- Email: [email protected]
Drug Therapy for Chronic Hepatitis B in Children
Drug Therapy
DRUG THERAPY FOR CHRONIC HEPATITIS B IN CHILDREN Sheena Sharma* and Anupam Sibal** From the Research Fellow* and Senior Consultant, Pediatric Gastroenterologist and Hepatologist**, Apollo Centre for Advance Pediatrics, Indraprastha Apollo Hospitals, Sarita Vihar, New Delhi - 110044, India. Correspondence to: Dr. Anupam Sibal, Director Medical Services and Senior Consultant, Pediatric Gastroenterologist and Hepatologist, Indraprastha Apollo Hospitals, Sarita Vihar, New Delhi - 110 044, India. E-mail: [email protected] Key words: Lamivudine, Interferon, Chronic viral hepatitis
HEPATITIS B VIRUS (HBV) affects more than 350 million people worldwide, which amounts to approximately 5% of the world’s population and accounts for around 1 million deaths per year. There is a big geographic difference in the prevalence of this disease, with only 0.1% - 1% hepatitis B surface antigen (HBsAg) positive patients in Europe and North America compared to 20% infected people in SouthEast Asia and certain parts of Africa.
aminotransferases do not necessarily exclude hepatic inflammation and a liver biopsy is imperative to determine the histologic activity. In spite of being an invasive procedure, a liver biopsy is a low risk and benign method to obtain an objective status of the liver for the clinician to decide on further management4. Side effects of IFN are fever, flu-like symptoms, arthralgia, anorexia, bone marrow suppression, growth impairment and irritability. IFN is contraindicated in case of decompensated liver disease, cytopenia, autoimmune diseases and severe renal or cardiac diseases. The recommended dose of IFN for children is 5 or 6 MU/m2 subcutaneous thrice weekly for 6 months, with monitoring of biochemistry after 2 weeks initially and then monthly till 6 months beyond end of treatment. Results of IFN in trials vary from 20-60% and it is debatable whether IFN treatment, compared to results of untreated patients, might just accelerate the natural clearance of HBV infection [3,5]. Bortolotti et al. have examined the long-term effects of IFN treatment in children with HBV and have seen HbeAg clearance rates of 60%, versus 65% of control group and HBsAg loss in 25% of the cases after a 5-year follow-up [6]. Suboptimal benefits of IFN coupled with side effects and high cost have prompted a search for new drugs. Trials have been performed with pegylated IFN (peg-IFN) demonstrating promising results in treatment of hepatitis B, but no pediatric data is available till now [7,8].
Spontaneous viral clearance, prolonged latency and progressive damage to the liver are the variable courses of the disease. The younger the patient is at time of infection with HBV, the higher the risk to develop chronic infection and cirrhosis [1]. Compared to adults, with a 10% risk to acquire HBV after exposure, the risk value increases remarkably to 25-30% in children below 5 years and can be 90% in untreated newborns of hepatitis B e antigen (HBeAg) positive mothers. Accordingly, the risk to develop hepatocellular carcinoma (HCC) increases substantially with confirmed HBV infection at early age than compared to acquisition at a later stage [2]. HCC is the second most frequent cause of death from cancer worldwide, with only lung cancer being more common. Also, hepatitis B surface antigen (HBsAg) positive children show slow spontaneous clearance of HBsAg (0.6% per year) and low rates of surface antibody development. These are, therefore, compelling reasons to treat children with hepatitis B.
Lamivudine
Interferon
Lamivudine (LAM) is a nucleoside analogue that prevents HBV DNA synthesis by competitively inhibiting the viral reverse-transcriptase and DNA-polymerase stages of virus replication and by terminating proviral DNA chain extension. Whereas IFN has undesirable side effects and its administration requires repeated injections for six months, LAM has shown a better safety profile with fewer side effects and can be given orally [9].
