EMA Advises Compassionate Use for HCV Drug Combination

International Approvals > Medscape Medical News

Troy Brown
February 21, 2014

The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has recommended a fixed-dose combination of ledipasvir and sofosbuvir (Gilead Sciences, Inc) for chronic hepatitis C virus (HCV) treatment in a compassionate-use program, the EMA announced today.

The drug combination contains the nucleotide analog polymerase inhibitor sofosbuvir (400 mg) and the NS5A inhibitor ledipasvir (90 mg), according to a company statement.

The committee recommended the drug combination to be used in those who urgently need therapy to prevent liver disease progression.

Compassionate-use programs are established at the level of individual member states to provide access to treatments that are still being developed and have not yet received marketing authorization to patients with life-threatening, long-lasting, or seriously disabling disease and no available treatment options.

Sweden requested the CHMP's opinion on providing early access under the compassionate-use program for the ledipasvir/sofosbuvir combination, with or without ribavirin, to adults with genotype 1 HCV infection and advanced liver disease who have a high risk for liver decompensation or death within 12 months without treatment.

In clinical trials, the ledipasvir/sofosbuvir combination, with or without ribavirin, was highly effective for those with genotype 1 virus when used for 12 or 24 weeks. Patients included those with compensated cirrhosis (scarring of the liver with normal liver function) and those in whom previous treatment with the protease inhibitors telaprevir or boceprevir was ineffective. Many of these patients urgently need effective therapy to stop the progression of liver injury in disease that is already very advanced.

This is the third opinion the CHMP has given since October 2013 on the compassionate use of treatments in development for HCV treatment.

The CHMP aims to follow a standard approach regarding the compassionate-use program for new medicinal products with regard to the criteria and conditions of their use before their authorization under member states' legislation.

The CHMP's opinion describes which patients may benefit from the medication, explains how to use the medication, and provides safety information to the EU member states that are considering developing a compassionate-use program; these recommendations are not mandatory.

The agency will publish the assessment report and conditions of use of the ledipasvir/sofosbuvir combination with or without ribavirin in this setting on its Web site in the near future.

Sofosbuvir was granted marketing authorization valid throughout the European Union under the trade name Sovaldi on January 16, 2014.

The US Food and Drug Administration approved sofosbuvir in December 2013.

Source

Also See: European Medicines Agency advises on compassionate use of a new combination therapy for chronic hepatitis C

Impact of Combination Interferon Therapy on the Body Weight, Body Fat and Lean Body Mass of Chronic HCV Infected Patients

Journal of Antivirals & Antiretrovirals

Research Article
Open Access

Ibrar Alam1,2, Ijaz Ali1, Sajid Ali3, Iftikhar Alam4,5, Farzana1 and 1 Naseem1

Corresponding Author :
Sajid Ali
Assistant Professor, Centre of Biotechnology and Microbiology
University of Peshawar, Pakistan
Tel: 92-0346911693
E-mail: vet_sajid@yahoo.com

Received November 26, 2013; Accepted December 29, 2013; Published December 31, 2013

Citation: Alam I, Ali I, Ali S, Alam I, Farzana, et al. (2013) Impact of Combination Interferon Therapy on the Body Weight, Body Fat and Lean Body Mass of Chronic HCV Infected Patients. J Antivir Antiretrovir 6:001-005. doi: 10.4172/jaa.1000087

Copyright: © 2013 Alam I, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Keywords: Body composition; Body fat; Interferon therapy; Hepatitis C

Introduction

Hepatitis C is a contagious disease of liver caused by the hepatitis C virus (HCV) [1] which is an enveloped ribo-nucleic acid (RNA) virus with a diameter of 50 nm and is classified as a separate genus (Hepacivirus) within the Flaviviridae family. The prevalence of HCV infection is estimated to be 2.2-3.0% (130-170 million people) worldwide [2].

About 15 to 20% of HCV infections progress to potentially serious cirrhosis and end-stage liver disease [3]. Patients with cirrhosis often have an abnormal body composition with clinical signs of proteinenergy malnutrition and a relative increase in body weight due to ascites or edema [4-6]. Ascites is a condition that is becoming treatable with diuretics, albumin preparations, ascetic reperfusion, and transjugular intrahepatic portosystemic shunting, but the prognosis of patients with ascites remains poor [7,8]. According to all consensus guidelines (EASL 2011, NICE 2010, AASLD 2009), the current standard of care (SoC) for HCV is the combination of interferon (IFN) and/or ribavirin (RBV) for 24-48 weeks, depending primarily on the viral genotype, virological response (SVR) (defined as undetectable HCV RNA level at 6 months after treatment completion).

Interferon (IFN) has been extensively used for treatment of HCV. The current therapy for HCV infection in developing countries is combination of either Telaprevir or Boceprevir (Protease inhibitors) with Ribavirin (RBV) and Interferon (IFN) for genotype 1 patients. This therapy has shown improved cure rate (60-80 percent), a significant increase in compare to prior therapy with improved SVR and significant reduction in treatment time (12-36 weeks).

Approximately 10-15 % of patients are forced to discontinue IFN therapy due to side effects/adverse effects associated with the therapy/ The rate of treatment withdrawal has been reported to be substantially higher. In addition, dose reduction of IFN and/or RBV owing to side effects/adverse effects is in the range of 25-40 % of patients. Studies suggest that dose reduction should be implemented at the earliest possible stage, when slight signs of side effects/adverse effects are noted [9].

A large regional and global variability exists in the nature of side/ adverse effects associated with HCV. There is also difference hence in the strategies employed to mitigate the impact of side/adverse effects during the treatment. The most common side/adverse effects include influenza-like symptoms (such as fatigue, headache, fever, and rigors). These occur in virtually all patients after the first doses of IFN, but usually subside after the first month of treatment. Dermatologic effects (alopecia, dermatitis) and gastrointestinal symptoms (nausea, diarrhea) are also very frequent. The most prevailing severe side effects/adverse effects are hematologic, neuropsychiatric and autoimmune [10].

Fellay et al. [11] has reported that anemia as an adverse effect of IFN therapy, is common in as much as 30% of the treated patients. For evaluation of anemia, usually the lowest hemoglobin (Hb) values are recorded 6-8 weeks after treatment has been started and stay at the same level throughout the remaining therapy period. There are higher chances of severe anemia to occur, with hemoglobin levels as much below as<10 g/dL and approximately 10-15 % of patients suffer from severe anemia [11].

In most clinics and health care centers, patients are weighed almost at every visit. However measuring weight alone can be a misleading indicator of nutritional status, particularly in HCV patients, because lean body mass is lost in preference to fat and in addition to it, there is no way to distinguish between body fat (BF), and lean body mass (LBM) when weight measurements alone are used [12]. Serial weight measurements have been used by the Centers for Disease Control and Prevention (CDC) as a way to identify the wasting syndrome and predict the development of AIDS [13]. However, measurement of body weight alone failed to identify dramatic losses in body cell mass and other body composition parts [14]. Thus, further measures of body composition are also needed, to identify losses or gains of lean body mass, body fat or body cell mass associated with increased mortality [13]. The present study was aimed to prospectively evaluate effects of combination antiviral therapy on total body weight, body fat and lean body mass of HCV infected adult individuals.

To investigate the effect of antiviral therapy, we carried out a crosssectional prospective study, to evaluate changes in various parameters of body composition such as body weight, body fat (BF) and lean body mass (LBM).

Materials and Methods

The present study was conducted at the Institute of Biotechnology and Genetic Engineering (IBGE) KPK Agricultural University, Peshawar and Khyber Teaching Hospital (KTH), Peshawar, Khyber Pakhtunkhwa of Pakistan.

Inclusion criteria were: adult male, having HCV, non-diabetic with no other reported infectious and/or non-infectious diseases, non-smoker and non-drug-users. In addition only those patients were included who had no recent history of intentional or unintentional weight loss or changes in other body composition parameters. All those subjects were excluded who had a recent history of any metabolic complications and/or medical disorder. A total of 30 subjects of local Pashtun ethnicity participated willingly in the study. The subjects were divided into two groups. One group started with IFN-combination (On therapy group) while the other group did not take any therapy during the study period. IFN-α 2b dose was 3 mU thrice a week plus Ribavirin 1000 mg/day. All the patients of the study, who visited the OPD were assessed and interviewed thoroughly. The following procedures were adapted for data collection.

• Screening for diagnosis to make sure they are suffering from HCV

• 24-hours Dietary Recall (Performa)

• Biochemical Tests and differential blood counts.

• Body composition Assessment using Bio-electric Impedance (BIA)

Screening

Initially all the subjects were screened for anti-Hepatitis C virus antibodies by Immuno-Chromatographic Tests (ICT) (Abbot and Awrate). Samples diagnosed as positive by ICT technique were further evaluated using ELISA (BIOKIT, S.A, Barcelona-Spain) according to the manufacturer’s instructions. All the ELISA positive samples were processed for RNA extraction. According to manufactures’ instructions we extracted HCV RNA from 200 μl sample of serum by using Ana-gen RNA extraction Kit (Ana-gen, USA). Qualitative HCV RNA extraction and HCV genotyping was carried out according to our previous work [15]. All the products of PCR (1st and 2nd rounds) were analyzed on 1.8% agarose gel prepared in 0.5% TBE buffer, stained with Ethedium bromide. Using Alpha quant (Alpha Innotech) gels were photographed.

Assessment of body composition and determination of blood chemistry

BIA is recommended in measurement of body composition in healthy as well as individuals with chronic disease conditions [16]. Bioelectrical impedance analysis (BIA) was performed to measure body weight, body fat and lean body mass of the study subjects by using Bodystat® Quanscan 4000 Hydration/Body composition Monitoring Unit, Isle of man, UK [17].

