Hepatitis B Virus with Primary Resistance to Adefovir
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《新英格兰医药杂志》
To the Editor: Schildgen et al. (April 27 issue)1 describe the results of tenofovir treatment in three patients infected with adefovir-resistant variant hepatitis B virus (HBV) that had a valine at position 233 of the reverse-transcriptase domain instead of isoleucine (rtI233V). We recently published the results of two trials in which entecavir demonstrated superiority over lamivudine in patients with chronic hepatitis B that was positive for antibody against hepatitis B e antigen (HBeAg)2 and in patients with HBeAg-negative chronic hepatitis B.3
Four of the patients with HBeAg-positive chronic hepatitis B and four of those with HBeAg-negative chronic hepatitis B were infected with a strain that had the rtI233V mutation and received entecavir therapy. After 48 weeks, all six patients with paired liver-biopsy specimens that could be evaluated had histologic improvement, and two of the four HBeAg-positive patients had seroconversion.
Seven of the eight patients had undetectable viral loads (<300 copies of HBV DNA per milliliter) by week 36, and the mean decrease from baseline was 6.75 log (on a base-10 scale) copies per milliliter in the HBeAg-positive group and 5.11 log copies per milliliter in the HBeAg-negative group (Figure 1). We tested the in vitro susceptibility to entecavir of one HBV isolate with the rtI233V (and V191I) mutation from our viral archive and found a median effective concentration of 1.4 nM, as compared with 4 nM for wild-type virus.
Figure 1. Decrease in HBV DNA Levels during 48 Weeks of Entecavir Therapy in Eight Patients with an rtI233V Mutation in HBV Conferring Primary Resistance to Adefovir.
The limit of detection of the polymerase-chain-reaction assay was 300 copies per milliliter. Data on the HBV DNA burden at 24 weeks were not available for Patient 4.
Ting-Tsung Chang, M.D.
National Cheng Kung University Hospital
Tainan 704, Taiwan
ttchang@mail.ncku.edu.tw
Ching-Lung Lai, M.D.
Queen Mary Hospital
Hong Kong, China
Dr. Lai reports having received research fees, advisory fees, and lecture fees from Idenix Pharmaceuticals, and research and lecture fees from Lg Life Sciences.
References
Schildgen O, Sirma H, Funk A, et al. Variant of hepatitis B virus with primary resistance to adefovir. N Engl J Med 2006;354:1807-1812.
Chang TT, Gish RG, de Man R, et al. A comparison of entecavir and lamivudine for HBeAg-positive chronic hepatitis B. N Engl J Med 2006;354:1001-1010.
Lai CL, Shouval D, Lok AS, et al. Entecavir versus lamivudine for patients with HBeAg-negative chronic hepatitis B. N Engl J Med 2006;354:1011-1020.
The authors reply: Chang and Lai describe eight patients infected with an HBV variant carrying the novel rtI233V mutation we recently identified in three German patients. It causes primary resistance to adefovir, and it was also recently described in one Australian patient in whom adefovir therapy failed.1
Chang and Lai report that their patients were very efficiently treated with entecavir. We greatly appreciate their rapid comments for two reasons. First, their data, in agreement with ours, indicate that the rtI233V mutation occurs in approximately 2 percent of all patients with chronic hepatitis B (8 of 434 patients). Thus, our finding was not an isolated observation. It remains surprising that the mutation was not detected in earlier studies of adefovir.2,3
Second, the observations by Chang and Lai show entecavir to be a highly efficient therapy option for patients with the rtI233V mutation who have no response to adefovir, since tenofovir, which is what we used in our study, is still not licensed for HBV therapy. Since the receipt of lamivudine therapy for more than 12 weeks was an exclusion criterion in their studies, it is very likely that their patients were sensitive to lamivudine. Thus, it remains unknown how useful entecavir would be in patients with lamivudine-resistant rtI233V mutations. In our study, two patients with a response to tenofovir were resistant to lamivudine.
Oliver Schildgen, Ph.D.
Institute for Medical Microbiology, Immunology,
and Parasitology
D-53105 Bonn, Germany
Hüseyin Sirma, M.D.
Heinrich-Pette-Institute
D-20251 Hamburg, Germany
Wolfram Gerlich, Ph.D.
Institute for Medical Virology
D-35392 Giessen, Germany
wolfram.h.gerlich@viro.med.uni-giessen.de
References
Bartholomeusz A, Kuiper M, Angus P, et al. Molecular analysis of HBV polymerase mutations associated with dual adefovir and lamivudine resistance. J Hepatol 2006;44:Suppl 2:S179-S179.
