In
the first study, reported in the January 3, 2008 advance online edition of the
Journal of Hepatology, researchers sought to identify mutations associated
with adefovir treatment failure, and to determine virological response to subsequent
treatment with tenofovir, either
alone or in combination with emtricitabine
(Emtriva; the 2 drugs are co-formulated in the Truvada
combination pill). Serum samples from 13 patients were analyzed before and
after changing therapy using direct sequencing and clonal analysis.
Results
•
The adefovir resistance
mutations rtA181V and rtN236T were detected on direct HBV sequencing in 3 of 8
patients who experienced virological breakthrough.
•
Among patients with suboptimal
virological response, clonal analysis revealed the rtA181T, rtI233V, and rtN236T
mutations in 3 individuals.
•
10 patients received
subsequent tenofovir, 8 of whom achieved virological response.
•
1 person had adefovir
resistance at baseline and demonstrated persistence of adefovir resistance mutations
during tenofovir treatment; addition of emtricitabine resulted in a further HBV
DNA decrease.
•
1 patient had no evidence
of adefovir resistance at baseline, but demonstrated selection of adefovir resistance
mutations during tenofovir treatment.
•
All 3 patients who received
tenofovir + emtricitabine achieved undetectable HBV DNA within 3-12 months, including
2 who had adefovir resistance at baseline.
In
conclusion, the authors wrote, "Tenofovir monotherapy is effective for patients
with virologic breakthrough or suboptimal response to adefovir, but combination
therapy with a nucleoside analogue should be considered in patients with adefovir
resistance. No novel mutations were detected."
Switching
from Tenofovir to Adefovir
In
the second study, reported in the February 2008 issue of the same journal, researchers
in Rotterdam, Netherlands, studied 10 patients taking tenofovir
+ lamivudine (Epivir) to treat lamivudine-resistant
chronic HBV. After adefovir was approved, all switched to adefovir
monotherapy.
Results
•
The median tenofovir
treatment duration was 78 weeks, resulting in a median HBV DNA viral load reduction
of 5.4 log10 copies/mL (range 6.8-2.3) from baseline (P = 0.005).
•
2 patients experienced
an increase > 1 log10 copies/mL while on tenofovir.
•
After switching to adefovir,
6 out of 10 patients (60%) had an HBV DNA > 4 log10 copies/mL and the median
HBV DNA level increased from 2.8 to 4.5 log10 copies/mL (P = 0.017).
•
Factors associated with
virological rebound were HBV DNA PCR positivity at the time of the drug switch
and having HBV genotype B or D.
•
There was evidence that
ALT levels at the beginning of tenofovir treatment might also be a factor.
•
3 patients who restarted
tenofovir experienced rapid declines in HBV DNA.
"Tenofovir
is a potent antiviral drug," the authors concluded. "Switching to
adefovir resulted in viral relapse in 60% of patients and re-treatment with tenofovir
resulted again in viral decline, which suggests that tenofovir is a more potent
antiviral agent."
Together,
these 2 studies suggest that tenofovir may have stronger anti-HBV activity than
adefovir. The existence of some degree of cross-resistance is not surprising,
since the drugs are structurally similar. HBV can eventually develop resistance
to any nucleoside analog used as monotherapy, which suggests that combination
therapy is likely to lead to better long-term outcomes.
02/01/08
References
J
Tan, B Degertekin, SN Wong, and others. Tenofovir monotherapy is effective in
hepatitis B patients with antiviral treatment failure to adefovir in the absence
of adefovir-resistant mutations. Journal of Hepatology. January 3, 2008
[Epub ahead of print].
WF
Leemans, HL Janssen, HG Niesters, and others. Switching patients with lamivudine
resistant chronic hepatitis B virus from tenofovir to adefovir results in less
potent HBV-DNA suppression. Journal of Viral Hepatitis 15(2): 108-114.
February 2008.