Routine blood chemistry for albumin, ALT (Alanin Aminotransferase) and hemoglobin were determined.

The study was approved by the Board of Studies, IBGE, AUP. Written consents of willing to participate in the study were obtained from all patients.

Statistical analysis

The data were statistically analyzed using SAS (Version 7.0. SAS, USA). Data were expressed in mean (STD). Student’s t-test was performed to explore the difference between means of variables of interest. A p value of ≤ 0.05 was considered as significant.

Results

The current study was conducted to investigate the changes in body composition as a result of interferon (IFN) therapy in HCV positive patients. A total of 30 male patients participated in the study. These patients were divided into two distinct groups i.e. ‘on therapy’ group (N, 20) and ‘no therapy’ group (N, 10). HCV positive patients ‘on therapy’ used the IFN treatment and were followed for the 6 months of treatment. As a control, HCV positive patients on ‘no therapy’ were also followed for the 6 months after they were first diagnosed.

The age and other characteristics of the patients are presented in Table 1. The mean age (p=0.39), weight (p=0.64), and BMI (p=0.56) of the two groups of HCV positive patients at baseline did not differ significantly. Table 1 also shows the mean body fat, lean body mass, intracellular and extracellular body water and phase angle of HCV positive patients which shows a homogeneous population of the study with respect to age and body weight. As clear from Table 1, these values did not differ significantly for the two groups (p, for all trends>0.05).

Tables 2 and 3 show respectively, the mean values of nutrient intake (energy and protein), selected blood biochemistry (albumin, ALT, hemoglobin) and differential blood counts of the HCV positive patients at baseline. As can be seen, these figures did not differ significantly for the two groups of HCV positive patients (i.e. on therapy and no therapy) (p, for all trends>0.05).

The mean difference in body weight of HCV patients ‘on therapy’ and on ‘no therapy’ are shown in Figure 1. As shown, there was a significant (p ≤ 0.05) reduction in Body Weight (62.93 ± 8.27 Kg at baseline vs. 57.13 ± 7.54 Kg at month 6) in HCV patients ‘on therapy’ group, whereas, a non-significant decrease in body weight in HCV patients on ‘no therapy’ (61.31 ± 11.73 Kg at baseline vs.60.72 ± 13.81 Kg at month 6).

As evident from Figure 2 there was significant (p ≤ 0.05) reduction in body fat (11.4 ± 6.57 Kg at baseline vs. 9.1 ± 6.36 Kg at month 6) observed in HCV patients ‘on therapy’, whereas, a non-significant increase occurred in HCV patients on ‘no therapy’ (body fat 9.02 ± 2.8 Kg at baseline vs. 9.41 ± 2.55 Kg at month 6; p=0.213).

Figure 3 shows the changes in LBM in the HCV patients ‘on therapy’ (blue line) and HCV patients on ‘no therapy’ (red line). There was a significant (p ≤ 0.05) mean reduction in LBM in HCV patients on therapy (51.6 ± 8.93 Kg LBM at baseline vs. 48.0 ± 8.64 Kg LBM at month 6) (Figure 3). In HCV patients on ‘no therapy’, there was a nonsignificant difference between the LBM at baseline (51.86 ± 10.16 Kg) and at month 6 (51.87 ± 11.14 Kg) (Figure 3).

Discussion

Hepatitis C is highly prevalent in Pakistan [15]. Treatment options for Hepatitis C include conventional IFN alone or in combination with Ribavirin. However, IFN-based therapy has several diverse effects (manifested in the form of weight loss etc) due to which, most often the treatment is discontinued [9]. As has been considered previously, beside body weight body fat (BF), lean body mass (LBM), extracellular and intracellular water (ECW and ICW), phase angle, and body cell mass (BCM) are some important parameters for assessing the health and nutritional status of individuals [18-20].

Data on changes in body composition in patients with HCV infection before and during treatment are not reported extensively, particularly in developing countries, where the infection may have different dimensions of prevalence and therapeutic approaches. This study was conducted on HCV patients in order to investigate the immediate effects of interferon-α (IFN-α) therapy on some selected parameters of body composition. Data on body composition is an important factor for treatment decisions, especially if supplemental therapy is needed. IFN-α and/or ribavirin treatment in HCV has been reported to be very often associated with fatigue, cephalgia, weight loss, flu-like syndromes, and anorexia [21]. All these contraindication may have adverse implications for changes in nutritional status and body composition [22].

HCV infection may adversely affect energy balance of the body leading to a reduction of both somatic proteins of fat-free mass (FFM) and of visceral proteins in the elderly patients. In addition, body composition is altered in patients with HCV because of proteinenergy malnutrition, altered micronutrient status, and variable fluid homeostasis [22].

In our study the percentage of individuals that experienced a reduction in total body weight during interferon therapy are higher than the 11-29%, reported by other studies [21,23]. The original studies mainly relied on patients for reporting of weight reduction rather than on prospective measurement, this may result in the difference in the percentage of subjects that experienced weight loss. Alternatively, a loss more than a pre-specified mass or percentage of baseline in some analysis is defined as weight loss. The observations prepared by other studies are, however, reliable with our own. As an example, an experiment of eleven children that were on interferon therapy for HCV showed a weight reduction and nutritional status was impaired in all of the subjects [24]. Another study reported that a reduction of body weight was observed; at the end of 4 weeks 91.2% of the patients showed a reduction in weight, at 12 weeks 93.7%, at 24 weeks 94.7% and at the end of 48 weeks of treatment a reduction in weight was observed in 89.6% of the patients. At 4 weeks median weight losses were 2.3% of pretreatment weight, at 12 weeks 4.6%, at 24 weeks 6.3%, at 52 weeks 8.9% of the treatment. Median weight had increased to 96.4% of the pre-treatment 12 weeks after the completion of the treatment, and this had increased to 99% by 24 weeks [25].

As can be seen in our study (Figures 1-3), changes in body weight and other body compartments (i.e. body fat and lean body mass) occurred mostly in the first four months of the treatment. These results are consistent with those reported by Gottrand et al. [24] and Lebensztjen et al. [26]. The former reported weight loss in HCV patients during the first three months of IFN therapy, while the latter reported these changes mainly in the second month of therapy. The onset and timing of weight loss is important as decisions regarding continuation, cessation, or modification in the dose and treatment regimen depend on the time when and how changes in body weight start.

In our study, all patients ‘on therapy’ lost weight with the greatest effect being demonstrated early in treatment (months 2 - 4) (Figure 1). All patients ‘on therapy’ lost body fat and again the greatest effect being demonstrated early in treatment (months 2 - 4) (Figure 2). The loss in lean body mass (LBM) was also experienced by all patients ‘on therapy’; however, the loss in LBM was uniform throughout the study period (Figure 3). In the HCV positive subjects who were on ‘no therapy’, the mean body weight loss was 0.59 (± 0.018) Kg and the difference between mean body weight at month 6 (60.72 ± 12.80) and mean body weight at baseline (61.31 ± 12.86 SD) was not statistically significant (p=0.20). Similarly, no significant changes in body fat and lean body mass were recorded for patients with ‘no therapy’ (Figures 2 and 3, respectively).

Winding up, interferon therapy (IFN) results in weight loss as a side effect in hepatitis C infected individuals. Adding together, the therapy affects other compartments of body composition adversely. The study is limited in that it could recruit male patients only with relatively smaller sample size. Future studies based on the finding of the present study will include female subjects from possibly all segment of population to generalize the results.

References

1. Ray CG, Ryan KJ (2004) Sherris Medical Microbiology. McGraw Hill, New York, USA.

2. Lavanchy D (2009) The global burden of hepatitis C. Liver Int 29 Suppl 1: 74-81.

3. Liang TJ, Rehermann B, Seeff LB, Hoofnagle JH (2000) Pathogenesis, natural history, treatment, and prevention of hepatitis C. Ann Intern Med 132: 296-305.

4. McCullough AJ, Mullen KD, Kalhan SC (1991) Measurements of total body and extracellular water in cirrhotic patients with and without ascites. Hepatology 14: 1102-1111.

5. Panella C, Guglielmi FW, Mastronuzzi T, Francavilla A (1995) Whole-body and segmental bioelectrical parameters in chronic liver disease: effect of gender and disease stages. Hepatology 21: 352-358.

6. Prijatmoko D, Strauss BJ, Lambert JR, Sievert W, Stroud DB, et al. (1993) Early detection of protein depletion in alcoholic cirrhosis: role of body composition analysis. Gastroenterology 105: 1839-1845.

7. Moore KP, Wong F, Gines P, Bernardi M, Ochs A, et al. (2003) The management of ascites in cirrhosis: report on the consensus conference of the International Ascites Club. Hepatology 38: 258-266.

8. Salerno F, Borroni G, Moser P, Badalamenti S, Cassarà L, et al. (1993) Survival and prognostic factors of cirrhotic patients with ascites: a study of 134 outpatients. Am J Gastroenterol 88: 514-519.

9. Dieterich DT, Rizzetto M, Manns MP (2009) Management of chronic hepatitis C patients who have relapsed or not responded to pegylated interferon alfa plus ribavirin. J Viral Hepat 16: 833-843.

10. Sulkowski M, Shiffman ML, Afdhal NH, Reddy KR, McCone J, et al. (2009) 10 Declines in Hemoglobin Is Associated with Sustained Virologic Response (SVR) Among HCV Genotype 1-Infected Persons Treated with Peginterferon (PEG)/Ribavirin (RBV): Analysis from the Ideal Study. Gastroenterology 136: A-790-A-791.

