Emerging Drug List ADEFOVIR DIPIVOXIL FOR

Emerging Drug List CANADIAN COORDINATING OFFICE FOR HEALTH ADEFOVIR DIPIVOXIL FOR HEPATITIS B VIRUS INFECTION TECHNOLOGY ASSESSMENT

NO. 48 SEPTEMBER 2003 Generic (Trade Name): Adefovir dipivoxil (HepseraTM)

Manufacturer: Gilead Sciences, Inc.

Indication: For the treatment of adults showing evidence of active hepatitis B viral replication and either persistent elevations in serum aminotransferases (alanine aminotransferase (ALT) or aspartate aminotransferase) or histologically active disease.1

Current Regulatory Adefovir dipivoxil received marketing approval from the Food and Drug Administration Status: (FDA) for the above indication in September 2002.2 In March 2003, all 15 member states of the European Union approved its use in adults with compensated liver disease, evidence of active viral replication, persistently elevated serum ALT levels and histological evidence of active liver inflammation fibrosis or decompensated liver disease. Regula- tory filings have also been made in Australia, Switzerland, Turkey and Canada.3

Gilead will co-market adefovir with GlaxoSmithKline (GSK) under the brand name HepseraTM in the US, Canada, eastern and western Europe, Australia and New Zealand. GSK will exclusively market the drug elsewhere.4 Adefovir had been investigated in the US as a HIV treatment. This investigation was abandoned in 1999 after the FDA requested further clinical data to support the new drug application.5

Description: It is thought that adefovir dipivoxil reduces viral load by inhibiting an enzyme responsible for viral replication−nucleotide reverse transcriptase. Adefovir dipivoxil is metabolized to adefovir, which by itself has limited oral bioavailability. After oral administration, adefovir peak levels are achieved in 30 minutes to four hours, while its mean terminal elimination half-life is approximately 7.5 hours. Its approved dosage is 10 mg daily. The optimal treatment duration is unknown. Adefovir is mainly renally excreted via glomerular filtration and active tubular secretion, so dosage adjustments are required in the presence of renal impairment. Adefovir is not a known inhibitor or a substrate of common cytochrome p450 enzymes; its ability to induce enzymes has not been elucidated.1

Current Treatment: Interferon alfa (Intron® A, Schering; Roferon®-A, Roche) and lamivudine (Heptovir,® - GSK) have been used to decrease viral levels and abnormal liver enzymes in individuals with active chronic hepatitis B infection.6 These responses are seldom sustained after treatment is ended. There is evidence to suggest that interferon can reduce the incidence of hepatocellular carcinoma.7 Monotherapy is generally recommended, although the effects of polytherapy are being investigated. Other unapproved drugs or strategies under investigation include famciclovir, entecavir, emtricitabine and pretreatment with glucocorticosteroids.8 Guidance papers can assist in the selection and optimization of therapy.9-12

The Canadian Coordinating Office for Health Technology Assessment (CCOHTA) is a non-profit organization funded by the federal, provincial and territorial governments. (www.ccohta.ca) Emerging Drug List CANADIAN COORDINATING OFFICE FOR HEALTH ADEFOVIR DIPIVOXIL FOR HEPATITIS B VIRUS INFECTION TECHNOLOGY ASSESSMENT

Cost: In the US, a month of therapy with HepseraTM costs US$440 (wholesaler acquisition cost for 30 tablets).2

Evidence: Adefovir dipivoxil in addition to or versus standard therapy: In a 48-week study, individuals with evidence of active lamivudine-resistant hepatitis B viral replication (HbeAg positive), compensated liver disease and adequate renal function (n=59) were randomized to receive adefovir 10 mg, adefovir 10 mg with lamivudine, or continued lamivudine therapy as a control. The effect of treatment on liver histology or fibrosis was not reported. The mean decrease in serum hepatitis B virus (HBV) DNA (±standard

deviation) at 16 weeks was 3.11±0.94, 2.95±0.64 and 0.00±0.28 log10 copies/mL in the adefovir, combination and lamivudine groups respectively.1

Adefovir 10 mg daily for 48 weeks was added to existing anti-HIV therapy, including lamivudine 150 mg twice daily, in a cohort of 35 hepatitis B (HbsAg) positive individuals (five with cirrhosis) infected with HIV. Reductions in histology-fibrosis scores were observed in a subset of 14 patients who underwent liver biopsies. Further reductions in HBV DNA concentrations were detectable in 31 assessable patients, with two patients exhibiting HbeAg seroconversion. The markers for HIV disease were not significantly changed.13

Adefovir dipivoxil versus placebo: The descriptions of two randomized trials focusing on individuals with compensated liver disease and adequate renal function have been published.14,15 Hadziyannis et al. randomized individuals with detectable chronic HBV infection and without evidence of hepatitis B viral replication (HbeAg negative) to either adefovir 10 mg daily (n=123) or placebo (n=67). At 48 weeks, an improved histologic response was more frequently reported in the adefovir arms (absolute difference 30.3%, 95% CI: 15.4 to 45.2).

