Ed sub-optimal monotherapy or adverse events associated with unnecessary combination treatment. Under the Roadmap, nucleosides with a low genetic barrier to resistance (e.g. lamivudine) are intensified with a non-cross-resistant second agent if any HBV replication is still measurable at Week 24. Although Linolenic acid methyl ester supplier telbivudine is more potent than lamivudine with less ontreatment resistance [5,15], it is closest to lamivudine in terms of the features informing JI-101 Roadmap decisions; and intensification was applied to any patient with detectable Week 24 viremia. The requirement for 11967625 a non-cross-resistant second agent predicates the use of adefovir or tenofovir [6], with tenofovir the better choice due to greater potency [10]. Over half the patients achieved undetectable Week 24 viremia on telbivudine alone, and, following tenofovir intensification of the remaining 45 , the overall proportion of undetectable HBV DNA was greater than 90 at Week 52. The additional reduction in HBV DNA seen following tenofovir intensification of viremic patients is presumably due to additive antiviral activity. There was no in-study comparator to estimate the treatment effect of tenofovir intensification over continued telbivudine monotherapy in viremic patients. Nor was tenofovir monotherapy investigated, or the effect of switching viremic patients to tenofovir as opposed to adding it to telbivudine. However, historical data suggest that intensification would have significantly improved Week 52 outcomes over what would have been seen had telbivudine monotherapy been continued. In GLOBE [15] a broadly similar rate of undetectable viremia at Week 24 (45 ) was seen in HBeAg+ telbivudine patients to that seen here (55 ), but with a substantially lower rate of undetectable DNA at Week 52 (60 ). GLOBE also showed lower rates of undetectable HBV DNA, ALT normalization and HBeAg seroconversion at Week 52, and higher rates of drug resistance at Week 48, for patients with detectable Week 24 viremia [15], although the design of these analyses precludes cross-study comparison. Similar results were observed in a study of telbivudine versus lamivudine in over 300 1655472 Chinese patients [22]. Finally, in the two-year GLOBE analyses, 82 (166/203) of HBeAg+ patients with undetectable Week 24 HBV remained undetectable through two years, but only 36 (89/247) of those with detectable Week 24 DNA were undetectable at the end of Year 2 [23].Telbivudine 6 Conditional Tenofovir: 52-Week DataFigure 4. Week 52 glomerular filtration rate (MDRD) changes, by baseline rate and treatment (efficacy population). doi:10.1371/journal.pone.0054279.gHBeAg clearance and seroconversion rates were very high (Table 2), with most (approximately 85 of cases) occurring in those with undetectable Week 24 viremia who remained on telbivudine monotherapy. Effective clearance and seroconversion of HBeAg therefore appears to be a function of early and complete virologic suppression. The 6 rate of HBsAg loss at 1 year of treatment was also substantially higher than the typically reported per-annum rates of ,1 on nucleosides and approximately 3 on interferon treatment [24,25]. The association of HBsAg response with intensification (5/6 cases of loss and all three cases of seroconversion) suggests a potential synergistic effect between tenofovir and telbivudine that merits longer-term investigation in a larger dataset. Safety and tolerability were consistent with GLOBE, and, other than myalgia, muscle-related events were rar.Ed sub-optimal monotherapy or adverse events associated with unnecessary combination treatment. Under the Roadmap, nucleosides with a low genetic barrier to resistance (e.g. lamivudine) are intensified with a non-cross-resistant second agent if any HBV replication is still measurable at Week 24. Although telbivudine is more potent than lamivudine with less ontreatment resistance [5,15], it is closest to lamivudine in terms of the features informing Roadmap decisions; and intensification was applied to any patient with detectable Week 24 viremia. The requirement for 11967625 a non-cross-resistant second agent predicates the use of adefovir or tenofovir [6], with tenofovir the better choice due to greater potency [10]. Over half the patients achieved undetectable Week 24 viremia on telbivudine alone, and, following tenofovir intensification of the remaining 45 , the overall proportion of undetectable HBV DNA was greater than 90 at Week 52. The additional reduction in HBV DNA seen following tenofovir intensification of viremic patients is presumably due to additive antiviral activity. There was no in-study comparator to estimate the treatment effect of tenofovir intensification over continued telbivudine monotherapy in viremic patients. Nor was tenofovir monotherapy investigated, or the effect of switching viremic patients to tenofovir as opposed to adding it to telbivudine. However, historical data suggest that intensification would have significantly improved Week 52 outcomes over what would have been seen had telbivudine monotherapy been continued. In GLOBE [15] a broadly similar rate of undetectable viremia at Week 24 (45 ) was seen in HBeAg+ telbivudine patients to that seen here (55 ), but with a substantially lower rate of undetectable DNA at Week 52 (60 ). GLOBE also showed lower rates of undetectable HBV DNA, ALT normalization and HBeAg seroconversion at Week 52, and higher rates of drug resistance at Week 48, for patients with detectable Week 24 viremia [15], although the design of these analyses precludes cross-study comparison. Similar results were observed in a study of telbivudine versus lamivudine in over 300 1655472 Chinese patients [22]. Finally, in the two-year GLOBE analyses, 82 (166/203) of HBeAg+ patients with undetectable Week 24 HBV remained undetectable through two years, but only 36 (89/247) of those with detectable Week 24 DNA were undetectable at the end of Year 2 [23].Telbivudine 6 Conditional Tenofovir: 52-Week DataFigure 4. Week 52 glomerular filtration rate (MDRD) changes, by baseline rate and treatment (efficacy population). doi:10.1371/journal.pone.0054279.gHBeAg clearance and seroconversion rates were very high (Table 2), with most (approximately 85 of cases) occurring in those with undetectable Week 24 viremia who remained on telbivudine monotherapy. Effective clearance and seroconversion of HBeAg therefore appears to be a function of early and complete virologic suppression. The 6 rate of HBsAg loss at 1 year of treatment was also substantially higher than the typically reported per-annum rates of ,1 on nucleosides and approximately 3 on interferon treatment [24,25]. The association of HBsAg response with intensification (5/6 cases of loss and all three cases of seroconversion) suggests a potential synergistic effect between tenofovir and telbivudine that merits longer-term investigation in a larger dataset. Safety and tolerability were consistent with GLOBE, and, other than myalgia, muscle-related events were rar.