11. Fellay J, Thompson AJ, Ge D, Gumbs CE, Urban TJ, et al. (2010) ITPA gene variants protect against anaemia in patients treated for chronic hepatitis C. Nature 464: 405-408.

12. Wanke C, Polsky B, Kotler D (2002) Guidelines for using body composition measurement in patients with human immunodeficiency virus infection. AIDS Patient Care STDS 16: 375-388.

13. Knox TA, Zafonte-Sanders M, Fields-Gardner C, Moen K, Johansen D, et al. (2003) Assessment of nutritional status, body composition, and human immunodeficiency virus associated morphologic changes. Clin Infect Dis 36: S63-S68.

14. Kotler DP, Tierney AR, Wang J, Pierson RN Jr (1989) Magnitude of body-cell-mass depletion and the timing of death from wasting in AIDS. Am J Clin Nutr 50: 444-447.

15. Khan NU, Ali I, Ahmad NU, Iqbal A, Rehman LU, et al. (2011) Prevalence of active HCV infection among the blood donors of Khyber Pakhtunkwa and FATA region of Pakistan and evaluation of the screening tests for anti-HCV. Virol J 8: 154.

16. Gordner RL, Selden C, Foster WR (1994) Bioelectric impedance analysis in body composition measurement: program and abstracts: December 12-14, National Institutes of Health.

17. Kahraman A, Hilsenbeck J, Nyga M, Ertle J, Wree A, et al. (2010) Bioelectrical impedance analysis in clinical practice: implications for hepatitis C therapy BIA and hepatitis C. Virol J 7: 191.

18. Chertow GM, Lazarus JM, Lew NL, Ma L, Lowrie EG (1997) Bioimpedance norms for the hemodialysis population. Kidney Int 52: 1617-1621.

19. Earthman C, Traughber D, Dobratz J, Howell W (2007) Bioimpedance spectroscopy for clinical assessment of fluid distribution and body cell mass. Nutr Clin Pract 22: 389-405.

20. Kaysen GA, Zhu F, Sarkar S, Heymsfield SB, Wong J, et al. (2005) Estimation of total-body and limb muscle mass in hemodialysis patients by using multifrequency bioimpedance spectroscopy. Am J Clin Nutr 82: 988-995.

21. Manns MP, McHutchison JG, Gordon SC, Rustgi VK, Shiffman M, et al. (2001) Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet 358: 958-965.

22. Antaki F, French MM, Moonka DK, Gordon SC (2008) Bioelectrical impedance analysis for the evaluation of hepatic fibrosis in patients with chronic hepatitis C infection. Dig Dis Sci 53: 1957-1960.

23. Fried MW (2002) Side effects of therapy of hepatitis C and their management. Hepatology 36: S237-244.

24. Gottrand F, Michaud L, Guimber D, Ategbo S, Dubar G, et al. (1996) Influence of recombinant interferon alpha on nutritional status and growth pattern in children with chronic viral hepatitis. Eur J Pediatr 155: 1031-1034.

24. Seyam MS, Freshwater DA, O'Donnell K, Mutimer DJ (2005) Weight loss during pegylated interferon and ribavirin treatment of chronic hepatitis C*. J Viral Hepat 12: 531-535.

26. Lebensztejn DM, Zagorecka E, Kaczmarski M, Piotrowska-Jastrzebska J (2001) [The assessment of nutritional status in children with chronic hepatitis B treated with interferon alpha]. Pol Merkur Lekarski 11: 29-31.

27. Fernandes SA, Gonzalez MC, Bassani L, Miranda D, Pivatto B, et al. (2013) Is the Phase Angle, a Prognostic Indicator for Nutritional Status in Cirrhotic Patients? J Antivir Antiretrovir S3:004.

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European Medicines Agency advises on compassionate use of a new combination therapy for chronic hepatitis C

21/02/2014

Combination of ledipasvir and sofosbuvir to be used in patients in urgent need of therapy to prevent progression of liver disease

The European Medicines Agency’s Committee for Medicinal Products for Human Use(CHMP) has given an opinion on the use of a fixed-dose combination of ledipasvir and sofosbuvir in the treatment of chronic (long-term) hepatitis C virus (HCV) infection in a compassionate-use programme.

Compassionate-use programmes are set up at the level of individual Member States. They are intended to give patients with a life-threatening, long-lasting or seriously disabling disease with no available treatment options access to treatments that are still under development and that have not yet received amarketing authorisation.

In this specific case, Sweden requested an opinion from the CHMP on the conditions under which early access through compassionate use could be given to a combination of ledipasvir and sofosbuvir, with or without ribavirin, for adult patients with genotype 1 HCV infection and advanced liver disease, who are at a high risk of their liver being no longer able to function normally (decompensation) or death within 12 months if left untreated.

In clinical trials, the combination of ledipasvir and sofosbuvir, with or without ribavirin, used for 12 or 24 weeks, has shown high efficacy in treating patients with genotype 1 virus, including patients with compensated cirrhosis (scarring of the liver but normal liver function) and patients who have previously failed treatment with the protease inhibitors telaprevir or boceprevir (other treatments for hepatitis C). Many of these patients have very advanced liver disease and are in urgent need of effective therapy in order to halt the progression of liver injury.

This is the third opinion provided by the CHMP since October 2013 oncompassionate use of medicines in development for the treatment of hepatitis C.

The aim of the CHMP assessment and opinion on a compassionate-use programme for new medicinal products is to ensure a common approach, whenever possible, regarding the criteria and conditions of their use prior to their authorisation under Member States' legislation. The opinion provides recommendations to the EU Member States that are considering setting up such a programme, and its implementation is not mandatory. In addition to describing which patients may benefit from the medicine, it explains how to use it and gives information on safety.

The assessment report and conditions of use of the combination of ledipasvir and sofosbuvir with or without ribavirin in this setting will be published shortly on the Agency's website.

Notes

• The fixed-dose combination of ledipasvir and sofosbuvir is being developed by Gilead Sciences.
• Sofosbuvir, which is part of this compassionate-use opinion, was granted a marketing authorisation valid throughout the European Union on 16 January 2014. For more information, see Sovaldi.

European Medicines Agency advises oncompassionate use of a new combination therapy for chronic hepatitis C – PDF (English only) 21/02/2014

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Prognostic factors of hepatic decompensation and hepatocellular carcinoma in patients with transfusion-acquired HCV infection

Liver Int. 2014 Feb 16. doi: 10.1111/liv.12502. [Epub ahead of print]

Zavaglia C¹, Silini E, Mangia A, Airoldi A, Piazzolla V, Vangeli M, Stigliano R, Foschi A, Mazzarelli C, Tinelli C.

Abstract

AIMS: Aim of the study was to assess if host (immunogenetic traits, age, sex), exogenous (alcohol) or viral factors (viral type, past HBV infection) might affect the progression of chronic hepatitis C to liver decompensation or the development of HCC in a cohort of patients exposed to a single blood transfusion prior to the introduction of anti-HCV screening.

METHODS: Two hundred and forty-eight patients with a history of a single exposure to blood or blood products prior to 1990 were retrospectively considered. Patients were devoid of other risk factors of liver disease or immunosuppression and naïve to antiviral therapies. Eight baseline variables were assessed: age at transfusion, sex, HBV core antibody, immunogenetic profile (DRB1*11, DRB1*1104, DRB1*07), HCV genotype and alcohol consumption.

RESULTS: The follow-up was 22 (SD 11) years. Sixty-eight patients (27%) progressed to hepatic decompensation over a median period of 22.5 years (IQR: 14-30) and 41 patients (16%) developed HCC over a median period of 31 years (IQR: 24 - 38). The cumulative incidence of liver failure was 0.4% (95%CI: 0.1 - 3.1), 4.9% (95%CI: 2.6 - 9.3) and 16.2% (95%CI: 10.4 - 24.7) at 10, 20 and 30 years after blood transfusion, respectively. By univariate analysis, only age at transfusion was correlated with the risk of decompensation. Stratifying the age of transfusion by tertiles, the incidence of hepatic decompensation was 0.7% per year in patients transfused at ≤24 years of age as compared with 1.2% and 1.9% per year in those transfused at 25-35 and >36 years of age, respectively (HR 5.5, 95%CI: 2.78-10.7, p<0.001). The risk of HCC development was correlated by univariate analysis with age at transfusion (as continuous variable, HR 1.12, 95% CI 1.08-1.16 per year of age, p<0.001, >36 compared to ≤24 years, HR 10.3, 95% CI 3.9-26.9, p<0.001) and male sex (HR 4.2, 95% CI 1.7-10, p=0.001). Multivariate analysis confirmed age at transfusion and male sex as independent predictors of HCC development (HR 1.12 per year [95% CI: 1.08-1.16], p<0.001 and HR 5.4 [95% CI 2.2-13.2], p<0.001, respectively)

CONCLUSIONS: In patients with transfusion-acquired HCV infection, age at transfusion affect the risk for hepatic decompensation. Age at transfusion and male sex are also independent risk factors for HCC development. This article is protected by copyright. All rights reserved.

This article is protected by copyright. All rights reserved.

KEYWORDS: HCV , blood transfusion, chronic hepatitis C, hepatic decompensation, hepatocellular carcinoma

PMID: 24529078 [PubMed - as supplied by publisher]

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Drug Can Possibly Treat Acetaminophen Poisoning

Thu, 02/20/2014 - 2:07pm

The human liver can safely process up to 4 grams (8 pills) of acetaminophen, best known as Tylenol, over 24 hours. Surpassing that amount risks poisoning or killing liver cells. (Source: Harvard University/B. D. Colen)

Harvard stem cell scientists studying the effect of nitric oxide on liver growth and regeneration appear to have serendipitously discovered a markedly improved treatment for liver damage caused by acetaminophen toxicity, the root of half of the hospital visits involving acute liver failure in the United States.

