Antiviral therapy for chronic hepatitis B: Challenges in Hong Kong
Authors: Henry Lik-Yuen Chan
Journal: Journal of Hepatology (2009)

I read with great interest the review article by Prof. Liaw published in a recent issue of this journal [[1]Liaw Y.F. Antiviral therapy of chronic hepatitis B: opportunities and challenges in Asia.J Hepatol. 2009; 51: 403-410Abstract Full Text Full Text PDF PubMed Scopus (113) Google Scholar]. The article highlighted the reality and difficulties many patients and clinicians in Asian countries are now facing in the treatment of chronic hepatitis B. Although the more recent antiviral agents (entecavir and tenofovir) have strong antiviral potency and very low risk of drug resistance, these drugs may not be available to all patients in need. This is due to the restricted reimbursement criteria in place in different countries as well as the low income of the population in some areas.In 2008, the gross national income per capita in Hong Kong was approximately USD 30,380, which was comparable to that of Singapore, Japan, Australia and Europe [[1]Liaw Y.F. Antiviral therapy of chronic hepatitis B: opportunities and challenges in Asia.J Hepatol. 2009; 51: 403-410Abstract Full Text Full Text PDF PubMed Scopus (113) Google Scholar]. Instead of full reimbursement for antiviral drugs, Hong Kong has very restricted criteria of reimbursement. Before July 2008, lamivudine was the only drug reimbursable to patients with significant disease activity while adefovir could only be reimbursed for patients with lamivudine resistance and significant disease activity. After July 2008, lamivudine was not reimbursable to treat new patients. Instead, entecavir could be reimbursed for patients with alanine aminotransferase (ALT) higher than 5 times the upper limit of normal (ULN) and patients with decompensated liver cirrhosis. Use of these antiviral drugs outside the listed indications as well as other antiviral agents (peginterferon, telbivudine, tenofovir) was at the patients’ own expense.We performed a drug expenditure audit over 4 weeks between November and December 2008. Four hundred and forty-four chronic hepatitis B patients attended the outpatient clinic during the audit period. One hundred and sixty-three (37%) patients had received antiviral therapy, 121 (27%) were indicated for antiviral treatment but not treated while the remaining 160 (36%) were not indicated for treatment. As hepatitis B virus (HBV) DNA and liver biopsy were not routine tests, we arbitrarily defined patients who had evidence of liver cirrhosis and those who had elevated ALT were indicated for antiviral treatment. This would be an underestimate as a significant proportion of patients who had high normal ALT might already have advanced liver fibrosis, particularly the older patients with elevated HBV DNA [2Wong G.L.H. Wong V.W.S. Choi P.C.L. Chan A.W.H. Chim A.M.L. Yiu K.K.L. et al.Clinical factors associated with liver stiffness in hepatitis B e antigen-positive chronic hepatitis B.Clin Gastroenterol Hepatol. 2009; 7: 227-233Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar, 3Wong G.L.H. Wong V.W.S. Choi P.C.L. Chan A.W.H. Chim A.M.L. Yiu K.K.L. et al.Evaluation of alanine transaminase and hepatitis B virus DNA to predict liver cirrhosis in hepatitis B e antigen-negative chronic hepatitis B using transient elastography.Am J Gastroenterol. 2008; 103: 3071-3081Crossref PubMed Scopus (61) Google Scholar]. The exact reasons why some patients did not receive antiviral treatment were not explored in this audit. One obvious reason was that a significant proportion of untreated patients did not meet the criteria for reimbursement and could not afford the high cost of the antiviral medications.Overall, only 27 of 444 (6.1%) patients in our clinic were treated under the hospital reimbursement scheme. One hundred and thirty-six (83%) of the 163 treated patients were purchasing their antiviral medications without reimbursement. These numbers again reflect the inadequacy of the highly restricted reimbursement policy in force in Hong Kong. In our previously conducted cross-sectional studies including over 1500 chronic hepatitis B patients, approximately 3.5% of hepatitis B e antigen (HBeAg)-positive patients and 2% of HBeAg-negative patients had ALT levels higher than 5 times ULN [2Wong G.L.H. Wong V.W.S. Choi P.C.L. Chan A.W.H. Chim A.M.L. Yiu K.K.L. et al.Clinical factors associated with liver stiffness in hepatitis B e antigen-positive chronic hepatitis B.Clin Gastroenterol Hepatol. 