Management of entecavir-resistant chronic hepatitis B with adefovir-based combination therapies

Hyoung Su Kim, Hyung Joon Yim, Myoung Kuk Jang, Ji Won Park, Sang Jun Suh, Yeon Seok Seo, Ji Hoon Kim, Bo Hyun Kim, Sang Jong Park, Sae Hwan Lee, Sang Gyune Kim, Young Seok Kim, Jung Il Lee, Jin Woo Lee, In Hee Kim, Tae Yeob Kim, Jin Wook Kim, Sook Hyang Jeong, Young Kul Jung, Hana Park & 1 others Seong Gyu Hwang

Research output: Contribution to journalArticle

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Abstract

AIM: To evaluate the long-term efficacy adefovir (ADV)-based combination therapies in entecavir (ETV)-resistant chronic hepatitis B (CHB) patients. METHODS: Fifty CHB patients with genotypic resistance to ETV at 13 medical centers in South Korea were included for the analysis. All the patients received rescue therapy with the combination of ADV plus ETV (ADV/ETV, n = 23) or ADV plus lamivudine (LMV) (ADV/LMV, n = 27) for more than 12 mo. Patients were monitored at least every 3-4 mo during ADV-based combination therapy by clinical examination as well as biochemical and virological assessments. Hepatitis B virus (HBV) DNA levels were measured by realtime PCR and logarithmically transformed for analysis. Cumulative rates of virologic response (VR; HBV DNA < 20 IU/mL) were calculated using the Kaplan-Meier method, and the difference was determined by a logrank test. Multivariate logistic regression and Cox proportional hazards models were used to identify independent risk factors significantly associated with short-term and long-term VR, respectively. RESULTS: Baseline median HBV DNA levels were 5.53 (2.81-7.63) log10 IU/mL. The most commonly observed ETV genotypic mutation sites were rt184 and rt202. Patients were treated for a median of 27 (12-45) mo. Overall, cumulative VR rates at 6, 12, 24, and 36 mo were 26%, 36%, 45%, and 68%, respectively. Patients treated with the ADV/ETV combination showed higher cumulative VR rates (35%, 43%, 65%, and 76%, respectively) than those with the ADV/LAM combination (18%, 30%, 30%, and 62%, respectively; P = 0.048). In the multivariate analysis, low baseline HBV DNA levels (< 5.2 log10 IU/mL) and initial virologic response at 3 mo (IVR-3; HBV DNA < 3.3 log10 IU/mL after 3 mo) were independent predictive factors for VR. Patients with favorable predictors achieved cumulative VR rates up to 90% at 36 mo. During the same period, the cumulative incidence of virologic breakthrough was as low as 6% in patients with the both favorable predictors. CONCLUSION: If tenofovir is not available, ADV/ETV combination could be considered in ETV-resistant patients with low HBV DNA titers, and may be continued if IVR-3 is achieved.

Original languageEnglish
Pages (from-to)10874-10882
Number of pages9
JournalWorld Journal of Gastroenterology
Volume21
Issue number38
DOIs
Publication statusPublished - 2015 Oct 14

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Chronic Hepatitis B
Hepatitis B virus
DNA
Lamivudine
Therapeutics
Tenofovir
entecavir
adefovir
Republic of Korea
Viral Load
Proportional Hazards Models
Multivariate Analysis
Logistic Models
Polymerase Chain Reaction
Mutation
Incidence

Keywords

  • Adefovir
  • Chronic hepatitis B
  • Entecavir
  • Lamivudine
  • Resistance

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Management of entecavir-resistant chronic hepatitis B with adefovir-based combination therapies. / Kim, Hyoung Su; Yim, Hyung Joon; Jang, Myoung Kuk; Park, Ji Won; Suh, Sang Jun; Seo, Yeon Seok; Kim, Ji Hoon; Kim, Bo Hyun; Park, Sang Jong; Lee, Sae Hwan; Kim, Sang Gyune; Kim, Young Seok; Lee, Jung Il; Lee, Jin Woo; Kim, In Hee; Kim, Tae Yeob; Kim, Jin Wook; Jeong, Sook Hyang; Jung, Young Kul; Park, Hana; Hwang, Seong Gyu.

In: World Journal of Gastroenterology, Vol. 21, No. 38, 14.10.2015, p. 10874-10882.