The human liver can safely process up to 4 grams (8 pills) of acetaminophen, best known as Tylenol, over 24 hours. Surpassing that amount risks poisoning or killing liver cells. Accidental acetaminophen overdoses commonly occur when people who feel sick but don’t know the dangers posed by the over-the-counter pain and fever reducer exceed the safe dosage. Such poisoning kills hundreds of people each year.

Writing in the journal Cell Reports, the researchers described how nitric oxide, which is commonly used to relax cardiac blood vessels in patients with heart disease, enhances liver growth and regeneration, independent of its effect on blood vessels. Using zebrafish and mice, the research team also showed how manipulating these pathways with drugs could improve treatment of toxic liver injury caused by acetaminophen overdose.

The only federally approved treatment for acetaminophen toxicity, N-acetylcysteine (NAC), is most effective if a patient seeks medical help within 8 to 12 hours of overdose. Unfortunately, most overdose-specific symptoms, such as confusion and intestinal bleeding, don’t occur until the liver injury is critical.

“We tried to model that in our studies where we gave fish Tylenol first, waited 18 hours, and gave them a new nitric oxide-based drug combined with the clinically approved drug,” said study co-senior author Wolfram Goessling of the Harvard Stem Cell Institute. “These drugs worked together to improve liver injury even when out of the previously established therapeutic window, and so we think there’s significant potential for clinical application.”

Goessling and his research associates happened upon the nitric oxide-liver injury connection while investigating the signaling pathways that are important for liver development. Goessling’s lab, which he shares with study co-senior author Trista North, screened thousands of known drugs on zebrafish embryos to see which produced a bigger or smaller liver. The compounds with the most dramatic effect were a family of drugs that affect nitric oxide and nitric oxide signaling.

Andrew Cox, a postdoctoral fellow in Goessling’s lab, conducted a series of experiments to show that nitric oxide enhanced liver formation during organ development in zebrafish and that blocking nitric oxide led to smaller, less-developed livers. Further investigation found that nitric oxide worked through different pathways in the liver than it did in the blood vessels, where its ability to regulate blood flow has been well established.

“During these experiments, we found a recently recognized pathway, called protein nitrosylation, where the activity of proteins gets changed by nitric oxide,” Goessling said. “We think that’s the basic principle behind how it works in liver development.”

The members of Goessling and North’s lab found it was possible to enhance liver growth and regeneration by disrupting the nitrosylation pathway so that nitric oxide could better change proteins in the liver. They found a nitrosylation enhancer currently used in clinical trials for other purposes and began testing it in clinical models of illnesses such as Tylenol overdose, where it proved successful.

“This potential drug doesn’t only work in fish,” Goessling said. “We did use mouse models to show that this might have relevance to human disease.”

If the nitrosylation drug for liver toxicity reaches clinical trials, it would join a handful of other drugs developed from zebrafish research that originated from Harvard Stem Cell Institute labs.

Last year, a compound discovered by North and Goessling while they were working as postdoctoral fellows in the lab of Leonard Zon was found to expand cord blood during hematopoietic stem cell transplants in a Phase 1b clinical trial. Another drug for melanoma, also discovered in the Zon lab, reached the federal Food and Drug Administration approval process in 2011.

Date: February 20, 2014

Source: Harvard University

Source

Active at night, sleepy all day - Sleep disturbances in patients with hepatitis C virus infection

Provided by NATAP

Download the PDF here

Article in Press

Journal of Hepatology 2014
Meike Heeren, Faina Sojref, Ramona Schuppner, Hans Worthmann, Henning Pflugrad, Anita B. Tryc, Thomas Pasedag, Karin Weissenborn
Department of Neurology, Hannover Medical School, Hannover, Germany

"The purpose of this study was to characterize the feature and degree of sleep disturbances in HCV-infected patients without relevant liver disease and to clarify the patients' symptoms. Furthermore we were interested to analyze the relationship between sleep disturbances, neuropsychiatric symptoms and health-related quality of life.......In conclusion, our data showed altered sleep quality in a group of patients with HCV infection associated neuropsychiatric symptoms but only mild liver disease.....wrist actigraphy showed sleep disturbances reflected by a higher nocturnal activity and poorer sleep efficiency........Our data indicate that chronic fatigue is associated with bad sleep quality and increased nocturnal activity in HCV-infected patients.....The patients achieved higher scores for depression, fatigue and sleep disturbances and lower quality of life scores than the healthy controls. Actigraphy showed higher nocturnal activity and worse sleepefficiency in the patients, while the 24-h activity level did not differ between groups. Fatigue and quality of life scores correlated with bad sleep quality and daytime sleepiness."

HIV & Sleep

Disturbances......http://www.natap.org/2012/HIV/050412_06.htm

"On the basis of experimental studies it is known that sleep disturbances are associated with alterations of the immune system.......The alteration of cytokine levels both in the periphery as well as in the brain itself could well be involved in the development of sleep disturbances in HCV-infected patients.......In conclusion, our data showed altered sleep quality in a group of patients with HCV infection associated neuropsychiatric symptoms but only mild liver disease.......In summary sleep-wake disturbances are common in cirrhotic patients. The patients suffer from daytime sleepiness and bad sleep quality and some studies showed a phase delay in the sleep patterns of cirrhotic patients. Our patient group with only mild liver disease showed a different feature of sleep disturbances."

------------------------------

ABSTRACT

Background & Aims
More than 50% of patients with chronic hepatitis C with only mild liver disease complain about chronic fatigue, daytime sleepiness and poor sleep quality. The aim of the present study was to characterize and objectify the sleep disturbances in hepatitis C virus-infected patients.

Methods
Twenty-five women who had been infected with hepatitis C virus contaminated anti-D immunoglobulin in 1978/79 and 22 age-matched female healthy controls underwent actigraphy over a period of 5days to measure motor activity and thereby sleep-wake-rhythm and in addition completed questionnaires for depression, health-related quality of life, fatigue and sleep, and a sleep diary. Liver cirrhosis, a history of neurological or psychiatric disease, history of intravenous drug abuse, shift work, or current medication with effect upon the central nervous system were exclusion criteria.

Results
The patients achieved higher scores for depression, fatigue and sleep disturbances and lower quality of life scores than the healthy controls. Actigraphy showed higher nocturnal activity and worse sleep efficiency in the patients, while the 24-h activity level did not differ between groups. Fatigue and quality of life scores correlated with bad sleep quality and daytime sleepiness.

Conclusions
Our data indicate that chronic fatigue is associated with bad sleep quality and increased nocturnal activity in HCV-infected patients suggesting an alteration of sleep architecture behind fatigue in HCV-associated encephalopathy.

Introduction

About 170 million people worldwide suffer from chronic infection with the hepatitis C virus (HCV), the global prevalence is about 2.35%. In 80% acute hepatitis C infection leads to chronic hepatitis whereas between 1 and 20% - dependent on the presence or absence of risk factors such as older age, male sex, alcohol abuse, or diabetes for example - develop liver cirrhosis [1], [2]. An extremely low rate of liver cirrhosis has been observed in the so-called German Anti-D cohort, a group of women who have been infected with HCV contaminated anti-D immunoglobulin in 1978/79 in Eastern Germany. Wiese et al. reported that only 2% of 1980 women who underwent a follow-up examination 25years after the infection showed liver cirrhosis or a pre-cirrhotic stage while 62% "complained of constitutional symptoms such as reduced exertional capacity, weakness and fatigue, abdominal distention, arthralgia, myalgia, or headaches" [2].

Hepatologists are well aware of the extrahepatic manifestations of the HCV-infection and it has been acknowledged recently that the central nervous system is most frequently affected [3].

Symptoms like chronic fatigue, mood disturbances and cognitive dysfunction occur in HCV infected patients with none or only mild liver disease and are accompanied with a reduction of health-related quality of life. The most frequent symptom with more than half of the patients affected is fatigue. Of note, this holds true also in the absence of advanced liver disease or ongoing antiviral therapy with interferon alpha [4]. In detail, chronic HCV infected patients complain about daytime fatigue and poor sleep quality. Up to now these symptoms are not well described in the literature and the pathogenesis is still unclear [5].

The purpose of this study was to characterize the feature and degree of sleep disturbances in HCV-infected patients without relevant liver disease and to clarify the patients' symptoms. Furthermore we were interested to analyze the relationship between sleep disturbances, neuropsychiatric symptoms and health-related quality of life.

Patients and methods

Patients and controls

One-hundred-forty-three members of HCV patient support groups for women who had been infected with HCV-contaminated anti-D immunoglobulin in 1978/79 were contacted in writing and asked if they were interested in taking part in the study. These patients were considered especially suitable to study the effect of HCV-infection upon sleep features and quality because neither co-infection, nor substance abuse or other concomitant disorders could probably bias the results. Eleven patients had moved and their current address was not available, two patients refused to take part in the study. Forty-two women answered our letter and showed interest (Fig. 1).

These 42 women were contacted via phone for a structured interview concerning the exclusion criteria such as liver cirrhosis, a history of neurological or psychiatric disease, history of intravenous drug abuse, shift work, or current medication with effect upon the central nervous system. Thereafter 17 patients had to be excluded from the study because of current therapy with antidepressants (n=10), opioids or benzodiazepine (n=5) or current interferon therapy (n=2) (Fig. 1).

