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Antiviral Agents

Low-Level Persistence of Drug Resistance Mutations in Hepatitis B Virus-Infected Subjects with a Past History of Lamivudine Treatment

Severine Margeridon-Thermet, Evguenia S. Svarovskaia, Farbod Babrzadeh, Ross Martin, Tommy F. Liu, Mary Pacold, Elizabeth C. Reuman, Susan P. Holmes, Katyna Borroto-Esoda, Robert W. Shafer
Severine Margeridon-Thermet
aDepartment of Medicine, Division of Infectious Diseases, Stanford University, Stanford, California, USA
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Evguenia S. Svarovskaia
bGilead Sciences, Foster City, California, USA
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Farbod Babrzadeh
cStanford Genome Technology Center, Stanford University, Stanford, California, USA
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Ross Martin
bGilead Sciences, Foster City, California, USA
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Tommy F. Liu
aDepartment of Medicine, Division of Infectious Diseases, Stanford University, Stanford, California, USA
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Mary Pacold
aDepartment of Medicine, Division of Infectious Diseases, Stanford University, Stanford, California, USA
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Elizabeth C. Reuman
aDepartment of Medicine, Division of Infectious Diseases, Stanford University, Stanford, California, USA
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Susan P. Holmes
dDepartment of Statistics, Stanford University, Stanford, California, USA
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Katyna Borroto-Esoda
bGilead Sciences, Foster City, California, USA
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Robert W. Shafer
aDepartment of Medicine, Division of Infectious Diseases, Stanford University, Stanford, California, USA
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DOI: 10.1128/AAC.01601-12
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  • Fig 1
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    Fig 1

    Distribution of months of past lamivudine (LAM) treatment (A) and of months since LAM discontinuation (B) among the 46 LAM-experienced subjects.

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    Fig 2

    Months since discontinuation of lamivudine (LAM) for the 10 subjects with and 36 subjects without viruses containing LAM resistance mutations (median: 11.2 versus 30.5 months; P = 0.0001, Mann-Whitney test).

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    Fig 3

    Inverse relationship between the time since lamivudine (LAM) discontinuation and the log-transformed value of the most prevalent LAM resistance mutations within each of the 46 LAM-experienced subjects (r = 0.69, P < 0.001; Spearman's rank correlation coefficient). A single point (x = 30.5 months and y = 0.1%) is used to represent the 36 subjects who had discontinued LAM a median of 30.5 months prior to sampling and who did not have detectable LAM resistance mutations.

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  • Table 1

    Virological characteristics of the HBV samples from 91 study subjectsa

    ParameterSubject treatment category
    NaiveLAMLAM+IFNIFN
    No. of samples26252119
    Study subject gender, no. (%)
        Females7 (26.9)7 (28)7 (33.3)4 (21)
        Males19 (73.1)18 (72)14 (66.7)15 (79)
    Median age in yrs (IQR)45 (37–52)45 (35–55)50 (38–56)47 (36–54)
    Ethnicity, no. (%)
        White14 (53.8)18 (72)18 (85.7)17 (89.5)
        Black1 (4)2 (9.5)
        Asian10 (38.5)6 (24)1 (4.8)2 (10.5)
        Other2 (7.7)
    Median virus levelb (IQR)6.3 (5.4–7.2)6.6 (5.2–7.3)6.6 (5.7–8.0)7.1 (6.1–7.7)
    LAM treatment duration, median no. of mos. (IQR)
        On LAM20 (9–33)30 (19–43)
        Off LAM26 (12–36)13 (12–24)
    HBeAg+ (%)19201411
    Genotypes (%)D (54), B (23), A (11.5), C (11.5)D (58), C (22), A (20)D (71), A (19), B (5), E (5)D (89), C (11)
    • ↵a No subject was on therapy at the time of virological testing. Naive, naive subjects that had never received antiviral therapy; LAM, subjects with a history of receiving lamivudine (LAM); LAM+IFN, subjects with a history of receiving LAM + interferon (IFN); IFN, subjects with a history of receiving IFN but not LAM.

    • ↵b Virus levels were measured as the log10 IU/ml.

  • Table 2

    HBV drug resistance mutations detected by Sanger sequencing and ultradeep pyrosequencing

    Patient no.Treatment history (no. of months)Sanger sequence DRMsUDPS DRM(s) (%)a
    On LAMOff LAM
    4213.57M204M/I, L80L/IM204I (41.2), L80I (31.3), L80V (4.1), M204V (0.5)
    81334M204I, L80I/VM204I (99.8), L80V (67.2), L80I (32.3)
    731213.5M204M/L/IM204I (15.8), L180M (13.2), M204V (2.2)
    8536.510L180L/ML180 M (80.7), L80V (4.8)
    5127.5A181A/TA181T (51.5)
    8236.512NoneL180 M (69.8), V173L (69.6), M204V (1.0)
    36107NoneM204I (9.2), L80I (8.2), L180M (1.8)
    7511.514NoneM204V (2.0), L180M (1.7)
    873619.5NoneM204I (0.8), L80I (0.7)
    72313.5NoneM204I (0.6), L180M (0.5)
    • ↵a Mutations in boldface type were detected solely by ultradeep pyrosequencing (UDPS). Underlined mutations (either rtM204V or rtM204I) are primary LAM resistance mutations that were not detected by Sanger sequencing. The parenthetical percentages indicate the proportion of UDPS reads at an amino position encoded by the preceding drug resistance mutation. rtM204L, a mutation of unknown significance was present in 41.4 and 2.8% of sequence reads of the plasma samples from subjects 73 and 72, respectively. rtA181S, another mutation of unknown significance, was present in 0.7 and 1.9% of sequence reads of the plasma samples from subjects 5 and 75, respectively.

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      Tables S1 and S2 and Fig. S1.

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Low-Level Persistence of Drug Resistance Mutations in Hepatitis B Virus-Infected Subjects with a Past History of Lamivudine Treatment
Severine Margeridon-Thermet, Evguenia S. Svarovskaia, Farbod Babrzadeh, Ross Martin, Tommy F. Liu, Mary Pacold, Elizabeth C. Reuman, Susan P. Holmes, Katyna Borroto-Esoda, Robert W. Shafer
Antimicrobial Agents and Chemotherapy Dec 2012, 57 (1) 343-349; DOI: 10.1128/AAC.01601-12

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Low-Level Persistence of Drug Resistance Mutations in Hepatitis B Virus-Infected Subjects with a Past History of Lamivudine Treatment
Severine Margeridon-Thermet, Evguenia S. Svarovskaia, Farbod Babrzadeh, Ross Martin, Tommy F. Liu, Mary Pacold, Elizabeth C. Reuman, Susan P. Holmes, Katyna Borroto-Esoda, Robert W. Shafer
Antimicrobial Agents and Chemotherapy Dec 2012, 57 (1) 343-349; DOI: 10.1128/AAC.01601-12
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