At present the standard therapy of chronic HBV infection among children is interferon-alpha (IFN). As per the consensus advice of 1999, the indications for treatment of children with IFN are HBsAg positivity, HBeAg positivity more than 6 months, active viral replication (HBV DNA positivity) and elevated serum alanine aminotransferase (ALT) more than twice the normal value in children older than two years [3]. These criteria, however, exclude a majority of Asian children with normal serum ALT levels, who have perinatally acquired disease. Normal values of serum
Clinical trials have been performed among children with a recommended dose of 3 mg/kg with a maximum dose of 100
54
Apollo Medicine, Vol.1, September 2004
Drug Therapy
mg, which have shown a satisfactory tolerability profile [10,11]. A clinical trial performed by Jonas et al. comparing LAM to placebo among children, has shown a significant increase of virologic response (23% of treated children versus 13% untreated) after 52 weeks [10]. Another study by Kocak, et al. has shown HBV DNA clearance of 64.8% but HBeAg clearance of 7.4% with less than 6% with seroconversion to anti-HBeAg [12]. Children with low viral replication (low HBV DNA levels), severe histologic activity and high baseline ALT seem to show better results in terms of seroconversion after treatment with LAM. There are, however, concerns about reappearance of HBV DNA replication on stopping LAM. Monotherapy with LAM might only be effective for short treatment periods, since a major problem is the development of resistance to LAM treatment with the emergence of mutant HBV species. Certain HBV species show mutations in the tyrosine-methionine-aspartateaspartate (YMDD) locus of the HBV-RNA-dependent DNA polymerase and therefore develop resistance to therapy with LAM after 6-9 months. Studies suggest that the incidence of YMDD mutations increases with the duration of treatment, from 19% after 52 weeks to 38% and 67% after 2 and 4 years [13,14]. The initial positive response to LAM treatment may then be followed by virological rebound and exacerbation of hepatitis [14]. There is no consensus on how to manage patients who develop a mutation. This phenomenon poses a great difficulty in managing the ideal treatment time and in balancing positive response to adverse effects. This uncertainty of treatment is of paramount importance in pediatrics, as children may require LAM therapy for an indefinite length of time with an inevitable risk of mutation and relapse with a wild type virus. Concerns have, therefore, been expressed about the use of LAM outside research trials and LAM has not been licensed for use in hepatitis B in children universally.
safety profile similar to LAM, it has shown to be more effective in viral suppression compared to LAM, in wild type and in LAM resistant infections with HBV. Both Entecavir and Adefovir may play an important role in the further development of antiviral treatment of HBV. Combination Therapy There has been interest in using a combination of IFN or peg-IFN with LAM, hoping that the combination might have additional antiviral effects [7,21]. What remains to be identified is the most appropriate regimen: (a) LAM and IFN from day one, followed by LAM alone or (b) LAM initially followed by IFN and LAM and then LAM alone or (c) IFN initially followed by LAM and IFN and then LAM for a longer period. There is no pediatric data available on the combination of LAM and peg-IFN. As peg-IFN is largely replacing IFN, studies using peg-IFN with LAM are eagerly awaited. The only pediatric studies on combination therapy have used IFN and LAM. While Selimoglu et al. compared a combination treatment to IFN monotherapy [22], Dikici, et al. compared different regimens of IFN and LAM combination [21]. No significant benefit in terms of results could be seen in either of the trials. A LAM and adefovir combination for long term antiviral therapy has been studied in adults [18]. Long-term studies will be needed in providing information on the appropriate treatment time and in proving durable viral remission. Recently, apart from these nucleoside analogues, trials with emtricitabine and clevudine have been undertaken. These studies are still in a preliminary stage and no data for newer treatments in children is available yet. Hepatitis B vaccination remains to be of great importance as further search for antiviral drugs continues. REFERENCES 1. Chongsrisawat V, Poovorawan Y. Management of chronic hepatitis B and C virus infections. Indian J Pediatr 2002 Feb; 69(2): 149-154.
Famciclovir Famciclovir is known to induce seroconversion, but seems to show weaker suppression than LAM [15] and therefore might be useful only in combination with LAM or other antiviral agents [16].
2. Hsieh CC, Tzonou A, Zavitsanos X, Kaklamani E, Lan SJ, Trichopoulos D. Age at first establishment of chronic hepatitis B virus infection and hepatocellular carcinoma risk. A birth order study. American Journal of Epidemiology 1992; 136(9): 1115-1121.
Adefovir dipivoxil
3. Jara P, Bortolotti F. Interferon-alpha treatment of chronic hepatitis B in childhood: a consensus advice based on experience in European children. J Pediatr Gastroenterol Nutr 1999 Aug; 29(2): 163-170.
Adefovir dipivoxil, an acyclic nucleotide monophosphate analogue, might play a significant role in the treatment of chronic HBV infection. It seems to have potent activity against wild type and LAM resistant HBV [17]. Promising results on long-term treatment with Adefovir among adults have suggested no development of any resistance after up to 60 weeks of therapy [18]. No pediatric data is available.
