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Tenofovir Dosing in HBV
May 2005
Below are Two Letters To The Editor
Tenofovir in chronic hepatitis B
P. Del Poggio, C. Jamoletti, M. Zaccanelli
Hepatology Unit, Ospedale di Treviglio (Bg), Italy
Tenofovir in Chronic Hepatitis B
To the Editor:

In their recent paper Van Bommel et al. demonstrated a greater antiviral activity of tenofovir at a dose of 300 mg/day compared to adefovir against lamivudine-resistant hepatitis B virus.[1] This is the standard approved dose for HIV and HBV coinfected patients,[2] but it may not be the optimal dose for HIV negative patients. Hepatitis B virus has a greater susceptibility to nucleotide analogues compared to HIV[3] and is certainly less likely to develop resistant mutants. In the initial studies adefovir was used at doses up to 120 mg/day in order to achieve significant HIV inhibition, a dosage well above the approved dose for chronic hepatitis B. It is therefore feasible that tenofovir, like its parent drug adefovir could be used at a lower dosage in patients with HBV infection alone.
To test this hypothesis we treated 10 chronic hepatitis B patients (8 of them had cirrhosis) with 75 mg/day of tenofovir for a median period of 82 weeks (range 44-144). The patients had a median age of 64 years (range 40-76), were all HBeAg negative, and had no other comorbidities. All had received lamivudine for a median duration of 24 months (range 10-39) and were shifted to tenofovir immediately after stopping lamivudine. Five of them had developed YMDD resistance, the others had wild-type virus and were changed to tenofovir to prevent the emergence of lamivudine resistance. Before starting tenofovir, 4 of the 5 patients with YMDD resistance had normal levels of alanine aminotransferase, negative serum branched HBV DNA (Versant HBV DNA 3.0 Bayer, sensitivity <2000 copies/mL), but viral HBV DNA could be detected by polymerase chain reaction (PCR; Innolipa HBV DR Amplification, Innogenetics, Ghent, Belgium, sensitivity <1000 copies/mL) with the presence of YMDD-resistant mutants (Innolipa Line Probe Assay, Innogenetics). The other patient with YMDD mutants had elevated levels of alanine aminotransferase and a serum HBV DNA of 4.8 ~ 106 copies/mL (b-DNA). Four of the 5 patients with lamivudine resistance, including the patient with high viremia, became HBV DNA negative by PCR assay after 2-6 months of tenofovir and remained negative throughout the entire period of treatment (median 64 weeks, range 44-144) The 5 patients without YMDD mutants were shifted from lamivudine to tenofovir when their serum HBV-DNA was undetectable by PCR and remained PCR negative while receiving tenofovir (median 84 weeks, range 64-100). The drug was well tolerated and no side effects were reported. In addition, no viral breakthrough was observed, confirming the low potential of this drug to induce phenotypic resistance, even using a dose as low as 75 mg.
These excellent results have been observed in only 10 patients, all except one with very low HBV DNA levels, so they may not be generalized to all chronic hepatitis B patients, especially those with high viremia. We think, however, that a dose escalation study with a dose ranging from 75 to 300 mg/day may be warranted. The issue is clearly not safety, but cost and the fact that giving the lowest effective dose could significantly reduce the economic burden of this therapy.
1 Van Bommel F, Wunsche T, Mauss S, Reinke P, Bergk A, Schurmann D, et al. Comparison of Adefovir and Tenofovir in the treatment of lamivudine-resistant hepatitis B virus infection. HEPATOLOGY 2004; 40: 1421-1425. Links
2 Soriano V, Mir˜ JM, Garcia-Samaniego J, Torre-Cisneros J, Nunez M, del Romero J, et al. Consensus Conference on chronic viral hepatitis and HIV infection: updated Spanish recommendations. J Viral Hepat 2004; 11: 2-18. Links
3 Danta M, Dusheiko G Adefovir dipivoxil: review of a novel acyclic nucleoside analogue Int J Clin Pract 2004; 58: 877-886. Links
Thomas Berg, M.D., Florian van Bmmel, M.D. Medizinische Klinik mit Schwerpunkt Hepatologie und Gastroenterologie, CharitŽ - Campus Virchow-Klinikum, UniversitŠtsmedizin Berlin, Berlin, Germany
We thank Dr. Del Poggio and colleagues for their comments outlining their experience in treating hepatitis B e antigen (HBeAg)-negative patients with tenofovir. In their study they showed that even a tenofovir dosage of 75 mg/day was able to induce and maintain virological response in patients with and without genotypic lamivudine-resistant hepatitis B virus (HBV) infection. From this they postulated that a tenofovir escalation study with a dose ranging from 75 to 300 mg/day should be performed, also pointing out that the economic burden of this therapy also justifies such a study.
Analyzing the data presented we only can warn against drawing such far-reaching conclusions. First, there are striking differences regarding the disease activity of the two populations of HBV-infected patients seen in Treviglio and Berlin.[1] In our study all lamivudine-resistant patients had high HBV DNA levels (mean, 2.7 ~ 109 copies/mL), whereas only 1 of the 10 chronically HBV-infected patients from Italy had detectable viremia in the presence of a lamivudine-resistant mutation when he was switched from lamivudine to tenofovir. Second, there is general agreement that early and effective reduction of HBV replication is most important in preventing the selection of drug-resistant mutants.[2][3] Therefore, our observed rapid antiviral effect of tenofovir even in the presence of high viral load is a strong argument in favor of using the safe dose of 300 mg, which in addition may guarantee the prevention of mutants better than dosages of 75 mg. In this respect, our recent observation that we could reduce the viral load even below 6 IU/mL as verified by the more sensitive real-time PCR technology (Cobas TaqMan, Roche Diagnostics Systems, Pleasanton, CA; detection limit 6 IU/mL) in 50% of the tenofovir-treated patients already at week 48 strongly speaks for the use of this kind of tenofovir dosing and the probability to cope effectively even with minimal residual HBV replication (van Bmmel F and Berg T, unpublished data, 2005).
1 van Bmmel F, WŸnsche T, Mauss S, Reinke P, Bergk A, SchŸrmann D, et al. Comparison of adefovir and tenofovir in the treatment of lamivudine-resistant hepatitis B virus infection. HEPATOLOGY 2004; 40: 1421-1425. Links
2 Yuen MF, Sablon E, Hui CK, Yuan HJ, Decraemer H, Lai CL. Factors associated with hepatitis B virus DNA breakthrough in patients receiving prolonged lamivudine therapy. HEPAOLOGY 2001; 34: 785-791. Links
3 Germanidis G, Marcellin P, Lau G, Bonino F, Farci P, Hadziyannis S, Jin R, et al. Profound on-treatment viral suppression with peginterferon alfa-2a (40KD) plus lamivudine combination therapy limits the development of YMDD mutations, but does not improve sustained response rates over peginterferon alfa-2a (40kD) alone. HEPATOLOGY 2004; 40(Suppl 1): 653A. Links
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