In Vitro Activity of 2,4-Diamino-6-[2-(Phosphonomethoxy)Ethoxy]-Pyrimidine against Multidrug-Resistant Hepatitis B Virus Mutants

Brunelle, Marie-Noëlle; Lucifora, Julie; Neyts, Johan; Villet, Stéphanie; Holy, Antony; Trépo, Christian; Zoulim, Fabien

doi:10.1128/aac.01440-06

Cited by 42 publications

(30 citation statements)

References 32 publications

(50 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The ETV‐resistant level of clone A1+MV seemed to be high, although the essential role of LAM‐resistant mutations to ETV is well known. Moreover, rtL180M/M204V‐associated high‐level resistance to ETV has been reported in patient‐derived strains but not laboratory strains 21. Such high‐level ETV resistance attributable to these mutations may be peculiar to the ETV refractory patient‐derived clone, and other amino acid residues in the RT region or other regions may be associated with this ETV resistance.…”

Section: Discussionmentioning

confidence: 97%

Resistance mutations of hepatitis B virus in entecavir‐refractory patients

Yamada

Sugiyama

Nitta

et al. 2017

Hepatology Communications

View full text Add to dashboard Cite

The emergence of resistance mutations in the reverse transcriptase gene of hepatitis B virus (HBV) is associated with treatment failure. Entecavir (ETV) is one of the most potent anti‐HBV reagents; it has a very low resistance rate and is used as the first‐line treatment for chronic hepatitis B. In this study, we isolated HBVs in 4 ETV‐refractory patients (2 with viral breakthrough, 1 with partial virological response, and 1 with flare‐up) and assessed ETV resistance using replication‐competent 1.38‐fold HBV genome‐length molecular clones. The full genome sequences of infected HBVs in ETV‐refractory patients were determined. The HBV molecular clones were generated with the patient‐derived sequences. After transfection of these molecular clones into HepG2 cells, viral replications and ETV susceptibilities were evaluated by measuring the amount of intracellular core‐particle‐associated HBV DNA using Southern blotting and real‐time polymerase chain reaction. Among these cases, ETV‐resistant variants were detected in 2 patients with viral breakthrough and responsible amino acid mutations in reverse transcriptase were successfully identified in these variants. No ETV‐resistant mutation was detected in the other cases. The identified ETV‐resistant mutations did not confer resistance to tenofovir disoproxil fumarate. Conclusion: The HBV replication model with patient‐derived sequences is useful for assessing replication efficiency, susceptibility to anti‐HBV reagents, and responsible resistance mutations and can aid in choosing the appropriate treatment strategy for treatment‐failure cases of chronic hepatitis B. (Hepatology Communications 2017;1:110‐121)

show abstract

Section: Discussionmentioning

confidence: 97%

Resistance mutations of hepatitis B virus in entecavir‐refractory patients

Yamada

Sugiyama

Nitta

et al. 2017

Hepatology Communications

View full text Add to dashboard Cite

show abstract

“…ETV displays a unique cross-resistance pattern, with antiviral activity against both LVDr and ADVr HBV. 21,[35][36][37][38] Conversely ETVr HBV is susceptible to ADV and tenofovir. 8,35 This profile suggests a role for ETV as a cornerstone of HBV therapy.…”

Section: Discussionmentioning

confidence: 99%

Long-term monitoring shows hepatitis B virus resistance to entecavir in nucleoside-naïve patients is rare through 5 years of therapy

