National Horizon Scanning Centre Clevudine (Levovir) for hepatitis B August 2008 This technology summary is based on information available at the time of research and a limited literature search. It is not intended to be a definitive statement on the safety, efficacy or effectiveness of the health technology covered and should not be used for commercial purposes. The National Horizon Scanning Centre Research Programme is part of the National Institute for Health Research August 2008 National Horizon Scanning Centre News on emerging technologies in healthcare Clevudine (Levovir) for hepatitis B Target group • Chronic hepatitis B. Technology description Clevudine (Levovir) is an oral, synthetic pyrimidine nucleoside analogue in development for the treatment of hepatitis B viral (HBV) infection. The drug inhibits hepatitis B virus DNA synthesis by causing deformation of the chain polymerisation geometry. Clevudine is administered 30mg once daily. Innovation and/or advantages Clevudine may have more potent activity against HBV than adefovir. Developer Pharmasset Availability, launch or marketing dates, and licensing plans: In phase III clinical trials. Relevant guidance • NICE technology appraisal in development. Tenofovir disoproxil fumarate for the treatment of chronic hepatitis B. Expected May 20091. • NICE technology appraisal. Entecavir for the treatment of chronic hepatitis B. 20082. • NICE technology appraisal. Telbivudine for the treatment of chronic hepatitis B. 20083. • NICE technology appraisal. Hepatitis B (chronic) - adefovir dipivoxil and pegylated interferon alpha-2a adefovir dipivoxil and peginterferon alfa-2a for the treatment of chronic hepatitis B. 20064. • British HIV Association (BHIVA) guideline. HIV and chronic hepatitis: co-infection with HIV and hepatitis B virus infection. 20045. Clinical need and burden of disease Chronic hepatitis B is defined as persistence of HBV infection for more than six months6. HBeAg positive chronic hepatitis B occurs during the early phases of chronic HBV infection and is characterised by extremely high HBV replication and persistently or intermittently increased aminotransferase levels. HBeAg negative chronic hepatitis B, represents a later phase in the course of chronic HBV infection and is a potentially severe and progressive form of chronic liver disease with very rare spontaneous remissions, frequent progression to cirrhosis and increased risk of the development of hepatocellular carcinoma7. The World Health Organization (WHO) estimates that in the UK the prevalence of chronic hepatitis B infection is 0.3% of the general population (an estimated 160,200 cases in England and Wales)8,9. It is estimated that there are between 7,000 and 7,700 new cases of chronic hepatitis B in England and Wales each year4,10. Existing comparators and treatments Chronic carriers of hepatitis B virus with abnormal liver function tests should be considered for antiviral therapy. The aim is to suppress viral replication and facilitate 2 August 2008 National Horizon Scanning Centre News on emerging technologies in healthcare seroconversion. The choice of treatment is a matter of debate. Current options are only effective in around 40% of patients and they are often associated with limited efficacy, poor tolerability or resistance problems. A review of three studies indicates that 24% of patients are lamivudine-resistant after one year of treatment, rising to 30%, 49% and 66% over years two, three and foura. The current treatment options for chronic hepatitis B are: • Lamivudine, an oral nucleoside analogue reverse transcriptase inhibitor. • Interferon alfa (IFNα) and peginterferon alfa-2a (pegIFNα) [intravenous or sub- cutaneous]. • Adefovir dipivoxil, an oral nucleotide reverse transcriptase inhibitor (effective in lamivudine-resistant, and IFNα/pegIFNα-resistant chronic hepatitis B). • Entecavir, an oral nucleoside analogue DNA polymerase and reverse transcriptase inhibitor, licensed for the treatment of HBV with compensated liver disease. • Telbivudine, an oral L-nucleoside analogue DNA polymerase inhibitor. Efficacy and safety Trial code NCT0049600211; Study 305 (CI-PSI-5628- NCT0049615812; Study 306 (CI-PSI-5628- 06-305): HBeAg positive; clevudine vs 06-306): HBeAg negative; clevudine vs adefovir; phase III. adefovir; phase III. Sponsor Pharmasset Pharmasset Status Ongoing Ongoing Location US, Canada, Brazil, Europe (including UK) US, Canada, Brazil, Europe (including UK) Australia, New Zealand, Asia. Australia, New Zealand, Asia. Design Randomised, double-blind, controlled. Randomised, double-blind, controlled. Participants n=376; >16 years; chronic hepatitis B n=480; >16 years; chronic hepatitis B in trial HBeAg positive; newly diagnosed. HBeAg negative; newly diagnosed. Randomised to adefovir 30mg or clevudine Randomised to adefovir 30mg or clevudine 30mg once-daily. 