Research output: Contribution to journalArticle

Kim, HS, Yim, HJ, Jang, MK, Park, JW, Suh, SJ, Seo, YS, Kim, JH, Kim, BH, Park, SJ, Lee, SH, Kim, SG, Kim, YS, Lee, JI, Lee, JW, Kim, IH, Kim, TY, Kim, JW, Jeong, SH, Jung, YK, Park, H & Hwang, SG 2015, 'Management of entecavir-resistant chronic hepatitis B with adefovir-based combination therapies', World Journal of Gastroenterology, vol. 21, no. 38, pp. 10874-10882. https://doi.org/10.3748/wjg.v21.i38.10874
Kim, Hyoung Su ; Yim, Hyung Joon ; Jang, Myoung Kuk ; Park, Ji Won ; Suh, Sang Jun ; Seo, Yeon Seok ; Kim, Ji Hoon ; Kim, Bo Hyun ; Park, Sang Jong ; Lee, Sae Hwan ; Kim, Sang Gyune ; Kim, Young Seok ; Lee, Jung Il ; Lee, Jin Woo ; Kim, In Hee ; Kim, Tae Yeob ; Kim, Jin Wook ; Jeong, Sook Hyang ; Jung, Young Kul ; Park, Hana ; Hwang, Seong Gyu. / Management of entecavir-resistant chronic hepatitis B with adefovir-based combination therapies. In: World Journal of Gastroenterology. 2015 ; Vol. 21, No. 38. pp. 10874-10882.
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abstract = "AIM: To evaluate the long-term efficacy adefovir (ADV)-based combination therapies in entecavir (ETV)-resistant chronic hepatitis B (CHB) patients. METHODS: Fifty CHB patients with genotypic resistance to ETV at 13 medical centers in South Korea were included for the analysis. All the patients received rescue therapy with the combination of ADV plus ETV (ADV/ETV, n = 23) or ADV plus lamivudine (LMV) (ADV/LMV, n = 27) for more than 12 mo. Patients were monitored at least every 3-4 mo during ADV-based combination therapy by clinical examination as well as biochemical and virological assessments. Hepatitis B virus (HBV) DNA levels were measured by realtime PCR and logarithmically transformed for analysis. Cumulative rates of virologic response (VR; HBV DNA < 20 IU/mL) were calculated using the Kaplan-Meier method, and the difference was determined by a logrank test. Multivariate logistic regression and Cox proportional hazards models were used to identify independent risk factors significantly associated with short-term and long-term VR, respectively. RESULTS: Baseline median HBV DNA levels were 5.53 (2.81-7.63) log10 IU/mL. The most commonly observed ETV genotypic mutation sites were rt184 and rt202. Patients were treated for a median of 27 (12-45) mo. Overall, cumulative VR rates at 6, 12, 24, and 36 mo were 26{\%}, 36{\%}, 45{\%}, and 68{\%}, respectively. Patients treated with the ADV/ETV combination showed higher cumulative VR rates (35{\%}, 43{\%}, 65{\%}, and 76{\%}, respectively) than those with the ADV/LAM combination (18{\%}, 30{\%}, 30{\%}, and 62{\%}, respectively; P = 0.048). In the multivariate analysis, low baseline HBV DNA levels (< 5.2 log10 IU/mL) and initial virologic response at 3 mo (IVR-3; HBV DNA < 3.3 log10 IU/mL after 3 mo) were independent predictive factors for VR. Patients with favorable predictors achieved cumulative VR rates up to 90{\%} at 36 mo. During the same period, the cumulative incidence of virologic breakthrough was as low as 6{\%} in patients with the both favorable predictors. CONCLUSION: If tenofovir is not available, ADV/ETV combination could be considered in ETV-resistant patients with low HBV DNA titers, and may be continued if IVR-3 is achieved.",
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T1 - Management of entecavir-resistant chronic hepatitis B with adefovir-based combination therapies

