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Home , Asunaprevir, Beclabuvir

Horizon Scanning Centre January 2015

Asunaprevir, and fixed dose combination for virus , genotype 1 – first or second line

SUMMARY NIHR HSC ID: 8338

Asunaprevir, beclabuvir and daclatasvir combination therapy is intended to be used as first line or second line therapy for the treatment of genotype 1, (HCV) infection in adult patients with compensated liver disease (including cirrhosis). If licensed it will offer an -free, 12 This briefing is week oral treatment option for this patient group. The therapy is an oral, fixed dose combination tablet containing asunaprevir, an antiviral NS3 protease based on inhibitor, beclabuvir, an active HCV non-nucleoside NS5B polymerase information inhibitor, and daclatasvir, a HCV NS5A inhibitor. The individual agents, available at the time asunaprevir and beclabuvir, along with the combination therapy, do not of research and a currently have Marketing Authorisation in the EU for any indication, however limited literature daclatasvir in combination with other medicinal products has been licensed in search. It is not the EU for the treatment of HCV infection (genotypes 1, 3 and 4) in adults. intended to be a definitive statement The true incidence of HCV infection is difficult to establish, as an estimated on the safety, 86% of infected individuals are unaware of their infection status. Recent efficacy or estimates suggest that in England there are around 160,000 individuals who effectiveness of the are chronically infected with HCV infection and in 2010, there were 10,380 health technology new diagnoses in the UK. In 2012-13, there were 2,265 hospital admissions covered and should due to chronic HCV infection. Estimates suggest that by 2020, if left not be used for untreated, approximately 16,000 individuals will be living with HCV-related commercial cirrhosis or hepatocellular carcinoma in England. purposes or commissioning Many new oral pharmaceutical technologies are becoming available for HCV without additional infection and the approach to treating HCV infection is likely to change information. rapidly over the coming years. The current standard treatment for HCV infection is combination therapy with alfa and for varying periods according to genotype. Patients with genotype 1 are treated with triple combination therapy of pegylated interferon and ribavirin with the addition of one of the first generation protease inhibitors, or . Asunaprevir, beclabuvir and daclatasvir fixed dose combination therapy is currently in phase III clinical trials comparing its effect on the proportion of patients achieving a sustained virological response at 12 weeks against treatment with placebo. The trials are expected to complete in June and September 2015.

This briefing presents independent research funded by the National Institute for Health Research (NIHR). The views expressed are those of the author and not necessarily those of the NHS, the NIHR or the Department of Health.

NIHR Horizon Scanning Centre, University of Birmingham Email: [email protected] Web: http://www.hsc.nihr.ac.uk NIHR Horizon Scanning Centre

TARGET GROUP

• Hepatitis C virus (HCV) infection: genotype 1; treatment naïve or treatment experienced patients – first or second line.

TECHNOLOGY

DESCRIPTION

Asunaprevir (ASV, BMS-650032), beclabuvir (BCV, BMS-791325) and daclatasvir (DCV, Daklinza, BMS-790052) together form an oral, fixed dose combination (FDC) tablet. Asunaprevir is an antiviral NS3 protease inhibitor, beclabuvir is an active HCV non- nucleoside NS5B polymerase inhibitor, and daclatasvir is an HCV NS5A inhibitor. NS3 is an essential enzyme in the biogenesis of components necessary for hepatitis C virus replication as it mediates the cleavage and release of four non-structural HCV proteins, NS4A, NS4B, NS5A and NS5B. Inhibition of NS3/4a and NS5A therefore prevents HCV viral replication.

This specific triple therapy combination (also referred to as 3 Direct Acting Antivirals [3DAA]) is intended for the first line or second line treatment of patients with genotype 1 HCV infection with compensated liver disease (including cirrhosis). In phase III clinical trials, a single FDC tablet containing asunaprevir 200mg, beclabuvir 75mg, and daclatasvir 30mg was administered twice daily for 12 weeks1,2,3,4. The individual agents, asunaprevir and beclabuvir, along with the 3DAA FDC tablet, do not currently have Marketing Authorisation in the EU for any indication. Daclatasvir in combination with other medicinal products has been licensed in the EU for the treatment of HCV infection (genotypes 1, 3 and 4) in adults. Very common (>10%) adverse events (AEs) include headache, nausea and fatigue.

