NS5A inhibitors for the treatment of hepatitis C infection.

Today, we are witnessing a new era for the treatment of hepatitis C with excellent rates of virologic response and very good safety profiles. Among the many classes of direct-acting antivirals, the inhibitors of nonstructural protein 5A are particularly interesting. NS5A is a phosphorylated protein with a relevant role in viral replication. HCV-NS5A inhibitors show high potency, very good safety profile and high barrier to resistance. The amazing in vitro effectiveness of this class is associated with great efficacy in clinical trials in combination protocols with antivirals of other classes, with sustained virological response (SVR) obtained in more than 90% of patients. Herein, we sought to review the current knowledge regarding the NS5A protease complex inhibitors with special emphasis on clinical efficacy and development of viral resistance.

Bile salt export pump deficiency disease: two novel, late onset, ABCB11 mutations identified by next generation sequencing.

 Progressive familial intrahepatic cholestasis (PFIC) is a heterogeneous group of autosomal recessive cholestatic diseases of childhood and represents the main indication for liver transplantation at this age; PFIC2 involves ABCB11 gene, that encodes the ATPdependent canalicular bile salt export pump (BSEP). Benign intrahepatic cholestasis (BRIC) identifies a group of diseases involving the same genes and characterized by intermittent attacks of cholestasis with no progression to liver cirrhosis. Diagnosis with standard sequencing techniques is expensive and available only at a few tertiary centers. We report the application of next generation sequencing (NGS) in the diagnosis of the familial intrahepatic cholestasis with a parallel sequencing of three causative genes. We identified the molecular defects in ABCB11 gene in two different probands who developed a severe cholestatic disease of unknown origin. In the first patient a compound heterozygosity for the novel frameshift mutation p.Ser1100GlnfsX38 and the missense variant p.Glu135Lys was detected. In the second patient, triggered by contraceptive therapy, we identified homozygosity for a novel missense variant p.Ala523Gly. In conclusion, these mutations seem to have a late onset and a less aggressive clinical impact, acting as an intermediate form between BRIC and PFIC.

Alopecia universalis after discontinuation of pegylated interferon and ribavirin combination therapy for hepatitis C: a case report.

For the last decade, the combination therapy of pegylated interferon (Peg-IFN) plus ribavirin (RBV) has been considered as the standard of care treatment for chronic hepatitis C virus (HCV) infection. However, it has been associated with an increased incidence of many adverse cutaneous reactions and emergence of autoantibodies or even autoimmune diseases. We report a case of irreversible alopecia universalis (AU) with complete hair loss extended to the whole body, which started after discontinuation of Peg-IFN/RBV combination therapy for chronic HCV infection. In conclusion, this case represents an uncommon presentation of a common disease. Physicians must be aware of the potential adverse reactions of an antiviral therapy containing IFN, which might occur even after the discontinuation, and fully inform the patient at the beginning of his treatment course. We hope that interferon-free regimens will utterly supplant interferon-based therapy for most or all HCV patients avoiding the emergence of autoimmune manifestations.

Quality of life of hepatitis B virus surface antigen-positive patients with suppressed viral replication: comparison between inactive carriers and nucleot(s)ide analog-treated patients.

OBJECTIVE: Hepatitis B virus infection is a relevant health problem with more than 400 million infected people worldwide. Our aim was to analyze quality of life of hepatitis B virus surface antigen-positive patients in inactive status or treated with antivirals. PATIENTS AND METHODS: Patients referred to our center between February and October 2016 were prospectively enrolled. Half-structured interview was used for examining psychological symptoms and Illness Behavior Questionnaire for exploring attitudes toward illness. We used World Health Organization Quality of Life-short version survey for studying quality of life and logistic regression to find possible predictors of nonadequate quality of life. RESULTS: The study involved 102 patients. At Illness Behavior Questionnaire test, psychological perception of illness (21.6%), and denial of illness itself (13.7%) were the most frequent conditions. Inactive and treated subgroups were comparable for almost all variables and scores, but patients on treatment were significantly more often male, older, and cirrhotic. Sleep disturbance emerged as an independent predictor of inadequate quality of life in Physical health, anxiety in Social relationship, and both anxiety and hostility in Environmental health domain. CONCLUSION: Inactive carriers and patients on treatment showed the same global quality of life, but the second group was older and more frequently with an advanced liver disease. Further studies might specifically evaluate the impact of antiviral therapy on quality of life.

Differences in liver stiffness values obtained with new ultrasound elastography machines and Fibroscan: A comparative study.

