Effectiveness of 8-week sofosbuvir/ledipasvir in the adolescent chronic hepatitis C-infected patients.

BACKGROUND: The sustained virological response (SVR) rate for the 12-week sofosbuvir (SOF)/ledipasvir (LVD) treatment of adolescent genotype-4 patients is high. The aim of this study is to evaluate 8 versus 12-week treatment efficacy and safety in adolescent genotype-4 patients. PATIENTS AND METHODS: In total, 157 chronic hepatitis C-infected adolescent patients (mean age 14±2 years, 62% males) were included in this study. All patients received a morning dose of SOF (400 mg)/LVD (90 mg) as a single tablet for 8 and 12 weeks. Laboratory and biochemical monitoring were performed at weeks 4 and 8, end of treatment (8/12) and 12 weeks after the end of treatment (SVR12). RESULTS: In total, SVR12 was 98% [95% confidence interval (CI): 96-100] for all treated patients. For patients treated for 12 weeks, SVR12 was 97.6% (95% CI: 96-101) (82/84 patients), and 98.6% (95% CI: 93-101) (72/73) patients for those treated for 8 weeks. For both regimens, no serious adverse effects, treatment discontinuation or cases of death were detected. The main adverse effects for the 8-week patient group were fatigue (2.8%), headache (1.4%), nausea (1.4%) and epigastric tenderness (1.4%). For the 12-week-treated group, adverse events were epigastric tenderness (1.2%), nausea (1.2%), diarrhoea (2.4%) and rash (2.4%). Three patients were lost to follow-up: two were in the 12-week treatment group and one was in the 8-week group. All of them reached end of treatment but were lost before SVR12. No relapsers were observed in either group. CONCLUSION: Eight weeks of treatment of SOF/LVD combination is equally effective and safe as 12 weeks in adolescent genotype-4 patients.

Cost-effectiveness analysis of Daclatasvir/Sofosbuvir for the treatment of the HCV patients failed after the first line with second generation of DAAs in Italy.

BACKGROUND: Daclatasvir (DCV) combinated with Sofosbuvir (SOF) has shown good efficacy and safety profile for HCV patients. The aim was to evaluate the cost-effectiveness of DCV/SOF regimen versus HCV alternative treatments for patients who failed to achieve the SVR12 after a first DAA treatment from Italian perspective (PITER cohort). METHODS: A Markov model of HCV chronically infected patients was used to develop two scenarios: 1) DCV+ SOF versus Ledipasvir (LDV)+ SOF in Genotype (Gt)1 and Gt4; 2) DCV+ SOF versus no retreatment option in Gt1, Gt3, and Gt4. The percentage of patients who failed the first line with SOF/Simeprevir/Ribavirin (RBV) or SOF/RBV and were retreated or not according to evidences from PITER cohort, were used to populate the model. HCV resources consumption and SVR rates were quantified using PITER data. Transition probabilities and utility rates were derived from the literature. The outcomes were expressed in terms of Quality adjusted life years (QALYs). Probabilistic sensitivity analysis (PSA) was performed considering a cost-effectiveness threshold of € 30,000/QALY. RESULTS: In the base-case analysis, DCV+ SOF represents a cost-effectiveness therapy with ICERs lower than the threshold. The PSA showed robust results, ICERs remain below the threshold in 94% and 99% simulations in Scenario 1 and 2, respectively.

Hepatitis C virus serologic relapse after treatment with direct-acting antivirals is dependent on viral RNA levels in peripheral blood mononuclear cells and the grade of liver cirrhosis.