INNOVATION and/or ADVANTAGES

If licensed, asunaprevir, beclabuvir and daclatasvir triple combination therapy will offer an interferon-free, 12 week oral treatment option for treatment naïve or treatment experienced patients with HCV infection genotype 1. In addition, the combination of three direct acting antiviral HCV inhibitors from different classes may achieve synergy in their mechanisms of action that could also lead to a reduction in the development of treatment resistance.

DEVELOPER

Bristol-Myers Squibb.

AVAILABILITY, LAUNCH OR MARKETING

In phase III clinical trials.

PATIENT GROUP

BACKGROUND

HCV is a member of the flaviviridae family of spherical, enveloped, positive-strand RNA viruses. There are nine different HCV genotypes; genotype 3 is the most common in the UK and responsible for 50% of cases, closely followed by genotype 1, which is responsible for

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46% of cases5,6, and until recently, was the most resistant to treatment7. The virus is acquired primarily through percutaneous exposure to contaminated blood8. Most acute with HCV are asymptomatic with only 20% developing overt symptoms9. Approximately 80% of people who are infected go on to develop chronic HCV8, symptoms of which include malaise, weakness and anorexia9. Chronic HCV is categorised as mild, moderate or severe depending on the extent of liver damage8. Approximately 30% of chronically infected people develop cirrhosis within 20-30 years, and some of these develop hepatocellular carcinoma (HCC)8. End-stage liver disease or HCC may require liver transplantation8. Factors known to increase the rate of progression include age, ethnicity, male sex, excessive alcohol consumption and HIV co-infection10,11.

NHS or GOVERNMENT PRIORITY AREA

This topic is relevant to: • NHS England. 2013/14 NHS Standard Contract for Specialised Services for Infectious Disease (adult) B07/S/a. • NHS England. 2013/14 NHS Standard Contract for High Security Infectious Disease Unit (All Ages). B07/S/b. • NHS England. 2013/14 NHS Standard Contract for Hepatobiliary and Pancreas (Adult). A02/S/a. • NHS England. Interim Clinical Commissioning Policy Statement: + Daclatasvir/ +/- Ribavirin for defined patients with Hepatitis C. A02/PS/b. April 2014. • The Blood Borne Virus Action Plan for Wales 2010-2015. 2010. • The National Service Framework for Long-term Conditions. 2005. • The Hepatitis C Action Plan for England. 2004.

CLINICAL NEED and BURDEN OF DISEASE

The true incidence of HCV infection is difficult to establish, as an estimated 86% of infected individuals are unaware of their infection status12. Recent estimates suggest that in England there are around 160,000 individuals who are chronically infected with HCV infection, equating to 0.4% of the adult population13; in 2010, there were 10,380 new diagnoses in the UK12. Estimates suggest that by 2020, if left untreated, around 15,840 individuals will be living with HCV-related cirrhosis or HCC in England6. An estimated 30.6% of people with HCV infection currently receive antiviral treatment12.

Throughout the UK, injecting drug use continues to be the most important risk factor for HCV infection13. The prevalence of HCV infection amongst those who inject drugs is estimated at 55% (based on London data) and approximately 50% of those who inject drugs will be on a form of opiate replacement therapy14. Approximately 9% of patients with HIV are co-infected with hepatitis C in the UK; 83% of HIV positive patients who are injecting drug users also have hepatitis C15. In those on haemodialysis for chronic kidney disease in the UK, the mean prevalence of HCV infection is 2.7%16. Prevalence of HCV infection in these patients increases with the number of years on dialysis (7.3% in year 2, to 58.3% in those on dialysis for more than 23 years)14. HCV infection in those on long-term dialysis also has a significant impact on the mortality of patients (a relative risk for all-cause mortality of 1.35, 95% CI 1.25 to 1.47)17.

In 2012-13, there were 2,265 hospital admissions due to chronic HCV infection (ICD-10 B18.2) in England, resulting in 2,452 finished consultant episodes and 2,746 bed days18. In 2013, chronic HCV infection (ICD-10 B18.2) accounted for 189 deaths in England and Wales19.

