HBV resistance to lamivudine at undetectable and low levels of viremia

Mark Mascolini for

Mutations in hepatitis B virus (HBV) reverse transcriptase conferring resistance to lamivudine arose in sizeable proportions of people with low-level viremia and even in those with undetectable HBV loads, according to results of a 64-patient study by Carlo Perno (University of Rome Tor Vergata) and collaborators at other centres.

The study involved 64 people with HBV but not HIV infection:

  • In 25 people lamivudine monotherapy was failing for the first time and HBV loads ranged from 12 to 345 IU/mL (69 to 2000 copies/mL).
  • Another 24 patients taking first-line lamivudine monotherapy had an HBV load below 12 IU/mL.
  • Fifteen people taking first-line lamivudine plus adefovir had an HBV load below 12 IU/mL.

Perno and colleagues used phylogenetic analysis to ensure that cross-contamination or PCR errors did not distort their results.

From the first group of 25 patients with HBV viremia between 12 and 345 IU/mL, the investigators successfully sequenced HBV in 22 (88%). In the 39 people with a load below 12 IU/mL, they sequenced HBV in 10 (26%).

In the 22 people with sequenced virus and lamivudine monotherapy failing at a load between 12 and 345 IU/mL, median time on lamivudine measured 243 weeks (interquartile range [IQR] 110 to 291). Mutations could be seen in 17 of these 22 (77%), including 8 with M204V, 7 with M204I, 1 with M204I/V, and 1 with A181T. (M204 mutations in HBV are equivalent to M184 mutations in HIV.)

These primary resistance mutations arose with 1 compensatory mutation in 14% and with 2 or more compensatory mutations in the others. This finding, the investigators suggested, underscores “the existence of complex patterns of lamivudine resistance mutations even at the very early stages of virological rebound.”

In 10 patients whose virus could be sequenced at a load below 12 IU/mL, Perno detected mutations in 4 (40%), the M204V mutation in 2 people, M204I in 1, and M204I plus the adefovir-related V84M in 1. Detection of mutations predicted later HBV rebound and liver enzyme flares.

Perno and coworkers recommended monitoring for HBV resistance mutations even in patients with low viremia. They believe their findings “should be considered in setting up a rational therapeutic sequencing, potentially including pro-active switch strategies.” Perno urged fellow infectious disease specialists to focus more closely on hepatitis virus research to avoid repeating errors committed in the early days of antiretroviral therapy.


Svicher V, Alteri C, Gori C, et al. Lamivudine resistance mutations in HBV reverse transcriptase can be selected even at extremely low levels of viral replication. XVIII International Drug Resistance Workshop. 9-13 June 2009, Fort Myers, Florida. Abstract 24.

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