The disappearance of hepatitis C virus (HCV) from serum and tissues for 12 weeks after the end of treatment (EOT) with direct-acting antivirals (DAAs) is known as a "sustained virologic response" (SVR) and occurs more frequently in non-cirrhotic patients than in cirrhotic patients. In this study, we evaluated the outcome of HCV treatment with sofosbuvir (SOF) plus ledipasvir (LDV) at both EOT and 12 weeks after EOT in patients with and without hepatic cirrhosis to address the relationship of serologic relapse to persistent infection of PBMCs and the frequency of hepatic encephalopathy and hepatocellular carcinoma (HCC) after treatment. Seventy-five patients with post-HCV liver cirrhosis were assigned to one of three groups (A, B, and C), each of which included 25 patients and corresponded to the patients' Child-Turcotte-Pugh (CTP) classification. All of the patients received a daily dose of SOF (400 mg) plus LDV (90 mg) for 24 weeks and were tested using HCV single-strand reverse transcription (SRT) and PCR analysis of PBMCs at both EOT and 12 weeks after EOT. Fourteen (18.7%) out of 75 patients (all study populations) had intra-PBMC HCV RNA, but only nine of them (64.3%) developed HCV RNA serum relapse (seroconversion) 12 weeks after EOT (P < 0.001). Encephalopathy was significantly higher in group C at EOT and 12 weeks after EOT (P < 0.05). Development of HCC was observed in decompensated patients of group C (2 out of 5 = 40.0%) 12 weeks post-EOT (P = 0.03). In conclusion, detection of HCV RNA within PBMCs at the EOT provides an indication of potential relapse after 12 weeks. Moreover, development of encephalopathy and HCC after HCV eradication by SOF plus LDV therapy is perhaps a future warning for post-treatment hepatic decompensation in cirrhotic patients.

High efficacy of direct-acting anti-viral agents in hepatitis C virus-infected cirrhotic patients with successfully treated hepatocellular carcinoma.

BACKGROUND: The efficacy of direct-acting anti-viral (DAA) therapy in patients with a history of hepatocellular carcinoma (HCC) is unknown. AIM: We prospectively evaluated whether previously treated HCC affects DAA efficacy in a large real-life cohort of cirrhotic patients. METHODS: From January to December 2015 all consecutive HCV mono-infected patients with cirrhosis and/or history of HCC attending 10 Italian tertiary liver centres were enrolled. Baseline characteristics and response to therapy were recorded. 1927 patients were enrolled (mean age: 62.1 ± 10.9 years; 1.205 males). Genotype 1 was the most frequent (67.9%) followed by genotypes 3 (12.4%), 2 (11.2%) and 4 (8.6%). 88.4% and 10.9% of cases were classified Child A and B, respectively, and 14 (<1%) cases were classified Child C. Ascites and hepatic encephalopathy occurred in 10.7% and 3.2% of patients, respectively. Varices were detected in 39.3% of patients. Suboptimal and optimal treatment was prescribed: 15.9% of patients received sofosbuvir/simeprevir, 33.4% sofosbuvir/ledipasvir, 20.2% a Viekirax + Exviera regimen, 15.7% sofosbuvir/ribavirin, 9.9% sofosbuvir/daclatasvir and 3.4% Viekirax; 1.3% of patients received an interferon-based regimen. RESULTS: The sustained virologic response (SVR) rate at intention-to-treat analysis was 95.1%. It differed significantly across Child classes, that is, 96.3%, 86.1% and 71.4% Child A, B and C, respectively (P < 0.0001) and across genotypes (P = 0.002). The SVR rate did not differ between patients with (95.0%) and those without previous HCC (95.1%). At multivariable analysis, SVR was significantly associated with HCV genotype, Child class. CONCLUSION: This large real-life study proves that the efficacy of DAA in cirrhotic patients is not impaired by successfully treated HCC.

Effectiveness, treatment completion and safety of sofosbuvir/ledipasvir and paritaprevir/ritonavir/ombitasvir + dasabuvir in patients with chronic kidney disease: an ERCHIVES study.