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RELEVANT GUIDANCE

NICE Guidance

• NICE technology appraisal in development. Hepatitis C (chronic) – // (with or without ) (ID731). Expected date of issues September 2015. • NICE technology appraisal in development. Hepatitis C (chronic) – daclatasvir (ID766). Expected date of issue August 2015. • NICE technology appraisal in development. Hepatitis C (chronic) – ledipasvir-sofosbuvir (ID742). Expected date of issue June 2015. • NICE technology appraisal in development. for treating genotype 1 chronic hepatitis C (ID670). Expected date of issue February 2015. • NICE technology appraisal in development. for treating genotype 1 or 4 chronic hepatitis C (ID668). Expected date of issue January 2015. • NICE technology appraisal in development. Hepatitis C (chronic) - sofosbuvir (ID654). Expected date of issue January 2015. • NICE technology appraisal. Peginterferon alfa and ribavirin for treating chronic hepatitis C in children and young people (TA300). November 2013. • NICE technology appraisal. Boceprevir for the treatment of genotype 1 chronic hepatitis C (TA253). April 2012. • NICE technology appraisal. Telaprevir for the treatment of genotype 1 chronic hepatitis C (TA252). April 2012. • NICE technology appraisal. Peginterferon alfa and ribavirin for the treatment of chronic hepatitis C (TA200). September 2010. • NICE technology appraisal. Peginterferon alfa and ribavirin for the treatment of mild chronic hepatitis C (TA106). August 2006. • NICE technology appraisal. Interferon alfa (pegylated and non-pegylated) and ribavirin for the treatment of chronic hepatitis C (TA75). January 2004.

• NICE clinical guideline in development. Hepatitis C: diagnosis and management of hepatitis C. Expected date of issue to be confirmed. • NICE public health guidance. Hepatitis B and C – ways to promote and offer testing to people at risk of infection (PH43). December 2012.

Other Guidance

• Public Health England. UK Standards for Microbiology Investigations – vertical and perinatal transmission of hepatitis C. 201420. • European Association for the Study of the Liver. EASL Recommendations on treatment of Hepatitis C. 201421. • American Association for the Study of Liver Diseases. Recommendations for testing, managing, and treating hepatitis C. 201422. • Scottish Intercollegiate Guidelines Network. Management of hepatitis C. (SIGN 133). 201323. • British HIV Association. British HIV Association guidelines for the management of hepatitis viruses in adults infected with HIV. 201324. • NHS Clinical Knowledge Summary. Hepatitis C. 201025. • Department of Health. Hepatitis C: quick reference guide for primary care. 200926. • Royal College of General Practitioners. Guidance for the prevention, testing, treatment and management of hepatitis C in primary care. 200710.

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• British HIV Association. British HIV Association guidelines for the management of coinfection with HIV-1 and hepatitis B or C virus 201027. • British Association of Sexual Health and HIV. United Kingdom national guideline on the management of the viral hepatitides A, B & C. 200828. • British Society of Gastroenterology. Guidance on the treatment of hepatitis C incorporating the use of pegylated interferon. 200329.

CURRENT TREATMENT OPTIONS

The standard treatment for HCV infection is combination therapy with pegylated interferon alfa and ribavirin for varying periods according to genotype; this is successful in clearing the virus in between 40% and 80% of those treated10. Patients with genotype 1 are treated with triple combination therapy (pegylated interferon and ribavirin with the addition of one of the first generation protease inhibitors, telaprevir or boceprevir)30,31 for a duration influenced by pre-treatment factors (including cirrhosis) and on-treatment response to therapy32. Simeprevir, a second generation protease inhibitor (currently under NICE appraisal)33 may become standard of care, replacing telaprevir and boceprevir in triple combination therapy34. Similarly, sofosbuvir is also undergoing NICE appraisal for HCV infection (genotypes 1 and 4)35. Simeprevir, sofosbuvir and daclatasvir have recently been licensed for use in patients with HCV infection in the EU. All patients with chronic HCV infection are considered for therapy, irrespective of the stage of their disease10.

Expert opinion indicates that the field is rapidly evolving and as new drug technologies (e.g. sofosbuvir, simeprevir and daclatasvir) become available, standard treatment will dramatically change in favour of oral short duration therapy. It is suggested this might occur in two stages; firstly the use of new agents in combination with interferon and ribavirin, which would then be later superseded by the removal of interferon in favour of all oral combinations36.