Finally, twenty-five women were included into the study. The time span since infection was more than 30years and the genotype of the virus 1b in all patients. Liver cirrhosis or severe fibrosis was excluded by calculation of the APRI (aspartate aminotransferase-to-platelet ratio index) score [6], by ultrasound of the liver and/or by liver biopsy.

22 age-adjusted female control subjects were recruited from the clinic staff as well as family and friends of working group members applying the same exclusion criteria as for the patients. Patients and controls gave their written informed consent.

The study has been performed according to the 1975 Declaration of Helsinki and has been approved by the local ethics committee.

Questionnaires

The patients and controls completed several questionnaires including the Pittsburgh sleep quality index (PSQI) [7], the Epworth sleepiness scale (ESS) [8], the fatigue impact scale (FIS) [9], the Beck depression inventory (BDI) [10], the hospital anxiety and depression scale (HADS) [11] and the SF-36 [12]. The PSQI is a subjective measure of sleep quality over the previous 4weeks. The questionnaire consists of 17 items based on components of quality, latency, duration, efficiency, disturbance, use of sleeping medication and daytime dysfunction. The global score varies between 0 and 21. A score 5 can be considered suggestive of significant sleep disturbance. The ESS intends to measure daytime sleepiness. Each item is rated on a 4-point scale. The global score ranges between 0 and 24, with 10 as a cut-off score for pathological daytime sleepiness. The FIS is a self-report scale to measure the impact of fatigue upon patients' daily living activities. It contains 40 items with a scale from 0 to 4. The total score varies between 0 (no fatigue) and 160 (severe fatigue), we choose 50 as a suggested cut-off for pathological fatigue considering own data from healthy controls from former studies. The BDI is a self report scale to measure depression. The questionnaire contains 21 items and a 4-point response scale, ranging from 0 (minimal) to 3 (severe). The global score ranges from 0 to 63, a score 18 can be considered as pathologic. The Hospital Anxiety and Depression Scale (HADS) has been developed for use in in-hospital patients with internal disease to assess emotional alterations. It is a 14 items scale, each scored from 0 to 3. The global range varies between 0 and 21 for anxiety and depression, respectively, with a score 11 indicating anxiety or depression. The Short-Form questionnaire (SF-36) is a survey with 36 questions to measure health-related quality of life (QoL). It provides scores for 8 health domains which can be summarized to a physical and a mental score with a maximum of 400 points for each of the two domains. The cut-off depends on age and sex. The patients' results were evaluated accordingly.

Sleep diary

The patients were requested to fill in a sleep diary to record the "in bed time", time to sleep onset, number of awakenings, "out of bed time", daytime nap, coffee and alcohol consume for the days studied.

Actigraphy

Actigraphy was used to measure motor activity of the subjects throughout a period of 5days. The actigraph is a small device (38mmX37mmX18mm, weight 26g) which is worn on the wrist of the non-dominant hand. We used the accelerometer ActiGraph Monitor GT1M and GT3X (ActiGraph, Pensacola, USA). Both contain a sensor which detects motion with linear piezoelectric accelerometer in a vertical axis [13]. The signal is summarized over epochs of 60s, and given as counts per minute (cpm). Patients and controls were advised to wear the device from Sunday to Saturday 24h per day and to only take it off for washing the dishes or taking a shower. The data stored were downloaded to a computer using the ActiLife 5.0 software. Because of the varying sleep-wake-rhythm during the weekend only data covering the time span from Monday 12pm until Friday 12pm were considered for further analysis.

\e used the floating window algorithm and 20min of consecutive zero counts to identify the non-wear time. Afterwards the data were visually inspected to ensure that information recorded in the sleep diary corresponded with the accelerometer output. The periods of non-wear time as indicated by the participants were excluded from further analysis.

For the sleep scoring we completed the stored data by adding the "in bed time" and "out of bed time" from the sleep diary. The software provides the following parameters:

Sleep onset (the first minute that the algorithm scores "asleep"), total sleep time (the total number of minutes scored as "asleep"), sleep efficiency (number of sleep minutes divided by the total number of minutes the patient was in bed), wake after sleep onset (WASO; the total number of minutes the subject was awake after sleep onset occurred), average awakening (the average length in minutes of all awakening episodes), total counts (total actigraphy counts summed up for the entire sleep period).

The total numbers of epochs stored during the measurement (4X24h) were averaged to measure different categories of activity intensity in a 24h period. We selected 100 counts per minute (cpm) as a cut-point for sedentary behaviour, 100-759cpm for light physical activity, 760-1951cpm for lifestyle physical activity, 1952-5724cpm for moderate physical activity and >5725cpm for vigorous physical activity [14], [15]. In addition we combined the moderate physical activity and vigorous physical activity counts into one class (MVPA >1952cpm) for further analysis as described by Matthews et al. [14]. In addition to the "counts" the data provided bouts of activity. A minimum bout length was 10min, the minimum count level to be considered as bout was 1953cpm and the drop time was 2min [15], [16].

Statistical analysis

Statistical analysis was done using SPSS Version 20. If the data were normally distributed, the results of the questionnaires and actigraphy parameters are summarised as mean values and standard deviations. For not normally distributed data the results are given as median and 25th-75th percentile. A comparison between patients' and control data was performed using the unpaired Student's t test or the Mann-Whitney-U-test accordingly. Spearman correlation was used to look for a relationship between fatigue, QoL and sleep parameters and the actigraphy results because they were not normally distributed. The level of significance was set at a p value of <0.05. In case of multiple comparisons the Bonferroni-Holm correction was applied.

Results

The data of 5 patients and 3 controls had to be excluded from further analysis due to device dysfunction (n=3), insufficient number of monitoring days (n=4) or missing sleep diary (n=1). Thus finally data of 20 patients (age 56.8±4.2) and 19 controls (age 55.3±4.2) were considered for analysis. Six patients had been treated with interferon more than 7years ago. Eight patients were HCV PCR negative, seven spontaneously and one after therapy.

Liver cirrhosis was excluded based on clinical, ultrasound and laboratory data. Liver biopsy has in addition been performed in 3 patients and showed ISHAK 1 fibrosis in 2 and ISHAK 2 fibrosis in one patient. In the other 17 patients liver biopsy was not indicated considering the clinical course as well as ultrasound and laboratory findings. In these patients the APRI score was in median 0.14 (25th-75th percentile: 0.120-0.265).

Five patients are current smokers and 9 patients reported light to moderate alcohol consumption. In the control group 4 women are current smokers and 14 reported light-to-moderate alcohol consumption.

Questionnaires

The results of the questionnaires differed significantly between the HCV-infected patients and the controls, while there was no difference between PCR positive and PCR negative patients (Table 1), or patients with or without alcohol or nicotine consumption. The patients scored higher in the FIS than the controls (p<0.001) showing pathological FIS scores (>50) in 14 (70%). They also showed significantly worse sleep quality. Nineteen of the 20 patients (95%) had a PSQI score indicating sleep disturbances. The patients had also significantly higher ESS scores; 50% showed scores representing pathological daytime sleepiness. Also the depression, anxiety and QoL scores differed significantly between patients and controls (all p<0.05). Thirteen patients (65%) revealed a pathological result in the anxiety subscore and 8 (40%) in the depression subscore of the HADS. Fifty percent of the patients showed pathological results in the BDI (Table 1). The patients had significantly worse quality of life scores compared to the controls (for SF-36 sum-score, physical and mental sub-score p<0.001).

Wrist actigraphy

\he patients showed a significantly higher nocturnal activity than the controls while the time they spent in bed was significantly longer. The time the patients were awake after sleep onset (WASO) and average awakening length at night were also significantly longer. Accordingly they had a worse sleep efficiency than the healthy women (Table 2, Fig. 2).

A subgroup analysis between the PCR positive and negative patients did not show significant group differences except of for the minutes of wake after sleep onset (p=0.036), where the PCR negative patients exceeded the PCR positive ones (Table 2).

For analysis on a daily basis we separated for the activity level. In a 24h period the patients and controls engaged most of the time in sedentary. We could only show that the controls stay a longer time in light physical activity in comparison to the patients. The other activity parameters did not differ significantly between both groups (Table 3). In contrast to the activity level for the night (total counts in entire sleep period, Table 2) the activity level over a whole day (total counts in bouts/24h) was almost the same in the two groups thereby indicating a higher daytime activity in the controls compared to the patients (Table 3).

Using Spearman rank correlation analysis we found a significant relationship in the patient group between the FIS, the PSQI and the ESS respectively (p<0.001). Patients with a higher fatigue score had worse sleep quality and more severe daytime sleepiness. There was no significant correlation between the results of the FIS, the PSQI, the ESS and the actigraphy parameters (Table 4, Table 5). Accordingly the SF 36 results (sum-score, physical and mental score) correlated negatively with the sleep questionnaires (p<0.05) but not with the actigraphy data (Table 4).

Discussion

In the last two decades there has been growing evidence that infection with the hepatitis C virus can lead to brain dysfunction in the absence of severe liver disease [3], [17], [18], [19], [20]. The patients complain about chronic fatigue, cognitive dysfunction, a reduced quality of life and depression. Furthermore they report sleep disturbances such as daytime sleepiness and poor sleep quality [21]. The pathology behind is unclear, as is the interrelationship between these different symptoms.

In the present study we examined 20 women, who had been infected with HCV more than 30years ago but had not developed relevant liver disease, and 19 age-adjusted female healthy controls using a battery of sleep questionnaires and wrist actigraphy.