BACKGROUND: Chronic kidney disease (CKD) was a relative contraindication to hepatitis C virus (HCV) treatment in the interferon/ribavirin era. AIM: To determine the efficacy, tolerability and safety of sofosbuvir/ledipasvir (SOF/LDV) and paritaprevir/ritonavir/ombitasvir/dasabuvir (PrOD) regimens in persons with CKD. METHODS: We identified persons initiated on a SOF/LDV or PrOD regimen from October 30, 2014 to April 30, 2016. We excluded those with missing HCV genotype or eGFR values. We determined treatment completion and sustained virologic response (SVR) rates, and proportion developing worsening renal function or grade 3/4 haematologic toxicity. RESULTS: Among 13 663 persons on SOF/LDV±ribavirin, 14% and 1% persons had CKD Stage 3 and 4-5 respectively, 67.8% completed treatment, 98.2% achieved SVR. Treatment completion or SVR rates did not decline with advanced CKD or ribavirin administration. Among 3961 persons on PrOD±ribavirin, 9% and 3% persons had CKD Stage 3 and 4-5, respectively, 74.0% completed treatment and 98.2% achieved SVR. A decrease in treatment completion rates was seen in CKD stage 4-5 and those on ribavirin, but this did not impact SVR rates. A >10 mL/min/1.73 m2 drop in eGFR from baseline was observed in 30%-38% of persons with baseline eGFR ≥60 mL/min/1.73 m2 , but in only 0%-6% with CKD4-5. Grade 3/4 anaemia was more frequent in persons with CKD4-5, but ribavirin co-administration did not appear to affect this. CONCLUSIONS: SOF/LDV and PrOD achieved high SVR rates in CKD population. Treatment completion rates were lower than expected. A decline in eGFR and development of anaemia were observed in a substantial proportion of persons, but the clinical implications remain unclear.

Treatment of Chronic Hepatitis C Virus Infection With Crushed Ledipasvir/Sofosbuvir Administered via a Percutaneous Endoscopic Gastrostomy Tube.

INTRODUCTION: Ledipasvir/sofosbuvir (Harvoni®) is a fixed-dose tablet indicated for the treatment of chronic hepatitis C virus (HCV) infection. There are currently no data available on the safety and efficacy of crushed ledipasvir/sofosbuvir tablets. CASE SUMMARY: This report describes the first documented case of successful treatment of chronic HCV infection in a patient crushing ledipasvir/sofosbuvir for administration via a percutaneous endoscopic gastrostomy (PEG) tube. The patient was treatment experienced and had evidence of compensated cirrhosis. Treatment duration was 24 weeks, and HCV RNA was undetectable 12 weeks after completion of treatment (SVR12) which is the accepted measure of a clinical cure. DISCUSSION: Issues may arise during or prior to starting HCV treatment that necessitate crushing tablets. Stopping or interrupting HCV treatment could lead to development of resistance or treatment failure. CONCLUSION: This is the first published case in which crushed ledipasvir/sofosbuvir administered via a PEG tube is documented as a safe and effective option for treatment of chronic HCV infection.

Efficacy and safety of direct antiviral agents in a cohort of cirrhotic HCV/HIV-coinfected patients.

Background: New direct-acting antiviral agents (DAAs) have shown great efficacy and tolerability in clinical trials and real-life cohorts. However, data are scarce regarding efficacy and safety in cirrhotic HCV/HIV-coinfected patients. Methods: A multicentre prospective analysis was performed in 13 Spanish hospitals, including all cirrhotic HCV/HIV-coinfected patients starting DAA combinations from January to December 2015. Sustained virological response 12 weeks after treatment (SVR12) was analysed. Withdrawal due to toxicity and/or hepatic decompensation and change in liver stiffness measurement (LSM) after HCV treatment were evaluated. Results: Patients (n = 170) were mostly male (n = 125; 74.3%) with the following HCV genotype (Gt) distribution: Gt-1a, 68 (40%); Gt-1b, 21 (12.4%); Gt-4, 47 (27.6%); and Gt-3, 26 (15.3%). Baseline median LSM was 20.6 kPa (IQR 16.1-33.7) and log10 HCV-RNA 6.1 IU/mL (IQR 5.7-6.5). Most patients had a Child-Pugh class A score (n = 127; 74.7%) and 28 (16.5%) had prior hepatic decompensation. There were 89 (52.4%) pretreated patients with 40.4% (n = 36) of null responders. Preferred regimens were as follows: sofosbuvir/ledipasvir + ribavirin, 43 (25.3%) patients; sofosbuvir + simeprevir + ribavirin, 34 (20%); sofosbuvir/ledipasvir, 26 (15.3%) and sofosbuvir + daclatasvir + ribavirin, 25 (14.7%). Overall SVR12 was 92.9% (158/170), without differences between genotypes. Pretreated patients had lower SVR12 rates compared with naive (88.8% versus 97.5%; P = 0.026). Treatment failures were as follows: 7 (4.1%) relapses; 2 (1.2%) lost to follow-up; 1 (0.6%) toxicity-related discontinuation; 1 (0.6%) hepatic decompensation; and 1 (0.6%) viral breakthrough. On-treatment hepatic decompensation was recorded in four (2.4%) patients (encephalopathy and ascites, two each). Paired LSM in 33 patients showed a decrease of 5.6 kPa (95% CI 1.8-9.2; P = 0.004). Conclusions: In our cohort of cirrhotic HCV/HIV-coinfected patients, DAAs were highly safe and efficacious. Viral eradication was associated with a significant decrease in liver stiffness.

