Suboptimal response to adefovir dipivoxil therapy for chronic hepatitis B in nucleoside-naive patients is not due to pre-existing drug-resistant mutants.
BACKGROUND
Adefovir dipivoxil (ADV) has demonstrated activity against wild-type and lamivudine-resistant hepatitis B virus (HBV). After 1 year of therapy, a median 3.5-4.0 log10 decrease in viral load is observed. Our aim was to characterize the different profiles of response to ADV in relation to the in vitro susceptibility of viral strains to ADV.


METHODS
In an international Phase III randomized, placebo-controlled study of ADV in patients positive for hepatitis B virus e antigen (HBeAg), different profiles of virological response to ADV 10 mg/day were identified at week 48. The top 25% patients (quartile 1, Q1) showed > 4.91 log10 reduction in serum HBV DNA at week 48, in Q2 patients demonstrated a 3.52 to 4.90 log10 reduction of viral load, whereas in Q3 a 2.22 to 3.51 log10 reduction in viral load was observed. The bottom 25% of patients (Q4) showed < 2.22 log10 reduction in HBV DNA levels. The influence of baseline characteristics and drug compliance on response was investigated. The replication capacity and drug susceptibility of HBV genomes of selected clinical isolates that were considered representative of the treatment response quartiles were analysed using a phenotypic assay.


RESULTS
The lowest quartile of response (Q4) appears to have worse compliance. Higher alanine aminotransferase levels at baseline are associated with improved response. Phenotypic analysis of viral strains in vitro in Huh7 and HepG2 cells showed that HBV genomes remained susceptible to ADV, regardless of treatment response observed in patients.


CONCLUSIONS
Suboptimal response to ADV might result from a host pharmacological effect or from patient compliance issues rather than from a reduced susceptibility of HBV to ADV.
INSERM, U871, 69003 Lyon, France.
Sandra
S
Carrouée-Durantel
David
D
Durantel
Bettina
B
Werle-Lapostolle
Christian
C
Pichoud
Lieve
L
Naesens
Johan
J
Neyts
Christian
C
Trépo
Fabien
F
Zoulim
D000225:Adenine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000293:Adolescent; D000328:Adult; D045744:Cell Line, Tumor; D004279:DNA, Viral / Q000097:blood; D004305:Dose-Response Relationship, Drug; D024882:Drug Resistance, Viral / Q000235:genetics*; D005060:Europe; D005260:Female; D005838:Genotype; D006515:Hepatitis B virus / Q000187:drug effects* / Q000235:genetics; D019694:Hepatitis B, Chronic / Q000188:drug therapy* / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D063065:Organophosphonates / Q000627:therapeutic use*; D010349:Patient Compliance; D010641:Phenotype; D018894:Reverse Transcriptase Inhibitors / Q000627:therapeutic use*; D013997:Time Factors; D017211:Treatment Failure; D014481:United States; D019562:Viral Load; D014779:Virus Replication
D004279:DNA, Viral; D063065:Organophosphonates; D018894:Reverse Transcriptase Inhibitors; D000225:Adenine; C106812:adefovir dipivoxil