No resistance to tenofovir disoproxil fumarate detected after up to 144 weeks of therapy in patients monoinfected with chronic hepatitis B virus

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Hepatology. 2011 Mar;53(3):763-73. doi: 10.1002/hep.24078. Epub 2010 Dec 22.

No resistance to tenofovir disoproxil fumarate detected after up to 144 weeks of

therapy in patients monoinfected with chronic hepatitis B virus.

Snow-Lampart A, Chappell B, Curtis M, Zhu Y, Myrick F, Schawalder J, Kitrinos K,

Svarovskaia ES, MD, Sorbel J, Heathcote J, Marcellin P, Borroto-Esoda K.

Gilead Sciences, Incorporated, Durham, NC. alampart09@....

Abstract

Tenofovir disoproxil fumarate (TDF) is a nucleotide analogue with potent

activity against human immunodeficiency virus type 1 and hepatitis B virus

(HBV). To date, no reports of HBV clinical resistance to TDF have been

confirmed. In two phase 3 studies (GS-US-174-0102 and GS-US-174-0103), 375

hepatitis B e antigen-negative (HBeAg(-) ) patients and 266 HBeAg(+) patients

with chronic hepatitis B (some nucleoside-naive and some lamivudine-experienced)

were randomized 2:1 to receive TDF (n = 426) or adefovir dipivoxil (ADV; n =

215) for 48 weeks. After week 48, eligible patients received open-label TDF with

no interruption. The studies are being continued through week 384/year 8; week

144 data are presented here. Per protocol, viremic patients (HBV DNA level ™ 400

copies/mL or 69 IU/mL) had the option of adding emtricitabine (FTC) at or after

week 72. Resistance analyses of HBV polymerase/reverse transcriptase (pol/RT)

were based on population dideoxy sequencing. Phenotypic analyses were conducted

in HepG2 cells with recombinant HBV derived from patient serum. Most patients

maintained TDF monotherapy treatment across both studies (607/641, 95%). A

resistance analysis of HBV pol/RT was performed at the baseline for all

patients, for viremic patients at week 144 or at the last time when they were on

TDF monotherapy (34 on TDF and 19 on ADV-TDF), and for patients who remained

viremic after the addition of FTC (7/20 on TDF and 5/14 on ADV-TDF). No patient

developed amino acid substitutions associated with resistance to TDF.

Virological breakthrough on TDF monotherapy was infrequent over 144 weeks

(13/426, 3%) and was attributed to documented nonadherence in most cases (11/13,

85%). Persistent viremia (™400 copies/mL) through week 144 was rare (5/641,

0.8%) and was not associated with virological resistance to TDF by population or

clonal analyses. Conclusion: No nucleoside-naive or nucleoside-experienced

patient developed HBV pol/RT mutations associated with TDF resistance after up

to 144 weeks of exposure to TDF monotherapy. (HEPATOLOGY 2010).Copyright ¿ 2010

American Association for the Study of Liver Diseases.

PMID: 21374657 [PubMed - in process]