Treatment of Patients With Hepatitis C Virus Infection With Ledipasvir-Sofosbuvir in the Liver Transplant Setting.

BACKGROUND: Hepatitis C virus (HCV) infection is a major cause of liver cirrhosis and hepatocellular carcinoma and the leading indication for liver transplantation. In the Middle East, genotype 4 HCV infection is the most common genotype. However, limited data exists on the treatment of genotype-4 in the liver transplant setting. We evaluated the safety and efficacy of ledipasvir (LDV)-sofosbuvir (SOF) in treating HCV genotype-4 infected patients with cirrhosis or postliver transplantation. METHODS: This prospective, single-arm, observational study includes cohort of patients with cirrhosis before liver transplantation (cohort A) and a cohort of postliver transplantation patients (cohort B). Patients received LDV/SOF (90-400 mg) once daily for 12 to 24 weeks with or without ribavirin (RBV). Patients with creatinine clearance below 30 were excluded. RESULTS: A total of 111 patients (61 cirrhotic; 50 postliver transplants) with HCV genotype 4 were treated in King Faisal Specialist Hospital and Research Center; 55% cohort A and 44% cohort B received RBV. Sustained virological response sustain virological response (SVR)12 was 91.8% and 86% of cohorts A and B, respectively. There were no treatment-related mortality or serious adverse effects. RBV dose reduction occurred in 25% without any treatment discontinuation. SVR12 rates in cohort A were significantly higher in patients with a viral load below 800 000 (100% vs 83.9%, P value = 0.022). Viral load did not impact SVR rates in cohort B. The use of RBV did not increase SVR12 and was associated with anemia. CONCLUSIONS: LDV/SOF without RBV is an effective and safe treatment option for patients with HCV genotype 4 infection in preliver and postliver transplant settings.

Eight-week ledipasvir/sofosbuvir in non-cirrhotic, treatment-naïve hepatitis C genotype-1 patients with hepatitis C virus-RNA < 6 million: Single center, real world effectiveness and safety.

AIM: To evaluate sustained viral response (SVR) of 8-wk ledipasvir/sofosbuvir therapy among non-cirrhotic, genotype-1 hepatitis C virus (HCV) patients with RNA < 6 million IU/mL. METHODS: We performed a retrospective cohort study to examine SVR rates, predictors of treatment failure and safety analysis of 8-wk ledipasvir/sofosbuvir (LDV/SOF) therapy among non-cirrhotic, genotype 1 HCV patients with viral load < 6 million IU/mL. Primary outcome was an achievement of SVR at 12 wk after treatment. Secondary outcomes were identifying predictors of treatment failure and adverse events during treatment. RESULTS: Total 736 patients: 55% males, 51% Caucasians and 65% were genotype 1a. Non-cirrhotic state of 53% was determined by clinical judgment (imaging, AST, platelet count) and 47% had documented liver fibrosis testing (biopsy, vibration-controlled transient elastography, serum biomarkers). Overall SVR12 was 96%. No difference in SVR12 was seen between patients whose non-cirrhotic state was determined by clinical judgment and patients who had fibrosis testing. Age groups, gender, ethnicity and genotype 1 subtype did not predict SVR. Non-cirrhotic state determined by clinical judgment based on simple, non-invasive tests were not associated with lower SVR [OR = 1.02, 95%CI: 0.48-2.17, P = 0.962]. The AUROC for hepatitis C RNA viral load was 0.734 (P < 0.001, 95%CI: 0.66-0.82). HCV RNA 2.2 million IU/mL was identified as the cutoff value with sensitivity 73% and specificity 64%. HCV RNA < 2.2 million IU/mL was associated with significantly higher SVR 98% with OR = 0.22 (95%CI: 0.1-0.49, P < 0.001) compared to SVR 92% in HCV RNA ≥ 2.2 million IU/mL. No death or morbidities were reported. CONCLUSION: Our outcomes validate safety and effectiveness of 8-wk LDV/SOF therapy in non-cirrhotic, untreated HCV genotype 1 patients with HCV RNA < 6 million IU/mL.

