, 15–30% of patients show drug-resistance, needing the addition of more drugs; meanwhile, polytherapy often results in poor therapeutic adherence, classified as “pseudo-resistant” hypertension. In this context, Therapeutic Drug Monitoring (TDM) of antihypertensive drugs, which consists in the measurement of drug concentration in biological matrices, may help to discern problems in drug pharmacokinetics/pharmacodynamics from cases of poor therapeutic adherence, also considering that not-pharmacological alternative consists in invasive surgery. It has been hence validated an UHPLC-MS/MS method for simultaneous TDM on plasma samples of ten antihypertensive drugs: amlodipine, atenolol, clonidine, chlortalidone, doxazosin, hydrochlorothiazide, nifedipine, olmesartan, ramipril and telmisartan. Design and method: This method has been validated according to FDA guidelines. 200 &mgr;l of sample, standard and quality control, added with 40 &mgr;l of internal standard working solution, undergo a simple protein precipitation protocol, followed by drying step, and resulting extracts are resuspended in water:acetonitrile 90:10 (v:v; +0.05% formic acid) and then analyzed through a Shimadzu NexeraX2® UHPLC system coupled with a LCMS-8050® tandem mass detector. The validated method was tested on real samples from patients with RH/pseudo-RH, all giving informed consent. Results: All analytical parameters of the method fitted FDA guidelines for all the analytes. 42 patients have been enrolled (SEAL study). TDM revealed that 55% of patients (n = 23) had detectable concentration of all prescribed drugs (considered fully adherent), 26% (n = 11) resulted partially non-adherent (only part of the prescribed drugs was detectable) and 19% (n = 8) were totally not-adherent (no drugs were detected). Through univariate/multivariate logistic regression, the diastolic pressure and the “white-coat” increase in heart rate resulted the best predictors of poor adherence. Through ROC curve analysis a diastolic pressure over 124 mmHg resulted predictive of total inadherence. Conclusions: TDM can be a gold-standard for evaluating therapeutic adherence and this method results eligible for a clinical routine use. We managed to discern cases of inadherence, preserving some patients from an invasive and expensive surgery. Figure. No caption available.

P1187 A CONCENTRATION-DEPENDENT PHARMACOKINETIC INTERACTION WITH TELAPREVIR INCREASES RIBAVIRIN CONCENTRATIONS AND LEADS TO HIGHER HAEMOGLOBIN DROP

P1187 A CONCENTRATION-DEPENDENT PHARMACOKINETIC INTERACTION WITH TELAPREVIR INCREASES RIBAVIRIN CONCENTRATIONS AND LEADS TO HIGHER HAEMOGLOBIN DROP A. De Nicolo, A. Ciancio, L. Boglione, A. Mohamed Abdi, A. Smedile, G.P. Caviglia, G. Di Perri, M. Rizzetto, A. D’Avolio. Medical Sciences, Unit of Infectious Deseases, University of Turin, Medical Sciences, University of Turin, Gastroenterology, Turin, Italy E-mail: amedeo.denicolo@unito.it