Hiromitsu Kumada1, Kazuhiko Koike2, Kazuaki Suyama3, Hiroshi Ito3, Hiroshi Itoh4, Wataru Sugiura5. 1. Department of Hepatology, Toranomon Hospital, Tokyo, Japan. 2. Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan. 3. Medicines Development, GlaxoSmithKline K.K., Tokyo, Japan. 4. Biomedical Data Sciences, GlaxoSmithKline K.K., Tokyo, Japan. 5. Medical Affairs, GlaxoSmithKline K.K., Tokyo, Japan.
Abstract
AIM: Acquisition of nucleos(t)ide analog (NA) inhibitor resistance is critical in successful chronic hepatitis B treatment. As the pattern of tenofovir disoproxil fumarate (TDF) resistance mutations differs from that of other antiviral drugs, we sought to clarify the salvaging potential of TDF in patients with hepatitis B virus (HBV) infection who are poor responders or resistant to other NAs. METHODS: A prospective, multicenter, single-arm, open-label study was carried out from December 2011 to October 2014. Poor responders defined as subjects with serum HBV-DNA levels >4 log10 copies/mL were enrolled. Subjects receiving lamivudine (LAM) + adefovir pivoxil (ADV) before the initiation of the study were switched to LAM + TDF. Subjects on entecavir hydrate (ETV) with or without ADV were switched to ETV + TDF. The primary efficacy end-point was the proportion of subjects achieving HBV-DNA <2.1 log10 copies/mL (LLQ) at week 24. The secondary efficacy end-points were the proportion of subjects with LLQ at weeks 48 and 96, serum alanine aminotransferase normalization, hepatitis B envelope antigen/antibody and hepatitis B surface antigen/antibody seroconversion. RESULTS: Thirty-four subjects were enrolled, 21 subjects were switched to ETV + TDF, and 13 subjects were switched to LAM + TDF. Drug resistance mutations were determined in 85% of the subjects at the time of the enrolment. The proportion of subjects who achieved LLQ was 59%, 62%, and 71% at weeks 24, 48, and 96, respectively. No serious adverse event related to TDF was reported. CONCLUSION: Our study clearly showed that TDF containing regimens were effective in salvaging poor responders and/or those who are drug-resistant to other NAs. This study is registered with ClinicalTrials.gov (NCT01475851) and the GSK Clinical Study Register (GSK LOC115912).
AIM: Acquisition of nucleos(t)ide analog (NA) inhibitor resistance is critical in successful chronic hepatitis B treatment. As the pattern of tenofovir disoproxil fumarate (TDF) resistance mutations differs from that of other antiviral drugs, we sought to clarify the salvaging potential of TDF in patients with hepatitis B virus (HBV) infection who are poor responders or resistant to other NAs. METHODS: A prospective, multicenter, single-arm, open-label study was carried out from December 2011 to October 2014. Poor responders defined as subjects with serum HBV-DNA levels >4 log10 copies/mL were enrolled. Subjects receiving lamivudine (LAM) + adefovirpivoxil (ADV) before the initiation of the study were switched to LAM + TDF. Subjects on entecavir hydrate (ETV) with or without ADV were switched to ETV + TDF. The primary efficacy end-point was the proportion of subjects achieving HBV-DNA <2.1 log10 copies/mL (LLQ) at week 24. The secondary efficacy end-points were the proportion of subjects with LLQ at weeks 48 and 96, serum alanine aminotransferase normalization, hepatitis B envelope antigen/antibody and hepatitis B surface antigen/antibody seroconversion. RESULTS: Thirty-four subjects were enrolled, 21 subjects were switched to ETV + TDF, and 13 subjects were switched to LAM + TDF. Drug resistance mutations were determined in 85% of the subjects at the time of the enrolment. The proportion of subjects who achieved LLQ was 59%, 62%, and 71% at weeks 24, 48, and 96, respectively. No serious adverse event related to TDF was reported. CONCLUSION: Our study clearly showed that TDF containing regimens were effective in salvaging poor responders and/or those who are drug-resistant to other NAs. This study is registered with ClinicalTrials.gov (NCT01475851) and the GSK Clinical Study Register (GSK LOC115912).