EFFICACY and SAFETY

Trial NCT01979939, UNITY 1, NCT01973049, UNITY 2, NCT02123654, UNITY 3, AI443-102, 2013-002468- AI443-113, 2013-002458- AI443-117; DCV and ASV 20; fixed dose combination 66; fixed dose combination in combination with BCV or therapy of daclatasvir therapy DCV, ASV and placebo; phase III. (DCV), asunaprevir (ASV), BCV with or without and beclabuvir (BCV); ribavirin (RBV); phase III. phase III. Sponsor Bristol-Myers Squibb. Bristol-Myers Squibb. Bristol-Myers Squibb. Status Complete but unpublished. Complete but unpublished. Ongoing. Source of Press release37, trial Press release37, trial Trial registry3. information registry1, manufacturer. registry2, manufacturer. Location EU (not UK), USA, Australia, Canada, France Japan. Canada, Australia and and USA. Puerto Rico. Design Non-randomised. Randomised, placebo- Randomised, placebo- controlled. controlled. Participants n=415; aged 18 years and n=202; aged 18 years and n=286; aged 20 years and older; chronic HCV older; chronic HCV older; chronic HCV infection genotype (GT) 1; infection GT 1; infection GT 1; HCV RNA HCV RNA ≥10,000IU/ml at compensated cirrhosis; ≥10,000IU/ml. screening; treatment-naïve HCV RNA ≥10,000IU/ml at (TN) or treatment screening; TN or TE. experienced (TE).

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Schedule Subjects received FDC Subjects were divided into Subjects randomised to: tablet of DCV 30mg, ASV two groups: TN and TE, Arm 1: FDC tablet of DCV 200mg and BCV 75mg, and all received a FDC 30mg, ASV 200mg and administered orally twice a tablet of DCV 30mg, ASV BCV 75mg, orally twice day to TN and TE subjects. 200mg and BCV 75mg, daily for 12 weeks plus orally twice a day. Subjects DCV placebo once daily within each group were and ASV placebo twice also randomised to receive daily for 24 weeks. RBV 200mg or placebo, Arm 2: DCV 60mg once orally twice daily. daily and ASV 100mg twice daily for 24 weeks plus placebo of FDC tablet of DCV, ASV and BCV orally twice daily for 12 weeks. Open-label arm: FDC tablet of DCV 30mg, ASV 200mg and BCV 75mg, orally twice a day for 12 weeks. Follow-up Active treatment for 12 Active treatment for 12 Active treatment period 12 weeks, follow-up 24 weeks, follow-up 24 or 24 weeks, follow-up 48 weeks. weeks. weeks. Primary Proportion of treated Proportion of subjects in Proportion of TN non- outcome/s subjects in TN group with TN group with SVR12. cirrhotic subjects treated sustained virologic with DCV/ASV/BCV FDC response at 12 weeks tablet achieving SVR12. (SVR12). Secondary Proportion of subjects in Proportion of subjects in Proportion of all TN outcome/s TE group with SVR12; TE group with SVR12; subjects achieving SVR12 proportion of subjects with proportion of subjects with with DCV/ASV/BCV FDC undetectable levels of HCV undetectable levels of HCV tablet or DCV/ASV RNA; safety; proportion of RNA; safety; proportion of combination; proportion of subjects with anaemia; subjects with anaemia; interferon experienced pharmacodynamics; pharmacodynamics; subjects achieving SVR12 proportion of subjects in proportion of subjects in with DCV/ASV/BCV FDC each group achieving each group achieving tablet; proportion of SVR12 associated with the SVR12 associated with the subjects with undetectable following: infection with following: infection with levels of HCV RNA; safety; HCV GT-1a or GT-1b, HCV GT-1a or GT-1b, and proportion of subjects with single nucleotide single nucleotide anaemia; proportion of polymorphism status, and polymorphism status. subjects in each group stage of liver disease. achieving SVR12 associated with the following: infection with HCV GT-1a or GT-1b, single nucleotide polymorphism status, and stage of liver disease; pharmacodynamics. Key results Proportion of subjects Proportion of subjects - achieving SVR12 achieving SVR12 Overall: 91% (379/415); Cirrhotic subjects: 93% TN subjects: 92% (188/202), (287/312), Without RBV, 90% 90% (206/229) in GT-1a (92/102), and 98% (81/83) in GT-1b, With RBV, 96% (96/100); TE subjects: 89% (92/103), TN subjects: overall, 96% 85% (64/75) in GT-1a and (107/112),

