A Eliglustat 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 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 BTZ-043 site 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 rare. Of 13 patients with myalgia, most (12/13) experienced mild events and most (12/13) resolved sponataneously. No renal toxicity was observed after 24 weeks of tenofovir plus telbivudine. Mean GFR at week 52 was significantly higher than baseline in both the monotherapy and intensification groups. These findings are consistent with both 2-year clinical data from a study of telbivudine versus lamivudine in decompensated HBV disease [26]. Furthermore, retrospective analyses of seven studies (2500 patients) in both compensated and decompensated disease showed consisten.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 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 rare. Of 13 patients with myalgia, most (12/13) experienced mild events and most (12/13) resolved sponataneously. No renal toxicity was observed after 24 weeks of tenofovir plus telbivudine. Mean GFR at week 52 was significantly higher than baseline in both the monotherapy and intensification groups. These findings are consistent with both 2-year clinical data from a study of telbivudine versus lamivudine in decompensated HBV disease [26]. Furthermore, retrospective analyses of seven studies (2500 patients) in both compensated and decompensated disease showed consisten.
