Correspondence
Telbivudine versus Lamivudine in Patients with Chronic Hepatitis B
N Engl J Med 2008; 358:1517-1518April 3, 2008
- Article
To the Editor:
We would like to raise four points with respect to the report by Lai et al. (Dec. 20, 2007, issue)1 on the 1-year results of their study comparing telbivudine with lamivudine in patients with hepatitis B virus (HBV) infection. First, the authors elucidate the role of the viral load at week 24 as a predictor for response and resistance. A decrease in the HBV viral load below 1000 copies per milliliter at week 12 has been reported to correlate with response and absence of resistance.2 More recently, a “week-4 prediction” was suggested for a viral-load decrease below 4 log10 copies per milliliter.3 Does this hold true for lamivudine and telbivudine in the study by Lai et al.?
Second, telbivudine seems to select the M204I mutations only. M204V, frequently selected with lamivudine therapy, seems to be required for resistance to entecavir; full sensitivity to entecavir is retained with M204I in vitro.4 If these findings are confirmed, sequential telbivudine–entecavir might be an important therapeutic option, whereas sequential lamivudine–entecavir has been associated with an increased rate of resistance.5
Third, have the authors determined whether the HBV genotype plays a role in determining the path of resistance development?
Finally, do the mutations found alter the hepatitis B surface antigen (HbsAg) protein sequence?
Hans L. Tillmann, M.D.
John G. McHutchison, M.D.
Duke Clinical Research Institute, Durham, NC 27705
hans.tillmann@duke. edu Dr. Tillmann reports receiving consulting fees from Bristol-Myers Squibb, GlaxoSmithKline, and Novartis and research grants from Novartis and Roche. Dr. McHutchison reports receiving consulting fees from GlaxoSmithKline, Idenix, Novartis, and Gilead and research grants from GlaxoSmithKline, Bristol-Myers Squibb, Gilead, Novartis, and Roche. No other potential conflict of interest relevant to this letter was reported.
5 References1
Lai C-L ,Gane E ,Liaw Y-F , et al. Telbivudine versus lamivudine in patients with chronic hepatitis B. N Engl J Med 2007;357:2576-2588
Full Text | Web of Science | Medline2
Puchhammer-Stockl E ,Mandl CW ,Kletzmayr J , et al. Monitoring the virus load can predict the emergence of drug-resistant hepatitis B virus strains in renal transplantation patients during lamivudine therapy. J Infect Dis 2000;181:2063-2066
CrossRef | Web of Science | Medline3
Yuen MF ,Fong DY ,Wong DK ,Yuen JC ,Fung J ,Lai CL . Hepatitis B virus DNA levels at week 4 of lamivudine treatment predict the 5-year ideal response. Hepatology 2007;46:1695-1703
CrossRef | Web of Science | Medline4
Colonno RJ ,Rose R ,Baldick CJ , et al. Entecavir resistance is rare in nucleoside naïve patients with hepatitis B. Hepatology 2006;44:1656-1665
CrossRef | Web of Science | Medline5
Tenney DJ ,Rose RE ,Baldick CJ , et al. Two-year assessment of entecavir resistance in lamivudine-refractory hepatitis B virus patients reveals different clinical outcomes depending on the resistance substitutions present. Antimicrob Agents Chemother 2007;51:902-911
CrossRef | Web of Science | Medline
Author/Editor Response
Tillmann and McHutchison raise four points. In response to their first point, exploratory analyses of the Globe study data indicated that an HBV DNA level of less than 3 log10 copies per milliliter at week 4 or 12 had excellent positive predictive values, similar to the value for week 24, but an HBV DNA level of less than 3 log10 copies at week 4 or 12 had poorer negative predictive values than the value for week 24. Second, the HBV polymerase mutations affecting the sensitivity to current antiviral agents appear to segregate in two resistance profiles — to nucleosides (lamivudine, entecavir, telbivudine, and emtricitabine) and to nucleotides (adefovir and tenofovir).1 Clinical data indicate that resistance to a nucleoside is controlled by early addition of a nucleotide,2 and future studies will determine the potential benefits of using a combination of drugs right at the beginning of treatment. Third, there was no relationship between resistance and HBV genotype within this data set, which comprised data primarily from patients with genotype B or C (77% of the patients in the study). Finally, the guanidine-to-thymidine substitution at nucleotide position 743, which results in the M204I amino acid substitution in the polymerase, is associated with a change from tryptophan to leucine at position 196 of the HBsAg reading frame.3
3 ReferencesChing-Lung Lai, M.D.
Queen Mary Hospital, Hong Kong, China
hrmelcl@hkucc.hku. hk Edward Gane, M.D.
Middlemore Hospital, Auckland 1133, New ZealandNathaniel A. Brown, M.D.
Idenix Pharmaceuticals, Cambridge, MA 021391
Lok AS ,Zoulim F ,Locarnini S , et al. Antiviral drug-resistant HBV: standardization of nomenclature and assays and recommendations for management. Hepatology 2007;46:254-265
CrossRef | Web of Science | Medline2
Lampertico P ,Vigano M ,Manenti E ,Iavarone M ,Lunghi G ,Colombo M . Adefovir rapidly suppresses hepatitis B in HBeAg-negative patients developing genotypic resistance to lamivudine. Hepatology 2005;42:1414-1419
CrossRef | Web of Science | Medline3
Allen MI ,Deslauriers M ,Andrews CW , et al. Identification and characterization of mutations in hepatitis B virus resistant to lamivudine. Hepatology 1998;27:1670-1677
CrossRef | Web of Science | Medline
- Citing Articles (2)
Citing Articles
1
Ming-Hua Zheng, Ke-Qing Shi, Zhi-Juan Dai, Chao Ye, Yong-Ping Chen. (2010) A 24-week, parallel-group, open-label, randomized clinical trial comparing the early antiviral efficacy of telbivudine and entecavir in the treatment of hepatitis B e antigen-positive chronic hepatitis B virus infection in adult Chinese patients. Clinical Therapeutics 32:4, 649-658
CrossRef2
Martin Potter, Marina B Klein. (2009) Co-infections and co-therapies: treatment of HIV in the presence of hepatitis C and hepatitis B. HIV Therapy 3:2, 189-207
CrossRef