Like HCV-infected patients in former studies [4], [19], [20] the patients revealed increased scores for depression and anxiety, and decreased QoL scores. Sleep questionnaires indicated a significant alteration of sleep quality, and in accordance with the characteristic complaints wrist actigraphy showed sleep disturbances reflected by a higher nocturnal activity and poorer sleep efficiency.

It must be emphasized that our patients had no significant liver disease, since sleep disturbances are known as a frequent complication of liver cirrhosis. C—rdoba et al. [22] studied 20 patients with liver cirrhosis and 20 healthy controls with a sleep questionnaire and actigraphy for 5 consecutive days. The cirrhotic patients showed a fragmented sleep at night, a higher nocturnal activity and a reduced physical activity over a 24h period compared to the controls. Patients with unsatisfactory sleep showed a shift of activity toward later hours of the day. In 2008 Mostacci et al. [23] studied 178 patients with a diagnosis of non-alcohol-related liver cirrhosis and 178 healthy controls. Patients with cirrhosis showed a significantly higher prevalence of daytime sleepiness and bad sleep quality with difficulties in falling asleep and frequent nocturnal awakenings. Those patients with minimal hepatic encephalopathy had more pronounced daytime sleepiness and night time sleep disturbances in contrast to the other cirrhotic patients. A comparison between the patient groups with pathological and normal blood ammonia level did not show any differences in the parameters of sleep quality and sleep habits. Montagnese and co-workers [24] assessed sleep-wake-disturbances in 87 patients with liver cirrhosis with and without minimal/overt hepatic encephalopathy and 19 healthy controls. They found higher PSQI und ESS scores in the patients compared to the control group. In contrast to the study of Mostacci and co-workers there was no significant correlation between the sleep questionnaires and the presence of hepatic encephalopathy. In concordance to the findings of C—rdoba and co-workers evening type cirrhotic patients took longer to fall asleep and the sleep quality was worse than in patients with earlier sleep timing.

In summary sleep-wake disturbances are common in cirrhotic patients. The patients suffer from daytime sleepiness and bad sleep quality and some studies showed a phase delay in the sleep patterns of cirrhotic patients.

Our patient group with only mild liver disease showed a different feature of sleep disturbances. Although they showed a higher nocturnal activity as well, they had a similar 24h activity level compared to controls and no shift in the sleep-wake-rhythm. Thus the pathogenesis behind is probably different from that in cirrhotic patients with sleep disorder.

Our patient group consists of women who had been infected with hepatitis C virus contaminated anti-D immunoglobulin in the 1970s. Patients with risk factors for developing fatigue (independent of the HCV infection) like intravenous drug abuse and co-infection with the human immunodeficiency virus (HIV) were excluded. Fatigue and depression are known as side effects of interferon therapy in HCV patients [25]. Of note, interferon therapy had been finished at least 7years ago in the 6 patients of our group who had ever been treated. None of the subjects in this study took any medication that could be hold responsible for fatigue and sleep disturbances. However, nearly half of the patients (and 73% of the controls) reported slight to moderate alcohol consumption and 25% had a smoking habit. According to Yamini et al. [26] both factors are associated with the presence of depression, fatigue and sleep disturbances in patients with HCV-infection. They evaluated clinical data of 800 HCV-infected patients for the impact of past and current tobacco use or drinking habits, comorbidities such as diabetes mellitus or hyperlipidemia, history of interferon treatment, fibrosis stage and others upon the presence of depression, fatigue and difficulty sleeping in these patients. The analysis showed a significant relationship between past and present tobacco use and past alcohol use and the presence of depression, between past and present tobacco use and current alcohol use and fatigue, as well as between past and present tobacco use and difficulty sleeping in these patients. In contrast social drinking was associated with a lower risk of difficulty sleeping. Of note, their patient cohort differed significantly from that examined in our study: about half of their patients had a history of drug abuse, one third were heavy drinkers, more than 50% were male and about 50% had advanced fibrosis (28%) or cirrhosis (18%). Depression was present in about 30%, fatigue in 45% and difficulty sleeping in only 3.8%. Considering these differences and the fact that both, smoking and drinking habits of the patients in our cohort were only slight to moderate these factors are unlikely having influenced the results.

Eight of our 20 patients were HCV PCR negative, 7 of them had cleared the virus spontaneously. These HCV PCR negative patients were included into the study and treated as homologous to the HCV PCR positive patients because we have repeatedly shown in previous studies that both, HCV PCR positive and negative patients may develop HCV-infection-associated encephalopathy and present with identical symptoms and findings in brain imaging such as magnetic resonance spectroscopy, Fluor-Desoxy-Glucose positron emission tomography and single photon emission tomography [19], [20], [27]. Accordingly we did not find a significant difference between both patient groups in the present study as well. In the past several studies have shown that the virus replicates in the brain [28], [29], [30], [31]. Different quasispecies of the virus have been detected post-mortem in the liver and the brain of HCV-infected patients. In 2002 Radkowski et al. detected negative strand HCV-RNA, a viral replication intermediary, in autopsy brain tissue of three out of six HCV-infected patients.

As an indication for viral brain compartmentalization in two of these patients viral sequences amplified from the brain differed from those circulating in serum. Based on a sequence analysis of two different viral regions it was suggested that the brain-derived HCV variants were more closely related to the virus present in the lymphoid system than to virus circulating in serum [28]. Forton et al. also described a close relationship between HCV variants present in brain tissue and in lymph nodes [30]. HCV-RNA was also found in the cerebrospinal fluid (CSF) of eight out of 13 patients. Again the sequences of the brain (CSF) derived virus were closer to those found in peripheral blood mononuclear cells (PBMC) than to those circulating in serum of the patients [30], [31]. HCV-RNA positive and negative strands were detected in CD68-positive cells in the brain, which indicates that the cells harboring HCV are macrophages/microglia. It is suggested that HCV-infected macrophages/monocytes enter the brain via the blood-brain-barrier and induce a neuroinflammatory response that might be causative for the development of neuropsychiatric symptoms [29].

We found a significant correlation between the degree of fatigue as represented by the FIS score and the daytime sleepiness and sleep quality (ESS and PSQI). The findings are in line with the results from Carlson et al. [32] who studied 59 hepatitis C patients with different stages of liver disease. They found a significant relationship between the PSQI and FSS (Fatigue Severity Scale) regardless of the stage of liver disease.

We could not find any significant correlations between the results of the fatigue and sleep questionnaires and the actigraphy parameters. In other words the subjective perception of bad sleep quality must not be accompanied with an equivalent amount of nocturnal motor activity. In sleep research actigraphy is a validated tool for activity based sleep-wake monitoring, which was established by The American Sleep Disorders Association [33], [34], [35], [36]. Of note, some patients having difficulties in falling asleep may have the habit lying in bed for a longer period without movement, others move around in bed very often to try to fall asleep. Thus a possible limitation of the validity of actigraphy is detecting wakefulness during a sleep period [33].

\ limitation of our study is the short actigraphy analysis period of 5 out of 7 recorded days. The International Classification of Sleep Disorders (established by the American Academy of Sleep Medicine) requires a minimum of 7days of actigraphy performed in addition to a sleep diary for being able to demonstrate consistency in the pathology of circadian rhythm disorders. Acebo et al. [37] showed that 5 nights of measuring give reliable estimates for evaluating sleep start time, wake minutes and sleep efficiency. Therefore we choose the recording of the five working days of the week for further analysis taking into account that the weekends are usually characterized by alterations of the sleep habits.

The increased HADS and BDI scores and the significant correlation between HADS and BDI scores and ESS and PSQI scores suggest depression as a possible reason for altered sleep quality in our patients. Former studies in patients with depression had shown a relationship between the extent of depression and actigraphy parameters [38]. This could not be observed in our study. While these findings appear inconsistent on the first view they are comprehensible considering the findings of Golden et al. [39] who were able to show that HADS and BDI scores are falsely positive in patients with HCV infection and do not represent the extent of depression.

On the basis of experimental studies it is known that sleep disturbances are associated with alterations of the immune system. Krueger proposed that sleep is a process which is influenced by cytokines, a part of the peripheral and central immune system [40]. Gershon et al. discussed cytokine effects upon the brain as possible mechanism for the development of fatigue in HCV-infected patients [41]. In 2011 de Almeida studied chronic hepatitis C patients to find an association between the degree of sleep quality (provided by the PSQI and FSS) and peripheral blood immunological and virological biomarkers. They detected a different immunological profile in patients with good sleep quality compared to those with bad sleep quality [42]. Wilkinson et al. detected an upregulation of proinflammatory cytokines IL-1, TNF-alpha, IL-12, and IL-18 in post-mortem brain tissue of hepatitis C patients [43]. The alteration of cytokine levels both in the periphery as well as in the brain itself could well be involved in the development of sleep disturbances in HCV-infected patients.

Finally both pathways might play a role in the development of extrahepatic manifestations of chronic hepatitis C virus infection including sleep disturbances: The virus may induce the peripheral immune system which activates proinflammatory cytokines, while the cytokines may alter brain activity by modifying the neurotransmitter systems. Moreover the hepatitis C virus may induce cerebral cytokine production after crossing the blood brain-barrier and thereby alter neurotransmission.

In conclusion, our data showed altered sleep quality in a group of patients with HCV infection associated neuropsychiatric symptoms but only mild liver disease. The extent and the pathogenesis of sleep disorders in patients who had been infected by HCV has to be clarified in further studies considering the cytokine hypothesis as well as recent findings upon altered neurotransmission in HCV-associated encephalopathy [18], [20], [22], [44].

