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SURVEILLANCE FOR HEPATITIS B VIRUS (HBV) ANTIVIRAL RESISTANCE (AVR) IN CLINICAL PRACTICE: WHAT HAVE WE LEARNED SO FAR?

S Fung¹, T Mazzulli¹, J Doutreloigne², V Popovic³, E Sablon^2
1Department of Medicine, University of Toronto, Toronto; ²Infectious Diseases R&D Unit, Innogenetics NV, Gent, Belgium; ³Gilead Sciences Canada, Mississauga

BACKGROUND: The risk of AVR is a major concern in the treatment of chronic hepatitis B, but the prevalence in clinical practice is unknown. Early detection of AVR followed by prompt addition of salvage therapy can improve clinical outcomes. Aims: To determine the prevalence of AVR in treated HBV patients, to estimate the prevalence of pre-existing AVR in treatment-naïve patients and to determine the clinical utility of resistance testing.
Patients and METHODS: Adult patients attending the liver clinics of University Health Network and Mount Sinai Hospital (Toronto, ON) on oral antiviral therapy from 08/06 - 04/07 were prospectively monitored for AVR. Criteria for resistance testing included previous treatment failure, virologic breakthrough (> 1 log10 IU/ml rise in HBV DNA) and suboptimal response (HBV DNA > 4 log10 IU/ml after 6-12 months). HBV DNA was quantified by PCR (TaqMan, LLOD 6 IU/ml), HBV genotype and resistance mutations were detected using a line probe assay (INNO-LiPA HBV DRv2 and DRv3) and direct sequencing.
RESULTS: 133 adult patients (79% male, 44% cirrhosis, mean age 48±12 yrs) were included. 78% were Asian, 57% HBeAg+ve and mean HBV DNA at time of resistance testing was 5.4±2.1 log10 IU/ml. HBV genotypes A, B, C and D were found in 6%, 20%, 54% and 10% patients, respectively. 90% patients received lamivudine (LAM) for a mean of 29 months, 40% adefovir dipivoxil (ADV) for a mean of 13 months, 33% combination LAM + ADV, 4% tenofovir (TDF) and 2% entecavir (ETV). The prevalence of AVR mutations in treated patients is shown below. The most common mutations were those associated with resistance to LAM in 65% (87/133) patients. In treatment-naïve patients, pre-existing LAM-, ADV- and ETV-resistant mutations were found in 15%, 0% and 7%, respectively.
                    

RT Mutation	L180M	M204V/I	A181V/T	N236T	A194T	T184G	S202I
Prevalence (%)	40	58	8	5	1	1	8

CONCLUSIONS: Lamivudine-resistant mutation in treated patients is very common, whereas mutations to all other agents are less common in clinical practice. The high prevalence of lamivudine resistance must be considered when selecting initial and salvage regimens, since cross-resistance will restrict future treatment options.

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