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100% (28/28) in GT-1b. Without RBV, 93% (53/57), With RBV, 98% (54/55); Virological failures TE subjects: overall 90% TN subjects: 8% (25/312), (81/90), 9 of which were on- Without RBV, 87% (39/45), treatment failures (6 With RBV, 93% (42/45). virological breakthroughs, 3 end of treatment Proportion of subjects detectable), and 16 which achieving SVR12 by were post-treatment genotype failures (15 relapsed and 1 GT-1a, 91% (136/149), lost to follow-up); GT-1b, 98% (51/52); TE subjects: 10.7% TN GT-1a subjects: (11/103), 4 of which were overall, 94% (74/79), on-treatment failures (2 Without RBV, 90% (36/40), virological breakthroughs, With RBV, 97% (38/39); 2 end of treatment TN GT-1b subjects: detectable) and 7 which overall, 100% (32/32), were post-treatment Without RBV, 100% failures (6 relapsed and 1 (17/17), died [unrelated to study With RBV, 100% (15/15); drug]). TE GT-1a subjects: overall, 89% (62/70), Baseline NS5A resistance Without RBV, 86% (30/35), associated variants were With RBV, 91% (32/35); detected in 34/302 GT-1a TE GT-1b subjects: overall, subjects (SVR12 achieved 95% (19/20), in 25/34 GT-1a subjects) Without RBV, 90% (9/10), and 17/106 GT-1b subjects With RBV, 100% (10/10). (SVR12 achieved in all 17 GT-1b subjects). Virological failures Total of 13 virological failures; TN subjects: post- treatment relapse without RBV, 7% (4/57); no virological breakthroughs; TE subjects: post- treatment relapse, without RBV, 11% (5/45), and with RBV, 2% (1/45); virological breakthroughs, without RBV, 2% (1/45), with RBV, 4% (2/45). Adverse Most common AEs Most common AEs (>10%) - effects (>10%): headache (26%), (without RBV, and with (AEs) fatigue (17%), diarrhoea RBV): fatigue (12%, 28%), (14%), and nausea (13%). headache (17%, 23%), nausea (14%, 17%), Rate of overall serious diarrhoea (13%, 9%), AEs, 2% (n=7, all insomnia (6%, 15%) and considered to be unrelated pruritus (6%, 15%). to study drugs). Rate of overall serious Rate of AEs leading to AEs, 4.5% (n=9, 3 of which discontinuation, 0.7% (n=3, were considered all subjects achieved treatment-related) SVR12). Treatment anaemia, ALT and total discontinuation due to bilirubin elevations, RBV

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elevated levels of ALT in 2 overdose. subjects which resolved on discontinuation. Rate of AEs leading to discontinuation, 1.5% (n=3, 1 death occurred post all subjects achieved treatment due to heroin SVR12). 2 subjects overdose, not considered discontinued RBV due to related to study drugs. anaemia or cough and 1 subject discontinued all study due to anaemia followed by ALT and total bilirubin elevations.

No deaths occurred. Expected Study completion date Study completion date Study completion date reporting reported as November reported as November reported as September date 2014. 2014. 2015.

Trial NCT02170727, UNITY 4, AI443-123; DCV, ASV and BCV; phase III. Sponsor Bristol-Myers Squibb. Status Ongoing. Source of Trial registry4. information Location Korea, Russia, and Taiwan. Design Uncontrolled, single arm. Participants n=160 (planned); aged 18 years and older; chronic HCV infection GT 1; without cirrhosis or with compensated cirrhosis (Child Pugh Class A); HCV RNA ≥10,000IU/ml at screening; TN or TE. Schedule Subjects receive FDC tablet of DCV 30mg, ASV 200mg and BCV 75mg orally, twice daily. Follow-up Active treatment period 12 weeks, follow-up 24 weeks. Primary Proportion of subjects with SVR12 in TN group. outcome/s Secondary Proportion of subjects with SVR12 in TE group; proportion of subjects with outcome/s undetectable levels of HCV RNA; safety; proportion of subjects with anaemia; pharmacodynamics; proportion of subjects in each group achieving SVR12 associated with the following: infection with HCV GT-1a or GT-1b, and single nucleotide polymorphism status, and stage of liver disease; pharmacodynamics. Expected Study completion date reported as June 2015. reporting date

ESTIMATED COST and IMPACT

COST

The cost of asunaprevir, beclabuvir and daclatasvir triple therapy is not yet known. The cost of other selected treatments for HCV infection are summarised in the table below38.