2009; 7: 227-233Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar, 3Wong G.L.H. Wong V.W.S. Choi P.C.L. Chan A.W.H. Chim A.M.L. Yiu K.K.L. et al.Evaluation of alanine transaminase and hepatitis B virus DNA to predict liver cirrhosis in hepatitis B e antigen-negative chronic hepatitis B using transient elastography.Am J Gastroenterol. 2008; 103: 3071-3081Crossref PubMed Scopus (61) Google Scholar]. The prevalence of clinical liver cirrhosis was approximately 16% among HBeAg-negative patients in our clinic, and the prevalence of decompensated cirrhosis was expected to be lower [[4]Chan H.L.Y. Leung N.W.Y. Hussain M. Wong M.L. Lok A.S.F. Hepatitis B e antigen-negative chronic hepatitis B in Hong Kong.Hepatology. 2000; 31: 763-768Crossref PubMed Scopus (183) Google Scholar]. In other words, the number of patients eligible for reimbursement under the current policy would only be a minority of all those who should be indicated for antiviral treatment according to the Asian-Pacific recommendations [[5]Liaw Y.F. Leung N. Kao J.H. Piratvisuth T. Gane E. Han K.H. et al.Asian-Pacific consensus statement on the management of chronic hepatitis B: a 2008 update.Hepatol Int. 2008; 2: 263-283Crossref PubMed Scopus (814) Google Scholar].The most commonly used antiviral medication was entecavir (Fig. 1). Seventy-two (44% of the treated) patients were on entecavir but only one of them was reimbursed. This was partly related to a very recent change in reimbursement policy and the restricted criteria for reimbursement. Adefovir was used in 32 (20% of the treated) patients and 7 of them were reimbursed. Thirteen of the 32 patients on adefovir were using combination treatment with lamivudine or entecavir for lamivudine resistance. Although adefovir was used primarily as a salvage therapy for lamivudine resistance, patients who had adefovir started on virological breakthrough with normal ALT did not meet the criteria for reimbursement due to the lack of disease activity. The financial restrictions inevitably delayed the commencement of adefovir for the best treatment outcome [[6]Lampertico P. Vigano M. Manenti E. Iavarone M. Lunghi G. Colombo M. Adefovir rapidly suppresses hepatitis B in HBeAg-negative patients developing genotypic resistance to lamivudine.Hepatology. 2005; 42: 1414-1419Crossref PubMed Scopus (251) Google Scholar]. In a recent report, 14 of the 26 patients with lamivudine resistance had ALT higher than 2 times ULN when adefovir was started in our clinic, and this was translated to a suboptimal viral suppression in the long term [[7]Chan H.L.Y. Wong V.W.S. Tse C.H. Chim A.M.L. Chan H.Y. Wong G.L.H. et al.Early virological suppression is associated with good maintained response to adefovir dipivoxil in lamivudine resistant chronic hepatitis B.Aliment Pharmacol Ther. 2007; 25: 891-898Crossref PubMed Scopus (36) Google Scholar].I agree with Prof. Liaw that application of the roadmap approach by starting with a cheaper antiviral agent and switching to other agent(s) if HBV DNA is still detectable at 24 weeks of treatment should be explored [[1]Liaw Y.F. Antiviral therapy of chronic hepatitis B: opportunities and challenges in Asia.J Hepatol. 2009; 51: 403-410Abstract Full Text Full Text PDF PubMed Scopus (113) Google Scholar]. In a recent cost-effectiveness analysis in Hong Kong, the roadmap approach starting with telbivudine or lamivudine and switching to entecavir if HBV DNA suppression is detectable at week 24 may be a cost-effective alternative to monotherapy with entecavir to all patients [[8]Tsoi K.K.F. Lui Y.Y.N. Wong V.W.S. Chan H.L.Y. Cost-effectiveness analysis of anti-viral treatment strategies based on the roadmap model in chronic hepatitis B virus (HBV) infection.Hepatol Int. 2009; 3: 105Google Scholar]. At present, tenofovir is not registered for the indication of chronic hepatitis B in Hong Kong and can only be prescribed after application for off-label use. The cost of tenofovir is currently higher than that of entecavir, but it will be an attractive alternative if its cost can be lowered as in the case of Europe. To facilitate the use of the limited resources to treat the large number of chronic hepatitis B patients in Asia, proper local cost-effective analysis should be performed before a reimbursement policy is reinforced. I read with great interest the review article by Prof. Liaw published in a recent issue of this journal [[1]Liaw Y.F. Antiviral therapy of chronic hepatitis B: opportunities and challenges in Asia.J Hepatol. 