30mg once-daily. Follow-up Treatment for 48 weeks, monitoring for 96 Treatment for 48 weeks, monitoring for 96 weeks. weeks. Primary Undetectable HBV DNA (less than 300 Undetectable HBV DNA (less than 300 outcome copies/mL) and normal liver enzymes at 48 copies/mL) and normal liver enzymes at 48 weeks. weeks. Secondary Liver histology, hepatitis B e-antigen (eAg) Liver histology, hepatitis B e-antigen (eAg) outcomes seroconversion, HBV hepatic (cccDNA), seroconversion, HBV hepatic (cccDNA), eAg and surface antigen (sAg). eAg and surface antigen (sAg). Expected Study started October 2007. Study started October 2007. reporting date Trial name HBeAg negative; clevudine vs placebo13. Sponsor Sungkyunkwan University Samsung Medical Center, South Korea. Status Published. Location South Korea. Design Randomised, double blind, placebo controlled. Participants n=86; adults 18-60 years; chronic hepatitis B HBeAg negative; previously untreated. in trial Randomised to clevudine 30mg (n=63) or placebo (n=23) for 24 weeks. Follow-up Additional 24 weeks after treatment cessation. Primary HBV DNA log10 change from baseline. a Expert opinion 3 August 2008 National Horizon Scanning Centre News on emerging technologies in healthcare outcome Secondary Undetectable HBV DNA (<300 copies/mL) and normal liver enzymes (alanine outcomes aminotransferase [ALT]). Key results Median changes in HBV DNA from baseline were -4.25 and -0.48 log10 copies/mL at week 24 in the clevudine and placebo group respectively (p<0.0001). Viral suppression in the clevudine group was sustained after withdrawal of therapy with 3.11 log10 reduction at week 48. At week 24 and 48, 92.1% in the clevudine group and 16.4% in the placebo group had undetectable serum HBV DNA levels by PCR assay test (<300 copies/mL). 74.6% and 33.3% achieved ALT normalisation in the clevudine and placebo groups respectively. ALT normalisation was maintained in the clevudine group during post- treatment follow-up. Adverse Clevudine was generally well tolerated. effects Estimated cost and cost impact The cost of clevudine is currently not known. The monthly cost of current alternative treatments for chronic HBV infection isb: Drug Brand name Dose Approximate monthly cost per patient Lamivudine Zeffix (GSK) 100mg daily £78 Adefovir Hepsera (Gilead) 10mg daily £315 Interferon alpha IntronA (Schering- 5-10 million IU 3 times per £259-£518 (SC) Plough) week Roferon-A (Roche) 2.5-5 million IU/m2 3 times £271-£542 per week PegInterferon Pegasys (Roche) 180 μg once weekly £528 alpha (SC) Potential or intended impact – speculative Patients ; Reduced morbidity Reduced mortality or increased ; Improved quality of life for survival patients and/or carers Quicker, earlier or more accurate Other: None identified diagnosis or identification of disease Services Increased use Service reorganisation required Staff or training required Decreased use Other: ; None identified Costs ; Increased unit cost compared to Increased costs: more patients Increased costs: capital alternative: depends on coming for treatment investment needed comparative price. New costs: Savings: Other: b British National Formulary No.55, March 2008. 4 August 2008 National Horizon Scanning Centre News on emerging technologies in healthcare References 1 National Institute for Health and Clinical Excellence. Tenofovir disoproxil fumarate for the treatment of chronic hepatitis B. Technology appraisal in development. Expected May 2009. 2 National Institute for Health and Clinical Excellence. Entecavir for the treatment of chronic hepatitis B. Technology appraisal TA153. August 2008. 3 National Institute for Health and Clinical Excellence. Telbivudine for the treatment of chronic hepatitis B. Technology appraisal TA154. August 2008 4 National Institute for Health and Clinical Excellence. Hepatitis B (chronic) - adefovir dipivoxil and pegylated interferon alpha-2a adefovir dipivoxil and peginterferon alfa-2a for the treatment of chronic hepatitis B. Technology Appraisal TA096, February 2006. 5 British HIV Association (BHIVA) Guideline. HIV and chronic hepatitis: Co-infection with HIV and hepatitis B virus infection. October 2004. Available at: http://www.bhiva.org/cms1191559.aspx (accessed 16.6.08). 6 Merck Manual online. Chronic hepatitis. Available at: http://www.merck.com/mmpe/sec03/ch027/ch027 c.html?qt=hepatitis%20b&alt=sh (accessed 16.6.08). 7 Papatheodoridis GV, Hadziyannis SJ. Current management of chronic hepatitis B. Available at: http://www. medscape.com/viewarticle/466788 (accessed 18.6.08) 8 Department of Health. Children in need and bloodborne viruses: HIV and hepatitis. November 2004. 9 Health Protection Agency. General