Marcellin et al. randomized patients with detectable HbeAg and chronic HBV infection to receive placebo (n=170), adefovir 10 mg (n=172) or adefovir 30 mg (n=173). Histologic improvement was noted in 53%, 59% and 25% of patients who received adefovir 10 mg, 30 mg and placebo respectively (P<0.001 active versus placebo). Viral resistance was not detected during these trials.

Limited data are available on the off-label use of adefovir by patients with decompensated liver disease.16,17 The results of phase I and II trials, open-label trials and resistance surveillance have also been published.1,13,16-22

Adverse Effects: Adefovir seems to have a negligible effect on 48-week mortality and serious morbidity, as indicated by the occurrence of death and serious or severe adverse events in placebo-controlled trials.23 Adefovir can cause laboratory abnormalities that require medical attention.

Nephrotoxicity, as seen in dose-dependent increases in serum creatinine and decreases in serum phosphorous, is a recognized limitation of adefovir. In individuals who entered randomized placebo-controlled trials with adequate renal function, the incidence of treatment-emergent nephrotoxicity was 4% after 48 weeks. With a longer duration of treatment, the cumulative risk reached 10% by 96 weeks in a Kaplan-Meier analysis. In a cohort of patients awaiting liver transplantation and who had varying degrees of renal function, treatment-emergent nephrotoxicity occurred at a higher frequency. During earli- er investigations of adefovir 60 mg to 120 mg, nephrotoxicity also occurred in individuals with HIV. As a result, the manufacturer suggests that renal function be assessed during adefovir treatment, particularly in those patients at risk for or with kidney disease.

Acute exacerbations of hepatitis, as shown by an increase in enzyme markers of liver damage after drug discontinuation, occurred in a significant proportion (>50%) of partici- pants in placebo-controlled trials. As a result, it is recommended that hepatic function be monitored after the cessation of treatment.1

The pooled placebo-controlled studies indicate that asthenia, headache, abdominal pain, nausea, flatulence, diarrhea and dyspepsia were reported in 3% or more of patients, paralleling the rate reported in the placebo group.

Commentary: There are no long-term trials comparing adefovir with current therapies from which to make a decision regarding its use. Short-term comparative trials describing surrogate endpoint responses and treatment-emergent morbidity in treatment-naive patients are also lacking. The evidence on surrogate endpoint responses in patients with docu- mented lamivudine resistance is noteworthy. A lack of detected viral resistance is also worth mention, although this resistance may become inevitable.24 Differences in treatment-emergent morbidity between lamivudine and adefovir recipients have not been described. They would help define the role of adefovir. In particular, its potential nephrotoxicity during treatment and hepatotoxicity upon cessation need to be weighed against any therapeutic advantages.

References: 1. Hepsera™ full prescribing information. Foster City (CA): Gilead Sciences, Inc.; 2002. Available: http://www.gilead.com/pdf/hepsera_pi.pdf. 2. FDA approves Gilead's Hepsera™ for the treatment of chronic hepatitis B [press release]. Foster City (CA): Gilead Sciences, Inc.; 2002 Sep 20. Available: http://www.hepsera.com/1000b.asp (accessed 2003 May 14).

