February 21, 2014

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.

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

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

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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.

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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.

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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.

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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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