9 mL/min and 8.3 mL/min, respectively, in the monotherapy selleck chem group; and 7.4 mL/min and 6.2 mL/min, respectively, in the intensification group (P<0.01 for all comparisons). Figure 4 shows week 52 GFR changes (MDRD) stratified by baseline GFR. No significant GFR decline was noted in patients with low baseline GFR, although numbers were small. Figure 4 Week 52 glomerular filtration rate (MDRD) changes, by baseline rate and treatment (efficacy population). Discussion In providing a framework for the conditional intensification of monotherapy, the Roadmap [16] provides a rational approach to improve long-term outcomes, while minimizing the risk of drug resistance due to continued 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 on-treatment 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 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 Carfilzomib comparison. Similar results were observed in a study of telbivudine versus lamivudine in over 300 Chinese patients [22].