Source

Impact of interferon free regimens on clinical and cost outcomes for chronic hepatitis C genotype 1 patients

Journal of Hepatology
Volume 60, Issue 3 , Pages 530-537, March 2014

Zobair M. Younossi, Mendel E. Singer, Heshaam M. Mir, Linda Henry, Sharon Hunt

Received 12 August 2013; received in revised form 21 October 2013; accepted 7 November 2013. published online 20 November 2013.

See Focus, pages 471–472

Abstract

Background & Aims
Hepatitis C (HCV) is a common cause of chronic liver disease worldwide. Current standard treatment for genotype-1 patients uses a triple combination of pegylated-interferon alpha (IFN), ribavirin (RBV) and a direct-acting antiviral agent (DAA) with 75–80% sustained virologic response (SVR) rates. The aim is to determine cost-effectiveness of staging-guided vs. treat all HCV genotype-1 patients with interferon-based vs. interferon-free regimens.

Methods
A decision analytic Markov model simulating patients until death compared four strategies for treating HCV genotype-1: Triple therapy (IFN, RBV, DAA) with staging-guidance or treat all, and oral IFN-free regimen with staging-guidance or treat all. Strategies with staging initiated treatment at fibrosis stages F2-F4, with staging repeated every 5years until age 70. The reference case was a treatment-naïve 50-year-old. Analysis was repeated for 50% increase in cost of oral therapy. Effectiveness was measured in quality-adjusted life years (QALYs).

Results
Treatment of all patients with oral IFN-free regimen was the most cost-effective strategy, with an ICER of $15,709/QALY at baseline cost of oral therapy. The ICER remained below $50,000/QALY in sensitivity analyses for baseline and +50% cost of oral therapy scenarios. The treat all strategy was also the most effective strategy; associated with the lowest risk of developing advanced liver disease.

Conclusions
Treating all HCV patients with oral IFN-free regimen reduced the number of patients developing advanced liver disease and increased life expectancy. Additionally, IFN-free regimen without staging may be the most cost-effective approach for treating HCV genotype-1 patients. The efficacy and safety of these regimens must be confirmed using randomized clinical trials.

Abbreviations: HCV, hepatitis C, IFN, pegylated, interferon alpha, RBV, ribavirin, DAA, direct, acting antiviral agent, SVR, sustained virologic response, IFN, BV, DAA, Triple therapy, ICER, incremental cost, effectiveness analysis, QALYs, quality, adjusted life years (a standard metric that incorporates both length and quality of life), CHC, chronic hepatitis C, HIV, immunodeficiency virus, TVR, telaprevir, BOC, boceprevir, GT, genotype, F2 or F4, moderate or advanced fibrosis, F0, F1, mild fibrosis, WAC, wholesale acquisition cost, NADAC, National Average Drug Acquisition Cost, CMS, Centers for Medicare and Medicaid Services

Keywords: Interferon-free oral treatment, Cost-effectiveness analysis, Markov model, HCV, DAA

Source

Randomized trial of daclatasvir and asunaprevir with or without PegIFN/RBV for hepatitis C virus genotype 1 null responders

Journal of Hepatology
Volume 60, Issue 3 , Pages 490-499, March 2014

Anna S. Lok, David F. Gardiner, Christophe Hézode, Eric J. Lawitz, Marc Bourlière, Gregory T. Everson, Patrick Marcellin, Maribel Rodriguez-Torres, Stanislas Pol, Lawrence Serfaty, Timothy Eley, Shu-Pang Huang, Jianling Li, Megan Wind-Rotolo, Fei Yu, Fiona McPhee, Dennis M. Grasela, Claudio Pasquinelli

Received 8 August 2013; received in revised form 24 September 2013; accepted 14 October 2013. published online 28 October 2013.

See Focus, pages 471–472

Abstract

Background & Aims

Patients with chronic hepatitis C virus (HCV) infection and prior null response (<2 log HCV RNA decline after greater than or equal to12weeks of PegIFN/RBV) have limited options. We evaluated daclatasvir plus once- or twice-daily asunaprevir in non-cirrhotic genotype 1 null responders.

Methods

In this randomized, phase 2a, open-label, 24-week treatment study, 101 patients received daclatasvir (60mg) once-daily. In addition, 38 genotype 1b patients received asunaprevir (200mg) twice- (DUAL A1) or once-daily (DUAL A2); 36 genotype 1a and 5 genotype 1b patients received asunaprevir twice- (QUAD B1) or once-daily (QUAD B2) plus PegIFN/RBV; and 18 genotype 1a and 4 genotype 1b patients received asunaprevir twice-daily plus ribavirin (TRIPLE B3). The primary endpoint was undetectable HCV RNA 12weeks post-treatment (sustained virologic response, SVR12).

Results

Across all groups, mean HCV RNA was greater than or equal to 6 log IU/ml, and 99% of patients had a non-CC IL28B genotype. SVR12 rates were 78% (A1), 65% (A2), 95% (B1), and 95% (B2). In B3, most genotype 1a patients experienced virologic breakthrough. The most common adverse events were headache, diarrhea, and asthenia. Grade 3–4 aminotransferase elevations were infrequent and not treatment-limiting.

Conclusions

In genotype 1 null responders, daclatasvir plus twice-daily asunaprevir DUAL therapy is effective for most genotype 1b patients, and daclatasvir, asunaprevir, and PegIFN/RBV QUAD therapy is effective for nearly all genotype 1a and 1b patients; but neither DUAL nor TRIPLE therapy is effective for genotype 1a patients. Interferon-free regimens including daclatasvir and twice-daily asunaprevir for genotype 1 null responders should be tailored to subtype.

Abbreviations: HCV, hepatitis C virus, PegIFNα, pegylated interferon alfa-2a, RBV, ribavirin, SVR, sustained virologic response, QUAD,quadruple, DAA, direct-acting antiviral, SVR24, sustained virologic response at 24weeks post-treatment, LLOQ, lower limit of quantification,LOD, limit of detection, SNP, single nucleotide polymorphism, SVR12, sustained virologic response at 12weeks post-treatment, SVR4,sustained virologic response at 4weeks post-treatment, ALT, alanine aminotransferase, AST, aspartate aminotransferase

Keywords: Direct-acting antiviral agents, Sustained virologic response, Hepatitis C treatment, Protease inhibitor, HCV NS5A inhibitor, Non-responders

Source

Rutgers scientists identify structure of virus that could lead to hepatitis C vaccine

PUBLIC RELEASE DATE: 19-Feb-2014

Contact: Robin Lally
rlally@ucm.rutgers.edu  
848-932-0557
Rutgers University

Infection is a major global health problem affecting 160 million people worldwide

This is Joseph Marcotrigiano, associate professor of chemistry and chemical biology, Rutgers University. Credit: Nick Romanenko, Rutgers University

Rutgers University scientists have determined the structure of a hepatitis C surface protein, a finding that could assist in the development of a vaccine to halt the spread of the the deadly disease that has infected 3.2 million Americans.

Joseph Marcotrigiano, associate professor of chemistry and chemical biology, says this new research – published online today in Nature – describes an outer region of hepatitis C that enables the virus to evade the body's natural immune system response, causing persistent, chronic infection.

Hepatitis C is constantly mutating, allowing it to infect a host cell and evade the immune responses, causing chronic infection that can be difficult to treat. By identifying the structure of virus's outer protein, Marcotrigiano, the study's lead author, says scientists will be better able to develop a vaccine that targets the immune system to vulnerable regions of the virus in order to prevent infection.

"Viruses are smart and it is a constant battle to keep them out," says Marcotrigiano who collaborated on the research with colleagues from the Center for Advanced Biotechnology and Medicine at Rutgers and Emory University School of Medicine. "That's why the development of a vaccine is so important. It's always better to prevent infection through an effective vaccine then to treat after a chronic infection has been established."

Hepatitis C virus is a major global health problem with 160 million people infected throughout the world, about four times more individuals than those with HIV. Most of those infected do not show symptoms until the virus – the number one cause of liver transplantation – has caused severe liver damage.

The virus is mainly spread through contact with an infected person's blood, such as sharing of needles. Prior to 1992, when donated blood began being tested, the virus was also spread through blood transfusions and organ donation.

Recently, the Food and Drug Administration approved several new drugs that could cure many patients infected with hepatitis C in as little as 12 weeks. However, at about $1000 per pill, this may not be a cost-effective solution to hepatitis C virus.

Developing a vaccine against hepatitis C would not only prevent people from acquiring the disease, Marcotrigiano says, but would also be the most cost-conscious health intervention.

Michael Houghton, a researcher at the University of Alberta in Canada, has been developing a vaccine that is currently being tested clinically. Houghton, who led a team that discovered the hepatitis C virus in 1989, says the Rutgers finding is important because knowing the structure of the virus will help in the development of a vaccine that enables the immune system to produce more infection-fighting antibodies that can neutralize the virus.

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University of Westminster develops groundbreaking method to test hepatitis C cure

BIOMEDICAL SCIENCES 17 FEBRUARY 2014

Researchers at the University of Westminster have developed a groundbreaking method which can be used to test a new innovative cure for hepatitis C, a liver disease caused by the hepatitis C virus (HCV).

The cure is the first of its kind ever to be tested in humans and comes in the form of a drug based on gene therapy which is under development by the Australian company Benitec Biopharma.

Around 150 million people worldwide are infected with hepatitis C, and more than 350,000 people die every year from hepatitis C related liver diseases. Hepatitis C is one of the leading causes of liver cirrhosis and cancer, and one of the most common and seriously infectious conditions in the world (according to the World Health Organisation (WHO)).