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Drug Dose 12 week cost 24 week cost Peginterferon alfa-2a (Pegasys) 180µg SC, once weekly £1,493 £2,986 Peginterferon alfa-2b 100µg-120µga SC, £1,595-£1,914 £3,190-£3,828 (ViraferonPeg) once weekly Ribavirin (Rebetol) 1,000mg oral, daily £804 £1,608 Telaprevir (Incivo) 2,250mg oral, daily £22,398 n/a Boceprevir (Victrelis) 2,400mg oral, daily £8,400 £16,800 Simeprevir (Olysio) 150mg oral, once daily £22,398 £44,796 Sofosbuvir (Sovaldi) 400mg oral, daily £34,983 £69,966

IMPACT - SPECULATIVE

Impact on Patients and Carers

 Reduced mortality/increased length of survival  Reduced symptoms or disability

 Other:  No impact identified

Impact on Health and Social Care Services

 Increased use of existing services  Decreased use of existing services: 12 week oral treatment regimen

 Re-organisation of existing services  Need for new services

 Other:  None identified

Impact on Costs and Other Resource Use

 Increased drug treatment costs  Reduced drug treatment costs

 Other increase in costs:  Other reduction in costs:

 Other: uncertain unit cost compared to  None identified existing treatments

Other Issues

 Clinical uncertainty or other research question  None identified identified:

REFERENCES

1 ClinicalTrials.gov. UNITY 1: A study of an investigational treatment regimen of daclatasvir (DCV) + asunaprevir (ASV) + BMS-791325 in a fixed dose combination (the DCV 3DAA (Direct Acting Antiviral) regimen) for 12 weeks for the treatment of chronic hepatitis C virus (HCV) genotype 1 infection in non-cirrhotic subjects. http://clinicaltrials.gov/ct2/show/study/NCT01979939 Accessed 09 December 2014. 2 ClinicalTrials.gov. UNITY 2: A study of an investigational treatment regimen of DCV+ASV+BMS- 791325 in a fixed dose combination (the DCV 3DAA (Direct Acting Antiviral) regimen) with or without RBV for 12 weeks for the treatment of chronic hepatitis C virus (HCV) genotype 1 infection in subjects with compensated cirrhosis. http://www.clinicaltrial.gov/ct2/show/study/NCT01973049 Accessed 09 December 2014. 3 ClinicalTrials.gov. UNITY 3: A Japanese phase 3 study of a daclatasvir/asunaprevir/BMS-791325 in subjects with genotype 1 chronic hepatitis C. http://clinicaltrials.gov/show/NCT02123654 Accessed 09 December 2014.

a Based on the average bodyweight (Health Survey for England (HSE)) 2010: adults 77.9kg.