3. Gilead Sciences hepatitis B drug Hepsera™ approved for marketing in the European Union [press release]. Foster City (CA): Gilead Sciences, Inc.; 2003 Mar 11. Available: http://www.gilead.com/wt/sec/pr_1047342957 (accessed 2003 May 14). 4. Gilead and GlaxoSmithKline announce international licensing agreement for investigational chronic hepatitis B drug Adefovir Dipivoxil [press release]. Foster City (CA): Gilead Sciences, Inc.; 2002 Apr 29. Available: http://www.gilead.com/wt/sec/pr_1019863560 (accessed 2003 May 14). 5. Gilead Sciences announces termination of its U.S. development program for adefovir dipivoxil for HIV [press release]. Foster City (CA): Gilead Sciences, Inc.; 1999 Dec 3. Available: http://www.gilead.com/wt/sec/pr_944254502 (accessed 2003 May 14). 6. CPS: compendium of pharmaceuticals and specialties. 38th ed. Ottawa: Canadian Pharmacists Association; 2003. 7. Lin SM, Sheen IS, Chien RN, Chu CM, Liaw YF. Long-term beneficial effect of interferon therapy in patients with chronic hepatitis B virus infection. Hepatology 1999;29(3):971-5. 8. Mellerup MT, Krogsgaard K, Mathurin P, Gluud C, Poynard T. Sequential combination of glucocorticosteroids and alfa interferon versus alfa interferon alone for HBeAg-positive chronic hepatitis B. Cochrane Database Syst Rev 2002;(2):CD000345. 9. Jain AB, Fung JJ. Advances in hepatitis B virus infection. Transplant Proc 2003;35(1):342-4. 10. Karayiannis P. Hepatitis B virus: old, new and future approaches to antiviral treatment. J Antimicrob Chemother 2003;51(4):761-85. 11. EASL International Consensus Conference on Hepatitis B. 13-14 September, 2002: Geneva, Switzerland. Consensus statement (short version). J Hepatol 2003;38(4):533-40. 12. Conjeevaram HS, Lok AS. Management of chronic hepatitis B. J Hepatol 2003;38 Suppl 1:S90-103. 13. Benhamou Y, Bochet M, Thibault V, Calvez V, Fievet MH, Vig P, et al. Safety and efficacy of adefovir dipivoxil in patients co-infected with HIV-1 and lamivudine-resistant hepatitis B virus: an open- label pilot study. Lancet 2001;358(9283):718-23. 14. Marcellin P, Chang TT, Lim SG, Tong MJ, Sievert W, Shiffman ML, et al. Adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic hepatitis B. N Engl J Med 2003;348(9):808-16. 15. Hadziyannis SJ, Tassopoulos NC, Heathcote EJ, Chang TT, Kitis G, Rizzetto M, et al. Adefovir dipivoxil for the treatment of hepatitis B e antigen-negative chronic hepatitis B. N Engl J Med 2003;348(9):800-7. 16. Cada D, Levien T, Baker DE. Adefovir dipivoxil. Hosp Pharm 2003;38(2):144-54. 17. Adefovir dipivoxil for the treatment of chronic hepatitis B: NDA 21-449 [FDA Advisory Committee briefing document]. Foster City (CA): Gilead Sciences, Inc.; 2002 Jul 5. Available: http://www.fda.gov/ohrms/dockets/ac/02/briefing/3885B1_01_Gilead.pdf (accessed 2003 May 21). 18. Tillmann HL, Bock CT, Bleck JS, Rosenau J, Boker KH, Barg-Hock H, et al. Successful treatment of fibrosing cholestatic hepatitis using adefovir dipivoxil in a patient with cirrhosis and renal insufficien- cy. Liver Transpl 2003;9(2):191-6. 19. Thabut D, Thibault V, Benhamou Y, Bernard B, Aubron-Olivier C, Poynard T, et al. Successful control of subfulminant hepatitis related to lamivudine-resistant hepatitis B virus in an HIV-infected patient. AIDS 2001;15(18):2463-4.

20. Walsh KM, Woodall T, Lamy P, Wight DG, Bloor S, Alexander GJ. Successful treatment with adefovir dipivoxil in a patient with fibrosing cholestatic hepatitis and lamivudine resistant hepatitis B virus. Gut 2001;49(3):436-40. 21. Perrillo R, Schiff E, Yoshida E, Statler A, Hirsch K, Wright T, et al. Adefovir dipivoxil for the treatment of lamivudine-resistant hepatitis B mutants. Hepatology 2000;32(1):129-34. 22. Yang H, Westland CE, Delaney WE, Heathcote EJ, Ho V, Fry J, et al. Resistance surveillance in chronic hepatitis B patients treated with adefovir dipivoxil for up to 60 weeks. Hepatology 2002;36(2):464-73. 23. Center for Drug Evaluation and Research, Food and Drug Administration. Hepsera (Adefovir Dipivoxil) tablets. Company: Gilead Sciences, Inc. Application no.: 21-449. Medical review(s): part 2. Rockville (MD): The Center; 2002 Sep 20. Available: http://www.fda.gov/cder/approval/index.htm. 24. Shaw T, Bowden S, Locarnini S. Chemotherapy for hepatitis B: new treatment options necessitate reappraisal of traditional endpoints. Gastroenterology 2002;123(6):2135-40.

This series highlights medical technologies that are not yet in widespread use in Canada and that may have a significant impact on health care. The contents are based on information from early experience with the technology; however, further evidence may become available in the future. These summaries are not intended to replace professional medical advice. They are compiled as an information service for those involved in planning and providing health care in Canada. These summaries have not been externally peer reviewed.

ISSN 1496-8398 (online only)

The Canadian Coordinating Office for Health Technology Assessment (CCOHTA) is a non-profit organization funded by the federal, provincial and territorial governments. (www.ccohta.ca)