4. EASL International Consensus Conference on Hepatitis B (13-14 Sept. 2002). J Hepatol 38 (2003): 533-540. 5. Zucker SD. All kidding aside with the use of lamivudine in children with chronic hepatitis B. Gastroenterology 2002 Nov; 123(5): 1741-1743.
Entecavir
6. Bortolotti F, Jara P, et al. Long term effect of alpha interferon in children with chronic hepatitis B. Gut 2000 (May); 46: 715718.
Entecavir is a guanosine nucleoside analogue and has been tested in clinical trials among adults [19,20]. With a 55
Apollo Medicine, Vol.1, September 2004
Drug Therapy 7. Chan HL, Wong ML, Leung NW, Hui AY, Flung LC, Chan FK, Sung JJ, The Chinese University of Hong Kong, Shatin, Hong Kong. Pegylated Interferon Has Additional Antiviral Effect on Lamivudine in the Treatment of Chronic Hepatitis B - abstract 1846. hbv research archives.
of therapy. J Med Virol 2002 Jul; 67(3): 334-338. 16. Shapira R, Daudi N, Klein A, Shouval D, Mor E, Tur-Kaspa R, Dinari G, Ben-Ari Z. Seroconversion after the addition of famciclovir therapy in a child with hepatitis B virus infection after liver transplantation who developed lamivudine resistance. Transplantation 2002 Mar 15; 73(5): 820-822.
8. Cooksley WG. Treatment with interferons (including pegylated interferons) in patients with hepatitis B. Semin Liver Dis 2004;24 Suppl 1: 45-53. 9. Sokal E. Drug treatment of pediatric chronic hepatitis B. Pediatr Drugs 2002; 4(6): 361-369.
17. Jeffers L, Heathcote E, Wright T, et al. A phase II doseranging, placebo controlled trial of adefovir dipivoxil for the treatment of chronic hepatitis B virus infection. Antiviral Res 1998; 37:A197.
10. Jonas MM, Kelly DA, Mizerski J, Badia IB, Areias JA, Schwarz KB, Little NR, Greensmith MJ, Gardner SD, Bell MS, Sokal EM; International Pediatric Lamivudine Investigator Group. Clinical trial of lamivudine in children with chronic hepatitis B. N Engl J Med 2002 May 30; 346(22): 1706-1713.
18. Yang H, Westland CE, Delaney WE 4th, Heathcote EJ, Ho V, Fry J, Brosgart C, Gibbs CS, Miller MD, Xiong S. Resistance surveillance in chronic hepatitis B patients treated with adefovir dipivoxil for up to 60 weeks. Hepatology 2002 Aug; 36(2): 464-473.
11. Keam SJ, Scott LJ. Lamivudine: in children and adolescents with chronic hepatitis B virus infection. Paediatr Drugs 2002; 4(10): 687-694; discussion 695-696.
19. Lai CL, et al. Entecavir vs lamivudine in chronic hepatitis B. J.Hepatol.2001; 34(Suppl): 24. 20. Hadziyannis S, et al. Entecavir in patients with chronic hepatitis B failing lamivudine. AASLD. Hepatology 2001; 34:340A.
12. Kocak N, Ozen H, Saltuk IN, Gurakan F, Yuce A. Lamivudine for Children With Chronic Hepatitis B. Am J Gastroenterol 2000; 95: 2989-2990.
21. Dikici B, Bosnak M, Bosnak V, Dagli A, Davutoglu M, Yagci RV, Haspolat K. Comparison of treatments of chronic hepatitis B in children with lamivudine and alpha-interferon combination and alpha-interferon alone. Pediatr Int 2002 Oct; 44(5): 517-521.
13. Liaw YF. Management of YMDD mutations during lamivudine therapy in patients with chronic hepatitis B. J Gastroenterol Hepatol 2002 Dec; 17 Suppl 3: S333-S337. 14. Leung N. Clinical experience with Lamivudine. Semin Liver Dis. 2002; 22 Suppl 1: 15-22.
22. Selimoglu MA, Aydogdu S, Unal F, Zeytinoglu A, Yuce G, Yagci RV. Alpha interferon and lamivudine combination therapy for chronic hepatitis B in children. Pediatr Int 2002 Aug; 44(4): 404-408.