Although treatments are already available for hepatitis C, these are lengthy, have low chances of success, cause significant side-effects, or the virus is already becoming resistant. The new drug, TT-034, developed by Benitec Biopharma, is based on the biological mechanism for which the Nobel Prize in Physiology or Medicine was awarded in 2006. Unlike anything else currently available to patients, this treatment works with a single injection to directly destroy the hepatitis C virus and remove the infection. The drug is currently undergoing clinical trials in the US with results expected in the coming months.

Dr Sterghios A. Moschos, MSB, Director of Westminster Genomic Services at the University of Westminster, developed the comprehensive and innovative method by adapting state-of-the-art genome sequencing technologies to show exactly how the new drug works. The research was conducted in collaboration with the European Bioinformatics Institute and Benitec Biopharma.

Dr Moschos said: “Our entirely new method to test the new drug has had a major impact on building robust confidence in this innovative therapy. For the first time ever we have shown that there are more ways to hit the hepatitis C infection than previously thought possible, and that this treatment works like a combination of multiple drugs. Our approach has helped Benitec Biopharma, to obtain permission to start clinical trials much earlier than we expected. This is unprecedented for gene therapy, particularly for a disease for which treatments already exist.”

For further information you can read the research paper published on Molecular Therapy Nucleic Acids at nature.com.

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About the University of Westminster:

The University of Westminster boasts a vibrant learning environment attracting more than 20,000 students from over 150 nations and we continue to invest in our future with new developments, research projects and new ideas.

We offer highly attractive practice-based courses which are independently rated as excellent, many with international recognition. Our distinguished 175-year history has meant we lead the way in many areas of research, particularly politics, media, art and design, architecture and biomedical sciences, and our position in the city of London allows us to continue to build on our close connections with leading figures and organisations in these areas as well as in the worlds of business, information technology, politics and law.

Our commitment to educating graduates for the needs of professional life attracts high quality students from within the UK and around the globe.

Internationalism, employability and sustainability are key elements in the University of Westminster’s vision for the future and we strive to ensure the very highest standards are met and maintained.

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Direct Acting Antiviral Combinations

Provided by NATAP

By Jules Levin, NATAP

.......as you can see the SVR rates will be 96-100%. The lowest SVR rates are in the hardest to treat patients: patients who have both cirrhosis and who are prior non-responders. But I expect we can improve SVR rates in studies in these patients too. Some companies are conducting studies by adding another drug to their regimen, see below last parapgraph/link.

Here is a brief simple table, below the table are links to these studies:
These are results for genotype 1 patients with most but not all the regimens in research studies now. This table does not include Simeprevir+Peg/Rbv which was FDA approved in Dec/13. I included the regimens approved by the FDA for mono and connected in December/13 which are: Sofosbuvir (Sovaldi) + Peg/Rbv, approved for mono & coinfected; Sofosbuvir+Rbv approved for both mono & Coinfected. It is widely believed & the data so far supports this, that HCV/HIV connected will respond the same as mono infected to DAA orals, which is why the FDA gave approval for these aforementioned regimens for coinfection. Gilead & Abbvie have studies ongoing now in coinfection, I think when the FDA does provide the expected approvals later this year both Gilead & Abbvie's regimens I think there will be approvals for coinfection too. BMS is in phase 3 now with daclatasvir+sofosbuvir & expected in Western Europe will be expanded access programs, and studies of this regimen just started, here is link to these studies Daclatasvir+Sofosbuvir-new studies, Daclatasvir Phase 3 IFN-free, EMA Compassionate Use, Accelerated EMA Marketing Review Recommendation

There is no data in coinfection with simprevir+sofosbuvir (COSMOS Study), but it can be considered & the ART interactions with the protease simeprevir must be considered. The same can be said for daclatasvir+sofosbuvir, although the interactions with sofosbuvir & ARTs have been reported at a conference & they are not expected to be clinically significant, there are interactions between ARTs & daclatasvir that also were reported at a conference so they too can be adjusted for.

I did not include in this table Achillion data, Presidio data (NS5A), data from Faldaprevir+Peg/Rbv or the 3 drug DAA oral IFN-free Faldaprevir regimen. As you may know recently development of the non-nuke DAA used in the Faldaprevir 3-DAA study was discontinued which included the Presidio NS5A). I did not include Vertex or Idenix data. Vertex is in phase 2 with VX-135 a nucleotide, same class as sofosbuvir. Idenix is in development of several classes of drugs including a NS5A (same class as Ledipasvir, daclatasvir) & nucleotides. Achillion is in development with a protease, a NS5A and a nucleotide.

Merck is in phase 2 lovely quickly into phase 3. BMS is in phase 3. Roche also presented data recently at AASLD in November/13 but their data was disappointing.

Sofosbuvir+Peg/Rbv in HCV/HIV Coinfected (91% SVR) 12 weeks:
Sofosbuvir and Peginterferon Alfa-2a/Ribavirin for Treatment-Naïve Genotype 1-4 HCV-Infected Patients Who Are Coinfected With HIV
http://www.natap.org/2013/IDSA/IDSA_24.htm

Sofosbuvir+Ribavirin in coinfected patients:
AASLD: All-Oral Therapy With Sofosbuvir Plus Ribavirin For the Treatment of HCV Genotype 1, 2, and 3 Infection in Patients Co-infected With HIV (PHOTON-1) - (11/06/13)

This is the most recent data from the COSMOS Study which studied 2 DAAs, sofosbuvir + the protease simeprevir:
AASLD: SVR results of a once-daily regimen of simeprevir (SMV, TMC435) plus sofosbuvir (SOF, GS-7977) with or without ribavirin in cirrhotic and non-cirrhotic HCV genotype 1 treatment-naïve and prior null responder patients: The COSMOS study - (11/05/13)

Here is the latest study data, slides presented on daclatasvir+sofosbuvir in treatment-naives & in protease failures:
EASL/2012: Potent Viral Suppression With the All-Oral Combination of Daclatasvir (NS5A Inhibitor) and GS-7977 (Nucleotide NS5B Inhibitor), +/- Ribavirin, in Treatment-Naive Patients With Chronic HCV GT1, 2, or 3 (100% SVR gt1, 91% gt2) - (04/19/12)

EASL: Sustained Virologic Response With Daclatasvir Plus Sofosbuvir ± Ribavirin (RBV) in Chronic HCV Genotype (GT) 1-Infected Patients Who Previously Failed Telaprevir (TVR) or Boceprevir (BOC) - (04/27/13)

Here is the very recent journal publication of these studies:
Daclatasvir plus Sofosbuvir for Previously Treated or Untreated Chronic HCV Infection - (01/17/14)

Here is the latest Abbvie data reported by them of their phase 3 data in a press release just recently:
AbbVie Completes Largest Phase III Program of an All-Oral, Interferon-Free Therapy for the Treatment of Hepatitis C Genotype 1 - (01/31/14)

This is the most recent data reported by Gilead, it is their phase 3 results: GILEAD ANNOUNCES SVR12 RATES FROM THREE PHASE 3 STUDIES EVALUATING A ONCE-DAILY FIXED-DOSE COMBINATION OF SOFOSBUVIR AND LEDIPASVIR FOR GENOTYPE 1 HEPATITIS C PATIENTS - For Immediate Release - (12/18/13)

This is the latest presentation of BMS data for their 3 DAA regimen at AASLD November:
AASLD: Phase 2b Study of the Interferon-Free and Ribavirin-Free Combination of Daclatasvir, Asunaprevir, and BMS-791325 for 12 Weeks in Treatment-Naive Patients With Chronic HCV Genotype 1 Infection - (11/05/13)

This is the most recent Merck data for their 2-drug DAA combination presented at AASLD in November:
AASLD: High Efficacy and Safety of the All-Oral Combination Regimen, MK-5172 / MK-8742 ± RBV for 12 Weeks in HCV Genotype 1 Infected Patients: The C-WORTHY Study - (11/05/13)

Roche
AASLD: Interferon-free Regimen Containing Setrobuvir in Combination with Ritonavir-boosted Danoprevir and Ribavirin with or without Mericitabine in HCV Genotype 1 Treatment-naive Patients: Interim Results from the ANNAPURNA Study - (11/14/13)

As reported by Jurgen Rockstroh, MD, in his NATAP AASLD report [http://www.natap.org/2013/AASLD/AASLD_109.htm], in the NIAID SYNERGY Trial [http://www.natap.org/2013/AASLD/AASLD_30.htm] 60 HCV mono-infected, treatment naïve, GT-1, patients were consecutively enrolled into 3 arms of a phase 2 clinical trial and received: Arm A - sofosbuvir with ledipasvir (400mg/90mg respectively once daily in a fixed dose combination (FDC)) for 12 weeks, Arm B - FDC + GS-9669 (500mg/day), a non nucleoside NS5B inhibitor for 6 weeks, or Arm C - FDC + GS-9451 (80mg/day), an HCV protease inhibitor for 6 weeks (47). 80-95% of study participants were African-American. In this exploratory trial virological responses were very good with 100% SVR12 in the SOF/LDV (12 weeks arm) (n=20), 90% SVR4 in the SOF/LDV/9669 (6 weeks arm) (n=20) and again 100% SVR4 in the SOF/LDV/9451 (6 weeks arm) (n=20). Only one relapse occurred in the SOF/LDV/9669 arm. Tolerability in all arms was good with no treatment related discontinuation or SAEs. Again this 3 DAA combination study underlines that multiple DAA combinations will work and allow to get rid of interferon as well as ribavirin which is accompanied by greatly improved tolerability. Also the combination of 3 DAAs may allow to shorten treatment duration to 6 weeks at least in easier to treat naïve patient populations which may be very important in the more adherence challenged patient groups.

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