Hadziyannis SJ, Tassopoulos NC, Heathcote EJ, et al. Long-term therapy with adefovir dipivoxil for HBeAg-negative chronic hepatitis B. N Engl J Med 2005;352:2673-2681.
Marcellin P, Chang TT, Lim SG, et al. Adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic hepatitis B. N Engl J Med 2003;348:808-816.
Four of the patients with HBeAg-positive chronic hepatitis B and four of those with HBeAg-negative chronic hepatitis B were infected with a strain that had the rtI233V mutation and received entecavir therapy. After 48 weeks, all six patients with paired liver-biopsy specimens that could be evaluated had histologic improvement, and two of the four HBeAg-positive patients had seroconversion.
Seven of the eight patients had undetectable viral loads (<300 copies of HBV DNA per milliliter) by week 36, and the mean decrease from baseline was 6.75 log (on a base-10 scale) copies per milliliter in the HBeAg-positive group and 5.11 log copies per milliliter in the HBeAg-negative group (Figure 1). We tested the in vitro susceptibility to entecavir of one HBV isolate with the rtI233V (and V191I) mutation from our viral archive and found a median effective concentration of 1.4 nM, as compared with 4 nM for wild-type virus.
Figure 1. Decrease in HBV DNA Levels during 48 Weeks of Entecavir Therapy in Eight Patients with an rtI233V Mutation in HBV Conferring Primary Resistance to Adefovir.
The limit of detection of the polymerase-chain-reaction assay was 300 copies per milliliter. Data on the HBV DNA burden at 24 weeks were not available for Patient 4.
Ting-Tsung Chang, M.D.
National Cheng Kung University Hospital
Tainan 704, Taiwan
ttchang@mail.ncku.edu.tw
Ching-Lung Lai, M.D.
Queen Mary Hospital
Hong Kong, China
Dr. Lai reports having received research fees, advisory fees, and lecture fees from Idenix Pharmaceuticals, and research and lecture fees from Lg Life Sciences.
References
Schildgen O, Sirma H, Funk A, et al. Variant of hepatitis B virus with primary resistance to adefovir. N Engl J Med 2006;354:1807-1812.
Chang TT, Gish RG, de Man R, et al. A comparison of entecavir and lamivudine for HBeAg-positive chronic hepatitis B. N Engl J Med 2006;354:1001-1010.
Lai CL, Shouval D, Lok AS, et al. Entecavir versus lamivudine for patients with HBeAg-negative chronic hepatitis B. N Engl J Med 2006;354:1011-1020.
The authors reply: Chang and Lai describe eight patients infected with an HBV variant carrying the novel rtI233V mutation we recently identified in three German patients. It causes primary resistance to adefovir, and it was also recently described in one Australian patient in whom adefovir therapy failed.1
Chang and Lai report that their patients were very efficiently treated with entecavir. We greatly appreciate their rapid comments for two reasons. First, their data, in agreement with ours, indicate that the rtI233V mutation occurs in approximately 2 percent of all patients with chronic hepatitis B (8 of 434 patients). Thus, our finding was not an isolated observation. It remains surprising that the mutation was not detected in earlier studies of adefovir.2,3
Second, the observations by Chang and Lai show entecavir to be a highly efficient therapy option for patients with the rtI233V mutation who have no response to adefovir, since tenofovir, which is what we used in our study, is still not licensed for HBV therapy. Since the receipt of lamivudine therapy for more than 12 weeks was an exclusion criterion in their studies, it is very likely that their patients were sensitive to lamivudine. Thus, it remains unknown how useful entecavir would be in patients with lamivudine-resistant rtI233V mutations. In our study, two patients with a response to tenofovir were resistant to lamivudine.
Oliver Schildgen, Ph.D.
Institute for Medical Microbiology, Immunology,
and Parasitology
D-53105 Bonn, Germany
Hüseyin Sirma, M.D.
Heinrich-Pette-Institute
D-20251 Hamburg, Germany
Wolfram Gerlich, Ph.D.
Institute for Medical Virology
D-35392 Giessen, Germany
wolfram.h.gerlich@viro.med.uni-giessen.de
References
Bartholomeusz A, Kuiper M, Angus P, et al. Molecular analysis of HBV polymerase mutations associated with dual adefovir and lamivudine resistance. J Hepatol 2006;44:Suppl 2:S179-S179.
Hadziyannis SJ, Tassopoulos NC, Heathcote EJ, et al. Long-term therapy with adefovir dipivoxil for HBeAg-negative chronic hepatitis B. N Engl J Med 2005;352:2673-2681.
Marcellin P, Chang TT, Lim SG, et al. Adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic hepatitis B. N Engl J Med 2003;348:808-816.