15. Lai CL, Yuen MF, Hui CK, Garrido-Lestache S, Cheng CT, Lai YP. Comparison of the efficacy of lamivudine and famciclovir in Asian patients with chronic hepatitis B: results of 24 weeks
Apollo Medicine, Vol.1, September 2004
56
DRUG THERAPY FOR CHRONIC HEPATITIS B IN CHILDREN Sheena Sharma* and Anupam Sibal** From the Research Fellow* and Senior Consultant, Pediatric Gastroenterologist and Hepatologist**, Apollo Centre for Advance Pediatrics, Indraprastha Apollo Hospitals, Sarita Vihar, New Delhi - 110044, India. Correspondence to: Dr. Anupam Sibal, Director Medical Services and Senior Consultant, Pediatric Gastroenterologist and Hepatologist, Indraprastha Apollo Hospitals, Sarita Vihar, New Delhi - 110 044, India. E-mail: [email protected] Key words: Lamivudine, Interferon, Chronic viral hepatitis
HEPATITIS B VIRUS (HBV) affects more than 350 million people worldwide, which amounts to approximately 5% of the world’s population and accounts for around 1 million deaths per year. There is a big geographic difference in the prevalence of this disease, with only 0.1% - 1% hepatitis B surface antigen (HBsAg) positive patients in Europe and North America compared to 20% infected people in SouthEast Asia and certain parts of Africa.
aminotransferases do not necessarily exclude hepatic inflammation and a liver biopsy is imperative to determine the histologic activity. In spite of being an invasive procedure, a liver biopsy is a low risk and benign method to obtain an objective status of the liver for the clinician to decide on further management4. Side effects of IFN are fever, flu-like symptoms, arthralgia, anorexia, bone marrow suppression, growth impairment and irritability. IFN is contraindicated in case of decompensated liver disease, cytopenia, autoimmune diseases and severe renal or cardiac diseases. The recommended dose of IFN for children is 5 or 6 MU/m2 subcutaneous thrice weekly for 6 months, with monitoring of biochemistry after 2 weeks initially and then monthly till 6 months beyond end of treatment. Results of IFN in trials vary from 20-60% and it is debatable whether IFN treatment, compared to results of untreated patients, might just accelerate the natural clearance of HBV infection [3,5]. Bortolotti et al. have examined the long-term effects of IFN treatment in children with HBV and have seen HbeAg clearance rates of 60%, versus 65% of control group and HBsAg loss in 25% of the cases after a 5-year follow-up [6]. Suboptimal benefits of IFN coupled with side effects and high cost have prompted a search for new drugs. Trials have been performed with pegylated IFN (peg-IFN) demonstrating promising results in treatment of hepatitis B, but no pediatric data is available till now [7,8].
Spontaneous viral clearance, prolonged latency and progressive damage to the liver are the variable courses of the disease. The younger the patient is at time of infection with HBV, the higher the risk to develop chronic infection and cirrhosis [1]. Compared to adults, with a 10% risk to acquire HBV after exposure, the risk value increases remarkably to 25-30% in children below 5 years and can be 90% in untreated newborns of hepatitis B e antigen (HBeAg) positive mothers. Accordingly, the risk to develop hepatocellular carcinoma (HCC) increases substantially with confirmed HBV infection at early age than compared to acquisition at a later stage [2]. HCC is the second most frequent cause of death from cancer worldwide, with only lung cancer being more common. Also, hepatitis B surface antigen (HBsAg) positive children show slow spontaneous clearance of HBsAg (0.6% per year) and low rates of surface antibody development. These are, therefore, compelling reasons to treat children with hepatitis B.
Lamivudine
Interferon
Lamivudine (LAM) is a nucleoside analogue that prevents HBV DNA synthesis by competitively inhibiting the viral reverse-transcriptase and DNA-polymerase stages of virus replication and by terminating proviral DNA chain extension. Whereas IFN has undesirable side effects and its administration requires repeated injections for six months, LAM has shown a better safety profile with fewer side effects and can be given orally [9].