Effectiveness, safety and clinical outcomes of direct-acting antiviral therapy in HCV genotype 1 infection: Results from a Spanish real-world cohort.

BACKGROUND & AIMS: Clinical trials evaluating second-generation direct-acting antiviral agents (DAAs) have shown excellent rates of sustained virologic response (SVR) and good safety profiles in patients with chronic hepatitis C virus (HCV) genotype 1 infection. We aimed to investigate the effectiveness and safety of two oral DAA combination regimens, ombitasvir/paritaprevir/ritonavir plus dasabuvir (OMV/PTV/r+DSV) and ledipasvir/sofosbuvir (LDV/SOF), in a real-world clinical practice. METHODS: Data from HCV genotype 1 patients treated with either OMV/PTV/r+DSV±ribavirin (RBV) (n=1567) or LDV/SOF±RBV (n=1758) in 35 centers across Spain between April 1, 2015 and February 28, 2016 were recorded in a large national database. Demographic, clinical and virological data were analyzed. Details of serious adverse events (SAEs) were recorded. RESULTS: The two cohorts were not matched with respect to baseline characteristics and could not be compared directly. The SVR12 rate was 96.8% with OMV/PTVr/DSV±RBV and 95.8% with LDV/SOF±RBV. No significant differences were observed in SVR according to HCV subgenotype (p=0.321 [OMV/PTV/r+DSV±RBV] and p=0.174 [LDV/SOF]) or degree of fibrosis (c0.548 [OMV/PTV/r/DSV±RBV] and p=0.085 [LDV/SOF]). Only baseline albumin level was significantly associated with failure to achieve SVR (p<0.05) on multivariate analysis. Rates of SAEs and SAE-associated treatment discontinuation were 5.4% and 1.7%, in the OMV/PTV/r+DSV subcohort and 5.5% and 1.5% in the LDV/SOF subcohort, respectively. Hepatocellular carcinoma (HCC) recurred in 30% of patients with a complete response to therapy for previous HCC. Incident HCC was reported in 0.93%. CONCLUSIONS: In this large cohort of patients managed in the real-world setting in Spain, OMV/PTV/r+DSV and LDV/SOF achieved high rates of SVR12, comparable to those observed in randomized controlled trials, with similarly good safety profiles. LAY SUMMARY: In clinical trials, second-generation direct-acting antiviral agents (DAAs) have been shown to cure over 90% of patients chronically infected with the genotype 1 hepatitis C virus and have been better tolerated than previous treatment regimens. However, patients enrolled in clinical trials do not reflect the real patient population encountered in routine practice. The current study, which includes almost 4,000 patients, demonstrates comparable rates of cure with two increasingly used DAA combinations as those observed in the clinical trial environment, confirming that clinical trial findings with DAAs translate into the real-world setting, where patient populations are more diverse and complex.

Ledipasvir plus sofosbuvir as salvage therapy for HCV genotype 1 failures to prior NS5A inhibitors regimens.

There is little information on retreatment efficacy and predictors of the combination of ledipasvir and sofosbuvir (ledipasvir/sofosbuvir) for patients who fail to respond to NS5A inhibitors. NS5A resistance variants are known to persist for long periods after such treatment. Here, we evaluated 54 patients with chronic HCV genotype 1b infection, free of decompensated cirrhosis, and hepatocellular carcinoma, for sustained virological response after 12 weeks (SVR12) of once-daily treatment with 90 mg ledipasvir and 400 mg sofosbuvir. Intention-to-treat analysis showed SVR12 of 70%. Using ultra-deep sequencing, non-responder to ledipasvir/sofosbuvir showed no change in the rates of detection of NS5A and NS5B resistant-variants at re-elevation of viral loads, relative to baseline. According to response to prior treatment, SVR12 rates were 18, 69, 94, and 100% in non response, viral breakthrough, relapse, and discontinuation due to adverse events, respectively. SVR12 rates in non response were significantly lower than those of the others. Multivariate analysis identified response to previous treatment (failure except for non response) and FIB4 index (<3.25) as significant determinants of SVR12. The SVR12 rates were significantly lower in patients with FIB4 index of ≥3.25 and had not responded to prior treatment, relative to others. The specificity, and positive- and negative-predictive values were high for prediction of poor response based on the combination of two predictors. In conclusion, our study indicated that ledipasvir/sofosbuvir is a potentially useful salvage treatment for patients who fail prior NS5A inhibitors-based therapy. Response to prior treatment was an important predictor of retreatment efficacy.

