Horizon Scanning Technology Summary. Tenofovir disoproxil fumarate for hepatitis B. National Horizon Scanning Centre. April 2007

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1 Horizon Scanning Technology Summary National Horizon Scanning Centre Tenofovir disoproxil fumarate for hepatitis B April 2007 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.

2 National Horizon Scanning Centre Tenofovir disoproxil fumarate for hepatitis B Target group Adults with active chronic hepatitis B: - Treatment experienced - Treatment naïve - Lamivudine-resistant Technology description Tenofovir disoproxil fumarate (TDF, Tenofovir DF) is an oral lipophilic ester pro-drug of tenofovir. TDF belongs to the nucleotide analogue class of antiviral compounds, which block reverse transcriptase. Nucleotide compounds form reservoirs in both infected and non-infected cells, and therefore have the potential for infrequent dosing and prophylactic use. TDF is administered at 300mg once daily. TDF is already launched for the treatment of patients with HIV. TDF is also used, but not specifically licensed, as an individual treatment, or as a combination therapy with either emtricitabine or lamivudine, for HIV and hepatitis B virus (HBV) co-infected patients. Innovation and/or advantages TDF may have a better resistance profile than lamivudine and adefovir, although this needs to be demonstrated in clinical practice. Developer Gilead Sciences Inc. Place of use Home care e.g. home dialysis Secondary care e.g. general, non-specialist hospital General public e.g. over the counter Community or residential care e.g. district nurses, physio Tertiary care e.g. highly specialist services or hospital Primary care e.g. used by GPs or practice nurses Emergency care e.g. paramedic services, trauma care Availability, launch or marketing dates, and licensing plans: Phase III clinical trials are being conducted for TDF as a monotherapy for HBV. NHS or Government priority area: Cancer Cardiovascular disease Children Diabetes Chronic conditions Mental health Older people Public health Renal disease Women s health None identified Sexual health; communicable disease Relevant guidance NICE Technology Appraisal, TA096. Adefovir dipivoxil and peginterferon alfa-2a for the treatment of chronic hepatitis B. February NICE Technology Appraisal. Telbivudine and Entecavir for hepatitis B are in the scoping phase for appraisal in wave 14. British HIV Association (BHIVA) Guideline. HIV and Chronic Hepatitis: Coinfection with HIV and Hepatitis B virus infection. October April

3 National Horizon Scanning Centre British Association for Sexual Health and HIV. United Kingdom national guideline on the management of the viral hepatides A, B & C. November Clinical need and burden of disease Chronic hepatitis B is defined as persistence of HBV infection for more than six months. The damage to the liver is not due to the actual virus, but to the body s own immune reaction to it. The prevalence of chronic hepatitis B is estimated at between 0.2% and 0.3% of the UK general population (an estimated 106,800 to 160,200 cases in England and Wales) 1. It is estimated that there are between 7,000 and 7,700 new cases of chronic hepatitis B in England and Wales each year (immigration to the UK accounting for the majority) 2,3. 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 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 four a. The current treatment options for HBV are: Lamivudine, an oral nucleoside analogue reverse transcriptase inhibitor. Interferon alfa (IFNα) and peginterferon alfa-2a (pegifnα) (iv or sub-cutaneous). Use is limited by a response rate of less than 50%, and relapse is frequent. Adefovir dipivoxil, an oral nucleotide reverse transcriptase inhibitor, is effective in lamivudine-resistant, and IFNα/pegIFNα-resistant chronic hepatitis B. Entecavir, an oral nucleoside analogue DNA polymerase and reverse transcriptase inhibitor, has recently been licensed for the treatment of HBV. Telbivudine, an oral L-nucleoside analogue DNA polymerase inhibitor, is in the process of being licensed for HBV. Efficacy and safety Trial name or code TDF vs. adefovir dipivoxil (NCT ; Study 102 4,5 ) Treatment naïve or Lamivudinetreated TDF vs. adefovir dipivoxil (NCT ; Study 103 4,6 ) Treatment naïve Sponsor Gilead Sciences Gilead Sciences Status Ongoing - study start June 2005 Ongoing - study start May 2005 Location US, Europe (including UK) US, Europe (including UK) Design Participants in trial a Expert opinion Phase III, randomised, doubleblind, active control n=300, HBeAg- negative/ anti-hbe positive (presumed pre-core mutant) chronic hepatitis B. Nucleoside or nucleotide naïve (no prior therapy for greater than 12 weeks), but up to 120 patients with greater than 12 weeks prior lamivudine experience will be Phase III, randomised, double-blind, active control n=240, HBeAg-positive chronic hepatitis B. 160 patients to receive TDF 300 mg/day, 80 patients to receive adefovir dipivoxil 10 mg/day. Nucleoside or nucleotide naïve (no prior therapy for greater than 12 weeks). For a 48 week period. April