At present the standard therapy of chronic HBV infection among children is interferon-alpha (IFN). As per the consensus advice of 1999, the indications for treatment of children with IFN are HBsAg positivity, HBeAg positivity more than 6 months, active viral replication (HBV DNA positivity) and elevated serum alanine aminotransferase (ALT) more than twice the normal value in children older than two years [3]. These criteria, however, exclude a majority of Asian children with normal serum ALT levels, who have perinatally acquired disease. Normal values of serum
Clinical trials have been performed among children with a recommended dose of 3 mg/kg with a maximum dose of 100
54
Apollo Medicine, Vol.1, September 2004
Drug Therapy
mg, which have shown a satisfactory tolerability profile [10,11]. A clinical trial performed by Jonas et al. comparing LAM to placebo among children, has shown a significant increase of virologic response (23% of treated children versus 13% untreated) after 52 weeks [10]. Another study by Kocak, et al. has shown HBV DNA clearance of 64.8% but HBeAg clearance of 7.4% with less than 6% with seroconversion to anti-HBeAg [12]. Children with low viral replication (low HBV DNA levels), severe histologic activity and high baseline ALT seem to show better results in terms of seroconversion after treatment with LAM. There are, however, concerns about reappearance of HBV DNA replication on stopping LAM. Monotherapy with LAM might only be effective for short treatment periods, since a major problem is the development of resistance to LAM treatment with the emergence of mutant HBV species. Certain HBV species show mutations in the tyrosine-methionine-aspartateaspartate (YMDD) locus of the HBV-RNA-dependent DNA polymerase and therefore develop resistance to therapy with LAM after 6-9 months. Studies suggest that the incidence of YMDD mutations increases with the duration of treatment, from 19% after 52 weeks to 38% and 67% after 2 and 4 years [13,14]. The initial positive response to LAM treatment may then be followed by virological rebound and exacerbation of hepatitis [14]. There is no consensus on how to manage patients who develop a mutation. This phenomenon poses a great difficulty in managing the ideal treatment time and in balancing positive response to adverse effects. This uncertainty of treatment is of paramount importance in pediatrics, as children may require LAM therapy for an indefinite length of time with an inevitable risk of mutation and relapse with a wild type virus. Concerns have, therefore, been expressed about the use of LAM outside research trials and LAM has not been licensed for use in hepatitis B in children universally.
safety profile similar to LAM, it has shown to be more effective in viral suppression compared to LAM, in wild type and in LAM resistant infections with HBV. Both Entecavir and Adefovir may play an important role in the further development of antiviral treatment of HBV. Combination Therapy There has been interest in using a combination of IFN or peg-IFN with LAM, hoping that the combination might have additional antiviral effects [7,21]. What remains to be identified is the most appropriate regimen: (a) LAM and IFN from day one, followed by LAM alone or (b) LAM initially followed by IFN and LAM and then LAM alone or (c) IFN initially followed by LAM and IFN and then LAM for a longer period. There is no pediatric data available on the combination of LAM and peg-IFN. As peg-IFN is largely replacing IFN, studies using peg-IFN with LAM are eagerly awaited. The only pediatric studies on combination therapy have used IFN and LAM. While Selimoglu et al. compared a combination treatment to IFN monotherapy [22], Dikici, et al. compared different regimens of IFN and LAM combination [21]. No significant benefit in terms of results could be seen in either of the trials. A LAM and adefovir combination for long term antiviral therapy has been studied in adults [18]. Long-term studies will be needed in providing information on the appropriate treatment time and in proving durable viral remission. Recently, apart from these nucleoside analogues, trials with emtricitabine and clevudine have been undertaken. These studies are still in a preliminary stage and no data for newer treatments in children is available yet. Hepatitis B vaccination remains to be of great importance as further search for antiviral drugs continues. REFERENCES 1. Chongsrisawat V, Poovorawan Y. Management of chronic hepatitis B and C virus infections. Indian J Pediatr 2002 Feb; 69(2): 149-154.
Famciclovir Famciclovir is known to induce seroconversion, but seems to show weaker suppression than LAM [15] and therefore might be useful only in combination with LAM or other antiviral agents [16].
2. Hsieh CC, Tzonou A, Zavitsanos X, Kaklamani E, Lan SJ, Trichopoulos D. Age at first establishment of chronic hepatitis B virus infection and hepatocellular carcinoma risk. A birth order study. American Journal of Epidemiology 1992; 136(9): 1115-1121.
Adefovir dipivoxil
3. Jara P, Bortolotti F. Interferon-alpha treatment of chronic hepatitis B in childhood: a consensus advice based on experience in European children. J Pediatr Gastroenterol Nutr 1999 Aug; 29(2): 163-170.
Adefovir dipivoxil, an acyclic nucleotide monophosphate analogue, might play a significant role in the treatment of chronic HBV infection. It seems to have potent activity against wild type and LAM resistant HBV [17]. Promising results on long-term treatment with Adefovir among adults have suggested no development of any resistance after up to 60 weeks of therapy [18]. No pediatric data is available.