[New era in the treatment of chronic hepatitis C - novel direct acting antivirals]. / Korszakváltás a krónikus C-vírus hepatitis terápiájában - új direkt ható antivirális szerek.

Chronic hepatitis C, without treatment, can cause liver cirrhosis, liver failure and liver cancer. The availability of new oral direct acting antivirals, such as the protease inhibitors simeprevir, asunaprevir and paritaprevir, the NS5A inhibitors daclatasvir, ledipasvir, and ombitasvir, the polymerase inhibitors Sofosbuvir and dasabuvir have resulted an enormous progress in the treatment of chronic hepatitis C, leading to >90% sustained viral response rates. Even the hard-to-treat or previously treatment ineligible patients can be cured with the combination of these drugs. Furthermore the treatment duration is much shorter, and the side effects are minimal. Today, treatment of all hepatitis C virus infected patients is recommended, and the best choices are the interferon-free options. Eradication of hepatitis C virus has become realistic, however, appropriate screening programs are mandatory to achieve this goal.

Emerging options for treating hepatitis C infection.

Hepatitis C infection can cause chronic liver disease and liver carcinoma and can necessitate liver transplantation. Of the more than 3 million people infected with hepatitis C, more than two-thirds were born between 1945 and 1965. Many individuals are unaware that they're infected, which can delay treatment and lead to disease progression. Once infection is diagnosed, typical treatment regimens can involve multiple medications and side effects that can make it challenging for some people to complete therapy. In October 2014 the U.S. Food and Drug Administration (FDA) approved Harvoni®, a fixed dose combination pill of ledipasvir/sofosbuvir that provides a new option for treatment.

Endogenous intrahepatic IFNs and association with IFN-free HCV treatment outcome.

BACKGROUND. Hepatitis C virus (HCV) infects approximately 170 million people worldwide and may lead to cirrhosis and hepatocellular carcinoma in chronically infected individuals. Treatment is rapidly evolving from IFN-α-based therapies to IFN-α-free regimens that consist of directly acting antiviral agents (DAAs), which demonstrate improved efficacy and tolerability in clinical trials. Virologic relapse after DAA therapy is a common cause of treatment failure; however, it is not clear why relapse occurs or whether certain individuals are more prone to recurrent viremia. METHODS. We conducted a clinical trial using the DAA sofosbuvir plus ribavirin (SOF/RBV) and performed detailed mRNA expression analysis in liver and peripheral blood from patients who achieved either a sustained virologic response (SVR) or relapsed. RESULTS. On-treatment viral clearance was accompanied by rapid downregulation of IFN-stimulated genes (ISGs) in liver and blood, regardless of treatment outcome. Analysis of paired pretreatment and end of treatment (EOT) liver biopsies from SVR patients showed that viral clearance was accompanied by decreased expression of type II and III IFNs, but unexpectedly increased expression of the type I IFN IFNA2. mRNA expression of ISGs was higher in EOT liver biopsies of patients who achieved SVR than in patients who later relapsed. CONCLUSION. These results suggest that restoration of type I intrahepatic IFN signaling by EOT may facilitate HCV eradication and prevention of relapse upon withdrawal of SOF/RBV. TRIAL REGISTRATION. ClinicalTrials.gov NCT01441180.

Investigational nucleoside and nucleotide polymerase inhibitors and their use in treating hepatitis C virus.

