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.

HCV NS3 naturally occurring variants in HIV/HCV coinfected DAA-naïve patients: consideration for HCV genotyping resistance testing.

PURPOSE: Data on the frequency of HCV naturally occurring drug-resistant variants (RAVs) at baseline in HIV/HCV coinfected patients are scarce. METHODS: NS3-HCV RAVs were studied by full-population direct sequencing from plasma specimens of 345 DAA-naïve patients with HCV chronic hepatitis (159 of them with HIV/HCV-coinfection). RESULTS: NS3 RAVs were identified in 31.5 % of patients, with a significant proportion of HIV/HCV coinfected DAA-naïve patients compared to those with HCV monoinfection (38 vs. 25 % p = 0.0104, OR 1.84; 95 % CI 1.162-2.916). CONCLUSIONS: HCV resistance genotyping test before treatment may be worth in special populations such as HIV/HCV coinfection to optimize patient treatment.

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.

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.

Pharmacogenetics of tenofovir drug transporters in the context of HBV: Is there an impact?

BACKGROUND: Current treatments for chronic hepatitis B management include orally administered nucleos(t)ide analogues, such as tenofovir (TDF), which is an acyclic adenine nucleotide analogue used both in HBV and human immune deficiency virus (HIV). The course of HBV infection is mainly dependent on viral factors, such as HBV genotypes, immunological features and host genetic variables, but a few data are available in the context of HBV, in particular for polymorphisms of genes encoding proteins involved in drug metabolism and elimination. Consequently, the aim of this study was to evaluate the potential impact of genetic variants on TDF plasma and urine concentrations in patients with HBV, considering the role of HBV genotypes. METHODS: A retrospective cohort study at the Infectious Disease Unit of Amedeo di Savoia Hospital, Torino, Italy, was performed. Pharmacokinetic analyses were performed through liquidi chromatography, whereas pharmacogenetic analyses through real-time PCR. FINDINGS: Sixty - eight patients were analyzed: ABCC4 4976 C>T genetic variant showed an impact on urine TDF drug concentrations (p = 0.014). In addition, SLC22A6 453 AA was retained in the final regression multivariate model considering factors predicting plasma concentrations, while ABCC4 4976 TC/CC was the only predictor of urine concentrations in the univariate model. INTERPRETATION: In conclusion, this is the first study showing a potential impact of genetic variants on TDF plasma and urine concentrations in the HBV context, but further studies in different and larger cohorts of patients are required.

Sequential therapy with entecavir and PEG-INF in patients affected by chronic hepatitis B and high levels of HBV-DNA with non-D genotypes.

Complete eradication of hepatitis B virus (HBV) is rarely achieved. Treatment options include currently available nucleos(t)ide analogues and pegylated interferon. The aim of our exploratory study was to assess the effectiveness of sequential therapy for chronic hepatitis B (CHB) vs the current standard of care. We evaluated an association with entecavir and pegylated interferon alfa-2a (PEG-IFN) in 20 patients with hepatitis B, high HBV viremia and genotypes A, B, C and E. Patients received entecavir alone for 12 weeks, then entecavir and PEG-IFN for 12 weeks, lastly PEG-IFN alone for 36 weeks. The results were compared with 20 patients (control group) treated in the past with 48 weeks of PEG-IFN monotherapy. Our results show that complete sustained virological response (SVR) and partial SVR were, respectively, 60% and 80% in the study group and 10% and 30% in the control group; anti-HBe seroconversion rate were 76.9% vs 15%, and anti-HBs seroconversion were 20% vs 0%, respectively. We found a correlation among different genotypes and virological and serological outcomes - genotype C has a better virological response, while genotype A had a better serological response, and E genotype had a poor response. These results show that a sequential approach is a promising strategy of treatment in patients with CHB and high viremia in comparison with PEG-IFN monotherapy. The E genotype seems to have the worse rate of response and requires other treatment strategies.

Risk factors and incidence of long-COVID syndrome in hospitalized patients: does remdesivir have a protective effect?

BACKGROUND: The definition of 'long-COVID syndrome' (LCS) is still debated and describes the persistence of symptoms after viral clearance in hospitalized or non-hospitalized patients affected by coronavirus disease 2019 (COVID-19). AIM: In this study, we examined the prevalence and the risk factors of LCS in a cohort of patients with previous COVID-19 and followed for at least 6 months of follow-up. DESIGN: We conducted a prospective study including all hospitalized patients affected by COVID-19 at our center of Infectious Diseases (Vercelli, Italy) admitted between 10 March 2020 and 15 January 2021 for at least 6 months after discharge. Two follow-up visits were performed: after 1 and 6 months after hospital discharge. Clinical, laboratory and radiological data were recorded at each visit. RESULTS: A total of 449 patients were included in the analysis. The LCS was diagnosed in 322 subjects at Visit 1 (71.7%) and in 206 at Visit 2 (45.9); according to the post-COVID-19 functional status scale we observed 147 patients with values 2-3 and 175 with values >3 at Visit 1; at Visit 2, 133 subjects had the score between 2-3 and 73 > 3. In multivariate analysis, intensive care unit (ICU) admission (OR = 2.551; 95% CI = 1.998-6.819; P = 0.019), time of hospitalization (OR = 2.255; 95% CI = 1.018-6.992; P = 0.016) and treatment with remdesivir (OR = 0.641; 95% CI = 0.413-0.782; P < 0.001) were independent predictors of LCS. CONCLUSIONS: Treatment with remdesivir leads to a 35.9% reduction in LCS rate in follow-up. Severity of illness, need of ICU admission and length of hospital stay were factor associated with the persistence of PCS at 6 months of follow-up.

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.

The development of the suprarenal gland: surgical and anatomical considerations.

BACKGROUND: Aim of this research is to study the situation and relationships of the adrenal gland in the first stage of development in order to give some contributes for the application of laparoscopic adrenalectomy; in the meantime we describe the series of the debate changes occurring in the constitution of the cortex and medulla. METHODS: Analysis of histologic slices of thoraco-abdominal and abdominal regions of human embryos and fetuses ranging from the fifth (12 mm CR) to the twentieth week (170 mm CR). RESULTS: At 12 mm CR an unique type of cells is present in the cortex; at 16 mm CR there are two different groups of cells. Sympathogonia enter into the cortex at 16 mm CR. The right adrenal gland seems enclosed into the liver and a ligament containing the middle adrenal vein reaches the vena cava inferior sulcus. The left adrenal gland, through the coelomic cavity, is in relationship with the stomach, the medial border of the spleen and the pancreatic body contained in the primitive dorsal mesogastrium. CONCLUSIONS: The timing of penetration of the ganglion cells into the cortex is defined as well as the hypothesis that the matrix of the fetal and definitive cortex is the same: moreover the study of the early development allows to understand the main characteristics of both the adrenal glands which are significant for a rational and differential laparoscopic approach.