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4 ClinicalTrials.gov. A phase 3 study of a daclatasvir/asunaprevir/BMS-791325 fixed dose combination (FDC) in subjects with chronic hepatitis C genotype 1 (UNITY 4). http://clinicaltrials.gov/show/NCT02170727 Accessed 09 December 2014. 5 Mohsen A and Norris S. Hepatitis C (Chronic). Clinical Evidence 2010;02:921. 6 Public Health England. Hepatitis C in the UK: 2013 report. London: PHE; July 2013. 7 NIHR Horizon Scanning Centre. Peginterferon lambda-1a for hepatitis C. University of Birmingham, July 2014. http://www.hsc.nihr.ac.uk/ 8 National Institute for Health and Clinical Excellence. Peginterferon alfa and ribavirin for the treatment of chronic hepatitis C. Technology appraisal TA200. London: NICE; September 2010. 9 National Institute for Health and Clinical Excellence. Peginterferon alfa and ribavirin for the treatment of mild chronic hepatitis C. Technology appraisal TA106. London: NICE; August 2006. 10 Royal College of General Practitioners. Guidance for the prevention, testing, treatment and management of hepatitis C in primary care. London: RCGP; May 2007. 11 Mann AG, Trotter CL, Balogun MA et al. Hepatitis C in ethnic minority populations in England. Journal of Viral Hepatitis 2008;15:421-426. 12 Patruni B and Nolte E. Hepatitis C. A projection of the healthcare and economic burden in the UK. The Hepatitis C Trust. 2013. 13 Public Health England. Hepatitis C in the UK: 2014 report. London: PHE; July 2014. 14 London Joint Working Group on Substance Misuse and Hepatitis C. Public Health Report on Commissioning of HCV services in London for People who Inject Drugs. NHS North West London. April 2013. 15 National AIDS Trust. Report: January 2012 - Hepatitis C and HIV Co-infection. London: NAT; January 2012. 16 Fissel RB, Bragg-Gresham JL, Woods JD et al. Patterns of hepatitis C prevalence and seroconversion in hemodialysis units from three continents: The DOPPS. Kidney International; 2004:65:2335-2342. 17 Fabrizi F, Dixit V and Messa P. Impact of hepatitis C on survival in dialysis patients: a link with cardiovascular mortality? Journal of Viral Hepatitis; 2012:19(9):601-607. 18 Health & Social Care Information Centre. Hospital episode statistics, admitted patient care, England – 2012-13. www.hscic.gov.uk 19 Office for National Statistics. Mortality statistics: deaths registered in 2013 (Series DR) Table 5. www.ons.gov.uk 20 Public Health England. UK Standards for Microbiology Investigations – vertical and perinatal transmission of hepatitis C. Standards Unit 2014;8(2):1-13. 21 European Association for the Study of the Liver. EASL Recommendations on treatment of Hepatitis C. Geneva: EASL; April 2014. 22 American Association for the Study of Liver Diseases. Recommendations for testing, managing, and treating hepatitis C. March 2014. 23 Scottish Intercollegiate Guidelines Network. SIGN 133 - Management of hepatitis C; A National clinical guideline. Edinburgh: SIGN; July 2013. 24 British HIV Association. British HIV Association guidelines for the management of hepatitis viruses in adults infected with HIV 2013. HIV Medicine; 2013:14:1-71. 25 NHS Clinical Knowledge Summary. Hepatitis C. March 2010. http://cks.nice.org.uk/hepatitis- c#!topicsummary Accessed 10 December 2014. 26 Department of Health. Hepatitis C: quick reference guide for primary care. London; DH; January 2009. 27 British HIV Association. British HIV Association guidelines for the management of coinfection with HIV-1 and hepatitis B or C virus 2010. HIV Medicine 2010;11:1-30. 28 British Association of Sexual Health and HIV. United Kingdom national guideline on the management of the viral hepatitis A, B & C 2008. London: BASHH; 2008. 29 British Society of Gastroenterology. Guidance on the treatment of Hepatitis C incorporating the use of pegylated . London: BSG; March 2003. 30 National Institute for Health and Clinical Excellence. Telaprevir for the treatment of genotype 1 chronic hepatitis C. Technology appraisal TA252. London: NICE; April 2012. 31 National Institute for Health and Clinical Excellence. Boceprevir for the treatment of genotype 1 chronic hepatitis C. Technology appraisal TA253. London: NICE; April 2012. 32 NIHR Horizon Scanning Centre. Simeprevir for chronic hepatitis C infection. University of Birmingham, September 2012. http://www.hsc.nihr.ac.uk/

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33 National Institute for Health and Care Excellence. Hepatitis C (chronic) – simeprevir [ID668]. Technology appraisal in development. London: NICE; Expected January 2015. 34 NIHR Horizon Scanning Centre. Daclatasvir and sofosbuvir (Sovaldi) with and without ribavirin for chronic hepatitis C infection. University of Birmingham, March 2014. http://www.hsc.nihr.ac.uk/ 35 National Institute for Health and Care Excellence. Hepatitis C (chronic) – sofosbuvir [ID654]. Technology appraisal in development. London: NICE; Expected January 2015. 36 NIHR Horizon Scanning Centre. MK-5172 and MK-8742 fixed dose combination for chronic hepatitis C infection (genotypes 1, 4, 5 and 6). University of Birmingham, July 2014. http://www.hsc.nihr.ac.uk/ 37 Bristol-Myers Squibb. Phase 3 UNITY trials demonstrate high cure rates for investigational, all- oral daclatasvir TRIO fixed dose combination in genotype 1 hepatitis C patients, including those with cirrhosis. November 2014. http://news.bms.com/press-release/rd-news/phase-3-unity-trials- demonstrate-high-cure-rates-investigational-all-oral-dacl 38 The Royal Pharmaceutical Society. British National Formulary. BNF 2014. https://www.medicinescomplete.com/mc/bnf/current/

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