2009; 51: 403-410Abstract Full Text Full Text PDF PubMed Scopus (113) Google Scholar]. The article highlighted the reality and difficulties many patients and clinicians in Asian countries are now facing in the treatment of chronic hepatitis B. Although the more recent antiviral agents (entecavir and tenofovir) have strong antiviral potency and very low risk of drug resistance, these drugs may not be available to all patients in need. This is due to the restricted reimbursement criteria in place in different countries as well as the low income of the population in some areas. In 2008, the gross national income per capita in Hong Kong was approximately USD 30,380, which was comparable to that of Singapore, Japan, Australia and Europe [[1]Liaw Y.F. Antiviral therapy of chronic hepatitis B: opportunities and challenges in Asia.J Hepatol. 2009; 51: 403-410Abstract Full Text Full Text PDF PubMed Scopus (113) Google Scholar]. Instead of full reimbursement for antiviral drugs, Hong Kong has very restricted criteria of reimbursement. Before July 2008, lamivudine was the only drug reimbursable to patients with significant disease activity while adefovir could only be reimbursed for patients with lamivudine resistance and significant disease activity. After July 2008, lamivudine was not reimbursable to treat new patients. Instead, entecavir could be reimbursed for patients with alanine aminotransferase (ALT) higher than 5 times the upper limit of normal (ULN) and patients with decompensated liver cirrhosis. Use of these antiviral drugs outside the listed indications as well as other antiviral agents (peginterferon, telbivudine, tenofovir) was at the patients’ own expense. We performed a drug expenditure audit over 4 weeks between November and December 2008. Four hundred and forty-four chronic hepatitis B patients attended the outpatient clinic during the audit period. One hundred and sixty-three (37%) patients had received antiviral therapy, 121 (27%) were indicated for antiviral treatment but not treated while the remaining 160 (36%) were not indicated for treatment. As hepatitis B virus (HBV) DNA and liver biopsy were not routine tests, we arbitrarily defined patients who had evidence of liver cirrhosis and those who had elevated ALT were indicated for antiviral treatment. This would be an underestimate as a significant proportion of patients who had high normal ALT might already have advanced liver fibrosis, particularly the older patients with elevated HBV DNA [2Wong G.L.H. Wong V.W.S. Choi P.C.L. Chan A.W.H. Chim A.M.L. Yiu K.K.L. et al.Clinical factors associated with liver stiffness in hepatitis B e antigen-positive chronic hepatitis B.Clin Gastroenterol Hepatol. 2009; 7: 227-233Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar, 3Wong G.L.H. Wong V.W.S. Choi P.C.L. Chan A.W.H. Chim A.M.L. Yiu K.K.L. et al.Evaluation of alanine transaminase and hepatitis B virus DNA to predict liver cirrhosis in hepatitis B e antigen-negative chronic hepatitis B using transient elastography.Am J Gastroenterol. 2008; 103: 3071-3081Crossref PubMed Scopus (61) Google Scholar]. The exact reasons why some patients did not receive antiviral treatment were not explored in this audit. One obvious reason was that a significant proportion of untreated patients did not meet the criteria for reimbursement and could not afford the high cost of the antiviral medications. Overall, only 27 of 444 (6.1%) patients in our clinic were treated under the hospital reimbursement scheme. One hundred and thirty-six (83%) of the 163 treated patients were purchasing their antiviral medications without reimbursement. These numbers again reflect the inadequacy of the highly restricted reimbursement policy in force in Hong Kong. In our previously conducted cross-sectional studies including over 1500 chronic hepatitis B patients, approximately 3.5% of hepatitis B e antigen (HBeAg)-positive patients and 2% of HBeAg-negative patients had ALT levels higher than 5 times ULN [2Wong G.L.H. Wong V.W.S. Choi P.C.L. Chan A.W.H. Chim A.M.L. Yiu K.K.L. et al.Clinical factors associated with liver stiffness in hepatitis B e antigen-positive chronic hepatitis B.Clin Gastroenterol Hepatol. 