AU - Kim, Hyoung Su

AU - Yim, Hyung Joon

AU - Jang, Myoung Kuk

AU - Park, Ji Won

AU - Suh, Sang Jun

AU - Seo, Yeon Seok

AU - Kim, Ji Hoon

AU - Kim, Bo Hyun

AU - Park, Sang Jong

AU - Lee, Sae Hwan

AU - Kim, Sang Gyune

AU - Kim, Young Seok

AU - Lee, Jung Il

AU - Lee, Jin Woo

AU - Kim, In Hee

AU - Kim, Tae Yeob

AU - Kim, Jin Wook

AU - Jeong, Sook Hyang

AU - Jung, Young Kul

AU - Park, Hana

AU - Hwang, Seong Gyu

PY - 2015/10/14

Y1 - 2015/10/14

N2 - AIM: To evaluate the long-term efficacy adefovir (ADV)-based combination therapies in entecavir (ETV)-resistant chronic hepatitis B (CHB) patients. METHODS: Fifty CHB patients with genotypic resistance to ETV at 13 medical centers in South Korea were included for the analysis. All the patients received rescue therapy with the combination of ADV plus ETV (ADV/ETV, n = 23) or ADV plus lamivudine (LMV) (ADV/LMV, n = 27) for more than 12 mo. Patients were monitored at least every 3-4 mo during ADV-based combination therapy by clinical examination as well as biochemical and virological assessments. Hepatitis B virus (HBV) DNA levels were measured by realtime PCR and logarithmically transformed for analysis. Cumulative rates of virologic response (VR; HBV DNA < 20 IU/mL) were calculated using the Kaplan-Meier method, and the difference was determined by a logrank test. Multivariate logistic regression and Cox proportional hazards models were used to identify independent risk factors significantly associated with short-term and long-term VR, respectively. RESULTS: Baseline median HBV DNA levels were 5.53 (2.81-7.63) log10 IU/mL. The most commonly observed ETV genotypic mutation sites were rt184 and rt202. Patients were treated for a median of 27 (12-45) mo. Overall, cumulative VR rates at 6, 12, 24, and 36 mo were 26%, 36%, 45%, and 68%, respectively. Patients treated with the ADV/ETV combination showed higher cumulative VR rates (35%, 43%, 65%, and 76%, respectively) than those with the ADV/LAM combination (18%, 30%, 30%, and 62%, respectively; P = 0.048). In the multivariate analysis, low baseline HBV DNA levels (< 5.2 log10 IU/mL) and initial virologic response at 3 mo (IVR-3; HBV DNA < 3.3 log10 IU/mL after 3 mo) were independent predictive factors for VR. Patients with favorable predictors achieved cumulative VR rates up to 90% at 36 mo. During the same period, the cumulative incidence of virologic breakthrough was as low as 6% in patients with the both favorable predictors. CONCLUSION: If tenofovir is not available, ADV/ETV combination could be considered in ETV-resistant patients with low HBV DNA titers, and may be continued if IVR-3 is achieved.

AB - AIM: To evaluate the long-term efficacy adefovir (ADV)-based combination therapies in entecavir (ETV)-resistant chronic hepatitis B (CHB) patients. METHODS: Fifty CHB patients with genotypic resistance to ETV at 13 medical centers in South Korea were included for the analysis. All the patients received rescue therapy with the combination of ADV plus ETV (ADV/ETV, n = 23) or ADV plus lamivudine (LMV) (ADV/LMV, n = 27) for more than 12 mo. Patients were monitored at least every 3-4 mo during ADV-based combination therapy by clinical examination as well as biochemical and virological assessments. Hepatitis B virus (HBV) DNA levels were measured by realtime PCR and logarithmically transformed for analysis. Cumulative rates of virologic response (VR; HBV DNA < 20 IU/mL) were calculated using the Kaplan-Meier method, and the difference was determined by a logrank test. Multivariate logistic regression and Cox proportional hazards models were used to identify independent risk factors significantly associated with short-term and long-term VR, respectively. RESULTS: Baseline median HBV DNA levels were 5.53 (2.81-7.63) log10 IU/mL. The most commonly observed ETV genotypic mutation sites were rt184 and rt202. Patients were treated for a median of 27 (12-45) mo. Overall, cumulative VR rates at 6, 12, 24, and 36 mo were 26%, 36%, 45%, and 68%, respectively. Patients treated with the ADV/ETV combination showed higher cumulative VR rates (35%, 43%, 65%, and 76%, respectively) than those with the ADV/LAM combination (18%, 30%, 30%, and 62%, respectively; P = 0.048). In the multivariate analysis, low baseline HBV DNA levels (< 5.2 log10 IU/mL) and initial virologic response at 3 mo (IVR-3; HBV DNA < 3.3 log10 IU/mL after 3 mo) were independent predictive factors for VR. Patients with favorable predictors achieved cumulative VR rates up to 90% at 36 mo. During the same period, the cumulative incidence of virologic breakthrough was as low as 6% in patients with the both favorable predictors. CONCLUSION: If tenofovir is not available, ADV/ETV combination could be considered in ETV-resistant patients with low HBV DNA titers, and may be continued if IVR-3 is achieved.

KW - Adefovir

KW - Chronic hepatitis B

KW - Entecavir

KW - Lamivudine

KW - Resistance

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