4 eligible. 200 patients to receive TDF 300 mg/day, 100 patients to receive adefovir dipivoxil 10 mg/day. For a 48 week period. Follow-up 48 weeks 48 weeks Primary outcome Complete response at week 48 (defined as serum HBV DNA level below 400 copies/ml) Secondary outcomes Expected reporting date Trial name or code Improvement in liver histology scores (defined as at least a twopoint reduction in the Knodell necroinflammatory score without worsening in fibrosis) National Horizon Scanning Centre August 2007 September 2007 BE-LOW Study: entecavir plus TDF vs. entecavir (NCT ) Treatment-naïve Complete response at week 48 (defined as serum HBV DNA level below 400 copies/ml) Improvement in liver histology scores (defined as at least a twopoint reduction in the Knodell necroinflammatory score without worsening in fibrosis) TDF vs. TDF & emtricitabine (NCT ) Treatment experienced Sponsor Bristol-Myers Squibb Gilead Sciences Status Ongoing - study start March 2007 Ongoing - study start March 2006 Location India US, Europe Design Phase III, randomised, active control, open label Phase II, randomised, double-blind, active control Participants in trial n=384 (expected). Treatment naïve. n=90 (expected). Patient currently on treatment with adefovir dipivoxil for chronic hepatitis B with persistent viral replication (detectable HBV DNA). Arm 1: TDF 300mg. Arm 2: TDF 300mg plus emtricitabine 200mg. Follow-up 48 weeks, 96 weeks 48 weeks, 96 weeks Primary outcome Secondary outcomes Expected reporting date HBV DNA <50 IU/ml (approximately 300 copies/ml) at week 96 HBV DNA <50 IU/ml (approximately 300 copies/ml) at week 48. Reduction in HBV DNA by PCR; alanine aminotransferase (ALT) normalisation; HBeAg loss; HBe seroconversion; HBs seroconversion; adverse effects. Unknown Plasma HBV DNA <169 copies/ml at week 48 Change from baseline in log 10 plasma HBV DNA; plasma HBV DNA <169 copies/ml; Change in ALT levels; ALT normalisation; Drug resistant mutations; HBsAg/HBeAg loss and seroconversion. August 2007 (48 week interim results) May 2009 (96 week final report) April

5 Estimated cost and cost impact National Horizon Scanning Centre The cost of TDF for hepatitis B is unknown. The cost of 28 days treatment with 245 mg tenofovir disoproxil (as fumerate) for HIV is 238 b. The monthly cost of current alternative treatments for chronic HBV infection is c : Drug Brand name Dose Monthly cost per patient (based on 28 days) Lamivudine Zeffix (GSK) 100mg daily 78 Adefovir dipivoxil Hepsera (Gilead) 10mg daily 294 Entecavir Baraclude (BMS) 0.5-1mg daily 353 Telbivudine Tyzeka (Idenix and Not licensed yet Unknown Novartis) Expected Q Interferon alpha IntronA 5-10 million IU 3 times 518 (Schering-Plough) per week Roferon-A (Roche) 2.5 million IU to million IU/m 2 body surface 3 times per week PegInterferon alpha Pegasys (Roche) 180 µg once weekly 528 Potential or intended impact speculative Patients Reduced morbidity Quicker or more accurate diagnosis Reduced mortality or increased survival Earlier identification of disease Improved quality of life for patients and/or carers Services Increased use e.g. length of stay, Service reorganisation required out-patient visits Decreased use e.g. shorter length of stay, reduced referrals Staff or training required Costs Increased unit cost compared to alternative New costs: Increased costs: When used as an additive rather than alternative treatment. Savings: Possible if used as alternative treatment and is cheaper than alternatives. Increased costs: capital investment needed References 1 Department of Health. Children in need and bloodborne viruses: HIV and hepatitis. November National Institute for Health & Clinical Excellence. Adefovir dipivoxil and peginterferon alfa-2a for the treatment of chronic hepatitis B. Technology Appraisal Guidance Number TA096, Feb Shepherd J, Jones J, Takeda A, Price A. Adefovir dipivoxil and pegylated interferon alfa-2a for the treatment of chronic hepatitis B - a systematic review and economic evaluation. Technology assessment report commissioned by the HTA Programme on behalf of The National Institute for Health and Clinical Excellence. Southampton Health Technology Assessment Centre, May Gilead Sciences Inc. Gilead Science announces initiation of phase II clinical program evaluating tenofovir disoproxil fumerate for the treatment of chronic hepatitis B virus. News Release, 19 th July Available at: Hhttp://investors.gilead.comH [accessed 20/03/07]. b British National Formulary, March 2007: 53 April

6 National Horizon Scanning Centre 5 ClinicalTrials.gov. A study to compare tenofovir versus Hepsera (adefovir) for the treatment of NBeAg chronic hepatitis B (Identifier: NCT ). Available at: Hhttp:// [accessed 14/02/07]. 6 ClinicalTrials.gov. A study to compare tenofovir versus Hepsera (adefovir) for the treatment of hepatitis Be antigen (HBeAg) positive chronic hepatitis B. (Identifier: NCT ). Available at: Hhttp:// [accessed 14/02/07]. 7 ClinicalTrials.gov. Entecavir plus tenofovir combination therapy versus entecavir monotherapy in naïve subjects with chronic hepatitis B (Identifier: NCT ). Available at: Hhttp:// [accessed 14/02/07]. 8 ClinicalTrials.gov. Treatment of persistant viremia (virus in blood) in chronic Hepatitis B subjects already receiving Adefovir Dipivoxil (Identifier: NCT ). Available at: Hhttp:// [accessed 14/02/07]. The National Horizon Scanning Centre is a constituent of the NHS National Institute for Health Research and is managed under contract from the Department of Health's R&D Division. The views expressed in NHSC publications are those of the author(s). They are not necessarily shared by the Department of Health and should not be taken as representing Government policy. The National Horizon Scanning Centre, Department of Public Health and Epidemiology University of Birmingham, Edgbaston, Birmingham, B15 2TT, England Tel: +44 (0) Fax +44 (0) April