INTRODUCTION: About 150 million people worldwide are estimated to be chronically infected with the hepatitis C virus (HCV). Successful antiviral treatment can stop the progression of the disease toward liver cirrhosis, hepatocellular carcinoma and death. IFN has been the drug of choice and the backbone of all combinations in the past two decades. However, an IFN-free combination (sofosbuvir and ribavirin) has been recently approved for genotypes 2 and 3 patients with many other drugs in preclinical and clinical development. AREAS COVERED: This review focuses on investigational nucleoside or nucleotide inhibitors of viral polymerase that are potential treatments of HCV. The article reviews drugs that are currently under investigational status. EXPERT OPINION: Currently, mericitabine has the most robust data but its efficacy appears to be less than optimal. Other drugs such as ALS-2200 (and its diastereomer VX-135) and BMS-986094 are promising but the data in humans are too scanty to draw conclusions about their future role at this current point in time. Other promising molecules are LG-7501, ACH-3422 and EP-NI266, although no clinical studies have been performed thus far, so this must be rectified. Another drug of promise GS-6620 has displayed a high degree of pharmacokinetic and pharmacodynamic variability, which makes further development unlikely.

Emerging treatments for hepatitis C.

INTRODUCTION: About 2.35% of the world population can be infected with hepatitis C virus (HCV) responsible for chronic hepatitis, liver cirrhosis and hepatocellular carcinoma. Currently available interferon-based medication is successful in up to 75% of the patients infected with HCV genotypes 1, 2 or 3 and lower efficacy in other genotypes. Unfortunately sustained virologic response (SVR) rate in genotype 1 infected non-responders to previous therapy with advanced hepatic fibrosis even after retreatment with the first generation direct acting antivirals (DAA) is about 40% only. AREAS COVERED: The second generation DAA, which have recently been submitted for registration (Sofosbuvir and Simeprevir) still need combination with PegIFNα and RBV in patients infected with HCV genotype 1. There is a need for more effective antiviral therapy for difficult to treat patients who are interferon intolerant, developed liver cirrhosis or non-responders to previous therapies. Therefore, IFN-free regimens are step for future therapies consisting of combinations of novel investigational DAA and host targeting agents. EXPERT OPINION: The introduction of novel DAA with a good safety profile and high barrier to resistance can lead to SVR rates exceeding 90% in treatment naïve patients and non-responders to previous therapy infected with different genotypes.

Improving the quality of infant sleep through the inclusion at supper of cereals enriched with tryptophan, adenosine-5'-phosphate, and uridine-5'-phosphate.

The present study evaluated whether the administration of cereals enriched with nutrients that are facilitators of sleep could help improve the sleep of infants who had sleep disorders at night time. Thirty infants aged 8-16 months with sleep disorders involving at least three nocturnal waking episodes took part in the study. They were given a night-time 'sleep facilitating cereal' product containing 225 mg tryptophan, 5.3 mg adenosine-5'-P, and 6.3 mg uridine-5'-P per 100 g of product. These cereals were given in a double-blind procedure lasting 5 weeks, with ingestion of the cereal between 18:00 and 06:00. In the control week, the children received a standard cereal (75 mg tryptophan/100 g product without nucleotides) dissolved in a standard formula milk (231.5 mg tryptophan, 2.6 mg adenosine-5'-P, 5 mg uridine-5'-P, per 100 g product). In one experimental week, the children received the night-time sleep facilitating cereal together with the standard formula milk. In another week, they received the sleep facilitating cereal together with a night milk specially formulated to attain the sleep rhythm (480 mg tryptophan, 8.8 mg uridine-5'-P, and 7.6 mg adenosine-5'-P per 100 g product). The three experimental weeks were separated by two wash-out weeks in which the milk and cereal administered was identical in composition to that of the control week. All the infants received a programmed writer actimeter which they wore continually, attached to their ankles, to record their motor activity. The recorded activity was used to calculate information about the time in bed, assumed sleep, actual sleep, sleep efficiency, sleep latency, immobility, and total activity. The infants receiving the enriched cereal during the time of darkness showed improvements in their sleep parameters, regardless of whether the milk they took at night was standard or enriched with tryptophan, adenosine-5'-P, and uridine-5'-P. In summary, the administration of enriched cereals led to an improvement in sleep, regardless of the type of infant milk used. These results support the concept of chrononutrition since they confirm that the sleep/wake rhythm can be influenced by diet.