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EASL 2012: Telbivudine Effective for Hepatitis B Patients Selected with Roadmap


Telbivudine (Tyzeka) is an effective treatment for chronic hepatitis B with minimal emergence of drug resistance when using the "Roadmap" algorithm for selecting appropriate patients and deciding when to add other agents, according to a trio of studies presented at the 47th International Liver Congress (EASL 2012) last month in Barcelona.

Telbivudine (also known as LDT) is a nucleoside analog with potent activity against hepatitis B virus (HBV), but it has a relatively low genetic barrier to resistance.

The Roadmap concept provides an optimized approach to reduce the incidence of virological breakthrough and genotypic resistance during nucleoside/nucleotide analog treatment of chronic hepatitis B. In April 2011, the U.S. Food and Drug Administration (FDA) announced a label change that incorporates this approach, stating that telbivudine should be limited to people with low baseline HBV DNA and should be stopped if viral load is still detectable at 24 weeks.

Fabien Zoulim from INSERM in Lyon looked at resistance rates after 1 and 2 years on telbivudine among participants treated according to the Roadmap in the pivotal GLOBE trial. At baseline hepatitis B "e" antigen (HBeAg) positive patients (n=57) had HBV DNA < 9 log copies/mL and HBeAg negative patients (n=86) had < 7 log copies/mL; ALT was > 2 times the upper limit of normal (ULN). At week 24 of lamivudine monotherapy they had undetectable viral load.

After 1 year on treatment, 97% of HBeAg positive and 98% of HBeAg negative patients still had undetectable HBV DNA; 40% of the HBeAg positive participants experience HBeAg seroconversion. After 2 years on telbivudine, the corresponding rates were 89% and 91% undetectable, with 52% HBeAg seroconversion. No patients had resistance mutations at year 1 and only about 2% did so at 2 years.

"In patients with defined baseline characteristics and undetectable week 24 HBV DNA, no resistance after 1 year was reported," the researchers concluded. "2-year resistance is very low."

In a related study, Jinlin Hou from Nanfang Medical University and colleagues looked at viral breakthrough and resistance in more than 600 HBeAg positive Chinese patients receiving telbivudine in the EFFORT study. At baseline they had HBV DNA > 5 log copies/mL and ALT 2-10 x ULN.

All patients started on telbivudine monotherapy. In the Roadmap arm people with HBV DNA > 300 copies/mL at week 24 added adefovir (Hepsera) while those with lower levels stayed on monotherapy. The control group received telbivudine monotherapy for the entire 104 weeks.

About two-thirds (68%) of participants in the Roadmap group added adefovir. In a 76-week analysis, Roadmap patients were significantly more likely to achieve HBV DNA < 300 copies/mL compared with the stable telbivudine monotherapy group (74% vs 61%, respectively). They were also less likely to have HBV DNA remaining above 4 log (6 vs 22), experience viral breakthrough (1.8% vs 13%), or develop genotypic resistance (1.4% vs 11%). In a multivariate analysis, HBV DNA > 300 copies/mL at week 24 was associated with much higher risk of viral breakthrough on telbivudine monotherapy (OR 11.7, or nearly 12-fold higher risk).

"The week 24 optimized strategy improves HBV DNA suppression and reduces the incidences of virological breakthrough and genotypic resistance dramatically," the researchers summarized. "The failure to achieve early virological response predicts the development of virological breakthrough."

Finally, Teerha Piratvisuth from Songklanagarind Hospital in Hat Yai, Thailand, and colleagues analyzed 2-year outcomes among more than 100 HBeAg positive patients who started treatment with telbivudine monotherapy in the Roadmap study A2410. In this study participants with HBV DNA > 300 copies/mL at week 24 could add tenofovir (Viread).

At week 24, 55% of participants achieved undetectable viral load, and all patients with detectable HBV DNA added tenofovir. At week 104, 94% had undetectable HBV DNA, 50% experienced HBeAg loss, 44% achieved HBeAg seroconversion, 7% experienced hepatitis B surface antigen (HBsAg) loss, and 4% achieved HBsAg seroconversion.

A single patient in the telbivudine monotherapy arm experienced viral breakthrough at week 72 and was found to have the M204I mutation; this person again achieved undetectable HBV DNA after adding tenofovir. In addition, 1 monotherapy patient experienced a HBV DNA "blip" that returned to undetectable without changing therapy. Treatment was well-tolerated with no cases of muscle damage (a potential side effect of telbivudine) and overall improvement in kidney function (a potential concern with tenofovir).

"Telbivudine Roadmap with tenofovir add-on at 24 weeks in patients with detectable HBV DNA improved GFR [a measure of kidney function] in both [telbivudine-] and [telbivudine + tenofovir-] treated patients," with "favorable efficacy and safety profiles," the investigators concluded.

In an overview of research on the final day of the conference, Jean-Michel Pawlotsky from the University of Paris highlighted the "revival" of telbivudine thanks to the Roadmap. "You can be confident that if you apply the Roadmap you will achieve good results," he said.



F Zoulim, S Zeuzem, T Piratvisuth, et al. Genotypic Resistance Reduced to Very Low Levels in Chronic Hepatitis B (CHB) Patients Treated Over 2-Years with Telbivudine (LDT) When Considering Baseline Characteristics and Roadmap. 47th International Liver Congress (EASL 2012). Barcelona, April 18-22, 2012. Abstract 496.

J Hou, J Sun, Q Xie, et al. Virological Breakthrough and Genotypic Resistance in a Randomized, Controlled Study on Telbivudine Treatment Applying Roadmap Concept in CHB: W76 Interim Analysis of EFFORT Study. Abstract 515. 47th International Liver Congress (EASL 2012). Barcelona, April 18-22, 2012.

T Piratvisuth, P Komolmit, T Tanwandee. 2-Year Results of Telbivudine (LDT) Roadmap Study Verify the Optimal Efficacy and Safety Results in HBeAg Positive Chronic Hepatitis B (CHB) Patients. Abstract 539. 47th International Liver Congress (EASL 2012). Barcelona, April 18-22, 2012.