2009; 7: 227-233Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar, 3Wong G.L.H. Wong V.W.S. Choi P.C.L. Chan A.W.H. Chim A.M.L. Yiu K.K.L. et al.Evaluation of alanine transaminase and hepatitis B virus DNA to predict liver cirrhosis in hepatitis B e antigen-negative chronic hepatitis B using transient elastography.Am J Gastroenterol. 2008; 103: 3071-3081Crossref PubMed Scopus (61) Google Scholar]. The prevalence of clinical liver cirrhosis was approximately 16% among HBeAg-negative patients in our clinic, and the prevalence of decompensated cirrhosis was expected to be lower [[4]Chan H.L.Y. Leung N.W.Y. Hussain M. Wong M.L. Lok A.S.F. Hepatitis B e antigen-negative chronic hepatitis B in Hong Kong.Hepatology. 2000; 31: 763-768Crossref PubMed Scopus (183) Google Scholar]. In other words, the number of patients eligible for reimbursement under the current policy would only be a minority of all those who should be indicated for antiviral treatment according to the Asian-Pacific recommendations [[5]Liaw Y.F. Leung N. Kao J.H. Piratvisuth T. Gane E. Han K.H. et al.Asian-Pacific consensus statement on the management of chronic hepatitis B: a 2008 update.Hepatol Int. 2008; 2: 263-283Crossref PubMed Scopus (814) Google Scholar]. The most commonly used antiviral medication was entecavir (Fig. 1). Seventy-two (44% of the treated) patients were on entecavir but only one of them was reimbursed. This was partly related to a very recent change in reimbursement policy and the restricted criteria for reimbursement. Adefovir was used in 32 (20% of the treated) patients and 7 of them were reimbursed. Thirteen of the 32 patients on adefovir were using combination treatment with lamivudine or entecavir for lamivudine resistance. Although adefovir was used primarily as a salvage therapy for lamivudine resistance, patients who had adefovir started on virological breakthrough with normal ALT did not meet the criteria for reimbursement due to the lack of disease activity. The financial restrictions inevitably delayed the commencement of adefovir for the best treatment outcome [[6]Lampertico P. Vigano M. Manenti E. Iavarone M. Lunghi G. Colombo M. Adefovir rapidly suppresses hepatitis B in HBeAg-negative patients developing genotypic resistance to lamivudine.Hepatology. 2005; 42: 1414-1419Crossref PubMed Scopus (251) Google Scholar]. In a recent report, 14 of the 26 patients with lamivudine resistance had ALT higher than 2 times ULN when adefovir was started in our clinic, and this was translated to a suboptimal viral suppression in the long term [[7]Chan H.L.Y. Wong V.W.S. Tse C.H. Chim A.M.L. Chan H.Y. Wong G.L.H. et al.Early virological suppression is associated with good maintained response to adefovir dipivoxil in lamivudine resistant chronic hepatitis B.Aliment Pharmacol Ther. 2007; 25: 891-898Crossref PubMed Scopus (36) Google Scholar]. I agree with Prof. Liaw that application of the roadmap approach by starting with a cheaper antiviral agent and switching to other agent(s) if HBV DNA is still detectable at 24 weeks of treatment should be explored [[1]Liaw Y.F. Antiviral therapy of chronic hepatitis B: opportunities and challenges in Asia.J Hepatol. 2009; 51: 403-410Abstract Full Text Full Text PDF PubMed Scopus (113) Google Scholar]. In a recent cost-effectiveness analysis in Hong Kong, the roadmap approach starting with telbivudine or lamivudine and switching to entecavir if HBV DNA suppression is detectable at week 24 may be a cost-effective alternative to monotherapy with entecavir to all patients [[8]Tsoi K.K.F. Lui Y.Y.N. Wong V.W.S. Chan H.L.Y. Cost-effectiveness analysis of anti-viral treatment strategies based on the roadmap model in chronic hepatitis B virus (HBV) infection.Hepatol Int. 2009; 3: 105Google Scholar]. At present, tenofovir is not registered for the indication of chronic hepatitis B in Hong Kong and can only be prescribed after application for off-label use. The cost of tenofovir is currently higher than that of entecavir, but it will be an attractive alternative if its cost can be lowered as in the case of Europe. To facilitate the use of the limited resources to treat the large number of chronic hepatitis B patients in Asia, proper local cost-effective analysis should be performed before a reimbursement policy is reinforced.