4. EASL International Consensus Conference on Hepatitis B (13-14 Sept. 2002). J Hepatol 38 (2003): 533-540. 5. Zucker SD. All kidding aside with the use of lamivudine in children with chronic hepatitis B. Gastroenterology 2002 Nov; 123(5): 1741-1743.
Entecavir
6. Bortolotti F, Jara P, et al. Long term effect of alpha interferon in children with chronic hepatitis B. Gut 2000 (May); 46: 715718.
Entecavir is a guanosine nucleoside analogue and has been tested in clinical trials among adults [19,20]. With a 55
Apollo Medicine, Vol.1, September 2004
Drug Therapy 7. Chan HL, Wong ML, Leung NW, Hui AY, Flung LC, Chan FK, Sung JJ, The Chinese University of Hong Kong, Shatin, Hong Kong. Pegylated Interferon Has Additional Antiviral Effect on Lamivudine in the Treatment of Chronic Hepatitis B - abstract 1846. hbv research archives.
of therapy. J Med Virol 2002 Jul; 67(3): 334-338. 16. Shapira R, Daudi N, Klein A, Shouval D, Mor E, Tur-Kaspa R, Dinari G, Ben-Ari Z. Seroconversion after the addition of famciclovir therapy in a child with hepatitis B virus infection after liver transplantation who developed lamivudine resistance. Transplantation 2002 Mar 15; 73(5): 820-822.
8. Cooksley WG. Treatment with interferons (including pegylated interferons) in patients with hepatitis B. Semin Liver Dis 2004;24 Suppl 1: 45-53. 9. Sokal E. Drug treatment of pediatric chronic hepatitis B. Pediatr Drugs 2002; 4(6): 361-369.
17. Jeffers L, Heathcote E, Wright T, et al. A phase II doseranging, placebo controlled trial of adefovir dipivoxil for the treatment of chronic hepatitis B virus infection. Antiviral Res 1998; 37:A197.
10. Jonas MM, Kelly DA, Mizerski J, Badia IB, Areias JA, Schwarz KB, Little NR, Greensmith MJ, Gardner SD, Bell MS, Sokal EM; International Pediatric Lamivudine Investigator Group. Clinical trial of lamivudine in children with chronic hepatitis B. N Engl J Med 2002 May 30; 346(22): 1706-1713.
18. Yang H, Westland CE, Delaney WE 4th, Heathcote EJ, Ho V, Fry J, Brosgart C, Gibbs CS, Miller MD, Xiong S. Resistance surveillance in chronic hepatitis B patients treated with adefovir dipivoxil for up to 60 weeks. Hepatology 2002 Aug; 36(2): 464-473.
11. Keam SJ, Scott LJ. Lamivudine: in children and adolescents with chronic hepatitis B virus infection. Paediatr Drugs 2002; 4(10): 687-694; discussion 695-696.
19. Lai CL, et al. Entecavir vs lamivudine in chronic hepatitis B. J.Hepatol.2001; 34(Suppl): 24. 20. Hadziyannis S, et al. Entecavir in patients with chronic hepatitis B failing lamivudine. AASLD. Hepatology 2001; 34:340A.
12. Kocak N, Ozen H, Saltuk IN, Gurakan F, Yuce A. Lamivudine for Children With Chronic Hepatitis B. Am J Gastroenterol 2000; 95: 2989-2990.
21. Dikici B, Bosnak M, Bosnak V, Dagli A, Davutoglu M, Yagci RV, Haspolat K. Comparison of treatments of chronic hepatitis B in children with lamivudine and alpha-interferon combination and alpha-interferon alone. Pediatr Int 2002 Oct; 44(5): 517-521.
13. Liaw YF. Management of YMDD mutations during lamivudine therapy in patients with chronic hepatitis B. J Gastroenterol Hepatol 2002 Dec; 17 Suppl 3: S333-S337. 14. Leung N. Clinical experience with Lamivudine. Semin Liver Dis. 2002; 22 Suppl 1: 15-22.
22. Selimoglu MA, Aydogdu S, Unal F, Zeytinoglu A, Yuce G, Yagci RV. Alpha interferon and lamivudine combination therapy for chronic hepatitis B in children. Pediatr Int 2002 Aug; 44(4): 404-408.
15. Lai CL, Yuen MF, Hui CK, Garrido-Lestache S, Cheng CT, Lai YP. Comparison of the efficacy of lamivudine and famciclovir in Asian patients with chronic hepatitis B: results of 24 weeks
Apollo Medicine, Vol.1, September 2004
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