Τομέας Παθολογίας
Library of the School of Health Sciences

2014-01-15

2014

Παπαδημητρόπουλος Βασίλειος

Χατζηγιάννης Στέφανος, Ντουράκης Σπυρίδων, Βαφειάδη - Ζουμπούλη Ειρήνη

Ανίχνευση μεταλλαγμένων στελεχών του HBV κατά τη θεραπεία με νουκλεοσιδικά ανάλογα ασθενών με χρόνια ηπατίτιδα Β

Greek

Detection of mutant strains of HBV during treatment with nucleoside analogues in patients with chronic hepatitis B

In this study included 125 treatment-naive patients with HBeAg negative chronic
hepatitis B who started long-term monotherapy with lamivudine 100 mg daily (78
patients, 58 with compensated and 20 with decompensated liver disease) or
adefovir 10mg daily (47 patients with decompensated disease), and 42 patients
with HBeAg negative chronic hepatitis B and resistance to lamivudine (all with
compensated disease) who received either a combination of lamivudine and
adefovir (28 patients) or monotherapy adefovir (14 patients).
Of the patients who started treatment with lamivudine, viral breakthrough was
observed in 45 of 78 (58%) patients from 6 months to 9 years after the start of
administration of lamivudine. Analyzing separately the subgroup of 39 patients
who completed the ten-year follow-up found that viral breakthrough was observed
in 30 of them (77%).
Genome analysis to detect mutations conducted in 34 patients. 9 patients had
the mutation M204I (27%), 14 had the combination M204I + L180M (41%), and the
remaining 11 had the combined mutations M204V + L180M (32%).
After viral breakthrough, all patients with initial virological and biochemical
response showed biochemical breakthrough in a period of two years. Patients who
had biochemical breakthrough in the first 6 months after virological rebound
had significantly higher HBV DNA levels than those who did not have this rapid
(within 6
months) biochemical rebound (median HBV DNA 20272 vs. 1813 copies/ml, P=0.01).
Of the patients who started adefovir, mutants resistant to adefovir observed in
7 patients (15%). One patient experienced viral escape in the first year of
treatment, 2 patients in the second year and the remaining 3 in the third year
of treatment. Four patients had the N236T mutation and the other three had the
A181V mutation. Of the 15 patients who had no complete virological response at
12 months, 3 of them developed resistance (20%), while of the 32 patients who
achieved a complete virological response at 12 months, resistance developed by
the four of them (12%). Of the 4 patients with initial complete virologival and
biochemical response, biochemical breakthrough was observed in 2 of them.
Of the patients with resistance to lamivudine, receiving adefovir monotherapy
or combination adefovir and lamivudine therapy, mutants to adefovir found only
in the monotherapy group (in the 3 patients who did not achieve a complete
virologic response). The appearance of resistance found at 15, 18, and 18
months respectively with selection of the N236T mutant in the first patient,
the A181V in the second patient and mixed population of N236T and A181V in the
third. Genotyping resistance followed virological and biochemical breakthrough
was observed in 2 patients and only virological rebound in the third (with
mixed population).
The final outcome of patients studied in the largest group of those who started
antiviral treatment with lamivudine and not lost to follow-up (55 out of 78
patients). All patients who developed viral escape due to emergence of
resistance in lamivudine recieved second-line antiviral therapy depending on
the availability of antivirals in the corresponding period of monitoring. 14
patients died and 2 underwent liver
transplantation. Eight of the patients developed hepatocellular cancer (14%,
8/55) and ten patients lost HBsAg (18%, 10/55).
In conclusion, the nucleos(t)ides lamivudine and adefovir are related with
emergence and predominance of mutant strains resistant to the action of drugs
resulting in the breakthrough of viral replication. The development of
resistance is more common in the first year of treatment but the possibility is
not eliminated even after almost ten years of administration of the drugs.
Adding on another anti-virus that does not show cross-resistance and not switch
to, it seems the best choice among the antivirals lamivudine and adefovir as
this strategy eliminates the risk of recurrence of viral escape mutants because
of emergence new resistant strains.

Chronic hepatitis B, Mutants, Viral resistance, Lamivudine, Adefovir

No

0

Yes

251

187

File access is restricted only to the intranet of UoA.

https://pergamos.lib.uoa.gr/uoa/dl/object/1305692