et al. 2009

View full text Add to dashboard Cite

Patients with chronic hepatitis B virus (HBV) infection who develop antiviral resistance lose benefits of therapy and may be predisposed to further resistance. Entecavir (ETV) resistance (ETVr) results from HBV reverse transcriptase substitutions at positions T184, S202, or M250, which emerge in the presence of lamivudine (LVD) resistance substitutions M204I/V ؎ L180M. Here, we summarize results from comprehensive resistance monitoring of patients with HBV who were continuously treated with ETV for up to 5 years. Monitoring included genotypic analysis of isolates from all patients at baseline and when HBV DNA was detectable by polymerase chain reaction (>300 copies/mL) from Years 1 through 5. In addition, genotyping was performed on isolates from patients experiencing virologic breakthrough (>1 log 10 rise in HBV DNA). In vitro phenotypic ETV susceptibility was determined for virologic breakthrough isolates, and for HBV containing novel substitutions emerging during treatment. The results over 5 years of therapy showed that in nucleoside-naïve patients, the cumulative probability of genotypic ETVr and genotypic ETVr associated with virologic breakthrough was 1.2% and 0.8%, respectively. In contrast, a reduced barrier to resistance was observed in LVD-refractory patients, as the LVD resistance substitutions, a partial requirement for ETVr, preexist, resulting in a 5-year cumulative probability of genotypic ETVr and genotypic ETVr associated with breakthrough of 51% and 43%, respectively. Importantly, only four patients who achieved <300 copies/mL HBV DNA subsequently developed ETVr. Conclusion: Long-term monitoring showed low rates of resistance in nucleoside-naïve patients during 5 years of ETV therapy, corresponding with potent viral suppression and a high genetic barrier to resistance. These findings support ETV as a primary therapy that enables prolonged treatment with potent viral suppression and minimal resistance. ( A pproximately 400 million people worldwide have chronic hepatitis B virus (HBV) infections, with a risk for chronic, life-threatening liver disease. 1 Antiviral therapy for HBV can provide suppression of viral replication and halt disease progression. 2,3 However, therapeutic benefits are diminished with the emergence of drug-resistant virus, which occurs most often with prolonged therapy and incomplete viral suppression. 4 Resistance to nucleoside/nucleotide antivirals arises through substitutions in the HBV polymerase reverse transcriptase domain (RT), that arise spontaneously through low-fidelity replication and are enriched through drug-selective pressure. 2,3 Antiviral therapies are characterized by their barrier to resistance, which includes three components: (1) the potency of the antiviral in suppressing viral replication, (2) a "genetic barrier", i.e., the number of genetic changes required to effectively reduce drug susceptibility that results in virologic breakthrough, and (3) the replication fitness of the resistant virus. These factors act together to determine the levels of resis...

show abstract

“…Although there is cumulative clinical and published evidence that indicates that TDF has substantial antiviral efficacy against resistant strains of HBV, especially in lamivudine resistance, none of these studies tested the efficacy of TDF against wild-type HBV in NA-naïve patients (7)(8)(9)(10). Several in vitro studies showed almost unaltered or slightly decreased efficacy of TDF against lamivudine-resistant strains of HBV in comparison with that against the wild-type virus (11)(12)(13)(14). Nevertheless, the clinical implications of lamivudine resistance in CHB patients treated with TDF have not been completely elucidated yet.…”

mentioning

confidence: 99%

Efficacy of Tenofovir in Patients with Lamivudine Failure Is Not Different from That in Nucleoside/Nucleotide Analogue-Naïve Patients with Chronic Hepatitis B

Baran

Soyer

Örmeci

et al. 2013

Antimicrob Agents Chemother

View full text Add to dashboard Cite

We evaluated the efficacy of tenofovir disoproxil fumarate (TDF) in patients with lamivudine failure (LAM-F) in comparison with that in nucleoside/nucleotide analogue (NA)-naïve patients with chronic hepatitis B (CHB). The criteria for inclusion were being NA naïve or having previous LAM-F and receiving TDF therapy for at least 6 months. Biochemical and virological tests were performed at the baseline, at 3-month intervals in the first year, and every 6 months thereafter. The primary outcome measure for efficacy was a complete virological response (CVR), defined as an HBV DNA level of <20 IU/ml. CVR rates were calculated by Kaplan-Meier analysis, and a multivariate Cox proportional-hazard model was generated in order to find predictive factors independently associated with the time to a CVR. We included 197 patients in the study (136 males; mean age, 43 ؎ 12 years; 105 patients were NA naïve). Sixty-five patients had hepatitis B e antigen (HBeAg)-positive CHB. The median duration of TDF treatment was 29 (range, 6 to 52) months. Seventy-one patients (77%) in the LAM-F group were treated with TDF add-on therapy. The CVR rates of the NA-naïve and LAM-F groups were comparable in HBeAg-negative (94% versus 96% at month 36, P ‫؍‬

show abstract

In Vitro Activity of 2,4-Diamino-6-[2-(Phosphonomethoxy)Ethoxy]-Pyrimidine against Multidrug-Resistant Hepatitis B Virus Mutants

Cited by 42 publications

References 32 publications

Resistance mutations of hepatitis B virus in entecavir‐refractory patients

Resistance mutations of hepatitis B virus in entecavir‐refractory patients

Long-term monitoring shows hepatitis B virus resistance to entecavir in nucleoside-naïve patients is rare through 5 years of therapy

Efficacy of Tenofovir in Patients with Lamivudine Failure Is Not Different from That in Nucleoside/Nucleotide Analogue-Naïve Patients with Chronic Hepatitis B

Contact Info

Product

Resources

About