We read with great interest the article by Yeon et al, reporting resistance rates to adefovir dipivoxil (ADV) in 25% of patients with lamivudine‐resistant hepatitis B virus (HBV) after 24 months of ADV treatment (Gut 2006;55:1488–95). How should we deal with these new important data on ADV resistance? The acyclic nucleotide analogue tenofovir disoproxil fumarate (TDF) was recently shown to be effective in patients with lamivudine‐resistant HBV, with incomplete virological response to ADV.1 However, little is known about the efficacy of TDF in patients with lamivudine‐resistant and ADV‐resistant HBV as described by Yeon et al.
We report data on six male patients (median age 48 years, range 34–64 years), who have been treated with TDF for at least 6 months. Five out of six patients were hepatitis B e (Hbe) antigen negative, and documented cirrhosis (Child–Pugh stage A) was present in two of them. Earlier treatments included lamivudine (median treatment duration 45 months, range 16–72 months), followed by ADV (median treatment duration 24 months, range 11–45). ADV resistance was suspected when virological breakthrough (HBV DNA ⩾4 log10 copies/ml; COBAS TaqMan, Roche, Grenzach‐Whylen, Germany; lower limit of quantification 1.85 log10 copies/ml) occurred. In four of six patients, the typical HBV polymerase mutations rtA181V, rtA181T or rtN236T were shown (table 1). At that time, HBV DNA considerably increased in all patients (median HBV DNA 7.64, range 5.57–8.64, log10 copies/ml), and alanine aminotransferase (ALT) levels (median 183 IU/l, range 34–358 IU/l) were elevated in five of six patients. None of these patients had evidence of hepatic decompensation. Subsequently, treatment with ADV was stopped and TDF (300 mg/day) was started. Patients were followed after 4, 12 and 24 weeks. At 12 and 24 weeks, ALT level considerably decreased in all five patients with raised level at baseline. Moreover, four of six patients had ALT level within the normal range at week 24. After 24 weeks of TDF treatment, the median HBV DNA decline was 4.24 log10 copies/ml (range 3.27–4.87), and none of the patients had evidence of resistance (table 1). No side effects occurred during treatment with TDF.
Table 1 Characteristics of patients with lamivudine‐resistant and adefovir dipivoxil‐resistant chronic hepatitis B virus treated with tenofovir disoproxil fumarate.
| ALT (IU/l) | HBV DNA (log10 copies/ml)** | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Patient | HBe‐Ag | HBV genotype | ADV‐resistant mutation* | Baseline | 4 weeks | 12 weeks | 24 weeks | Baseline | 4 weeks | 12 weeks | 24 weeks | |
| 1 | Negative | D | Negative | 187 | 21 | 16 | 12 | 6.03 | 4.10 | 2,13 | Negative | |
| 2 | Negative | D | rtA181T rtN236T | 358 | ND | 68 | 40 | 7.25 | ND | 4.62 | 3.28 | |
| 3 | Negative | D | rtN236T | 85 | 76 | 65 | 63 | 5.57 | 4.54 | 3.59 | 2.30 | |
| 4 | Negative | D | Negative | 178 | 183 | 56 | 30 | 8.63 | 7.64 | 4.37 | 4.44 | |
| 5 | Negative | D | rtA181V | 34 | ND | 36 | 41 | 8.64 | ND | 6.09 | 3.95 | |
| 6 | Positive | D | rtA181V | 339 | 275 | 173 | 92 | 8.04 | 5.46 | 4.54 | 3.17 | |
ADV, adefovir dipivoxil; ALT; alanine aminotransferase; HBV, hepatitis B virus; Hbe‐Ag, hepatitis B antigen; ND, not done.
*ADV‐resistant mutations were detected as previously described4
**lower limit of quantification: 1.85 log10 copies/ml.
Taken together, we showed that TDF is highly effective in patients with lamivudine‐resistant and ADV‐resistant chronic HBV. TDF leads to a rapid virological response and normalisation of ALT levels in most patients. The efficacy of TDF in lamivudine‐resistant and ADV‐resistant HBV strains seems comparable to that in lamivudine‐resistant HBV. In the latter patients, van Bömmel et al. found a mean decline HBV DNA of 5.2 log10 copies/ml after 24 weeks of treatment,2 which is in accordance with our data.
The rapid antiviral effect of TDF makes it an attractive salvage treatment for patients with lamivudine‐resistant and ADV‐resistant chronic HBV, especially for those with decompensated chronic liver disease.3 Moreover, recent studies strongly suggest that TDF may be the treatment of choice in patients co‐infected with HIV and HBV.4,5 However, prospective studies in patients with chronic HBV are needed to assess the long‐term antiviral efficacy and the potential for emergence of TDF resistance.
Footnotes
Competing interests: None.
References
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