BACKGROUND AND AIMS: Whether Fibroscan thresholds can be immediately adopted for none, some or all other shear wave elastography techniques has not been tested. The aim of the present study was to test the concordance of the findings obtained from 7 of the most recent ultrasound elastography machines with respect to Fibroscan. METHODS: Sixteen hepatitis C virus-related patients with fibrosis ≥2 and having reliable results at Fibroscan were investigated in two intercostal spaces using 7 different elastography machines. Coefficients of both precision (an index of data dispersion) and accuracy (an index of bias correction factors expressing different magnitudes of changes in comparison to the reference) were calculated. RESULTS: Median stiffness values differed among the different machines as did coefficients of both precision (range 0.54-0.72) and accuracy (range 0.28-0.87). When the average of the measurements of two intercostal spaces was considered, coefficients of precision significantly increased with all machines (range 0.72-0.90) whereas of accuracy improved more scatteredly and by a smaller degree (range 0.40-0.99). CONCLUSIONS: The present results showed only moderate concordance of the majority of elastography machines with the Fibroscan results, preventing the possibility of the immediate universal adoption of Fibroscan thresholds for defining liver fibrosis staging for all new machines.

Efficacy and Safety of Daclatasvir in Hepatitis C: An Overview.

Hepatitis C virus (HCV) infection is a growing public health concern, with 184 million people infected worldwide. During the past decade, interferon has been the backbone of HCV treatment, even though it remains far from ideal. The latest development of the new direct antivirals has drastically changed the treatment approach for chronic hepatitis C (CHC). Inhibitors of the HCV NS5A region have garnered remarkable interest among treating physicians, due to their high potency and favourable safety profile. In particular, treatment with daclatasvir (DCV) has yielded high rates of vriologic response in patients infected with genotype (Gt) 1 and Gt 3, when used in combination with other antivirals of a different class, such as sofosbuvir. Although few data are available for DCV treatment of the other Gts, the results in patients with Gt 2 and Gt 4 infection appear promising, as do those for unique patient populations. NS5A-resistant viral variants can pre-exist or emerge after treatment failure for the HCV NS5A inhibitors. Nonetheless, DCV-resistant viral variants continue to be sensitive to interferon and other classes of antivirals such as NS3/4A and NS5B inhibitors. Herein, we aimed to provide an overview of the current knowledge about DCV in the treatment of CHC.

Prospective, observational real-life study on eligibility for and outcomes of antiviral treatment with peginterferon α plus ribavirin in chronic hepatitis C.

BACKGROUND: We aimed to investigate eligibility, reasons for treatment discontinuation and characteristics of chronic hepatitis C patients with treatment failure to peginterferon/ribavirin in clinical practice. METHODS: 1128 chronic hepatitis C patients, from 45 Italian Hepatology centres, were enrolled in this phase-4, prospective, observational study from January 2009 to February 2010. RESULTS: 687/1118 patients (61.4%) were eligible for antiviral treatment, of which 598 (87.0%) agreed with the physician's decision. Outcome information was available in 500/598 patients, among whom 348 (69.6%) completed treatment. Treatment was discontinued in 152 patients due to: lack of response (28.9%), personal reasons (29.6%), adverse events (38.2%), and decompensation (1.3%). Sustained virological response was obtained in 263/500 (52.6%), 71 (14.2%) relapsed and 61 (12.2%) were non-responders. Treatment outcome was not available in 105 (21%): lost while receiving treatment (33.3%), lost during follow-up (25.7%), withdrawn for adverse events (19.1%) or for administrative reasons (21.9%). CONCLUSION: In clinical practice, only 61% of chronic hepatitis C patients are considered eligible for peginterferon/ribavirin. Of these, 13% refuse treatment. Approximately 30% do not complete the scheduled treatment and, despite this, the sustained virological response rate is similar to that of randomized-controlled trials. In the era of new antiviral combinations, these findings have important implications for assessing eligibility and estimating drop-out rates.

ABT-450: a novel agent for the treatment of CHC genotype 1: focus on treatment-experienced patients.

Chronic hepatitis C (CHC) constitutes a major health concern. Hepatitis C virus eradication by antiviral treatment can markedly reduce the risk of developing cirrhosis, hepatocellular carcinoma and liver-related death. A plethora of new direct antiviral agents have been developed and are being explored in clinical trials. One of the newest members of this family is the NS3/4A protease inhibitor ABT-450. The multi-targeted approach combining ritonavir-enhanced ABT-450 with ombitasvir and dasabuvir has been evaluated for the treatment of CHC Gt1 in treatment-naïve and treatment-experienced adults. In this article, we sought to discuss the current knowledge on ABT-450-containing regimens, with special emphasis on treatment-experienced CHC Gt1 patients. This new combination was found to be potent, safe and well tolerated. Future Phase III trials with larger sample size in patients with decompensated cirrhosis, non-Gt1, end-stage renal disease and liver transplant recipients are eagerly awaited.